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GOOD MORNING EVERYONE  I

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AM FRANCESCA, BOSETTI, AT

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NINDS, AND I WOULD LIKE TO THANK

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YOU FOR JOINING US IN THIS

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WORKSHOP THAT IS SPONSORED BY

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THE NATIONAL INSTITUTES OF

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NEUROLONICAL DISORDER AND TROAK,

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AND THE NATIONAL INSTITUTE ON

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AGING TO ADDRESS CRITICAL AND

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EMERGING ISSUE IF THE FIELD OF

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ALZHEIMER'S DEC RESEARCH AND

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TREATMENT, AMYLOID RELATED

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IMAGING ABNORMALITIES OR ARIA, A

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RAINCHL OF NEUROLOGICAL IMAGING

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THAT APPEAR TO BE SERIOUS SIDE

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CENTER FOR EXCELLENCE ON AGINGS

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OF ANTIBETTA AMYLOID

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IMMUNOTHERAPY EMPLOY ALZHEIMER'S

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DISEASE IS A DEVASTATING

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NEURODEGENERATIVE DISORDER

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CHARACTERIZED BY COGNITIVE

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IMPAIRMENT.

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FOR YEARS RESEARCHERS FOCUS ON

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BETA AMYLOID PLAQUE WHICH

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ACCUMULATE IN THE BRAIN OF

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ALZHEIMER'S PATIENTS AS A

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CENTRAL TARGET FOR POTENTIAL

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TREATMENT.

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ANTI-BETA-AMYLOID EMUNE O

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THERAPY ANDA UPONY IPT GREATER

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VOLVE USING ANTIBODIES TO TARGET

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AND REMOVE THESE BETA AMYLOID

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PLAQUES FROM THE BRAIN AND

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EMERGE AS A PROMISING STRATEGY

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EMPLOY DATA FROM RECENT TRIALS

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IMPLICATE THE AGENTS HAVE THE

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FIRST EFFECTIVE DISEASE

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MODIFYING THERAPIES AGAINST

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ALZHEIMER'S DISEASE AND HAVE LED

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TO THE FDA RECENT APPROVAL OF

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[INDISCERNIBLE] UNDER AN

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ACCELERATED APPROVAL PATHWAY

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BASED ON THE FACTS ON THE

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SURROGATE END POINTS OF

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REDUCTION OF AMYLOID PLAQUE IN

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THE BRAIN OF PATIENTS WITH

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ALZHEIMER'S DEC.

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THE CLINICAL IMPLICATIONS OF

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ARIA ARE MULTIFACETED EMPLOY FOR

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PATIENTS OCCURRENCE AND SEVERITY

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OF ARIA CAN VARY WIDELY BETWEEN

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INDIVIDUALS AND CAN LEAD TO

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UNEXPECTED ADVERSE EVENTS AND

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WORSEN QUALITY OF LIFE.

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FOR HEALTHCARE, IT RAISES

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QUESTIONS ABOUT COSTS, ACCESS

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AND HEALTH DISPARITIES.

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FOR CLINICIANS IT POSES A

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CHALLENGE IN DETERMINING THE

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APPROPRIATE COURSE OF TREATMENT

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FOR MANAGING THE COMPLICATIONS.

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FOR RESEARCHERS, IT RAISES

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IMPORTANT QUESTIONS ABOUT THE

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MECHANISMS BEHIND THE

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DEVELOPMENT OF ARIA AND METHODS

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TO MITIGATE ITS OCCURRENCE.

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MANY QUESTIONS REMANY UNANSWERED

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EMPLOY HOW CAN WE  PREDICT WITH

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THE HIGHEST WAYS OF ARIA, ARE

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THERE RISKS WHILE MANY TAINING

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THERAPEUTIC BENEFITS AND BETTER

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AMYLOID IMMUNOTHERAPY.

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IN WHAT ARE THE ON LONG-TERM

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CONSEQUENCES OF ACTIVE FUNCTION

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AND OVERALL HEALTH?

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AND WHAT ARE THE BIOLOGICAL

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MECHANISMS INVOLVED?

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WE ALSO DON'T FULLY APPRECIATE

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THE LONG-TERM EFFECTS OF THE

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TREATMENT, THE IMPACT OF

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CO-MORBIDITIES, CONCOMITANT

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THERAPY LIKE ANTICOAGULATION AS

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WELL AS THE EFFECT OF AGE,

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GENDER AND GENETIC RISK FACTORS.

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IN THIS WORKSHOP WE WILL DISCUSS

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SCIENTIFIC GAPS AND FUTURE

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OPPORTUNITIES WITH LEADERS FROM

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ACADEMIA, INDUSTRY, REGULATORY

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AND FUNDING EAMTIONS AND

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PATIENTS ADVOCACY ORGANIZATIONS

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WITH A MULTIDISCIPLINEAR EXPE

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COLLABORATIVE SPIRIT FOR THE

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BEST POSSIBLE OUTCOMES FOR THOSE

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AFFECTED BY THE DISEASE.

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FINALLY SOME HOUSEKEEPING NOTES,

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WE ASK THE SPEAKERS TO STRICTLY

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ADHERE TO THE PRESENTATION WITH

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5 MINUES IF ARE QUESTIONS, IT

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WILL BE ENFORCED.

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A SPECIAL THANKS TO ALL MY NIH

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COLLEAGUES AND PARTICULARLY

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DR. HAYBERNE, DR. HARK

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CIRCUMSTANCE SANI THAT HELPED

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WITH THE PLANNING OF THIS

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WORKSHOP, AND TO ALL THE NIH

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MODERATORS AND EXTERNAL

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MODERATOR ANDS TO STEPHANIE

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TILLER AND HER TEAM WHO WORKED

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VERY HARD AROUND THE CLOCK TO

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MAKE THE LOGISTICS OF THIS

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WORKSHOP POSSIBLE EMPLOY

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STEPHANIE WILL BE AT THE

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REGISTRATION TABLE OUTSIDE, IF

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YOU HAVE QUESTIONS ABOUT YOUR

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TRAVEL OR NEED ANY OTHER

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INFORMATION.

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ALSO A REMINDER THAT THERE ARE

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NO LUNCH OPTIONS WITHIN WALKING

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DISTANCE SO IF YOU HAVE NOT

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PREORDERED A LUNCH, YOU MAY WANT

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TO ASK STEPHANIE AND YOU WILL

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HAVE THE OPPORTUNITY TO ADD A

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LUNCH UNTIL 9:30 THIS MORNING TO

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PREORDER OR OTHERWISE YOU CAN

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CONSIDER YOUR OWN FOOD DELIVERY

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OPTIONS.

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AND WITHOUT FURTHER ADO, IT IS

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MY PLEASURE TO NOW WELCOME

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DR. WALTER KOROSHETZ, THE

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DIRECTOR OF THE NATIONAL

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INNSITUTE OF NEUROLOGICAL

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DISORDERS AND STROKE FOR THE

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OPENING REMARKS, THANK YOU.

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>> HEY, THANK YOU
FRANCESCA AND

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THANKS EVERYBODY FOR COMING.

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LETS OF OLD FRIENDS AND

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HOPEFULLY MAKE SOME NEW FREBDS

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IN THE NEXT FEW DAYS.

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REALLY IMPORTANT TOPIC.

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JUST TO OFFER A COUPLE OF

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OPENING COMMENTS, WHICH YOU CAN

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TAKE THEM OR LEAVE THEM.

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--AND YOU KNOW ON THE SIDE OF

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NEURODEGENERATION FOR YEARS

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[INAUDIBLE DUE TO AWAY FROM MIC

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]

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TRYING TO GET THIS TREATMENT

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FORRAL JEIMERS THAT LED US DOWN

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A PATHWAY WHICH WE ALL ANYHOW

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WAS IMPORTANT WHICH IS TO GET

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THE AMYLOID OUT OF THE BRAIN.

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WE HAVE THERAPIES THAT GET

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AMYLOID OUT OF THE BRAIN BUT

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HOUSTON WE HAVE A PROBLEM.

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AND THE PROBLEM IS PRETTY

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OBVIOUS, IT'S NOT SO STARING YOU

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IN THE FACE, WITH A MRI SCAN,

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YOU HAVE PLAQUE AREAS

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[INDISCERNIBLE]--REAL EASY TO

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SEE AND THEN HAVE YOU THE

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PROBLEM WITH HEMORRHAGE, THE

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EFFECTSOT BRAIN BOTH SHORT-TERM

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AND LONG-TERM. 

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THE BLOODING IS THE FINAL RESULT

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OF A LEAKY BLOOD BRAIN BARRIER,

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[AUDIO UNCLEAR DUE TO MIC NOT ON

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]

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--BUT WE'RE HERE TO TRY TO SEE

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WHAT WE CAN DO ABOUT THIS

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PROBLEM BECAUSE IT'S TANNING IN

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FRONT OF US AND PROBABLY NOT

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GOING AWAY.

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MAYBE WE SHOULD HAVE KNOWN IT

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WAS COMING BECAUSE FROM THE

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LESSONS LEARNS FROM

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[INDISCERNIBLE] GEOGRAPHY AROUND

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[INDISCERNIBLE] DOING THESE

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EXQUISITE PATHOLOGICAL STUDIES

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OF [INDISCERNIBLE] AND THE

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DIFFERENT TAIJS IN THE LAST DAY

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IF I RECALL CORRECTLY, IT WAS

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[INDISCERNIBLE].

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--IN HYPER TENSIVE DISEASE BUT

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JOHN PAUL [INDISCERNIBLE]

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BASICALLY IDENTIFIED IT AS THE

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PATHOLOGIC FEATURE THAT'S

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RELATED TO THE PLEADING AND

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PEOPLE HAVE CEREBRAL ARVELGIO

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OPEN MEETINGATHY, BUT WHAT I HAD

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FORGOTTEN BUT I WAS REMINDED OF

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IT IN THE LAST MEETING IS THE

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AREA OF PLEAD, THE AREA OF

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NECROSIS BUT THERE'S NO AMYLOID

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LEFT, IT'S BEEN CLEARED FROM THE

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BLOOD VESSELS SO NOW HERE WE ARE

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CLEARING AMYLOID FROM THE BRAIN,

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WE DON'T KNOW, IT MAY BE

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CLEARING FROM THE BLOOD VESSEL,

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WE MAY BE SETTING UP THE SAME

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PATHOLOGY THAT YAWN PAUL

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DESCRIBED IN SEVERAL ANCHLY

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OPERATING GLOBALLYATHY YEARS

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AGO, BUT THOSE ARE THE QUESTIONS

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WE HAVE TO ANSWER AND HOW WE CAN

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INTERVENE IN THOSE MECHANISMS

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AND THIS PROBLEM IS AS I SAID

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NOT GOING AWAY, THIS PROBLEM

208
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ONLY GETS BIGGER.

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RIGHT NOW WE HAVE INITIAL HOW DO

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WE TREAT PEOPLE, HOW DO WE

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MANAGE PEOPLE WHO HAVE THIS?

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THIS IS LIKE JUST THE BEGINNING

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THOUGH BECAUSE THE FUTURE IS

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REALLY TRYING TO TREAT THIS

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DISEASE EARLIER AND EARLIER,

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WHICH MEANS PEOPLE--THE

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TREATMENT IS SAFER AND SAFER,

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THERE'S A GROUP I'M WORKING WITH

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THAT ARE LOOKING AT VACCINES AND

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IMMUNIZE PEOPLE AGAINST AMYLOID

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AS A WAY OF TREATMENT, SO THIS

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LOOKING DOWN THE FUTURE, I THINK

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THIS ABILITY WE HAVE NOW TO GET

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AMYLOID OUT OF THE BRAIN IS ONLY

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GOING TO BECOME MORE AND MORE

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IMPORTANT AND SO THIS ISSUE OF

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THE  BLOOD BRAIN BARRIER AS WE

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REMOVE AMYLOID BECOMES VERY,

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VERY IMPORTANT EMPLOY SO WE NEED

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GOOD IDEAS FROM AROUND THE

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TABLE, WE HAVE INDUSTRY PEOPLE,

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MEDICAL PEOPLE, PERFECT

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OPPORTUNITY TO GET IDEAS GOING.

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OT OTHER HAND I CAN'T SAY VERY

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FREQUENTLY BUT NIH HAS FUNDING

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FOR THIS PROJECT.

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WE HAVE AT THE AIMING INNSITUTE

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AT NINDS, FUNDING, WE HAVE HAD

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RFOOTWORK As OUT FOR SIDES IN

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THIS AREA WE GOT LIKE 1

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APPLICATION OR SOMETHING LIKE

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THAT, 2.

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SO PEOPLE CAN, YOU KNOW DIDN'T

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REALLY REALIZE HOW IMPORTANT IT

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IS AND I THINK THOU WE DO AND SO

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WE REALLY THINK THIS IS WORTH

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THE INVESTMENT FOR A LOT OF

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DIFFERENT REASONS AS I MENTION

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BUT IT'S NOT A--IT'S PROBABLY

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NOT GOING TO BE SIMPLE.

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SO WE NEED SOME REALLY, REALLY

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GOOD IDEAS, INNOVATIVE IDEAS FOR

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THIS STUDY.

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SO REALLY LOOKING FORWARD TO THE

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NEXT FEW DAYS, I WANT TO THANK

256
00:11:54,851 --> 00:11:56,486
FRANCESCA AND ELIEZER, AND VERY

257
00:11:56,486 --> 00:11:57,654
GOOD AND FRAN CHESK KACCT SHOULD

258
00:11:57,654 --> 00:12:08,164
WE GO NEXT TO THE MODERATORS?

259
00:12:18,041 --> 00:12:18,641
VERY GOOD.

260
00:12:18,641 --> 00:12:20,176
>> SO WHILE PEOPLE SIT, I
FORGOT

261
00:12:20,176 --> 00:12:25,381
TO MAKE AN ANNOUNCEMENT THAT THE

262
00:12:25,381 --> 00:12:27,850
WIFI SHOULD BE UP THIS 10

263
00:12:27,850 --> 00:12:38,327
MINUTES OR SO, SO THANKS FOR

264
00:12:41,264 --> 00:12:42,298
YOUR PATIENCE.

265
00:12:42,298 --> 00:12:43,700
>> OKAY, SO WE'RE GOING TO
MOVE

266
00:12:43,700 --> 00:12:45,368
RIGHT ALONG TODAY BECAUSE WE

267
00:12:45,368 --> 00:12:47,270
DON'T HAVE A LOT OF EXTRA TIME

268
00:12:47,270 --> 00:12:48,905
EMPLOY WE WANT TO HAVE LOTS OF

269
00:12:48,905 --> 00:12:50,640
TIME FOR DISCUSSION FOR THIS

270
00:12:50,640 --> 00:12:52,642
IMPORTANT TOPEC SO WITHOUT

271
00:12:52,642 --> 00:12:58,815
FURRINGER ADO, I'M JUST GOING TO

272
00:12:58,815 --> 00:13:00,516
ASK THE FIRST SPEAKER--I BETTER

273
00:13:00,516 --> 00:13:11,060
PUT MY GLASSES ON, DR.  STEPHEN

274
00:13:17,400 --> 00:13:21,104
SALLOWAY, FIRST SPEAKER NI'M

275
00:13:21,104 --> 00:13:23,206
READING--IT'S DAVID CLIFFORD, SO

276
00:13:23,206 --> 00:13:23,706
SORRY.

277
00:13:23,706 --> 00:13:24,507
TAKE IT AWAY.

278
00:13:24,507 --> 00:13:26,609
NSO I'M KIND OF A NEW FACE IN

279
00:13:26,609 --> 00:13:28,945
THE ROOM FOR ALZHEIMER'S

280
00:13:28,945 --> 00:13:30,179
DISEASE, I FIGURED I WAS INVITED

281
00:13:30,179 --> 00:13:33,082
BECAUSE I WAS A GRAY HAIRED

282
00:13:33,082 --> 00:13:34,150
PERSON THAT HAD BEEN KNOCKED

283
00:13:34,150 --> 00:13:36,152
DOWN IN THE WEEDS OF TREATING

284
00:13:36,152 --> 00:13:37,186
THIS DISEASE.

285
00:13:37,186 --> 00:13:38,888
NOW WHERE ARE MY CONTROLS IN

286
00:13:38,888 --> 00:13:39,722
THERE THEY ARE.

287
00:13:39,722 --> 00:13:41,224
SO I'M REALLY HONORED OF COURSE

288
00:13:41,224 --> 00:13:44,427
TO GET TO KICK THIS OFF AND I

289
00:13:44,427 --> 00:13:47,997
WILL TRY TO GIVE YOU A REALLY

290
00:13:47,997 --> 00:13:49,265
HIGH ALTITUDE VIEW OF THE WAY

291
00:13:49,265 --> 00:13:50,967
I'M SEEING THIS FIELD AND THEN

292
00:13:50,967 --> 00:13:52,335
IN QUESTIONS PERHAPS IT I CAN

293
00:13:52,335 --> 00:13:53,703
DIG INTO WHERE I'VE BEEN WORKING

294
00:13:53,703 --> 00:13:57,907
WHICH IS IN THE DOMAIN NABTLY

295
00:13:57,907 --> 00:13:58,574
INHERIT ALZHEIMER'S FIELD, SO

296
00:13:58,574 --> 00:14:03,079
THIS IS NOT ADVANCING.

297
00:14:03,079 --> 00:14:05,615
SO I'M--I DON'T THINK I HAVE ANY

298
00:14:05,615 --> 00:14:06,382
MAJOR CONFLICTS HERE, BUT YOU

299
00:14:06,382 --> 00:14:08,584
SHOULD BE,A WARE THAT I'VE

300
00:14:08,584 --> 00:14:11,888
WORKED IN THE DIANE TU THAT HAD

301
00:14:11,888 --> 00:14:13,556
SUPPORT FROM PHARMA OF COURSE

302
00:14:13,556 --> 00:14:14,657
THAT'S BEEN VERY KEY.

303
00:14:14,657 --> 00:14:19,595
I THOUGHT THAT I WOULD TART OUT

304
00:14:19,595 --> 00:14:20,997
REALLY WITH THE AMYLOID HIGHWAY

305
00:14:20,997 --> 00:14:22,732
POGHT SIS BECAUSE HERE WE WILL

306
00:14:22,732 --> 00:14:25,601
SPEND A DAY AND HALF WORKING ON,

307
00:14:25,601 --> 00:14:26,636
TALKING ABOUT AMYLOID THERAPIES

308
00:14:26,636 --> 00:14:28,805
AND YOU KNOW AMYLOID HAS BEG

309
00:14:28,805 --> 00:14:31,774
YOUR PARDON MALIGNED AS A TARGET

310
00:14:31,774 --> 00:14:35,011
WITH ALL THE DECADES OFATIVELYY

311
00:14:35,011 --> 00:14:36,846
WE HAD ADDRESSING IT, BUT I JUST

312
00:14:36,846 --> 00:14:38,281
WANTED TO TOP A MINUTE AND

313
00:14:38,281 --> 00:14:40,349
REMIND YOU THAT THIS IS A

314
00:14:40,349 --> 00:14:42,952
TOTALLY NORMAL PROTEIN IN THE

315
00:14:42,952 --> 00:14:43,653
BRAIN.

316
00:14:43,653 --> 00:14:44,720
IT'S SURPRISINGLY DYNAMIC AND I

317
00:14:44,720 --> 00:14:49,158
WAS JUST BLOWN AWAY WHEN RANDY

318
00:14:49,158 --> 00:14:52,295
BRATEMAN SHOWED A TURNOVER OF

319
00:14:52,295 --> 00:14:53,529
AMYLOID OF LESS THAN A DAY AND

320
00:14:53,529 --> 00:14:55,565
THIS IS A PROTEIN THAT'S

321
00:14:55,565 --> 00:14:56,899
CONSTANTLY BEING MADE AND

322
00:14:56,899 --> 00:14:58,067
THROWN,A WAY, AND THAT PROCESS

323
00:14:58,067 --> 00:15:02,705
OF A FLOW OF THIS PROTEIN IS OF

324
00:15:02,705 --> 00:15:05,508
COURSE, A CRITICAL BIOLOGIC

325
00:15:05,508 --> 00:15:10,813
PROCESS AND IT'S DISTURBED WHEN

326
00:15:10,813 --> 00:15:11,914
ALZHEIMER DISEASE DEVELOPS AND

327
00:15:11,914 --> 00:15:14,016
EITHER THERE'S TOO MUCH OR

328
00:15:14,016 --> 00:15:17,119
THERE'S TOO LITTLE OR

329
00:15:17,119 --> 00:15:18,554
INAPPROPRIATE REMOVAL OR IT'S

330
00:15:18,554 --> 00:15:20,790
ACCUMULATING IN THE BRAIN IN IN

331
00:15:20,790 --> 00:15:22,325
TOXIC FORM AND WE HAVE THESE

332
00:15:22,325 --> 00:15:28,030
EXAMPLES THAT ARE VERY DRAMATIC

333
00:15:28,030 --> 00:15:29,832
FROM THE FAMILIAL MUTATIONS THAT

334
00:15:29,832 --> 00:15:31,834
ABSOLUTELY GIVE AN EARLY ONSET

335
00:15:31,834 --> 00:15:33,202
OF THE CLINICAL DISEASE OR IN

336
00:15:33,202 --> 00:15:40,109
DOWNS PATIENT WHO IS HAVE

337
00:15:40,109 --> 00:15:42,245
TRISONWR 21 OF THE APUNISHING

338
00:15:42,245 --> 00:15:45,114
P YEEP, AND THEY CLEARLY LINK AD

339
00:15:45,114 --> 00:15:46,549
TO THE BIOLOGY WE'RE TRYING TO

340
00:15:46,549 --> 00:15:48,217
ADDRESS AND THE WHOLE TECHNOLOGY

341
00:15:48,217 --> 00:15:52,054
TRANSFER WAS REALLY, PUT A

342
00:15:52,054 --> 00:15:54,757
CHERRYOT TOP WHEN THE ISOTOPE

343
00:15:54,757 --> 00:15:57,026
LANDIC VERSION SAW A DIFFERENT

344
00:15:57,026 --> 00:16:06,102
VERSION OF A-P-P, THAT MADE LESS

345
00:16:06,102 --> 00:16:07,536
AMYLOIDOGENIC DISEASE, AND

346
00:16:07,536 --> 00:16:09,572
THERE'S SOMETHING WORTH PURSUING

347
00:16:09,572 --> 00:16:10,907
A DIRECT THERAPY INTERFERING

348
00:16:10,907 --> 00:16:12,875
WITH ITS BIOLOGY.

349
00:16:12,875 --> 00:16:16,245
NOW THE EASY WAYS OF ADDRESSING

350
00:16:16,245 --> 00:16:18,347
THE BETA SINK RATAISS--SYNTH

351
00:16:18,347 --> 00:16:20,783
HAVE BEEN TAUGHT AND HAVE FAILED

352
00:16:20,783 --> 00:16:25,621
AND THAT'S WHY WE'RE WORKING ON

353
00:16:25,621 --> 00:16:28,324
THE NOTION OF THE MONOCLONALS

354
00:16:28,324 --> 00:16:29,525
BEING BUT YOU HAVE TO REALIZE

355
00:16:29,525 --> 00:16:32,128
THERE ARE MULTIPLE TARGETS,

356
00:16:32,128 --> 00:16:32,995
MONOCLONALS ARE VERY SPECIFIC,

357
00:16:32,995 --> 00:16:36,299
THEY CAN BE DESIGNED TO LOOK FOR

358
00:16:36,299 --> 00:16:40,069
A SPECIFIC ENTITY AND WE HAVE

359
00:16:40,069 --> 00:16:42,004
MONITOR MERS, LIGGA MERS AND

360
00:16:42,004 --> 00:16:43,739
PLAQUES AND THERE'S A LOT OF

361
00:16:43,739 --> 00:16:45,107
CONCERN TAKEN--THEY WE DON'T

362
00:16:45,107 --> 00:16:47,677
RULE KNOW THE TOXIC ENTITIES

363
00:16:47,677 --> 00:16:49,145
THAT DRIVE THIS DEC AND WOULD IT

364
00:16:49,145 --> 00:16:51,781
BE GOOD ENOUGH TO PULL OFF THE

365
00:16:51,781 --> 00:16:54,216
THINGS EARLY IN THE MONOMERSTAGE

366
00:16:54,216 --> 00:16:57,787
SO THERE ARE LESS BELLING PLOKS

367
00:16:57,787 --> 00:16:59,221
FOR PLAQUES AND THEIR OLIGMERS

368
00:16:59,221 --> 00:17:02,291
MIGHT BE THE TOXIC DRIVING THE

369
00:17:02,291 --> 00:17:03,326
DEC, WELL, THAT'S AN IMPORTANT

370
00:17:03,326 --> 00:17:05,728
NOTION IS HAS BEEN TESTED AND

371
00:17:05,728 --> 00:17:09,031
SIMILARLY ARE THESE PLAQUES THAT

372
00:17:09,031 --> 00:17:10,266
ARE PATHOLODGEECLY DRAMATIC, ARE

373
00:17:10,266 --> 00:17:16,138
THEY THE ENTITY OR ARE THEY A

374
00:17:16,138 --> 00:17:17,440
SYNCH THAT PROTECTING US FROM

375
00:17:17,440 --> 00:17:19,308
THE TOXICITY OF THAT AGENT.

376
00:17:19,308 --> 00:17:21,143
WELL, WE NOW HAVE MULTIPLE LARGE

377
00:17:21,143 --> 00:17:22,378
CLINICAL TRIAL ANDS IN THE ROOM

378
00:17:22,378 --> 00:17:24,847
AND THIS MEETING ARE MOST OF THE

379
00:17:24,847 --> 00:17:27,984
SENIOR AUTHORS FOR THESE TRIALS.

380
00:17:27,984 --> 00:17:31,120
SO JUST TO RECOGNIZE THAT THIS

381
00:17:31,120 --> 00:17:32,188
INVESTMENT THAT'S MOVED ON TO

382
00:17:32,188 --> 00:17:34,323
PHASE 3 TRIAL SYSTEM WHERE WE

383
00:17:34,323 --> 00:17:37,259
ARE NOW AND I WANT POINT OUT

384
00:17:37,259 --> 00:17:41,097
THAT THE WHOLE FIELD HAS BEEN

385
00:17:41,097 --> 00:17:43,399
DRIVEN AND AIDED BY THE

386
00:17:43,399 --> 00:17:44,233
DEVELOPMENT OF AMYLOID PET

387
00:17:44,233 --> 00:17:47,103
SCANNING SO THAT WE COULD

388
00:17:47,103 --> 00:17:50,573
IDENTIFY IN LIFE, WITH

389
00:17:50,573 --> 00:17:52,141
DEVELOPMENT OF THESE PATHOLOGIC

390
00:17:52,141 --> 00:17:53,809
PLAQUES THAT WE'RE SO CLOSELY

391
00:17:53,809 --> 00:17:55,244
ASSOCIATED WITH THE DISEASE, BUT

392
00:17:55,244 --> 00:17:58,180
THESE TRIALS ARE DONE AT THE

393
00:17:58,180 --> 00:18:01,951
VERY MOST STUPID TIME TO ADDRESS

394
00:18:01,951 --> 00:18:03,652
AN AMYLOID DRIVEN DEC, AT THE

395
00:18:03,652 --> 00:18:05,855
END OF THE DAY WHEN THE DISEASE

396
00:18:05,855 --> 00:18:06,455
IS ALREADY TEABED.

397
00:18:06,455 --> 00:18:07,923
AND I THINK OF COURSE WE ALL

398
00:18:07,923 --> 00:18:09,258
BELIEVE THAT'S BEEN PART OF THE

399
00:18:09,258 --> 00:18:12,161
PROBLEM BUT IT'S BEEN A PROBLEM

400
00:18:12,161 --> 00:18:16,098
BECAUSE WE COULDN'T ACCURATELY

401
00:18:16,098 --> 00:18:17,233
PREDICT EARLIER WHO WOULD GIVE

402
00:18:17,233 --> 00:18:22,338
US A TRIAL THAT WAS DOABLE.

403
00:18:22,338 --> 00:18:23,739
BUT THIS DYNAMIC 20 YEAR PROCESS

404
00:18:23,739 --> 00:18:24,540
IS REALLY INKRE TINS BELIEVE AND

405
00:18:24,540 --> 00:18:25,975
I LOVE TO SHOW THESE PICTURES

406
00:18:25,975 --> 00:18:29,045
THAT CAME OUT OF OUR DOMINANTLY

407
00:18:29,045 --> 00:18:30,713
INHERITED EXPERIENCE AND THE

408
00:18:30,713 --> 00:18:35,785
TIMING OF THIS SHOWS THERE IN

409
00:18:35,785 --> 00:18:38,054
THE PRECLINICAL REGION, THE

410
00:18:38,054 --> 00:18:38,687
BRIGHTER COLORS APPEARING, IF

411
00:18:38,687 --> 00:18:40,356
YOU LOOK AT THE BOTTOM THIS IS 5

412
00:18:40,356 --> 00:18:41,991
YEARS BEFORE THE ONSET OF

413
00:18:41,991 --> 00:18:46,195
DEMENTIA, AND THEN AS THE

414
00:18:46,195 --> 00:18:48,130
[INDISCERNIBLE] ARE GETTING A

415
00:18:48,130 --> 00:18:49,398
BIG AMYLOID DEPOSIT AND WE SEE

416
00:18:49,398 --> 00:18:55,304
IN THE NEXT SCAN AND THE DG

417
00:18:55,304 --> 00:18:57,173
SCAN, AND THEN DAMAGE AS THE

418
00:18:57,173 --> 00:18:59,508
CORTEX BECOMES THIN AS THE DEC

419
00:18:59,508 --> 00:19:00,776
WASTES THE BRAIN.

420
00:19:00,776 --> 00:19:04,213
SO A VERY DRAMATIC DYNAMIC

421
00:19:04,213 --> 00:19:05,681
PROCESS OF RAPIDLY TURNING OVER

422
00:19:05,681 --> 00:19:07,950
PROTEIN IS WHAT WE HAVE TO

423
00:19:07,950 --> 00:19:12,021
ADDRESS BIOLOGICALLY WITH DRUGS.

424
00:19:12,021 --> 00:19:13,856
MOP O CLONAL ANTIBODIES ARE

425
00:19:13,856 --> 00:19:15,858
TERRIBLE DRUGS TO TREAT THE

426
00:19:15,858 --> 00:19:17,226
BRAIN WITH, AREN'T THEY IN AND

427
00:19:17,226 --> 00:19:18,661
WE'RE ONLY STUCK WITH THEM

428
00:19:18,661 --> 00:19:22,264
BECAUSE EVERYTHING ELSE HAS

429
00:19:22,264 --> 00:19:23,699
FAILED BUT HERE WE ARE, AND THE

430
00:19:23,699 --> 00:19:27,603
HAPPY THING IS THAT ALTHOUGH

431
00:19:27,603 --> 00:19:29,638
THERE ARE BIG PROTEINS THAT

432
00:19:29,638 --> 00:19:31,540
DON'T GET THROUGH THE BLOOD

433
00:19:31,540 --> 00:19:33,075
BRAIN BARRIER VERY WELL, ENOUGH

434
00:19:33,075 --> 00:19:34,610
DOES AND IT'S CLEAR WE CAN

435
00:19:34,610 --> 00:19:36,912
ADDRESS IT AND SO WITH A LOT OF

436
00:19:36,912 --> 00:19:39,348
INVESTMENT, WE CAN GIVE ENOUGH

437
00:19:39,348 --> 00:19:40,349
KRUG TO MATTER IN THE BRAIN AND

438
00:19:40,349 --> 00:19:41,684
THEN WE HAVE TO PICK THE TARGET

439
00:19:41,684 --> 00:19:46,856
AND SO WE HAVE THIS ARRAY OF

440
00:19:46,856 --> 00:19:47,389
POSSIBLE TARGETS.

441
00:19:47,389 --> 00:19:51,660
WOULD IT BE BETTER TO HIT EARLY

442
00:19:51,660 --> 00:19:55,397
PARTS AND EMPTY THE SINK OF THE

443
00:19:55,397 --> 00:19:58,100
COMPONENTS OF AMYLOID BEFORE IT

444
00:19:58,100 --> 00:19:59,168
FORMS FIEB RULES.

445
00:19:59,168 --> 00:20:01,203
WELL THAT'S A GOOD HYPOTHESIS

446
00:20:01,203 --> 00:20:02,938
AND SOME COULD BEING TARGETED

447
00:20:02,938 --> 00:20:04,140
THERE, AND THAT'S A GOOD

448
00:20:04,140 --> 00:20:05,541
MECHANISM BUT ARE THE PLAQUES

449
00:20:05,541 --> 00:20:06,575
THEMSELVES A CRITICAL TARGET AND

450
00:20:06,575 --> 00:20:08,177
I WOULD PONENT OUT THAT

451
00:20:08,177 --> 00:20:09,378
ANTIBODIES DON'T CLEAR PLAQUES.

452
00:20:09,378 --> 00:20:13,082
THEY HAVE TO ENGAGE THE

453
00:20:13,082 --> 00:20:14,683
MICROFLEEL SYSTEM AND THAT'S

454
00:20:14,683 --> 00:20:18,053
WHAT CLEARS THE PLAQUES AND SO

455
00:20:18,053 --> 00:20:20,456
THAT'S THE MECHANISM BY WHICH

456
00:20:20,456 --> 00:20:21,190
BIOLOGICALLY THESE DRUGS ARE

457
00:20:21,190 --> 00:20:22,391
WORKING AND THEN OF COURSE IF

458
00:20:22,391 --> 00:20:24,727
YOU ARE GIVEN THIS PROTEIN, YOU

459
00:20:24,727 --> 00:20:30,399
CAN'T SWALLOW THE PILLS BECAUSE

460
00:20:30,399 --> 00:20:31,500
YOU JUST [INDISCERNIBLE], SO YOU

461
00:20:31,500 --> 00:20:36,172
HAVE TO GIVE IV OR SUBCUE AND

462
00:20:36,172 --> 00:20:37,439
THAT'S VERY INCONVENIENT AND

463
00:20:37,439 --> 00:20:38,374
TROUBLESOME AND EXPENSIVE AND

464
00:20:38,374 --> 00:20:39,575
IT'S ONLY MADE POSSIBLE BECAUSE

465
00:20:39,575 --> 00:20:41,577
ONCE THEY'RE IN THE BLOOD

466
00:20:41,577 --> 00:20:42,978
STREAM, THEY LAST FOR QUITE A

467
00:20:42,978 --> 00:20:46,415
WHILE AND SO YOU HAVE LONG HALF

468
00:20:46,415 --> 00:20:46,615
LIVES.

469
00:20:46,615 --> 00:20:51,086
SO THESE ARE THE TARGETS AND IT

470
00:20:51,086 --> 00:20:52,454
TURNS OUT THAT THE TARGETS THAT

471
00:20:52,454 --> 00:20:57,026
FAILED TO DIRECTLY ADDRESS THE

472
00:20:57,026 --> 00:21:02,431
AMYLOID PLAQUE HAVE BEEN

473
00:21:02,431 --> 00:21:04,099
SOLANEZUMAB, AND CRENEZUMAB, AND

474
00:21:04,099 --> 00:21:06,168
THATY BECAUSE IT'S AN IGD EABT

475
00:21:06,168 --> 00:21:08,337
BODY, THE REST OF THEM DO

476
00:21:08,337 --> 00:21:09,071
ADDRESS PLAQUES WITH THE LATEST

477
00:21:09,071 --> 00:21:17,780
BREATHER IN THE FIELD, DONANEMAB

478
00:21:17,780 --> 00:21:20,482
MOST DIRECTLY CAN EXCLUSIVELY AN

479
00:21:20,482 --> 00:21:21,350
ANTIPLAQUE ANTIBODY SO IF YOU

480
00:21:21,350 --> 00:21:23,018
HAD THE NOTION THAT ALL THE

481
00:21:23,018 --> 00:21:24,687
DISEASE WAS DRIVEN BY TOXIC

482
00:21:24,687 --> 00:21:28,090
FORMS, THIS MIGHT NOT WORK AT

483
00:21:28,090 --> 00:21:29,658
ALL BUT WHAT WE'VE SEEN OF

484
00:21:29,658 --> 00:21:33,229
COURSE IS THAT IN FACT

485
00:21:33,229 --> 00:21:34,964
CORRELATED WITH SUCCESS IN

486
00:21:34,964 --> 00:21:37,299
LOCKING THE PROGRESSION OF

487
00:21:37,299 --> 00:21:40,169
COGNITIVE LOSS AND FUNCTIONAL

488
00:21:40,169 --> 00:21:42,304
LOSS IN THE DEC IS MOST TIGHTLY

489
00:21:42,304 --> 00:21:44,640
CORRELATED WITH THE ABILITY TO

490
00:21:44,640 --> 00:21:45,708
CLEAR THE EVIDENCE AMYLOID

491
00:21:45,708 --> 00:21:47,309
PLAQUES IN THE BRAINS OF

492
00:21:47,309 --> 00:21:49,745
PATIENTS IN THESE LARGE CLINICAL

493
00:21:49,745 --> 00:21:49,979
TRIALS.

494
00:21:49,979 --> 00:21:56,619
THE DRUGS THAT FAILED TO CLEAR

495
00:21:56,619 --> 00:22:00,990
PLAQUES SUFFICIENTLY,

496
00:22:00,990 --> 00:22:02,491
SOLANEZUMAB, CHENEZUMAB, ALL

497
00:22:02,491 --> 00:22:03,692
REALLY FAIL TO PROTECT AS YOU

498
00:22:03,692 --> 00:22:05,060
SEE THE PROGRESSION OF THE DEC

499
00:22:05,060 --> 00:22:08,364
REFLECTED FOR INITANCE IN THE

500
00:22:08,364 --> 00:22:10,099
CDR, SOME OF BOX SCORE WHICH IS

501
00:22:10,099 --> 00:22:12,134
A MEASURE THAT IS WEIGHTED

502
00:22:12,134 --> 00:22:18,107
TOWARD COGNITIVE DECLEAN BUT

503
00:22:18,107 --> 00:22:20,909
ALSO INCLUDES LIFE FUNCTIONAL

504
00:22:20,909 --> 00:22:21,243
DECLINE.

505
00:22:21,243 --> 00:22:23,612
IN CONTRAST, AS THE AGENTS HAVE

506
00:22:23,612 --> 00:22:25,948
BECOME MORE SUCCESSFUL AT

507
00:22:25,948 --> 00:22:26,849
ADDRESSING PLAQUES, THEY'VE

508
00:22:26,849 --> 00:22:31,654
BEGUN TO SHOW EFFICACY AND

509
00:22:31,654 --> 00:22:32,321
[INDISCERNIBLE] HAD THE

510
00:22:32,321 --> 00:22:36,759
EXPERIENCE OF HAVING THE TRIALS

511
00:22:36,759 --> 00:22:39,995
SHORTENED BY A FUTILITY ANALYSIS

512
00:22:39,995 --> 00:22:42,431
THAT WAS PREMATURE AND RESULTING

513
00:22:42,431 --> 00:22:44,033
IN A HUNG URIE BASICALLY WITH

514
00:22:44,033 --> 00:22:47,102
THE CLINICAL RESULTS OF THE 2

515
00:22:47,102 --> 00:22:47,870
LARGE TRIALS, BUT VERY CLEAR

516
00:22:47,870 --> 00:22:52,675
EVIDENCE THAT IT WAS MAKING A

517
00:22:52,675 --> 00:22:54,410
SIGNIFICANT IMPACT ON AMYLOID ON

518
00:22:54,410 --> 00:22:56,378
THE BRAIN OF THE PARTICIPANTS AS

519
00:22:56,378 --> 00:22:58,414
WELL AS A REAL IMPACT ON

520
00:22:58,414 --> 00:23:03,452
PERFORMANCE AND SO, THE LATEST

521
00:23:03,452 --> 00:23:06,221
OF THESE TRIALS, REALLY REPORT

522
00:23:06,221 --> 00:23:08,724
SIGNIFICANT CHANGE IN THIS

523
00:23:08,724 --> 00:23:10,993
DECLINING COURSE OF FUNCTIONAL

524
00:23:10,993 --> 00:23:12,895
IMPAIRMENT WHERE THE PLACEBO

525
00:23:12,895 --> 00:23:15,497
CURVES JUST HAVE THIS STEADY

526
00:23:15,497 --> 00:23:17,066
ONGOING COURSE OF DECLINE OVER A

527
00:23:17,066 --> 00:23:21,337
YEAR AND A HALF OF SO OF STUDY

528
00:23:21,337 --> 00:23:23,072
ASK DOUBLE PLIENDED CONTROL

529
00:23:23,072 --> 00:23:25,808
EXPERIMENTS, THE DRUGS ARE

530
00:23:25,808 --> 00:23:26,709
CLEARLY BENDING THAT CURVE

531
00:23:26,709 --> 00:23:30,446
ALTHOUGH NOT MAKING IT FLAT IN

532
00:23:30,446 --> 00:23:32,648
ALL CASES BUT ON AVERAGE A VERY

533
00:23:32,648 --> 00:23:34,583
SIGNIFICANT CHANGE THAT I THINK

534
00:23:34,583 --> 00:23:39,254
WE ALL BELIEVE IS CLINICALLY

535
00:23:39,254 --> 00:23:40,789
IMPACTFUL, SO THIS HAS BEEN

536
00:23:40,789 --> 00:23:42,157
DONE, THERE'S THIS CORRELATION

537
00:23:42,157 --> 00:23:45,294
AND IT APPEARS TO BE RELATED TO

538
00:23:45,294 --> 00:23:46,495
THE ABILITY TO CLEAR PLAQUE FROM

539
00:23:46,495 --> 00:23:49,331
THE BRAIN AND IN FACT, THE

540
00:23:49,331 --> 00:23:55,871
STRATEGY THAT WAS USED IN

541
00:23:55,871 --> 00:23:57,239
DEVELOPING LECANEMAB, WAS A

542
00:23:57,239 --> 00:23:59,074
CAREFUL STUDY TO SELECT A DOSE

543
00:23:59,074 --> 00:24:01,677
THAT WOULD OPTIMALLY BE

544
00:24:01,677 --> 00:24:05,414
TOLERATED AND CLEAR THE AMYLOID

545
00:24:05,414 --> 00:24:08,484
PLAQUE IN A SOMEWHAT DIFFICULT

546
00:24:08,484 --> 00:24:13,922
BI-WEEKLY ADMINITRATION SCHEME

547
00:24:13,922 --> 00:24:15,124
WAS USED TO OPTIMALLY DRIVE THE

548
00:24:15,124 --> 00:24:16,158
TARGET AND IT RESULTED IN

549
00:24:16,158 --> 00:24:18,060
EXACTLY WHAT WAS PREDICTED IN

550
00:24:18,060 --> 00:24:22,331
THE PHASE 3 TRIAL AND IN THE

551
00:24:22,331 --> 00:24:24,600
CLINICAL RESULTS THAT WERE

552
00:24:24,600 --> 00:24:26,568
REALLY SOUGHT AND A VERY SIMILAR

553
00:24:26,568 --> 00:24:28,637
PATTERN PERHAPS WITH AN EACH

554
00:24:28,637 --> 00:24:31,974
MORE AGGRESSIVE CLEARANCE, IS

555
00:24:31,974 --> 00:24:40,282
DEMON TRAITED WITH THE

556
00:24:40,282 --> 00:24:41,650
DONANEMAB, WHICH IS EXCLUSIVE TO

557
00:24:41,650 --> 00:24:45,554
PLAQUES AND RESULTED IN AN 80%

558
00:24:45,554 --> 00:24:49,124
CLEARANCE OF THE PET EVIDENT

559
00:24:49,124 --> 00:24:50,559
AMYLOID IN THE PARTICIPANTS IN

560
00:24:50,559 --> 00:24:53,162
THIS TRIAL AND A NOTABLE SLOWING

561
00:24:53,162 --> 00:24:55,931
OF THE PROGRESSION OF THE REAL

562
00:24:55,931 --> 00:24:58,367
DISABILITY THAT COMES ON IN THE

563
00:24:58,367 --> 00:25:01,203
COURSE OF ALZHEIMER DISEASE, SO

564
00:25:01,203 --> 00:25:06,675
THE PRICE OF THIS IS WHAT THIS

565
00:25:06,675 --> 00:25:13,515
MEETING IS LARGELY ARIA AND SO

566
00:25:13,515 --> 00:25:19,988
ARIA AND FAIL TO CLEAR BUT

567
00:25:19,988 --> 00:25:21,757
ASSOCIATED WITH THIS PROCESS

568
00:25:21,757 --> 00:25:24,059
CRITICAL EFFICACY OF THIS DRIVES

569
00:25:24,059 --> 00:25:27,663
ASK THE PROCESS IS THESE IMAGING

570
00:25:27,663 --> 00:25:29,198
ABNORMALITIES WHICH ARE SEEN ON

571
00:25:29,198 --> 00:25:32,367
MRI SCANS AND THEY COME IN 2

572
00:25:32,367 --> 00:25:35,037
FLAVORS, 1 IS THE EDEMA AND YOU

573
00:25:35,037 --> 00:25:36,939
CAN SEE ON THE TOP ROW HERE, I

574
00:25:36,939 --> 00:25:40,275
AM NOT SURE IF I CAN--HOW DO I

575
00:25:40,275 --> 00:25:41,510
DID THAT, I CAN'T POINT VERY

576
00:25:41,510 --> 00:25:43,679
WELL, BUT IN THE TOP ROW OF

577
00:25:43,679 --> 00:25:46,281
SCANS, YOU CAN SEE IN THE

578
00:25:46,281 --> 00:25:48,417
OCCIPITAL REGION OF THE BRAIN,

579
00:25:48,417 --> 00:25:51,153
THE DEVELOPMENT OF BRIGHT FLARE

580
00:25:51,153 --> 00:25:54,890
POSITIVE REGIONS THAT SHOW

581
00:25:54,890 --> 00:25:58,827
GREATERUAR ER WATER IN TISSUE IE

582
00:25:58,827 --> 00:26:00,329
FOCAL AREAS OF THE BRAIN AND IF

583
00:26:00,329 --> 00:26:01,864
YOU LOOK AT THE BOTTOM, YOU CAN

584
00:26:01,864 --> 00:26:05,534
SEE THAT THE BRIGHT COLORS THAT

585
00:26:05,534 --> 00:26:06,835
SHOW THE DEPOSIT OF AMYLOID IN

586
00:26:06,835 --> 00:26:09,638
THE BRAINS OF THESE PATIENTS

587
00:26:09,638 --> 00:26:12,774
BEFORE THAT ARE NOTABLILY IN THE

588
00:26:12,774 --> 00:26:23,285
SAME REGIONS THAT DEVELOP THIS

589
00:26:26,855 --> 00:26:28,924
AMYLOID IMAGING, AND THE OTHER 1

590
00:26:28,924 --> 00:26:30,592
IS THE DEPOSITS THAT ARE OFTEN

591
00:26:30,592 --> 00:26:33,028
CLUSTERED IN THE REGION OF THE

592
00:26:33,028 --> 00:26:35,564
ARIA E BUT ALSO CAN OCCUR

593
00:26:35,564 --> 00:26:36,398
RANDOMLY, INDEPENDENTLY IN OTHER

594
00:26:36,398 --> 00:26:39,935
AREAS OF THE  BRAIN AND WE

595
00:26:39,935 --> 00:26:45,407
BELIEVE HAVE TO DO WITH  PERHAPS

596
00:26:45,407 --> 00:26:48,744
THE AMYLOID IN BLOOD VESSEL

597
00:26:48,744 --> 00:26:50,445
WALLS, BEING CHANGED,

598
00:26:50,445 --> 00:26:53,081
DESTABILIZED, INFLAMED AND

599
00:26:53,081 --> 00:26:55,684
CAUSING THESE LEAKAGES WHICH ARE

600
00:26:55,684 --> 00:26:58,320
USUALLY ASYMPTOMATIC.

601
00:26:58,320 --> 00:27:01,423
THE ARIA E REMARKABLY IS USUALLY

602
00:27:01,423 --> 00:27:03,025
ASIMPLE TOMATIC AND THEREFORE

603
00:27:03,025 --> 00:27:04,826
CAN BE PICKED UP MOST COMMONLY

604
00:27:04,826 --> 00:27:06,228
WITH COSTLY MRI SCANS THROUGH

605
00:27:06,228 --> 00:27:09,698
THE TRIAL AND AS YOU SEE IN THE

606
00:27:09,698 --> 00:27:14,603
TOP ROW IMEAN IF YOU STOP THE

607
00:27:14,603 --> 00:27:16,738
AMYLOID AGENT, TYPICALLY THE

608
00:27:16,738 --> 00:27:20,475
PATHOLOGIC APPEARANCE IN THE

609
00:27:20,475 --> 00:27:21,810
SCAN REVERSES ESSENTIALLY

610
00:27:21,810 --> 00:27:25,314
COMPLETELY TO MY EYE SO IT'S A

611
00:27:25,314 --> 00:27:26,181
REMARKABLE THING.

612
00:27:26,181 --> 00:27:28,417
WHEN YOU COMPARE THESE DIFFERENT

613
00:27:28,417 --> 00:27:29,985
AGENTS, IT'S A VERY DIFFICULT

614
00:27:29,985 --> 00:27:31,620
COMPARISON BECAUSE THE

615
00:27:31,620 --> 00:27:33,555
POPULATIONS THAT WERE PUT INTO

616
00:27:33,555 --> 00:27:34,923
THE STUDIES OR DEFINITE IN THE

617
00:27:34,923 --> 00:27:40,829
DEGREE TO WHICH THE DISEASE HAS

618
00:27:40,829 --> 00:27:42,631
PROGRESSED AND APOE4 IS CLEARLY

619
00:27:42,631 --> 00:27:48,937
A  RISK FACTOR AND THE NUMBER OF

620
00:27:48,937 --> 00:27:51,406
APOE CARRIERS AND THE WAY THEY

621
00:27:51,406 --> 00:27:52,474
WERE MANAGED IN DIFFERENT IN THE

622
00:27:52,474 --> 00:27:52,708
TRIALS.

623
00:27:52,708 --> 00:27:55,444
SO IT'S HARD TO HAVE A TO HAVE A

624
00:27:55,444 --> 00:27:57,112
HEAD-TO-HEAD COMPARISON, IS IT

625
00:27:57,112 --> 00:27:58,347
THE ANTIBODIES THE WAY THEY WERE

626
00:27:58,347 --> 00:28:00,215
GIVEN OR THE POPPULESS BUT

627
00:28:00,215 --> 00:28:00,816
THAT'S CLEARLY AN IMPORTANT

628
00:28:00,816 --> 00:28:05,687
QUESTION THAT WE HAVE TO

629
00:28:05,687 --> 00:28:05,988
ADDRESS.

630
00:28:05,988 --> 00:28:09,057
BEYOND ARIA, WE HAVE

631
00:28:09,057 --> 00:28:09,925
SURPRISINGLY FEW COMPLICATIONS

632
00:28:09,925 --> 00:28:11,960
WITH USING THESE DRUGS.

633
00:28:11,960 --> 00:28:13,228
THERE ARE MODEST INFUSION

634
00:28:13,228 --> 00:28:16,164
REACTIONS THAT ARE PRETTY

635
00:28:16,164 --> 00:28:16,765
TOLERABLE AND MANAGEABLE AND

636
00:28:16,765 --> 00:28:19,801
WHEN YOU LOOK AT THE TBLOABAL

637
00:28:19,801 --> 00:28:20,969
SAFETY POPULATION OF THESE

638
00:28:20,969 --> 00:28:22,838
STUDIES, IT ACTUALLY IS VERY

639
00:28:22,838 --> 00:28:25,107
GOOD WITH A GOOD BALANCE BETWEEN

640
00:28:25,107 --> 00:28:29,144
THE PLACEBO AND THE TREATED

641
00:28:29,144 --> 00:28:30,679
PATIENTS, SO IT SEEMS LAKE

642
00:28:30,679 --> 00:28:34,416
THERE'S NOT A HEAVY BURDEN OF

643
00:28:34,416 --> 00:28:36,284
SERIOUS TOXICITY IN SAEs OR IN

644
00:28:36,284 --> 00:28:38,320
DEATHS, BUT THE DEATHS THAT WE

645
00:28:38,320 --> 00:28:41,423
HAVE SEEN IN THE TRIALS HAVE

646
00:28:41,423 --> 00:28:44,726
OFTEN BEEN RELATED TO HEMORRHAGE

647
00:28:44,726 --> 00:28:49,965
AND PREDICTERS OF A GREATER

648
00:28:49,965 --> 00:28:51,299
HEMOGGAGIC TENDENCY INCLUDING

649
00:28:51,299 --> 00:28:56,438
TPA OR PREEXISTING EVIDENT OF

650
00:28:56,438 --> 00:28:57,472
AMYLOID ANCHLY OPERATING

651
00:28:57,472 --> 00:28:58,273
GLOBALLYATHY.

652
00:28:58,273 --> 00:28:59,908
SO WE'RE AT AN EXCITING TIME.

653
00:28:59,908 --> 00:29:01,143
THE BUSINESS OF GETTING THESE

654
00:29:01,143 --> 00:29:02,644
DRUGS INTO USE SO THEY CAN

655
00:29:02,644 --> 00:29:03,245
REALLY MAKERS AND A DIFFERENCE

656
00:29:03,245 --> 00:29:06,682
IN THE WORLD IS GOING TO VERY

657
00:29:06,682 --> 00:29:07,916
HEAVILY TALK ABOUT THE TIME

658
00:29:07,916 --> 00:29:10,852
THEY'RE USED AND IT MAY BE--I

659
00:29:10,852 --> 00:29:12,354
TRULY BELIEVE THAT EARLIER USE

660
00:29:12,354 --> 00:29:15,390
WILL BE MUCH SAFER THAN LATER

661
00:29:15,390 --> 00:29:17,592
USE AND WILL HOPE THAT PANS OUT.

662
00:29:17,592 --> 00:29:19,661
WE'VE GOT TO GET THE PRACTICAL

663
00:29:19,661 --> 00:29:21,830
BUSINESS OF HOW DO YOU SELECT

664
00:29:21,830 --> 00:29:22,364
THE RIGHT POPULATION?

665
00:29:22,364 --> 00:29:25,200
YOU CAN BE THE USE AN

666
00:29:25,200 --> 00:29:26,468
ANTIAMYLOID THERAPY IF THERE'S

667
00:29:26,468 --> 00:29:27,636
NOT AMYLOID IN THE BRAIN.

668
00:29:27,636 --> 00:29:29,371
WE HAVE TO PROVE THAT IF WE ASK

669
00:29:29,371 --> 00:29:31,006
AND SUGCREST TO PEOPLE THAT THEY

670
00:29:31,006 --> 00:29:33,675
TAKE THIS RISK, AND SO MOVING ON

671
00:29:33,675 --> 00:29:35,310
TO PRACTICAL MEASURES TO SCREEN

672
00:29:35,310 --> 00:29:36,945
LARGE NUMBERS OF PEOPLE AND

673
00:29:36,945 --> 00:29:38,213
REALLY RELIABLY KNOW THE AMYLOID

674
00:29:38,213 --> 00:29:40,215
AT THAT TIMEUS IN THEIR BRAIN

675
00:29:40,215 --> 00:29:46,788
AND CRITICAL, AS IS TO REALLY

676
00:29:46,788 --> 00:29:48,090
FULLY UNDERSTAND AS MUCH OF THE

677
00:29:48,090 --> 00:29:50,525
RISKS THAT DRIVE THE DANGER SIDE

678
00:29:50,525 --> 00:29:51,727
FOR USING THESE THERAPIES.

679
00:29:51,727 --> 00:29:53,595
AND THEN A PRACTICAL STRATEGY,

680
00:29:53,595 --> 00:29:54,963
YOU KNOW WE JUST CAN'T HAVE

681
00:29:54,963 --> 00:29:56,164
PEOPLE COMING IN EVERY 2 WEEKS

682
00:29:56,164 --> 00:29:59,901
FOR THE REST OF THEIR LIVES FOR

683
00:29:59,901 --> 00:30:02,037
IV INFUSIONS.

684
00:30:02,037 --> 00:30:03,672
SO ONCE WE'VE CLEARED PLAQUES

685
00:30:03,672 --> 00:30:05,941
WHAT DO WE DO WITH THEM?

686
00:30:05,941 --> 00:30:08,143
HOW DO WE MAKE SURE THAT WHAT

687
00:30:08,143 --> 00:30:09,544
BENEFITS WE ACCRUED WILL BE LONG

688
00:30:09,544 --> 00:30:12,848
LASTING AND SO THAT'S A CRITICAL

689
00:30:12,848 --> 00:30:14,049
PART THAT WE'VE REALLY GOT TO

690
00:30:14,049 --> 00:30:15,283
EXPLORE AND FIGURE OUT EMPLOY SO

691
00:30:15,283 --> 00:30:16,818
I WAS PROBABLY INVITED BECAUSE

692
00:30:16,818 --> 00:30:19,888
I'M NAIVE TO THE FIELD AND I AM

693
00:30:19,888 --> 00:30:22,891
PRETTY NAIVE BUT I'M MOT TOTAL

694
00:30:22,891 --> 00:30:24,659
NAIVE AND YOU 2 I'M SURE ARE NOT

695
00:30:24,659 --> 00:30:31,133
BUT JUST A REMINDER THAT

696
00:30:31,133 --> 00:30:31,967
ADDRESSING ALZHEIMER'S DISEASE

697
00:30:31,967 --> 00:30:34,436
WILL NOT BE JUST ABOUT TREATING

698
00:30:34,436 --> 00:30:35,804
AMYLOID, WE HAVE TO DEAL WITH

699
00:30:35,804 --> 00:30:36,805
THE ENTIRE LIFE CYCLE.

700
00:30:36,805 --> 00:30:38,573
WE HAVE TO DEAL WITH TAU AND

701
00:30:38,573 --> 00:30:39,508
WHAT'S ANYTHING ON WITH THAT, WE

702
00:30:39,508 --> 00:30:41,376
HAVE TO DEAL WITH THE

703
00:30:41,376 --> 00:30:42,144
INFLAMMATORY FACTOR ISSUES THE

704
00:30:42,144 --> 00:30:43,779
GOOD PARTS OF IT AND THE BAD

705
00:30:43,779 --> 00:30:47,182
PARTS OF IT AND UNDERSTAND THAT

706
00:30:47,182 --> 00:30:49,618
AND MAXIMIZE, THE OUTCOMES AND I

707
00:30:49,618 --> 00:30:51,520
THINK WE CAN--WE'RE ON OUR WAY

708
00:30:51,520 --> 00:30:54,022
TO TREATING A DREADFUL, DREADFUL

709
00:30:54,022 --> 00:30:55,991
DISEASE VERY EFFECTIVELY AND

710
00:30:55,991 --> 00:30:56,758
THAT'S EXCITING.

711
00:30:56,758 --> 00:31:00,095
SO I WILL END WITH THAT THANKING

712
00:31:00,095 --> 00:31:03,365
THE PEOPLE AT WASH-U THAT

713
00:31:03,365 --> 00:31:06,201
MENTORED ME AND ESPECIALLY MY

714
00:31:06,201 --> 00:31:14,009
TUTORS AS I HAVE COME IN CAN

715
00:31:14,009 --> 00:31:17,512
MONITORING ARIA THERE, RANDY

716
00:31:17,512 --> 00:31:19,648
BATEMAN GAVE ME MY FIRST TUTOR,

717
00:31:19,648 --> 00:31:30,158
SO VERY HONORED TO BE WITH YOU

718
00:31:30,492 --> 00:31:30,692
TODAY.

719
00:31:30,692 --> 00:31:32,027
NWONDERFUL TALK AND WE'LL HAVE

720
00:31:32,027 --> 00:31:32,894
TIME DURING THE DISCUSSION

721
00:31:32,894 --> 00:31:33,728
PERIOD.

722
00:31:33,728 --> 00:31:38,500
WE WILL CONTINUE NOW TO KEEP ON

723
00:31:38,500 --> 00:31:40,502
TIME.

724
00:31:40,502 --> 00:31:47,609
DR. REISA SPERLING MASSACHUSETTS

725
00:31:47,609 --> 00:31:51,146
GENERAL HOSPITAL.

726
00:31:51,146 --> 00:31:51,947
>> THANK YOU.

727
00:31:51,947 --> 00:31:53,648
SO I THINK I WAS INVITED BECAUSE

728
00:31:53,648 --> 00:31:55,150
I AM IN THE WEEDS SO THANK YOU

729
00:31:55,150 --> 00:31:56,818
FOR THIS SO I CAN ACTUALLY SEE

730
00:31:56,818 --> 00:31:58,153
YOU GUYS WHILE I SPEAK AND

731
00:31:58,153 --> 00:31:59,554
THANKS SO MUCH FOR THE

732
00:31:59,554 --> 00:32:01,089
INVITATION TO COME TO THIS.

733
00:32:01,089 --> 00:32:04,559
I WORKED A LOT ON ARIA 10 OR 12

734
00:32:04,559 --> 00:32:06,394
YEARS AGO AS I WILL SHOW YOU AND

735
00:32:06,394 --> 00:32:07,562
THEN I SOMEWHAT STOPPED BECAUSE

736
00:32:07,562 --> 00:32:09,764
I'M WORKING ON GOING EARLIER IN

737
00:32:09,764 --> 00:32:11,666
PREVENTION TRIALS BUT I NOW SEE

738
00:32:11,666 --> 00:32:12,968
THAT ARIA'S IN THE WAKE OF MY

739
00:32:12,968 --> 00:32:15,537
BEING ABLE TO GIVE THIS TO 50

740
00:32:15,537 --> 00:32:17,839
AND 60 YEARS AROUND THE WORLD.

741
00:32:17,839 --> 00:32:18,607
SO COMING BACK.

742
00:32:18,607 --> 00:32:22,611
ALL RIGHT, LET ME FIRST--HERE

743
00:32:22,611 --> 00:32:25,146
ARE MY DISCLOSURES AND I WANT TO

744
00:32:25,146 --> 00:32:26,648
ACKNOWLEDGE THE FUNDING.

745
00:32:26,648 --> 00:32:28,550
SO I'M GOING START WITH ACTUALLY

746
00:32:28,550 --> 00:32:30,886
SHOWING YOU SOME IMANNUALS

747
00:32:30,886 --> 00:32:32,020
AGAIN, TO REMIND YOU OF WHAT

748
00:32:32,020 --> 00:32:36,024
THIS LOOKS LIKE IN THE BRAIN AND

749
00:32:36,024 --> 00:32:37,225
ESPECIALLY THE INCREDIBLE

750
00:32:37,225 --> 00:32:39,127
SPECTRUM OF WHAT ARIA CAN LOOK

751
00:32:39,127 --> 00:32:41,363
LOOK AND I'M GOING TO GEF YOU A

752
00:32:41,363 --> 00:32:46,368
BRIEF HISTORY ON IN MY CASE A

753
00:32:46,368 --> 00:32:47,269
HERSTORY, ON ARIA PARTLY BECAUSE

754
00:32:47,269 --> 00:32:48,703
IT WAS REALLY HELPFUL TO GO BACK

755
00:32:48,703 --> 00:32:50,639
AND SEE WHERE WE'VE BEEN AND

756
00:32:50,639 --> 00:32:51,406
WHERE WE'RE GOING.

757
00:32:51,406 --> 00:32:57,412
SO I ACTUALLY THINK THE STORY

758
00:32:57,412 --> 00:33:06,388
STARTS BACK IN FIRST VACCINE IN

759
00:33:06,388 --> 00:33:09,124
1982 WHERE MENINETWORK

760
00:33:09,124 --> 00:33:10,358
GOENCEPHALITIS IN 6%, THIS WAS

761
00:33:10,358 --> 00:33:13,628
ONLY BAH THE C-TERMINUS IS

762
00:33:13,628 --> 00:33:16,097
ACTIVATING T-CELLS SO WE DON'T

763
00:33:16,097 --> 00:33:16,998
HAVE TO WORRY ABOUT THIS GOING

764
00:33:16,998 --> 00:33:19,467
FORWARD AND I DO THINK THAT

765
00:33:19,467 --> 00:33:21,202
ANTIBODIES ARE QUITE DIFFERENT

766
00:33:21,202 --> 00:33:23,338
THAN A VACCINE WITH AN ADYU VENT

767
00:33:23,338 --> 00:33:24,806
BUT I THINK THERE'S AN OVERLAP

768
00:33:24,806 --> 00:33:26,408
IN WHAT ACTUALLY OCCURS IN THE

769
00:33:26,408 --> 00:33:29,244
BRAIN AS WE'RE REMOVING AMYLOID

770
00:33:29,244 --> 00:33:30,111
AND THESE MREFRESH YOUR

771
00:33:30,111 --> 00:33:31,012
RECOLLECTION I CHANGES WHICH I

772
00:33:31,012 --> 00:33:32,647
WILL SHOW YOU IN A MOMENT WERE

773
00:33:32,647 --> 00:33:34,816
OBSERVED IN THE SETTING OF

774
00:33:34,816 --> 00:33:35,784
CLINICAL SYMPTOMS AND

775
00:33:35,784 --> 00:33:36,418
IMPORTANTLY THOUGH, THERE WAS

776
00:33:36,418 --> 00:33:38,887
QUITE A LOT OF CELLS IN THE CSF

777
00:33:38,887 --> 00:33:41,456
SO IT WAS CLEARLY AN

778
00:33:41,456 --> 00:33:43,625
INFLAMMATORY PROCESS, SO WE

779
00:33:43,625 --> 00:33:44,693
THOUGHT, OKAY, WE'RE GOING PAST

780
00:33:44,693 --> 00:33:44,893
THAT.

781
00:33:44,893 --> 00:33:46,227
WE WILL FIX THIS, WE WILL GO

782
00:33:46,227 --> 00:33:48,463
ABOUT THE MOP O CLON AT ASPECT

783
00:33:48,463 --> 00:33:54,336
BODY, FOCUSED MORE ON THE END

784
00:33:54,336 --> 00:34:03,678
TERMINUS AND WE STARTED STUDIES

785
00:34:03,678 --> 00:34:08,016
ON BAPINEUZUMAB, AND 3 OUT OF 10

786
00:34:08,016 --> 00:34:09,050
INDIVIDUALS DEVELOPED ARIA AND I

787
00:34:09,050 --> 00:34:11,686
KNOW THOSE WELL BECAUSE I WAS

788
00:34:11,686 --> 00:34:14,322
THE SITE P. I. AND 2 OF THE 3

789
00:34:14,322 --> 00:34:15,523
HAD SUBTLE SYMPTOMS BUT WE KEPT

790
00:34:15,523 --> 00:34:17,258
GOING, WE SAID OKAY, WE WILL GO

791
00:34:17,258 --> 00:34:18,827
TO A LOWER DOSE AND WE MOVED

792
00:34:18,827 --> 00:34:20,161
INTO PHASE 2, I WAS THRILLED TO

793
00:34:20,161 --> 00:34:22,931
BE ABLE TO WORK ON THIS WITH

794
00:34:22,931 --> 00:34:24,699
STEVE SALLOWAY AND OTHER TEAMS

795
00:34:24,699 --> 00:34:27,535
IN FACE 2 AND WE STARTED TO SEE

796
00:34:27,535 --> 00:34:30,438
MULTIPLE CASES EVEN AT THE MITSD

797
00:34:30,438 --> 00:34:32,240
DOSE, BUT THE MIDDLE DOZE AND A

798
00:34:32,240 --> 00:34:34,142
FEW PEOPLE GOT CSF AND IT WAS

799
00:34:34,142 --> 00:34:35,543
INFLAMMATORY AND THE MORE SEVERE

800
00:34:35,543 --> 00:34:37,312
CASES BUT NOT IN EVERYONE, THERE

801
00:34:37,312 --> 00:34:39,414
ARE PEOPLE IN SYMPTOMS WITH NO

802
00:34:39,414 --> 00:34:40,281
CELLS.

803
00:34:40,281 --> 00:34:48,857
AND IMPORTANTLY WALTER WE DID DO

804
00:34:48,857 --> 00:34:51,960
GADA LYNNIUM, BUT WE DID DO GAD

805
00:34:51,960 --> 00:34:54,662
IN QUITE A PEW INDIVIDUALS.

806
00:34:54,662 --> 00:34:57,032
AT THIS POINT THE FDA SENT A

807
00:34:57,032 --> 00:34:59,000
LETTER TO ALL THE SPONSORS AND

808
00:34:59,000 --> 00:35:00,869
THE ALZHEIMER'S ASSOCIATION

809
00:35:00,869 --> 00:35:02,570
CALLED UP MARIA AND SHE

810
00:35:02,570 --> 00:35:05,240
CONVOANED A WORK GROUP ACROSS

811
00:35:05,240 --> 00:35:06,241
ACADEMICS, THE FDA, CUTCHES, AND

812
00:35:06,241 --> 00:35:10,412
I HAVE TO SAY, TO THIS DAY, THIS

813
00:35:10,412 --> 00:35:11,946
COMMITTEE REMAINS THE MOST

814
00:35:11,946 --> 00:35:13,415
USEFUL COMMITTEE I'VE EVER BEEN

815
00:35:13,415 --> 00:35:14,816
ON BECAUSE IT ACTUALLY CHANGED

816
00:35:14,816 --> 00:35:17,819
POLARIZEDEE AND SO SHOUT OUT TO

817
00:35:17,819 --> 00:35:20,989
THE REGULATORS, THIS WAS BACK IN

818
00:35:20,989 --> 00:35:23,324
THE RUSTY CATS DAYS ABOUT YOU IT

819
00:35:23,324 --> 00:35:24,626
SHOWED ME WHAT ALL WORKING

820
00:35:24,626 --> 00:35:27,095
TOGETHER CAN REALLY DO TO SOLVE

821
00:35:27,095 --> 00:35:27,462
THESE PROBLEMS.

822
00:35:27,462 --> 00:35:28,496
SO IT'S THRILLING TO BE HERE AND

823
00:35:28,496 --> 00:35:30,598
WE HAVE TO KEEP WORKING ON IT.

824
00:35:30,598 --> 00:35:33,101
NOW I FOR THE PAST 10IERS OR SO

825
00:35:33,101 --> 00:35:36,504
HAVE BEEN ACCUSED OF NAMING ARIA

826
00:35:36,504 --> 00:35:37,639
SOMETHING BEAUTIFUL BECAUSE TO

827
00:35:37,639 --> 00:35:39,140
MAKE PEOPLE NOT THINK ABOUT IT

828
00:35:39,140 --> 00:35:41,376
AS BEING WORSE BUT I DO WANT TO

829
00:35:41,376 --> 00:35:42,977
MENTION THAT THE ALTERNATIVE

830
00:35:42,977 --> 00:35:44,846
PROPOSED BY CLIFF JACK WAS

831
00:35:44,846 --> 00:35:47,515
FLIRP, WHICH IS SOMETHING ABOUT

832
00:35:47,515 --> 00:35:50,218
FLUID RETENTION RECOVERY PULSES,

833
00:35:50,218 --> 00:36:00,428
SO ARIA WON.

834
00:36:01,229 --> 00:36:01,529
OKAY.

835
00:36:01,529 --> 00:36:03,298
SO HERE TO SHOW YOU IMAGES ON

836
00:36:03,298 --> 00:36:07,836
THE LEFT, SO HAD IS THE VERY IPT

837
00:36:07,836 --> 00:36:09,771
GREATER FLAMMATORY SIDE OF ARIA,

838
00:36:09,771 --> 00:36:13,575
BUT SHOWING RIGHT FROM IMAGES

839
00:36:13,575 --> 00:36:14,209
FROM TEEF SALIBRARY LOWAY'S

840
00:36:14,209 --> 00:36:15,743
PAPER AND MY PAPERS AND I THINK

841
00:36:15,743 --> 00:36:17,045
WHEN IT LOOKS LEAK IN THE BRAIN

842
00:36:17,045 --> 00:36:20,215
CAN OVERLAP AND I THINK THERE'S

843
00:36:20,215 --> 00:36:22,450
REALLY A SPECTRUM OF WHAT AN

844
00:36:22,450 --> 00:36:23,985
INFLAMMATORY AND CLEARANCE OF

845
00:36:23,985 --> 00:36:25,253
WHAT AMYLOID CAN LOOK LEAK IN

846
00:36:25,253 --> 00:36:27,222
THE BRAIN, ALTHOUGH CERTAINLY

847
00:36:27,222 --> 00:36:33,061
THE ACTIVE IMMUNIZATION WAS MUCH

848
00:36:33,061 --> 00:36:34,129
MORE CLEAR.

849
00:36:34,129 --> 00:36:35,630
I ALSO LOOKED BACK TO SAY WHAT

850
00:36:35,630 --> 00:36:37,432
DO WE THINK THEN AND WHAT DO WE

851
00:36:37,432 --> 00:36:37,899
KNOW NOW?

852
00:36:37,899 --> 00:36:39,801
AND I HAVE TO SAY THIS HAS NOT

853
00:36:39,801 --> 00:36:44,672
CHAIRVELGED VERY MUCH SO THE 2

854
00:36:44,672 --> 00:36:46,908
BIG RISK FACTORS FOR ARIA E,

855
00:36:46,908 --> 00:36:49,310
ANYWAY ARE THE DOSE, THE C-MAX

856
00:36:49,310 --> 00:36:51,246
OF THE ANTIBODY INFUSION SEEMS

857
00:36:51,246 --> 00:36:54,015
TO BE ASSOCIATED AND WHETHER YOU

858
00:36:54,015 --> 00:36:56,151
ARE IN APOE 4 CARRIER AND HERE'S

859
00:36:56,151 --> 00:36:57,652
DATA AND DAVID ALREADY SHOWED

860
00:36:57,652 --> 00:36:59,654
YOU SOME NICE DATA ON THIS BUT

861
00:36:59,654 --> 00:37:01,723
THERE REALLY IS A STEP-WISE

862
00:37:01,723 --> 00:37:04,192
RELATIONSHIP BETWEEN THE NUMBER

863
00:37:04,192 --> 00:37:06,895
OF APOE4 ALLELES AND THE RISK OF

864
00:37:06,895 --> 00:37:09,397
ARIA AND THIS IS PRETTY MUCH

865
00:37:09,397 --> 00:37:12,300
TRUE ACROSS ALL ANTIBODIES, ALL

866
00:37:12,300 --> 00:37:12,800
THAT MOVE AMYLOID.

867
00:37:12,800 --> 00:37:15,470
ALL RIGHT, SO HERE'S ANOTHER

868
00:37:15,470 --> 00:37:17,772
TABLE, THIS 1 ACTUALLY CAME FROM

869
00:37:17,772 --> 00:37:19,474
CHRIS VAN DIEK AND I KEEP

870
00:37:19,474 --> 00:37:21,276
UPDATING IT, VERY SIMILAR TO

871
00:37:21,276 --> 00:37:22,410
WHAT DAVID KINDLY SHOWED YOU BUT

872
00:37:22,410 --> 00:37:24,479
I DO WANT TO MAKERS AND A COUPLE

873
00:37:24,479 --> 00:37:26,047
OF MINOR POINTS ON THIS, 1 IS

874
00:37:26,047 --> 00:37:28,449
THAT IT DID SEEM TO MATTER ATH

875
00:37:28,449 --> 00:37:31,019
BIT WHETHER AUTOIIMRKS 1 OR 4 IN

876
00:37:31,019 --> 00:37:32,854
TERMS OF THAT, BUT I THINK 1 OF

877
00:37:32,854 --> 00:37:39,994
THE  BIGGEST THING SYSTEM WHETHR

878
00:37:39,994 --> 00:37:42,931
THEY CAN ACTIVATE MICROTBLIA TO

879
00:37:42,931 --> 00:37:44,532
SEE THE CONFIRMATION THAT'S

880
00:37:44,532 --> 00:37:45,500
STICKING OUT AND ACCESSIBLE.

881
00:37:45,500 --> 00:37:47,535
I THINK THIS IS IMPORTANT, IMEN

882
00:37:47,535 --> 00:37:49,704
I HIGHLIGHTED HERE, IN PLURIBU,

883
00:37:49,704 --> 00:37:52,807
WHERE THE RELATIONSHIP BETWEEN

884
00:37:52,807 --> 00:37:54,475
THE--BEING ABLE TO SEE THE FIBER

885
00:37:54,475 --> 00:37:55,910
IN PARTICULAR IN THAT

886
00:37:55,910 --> 00:37:57,078
CONFIRMATION OR STICKING OUT AND

887
00:37:57,078 --> 00:37:58,279
I WILL ALSO POINT OUT AND I

888
00:37:58,279 --> 00:38:01,583
CAN'T WAIT TO HEAR TEEF GREEN

889
00:38:01,583 --> 00:38:03,885
BERG TALK MORE ABOUT THIS BUT IT

890
00:38:03,885 --> 00:38:05,353
BARGAINED ME ABOUT WHY ARE WE

891
00:38:05,353 --> 00:38:07,455
GOING AFTER TO VESSELS AS WELL

892
00:38:07,455 --> 00:38:08,990
AS TRAINING IT FOR POLITICALS

893
00:38:08,990 --> 00:38:10,225
BUT THE CONFIRMATION IN VESSELS,

894
00:38:10,225 --> 00:38:12,393
YOU CAN SEE THE SAME STUFF AND

895
00:38:12,393 --> 00:38:16,598
CONFIRMATION STICKING OUT AND I

896
00:38:16,598 --> 00:38:17,298
THINK THAT'S IMPORTANT.

897
00:38:17,298 --> 00:38:19,467
SO 1 OF THE IMPORTANT THING THAT

898
00:38:19,467 --> 00:38:21,669
I THINK WE'VE LEARNED IS THAT

899
00:38:21,669 --> 00:38:24,639
ARIA IS ASSOCIATE WIDE AMYLOID

900
00:38:24,639 --> 00:38:25,907
CLEARANCE AND WE FIRST KNEW THIS

901
00:38:25,907 --> 00:38:30,345
BACK IF 2012 WHERE WE COULD SEE

902
00:38:30,345 --> 00:38:31,879
VERY FOCAL AT TIMES CLEARANCE OF

903
00:38:31,879 --> 00:38:35,083
AMYLOID IN THE SETTING WHERE YOU

904
00:38:35,083 --> 00:38:38,853
GET ARIA E AND LATER OFTEN ARIA

905
00:38:38,853 --> 00:38:41,222
H, SO THIS IS 1 EXAMPLE THAT I

906
00:38:41,222 --> 00:38:42,724
THINK WAS USEFUL SO YOU CAN SEE

907
00:38:42,724 --> 00:38:46,461
THAT THERE PERSON'S GOT A LOT OF

908
00:38:46,461 --> 00:38:48,296
FRONTAL AMYLOID AT 6 WEEKS WHICH

909
00:38:48,296 --> 00:38:49,564
IS TYPICAL, VERY EARLY, AFTER

910
00:38:49,564 --> 00:38:54,369
THE SECTION INN FUSION OF THIS

911
00:38:54,369 --> 00:38:57,939
ASPECT BODY, YOU CAN SEE THE

912
00:38:57,939 --> 00:38:59,274
CHANGES ON FLAIR, AND THEN YOU

913
00:38:59,274 --> 00:39:04,612
SEE THIS RESOLVE AS YOU HEARD BY

914
00:39:04,612 --> 00:39:05,813
THE COUPLE SCANS LATER BUT YOU

915
00:39:05,813 --> 00:39:08,650
CAN SEE PRETTY FOCAL CLEARANCE

916
00:39:08,650 --> 00:39:10,084
IN THIS CASE WHERE THE ARIA WAS

917
00:39:10,084 --> 00:39:13,187
OCCURRING AND I HOPE CAN YOU SEE

918
00:39:13,187 --> 00:39:17,792
THESE TRAIN TRACKS OF HEMEAT

919
00:39:17,792 --> 00:39:21,829
SITTEROSEIS WHICH WE REFER TO AS

920
00:39:21,829 --> 00:39:23,364
ARIA H, AND WE SEE CASES LIKE

921
00:39:23,364 --> 00:39:25,700
THIS WHERE YOU GET THE FOCAL

922
00:39:25,700 --> 00:39:26,968
CLEARANCE RELATED TO WHERE THE

923
00:39:26,968 --> 00:39:27,769
ARIA IS.

924
00:39:27,769 --> 00:39:32,106
SO I THINK WE'VE SINCE THEN

925
00:39:32,106 --> 00:39:33,574
LEARNED THAT IMRAITER AMYLOID

926
00:39:33,574 --> 00:39:35,243
PET REDUCTION IS ASSOCIATE WIDE

927
00:39:35,243 --> 00:39:39,147
A HIGHER RISK OF ARIA E BUT I

928
00:39:39,147 --> 00:39:40,448
WILL BRING OUT 2 POTENTIAL

929
00:39:40,448 --> 00:39:43,017
OUTLIERS THAT I THINK ARE

930
00:39:43,017 --> 00:39:43,351
ILLUSTRATIVE.

931
00:39:43,351 --> 00:39:47,889
SO THE DOCTOR MENTIONED

932
00:39:47,889 --> 00:39:48,690
GANTENERUMAB, AND THIS WAS

933
00:39:48,690 --> 00:39:50,892
INTERESTING BECAUSE THEY USED

934
00:39:50,892 --> 00:39:53,494
SUBCUE FORMULES WHICH IN THEORY

935
00:39:53,494 --> 00:39:55,330
MIGHT TBIF YOU LESS ARIA AND

936
00:39:55,330 --> 00:39:56,898
THEY DID A SLOW TITRATION OVER

937
00:39:56,898 --> 00:39:59,634
TIME WHICH I THINK RESULTED IN

938
00:39:59,634 --> 00:40:01,569
LESS AMYLOID REMOVAL THAN THEY

939
00:40:01,569 --> 00:40:02,270
HOPED.

940
00:40:02,270 --> 00:40:04,706
THEY HAD A PRETTY HIGH RATE OF

941
00:40:04,706 --> 00:40:06,341
ARIA, THOUGH THAT OCCURRED IN

942
00:40:06,341 --> 00:40:14,849
THE SAME PATTERN AS WE EXPECTED

943
00:40:14,849 --> 00:40:15,817
ACROSS APOE CARRIERS AND THE

944
00:40:15,817 --> 00:40:16,851
EVENTS HERE WERE DESCROWBTED

945
00:40:16,851 --> 00:40:18,686
MORE OVER THE COURSE OF A TRIAL.

946
00:40:18,686 --> 00:40:20,121
NIGHT RIGHT AFTER EACH INFUSION.

947
00:40:20,121 --> 00:40:22,890
SO IT WAS DIFFERENT THAN THE

948
00:40:22,890 --> 00:40:26,494
C-MAX LOOK AND IT HAD LES THAN I

949
00:40:26,494 --> 00:40:27,795
WILL SAY EXPECTED AMYLOID PET

950
00:40:27,795 --> 00:40:29,330
REDUCTION BECAUSE IT WAS A 2

951
00:40:29,330 --> 00:40:35,002
YEAR TRIAL AND ON AVERAGE THEY

952
00:40:35,002 --> 00:40:43,344
ONLY HAVE 53 CENTILLOIDS, 10

953
00:40:43,344 --> 00:40:46,214
MEGS, AND HAD SIMILAR RATES THAT

954
00:40:46,214 --> 00:40:47,648
ARE DISTRIBUTED ACROSS CARRIER

955
00:40:47,648 --> 00:40:50,218
ANDS THOSE ARE CARRIERS AND NONE

956
00:40:50,218 --> 00:40:51,452
CARRIERS ARE IN THAT STEP, BUT

957
00:40:51,452 --> 00:40:53,755
IT SAYS THEE WEEKS WHICH SHOULD

958
00:40:53,755 --> 00:40:55,757
BE 3 MONTHS, SORRY ABOUT ALL OF

959
00:40:55,757 --> 00:40:56,991
THAT, ALMOST ALL THE EVENTS

960
00:40:56,991 --> 00:40:58,960
OCCURRED AFTER THE FESTER COUPLE

961
00:40:58,960 --> 00:40:59,994
OF INFUSIONS ASK LITERALLY ALL

962
00:40:59,994 --> 00:41:03,097
OF THEM BEFORE ABOUT 3 MONTHS.

963
00:41:03,097 --> 00:41:06,834
SO AND HERE I WILL SAY SLIGHTLY

964
00:41:06,834 --> 00:41:09,871
GRADER THAN REMOVAL, THIS IS

965
00:41:09,871 --> 00:41:10,638
WHAT [INDISCERNIBLE] EXPECTED

966
00:41:10,638 --> 00:41:13,641
BUT SLIGHTLY MORE THAN I

967
00:41:13,641 --> 00:41:15,276
EXPECTED GIVEN IT'S GOING AFTER

968
00:41:15,276 --> 00:41:16,677
PROTOFIEB RULES, BUT IT'S

969
00:41:16,677 --> 00:41:20,448
CLEARING PLAQUE AS WELL AND THEY

970
00:41:20,448 --> 00:41:24,552
HAD A 59 CENTILLOID IN 18

971
00:41:24,552 --> 00:41:24,786
MONTHS.

972
00:41:24,786 --> 00:41:26,187
I WILL TALK ABOUT THIS BECAUSE

973
00:41:26,187 --> 00:41:27,488
STEVE AND I TALKED ABOUT THIS

974
00:41:27,488 --> 00:41:31,759
BEFORE IS ARIA ACTUALLY A MARKER

975
00:41:31,759 --> 00:41:32,593
OF POTENTIAL TREATMENT RESPONSE

976
00:41:32,593 --> 00:41:34,395
IN SO OVERALL TOTALLY WE NEED TO

977
00:41:34,395 --> 00:41:36,097
MANAGE THIS AND HOPEFUL WILY GET

978
00:41:36,097 --> 00:41:46,641
RID OF IT BUT IT DOES SEEM TO BE

979
00:41:47,008 --> 00:41:48,676
ASSOCIATED WITH IMRAITER

980
00:41:48,676 --> 00:41:48,943
RESPONSE.

981
00:41:48,943 --> 00:41:50,611
I WILL SAY THERE'S MIXED EVIDENT

982
00:41:50,611 --> 00:41:54,515
ABOUT WHETHER IT'S ASSOCIATED

983
00:41:54,515 --> 00:41:57,652
WITH GREATER RATES OF ATROPHY OR

984
00:41:57,652 --> 00:41:59,320
NEURODEGENERATION, SO EVEN IN

985
00:41:59,320 --> 00:42:00,588
THE FIRST SPHENE 92 TRIAL IT WAS

986
00:42:00,588 --> 00:42:04,892
NOTICED THERE WAS THIS EXPANSION

987
00:42:04,892 --> 00:42:07,562
OF THE VENTRICLES AND GRAY

988
00:42:07,562 --> 00:42:12,834
MATTER ATROPHY AS NICK FOX SAID

989
00:42:12,834 --> 00:42:15,436
THIS CAUSES HYDROKEVA LIAISONS,

990
00:42:15,436 --> 00:42:17,538
I THINK THIS STILL EXISTS THAT

991
00:42:17,538 --> 00:42:20,374
THIS RAPID CLEARANCE IS SOC WIDE

992
00:42:20,374 --> 00:42:22,910
BLOCKAGE OF THE ARACHNOID VILLI

993
00:42:22,910 --> 00:42:24,345
AND THAT MAY RELATE TO ECPANGZ

994
00:42:24,345 --> 00:42:26,481
BUT YOU DO SEE GREAT MATTER

995
00:42:26,481 --> 00:42:27,582
ATROPHY AS WELL.

996
00:42:27,582 --> 00:42:28,716
BUT INTERESTINGLY, IT'S IN MOST

997
00:42:28,716 --> 00:42:30,618
OF THE CORTEX WHERE THE AMYLOID

998
00:42:30,618 --> 00:42:33,621
SITTING IN YOU SEE LESS

999
00:42:33,621 --> 00:42:34,889
HYPOCAMPAL ARK TROPHY OR AT

1000
00:42:34,889 --> 00:42:36,891
LEAST THERE'S LOTS OF LESS

1001
00:42:36,891 --> 00:42:38,926
AMYLOID WHICH MAY BE A CLUE TO

1002
00:42:38,926 --> 00:42:40,661
WHAT THIS ATROPHY MIGHT BE.

1003
00:42:40,661 --> 00:42:43,898
AND RECENTLY THERE'S BEEN

1004
00:42:43,898 --> 00:42:46,501
REPORTS OF REDUCTION IN G-FAB,

1005
00:42:46,501 --> 00:42:48,169
NFL AND PLAZ MIDS THAT TAU, THIS

1006
00:42:48,169 --> 00:42:51,038
WAS BACK IN THE BAPI DAYS WE

1007
00:42:51,038 --> 00:42:54,775
COULD SEE THAT ARIA WAS

1008
00:42:54,775 --> 00:42:56,511
ASSOCIATED WITH MORE OF A

1009
00:42:56,511 --> 00:42:58,579
REDUCTION IN P-TARK U.

1010
00:42:58,579 --> 00:43:00,047
THIS IS DOING SOMETHING

1011
00:43:00,047 --> 00:43:02,016
POTENTIALLY GOOD AND THE

1012
00:43:02,016 --> 00:43:02,617
NEURODEGENERATION SIDE WHILE

1013
00:43:02,617 --> 00:43:05,453
IT'S MOVING THE AMYLOID.

1014
00:43:05,453 --> 00:43:07,288
YOU ALREADY SAW THIS DATA FROM

1015
00:43:07,288 --> 00:43:08,256
DAVID BUT ALSO WE HAVE BEEN

1016
00:43:08,256 --> 00:43:10,391
WORKING ON WHAT IS THE LINE

1017
00:43:10,391 --> 00:43:12,226
BETWEEN AMYLOID REMOVAL AND

1018
00:43:12,226 --> 00:43:13,394
COGNITIVE OR CLINICAL BENEFIT.

1019
00:43:13,394 --> 00:43:15,730
THERE'S LOTS OF GRAPHICS LIKE

1020
00:43:15,730 --> 00:43:20,935
THIS BUT THERE IS A RELATIONSHIP

1021
00:43:20,935 --> 00:43:22,703
AGAIN BETWEEN THE REMOVAL AND

1022
00:43:22,703 --> 00:43:24,639
THE COGNITIVE DECLINE AND THE

1023
00:43:24,639 --> 00:43:27,141
RELATIONSHIP OF LIKELIHOOD OF

1024
00:43:27,141 --> 00:43:30,011
DEVELOPING ARIA.

1025
00:43:30,011 --> 00:43:31,479
NOW I WILL ESPOUSE 1

1026
00:43:31,479 --> 00:43:32,747
CONTROVERSIAL THEORY ABOUT THIS

1027
00:43:32,747 --> 00:43:34,081
BECAUSE IT HASN'T GO AWAY FOR

1028
00:43:34,081 --> 00:43:36,150
ME, WHICH IS THAT WHEN YOU

1029
00:43:36,150 --> 00:43:39,587
DISRUPT THE BLOOD BRAIN BARRIER

1030
00:43:39,587 --> 00:43:40,488
AND POTENTIALLY ALLOW MORE

1031
00:43:40,488 --> 00:43:41,989
THINGS TO CROSS, YOU ALLOW

1032
00:43:41,989 --> 00:43:43,691
ANTIBODIES TO CROSS AND THERE'S

1033
00:43:43,691 --> 00:43:47,194
DATA FROM WAY BACK IN 2013 THAT

1034
00:43:47,194 --> 00:43:49,297
IN AN ANIMAL MODEL OF ARIA, YOU

1035
00:43:49,297 --> 00:43:54,835
SAW MORE ANTIBODIES BIENING AND

1036
00:43:54,835 --> 00:43:56,337
MORE MICROFLI COLSISSA

1037
00:43:56,337 --> 00:43:57,305
ACTIVATION AROUND PLAQUE AND

1038
00:43:57,305 --> 00:43:59,106
IMPORTANTLY, I WAS TALKING TO

1039
00:43:59,106 --> 00:44:00,474
OTHER COLLEAGUES HERE, CHANGING

1040
00:44:00,474 --> 00:44:01,742
THE VESSELS, BEING ABLE TO CLEAR

1041
00:44:01,742 --> 00:44:05,580
THE AMYLOID OUT OF THE VESSELS,

1042
00:44:05,580 --> 00:44:07,415
I THINK HELPED THE VASCULATURE

1043
00:44:07,415 --> 00:44:14,455
IN CLEARANCE OF MULTIPLE OP A

1044
00:44:14,455 --> 00:44:16,157
THIES, POTENTIALLY, I THINK

1045
00:44:16,157 --> 00:44:17,458
MAKING THE VESSELS WORK BETTER

1046
00:44:17,458 --> 00:44:19,594
MIGHT HELP US IN CLEARING NOT

1047
00:44:19,594 --> 00:44:28,069
JUST AMYLOID BUT OTHER PROTEINS

1048
00:44:28,069 --> 00:44:30,204
AS WELL, I TALKED ABOUT ARIA E

1049
00:44:30,204 --> 00:44:32,473
BUT I WILL TURN TO TALK ABOUT

1050
00:44:32,473 --> 00:44:34,375
ARIA H AND THIS IS MORE

1051
00:44:34,375 --> 00:44:35,376
CHALLENGING, I THINK TO STUDY

1052
00:44:35,376 --> 00:44:37,144
BECAUSE IT DID OCCUR IN THE

1053
00:44:37,144 --> 00:44:41,082
NATURAL HISTORY OF ALZHEIMER'S

1054
00:44:41,082 --> 00:44:42,950
DEC, THIS IS A CASE FROM THE

1055
00:44:42,950 --> 00:44:48,589
MAYO CLINIC AND APOE 33 CARRIER

1056
00:44:48,589 --> 00:44:49,991
WHO HAD SPONTANIOUS ARIA H AND

1057
00:44:49,991 --> 00:44:52,860
YOU CAN SEE THE MULTIPLE

1058
00:44:52,860 --> 00:44:53,928
MICROHEMMAGES HERE AND AGAIN,

1059
00:44:53,928 --> 00:44:55,730
THIS HAS A PET SCAN SHOWING THIS

1060
00:44:55,730 --> 00:45:06,240
IS A PERSON WHO HAD VERY--WHO

1061
00:45:12,880 --> 00:45:15,683
ARE AMYLOID POSITIVE EVEN BEFORE

1062
00:45:15,683 --> 00:45:16,517
THEY HAVE SYMPTOMS.

1063
00:45:16,517 --> 00:45:17,585
WE'VE ALREADY TALKED ABOUT AND I

1064
00:45:17,585 --> 00:45:24,258
THINK THIS WILL BE IMPORTANT,

1065
00:45:24,258 --> 00:45:25,926
HEMASID RIN DEPOSIT IS ARK ROUND

1066
00:45:25,926 --> 00:45:29,430
HERE, THIS TO BE IS A RISK

1067
00:45:29,430 --> 00:45:30,931
FACTOR FOR MACROHEMORRHAGE LATER

1068
00:45:30,931 --> 00:45:32,133
AND I'M SURE TEEF OR OTHERS WILL

1069
00:45:32,133 --> 00:45:33,768
TALK ABOUT THIS AND OF COURSE

1070
00:45:33,768 --> 00:45:35,603
UNFORTUNATELY WHAT WE ALL WANT

1071
00:45:35,603 --> 00:45:38,873
TO AVOID WHICH IS MULTIPLE

1072
00:45:38,873 --> 00:45:40,808
HEMORRHAGES WHERE THIS BECOMES

1073
00:45:40,808 --> 00:45:45,613
REALLY A SERIOUS MEDICAL ISSUE.

1074
00:45:45,613 --> 00:45:48,315
SO I DO THINK THERE'S A STRONG

1075
00:45:48,315 --> 00:45:49,650
RELATIONSHIP BETWEEN APOE AND

1076
00:45:49,650 --> 00:45:51,352
ARIA E AND ARIA H AND I WILL SAY

1077
00:45:51,352 --> 00:45:53,054
THAT I WILL GO FURTHER AND SAY,

1078
00:45:53,054 --> 00:45:55,856
I THINK THEY ARE THE SAME

1079
00:45:55,856 --> 00:45:56,290
TECHNOLOGY TRANSFER.

1080
00:45:56,290 --> 00:46:01,495
I THINK THEY SHARE A

1081
00:46:01,495 --> 00:46:02,863
PATHOPHYSIOLOGY THAT ARIA E IS

1082
00:46:02,863 --> 00:46:04,999
JUST A LEAKAGE OF THE FLUID

1083
00:46:04,999 --> 00:46:06,967
WHICH IS TRAN YEBT ON FLAIR AND

1084
00:46:06,967 --> 00:46:09,136
IT GOES AWAY BECAUSE IT ABSORBS

1085
00:46:09,136 --> 00:46:11,505
OR DISSIPATES AND I THINK ARIA

1086
00:46:11,505 --> 00:46:13,441
IS THE LEAKAGE OF RED BLOOD

1087
00:46:13,441 --> 00:46:16,110
CELLS SO THAT THE HEMEAT O SIT

1088
00:46:16,110 --> 00:46:19,513
RIN IS THERE AND UNLIKE FLAIR

1089
00:46:19,513 --> 00:46:21,515
SEQUENCES LOOKING AT ARIA E, THE

1090
00:46:21,515 --> 00:46:23,084
ARIA H THE ECHO YOU WILL HAVE IT

1091
00:46:23,084 --> 00:46:24,885
FOR LIFE, CAN YOU SEE THIS FOR

1092
00:46:24,885 --> 00:46:29,790
YEARS AND YEARS MAYBE DECADES

1093
00:46:29,790 --> 00:46:31,859
LATER AND SO IT'S THERE.

1094
00:46:31,859 --> 00:46:33,728
THEY ARE OFTEN CO LOCALIZED AS A

1095
00:46:33,728 --> 00:46:35,162
SHOWED YOU BUT NOT ALWAYS WHICH

1096
00:46:35,162 --> 00:46:36,297
IS REALLY INTERESTING, SO OFTEN

1097
00:46:36,297 --> 00:46:40,000
YOU WILL SEE THIS AND ARIA H IN

1098
00:46:40,000 --> 00:46:41,135
THAT AREA AS I SHOWED THE

1099
00:46:41,135 --> 00:46:42,503
EXAMPLE OF THE TREAN TRACKS BUT

1100
00:46:42,503 --> 00:46:43,804
TIMES THEY ARE IN VERY DIFFERENT

1101
00:46:43,804 --> 00:46:45,106
PARTS OF THE PREAP XI THINK

1102
00:46:45,106 --> 00:46:46,540
THAT'S JUST BECAUSE WE MISSED

1103
00:46:46,540 --> 00:46:48,576
THE AREFRESH YOUR RECOLLECTION

1104
00:46:48,576 --> 00:46:51,345
IA E AND I'VE COME TO THINK

1105
00:46:51,345 --> 00:46:54,415
THERE'S ARIA H THERE WAS ONCE A

1106
00:46:54,415 --> 00:46:57,752
PUFF OF ARIA E BUT WE MISSED IT

1107
00:46:57,752 --> 00:46:58,853
BECAUSE IT'S TRANSIENT.

1108
00:46:58,853 --> 00:47:00,221
THE RISK FACTORS PANE ARE QUITE

1109
00:47:00,221 --> 00:47:01,255
SIMILAR ALTHOUGH SOME OF

1110
00:47:01,255 --> 00:47:05,259
THE--AND I WILL SHOW YOU THE

1111
00:47:05,259 --> 00:47:07,294
DATA SOME OF THESE SHOW LOTS OF

1112
00:47:07,294 --> 00:47:08,863
RISK WITH TREATMENT AND DON'T SO

1113
00:47:08,863 --> 00:47:11,398
MUCH DIFFERENCES IN ARIA H AND

1114
00:47:11,398 --> 00:47:12,199
IT'S HARDER TO TRACK THE

1115
00:47:12,199 --> 00:47:15,269
SYMPTOMS AND THE ARIA H BECAUSE

1116
00:47:15,269 --> 00:47:16,537
AGAIN, THE ONSET IS SOMETIMES

1117
00:47:16,537 --> 00:47:19,273
HARD TO SEAND HARD TO PINPOINT

1118
00:47:19,273 --> 00:47:23,978
ANYWAY TO GIVE YOU TEMPORAL

1119
00:47:23,978 --> 00:47:24,512
ASSOCIATIONS.

1120
00:47:24,512 --> 00:47:31,952
SO HERE ARE 2 I WILL JUST

1121
00:47:31,952 --> 00:47:33,053
HIGHLIGHT THE [INDISCERNIBLE]

1122
00:47:33,053 --> 00:47:33,587
AND [INDISCERNIBLE].

1123
00:47:33,587 --> 00:47:35,923
I HAVE JUST 1 MORE SLIDE.

1124
00:47:35,923 --> 00:47:42,797
I HAVE SHOWN HERE YOU HERE,

1125
00:47:42,797 --> 00:47:43,931
DONANEMAB IS HIGHER, AND I WANT

1126
00:47:43,931 --> 00:47:47,201
TO SEE IF THE RATES PERMONTH

1127
00:47:47,201 --> 00:47:49,603
DECREASED BECAUSE I THINK 1 OF

1128
00:47:49,603 --> 00:47:52,072
THE QUESTIONS IS:  IS THIS

1129
00:47:52,072 --> 00:47:55,676
RELATED TO THE RAPIDITY OF

1130
00:47:55,676 --> 00:47:56,577
AMYLOID REMOVAL OR IS THIS

1131
00:47:56,577 --> 00:47:58,212
RELATED TO THE TARGETING

1132
00:47:58,212 --> 00:48:00,681
SYSTEMYS BECAUSE AGAIN DONAEMAB

1133
00:48:00,681 --> 00:48:02,817
IS GOING AFTER THE PROTOFIEB

1134
00:48:02,817 --> 00:48:03,317
RULES, IT DEVELOPMENTAL

1135
00:48:03,317 --> 00:48:05,986
ENDOCRINOLOGY FIT LE PULLS DOWN

1136
00:48:05,986 --> 00:48:11,091
FIEB RULES AND I DON'T KNOW IF

1137
00:48:11,091 --> 00:48:12,927
OR SOMEONE ELSE WILL TALK ABOUT

1138
00:48:12,927 --> 00:48:15,129
THIS BUT THIS PARTICULAR

1139
00:48:15,129 --> 00:48:16,931
ANTIBODY WENT AFTER THE ARTIC

1140
00:48:16,931 --> 00:48:19,433
MUTATION WHICH IS AN INTERESTING

1141
00:48:19,433 --> 00:48:20,167
AUTOSOMAL DOMINANT MUTATION THAT

1142
00:48:20,167 --> 00:48:21,869
DOESN'T SHOW A LOT OF FIBULAR

1143
00:48:21,869 --> 00:48:24,438
PLAQUE WHEN THEY DIE BUT THEY DO

1144
00:48:24,438 --> 00:48:27,775
SO C.ASM A. AND THIS IS BACK

1145
00:48:27,775 --> 00:48:29,510
SHOWN BACK IN NORBERG'S PAPER OF

1146
00:48:29,510 --> 00:48:32,713
15 YEARS AGO SO THERE IS

1147
00:48:32,713 --> 00:48:35,049
SOMETHING ABOUT THIS PARTICULAR

1148
00:48:35,049 --> 00:48:36,884
PROTOFIEB RULE THAT MIGHT BE

1149
00:48:36,884 --> 00:48:38,819
DIFFERENT IN HOW IT TREATS

1150
00:48:38,819 --> 00:48:39,820
PLAQUE AND VASCULAR AMYLOID.

1151
00:48:39,820 --> 00:48:40,454
AND THEN THE RECOLLECT

1152
00:48:40,454 --> 00:48:41,422
TECHNOLOGY TRANSFER I WANT TO

1153
00:48:41,422 --> 00:48:44,859
PONENT OUT IS THIS, THAT WHEN

1154
00:48:44,859 --> 00:48:47,394
YOU LOOK AT ISOLATED ARIA H,

1155
00:48:47,394 --> 00:48:51,398
MEANING NOT WHERE THERE'SATTIA E

1156
00:48:51,398 --> 00:48:53,567
IN THE CASE, YOU ACTUALLY SEE A

1157
00:48:53,567 --> 00:48:54,835
VERY SIMILAR RELATIONSHIP

1158
00:48:54,835 --> 00:48:57,171
BETWEEN PLACEBO, RATES AND

1159
00:48:57,171 --> 00:48:59,740
PLACEBO AND THE ANTIBODY.

1160
00:48:59,740 --> 00:49:01,442
AGAIN, SUGGESTING THAT ARIA H OR

1161
00:49:01,442 --> 00:49:02,710
MEEK ROUGH ATOM HEMMAGES ARE

1162
00:49:02,710 --> 00:49:04,812
OCCURRING IN THE NATURAL HISTORY

1163
00:49:04,812 --> 00:49:06,013
OF DISEASE AND AGAIN IT'S REALLY

1164
00:49:06,013 --> 00:49:10,017
WHEN WE SEE THE ARIA E, AND ARIA

1165
00:49:10,017 --> 00:49:14,154
H TOGETHER THAT IT'S MORE OF A

1166
00:49:14,154 --> 00:49:23,530
TREATMENT RELATEDAT ROUGH

1167
00:49:23,530 --> 00:49:26,066
ATOMIENIC C. A. A.

1168
00:49:26,066 --> 00:49:32,039
OKAY, THERE ARE 2 MAIN YEARS AND

1169
00:49:32,039 --> 00:49:33,607
STEVE AND I HAVE BEEN TALKING

1170
00:49:33,607 --> 00:49:35,609
ABOUT THIS FOR ARIA FOR A LONG

1171
00:49:35,609 --> 00:49:37,978
TIME, THIS IS A RESPONSE TO

1172
00:49:37,978 --> 00:49:39,880
AMYLOID THAT'S MOVING FROM THE

1173
00:49:39,880 --> 00:49:41,282
PLAQUES INTO THE PERIVASCULAR

1174
00:49:41,282 --> 00:49:42,416
SPACE PERHAPS, I WAS TALKING TO

1175
00:49:42,416 --> 00:49:43,784
SOMEONE ABOUT THE ROLE OF

1176
00:49:43,784 --> 00:49:48,255
APUNISHING OE IN THAT, AND THIS

1177
00:49:48,255 --> 00:49:49,657
IS SUPPORTED, I THINK BY SOME

1178
00:49:49,657 --> 00:49:52,493
WORK IN HERE TOMORROW ARK ROUND

1179
00:49:52,493 --> 00:49:54,328
THE C. A. A. R. I. SYNDROMES

1180
00:49:54,328 --> 00:49:56,130
WHERE YOU SEE IT INFLAMMATION

1181
00:49:56,130 --> 00:49:57,665
AND A DISCIPLINARY BEFORE PEOPLE

1182
00:49:57,665 --> 00:50:03,304
GET ARIA AND SYMPTOMS THEIR

1183
00:50:03,304 --> 00:50:03,671
ANTIBODIES RISE.

1184
00:50:03,671 --> 00:50:05,339
BUT I HAVE TO SAY THAT THE

1185
00:50:05,339 --> 00:50:07,274
TIMING OF ARIA E IN THE ASPECT

1186
00:50:07,274 --> 00:50:09,310
BODY TRIALS HAS ALWAYS BOTHERED

1187
00:50:09,310 --> 00:50:10,744
ME FOR THIS BEING THE PRIMARY

1188
00:50:10,744 --> 00:50:12,012
TECHNOLOGY TRANSFER BECAUSE THE

1189
00:50:12,012 --> 00:50:13,647
ARIA E OCCURS EARLY, IT OCCURS

1190
00:50:13,647 --> 00:50:15,482
VERY EARLY WHEN PEOPLE GETTICISM

1191
00:50:15,482 --> 00:50:17,184
TOPS DPG FOR A WEBBING OR 2,

1192
00:50:17,184 --> 00:50:21,555
THEY HAVEN'T MOVED ALL THAT MUCH

1193
00:50:21,555 --> 00:50:22,823
AMYLOID YET AND WE DOSE THEM

1194
00:50:22,823 --> 00:50:25,392
AGAIN IN THE PHASE 2 STUDIES OF

1195
00:50:25,392 --> 00:50:27,895
BAPI, WE DOSED A LOT OF PEOPLE

1196
00:50:27,895 --> 00:50:30,464
THROUGH ARIA, AND IT GOT LESS

1197
00:50:30,464 --> 00:50:31,131
OVERTIME EVEN THOUGH WE WERE

1198
00:50:31,131 --> 00:50:32,666
GIVING MORE AND MORE AND MORE

1199
00:50:32,666 --> 00:50:34,468
ANTIBODIES TO REF UP THE

1200
00:50:34,468 --> 00:50:35,502
INFLAMMATORY PROCESS, AND ALSO

1201
00:50:35,502 --> 00:50:39,873
THE TIMING OF THE AMYLOID

1202
00:50:39,873 --> 00:50:40,874
REDUCTION, ALTHOUGH IT'S EARLY

1203
00:50:40,874 --> 00:50:41,809
AUTOTILL CONTINUING WHEN THE

1204
00:50:41,809 --> 00:50:44,111
ARIA IS GONE EMPLOY SO AGAIN,

1205
00:50:44,111 --> 00:50:46,213
THERE'S NOT A PERFECT MATCH

1206
00:50:46,213 --> 00:50:49,583
BETWEEN THE INFLAMMATORY AND

1207
00:50:49,583 --> 00:50:51,485
ACTIVATION AND THE TIMING.

1208
00:50:51,485 --> 00:50:53,187
THE OTHER POSSIBILITY IS THAT

1209
00:50:53,187 --> 00:50:55,222
WE'RE REALLY ACTUALLY CHANGING

1210
00:50:55,222 --> 00:50:56,957
THE VESSEL STRUCTURE WHERE WE'RE

1211
00:50:56,957 --> 00:50:58,759
PULLING THE AMYLOID OUT OF THE

1212
00:50:58,759 --> 00:51:01,462
SMOOTH VESSELS MUCH I THINK THIS

1213
00:51:01,462 --> 00:51:03,197
IS LESS LIKELY ALTHOUGH THAT

1214
00:51:03,197 --> 00:51:04,298
KRRK-MAX, THE FACT THAT YOU GET

1215
00:51:04,298 --> 00:51:06,033
THIS VERY EARLY AND IT'S RELATED

1216
00:51:06,033 --> 00:51:07,234
TO HOW MUCH ANTIBODY YOU'RE

1217
00:51:07,234 --> 00:51:09,136
PUTTING IN THE BLOOD STREAM AND

1218
00:51:09,136 --> 00:51:10,604
IT IS THE CASE EVEN THOUGH IT'S

1219
00:51:10,604 --> 00:51:12,506
HARD TO MOBILIZE, I GUESS THE

1220
00:51:12,506 --> 00:51:14,742
AMYLOID OUT OF THE VESSELS THAT

1221
00:51:14,742 --> 00:51:16,677
YOU'RE SEEING, THOSE ANTIBODIES

1222
00:51:16,677 --> 00:51:18,445
ARE SEEING THAT END TERPINOUS

1223
00:51:18,445 --> 00:51:22,082
STICKING OUT OF THE VESSEL AS

1224
00:51:22,082 --> 00:51:22,282
WELL.

1225
00:51:22,282 --> 00:51:23,617
AND THIS IS DPEAN SUPPORTED BY

1226
00:51:23,617 --> 00:51:24,051
THE TIMING.

1227
00:51:24,051 --> 00:51:27,454
ALTHOUGH I HAVE TO SAY THIS

1228
00:51:27,454 --> 00:51:28,956
THEORY WAS COMPLETELY DISCOUNTED

1229
00:51:28,956 --> 00:51:34,028
IN MY THINKING BY THIS NEXT

1230
00:51:34,028 --> 00:51:42,002
REPORT WHICH IS ELECTOR REPORTED

1231
00:51:42,002 --> 00:51:42,936
TREM2 CAUSING AMYLOID, SO HERE

1232
00:51:42,936 --> 00:51:44,004
ARE 2 CASES AT A HAD.

1233
00:51:44,004 --> 00:51:45,272
I WAS PROBABLY THE ONLY 1 IN THE

1234
00:51:45,272 --> 00:51:46,907
WORLD THAT WAS THRILLED THIS

1235
00:51:46,907 --> 00:51:48,142
CAUSED ARIA BECAUSE IT WILL ITS

1236
00:51:48,142 --> 00:51:50,911
US ABOUT MECH INFORM, I'M SURE,

1237
00:51:50,911 --> 00:51:53,414
ELECTRA WAS NOT HAPPY AND

1238
00:51:53,414 --> 00:51:57,284
UNFORTUNATELY DID HAVE TO CHANGE

1239
00:51:57,284 --> 00:52:01,488
DOSING IN THEIR APOE CARRIERS

1240
00:52:01,488 --> 00:52:09,963
BUT I THINK IT'S IMPORTANT ABOUT

1241
00:52:09,963 --> 00:52:12,032
AM, AND THIS BODY IS NOT SEEING

1242
00:52:12,032 --> 00:52:13,567
THIS IN THE VESSELS AND I HAVE

1243
00:52:13,567 --> 00:52:15,602
TO SAY I'M MAKING A DICHOTOMY

1244
00:52:15,602 --> 00:52:16,970
HERE BUT CERTAINLY IT'S SOME OF

1245
00:52:16,970 --> 00:52:19,239
EACH BECAUSE AGAIN IF YOU

1246
00:52:19,239 --> 00:52:20,641
DISRUPT THE VESSEL WALL AND YOU

1247
00:52:20,641 --> 00:52:21,909
GET MORE ANTIBODY CROSSING,

1248
00:52:21,909 --> 00:52:25,379
SETTING UP MORE OF A MICRODPLEEL

1249
00:52:25,379 --> 00:52:27,614
OR INFLA AMATORY RESPONSE, THAT

1250
00:52:27,614 --> 00:52:29,416
WILL BE SOMEWHAT

1251
00:52:29,416 --> 00:52:29,950
SELF-PERPETUATING.

1252
00:52:29,950 --> 00:52:36,190
SO WHAT DO WE NOT YET KNOW ABOUT

1253
00:52:36,190 --> 00:52:37,357
ARIA SO 1 OF THE BIGGEST THINGS

1254
00:52:37,357 --> 00:52:38,926
WE NEED TO UNDERSTAND IS WHAT IS

1255
00:52:38,926 --> 00:52:41,695
THE RISK FOR RELATIVELY RARE

1256
00:52:41,695 --> 00:52:41,962
CASES?

1257
00:52:41,962 --> 00:52:44,264
IN GENERAL THEY LACK OVER ALL

1258
00:52:44,264 --> 00:52:46,433
SAME RISK FACTORS MORE LIKELY

1259
00:52:46,433 --> 00:52:47,334
CERTAINLY--CERTAINLY 4 CARRIERS,

1260
00:52:47,334 --> 00:52:49,837
MORE LIKELY WITH HIGH DOSE BUT

1261
00:52:49,837 --> 00:52:51,738
THERE'S A REALLY POOR

1262
00:52:51,738 --> 00:52:52,906
CORRESPONDENCE BETWEEN HOW BAD

1263
00:52:52,906 --> 00:52:54,541
THE MRI LOOKS AND THE SYMPTOMS,

1264
00:52:54,541 --> 00:52:57,611
SO PEOPLE CAN GET VERY

1265
00:52:57,611 --> 00:52:58,846
SYMPTOMATIC AND VICE VERSA, SOME

1266
00:52:58,846 --> 00:53:00,914
OF THOSE MRs I SHOWED YOU WITH

1267
00:53:00,914 --> 00:53:03,617
RIP ROARING, DEMA THOSE PEOPLE

1268
00:53:03,617 --> 00:53:04,585
ARE LARGELY ASYMPTOMATIC.

1269
00:53:04,585 --> 00:53:06,320
I SUSPECT THOUGH THAT MORE

1270
00:53:06,320 --> 00:53:07,988
INFLATION ASSOCIATED WITH

1271
00:53:07,988 --> 00:53:10,090
IMRAITER SYMPTOMS SO WOE

1272
00:53:10,090 --> 00:53:11,959
DEFINITELY NEED BETTER

1273
00:53:11,959 --> 00:53:12,926
PERRIFFERAL BIOMARKERS MUCH IS

1274
00:53:12,926 --> 00:53:14,962
IT DONE?

1275
00:53:14,962 --> 00:53:16,163
OKAY, NEED TO TALK ABOUT THE

1276
00:53:16,163 --> 00:53:18,565
RISK FOR H CASES AND ESPECIALLY

1277
00:53:18,565 --> 00:53:20,267
TRY TO DECREASE THE RISK AND

1278
00:53:20,267 --> 00:53:22,169
I'LL END THERE BY SAYING I THINK

1279
00:53:22,169 --> 00:53:25,906
I TOTALLY ARK FREE WITH 1 OF

1280
00:53:25,906 --> 00:53:27,274
THE--AGREE WITH 1 OF THE WAYS TO

1281
00:53:27,274 --> 00:53:29,109
DECREASE THIS RISK IS TO GO

1282
00:53:29,109 --> 00:53:30,844
EARLIER AND PEOPLE WHO DON'T YET

1283
00:53:30,844 --> 00:53:32,146
HAVE AMYLOID THOUGHT INTO L

1284
00:53:32,146 --> 00:53:34,648
VESESYS SO WE CAN PREVENT

1285
00:53:34,648 --> 00:53:35,582
AMYLOID ARK KIEWMULATION BEFORE

1286
00:53:35,582 --> 00:53:37,084
IT ENDS XI WANT TO EPPED WITH

1287
00:53:37,084 --> 00:53:38,585
GRATITUDE FOR THE GREAT PEOPLE

1288
00:53:38,585 --> 00:53:40,320
I'VE WORKED WITH ON THIS FOR SO

1289
00:53:40,320 --> 00:53:44,124
LONG. 

1290
00:53:44,124 --> 00:53:44,992
THANK YOU.

1291
00:53:44,992 --> 00:53:47,461
>> OKAY, THANK YOU SO MUCH

1292
00:53:47,461 --> 00:53:49,096
REFRESH YOUR RECOLLECTION EISA,

1293
00:53:49,096 --> 00:53:50,330
THAT WAS TERRIFIC.

1294
00:53:50,330 --> 00:53:54,468
THE NEXT SPEAKER IS STEVE

1295
00:53:54,468 --> 00:53:57,070
GREENBERG FROM MGH, HE'S AN

1296
00:53:57,070 --> 00:53:59,273
EXPERT IN CAA, AND CAA-RELATED

1297
00:53:59,273 --> 00:54:00,674
INFLAMMATION AND I THINK SOME OF

1298
00:54:00,674 --> 00:54:05,279
OUR MORE SERIOUS CASES WITH ARIA

1299
00:54:05,279 --> 00:54:10,050
ARE A TYPE OF ANGIEITEIS THAT

1300
00:54:10,050 --> 00:54:10,584
RESEMBLE CAA.

1301
00:54:10,584 --> 00:54:17,624
SO WE'RE LOOKING FORWARD TO

1302
00:54:17,624 --> 00:54:17,858
THIS.

1303
00:54:17,858 --> 00:54:19,760
>> I THINK I KNOW
EVERYBODY IN

1304
00:54:19,760 --> 00:54:22,729
THE AUDIENCE, THERE WAS 1 OTHER

1305
00:54:22,729 --> 00:54:25,766
ALTERNATIVE, 1 OTHER ALTERNATIVE

1306
00:54:25,766 --> 00:54:29,002
TO ARIA, IT'S REGIONAL SEN

1307
00:54:29,002 --> 00:54:31,471
ILLEGALSEN SEVERE MITRAL LO

1308
00:54:31,471 --> 00:54:33,307
PATHIC IT'S TURNED OUT REISA

1309
00:54:33,307 --> 00:54:34,441
TERM, AND SHE DIDN'T GO FOR

1310
00:54:34,441 --> 00:54:35,042
THAT.

1311
00:54:35,042 --> 00:54:37,010
SO THESE ARE MY DISCLOSURES AND

1312
00:54:37,010 --> 00:54:38,812
I SHOULD MEPGZ PRIOR TO THE 2

1313
00:54:38,812 --> 00:54:43,383
YEAR WINDOW I DID SAFETY

1314
00:54:43,383 --> 00:54:44,384
MONITORING FOR [INDISCERNIBLE]

1315
00:54:44,384 --> 00:54:45,953
AND [INDISCERNIBLE] SO I'VE BEEN

1316
00:54:45,953 --> 00:54:47,221
INVOLVE MOSTLY AS A SAFETY

1317
00:54:47,221 --> 00:54:48,055
MONITOR IN IN FIELD.

1318
00:54:48,055 --> 00:54:50,691
I WANT TO GIVE 1 AREA IN

1319
00:54:50,691 --> 00:54:52,092
BACKGROUND INTO CAA, HAD IS

1320
00:54:52,092 --> 00:54:53,627
OBVIOUSLY BEEN PART OF A LOT OF

1321
00:54:53,627 --> 00:54:55,128
THE DISCUSSION AND WILL TYPESET

1322
00:54:55,128 --> 00:55:01,268
TO BE, AND THEN FOCUS ON THIS

1323
00:55:01,268 --> 00:55:03,170
QUESTION THAT INTRODUCE THE

1324
00:55:03,170 --> 00:55:03,604
RELATIONSHIP BETWEEN

1325
00:55:03,604 --> 00:55:05,205
INFLAMMATORY SITUATION ASK ARIA,

1326
00:55:05,205 --> 00:55:07,274
AND STARTING WITH THE PATHOLOGIC

1327
00:55:07,274 --> 00:55:09,209
FRAMEWORK, HERE I WILL TALK

1328
00:55:09,209 --> 00:55:10,477
THANK JUST A SUBSET OF MANY

1329
00:55:10,477 --> 00:55:11,445
PEOPLE ININVOLVED WITH THE WORK

1330
00:55:11,445 --> 00:55:20,654
WE'VE DONE OVER THE YEARS IN

1331
00:55:20,654 --> 00:55:22,289
CAA, AND COLLABORATION IN PEOPE

1332
00:55:22,289 --> 00:55:25,525
STUDYING THE DUTCH TIME OF CAA,

1333
00:55:25,525 --> 00:55:28,729
WHICH HAS BEEN INFORMATIVE IN

1334
00:55:28,729 --> 00:55:30,230
THE FAMILIAL ALZHEIMER'S BEEN

1335
00:55:30,230 --> 00:55:33,734
ABOUT THE PATHOGENIC TEPS IN A.

1336
00:55:33,734 --> 00:55:33,900
D.

1337
00:55:33,900 --> 00:55:35,602
SO THIS IS A BACKGROUND PEEL

1338
00:55:35,602 --> 00:55:37,237
WILL BE FAMILIAR WITH.

1339
00:55:37,237 --> 00:55:38,739
AND WALTER MENINGED HIS TEACHER

1340
00:55:38,739 --> 00:55:41,241
AND MY TEACHER IN THIS AREA WAS

1341
00:55:41,241 --> 00:55:42,442
JOHN PAUL [INDISCERNIBLE] WHO IS

1342
00:55:42,442 --> 00:55:44,011
RESPONSIBLE FOR ALL THE

1343
00:55:44,011 --> 00:55:45,178
PATHOLOGIC IMAGES YOU SEE HERE,

1344
00:55:45,178 --> 00:55:47,781
O THIS IS REALLY 1 OF JUST, I

1345
00:55:47,781 --> 00:55:49,650
WOULD ARGUE 2 COMMON ANAL

1346
00:55:49,650 --> 00:55:54,154
RELATED SMALL VESSEL

1347
00:55:54,154 --> 00:56:03,897
PATHOLOGIES, ALONG WITH

1348
00:56:03,897 --> 00:56:05,299
SCLEROSIS, AND WOP META,A

1349
00:56:05,299 --> 00:56:07,668
MALSIS, AND APPROXIMATELY 80% OF

1350
00:56:07,668 --> 00:56:09,670
THAL JEIMERS BREANS AND MODERATE

1351
00:56:09,670 --> 00:56:10,904
TO SEVERE CAARK THE LEVEL THAT

1352
00:56:10,904 --> 00:56:14,107
WE THINK WITH BE CAUSAATIVE OF

1353
00:56:14,107 --> 00:56:16,476
SYMPTOMS IN 50% SO IT'S QUITE,

1354
00:56:16,476 --> 00:56:19,046
QUITE HIGH OVERLAP, THE

1355
00:56:19,046 --> 00:56:20,614
PATHOLOGIC IMAGES SHOWN HERE

1356
00:56:20,614 --> 00:56:24,318
DEMON TRAIT THE PROGRESSION FROM

1357
00:56:24,318 --> 00:56:25,385
THE FIRST DEPOSITS IN THE OUTER

1358
00:56:25,385 --> 00:56:31,992
PART OF THE MEDIA  LIKELY BECAUE

1359
00:56:31,992 --> 00:56:33,327
OF THE PERIVASCULAR DEPARTMENT

1360
00:56:33,327 --> 00:56:35,429
IS LOCATED AND REPLACING SMOOTH

1361
00:56:35,429 --> 00:56:37,364
MUSCLE CELLS AND THE LEADING TO

1362
00:56:37,364 --> 00:56:38,298
THE NECROSIS STAGES AND I WILL

1363
00:56:38,298 --> 00:56:41,668
COME BACK TO THE POINTS THAT

1364
00:56:41,668 --> 00:56:43,370
WALTER RAISED ABOUT THE ROLE OF

1365
00:56:43,370 --> 00:56:45,639
ACTIVE ENFLAMMA ARE TOY STEP IN

1366
00:56:45,639 --> 00:56:54,648
REMOVING AMYLOID IN SPON SPONTAS

1367
00:56:54,648 --> 00:56:58,051
CAA, AND MENTIONED FOR TOXIC

1368
00:56:58,051 --> 00:56:59,186
PROTEINS SO HEMORRHAGIC LESIONS

1369
00:56:59,186 --> 00:57:01,888
HAVE BEEN THE HALLMARK OF

1370
00:57:01,888 --> 00:57:05,225
DIAGNOSTIC FACTOR FOR CAA AND

1371
00:57:05,225 --> 00:57:07,094
RECENT MENTION THE LARGE

1372
00:57:07,094 --> 00:57:08,662
HEMORRHAGES AND MICROPLEADS BUT

1373
00:57:08,662 --> 00:57:12,499
ALSO THE CORTICALE SUPERFICIAL

1374
00:57:12,499 --> 00:57:15,068
CLEROSEIS WHICH IS A HEMORRHAGIC

1375
00:57:15,068 --> 00:57:16,470
MANIFESTATION OF CARK A, AND

1376
00:57:16,470 --> 00:57:19,673
THEN A WIDE RANGE OF

1377
00:57:19,673 --> 00:57:22,042
NONHEMORRHAGIC LESIONS, WHITE

1378
00:57:22,042 --> 00:57:24,344
MATTER, HYPER TENSITYS,

1379
00:57:24,344 --> 00:57:25,345
DIFFUSION DENSER CHANGES,

1380
00:57:25,345 --> 00:57:28,582
MICROINFARCTS AND THEN THE LARM

1381
00:57:28,582 --> 00:57:29,683
PERIVASCULAR SPACES IN THE

1382
00:57:29,683 --> 00:57:31,685
SEMESTERIOLE VALLEY THAT ARE

1383
00:57:31,685 --> 00:57:34,087
REFLEKS OF THAT ALTERED VASCULAR

1384
00:57:34,087 --> 00:57:36,223
PHYSIOLOGY AND ALTERED CLEARANCE

1385
00:57:36,223 --> 00:57:38,725
OF AMYLOID AND IN FACT, THIS HAS

1386
00:57:38,725 --> 00:57:40,827
BEEN INCORPORATED IN THE MOST

1387
00:57:40,827 --> 00:57:42,963
RECENT UPDATING OF THE BOSTON

1388
00:57:42,963 --> 00:57:47,968
CRITERIA ARK HAL SIS LED BY

1389
00:57:47,968 --> 00:57:50,270
ANDREAS, AND THE COLLABORATION

1390
00:57:50,270 --> 00:57:52,272
THAT EXTENDED THE DIAGNOSTIC

1391
00:57:52,272 --> 00:57:54,641
FEATURES, THAT INCLUDE NOT JUST

1392
00:57:54,641 --> 00:57:55,542
THE HEMORRHAGIC MARKERS THAT

1393
00:57:55,542 --> 00:57:58,345
HAVE BEEN THE HALLMARK FOR

1394
00:57:58,345 --> 00:58:01,615
DIGITEXTING KRRK ARKANSAS PAYS

1395
00:58:01,615 --> 00:58:03,750
BUT TO INCLUDE NONSIMILAR

1396
00:58:03,750 --> 00:58:05,619
HEMORRHAGIC MARKERS IN THIS

1397
00:58:05,619 --> 00:58:07,954
MULTISPOT PATTERN OF WHITE

1398
00:58:07,954 --> 00:58:10,123
MATTER HYPER DENSITIES AND

1399
00:58:10,123 --> 00:58:12,959
IMPROVING BOTH THE SENSITIVITY

1400
00:58:12,959 --> 00:58:14,828
OR IMPROVING SENSITIVITY WITHOUT

1401
00:58:14,828 --> 00:58:16,630
COMPROMISING THE SPECIFICITY OF

1402
00:58:16,630 --> 00:58:17,230
THE DIAGNOSTIC CRITERIA.

1403
00:58:17,230 --> 00:58:23,470
AS CAN YOU SEE ON THE RIGHT THAT

1404
00:58:23,470 --> 00:58:26,239
IN THE POOLED AWPS BASED

1405
00:58:26,239 --> 00:58:28,442
ANALYSIS THIS IS QUITE SENSITIVE

1406
00:58:28,442 --> 00:58:29,976
AND SPECIFIC FOR HEMORRHAGIC

1407
00:58:29,976 --> 00:58:32,212
PRESENTATIONS ABOUT YOU FOR

1408
00:58:32,212 --> 00:58:33,647
PEOPLE WHO DON'T HAVE

1409
00:58:33,647 --> 00:58:34,181
MACROHEDGEERAGES, THE

1410
00:58:34,181 --> 00:58:35,582
SENSITIVITY IS LOWER MEANING

1411
00:58:35,582 --> 00:58:40,620
WE'RE STILL NOT CAPTURING THE

1412
00:58:40,620 --> 00:58:42,923
STILL PATHOLOGICALLY ADVANCED

1413
00:58:42,923 --> 00:58:46,760
BUT NOT YET GROSSLY HEMORRHAGIC

1414
00:58:46,760 --> 00:58:48,562
STAGES OF CACE AND THERE'S TILL

1415
00:58:48,562 --> 00:58:49,796
A LOT WE'RE NOT DIAGNOSING AND

1416
00:58:49,796 --> 00:58:52,632
THIS COMES UP IN THE ROLE OF

1417
00:58:52,632 --> 00:58:55,302
UPDIAGNOSED CAA AS A POTENTIAL

1418
00:58:55,302 --> 00:58:57,404
TRIGGER FORRIA, AND THEN THE

1419
00:58:57,404 --> 00:58:58,805
PATHOGENIC FRAMEWORK IS BASED ON

1420
00:58:58,805 --> 00:59:02,876
STUDIES PRIMARILY OF THE DUTCH

1421
00:59:02,876 --> 00:59:03,977
TYPE HEREDITARY CAA.

1422
00:59:03,977 --> 00:59:05,312
AND THIS IS MEANT TO BE

1423
00:59:05,312 --> 00:59:07,214
ACONDITION TO OUR UNDERSTANDING

1424
00:59:07,214 --> 00:59:09,049
FOR THE PRESYMPTOMATIC TAIJS OF

1425
00:59:09,049 --> 00:59:10,650
ALZHEIMER'S DISEASE WHERE

1426
00:59:10,650 --> 00:59:12,219
THERE'S INITIAL AMYLOID

1427
00:59:12,219 --> 00:59:14,921
DEPOSITION IN THE DUTCH TYPE

1428
00:59:14,921 --> 00:59:19,493
HEREDITARY CAA HAPPENS ON THE

1429
00:59:19,493 --> 00:59:20,894
ORDER OF 3 DECADES BEFORE FIRST

1430
00:59:20,894 --> 00:59:23,096
HEMORRHAGE, CAN YOU MEASURE 2

1431
00:59:23,096 --> 00:59:25,866
DECADES BEFORE HEMORRHAGE,

1432
00:59:25,866 --> 00:59:27,734
ALTERED VASCULAR PHYSIOLOGY,

1433
00:59:27,734 --> 00:59:28,635
VASCULAR REACTIVITY TO

1434
00:59:28,635 --> 00:59:30,270
PHYSIOLOGIC STIMULATION AND THEN

1435
00:59:30,270 --> 00:59:33,874
A DECADE BEFORE IT CAN ALREADY

1436
00:59:33,874 --> 00:59:34,841
MEASURE NONHEMORRHAGIC CHANGES

1437
00:59:34,841 --> 00:59:36,309
AND THE INDIVIDUAL LEVEL DATA

1438
00:59:36,309 --> 00:59:39,913
SHOWN ON THE RIGHT, THE--WE

1439
00:59:39,913 --> 00:59:41,314
DON'T MAKE MUCH OUT OF WHERE THE

1440
00:59:41,314 --> 00:59:43,517
LINES CROSS BECAUSE THAT JUST

1441
00:59:43,517 --> 00:59:49,256
REFLECTS THE STANDARD DEVIATION,

1442
00:59:49,256 --> 00:59:53,827
BUT THE CLEAR PROGRESSION OF

1443
00:59:53,827 --> 00:59:55,929
FIRST AMYLOID DEPOSITION AND

1444
00:59:55,929 --> 00:59:56,830
VASCULAR REACTIVITY IMAGES AND

1445
00:59:56,830 --> 00:59:59,199
THEN WHITE YOUR AND AT ITS MOST

1446
00:59:59,199 --> 01:00:01,968
ADVANCED TAIJ IS HEMORRHAGE.

1447
01:00:01,968 --> 01:00:03,470
AND FOCUSING ON THE HEMORRHAGE

1448
01:00:03,470 --> 01:00:06,873
STAGE AND THIS IS THE POINT THAT

1449
01:00:06,873 --> 01:00:08,608
WALTER ALLUDED TO IN HIS

1450
01:00:08,608 --> 01:00:11,111
INTRODUCTION, IT'S BEAUTIFUL

1451
01:00:11,111 --> 01:00:13,947
WORK BY COLLEAGUES USING EXVF O

1452
01:00:13,947 --> 01:00:15,982
IMAGING OF TO IDENTIFY

1453
01:00:15,982 --> 01:00:19,586
MICROPLEADS AND THEN LOOK AT THE

1454
01:00:19,586 --> 01:00:23,523
PATHOLOGY ASSOCIATED WITH

1455
01:00:23,523 --> 01:00:25,325
MICROBLOODING AND AS IS SHOWN IN

1456
01:00:25,325 --> 01:00:27,294
THE LEFT, THERE'S THIS

1457
01:00:27,294 --> 01:00:28,828
INTERESTING VASCULAR REMODELING,

1458
01:00:28,828 --> 01:00:31,965
LIKE REMODELING YOUR BATHROOM

1459
01:00:31,965 --> 01:00:33,967
BUT IN FACT, IT'S THIS--THE

1460
01:00:33,967 --> 01:00:38,371
VESSELS THAT ARE MOST CLOSELY

1461
01:00:38,371 --> 01:00:40,473
ASSOCIATED WITH MICROPLEADS ARE

1462
01:00:40,473 --> 01:00:45,679
DEVOID OF AMYLOID, THEY'RE NOT

1463
01:00:45,679 --> 01:00:47,280
AT ALL DEVOID OF MUSCLES BUT YOU

1464
01:00:47,280 --> 01:00:49,049
CAN SEE THEM REPLACED WITH FIEB

1465
01:00:49,049 --> 01:00:52,886
RIN O GEN AND OTHER JUNK THAT

1466
01:00:52,886 --> 01:00:55,055
HAS NOW INFILTRATED INTO THE

1467
01:00:55,055 --> 01:00:56,089
VESSEL WALL AND THE PARTNERSHIP

1468
01:00:56,089 --> 01:00:58,491
ON THE RIGHT YOU WILL SEE THAT

1469
01:00:58,491 --> 01:00:59,759
AROUND THESE GRADE 4 VESSELS,

1470
01:00:59,759 --> 01:01:03,163
THE 1S THAT HAVE THE VUSESLE

1471
01:01:03,163 --> 01:01:05,198
REMODELING THERE'S INCREASED

1472
01:01:05,198 --> 01:01:08,668
GFAPP, INCREASED CD68 STAINING,

1473
01:01:08,668 --> 01:01:14,841
FOR ASTRO SIGNIFYITOSEIS AND

1474
01:01:14,841 --> 01:01:16,309
MICROFLEEL, I'M NOT SHOWING HERE

1475
01:01:16,309 --> 01:01:18,912
BUT IN MARROW STUDY THERE'S

1476
01:01:18,912 --> 01:01:20,180
INCREASED ITG STAINING IN THE

1477
01:01:20,180 --> 01:01:22,015
BRAIN AROUND THE VESSELS ARGUING

1478
01:01:22,015 --> 01:01:24,317
FOR SOME LEVEL OF BLOOD BRAIN

1479
01:01:24,317 --> 01:01:25,385
BARRIER BREAK DOWN.

1480
01:01:25,385 --> 01:01:27,754
SO THIS RAISES THE IDEA THAT

1481
01:01:27,754 --> 01:01:30,323
THERE'S A KIND OF INFLAMMATORY

1482
01:01:30,323 --> 01:01:33,326
COMPONENT TO, AND THIS IS ALL

1483
01:01:33,326 --> 01:01:34,194
SPONTANEOUSLY OCCURRING, NOT

1484
01:01:34,194 --> 01:01:35,629
PART OF AN ANTIBODY TRIAL.

1485
01:01:35,629 --> 01:01:37,564
SO TO SUMMARIZE WHAT I SAID SO

1486
01:01:37,564 --> 01:01:39,666
FAR, IT'S LIKELY THIS CAA LIKE

1487
01:01:39,666 --> 01:01:41,334
A. D. IS A DECADES LOPPING

1488
01:01:41,334 --> 01:01:42,769
PROCESS THAT WE HAPPENING IS

1489
01:01:42,769 --> 01:01:47,607
DRIVEN BY THE FAILURE OF

1490
01:01:47,607 --> 01:01:48,441
PERIVASCULAR AMYLOID CLEARANCE.

1491
01:01:48,441 --> 01:01:52,479
IF THE STEP IS INVOLVED FROM

1492
01:01:52,479 --> 01:01:53,913
HEMORRHAGIC TO TO THE BRAIN

1493
01:01:53,913 --> 01:01:56,483
INJURY AND SUGGESTION THAT EVEN

1494
01:01:56,483 --> 01:01:58,985
IN WHAT'S APPARENTLY

1495
01:01:58,985 --> 01:02:02,122
NONINFLAMMATORY CAA, MAY HAVE AN

1496
01:02:02,122 --> 01:02:03,590
INFLAMMATORY COMPOENT.

1497
01:02:03,590 --> 01:02:05,892
NOW TURNING TO CAI AND ARIA,

1498
01:02:05,892 --> 01:02:10,697
THESE HAVE BECOME FAMILIAR IN

1499
01:02:10,697 --> 01:02:12,999
THE CA COMMUNITY AND A NUMBER OF

1500
01:02:12,999 --> 01:02:15,001
NEUROLOGISTS AND IMAGES THAT

1501
01:02:15,001 --> 01:02:16,002
WILL TRIKE PEOPLE INVOLVED IN

1502
01:02:16,002 --> 01:02:17,804
THE TRIALS AND IT'S LOOK BEING

1503
01:02:17,804 --> 01:02:19,572
LIKE ARIA AND THAT'S THE POINT

1504
01:02:19,572 --> 01:02:22,242
OF MY TALK AND THESE ARE

1505
01:02:22,242 --> 01:02:23,009
SYNDROMES WHERE PEOPLE--OF

1506
01:02:23,009 --> 01:02:25,078
COURSE WE DON'T SEE THE ARK

1507
01:02:25,078 --> 01:02:26,713
SYMPTOMATIC PEOPLE UNLESS WE

1508
01:02:26,713 --> 01:02:29,616
HAPPEN TO CATCH THEM BUT PEOPLE

1509
01:02:29,616 --> 01:02:31,818
ARE PRESENTING SYMPTOMATICALLY

1510
01:02:31,818 --> 01:02:32,585
WITH MORE RAPID COGNITIVE

1511
01:02:32,585 --> 01:02:34,554
DECLINE THAN THEIR BASE LINE

1512
01:02:34,554 --> 01:02:37,023
SEIZURE, HEADACHES, THE CSF IS

1513
01:02:37,023 --> 01:02:38,525
ALMOST ALWAYS CHOSE ELERATED

1514
01:02:38,525 --> 01:02:40,427
PROTEIN ALTHOUGH OFTEN A NORMAL

1515
01:02:40,427 --> 01:02:42,996
CELL COUNT AND INTERESTING POINT

1516
01:02:42,996 --> 01:02:47,300
THAT WAS ALLUDED TO IN THE

1517
01:02:47,300 --> 01:02:51,204
DIFFERENT CSF FORMULA IN THE

1518
01:02:51,204 --> 01:02:58,411
AMFEIGN 92 CASES.

1519
01:02:58,411 --> 01:03:02,882
MRI WITH THE VASE O GENIC EDEMA,

1520
01:03:02,882 --> 01:03:06,086
BUT MANY OF THESE PEOPLE WERE

1521
01:03:06,086 --> 01:03:06,920
BIOPSIED ESPECIALLY WHEN THE

1522
01:03:06,920 --> 01:03:08,822
DIAGNOSE WAS DIFFICULT TO MAKE

1523
01:03:08,822 --> 01:03:10,690
BY IMAGING ALONE AND THE TYPICAL

1524
01:03:10,690 --> 01:03:13,493
PATTERNS AS SHOWN HERE WAS THE

1525
01:03:13,493 --> 01:03:14,861
INFILTRATION, NOT SO MUCH WITHIN

1526
01:03:14,861 --> 01:03:16,596
THE VESSEL WALL BUT AROUND THE

1527
01:03:16,596 --> 01:03:18,998
VESSEL WALL BUT TRIECTLY AROUND

1528
01:03:18,998 --> 01:03:24,771
THE AMYLOID CONTAINING SEGMENTS

1529
01:03:24,771 --> 01:03:27,607
SO C AA, IS A PATCHY PATHOLOGY,

1530
01:03:27,607 --> 01:03:31,010
YOU WOULD NOT SEE THIS AROUND

1531
01:03:31,010 --> 01:03:33,813
VESSEL SEGMENTS BUT AROUND THE

1532
01:03:33,813 --> 01:03:34,647
AMYLOID VESSEL SEGMENTS.

1533
01:03:34,647 --> 01:03:36,816
A LOT OF VISUAL EVIDENT THIS IS

1534
01:03:36,816 --> 01:03:39,652
AN AUTOIMMUNE RESPONSE TO

1535
01:03:39,652 --> 01:03:41,454
AMYLOID SUCH AS MULTINUCLEATED

1536
01:03:41,454 --> 01:03:43,490
CELLS THAT HAD AMYLOID TAPING

1537
01:03:43,490 --> 01:03:48,061
THAT HAD BEEN UNGULFED INTO THE

1538
01:03:48,061 --> 01:03:48,862
MULTINUCLEATED GIANT CELL.

1539
01:03:48,862 --> 01:03:52,365
SO TO YOUR EYE THIS LOOKS LIKA

1540
01:03:52,365 --> 01:03:58,138
AN ANTIAMYLOID INFLAMMATORY SIN

1541
01:03:58,138 --> 01:03:58,805
TROAM.

1542
01:03:58,805 --> 01:04:00,473
[INDISCERNIBLE] WAS, WOOING

1543
01:04:00,473 --> 01:04:03,777
BOSTON PROPOSED THIS CRITERIA

1544
01:04:03,777 --> 01:04:05,311
FOR PROBABLY CAA RELATED

1545
01:04:05,311 --> 01:04:06,646
INFLAMMATION AND IT'S BEST TO

1546
01:04:06,646 --> 01:04:07,814
SEE IT ESPECIALLY IN THE IDEA IS

1547
01:04:07,814 --> 01:04:10,016
THAT IF YOU SEE THE PATTERN YOU

1548
01:04:10,016 --> 01:04:12,352
DON'T HAVE TO PERFORM A BIOPSY,

1549
01:04:12,352 --> 01:04:14,254
IT'S GOOD FOR THE PATIENTS IT'S

1550
01:04:14,254 --> 01:04:15,922
ACTUALLY BAD PER SCIENCE BECAUSE

1551
01:04:15,922 --> 01:04:19,292
WE NO LONGER REGULARLY GET

1552
01:04:19,292 --> 01:04:21,194
TISSUE FROM PEOPLE WHERE THE

1553
01:04:21,194 --> 01:04:23,530
DIAGNOSIS IS RELATIVELY CLEAR

1554
01:04:23,530 --> 01:04:23,797
CUT.

1555
01:04:23,797 --> 01:04:29,035
AND THEN I WILL MAKE THE ARGUE

1556
01:04:29,035 --> 01:04:31,104
AM AND REISA RAISED THIS

1557
01:04:31,104 --> 01:04:32,906
QUESTION, BUT THERE'S A LOT TO

1558
01:04:32,906 --> 01:04:35,108
SAY THAT CARKANSAS RELATED

1559
01:04:35,108 --> 01:04:45,652
INFLAMMATION ISI 85ULENT OF THE

1560
01:04:55,461 --> 01:04:56,196
SPONTANEOUS VERSION OF--WE WANT

1561
01:04:56,196 --> 01:05:00,633
TO MAKE THE DIAGNOSIS OUTSIDE

1562
01:05:00,633 --> 01:05:04,671
AND THE PATTERN WITH THE

1563
01:05:04,671 --> 01:05:06,706
VASO-GENIC AND THE SURROUNDING

1564
01:05:06,706 --> 01:05:08,942
AREA, AROUNDLET EDEMA LOOKING

1565
01:05:08,942 --> 01:05:11,044
ARE VERY MUCH LIKE WHAT REISA

1566
01:05:11,044 --> 01:05:11,811
SHOWED IN THE PREVIOUS STUDY AND

1567
01:05:11,811 --> 01:05:15,381
I WILL NOT TAKE AWAY FROM THE

1568
01:05:15,381 --> 01:05:17,083
TALK TOMORROW BUT JUST TO SHOW A

1569
01:05:17,083 --> 01:05:18,585
COUPLE, I HOPE YOU WILL FORGIVE

1570
01:05:18,585 --> 01:05:22,689
ME OF HIS WORK, YOU KNOW REALLY

1571
01:05:22,689 --> 01:05:24,123
STRENGTHENING THIS TIE, THE

1572
01:05:24,123 --> 01:05:28,428
FINDING OF  AUTOANTIBODY IN

1573
01:05:28,428 --> 01:05:30,263
SPINAL FLUID OF PEOPLE WITH

1574
01:05:30,263 --> 01:05:38,671
ACTIVE PHASE OF THE A. P. OF

1575
01:05:38,671 --> 01:05:39,505
CAARK-RELATED INFLAMMATION AND

1576
01:05:39,505 --> 01:05:42,542
HOSE PET IS IT THES USING THE

1577
01:05:42,542 --> 01:05:45,044
MARKER FOR MICROFLI COLSISSA

1578
01:05:45,044 --> 01:05:47,981
SHOWING A PARTIAL OVERLAP OF

1579
01:05:47,981 --> 01:05:50,049
BASIC EDEMA AND MICROGLIAL

1580
01:05:50,049 --> 01:05:50,950
ACCUMULATION EMPLOY SO AGAIN TO

1581
01:05:50,950 --> 01:05:56,990
MAKE THIS ARGUE AM, THERE'S BOTH

1582
01:05:56,990 --> 01:05:57,624
SYNDROMES SHOW INCREASED,

1583
01:05:57,624 --> 01:05:59,259
OVERREPRESENT EGG OF E4,

1584
01:05:59,259 --> 01:06:02,528
PARTICULARLY HOMOWRIEG OATS, SO,

1585
01:06:02,528 --> 01:06:06,599
SHOWN AT THE TOP WAS A SERIES

1586
01:06:06,599 --> 01:06:08,701
THAT ROBBIE [INDISCERNIBLE]

1587
01:06:08,701 --> 01:06:09,736
PUBLISHED A COUPLE YEARS AGO AND

1588
01:06:09,736 --> 01:06:12,538
AT THE BOTTOM THIS IS FROM THE

1589
01:06:12,538 --> 01:06:15,208
STUDY ASK SIMILAR RESULTS OF

1590
01:06:15,208 --> 01:06:18,478
COURSE IN OTHER ANTIBODY STUDIES

1591
01:06:18,478 --> 01:06:20,880
SHOWING AN OVERREPRESENTATION OF

1592
01:06:20,880 --> 01:06:23,483
E4 CARRIERS IN PARTICULAR, E4

1593
01:06:23,483 --> 01:06:26,953
HYM O ZYGOTES, SHARED RISK

1594
01:06:26,953 --> 01:06:28,488
FACTOR PREEXISTING MIKE ON

1595
01:06:28,488 --> 01:06:29,989
BLEEDS, THE LOCATION OF THE

1596
01:06:29,989 --> 01:06:34,093
EDEMA AND THE ROLE OF AUTO,

1597
01:06:34,093 --> 01:06:36,663
EITHER EXOGENOUS OR ENDOGENOUS

1598
01:06:36,663 --> 01:06:37,697
ANTIBODIES TO AMYLOID, AND JUST

1599
01:06:37,697 --> 01:06:40,233
TO MENTION A LITTLE BIT ABOUT

1600
01:06:40,233 --> 01:06:44,904
THE CLINICAL SYNDROME SO THIS IS

1601
01:06:44,904 --> 01:06:46,039
AN IMPERRIC IMMUNOSUPPRESSIVE

1602
01:06:46,039 --> 01:06:48,942
REGIMEN THAT WE USE AT OUR

1603
01:06:48,942 --> 01:06:50,677
HOSPITAL, THERE ARE NO

1604
01:06:50,677 --> 01:06:52,645
RANDOMIZED DATA OR ANYTHING

1605
01:06:52,645 --> 01:06:53,813
CLOSE TO RANDOMIZED DAILY BASIS

1606
01:06:53,813 --> 01:06:58,384
THEA IN THIS FIELD BUT IN THIS

1607
01:06:58,384 --> 01:07:01,721
PAPER PRACTICES ROBBIE REGENHART

1608
01:07:01,721 --> 01:07:03,122
PUBLISHED IN OUR GROUP, SOME

1609
01:07:03,122 --> 01:07:06,559
PEOPLE DO GET BETTER SO IT'S NOT

1610
01:07:06,559 --> 01:07:07,860
COMPLETE GIVEN THAT TREATMENT IS

1611
01:07:07,860 --> 01:07:10,730
REQUIRED BUT THERE IS AMONG

1612
01:07:10,730 --> 01:07:12,665
PEOPLE IN THE NONRANDOMMIZED

1613
01:07:12,665 --> 01:07:15,168
BSKSAL STUDY WHO RECEIVED IMMUNO

1614
01:07:15,168 --> 01:07:16,936
SUPPRESS OF TREATMENT BY THIS

1615
01:07:16,936 --> 01:07:20,506
PROTOCOL HAD BOTH CLINICAL AND

1616
01:07:20,506 --> 01:07:22,041
RADIO GRAPHIC IMPROVEMENT THAT

1617
01:07:22,041 --> 01:07:23,876
APPEARED TO BE IN RESPONSE TO

1618
01:07:23,876 --> 01:07:26,112
THIS, DOESN'T SEEM TO BE JUST

1619
01:07:26,112 --> 01:07:28,081
REGRESSION TO THE MEAN BUT

1620
01:07:28,081 --> 01:07:29,215
RESPONSE TO THE

1621
01:07:29,215 --> 01:07:29,649
IMMUNOSUPPRESSION.

1622
01:07:29,649 --> 01:07:32,552
AND JUST AN INTERESTING

1623
01:07:32,552 --> 01:07:34,420
OBSERVATION WHERE I DON'T KNOW

1624
01:07:34,420 --> 01:07:36,122
HOW TO PLACE THE

1625
01:07:36,122 --> 01:07:36,756
INPOLICEMANNATION SYNDROME THAT

1626
01:07:36,756 --> 01:07:40,093
THERE WAS A LOWER RISK OF

1627
01:07:40,093 --> 01:07:41,861
OCCURRENCE, FOR MANY PEOPLE,

1628
01:07:41,861 --> 01:07:43,629
PARTICULARLY THE UNTREATED

1629
01:07:43,629 --> 01:07:44,464
PEOPLE WOULD SPONTANEOUSLY GET

1630
01:07:44,464 --> 01:07:46,599
BETTER AND SHOW A REPEATED

1631
01:07:46,599 --> 01:07:49,469
FLAIR, THE REPEATED PLAYERS OF

1632
01:07:49,469 --> 01:07:50,937
THE CAA RELATED INFORMATION WERE

1633
01:07:50,937 --> 01:07:53,339
IN THE BRAIN LOCATIONS SINCE THE

1634
01:07:53,339 --> 01:07:55,141
INITIAL PRESENTATION AND AGAIN

1635
01:07:55,141 --> 01:07:56,376
IS QUITE--I THINK BIOLOGICALLY

1636
01:07:56,376 --> 01:07:59,312
QUITE INTERESTING BUT THE PEOPLE

1637
01:07:59,312 --> 01:08:00,680
WHO RECEIVED IMMUNOSUPPRESSION

1638
01:08:00,680 --> 01:08:03,116
WERE LESS LIKELY, NOT--MORE

1639
01:08:03,116 --> 01:08:05,184
LIKELY TO SHOW SHORT-TERM I

1640
01:08:05,184 --> 01:08:07,653
IMPROVEMENT AND LESS LIKELY TO

1641
01:08:07,653 --> 01:08:08,354
HAVE RECURRENCE OVERTIME AND

1642
01:08:08,354 --> 01:08:09,889
THIS IS AN ARGUMENT THAT COMES

1643
01:08:09,889 --> 01:08:12,925
UP TIMES ABOUT WHETHER TO TREAT

1644
01:08:12,925 --> 01:08:17,330
SOMEBODY WITH MINIMAL SYMPTOM

1645
01:08:17,330 --> 01:08:21,167
ANDS CAARK-RELATED

1646
01:08:21,167 --> 01:08:22,001
 INFLAMMATION

1647
01:08:22,001 --> 01:08:23,603
IN TREATS PEOPLE WITH SYMPTOMS.

1648
01:08:23,603 --> 01:08:26,072
AND TO COMMENT ON THE NEXT FEW

1649
01:08:26,072 --> 01:08:34,113
SLIDES ON THE BLEEDING

1650
01:08:34,113 --> 01:08:34,447
RELATIONSHIPS.

1651
01:08:34,447 --> 01:08:36,082
I THINK IT'S IMPORTANT TO SAY

1652
01:08:36,082 --> 01:08:37,617
THAT ARIA H AND E ARE IMPOSSIBLE

1653
01:08:37,617 --> 01:08:41,054
TO BUILD MATILY LNK EXCLUDE THIS

1654
01:08:41,054 --> 01:08:44,657
IS PRESUMABLILY SEPARATE FOR THE

1655
01:08:44,657 --> 01:08:47,960
APPEARANCE OF MICROBLEEDS AS

1656
01:08:47,960 --> 01:08:49,529
REISA ALLUDED TO BUT

1657
01:08:49,529 --> 01:08:52,131
MICROBLEEDING AND QUITE COMMON.

1658
01:08:52,131 --> 01:08:54,033
HEMORRHAGE IN THE THERE IS RARE,

1659
01:08:54,033 --> 01:08:57,103
BUT OTHERS HAD AS WELL, BUT IT'S

1660
01:08:57,103 --> 01:08:59,605
AN UNCOMMON FEATURE AND RAISES

1661
01:08:59,605 --> 01:09:01,741
INTERESTING QUESTIONS ABOUT WHY

1662
01:09:01,741 --> 01:09:07,113
A BLEED IS A MICROBLEED RATHER

1663
01:09:07,113 --> 01:09:10,616
THAN A MACROBLEED. 

1664
01:09:10,616 --> 01:09:12,718
I THINK SHERRY IS PRESENTING ON

1665
01:09:12,718 --> 01:09:14,454
THIS SO I WON'T STEP ON THAT,

1666
01:09:14,454 --> 01:09:20,426
BUT IN THE SETTING OF TP

1667
01:09:20,426 --> 01:09:22,261
A TREATMENT HAD MULTIFOCAL

1668
01:09:22,261 --> 01:09:23,463
MACROBLEEDING SO EVEN THOUGH

1669
01:09:23,463 --> 01:09:25,898
IT'S A RELATIVELY MINOR PART OF

1670
01:09:25,898 --> 01:09:27,667
THE SPONTAKENIOUS SYNDROME, IT

1671
01:09:27,667 --> 01:09:29,068
RAISES IMPORTANT CLINICAL

1672
01:09:29,068 --> 01:09:31,270
QUESTIONS.

1673
01:09:31,270 --> 01:09:33,940
SO I WILL CONCLUDE HERE SO THAT

1674
01:09:33,940 --> 01:09:37,009
I WILL MAKE THE ARGUMENT TO THE

1675
01:09:37,009 --> 01:09:37,577
FIRST APPROXIMATION THAT

1676
01:09:37,577 --> 01:09:41,047
ARE--ADMINISTRATIVE RAW DATA IS

1677
01:09:41,047 --> 01:09:41,681
THE KRRK AA-REFRESH YOUR

1678
01:09:41,681 --> 01:09:45,184
RECOLLECTION I AND ARIA

1679
01:09:45,184 --> 01:09:46,452
INPOLICEMANNATION, SHORT-TERM

1680
01:09:46,452 --> 01:09:48,354
AND LONG-TERM RESPONSE TO

1681
01:09:48,354 --> 01:09:54,227
IMMUNOSUPPRESSION, I THINK THIS

1682
01:09:54,227 --> 01:09:55,361
WILL REGENERALLIZE ARIA, WHETHER

1683
01:09:55,361 --> 01:09:56,529
THIS IS PREVENTING THE

1684
01:09:56,529 --> 01:09:57,897
GENERATION OF ASPECT BODIES IN

1685
01:09:57,897 --> 01:10:01,033
WHICH CASE IT WON'T HELP IN

1686
01:10:01,033 --> 01:10:03,302
TRIAL RELATED ARIA TREATMENT,

1687
01:10:03,302 --> 01:10:12,812
RELATED ARIA OR IF IT'S REDUCING

1688
01:10:12,812 --> 01:10:13,813
THE RESPONSE AND WE DON'T HAVE A

1689
01:10:13,813 --> 01:10:16,782
GOOD WAY TO KNOW THAT FROM THE

1690
01:10:16,782 --> 01:10:18,851
SPONTAKENIOUS SYNDROME AND THEN

1691
01:10:18,851 --> 01:10:21,254
SYMPTOMATIC ICH IS RARE BUT

1692
01:10:21,254 --> 01:10:22,321
RAISES CONCERNS ABOUT

1693
01:10:22,321 --> 01:10:23,489
ANTITHROMBOTTICS AND I JUST

1694
01:10:23,489 --> 01:10:26,292
SHOWED HERE 1 OF MANY STUDIES

1695
01:10:26,292 --> 01:10:28,194
SHOWING THAT ANTICO AGULATE

1696
01:10:28,194 --> 01:10:29,729
RELATED HEMORRHAGE IS 1 OF THE

1697
01:10:29,729 --> 01:10:32,198
MOST DEADLY DISEASES IN

1698
01:10:32,198 --> 01:10:33,766
MEDICINE, IT'S SHORT-TERM

1699
01:10:33,766 --> 01:10:34,901
MORTALITY, 50% ARE NOT THAT MANY

1700
01:10:34,901 --> 01:10:38,638
DISEASES HA HAVE A SHORT-TERM

1701
01:10:38,638 --> 01:10:39,739
MORTALITY OF 50%.

1702
01:10:39,739 --> 01:10:42,175
SO AND CONSIDERATION IN

1703
01:10:42,175 --> 01:10:44,644
PARTICULAR OF ANTICO AGULATES OR

1704
01:10:44,644 --> 01:10:46,746
THROMBO LYTICS IN THE SEEING OF

1705
01:10:46,746 --> 01:10:49,682
ARIA RAISES WHAT CAN BE A TRULY

1706
01:10:49,682 --> 01:10:50,483
DIRE COMPLICATIONS AND WITH THAT

1707
01:10:50,483 --> 01:11:00,860
I THANK YOU VERY MUCH.

1708
01:11:03,229 --> 01:11:04,530
>> THANK YOU, THE FLOOR IS
OPEN.

1709
01:11:04,530 --> 01:11:07,099
WE HAVE A COUPLE OF MINUTES FOR

1710
01:11:07,099 --> 01:11:10,536
QUESTIONS MUCH 

1711
01:11:10,536 --> 01:11:10,803
QUESTIONS.

1712
01:11:10,803 --> 01:11:15,775
PLEASE COME TO THE MIKE AND

1713
01:11:15,775 --> 01:11:17,043
BRUCE WROWRS AND ASK QUUR

1714
01:11:17,043 --> 01:11:21,347
QUESTION SPHRKS I AM LIAA FROM

1715
01:11:21,347 --> 01:11:22,648
UNIVERSITY, THE ENLARGEMENT OF

1716
01:11:22,648 --> 01:11:24,317
THE VENTRICLES YOU ARE DRIEBING,

1717
01:11:24,317 --> 01:11:26,886
DO YOU THINK THIS IS A SIGN OF

1718
01:11:26,886 --> 01:11:28,387
IMPAIRED PLURIBU EDUCATIONAL

1719
01:11:28,387 --> 01:11:38,864
HOMEIO STASES OR REFLECTING

1720
01:11:43,336 --> 01:11:44,971
ATROPHY?

1721
01:11:44,971 --> 01:11:48,307
>> SO I DON'T WE THINK WE
KNOW

1722
01:11:48,307 --> 01:11:51,611
EMPLOY NICK FOX AND OTHERS THINK

1723
01:11:51,611 --> 01:11:55,381
IT WAS A TRANSIENT INCREASE IN

1724
01:11:55,381 --> 01:11:57,149
A-BETA IN THE CSF WHEN YOU GET

1725
01:11:57,149 --> 01:11:59,485
THE ANTIBODIES OR THE VACCINE.

1726
01:11:59,485 --> 01:12:00,319
WHETHER THAT'S CHANGING IT

1727
01:12:00,319 --> 01:12:01,487
BECAUSE IT'S ONLY OUT OF

1728
01:12:01,487 --> 01:12:03,122
PROPORTION TO THE GRAY MATTER

1729
01:12:03,122 --> 01:12:03,356
LOSS.

1730
01:12:03,356 --> 01:12:07,260
BEAUTIFUL TODAYS OF THIS, THE

1731
01:12:07,260 --> 01:12:07,927
VENTRICULAR ENLARGEMENTS EARLIER

1732
01:12:07,927 --> 01:12:09,328
AND EARLIER THAN THE GRAY MATTER

1733
01:12:09,328 --> 01:12:12,231
LOSS SO PROBABLY SOME OF EACH.

1734
01:12:12,231 --> 01:12:13,733
>> THE SECOND QUESTION I
HAVE

1735
01:12:13,733 --> 01:12:15,601
QUICKLY IS HOW DO THE PRACTICING

1736
01:12:15,601 --> 01:12:17,336
MENTORSHIP SKILLS ONCE THEY ARE

1737
01:12:17,336 --> 01:12:19,538
EATEN UP OR UNGULFED WITH

1738
01:12:19,538 --> 01:12:22,842
ANTIBODY TREATMENTS, HOW DID

1739
01:12:22,842 --> 01:12:23,409
THEY DISAPPEAR?

1740
01:12:23,409 --> 01:12:27,947
>> THEY GO IN THE KIDNEY,
THAT

1741
01:12:27,947 --> 01:12:28,948
MUCH I KNOW.

1742
01:12:28,948 --> 01:12:31,317
>> DO WE NEED THE

1743
01:12:31,317 --> 01:12:31,951
[INDISCERNIBLE] DISRUPTIONS TO

1744
01:12:31,951 --> 01:12:33,986
GET RID OF THEM NYES, I GUESS

1745
01:12:33,986 --> 01:12:35,254
THAT'S ANOTHER QUESTION, MAYBE

1746
01:12:35,254 --> 01:12:37,657
OTHERS CAN ANSWER THAT IN NI

1747
01:12:37,657 --> 01:12:38,658
THINK WE'RE FIGURE--WE'RE MOW

1748
01:12:38,658 --> 01:12:40,293
GETTING INTO THE TERRITORY WHERE

1749
01:12:40,293 --> 01:12:41,560
WE SHOULD MOVE ON TO THE NEXT

1750
01:12:41,560 --> 01:12:43,262
TALK AND CONTINUE THE

1751
01:12:43,262 --> 01:12:46,799
DISCUSSION, WE JUST HAD TIME FOR

1752
01:12:46,799 --> 01:12:53,406
LIKE 1 QUESTION.

1753
01:12:53,406 --> 01:12:56,142
SORRY ABOUT THAT SO DR. JAMES

1754
01:12:56,142 --> 01:12:58,878
NIERK KRRK CORRELATED

1755
01:12:58,878 --> 01:13:00,913
LL UNIVERSITY OF SOUTH HAMPTON.

1756
01:13:00,913 --> 01:13:02,014
>> HI, HELLO THERE,
HOPEFULLY

1757
01:13:02,014 --> 01:13:07,353
YOU CAN HEAR ME.

1758
01:13:07,353 --> 01:13:08,788
YES, I AM VIRTUAL, YEAH.

1759
01:13:08,788 --> 01:13:13,159
MANY APOLOGIES THAT I CAN'T YOIN

1760
01:13:13,159 --> 01:13:16,162
YOU IN PERSON TO DISCUSS THIS

1761
01:13:16,162 --> 01:13:16,729
IMPORTANT TOPIC.

1762
01:13:16,729 --> 01:13:18,597
I WILL GIVE MY TALK ON ZOOM BY

1763
01:13:18,597 --> 01:13:21,901
SHARING MY KREEN IF THAT WILL

1764
01:13:21,901 --> 01:13:22,835
WORK.

1765
01:13:22,835 --> 01:13:27,940
IT'S TELLING ME I CAN'T SHARE MY

1766
01:13:27,940 --> 01:13:28,741
SCREEN BECAUSE ANOTHER

1767
01:13:28,741 --> 01:13:33,512
PARTICIPANT IS SHARING  SHARING.

1768
01:13:33,512 --> 01:13:37,483
LET ME JUST TRY THAT AGAIN.

1769
01:13:37,483 --> 01:13:42,722
YEP, HOPEFULLY YOU CAN SEE MY

1770
01:13:42,722 --> 01:13:43,889
SHIED THERE AND HEAR ME.

1771
01:13:43,889 --> 01:13:45,591
I WANT TO DO MY SCREEN SHARING

1772
01:13:45,591 --> 01:13:49,095
SO THAT YOU CAN SEE MY POINTS SO

1773
01:13:49,095 --> 01:13:50,229
I CAN POINT AROUND VARIOUS

1774
01:13:50,229 --> 01:13:53,265
THINGS I WANT TO SHOW.

1775
01:13:53,265 --> 01:13:54,667
SO THIS IS THE TITLE I'VE BEEN

1776
01:13:54,667 --> 01:13:58,237
GIVEN BE TO TALK TO.

1777
01:13:58,237 --> 01:14:04,677
NEUROPATHOLOGY OF ARIA IN

1778
01:14:04,677 --> 01:14:06,212
PATIENTS GIVEN ANTIBETTA

1779
01:14:06,212 --> 01:14:09,315
ANTIBODIES. 

1780
01:14:09,315 --> 01:14:10,316
HERE ARE DISCLOSURES.

1781
01:14:10,316 --> 01:14:11,283
>> YAIMS WAIT FOR JUST A

1782
01:14:11,283 --> 01:14:12,651
SECURITIZATION., I THINK YOUR

1783
01:14:12,651 --> 01:14:14,220
SLIDES AREN'T SHOWING YET,

1784
01:14:14,220 --> 01:14:18,758
SOMEONE WILL FIGURE IT OUT.

1785
01:14:18,758 --> 01:14:20,659
>> OKAY.

1786
01:14:20,659 --> 01:14:24,397
SORRY, IS THAT BETTER?

1787
01:14:24,397 --> 01:14:25,097
NYOU'RE GREAT TO GO.

1788
01:14:25,097 --> 01:14:27,199
>> YOU CAN SEE THAT ALL
RIGHT

1789
01:14:27,199 --> 01:14:27,366
IN.

1790
01:14:27,366 --> 01:14:29,235
>> YES NWE LOST YOU BUT WE
GOT

1791
01:14:29,235 --> 01:14:29,635
THE SLIDES.

1792
01:14:29,635 --> 01:14:32,705
SO THIS IS THE TIELTS I'VE BEEN

1793
01:14:32,705 --> 01:14:35,307
GIVEN NEUROPATHOLOGY PATIENTS

1794
01:14:35,307 --> 01:14:39,845
WITH ARIA. 

1795
01:14:39,845 --> 01:14:43,649
'RE GIVEN ANTIBETTA ANTIBODIES.

1796
01:14:43,649 --> 01:14:46,619
THE PROBLEM IS WE DON'T HAVE ANY

1797
01:14:46,619 --> 01:14:49,922
NEUROPATHOLOGY OF ARIA IN PEASHS

1798
01:14:49,922 --> 01:14:53,092
WHO HAVE HAD PASSIVE IMMUNIZE

1799
01:14:53,092 --> 01:14:54,427
WITH ANTIBODY THERAPY AS LEAST

1800
01:14:54,427 --> 01:14:56,762
AS FAR AS I'M AWARE AND I THINK

1801
01:14:56,762 --> 01:14:57,596
THAT'S AN IMPORTANT POINT TO

1802
01:14:57,596 --> 01:14:59,565
MAKE EMPLOY WE NEED SOME TISSUE

1803
01:14:59,565 --> 01:15:04,069
STUDIES IN PATE WHO IS HAD THESE

1804
01:15:04,069 --> 01:15:05,704
PASSIVE VACCINES AND HAD ARIA,

1805
01:15:05,704 --> 01:15:07,706
BUT I WILL ARGUE THERE ARE CLOSE

1806
01:15:07,706 --> 01:15:12,411
SIMILARITIES WITH THE SIDE

1807
01:15:12,411 --> 01:15:13,846
EFFECTS EXPERIENCED 1792 WHICH

1808
01:15:13,846 --> 01:15:20,419
AT THE TIME WAS TERMED MENING

1809
01:15:20,419 --> 01:15:21,787
OENCEPHALITIS.

1810
01:15:21,787 --> 01:15:25,624
THIS IS THE FIRST TODAY AND

1811
01:15:25,624 --> 01:15:27,126
IMMUNOTHERAPY IN ALZHEIMER'S

1812
01:15:27,126 --> 01:15:29,762
TEASE SO IN SPHENE 92 WAS

1813
01:15:29,762 --> 01:15:32,698
IMMUNIZATION WITH FULL LENGTH,

1814
01:15:32,698 --> 01:15:34,300
PEPTIDE ANDS ADJUVANT CAN THIS

1815
01:15:34,300 --> 01:15:37,336
FIRST STUDY WAS A SMALL STUDY OF

1816
01:15:37,336 --> 01:15:39,638
80 PATIENTS; MILD TO MODERATE

1817
01:15:39,638 --> 01:15:40,172
ALZHEIMER'S DEC.

1818
01:15:40,172 --> 01:15:43,609
AND WE'VE BEEN FOLLOWING UP WITH

1819
01:15:43,609 --> 01:15:45,978
PATIENTS IN THAT FIRST STUDY

1820
01:15:45,978 --> 01:15:48,080
OVER MANY YEARS AND WE'VE SEEN

1821
01:15:48,080 --> 01:15:50,816
THE BRAINS OF 22 OF THE 80

1822
01:15:50,816 --> 01:15:52,318
PATIENTS WHO WERE IN THAT

1823
01:15:52,318 --> 01:15:54,887
INITIAL STUDY SO THESE ARE

1824
01:15:54,887 --> 01:16:00,226
HISTOLOGICAL SECTIONS OF

1825
01:16:00,226 --> 01:16:01,660
SEEREBERAL HEMISPHERE, THE BLACK

1826
01:16:01,660 --> 01:16:04,363
STAINING HERE IS IMMUNO

1827
01:16:04,363 --> 01:16:05,531
CHEMISTRY, SHOWING WHERE THE

1828
01:16:05,531 --> 01:16:07,533
PLOTS ARE IN THE CORTEX.

1829
01:16:07,533 --> 01:16:09,602
FIVE PATIENTS STARTED TO HAVE

1830
01:16:09,602 --> 01:16:11,270
VERY SENSITIVE PLOT CLEARANCE,

1831
01:16:11,270 --> 01:16:13,706
NO PLAQUES IN THE BRAIN, OTHERS

1832
01:16:13,706 --> 01:16:17,243
HAD LARGE PATCHES OR SMALLER

1833
01:16:17,243 --> 01:16:18,911
PATCHES OF PLAQUE REMOVAL.

1834
01:16:18,911 --> 01:16:24,683
THIS IS SOME QUALIFICATION OF

1835
01:16:24,683 --> 01:16:30,356
AB LOAD IN THE IMMUNIZED

1836
01:16:30,356 --> 01:16:34,727
ALZHEIMER GROUP AND THE GROUP OF

1837
01:16:34,727 --> 01:16:35,528
UPTREATED ALZHEIMER'S DEC, ABOUT

1838
01:16:35,528 --> 01:16:37,396
YOU IN CONTRAST TO THE PLAQUE

1839
01:16:37,396 --> 01:16:38,998
REMOVAL, IT WAS A VERY

1840
01:16:38,998 --> 01:16:40,666
SUBSTANTIAL INKRES IN THE

1841
01:16:40,666 --> 01:16:44,803
SEVERITY OF THE CAA WHEN WE

1842
01:16:44,803 --> 01:16:45,538
QUANTIFY THE CAA.

1843
01:16:45,538 --> 01:16:47,139
SO BOTTOM ROW OF IMAGES HERE IS

1844
01:16:47,139 --> 01:16:50,242
TRYING TO SHOW IN EFFECT A TIME

1845
01:16:50,242 --> 01:16:53,312
SEQUENCE OF WHAT'S HAPPENING

1846
01:16:53,312 --> 01:16:54,713
HERE.

1847
01:16:54,713 --> 01:16:55,214
SO UNTREATED ALZHEIMER'S

1848
01:16:55,214 --> 01:16:59,885
DISEASE, HERE ON THE LEFT IS ARE

1849
01:16:59,885 --> 01:17:03,188
THE PLOTS, THEN AFTER TREATMENT

1850
01:17:03,188 --> 01:17:04,990
THEY DISAGGREGATE IN THE WALLS.

1851
01:17:04,990 --> 01:17:06,625
AT THE LATER STAGE THE PLAQUES

1852
01:17:06,625 --> 01:17:08,394
HAVE GONE BUT A LOT OF SEVERE

1853
01:17:08,394 --> 01:17:10,296
CARK A, OF THE BLOOD VESSELS AND

1854
01:17:10,296 --> 01:17:13,899
THEN IN THE LATER CASES

1855
01:17:13,899 --> 01:17:15,935
SUGIETION THAT AT A LATER STAGE

1856
01:17:15,935 --> 01:17:19,371
THE PLAQUES HAVE GONE AND CAA,

1857
01:17:19,371 --> 01:17:21,941
HAVE GONE FROM THE

1858
01:17:21,941 --> 01:17:32,351
[INDISCERNIBLE] AS WELL.

1859
01:17:32,918 --> 01:17:35,387
SO WE'VE LONG KNOWN ABOUT THE

1860
01:17:35,387 --> 01:17:38,824
CONCENTRICS OF THIS AND HOW THE

1861
01:17:38,824 --> 01:17:40,192
APPEARANCE ARISES THAT IT'S

1862
01:17:40,192 --> 01:17:43,929
DEPOSITED IN THE VESSEL AND THE

1863
01:17:43,929 --> 01:17:46,732
MEDIA HERE AND SO THE SEVERE

1864
01:17:46,732 --> 01:17:49,134
CARK A, THE ABETTA FIBERALS

1865
01:17:49,134 --> 01:17:49,969
DESTROY THE SMOOTH MUSCLE CELLS

1866
01:17:49,969 --> 01:17:52,404
IN THE MEDIA OF THE BLOOD VESSEL

1867
01:17:52,404 --> 01:17:53,939
AND THEN THE AMYLOID IS REMOVED

1868
01:17:53,939 --> 01:17:55,341
FROM THE VESSEL WALL, LEAVING

1869
01:17:55,341 --> 01:17:57,343
THE SPACE WHERE THE MEDIA SMOOTH

1870
01:17:57,343 --> 01:18:01,647
MUSCLE CELLS HAD BEEN, SO THIS

1871
01:18:01,647 --> 01:18:05,084
IS A VERY WELL KNOWN FEATURE OF

1872
01:18:05,084 --> 01:18:08,520
PATIENTS WITH SEVERE CAA.

1873
01:18:08,520 --> 01:18:11,757
AND SO, WHEN WE QUANTIFIED THIS

1874
01:18:11,757 --> 01:18:13,559
SPECIFIC FEATURE IN THE

1875
01:18:13,559 --> 01:18:14,627
IMMUNIZED AD CASES THERE WAS

1876
01:18:14,627 --> 01:18:17,529
MORE OF IT, MORE CONCENTRICS FOR

1877
01:18:17,529 --> 01:18:19,798
THE WALL IN THE UNTREATED

1878
01:18:19,798 --> 01:18:21,166
ALZHEIMER CASES.

1879
01:18:21,166 --> 01:18:24,336
SO REFLECTING SEVERE CARK A, AND

1880
01:18:24,336 --> 01:18:26,472
THEN REMOVAL OF A-BETA PRACTICES

1881
01:18:26,472 --> 01:18:29,141
THE VESSEL WALLS.

1882
01:18:29,141 --> 01:18:30,909
THERE WERE ALSO MICROBLEEDS, YOU

1883
01:18:30,909 --> 01:18:36,615
CAN SEE HERE STAINING THE

1884
01:18:36,615 --> 01:18:41,920
SHOWING CLUSTERS OF OF IRON

1885
01:18:41,920 --> 01:18:44,189
CLICKS, THIS IS THE NUMBER OF

1886
01:18:44,189 --> 01:18:45,057
MICROPLEADS AND QUITE VARIABLE,

1887
01:18:45,057 --> 01:18:47,393
CAN YOU SEE THE CASES HAVE QUITE

1888
01:18:47,393 --> 01:18:50,462
A LARGE NUMBER OF MICROBLEEDS

1889
01:18:50,462 --> 01:18:51,563
COMPARED TO UNTREATED

1890
01:18:51,563 --> 01:18:52,698
ALZHEIMER'S DEC DOWN HERE.

1891
01:18:52,698 --> 01:18:54,166
THERE WERE ALSO OTHER LESIONS

1892
01:18:54,166 --> 01:18:58,037
THAT DIDN'T OBVIOUSLY CONTAIN

1893
01:18:58,037 --> 01:18:58,871
IRON PIGAMENT, HE'S

1894
01:18:58,871 --> 01:19:00,172
MICROVASCULAR LESIONS ARE NOT

1895
01:19:00,172 --> 01:19:03,208
ENTEARLY CLER WHETHER THEY WERE

1896
01:19:03,208 --> 01:19:04,910
MICROPLEADS IN WHICH THE PIGMENT

1897
01:19:04,910 --> 01:19:08,047
HAD BEEN CLEARED OR WHETHER THEY

1898
01:19:08,047 --> 01:19:10,416
WERE MICROINFARCTS BUT THEY WERE

1899
01:19:10,416 --> 01:19:11,383
ALSO PRESENT.

1900
01:19:11,383 --> 01:19:12,351
SO THESE ARE IMANNUALS FROM THE

1901
01:19:12,351 --> 01:19:16,355
1 OUT OF THE 22 CASES THAT WE

1902
01:19:16,355 --> 01:19:18,991
COULD STUDY THE NEUROPATHOLOGY

1903
01:19:18,991 --> 01:19:19,825
OF WHO HAD ARE--ADMINISTRATIVE

1904
01:19:19,825 --> 01:19:21,527
KRAMER, I THINK WE COULD CALL

1905
01:19:21,527 --> 01:19:22,528
THIS ARIA NOW.

1906
01:19:22,528 --> 01:19:24,630
SO THIS WAS THE MRI KAN--KANA

1907
01:19:24,630 --> 01:19:27,800
DURING LIFE, SO CAN YOU SEE THIS

1908
01:19:27,800 --> 01:19:30,102
FOCAL WHITE MATTER SIGNAL CHANGE

1909
01:19:30,102 --> 01:19:34,940
IN THE OCCIPITAL LOBE HERE,

1910
01:19:34,940 --> 01:19:36,942
POSTMORTEM OCCIPITAL LOBE SHOWS

1911
01:19:36,942 --> 01:19:38,577
STAINING FOR MILEIN, AND WHITE

1912
01:19:38,577 --> 01:19:41,346
MATTER AND HIGH POWER SHOWS

1913
01:19:41,346 --> 01:19:45,984
AGAIN MILEN TAINING AND SOME

1914
01:19:45,984 --> 01:19:46,685
ENLARGED PERIVASCULAR SPACES

1915
01:19:46,685 --> 01:19:48,420
WHICH HAS TEEF MENTIONED CAN BE

1916
01:19:48,420 --> 01:19:50,522
ASSOCIATE WIDE SEVERE CARK A,

1917
01:19:50,522 --> 01:19:53,559
AND THE UNDERLYING CORTEX AND

1918
01:19:53,559 --> 01:19:55,527
MEN I THINKIS, SO THIS IS HIGHER

1919
01:19:55,527 --> 01:20:02,501
POWER HAVE  VIEWS OF THAT CASE,E

1920
01:20:02,501 --> 01:20:04,603
CAA, WITH ABSENCE OF SURROUNDING

1921
01:20:04,603 --> 01:20:06,271
PLOTS AND CORTEX, OVER HERE TOP

1922
01:20:06,271 --> 01:20:09,074
LEFT, YOU CAN SEE THIS IS

1923
01:20:09,074 --> 01:20:10,109
CONCENTRIC, POLITTING OF THE

1924
01:20:10,109 --> 01:20:12,878
VESSEL WALL WHICH I THINK

1925
01:20:12,878 --> 01:20:15,981
REFLECTS AMYLOID REMOVAL, SOME

1926
01:20:15,981 --> 01:20:17,382
INPOLICEMANNATORY CELLS,

1927
01:20:17,382 --> 01:20:18,884
CLUSTERED AROUND WHICH CHEMISTRY

1928
01:20:18,884 --> 01:20:22,054
SHOWS T-HISM O SIGHTS AND THE

1929
01:20:22,054 --> 01:20:23,922
WHITE MATTER, THIS IS THE

1930
01:20:23,922 --> 01:20:25,624
REFLECTION OF WHITE MATTER AND

1931
01:20:25,624 --> 01:20:36,068
HERE'S A MICROPLEAD IN THE

1932
01:20:36,902 --> 01:20:37,436
CORTEX.

1933
01:20:37,436 --> 01:20:39,571
THAT 11 CASE IF OUR SERIES, THE

1934
01:20:39,571 --> 01:20:40,339
SEBS QUENT CLINICAL TRIAL THAT

1935
01:20:40,339 --> 01:20:45,110
WAS DONE SO THIS IS DESCRIBED BY

1936
01:20:45,110 --> 01:20:47,679
[INDISCERNIBLE] AND LIKEWISE

1937
01:20:47,679 --> 01:20:50,082
SHOWS PALLET OF MILEIN STAINING

1938
01:20:50,082 --> 01:20:51,683
IN THE WHITE MATTER HERE

1939
01:20:51,683 --> 01:20:52,785
ASSOCIATE WIDE SEVERE KRRK ARK

1940
01:20:52,785 --> 01:20:58,791
A, AND INFLATION SORB WIDE THE

1941
01:20:58,791 --> 01:20:59,558
ABNORMAL BLOOD VESSELS.

1942
01:20:59,558 --> 01:21:01,460
SO AS FAR AS I'M AWARE, THESE

1943
01:21:01,460 --> 01:21:04,897
ARE THE 2 CASES WHERE THEY'RE

1944
01:21:04,897 --> 01:21:06,832
THERE, AND BOTH WITHIN 1592 AND

1945
01:21:06,832 --> 01:21:11,036
THE VACCINE AND WE REALLY NEED

1946
01:21:11,036 --> 01:21:14,072
SOME TOPOLOGY OF ARIA IN PASSIVE

1947
01:21:14,072 --> 01:21:16,542
IMMUNOTHERAPY TO SEE WHAT

1948
01:21:16,542 --> 01:21:18,610
SIMILARITIES AND DIFFERENCES

1949
01:21:18,610 --> 01:21:19,511
THEY MAY BE.

1950
01:21:19,511 --> 01:21:23,682
SO ON THE BASIS OF THOSE 2 CASES

1951
01:21:23,682 --> 01:21:24,883
AND BACKGROUND BIOLOGICAL

1952
01:21:24,883 --> 01:21:31,790
THINKING, SOME YEARS AGO, WE

1953
01:21:31,790 --> 01:21:34,159
DEVISED THIS SCHEME.

1954
01:21:34,159 --> 01:21:35,994
WE DEVISED THIS AS A

1955
01:21:35,994 --> 01:21:38,096
PATHOLOGICAL SYSTEM FOR ARIA.

1956
01:21:38,096 --> 01:21:40,199
SO HERE'S A PLAQUE IN THE CORTEX

1957
01:21:40,199 --> 01:21:43,769
OF SOMEBODY WITH ALZHEIMER'S

1958
01:21:43,769 --> 01:21:46,805
DISEASE, SO ANTIBETTA ANTIBODIES

1959
01:21:46,805 --> 01:21:48,440
ENTER THE BRAIN BEHIND THE

1960
01:21:48,440 --> 01:21:50,108
PLAQUE AND DISRUPT THE PLAQUE

1961
01:21:50,108 --> 01:21:51,910
THIS RESULTS IN INCREASED

1962
01:21:51,910 --> 01:21:53,745
SOLUBLE WHICH TRACKS TO THE

1963
01:21:53,745 --> 01:21:54,413
VASCULATURE RESULNOTHING

1964
01:21:54,413 --> 01:21:58,650
INCREASE IN SEVERITY OF CAA, THE

1965
01:21:58,650 --> 01:21:59,918
ANTIBETTA ANTIABOUT BODIES MAY

1966
01:21:59,918 --> 01:22:00,886
BE BIEBDING DIRECTLY TO THE

1967
01:22:00,886 --> 01:22:04,823
VESSEL WALLS AND THERE MAY BE AN

1968
01:22:04,823 --> 01:22:05,891
IPT GREATER FLAMMATORY REACTION

1969
01:22:05,891 --> 01:22:09,161
ASSOCIATED WITH THESE CHANGES IN

1970
01:22:09,161 --> 01:22:11,396
THE BLOOD VESSELS AND ALTOGETHER

1971
01:22:11,396 --> 01:22:12,598
THESE CHANGES ARE TOGETHER IN

1972
01:22:12,598 --> 01:22:13,665
THE MICROPLEAD ANDS ALSO IN THE

1973
01:22:13,665 --> 01:22:15,634
WHITE MATTER AND THE MOUSE IN

1974
01:22:15,634 --> 01:22:19,571
THE UNDERLYING WHITE MATTER WHY

1975
01:22:19,571 --> 01:22:21,907
THE PLAQUES ARE BEING REMOVED.

1976
01:22:21,907 --> 01:22:24,676
SO WE SUGGIESTED AT THE TIME

1977
01:22:24,676 --> 01:22:27,312
THIS WAS AN PATHOLOGICAL PROCESS

1978
01:22:27,312 --> 01:22:30,415
AND THAT THIS WOULD LIKELY BE

1979
01:22:30,415 --> 01:22:34,720
RELEVANT TO MOST PROT COLS, MOST

1980
01:22:34,720 --> 01:22:35,921
THERAPEUTIC PROTOCOLS THAT

1981
01:22:35,921 --> 01:22:38,557
RESULTED IN REMOVAL OF PLAQUES

1982
01:22:38,557 --> 01:22:39,625
FROM THE SEEREBERAL CORTEX AND

1983
01:22:39,625 --> 01:22:42,761
IT HAS PROVED TO BE.

1984
01:22:42,761 --> 01:22:45,264
SO THESE ARE JUST SOME MORE

1985
01:22:45,264 --> 01:22:49,668
IMAGES FROM OUR SINGLE CASE FROM

1986
01:22:49,668 --> 01:22:51,670
THE 1792, AT LOW POWER SO CAN

1987
01:22:51,670 --> 01:22:55,140
YOU SEE THE CORRELATE THAT WITH

1988
01:22:55,140 --> 01:23:03,181
THE CARTOON AND SOME OF THE MRI

1989
01:23:03,181 --> 01:23:04,616
SCANS THEY'RE SEEING YOU CAN SEE

1990
01:23:04,616 --> 01:23:06,184
WILL PLOT ABSENT FROM THE CORTEX

1991
01:23:06,184 --> 01:23:09,888
HAVE BEEN REMOVED HERE AND YET

1992
01:23:09,888 --> 01:23:14,593
THE SEVERE CAARK IN THE

1993
01:23:14,593 --> 01:23:17,629
MENINGIES AND CORTEX, THERE ARE

1994
01:23:17,629 --> 01:23:18,730
PERIVASCULAR SPACES IN THE

1995
01:23:18,730 --> 01:23:20,465
UNDERLYING WHITE MATTER AND THIS

1996
01:23:20,465 --> 01:23:23,101
IS CORRESPONDING HD SECTIONS

1997
01:23:23,101 --> 01:23:26,772
AGAIN, HERE'S CONTEXT, OVERLYING

1998
01:23:26,772 --> 01:23:28,607
MENINGIAL VESSELS AND

1999
01:23:28,607 --> 01:23:31,777
INFLAMMATORY CELLS AND

2000
01:23:31,777 --> 01:23:36,114
LYMPHOCYTES ASSOCIATE WIDE THOSE

2001
01:23:36,114 --> 01:23:37,282
CAA INFECTED BLOOD VESSELS, AND

2002
01:23:37,282 --> 01:23:40,986
IN THE CORTEX HERE AND THE WHITE

2003
01:23:40,986 --> 01:23:42,921
MATTER CHANGES AFFECTED BY THE

2004
01:23:42,921 --> 01:23:44,156
PACES HERE.

2005
01:23:44,156 --> 01:23:46,825
O OF COURSE, THESE ARE THE

2006
01:23:46,825 --> 01:23:49,061
ARTERIES TURNED THRAW A RIGHT

2007
01:23:49,061 --> 01:23:52,197
ANGLE AND THEY PENETRATE THE

2008
01:23:52,197 --> 01:23:53,799
CEREBRAL CORTEX AND THEY GO ON

2009
01:23:53,799 --> 01:23:55,834
TO SUPPLY THE UNDERLYING WHITE

2010
01:23:55,834 --> 01:23:57,936
MATTER SO THESE ARE ALL THE SAME

2011
01:23:57,936 --> 01:24:02,207
BLOOD VESSELS HERE THAT ARE

2012
01:24:02,207 --> 01:24:02,808
AFFECTED.

2013
01:24:02,808 --> 01:24:08,046
SO THIS IS SOME NICE IMAGING AND

2014
01:24:08,046 --> 01:24:10,449
HISTOLOGY CORRELATION DONE ON

2015
01:24:10,449 --> 01:24:12,117
THIS COHORT BY SUSAN KD--SALLY

2016
01:24:12,117 --> 01:24:14,553
WAAND COLLEAGUES IN BOSTON.

2017
01:24:14,553 --> 01:24:15,454
THESE MREFRESH YOUR RECOLLECTION

2018
01:24:15,454 --> 01:24:17,489
I SCANS OF BRAIP SLICES, THAT

2019
01:24:17,489 --> 01:24:24,129
ARE BEEN DONE IN IMMUNIZED CASES

2020
01:24:24,129 --> 01:24:25,097
AND UNTREATED ALZHEIMER'S STEEZ

2021
01:24:25,097 --> 01:24:27,265
AND THE DIFFERENCE BETWEEN CASES

2022
01:24:27,265 --> 01:24:29,901
AND CONTROLS OF THESE BANDS AND

2023
01:24:29,901 --> 01:24:32,304
THESE CORTEX, AND I THINK YOU

2024
01:24:32,304 --> 01:24:34,373
WILL CALL THIS SUPERFICIAL

2025
01:24:34,373 --> 01:24:37,609
[INDISCERNIBLE] ON THE IMAGING

2026
01:24:37,609 --> 01:24:39,077
SO NOT PRESENT IN THE CONTROLS.

2027
01:24:39,077 --> 01:24:45,183
THIS IS THE CORRELATION OF THE

2028
01:24:45,183 --> 01:24:46,184
IMAGING WITH THE HISTOLOGY SO

2029
01:24:46,184 --> 01:24:48,220
THIS HAS BEEN SHOWN THAT WHERE

2030
01:24:48,220 --> 01:24:50,789
THESE SIGNAL CHANGE IN THE

2031
01:24:50,789 --> 01:24:53,392
CORTEX, THE PIGMENT ALSO OTHER

2032
01:24:53,392 --> 01:24:56,495
CALCIUM, ACCUMULATION AND THIS

2033
01:24:56,495 --> 01:25:01,333
IS ALL ASSOCIATE WIDE SEVERE

2034
01:25:01,333 --> 01:25:01,533
CAA.

2035
01:25:01,533 --> 01:25:02,834
A HIGHER POWER IT WAS POSSIBLE

2036
01:25:02,834 --> 01:25:07,839
TO SEE THAT THIS IRON PIGMENT IN

2037
01:25:07,839 --> 01:25:09,841
THE SUPERFICIAL CEREBRAL CORTEX,

2038
01:25:09,841 --> 01:25:10,642
IS A OCCURRING PARTICULARLY IN

2039
01:25:10,642 --> 01:25:12,811
AREAS WHERE THERE IS NO ABETTA,

2040
01:25:12,811 --> 01:25:13,745
I PRESUME THE ABETTA HAS BEG

2041
01:25:13,745 --> 01:25:15,747
YOUR PARDON CLEARED IN THESE

2042
01:25:15,747 --> 01:25:18,650
AREAS WHERE THE IRON PIGMENT IS

2043
01:25:18,650 --> 01:25:27,359
ACCUMULATE AND THE QUANTITATIVE

2044
01:25:27,359 --> 01:25:28,827
ANALYSIS SUGGESTS THAT BUT THERE

2045
01:25:28,827 --> 01:25:32,431
WAS AT LEAST ABETTA HAS CLEARED

2046
01:25:32,431 --> 01:25:34,900
AND THE IRON DEPOSITS ARE

2047
01:25:34,900 --> 01:25:42,207
APPEARING IN THOSE REGIONS

2048
01:25:42,207 --> 01:25:43,208
PARTICULARLY.

2049
01:25:43,208 --> 01:25:46,111
SO THAT'S ARIA H, ARIA E IS

2050
01:25:46,111 --> 01:25:47,012
EXTRA CELLULAR ACCUMULATION OF

2051
01:25:47,012 --> 01:25:47,212
WATER.

2052
01:25:47,212 --> 01:25:53,752
WE KNOW THE WATER OF TRANSPORT

2053
01:25:53,752 --> 01:25:59,991
IN THE CNS IS AQUA PORIN 4, IT

2054
01:25:59,991 --> 01:26:04,663
IS RAPIDLY IN THE BRAIN, AND WE

2055
01:26:04,663 --> 01:26:07,099
KNOW THE CAA IS IN THE DISEASE

2056
01:26:07,099 --> 01:26:10,535
AND IT IS IN POSITION OF AH

2057
01:26:10,535 --> 01:26:12,304
QUAPORIN 4 COULD OFFER UP A

2058
01:26:12,304 --> 01:26:16,875
POTENTIAL LINK TO THE CHEANKS

2059
01:26:16,875 --> 01:26:17,476
FOLLOWING IMMUNIZATION AND THE

2060
01:26:17,476 --> 01:26:19,077
DEVELOP AM OF ARIA E.

2061
01:26:19,077 --> 01:26:24,616
SO THIS IS A NICE STUDY DONE BY

2062
01:26:24,616 --> 01:26:27,085
[INDISCERNIBLE] AND COLLEAGUES

2063
01:26:27,085 --> 01:26:28,487
HERE TO LAMB PHARMACEUTICALS SO

2064
01:26:28,487 --> 01:26:33,425
THIS IS MICE WHO HAVE GIVEN

2065
01:26:33,425 --> 01:26:33,692
ANTIBODY.

2066
01:26:33,692 --> 01:26:36,728
AND THAT INDEED FOUND INCREASE

2067
01:26:36,728 --> 01:26:38,864
IN CAPILLARY CAA IN THESE MICE

2068
01:26:38,864 --> 01:26:42,567
AND THEY LOOK THAT THE WHICH YOU

2069
01:26:42,567 --> 01:26:46,338
CAN SEE AROUND CAPILLARIES HERE

2070
01:26:46,338 --> 01:26:49,407
AND THIS IS AQUAPORIN 4, THIS IS

2071
01:26:49,407 --> 01:26:51,610
ARK ROUND THE WALLS OF THE

2072
01:26:51,610 --> 01:26:53,445
AQUAPORIN 4 WAS FROM THE END

2073
01:26:53,445 --> 01:26:53,778
FEET.

2074
01:26:53,778 --> 01:26:56,882
THEY DID IN NICE ELECTRON

2075
01:26:56,882 --> 01:26:58,750
MICROSCOPY, SO THIS IS CROSS

2076
01:26:58,750 --> 01:26:59,784
SECTION HERE.

2077
01:26:59,784 --> 01:27:03,221
THIS IS AN ASTRO SIGHT INTO THE

2078
01:27:03,221 --> 01:27:05,991
CAPILLARY AND THE AMYLOID

2079
01:27:05,991 --> 01:27:07,859
FIBERALS DISPLACING THE ASTRO

2080
01:27:07,859 --> 01:27:12,230
SIGHT AWAY FROM THE CAPILLARY.

2081
01:27:12,230 --> 01:27:13,965
SO WE'VE TRIED AS WELL AS WE

2082
01:27:13,965 --> 01:27:19,371
COULD TO LOOK AT CAPILLARY CAA

2083
01:27:19,371 --> 01:27:21,072
AND AQUAPORIN 4 IN OUR PATIENTS

2084
01:27:21,072 --> 01:27:24,743
IN 1992, SO THIS IS ABETTA

2085
01:27:24,743 --> 01:27:28,880
AND/OR IMMEDIATE AYAISENT TO THE

2086
01:27:28,880 --> 01:27:33,051
WALLS, SO IT'S CAPILLARY ANCHLIO

2087
01:27:33,051 --> 01:27:36,321
PATHY, AND THE IMMUNIZED CASES,

2088
01:27:36,321 --> 01:27:38,557
ALL THESE HAVE BEEN ASSOCIATION

2089
01:27:38,557 --> 01:27:41,893
OF CAPILLARIES AND NO PLAQUES

2090
01:27:41,893 --> 01:27:43,161
AROUND IT.

2091
01:27:43,161 --> 01:27:46,364
QUANTICTION SHOWED SIGNIFICANT

2092
01:27:46,364 --> 01:27:47,566
LE MORE CAPILLARY ANGIE

2093
01:27:47,566 --> 01:27:50,368
OPERATING GLOBALLY RAGHTY AND IN

2094
01:27:50,368 --> 01:27:52,204
THE ALZHEIMER'S DEC AND CLOSE TO

2095
01:27:52,204 --> 01:28:02,714
SIGNIFICANT RELATIONSHIP WITH

2096
01:28:10,055 --> 01:28:16,328
HIP WITH POSSESSION OF E4.

2097
01:28:16,328 --> 01:28:18,763
--WITH WE QUANTIFY THE AQUAPORIN

2098
01:28:18,763 --> 01:28:21,833
4 WE COULDN'T REALLY DETECT THE

2099
01:28:21,833 --> 01:28:23,301
DIFFERENCE BETWEEN THEPUNIZED

2100
01:28:23,301 --> 01:28:24,936
AND UNTREATED ALZHEIMER HEMER'S

2101
01:28:24,936 --> 01:28:26,338
CASES BUT THEN OBVIOUSLY A

2102
01:28:26,338 --> 01:28:28,673
DRAWBACK HERE IS THAT MRI

2103
01:28:28,673 --> 01:28:30,308
IMAGING IN NAINITIAL TRIAL

2104
01:28:30,308 --> 01:28:31,109
WASN'T PERFORMED SYSTEMAT

2105
01:28:31,109 --> 01:28:32,544
BEINGLY SO WE DON'T REALLY HAVE

2106
01:28:32,544 --> 01:28:34,246
ANY IDEA HOW MANY OF THE PEASHTS

2107
01:28:34,246 --> 01:28:37,549
MIGHT OR MAY MOT HAVE HAD

2108
01:28:37,549 --> 01:28:38,316
ARE--ADMINISTRATIVE RAAND AT

2109
01:28:38,316 --> 01:28:44,189
WHAT STAGE IN RELATION TO THE

2110
01:28:44,189 --> 01:28:47,592
[INDISCERNIBLE] WHO HAD ARIA. 

2111
01:28:47,592 --> 01:28:50,795
SO TEEF MENTIONED THE CONDITION

2112
01:28:50,795 --> 01:28:52,597
OF SPONTANEOUS CAA RELATED

2113
01:28:52,597 --> 01:28:53,632
INFLATION AND I ARK TBREE VERY

2114
01:28:53,632 --> 01:28:56,334
MUCH THIS IS A VERY USEFUL

2115
01:28:56,334 --> 01:28:58,536
COMPARITTOR OR MODEL FOR WHAT'S

2116
01:28:58,536 --> 01:29:02,307
HAPPENING IN THE TREATED

2117
01:29:02,307 --> 01:29:05,677
ALZHEIMER PATIENTS, SO ABETTA

2118
01:29:05,677 --> 01:29:06,845
ANTIBODIES SEVERE CAA,

2119
01:29:06,845 --> 01:29:08,680
INFLAMMATION ASSOCIATE WIDE THE

2120
01:29:08,680 --> 01:29:11,650
VASCULATURE AND ARIA E LIKE

2121
01:29:11,650 --> 01:29:11,916
FEATURES.

2122
01:29:11,916 --> 01:29:17,389
SO TEEF --TEEF SAID THIS WAS AN

2123
01:29:17,389 --> 01:29:20,392
AUTOIMMUNE REACTION, SO IN TERMS

2124
01:29:20,392 --> 01:29:21,259
HERE OF STUDYING PATHOPHYSIOLOGY

2125
01:29:21,259 --> 01:29:24,162
AND AT TIMES IN PATIENTS

2126
01:29:24,162 --> 01:29:25,930
BIOPSIES ARE PERFORMED MRI SCANS

2127
01:29:25,930 --> 01:29:28,033
MORE OR LESS AT THE SAME TIME,

2128
01:29:28,033 --> 01:29:31,336
SO TISSUES AVAILABLE FOR STUDY,

2129
01:29:31,336 --> 01:29:33,738
AND I WILL SUGGEST THAT

2130
01:29:33,738 --> 01:29:35,040
CERTAINLY IN CASES THAT I SEE,

2131
01:29:35,040 --> 01:29:37,842
THAT THE SORT OF MORPHOLOGICAL

2132
01:29:37,842 --> 01:29:39,644
HISTOLOGICAL PAT E-PRESCRIBINGS

2133
01:29:39,644 --> 01:29:42,147
OF ABETTA IMMUNO CHEMISTRY IN

2134
01:29:42,147 --> 01:29:43,214
THIS CONDITION VVERY CLOSE

2135
01:29:43,214 --> 01:29:47,052
PARALLELS WITH WHAT WE SAW IN

2136
01:29:47,052 --> 01:29:49,688
THE IMMUNIZED A. D. PASHS IN

2137
01:29:49,688 --> 01:29:51,022
1972 AND I THINK EFFECT UFLY

2138
01:29:51,022 --> 01:29:54,326
THESE PATES WHO ARE IMMUNIZING

2139
01:29:54,326 --> 01:29:56,294
THEMSELVES AGAIN ABETTA AND

2140
01:29:56,294 --> 01:29:58,229
REMOVING PLAQUES SO THIS IS

2141
01:29:58,229 --> 01:30:01,533
CERTAINLY A USEFUL MODEL I WOULD

2142
01:30:01,533 --> 01:30:03,101
A

2143
01:30:03,101 --> 01:30:04,569
AGREE FOR STUDY OF ARIA.

2144
01:30:04,569 --> 01:30:07,038
SO HERE ARE CONCLUSIONS.

2145
01:30:07,038 --> 01:30:09,507
SO ARIA IS DID YOU TO DYNAMIC

2146
01:30:09,507 --> 01:30:11,242
CHANGES IN THE ABETTA.

2147
01:30:11,242 --> 01:30:13,278
THERE'S A SHIFT FROM PLAQUES TO

2148
01:30:13,278 --> 01:30:15,814
THE WALLS OF BLOOD VESSELS

2149
01:30:15,814 --> 01:30:17,248
INCREASING SEVERITY OF CAA AT

2150
01:30:17,248 --> 01:30:19,150
LEAST DURING THE PROCESS OF

2151
01:30:19,150 --> 01:30:21,086
PLAQUE REMOVAL AND THEN A

2152
01:30:21,086 --> 01:30:23,688
SUBSEQUENT PHASE OF MORE

2153
01:30:23,688 --> 01:30:25,023
CLEARANCE OF ABETTA FROM THE

2154
01:30:25,023 --> 01:30:28,660
VESSEL WALLS OR REDUCTION IN CAA

2155
01:30:28,660 --> 01:30:31,463
IN THE LONGER TERM.

2156
01:30:31,463 --> 01:30:33,064
SO THE ABETTA REMOVAL FROM THE

2157
01:30:33,064 --> 01:30:34,099
VESSEL WALLS COULD BE HAPPENING

2158
01:30:34,099 --> 01:30:35,867
AT THE SAME TIME AS THE

2159
01:30:35,867 --> 01:30:37,402
DEPOSITION OF ABETTA IN VESSEL

2160
01:30:37,402 --> 01:30:38,002
WALLS.

2161
01:30:38,002 --> 01:30:44,142
SO REALLY DYNAMIC PICTURE. 

2162
01:30:44,142 --> 01:30:45,744
ASSOCIATED INFLAMM EGG, WHICH I

2163
01:30:45,744 --> 01:30:48,213
ATBRE, WE DON'T KNOW FOR SURE

2164
01:30:48,213 --> 01:30:48,913
YET WITH THE INPRELIMINARIATORY

2165
01:30:48,913 --> 01:30:50,782
REACTION IS A NECESSARY

2166
01:30:50,782 --> 01:30:56,087
COMPONENT OF THE PATHOPHYSIOLOGY

2167
01:30:56,087 --> 01:30:59,090
OR WHETHER JUST THIS SHIFTING OF

2168
01:30:59,090 --> 01:31:00,959
ABETTA IS ENOUGH PRODUCE THE

2169
01:31:00,959 --> 01:31:02,360
ARIA LIKE CHANGES.

2170
01:31:02,360 --> 01:31:04,529
SIMPLE COMMENTS THAT ARE KIND OF

2171
01:31:04,529 --> 01:31:06,631
OBVIOUS REALLY BUT THEY'RE WORTH

2172
01:31:06,631 --> 01:31:08,032
JUSTITATING SO ARIA H IS LAKELY

2173
01:31:08,032 --> 01:31:11,136
DO YOU TO INTEGRITY OF THE WALLS

2174
01:31:11,136 --> 01:31:11,603
OF SMALL ARTERIES AND

2175
01:31:11,603 --> 01:31:13,538
ARE--ADMINISTRATIVE TERIOLE ANDS

2176
01:31:13,538 --> 01:31:15,940
THE CORTEX, ARIA E LIKELY DUE TO

2177
01:31:15,940 --> 01:31:17,409
FAILURE TO CONTROL WATER FLUX OF

2178
01:31:17,409 --> 01:31:20,278
THE BLOOD BRAIN BARRIER,

2179
01:31:20,278 --> 01:31:22,180
POTENTIAL ROLE FOR CAPILLARY

2180
01:31:22,180 --> 01:31:28,019
CAA, OR IN 4, AMONG OTHER

2181
01:31:28,019 --> 01:31:28,486
[INDISCERNIBLE].

2182
01:31:28,486 --> 01:31:31,156
RISK FACTORS WE KNOW POSSESSION

2183
01:31:31,156 --> 01:31:33,758
OF E4, POTENTIALLY IF THE SEVERE

2184
01:31:33,758 --> 01:31:36,027
CAA IS PART OF THE PATIENT'SAL

2185
01:31:36,027 --> 01:31:40,198
JEIMER PROCESS THAT MIGHT BE

2186
01:31:40,198 --> 01:31:41,499
IMPORTANT BUT QUITE DIFFICULT TO

2187
01:31:41,499 --> 01:31:43,868
GET A HANDLE ON.

2188
01:31:43,868 --> 01:31:44,702
LIMITATIONS THERE'S LITTLE

2189
01:31:44,702 --> 01:31:45,770
TISSUE AVAILABLE TO STUDY EMPLOY

2190
01:31:45,770 --> 01:31:49,274
AS I SAY, I THINK I'M RIGHT IN

2191
01:31:49,274 --> 01:31:51,409
AT AING THERE'S NO STUDIES YET

2192
01:31:51,409 --> 01:31:55,547
OF ARIA PATHOLOGY IN PATIENTS

2193
01:31:55,547 --> 01:31:57,916
WHO HAVE AN AB ANTIABOUTS AND WE

2194
01:31:57,916 --> 01:31:59,517
NEED TO TODAY IT AND FIND OUT

2195
01:31:59,517 --> 01:32:01,519
WHAT'S GOING ON AND THAT'S

2196
01:32:01,519 --> 01:32:02,821
COMPOUNDED OR GO TOGETHER WITH

2197
01:32:02,821 --> 01:32:04,856
THE DIFFICULTIES IN IMAGING THE

2198
01:32:04,856 --> 01:32:09,794
SPECIFIC CAA AND INFLAMMATION IN

2199
01:32:09,794 --> 01:32:10,862
LIVE PATIENTS.

2200
01:32:10,862 --> 01:32:13,598
AND ANALOGY WITH THE CAA RELATED

2201
01:32:13,598 --> 01:32:18,603
INFLAMMATION IS VERY IMPORTANT

2202
01:32:18,603 --> 01:32:19,604
AND THERE'S TISSUE AVAILABILITY

2203
01:32:19,604 --> 01:32:20,672
IN THIS CONDITION AND I'M SURE

2204
01:32:20,672 --> 01:32:22,407
THERE ARE SEVERAL GROUPS THAT

2205
01:32:22,407 --> 01:32:25,643
ARE TODAYING IN CONDITION QUITE

2206
01:32:25,643 --> 01:32:27,946
INTENSIVELY, NOTE THAT IN THE UK

2207
01:32:27,946 --> 01:32:30,148
WE ARE WORKING WITH OUR UK

2208
01:32:30,148 --> 01:32:32,016
NETWORK TO GATHER TOGETHER A

2209
01:32:32,016 --> 01:32:34,052
COHORT OF AS MANY CASES AS WE

2210
01:32:34,052 --> 01:32:36,688
CAN FOR THIS CONDITION FOR THIS

2211
01:32:36,688 --> 01:32:39,190
INTENSIVE STUDY AND I MATE SAY

2212
01:32:39,190 --> 01:32:41,659
THE WORD FUNDING WAS MENTIONED,

2213
01:32:41,659 --> 01:32:42,827
I MIGHT SAY WE DON'T HAVE THAT

2214
01:32:42,827 --> 01:32:43,995
STAGE FOR THESE STUDIES WHICH I

2215
01:32:43,995 --> 01:32:49,300
THINK ARE IMPORTANT THINGS TO DO

2216
01:32:49,300 --> 01:32:51,135
EMPLOY PASSIVE IMMUNOTHERAPY

2217
01:32:51,135 --> 01:32:56,207
PROTOCOLS, ROWBSLY THAT PERMIT

2218
01:32:56,207 --> 01:33:03,047
ANDS IT CONTRASTS, MODULATE THE

2219
01:33:03,047 --> 01:33:04,983
THERAPY BY IMAGING

2220
01:33:04,983 --> 01:33:08,686
[INDISCERNIBLE] ARIA AND THE

2221
01:33:08,686 --> 01:33:11,356
FINAL POINT I ARE THAT I NEED TO

2222
01:33:11,356 --> 01:33:18,296
EMPHASIS, IF EVIDENT THAT IS

2223
01:33:18,296 --> 01:33:19,831
SUPPORTED ACTIVE AB IMMUNIZATION

2224
01:33:19,831 --> 01:33:22,934
FOR PREVENTION OF AD, BEFORE THE

2225
01:33:22,934 --> 01:33:23,701
BRAIN CONTAINS SIGNIFICANT AB,

2226
01:33:23,701 --> 01:33:25,637
IT SEEMS LIKE ARIA WOULD NOT

2227
01:33:25,637 --> 01:33:26,738
OCCUR, SO THAT'S AN IMPORTANT

2228
01:33:26,738 --> 01:33:28,740
POINT TO BEAR IN MIND, I THINK

2229
01:33:28,740 --> 01:33:30,141
AND SO JUST FINALLY SOME OF THE

2230
01:33:30,141 --> 01:33:31,643
MAN COLLABORATORS WHO WORKED ON

2231
01:33:31,643 --> 01:33:33,411
THESE STUDIES OVER THE YEARS.

2232
01:33:33,411 --> 01:33:43,955
SO THANK YOU VERY MUCH FOR YOUR

2233
01:33:45,823 --> 01:33:51,062
ATTENTION. 

2234
01:33:51,062 --> 01:33:53,565
>> THANK YOU YAIMS, IT WAS
VERY

2235
01:33:53,565 --> 01:33:53,865
INTERESTING.

2236
01:33:53,865 --> 01:34:01,172
NEXT UP IS JOHN DETRE WHO WILL

2237
01:34:01,172 --> 01:34:03,975
TALK ABOUT ADVANCED METHODS IN

2238
01:34:03,975 --> 01:34:04,776
BBB IMAGING EMPLOY NTHANK YOU

2239
01:34:04,776 --> 01:34:06,077
FOR THE OPPORTUNITY TO

2240
01:34:06,077 --> 01:34:06,411
PARTICIPATE.

2241
01:34:06,411 --> 01:34:10,415
THIS IS SO FAR A REALLY

2242
01:34:10,415 --> 01:34:12,250
INFORMATIVE WORKSHOP AND I

2243
01:34:12,250 --> 01:34:14,319
DIDN'T PREPARE A DISCLOSURE

2244
01:34:14,319 --> 01:34:15,486
SLIDE, I GRATEFULLY ACKNOWLEDGE

2245
01:34:15,486 --> 01:34:18,156
SUPPORT FROM SEVERAL NETWORK IH

2246
01:34:18,156 --> 01:34:19,457
INSTITUTES INCLUDING NINDS AND

2247
01:34:19,457 --> 01:34:21,059
NIA BUT ACTUALLY NONE OF IT

2248
01:34:21,059 --> 01:34:24,195
RELATES TO ARIA OR BLOOD BRAIN

2249
01:34:24,195 --> 01:34:25,430
BARRIER IMAGING SO WHAT I'M

2250
01:34:25,430 --> 01:34:29,534
GOING TO SHOW TODAY IS VERY

2251
01:34:29,534 --> 01:34:31,069
OBJECTIVE SUMMARY OF THE TOPIC

2252
01:34:31,069 --> 01:34:37,342
AND I JUST ADDED MRI TO THE

2253
01:34:37,342 --> 01:34:39,911
TOPIC BECAUSE THERE'S ALREADY A

2254
01:34:39,911 --> 01:34:42,614
PLAN TO DO SERIAL MRI SCREENING

2255
01:34:42,614 --> 01:34:45,283
TO TO THE EXTENT THIS MIGHT BE A

2256
01:34:45,283 --> 01:34:47,452
HYBRID BETWEEN AN OVERVIEW AND A

2257
01:34:47,452 --> 01:34:48,753
CLINICAL RESEARCH IDEA

2258
01:34:48,753 --> 01:34:57,395
PRESENTATION I WANTED TO FOCUS

2259
01:34:57,395 --> 01:34:59,430
ON MRI METHODS.

2260
01:34:59,430 --> 01:34:59,697
LET'S SEE.

2261
01:34:59,697 --> 01:35:01,132
SO WE'VE HEARD THIS A COUPLE

2262
01:35:01,132 --> 01:35:03,201
TIMES ALREADY TODAY BUT TO

2263
01:35:03,201 --> 01:35:05,236
BRIEFLY SUMMARIZE THE

2264
01:35:05,236 --> 01:35:07,372
HYPOTHESIZED MECHANISMS OF ARIA,

2265
01:35:07,372 --> 01:35:10,642
YOU KNOW THERE'S THE LOSS OF

2266
01:35:10,642 --> 01:35:12,276
VESSEL WALL INTEGRITY ISSUE THE

2267
01:35:12,276 --> 01:35:13,878
BLOOD BRAIN BARRIER BREAK DOWN

2268
01:35:13,878 --> 01:35:16,314
WHICH ACTUALLY THERE ISN'T

2269
01:35:16,314 --> 01:35:20,018
REALLY A LOT OF OBJECTIVE

2270
01:35:20,018 --> 01:35:21,886
EVIDENT FOR, IT'S REALLY A

2271
01:35:21,886 --> 01:35:24,355
HYPOTHESIS, THE IDEA TAKEN--THEY

2272
01:35:24,355 --> 01:35:25,456
ANTIBODY MEDIATED INFLAMMATION

2273
01:35:25,456 --> 01:35:26,858
MAY CAUSE OR EXACERBATE THAT AS

2274
01:35:26,858 --> 01:35:31,396
WELL AS AN IDEA OF DISRUPTED

2275
01:35:31,396 --> 01:35:36,968
PERIVASCULAR FLOW AND KIND OF

2276
01:35:36,968 --> 01:35:37,235
CLEARANCE.

2277
01:35:37,235 --> 01:35:41,639
AND THE POINT ABOUT CAA RI BEING

2278
01:35:41,639 --> 01:35:52,183
A MODEL IS ALSO BEEN MENTIONED.

2279
01:35:52,550 --> 01:35:54,752
OKAY, WELL I BLEW PAST THE

2280
01:35:54,752 --> 01:35:55,920
NORMAL IMAGE HERE, I CAN GO

2281
01:35:55,920 --> 01:35:57,922
BACK, SO JUST TO BRIEFLY

2282
01:35:57,922 --> 01:35:59,624
SUMMARIZE AGAIN A LOT OF THIS

2283
01:35:59,624 --> 01:36:00,792
HAS BEEN COVERED ALREADY BUT

2284
01:36:00,792 --> 01:36:03,628
THIS IS A FIGURE FROM A REVIEW

2285
01:36:03,628 --> 01:36:07,865
ON IMAGING BLOOD BRAIN BIRRIER

2286
01:36:07,865 --> 01:36:09,200
SURFACESSIER ABNORMALITIES IN

2287
01:36:09,200 --> 01:36:14,806
ALZHEIMER'S DEC AND THE CELLULAR

2288
01:36:14,806 --> 01:36:17,041
COMPONENTS HERE ARE THE TIGHT

2289
01:36:17,041 --> 01:36:18,576
YUNKZ PROTEINS THAT SEAL EBD O

2290
01:36:18,576 --> 01:36:19,544
THELLIAL CELLS TOGETHER AND FORM

2291
01:36:19,544 --> 01:36:21,345
1 PART OF THE BLOOD BRAIN BEAR

2292
01:36:21,345 --> 01:36:26,317
IMRER AND THEN THE ASTRO SITTIC

2293
01:36:26,317 --> 01:36:28,986
INFEED WHERE THE AQUAPORIN 4

2294
01:36:28,986 --> 01:36:30,188
CHANNELS ARE LOCATED, THE

2295
01:36:30,188 --> 01:36:32,523
FUNCTION OF THE PLAID BRAIN

2296
01:36:32,523 --> 01:36:34,759
BARRIER ALLOWS PASSIVE DIFFUSION

2297
01:36:34,759 --> 01:36:36,327
OF SOME COMPOUNDS, ACTIVE

2298
01:36:36,327 --> 01:36:38,062
TRANSPORT OF OTHERS AND IN

2299
01:36:38,062 --> 01:36:38,963
PARTICULAR WATER EXCHANGE IS

2300
01:36:38,963 --> 01:36:42,467
THOUGHT TO OCCUR BY BOTH

2301
01:36:42,467 --> 01:36:42,767
MECHANISMS.

2302
01:36:42,767 --> 01:36:45,737
AND THE BLOOD BRAIN BARRIER HAS

2303
01:36:45,737 --> 01:36:47,171
BEEN PHYSIOLOGICALLY LINKED NOW

2304
01:36:47,171 --> 01:36:53,845
TO THE LYMPHATIC SYSTEM WITH THE

2305
01:36:53,845 --> 01:36:55,947
IDEA THAT PERIVASCULAR SPACES

2306
01:36:55,947 --> 01:36:57,682
ARE CONDUITS FOR CLEARANCE.

2307
01:36:57,682 --> 01:37:00,418
THE NEXT IMANNUAL SHOWS THE SAME

2308
01:37:00,418 --> 01:37:01,285
CARTOON IN ALZHEIMER'S DEC

2309
01:37:01,285 --> 01:37:02,420
SHOWING THAT MANY OF THESE COP

2310
01:37:02,420 --> 01:37:02,920
OPPOSITE BEHAVIORIAL

2311
01:37:02,920 --> 01:37:06,524
PHENOTYPENTS ARE KNOWN TO BE

2312
01:37:06,524 --> 01:37:07,725
AFFECTED AND HIGHLIGHTS SOME OF

2313
01:37:07,725 --> 01:37:11,929
THE METHODS I'M GOING TO BE

2314
01:37:11,929 --> 01:37:12,230
DISCUSSING.

2315
01:37:12,230 --> 01:37:14,265
SO BLOOD BRAIN BARRIER LEAKAGE

2316
01:37:14,265 --> 01:37:18,669
CAN BE QUANTIFIED USING CONTRAST

2317
01:37:18,669 --> 01:37:20,805
MRI AND BLOOD BRAIN BARRIER,

2318
01:37:20,805 --> 01:37:22,607
WATER EXCHANGE CAN ALSO BE ISSUE

2319
01:37:22,607 --> 01:37:26,377
MEASURED BY VARIATIONS OF THE

2320
01:37:26,377 --> 01:37:27,445
ARE--ADMINISTRATIVE TERIOLE

2321
01:37:27,445 --> 01:37:31,048
SPINDLING EXPERIMENT AND THEN

2322
01:37:31,048 --> 01:37:31,783
FINALLY MICROHEMORRHAGE IS

2323
01:37:31,783 --> 01:37:33,684
ANOTHER PORM OF BLOOD BRAIN

2324
01:37:33,684 --> 01:37:35,119
BARRIER LEAKAGE WHERE SOME BLOOD

2325
01:37:35,119 --> 01:37:44,228
HAS LEAKED OUT OF THE VESSELS.

2326
01:37:44,228 --> 01:37:45,630
WELL IS SURPRISINGLY LITTLE

2327
01:37:45,630 --> 01:37:49,500
PUBLISHED DATA ON EVEN CONTRAST

2328
01:37:49,500 --> 01:37:49,934
ENHANCED MRI IN

2329
01:37:49,934 --> 01:37:51,803
ARE--ADMINISTRATIVE RAW DATA, SO

2330
01:37:51,803 --> 01:37:56,240
REISA MENTIONED SOMETHING FROM

2331
01:37:56,240 --> 01:37:58,042
YEARS AGO, BUT YOU KNOW I BEING

2332
01:37:58,042 --> 01:38:06,818
ONLY FIND 2 REPORTS, 1 OF THEM

2333
01:38:06,818 --> 01:38:09,453
TALKED ABOUT PROMINENCE OF

2334
01:38:09,453 --> 01:38:11,556
CORTICALE VASCULAR LEAKAGE WHICH

2335
01:38:11,556 --> 01:38:13,391
ISN'T REALLY BLOOD BRAIN

2336
01:38:13,391 --> 01:38:14,559
BARRIER, LECCAGE, AND THEN 1

2337
01:38:14,559 --> 01:38:19,530
OTHER SLIGHT ENHANCE AM THAT WAS

2338
01:38:19,530 --> 01:38:21,732
NOT IMPRESSIVE HOWEVER IN ANGIO

2339
01:38:21,732 --> 01:38:24,535
AMYLOIDITEIS THERE HAVE BEEN

2340
01:38:24,535 --> 01:38:31,442
REPORTS OF BLOOD BARRIER

2341
01:38:31,442 --> 01:38:34,478
DISRUPTION, NOW SOME AMERICA RI

2342
01:38:34,478 --> 01:38:35,246
HAS CONTRASTED IMAGES SO IT

2343
01:38:35,246 --> 01:38:36,147
WOULD BE INTERESTING TO ELECTRIC

2344
01:38:36,147 --> 01:38:36,614
AT THOSE.

2345
01:38:36,614 --> 01:38:38,482
THERE IS A PAPER OUT IN MOUSE

2346
01:38:38,482 --> 01:38:40,785
MODEL THAT ACTUALLY SHOWED YOU

2347
01:38:40,785 --> 01:38:46,090
KNOW TBROSES BLOOD BRAIN BARRIER

2348
01:38:46,090 --> 01:38:47,959
DADA LIDIUM EPIHANSMENT IN

2349
01:38:47,959 --> 01:38:50,461
ASSOCIATION WITH PATHOLOGICAL

2350
01:38:50,461 --> 01:38:51,229
EVIDENCE OF MICROHEMORRHAGE AND

2351
01:38:51,229 --> 01:38:52,230
THIS OCCURRED IN THE TREATED

2352
01:38:52,230 --> 01:38:56,033
MICE SO THIS WAS A PRECLENICAL

2353
01:38:56,033 --> 01:38:56,767
STUDY.

2354
01:38:56,767 --> 01:39:01,739
SO THAT THE WAY TO QUANTIFY

2355
01:39:01,739 --> 01:39:02,974
BLOOD BRAIN BARRIER,

2356
01:39:02,974 --> 01:39:05,343
PERMEABILITY WITH CONTRAST MRI,

2357
01:39:05,343 --> 01:39:07,812
USING A DYNAMIC IMAGING PROTOCOL

2358
01:39:07,812 --> 01:39:11,849
THOO ISN'T USED TYPICALLY

2359
01:39:11,849 --> 01:39:14,518
CLINICALLY SO A CLINICAL BLOOD

2360
01:39:14,518 --> 01:39:15,720
BRAIN BARRIER DISRUPTION IS

2361
01:39:15,720 --> 01:39:17,088
LOOKING AT THE SCAN BEFORE AND

2362
01:39:17,088 --> 01:39:19,123
AFTER CONTRAST TO SEE

2363
01:39:19,123 --> 01:39:21,926
APPROXIMATE ANYTHING ENHANCED. 

2364
01:39:21,926 --> 01:39:23,227
BUT IT'S ALSO POSSIBLE ALTHOUGH

2365
01:39:23,227 --> 01:39:26,230
SOMEWHAT TIME CONSUMING TO DO

2366
01:39:26,230 --> 01:39:27,932
SERIAL IMANNUALING APPROXIMATE

2367
01:39:27,932 --> 01:39:31,402
CAN TO MODEL THIS PARAMETER

2368
01:39:31,402 --> 01:39:32,637
T-TRANSWHICH IS THE RATE OF

2369
01:39:32,637 --> 01:39:36,007
TRANSFER OF DAILY BASISSEDDA

2370
01:39:36,007 --> 01:39:37,808
LYNNIUM ACROSS THE BROOD BRAIN

2371
01:39:37,808 --> 01:39:39,543
BARRIER, THERE'S SIMPLE AND MORE

2372
01:39:39,543 --> 01:39:40,611
COMP LEICATEED MODELS, MOST

2373
01:39:40,611 --> 01:39:45,049
STUDIES USE THIS SIMPLIFIED

2374
01:39:45,049 --> 01:39:48,653
MODEL WHICH MODELS 2 PARAMETERS,

2375
01:39:48,653 --> 01:39:51,155
THE K-TRANSAND THEVILLEUME HAD

2376
01:39:51,155 --> 01:39:54,992
INTO WHICH THE GADDA LIBRARY

2377
01:39:54,992 --> 01:39:56,060
FOUNDATIONIUM HAS PERMEATED AND

2378
01:39:56,060 --> 01:39:59,363
THAT HAS BEEN STUDIED A BIT IN

2379
01:39:59,363 --> 01:40:00,998
AGING AND DIMENSIONIA AND THIS

2380
01:40:00,998 --> 01:40:06,737
IS A WELL KNOWN PAPER THAT

2381
01:40:06,737 --> 01:40:09,140
APPLIED THIS GADDA LYNNIUM BASED

2382
01:40:09,140 --> 01:40:11,475
DYNAMIC IMANNUALING TO THE BRAIN

2383
01:40:11,475 --> 01:40:12,476
IN AGING AND THEY FOUND THAT

2384
01:40:12,476 --> 01:40:14,545
THERE WAS AN INCREASED

2385
01:40:14,545 --> 01:40:16,747
PERMIABILITY IN AGING THAT WAS

2386
01:40:16,747 --> 01:40:19,016
FURTHER INCREASED IN MCI

2387
01:40:19,016 --> 01:40:28,092
PRIMARILY IN THE REAMION OF THE

2388
01:40:28,092 --> 01:40:28,659
HYPOCAMPUS.

2389
01:40:28,659 --> 01:40:30,528
WHICH IS AN AREA AFFECTED BY

2390
01:40:30,528 --> 01:40:32,430
ARIA BUT AS REISA MENTIONED IN

2391
01:40:32,430 --> 01:40:34,432
HER TALK IT'S NOT AN AREA THAT

2392
01:40:34,432 --> 01:40:38,436
HAS TYPICALLY THE MOST OF

2393
01:40:38,436 --> 01:40:39,337
AMYLOID IN IT.

2394
01:40:39,337 --> 01:40:41,605
THERE WAS 1 PAPER THAT SUGGEST

2395
01:40:41,605 --> 01:40:44,008
THAD PERMEABILITY MAY ALSO BE

2396
01:40:44,008 --> 01:40:45,843
INCREASED IN PATIENTS WITH

2397
01:40:45,843 --> 01:40:46,544
CEREBRAL SMALL VESSEL DES BUT

2398
01:40:46,544 --> 01:40:55,453
THE DAILY BASIS THEA WERE NOT

2399
01:40:55,453 --> 01:40:56,053
VERY CONVINCING.

2400
01:40:56,053 --> 01:40:57,989
SO THE OTHER APPROACH IS

2401
01:40:57,989 --> 01:40:58,823
ARE--ADMINISTRATIVE TERIOLE SPIN

2402
01:40:58,823 --> 01:41:00,324
LABELING WHICH IS AN AREA I DO

2403
01:41:00,324 --> 01:41:01,859
WORK IN AND IN

2404
01:41:01,859 --> 01:41:03,794
ARE--ADMINISTRATIVE TERIOLE SPIN

2405
01:41:03,794 --> 01:41:08,199
LABELING WE DID NOT ADMINISTER

2406
01:41:08,199 --> 01:41:13,971
EXOGENOUS TRACER BUT RATHER AN

2407
01:41:13,971 --> 01:41:14,538
ENDOGENOUS TRACER, OUR

2408
01:41:14,538 --> 01:41:15,139
ARE--ADMINISTRATIVE TERIOLE

2409
01:41:15,139 --> 01:41:17,408
BLOOD WATER IS ON ITS WAY TO THE

2410
01:41:17,408 --> 01:41:17,608
BRAIN.

2411
01:41:17,608 --> 01:41:20,077
AND AT 3 TESLA, YOU CAN EXCHANGE

2412
01:41:20,077 --> 01:41:22,713
ABOUT 1% OF THE BRAIN WATER WITH

2413
01:41:22,713 --> 01:41:23,647
ARE--ADMINISTRATIVE TERIOLE SPIN

2414
01:41:23,647 --> 01:41:24,582
LABELING THAT'S NOT EASY TO SEE

2415
01:41:24,582 --> 01:41:27,184
BUT THERE ARE WAYS TO SUPPRESS

2416
01:41:27,184 --> 01:41:28,352
THE STATIC SIGNATURES UNTIL AND

2417
01:41:28,352 --> 01:41:35,793
SO CAN YOU ACTUALLY GET  A FAIRY

2418
01:41:35,793 --> 01:41:37,828
DESCENT LOOKING THROW OUT OF

2419
01:41:37,828 --> 01:41:38,129
THIS.

2420
01:41:38,129 --> 01:41:39,864
NOW THE BASIC MODELING OF THIS

2421
01:41:39,864 --> 01:41:42,299
BLOOD FLOW MAP DID NOT CONSIDER

2422
01:41:42,299 --> 01:41:44,435
THERE'S LIMITATION TO BLOOD

2423
01:41:44,435 --> 01:41:45,269
BRAIP BARRIER PERMEABILITY AND I

2424
01:41:45,269 --> 01:41:47,705
WOULD SAY THE TEACHING THAT I

2425
01:41:47,705 --> 01:41:49,206
GOT IN SAY MEDICAL SCHOOL WAS

2426
01:41:49,206 --> 01:41:51,208
THAT THE BLOOD BRAIN BARRIER IS

2427
01:41:51,208 --> 01:41:54,045
FULLY PERMEABLE TO WATER BUT IT

2428
01:41:54,045 --> 01:41:56,580
TURNS OUT IT ISN'T FULLY

2429
01:41:56,580 --> 01:41:58,282
PERMEABLE TO WATER SO THERE ARE

2430
01:41:58,282 --> 01:42:01,018
WAYS TO MODEL THE INTERCOM

2431
01:42:01,018 --> 01:42:02,286
PARTMENTAL EXCHANGE OF THIS SPEN

2432
01:42:02,286 --> 01:42:07,725
LABEL EMPLOY SO CAN YOU THEN TRY

2433
01:42:07,725 --> 01:42:09,393
TO QUANTIFY THIS PERMEABILITY.

2434
01:42:09,393 --> 01:42:11,328
NOW HERE YOU'RE TRYING TO FIT A

2435
01:42:11,328 --> 01:42:14,732
VERY MUCH MORE COMPLEX MODEL TO

2436
01:42:14,732 --> 01:42:16,434
THIS TINY 1% SIGNAL AND SO YOUR

2437
01:42:16,434 --> 01:42:18,536
NOT GOING TO GET QUITE AS NICE

2438
01:42:18,536 --> 01:42:22,106
OF AN IMAGE, THIS IS AN EXAMPLE

2439
01:42:22,106 --> 01:42:24,341
OF WHAT A WATER PERMEABILITY MAP

2440
01:42:24,341 --> 01:42:25,543
LOOKS LIKE.

2441
01:42:25,543 --> 01:42:27,945
THERE'S A FEW DIFFERENT WAYS TO

2442
01:42:27,945 --> 01:42:30,114
DIFFERENTIATE THE INTRA RASCULAR

2443
01:42:30,114 --> 01:42:31,882
AND KRAMER VASCULAR SIGNAL IS

2444
01:42:31,882 --> 01:42:33,651
WHICH IS WHAT YOU NEED TO DO SO

2445
01:42:33,651 --> 01:42:35,553
THE VARIATION ON THIS EXPERIMENT

2446
01:42:35,553 --> 01:42:37,288
DOES AN ASL EXPERIMENT WITH OR

2447
01:42:37,288 --> 01:42:38,355
WITHOUT SUPPRESSION OF 1 OF

2448
01:42:38,355 --> 01:42:41,725
THESE COMPART UPONS AND THE 1

2449
01:42:41,725 --> 01:42:44,095
THAT'S BEEN TODAYS MOST WAS

2450
01:42:44,095 --> 01:42:45,596
INITIATED BY DANNY WANG WHO WAS

2451
01:42:45,596 --> 01:42:50,701
IN MY LAB AT THE TIME THAT USES

2452
01:42:50,701 --> 01:42:53,471
A PSEUDODIFFUSION EFFECTS OR

2453
01:42:53,471 --> 01:42:53,871
VASCULAR CRUSHING.

2454
01:42:53,871 --> 01:42:57,208
THIS 1'S AN EXAMPLE OF 1 OF

2455
01:42:57,208 --> 01:43:01,512
THOSE EMPLOY SO THAT'S BEEN MOST

2456
01:43:01,512 --> 01:43:03,180
STUDIED AND I WILL BRIEFLY

2457
01:43:03,180 --> 01:43:04,115
SUMMARIZE SOME OF THAT.

2458
01:43:04,115 --> 01:43:08,052
SO HERE'S AN EXAMPLE OF THESE

2459
01:43:08,052 --> 01:43:10,121
PROFUSION IMAGES YIERED WITH AND

2460
01:43:10,121 --> 01:43:11,956
WITHOUT VASCULAR CRUSHING SO

2461
01:43:11,956 --> 01:43:14,558
THESE ARE THE B-VALUES AND THIS

2462
01:43:14,558 --> 01:43:18,496
IS HAS BEEN APPLIED TO MULTIPLE

2463
01:43:18,496 --> 01:43:20,397
KIND OF CONVENIENT SAMPLES AND

2464
01:43:20,397 --> 01:43:24,969
IT EXPLOITS THE DIFFERENCE IN

2465
01:43:24,969 --> 01:43:25,870
DIFFUSION COENTIOUS FICIENT

2466
01:43:25,870 --> 01:43:29,673
BETWEEN BRAIN TISSUE AND

2467
01:43:29,673 --> 01:43:30,741
CAPILLARY FLOWING BLOOD, WATER

2468
01:43:30,741 --> 01:43:34,979
AND WHAT THEY FOUND IS THAT THIS

2469
01:43:34,979 --> 01:43:36,046
PERMEABILITY ACTUALLY UNLIKE

2470
01:43:36,046 --> 01:43:38,382
WHAT WAS FOUND WITH CONTRAST,

2471
01:43:38,382 --> 01:43:40,918
THAT THE WATER PERMEABILITY

2472
01:43:40,918 --> 01:43:42,386
ACTUALLY DECREASES WITH AGE AND

2473
01:43:42,386 --> 01:43:45,022
IT ALSO SEEMS TO DECREASE WITH

2474
01:43:45,022 --> 01:43:47,057
VASCULAR RISK FACTORS AND

2475
01:43:47,057 --> 01:43:49,293
FURTHER DECREASE WITH AMYLOID

2476
01:43:49,293 --> 01:43:51,128
ARK KIEWMULATION, SO IF

2477
01:43:51,128 --> 01:43:52,530
ANYTHING, YOU KNOW WATER

2478
01:43:52,530 --> 01:43:54,965
PERMEABILITY IS GOING IN THE

2479
01:43:54,965 --> 01:43:57,635
OPPOSITE DIRECTION OF WHAT

2480
01:43:57,635 --> 01:43:58,702
PEOPLE FOUND, LIMITED KNOWLEDGE

2481
01:43:58,702 --> 01:44:04,108
WE HAVE OF BLOOD BRAIN BARRIER

2482
01:44:04,108 --> 01:44:06,076
PERMEABILITY TO GD CONTRAST.

2483
01:44:06,076 --> 01:44:07,678
SO TO COMPARE THESE 2 METHODS 1

2484
01:44:07,678 --> 01:44:09,079
BIG DIFFERENCE IS THE TRACER

2485
01:44:09,079 --> 01:44:12,616
SIZE, WATER IS A TINY MOLECULE,

2486
01:44:12,616 --> 01:44:14,685
GD COMPLEXES ARE BIGGER

2487
01:44:14,685 --> 01:44:17,855
MOLECULES, AND SO 1 IDEA IS THAT

2488
01:44:17,855 --> 01:44:20,057
YOU KNOW WATER PERMEABILITY WILL

2489
01:44:20,057 --> 01:44:21,559
BE MORE SENSITIVE BECAUSE IT'S A

2490
01:44:21,559 --> 01:44:23,694
LITTLE MOLECULE AND IT WILL TAKE

2491
01:44:23,694 --> 01:44:25,429
EARLIER LEAK BUT I'M NOT SURE

2492
01:44:25,429 --> 01:44:26,864
THAT'S SUPPORTED BY THE FINDINGS

2493
01:44:26,864 --> 01:44:28,566
WHICH ARE KIND OF IN THE

2494
01:44:28,566 --> 01:44:30,868
OPPOSITE DIRECTION EMPLOY SO,

2495
01:44:30,868 --> 01:44:33,070
BUT YOU MODEL A VERY SIMILAR

2496
01:44:33,070 --> 01:44:43,347
PARAMETER THAT YOU KNOW THE TIME

2497
01:44:43,347 --> 01:44:48,652
CONSTANT OR RATE CONSTANT THE

2498
01:44:48,652 --> 01:44:49,820
CONTRAST MODELING TAKES ABOUT 15

2499
01:44:49,820 --> 01:44:52,289
MINUTES OR MORE OF DATA AND IT'S

2500
01:44:52,289 --> 01:44:54,892
HARD TO MEASURE 1 OF THESE KW

2501
01:44:54,892 --> 01:44:56,627
MAPS WITH LESS THAN ABOUT 8 TO

2502
01:44:56,627 --> 01:44:57,828
10 MINUTES OF DAILY BASIS THEA

2503
01:44:57,828 --> 01:45:00,431
AND THE MECHANISM IS PROBABLY

2504
01:45:00,431 --> 01:45:01,398
DIFFERENT THAT THEY'RE SAMPLING

2505
01:45:01,398 --> 01:45:02,700
WHICH COULD BE USEFUL WHEN

2506
01:45:02,700 --> 01:45:04,902
APPLIED TO SOME OF THE

2507
01:45:04,902 --> 01:45:07,137
HYPOTHESIS THAT PEOPLE HAVE

2508
01:45:07,137 --> 01:45:10,074
ABOUT MECH INFORMS OF ARIA.

2509
01:45:10,074 --> 01:45:11,175
ONE CONCERN I WOULD HAVE ABOUT

2510
01:45:11,175 --> 01:45:14,178
BOTH OF THESE METHODS IS THAT

2511
01:45:14,178 --> 01:45:17,815
THESE PARAMETRIC IMAGES ARE KIND

2512
01:45:17,815 --> 01:45:23,988
OF LOW QUALITY AND IN TERMS OF

2513
01:45:23,988 --> 01:45:24,555
CLINICALLY RELATED KREENING

2514
01:45:24,555 --> 01:45:31,528
MIGHT BE HARD TO PICK UP.

2515
01:45:31,528 --> 01:45:32,997
AND MIGHT BE MORE SENSITIVE AND

2516
01:45:32,997 --> 01:45:40,271
THIS IS REALLY VERY NEW, BUT,

2517
01:45:40,271 --> 01:45:43,507
DAVE'S LAB AND HARVARD, CAME UP

2518
01:45:43,507 --> 01:45:46,010
WITH AN ALTERNATIVE WATER

2519
01:45:46,010 --> 01:45:46,877
EXCHANGE MODEL THAT INSTEAD OF

2520
01:45:46,877 --> 01:45:50,714
TRYING TO WORK WITH THAT TINY 1%

2521
01:45:50,714 --> 01:45:56,387
OF BLOOD WATER THAT COMES FROM

2522
01:45:56,387 --> 01:45:57,454
ARTERIES INSTEAD LOOKS AND ALL

2523
01:45:57,454 --> 01:46:01,592
THE WATER, THE BRAIN TISSUE, AND

2524
01:46:01,592 --> 01:46:04,461
THE BLOOD WATER IN THE BRAIN AND

2525
01:46:04,461 --> 01:46:08,065
LOOKING AT EXCHAIVENL BETWEEN

2526
01:46:08,065 --> 01:46:10,734
THAT AND INTERTITTIAL FLUID OR

2527
01:46:10,734 --> 01:46:12,269
KRRK SF SPACES.

2528
01:46:12,269 --> 01:46:16,840
AND SO THAT 1, PRODUCES ABOUT A

2529
01:46:16,840 --> 01:46:17,741
HUNDRED FOLD SIGNAL INCREASE

2530
01:46:17,741 --> 01:46:20,344
BECAUSE, YOU KNOW YOU'RE NOT

2531
01:46:20,344 --> 01:46:25,282
STARTING WITH 1% OF THE SIGNAL,

2532
01:46:25,282 --> 01:46:26,950
YOU CAN GET THIS IS AN IMAGE IN

2533
01:46:26,950 --> 01:46:31,422
A SINGLE PERSON THAT IS MAYBE

2534
01:46:31,422 --> 01:46:32,990
BORDERING ON INTERPRETABLE, SO

2535
01:46:32,990 --> 01:46:34,358
THIS APPROACH AS PROMISE BUT IS

2536
01:46:34,358 --> 01:46:34,758
VERY NEW.

2537
01:46:34,758 --> 01:46:36,727
I WOULD ALSO LIKE TO HIGHLIGHT A

2538
01:46:36,727 --> 01:46:40,698
METHOD THAT WAS REPORTED BY HANZ

2539
01:46:40,698 --> 01:46:42,199
[INDISCERNIBLE]'S LAB A FEW

2540
01:46:42,199 --> 01:46:44,735
YEARS AGO THAT DOESN'T EXACTLY

2541
01:46:44,735 --> 01:46:47,404
TRY TO MEASURE THE PERMEABILITY

2542
01:46:47,404 --> 01:46:50,174
OF WATER FROM BLOOD TO BRAIN BUT

2543
01:46:50,174 --> 01:46:52,076
RATHER LOOKS AT HOW MUCH BLOOD

2544
01:46:52,076 --> 01:46:53,711
REMAINS IN THE SAGITTAL SINUS

2545
01:46:53,711 --> 01:46:54,978
AFTER IT PASSES THROUGH THE

2546
01:46:54,978 --> 01:46:59,416
BRAIN, SO IT'S KIND OF LOOKING

2547
01:46:59,416 --> 01:47:00,551
AT THE OTHER HALF OF THIS

2548
01:47:00,551 --> 01:47:01,719
CERTAINLY--CERTAINLY QUAIGZ,

2549
01:47:01,719 --> 01:47:03,187
WHAT IS NOT EXTRACTED AND SO

2550
01:47:03,187 --> 01:47:08,859
THAT, YOU KNOW THAT DOESN'T TRY

2551
01:47:08,859 --> 01:47:10,627
TO SPATIALLY LOCALIZE THE

2552
01:47:10,627 --> 01:47:10,961
EXCHANGE.

2553
01:47:10,961 --> 01:47:12,229
IT DRIVES A SINGLE MEASURE FOR

2554
01:47:12,229 --> 01:47:14,865
THE WHOLE BRAIN BUT TO THE

2555
01:47:14,865 --> 01:47:15,599
EXTENT THAT SOME OF THESE CENTER

2556
01:47:15,599 --> 01:47:16,867
FOR EXCELLENCE ON AGINGS IN

2557
01:47:16,867 --> 01:47:19,870
ARE--ADMINISTRATIVE RAMAY BE

2558
01:47:19,870 --> 01:47:21,238
RATHER DIFFUSE, THIS COULD BE AN

2559
01:47:21,238 --> 01:47:22,639
APPROACH THAT IS SENSITIVE AND

2560
01:47:22,639 --> 01:47:28,379
HIS LAB, HAS SHOWN THAT IT'S

2561
01:47:28,379 --> 01:47:29,246
REPRODUCIBLE, PLUS SCANNER

2562
01:47:29,246 --> 01:47:31,548
PLATFORM ANDS SO THE

2563
01:47:31,548 --> 01:47:32,216
ACQUISITIONS RELATIVELY HOTTER

2564
01:47:32,216 --> 01:47:35,986
SO THIS MIGHT BE A NICE METHOD

2565
01:47:35,986 --> 01:47:37,254
TO TRY TO APPLY.

2566
01:47:37,254 --> 01:47:39,690
MOVING BEYOND THIS IDEA OF

2567
01:47:39,690 --> 01:47:41,759
STRICTLY LOOKING AT THINGS

2568
01:47:41,759 --> 01:47:43,961
EXCHANGED ACROSS THE BLOOD BRAIN

2569
01:47:43,961 --> 01:47:45,963
BARRIER, ANOTHER POTENTIALLY

2570
01:47:45,963 --> 01:47:52,302
USEFUL METHOD FOR THIS IS TO USE

2571
01:47:52,302 --> 01:47:54,104
ADVANCED IMAGING STRATEGIES TO

2572
01:47:54,104 --> 01:47:56,240
TRY TO QUANTIFY PERIVASCULAR

2573
01:47:56,240 --> 01:47:56,740
SPACE VOLUMES.

2574
01:47:56,740 --> 01:47:59,309
THESE ARE READILY VISIBLE,

2575
01:47:59,309 --> 01:48:00,411
PARTICULARLY IN ULTRA HIGH

2576
01:48:00,411 --> 01:48:00,944
RESOLUTION MREFRESH YOUR

2577
01:48:00,944 --> 01:48:03,547
RECOLLECTION I, THERE ARE WAYS

2578
01:48:03,547 --> 01:48:04,915
OF ENHANCING THEIR

2579
01:48:04,915 --> 01:48:06,150
[INDISCERNIBLE] LIKE USING LONG

2580
01:48:06,150 --> 01:48:08,652
ECHO TIME ANDS THEN THERE ARE A

2581
01:48:08,652 --> 01:48:15,959
NUMBER OF SIGNAL PROCESSING

2582
01:48:15,959 --> 01:48:18,896
EITHER STANDARD FILTERING SHOWN

2583
01:48:18,896 --> 01:48:21,298
HERE LIKE A FRANG I FILTERING

2584
01:48:21,298 --> 01:48:24,134
HERE FROM A GROUP AT USC OR

2585
01:48:24,134 --> 01:48:26,737
USING DEEP LEARNING METHODS THAT

2586
01:48:26,737 --> 01:48:27,971
COULD ALLOW VOLUMES TO BE

2587
01:48:27,971 --> 01:48:29,039
QUANTIFY AND THAT IS SOMETHING

2588
01:48:29,039 --> 01:48:31,341
THAT COULD BE MONITORED THROUGH

2589
01:48:31,341 --> 01:48:38,782
THE COURSE OF ANTIAMYLOID

2590
01:48:38,782 --> 01:48:39,149
THERAPY.

2591
01:48:39,149 --> 01:48:41,518
ANOTHER METHOD THAT MIGHT BEAC

2592
01:48:41,518 --> 01:48:43,220
PLIBBABLE IS DIFFUSION BASED

2593
01:48:43,220 --> 01:48:46,056
WATER IMAGING AND THE WAY WE SEE

2594
01:48:46,056 --> 01:48:47,157
ON T2 WEIGHTED MREFRESH YOUR

2595
01:48:47,157 --> 01:48:48,292
RECOLLECTION I IS FROM FREE

2596
01:48:48,292 --> 01:48:50,294
WATER, THAT'S WHAT HAS THE

2597
01:48:50,294 --> 01:48:52,062
LONGEST T2 BUT IT'S HARD TO

2598
01:48:52,062 --> 01:48:56,033
QUANTIFY THE AMOUNT OF FREE

2599
01:48:56,033 --> 01:48:58,368
WATER AND SO POTENTIALLY 1 OF

2600
01:48:58,368 --> 01:49:00,037
THESE DTI MODELS THAT ACTUALLY

2601
01:49:00,037 --> 01:49:04,308
SPECIFICALLY MODELS FREE WATER,

2602
01:49:04,308 --> 01:49:06,143
LIKE THIS NODDI MODEL COULD

2603
01:49:06,143 --> 01:49:07,678
PROVIDE A FREE WATER MAP THAT'S

2604
01:49:07,678 --> 01:49:09,746
SUFFICIENT TO QUANTIFY AND

2605
01:49:09,746 --> 01:49:16,820
DETECT CHANGES IN WATER

2606
01:49:16,820 --> 01:49:17,287
COMPARTMENTALIZATION.

2607
01:49:17,287 --> 01:49:18,589
YOU KNOW MICROHEMORRHAGES ARE

2608
01:49:18,589 --> 01:49:19,790
EVIDENCE POTENTIALLY OF BLOOD

2609
01:49:19,790 --> 01:49:21,124
BRAIN BARRIER BREAK DOWN AND I

2610
01:49:21,124 --> 01:49:23,460
JUST WANTED TO POINT OUT THIS IS

2611
01:49:23,460 --> 01:49:25,529
VERY CUTTING EDGE BUT MOST OF

2612
01:49:25,529 --> 01:49:27,631
THE CLINICAL TRIALS LOOK AT THE

2613
01:49:27,631 --> 01:49:30,634
GRADIENT ECHO IMAGE WHICH IS NOT

2614
01:49:30,634 --> 01:49:34,538
QUITE AS SENSITIVE AS

2615
01:49:34,538 --> 01:49:38,208
SUSCEPTIBILITY WEIGHTED IMAGE, I

2616
01:49:38,208 --> 01:49:41,645
THINK CLENICALLY THE

2617
01:49:41,645 --> 01:49:48,285
RECOMMENDATION IS TO STICK WITH

2618
01:49:48,285 --> 01:49:50,153
THE IMAGE, BUT IT WILL BT BE

2619
01:49:50,153 --> 01:49:52,923
HARD TO ADD A MORE SENSITIVE

2620
01:49:52,923 --> 01:49:53,557
IMAGE OF MICROHEMORRHAGE THAT

2621
01:49:53,557 --> 01:49:55,526
YOU CAN SEE THE SAME PATIENT YOU

2622
01:49:55,526 --> 01:49:57,861
CAN SEE HOW MUCH MORE

2623
01:49:57,861 --> 01:50:00,931
CONSPECUOUS AND MOW MANY MORE

2624
01:50:00,931 --> 01:50:02,499
MICROHEMORRHAGES ARE EVIDENT

2625
01:50:02,499 --> 01:50:04,301
WITH THIS FANCIER IMANNUALING

2626
01:50:04,301 --> 01:50:08,639
TECHNIQUE THAT ENHANCES THE

2627
01:50:08,639 --> 01:50:11,208
SUSCEPTIBILITY LESIONS BY

2628
01:50:11,208 --> 01:50:13,944
COMBINING BOTH MAGNITUDE DATA.

2629
01:50:13,944 --> 01:50:15,245
SO IN CONCLUSION THERE ARE A

2630
01:50:15,245 --> 01:50:17,748
NUMBER OF MRI METHODS THAT CAN

2631
01:50:17,748 --> 01:50:21,018
PROBE THE BLOOD BRAIN BARRIER IN

2632
01:50:21,018 --> 01:50:27,291
RELATED PHYSIOLOGY, I THINK

2633
01:50:27,291 --> 01:50:31,428
REALLY THIS GD ATRANSAND

2634
01:50:31,428 --> 01:50:32,262
ASLK ARE MEASURING TYPES OF

2635
01:50:32,262 --> 01:50:33,597
PERMEABILITY IN THE BLOOD BRAIN

2636
01:50:33,597 --> 01:50:35,666
BARRIER BUT THEY COULD BE USED

2637
01:50:35,666 --> 01:50:39,002
TO TEST SPECIFIC HYPOTHESIS IN

2638
01:50:39,002 --> 01:50:39,736
ARIA.

2639
01:50:39,736 --> 01:50:43,073
NEITHER OF THESE ARE EERK DEAL

2640
01:50:43,073 --> 01:50:44,107
FOR CLINICAL MONITORING, BAKELY

2641
01:50:44,107 --> 01:50:45,709
BECAUSE THEY ARE LONG

2642
01:50:45,709 --> 01:50:48,178
ACQUISITION TIME AND POOR IMAGE

2643
01:50:48,178 --> 01:50:49,546
QUALITY AND RESOLUTION.

2644
01:50:49,546 --> 01:50:51,915
THERE'S STILL APPLICABLE TO

2645
01:50:51,915 --> 01:50:53,383
COHORT STUDIES, IT'S POSSIBLE A

2646
01:50:53,383 --> 01:50:56,920
WHOLE BRAIN MEASURE LIKE THIS

2647
01:50:56,920 --> 01:50:58,622
WEBCAST TECHNIQUE TAKEN--THEY

2648
01:50:58,622 --> 01:50:59,556
JUST LOOKS THE WATER EXTRACTION

2649
01:50:59,556 --> 01:51:03,193
OVERALL COULD BE ARK PLIBBABLE.

2650
01:51:03,193 --> 01:51:05,162
THIS WHOLE FIELD OF IMANNUALING

2651
01:51:05,162 --> 01:51:06,196
FLUID EXCHANGE IN THE BRAIN IS

2652
01:51:06,196 --> 01:51:08,231
VERY NEW AND THERE'S A VERY

2653
01:51:08,231 --> 01:51:10,000
DYNAMIC AND I THINK THERE'S

2654
01:51:10,000 --> 01:51:13,003
GOING TO BE NEWER BETTER AND

2655
01:51:13,003 --> 01:51:16,306
MORE SENSITIVE METHODS COMING

2656
01:51:16,306 --> 01:51:17,941
DOWN THE PIKE AND THIS WILL BE

2657
01:51:17,941 --> 01:51:19,543
AN EXCITING, YOU KNOW TO THE

2658
01:51:19,543 --> 01:51:21,578
EXTENT THAT THEY'RE A HAMMER,

2659
01:51:21,578 --> 01:51:27,484
ARIA IS A NAIL AND I THINK

2660
01:51:27,484 --> 01:51:29,386
THERE'S A LOT OF FOR DOING

2661
01:51:29,386 --> 01:51:30,854
USEFUL AND INFORMATIVE RESEARCH

2662
01:51:30,854 --> 01:51:38,362
ON THIS AREA.

2663
01:51:38,362 --> 01:51:39,830
THANK YOU.

2664
01:51:39,830 --> 01:51:40,998
NTHANK YOU, THANK YOU VERY MUCH

2665
01:51:40,998 --> 01:51:42,666
JOHN, HOLD UP QUESTIONS FOR YAWN

2666
01:51:42,666 --> 01:51:44,101
AND INVITUP THE NEXT SPEAKER AND

2667
01:51:44,101 --> 01:51:45,202
WE MODIFIED THE PROGRAM A BIT

2668
01:51:45,202 --> 01:51:47,004
AND THERE WILL BE 15 MINUTES

2669
01:51:47,004 --> 01:51:48,672
FORA I DISCUSSION WITH THE

2670
01:51:48,672 --> 01:51:49,906
SPEAKERS AFTER THIS SESSION, SO

2671
01:51:49,906 --> 01:51:55,345
THE NEXT SPEAKER IS KAREN

2672
01:51:55,345 --> 01:51:57,014
SMIRNAKE S FROM BIOGEN WHO SHE

2673
01:51:57,014 --> 01:51:58,882
HAS A LOT OF ARIA AND OVERSIGHT

2674
01:51:58,882 --> 01:52:00,617
AND SHE WILL TALK ABOUT

2675
01:52:00,617 --> 01:52:02,419
IDENTIFYING AND MANAGING PEOPLE

2676
01:52:02,419 --> 01:52:06,857
AT RISK FOR ADVERSE EEIVETS DUE

2677
01:52:06,857 --> 01:52:11,061
TO ARIA.

2678
01:52:11,061 --> 01:52:11,628
>> THANK YOU.

2679
01:52:11,628 --> 01:52:13,730
IT'S A PLEASURE TO BE HERE IT

2680
01:52:13,730 --> 01:52:15,699
SEE SOME IN PERSON AND

2681
01:52:15,699 --> 01:52:17,401
COLLEAGUES FROM SEVERAL DECADES

2682
01:52:17,401 --> 01:52:27,210
AGO SO IT'S A PRIVILEGE TO BE

2683
01:52:27,210 --> 01:52:29,246
PART OF THIS BOTH TO THE

2684
01:52:29,246 --> 01:52:31,281
SCIENTIFIC ASPECTS OF IT, THE

2685
01:52:31,281 --> 01:52:34,184
ETIOLOGY AS WELL AS THE

2686
01:52:34,184 --> 01:52:35,419
MANAGEMENT.

2687
01:52:35,419 --> 01:52:37,187
AND AS SOMEONE WHO'S SPENT A

2688
01:52:37,187 --> 01:52:39,456
NUMBER OF YEARS IN PRACTICE AND

2689
01:52:39,456 --> 01:52:42,192
THEN WORKING IN THE DRUG SAFETY

2690
01:52:42,192 --> 01:52:47,197
PART OF INDUSTRY, THIS IS A

2691
01:52:47,197 --> 01:52:48,298
TRULY FASCINATING TIME BECAUSE

2692
01:52:48,298 --> 01:52:50,300
TYPICALLY WHEN YOU HAVE A NEW

2693
01:52:50,300 --> 01:52:52,002
ADVERSE DRUG REACTION, THE

2694
01:52:52,002 --> 01:52:53,737
COMMUNITY UNDERSTANDS WHAT THE

2695
01:52:53,737 --> 01:52:54,838
REACTION IS, WHAT'S NOVEL IS

2696
01:52:54,838 --> 01:52:56,006
THAT THAT DRUG CAUSES THE

2697
01:52:56,006 --> 01:52:58,008
REACTION EMPLOY AND IN THIS

2698
01:52:58,008 --> 01:52:59,910
CASE, THE REACTION ITSELF IS

2699
01:52:59,910 --> 01:53:01,478
NOVEL AND WE'RE STILL TRYING TO

2700
01:53:01,478 --> 01:53:03,613
UNDERSTAND IT, AND WE THOUGHT

2701
01:53:03,613 --> 01:53:06,817
COMES ANOTHER OBLIGATIONS

2702
01:53:06,817 --> 01:53:07,884
LIAISON GIGZ THAT WE WILL TOUCH

2703
01:53:07,884 --> 01:53:09,352
ON BROAFLY AND THAT IS HOW DO

2704
01:53:09,352 --> 01:53:10,854
WOE DRIEB THIS ON PATIENTS, HOW

2705
01:53:10,854 --> 01:53:16,293
DO WE INSURE THAT THE KIAG

2706
01:53:16,293 --> 01:53:18,261
KI--DIAGNOSTIC ABILITY IS THERE

2707
01:53:18,261 --> 01:53:19,563
THROUGHOUT THROUGHOUT THE HELT

2708
01:53:19,563 --> 01:53:21,598
CARE SYSTEM, IT'S A CHALLENGING

2709
01:53:21,598 --> 01:53:22,799
PROBLEM BUT ALSO A VERY EXCITING

2710
01:53:22,799 --> 01:53:23,967
OPPORTUNITY TO THINK ABOUT THE

2711
01:53:23,967 --> 01:53:26,503
SCIENCE AND THE CLINICAL

2712
01:53:26,503 --> 01:53:27,337
PRACTICE.

2713
01:53:27,337 --> 01:53:29,306
I WANT TO NOTE MY DISCLOSURES

2714
01:53:29,306 --> 01:53:33,610
AND I AM AN EMPLOYEE AND SHARE

2715
01:53:33,610 --> 01:53:35,145
HOLDER OF BIOGEN, AND I WILL BE

2716
01:53:35,145 --> 01:53:38,281
SHARING MY OWN VIEWS AND NOT

2717
01:53:38,281 --> 01:53:38,648
THOSE OF BIOGEN.

2718
01:53:38,648 --> 01:53:39,950
SO WHEN I WAS ASKED TO TALK

2719
01:53:39,950 --> 01:53:42,018
ABOUT THIS I THOUGHT ABOUT THE

2720
01:53:42,018 --> 01:53:42,219
TITLE.

2721
01:53:42,219 --> 01:53:44,488
WHAT HAVE WE LEARNED ABOUT

2722
01:53:44,488 --> 01:53:46,790
PATIENTS AT RISK FOR ADVERSE

2723
01:53:46,790 --> 01:53:48,925
EVENTS RELATED TO ARIA, WHAT DID

2724
01:53:48,925 --> 01:53:50,527
WE MEAN BY ADVERSE EVENTS

2725
01:53:50,527 --> 01:53:51,261
RELATED TO ORIA, AND I THINK

2726
01:53:51,261 --> 01:53:52,929
WHEN WE THINK ABOUT THAT WHAT

2727
01:53:52,929 --> 01:53:54,297
WE'RE MOST INTERESTED IN

2728
01:53:54,297 --> 01:54:02,606
PREVENTING ARE THE MORE SERIES

2729
01:54:02,606 --> 01:54:04,107
SYMPTOMS OF ARIA.

2730
01:54:04,107 --> 01:54:06,243
ARIA IS AN ADVERSE EVENT OF

2731
01:54:06,243 --> 01:54:08,178
SPECIAL INTEREST SO WHETHER IT

2732
01:54:08,178 --> 01:54:10,347
IS SYMPTOMATIC OR ASYMPTOMATIC

2733
01:54:10,347 --> 01:54:12,048
IT'S CAPTURED AS AN ADVERSE

2734
01:54:12,048 --> 01:54:12,649
EVENT.

2735
01:54:12,649 --> 01:54:14,584
AND IT'S CAPTURED IN CLINICAL

2736
01:54:14,584 --> 01:54:16,820
TRIAL POPULATION THAT HAVE

2737
01:54:16,820 --> 01:54:18,288
INCLUSION AND EXCLUSION CRITERIA

2738
01:54:18,288 --> 01:54:19,222
THAT HAVE BEEN INFOR THE

2739
01:54:19,222 --> 01:54:21,091
PURPOSED BY PRIOR WORK IN THIS

2740
01:54:21,091 --> 01:54:23,627
SPACE TO EXCLUDE PATIENTS WHO

2741
01:54:23,627 --> 01:54:25,662
HAVE SIGNIFICANT RISK FACTORS

2742
01:54:25,662 --> 01:54:29,966
FOR ARIA OR WHOM THEY HAVE

2743
01:54:29,966 --> 01:54:30,834
EVIDENCE OF CEREBRAL AMYLOID

2744
01:54:30,834 --> 01:54:31,835
ANGOPEN MEETINGATHY.

2745
01:54:31,835 --> 01:54:33,870
THE DATA ON THIS SLIDE IS FROM

2746
01:54:33,870 --> 01:54:36,740
THE PHASE 3 ENGEAJ AND EMERGE

2747
01:54:36,740 --> 01:54:39,042
TRIALS AND THE OVERALL WHETHER

2748
01:54:39,042 --> 01:54:42,012
IT'S ARIA E OR ARIA H ABOUT 41%

2749
01:54:42,012 --> 01:54:44,514
OF TRIAL PARTICIPANTS HAD ARIA

2750
01:54:44,514 --> 01:54:47,450
EMPLOY AND ONLY 10% OF

2751
01:54:47,450 --> 01:54:49,152
PARTICIPANTS HAD SYMPTOMS OF

2752
01:54:49,152 --> 01:54:51,221
ARIA AND THOSE WERE MOST

2753
01:54:51,221 --> 01:54:52,155
COMMONLY TECHNOLOGY TRANSFERS

2754
01:54:52,155 --> 01:54:53,290
LIKE HEADACHE, DIZZINESS ISSUES

2755
01:54:53,290 --> 01:54:54,724
NAUSEA AND GAIT DISTURBANCE BUT

2756
01:54:54,724 --> 01:54:57,360
THERE WAS A MAUL NUMBER OF

2757
01:54:57,360 --> 01:54:58,595
PATIENTS WHO HAD SERIOUS

2758
01:54:58,595 --> 01:55:01,031
SYMPTOMS OF ARIA, SO 0.3% IN

2759
01:55:01,031 --> 01:55:04,734
THESE TRIALS, AND THOSE INCLUDED

2760
01:55:04,734 --> 01:55:06,636
SEIZURES AND STATUS EPILEPTICS.

2761
01:55:06,636 --> 01:55:08,338
AND WHEN YOU ELECTRIC AT THESE

2762
01:55:08,338 --> 01:55:10,807
NUMBERS, YOU CAN SEE WHAT THE

2763
01:55:10,807 --> 01:55:11,908
CHALLENGE IS FOR CLINICAL

2764
01:55:11,908 --> 01:55:12,275
TRIALS.

2765
01:55:12,275 --> 01:55:13,977
WHAT WE ARE MOST INTERESTED IN

2766
01:55:13,977 --> 01:55:17,013
PREVENTING IS NOT VERY COMMON

2767
01:55:17,013 --> 01:55:17,981
EMPLOY APPROXIMATE SO WE THEN

2768
01:55:17,981 --> 01:55:19,149
HAVE TO SAY ARE THERE OTHER

2769
01:55:19,149 --> 01:55:20,617
THINGS WE CAN LEARN IN THE

2770
01:55:20,617 --> 01:55:23,587
TRIALS THAT HELP US TO CORRELATE

2771
01:55:23,587 --> 01:55:27,224
WHAT THE MRI FINDINGS MAY BE,

2772
01:55:27,224 --> 01:55:28,491
WHAT THE LESS SIGNIFICANT

2773
01:55:28,491 --> 01:55:30,493
SYMPTOMS MAY BE AND WHAT THE

2774
01:55:30,493 --> 01:55:32,295
SERIOUS SYMPTOMS MAY BE SO WE

2775
01:55:32,295 --> 01:55:34,564
CAN IESHES DENTIFY MEANS TO

2776
01:55:34,564 --> 01:55:44,941
MINIMIZE THESE SERIOUS

2777
01:55:49,946 --> 01:55:50,213
CONSEQUENCES.

2778
01:55:50,213 --> 01:56:00,323
THIS HAS BEEN  CLASSIFIED VERY

2779
01:56:00,323 --> 01:56:01,558
WELL, BUT REALLY THOUGHT TO BE

2780
01:56:01,558 --> 01:56:03,393
DUE TO THE EPITOPE THAT IS

2781
01:56:03,393 --> 01:56:05,061
TARGETED, THE FORM OF THE

2782
01:56:05,061 --> 01:56:15,505
AMYLOID THAT IS TARGETED.

2783
01:56:20,477 --> 01:56:26,783
THIS IS DATA ALSO FROM THE

2784
01:56:26,783 --> 01:56:28,151
ADUCANUMAB ENGAGE AND EMERGE AND

2785
01:56:28,151 --> 01:56:33,323
IN THE FIRST COLUMN HERE ARE THE

2786
01:56:33,323 --> 01:56:34,791
APOE4 HOMOZYGOTES, SO THOSE

2787
01:56:34,791 --> 01:56:37,460
REPRESENT 15% OF THE CLINICAL

2788
01:56:37,460 --> 01:56:38,261
TRIAL PARTICIPANTS.

2789
01:56:38,261 --> 01:56:41,698
THE MITSD COLUMN ARE THE

2790
01:56:41,698 --> 01:56:44,935
HETEROZYGOTES AND THE THIRD IS A

2791
01:56:44,935 --> 01:56:45,502
NONCARRIER.

2792
01:56:45,502 --> 01:56:47,203
SO ABOUT A THIRD WERE NONCARRIER

2793
01:56:47,203 --> 01:56:49,673
ANDS IF WE LOOK AT THE FIRST

2794
01:56:49,673 --> 01:56:51,608
ROW, THERE'S A MARKET

2795
01:56:51,608 --> 01:56:55,011
ASSOCIATION FOR ARIA E SO 66% IN

2796
01:56:55,011 --> 01:56:56,947
THE HOMOZYGOUS PATIENTS, ABOUT

2797
01:56:56,947 --> 01:56:59,416
36% IN THE HETEROZYGOUS AND 20%

2798
01:56:59,416 --> 01:57:02,085
IN THE NONCARRIERS.

2799
01:57:02,085 --> 01:57:04,988
AND WE SEE A SIMILAR

2800
01:57:04,988 --> 01:57:07,023
RELATIONSHIP BETWEEN APOE AND

2801
01:57:07,023 --> 01:57:12,896
ARIA H, SO 60% FOR BOTH

2802
01:57:12,896 --> 01:57:14,531
MICROHEMORRHAGE AND HOMOZYGOTES,

2803
01:57:14,531 --> 01:57:16,933
AND 26% IN HETEROZYGOTES AND IN

2804
01:57:16,933 --> 01:57:20,503
ABOUT 18% AND NONCARRIERS AND

2805
01:57:20,503 --> 01:57:22,672
CORRESPONDING TO THIS, ARE

2806
01:57:22,672 --> 01:57:25,041
HIGHER RATES OF DISTINNATION DUE

2807
01:57:25,041 --> 01:57:27,277
TO ARIA WHICH ARE LARGELY

2808
01:57:27,277 --> 01:57:27,677
PROTOCOL MANDATED.

2809
01:57:27,677 --> 01:57:29,179
IN THIS RESK FACTOR IS

2810
01:57:29,179 --> 01:57:30,313
CONSISTENT ACROSS THE STUDIES,

2811
01:57:30,313 --> 01:57:35,018
THE TOP PART OF THAL IS FROM A

2812
01:57:35,018 --> 01:57:42,425
RECENT REVIEW BY COLLEAGUES THAT

2813
01:57:42,425 --> 01:57:46,496
2 TODAYS OF KD--SALLY XA

2814
01:57:46,496 --> 01:57:50,900
HOMOZYGOUS APOE 4 GENO TYPE IS

2815
01:57:50,900 --> 01:57:52,969
ABOUT 7.2 FOLD COMPARED TO 6.2

2816
01:57:52,969 --> 01:57:54,504
FOLD FOR THE HETEROGENEOUS ORY

2817
01:57:54,504 --> 01:57:56,439
SWROIGOUS, AND EVEN A MORE

2818
01:57:56,439 --> 01:57:57,474
SIGNIFICANT RELATIONSHIP FOR

2819
01:57:57,474 --> 01:57:59,442
ARIA H.

2820
01:57:59,442 --> 01:58:01,544
SO APOE 4 STATUS IS SOMETHING

2821
01:58:01,544 --> 01:58:04,214
THAT'S CONSISTENT ACROSS THE

2822
01:58:04,214 --> 01:58:04,614
CLASS.

2823
01:58:04,614 --> 01:58:05,915
THE OTHER THING THAT CONSIST

2824
01:58:05,915 --> 01:58:07,183
EXTENT THIS HAS BEEN DISCUSSED

2825
01:58:07,183 --> 01:58:08,618
EARLIER IS THE TIMING OF ARIA,

2826
01:58:08,618 --> 01:58:12,522
SO THIS IS A FIGURE OF THE

2827
01:58:12,522 --> 01:58:15,258
PROBABILITY OF FIRST ARIA E WITH

2828
01:58:15,258 --> 01:58:17,060
TIME ON STUDY FOR ADJUSTICE

2829
01:58:17,060 --> 01:58:18,194
ACCESS KAN--KANAA MAB AND IN

2830
01:58:18,194 --> 01:58:22,999
THAT TOP LINE IS THE APOE4

2831
01:58:22,999 --> 01:58:23,666
HOMOZYGOUS PATIENT.

2832
01:58:23,666 --> 01:58:25,435
THE BOTTOM IN PLURIBU ARE

2833
01:58:25,435 --> 01:58:26,770
NONCARRIER ANDS THEN THE DARK

2834
01:58:26,770 --> 01:58:28,705
GREEN ARE THE HETEROZYGOUS

2835
01:58:28,705 --> 01:58:31,041
CARRIERS AND THIS' ALSO A ROLE

2836
01:58:31,041 --> 01:58:33,009
FOR TOTAL CARRIERS AND TOTAL

2837
01:58:33,009 --> 01:58:33,610
ARIA, TOTAL POPULATION.

2838
01:58:33,610 --> 01:58:35,912
SO WHAT YOU CAN SEE ARE A COUPLE

2839
01:58:35,912 --> 01:58:38,314
OF HINGS SO FIRST OF ALL

2840
01:58:38,314 --> 01:58:41,618
OVERTIME THAT INCIDENCE GOES

2841
01:58:41,618 --> 01:58:42,085
DOWN.

2842
01:58:42,085 --> 01:58:43,686
SECONDLY MOST OF THE INCREASE

2843
01:58:43,686 --> 01:58:45,088
OCCURS AT THE TIME WHEN THERE'S

2844
01:58:45,088 --> 01:58:45,922
AN MREFRESH YOUR RECOLLECTION I,

2845
01:58:45,922 --> 01:58:49,359
SO YOU SEE THERE'S BIG STEPS UP

2846
01:58:49,359 --> 01:58:52,028
AT THE TIME OF THE MRI, SO THAT

2847
01:58:52,028 --> 01:58:53,430
WILL ITS US VERY LITTLE IS

2848
01:58:53,430 --> 01:58:54,531
DETEBBED BY THE IN, REFRESH YOUR

2849
01:58:54,531 --> 01:58:55,598
RECOLLECTION I EVEN IN THE

2850
01:58:55,598 --> 01:58:56,599
SETTING OF CLINICAL TRIAL.

2851
01:58:56,599 --> 01:58:58,802
AND IN WE LOOK AT WHAT WE'VE

2852
01:58:58,802 --> 01:59:01,204
SEEN SO FAR, THE RELATIONSHIP

2853
01:59:01,204 --> 01:59:02,939
WITH APOE 4 AT THAT TIMEUS, THE

2854
01:59:02,939 --> 01:59:04,974
RELATIONSHIP WITH TIME ON STUDY,

2855
01:59:04,974 --> 01:59:06,309
AND THE RELATIONSHIP TO DOSE

2856
01:59:06,309 --> 01:59:08,378
WHICH HAS BEEN PREVIOUSLY

2857
01:59:08,378 --> 01:59:11,915
DISCUSSED, THERE'S A VERY GOOD

2858
01:59:11,915 --> 01:59:14,884
HYPOTHESIS THAT ARIA IS RELATED

2859
01:59:14,884 --> 01:59:17,253
TO THE AMYLOID BURDEN, WHETHER

2860
01:59:17,253 --> 01:59:19,422
THAT IS OVERALL OR IN SPECIFIC

2861
01:59:19,422 --> 01:59:21,891
AREAS, AND OR TO THE RATE OF

2862
01:59:21,891 --> 01:59:24,627
REMOVAL OF THAT AMYLOID.

2863
01:59:24,627 --> 01:59:27,063
THIS IS A QUESTION THAT HAS BEEN

2864
01:59:27,063 --> 01:59:28,565
DIFFICULT TO SHOW IN CLINICAL

2865
01:59:28,565 --> 01:59:32,936
TRIALS, WHETHER THERE IS SUCH A

2866
01:59:32,936 --> 01:59:35,405
RELATIONSHIP IN THE PET SUBSTUDY

2867
01:59:35,405 --> 01:59:37,040
OF ENGAGE AND EMERGE THERE,  IS

2868
01:59:37,040 --> 01:59:40,443
NOT AN ASSOCIATION FOUND BETWEEN

2869
01:59:40,443 --> 01:59:42,946
THE PET SUV OR IN PEASHS WITH OR

2870
01:59:42,946 --> 01:59:47,150
WITHOUT ARIA, LOOKINGA THE BASE

2871
01:59:47,150 --> 01:59:47,951
LINE PET CORE.

2872
01:59:47,951 --> 01:59:48,985
SIMILARLY THERE IS NOT A

2873
01:59:48,985 --> 01:59:49,953
RELATIONSHIP FOUND AND NOT SHOWN

2874
01:59:49,953 --> 01:59:51,988
ON THE SLIDE BETWEEN THE

2875
01:59:51,988 --> 01:59:55,358
REDUCTION IN PET SUVR AND THE

2876
01:59:55,358 --> 02:00:03,299
APOE4 4 GENO TYPE AND THERE IS

2877
02:00:03,299 --> 02:00:08,037
ANALYSIS, I THINK YOU MENTIONED

2878
02:00:08,037 --> 02:00:09,639
DR. PERLING WHERE YOU LOOK AT

2879
02:00:09,639 --> 02:00:10,740
ENTERVALENTINEDS OF REDUCTION IN

2880
02:00:10,740 --> 02:00:12,208
HOTTER INTERVALS AND THE

2881
02:00:12,208 --> 02:00:13,977
INCIDENCE OF ARIA EMPLOY SO 1

2882
02:00:13,977 --> 02:00:15,979
LIMITATION IS THAT THE TIMES OF

2883
02:00:15,979 --> 02:00:18,581
THE PET SUVR DURING THE STUDY IS

2884
02:00:18,581 --> 02:00:19,916
TYPICALLY AT ABOUT 6 MONTHS AND

2885
02:00:19,916 --> 02:00:21,918
A YEAR AND 18 MONTHS.

2886
02:00:21,918 --> 02:00:23,186
WHEREAS THE ARIAS EARLY SO WE

2887
02:00:23,186 --> 02:00:24,854
DON'T HAVE GREAT TEMPORAL

2888
02:00:24,854 --> 02:00:25,788
CORRELATION THERE AND THOSE

2889
02:00:25,788 --> 02:00:26,089
MEASURES.

2890
02:00:26,089 --> 02:00:26,856
AND THE OTHER TECHNOLOGY

2891
02:00:26,856 --> 02:00:28,992
TRANSFER IS THAT THIS IS A

2892
02:00:28,992 --> 02:00:29,926
FLOABAL SCORE AND WE'VE SEEN IN

2893
02:00:29,926 --> 02:00:31,861
SOME OF THE DATA THAT'S BEEN

2894
02:00:31,861 --> 02:00:34,831
PRESENTED THAT THERE MAY BE

2895
02:00:34,831 --> 02:00:37,901
REALLY GOOD CORRELATIONS BETWEEN

2896
02:00:37,901 --> 02:00:41,404
LOCAL AMYLOID LOAD AND THE

2897
02:00:41,404 --> 02:00:43,640
INCIDENCE AND RISK OF ARIA.

2898
02:00:43,640 --> 02:00:45,208
SO MOVING NOW TO ONCE PATIENTS

2899
02:00:45,208 --> 02:00:46,776
HAVE ARIA, IN THE CLINICAL

2900
02:00:46,776 --> 02:00:48,311
TRIALS, WHAT ARE THE

2901
02:00:48,311 --> 02:00:49,412
CHEARKTISTICS OF THAT ARIA AND

2902
02:00:49,412 --> 02:00:50,713
CAN WE LIMITED PARTNERSHIP

2903
02:00:50,713 --> 02:00:54,817
ANYTHING ABOUT RISK FACTORS FOR

2904
02:00:54,817 --> 02:00:55,451
CLINICALLY SIGNIFICANT ARIA.

2905
02:00:55,451 --> 02:00:56,486
AND THE FIRST POABT I WANT TO

2906
02:00:56,486 --> 02:01:05,228
MAKE IS THAT DURING TRIALS, THE

2907
02:01:05,228 --> 02:01:08,198
CHARACTERIZATION OF ARIA IS VERY

2908
02:01:08,198 --> 02:01:09,499
DETAILED IT'S 1 OF THE THINGS

2909
02:01:09,499 --> 02:01:10,300
THAT MAKING COMMUNICATION ABOUT

2910
02:01:10,300 --> 02:01:12,869
1 OF THE TECHNOLOGY TRANSFERS

2911
02:01:12,869 --> 02:01:13,836
ABOUT THE DIFFICULT SOMETIMES

2912
02:01:13,836 --> 02:01:15,538
EMPLOY SO EVERY EVENT IS

2913
02:01:15,538 --> 02:01:17,574
CHARACTERIZED BY THE RADIO

2914
02:01:17,574 --> 02:01:18,942
GRAPHIC SEVERITY AND SO FOR ARIA

2915
02:01:18,942 --> 02:01:20,977
E THAT'S SIZE AND NUMBER OF

2916
02:01:20,977 --> 02:01:23,179
AREAS OF EDEMA AND FOR ARIA H

2917
02:01:23,179 --> 02:01:29,052
IT'S THE NUMBER OF AREAS OF

2918
02:01:29,052 --> 02:01:30,520
MICROHEMORRHAGE OR SUPERFICIAL

2919
02:01:30,520 --> 02:01:32,689
SITTEROSEIS AND THOSE ARE ON A

2920
02:01:32,689 --> 02:01:34,123
SPECIFIC GRE AND THAT DEFINITION

2921
02:01:34,123 --> 02:01:35,625
WAS MADE USING THE PROTOCOLS WE

2922
02:01:35,625 --> 02:01:41,297
USE IN THOSE TRIALS EMPLOY

2923
02:01:41,297 --> 02:01:45,702
SYMPTOMS ARE ALSO RATED ON

2924
02:01:45,702 --> 02:01:45,969
SEVERITY.

2925
02:01:45,969 --> 02:01:47,203
THERE ARE A SERIES OF TRIALS

2926
02:01:47,203 --> 02:01:48,204
THAT ARE ON THE DEVELOPMENTAL

2927
02:01:48,204 --> 02:01:49,305
ENDOCRINOLOGY NEGZ OF THE

2928
02:01:49,305 --> 02:01:51,140
SERIOUS ADVERSE EVENTS MIGHT BE

2929
02:01:51,140 --> 02:01:53,409
THE ADVERSE EVENT OF ARIA OR IT

2930
02:01:53,409 --> 02:01:55,612
MIGHT BE THE CLINICAL EVENT.

2931
02:01:55,612 --> 02:01:57,247
AND SO, WHEN YOU HEAR A

2932
02:01:57,247 --> 02:01:59,849
PARTICULAR CASE OF ARIA, YOU MAY

2933
02:01:59,849 --> 02:02:04,721
ARE A PATIENT WITH MODERATE ARIA

2934
02:02:04,721 --> 02:02:06,656
E, MILD RAIA H AND HAD A SERIES

2935
02:02:06,656 --> 02:02:17,133
EVENT AND TERMINOLOGY CAN BE

2936
02:02:26,576 --> 02:02:27,644
KIND OF COMPLEX.

2937
02:02:27,644 --> 02:02:29,679
--SO THIS TABLE IS ALSO SET UP

2938
02:02:29,679 --> 02:02:32,348
THE SAME WAY WITH HOMOZYGOTES ON

2939
02:02:32,348 --> 02:02:33,783
THE LEFT AND NONCARRIERS AND THE

2940
02:02:33,783 --> 02:02:34,917
NUMBERS ON THE TOP OF THE

2941
02:02:34,917 --> 02:02:36,686
NUMBERS WOE HAVE SEEN BEFORE.

2942
02:02:36,686 --> 02:02:40,957
SO WHEN WE LOOK AT THE NUMBER OF

2943
02:02:40,957 --> 02:02:43,192
THE MRI SEVERITY IN PATIENTS WHO

2944
02:02:43,192 --> 02:02:46,296
ARE APOE 4 HOMOZYGOUS, WE SEE

2945
02:02:46,296 --> 02:02:49,032
23% ARE MILD, 62% ARE MODERATE

2946
02:02:49,032 --> 02:02:51,100
AND ABOUT 15% ARE SEVERE.

2947
02:02:51,100 --> 02:02:53,102
AND WITH WITHOUT READING EVERY

2948
02:02:53,102 --> 02:02:55,571
COLUMN, YOU CAN SEE REGARDLESS

2949
02:02:55,571 --> 02:02:56,539
OF THE APOE 4 AT THAT TIMEUS,

2950
02:02:56,539 --> 02:02:59,242
MOST OF THE ARIA IS MILD OR

2951
02:02:59,242 --> 02:03:00,677
MODERATE AND THE PERCENT AMILLIO

2952
02:03:00,677 --> 02:03:02,912
THAT IS SEVERE RAINCHLING

2953
02:03:02,912 --> 02:03:05,715
BETWEEN 11 AND 15%.

2954
02:03:05,715 --> 02:03:08,117
HOWEVER, THAT'S A PERCENTAGE OF

2955
02:03:08,117 --> 02:03:11,788
THE ARIA, SO IT IS ALSO TRUE

2956
02:03:11,788 --> 02:03:14,190
THAT THOSE 16 SEVERE CASES ON

2957
02:03:14,190 --> 02:03:18,294
MRI, ARE 16 OUT OF 159

2958
02:03:18,294 --> 02:03:19,262
HOMOZYGOTES, SO FOR HOMOZYGOUS

2959
02:03:19,262 --> 02:03:21,998
PATIENTS THAT ARE ENTERING THESE

2960
02:03:21,998 --> 02:03:23,499
TRIALS APPROXIMATELY 10% HAD A

2961
02:03:23,499 --> 02:03:25,635
SEVERE RADIO GRAPHIC ARIA E

2962
02:03:25,635 --> 02:03:28,971
COMPARED TO 4% FOR HETEROZYGOUS

2963
02:03:28,971 --> 02:03:31,174
AND 2% FOR NONCARRIERS SO IT DID

2964
02:03:31,174 --> 02:03:34,077
APPEAR THAT ONCE A PARTICIPANT

2965
02:03:34,077 --> 02:03:36,179
HAS ARIA, LARGELY IT'S THE

2966
02:03:36,179 --> 02:03:37,947
SIMILAR, NOW THERE ARE GOING TO

2967
02:03:37,947 --> 02:03:40,950
BE INDIVIDUAL CASE EXCEPTIONS

2968
02:03:40,950 --> 02:03:42,085
THAT WE'LL TALK ABOUT BUT OVER

2969
02:03:42,085 --> 02:03:44,487
ALL THAT RISK IS HIGHER FOR THE

2970
02:03:44,487 --> 02:03:44,787
HOMOZYGOTES.

2971
02:03:44,787 --> 02:03:46,889
AND THEN IN THE BOTTOM WE LOOK

2972
02:03:46,889 --> 02:03:50,093
AT THE SYMPTOMATIC STATUS AND WE

2973
02:03:50,093 --> 02:03:52,228
DON'T SEE OVERALL ANY

2974
02:03:52,228 --> 02:03:53,429
SIGNIFICANT DIFFERENCES IN THE

2975
02:03:53,429 --> 02:03:55,298
PERCENTAGE OF PATIENTS WHO HAVE

2976
02:03:55,298 --> 02:03:57,433
SYMPTOMS SEESHTED WITH ARIA,

2977
02:03:57,433 --> 02:03:59,836
REGARDLESS OF THE APOE4 GENO

2978
02:03:59,836 --> 02:04:00,036
TYPE.

2979
02:04:00,036 --> 02:04:03,239
SO THE NEXT QUESTION IS OKAY,

2980
02:04:03,239 --> 02:04:04,774
GENO TYPE HAS NOT GIVEN US A

2981
02:04:04,774 --> 02:04:06,676
HUGE LINK TO THE MRI SEVERITY

2982
02:04:06,676 --> 02:04:09,812
AND TO THE SYMPTOMATIC STATUS,

2983
02:04:09,812 --> 02:04:12,548
WHAT ABOUT A CORRELATION BETWEEN

2984
02:04:12,548 --> 02:04:14,016
THE MRI FINDING ITSELF AND THE

2985
02:04:14,016 --> 02:04:15,685
SYMPTOMS, IS THERE A CORRELATION

2986
02:04:15,685 --> 02:04:17,653
BETWEEN A GREATER MRI SEVERITY

2987
02:04:17,653 --> 02:04:19,055
AND A GREATER PERCENTAGE OF

2988
02:04:19,055 --> 02:04:22,225
PATIENTS WHO HAVE SYMPTOMS.

2989
02:04:22,225 --> 02:04:29,132
SO HAD IS THE TABLE, THIS IS THE

2990
02:04:29,132 --> 02:04:30,500
ADUCANUMAB ON THE RIGHT AND

2991
02:04:30,500 --> 02:04:32,568
PLACENTA SEEB ON THE LEFT.

2992
02:04:32,568 --> 02:04:34,504
THIS LOOKS AT EACH SECTION FOR

2993
02:04:34,504 --> 02:04:37,673
MILD ARIA, AND MILD ARIA, THIS

2994
02:04:37,673 --> 02:04:40,676
IS ALL ARIA, E AND H.

2995
02:04:40,676 --> 02:04:42,211
AND THE FIRST NRVEGZ IS THAT

2996
02:04:42,211 --> 02:04:45,815
MOST OF THESE EVENTS ARE

2997
02:04:45,815 --> 02:04:47,917
ASYMPTOMATIC REGARDLESS OF THE

2998
02:04:47,917 --> 02:04:49,619
MRI SEVERITY AND MAYBE SOME

2999
02:04:49,619 --> 02:04:51,421
EXPECTED OF THE MRIs, BUT WELL

3000
02:04:51,421 --> 02:04:52,855
IS A SLATE INCREASE IN THE

3001
02:04:52,855 --> 02:04:54,991
PERCENTAGE THAT ARE SYMPTOMATIC

3002
02:04:54,991 --> 02:04:57,260
AND SEVERE ON MRI.

3003
02:04:57,260 --> 02:05:00,897
BUT GENERATED, THERE ARE SO FEW

3004
02:05:00,897 --> 02:05:02,198
SERIOUS SYMPTOMS WHICH IS WHAT

3005
02:05:02,198 --> 02:05:03,399
WE'RE REALLY INTERESTED IN, THAT

3006
02:05:03,399 --> 02:05:05,268
THAT IS SOMETHING ON AN

3007
02:05:05,268 --> 02:05:06,702
AGGREGATE LEVEL THAT WE REALLY

3008
02:05:06,702 --> 02:05:15,645
ARE NOT ABLE TO ANALYZE FROM THE

3009
02:05:15,645 --> 02:05:16,746
CLINICAL TRIAL DATA.

3010
02:05:16,746 --> 02:05:19,415
SO MOVING TO ISOLATED

3011
02:05:19,415 --> 02:05:20,349
ARE--ADMINISTRATIVE KRAMER H

3012
02:05:20,349 --> 02:05:21,717
ISSUE ASK IN THIS SLOOD WE LOOK

3013
02:05:21,717 --> 02:05:24,187
AT BOTH IN THE FIRST 2 ROWS ASK

3014
02:05:24,187 --> 02:05:29,492
HERE CARRIERS ARE DEFINED AS

3015
02:05:29,492 --> 02:05:31,294
HETEROZYGOUS AND HOMEIO ZYGOUS,

3016
02:05:31,294 --> 02:05:34,030
WE DISCUSS THE HIGHER INCIDENCES

3017
02:05:34,030 --> 02:05:34,597
OF EACH.

3018
02:05:34,597 --> 02:05:35,565
NOW THE INTERESTING TECHNOLOGY

3019
02:05:35,565 --> 02:05:36,666
TRANSFER ABOUT ARIA H IS IF YOU

3020
02:05:36,666 --> 02:05:39,035
BREAK IT DOWN BY ARIA H THAT'S

3021
02:05:39,035 --> 02:05:40,570
CONCURRENT WITH ARIA E, MEANING

3022
02:05:40,570 --> 02:05:43,039
THERE IS SOME TEMPORAL OVERLAP,

3023
02:05:43,039 --> 02:05:45,875
IT'S EITHER DIAGNOSED ON THE

3024
02:05:45,875 --> 02:05:47,677
SAME MRI THAT THE ARIA E WAS

3025
02:05:47,677 --> 02:05:49,645
DIGITEXTED OR IT'S DIAGNOSED

3026
02:05:49,645 --> 02:05:51,447
BEFORE THE ARIA E RESULT AND

3027
02:05:51,447 --> 02:05:54,283
THIS IS THE THIRD ROW FROM THE

3028
02:05:54,283 --> 02:05:54,517
BOTTOM.

3029
02:05:54,517 --> 02:06:02,391
SO 21% OF THE ADUCANUMAB, AND

3030
02:06:02,391 --> 02:06:06,229
HOWEVER THE INCIDENCE OF

3031
02:06:06,229 --> 02:06:07,430
ISOLATED ARIA H WITHOUT ANY IS

3032
02:06:07,430 --> 02:06:09,031
VERY SIMILAR AND THIS IS

3033
02:06:09,031 --> 02:06:10,166
PHENOCROSS TRIAL ANDS THE OTHER

3034
02:06:10,166 --> 02:06:11,534
TECHNOLOGY TRANSFER THAT IS NOT

3035
02:06:11,534 --> 02:06:14,237
ON THE SIDE IS THE TIMING OF

3036
02:06:14,237 --> 02:06:14,637
THAT.

3037
02:06:14,637 --> 02:06:25,114
THIS IS ALSO BEEN MENTIONED

3038
02:06:41,597 --> 02:06:42,398
EARLIER TODAY--IN THE INTEREST

3039
02:06:42,398 --> 02:06:45,234
OF TIME I WON'T DISCUSS

3040
02:06:45,234 --> 02:06:46,369
RECURRENT ARIA, ABOUT CONTINUE%

3041
02:06:46,369 --> 02:06:48,237
OF PATES DID HAVE RECURRENT

3042
02:06:48,237 --> 02:06:49,739
ARE--ADMINISTRATIVE KRAMER, THE

3043
02:06:49,739 --> 02:06:50,840
PERCENTAGE WITH RECURRENCE IS

3044
02:06:50,840 --> 02:06:52,775
ALSO HIGHER IN HOMOZYGOUS

3045
02:06:52,775 --> 02:06:54,544
COMPARED TO HETEROWROIGOUS

3046
02:06:54,544 --> 02:06:55,711
COMPARED TO NONCARRIERS.

3047
02:06:55,711 --> 02:07:00,249
AND IN GENERAL, THOSE NEXT ARIA

3048
02:07:00,249 --> 02:07:03,986
EVENTS DO TEND TO BE LESS RADIO

3049
02:07:03,986 --> 02:07:06,422
GRAPHICALLY SEVERE AND LESS

3050
02:07:06,422 --> 02:07:07,857
SYMPTOMATIC SUGGIESTING MAYBE

3051
02:07:07,857 --> 02:07:09,358
AGAIN A CORRELATION WITH THE

3052
02:07:09,358 --> 02:07:11,761
AMYLOID LOAD BUT THERE ARE

3053
02:07:11,761 --> 02:07:22,305
NOTABLE EXCEPTIONS ON INDIVIDUAL

3054
02:07:24,040 --> 02:07:24,507
CASES.

3055
02:07:24,507 --> 02:07:28,911
AS DISCUSSED, THIS IS A

3056
02:07:28,911 --> 02:07:30,012
SUPPLEMENTARY FIGURE THAT A

3057
02:07:30,012 --> 02:07:31,781
COLLEAGUE AND I AND OTHERS CO

3058
02:07:31,781 --> 02:07:34,917
AUTHORED AND THIS LOOKS AT A

3059
02:07:34,917 --> 02:07:36,185
PROPORTIONAL RISK HAZARDS MODEL

3060
02:07:36,185 --> 02:07:38,287
FOR THE RISKS OF ARIA EMPLOY SO

3061
02:07:38,287 --> 02:07:41,390
WE DISCUSSED THE APOE 4 RISK

3062
02:07:41,390 --> 02:07:43,659
FACTOR, ADDITION THE PRESENCE OF

3063
02:07:43,659 --> 02:07:45,561
BASE LINE MICROHEMORRHAGES WAS A

3064
02:07:45,561 --> 02:07:47,296
RISK FACTOR FOR ARIA E AND IN

3065
02:07:47,296 --> 02:07:49,498
THE PAPER THERE'S A SIMILAR

3066
02:07:49,498 --> 02:07:51,133
SLIDE WITH CONCURRENT ARIA E AND

3067
02:07:51,133 --> 02:07:55,738
SO WE SEE THE SAME THING, APOE 4

3068
02:07:55,738 --> 02:07:56,839
STATUS AND BASE LINE

3069
02:07:56,839 --> 02:07:57,807
MICROHEMORRHAGES ARE RISK

3070
02:07:57,807 --> 02:07:58,040
FACTORS.

3071
02:07:58,040 --> 02:08:01,877
WE DID NOT FIND A CORRELATION

3072
02:08:01,877 --> 02:08:03,713
THAT BETWEEN AIM, GENDER, BASE

3073
02:08:03,713 --> 02:08:05,848
LINE DISEASE STATE OR

3074
02:08:05,848 --> 02:08:06,415
ANTITHROMBOTTIC MEDICATION

3075
02:08:06,415 --> 02:08:08,184
DURING THE STUDY NOTE THAGOREAN

3076
02:08:08,184 --> 02:08:11,921
IN NEEZ STUDIES ASPIRIN UP TO

3077
02:08:11,921 --> 02:08:13,956
325-MILLIGRAMS WAS PERMITTED AND

3078
02:08:13,956 --> 02:08:18,928
THERE'S VERY LITTLE EXPOSURE TO

3079
02:08:18,928 --> 02:08:19,695
ANTITHROMBOTTIC MEDICATIONS.

3080
02:08:19,695 --> 02:08:21,263
WHEREAS FOR ISOLATED ARIA H

3081
02:08:21,263 --> 02:08:22,965
ISSUES THE ONLY SIGNIFICANT RISK

3082
02:08:22,965 --> 02:08:25,534
IN THIS MODEL WAS AGE, SO A

3083
02:08:25,534 --> 02:08:27,203
SMALL INCROSE IN RISK WITH AGE,

3084
02:08:27,203 --> 02:08:28,137
SO AGAIN ADDITIONAL EVIDENT FROM

3085
02:08:28,137 --> 02:08:32,008
THE TRIALS THAT THESE ARE MA

3086
02:08:32,008 --> 02:08:33,676
DIFFERENT PRESENTATIONS, PERHAPS

3087
02:08:33,676 --> 02:08:35,011
OF SOMETHING SIMILAR, UNDERNEATH

3088
02:08:35,011 --> 02:08:39,248
BUT I THINK THAT REQUIRES SOME

3089
02:08:39,248 --> 02:08:39,649
ADDITIONAL WORK.

3090
02:08:39,649 --> 02:08:41,150
NOW YOU HEARD ME MENTION

3091
02:08:41,150 --> 02:08:42,184
INDIVIDUAL CASES A COUPLE OF

3092
02:08:42,184 --> 02:08:46,922
TIMES AND I THINK THIS IS WHERE

3093
02:08:46,922 --> 02:08:48,524
THE LIMITATIONS ARE OF THE

3094
02:08:48,524 --> 02:08:51,894
CLINICAL TRIAL DATA AND AS A

3095
02:08:51,894 --> 02:08:52,795
SAFETY PHYSICIAN, OFTEN WILL

3096
02:08:52,795 --> 02:08:54,330
TELL PEOPLE THAT WHEN YOU

3097
02:08:54,330 --> 02:08:55,831
ELECTRIC AT SAFETY, WE LEARN A

3098
02:08:55,831 --> 02:08:57,566
LOT FROM SMALL NUMBERS, RIGHT IN

3099
02:08:57,566 --> 02:08:59,068
SO WE'RE NOT GOING TO HAVE A

3100
02:08:59,068 --> 02:09:01,737
PATIENT COME IN AND GET

3101
02:09:01,737 --> 02:09:04,340
ANAPHYLAXIS RIGHT AFTER A DRUG,

3102
02:09:04,340 --> 02:09:07,343
AND SAY, OHS IT'S NOT

3103
02:09:07,343 --> 02:09:07,877
STATISTICALLY SIGNIFICANT.

3104
02:09:07,877 --> 02:09:09,345
SO COMPARE TO THE EFFICACY END

3105
02:09:09,345 --> 02:09:11,380
POINTS WE WILL LOOK AT EACH OF

3106
02:09:11,380 --> 02:09:13,983
THOSE INDIVIDUAL CASES.

3107
02:09:13,983 --> 02:09:15,618
AND THE CONCLUSION THAT SEIZURE

3108
02:09:15,618 --> 02:09:18,621
INCLUDING AT THAT TIMEUS

3109
02:09:18,621 --> 02:09:20,423
EPILEPTICUS CAN BE A SYMPTOM OF

3110
02:09:20,423 --> 02:09:23,325
ARIA WAS A RESULT OF THAT KIND

3111
02:09:23,325 --> 02:09:25,761
OF ANALYSIS SO OVERALL THE

3112
02:09:25,761 --> 02:09:26,762
SEIZURES OCCURRED EVEN MORE

3113
02:09:26,762 --> 02:09:30,466
COMMONLY IN THE PLACEBO COMPARE

3114
02:09:30,466 --> 02:09:32,201
TO THE ADUCANUMAB GROUP BUT WHEN

3115
02:09:32,201 --> 02:09:35,137
WE LOOKED AT PATES WITH ARIA E,

3116
02:09:35,137 --> 02:09:36,706
THAT WAS .7 OR .8.

3117
02:09:36,706 --> 02:09:37,940
AND IF YOU WERE LOOKING AT

3118
02:09:37,940 --> 02:09:40,576
NUMBERS YOU WOULD SAY MM-NOT SO

3119
02:09:40,576 --> 02:09:41,877
SURE EMPLOY BUT WHEN YOU LOOK AT

3120
02:09:41,877 --> 02:09:43,212
THE INDIVIDUAL DATA YOU CAN SEE

3121
02:09:43,212 --> 02:09:44,647
THEREYA A TEMPORAL CORRELATION

3122
02:09:44,647 --> 02:09:48,751
BETWEEN ARIA E AND THE SEIZURES

3123
02:09:48,751 --> 02:09:50,386
AND WE DEVELOP CONFIDENCE IN A

3124
02:09:50,386 --> 02:09:51,887
SMALL NUMBER OF CASES THAT CAN

3125
02:09:51,887 --> 02:09:53,956
YOU HAVE SEIZURE AS A MORE

3126
02:09:53,956 --> 02:09:55,858
SERIOUS SYMPTOM OF ARIA E AND I

3127
02:09:55,858 --> 02:09:57,159
THINK THIS IS IMPORTANT AND I

3128
02:09:57,159 --> 02:09:58,194
WOULD ENCOURAGE THOSE OF YOU

3129
02:09:58,194 --> 02:09:59,895
SEEING PATES IN CLINIC, THE MORE

3130
02:09:59,895 --> 02:10:01,197
DATA YOU CAN SHARE WITH THE

3131
02:10:01,197 --> 02:10:02,832
SPONSORS ISSUES THE BETTER WOOER

3132
02:10:02,832 --> 02:10:05,234
GOING TO BE ABLE TO DO THIS, YOU

3133
02:10:05,234 --> 02:10:07,303
DO STILL HAVE VERY DETAILED DATA

3134
02:10:07,303 --> 02:10:10,106
COLLECTION FOR ALL OF THESE

3135
02:10:10,106 --> 02:10:10,306
CASES.

3136
02:10:10,306 --> 02:10:14,310
SO MANAGE AM, THIS IS REALLY

3137
02:10:14,310 --> 02:10:14,910
IMPORTANT CAN CLINICAL TRIALS

3138
02:10:14,910 --> 02:10:16,812
ONLY GIVE US SO MUCH INFORMATION

3139
02:10:16,812 --> 02:10:19,482
ABOUT MANAGEMENT.

3140
02:10:19,482 --> 02:10:20,716
NOW THE GOOD NEWS AGAIN IS THAT

3141
02:10:20,716 --> 02:10:22,118
MOST OF THE EVENT IN THE

3142
02:10:22,118 --> 02:10:22,952
CLINICAL TRIALS USING THE MANAGE

3143
02:10:22,952 --> 02:10:26,922
NLT IN THE CLINICAL TRIALS,

3144
02:10:26,922 --> 02:10:28,891
WHICH WAS DOSE SUSEXCEPTION FOR

3145
02:10:28,891 --> 02:10:30,493
MODERATE OR SEVERE RADIO GRAPHIC

3146
02:10:30,493 --> 02:10:34,630
ARIA WHETHER THAT WAS E OR H,

3147
02:10:34,630 --> 02:10:37,399
AND DOSE DISCONTINUATION FOR

3148
02:10:37,399 --> 02:10:38,367
SERIOUS EVENTS FOR SEER

3149
02:10:38,367 --> 02:10:43,439
ARE--ADMINISTRATIVE KRAMER H AND

3150
02:10:43,439 --> 02:10:44,573
ONGOING MRI MONITORING THOSE ARE

3151
02:10:44,573 --> 02:10:46,041
CARRIED FORWARD AND THOSE ARE

3152
02:10:46,041 --> 02:10:46,308
IMPORTANT.

3153
02:10:46,308 --> 02:10:48,544
THEY'RE NOT RAPID

3154
02:10:48,544 --> 02:10:48,911
LOAMACYYACKING.

3155
02:10:48,911 --> 02:10:50,579
THESE ARE DRUGS THAT HAVE A LONG

3156
02:10:50,579 --> 02:10:52,815
HALF LIFE SO TEMPORARILY DOSE

3157
02:10:52,815 --> 02:10:54,350
CESS PENDING THAT CONCENTRATION

3158
02:10:54,350 --> 02:10:58,187
IS GOING TO GO DOWN OVER TIME

3159
02:10:58,187 --> 02:10:59,221
EMPLOY BUT NONETHELESS, THE

3160
02:10:59,221 --> 02:11:00,990
PROFILE IS STILL REASONABLY

3161
02:11:00,990 --> 02:11:01,991
FAVORABLE WITH THESE.

3162
02:11:01,991 --> 02:11:05,294
WE HAD VERY LITTLE EXPERIENCE IN

3163
02:11:05,294 --> 02:11:07,463
THE TRIALS OF STEROID USE, SO

3164
02:11:07,463 --> 02:11:09,799
THERE WAS TOO LITTLE EXPOSURE TO

3165
02:11:09,799 --> 02:11:11,901
STEROIDS WHICH WAS NOT PROTOCOL

3166
02:11:11,901 --> 02:11:13,469
MANDATED BUT SOME INVESTIGATORS

3167
02:11:13,469 --> 02:11:14,904
DID USE STEROIDS FOR US TO BE

3168
02:11:14,904 --> 02:11:17,006
ABLE TO DETECT WHETHER IT MADE A

3169
02:11:17,006 --> 02:11:17,940
DIFFERENCE OR NOT.

3170
02:11:17,940 --> 02:11:20,142
AND THIS IS AGAIN WHERE CLINICAL

3171
02:11:20,142 --> 02:11:22,611
YMENT, WE KNOW THAT THAT IT HAS

3172
02:11:22,611 --> 02:11:23,412
BEEN USED.

3173
02:11:23,412 --> 02:11:24,280
THE APPROPRIATE USE

3174
02:11:24,280 --> 02:11:25,981
RECOMMENDATIONS NOTE THE USE OF

3175
02:11:25,981 --> 02:11:26,949
STEROIDS.

3176
02:11:26,949 --> 02:11:28,050
THERE'S SOME REASON WHERE IT MAY

3177
02:11:28,050 --> 02:11:29,652
BE HELPFUL BUT THIS WAS NOT DONE

3178
02:11:29,652 --> 02:11:31,487
IN THE TRIAL ANDS YOU KNOW I

3179
02:11:31,487 --> 02:11:33,255
THINK LIKELY NOT NECESSARY FOR

3180
02:11:33,255 --> 02:11:35,524
THE MAIORITY OF ARIA CASES BUT

3181
02:11:35,524 --> 02:11:37,693
DO RECOGNIZE THERE ARE SOME

3182
02:11:37,693 --> 02:11:38,427
PARTICULAR SITUATIONS WHERE THAT

3183
02:11:38,427 --> 02:11:39,728
MAY BE TRUE AND I THINK AS WE

3184
02:11:39,728 --> 02:11:42,097
LEARN MORE ABOUT THE MECHANISM

3185
02:11:42,097 --> 02:11:43,299
OF ARIA, YOU KNOW OUR

3186
02:11:43,299 --> 02:11:44,333
UNDERSTANDING OF WHAT TREATMENT

3187
02:11:44,333 --> 02:11:48,470
MAY BE, WILL EVOLVE.

3188
02:11:48,470 --> 02:11:50,005
IN THE LAST COUPLE OF MINUTES I

3189
02:11:50,005 --> 02:11:52,007
WANT TO SAY WHAT WE WILL

3190
02:11:52,007 --> 02:11:52,708
CONTINUE TO LEARN.

3191
02:11:52,708 --> 02:11:57,847
SO EMBARK IS A UNIQUE TRIAL WHEN

3192
02:11:57,847 --> 02:11:59,782
THE ADUCANUMAB TRIALS WERE

3193
02:11:59,782 --> 02:12:00,883
PAUSED, PATIENTS WERE ALLOWED TO

3194
02:12:00,883 --> 02:12:02,952
THEN LATER WHO HAD BEEN IN THOSE

3195
02:12:02,952 --> 02:12:04,787
IS ITS ENROLL IN THE EMBARK

3196
02:12:04,787 --> 02:12:06,722
TRIAL, SOME OF THOSE WERE ON MA

3197
02:12:06,722 --> 02:12:08,924
SEEB O, SOME HAD BEEN ON LOWER

3198
02:12:08,924 --> 02:12:10,092
DOSES, SOME HAD BEEN ON HIGHER

3199
02:12:10,092 --> 02:12:11,694
DOSES AND THIS IS A STUDY TO

3200
02:12:11,694 --> 02:12:14,029
LOOK AT THE LONG-TERM SAFETY ASK

3201
02:12:14,029 --> 02:12:16,065
TOLERABILITY OF THOSE PASHTS.

3202
02:12:16,065 --> 02:12:17,933
WE WILL HAVE DATA TO BE ABLE TO

3203
02:12:17,933 --> 02:12:21,737
SHARE AT CTAD AND WE WILL BE

3204
02:12:21,737 --> 02:12:23,205
ABLE INTERESTING THINGS THAT

3205
02:12:23,205 --> 02:12:24,373
DATA SET ALONE CAN TEACH US SO

3206
02:12:24,373 --> 02:12:26,976
WHAT IS THE RISK OF ARIA IF YOU

3207
02:12:26,976 --> 02:12:28,611
REDICE AFTER A POWS, LONGER TERM

3208
02:12:28,611 --> 02:12:31,347
USE, SOME OF THOSE PATES HAD

3209
02:12:31,347 --> 02:12:31,881
MORE ADVANCED ALZHEIMER'S

3210
02:12:31,881 --> 02:12:38,254
DISEASE BY THE TIME THEY WERE IN

3211
02:12:38,254 --> 02:12:38,621
THIS TRIAL.

3212
02:12:38,621 --> 02:12:40,055
AND IS THERE A DIFFERENCE IN

3213
02:12:40,055 --> 02:12:43,292
PATE BHOS HAD HIGHER EXPOSURES,

3214
02:12:43,292 --> 02:12:48,898
I LOWER EXPOSURES, HIGHER ARIA,

3215
02:12:48,898 --> 02:12:51,433
THERE ARE A NUMBER OF ONGOING

3216
02:12:51,433 --> 02:12:53,769
TRIALS IN THE FIELD BUT FOR A

3217
02:12:53,769 --> 02:12:55,704
NUMBER OF MOLECULES AND WE WILL

3218
02:12:55,704 --> 02:13:00,142
LEARN A LOT SO THE CMAX

3219
02:13:00,142 --> 02:13:01,343
HYPOTHESIS, THE SUBQ IMPACT

3220
02:13:01,343 --> 02:13:03,178
ARIA, STAGE OF DOZE, CAN WE

3221
02:13:03,178 --> 02:13:04,880
CORRELATE STEAJ OF STEEZ WITH

3222
02:13:04,880 --> 02:13:06,448
AMYLOID LOAD AND IS THE

3223
02:13:06,448 --> 02:13:08,384
IMANNUALING GETTING BETTER IN

3224
02:13:08,384 --> 02:13:10,219
WILL WE BE ABLE TO GET MORE

3225
02:13:10,219 --> 02:13:13,322
SPECIFIC AND IMAGE PARTS OF THE

3226
02:13:13,322 --> 02:13:14,690
BRAIN WHERE THERE MIGHT BE ARIA

3227
02:13:14,690 --> 02:13:16,558
AND A LOCAL AMYLOID LOAD.

3228
02:13:16,558 --> 02:13:19,461
IN THE REAL WORLD WE HAVE

3229
02:13:19,461 --> 02:13:20,663
REGISTRY DATA ONGOING POST

3230
02:13:20,663 --> 02:13:21,430
MARKETING SURVEILLANCE AND I

3231
02:13:21,430 --> 02:13:22,865
HAVE TO GIVE A SHOUT OUT BECAUSE

3232
02:13:22,865 --> 02:13:26,402
I THINK IT'S SO IMPORTANT AS WE

3233
02:13:26,402 --> 02:13:29,071
FOCUS ON THE SCIENCE, WE NEED TO

3234
02:13:29,071 --> 02:13:31,573
EDUCATE THE HEALTHCARE SYSTEM,

3235
02:13:31,573 --> 02:13:33,842
RADIOLOGISTS WHO MAY NOT BE

3236
02:13:33,842 --> 02:13:35,010
FAMILIAR WITH THIS, PRIMARY

3237
02:13:35,010 --> 02:13:36,211
PHYSICIANS AND ER DOCKS WHO ARE

3238
02:13:36,211 --> 02:13:39,148
GOING TO SEE PATES ON THIS

3239
02:13:39,148 --> 02:13:40,482
THERAPY AND THEN THERE'S ANOTHER

3240
02:13:40,482 --> 02:13:41,817
INTERESTING PART IS THAT IS WORK

3241
02:13:41,817 --> 02:13:52,261
ON THE BEST WAY TO EXPLAIN

3242
02:13:52,661 --> 02:13:55,331
BENEFIT RISK ON IT A PATIENT

3243
02:13:55,331 --> 02:13:56,298
POPULATION IN AREAS BEYOND THE

3244
02:13:56,298 --> 02:13:56,532
SCIENCE.

3245
02:13:56,532 --> 02:13:59,668
SO WITH THEY WILL CONCLUDE AND

3246
02:13:59,668 --> 02:14:05,808
THANK YOU FOR THE OPPORTUNITY.

3247
02:14:05,808 --> 02:14:06,041
NTHANKS.

3248
02:14:06,041 --> 02:14:06,375
THANKS, KAREN.

3249
02:14:06,375 --> 02:14:07,743
I DOPE KNOW IF THAT'S ON.

3250
02:14:07,743 --> 02:14:09,645
LET'S HAVE THE SPEAKERS CUM AND

3251
02:14:09,645 --> 02:14:12,514
CAN THE LIGHTS COME UP AT ALL

3252
02:14:12,514 --> 02:14:15,217
WHERE WE CAN HAVE 15 MINUTES FOR

3253
02:14:15,217 --> 02:14:15,818
QUESTIONS AND ANSWERS.

3254
02:14:15,818 --> 02:14:17,553
PLEASE USE THE MIC, SO IF THE

3255
02:14:17,553 --> 02:14:28,097
SPEAKERS FROM THE SESSION COULD

3256
02:14:56,558 --> 02:14:56,892
ALL COME UP.

3257
02:14:56,892 --> 02:14:59,495
OKAY, GO ARK HEAD, NICE

3258
02:14:59,495 --> 02:15:00,763
PRESENTATIONS, LARRY WALKER FROM

3259
02:15:00,763 --> 02:15:01,163
EMORY UNIVERSITY.

3260
02:15:01,163 --> 02:15:08,137
SO I HAVE A--IN MY LIMITED

3261
02:15:08,137 --> 02:15:09,872
EXPERIENCE, CAPILLARY AMYLOID

3262
02:15:09,872 --> 02:15:12,608
ANCHL OPERATING GLOBALLYATHY IS

3263
02:15:12,608 --> 02:15:18,280
IN SEVERE CAPILLARY ONCHIOPATHY

3264
02:15:18,280 --> 02:15:21,216
AND MODERATE TO SEVERE OVERALL

3265
02:15:21,216 --> 02:15:24,019
ANGIO OPERATING GLOBALLYATHY

3266
02:15:24,019 --> 02:15:25,054
OCCURS IN 40-50%.

3267
02:15:25,054 --> 02:15:26,989
TO WHAT EXTENT MIGHT THE RISK OF

3268
02:15:26,989 --> 02:15:28,657
ARIA E IN PARTICULAR BE RELATED

3269
02:15:28,657 --> 02:15:37,966
TO THE PRESENCE OF CAPILLARY

3270
02:15:37,966 --> 02:15:39,034
AMYLOID ANGIE OPERATING

3271
02:15:39,034 --> 02:15:44,206
GLOBALLYATHY IN THESE INITANCES.

3272
02:15:44,206 --> 02:15:47,142
MWRAIMS, SAVE US, YES.

3273
02:15:47,142 --> 02:15:48,610
NYAIMS YOU HAVE--COULD YOU HEAR

3274
02:15:48,610 --> 02:15:51,547
THE QUESTION NYES, I DID.

3275
02:15:51,547 --> 02:15:51,880
YEAH.

3276
02:15:51,880 --> 02:15:56,351
YES I, GREE THAT IT CAN OCCUR IN

3277
02:15:56,351 --> 02:15:59,221
ALZHEIMER'S DEC AS PART OF THE

3278
02:15:59,221 --> 02:16:00,422
PATTERN OF ACCUMULATION THAT'S

3279
02:16:00,422 --> 02:16:03,058
FAIR LYE UNCOMMON AND OBVIOUSLY

3280
02:16:03,058 --> 02:16:06,628
IT'S USUALLY SURROUNDED BY THE

3281
02:16:06,628 --> 02:16:09,932
PLAQUES AND THE LARGERRESSLES

3282
02:16:09,932 --> 02:16:11,600
THE ARTERIOLES CONTAINING

3283
02:16:11,600 --> 02:16:15,370
ABETTA, AND I MENTIONED THE

3284
02:16:15,370 --> 02:16:18,107
AQUAPORIN 4 AND THE

3285
02:16:18,107 --> 02:16:19,475
[INDISCERNIBLE] WHICH

3286
02:16:19,475 --> 02:16:21,443
PARTICULARLY ARE RELATED TO THE

3287
02:16:21,443 --> 02:16:23,345
CAPILLARIES AND THE CAPILLARY

3288
02:16:23,345 --> 02:16:25,080
WAS QUITE PROMINENT IN SOME

3289
02:16:25,080 --> 02:16:29,985
AREAS THAT SEEM TO BE CLEARED OF

3290
02:16:29,985 --> 02:16:31,887
PLAQUES BY THE IMMUNOTHERAPY SO

3291
02:16:31,887 --> 02:16:35,057
YES, I AGREE THAT AND WHERE WE

3292
02:16:35,057 --> 02:16:36,391
QUAWPTIFIED IT, THE CAPILLARY

3293
02:16:36,391 --> 02:16:39,495
WAS INCREASED IN THE IMMUNIZED

3294
02:16:39,495 --> 02:16:40,963
PEASHTS FOR THE ALZHEIMER'S

3295
02:16:40,963 --> 02:16:43,932
DISEASE, AND SO IT'S MORE

3296
02:16:43,932 --> 02:16:44,733
PROMINENT AFTER TREATMENT.

3297
02:16:44,733 --> 02:16:51,006
AND I WOULD ADPREE, POTENTIALLY

3298
02:16:51,006 --> 02:16:53,242
MECH NIM FOR FOR GENERATION OF

3299
02:16:53,242 --> 02:16:55,544
ARIA E MEDIATED BY THE ASTRO

3300
02:16:55,544 --> 02:16:59,214
SIGHT AND CANNED WHAT IN

3301
02:16:59,214 --> 02:17:01,583
AQUAFORIN 4 NTO THE EXTENT THAT

3302
02:17:01,583 --> 02:17:05,187
CARI IS A GOOD MODEL OF ARIA, IF

3303
02:17:05,187 --> 02:17:07,389
IN FACT IT IS WHERE WE HAVE MORE

3304
02:17:07,389 --> 02:17:13,162
PATHOLOGY IN THE ACTIVE PHASE,

3305
02:17:13,162 --> 02:17:17,266
NOT REALLY ARK ROUND CAPE

3306
02:17:17,266 --> 02:17:18,634
ILLEGALSARYS IF OUR BIOPSY

3307
02:17:18,634 --> 02:17:19,701
SPECIMEN, SO AT LEAST YOU CAN

3308
02:17:19,701 --> 02:17:24,273
GET SOMETHING THAT LOOKS A LOT

3309
02:17:24,273 --> 02:17:25,207
LIKE ARIA WITHOUT CAPILLARIES

3310
02:17:25,207 --> 02:17:26,909
BEING THE MAIN SOURCE BUT IT'S A

3311
02:17:26,909 --> 02:17:35,784
REALLY GOOD THOUGHT THOUGH.

3312
02:17:35,784 --> 02:17:36,418
>> CAN YOU HEAR ME?

3313
02:17:36,418 --> 02:17:42,491
>> I THINK THE MIC'S NOT

3314
02:17:42,491 --> 02:17:42,724
WORKING.

3315
02:17:42,724 --> 02:17:44,960
NTHIS SOUNDS LIKE IT'S ON,

3316
02:17:44,960 --> 02:17:46,495
MARRIAN BUCK WALTER FROM

3317
02:17:46,495 --> 02:17:49,064
STANFORD, GREAT TALKS, I HAVE

3318
02:17:49,064 --> 02:17:54,169
LOTS OF QUESTIONS BUT

3319
02:17:54,169 --> 02:17:55,470
DR. SMIRNAKIS, IF THE OTHER

3320
02:17:55,470 --> 02:17:57,806
FINDING ARE CLEARLY RELATED TO,

3321
02:17:57,806 --> 02:17:58,807
POE 4 AND THE SYMPTOM ANDS SIDE

3322
02:17:58,807 --> 02:18:00,175
CENTER FOR EXCELLENCE ON AGINGS

3323
02:18:00,175 --> 02:18:02,945
ARE NOT, IS IT POSSIBLE THAT WE

3324
02:18:02,945 --> 02:18:12,454
NEED TO REALLY RETHINK WHAT

3325
02:18:12,454 --> 02:18:13,589
WE'RE EVALUATING?

3326
02:18:13,589 --> 02:18:14,623
ARE WE LOOKING AT SOMETHING ON

3327
02:18:14,623 --> 02:18:16,525
AN MREFRESH YOUR RECOLLECTION I

3328
02:18:16,525 --> 02:18:17,893
AS TO THE ANTIBODIES CLEARING

3329
02:18:17,893 --> 02:18:20,829
AMYLOID BUT NOT THE THING THAT'S

3330
02:18:20,829 --> 02:18:22,297
RESPONSIBLE FOR SYMPTOMS, IF

3331
02:18:22,297 --> 02:18:24,499
WE'RE NOT LOOKING AT THE THING

3332
02:18:24,499 --> 02:18:25,467
RESPONSIBLE FOR SYMPTOMS WHAT

3333
02:18:25,467 --> 02:18:26,802
MIGHT THAT BE, I WOULD LOVE TO

3334
02:18:26,802 --> 02:18:28,804
HEAR YOUR THOUGHTS ON THAT ASK

3335
02:18:28,804 --> 02:18:29,871
OTHER PEOPLE'S THOUGHTS.

3336
02:18:29,871 --> 02:18:31,840
NI CAN TART AND MAYBE ASK OTHERS

3337
02:18:31,840 --> 02:18:33,742
THAT HAVE SEEN IN OF THESE

3338
02:18:33,742 --> 02:18:37,246
PATIENTS IN CLINICS, TO COMMENT

3339
02:18:37,246 --> 02:18:37,913
AS WELL.

3340
02:18:37,913 --> 02:18:41,683
I THINK THE CHALLENGE IS THAT IT

3341
02:18:41,683 --> 02:18:44,052
IS SO SELDOM ASSOCIATED WITH

3342
02:18:44,052 --> 02:18:44,987
SIGNIFICANT SYMPTOMS THAT WE'RE

3343
02:18:44,987 --> 02:18:47,389
NOT ABLE TO DETECT IT IN THE

3344
02:18:47,389 --> 02:18:48,724
CLINICAL TRIAL DATA WHICH IS NOT

3345
02:18:48,724 --> 02:18:50,826
THE SAME THING AS SAYING THAT

3346
02:18:50,826 --> 02:18:52,127
THERE'S NOT A RELATIONSHIP.

3347
02:18:52,127 --> 02:18:56,898
IT MAY NOT BE A SIGNIFICANT OR A

3348
02:18:56,898 --> 02:18:58,800
STRONG RELATIONSHIP BUT I WOULD

3349
02:18:58,800 --> 02:19:00,168
BE INTERESTED, AND I THINK IT

3350
02:19:00,168 --> 02:19:03,171
WAS MAYBE DR. SPERLING WHO NOTE

3351
02:19:03,171 --> 02:19:05,007
THAD SOME OF THESE PEASH RS MORE

3352
02:19:05,007 --> 02:19:05,674
SIGNIFICANT MREFRESH YOUR

3353
02:19:05,674 --> 02:19:07,242
RECOLLECTION I FINDINGS THAN YOU

3354
02:19:07,242 --> 02:19:09,578
WOULD EXPECT FOR THEIR SYMPTOMS

3355
02:19:09,578 --> 02:19:13,515
AND SO, I THINK WHETHER IT'S THE

3356
02:19:13,515 --> 02:19:19,888
RESOLUTION OF IT OR THE--YEAH,

3357
02:19:19,888 --> 02:19:20,355
IEP NOT SURE.

3358
02:19:20,355 --> 02:19:21,990
>>  I WILL JUST SAY THAT I
DO

3359
02:19:21,990 --> 02:19:24,393
THINK THERE'S SOMETIMES A

3360
02:19:24,393 --> 02:19:24,760
MISMATCH.

3361
02:19:24,760 --> 02:19:26,161
I'M MORE CONVINCED THAT THE

3362
02:19:26,161 --> 02:19:27,496
SYMPTOMS ARE RELATED TO A

3363
02:19:27,496 --> 02:19:34,536
POTENTIAL IPT GREATER FLAMMA

3364
02:19:34,536 --> 02:19:35,370
TORRATORY COMPONENT.

3365
02:19:35,370 --> 02:19:37,873
WHERE SOMETIMES THERE'S A RIP

3366
02:19:37,873 --> 02:19:38,473
ROARING EDEMA AND YOU SLEEP

3367
02:19:38,473 --> 02:19:39,941
APNEA AND OBESITYY THAT IN

3368
02:19:39,941 --> 02:19:42,778
PREGNANT WOMEN AND OTHER THINGS

3369
02:19:42,778 --> 02:19:43,612
WHERE THERE'S TERRIBLE IMANNUAL

3370
02:19:43,612 --> 02:19:45,447
XG A MILD HEADACHE BUT I THINK

3371
02:19:45,447 --> 02:19:49,551
THE INFLAMM EGG IS KEY AND I

3372
02:19:49,551 --> 02:19:52,220
DON'T THINK ANYONE'S TALKED

3373
02:19:52,220 --> 02:19:53,655
ABOUT INPOLICEMANNATORY IMAGING,

3374
02:19:53,655 --> 02:19:55,490
THE LIGANDS ARE NOT THERE YET

3375
02:19:55,490 --> 02:19:57,793
BUT IT WOULD BE SUPER HELPFUL

3376
02:19:57,793 --> 02:19:59,261
HERE NYEAH, EVEN WITH PRESS,

3377
02:19:59,261 --> 02:20:00,729
NORMALLY WHAT WE SEE ON THE SCAN

3378
02:20:00,729 --> 02:20:05,834
IS RELATED TO THE PATIENTS

3379
02:20:05,834 --> 02:20:06,101
SYMPTOMS.

3380
02:20:06,101 --> 02:20:07,169
>>  I WILL BE OBSERVINGAL
ABOUT

3381
02:20:07,169 --> 02:20:07,369
THIS.

3382
02:20:07,369 --> 02:20:09,638
FIRST OF ALL I HATE TO THROW OUT

3383
02:20:09,638 --> 02:20:14,076
THESE IMAGES THAT ARE SO

3384
02:20:14,076 --> 02:20:14,776
DRAMATIC LOAMACYY OPPOSITE

3385
02:20:14,776 --> 02:20:16,078
ALTHOUGH IT WOULD BE IDEAL FOR

3386
02:20:16,078 --> 02:20:17,779
THE FIELD THAT WE DIDN'T EVEN

3387
02:20:17,779 --> 02:20:20,515
NEED TO BE BOTHER TO BE LOOKING.

3388
02:20:20,515 --> 02:20:24,920
I'VE PLAYED IN A LOT OF PLAY

3389
02:20:24,920 --> 02:20:26,455
PINS AND SO, BRINGING THE

3390
02:20:26,455 --> 02:20:29,424
EXPERIENCE I HAVE FOR MULTIPLE

3391
02:20:29,424 --> 02:20:30,959
SCLEROSIS, SO HERE'S A DEC WHEN

3392
02:20:30,959 --> 02:20:33,261
I WAS BORN IN DISP FIRST LEARNED

3393
02:20:33,261 --> 02:20:35,464
IT, DOESN'T HAVE MR SCANNERS AT

3394
02:20:35,464 --> 02:20:38,367
ALL AND WE THOUGHT, PEOPLE HAD

3395
02:20:38,367 --> 02:20:40,102
EXACKER BAGS 1S ONCE A YEAR, 1

3396
02:20:40,102 --> 02:20:41,803
EVERY OTHER YEAR, SOMETHING LIKE

3397
02:20:41,803 --> 02:20:44,673
THAT, AND THEN, I GOT INVOLVED

3398
02:20:44,673 --> 02:20:46,942
VERY EARLY WITH REPEATED MRI

3399
02:20:46,942 --> 02:20:51,046
SCANS AND LOW AND BEHOLD, THERE

3400
02:20:51,046 --> 02:20:54,883
WERE HUNDREDS OF ASYMPTOMATIC

3401
02:20:54,883 --> 02:20:57,652
QUITE DISTINCT INPOLICEMANNATORY

3402
02:20:57,652 --> 02:20:57,886
LESIONS.

3403
02:20:57,886 --> 02:20:59,388
AUTOIMMUNE INFLAMMATION IN THE

3404
02:20:59,388 --> 02:21:01,022
BRAIN THAT WAS ABSOLUTELY

3405
02:21:01,022 --> 02:21:02,924
OBVIOUS AND YOU COULD RUN A

3406
02:21:02,924 --> 02:21:04,459
WHOLE CLINICAL TRIAL JUST

3407
02:21:04,459 --> 02:21:07,829
SUPPRESSING THAT DARN STUFF, AND

3408
02:21:07,829 --> 02:21:09,297
THAT DID EVENTUALLY MATTER IN

3409
02:21:09,297 --> 02:21:12,801
THE COURSE OF THIS DEC, SO I

3410
02:21:12,801 --> 02:21:16,805
THINK YOU KNOW FIRST OF ALL

3411
02:21:16,805 --> 02:21:17,639
THESE ARE IMPORTANT.

3412
02:21:17,639 --> 02:21:18,306
THE SAME THING.

3413
02:21:18,306 --> 02:21:20,442
THE OTHER THING IS IN OUR

3414
02:21:20,442 --> 02:21:23,378
CLINICAL TRIALS I HAD 1 VERY

3415
02:21:23,378 --> 02:21:24,579
SERIOUS CASE WHERE THERE WAS

3416
02:21:24,579 --> 02:21:27,516
CLEAR CORRELATION OF THE

3417
02:21:27,516 --> 02:21:28,917
LOCALIZATION, SO THAT YOU KNOW

3418
02:21:28,917 --> 02:21:31,787
THE PATHOLOGY IS CAUSING THE

3419
02:21:31,787 --> 02:21:33,989
SYMPTOMS WHEN THERE IS CLEAR

3420
02:21:33,989 --> 02:21:37,292
CORRELATION AND THERE'S A VERY

3421
02:21:37,292 --> 02:21:38,960
HEAVY OCCIPITAL PREDOMINANCE OF

3422
02:21:38,960 --> 02:21:41,129
THIS INFLAMMATION, AND YOU KNOW

3423
02:21:41,129 --> 02:21:44,166
I HAD A PATIENT, SUDDEN

3424
02:21:44,166 --> 02:21:45,500
CORTICALE PLIENDNESS AND GAVE

3425
02:21:45,500 --> 02:21:46,234
STEROID ANDS THAT REVERSE

3426
02:21:46,234 --> 02:21:47,869
FEDERAL A MATTER OF A FEW DAYS

3427
02:21:47,869 --> 02:21:51,706
AND YOU KNOW THERE WAS NO

3428
02:21:51,706 --> 02:21:52,574
QUESTION THIS NEW PATHOLOGY I

3429
02:21:52,574 --> 02:21:57,012
SAW IN THE SCAN WAS RELATED TO

3430
02:21:57,012 --> 02:21:57,646
THE CLINICAL PICTURE.

3431
02:21:57,646 --> 02:22:00,782
SO YOU KNOW THESE ARE RELATED.

3432
02:22:00,782 --> 02:22:02,517
I GUARANTEE WE SHOULDN'T SPEND A

3433
02:22:02,517 --> 02:22:03,985
LOT OF TIME THINKING THEY

3434
02:22:03,985 --> 02:22:06,254
AREN'T.

3435
02:22:06,254 --> 02:22:07,422
TEMPERATURE.

3436
02:22:07,422 --> 02:22:09,458
>> YEAH, I MEAN I GUESS I
WAS

3437
02:22:09,458 --> 02:22:11,593
BEING A LITTLE BIT DELIBERATELY

3438
02:22:11,593 --> 02:22:14,329
PROVOCATIVE WITH MY QUESTION BUT

3439
02:22:14,329 --> 02:22:15,430
I DO THINK IT'S IMPORTANT ABOUT

3440
02:22:15,430 --> 02:22:20,135
MIGHT THERE BE A SECOND HIT LIKE

3441
02:22:20,135 --> 02:22:22,637
THERE'S EDEMA AND DR. SPERLING

3442
02:22:22,637 --> 02:22:25,407
JUST SAID, I THINK CLINICALLY IT

3443
02:22:25,407 --> 02:22:27,909
MIGHT BE THAT WITH BETTER MORE

3444
02:22:27,909 --> 02:22:29,878
CAREFUL NEUROLOGIC EXAMS, WE

3445
02:22:29,878 --> 02:22:31,146
MIGHT SEE SYMPTOMS LIKE YOU

3446
02:22:31,146 --> 02:22:32,547
MIGHT SUGGIEST THAT THAT MIGHT

3447
02:22:32,547 --> 02:22:34,049
BE REALLY IMPORTANT BECAUSE IT

3448
02:22:34,049 --> 02:22:35,116
STILL IS VERY STRIKING TO ME,

3449
02:22:35,116 --> 02:22:37,519
YOU COULD HAVE THESE IMAGING

3450
02:22:37,519 --> 02:22:38,987
ABNORMALITY ANDS BE QUOTE

3451
02:22:38,987 --> 02:22:41,156
ASYMPTOMATIC AND IT MAKES YOU

3452
02:22:41,156 --> 02:22:41,389
WONDER.

3453
02:22:41,389 --> 02:22:42,657
NI WANT TO BRENG UP AGAIN WE

3454
02:22:42,657 --> 02:22:45,093
HAVE PEOPLE WHO HAVE SUBSTANTIAL

3455
02:22:45,093 --> 02:22:46,728
MEMORY IMPAIRMENT TO REPORT ON

3456
02:22:46,728 --> 02:22:48,663
THIS AND PEOPLE DO I THINK, YOU

3457
02:22:48,663 --> 02:22:49,865
KNOW AGAIN THESE ARE MILD

3458
02:22:49,865 --> 02:22:52,100
PATIENTS BUT I STILL THINK

3459
02:22:52,100 --> 02:22:53,869
THEY--WE BRING THEM IN, SEE AN

3460
02:22:53,869 --> 02:22:54,970
MRI AND WE'RE LIKE WHAT HAPPENED

3461
02:22:54,970 --> 02:22:57,172
IN THE PAST WEEK AND THAT'S

3462
02:22:57,172 --> 02:22:57,372
HARD.

3463
02:22:57,372 --> 02:22:58,507
BUT ANOTHER REASON TO TREAT

3464
02:22:58,507 --> 02:23:00,809
EARLIER BECAUSE WE MAY BE ABLE

3465
02:23:00,809 --> 02:23:02,177
TO GET, BUT, I ABRAE WITH YOU

3466
02:23:02,177 --> 02:23:05,046
AND 1 THING I DIDN'T SAY THAT I

3467
02:23:05,046 --> 02:23:06,114
DON'T KNOW IF OTHER PEOPLE ARE

3468
02:23:06,114 --> 02:23:08,016
DATA BUT I DON'T THINK WE'VE HAD

3469
02:23:08,016 --> 02:23:11,653
A GOOD LOOK AT ASYMPTOMATIC ARIA

3470
02:23:11,653 --> 02:23:13,688
AND WHETHER IT CHANGES ANYTHING

3471
02:23:13,688 --> 02:23:16,291
ON COG NIG, OUR COGNITIVE TESTS

3472
02:23:16,291 --> 02:23:17,993
ARE NOT SUPER ENSELLATIVE AND WE

3473
02:23:17,993 --> 02:23:20,428
DO OFFER THEM 3 OR 6 MONTHS BUT

3474
02:23:20,428 --> 02:23:21,930
THAT'S SOMETHING I HAVE WONDERED

3475
02:23:21,930 --> 02:23:23,031
BECAUSE AGAIN, I THINK THERE ARE

3476
02:23:23,031 --> 02:23:25,033
GOOD THINGS THAT MIGHT

3477
02:23:25,033 --> 02:23:26,301
IMPROVEMENT IS THERE A TRANSIENT

3478
02:23:26,301 --> 02:23:28,603
DIP IF WE LOOKED HARD ENOUGH, I

3479
02:23:28,603 --> 02:23:29,170
DON'T KNOW.

3480
02:23:29,170 --> 02:23:31,273
NWE'VE BEEN LOOKING IF ARE THAT

3481
02:23:31,273 --> 02:23:33,775
BECAUSE I HAVE EXPERIENCE WITH

3482
02:23:33,775 --> 02:23:36,144
ASYMPTOMATIC THERAPY FOR THE

3483
02:23:36,144 --> 02:23:43,218
LAST DECADE NOW, AND WE'VE HAD

3484
02:23:43,218 --> 02:23:49,190
MULTIPLE CASES OF ARIA IN THE

3485
02:23:49,190 --> 02:23:50,659
DIAN-TISSUING U GROUP, IT'S

3486
02:23:50,659 --> 02:23:53,528
TRIKINGLY SIMILAR AND WE'VE HAD

3487
02:23:53,528 --> 02:23:55,297
THE OPPORTUNITY TO LOOK AT

3488
02:23:55,297 --> 02:23:56,598
DETERIORATION IN THEIR PERFOR

3489
02:23:56,598 --> 02:23:58,733
THE PURPOSANCE ON QUANTITATIVE

3490
02:23:58,733 --> 02:24:00,969
MEASURES SUBSEQUENT TO CASES OF

3491
02:24:00,969 --> 02:24:06,274
ARIA AND WE INFACT DON'T SEE A

3492
02:24:06,274 --> 02:24:07,409
SYSTEMATIC LOSS OF FUNCTION IN,

3493
02:24:07,409 --> 02:24:09,878
YOU KNOW A SMALL NUMBER OF

3494
02:24:09,878 --> 02:24:11,079
CASES, BUT IT'S A VERY CRITICAL

3495
02:24:11,079 --> 02:24:13,248
QUESTION AND WE HAVE BEEN

3496
02:24:13,248 --> 02:24:15,016
LOOKING AND WE'LL CONTINUE TO

3497
02:24:15,016 --> 02:24:20,088
LOOK EMPLOY O I THINK THAT IS AN

3498
02:24:20,088 --> 02:24:21,923
IMPORTANT ISSUE.

3499
02:24:21,923 --> 02:24:23,558
NYAISON [INDISCERNIBLE]--WE HAVE

3500
02:24:23,558 --> 02:24:26,294
A KEEP MOVING, BIEG LYNN UP

3501
02:24:26,294 --> 02:24:28,296
THERE, MICHAEL NHI, MIKE FROM

3502
02:24:28,296 --> 02:24:33,134
ARIZONA, I WANT TO FOLLOW UP ON

3503
02:24:33,134 --> 02:24:36,271
DR. NIERK COLL, AND HIGHLIGHT

3504
02:24:36,271 --> 02:24:37,739
THAT WITHIN THE PROGRAM THERE

3505
02:24:37,739 --> 02:24:41,443
HAD BEEN THRESHOLD PATHOLOGICAL

3506
02:24:41,443 --> 02:24:46,781
REPORTS WITH CONCURRENT ARIA.

3507
02:24:46,781 --> 02:24:52,420
SO 1 DR. SARK WELL, LOWAY KNOWS

3508
02:24:52,420 --> 02:24:53,521
WELL WITH INTERCEREBRAL

3509
02:24:53,521 --> 02:25:00,428
HEMORRHAGE ON THE PATHOLOGY, IT

3510
02:25:00,428 --> 02:25:01,930
SHOWED SUBACUTE ISHT CEREBRAL

3511
02:25:01,930 --> 02:25:06,067
HEM RANL, MILD CAA, MILD CAA,

3512
02:25:06,067 --> 02:25:07,602
THE TPA CASE THAT WAS REPORTED

3513
02:25:07,602 --> 02:25:09,137
HAS BEEN PUBLISHED IN THE NEW

3514
02:25:09,137 --> 02:25:11,139
ENGLAND YOWRNAL AND ALSO IN

3515
02:25:11,139 --> 02:25:14,409
ANOTHER PUBLICATION OF MULTIPLE

3516
02:25:14,409 --> 02:25:15,143
ABOUTS CEREBRAL HEMORRHAGES

3517
02:25:15,143 --> 02:25:17,112
TREATMENT IN THE APOE HYM O

3518
02:25:17,112 --> 02:25:19,981
ZYGOTE IN THE SETTING VERY SOON

3519
02:25:19,981 --> 02:25:23,685
AFTER RECEIVING TPA, AND THAT

3520
02:25:23,685 --> 02:25:27,856
PATHOLOGY HAD HONE AS WELL A

3521
02:25:27,856 --> 02:25:28,323
HISTOSIDIC VASCULITIS,

3522
02:25:28,323 --> 02:25:29,924
SUPPORTING IN OF THESE SEVERE

3523
02:25:29,924 --> 02:25:33,361
CASES MAY BE CAA, ARIA IN

3524
02:25:33,361 --> 02:25:37,766
APPEARANCE AND THEN THE THIRD

3525
02:25:37,766 --> 02:25:39,701
CASE WAS ANOTHER HOMOZYGOTE WITH

3526
02:25:39,701 --> 02:25:42,370
SEVERE ARIA E AND ALSO MULTIPLE

3527
02:25:42,370 --> 02:25:44,472
MICROHEMORRHAGES AND ASSOCIATION

3528
02:25:44,472 --> 02:25:47,375
WITH THAT, THAT ALSO PATHOLOGY

3529
02:25:47,375 --> 02:25:49,644
SIMILARLY SHOWED SEVERE CAA AND

3530
02:25:49,644 --> 02:25:51,846
EFTHIMIOSIO SIDIC TYPE OF

3531
02:25:51,846 --> 02:25:55,750
VASCULITIS SO THESE CASES THOUGH

3532
02:25:55,750 --> 02:25:57,485
VERY UNCOMMON DO SUPPORT THAT IN

3533
02:25:57,485 --> 02:26:01,389
SOME CASES THERE MAY BE AN

3534
02:26:01,389 --> 02:26:02,090
INFLAMMATORY COMPONENT NTHANK

3535
02:26:02,090 --> 02:26:03,825
YOU MICHAEL FOR SAYING THAT AND

3536
02:26:03,825 --> 02:26:06,795
LET ME MACK A PLUG, KAREN'S

3537
02:26:06,795 --> 02:26:09,130
HEARD THIS FROM ME FOR A WHILE

3538
02:26:09,130 --> 02:26:10,532
THAT THESE CASES, THESE REALLY

3539
02:26:10,532 --> 02:26:13,101
SEVERE OR FATAL CASES ARE NOT

3540
02:26:13,101 --> 02:26:14,469
THAT COMMON BUT THEY'RE SO

3541
02:26:14,469 --> 02:26:20,742
INFORMATIVE AND SO I JUF WANT TO

3542
02:26:20,742 --> 02:26:21,776
ENCOURAGE ALL TO REPORT THESE

3543
02:26:21,776 --> 02:26:27,115
CASES SO WE CAN LEARN FROM THEM.

3544
02:26:27,115 --> 02:26:27,682
THEY'RE CRITICAL.

3545
02:26:27,682 --> 02:26:29,350
AMERICA YEAH, TERMS OF THE

3546
02:26:29,350 --> 02:26:32,053
DOUBLE EDGED SWORD OF THE BLOOD

3547
02:26:32,053 --> 02:26:35,290
VESSEL FUNCTION WHAT HAPPENED TO

3548
02:26:35,290 --> 02:26:36,524
THE AMYLOID PET SCANS AND PEOPLE

3549
02:26:36,524 --> 02:26:42,897
WHO GOT TREATED WITH IMMUNE

3550
02:26:42,897 --> 02:26:43,264
SUPPRESSION?

3551
02:26:43,264 --> 02:26:45,333
NYOU KNOW THE AMYLOID PET HAS

3552
02:26:45,333 --> 02:26:48,837
NOT BEEN USED CLIPICALLY AND SO,

3553
02:26:48,837 --> 02:26:51,706
THERE SHOULD BE NO SYSTEMATIC

3554
02:26:51,706 --> 02:26:53,875
CLINICAL AMYLOID PET IN THOSE

3555
02:26:53,875 --> 02:26:54,342
GUYS.

3556
02:26:54,342 --> 02:26:59,114
I THINK THE QUESTION ABOUT

3557
02:26:59,114 --> 02:27:02,117
WHETHER IS INFLAMMATION OR NT,

3558
02:27:02,117 --> 02:27:03,118
AUTOIMMUNE RESPONSE GOOD OR BAD

3559
02:27:03,118 --> 02:27:07,388
FOR YOU, I THINK  IT'S HARD TO

3560
02:27:07,388 --> 02:27:07,555
SAY.

3561
02:27:07,555 --> 02:27:11,760
I DIDN'T HOE IT BUT THE AIM OF

3562
02:27:11,760 --> 02:27:12,961
ARIA PRESENTATION EARLIER IS

3563
02:27:12,961 --> 02:27:15,330
ABOUT 5 YEARS EARLIER THAN THE

3564
02:27:15,330 --> 02:27:17,031
AVERAGE AGE OF FIRST HEMORRHAGE

3565
02:27:17,031 --> 02:27:18,700
AMONG OUR PATIENTS SO I THINK

3566
02:27:18,700 --> 02:27:21,402
IT'S AN EARLY TRIP WIRE.

3567
02:27:21,402 --> 02:27:23,338
NI'M TALKING ABOUT THE PEOPLE IN

3568
02:27:23,338 --> 02:27:27,375
THE TRIAL WHO GOD TREATED WITH

3569
02:27:27,375 --> 02:27:32,647
PREDNISONE NYEAH, SO FOR

3570
02:27:32,647 --> 02:27:34,048
ADUCANUMAB, I DON'T THINK WE

3571
02:27:34,048 --> 02:27:35,183
HAVE THAT.

3572
02:27:35,183 --> 02:27:36,217
MOST PATIENTS TREATED WERE A

3573
02:27:36,217 --> 02:27:38,286
SMALL NUMBER AND I'M MOT SURE IF

3574
02:27:38,286 --> 02:27:40,421
THEY'RE THE SAME 1S IN THE

3575
02:27:40,421 --> 02:27:41,723
SUBSTUDY, BUT I'LL GO BACK AND

3576
02:27:41,723 --> 02:27:43,625
LOOK NTHE REASON I MENTIONED

3577
02:27:43,625 --> 02:27:44,993
CASES THERE WAS 1 CASE REPORT,

3578
02:27:44,993 --> 02:27:46,361
THAT'S WHY IT'S SO IMPORTANT TO

3579
02:27:46,361 --> 02:27:47,595
HAVE THESE CASES IN THE

3580
02:27:47,595 --> 02:27:50,131
LITERATURE OF A PATIENT TREATED

3581
02:27:50,131 --> 02:27:54,702
IN OPEN LABEL ADUCANUMAB, A

3582
02:27:54,702 --> 02:27:57,438
NEUROLOGIST WHO HAD SUBSEQUENT

3583
02:27:57,438 --> 02:27:59,707
PET IMAGING, HAD CORTICALE

3584
02:27:59,707 --> 02:28:01,943
STEROIDS, HAD PET INLAGING WITH

3585
02:28:01,943 --> 02:28:04,012
AMYLOID LOWERING IN THE AREAS OF

3586
02:28:04,012 --> 02:28:06,314
ARIA, IT'S A SING CASE, WE DON'T

3587
02:28:06,314 --> 02:28:07,949
HAVE A SYSTEMATIC.

3588
02:28:07,949 --> 02:28:08,983
>> WALTERIME FLAD YOU
BROUGHT IT

3589
02:28:08,983 --> 02:28:11,019
UP BECAUSE I KEPT THINKING ABOUT

3590
02:28:11,019 --> 02:28:11,619
IMMUNO THERAPY AND ACTIVITIES

3591
02:28:11,619 --> 02:28:12,654
AND PROJECTS COMPETENT CANCER

3592
02:28:12,654 --> 02:28:14,756
AND WHEN WE GIVE STEROIDS,

3593
02:28:14,756 --> 02:28:16,891
BECAUSE YOU HAVE TO DAMPEN IT

3594
02:28:16,891 --> 02:28:19,360
DOWN, YOU HAVE CAN STILL SEE A

3595
02:28:19,360 --> 02:28:22,430
RESPONSE BUT IF YOU GIVE SO MUCH

3596
02:28:22,430 --> 02:28:24,599
STEROIDS YOU OVERIT CAN THOSE

3597
02:28:24,599 --> 02:28:26,067
PEOPLE DON'T DO AS WELL LONG

3598
02:28:26,067 --> 02:28:27,669
E-PRESCRIBING TERM SO IT'S AN

3599
02:28:27,669 --> 02:28:28,870
IMPORTANT QUESTION NIN TERMS OF

3600
02:28:28,870 --> 02:28:32,040
TIMING WHETHER OR NOT YOU COULD

3601
02:28:32,040 --> 02:28:33,842
DO SOMETHING EARLY BEFORE YOU

3602
02:28:33,842 --> 02:28:37,278
HIT THEM WITH THE ANTIBODY, NOW

3603
02:28:37,278 --> 02:28:40,215
IF IT CLEARS THE ANTIBODY, YOU

3604
02:28:40,215 --> 02:28:46,487
DEFEAT YOUR PURPOSE BUT YEAH

3605
02:28:46,487 --> 02:28:51,860
EMPLOY NYEAH, LAST QUESTION.

3606
02:28:51,860 --> 02:28:52,260
>> SORRY.

3607
02:28:52,260 --> 02:28:54,062
NMARK FISHER FROM IRVINE,

3608
02:28:54,062 --> 02:28:57,065
QUESTION:  WITH ALL THE STUDIES

3609
02:28:57,065 --> 02:29:00,401
OF INFLAMMATION CAN CAA, I AM

3610
02:29:00,401 --> 02:29:01,803
WONDERING IF YOU CAN COMMENT ON

3611
02:29:01,803 --> 02:29:03,872
A CELL TYPE THAT HASN'T RECEIVED

3612
02:29:03,872 --> 02:29:05,673
A WHOLE LOT ATTENTION WHICH IS

3613
02:29:05,673 --> 02:29:09,777
THE MASS CELL MASS CELLS HAVE

3614
02:29:09,777 --> 02:29:11,346
PREDILECTION FOR MENING EEL

3615
02:29:11,346 --> 02:29:12,614
LOCALIZATION WHICH IS WHERE A

3616
02:29:12,614 --> 02:29:16,417
LOT OF THE ACTION IS IN CAA SO

3617
02:29:16,417 --> 02:29:18,052
WONDERING IF YOU CAN COMMENT ON

3618
02:29:18,052 --> 02:29:20,788
MASS CELL ACTIVATION AND MASS

3619
02:29:20,788 --> 02:29:25,126
CELL CONTRIBUTION TO CAA POGHT O

3620
02:29:25,126 --> 02:29:25,994
PHYSIOLOGY?

3621
02:29:25,994 --> 02:29:27,896
>> I DEFINITELY CAN, I
HAVEN'T

3622
02:29:27,896 --> 02:29:29,864
TAINED IT, JAMES YOU HAVE A

3623
02:29:29,864 --> 02:29:30,098
COMMENT?

3624
02:29:30,098 --> 02:29:32,433
>> YEAH, WELL WE LOOKED AT
MASS

3625
02:29:32,433 --> 02:29:33,868
CELLS SPECIFICALLY IN THE

3626
02:29:33,868 --> 02:29:35,770
CONTEXT OF MULTIPLE SCLEROSIS,

3627
02:29:35,770 --> 02:29:37,171
ACTUALLY AND THERE ARE VERY FEW

3628
02:29:37,171 --> 02:29:40,508
MASS CELLS IN THE BRAIN OR IN

3629
02:29:40,508 --> 02:29:44,245
THE MENENG ES, AND HAVEN'T

3630
02:29:44,245 --> 02:29:44,812
LOOKED IN CAA.

3631
02:29:44,812 --> 02:29:47,115
DON'T THINK THERE ARE MANY

3632
02:29:47,115 --> 02:29:47,315
THERE.

3633
02:29:47,315 --> 02:29:48,917
>> WELL I WANT TO THANK
THE

3634
02:29:48,917 --> 02:29:50,451
SPEAKERS FOR AN EXCELLENT

3635
02:29:50,451 --> 02:29:57,572
KICKOFF. THANK YOU.

3636
02:29:57,572 --> 02:29:59,107
ALL RIGHT, WE'RE GETTING

3637
02:29:59,107 --> 02:30:00,676
STARTED, I AM CLINT WRIGHT I'M

3638
02:30:00,676 --> 02:30:02,711
DIRECTOR OF THE DIRECTOR OF THE

3639
02:30:02,711 --> 02:30:04,980
RESEARCH AT NE NDS AND I WILL

3640
02:30:04,980 --> 02:30:08,650
RECEIVE THE CLENICAL TRIAL

3641
02:30:08,650 --> 02:30:10,819
NETWORKS AND ALSO ADVISE THE

3642
02:30:10,819 --> 02:30:11,453
IPSITUTE ON CLINICAL RESEARCH

3643
02:30:11,453 --> 02:30:14,723
PROBLEMS AND THIS IS A CLINICAL

3644
02:30:14,723 --> 02:30:15,157
RESEARCH PROBLEM.

3645
02:30:15,157 --> 02:30:18,226
THAT WE HAVE TO SORT OUT.

3646
02:30:18,226 --> 02:30:20,996
VERY NICE TO SEE SUCH AN

3647
02:30:20,996 --> 02:30:24,266
INGAUGED GROUP THIS MORNING WITH

3648
02:30:24,266 --> 02:30:24,900
A WONDERFUL SESSION.

3649
02:30:24,900 --> 02:30:28,837
SO WE'RE GOING TO FOLLOW IT UP

3650
02:30:28,837 --> 02:30:31,773
WITH A PANEL DISCUSSION AND WE

3651
02:30:31,773 --> 02:30:34,176
HAVE A NUMBER OF AND WE ARE A

3652
02:30:34,176 --> 02:30:35,010
NUMBER OF EXCELLENT PANELISTS

3653
02:30:35,010 --> 02:30:37,479
HERE XI WILL BRIEFLY, I WILL NOT

3654
02:30:37,479 --> 02:30:38,880
DO EXTENSIVE INTRODUCTIONS,

3655
02:30:38,880 --> 02:30:42,451
PEOPLE CAN KIND OF INTRODUCE

3656
02:30:42,451 --> 02:30:47,189
THEMSELVES BUT WE HAVE

3657
02:30:47,189 --> 02:30:49,891
DR. VISWANATISSUING HAN HERE

3658
02:30:49,891 --> 02:30:54,396
FROM HARVARD MEDICAL SCHOOL,

3659
02:30:54,396 --> 02:30:57,099
SUSAN CATALANNOR PRACTICES

3660
02:30:57,099 --> 02:30:59,434
BIOTHERAPEUTIC ANDS MICHAEL

3661
02:30:59,434 --> 02:30:59,901
IRISWRRK AREFRESH YOUR

3662
02:30:59,901 --> 02:31:02,070
RECOLLECTION REFRESH YOUR

3663
02:31:02,070 --> 02:31:04,840
RECOLLECTION Y, WITH SHEART

3664
02:31:04,840 --> 02:31:06,375
ATTACK ARI WITH CMS EMPLOY WE

3665
02:31:06,375 --> 02:31:07,142
WILL TALK ABOUT GAPS IN THIS

3666
02:31:07,142 --> 02:31:10,679
KRAIR SO THAT NETWORK INDS CAN

3667
02:31:10,679 --> 02:31:12,347
THINK ABOUT HOW WE MOVE FORWARD.

3668
02:31:12,347 --> 02:31:16,418
I WANTED TO MENTION THAT IN THE

3669
02:31:16,418 --> 02:31:21,690
WAKE OF THE MOST RECENT TRIALS

3670
02:31:21,690 --> 02:31:25,160
THAT HAVE SHOWN SOME EFFICACY IN

3671
02:31:25,160 --> 02:31:26,228
ANTIAMYLOID THERAPY, THERE ARE A

3672
02:31:26,228 --> 02:31:28,597
NUMBER OF INCLUSION AND

3673
02:31:28,597 --> 02:31:31,666
EXCLUSION CRITERIA THAT WERE

3674
02:31:31,666 --> 02:31:32,534
OBVIOUSLY APPLIED AND SO NOW

3675
02:31:32,534 --> 02:31:33,668
THAT PATIENTS ARE GOING TO BE

3676
02:31:33,668 --> 02:31:36,938
COMING IN AND ASKING FOR THIS

3677
02:31:36,938 --> 02:31:39,241
THERAPY, THERE ARE A NUMBER OF

3678
02:31:39,241 --> 02:31:40,442
AREAS AND ORDER ZONE AREAS WHERE

3679
02:31:40,442 --> 02:31:45,747
WE'RE GOING TO BE HAVING A LOT

3680
02:31:45,747 --> 02:31:46,782
OF QUESTIONS ABOUT WHO BENEFIT

3681
02:31:46,782 --> 02:31:48,316
ANDS WHO COULD BE HARMED BY IT

3682
02:31:48,316 --> 02:31:51,753
AND SO THERE'S A LOT OF--AS

3683
02:31:51,753 --> 02:31:54,256
EVERYONE IN THIS ROOM KNOWS

3684
02:31:54,256 --> 02:31:56,925
WELL, THERE'S AN ENORMOUS AMOUNT

3685
02:31:56,925 --> 02:31:58,260
OF CO-MORBIDITY.

3686
02:31:58,260 --> 02:32:01,763
AND THERE'S A LOT OF VASCULAR

3687
02:32:01,763 --> 02:32:09,104
DAMAGE THAT UNDERLIES OR THAT IS

3688
02:32:09,104 --> 02:32:10,405
COMORBID WITH ALZHEIMER'S

3689
02:32:10,405 --> 02:32:11,973
PATHOLOGY, A SUBSTANTIAL NUMBER

3690
02:32:11,973 --> 02:32:14,476
OF LOUIS BODY PATHOLOGY AS WELL,

3691
02:32:14,476 --> 02:32:24,920
SO HOW DO THOSE CO FACTORS

3692
02:32:26,388 --> 02:32:27,856
RELATE TO THIS POTENTIAL THERAPY

3693
02:32:27,856 --> 02:32:32,594
AND ARIA SPECIFICALLY.

3694
02:32:32,594 --> 02:32:34,629
SO WE HAVE ASH PROVAL TO RUN

3695
02:32:34,629 --> 02:32:35,764
TRIALS IN THIS AREA ASK WE NODE

3696
02:32:35,764 --> 02:32:39,234
TO UNDERSTAND THE GAPS AND

3697
02:32:39,234 --> 02:32:45,874
OPPORTUNITIES IN BEDDING WHO MAY

3698
02:32:45,874 --> 02:32:46,741
BE AT RISK.

3699
02:32:46,741 --> 02:32:48,543
SO THANK YOU I'M GOING TO START

3700
02:32:48,543 --> 02:32:53,014
BY ASKING THE PANELISTS STARTING

3701
02:32:53,014 --> 02:32:56,551
MAYBE RIGHT HERE,

3702
02:32:56,551 --> 02:32:57,352
DR. VISWANATHAN, SPEAK A BIT

3703
02:32:57,352 --> 02:32:59,488
ABOUT YOUR TAKE ON THE LAST

3704
02:32:59,488 --> 02:33:02,958
SESSION, YOUR TAKE ON THIS

3705
02:33:02,958 --> 02:33:07,262
SUBJECT AND MAYBE THINK ABOUT

3706
02:33:07,262 --> 02:33:08,663
SOME RESEARCH, GAPS AND

3707
02:33:08,663 --> 02:33:09,431
OPPORTUNITIES TO IDENTIFY AND

3708
02:33:09,431 --> 02:33:10,599
TALK ABOUT TOMORROW WHEN WE ARE

3709
02:33:10,599 --> 02:33:19,007
OUR BREAK OUT SESSIONS. 

3710
02:33:19,007 --> 02:33:19,407
>> GREAT.

3711
02:33:19,407 --> 02:33:21,109
THANKS, FOR ORGANIZING THIS

3712
02:33:21,109 --> 02:33:22,344
MEETING, I FIND THAT THE LESS

3713
02:33:22,344 --> 02:33:26,681
AMG TO BE QUITE INTERESTING AND

3714
02:33:26,681 --> 02:33:27,716
QUITE PROVOCATIVE IN SOME OF THE

3715
02:33:27,716 --> 02:33:37,325
QUESTIONS THAT WERE RAISED ABOUT

3716
02:33:37,325 --> 02:33:37,993
INMEDICARE AND MEDICAIDATION

3717
02:33:37,993 --> 02:33:40,729
THERAPY AND I'M A STROKE

3718
02:33:40,729 --> 02:33:42,898
NEUROLOGIST AND DEMENTIA

3719
02:33:42,898 --> 02:33:46,368
SPECIALIST AND YOU KNOW OUR

3720
02:33:46,368 --> 02:33:50,405
GROUP AND IN HIS TALK WE FOCUS

3721
02:33:50,405 --> 02:33:52,407
ON AMYLOID ANGIE OPERATING

3722
02:33:52,407 --> 02:33:54,142
GLOBALLYATHY AND THESE OTHER

3723
02:33:54,142 --> 02:33:55,777
PATHOLOGIES AND SO OUR EMPHASIS

3724
02:33:55,777 --> 02:33:57,112
OVER THE LAST DECADE OR SO, IT'S

3725
02:33:57,112 --> 02:34:01,416
BEG YOUR PARDON REALLY TO

3726
02:34:01,416 --> 02:34:03,318
INVESTIGATE THE CARI MECHANISM

3727
02:34:03,318 --> 02:34:08,790
AS A POTENTIAL MODEL OR AS A

3728
02:34:08,790 --> 02:34:11,960
POTENTIAL OVERLAP WITH THE

3729
02:34:11,960 --> 02:34:15,263
ALZHEIMER'S DEC APPLICATION OF

3730
02:34:15,263 --> 02:34:17,599
IMMUNOTHERAPY INVESTIGATING

3731
02:34:17,599 --> 02:34:20,502
FURTER AREAS ASSOCIATED WITH

3732
02:34:20,502 --> 02:34:26,007
CARI AND ALSO THE OTHER ASPECT

3733
02:34:26,007 --> 02:34:27,576
OF CAA RELATED IMMUNOTHERAPY FOR

3734
02:34:27,576 --> 02:34:33,014
CAA PATES ON THEIR OWN COULD BE

3735
02:34:33,014 --> 02:34:34,115
POTENTIAL AREA THAT WE WOULD

3736
02:34:34,115 --> 02:34:35,550
LIKE TO SEE GO FORWARD A LITTLE

3737
02:34:35,550 --> 02:34:38,720
BIT MORE AS MANY OF YOU MAY KNOW

3738
02:34:38,720 --> 02:34:44,726
THAT THERE HAS BEEN A TRIAL OF

3739
02:34:44,726 --> 02:34:47,229
IMMUNOTHERAPY AND AMYLOID ANG

3740
02:34:47,229 --> 02:34:50,265
IOPATHY, BUT NOT POSITIVE IN THE

3741
02:34:50,265 --> 02:34:55,036
SMALL TRIAL THAT WAS CONDUCTED.

3742
02:34:55,036 --> 02:35:00,242
IT DID OPEN AN AVENUE FOR

3743
02:35:00,242 --> 02:35:01,042
TREATMENT OF ANGASHING IOPATHY

3744
02:35:01,042 --> 02:35:04,980
ON ITS OWN BUT AS CLINT POINT

3745
02:35:04,980 --> 02:35:07,916
THES OUT MORE IN MY OPINION, THE

3746
02:35:07,916 --> 02:35:10,685
OVERLAP IN ANG IOPATHY AND

3747
02:35:10,685 --> 02:35:11,686
ALZHEIMER'S DEC WHICH REPRESENTS

3748
02:35:11,686 --> 02:35:13,488
A LARGE NUMBER OF PATES WE STUDY

3749
02:35:13,488 --> 02:35:16,324
IN OUR CENTER, SO GOING IN THIS

3750
02:35:16,324 --> 02:35:18,326
DIRECTION OF THESE OVERLAPPING

3751
02:35:18,326 --> 02:35:22,731
PATHOLOGIES AND HOW TO INCLUDE

3752
02:35:22,731 --> 02:35:24,065
THE MOST NUMBER OF INDIVIDUALS

3753
02:35:24,065 --> 02:35:25,934
WHO COULD BENEFIT FROM THERAPY

3754
02:35:25,934 --> 02:35:29,170
WOULD BE SOMETHING THAT I WILL

3755
02:35:29,170 --> 02:35:32,407
BE PARTICULARLY INTERESTED IN

3756
02:35:32,407 --> 02:35:32,974
PURSUING.

3757
02:35:32,974 --> 02:35:33,675
NTHANKS.

3758
02:35:33,675 --> 02:35:40,949
YOU KNOW IT DOESN'T ESCAPE

3759
02:35:40,949 --> 02:35:42,584
NOTICE AND LOOK AT PRINCIPLES

3760
02:35:42,584 --> 02:35:44,185
THAT ARE PRETTY WIDE AND

3761
02:35:44,185 --> 02:35:45,787
INDICATES QUITE A BIT OF

3762
02:35:45,787 --> 02:35:46,955
VARIABILITY, SO WHAT IS

3763
02:35:46,955 --> 02:35:49,057
EXPLAINING THAT VARIABILITY AND

3764
02:35:49,057 --> 02:35:51,159
I GUESS 1 THING THAT COMES TO

3765
02:35:51,159 --> 02:35:52,260
MIND, YOU'RE A STROKE

3766
02:35:52,260 --> 02:35:55,530
MIEWROLOGYIST, WHAT DO YOU THINK

3767
02:35:55,530 --> 02:35:57,032
ABOUT THE UNDERLYING HEALTH OF

3768
02:35:57,032 --> 02:35:59,634
THE VESSEL, NOT NECESSARILY FROM

3769
02:35:59,634 --> 02:36:01,636
AN AMYLOID ANG IOPATHY TANNED

3770
02:36:01,636 --> 02:36:05,840
POINT BUT FROM LET'S SAY SOME

3771
02:36:05,840 --> 02:36:07,976
OTHER LIPO HIELENOSEIS, OTHER

3772
02:36:07,976 --> 02:36:10,545
RISK FACTORS THAT MAY CONTRIBUTE

3773
02:36:10,545 --> 02:36:13,114
TO SMALL VESSEL DISEASE?

3774
02:36:13,114 --> 02:36:14,883
HAVE YOU THOUGHT ABOUT IT?

3775
02:36:14,883 --> 02:36:18,787
>> AND IN RELATION TO THE
WHOLE

3776
02:36:18,787 --> 02:36:20,355
COGNITIVE PICTURE OR IN NIN

3777
02:36:20,355 --> 02:36:23,024
TERMS OF THE REACTION TO THE

3778
02:36:23,024 --> 02:36:24,059
ANTIAMYLOID THERAPY.

3779
02:36:24,059 --> 02:36:25,794
NTHAT'S A GOOD THOUGHT.

3780
02:36:25,794 --> 02:36:26,995
THAT HASN'T REALLY BEEN

3781
02:36:26,995 --> 02:36:27,996
INVESTIGATED TOO MUCH AT LEAST

3782
02:36:27,996 --> 02:36:32,600
YET, I THINK WE NEED TO TRAIN

3783
02:36:32,600 --> 02:36:35,036
MORE PEOPLE LIKE STEVE AND

3784
02:36:35,036 --> 02:36:37,238
OTHERS WHO DO BOTH THAT'S KIND

3785
02:36:37,238 --> 02:36:39,074
OF REALLY BEEN QUITE SILOS IN

3786
02:36:39,074 --> 02:36:39,541
MANY WAYS.

3787
02:36:39,541 --> 02:36:43,178
WE'VE GOT INTO THIS AND WE'VE

3788
02:36:43,178 --> 02:36:44,312
TRAINED MORE THAN A FEW

3789
02:36:44,312 --> 02:36:45,714
COLLEAGUES NOW OVER THE YEARS

3790
02:36:45,714 --> 02:36:48,149
WHO ARE INTERESTED IN THIS SMALL

3791
02:36:48,149 --> 02:36:50,852
VESSEL DEC PATH OLDER PEOPLE BUT

3792
02:36:50,852 --> 02:36:55,590
THUS FAR THE PATHOLOGY HAS

3793
02:36:55,590 --> 02:36:58,460
REMAIN--THE FIELD HAS REMANIED

3794
02:36:58,460 --> 02:36:59,260
ISOLATED FROM ALZHEIMER'S

3795
02:36:59,260 --> 02:37:00,829
DISEASE AND AS CLINT POINTS OUT

3796
02:37:00,829 --> 02:37:03,698
IT COULD BE AN AREA TO

3797
02:37:03,698 --> 02:37:04,799
INVESTIGATE WITH INDIVIDUALS

3798
02:37:04,799 --> 02:37:06,434
WITH EXTENSIVE MAUL VESSEL

3799
02:37:06,434 --> 02:37:08,536
DISEASE AS CHARACTERIZED BY MRI

3800
02:37:08,536 --> 02:37:11,239
AND THE VARIETY OF DIFFERENT

3801
02:37:11,239 --> 02:37:12,607
IMAGES AND IMAGING MODALITIES

3802
02:37:12,607 --> 02:37:23,084
WE'VE SHOWN COULD THERE BE A

3803
02:37:23,551 --> 02:37:26,254
HIGHER RISK GROUP WHO MAY HAVE

3804
02:37:26,254 --> 02:37:27,689
ADVERSE SIDE EVENS ASSOCIATED

3805
02:37:27,689 --> 02:37:28,490
WITH THE THERAPY.

3806
02:37:28,490 --> 02:37:32,794
CERTAIN LE SOMETHING TO THINK

3807
02:37:32,794 --> 02:37:32,994
ABOUT.

3808
02:37:32,994 --> 02:37:34,629
>> THANK YOU.

3809
02:37:34,629 --> 02:37:37,332
NI WANT TO CLARIFY MY CURRENT

3810
02:37:37,332 --> 02:37:41,603
AFFIL YAIG IS WITH CAP

3811
02:37:41,603 --> 02:37:42,237
EDUCATIONALLA BIOTHERAPEUTICS,

3812
02:37:42,237 --> 02:37:44,305
IT'S GREAT TO BE HERE, GREAT

3813
02:37:44,305 --> 02:37:45,340
SESSIONS THIS MORNING AND ALSO

3814
02:37:45,340 --> 02:37:55,850
TO COME AND I THINK REALLY IS

3815
02:37:57,118 --> 02:37:58,787
RAISES THE QUESTION FOR ME TO

3816
02:37:58,787 --> 02:38:00,088
COME AND STUDY THE POPULATION

3817
02:38:00,088 --> 02:38:02,457
SPECIFICALLY SO I THINK WE KNOW

3818
02:38:02,457 --> 02:38:04,459
ENOUGH ABOUT THE MOLECULAR

3819
02:38:04,459 --> 02:38:05,627
MECHANISMS TO REALLY ACTUALLY

3820
02:38:05,627 --> 02:38:06,828
ARK PROACH THAT.

3821
02:38:06,828 --> 02:38:10,098
THE CURRENT TREATMENT OPTIONS,

3822
02:38:10,098 --> 02:38:13,067
THE MONOCLONAL ANTIBODIES

3823
02:38:13,067 --> 02:38:13,902
CLEARLY INTERACT WAAMYLOID AND

3824
02:38:13,902 --> 02:38:16,504
DO SO IN THE VASCULATURE.

3825
02:38:16,504 --> 02:38:19,040
TO A CERTAIN EXTENT WE'RE

3826
02:38:19,040 --> 02:38:20,608
ALREADY TESTING THIS IN ONGOING

3827
02:38:20,608 --> 02:38:20,842
TRIALS.

3828
02:38:20,842 --> 02:38:22,177
SO THEN THE QUESTION BECOMES DO

3829
02:38:22,177 --> 02:38:25,513
WE REALLY WANT TO ENROLL THOSE

3830
02:38:25,513 --> 02:38:27,115
AMYLOID PET NEGATIVE CAA

3831
02:38:27,115 --> 02:38:29,651
POSITIVE PATES THAT ARE NOT

3832
02:38:29,651 --> 02:38:30,285
CURRENTLY BEING STUDIED AND YOU

3833
02:38:30,285 --> 02:38:32,420
KNOW IF WE WERE TO DO SO, DO YOU

3834
02:38:32,420 --> 02:38:34,789
WANT TO EXCLUDE THE FOLKS WITH

3835
02:38:34,789 --> 02:38:36,624
THE HEAVY CAA LOAD OR THE FOLKS

3836
02:38:36,624 --> 02:38:38,026
AT LIFIC FROM ARIA, CERTAINLY

3837
02:38:38,026 --> 02:38:40,028
THAT WILL BE THE CASE THAT WOULD

3838
02:38:40,028 --> 02:38:40,929
SUGREST YOUR STUDYING FOLKS

3839
02:38:40,929 --> 02:38:51,439
EARLIER IN THE DISEASE, HA'S A

3840
02:38:55,944 --> 02:38:57,745
PREVENTION CONPARTICULAR.

3841
02:38:57,745 --> 02:38:59,981
THIS SUGGIESTS COST, STUDY, AND

3842
02:38:59,981 --> 02:39:01,483
DO WOE KNOW ENOUGH ABOUT THE

3843
02:39:01,483 --> 02:39:02,851
HISTORY TO MONITOR CHANGING AT

3844
02:39:02,851 --> 02:39:04,853
THE MOLECULAR LEVEL AND THE

3845
02:39:04,853 --> 02:39:06,821
PATHOLOGY AND CLINICAL

3846
02:39:06,821 --> 02:39:08,923
MEANINGFULNESS AND I THINK WE

3847
02:39:08,923 --> 02:39:09,757
MADE TREMENDOUS PROGRESS TO BE

3848
02:39:09,757 --> 02:39:13,695
ABLE TO DO THAT EMPLOY SO I

3849
02:39:13,695 --> 02:39:15,096
THINK THE ANSWER IS YES AND

3850
02:39:15,096 --> 02:39:19,767
CERTAINLY HAVING THAT

3851
02:39:19,767 --> 02:39:21,135
THERAPEUTIC SHOULD IT BE

3852
02:39:21,135 --> 02:39:23,271
IMPACTFUL GOES A LONG WAY

3853
02:39:23,271 --> 02:39:23,905
TOWARDS VALIDATING THOSE

3854
02:39:23,905 --> 02:39:26,474
CLINICAL MEASURES AS WELL, SO I

3855
02:39:26,474 --> 02:39:28,443
THINK IT'S--WE'RE GOING TO HEAR

3856
02:39:28,443 --> 02:39:30,211
MORE, I THINK TO COME IN THIS

3857
02:39:30,211 --> 02:39:31,713
SESSION ABOUT HOW TO CLINICALLY

3858
02:39:31,713 --> 02:39:34,549
MANAGE THE PATES WHO ARE AT RISK

3859
02:39:34,549 --> 02:39:37,218
FOR THESE ADVERSE EVENTS AND THE

3860
02:39:37,218 --> 02:39:38,419
VERY RARE SERIES ADVERSE EVENTS.

3861
02:39:38,419 --> 02:39:42,724
SO I THINK THAT THE KNOWLEDGE IS

3862
02:39:42,724 --> 02:39:45,693
THERE TO ACTUALLY START TO ASK

3863
02:39:45,693 --> 02:39:46,794
THESE QUESTIONS CLINICALLY.

3864
02:39:46,794 --> 02:39:47,829
NTHANK YOU, BEFORE WE MOVE ON, I

3865
02:39:47,829 --> 02:39:50,932
THINK YOU HAVE A TAKE ON LOUIS

3866
02:39:50,932 --> 02:39:56,070
BODY AND SINCE IT IS SO COMORBID

3867
02:39:56,070 --> 02:39:57,639
WITH ALZHEIMERS, I AM WONDERING

3868
02:39:57,639 --> 02:39:59,374
IF YOU HAVE ANY THOUGHTS ABOUT

3869
02:39:59,374 --> 02:40:01,843
THAT ESPECIALLY IN THE REALM OF

3870
02:40:01,843 --> 02:40:02,644
INFLAMMATION, WHETHER THAT COULD

3871
02:40:02,644 --> 02:40:04,412
HAVE ANYTHING TO DO WITH

3872
02:40:04,412 --> 02:40:07,282
REACTIONS THAT WE'RE SEEING.

3873
02:40:07,282 --> 02:40:09,117
IT HASN'T BEEN LOOKEDDA THE VERY

3874
02:40:09,117 --> 02:40:09,317
MUCH.

3875
02:40:09,317 --> 02:40:10,919
THERE'S NO QUESTION WHERE WE

3876
02:40:10,919 --> 02:40:12,954
LOOK, WE SEE INFLAMMATION.

3877
02:40:12,954 --> 02:40:16,257
AND THAT'S GOING TO BE A MAJOR

3878
02:40:16,257 --> 02:40:17,225
COMPONENT OF ANY CLINICAL

3879
02:40:17,225 --> 02:40:21,329
PROTOCOL THAT YOU WOULD ACTUALLY

3880
02:40:21,329 --> 02:40:25,333
CONSIDER IN TREATING THIS

3881
02:40:25,333 --> 02:40:30,471
POPULATION, DLB PATIENTS, YOU

3882
02:40:30,471 --> 02:40:31,005
KNOW ALZHEIMER'S PATIENTS.

3883
02:40:31,005 --> 02:40:33,708
SO I THINK IMETTING THAT RIGHT

3884
02:40:33,708 --> 02:40:34,909
OR UNDERSTANDING THAT CAN BE

3885
02:40:34,909 --> 02:40:41,749
TOUGH TO MODEL IN VASCULAR DES

3886
02:40:41,749 --> 02:40:44,452
EMPLOY IT'S A LITTLE TOUGH TO

3887
02:40:44,452 --> 02:40:47,488
GET A PKPD MODEL IN THE

3888
02:40:47,488 --> 02:40:50,291
CAPILLARY DEC VERSUS LARGER

3889
02:40:50,291 --> 02:40:53,895
VESSELS SO IT'S--SOME ASPECTS OF

3890
02:40:53,895 --> 02:40:54,362
THAT ARE CHALLENGING.

3891
02:40:54,362 --> 02:40:57,799
BUT AT THE END OF THE DAY, I

3892
02:40:57,799 --> 02:41:00,034
THINK, YOU KNOW THIS IS A

3893
02:41:00,034 --> 02:41:07,008
SERIOUS  DISEASE, IT'S AN UNMET

3894
02:41:07,008 --> 02:41:07,942
MAJOR HEALTH NEED?

3895
02:41:07,942 --> 02:41:10,111
I THINK WE KNOW ENOUGH TO SAFELY

3896
02:41:10,111 --> 02:41:12,080
TART TO ASK IF THESE THERAPIES

3897
02:41:12,080 --> 02:41:14,215
ARE GOING TO BE EFFECTIVE IN A

3898
02:41:14,215 --> 02:41:19,253
VARIETY OF CONTEXTS. 

3899
02:41:19,253 --> 02:41:21,389
>> SO AS WE MOVE FORWARD
IN

3900
02:41:21,389 --> 02:41:23,958
BIOMARKERS AND LOUIS BODY SEIZES

3901
02:41:23,958 --> 02:41:25,627
IT WILL HELP.

3902
02:41:25,627 --> 02:41:26,594
>> THERE'S NO QUESTION.

3903
02:41:26,594 --> 02:41:29,263
BIOMARKERS ACROSS THE BOARD,

3904
02:41:29,263 --> 02:41:31,265
IMAGING BIOMARKERS WILL BE

3905
02:41:31,265 --> 02:41:31,733
USEFUL.

3906
02:41:31,733 --> 02:41:32,567
>> THAIRNGS.

3907
02:41:32,567 --> 02:41:34,235
THAT WAS A GREAT TRANSITION

3908
02:41:34,235 --> 02:41:39,173
BECAUSE IN TERMS OF RESEARCH

3909
02:41:39,173 --> 02:41:41,409
OPPORTUNITIES I WAS THINKING OF

3910
02:41:41,409 --> 02:41:43,378
BIOMARKERS SPECIFICALLY FOR CAA

3911
02:41:43,378 --> 02:41:45,179
AND ARIA.

3912
02:41:45,179 --> 02:41:49,150
AND AT BIOMARKERS FOR SEVERAL

3913
02:41:49,150 --> 02:41:51,152
ROLES FOR THAT, SO 1 IS

3914
02:41:51,152 --> 02:41:52,954
BIOMARKERS OF CAA RISK THAT MAY

3915
02:41:52,954 --> 02:41:55,356
BE ABLE TO STRATIFY EVEN FURTHER

3916
02:41:55,356 --> 02:41:58,459
BEYOND THE CURRENT MRI SIGNALS

3917
02:41:58,459 --> 02:42:01,229
OR APOE GENO TYPE.

3918
02:42:01,229 --> 02:42:02,630
ALSO RECOGNIZING THAT THE

3919
02:42:02,630 --> 02:42:07,301
AMYLOID PET SCANS WE'RE GETTING

3920
02:42:07,301 --> 02:42:11,906
CAN DIFFERENTIATE CAA FROM

3921
02:42:11,906 --> 02:42:13,474
PATHWAY GIVES RENCH MALAREA, SO

3922
02:42:13,474 --> 02:42:16,878
THIS MAY REFLECT SEVERE CAA.

3923
02:42:16,878 --> 02:42:19,580
AND THEN MARKERS OF ACTIVE ARIA,

3924
02:42:19,580 --> 02:42:24,952
SO IF WE THINK THAT THERE'S VASE

3925
02:42:24,952 --> 02:42:28,156
O GENIC EDEMA, BREAK DOWN OF THE

3926
02:42:28,156 --> 02:42:29,524
BLOOD BRAIN BARRIER, WE MAY

3927
02:42:29,524 --> 02:42:30,625
EXPECT PROTEINS TO LEAK OUT FROM

3928
02:42:30,625 --> 02:42:33,795
THE BRAIN OR CONVERSELY PROTEINS

3929
02:42:33,795 --> 02:42:34,829
FROM PERIPHERY FIGURE INTO THE

3930
02:42:34,829 --> 02:42:41,636
BRAIN, SO THAT WOULD BE IF WE'RE

3931
02:42:41,636 --> 02:42:45,740
THINKING ABOUT NOW WHETHER TESTS

3932
02:42:45,740 --> 02:42:47,408
CAN REPLACE SCANS OR MAY BE IN

3933
02:42:47,408 --> 02:42:49,177
TERMS OF DETECTING ARIA AND

3934
02:42:49,177 --> 02:42:59,721
WOULD ALLOW MONITORING AS WELL. 

3935
02:43:02,190 --> 02:43:04,292
AND THEN, MARKERS OF OUTCOME, SO

3936
02:43:04,292 --> 02:43:05,593
WE FEEL LIKE LOOKING AT THIS IN

3937
02:43:05,593 --> 02:43:08,463
THE COURSE OF A CLINICAL TRIAL

3938
02:43:08,463 --> 02:43:10,598
IN BOTH UNBIASED AND SPECIFIC

3939
02:43:10,598 --> 02:43:12,266
WAYS TO TRY TO SAFELY IDENTIFY

3940
02:43:12,266 --> 02:43:15,236
BY O MARKERS THAT CAN HELP WITH

3941
02:43:15,236 --> 02:43:19,240
THE RISK DIAGNOSIS AND

3942
02:43:19,240 --> 02:43:23,711
MANAGEMENT. 

3943
02:43:23,711 --> 02:43:29,350
YEAH, DR. KOROSSHES CHETZ'S

3944
02:43:29,350 --> 02:43:30,685
QUESTION WAS REALLY WILL PEOPLE

3945
02:43:30,685 --> 02:43:34,322
STILL BENEFIT IF YOU HAVE TO

3946
02:43:34,322 --> 02:43:35,890
IMMUNO SUPPRESS THEM TO GET THEM

3947
02:43:35,890 --> 02:43:38,092
THROUGH THIS PHASE AND IT WOULD

3948
02:43:38,092 --> 02:43:39,494
BE GRAND IF THERE'S DATA THERE

3949
02:43:39,494 --> 02:43:44,565
AND WE NEED TO LOOK AT IT, I

3950
02:43:44,565 --> 02:43:44,799
THINK.

3951
02:43:44,799 --> 02:43:46,334
THE OTHER THING BABESSED ON THE

3952
02:43:46,334 --> 02:43:50,404
DISCUSSION THIS MORNING AND WHAT

3953
02:43:50,404 --> 02:43:51,973
YOU JUST RAISED IS THE

3954
02:43:51,973 --> 02:43:54,342
INTERACTION BETWEEN THE CENTRAL,

3955
02:43:54,342 --> 02:43:58,980
AND THE PERIPHERAL IMMUNE

3956
02:43:58,980 --> 02:44:01,182
SYSTEM, SO THINKING ABOUT ARIA

3957
02:44:01,182 --> 02:44:03,818
RELATED TO MICROFLEEL

3958
02:44:03,818 --> 02:44:04,552
ACTIVATION, THAT'S THE

3959
02:44:04,552 --> 02:44:06,888
REMODELING WITHIN THE CENTRAL

3960
02:44:06,888 --> 02:44:08,256
NERVOUS SYSTEM, RERSUS SOME OF

3961
02:44:08,256 --> 02:44:13,161
THESE CASES OF CAA RI WHICH INN

3962
02:44:13,161 --> 02:44:16,898
VOFFED T-CELLS AND THE

3963
02:44:16,898 --> 02:44:17,465
PERIPHERAL NERVOUS SYSTEM,

3964
02:44:17,465 --> 02:44:20,234
UNDERSTANDING THOSE INTERACTIONS

3965
02:44:20,234 --> 02:44:22,737
WILL BE VERY IMPORTANT.

3966
02:44:22,737 --> 02:44:27,241
>> THANK YOU VERY MUCH.

3967
02:44:27,241 --> 02:44:29,710
DR. LING WOULD YOU LIKE TO

3968
02:44:29,710 --> 02:44:30,511
PROVIDE A TAKE?

3969
02:44:30,511 --> 02:44:30,812
>> SURE.

3970
02:44:30,812 --> 02:44:36,717
AND I WOULD LIKE TO ADD TO THE

3971
02:44:36,717 --> 02:44:37,819
OPPORTUNITY TO THANK EVERYBODY

3972
02:44:37,819 --> 02:44:40,188
AND BEING A PART OF THIS PANEL.

3973
02:44:40,188 --> 02:44:43,591
AS FAR AS THE CMS PERSPECTIVE,

3974
02:44:43,591 --> 02:44:49,630
CMS ACTUALLY FOLLOWING THE 

3975
02:44:49,630 --> 02:44:51,165
STATUTORY AUTHORITY WHICH MEANS

3976
02:44:51,165 --> 02:44:53,768
THE COVERAGE AND PAYMENT

3977
02:44:53,768 --> 02:44:54,368
PRINCIPLES REALLY ALIGN WITH

3978
02:44:54,368 --> 02:44:57,972
WHAT IS REASONABLE IS NECESSARY

3979
02:44:57,972 --> 02:44:59,407
TO TO MEET THE HEALTHCARE NEEDS

3980
02:44:59,407 --> 02:45:01,676
OF THE PEOPLE WHO ARE RECEIVING

3981
02:45:01,676 --> 02:45:04,979
THE BENEFIT, THAT IS A MEDICARE

3982
02:45:04,979 --> 02:45:06,113
BENEFICIARY POPULATION, SO WHY

3983
02:45:06,113 --> 02:45:11,886
THAT IS REALLY IMPORTANT, IT

3984
02:45:11,886 --> 02:45:13,187
ACTUALLY GETS BACK TO SOME OF

3985
02:45:13,187 --> 02:45:15,223
THE REMARKS MADE BY DR. CLIFFORD

3986
02:45:15,223 --> 02:45:17,859
THIS MORNING AND REFLECTED IN

3987
02:45:17,859 --> 02:45:20,061
THE THINKING OF THE DOCTOR'S

3988
02:45:20,061 --> 02:45:21,462
QUESTION IS THAT THE POPULATION

3989
02:45:21,462 --> 02:45:26,734
OF PEOPLE WHO WE ARE SERVING IS

3990
02:45:26,734 --> 02:45:27,001
COMFLEX.

3991
02:45:27,001 --> 02:45:30,304
SO IF YOU THINK ABOUT AND

3992
02:45:30,304 --> 02:45:32,807
KNOWING THE PROPORTION OF PEOPLE

3993
02:45:32,807 --> 02:45:37,178
WHO ACTUALLY DEVELOP ARIA IS A

3994
02:45:37,178 --> 02:45:40,348
SUBSET OF PEOPLE WHO HAVE

3995
02:45:40,348 --> 02:45:42,583
DEMENTIA OR DEVELOP DEMENTIA AND

3996
02:45:42,583 --> 02:45:44,352
IN THE MEDICARE POPULATION LESS

3997
02:45:44,352 --> 02:45:46,787
THAN 5% WILL HAVE ONLY DEMENTIA.

3998
02:45:46,787 --> 02:45:49,490
SO WHAT YOU MENTIONED EARLIER

3999
02:45:49,490 --> 02:45:51,893
CLINTON WITH THE CO-MORBIDITIES,

4000
02:45:51,893 --> 02:45:54,128
IT'S--IT IS A REAL OPPORTUNITY

4001
02:45:54,128 --> 02:45:58,733
AND A CHALLENGE AT THE SAME

4002
02:45:58,733 --> 02:45:59,000
TIME.

4003
02:45:59,000 --> 02:46:01,602
BUT SINCE THE PEOPLE WHO YOU

4004
02:46:01,602 --> 02:46:04,372
WILL BE STUDYING AND THE

4005
02:46:04,372 --> 02:46:05,573
OBLIGATION IS TO STUDY PEOPLE

4006
02:46:05,573 --> 02:46:08,242
WHO LOOK LIKE THE MEDICARE

4007
02:46:08,242 --> 02:46:09,577
BENEFICIARY POPULATION IF WE ARE

4008
02:46:09,577 --> 02:46:14,115
TO TRANSLATE THE EVIDENT BO

4009
02:46:14,115 --> 02:46:16,317
POLICIES OF COVERAGE AND

4010
02:46:16,317 --> 02:46:17,952
PAYMENT, THEN YOU KNOW THEREIN I

4011
02:46:17,952 --> 02:46:20,254
THINK IS BOTH A CHALLENGE AND AN

4012
02:46:20,254 --> 02:46:20,554
OPPORTUNITY.

4013
02:46:20,554 --> 02:46:24,659
EACH 1 OF OUR BENEFICIARIES WHO

4014
02:46:24,659 --> 02:46:26,060
ISHT FACES WITH THE HEALTHCARE

4015
02:46:26,060 --> 02:46:30,097
SYSTEM ALSO HAS A REFLECTION OF

4016
02:46:30,097 --> 02:46:36,971
THAT INTERACTION IN THE

4017
02:46:36,971 --> 02:46:38,639
ADMACHINE TRAITIVE CLAIMS EMPLOY

4018
02:46:38,639 --> 02:46:39,907
SO I THINK THAT IS AN

4019
02:46:39,907 --> 02:46:42,443
OPPORTUNITY TO BE ABLE TO

4020
02:46:42,443 --> 02:46:43,277
DELINEATE THE PHENOTYPE THAT

4021
02:46:43,277 --> 02:46:44,278
GOES WITH THE OUTCOMES THAT

4022
02:46:44,278 --> 02:46:45,746
YOU'RE INTERESTED IN LOOKING AT

4023
02:46:45,746 --> 02:46:48,215
AND FOR US ULTIMATELY THE

4024
02:46:48,215 --> 02:46:53,654
QUESTION IS WHAT IS THE EVIDENT

4025
02:46:53,654 --> 02:46:55,823
THAT WILL HELP CARE TO TIP THE

4026
02:46:55,823 --> 02:46:59,493
BALANCE IN FAVOR OF MORE BENEFIT

4027
02:46:59,493 --> 02:47:03,731
AND LESS RISK OVER TIME AND WHAT

4028
02:47:03,731 --> 02:47:06,033
IS MEANINGFUL TO IMPROVE IS THAT

4029
02:47:06,033 --> 02:47:08,669
THE THERAPY HAS TO BE USEFUL IN

4030
02:47:08,669 --> 02:47:10,638
THE CARE CAN KEEPING OF THE

4031
02:47:10,638 --> 02:47:14,809
PEOPLE WHO WE SERVE.

4032
02:47:14,809 --> 02:47:16,510
IT SEEMS SO EASY TO SAY AND YET

4033
02:47:16,510 --> 02:47:17,044
HARD TO DO.

4034
02:47:17,044 --> 02:47:18,646
SO WHEN IT COMES TO THINKING

4035
02:47:18,646 --> 02:47:23,751
ABOUT WHAT SOME OF THE

4036
02:47:23,751 --> 02:47:25,786
OPPORTUNITIES ARE YOU KNOW CMS

4037
02:47:25,786 --> 02:47:27,521
DID PUBLISH A NATIONAL COVERAGE

4038
02:47:27,521 --> 02:47:29,156
DECISION THAT UNDER THE RUBRIC

4039
02:47:29,156 --> 02:47:31,292
OF COVERAGE WITH EVIDENCE

4040
02:47:31,292 --> 02:47:33,728
DEVELOPMENT AND THERE'S RIGHT

4041
02:47:33,728 --> 02:47:39,000
NOW THERE ARE 2 APPROVED TRIALS

4042
02:47:39,000 --> 02:47:44,605
UNDER THAT RUBIC BUT 1 OF THE

4043
02:47:44,605 --> 02:47:46,774
TRIALS ACTUALLY IS TREATMENT

4044
02:47:46,774 --> 02:47:49,276
PERCEIVES BUT IS COVERABLE WITH

4045
02:47:49,276 --> 02:47:52,213
PARTICIPATION IN A REGISTRY.

4046
02:47:52,213 --> 02:47:54,648
BUT THE CED TEAM REPRESENTED

4047
02:47:54,648 --> 02:47:56,751
HERE BY DR.IO HUTTER WHO IS 1 OF

4048
02:47:56,751 --> 02:48:01,889
OUR SENIOR MEDICAL OFFICERS AND

4049
02:48:01,889 --> 02:48:04,058
THE PROGRAM, THE POLICY IS AN

4050
02:48:04,058 --> 02:48:06,894
OPPORTUNITY THAT I THINK WITH

4051
02:48:06,894 --> 02:48:09,930
THE ADDRESSING THE QUESTIONS

4052
02:48:09,930 --> 02:48:20,441
THAT REALLY ALIGN AROUND RISKS

4053
02:48:25,312 --> 02:48:26,881
AND BENEFITS IN AT WHICH TIME

4054
02:48:26,881 --> 02:48:28,482
AND TIMING MATTERS, IF THOSE ARE

4055
02:48:28,482 --> 02:48:30,117
ADDRESSED THAT CAN BE A VEHICLE

4056
02:48:30,117 --> 02:48:32,787
TO COME IN UNDER CED THAT CAN

4057
02:48:32,787 --> 02:48:34,088
REALLY BENEFIT BOTH THE SCIENCE

4058
02:48:34,088 --> 02:48:36,891
BUT ULTIMATELY THE PEOPLE WHO WE

4059
02:48:36,891 --> 02:48:38,459
SERVE.

4060
02:48:38,459 --> 02:48:39,593
>> YEAH, THANK YOU.

4061
02:48:39,593 --> 02:48:42,496
YEAH, I THINK THERE'S QUESTIONS

4062
02:48:42,496 --> 02:48:44,799
THAT CAN BE ANSWERED IN TRIAL

4063
02:48:44,799 --> 02:48:46,967
CANS THEN THERE WILL BE A LOT OF

4064
02:48:46,967 --> 02:48:48,169
QUESTIONS WHERE IT'S GOING TO BE

4065
02:48:48,169 --> 02:48:49,737
DIFFICULT TO ANSWER THEM IN

4066
02:48:49,737 --> 02:48:51,105
TRIALS BECAUSE THEY'RE NOT GOING

4067
02:48:51,105 --> 02:48:53,074
TO BE VERY COMMON AND THE

4068
02:48:53,074 --> 02:48:54,341
REGISTRIES ARE ANYTHING TO HAVE

4069
02:48:54,341 --> 02:48:56,310
TO HELP US IN THAT REGARD AS

4070
02:48:56,310 --> 02:49:00,081
WELL AND SO I THINK IT'S IT'S

4071
02:49:00,081 --> 02:49:02,083
INTERESTING TO HEAR THAT

4072
02:49:02,083 --> 02:49:03,084
PERSPECTIVE AND REMEMBER THAT

4073
02:49:03,084 --> 02:49:05,953
THAT WE HAVE DIFFERENT SHOTS ON

4074
02:49:05,953 --> 02:49:08,689
GOAL, RIGHT AND SO THERE ARE

4075
02:49:08,689 --> 02:49:11,792
THESE TRIALS GOING ON.

4076
02:49:11,792 --> 02:49:14,762
THERE ARE PERHAPS NIH AND NINDS

4077
02:49:14,762 --> 02:49:18,599
TRIALS IN THE COMORBID AREAS,

4078
02:49:18,599 --> 02:49:19,800
NIA TRIALS PROBABLY AND THEN

4079
02:49:19,800 --> 02:49:23,404
THERE ARE THESE REG TREES AND

4080
02:49:23,404 --> 02:49:24,505
THEN THERE ARE CO-MORBIDITIES

4081
02:49:24,505 --> 02:49:28,008
THAT ARE VERY UNCOMMON, I MEAN,

4082
02:49:28,008 --> 02:49:29,176
WE ARE CONCERNED ABOUT

4083
02:49:29,176 --> 02:49:32,780
HEMORRHAGE RISK, THERE ARE

4084
02:49:32,780 --> 02:49:33,314
PEOPLE WITH PARTICULAR ARK

4085
02:49:33,314 --> 02:49:36,917
NATIONAL LIBRARY OF

4086
02:49:36,917 --> 02:49:37,551
MEDICINALLYS, VASCULAR ANOMALIES

4087
02:49:37,551 --> 02:49:39,153
THAT MAYBE SOME OF THEM WANT TO

4088
02:49:39,153 --> 02:49:40,387
GET TREATMENT CAN THEY WON'T

4089
02:49:40,387 --> 02:49:41,822
KNOW WHETHER IT'S SAFE TO DO

4090
02:49:41,822 --> 02:49:43,057
THAT AND WE PROBABLY WON'T BE

4091
02:49:43,057 --> 02:49:44,892
ABLE TO ANSWER THAT WITH TRIALS

4092
02:49:44,892 --> 02:49:46,861
RIGHT, WE WILL NEED REG TREES TO

4093
02:49:46,861 --> 02:49:49,063
ANSWER THOSE THINGS, I'M DONE,

4094
02:49:49,063 --> 02:49:54,235
YOU KNOW AVMs AND.

4095
02:49:54,235 --> 02:49:55,669
>> YEAH, WELL, THANKS FOR

4096
02:49:55,669 --> 02:49:56,370
EVERYBODY'S SORT OF TAKE ON THE

4097
02:49:56,370 --> 02:49:58,205
MORNING AND I THINK WE SHOULD

4098
02:49:58,205 --> 02:50:01,742
OPEN IT UP TO THE LARGER FROWP

4099
02:50:01,742 --> 02:50:04,478
AND HAVE A BACK AND FORTH

4100
02:50:04,478 --> 02:50:05,813
DISCUSSION, ARE THERE QUESTIONS

4101
02:50:05,813 --> 02:50:10,851
FOR PEOPLE ON THE PANEL IN

4102
02:50:10,851 --> 02:50:21,328
QUESTIONS FOR OTHERS REISA?

4103
02:50:37,645 --> 02:50:39,413
>> BUT I GUESS I'M
WONDERING

4104
02:50:39,413 --> 02:50:40,614
GIVEN THE COMMENTS IS THERE A

4105
02:50:40,614 --> 02:50:43,384
PHASE WHERE THERE IS EVER PET

4106
02:50:43,384 --> 02:50:46,554
NEGATIVITY BUT CAA POSITIVITY,

4107
02:50:46,554 --> 02:50:48,022
MEANING YOU DON'T HAVE ANY

4108
02:50:48,022 --> 02:50:51,358
AMYLOID OR AT LEAST IN THE

4109
02:50:51,358 --> 02:50:55,396
DISTRIBUTION, SO WHAT--GOOD

4110
02:50:55,396 --> 02:50:55,796
CATCH.

4111
02:50:55,796 --> 02:50:58,065
>> WHAT IS KNOWN ABOUT
THAT IN

4112
02:50:58,065 --> 02:50:59,233
THE EVOLUTION WHERE YOU'RE

4113
02:50:59,233 --> 02:51:00,034
FOLLOWING PEOPLE, I EMBASSY THIS

4114
02:51:00,034 --> 02:51:10,477
IS ALSO IN THE RARE DUTCH

4115
02:51:13,047 --> 02:51:13,714
MUTATION STUFF.

4116
02:51:13,714 --> 02:51:17,751
>> SO I THINK CERTAINLY,
THEY

4117
02:51:17,751 --> 02:51:20,321
CAN OCCUR SO EXTENSIVELY THAT

4118
02:51:20,321 --> 02:51:22,389
IT'S, IT CAN BE CHALLENGING BUT

4119
02:51:22,389 --> 02:51:23,958
THERE ARE CASES, YOU KNOW THAT

4120
02:51:23,958 --> 02:51:26,026
WE KNOW OF WHERE WE DON'T HAVE

4121
02:51:26,026 --> 02:51:27,261
THAT.

4122
02:51:27,261 --> 02:51:29,463
HAVE WE LOOKED AT THEM

4123
02:51:29,463 --> 02:51:30,231
SPECIFICALLY AND SYSTEMATIC

4124
02:51:30,231 --> 02:51:31,799
LOAMACYY WITH THE AMYLOID PET,

4125
02:51:31,799 --> 02:51:33,334
DO WOE HAVE ENOUGH EXAMPLES OF

4126
02:51:33,334 --> 02:51:35,536
THAT TO BE CONFIDENT IN I THINK

4127
02:51:35,536 --> 02:51:40,407
THAT'S A GOOD QUESTION.

4128
02:51:40,407 --> 02:51:41,675
>> AND REISA'S QUESTION IS

4129
02:51:41,675 --> 02:51:43,944
INTERESTING AS SUSAN POINTS OUT

4130
02:51:43,944 --> 02:51:48,015
FOR ANOTHER REASON, KIND OF

4131
02:51:48,015 --> 02:51:49,383
ANOTHER NUANCE AROUND CAA AND

4132
02:51:49,383 --> 02:51:51,619
CAA NATURAL HISTORY.

4133
02:51:51,619 --> 02:51:53,187
SO, WE'VE THOUGHT THESE PATIENTS

4134
02:51:53,187 --> 02:51:55,022
FOR A LONG TIME ON THE STROKE

4135
02:51:55,022 --> 02:51:57,391
SIDE, SO THAT'S HOW THESE CASES

4136
02:51:57,391 --> 02:51:59,460
WERE INITIALLY KRIEBED AS CAA

4137
02:51:59,460 --> 02:52:00,594
PEASHES WITH HEMORRHAGE BUT

4138
02:52:00,594 --> 02:52:01,695
THERE'S A WHOLE GROUP OF

4139
02:52:01,695 --> 02:52:03,297
PATIENTS WE STUDIED IN THE LAST

4140
02:52:03,297 --> 02:52:04,832
DECADE OR SO THAT DON'T EVER

4141
02:52:04,832 --> 02:52:06,767
DEVELOP STROKES SO THEY JUST

4142
02:52:06,767 --> 02:52:08,569
COME TO--COME TO OUR AMILLIO

4143
02:52:08,569 --> 02:52:10,871
JEIMER'S CLINICS OR OUR DEMENTIA

4144
02:52:10,871 --> 02:52:14,942
CLINICS ISSUE PATIENTS WITH

4145
02:52:14,942 --> 02:52:16,510
EITHER MILD COGNITIVE,

4146
02:52:16,510 --> 02:52:17,845
IMPAIRMENT OR FULL PLOAN DEMENT

4147
02:52:17,845 --> 02:52:20,147
RAW DATA AND WE CAM PAIR THESE

4148
02:52:20,147 --> 02:52:23,183
GROUPS IN CAA PATIENTS BOTH

4149
02:52:23,183 --> 02:52:27,521
HAVING MODERATE TO SEVERE CAA.

4150
02:52:27,521 --> 02:52:30,224
AND WHILST THE IMAGING FINDINGS

4151
02:52:30,224 --> 02:52:35,729
AND PATHOLOGIES SEEMS TO BE

4152
02:52:35,729 --> 02:52:37,431
LARGELY NONDISTINGUISHABLE, THE

4153
02:52:37,431 --> 02:52:38,632
[INDISCERNIBLE] IS TOTALLY

4154
02:52:38,632 --> 02:52:39,667
VARIED AND DIFFERENT.

4155
02:52:39,667 --> 02:52:41,168
SO TREATING THOSE CAA PATIENT

4156
02:52:41,168 --> 02:52:46,573
WHO IS DEVELOP STROKES WITH

4157
02:52:46,573 --> 02:52:50,044
ANTIAMYLOID THERAPY MAY NOT BE

4158
02:52:50,044 --> 02:52:51,245
IDEAL FOR OBTAINING COGNITIVE

4159
02:52:51,245 --> 02:52:53,781
OUTCOME AND THEN TREATING THE

4160
02:52:53,781 --> 02:52:55,416
DEMENTIA PATES FOR THINGS THAT

4161
02:52:55,416 --> 02:52:58,218
AREN'T RELATED TO STROKE, ALSO

4162
02:52:58,218 --> 02:52:59,620
SIMILARLY, WE MAY BE MISSING THE

4163
02:52:59,620 --> 02:53:02,056
BOAT, SO I THINK THE--1 OF THE

4164
02:53:02,056 --> 02:53:05,926
THINGS TO THINK ABOUT AROUND CAA

4165
02:53:05,926 --> 02:53:07,561
IS WHO ARE THE CAA PATIENTS,

4166
02:53:07,561 --> 02:53:09,863
WHAT TYPE OF CAA IT IS.

4167
02:53:09,863 --> 02:53:11,665
WE'RE NOT CAPABLE OF

4168
02:53:11,665 --> 02:53:14,168
DISTINGUISHING THAT YET, EARLY

4169
02:53:14,168 --> 02:53:15,336
AND OF COURSE, WHICH DIRECTION

4170
02:53:15,336 --> 02:53:17,071
THEY GO, BUT MAYBE DEVELOPING

4171
02:53:17,071 --> 02:53:19,540
BIOMARKERS TO TRY TO SEE THAT,

4172
02:53:19,540 --> 02:53:22,076
TOEE IF THEY'RE MORE OF--AND

4173
02:53:22,076 --> 02:53:24,244
THIS MAY BE KIND OF A MORE OF AN

4174
02:53:24,244 --> 02:53:27,414
AMYLOID OR A TAU IMAGING TYPE

4175
02:53:27,414 --> 02:53:32,186
APPROACH THAT WE'VE DONE IN

4176
02:53:32,186 --> 02:53:33,887
SMALL EPIDEMIOLOGIC TODAYS TO

4177
02:53:33,887 --> 02:53:36,090
DISTINGUISH THAT GROUP THAT WE

4178
02:53:36,090 --> 02:53:38,058
CAN CHARACTERIZE THEM WELL

4179
02:53:38,058 --> 02:53:45,299
ENOUGH TO TREAT AS REISA POINTS

4180
02:53:45,299 --> 02:53:45,566
OUT.

4181
02:53:45,566 --> 02:53:48,068
NI BEING ALSO FOLLOWING UP ON

4182
02:53:48,068 --> 02:53:50,337
STEVE'S PATHOLOGIC TODAYING OF

4183
02:53:50,337 --> 02:53:52,706
CAA, THE AMYLOID DEFINITION OF

4184
02:53:52,706 --> 02:53:54,074
VESSELS APPEARS TO OCCUR 20 OR

4185
02:53:54,074 --> 02:53:57,878
30 YEARS BEFORE THE

4186
02:53:57,878 --> 02:54:00,314
MICROHEDGEERAGE, SO FOLLOWING OF

4187
02:54:00,314 --> 02:54:02,216
COURSE, AND TEASING OUT MAYBE

4188
02:54:02,216 --> 02:54:12,726
CHALLENGING IN EMERGING ITS OF

4189
02:54:14,361 --> 02:54:17,231
TIME COURSE.

4190
02:54:17,231 --> 02:54:17,998
>> DR. CLIFFORD?

4191
02:54:17,998 --> 02:54:21,335
>> SO TO STIMULATE THE

4192
02:54:21,335 --> 02:54:24,638
DISCUSSION AND MICHAEL'S COMMENT

4193
02:54:24,638 --> 02:54:26,507
THE TIME COURSE OF DEPOSITION

4194
02:54:26,507 --> 02:54:29,042
DOESN'T SEEM TO CLOSELY LINK

4195
02:54:29,042 --> 02:54:29,910
WITH WHEN ARIA'S OCCURRING

4196
02:54:29,910 --> 02:54:32,279
EMPLOY I WANT TO BRING 1 OF THE

4197
02:54:32,279 --> 02:54:37,084
BEAUTIFUL THINGS ABOUT STUDYING

4198
02:54:37,084 --> 02:54:39,052
PREDOMINANTLY INHERIT THED

4199
02:54:39,052 --> 02:54:40,020
ALZHEIMER'S POPULATION IS THAT

4200
02:54:40,020 --> 02:54:43,023
IT GIVES US MAGIC GOGGLES MUCH

4201
02:54:43,023 --> 02:54:44,658
MORE PRECISELY WHERE IN THE

4202
02:54:44,658 --> 02:54:47,294
COURSE OF THIS DEC WE ARE

4203
02:54:47,294 --> 02:54:50,831
WORKING AND AS I'VE WATCHED THIS

4204
02:54:50,831 --> 02:54:53,066
POPULATION BEING TITRATED WITH

4205
02:54:53,066 --> 02:54:56,069
GRADUALLY INCREASING DOSES OF

4206
02:54:56,069 --> 02:54:58,439
EITHER THAT DIDN'T CAUSE THIS

4207
02:54:58,439 --> 02:55:02,676
PROBLEM AT ALL, OR WITH

4208
02:55:02,676 --> 02:55:04,978
GRADUALLY INCREASING DOSES OF

4209
02:55:04,978 --> 02:55:05,879
[INDISCERNIBLE] THAT CLEARLY CAN

4210
02:55:05,879 --> 02:55:08,682
CAUSE IT, WHAT IS VERY OBVIOUS

4211
02:55:08,682 --> 02:55:11,018
TO A GRAY HAIRED CLINICIAN AND

4212
02:55:11,018 --> 02:55:16,156
DOESN'T REQUIRE MACHINE LEARNING

4213
02:55:16,156 --> 02:55:18,492
IS THAT THE NEARNESS TO THE YEAR

4214
02:55:18,492 --> 02:55:23,597
OF ONSET OF DEMENTIA IS A VERY

4215
02:55:23,597 --> 02:55:25,399
IMPORTANT PARAMETER AND

4216
02:55:25,399 --> 02:55:28,101
INTERESTING THING IS THAT THE

4217
02:55:28,101 --> 02:55:29,603
DOMINANTLY INHERITED POPULATION,

4218
02:55:29,603 --> 02:55:33,006
THE YEAR OF ONSET IS NOT DRIVEN

4219
02:55:33,006 --> 02:55:34,141
BY APOE4, A FASCINATING THING,

4220
02:55:34,141 --> 02:55:39,580
YOU THINK IT WOULD BE BUT

4221
02:55:39,580 --> 02:55:41,882
WE'VE--WE'VE BASICALLY THROWN

4222
02:55:41,882 --> 02:55:43,584
OUT APOE BEFORE AS AN

4223
02:55:43,584 --> 02:55:44,551
INTERESTING PARAMETER TO GOVERN

4224
02:55:44,551 --> 02:55:46,019
THESE FOLKS BECAUSE IT DOESN'T

4225
02:55:46,019 --> 02:55:48,222
GOVERN WHEN THE DEC WILL FAN

4226
02:55:48,222 --> 02:55:50,891
FEST ITSELF AND YET, YEAR OF

4227
02:55:50,891 --> 02:55:53,093
ONSET IS VERY CRITICAL SO

4228
02:55:53,093 --> 02:55:54,194
WHAT--YOU KNOW I THINK WE NEED

4229
02:55:54,194 --> 02:55:57,998
TO BE THINKING THIS IS PART OF

4230
02:55:57,998 --> 02:56:00,734
THE DOWN STREAM BUSINESS THAT'S

4231
02:56:00,734 --> 02:56:04,538
DRIVING THE ONSET OF COGNITIVE

4232
02:56:04,538 --> 02:56:07,774
DETERIORATION RATHER THAN THE

4233
02:56:07,774 --> 02:56:10,878
AMYLOID ITSELF, THE SAME

4234
02:56:10,878 --> 02:56:11,912
MISTHINKING OF CHANGING AMYLOID

4235
02:56:11,912 --> 02:56:19,019
IS THE WAY TO FIX THIS  DISEASEO

4236
02:56:19,019 --> 02:56:20,888
WHAT OTHER DOWN TREME STUFF

4237
02:56:20,888 --> 02:56:22,656
HAPPENS YOU GET NEUROFIBULARY

4238
02:56:22,656 --> 02:56:25,058
TANGLES, WE'VE HAD AMYLOID

4239
02:56:25,058 --> 02:56:25,792
PHOSPHORYLATION CHANGES

4240
02:56:25,792 --> 02:56:27,528
THROUGHOUT THE DEC BUT AT THE

4241
02:56:27,528 --> 02:56:29,196
TIME THAT COGNITION CHANGES,

4242
02:56:29,196 --> 02:56:33,767
THAT'S WHEN WE GET THESE TANGLES

4243
02:56:33,767 --> 02:56:35,903
FORMING.

4244
02:56:35,903 --> 02:56:38,305
THERE'S MANAGE DOWN STREAM AND I

4245
02:56:38,305 --> 02:56:39,172
THINK CRITICALLY DESIGNING THE

4246
02:56:39,172 --> 02:56:40,474
TRIALS SO WE'RE LOOKING FOR

4247
02:56:40,474 --> 02:56:41,542
THOSE DOWN STREAM MARKERS IS

4248
02:56:41,542 --> 02:56:45,812
GOING TO BE THE MOST USEFUL WAY

4249
02:56:45,812 --> 02:56:47,681
AND IT'S REALLY DRIVE BY THIS

4250
02:56:47,681 --> 02:56:49,917
NOTION, IT'S NOT EVERYBODY WITH

4251
02:56:49,917 --> 02:56:51,518
THESE DOMINANTLY INHERITED

4252
02:56:51,518 --> 02:56:53,820
MUSEUM TAIGS AS AMYLOID DEPOSITS

4253
02:56:53,820 --> 02:56:56,356
FOR DECADES AND WE ARE NOT

4254
02:56:56,356 --> 02:56:59,092
SEEING ARIA EVEN WITH VERY HIGH

4255
02:56:59,092 --> 02:57:00,861
DOSES OF [INDISCERNIBLE] UNTIL

4256
02:57:00,861 --> 02:57:03,096
YOU GET NEAR OR PAST THE YEAR OF

4257
02:57:03,096 --> 02:57:05,098
ONSET, SO I THINK IT--I THINK

4258
02:57:05,098 --> 02:57:07,067
THERE ARE CRITICAL DOWN TREME

4259
02:57:07,067 --> 02:57:09,136
PARTS OF THE DEC THAT WE NEED TO

4260
02:57:09,136 --> 02:57:18,845
PAY VERY CLOSE ATTENTION TO.

4261
02:57:18,845 --> 02:57:20,080
>> THANK YOU.

4262
02:57:20,080 --> 02:57:21,648
>> I AM CURIOUS ABOUT THE

4263
02:57:21,648 --> 02:57:25,185
PANEL'S THINKING ABOUT THESE

4264
02:57:25,185 --> 02:57:26,687
REMARKS.

4265
02:57:26,687 --> 02:57:29,489
NOT ONLY--WHAT'S HAPPENING DOWN

4266
02:57:29,489 --> 02:57:31,892
STREAM BUT WE'RE ACUMING THINGS

4267
02:57:31,892 --> 02:57:34,428
ARE JUST LINEARLY PROGRESSING SO

4268
02:57:34,428 --> 02:57:36,096
THE QUESTION AND I'M SAYING

4269
02:57:36,096 --> 02:57:39,733
THIS, FROM A CLINICAL

4270
02:57:39,733 --> 02:57:44,137
PERSPECTIVE, WE SEE PEOPLE WHO

4271
02:57:44,137 --> 02:57:46,239
HAVE THE ABILITY TO COMPENSATE

4272
02:57:46,239 --> 02:57:47,074
ISSUES RIGHT?

4273
02:57:47,074 --> 02:57:51,078
AND SO TO--AND TO ADAPT, SO,

4274
02:57:51,078 --> 02:57:53,347
WHAT MIGHT BE AND WE KNOW

4275
02:57:53,347 --> 02:57:56,383
EDUCATION IS PART OF THAT

4276
02:57:56,383 --> 02:57:59,052
SIGNAL, BUT ARE THERE ALSO

4277
02:57:59,052 --> 02:58:02,089
SIGNALS AND INTERVENTIONS THAT

4278
02:58:02,089 --> 02:58:05,859
MIGHT HELP IN THAT SPACE AS WELL

4279
02:58:05,859 --> 02:58:08,528
AS WE'RE TRYING TO THINK ABOUT,

4280
02:58:08,528 --> 02:58:10,397
SO WHAT DID THIS MEAN AND WHAT

4281
02:58:10,397 --> 02:58:11,999
DO WE DO ABOUT IT?

4282
02:58:11,999 --> 02:58:13,867
IT'S A QUESTION THAT WE GET IN

4283
02:58:13,867 --> 02:58:18,605
THE CLINIC EVERY WEEK.

4284
02:58:18,605 --> 02:58:21,975
>> SO WHAT IS RESILIENCE?

4285
02:58:21,975 --> 02:58:23,276
NWHAT IS REJILLIENCE AND WHAT

4286
02:58:23,276 --> 02:58:28,482
WOULD PREDICT AND FOSTER THAT,

4287
02:58:28,482 --> 02:58:29,983
REGARDLESS OR DESPITE

4288
02:58:29,983 --> 02:58:31,251
PROGRESSION OF AMYLOID LOAD OR

4289
02:58:31,251 --> 02:58:33,220
WHATEVER LOAD THERE IS AND WE

4290
02:58:33,220 --> 02:58:37,357
SEE A LOT OF MICROVASCULAR DEC

4291
02:58:37,357 --> 02:58:39,359
THAT IS YET TO BE CLASSIFIED AND

4292
02:58:39,359 --> 02:58:40,661
I WISH THERE WERE A WAY FOR US

4293
02:58:40,661 --> 02:58:43,730
TO BE ABLE TO DETECT WHO IS AT

4294
02:58:43,730 --> 02:58:46,466
RISK BEFORE THEY COME INTO

4295
02:58:46,466 --> 02:58:50,137
CLINIC WITH MULTIPLE STROKES.

4296
02:58:50,137 --> 02:58:51,571
BUT THAT'S A DIFFERENT QUESTION,

4297
02:58:51,571 --> 02:59:01,982
SO CURIOUS ABOUT THAT. 

4298
02:59:02,582 --> 02:59:06,887
THANK YOU.

4299
02:59:06,887 --> 02:59:09,156
>> OTHER DOWN STREAM
TARGETS,

4300
02:59:09,156 --> 02:59:11,658
TAU MAY BE 1 ANGLE, DAMAGE TO

4301
02:59:11,658 --> 02:59:16,663
THE VASCULAR TREE IN OTHER

4302
02:59:16,663 --> 02:59:17,030
REGARDS.

4303
02:59:17,030 --> 02:59:19,332
>> AS CLINTON RAISED
BEFORE CAN

4304
02:59:19,332 --> 02:59:22,402
WE SURVEY THE HEALTH OF THE

4305
02:59:22,402 --> 02:59:24,237
SMALL BLOOD VESSELS OR THE LARGE

4306
02:59:24,237 --> 02:59:27,340
BLOOD VESSELS IN THE BRAIN,

4307
02:59:27,340 --> 02:59:30,077
SHERRY SAYS TO PREDICT THESE

4308
02:59:30,077 --> 02:59:34,381
PATIENTS THAT HAVE DEVELOPED

4309
02:59:34,381 --> 02:59:36,683
STROKES COULD THAT BE AN OPTION,

4310
02:59:36,683 --> 02:59:38,752
HAD IS MORE A QUESTION AROUND

4311
02:59:38,752 --> 02:59:41,855
RESILIENCE IS THAT THERE MAY BE

4312
02:59:41,855 --> 02:59:43,724
BIOMARKERS OF RESILIENCE AND WE

4313
02:59:43,724 --> 02:59:46,326
CAN ALL HUNT THOSE DOWN BUT

4314
02:59:46,326 --> 02:59:47,928
PATIENTS BRING RESILIENCE TO THE

4315
02:59:47,928 --> 02:59:48,995
CLINIC SO THEY'RE RESILIENT,

4316
02:59:48,995 --> 02:59:57,270
IT'S SOMETHING ALSO TO REMEMBER.

4317
02:59:57,270 --> 02:59:59,973
>> SPEAKING, I AM NOT M.
D.

4318
02:59:59,973 --> 03:00:02,175
I AM IMMUNOLOGIST, I WORK WITH

4319
03:00:02,175 --> 03:00:04,411
VACCINE FOR 23 YEARS SO DOWN

4320
03:00:04,411 --> 03:00:06,346
STREAM PROCESSING, IT'S

4321
03:00:06,346 --> 03:00:08,315
OBVIOUSLY TAU, OBVIOUSLY

4322
03:00:08,315 --> 03:00:09,382
INFLAMMATION, WHAT WE KNOW, BUT

4323
03:00:09,382 --> 03:00:15,589
I WILL LIKE TO JUST REMIND YOU

4324
03:00:15,589 --> 03:00:19,326
THAT MRI AND PET SCAN YOU SEE AG

4325
03:00:19,326 --> 03:00:20,961
IMREIGATED MOLECULES.

4326
03:00:20,961 --> 03:00:26,166
TODAY, WE KNOW THAT IT'S NOT

4327
03:00:26,166 --> 03:00:26,700
MAJOR PROBLEM.

4328
03:00:26,700 --> 03:00:32,038
THERE ARE TONS OF DATA SHOWING

4329
03:00:32,038 --> 03:00:34,541
THAT AGGREGATED SMALL MOLECULES

4330
03:00:34,541 --> 03:00:37,244
AND MUCH MORE IMPORTANT AND THEY

4331
03:00:37,244 --> 03:00:41,882
ARE IN THE BLOOD MARKEDLY YOU

4332
03:00:41,882 --> 03:00:44,651
CAN SEE IT IN THE PET SCAN SO

4333
03:00:44,651 --> 03:00:46,653
THAT'S SOME MAJOR POINT, WHAT

4334
03:00:46,653 --> 03:00:49,756
YOU ARE TARGETING AT WHAT TIME

4335
03:00:49,756 --> 03:00:50,991
AND TODAY SOMEONE SAID THAT WE

4336
03:00:50,991 --> 03:00:56,863
NEED TO USE A VACCINE BEFORE YOU

4337
03:00:56,863 --> 03:00:57,931
GET AGGREGATION SO YOU WILL NOT

4338
03:00:57,931 --> 03:01:00,667
HAVE ANY PROBLEM WITH THAT,

4339
03:01:00,667 --> 03:01:02,836
UNLIKELY YOU WILL HAVE ARIA

4340
03:01:02,836 --> 03:01:05,906
BECAUSE THERE IS NOTHING TO

4341
03:01:05,906 --> 03:01:12,312
TARGET AND AT THE SAME TIME YOU

4342
03:01:12,312 --> 03:01:15,482
CAN DELAY PEL MERRIZATION OF

4343
03:01:15,482 --> 03:01:17,050
AMYLOID AND TAU AND YOU WILL

4344
03:01:17,050 --> 03:01:21,388
HAVE 20 YEARS EARLIER WHERE YOU

4345
03:01:21,388 --> 03:01:22,622
WILL [INDISCERNIBLE] DEMENTIA

4346
03:01:22,622 --> 03:01:23,657
FOR MANY YEARS.

4347
03:01:23,657 --> 03:01:26,193
AND THAT IS WHY IT'S VERY

4348
03:01:26,193 --> 03:01:27,260
IMPORTANT THIS MONOCLONAL

4349
03:01:27,260 --> 03:01:27,694
ANTIBODY.

4350
03:01:27,694 --> 03:01:30,864
THIS WORK IS EXTREMELY

4351
03:01:30,864 --> 03:01:31,164
INTERESTING.

4352
03:01:31,164 --> 03:01:35,702
YOU KNOW THESE 20 YORES WHICH WE

4353
03:01:35,702 --> 03:01:39,773
ARE, THANKS TO FRANK HAVING THIS

4354
03:01:39,773 --> 03:01:41,374
IMMUNOTHERAPY, IT'S REALLY BIG

4355
03:01:41,374 --> 03:01:41,708
THING.

4356
03:01:41,708 --> 03:01:43,243
WE CAN SEE THAT IT'S WORKING.

4357
03:01:43,243 --> 03:01:45,478
YES WE DO HAVE A PROBLEM THAT WE

4358
03:01:45,478 --> 03:01:47,647
NEED TO CLEAR THE PROBLEM, AND

4359
03:01:47,647 --> 03:01:50,951
THEN WE HAVE A BIOMARKERS TODAY

4360
03:01:50,951 --> 03:01:52,719
WHICH IS DEFINITELY IN THE

4361
03:01:52,719 --> 03:01:54,354
BLOOD, BECAUSE THAT'S WHAT I

4362
03:01:54,354 --> 03:01:56,857
THINK MY INPUT CAN THINK TO LOOK

4363
03:01:56,857 --> 03:01:58,758
AT THAT AND TART IMMUNOTHERAPY

4364
03:01:58,758 --> 03:02:01,461
AS SOON AS POSSIBLE.

4365
03:02:01,461 --> 03:02:03,363
BEFORE INFLAMMATION AND EVEN

4366
03:02:03,363 --> 03:02:03,830
BEFORE THE TAU.

4367
03:02:03,830 --> 03:02:10,103
SO THAT I THINK ARE WHAT

4368
03:02:10,103 --> 03:02:11,905
IMMUNOTHERAPY SHOULD TART WITH.

4369
03:02:11,905 --> 03:02:15,742
THANK YOU .

4370
03:02:15,742 --> 03:02:17,043
>> I THINK THAT ECHOES
WHAT MANY

4371
03:02:17,043 --> 03:02:20,146
OF US ARE THINKING THAT

4372
03:02:20,146 --> 03:02:21,181
PREVENTION CONTEXT IS PROBABLY,

4373
03:02:21,181 --> 03:02:25,385
YOU KNOW THE MOST EFFECTIVE

4374
03:02:25,385 --> 03:02:28,989
TREATMENT THAT YOU CAN REALLY

4375
03:02:28,989 --> 03:02:31,858
CONSIDER JUST IN TERMS OF THE

4376
03:02:31,858 --> 03:02:32,559
MAGNITUDE OF TREATMENT OPTION

4377
03:02:32,559 --> 03:02:34,294
EMPLOY SO I THINK THAT'S VERY

4378
03:02:34,294 --> 03:02:35,428
MUCH WHERE THE COMMUNITY'S

4379
03:02:35,428 --> 03:02:37,163
THINKING HAS BEEN IN THE LAST

4380
03:02:37,163 --> 03:02:40,333
FEW YEARS AND HAS BEEN THE BASIS

4381
03:02:40,333 --> 03:02:42,569
FOR YOU KNOW THE LARGE

4382
03:02:42,569 --> 03:02:44,437
INITIATIVES WE'VE SEEN FROM NIH

4383
03:02:44,437 --> 03:02:45,805
TO SUPPORT THAT.

4384
03:02:45,805 --> 03:02:47,440
THOSE ARE EXTREMELY EXPENSIVE

4385
03:02:47,440 --> 03:02:50,143
TRIALS, AND THEY'RE NOT

4386
03:02:50,143 --> 03:02:54,981
SOMETHING THAT  INDUSTRY ENGAGES

4387
03:02:54,981 --> 03:02:58,051
IN WITHOUT SOME KIND OF SUPPORT.

4388
03:02:58,051 --> 03:02:59,286
THEY'RE VERY CHALLENGING TO

4389
03:02:59,286 --> 03:03:00,587
EFFECTIVE LIE IMPLEMENT AND DO

4390
03:03:00,587 --> 03:03:00,887
WELL.

4391
03:03:00,887 --> 03:03:02,789
SO IT'S A CONSIDERABLE CHALLENGE

4392
03:03:02,789 --> 03:03:04,958
AND IT'S A CONSIDERABLE HEALTH

4393
03:03:04,958 --> 03:03:10,697
PROBLEM AS A RESULT OF THAT,

4394
03:03:10,697 --> 03:03:11,331
STILL.

4395
03:03:11,331 --> 03:03:12,165
>> OKAY, WE HAVE 1 MORE
QUESTION

4396
03:03:12,165 --> 03:03:13,900
AND THEN WE NEED TO MOVE ON TO

4397
03:03:13,900 --> 03:03:17,203
THE NEXT, WE HAVE A WONDERFUL

4398
03:03:17,203 --> 03:03:19,005
BASIC NECKANISMS OVERVIEW, JUST

4399
03:03:19,005 --> 03:03:21,107
REINFORCE WHAT SUSAN JUST SAID

4400
03:03:21,107 --> 03:03:22,509
AS A CLINICIAN, THERE'S NO

4401
03:03:22,509 --> 03:03:23,977
DISEASE IN MEDICINE THAT DOESN'T

4402
03:03:23,977 --> 03:03:26,012
RESPOND TO THERAPY BETTER, THE

4403
03:03:26,012 --> 03:03:30,116
EARLIER YOU TREAT IT, AS A DRUG

4404
03:03:30,116 --> 03:03:31,618
DEVELOPER, PREVENTION TRIALS IN

4405
03:03:31,618 --> 03:03:34,454
IMPOSSIBLE TO DO, AND AS YOU

4406
03:03:34,454 --> 03:03:37,891
JUST SAID, FOR DEMENTIA, IT'S

4407
03:03:37,891 --> 03:03:38,625
VIRTUALLY IMPOSSIBLE TO DO

4408
03:03:38,625 --> 03:03:40,193
BECAUSE WE HAVE NO PREDICTION

4409
03:03:40,193 --> 03:03:42,128
ABOUT WHO'S GOING TO DEVELOP THE

4410
03:03:42,128 --> 03:03:43,630
DEMENTIA NO MATTER WHAT

4411
03:03:43,630 --> 03:03:45,065
BIOMARKER YOU CHOOSE, SO I

4412
03:03:45,065 --> 03:03:46,599
NOTICED THIS MORNING EVERYONE'RE

4413
03:03:46,599 --> 03:03:48,601
EVERYBODY KEEPS KIND OF

4414
03:03:48,601 --> 03:03:49,235
DEFALLING TO THE PREVENTION

4415
03:03:49,235 --> 03:03:51,004
PIECE, I THINK THAT'S A

4416
03:03:51,004 --> 03:03:52,872
DANGEROUS PLACE FOR US TO BE

4417
03:03:52,872 --> 03:03:55,375
TALKING ABOUT BECAUSE IT'S AN

4418
03:03:55,375 --> 03:03:56,076
IRRATIONAL GOAL.

4419
03:03:56,076 --> 03:03:58,111
OUR GOAL NEEDS TO TREAT THE

4420
03:03:58,111 --> 03:03:59,779
PROBLEM WE HAVE WHICH A PATIENT

4421
03:03:59,779 --> 03:04:02,215
SHOWS UP WITH DEMENTIA, WE TREAT

4422
03:04:02,215 --> 03:04:03,883
THEM, LET'S GET THEM BETTER,

4423
03:04:03,883 --> 03:04:05,819
LET'S NOT WORRY ABOUT A PROBLEM

4424
03:04:05,819 --> 03:04:16,196
WE CAN SOLVE IN 30 YEARS.

4425
03:04:16,196 --> 03:04:17,397
>> DISAGREE TOTALLY, WE
CAN

4426
03:04:17,397 --> 03:04:19,399
PREVENT ALL SORTS OF DECS WITH

4427
03:04:19,399 --> 03:04:21,334
VACCINES, WE CAN DO THE SAME

4428
03:04:21,334 --> 03:04:28,308
FORRAL JEIMER'S IF WE DO IT

4429
03:04:28,308 --> 03:04:28,675
RIGHT.

4430
03:04:28,675 --> 03:04:30,477
>> SO WE CAN DO BOTH AND

4431
03:04:30,477 --> 03:04:32,445
PREVENTION TRIALS ARE FEASIBLE,

4432
03:04:32,445 --> 03:04:35,315
THERE ARE ONGOING PREVENTION

4433
03:04:35,315 --> 03:04:36,116
TRIALS WITH [INDISCERNIBLE],

4434
03:04:36,116 --> 03:04:38,718
THERE IS THE ABILITY TO IDENTIFY

4435
03:04:38,718 --> 03:04:39,786
PEOPLE WITH ELEVATED AMYLOID

4436
03:04:39,786 --> 03:04:42,322
BEFORE THEY HAVE THE ONSET OF

4437
03:04:42,322 --> 03:04:42,989
SYMPTOMS OR COGNITIVELY IPT

4438
03:04:42,989 --> 03:04:43,990
GREATER TACT.

4439
03:04:43,990 --> 03:04:46,326
INITIALLY THAT WAS DONE

4440
03:04:46,326 --> 03:04:50,363
WITH--THAT'S DONE WITH PET SCANS

4441
03:04:50,363 --> 03:04:54,768
AND--AND CSF BUT INCREASINGLY

4442
03:04:54,768 --> 03:04:55,568
BLOOD-BASED BIOMARKERS THOSE

4443
03:04:55,568 --> 03:04:59,339
PEOPLE ARE AT RISK AND IF

4444
03:04:59,339 --> 03:05:00,273
THERE'S PREVENTAATIVE TREATMENT

4445
03:05:00,273 --> 03:05:01,775
INITIATED LIKE A STATIN, IT

4446
03:05:01,775 --> 03:05:03,443
WON'T BE AS EASY AS A STATIN BUT

4447
03:05:03,443 --> 03:05:06,212
I THINK THAT'S WHERE THE FIELD

4448
03:05:06,212 --> 03:05:06,746
IS GOING.

4449
03:05:06,746 --> 03:05:08,448
IT IS IMPORTANT TO TREAT THE

4450
03:05:08,448 --> 03:05:10,116
PATIENT WITH SYMPTOMS BUT WITH

4451
03:05:10,116 --> 03:05:11,518
ALL THESE TREATMENTS, THE

4452
03:05:11,518 --> 03:05:14,487
EARLIER YOU TREAT, THE EARLIER

4453
03:05:14,487 --> 03:05:16,890
YOU PREVENT THAT NERVE CELL LOSS

4454
03:05:16,890 --> 03:05:25,198
THAT IS IRREVERSIBLE.

4455
03:05:25,198 --> 03:05:29,269
>> DID YOU WANT TO A
SOMETHING

4456
03:05:29,269 --> 03:05:30,236
DR. LING?

4457
03:05:30,236 --> 03:05:31,771
>> JUST TO SAY THAT DON'T
THINK

4458
03:05:31,771 --> 03:05:33,440
OF THE PREVENTION AS PRIMARY

4459
03:05:33,440 --> 03:05:34,941
PREVEPGZ, I THINK THERE'S EVERY

4460
03:05:34,941 --> 03:05:40,146
OPPORTUNITY WE CAN TAKE TO

4461
03:05:40,146 --> 03:05:42,182
MITIGATE THE PROGRESSION OF THE

4462
03:05:42,182 --> 03:05:44,451
DISEASE, THE ABILITY TO

4463
03:05:44,451 --> 03:05:48,021
COMPENSATE DESPITE THE PRESENCE

4464
03:05:48,021 --> 03:05:49,155
OF ONGOING DEC EMPLOY I THINK,

4465
03:05:49,155 --> 03:05:51,424
YOU KNOW YOU HAVE A VERY NEW

4466
03:05:51,424 --> 03:05:56,329
AREA OF STUDY HERE, SO, MAKE

4467
03:05:56,329 --> 03:05:59,099
FRIEND, THINK NEW THOUGHTS, I

4468
03:05:59,099 --> 03:06:01,868
THINK THIS IS REALLY A

4469
03:06:01,868 --> 03:06:02,969
TREMENDOUS OPPORTUNITY TO

4470
03:06:02,969 --> 03:06:04,237
UNDERSTAND THE PROCESSES AND

4471
03:06:04,237 --> 03:06:07,040
WHAT MIGHT HELP THE PEOPLE WHO

4472
03:06:07,040 --> 03:06:09,609
LIVE WITH THESE PROCESSES IN

4473
03:06:09,609 --> 03:06:12,846
THEIR MINDS, SO THANK YOU SO

4474
03:06:12,846 --> 03:06:14,214
MUCH, WALTER.

4475
03:06:14,214 --> 03:06:15,315
NWELL THAT'S A GREAT PLACE TO

4476
03:06:15,315 --> 03:06:15,682
STOP.

4477
03:06:15,682 --> 03:06:17,951
I WILL LIKE TO THANK THE

4478
03:06:17,951 --> 03:06:19,185
PANELISTS VERY MUCH AND PEOPLE

4479
03:06:19,185 --> 03:06:20,353
WHO HAVE QUESTIONS AND WE WILL

4480
03:06:20,353 --> 03:06:23,756
NOW MOVE ON TO BASIC MECHANISMS

4481
03:06:23,756 --> 03:06:26,025
OVERVIEW AND IT'LL BE MODERATED

4482
03:06:26,025 --> 03:06:29,562
BY DR. MARK FISHER, AND

4483
03:06:29,562 --> 03:06:30,597
DR. DONNA WILCOCK AND I THINK

4484
03:06:30,597 --> 03:06:32,232
WE'RE DOING THIS RIGHT AWAY,

4485
03:06:32,232 --> 03:06:33,399
RIGHT IN AND THEN WE WILL TAKE

4486
03:06:33,399 --> 03:06:36,136
THE BREAK AFTER THAT?

4487
03:06:36,136 --> 03:06:46,679
OKAY, SEEMS LIKE WE WOULD TAKE A

4488
03:07:21,981 --> 03:07:23,583
BREAK NOW.

4489
03:07:23,583 --> 03:07:24,851
>> ALL RIGHT, THANK,
EVERYBODY

4490
03:07:24,851 --> 03:07:26,286
FOR STICKING AROUND EMPLOY WE

4491
03:07:26,286 --> 03:07:28,087
WILL SWITCH GEAR ANDS TALK IN

4492
03:07:28,087 --> 03:07:29,389
BASIC MECHANISMS NOW, SO IT'S MY

4493
03:07:29,389 --> 03:07:33,226
PLEASURE TO INTRODUCE MY CO

4494
03:07:33,226 --> 03:07:36,629
MODERATOR DR. MARK FISHER FROM

4495
03:07:36,629 --> 03:07:37,564
UC IRVINE.

4496
03:07:37,564 --> 03:07:40,667
THANKS MARK.

4497
03:07:40,667 --> 03:07:40,967
RESPIRATORY

4498
03:07:40,967 --> 03:07:44,337
>> THANK YOU DONNA AND I
WANT TO

4499
03:07:44,337 --> 03:07:47,707
THANK FRANCESCA AND NINDS FOR

4500
03:07:47,707 --> 03:07:51,978
THE INVITATION TO SPEAK TODAY.

4501
03:07:51,978 --> 03:07:54,814
AS I WAS DECIDING ON A TITLE OF

4502
03:07:54,814 --> 03:08:01,454
THIS PRESENTATION, I CONSIDERED

4503
03:08:01,454 --> 03:08:04,457
CALLING IT CEREBRAL AMYLOID

4504
03:08:04,457 --> 03:08:05,258
ANETWORK GASHING IOPATHY, VIEW

4505
03:08:05,258 --> 03:08:08,361
FROM THE WEST COAST BECAUSE IT'S

4506
03:08:08,361 --> 03:08:09,896
JUST ABOUT IMPOSSIBLE TO ESCAPE

4507
03:08:09,896 --> 03:08:11,197
THE LONG SHADOW OF ALL THE GREAT

4508
03:08:11,197 --> 03:08:19,005
WORK DONE BY THE BOSTON GROUP ON

4509
03:08:19,005 --> 03:08:19,172
CAA.

4510
03:08:19,172 --> 03:08:29,682
HOWEVER, I WILL SHARE WITH YOU

4511
03:08:32,518 --> 03:08:33,186
OUR TAKE.

4512
03:08:33,186 --> 03:08:37,123
O WE RECENTLY HAD THE

4513
03:08:37,123 --> 03:08:38,891
OPPORTUNITY TO REVIEW SEVERAL

4514
03:08:38,891 --> 03:08:42,395
MICROVASCULAR DEC IN A

4515
03:08:42,395 --> 03:08:44,197
RELATIVELY COMPREHENSIVE

4516
03:08:44,197 --> 03:08:44,430
FASHION.

4517
03:08:44,430 --> 03:08:47,934
WE LOOKED AT AGING,

4518
03:08:47,934 --> 03:08:53,473
HYPERTENSION, CHRONIC KIDNEY

4519
03:08:53,473 --> 03:08:53,873
DISEASE, CAROUSEL,

4520
03:08:53,873 --> 03:08:59,912
[INDISCERNIBLE] 

4521
03:08:59,912 --> 03:09:01,247
[INDISCERNIBLE] DISEASE AND

4522
03:09:01,247 --> 03:09:01,581
OTHERS.

4523
03:09:01,581 --> 03:09:06,085
WAWE CONCLUDED WAS THAT SEVERAL

4524
03:09:06,085 --> 03:09:07,553
MICROVASCULAR DEC MANAGE THE

4525
03:09:07,553 --> 03:09:10,590
PARADOX AND THE PARADOCK IS THAT

4526
03:09:10,590 --> 03:09:13,593
THE BRAIN PAIREN CHIMAL VASCULAR

4527
03:09:13,593 --> 03:09:17,463
DEC ARE RELATIVELY LIMITED AND

4528
03:09:17,463 --> 03:09:22,001
THESE CONSIST OF

4529
03:09:22,001 --> 03:09:23,036
[INDISCERNIBLE], DEMILEINATION,

4530
03:09:23,036 --> 03:09:23,670
MICROHEMORRHAGE,OT 1 HAND.

4531
03:09:23,670 --> 03:09:25,872
ON THE OTHER HAND THERE IS A

4532
03:09:25,872 --> 03:09:28,207
WIDE VARIETY OF

4533
03:09:28,207 --> 03:09:28,808
ARE--ADMINISTRATIVE TERIOLEAR

4534
03:09:28,808 --> 03:09:31,477
ABNORMALITIES THAT ARE

4535
03:09:31,477 --> 03:09:33,579
RELATIVELY DISTINCTIVE FOR EACH

4536
03:09:33,579 --> 03:09:36,582
PATHOLOGIC AND CLINICAL

4537
03:09:36,582 --> 03:09:37,150
PATHOLOGIC ENTITY SUGGESTING

4538
03:09:37,150 --> 03:09:40,687
THAT IT IS THE

4539
03:09:40,687 --> 03:09:41,287
ARE--ADMINISTRATIVE TERIOLE

4540
03:09:41,287 --> 03:09:43,256
ACTING AS FINAL COMMON PATHWAY,

4541
03:09:43,256 --> 03:09:47,493
SOURCE AND MEDIATOR OF THE

4542
03:09:47,493 --> 03:09:49,395
PAIREN CHIMAL INJURIES MANIFEST

4543
03:09:49,395 --> 03:09:50,196
IN SEVERAL MICROVASCULAR DEC SO

4544
03:09:50,196 --> 03:09:52,965
I WILL MAKE SURE MY COLLEAGUE

4545
03:09:52,965 --> 03:09:56,235
KERRY [INDISCERNIBLE] HAS COINED

4546
03:09:56,235 --> 03:10:02,275
THE TERM CEREBRAL ANGIO MIRROR

4547
03:10:02,275 --> 03:10:02,675
 MYOPATHY

4548
03:10:02,675 --> 03:10:13,186
IN WHICH THESE ARE SO  ARE SO

4549
03:10:28,101 --> 03:10:29,802
HIGHLY PREVALENT.

4550
03:10:29,802 --> 03:10:32,038
WE KNOW THIS IS NOT THE AREAS

4551
03:10:32,038 --> 03:10:32,905
THAT PARTICULARLY PROMINENT,

4552
03:10:32,905 --> 03:10:35,308
IT'S THE MEDIA WHERE ALL OR MOST

4553
03:10:35,308 --> 03:10:36,275
OF THE ACTION IS.

4554
03:10:36,275 --> 03:10:40,880
AND THIS IS WHERE WE SEE

4555
03:10:40,880 --> 03:10:42,448
PROGRESSIVE LOSS OF SMOOTH

4556
03:10:42,448 --> 03:10:44,951
MUSCLE CELLS, REPLACEMENT BY

4557
03:10:44,951 --> 03:10:46,652
BETA AMYLOID AND EVENTUALLY LOSS

4558
03:10:46,652 --> 03:10:49,489
OF BETA AMYLOID FROM THE VESSEL

4559
03:10:49,489 --> 03:10:54,227
WALL ITSELF PRECEDING DEVELOP AM

4560
03:10:54,227 --> 03:10:55,862
OF SERIES POINTSEBERAL

4561
03:10:55,862 --> 03:10:56,329
MICROHEMORRHAGES AND

4562
03:10:56,329 --> 03:10:56,929
MICROPLEADS.

4563
03:10:56,929 --> 03:10:58,631
SO SPEAKING OF MICROPLEADS WHAT

4564
03:10:58,631 --> 03:11:02,969
CAN WE SAY ABOUT SEVERAL

4565
03:11:02,969 --> 03:11:04,537
MICROPLEADS AND CEREBRAL

4566
03:11:04,537 --> 03:11:04,904
MICROHEMORRHAGE.

4567
03:11:04,904 --> 03:11:06,873
IN 2014 I ATTEMPTED TO COME UP

4568
03:11:06,873 --> 03:11:09,709
WITH A CLASISK SCHEME OF

4569
03:11:09,709 --> 03:11:10,376
MICROPLEAD ANDS MICROHEMORRHAGES

4570
03:11:10,376 --> 03:11:13,246
AND CAME UP WITH 3 DIFFERENT

4571
03:11:13,246 --> 03:11:13,546
CATEGORIES.

4572
03:11:13,546 --> 03:11:17,583
THE FIRST WAS WHAT I CALL

4573
03:11:17,583 --> 03:11:18,084
PRIMARY MICROPLEADS OR

4574
03:11:18,084 --> 03:11:19,385
MICROHEMORRHAGE AND THIS IS

4575
03:11:19,385 --> 03:11:20,453
WHERE THE INITIAL PRIMARY YOUR

4576
03:11:20,453 --> 03:11:25,792
IS TO THE VESSEL WALL, BOTH AT

4577
03:11:25,792 --> 03:11:27,326
THE ARTERIOLE, ARTERIOLEAR LEVEL

4578
03:11:27,326 --> 03:11:31,297
AND CAPILLARY LEVEL AND

4579
03:11:31,297 --> 03:11:32,465
CAPILLARY DERIVED MICROHOM

4580
03:11:32,465 --> 03:11:34,834
RAMMINGS ARE PROMINENT IN

4581
03:11:34,834 --> 03:11:37,637
VARIOUS ANIMAL MODELS OF SEVERAL

4582
03:11:37,637 --> 03:11:43,609
MICROHEMORRHAGE. 

4583
03:11:43,609 --> 03:11:50,550
IN ADDITION THERE WERE FAIRLY

4584
03:11:50,550 --> 03:11:53,786
SPECULATIVE AT THE TIME CALLED

4585
03:11:53,786 --> 03:11:54,253
PSEUDOMICROPLEADS.

4586
03:11:54,253 --> 03:11:58,791
THE IDEA HERE IS THAT PERHAPS

4587
03:11:58,791 --> 03:12:01,060
MICROPLEADS OR MICROHEMORRHAGES

4588
03:12:01,060 --> 03:12:02,361
COULD DEVELOP WITHOUT FRANK

4589
03:12:02,361 --> 03:12:03,396
DISRUPTION OF THE VESSEL WALL

4590
03:12:03,396 --> 03:12:08,234
AND THIS WAS INSPIRED BY SEVERAL

4591
03:12:08,234 --> 03:12:10,603
OBSERVATIONS BY BY JAN WAY AND

4592
03:12:10,603 --> 03:12:13,072
COLLEAGUES SHOWING RELEASE OF

4593
03:12:13,072 --> 03:12:16,375
IRON FROM OLIGO DENDRITIC CELL O

4594
03:12:16,375 --> 03:12:19,111
SIGHT TORES INDUCE BY ESCHEMIA,

4595
03:12:19,111 --> 03:12:21,047
AND THEN THERE'S 1 BY COLLEAGUES

4596
03:12:21,047 --> 03:12:24,984
DESCRIBING A PROCESS REFERRED TO

4597
03:12:24,984 --> 03:12:27,553
AS ANGY OFAGEY, SO CLOTS FROM

4598
03:12:27,553 --> 03:12:28,454
THE MICROVASCULATURE SO WHAT I

4599
03:12:28,454 --> 03:12:32,859
WILL LIKE TO DO NOW IS TRY TO

4600
03:12:32,859 --> 03:12:33,960
UPDATE THIS CLASS IIVES SCHEME

4601
03:12:33,960 --> 03:12:35,294
AND SO HOW IT MAY BE REEL

4602
03:12:35,294 --> 03:12:45,338
KEEPSAKES VABT TO--RELEVANT TO

4603
03:12:45,338 --> 03:12:46,806
OUR CEREBRAL ANGIO OPERATING

4604
03:12:46,806 --> 03:12:47,507
GLOBALLY RAGHTY.

4605
03:12:47,507 --> 03:12:54,680
SO THE NOTION IT IS ARTERIOLE

4606
03:12:54,680 --> 03:12:57,884
RUPTURE THAT RESULTS IN

4607
03:12:57,884 --> 03:12:58,918
MICROPLEADS OR HEMORRHAGES WAS

4608
03:12:58,918 --> 03:13:01,254
REPORTED EARLY ON AND WELL

4609
03:13:01,254 --> 03:13:02,955
ACCEPTED, IN TERMS OF CARK A,

4610
03:13:02,955 --> 03:13:04,190
THIS AN EXAMPLE OF A BEAUTIFUL

4611
03:13:04,190 --> 03:13:06,659
PAPER FROM THE BOSTON GROUP IN

4612
03:13:06,659 --> 03:13:10,663
WHICH THE VESSELS THAT YOU SEE

4613
03:13:10,663 --> 03:13:11,564
ARE GREEN, FLOURESCENTLY LABELED

4614
03:13:11,564 --> 03:13:14,267
AND THEN THERE IS AN IMMUNOSTAIN

4615
03:13:14,267 --> 03:13:15,701
OF FIEB RIN O GEN, THAT'S THE

4616
03:13:15,701 --> 03:13:18,404
RED STAIN AND IT SEEMS TO THAT

4617
03:13:18,404 --> 03:13:21,407
THE FIEB RIN ISACKING AS A

4618
03:13:21,407 --> 03:13:23,609
BRANCH AT THE POINT OF THE

4619
03:13:23,609 --> 03:13:24,043
ARTERIOLES.

4620
03:13:24,043 --> 03:13:26,112
THIS A STRONG SUGGIEST THAT

4621
03:13:26,112 --> 03:13:29,348
WE'RE DEALING WITH A PRIMARY

4622
03:13:29,348 --> 03:13:30,416
MICROHEMORRHAGIC PROCESS DUE TO

4623
03:13:30,416 --> 03:13:40,960
INJURY TO THE BLOOD VESSEL WALL.

4624
03:13:42,094 --> 03:13:47,166
WHAT ABOUT SECONDARY

4625
03:13:47,166 --> 03:13:47,466
MICROBLEEDS?

4626
03:13:47,466 --> 03:13:49,702
WE SEE INFARCTION AND

4627
03:13:49,702 --> 03:13:50,736
SUSCEPTIBILITY WEIGHTED IMAGING

4628
03:13:50,736 --> 03:13:52,805
AND THE MITTED PANEL, YOU SEE

4629
03:13:52,805 --> 03:13:56,175
THE MICROPLEAD WHICH IS

4630
03:13:56,175 --> 03:14:00,446
CONGRUENT WITH THE--WITH THE

4631
03:14:00,446 --> 03:14:00,846
INFARCTION.

4632
03:14:00,846 --> 03:14:06,452
HER'S ANOTHER EXAMPLE OF A BRAIN

4633
03:14:06,452 --> 03:14:09,488
STEM INFARCT AND A--AND A

4634
03:14:09,488 --> 03:14:11,857
MICROPLEAD SEEN ON

4635
03:14:11,857 --> 03:14:13,659
SUSCEPTIBILITY WEIGHTED IMAGING,

4636
03:14:13,659 --> 03:14:15,161
AGAIN, THESE CO LOCALIZE AND

4637
03:14:15,161 --> 03:14:21,067
THESE STRONGLY SUGGIEST A

4638
03:14:21,067 --> 03:14:22,468
MICROHEMORRHAGIC MICROINFARCTION

4639
03:14:22,468 --> 03:14:30,076
OR A HEMORRHAGIC INFARCTION.

4640
03:14:30,076 --> 03:14:31,444
NOW SECONDARY MICROBLEEDS HAVE

4641
03:14:31,444 --> 03:14:34,313
NOT BEEN TODAYED EXTENSIVELY IN

4642
03:14:34,313 --> 03:14:35,781
CAA BUT 1 PAPER THAT LOOKEDDA

4643
03:14:35,781 --> 03:14:37,049
THE THIS CAREFULLY WAS A STUDY

4644
03:14:37,049 --> 03:14:45,524
OUT OF FINLAND LOOKING AT 300

4645
03:14:45,524 --> 03:14:47,593
AUTOPSIES BRAINS AND ABOUT A

4646
03:14:47,593 --> 03:14:52,198
THIRD OF THEM EXHIBITED A

4647
03:14:52,198 --> 03:14:55,434
COMBINATION OF MICROHEMORRHAGE

4648
03:14:55,434 --> 03:14:57,003
AND IMMUNOSTAINING FOR CAA AND

4649
03:14:57,003 --> 03:15:03,776
WHAT THEY WERE PORTED WAS IN 40%

4650
03:15:03,776 --> 03:15:05,845
OF ALL THE MICROHEMORRHAGES

4651
03:15:05,845 --> 03:15:09,482
THERE WAS SOME ASSOCIATION WITH

4652
03:15:09,482 --> 03:15:10,716
CORTICAL MICROINFARCTION OR

4653
03:15:10,716 --> 03:15:13,753
INFARCTION BUT BEINGLY AMONG THE

4654
03:15:13,753 --> 03:15:15,755
LARGER MICROHEMORRHAGES, THAT

4655
03:15:15,755 --> 03:15:19,258
WAS 5 OR MORE SIDECKER ERPHAGES,

4656
03:15:19,258 --> 03:15:23,029
THERE WAS MORE THAN 40% CO

4657
03:15:23,029 --> 03:15:24,063
LOCALIZED WITH MICROINFARCTION

4658
03:15:24,063 --> 03:15:25,398
ANDS INFARCTIONS AND OF COURSE

4659
03:15:25,398 --> 03:15:28,701
THIS IS LIMITED DATA BUT IT DID

4660
03:15:28,701 --> 03:15:31,237
SUGGEST THAT SECONDARY

4661
03:15:31,237 --> 03:15:32,204
MICROPLEADS AND SECONDARY

4662
03:15:32,204 --> 03:15:36,942
MICROHEMORRHAGES MAY BE A NOT

4663
03:15:36,942 --> 03:15:40,780
UNCOMMON FEATURE OF CAA EMPLOY

4664
03:15:40,780 --> 03:15:43,749
BUT WHAT ABOUT

4665
03:15:43,749 --> 03:15:44,216
PSEUDOMICROBLEEDS.

4666
03:15:44,216 --> 03:15:48,654
WE GOT INTERESTED IN THIS WITH

4667
03:15:48,654 --> 03:15:49,255
OBSERVATIONS.

4668
03:15:49,255 --> 03:15:53,859
HERE IS AN EM VIEW OF A BRAIN

4669
03:15:53,859 --> 03:15:54,126
CAPILLARY.

4670
03:15:54,126 --> 03:15:55,661
WE SEE THE TIGHT YUNKZ POINTED

4671
03:15:55,661 --> 03:15:59,065
ON UTR BY THE REDAR OS AND THEN

4672
03:15:59,065 --> 03:16:02,034
YOU SEE--RED ARROWS AND THEN YOU

4673
03:16:02,034 --> 03:16:05,337
SEE THESE PLEASE TBROBBULES.

4674
03:16:05,337 --> 03:16:08,007
AND TURNS OUT THESE BLACK

4675
03:16:08,007 --> 03:16:09,742
GLOBULES ARE IRON AT THE BLOOD

4676
03:16:09,742 --> 03:16:10,876
BRAIN BARRIER EMPLOY WE DON'T

4677
03:16:10,876 --> 03:16:13,279
SEE THIS COMMONLY BUT WE DO IS

4678
03:16:13,279 --> 03:16:13,612
OCCASIONALLY.

4679
03:16:13,612 --> 03:16:15,948
WE SAW IT IN THIS PAPER, LATER

4680
03:16:15,948 --> 03:16:22,354
MORE RECENT PAPER LOOKING AT

4681
03:16:22,354 --> 03:16:24,356
CATISOL BRAINS WITH

4682
03:16:24,356 --> 03:16:25,925
[INDISCERNIBLE] AND

4683
03:16:25,925 --> 03:16:26,292
[INDISCERNIBLE].

4684
03:16:26,292 --> 03:16:26,859
WE ENCOUNTERED THIS AGAIN.

4685
03:16:26,859 --> 03:16:29,295
SO THE QUESTION THAT OCCURRED IS

4686
03:16:29,295 --> 03:16:34,567
HOW DOES IRON GET BO THE

4687
03:16:34,567 --> 03:16:35,034
PERI-SITE.

4688
03:16:35,034 --> 03:16:38,471
SO WE CONSIDERED THE POSSIBILITY

4689
03:16:38,471 --> 03:16:42,675
THAT MAYBE THE PERI-SITE IS

4690
03:16:42,675 --> 03:16:47,680
EXHIBITING ENDOTHELIAL,

4691
03:16:47,680 --> 03:16:48,314
EXHIBITING ARITHROPHAGOCYTOSIS.

4692
03:16:48,314 --> 03:16:52,384
SO WE LOOKED AT INTENSITY AND IN

4693
03:16:52,384 --> 03:16:56,322
PACT WHEN COCULTURING PERICITES

4694
03:16:56,322 --> 03:16:57,056
WITH FLUORESCENTLY LABELED BLOOD

4695
03:16:57,056 --> 03:17:02,394
LABELS THERE WAS A MODEST UPTAKE

4696
03:17:02,394 --> 03:17:03,095
BY THE PERCYTES.

4697
03:17:03,095 --> 03:17:06,565
WE WANTED TO HAVE A CONTROL FOR

4698
03:17:06,565 --> 03:17:08,834
THESE PERICYTES, AND IT TURNS

4699
03:17:08,834 --> 03:17:11,103
OUT IT WAS THE ENDOTHELIAL CELLS

4700
03:17:11,103 --> 03:17:13,239
THAT SHOWED A MARKED UPTAKE OF

4701
03:17:13,239 --> 03:17:15,541
THE RED BLOOD CELL FRAGMENTS.

4702
03:17:15,541 --> 03:17:18,611
MORE THAN 25 FOLD INCREASE

4703
03:17:18,611 --> 03:17:19,245
AND'MUNE FLUORESCENT INTENSITY,

4704
03:17:19,245 --> 03:17:21,881
SO THAT GOD OUR ATTENTION AND

4705
03:17:21,881 --> 03:17:24,683
FINALLY MY FORMER POST DOC

4706
03:17:24,683 --> 03:17:26,886
PICKED UP ON THIS AND BEGONE IN

4707
03:17:26,886 --> 03:17:29,088
A SERIES OF PAPERS WHICH I WILL

4708
03:17:29,088 --> 03:17:32,358
WALK YOU THROUGH, THIS IS A

4709
03:17:32,358 --> 03:17:35,694
AGAIN A COCULTURE WITH MOUSE

4710
03:17:35,694 --> 03:17:37,163
BRAIN ENDOTHELIAL CELLS AT THE

4711
03:17:37,163 --> 03:17:40,566
BOTTOM OF THE WELL ADDING RED

4712
03:17:40,566 --> 03:17:43,803
BLOOD CELLS OR RED BLOOD CELLS

4713
03:17:43,803 --> 03:17:49,542
THAT WERE TREATED WITH TBHP,

4714
03:17:49,542 --> 03:17:51,644
THAT'S TERRA BEAUTAL

4715
03:17:51,644 --> 03:17:52,678
HYDROPEROXIDE, PRODUCING

4716
03:17:52,678 --> 03:17:53,879
EXPOSURE AND TRESES OF SERIES

4717
03:17:53,879 --> 03:17:56,282
POINTSINE FROM THE RED CELL

4718
03:17:56,282 --> 03:17:58,517
MEMBRANE CAN REDUCING RED BLOOD

4719
03:17:58,517 --> 03:18:00,119
CELL DEFORMABILITY.

4720
03:18:00,119 --> 03:18:01,620
AND WHEN YOU COMPARE THOSE RED

4721
03:18:01,620 --> 03:18:02,521
BLOOD CELLS WHAT YOU SLEEP APNEA

4722
03:18:02,521 --> 03:18:04,824
AND OBESITYY IS THAT AGE RED

4723
03:18:04,824 --> 03:18:08,494
BLOOD CELLS IS THE PEROXIDE IS A

4724
03:18:08,494 --> 03:18:11,030
BIOCHEMICAL ANALLING PROCESS, SO

4725
03:18:11,030 --> 03:18:16,535
THESE BLOOD CELLS SHOW A MARKED

4726
03:18:16,535 --> 03:18:16,769
 MARKED

4727
03:18:16,769 --> 03:18:18,137
INCREASE COMPARED TO THE TREATED

4728
03:18:18,137 --> 03:18:20,873
BLOOD CELLS ANDOT RIGHT YOUEE

4729
03:18:20,873 --> 03:18:24,043
THIS ISA TIGHT 2 GFP MOUSE WITH

4730
03:18:24,043 --> 03:18:25,845
GREEN FLOURESCENTLY LABELED

4731
03:18:25,845 --> 03:18:28,314
VESSELS AND RED ARITHROCYTES IN

4732
03:18:28,314 --> 03:18:29,815
THE TREATED CELLS, YOU SEE THAT

4733
03:18:29,815 --> 03:18:32,751
THESE RED BLOOD CELLS ARE INTRA

4734
03:18:32,751 --> 03:18:35,187
VASCULAR, WHEREAS WITH THE TBHP

4735
03:18:35,187 --> 03:18:37,957
YOU YOU BEBIN TOEE AS THE ARROWS

4736
03:18:37,957 --> 03:18:41,727
POINT OUT, EXTRUSION OF RED

4737
03:18:41,727 --> 03:18:44,563
BLOOD CELLS, AND RED BLOOD CELL

4738
03:18:44,563 --> 03:18:44,830
FRAGMENTS.

4739
03:18:44,830 --> 03:18:47,099
SO THIS WAS FOLLOWED UP WITH

4740
03:18:47,099 --> 03:18:49,602
ANOTHER INVESTIGATION IN WHICH

4741
03:18:49,602 --> 03:18:51,237
THE AGED RED BLOOD CELLS WERE

4742
03:18:51,237 --> 03:18:52,371
INYECTED INTO THE MOUSE AND WHAT

4743
03:18:52,371 --> 03:18:56,809
WE SAW WAS A SUBITANTIAL

4744
03:18:56,809 --> 03:18:58,777
INCREASE IN MICROHEMORRHAGE LOBE

4745
03:18:58,777 --> 03:18:59,678
MANIFEST BY INCREASED PLURIBU

4746
03:18:59,678 --> 03:19:03,015
STAINING IN THE MICE THAT WERE

4747
03:19:03,015 --> 03:19:04,316
RECEIVING THE AGED RED BLOOD

4748
03:19:04,316 --> 03:19:07,486
CELLS AND IN A LATER PAPER THIS

4749
03:19:07,486 --> 03:19:11,891
IS STEM CELL DERIVED HUMAN

4750
03:19:11,891 --> 03:19:12,524
MICROVASCULAR BRAIN ENDOTHELIUM

4751
03:19:12,524 --> 03:19:18,264
AND YOU CAN SEE INCORPORATION OF

4752
03:19:18,264 --> 03:19:20,633
THE ARITHROCYTES INTO THE

4753
03:19:20,633 --> 03:19:21,200
ENDOTHELIAL CELLS.

4754
03:19:21,200 --> 03:19:25,037
WELL LET ME BRENG --BRING YOU UO

4755
03:19:25,037 --> 03:19:25,838
DATE WITH CURRENT

4756
03:19:25,838 --> 03:19:26,205
INVESTIGATIONS.

4757
03:19:26,205 --> 03:19:31,810
THIS IS WORK DONE WITH

4758
03:19:31,810 --> 03:19:32,344
COLLEAGUES AND OTHERS.

4759
03:19:32,344 --> 03:19:34,947
AND IN THESE STUDIES, WHAT WE

4760
03:19:34,947 --> 03:19:38,417
DID WAS WE ONCE AGAIN TOOK RED

4761
03:19:38,417 --> 03:19:43,923
BLOOD CELLS, TREATED THISEM WITH

4762
03:19:43,923 --> 03:19:45,624
TBHB, SO BIOCHEMICALLY ANALLING

4763
03:19:45,624 --> 03:19:46,492
THESE, INYECTING THEM INTO THE

4764
03:19:46,492 --> 03:19:48,961
MOUSE AND SUBYEKING THE MOUSE TO

4765
03:19:48,961 --> 03:19:52,564
1 WEEK OF INTRA VITAL MICROSCOPY

4766
03:19:52,564 --> 03:19:57,670
USING 2-PHOTON IMAGING ALONG

4767
03:19:57,670 --> 03:19:58,404
WITH POSTMORTEM ANALYSIS.

4768
03:19:58,404 --> 03:20:01,874
AND WHAT YOU SEE ON THE TOP IS

4769
03:20:01,874 --> 03:20:03,442
NORMAL RED BLOOD CELL TRANSIT

4770
03:20:03,442 --> 03:20:05,978
THROUGH THE CAPILLARIES AND THE

4771
03:20:05,978 --> 03:20:08,981
PBS TREATED RED BLOOD CELLS, AND

4772
03:20:08,981 --> 03:20:11,517
IN PANEL C YOU BEBIN TO SEE WHAT

4773
03:20:11,517 --> 03:20:13,552
ARE CALLED RED BLOOD CELL STALLS

4774
03:20:13,552 --> 03:20:14,987
IN THE CAPILLARIES AND IF YOU

4775
03:20:14,987 --> 03:20:17,323
PLOT THIS OUT IN THE D-PANEL YOU

4776
03:20:17,323 --> 03:20:19,925
SEE THAT WITHIN THE FIRST 24

4777
03:20:19,925 --> 03:20:22,461
HOURS, FOLLOWING INYEKS OF THE

4778
03:20:22,461 --> 03:20:25,197
AGE RED BLOOD CELLS, THERE'S A

4779
03:20:25,197 --> 03:20:27,666
SUBSTANTIAL INCREASE IN RED

4780
03:20:27,666 --> 03:20:38,177
BLOOD CELL STALLS IN THE BRAIN

4781
03:20:42,715 --> 03:20:43,315
CAPILLARIES.

4782
03:20:43,315 --> 03:20:45,551
NCAN WE HAVE A BIT OF HELP FROM

4783
03:20:45,551 --> 03:20:48,187
THE TEAM WHAT WE SAW IN THE

4784
03:20:48,187 --> 03:20:49,488
EXVIVO STUDIES WAS EXCLUSION OF

4785
03:20:49,488 --> 03:20:51,590
RED BLOOD CELLS AND FRAGMENTS

4786
03:20:51,590 --> 03:20:52,324
FROM THE MICROVASCULATURE AND

4787
03:20:52,324 --> 03:20:54,827
THESE ARE THE AGED RED BLOOD

4788
03:20:54,827 --> 03:20:56,428
CELLS, WE ALSO SAW THE BEGINNING

4789
03:20:56,428 --> 03:21:06,972
OF AN CORRELATED CLIEWGZ OF THE

4790
03:21:10,609 --> 03:21:12,945
CAPILLARY NETWORK HERE WITH THE

4791
03:21:12,945 --> 03:21:14,246
AGE PLAID CELLS, SHOWING

4792
03:21:14,246 --> 03:21:16,215
ACTIVATION IN THE FIRST 24 HOURS

4793
03:21:16,215 --> 03:21:18,450
AND EXTENDING OVER THE 7 DAY

4794
03:21:18,450 --> 03:21:18,751
EXPERIMENT.

4795
03:21:18,751 --> 03:21:25,224
NOW WHEN WOE  DID IMMUNOSTAINING

4796
03:21:25,224 --> 03:21:27,993
WE SAW FOE INTRA VASCULAR FIEB

4797
03:21:27,993 --> 03:21:30,829
RIN AND NO EXCESS EXTRA VASCULAR

4798
03:21:30,829 --> 03:21:32,364
FINE RIN O GENERATED SUGGIESTING

4799
03:21:32,364 --> 03:21:33,999
THERE'S NO CLOCK FORMATION IN

4800
03:21:33,999 --> 03:21:35,734
THE INTRA VASCULATURE AND ALSO

4801
03:21:35,734 --> 03:21:38,837
SUGGIESTING THERE WERE NO MAJOR

4802
03:21:38,837 --> 03:21:40,205
DISRUPTIONS OF THE BLOOD BRAIN

4803
03:21:40,205 --> 03:21:41,507
BAIPIER AND IMPORTANTLY IN THE

4804
03:21:41,507 --> 03:21:44,276
LAST PANEL ONCE AGAIN WE SEE A

4805
03:21:44,276 --> 03:21:51,517
VERY SUBITANTIAL INCREASE IN

4806
03:21:51,517 --> 03:21:54,286
MICROHEMORRHAGE AND MANIFEST

4807
03:21:54,286 --> 03:21:55,254
WITH PRESSURE PLURIBU STAINING.

4808
03:21:55,254 --> 03:21:56,622
I WILL TRY TO SHOW YOU WHAT THIS

4809
03:21:56,622 --> 03:22:04,129
LOOKS LIKE IN REALTIME.

4810
03:22:04,129 --> 03:22:05,898
AND I WILL NEED HELP FROM MY

4811
03:22:05,898 --> 03:22:06,932
FRIENDS IN THE BACK OF ROOM.

4812
03:22:06,932 --> 03:22:08,700
IF YOU CLICK ON HERE YOU SHOULD

4813
03:22:08,700 --> 03:22:13,338
BE ABLE TO--THERE YOU GO, OKAY.

4814
03:22:13,338 --> 03:22:15,340
O THIS IS ABOUT AN HOUR AFTER

4815
03:22:15,340 --> 03:22:18,110
INYEKS OF THE PBS TREATED RED

4816
03:22:18,110 --> 03:22:20,145
BLOOD CELLS, CAN YOU DO THAT FOR

4817
03:22:20,145 --> 03:22:21,713
THE BOTTOM IN THIS IS 24 HOURS,

4818
03:22:21,713 --> 03:22:24,450
SO THIS IS NORMAL TRANSIT OF THE

4819
03:22:24,450 --> 03:22:30,022
RED BLOOD CELLS, THROUGH THE

4820
03:22:30,022 --> 03:22:40,432
MICE, THROUGH THE MOUSE

4821
03:22:41,600 --> 03:22:46,538
MICROVASCULAR. 

4822
03:22:46,538 --> 03:22:50,242
OF THE SLUGGISH FLOW THIS IS

4823
03:22:50,242 --> 03:22:52,511
WITHIN AT THE BOTTOM, PLEASE

4824
03:22:52,511 --> 03:22:54,546
GO,A HEAD, THAT'S SOME

4825
03:22:54,546 --> 03:23:04,957
IMPROVEMENT BY 24 HOURS.

4826
03:23:05,891 --> 03:23:09,027
ANOTHER EXAMPLE, NO, NO, CAN WE

4827
03:23:09,027 --> 03:23:09,895
GO BACK 1 MORE SLIDE.

4828
03:23:09,895 --> 03:23:18,437
I THINK WE MISSED A SLIDE.

4829
03:23:18,437 --> 03:23:28,780
YEAH, LET'S GO HERE.

4830
03:23:46,899 --> 03:23:57,342
AND WHAT YOU SEE HERE, ON THE

4831
03:24:14,226 --> 03:24:17,563
RIGHT IS FLOW--WE ALSO SAW

4832
03:24:17,563 --> 03:24:18,397
SUBSTANTIAL MICROGLIAL

4833
03:24:18,397 --> 03:24:19,598
ACTIVATION THAT WAS SUSTAINED

4834
03:24:19,598 --> 03:24:21,466
OVER THE 7 DAY EXPERIMENT, AND

4835
03:24:21,466 --> 03:24:26,305
IMPORTANTLY THERE WAS

4836
03:24:26,305 --> 03:24:27,673
PROGRESSIVE DEVELOPMENT OF

4837
03:24:27,673 --> 03:24:29,541
PUNISHING RUSSIAN BLUE LESIONS

4838
03:24:29,541 --> 03:24:31,910
NOTABLE PARTICULARLY AT DAY 7

4839
03:24:31,910 --> 03:24:35,414
AND THE SUGGESTION IS THAT THESE

4840
03:24:35,414 --> 03:24:37,950
PROCESSES ARE PERHAPS TIED

4841
03:24:37,950 --> 03:24:42,054
TOGETHER BY ENDOTHELIAL ARK RYTH

4842
03:24:42,054 --> 03:24:42,854
ROUGH ATOM PHAGOCYTOSIS.

4843
03:24:42,854 --> 03:24:46,325
SO WHAT DOES THIS HAVE TO DO

4844
03:24:46,325 --> 03:24:48,660
WITH CAA?

4845
03:24:48,660 --> 03:24:50,996
WELL RED BLOOD CELL

4846
03:24:50,996 --> 03:24:52,497
ABNORMALITIES HAVE NOT BEEN

4847
03:24:52,497 --> 03:24:54,466
HAVING THE IN CAA, BUT THEY HAVE

4848
03:24:54,466 --> 03:24:56,034
BEEN LOOKEDDA THE QUITE

4849
03:24:56,034 --> 03:24:58,470
EXTENSIVE IN THE ALZHEIMER'S LIT

4850
03:24:58,470 --> 03:25:00,272
RAWR, IN FACT THERE'S MORE THAN

4851
03:25:00,272 --> 03:25:02,374
600 PAPERS WHO LOOK AT THIS, A

4852
03:25:02,374 --> 03:25:09,414
DEC OF WHICH OF COURSE CAA IS A

4853
03:25:09,414 --> 03:25:11,416
PROBLEM, THESE ARE BIOMARKERS OF

4854
03:25:11,416 --> 03:25:12,985
ALZHEIMER'S DISEASE BUT THERE

4855
03:25:12,985 --> 03:25:14,486
ARE A FEW INVESTIGATION THAT

4856
03:25:14,486 --> 03:25:17,723
EMPHASIZED THAT THE RED BLOOD

4857
03:25:17,723 --> 03:25:18,957
CELL ABNORMALITIES, REDUCED

4858
03:25:18,957 --> 03:25:20,259
DENORMABILITY ITSELF MAY

4859
03:25:20,259 --> 03:25:23,528
CONTRIBUTE TO THE PROGRESSION OF

4860
03:25:23,528 --> 03:25:25,264
ALZHEIMER'S PATHOLOGY AS YOU SEE

4861
03:25:25,264 --> 03:25:30,135
IN THIS RECENT PAPER. 

4862
03:25:30,135 --> 03:25:32,104
SO TO SUMMARIZE, SEVERAL

4863
03:25:32,104 --> 03:25:33,939
MICROVASCULAR DISEASE IS

4864
03:25:33,939 --> 03:25:37,175
CHARACTERIZED BY A HIGHLY

4865
03:25:37,175 --> 03:25:38,877
VARIABLE ARTERIOLE PATHOLOGY

4866
03:25:38,877 --> 03:25:41,046
WITH PROMINENT SMOOTH MUSCLE

4867
03:25:41,046 --> 03:25:45,984
CELL CHANGES COMBINED WITH A

4868
03:25:45,984 --> 03:25:55,460
LIMITED VARIETY OF PAIREN CHIMAL

4869
03:25:55,460 --> 03:25:57,829
INJURIES, AND CAA FITS WELL INTO

4870
03:25:57,829 --> 03:25:59,998
THIS SPECTRUM OF MICROVASCULAR

4871
03:25:59,998 --> 03:26:03,402
AND ANCHLIO MY O PATHIC

4872
03:26:03,402 --> 03:26:03,669
DISORDERS.

4873
03:26:03,669 --> 03:26:07,205
ON THE MICROBLEED SIDE WE CAN

4874
03:26:07,205 --> 03:26:09,207
CATEGORIZE MICROBLEEDS OR

4875
03:26:09,207 --> 03:26:11,643
MICROHEMMAGES AS PRIMARY,

4876
03:26:11,643 --> 03:26:12,477
SECONDARY AND PSEUDOMICROPLEADS.

4877
03:26:12,477 --> 03:26:18,950
AND THE IDEA OF A

4878
03:26:18,950 --> 03:26:20,052
MICROHEMORRHAGES HAPPENING IN

4879
03:26:20,052 --> 03:26:22,087
THE PRIMARY MUSCLE WALL, THESE

4880
03:26:22,087 --> 03:26:24,156
ARE WELL TEABED FOR CAA AND

4881
03:26:24,156 --> 03:26:26,825
BASED ON LIMITED DATA SECONDARY

4882
03:26:26,825 --> 03:26:30,228
MICROBLEEDS MAY WELL BE A COMMON

4883
03:26:30,228 --> 03:26:33,965
FEATURE OF CAA, THE ROLE OF

4884
03:26:33,965 --> 03:26:34,633
PSEUDOMICROPLEADS, BRAIN

4885
03:26:34,633 --> 03:26:39,404
CAPILLARY INTERACTIONS AND BRAIN

4886
03:26:39,404 --> 03:26:49,948
ENDOTHELIAL PHAGOCYTOSIS IN THE

4887
03:27:06,098 --> 03:27:07,232
ANGIOPATHY AND NTHANK YOU FOR

4888
03:27:07,232 --> 03:27:08,567
GIVING ME THE OPPORTUNITY TO

4889
03:27:08,567 --> 03:27:10,569
TALK TO YOU TODAY ABOUT THE

4890
03:27:10,569 --> 03:27:11,403
FOLLOWING ISSUES, YOU KNOW ASK

4891
03:27:11,403 --> 03:27:14,806
WHEN WE TALK ABOUT THE EFFECT OF

4892
03:27:14,806 --> 03:27:16,975
CAA IN APOE 4 IN NEUROVASCULAR

4893
03:27:16,975 --> 03:27:19,010
REGULATION AND THE ROLE OF

4894
03:27:19,010 --> 03:27:20,045
MACROPHAGES WHICH SOMEONE MAY

4895
03:27:20,045 --> 03:27:23,115
NOT BE VERY FAMILIAR WITH, IN

4896
03:27:23,115 --> 03:27:24,549
THIS PROCESSES, AND FINALLY,

4897
03:27:24,549 --> 03:27:27,786
WITH THE IMPLICATIONS OF THESE

4898
03:27:27,786 --> 03:27:31,723
CONSIDERATION MIGHT BE FOR

4899
03:27:31,723 --> 03:27:33,125
IMMUNOTHERAPY AND ALZHEIMERS AND

4900
03:27:33,125 --> 03:27:33,458
CAA IN ARIA.

4901
03:27:33,458 --> 03:27:35,360
SO AS YOU KNOW THE BLOOD VESSEL

4902
03:27:35,360 --> 03:27:37,396
OF THE BRAIN IS MORE THAN FEED

4903
03:27:37,396 --> 03:27:38,964
THE BRAIN WITHOXIEN AND

4904
03:27:38,964 --> 03:27:40,332
DPLUICOSE, THEY ON DO A LOT OF

4905
03:27:40,332 --> 03:27:41,466
OTHER THINGS WE'RE NOT FAMILIAR

4906
03:27:41,466 --> 03:27:44,403
WITH AND JUST NOW ARE BECOMING

4907
03:27:44,403 --> 03:27:45,470
TO BE MORE APPRECIATED.

4908
03:27:45,470 --> 03:27:48,240
SO WE KNOW THAT THE VESSELS OF

4909
03:27:48,240 --> 03:27:51,042
THE BRAIN COUPLE NEURAL ACTIVITY

4910
03:27:51,042 --> 03:27:54,646
WITH SEVERE BLOOD FLOW AND THE

4911
03:27:54,646 --> 03:27:55,747
PHENOMENAL CALLED COUPLING AND

4912
03:27:55,747 --> 03:27:57,849
THESE ARE CRITICAL FOR MAKING

4913
03:27:57,849 --> 03:28:02,320
FLOW REGULATION AND THEY DO THE

4914
03:28:02,320 --> 03:28:03,755
BLOOD BRAIN BARRIER AND ALL THAT

4915
03:28:03,755 --> 03:28:06,091
STUFF BUT THE VESSELS IN THE

4916
03:28:06,091 --> 03:28:09,861
BRAIN GET RID OF THE JUNK THAT

4917
03:28:09,861 --> 03:28:10,996
THE BRAIN GENERATES

4918
03:28:10,996 --> 03:28:14,833
CONTINUOUSLY, WE ARE TALKING

4919
03:28:14,833 --> 03:28:16,768
ABOUT THE BETA, TAU, AND IT IS

4920
03:28:16,768 --> 03:28:19,304
DONE BY A NUMBER OF MECHANO

4921
03:28:19,304 --> 03:28:20,705
PATHWAYS WHICH ARE NOT VERY WELL

4922
03:28:20,705 --> 03:28:21,773
UNDERSTOOD AND I THINK THE

4923
03:28:21,773 --> 03:28:22,908
EPPEDICATION OF THAT IS THAT

4924
03:28:22,908 --> 03:28:24,709
THERE ARE MORE REVIEWS ON IT,

4925
03:28:24,709 --> 03:28:28,313
THAN THE ORIGINAL PAPERS.

4926
03:28:28,313 --> 03:28:30,015
O THIS IS ALWAYS VERY CLEAR

4927
03:28:30,015 --> 03:28:32,684
INDICATION OF THE STRENGTH OF

4928
03:28:32,684 --> 03:28:35,420
THE INFORMATION MUCH SO 1 IS SO

4929
03:28:35,420 --> 03:28:36,788
CALLED LYMPHATIC PROBLEM, WHICH

4930
03:28:36,788 --> 03:28:40,158
THINGS GO FORWARD, THEN THERE IS

4931
03:28:40,158 --> 03:28:41,460
A PERIVASCULAR RETROGRADE

4932
03:28:41,460 --> 03:28:42,828
PATHWAY, WHICH THINGS GO

4933
03:28:42,828 --> 03:28:45,530
BACKWARD AND THEN THE SIMPLE

4934
03:28:45,530 --> 03:28:50,335
PAN, SIMPLE WOMAN APPROACH, OF

4935
03:28:50,335 --> 03:28:53,271
MIXING BETWEEN THE CSF AND THE

4936
03:28:53,271 --> 03:28:53,705
INTERSTITIAL FLUID.

4937
03:28:53,705 --> 03:28:56,541
NOW THE BOTTOM IS LINE IS THAT

4938
03:28:56,541 --> 03:28:58,076
HOWEVER, WHATEVER THESE THINGS

4939
03:28:58,076 --> 03:29:00,745
DO, THEY RELY ON THE HEALTH OF

4940
03:29:00,745 --> 03:29:02,047
THE BLOOD VESSELS.

4941
03:29:02,047 --> 03:29:04,316
SO THE VESSELS DIFFER, IF THE

4942
03:29:04,316 --> 03:29:06,918
VESSEL DOES NOT RELAX OR

4943
03:29:06,918 --> 03:29:08,019
CONTRACT, THESE THINGS WILL NOT

4944
03:29:08,019 --> 03:29:10,422
WORK, WHATEVER THEY ARE.

4945
03:29:10,422 --> 03:29:11,089
ALL RIGHT?

4946
03:29:11,089 --> 03:29:12,624
SO THESE ARE CRITICALLY LINKED

4947
03:29:12,624 --> 03:29:14,092
TO THE HEALTH OF THE BLOOD

4948
03:29:14,092 --> 03:29:14,392
VESSEL.

4949
03:29:14,392 --> 03:29:15,660
SO IT'S NOT SURPRISING THAT IF

4950
03:29:15,660 --> 03:29:17,362
YOU HAVE THINGS THAT SCREW UP

4951
03:29:17,362 --> 03:29:18,396
THE BLOOD VESSELS, YOU ARE GOING

4952
03:29:18,396 --> 03:29:20,232
TO GET ALL KIND OF ALTASD

4953
03:29:20,232 --> 03:29:23,568
RAYINGS INVOLVING NOT ONLY THE

4954
03:29:23,568 --> 03:29:26,104
FEEDING OF THE BRAIN BUT THE

4955
03:29:26,104 --> 03:29:27,973
TRADITIONAL VIEW OF STARVATION

4956
03:29:27,973 --> 03:29:30,242
IS PILOT PROJECT POXIA,

4957
03:29:30,242 --> 03:29:31,810
STARVATION BUT YOU WANT TO

4958
03:29:31,810 --> 03:29:33,478
EFFECT IMMUNE REGULATION, YOU

4959
03:29:33,478 --> 03:29:35,080
WILL AFFECT THE BLOOD BRAIN

4960
03:29:35,080 --> 03:29:36,648
BARRIER, ABILITY OF THE BRAIN TO

4961
03:29:36,648 --> 03:29:37,682
CLEAR THESE FACTORS AND TODAY WE

4962
03:29:37,682 --> 03:29:39,851
WILL TALK ABOUT YOU KNOW THE

4963
03:29:39,851 --> 03:29:43,755
ROLE OF CAA IN THE APOE 4 IN

4964
03:29:43,755 --> 03:29:44,322
THIS MECHANISMS.

4965
03:29:44,322 --> 03:29:48,393
YOU KNOW SO THAT'S--THE VASCULAR

4966
03:29:48,393 --> 03:29:50,495
REGULATION IN THE CAA SO IN THIS

4967
03:29:50,495 --> 03:29:52,998
PAPER, THEY LOOKED AT THE TYPE

4968
03:29:52,998 --> 03:29:56,001
OF CAA CAN THEY FOUND USING A

4969
03:29:56,001 --> 03:29:57,536
FUNCTIONAL [INDISCERNIBLE], SO

4970
03:29:57,536 --> 03:29:59,337
ACTIVATING THE BRAIN VISUAL

4971
03:29:59,337 --> 03:30:00,338
CORTEX USING IMMUNO CHECKER

4972
03:30:00,338 --> 03:30:08,313
BOARD AND THEN THE BOLD OKAY,

4973
03:30:08,313 --> 03:30:10,115
THIS GOOD ENOUGH FOR CLINICAL

4974
03:30:10,115 --> 03:30:11,917
STUDIES AT LEAST AND WHAT YOU

4975
03:30:11,917 --> 03:30:15,520
PUT, WHAT THEY FOUND WAS

4976
03:30:15,520 --> 03:30:18,156
ATTENUATION OF THIS DYNAMIC

4977
03:30:18,156 --> 03:30:19,858
RESPONSE DURING FUNCTIONAL

4978
03:30:19,858 --> 03:30:20,725
ACTIVATION.

4979
03:30:20,725 --> 03:30:23,562
AND WHEN DEPLAYED WITH THE

4980
03:30:23,562 --> 03:30:27,098
PATIENTS WITH SYMPTOMATIC AND

4981
03:30:27,098 --> 03:30:28,300
ASYMPTOMATIC PATIENTS, BEINGLY,

4982
03:30:28,300 --> 03:30:30,268
THE SYMPTOMATICS ALREADY HAD

4983
03:30:30,268 --> 03:30:31,169
NEURODYSFUNCTION, SO USING THIS

4984
03:30:31,169 --> 03:30:34,139
DISEASE AND WORK BY THE TEEF AND

4985
03:30:34,139 --> 03:30:37,175
COLLEAGUES HAS SHOWN THAT MAYBE

4986
03:30:37,175 --> 03:30:44,849
A VERY GOOD BIOMARKER OF CAA.

4987
03:30:44,849 --> 03:30:46,952
THOU THE QUESTION IS WHAT

4988
03:30:46,952 --> 03:30:47,652
MEDIATES THIS, SO WEB CONNECTED

4989
03:30:47,652 --> 03:30:52,991
WENT TO A MOUSE MODEL, WE WILL

4990
03:30:52,991 --> 03:30:54,459
HEAR FROM HIM IN AFTERNOON.

4991
03:30:54,459 --> 03:30:56,561
HE WILL TALK.

4992
03:30:56,561 --> 03:31:00,231
THIS IS A DUTCH-SWEDISH MUTATION

4993
03:31:00,231 --> 03:31:02,834
IN MOUSE, AND THIS

4994
03:31:02,834 --> 03:31:03,969
[INDISCERNIBLE] CAA, SO DR. PARK

4995
03:31:03,969 --> 03:31:07,105
IN OUR GROUP STUDIED THESE MICE

4996
03:31:07,105 --> 03:31:09,374
IN DIFFERENT ANALS BECAUSE YOU

4997
03:31:09,374 --> 03:31:10,875
KNOW ON THE ASSUMPTION THE

4998
03:31:10,875 --> 03:31:12,210
DISEASE MAY BE PROGRESSIVE,

4999
03:31:12,210 --> 03:31:15,547
RIGHT IN SO WE LOOK AT 3 MONTHS,

5000
03:31:15,547 --> 03:31:17,816
18 MONTHS, 24 MONTHS LOOKING AT

5001
03:31:17,816 --> 03:31:21,753
ALL THE CLASSICAL MECHANISMS,

5002
03:31:21,753 --> 03:31:23,855
REGULATING THE CIRCULATION,

5003
03:31:23,855 --> 03:31:25,590
NEURAL ACTIVITY, ENDOTHELIAL,

5004
03:31:25,590 --> 03:31:26,758
THE SMOOTH MUSCLE, WHICH IS THE

5005
03:31:26,758 --> 03:31:28,360
BUSINESS END OF THE VESSEL, YOU

5006
03:31:28,360 --> 03:31:29,694
HEARD ABOUT CAA AND THE SMOOTH

5007
03:31:29,694 --> 03:31:32,397
MUSCLE, YOU WILL HEAR MORE HERE

5008
03:31:32,397 --> 03:31:35,567
AND FINALLY [INDISCERNIBLE] 1 OF

5009
03:31:35,567 --> 03:31:37,235
THE MOST POWERFUL DILATORS IN

5010
03:31:37,235 --> 03:31:39,638
THE BRAIN AND WE FOUND THERE WAS

5011
03:31:39,638 --> 03:31:41,272
A PROGRESSIVE ACTINNUATION OF

5012
03:31:41,272 --> 03:31:43,675
THESE FACTORS WHICH REALLY WAS

5013
03:31:43,675 --> 03:31:48,580
MAXIMAL AT 24 MONTHS WHERE AT

5014
03:31:48,580 --> 03:31:51,716
THE TIME WHEN WE DID THE DATA

5015
03:31:51,716 --> 03:31:54,052
MEASUREMENT AND SO ON, WE FOUND

5016
03:31:54,052 --> 03:31:57,589
OUT THERE WAS MAXED OUT IN THE

5017
03:31:57,589 --> 03:32:00,492
BRAIN, 2 MONTHS OF AMYLOID AND

5018
03:32:00,492 --> 03:32:05,797
CAPILLARIES, AND THERE WAS ALSO

5019
03:32:05,797 --> 03:32:07,999
PERICITE LOSS SO THE VESSEL IS

5020
03:32:07,999 --> 03:32:10,001
FALLING APART AND WHAT YOU HEARD

5021
03:32:10,001 --> 03:32:11,703
BEFORE WAS FRAGMENTATION OF

5022
03:32:11,703 --> 03:32:12,671
SMOOTH MUSCLE CELLS.

5023
03:32:12,671 --> 03:32:14,539
SO ESSENTIA WILY THE VASCULAR

5024
03:32:14,539 --> 03:32:16,841
WALL WAS FALLING, THE VASCULAR

5025
03:32:16,841 --> 03:32:17,709
WALL WAS MEDIATING THE

5026
03:32:17,709 --> 03:32:19,244
REACTIVITY OF THE IT WAS

5027
03:32:19,244 --> 03:32:22,714
FOLLOWING APART.

5028
03:32:22,714 --> 03:32:24,149
RIGHT EMPLOY NOW THE NEXT

5029
03:32:24,149 --> 03:32:26,251
QUESTION IS WHAT IS CAUSING THE

5030
03:32:26,251 --> 03:32:26,518
EFFECTS.

5031
03:32:26,518 --> 03:32:30,655
PREVIOUS STUDIES HAVE SHOWN THAT

5032
03:32:30,655 --> 03:32:32,057
THIS VASCULAR EEIVETS THROUGH

5033
03:32:32,057 --> 03:32:38,263
FREE RADICALS BY

5034
03:32:38,263 --> 03:32:41,099
PRODUCINGOXIDATIVE STRESS THIS

5035
03:32:41,099 --> 03:32:42,634
IS BY IMMUNE RECEPTORS ON THE

5036
03:32:42,634 --> 03:32:45,303
BLOOD VESSELS AS WE WILL SEE IN

5037
03:32:45,303 --> 03:32:46,504
THE MACROPHAGE POPULATION AND

5038
03:32:46,504 --> 03:32:50,141
THIS IS THEACIVATION OF A REALLY

5039
03:32:50,141 --> 03:32:53,645
A VERY IMMUNOLOGY ENZYME, NOW,

5040
03:32:53,645 --> 03:32:57,182
WHICH IS A MAINLIOR SOURCE

5041
03:32:57,182 --> 03:32:58,283
OFOXIDATIVE STRESS IN

5042
03:32:58,283 --> 03:32:58,583
MACROPHAGES.

5043
03:32:58,583 --> 03:33:00,452
THAT'S WHAT THEY DO, THEY MAKE

5044
03:33:00,452 --> 03:33:01,519
RADICALS TO KILL CELLS AND SO

5045
03:33:01,519 --> 03:33:04,522
ON, AND THIS LEADS TO INFLATION

5046
03:33:04,522 --> 03:33:06,925
AND DISTRESS IN THE LUSKULAR

5047
03:33:06,925 --> 03:33:07,358
DYSFUNCTION.

5048
03:33:07,358 --> 03:33:09,094
SOPHISTICATED THE QUESTION IS IN

5049
03:33:09,094 --> 03:33:10,795
THE CAA MODEL DID RADICALS PLAY

5050
03:33:10,795 --> 03:33:13,031
A ROLE IN SO WE MEASURED FREE

5051
03:33:13,031 --> 03:33:14,232
RADICALS RADICAL PRODUCTION AND

5052
03:33:14,232 --> 03:33:15,633
THE BLOOD VESSELS OF THESE MICE

5053
03:33:15,633 --> 03:33:17,235
AND WE FOUND THERE WAS AN

5054
03:33:17,235 --> 03:33:19,104
INCREASE IN THIS PRODUCTION,

5055
03:33:19,104 --> 03:33:20,705
THEN WE FOWBD THAT BY APPLYING

5056
03:33:20,705 --> 03:33:26,211
ON THE BRAIN ITSELF, THE FREE

5057
03:33:26,211 --> 03:33:28,580
RAD CALIFORNIAS, FORMATION, AT

5058
03:33:28,580 --> 03:33:32,350
THE SAME TIME, WE SAW A RESCUE

5059
03:33:32,350 --> 03:33:34,586
OF THE NEUROVASCULAR

5060
03:33:34,586 --> 03:33:35,754
DYSFUNCTION, FOR EXAMPLE IN 3

5061
03:33:35,754 --> 03:33:37,722
MONTHS WE SAW A RESCUE.

5062
03:33:37,722 --> 03:33:40,391
HOWEVER AT 18 MONTHS WE DID NOT

5063
03:33:40,391 --> 03:33:41,126
SEE IT ANYMORE.

5064
03:33:41,126 --> 03:33:44,863
AND WE DIDN'T SEE MUCH CHANGE IN

5065
03:33:44,863 --> 03:33:46,231
THE MUSCLE REACTIVITY, WHY?

5066
03:33:46,231 --> 03:33:47,365
BECAUSE THE SMOOTH MUSCLE CELL

5067
03:33:47,365 --> 03:33:49,868
WAS NO LONGER THERE.

5068
03:33:49,868 --> 03:33:51,669
OR IF IT WAS THERE IT WAS IN

5069
03:33:51,669 --> 03:33:52,971
SPECS, SO AT THE TIME THE BOTTOM

5070
03:33:52,971 --> 03:33:56,107
LINE HERE IS THAT IF YOU WANT TO

5071
03:33:56,107 --> 03:33:58,676
MAKE THINGS BETTER, YOU HAVE TO

5072
03:33:58,676 --> 03:34:00,278
DO BEFORE THE PATHOGEN MUSCLE

5073
03:34:00,278 --> 03:34:02,647
FALLS APART OTHERWISE THAT WILL

5074
03:34:02,647 --> 03:34:05,383
NOT HELP REMARKABLILY WELL.

5075
03:34:05,383 --> 03:34:08,353
NOW, WHAT ARE THE SOURCES OF

5076
03:34:08,353 --> 03:34:09,654
THIS RADICAL [INDISCERNIBLE]

5077
03:34:09,654 --> 03:34:11,589
WHICH ARE SO BAD FOR THE BLOOD

5078
03:34:11,589 --> 03:34:13,725
VESSELS, WHETHER THE SOURCE IS A

5079
03:34:13,725 --> 03:34:15,760
CELL CALLED THE [INDISCERNIBLE]

5080
03:34:15,760 --> 03:34:18,363
MACROPHAGE IN PARTICULAR THE

5081
03:34:18,363 --> 03:34:19,297
PERIVASCULAR MACROPHAGES THAT

5082
03:34:19,297 --> 03:34:21,866
ARE ASSOCIATED WITH RESISTANCE

5083
03:34:21,866 --> 03:34:25,069
VESSELS IN THE BRAIN. 

5084
03:34:25,069 --> 03:34:28,673
THESE CELLS COME FROM

5085
03:34:28,673 --> 03:34:29,741
ARITHROADWAY PRECURSORS IN THE

5086
03:34:29,741 --> 03:34:31,476
DEVELOPMENT AND THEY GO ALL OVER

5087
03:34:31,476 --> 03:34:33,978
THE BODY, GIVE RISE TO THE SOLE

5088
03:34:33,978 --> 03:34:38,316
CALLED TISSUE RESIDENT

5089
03:34:38,316 --> 03:34:38,616
MACROPAGES.

5090
03:34:38,616 --> 03:34:41,186
IN THE BRAIN TISSUE RESIDENT

5091
03:34:41,186 --> 03:34:42,020
MACROPHAGES ARE THE MICROFLI

5092
03:34:42,020 --> 03:34:43,087
COLSISSA THAT WE LOVE AND HATE

5093
03:34:43,087 --> 03:34:43,822
AT THE SAME TIME.

5094
03:34:43,822 --> 03:34:47,258
WE ALL HAVE THE PERIVASCULAR

5095
03:34:47,258 --> 03:34:49,561
MACROPHAGES HERE.

5096
03:34:49,561 --> 03:34:52,764
AND THEN THE MENENG ES, WHERE

5097
03:34:52,764 --> 03:34:56,334
THE VESSELS ARE, VERY, VERY

5098
03:34:56,334 --> 03:34:58,303
IMPORTANT FOR CO REGULATION, AND

5099
03:34:58,303 --> 03:34:59,904
UNLIKE THE OTHER 3 CLASSES ARE

5100
03:34:59,904 --> 03:35:02,707
IN EXCHANGE WITH BONE MARROW

5101
03:35:02,707 --> 03:35:03,575
DERIVED MONOCYTES.

5102
03:35:03,575 --> 03:35:06,010
WE HAVE THE MICROGLIA IN THE

5103
03:35:06,010 --> 03:35:07,111
MACROFAJS ARE LOCKED INTO THE

5104
03:35:07,111 --> 03:35:10,582
BRAIN AND THEY HAVE A CAPACITY

5105
03:35:10,582 --> 03:35:13,918
OF SELF-RENEWAL ALL RIGHT?

5106
03:35:13,918 --> 03:35:15,954
SO THEY RENEW AT A VERY, VERY

5107
03:35:15,954 --> 03:35:16,254
SMALL RATE.

5108
03:35:16,254 --> 03:35:26,130
NOW THESE CELLS IF YOU LOOK AT

5109
03:35:26,130 --> 03:35:28,233
THEM SO IT'S LIKE HAVING A BOMB

5110
03:35:28,233 --> 03:35:29,868
TOUCHING THE VESSEL READ TO

5111
03:35:29,868 --> 03:35:31,469
EXPLODE ANYTIME YOU IMET ANY

5112
03:35:31,469 --> 03:35:34,639
IMMUNE SIGNAL THAT GETS TO THE

5113
03:35:34,639 --> 03:35:38,343
MACROPAGE, AND 1 OF THESE IMMUNE

5114
03:35:38,343 --> 03:35:41,079
IS A BETA WHICH I TOLD YOU

5115
03:35:41,079 --> 03:35:44,883
ACTIVATES THE CD36 RECEPTOR.

5116
03:35:44,883 --> 03:35:46,751
SO WE TESTED THIS HYPOTHESIS,

5117
03:35:46,751 --> 03:35:49,053
WHETHER IT'S THE RESIPTOR ON THE

5118
03:35:49,053 --> 03:35:50,121
MACROPHAGES ON THE TRIGGER

5119
03:35:50,121 --> 03:35:53,491
SETTING OFF THE BOMB TO GET THE

5120
03:35:53,491 --> 03:35:54,292
RADICALS GOING.

5121
03:35:54,292 --> 03:35:56,060
AND WE DID AN EXPERIMENT IN THE

5122
03:35:56,060 --> 03:36:04,002
DIFFERENT MODEL WHICH IS THE

5123
03:36:04,002 --> 03:36:06,204
BOTH IN BRACKS AND IN THE CAA SO

5124
03:36:06,204 --> 03:36:08,406
IF YOU WAIT UNTIL THEY GOT 15

5125
03:36:08,406 --> 03:36:10,708
MONTHS OLD, YOU HAVE A BEAUTIFUL

5126
03:36:10,708 --> 03:36:12,710
CAA DEVELOPING IN THE BRAIN OF

5127
03:36:12,710 --> 03:36:13,544
THESE MICE, PRETTY MUCH LIKE YOU

5128
03:36:13,544 --> 03:36:18,283
SEE IN THE PATIENTS EMPLOY AND

5129
03:36:18,283 --> 03:36:20,418
THEN WE FOUND THAT A BONE MARROW

5130
03:36:20,418 --> 03:36:23,288
BASED STRATEGY WHO DELETE CD36

5131
03:36:23,288 --> 03:36:25,857
SELECTIVELY FROM THE

5132
03:36:25,857 --> 03:36:26,658
MACROPHAGES.

5133
03:36:26,658 --> 03:36:27,792
FROM THE PERIVASCULAR

5134
03:36:27,792 --> 03:36:29,460
MACROFAINLS AND THE RESULTS ARE

5135
03:36:29,460 --> 03:36:32,363
SHOWN HERE SO THE NEGATIVE

5136
03:36:32,363 --> 03:36:33,865
MACROPHAGE IN THE BIO6 MICE LED

5137
03:36:33,865 --> 03:36:37,235
TO COMPLETE RESCUE OF THE

5138
03:36:37,235 --> 03:36:37,835
NEUROVASCULAR DYSFUNCTION,

5139
03:36:37,835 --> 03:36:40,438
IMPROVEMENT OF THE BEHAVIOR,

5140
03:36:40,438 --> 03:36:42,140
ALSO BY DIFFERENT KIND OF

5141
03:36:42,140 --> 03:36:42,774
BEHAVIORIAL PARADIGM.

5142
03:36:42,774 --> 03:36:45,109
SO AT LEAST, YOU KNOW THE BEST

5143
03:36:45,109 --> 03:36:46,811
WORK BETTER, THE MOUSE THINKING

5144
03:36:46,811 --> 03:36:49,447
BETTER, AS MUCH AS A MOUSE CAN

5145
03:36:49,447 --> 03:36:49,881
DO THINKING.

5146
03:36:49,881 --> 03:36:52,350
BUT WHAT ABOUT THE PATHOLOGY?

5147
03:36:52,350 --> 03:36:55,787
SO WHAT WE FOUND THAT THERE WAS

5148
03:36:55,787 --> 03:37:01,192
A REMARKABLE SUPPRESSION OF CAA,

5149
03:37:01,192 --> 03:37:03,594
SHOWN BY REDUCTION CAA BURDEN,

5150
03:37:03,594 --> 03:37:05,096
LOSS OF SMOOTH MUSCLE

5151
03:37:05,096 --> 03:37:06,831
SEGMENTATION, SO THE SMOOTH

5152
03:37:06,831 --> 03:37:08,566
MUSCLES WERE HOLING UP BETTER

5153
03:37:08,566 --> 03:37:11,135
AND THERE WAS NO CHANGE IN THE

5154
03:37:11,135 --> 03:37:11,736
PLAQUES, ALL RIGHT?

5155
03:37:11,736 --> 03:37:13,104
NOW THIS SUGGESTS THAT THEAC IS

5156
03:37:13,104 --> 03:37:16,140
IN THE BLOOD VESSEL.

5157
03:37:16,140 --> 03:37:20,645
WHATEVER THIS BUSINESS IS DOING

5158
03:37:20,645 --> 03:37:22,647
IS SOMEHOW PREVENTING A BETA

5159
03:37:22,647 --> 03:37:23,581
ACCUMULATION IN THE VASCULAR

5160
03:37:23,581 --> 03:37:28,853
WALL AND THIS LED US TO LOOK AT

5161
03:37:28,853 --> 03:37:30,755
THE CLEARANCE MECHANISMS PER B36

5162
03:37:30,755 --> 03:37:32,590
ON THE MACROPAGE ALLOW PERHAPS

5163
03:37:32,590 --> 03:37:37,261
THE BETA TO TICK TO THE

5164
03:37:37,261 --> 03:37:38,997
MACROPHAGE--TO VESSEL BECAUSE

5165
03:37:38,997 --> 03:37:40,598
[INDISCERNIBLE] LOSS FUNCTION TO

5166
03:37:40,598 --> 03:37:41,766
MAKE THE VESSEL LESS PRONE TO BE

5167
03:37:41,766 --> 03:37:43,167
ABLE TO GET RID OF THIS STUFF.

5168
03:37:43,167 --> 03:37:45,636
SO ALL RIGHT IN SO THIS IS NOT A

5169
03:37:45,636 --> 03:37:48,139
GREAT EXPERIMENT, IT'S A

5170
03:37:48,139 --> 03:37:49,173
PRELIMINARY EXPERIMENT BECAUSE

5171
03:37:49,173 --> 03:37:51,642
WE USE TOTAL XOK OUT MICE BUT WE

5172
03:37:51,642 --> 03:37:53,378
FOUND WAS THAT IF WE INYECT A

5173
03:37:53,378 --> 03:37:54,679
BETA INTO THE CORTECH, ALL RIGHT

5174
03:37:54,679 --> 03:37:57,015
IN AND THEN WE LOOK HOW MUCH OF

5175
03:37:57,015 --> 03:37:59,751
THAT IS RETAINED INTO THE

5176
03:37:59,751 --> 03:38:02,487
CORTEX, BY SAMPLING IT AND

5177
03:38:02,487 --> 03:38:03,988
MEASURING IT, ALL RIGHT AND AT

5178
03:38:03,988 --> 03:38:05,456
THE SAME TIME LOOK AT BETA AM

5179
03:38:05,456 --> 03:38:07,859
CANNING OUT OF THE SUPERIOR

5180
03:38:07,859 --> 03:38:09,227
SIDE, WHICH DRAINS THE CORTEX

5181
03:38:09,227 --> 03:38:12,463
WHERE WE INYEKED ALL RIGHT CAN

5182
03:38:12,463 --> 03:38:14,499
WE LOOK AT THE, AND INCLUDING

5183
03:38:14,499 --> 03:38:18,069
BLOOD, YOU SEE THE CD36 XOK OUT

5184
03:38:18,069 --> 03:38:19,771
MOUSE AND ABLE TO EMANATE BETTER

5185
03:38:19,771 --> 03:38:22,407
BECAUSE IT IS LESS THAN STICKS

5186
03:38:22,407 --> 03:38:24,008
IN THE BRAIN AND MORE IN

5187
03:38:24,008 --> 03:38:24,375
CIRCULATION.

5188
03:38:24,375 --> 03:38:30,048
WE DON'T KNOW IF THIS IS A

5189
03:38:30,048 --> 03:38:30,715
MICROPHAGE MEDIATED PHENOMENON,

5190
03:38:30,715 --> 03:38:32,683
WE ARE LOOKINGA THE IT NOW, BUT

5191
03:38:32,683 --> 03:38:35,386
IT WAS A GOOD SUGGESTION IN THE

5192
03:38:35,386 --> 03:38:38,156
CD36 IN THE MACROPHAGES, LOSS OF

5193
03:38:38,156 --> 03:38:40,558
DYSFUNCTION TO THE PRERADICALS

5194
03:38:40,558 --> 03:38:42,827
REDUCES BETA ADHERENCE AND

5195
03:38:42,827 --> 03:38:44,462
PROMOTES ACCUMULATION OF THE

5196
03:38:44,462 --> 03:38:46,030
ENDOVASCULAR WALL EMPLOY NOW CAA

5197
03:38:46,030 --> 03:38:51,936
IS ALSO A MAJOR PROBLEM HERE.

5198
03:38:51,936 --> 03:38:54,405
HOW AM I DOING, NOT SO BAD, THIS

5199
03:38:54,405 --> 03:38:59,477
IS ANOTHER RISK FACTOR FOR CAA

5200
03:38:59,477 --> 03:39:01,479
ANY ALSO AS WE HEARD

5201
03:39:01,479 --> 03:39:02,046
EXTENSIVELYAR ARIA.

5202
03:39:02,046 --> 03:39:05,583
SO WHAT IS THE ROLE ON APOE4 ON

5203
03:39:05,583 --> 03:39:09,654
THE BLOOD VESSEL TO AFFAIRS TEAM

5204
03:39:09,654 --> 03:39:10,321
LEADERRER THIS FUNCTIONS?

5205
03:39:10,321 --> 03:39:12,356
SO A FEW YEARS AGO WE MEASURE

5206
03:39:12,356 --> 03:39:14,559
BLOOD FLOW IN THE BRAIN THAT WE

5207
03:39:14,559 --> 03:39:16,427
HEARD FROM YAWN AND WE FOUND IT

5208
03:39:16,427 --> 03:39:19,030
WAS REDUCTION IN APOE 4 MICE, SO

5209
03:39:19,030 --> 03:39:23,201
NOW IT'S MICE WHICH WERE CREATED

5210
03:39:23,201 --> 03:39:26,537
BY INSERTING THE HUMAN APOE INTO

5211
03:39:26,537 --> 03:39:28,039
A MOUSE BUT THE EXPRESSION WAS

5212
03:39:28,039 --> 03:39:31,876
CONTROLLED BY THE MOUSE

5213
03:39:31,876 --> 03:39:32,143
PROMOTER.

5214
03:39:32,143 --> 03:39:34,645
SO APOE TBOT TO THE RIGHT PLACE

5215
03:39:34,645 --> 03:39:39,717
BUT WAS HUMAN APOE, OPPOSED TO

5216
03:39:39,717 --> 03:39:40,818
THE MOUSE APOE, AND WE FOUND

5217
03:39:40,818 --> 03:39:43,354
THERE WAS A REDUCTION, ARRESTING

5218
03:39:43,354 --> 03:39:45,423
PLOA AND ALTERATION IN ALL THE

5219
03:39:45,423 --> 03:39:47,058
FACTORS REGULATING THE

5220
03:39:47,058 --> 03:39:49,627
CIRCULATION, PRETTY MUCH LIKE A

5221
03:39:49,627 --> 03:39:51,529
BETA DID, EXACTLY LIKE AT LEAST

5222
03:39:51,529 --> 03:39:53,397
THE FUNCTIONAL LEVEL, AS A BETA

5223
03:39:53,397 --> 03:39:55,366
DID, BUT THE QUESTION IS WHERE

5224
03:39:55,366 --> 03:39:59,003
IS APOE COMING FROM IN YOU KNOW?

5225
03:39:59,003 --> 03:40:00,872
AND TO INTIEWS THIS ALSO FREE

5226
03:40:00,872 --> 03:40:03,508
RADICALS RADICAL PRODUCK THAT WE

5227
03:40:03,508 --> 03:40:06,644
DEMON TRAITED BY USING INHIBITOR

5228
03:40:06,644 --> 03:40:11,449
OF AN NADP H OXIDASE AND

5229
03:40:11,449 --> 03:40:13,117
PREVENTING VASCULAR DYSFUNCTION.

5230
03:40:13,117 --> 03:40:16,354
SO APOE 4 USES THIS AS VASCULAR

5231
03:40:16,354 --> 03:40:19,123
FUNCTION THROUGH FREE RADICAL

5232
03:40:19,123 --> 03:40:19,423
PRODUCTION.

5233
03:40:19,423 --> 03:40:21,993
NOW WHERE IS THE APOE 4 COMING

5234
03:40:21,993 --> 03:40:22,860
FROM TO MEDIATE.

5235
03:40:22,860 --> 03:40:26,297
SO BEING TO A RECENT MOUSE WHO

5236
03:40:26,297 --> 03:40:29,433
JUST DEVELOPED AND THIS PAPER IS

5237
03:40:29,433 --> 03:40:33,304
STILL [INDISCERNIBLE] WE WERE

5238
03:40:33,304 --> 03:40:37,074
ABLE TO TARGET THIS MACROPHAGES,

5239
03:40:37,074 --> 03:40:38,042
INCLUDING THE PERIVASCULAR

5240
03:40:38,042 --> 03:40:39,177
MICROPHAGES THEN WE CROSS THIS

5241
03:40:39,177 --> 03:40:42,747
MOUSE WITH A MOUSE WITH THE FLOX

5242
03:40:42,747 --> 03:40:45,416
APOE 4 AND WE WERE ABLE TO

5243
03:40:45,416 --> 03:40:49,153
SELECT UFLY DELETE APOE 4 FROM

5244
03:40:49,153 --> 03:40:49,787
THE PERIVASCULAR MICROPHAGES,

5245
03:40:49,787 --> 03:40:51,622
WHERE THE REST OF THE BRAIN WAS

5246
03:40:51,622 --> 03:41:00,331
APOE 4 POSITIVE ARE ALL RIGHT

5247
03:41:00,331 --> 03:41:06,237
ONLY THE MACROPHAGES ACTIVATED

5248
03:41:06,237 --> 03:41:09,907
APOE 4, BY ELIMINATING APOE 4

5249
03:41:09,907 --> 03:41:12,777
FROM THE BORDER OF THE

5250
03:41:12,777 --> 03:41:13,077
MACROPAGES.

5251
03:41:13,077 --> 03:41:17,748
SO THE DATA THEN SUGGESTS THAT

5252
03:41:17,748 --> 03:41:21,619
THE BRAIN MACROPHAGES,

5253
03:41:21,619 --> 03:41:23,120
PARTICULARLY, MENENG EALL, AND

5254
03:41:23,120 --> 03:41:25,056
THE SIDE, THE CONVERGENCE OF

5255
03:41:25,056 --> 03:41:27,358
THESE SIGNALS MEDIATING

5256
03:41:27,358 --> 03:41:30,061
THISOXIDATIVE STRESS AND THEP

5257
03:41:30,061 --> 03:41:31,896
NEUROVASCULAR DISFUNCTION EMPLOY

5258
03:41:31,896 --> 03:41:36,400
SO APOE 4 PRESUMABLY TO LRP TYPE

5259
03:41:36,400 --> 03:41:37,668
RECEPTOR, ACTIVATES PRERADICAL

5260
03:41:37,668 --> 03:41:39,470
PRODUCTION, A BETA TO THE CD36

5261
03:41:39,470 --> 03:41:42,573
RECEPTOR I'VE SHOWN YOU BEFORE

5262
03:41:42,573 --> 03:41:44,041
ACTIVATES THESE FREE RADICAL

5263
03:41:44,041 --> 03:41:50,147
PRACTICES DUKS, MOW THIS IMPAIRS

5264
03:41:50,147 --> 03:41:50,881
NEUROVASCULAR FUNCTION, FUNCTION

5265
03:41:50,881 --> 03:41:53,251
OF WHICH IS GETTING RID OF THIS

5266
03:41:53,251 --> 03:41:54,385
ASH BETA.

5267
03:41:54,385 --> 03:41:56,554
AND IN THIS THEN MOST LIKELY

5268
03:41:56,554 --> 03:42:01,492
LEAD TO THIS ARK KIEWMULATION,

5269
03:42:01,492 --> 03:42:02,660
BECAUSE THE VESSEL CANNOT GET

5270
03:42:02,660 --> 03:42:04,161
RID OF IT, ALL RIGHT.

5271
03:42:04,161 --> 03:42:07,465
NOW WHAT DOES THIS MEAN FOR CAA

5272
03:42:07,465 --> 03:42:08,866
AND FOR ARIA EMPLOY WELL, WE

5273
03:42:08,866 --> 03:42:10,801
HAVE HEARD BEFORE LIKE IN THIS

5274
03:42:10,801 --> 03:42:15,006
CASE, OF THIS PATIENT, THAT DIED

5275
03:42:15,006 --> 03:42:16,007
AFTER [INDISCERNIBLE], YOU CAN

5276
03:42:16,007 --> 03:42:18,976
SEE THERE IS A VERY EFFECTIVE

5277
03:42:18,976 --> 03:42:20,544
CLEARANCE OF PLAQUES BUT CAA IS

5278
03:42:20,544 --> 03:42:22,346
TILL THERE, AND THAT'S WHAT WE

5279
03:42:22,346 --> 03:42:25,850
HEARD BEFORE, FROM DR. NIERK

5280
03:42:25,850 --> 03:42:27,184
COLLs, IT'S EVEN WORSE.

5281
03:42:27,184 --> 03:42:29,987
SO MOST LIKELY HERE WE HAVE A

5282
03:42:29,987 --> 03:42:32,290
PROBLEM WITH ACCUMULATION OF

5283
03:42:32,290 --> 03:42:33,891
ABETTA PRESUMABLILY RESULTING

5284
03:42:33,891 --> 03:42:36,193
FROM THIS MACROPHAGE MEDIATED

5285
03:42:36,193 --> 03:42:37,361
ACCUMULATION DUE TO THE FACT

5286
03:42:37,361 --> 03:42:39,196
THAT THE VESSEL DOESN'T WORK

5287
03:42:39,196 --> 03:42:44,101
ANYMORE EMPLOY OKAY, NOW WHAT

5288
03:42:44,101 --> 03:42:47,138
ABOUT THE MACROPHAGES? 

5289
03:42:47,138 --> 03:42:49,540
YOU CAN SEE IT'S ALL THERE.

5290
03:42:49,540 --> 03:42:51,642
REMARKABLILY IN THE CAN I HAVE

5291
03:42:51,642 --> 03:42:53,444
YEAR-OLD WITHIN APUNISHING OE4

5292
03:42:53,444 --> 03:42:55,713
POS 55, HOMOZYGOUS WHO DIED

5293
03:42:55,713 --> 03:42:56,847
AFTER STROKE AND TISSUING

5294
03:42:56,847 --> 03:42:59,483
PUNISHINGA AND HAD BEEN TREATED,

5295
03:42:59,483 --> 03:43:02,420
APPROXIMATE YOU CAN SEE THAT

5296
03:43:02,420 --> 03:43:08,659
THERE WAS CD8 163 POSITIVE

5297
03:43:08,659 --> 03:43:12,496
MACROPHAGES SURROUNDING AMYLOID

5298
03:43:12,496 --> 03:43:14,832
RIDDEN VESSELS SO CD163 IS

5299
03:43:14,832 --> 03:43:15,866
MACROPHAGES AS YOU KNOW IN MICE

5300
03:43:15,866 --> 03:43:22,306
YOU BEING SEE THERE IS A

5301
03:43:22,306 --> 03:43:24,775
MACROPHAGE DRIVEN RESPONSE

5302
03:43:24,775 --> 03:43:25,843
SURROUNDING BETA ACCUMULATION IN

5303
03:43:25,843 --> 03:43:28,612
MOST LIKELY PLAYS A ROLE IN THIS

5304
03:43:28,612 --> 03:43:30,448
ALTERATION OF THE VASCULATURE

5305
03:43:30,448 --> 03:43:31,849
INFLAMMATION THAT LEADS TO ARIA

5306
03:43:31,849 --> 03:43:34,785
IN ACCUMULATION OF A BETA.

5307
03:43:34,785 --> 03:43:40,358
SO I SHOWED YOU BET IN APOE 4

5308
03:43:40,358 --> 03:43:41,192
REGULATION CAUSING PROGRESSIVE

5309
03:43:41,192 --> 03:43:42,460
DAMAGE, SO IF YOU WANT TO DO

5310
03:43:42,460 --> 03:43:44,095
ANYTHING, DO IT EARLY, ALL RIGHT

5311
03:43:44,095 --> 03:43:48,366
IN WHICH IS MEDIATED BY

5312
03:43:48,366 --> 03:43:50,234
OCIDATIVE TRESES TO REDUCE NADP

5313
03:43:50,234 --> 03:43:53,237
H TO ENZYME AND THEN THE BORDER

5314
03:43:53,237 --> 03:43:56,107
WITH THE MACROFEAJS ARE REALLY

5315
03:43:56,107 --> 03:43:57,908
THE CRITICAL CELL THAT MAKE THIS

5316
03:43:57,908 --> 03:43:59,176
RADICAL, SO THEY TOUCH THE

5317
03:43:59,176 --> 03:44:01,145
VESSEL READY TO GO OFF WITH

5318
03:44:01,145 --> 03:44:03,247
THERE IS AN IMMUNOLOGY SIGNAL

5319
03:44:03,247 --> 03:44:04,515
FOR THE PERIVASCULAR SPACE AND

5320
03:44:04,515 --> 03:44:07,184
WE'VE SEEN OUR A-BETA AND APOE

5321
03:44:07,184 --> 03:44:08,619
ARE ABLE TO DO THAT.

5322
03:44:08,619 --> 03:44:12,823
THIS MAY PLAY A ROLE IN THAT, SO

5323
03:44:12,823 --> 03:44:15,059
PERHAPS TARGETING THE IMMUNE

5324
03:44:15,059 --> 03:44:16,193
RECEPTORS ON THESE MACROPHAGES

5325
03:44:16,193 --> 03:44:19,230
MAY BE BENEFICIAL IN THE ALSO IN

5326
03:44:19,230 --> 03:44:22,466
THE COMPLICATION OF A BETA

5327
03:44:22,466 --> 03:44:22,800
IMMUNOTHERAPY.

5328
03:44:22,800 --> 03:44:32,009
THANK YOU VERY MUCH.

5329
03:44:32,009 --> 03:44:37,815
TO WE TAKE QUESTIONS?

5330
03:44:37,815 --> 03:44:38,783
>>  OKAY, SOPHISTICATEDY
WE WILL

5331
03:44:38,783 --> 03:44:42,453
TAKE SOME QUESTIONS FOR THE

5332
03:44:42,453 --> 03:44:50,261
FIRST 2 SPEAKERS.

5333
03:44:50,261 --> 03:44:52,663
NI HAVE A QUESTION, GREAT TALK

5334
03:44:52,663 --> 03:44:57,935
AS ALWAYS, THIS IS TO CONSTANTIN

5335
03:44:57,935 --> 03:45:00,704
O, SO WHEN YOU HAVE THE

5336
03:45:00,704 --> 03:45:02,339
PRODUCTION OF SUPEROXIDE

5337
03:45:02,339 --> 03:45:03,073
ANDSOXIDATIVE STRESS FROM THESE

5338
03:45:03,073 --> 03:45:04,942
CELLS DO YOU THINK IT'S REALLY

5339
03:45:04,942 --> 03:45:06,444
AFFECTING THE PERISIGHTS AND THE

5340
03:45:06,444 --> 03:45:08,979
SMOOTH MUSCLE CELLS AND CAUSING

5341
03:45:08,979 --> 03:45:10,214
DEKRESSED CONTRACTTILITY AND

5342
03:45:10,214 --> 03:45:12,183
PULSATILITY, OR DO YOU THINK

5343
03:45:12,183 --> 03:45:12,950
IT'S AFFECTING THE

5344
03:45:12,950 --> 03:45:13,617
ENDOTHEY'LLIAL CELLS, WHICH ARE

5345
03:45:13,617 --> 03:45:15,753
OBVIOUS LE ON THE OTHER SIDE OR

5346
03:45:15,753 --> 03:45:23,494
BOTH, IF YOU HAVE ANY EVIDENCE.

5347
03:45:23,494 --> 03:45:24,428
>> YES, BIOLOGICAL ANSWER,
ALL

5348
03:45:24,428 --> 03:45:26,030
RIGHT, SO THE TRESES WORKS IN

5349
03:45:26,030 --> 03:45:27,031
MULTIPLE WAYS.

5350
03:45:27,031 --> 03:45:29,033
I DON'T THINK THAT THE SMOOTH

5351
03:45:29,033 --> 03:45:30,801
MUSCLE CELL ARE THE PRIMARY

5352
03:45:30,801 --> 03:45:32,736
TARGETTA THE VERY BEGINNING, YOU

5353
03:45:32,736 --> 03:45:34,705
HAVE TO KILL THE SMOOTH MUSCLE

5354
03:45:34,705 --> 03:45:37,374
CELLS SO YOU NEED A LOT OF

5355
03:45:37,374 --> 03:45:38,943
RADICALS SO PRESUMABLY AT THE

5356
03:45:38,943 --> 03:45:40,878
BEGINNING THERE IS NO

5357
03:45:40,878 --> 03:45:41,545
DYSFUNCTION, NO DISTRACTION, ALL

5358
03:45:41,545 --> 03:45:43,581
RIGHT, SO WHAT YOU GET, A RAICAL

5359
03:45:43,581 --> 03:45:46,717
DO, THEY GET RID OF

5360
03:45:46,717 --> 03:45:48,419
[INDISCERNIBLE] IT WAS MADE BY

5361
03:45:48,419 --> 03:45:50,921
THE ENDOTHELIUM AND COMING FROM

5362
03:45:50,921 --> 03:45:52,623
THE NEURONS, ALL RIGHT,

5363
03:45:52,623 --> 03:45:53,924
ACTIVATED, RADICALS GET RID OF

5364
03:45:53,924 --> 03:45:54,458
THAT.

5365
03:45:54,458 --> 03:45:58,229
THEY ARE VERY, VERY WELL KNOWN,

5366
03:45:58,229 --> 03:45:59,830
THEY ARE A DEPLETER, ALL RIGHT,

5367
03:45:59,830 --> 03:46:02,032
THAT'S HOW YOU GET IN THE

5368
03:46:02,032 --> 03:46:05,503
ENDOTHELIAL DYSFUNCTION AND THE

5369
03:46:05,503 --> 03:46:06,337
NEUROVASCULAR UNCOUPLING, IF YOU

5370
03:46:06,337 --> 03:46:08,072
LET THIS THING GO ON AND ON, YOU

5371
03:46:08,072 --> 03:46:09,773
WILL GET THE SMOOTH MUSCLE CELLS

5372
03:46:09,773 --> 03:46:12,076
TO DIE, IN WHICH CASE NOTHING

5373
03:46:12,076 --> 03:46:13,344
WORKS, ALL RIGHT?

5374
03:46:13,344 --> 03:46:15,179
BECAUSE THEY--AS YOU CAN SEE, IN

5375
03:46:15,179 --> 03:46:16,580
THEN MODEL THEY FALL INTO

5376
03:46:16,580 --> 03:46:24,088
PIECES, SO JUST A GRADUAL VERY

5377
03:46:24,088 --> 03:46:24,922
NUANCED PROCESS, YEAH.

5378
03:46:24,922 --> 03:46:26,090
AMERICA REALLY GREAT TALKS BY

5379
03:46:26,090 --> 03:46:28,125
THE EAST COAST BY AND THE WEST

5380
03:46:28,125 --> 03:46:28,792
COAST GUY.

5381
03:46:28,792 --> 03:46:31,762
QUESTION ACTUALLY FOR THE WEST

5382
03:46:31,762 --> 03:46:34,532
COAST GUY, THE ENDOTHELIAL

5383
03:46:34,532 --> 03:46:36,367
ENGULFMENT OF AGED RED BLOOD

5384
03:46:36,367 --> 03:46:36,967
CELLS REALLY INTRIGUING CENTER

5385
03:46:36,967 --> 03:46:41,438
FOR  EFFECT.

5386
03:46:41,438 --> 03:46:43,674
I'M SPECULATING GETTING BACK TO

5387
03:46:43,674 --> 03:46:45,009
THE ANCHLIO MYOPATHY

5388
03:46:45,009 --> 03:46:46,477
TERMINOLOGY, ANY REASON TO THINK

5389
03:46:46,477 --> 03:46:47,878
THE HEALTH OF THE MEDIA HAS ANY

5390
03:46:47,878 --> 03:46:50,014
ROLE TO PLAY IN THE MECHANISM OR

5391
03:46:50,014 --> 03:46:50,714
COMPLETELY INDEPENDENT OF WHAT'S

5392
03:46:50,714 --> 03:46:53,284
GOING ON IN THE REST OF THE

5393
03:46:53,284 --> 03:46:57,955
VESSEL OUTSIDE THE ENDOTHELIUM. 

5394
03:46:57,955 --> 03:47:01,458
>> YEAH, REFERRING TO THE

5395
03:47:01,458 --> 03:47:02,459
ARITHROUGH ATOM PHAGOCYTOSIS?

5396
03:47:02,459 --> 03:47:04,061
>> YEAH, WHAT WE'RE SEEING
IS

5397
03:47:04,061 --> 03:47:10,000
PRETTY WELL IMITTED TO THE

5398
03:47:10,000 --> 03:47:12,236
ENDOTHELIUM AND THE ARITHROUGH

5399
03:47:12,236 --> 03:47:14,004
ATOM PHAGOCYTOSIS LOOKS LIKE

5400
03:47:14,004 --> 03:47:15,372
IT'S--IT REALLY DOES LOOK LIKE

5401
03:47:15,372 --> 03:47:18,943
IT'S LIMITED TO THE EBD O

5402
03:47:18,943 --> 03:47:19,476
THELIUM.

5403
03:47:19,476 --> 03:47:25,149
THE ENDOTHELIUM WAS ORIGINALLY

5404
03:47:25,149 --> 03:47:26,684
DESCRIBED IN 2008 BY

5405
03:47:26,684 --> 03:47:28,018
[INDISCERNIBLE] AND COLLEAGUES,

5406
03:47:28,018 --> 03:47:29,887
ACTUAL 3 THERE'S SOME SIMILARITY

5407
03:47:29,887 --> 03:47:31,655
ANDS SOME DIFFERENCES WITH WHAT

5408
03:47:31,655 --> 03:47:34,224
WE UNDERSTAND TO BE ANCHLIO

5409
03:47:34,224 --> 03:47:41,031
PHAGE COMPETENT IT'S INREGGING

5410
03:47:41,031 --> 03:47:43,400
COMPARISONS BUT THE PHAGOCYTOSIS

5411
03:47:43,400 --> 03:47:44,935
BY ENDOTHELIAL CELL HAS BEEN

5412
03:47:44,935 --> 03:47:46,870
WELL DESCRIBED BUT I'M NOT AWARE

5413
03:47:46,870 --> 03:47:49,106
OF THIS BEING DRIEBED FOR SMOOTH

5414
03:47:49,106 --> 03:47:52,109
MUSCLE CELLS NSO IT'S DRIVEN BY

5415
03:47:52,109 --> 03:47:53,844
PRIMARILY AIMING RED BLOOD CELLS

5416
03:47:53,844 --> 03:47:56,246
BUT NOT BY ANY PARTICULAR

5417
03:47:56,246 --> 03:47:56,647
PATHOLOGY.

5418
03:47:56,647 --> 03:47:58,782
>> IT'S JUST DRIVEN
PRIMARILY BY

5419
03:47:58,782 --> 03:48:00,117
ANALLING OF THE ARITHROCYTES AND

5420
03:48:00,117 --> 03:48:01,852
NOT PARTICULARLY BY ANYTHING

5421
03:48:01,852 --> 03:48:05,122
GOING ON, ANY AGING OF THE

5422
03:48:05,122 --> 03:48:05,356
VESSEL.

5423
03:48:05,356 --> 03:48:06,523
>> WELL THAT'S A GREAT
QUESTION

5424
03:48:06,523 --> 03:48:10,628
AND THAT'S AN ISSUE THAT NEEDS

5425
03:48:10,628 --> 03:48:14,198
TO BE ADDRESSED. 

5426
03:48:14,198 --> 03:48:16,066
HOW THE PHAGOCYTOSIS PROCESS IS

5427
03:48:16,066 --> 03:48:19,703
AFFECTED BY AGE, 1 WILL EXPECT

5428
03:48:19,703 --> 03:48:24,074
THAT THE LOGICAL HYPOTHESIS IS

5429
03:48:24,074 --> 03:48:26,110
THIS IS--THIS DECLINES WITH AGE

5430
03:48:26,110 --> 03:48:28,612
AND SOME OF [INDISCERNIBLE]

5431
03:48:28,612 --> 03:48:32,850
OBSERVATIONS SUGGEST THAT AGING

5432
03:48:32,850 --> 03:48:34,184
DID IMPACT NEGATIVELY ANGIE

5433
03:48:34,184 --> 03:48:37,254
OPHAGEY SO 1 WOULD EXPECT THAT

5434
03:48:37,254 --> 03:48:38,288
WITH AGING, NOT ONLY THE RED

5435
03:48:38,288 --> 03:48:41,058
BLOOD CELL IS AFFECTED BUT THE

5436
03:48:41,058 --> 03:48:44,395
CAPACITY TO CLEAR CAPILLARIES

5437
03:48:44,395 --> 03:48:46,296
MAY ALSO BE IMPAIR PERIOD WHAT

5438
03:48:46,296 --> 03:48:48,198
THE CURRENT CHIMAL CONSEQUENCES

5439
03:48:48,198 --> 03:48:52,870
OF THAT ARE, YOU KNOW THAT'S

5440
03:48:52,870 --> 03:48:53,837
WIDE OPEN.

5441
03:48:53,837 --> 03:48:55,372
>> WEE TAKE 1 ONLINE
QUESTION

5442
03:48:55,372 --> 03:48:57,174
AND WE WILL TAKE YOUR QUESTION,

5443
03:48:57,174 --> 03:49:05,582
TOO, 1 SECOND.

5444
03:49:05,582 --> 03:49:06,183
FOR DR. FISHER.

5445
03:49:06,183 --> 03:49:08,352
MY QUESTION IS WHAT YOU MEAN BY

5446
03:49:08,352 --> 03:49:11,055
AGE RED BLOOD CELL, RED BLOOD

5447
03:49:11,055 --> 03:49:12,823
CELL CYCLE EVERY 60 DAYS, CO YOU

5448
03:49:12,823 --> 03:49:15,092
MEAN RED BLOOD CELLS OBTAINED

5449
03:49:15,092 --> 03:49:16,994
FROM YOUNG VERSUS OLD SUBYEBS IN

5450
03:49:16,994 --> 03:49:19,697
SO DO YOU MEAN AGED IN TERMS OF

5451
03:49:19,697 --> 03:49:22,099
CYCLE OR DO YOU MEAN AGE THAT

5452
03:49:22,099 --> 03:49:23,834
IT'S COMING FROM OLDER

5453
03:49:23,834 --> 03:49:24,668
INDIVIDUALS?

5454
03:49:24,668 --> 03:49:26,870
NTHESE EXPERIMENTS WERE DONE

5455
03:49:26,870 --> 03:49:27,771
WITH BIOCHEMICALLY AGED RED

5456
03:49:27,771 --> 03:49:31,408
BLOOD CELLS, THIS IS A WELL

5457
03:49:31,408 --> 03:49:36,113
TEABED MODEL OF RED BLOOD CELLS

5458
03:49:36,113 --> 03:49:38,315
BY INDUCINGOXIDATIVE TRESES WITH

5459
03:49:38,315 --> 03:49:40,184
ATHP, AND IT DOES RESULT IN

5460
03:49:40,184 --> 03:49:43,821
EXPOSURE TO THE MEMBRANE

5461
03:49:43,821 --> 03:49:45,789
MARKEDLY REDUCED RED BLOOD CELL

5462
03:49:45,789 --> 03:49:47,157
FORMABILITY SO IT'S A

5463
03:49:47,157 --> 03:49:48,892
BIOCHEMICAL MODEL OF ANALLING.

5464
03:49:48,892 --> 03:49:50,594
THANK YOU DR. IN.

5465
03:49:50,594 --> 03:49:54,998
>> I'M AFRAID OF PULLING
THIS

5466
03:49:54,998 --> 03:49:55,466
DOWN.

5467
03:49:55,466 --> 03:49:57,367
CONSTANTIN O, AWESOME TALK AND

5468
03:49:57,367 --> 03:49:58,869
BEAUTIFUL DATA NCAN YOU MOVE IT

5469
03:49:58,869 --> 03:50:00,738
MORE NWITHOUT IT FALLING IN

5470
03:50:00,738 --> 03:50:05,743
NYEAH, GREAT. 

5471
03:50:05,743 --> 03:50:06,343
>> I WILL TRY.

5472
03:50:06,343 --> 03:50:07,811
BEAUTIFUL TALK EMPLOY NEW DATA

5473
03:50:07,811 --> 03:50:09,179
REALLY NICE.

5474
03:50:09,179 --> 03:50:10,214
I'M TRYING TO UNDERSTAND, YOU

5475
03:50:10,214 --> 03:50:12,216
KNOW WE WORK A LOT ON COMPLEMENT

5476
03:50:12,216 --> 03:50:13,550
SOIME TRYING TO FIGURE OUT YOU

5477
03:50:13,550 --> 03:50:15,986
KNOW YOU TALKED ABOUT INNATE

5478
03:50:15,986 --> 03:50:17,588
IMMUNITY AND WHERE COMPLEMENT

5479
03:50:17,588 --> 03:50:19,022
MIGHT FIT IN YOUR MODEL SO HAVE

5480
03:50:19,022 --> 03:50:20,324
YOU LOOKED AT ALLENTIOUS

5481
03:50:20,324 --> 03:50:22,192
SPECIALLY IN THE CD36 KNOCKOUT

5482
03:50:22,192 --> 03:50:28,832
MICE HAVE YOU LOOKED TO SEE? 

5483
03:50:28,832 --> 03:50:33,804
>> THERE IS A RECENT PAPER
FOR

5484
03:50:33,804 --> 03:50:35,973
IMMUNO COMPLEXES IN THE ARIA, IN

5485
03:50:35,973 --> 03:50:38,776
THE MODEL OF ARIA, YOU KNOW, IN

5486
03:50:38,776 --> 03:50:41,044
OTHER WORDS HAVE YOU A BETA

5487
03:50:41,044 --> 03:50:42,112
COMPLEXING WITH THE ANTIBODY,

5488
03:50:42,112 --> 03:50:45,082
NOW WHETHER THIS IMMUNE COMPLEX

5489
03:50:45,082 --> 03:50:45,983
COME PREFORM EXCLUDE THEN THEY

5490
03:50:45,983 --> 03:50:50,420
GET TO THE VESSEL AND THEY CAUSE

5491
03:50:50,420 --> 03:50:52,122
INFLAMMATION OR WHETHER THE

5492
03:50:52,122 --> 03:50:54,258
ANTIBODY BIEBDS TO THE BETA ON

5493
03:50:54,258 --> 03:50:55,526
THE VESSEL REMAINS TO BE

5494
03:50:55,526 --> 03:50:58,796
DETERMINED BUT THERE IS A

5495
03:50:58,796 --> 03:51:00,030
COMPLEMENT MEDIATED PHENOMENON

5496
03:51:00,030 --> 03:51:02,499
ACCORDING IN THAT MODEL THAT IF

5497
03:51:02,499 --> 03:51:04,268
WE SEE THE RECEPTOR MEDIATED SO

5498
03:51:04,268 --> 03:51:05,736
THERE IS SOMETHING GOING ON

5499
03:51:05,736 --> 03:51:07,171
ALONG THOSE LINES, YEAH IN.

5500
03:51:07,171 --> 03:51:10,140
>> YEAH, YEAH, I THINK
THERE'S

5501
03:51:10,140 --> 03:51:12,242
COMPLEMENT ACTIVATION IN CAA TO

5502
03:51:12,242 --> 03:51:14,878
BE BEGIN WITH, AND THEN WHEN YOU

5503
03:51:14,878 --> 03:51:18,048
ADD AN ANTIBODY THAT'S FINDING

5504
03:51:18,048 --> 03:51:19,583
FIBULARY AMYLOID BUT NOT OTHERS,

5505
03:51:19,583 --> 03:51:21,985
HAS TO BE BINDING, TO ME THAT'S

5506
03:51:21,985 --> 03:51:23,921
EVIDENT THAT THE ANTIBODIES ARE

5507
03:51:23,921 --> 03:51:25,189
PROBABLY BINDING THE VASCULAR

5508
03:51:25,189 --> 03:51:27,090
AMYLOID AND THEN INDUCING THIS

5509
03:51:27,090 --> 03:51:31,728
COMPLEMENT REACTION OF CLASSICAL

5510
03:51:31,728 --> 03:51:32,029
CONFIDENCE.

5511
03:51:32,029 --> 03:51:32,362
THANK YOU.

5512
03:51:32,362 --> 03:51:36,600
>> THANK YOU .

5513
03:51:36,600 --> 03:51:38,735
>> IN YOUR TALK YOU
ECHICIZE THE

5514
03:51:38,735 --> 03:51:40,404
ROLE OF SMOOTH MUSCLE CELL IN

5515
03:51:40,404 --> 03:51:43,240
THE DRIVING FORCE FOR SORT OF

5516
03:51:43,240 --> 03:51:45,776
THE LYMPHATIC SYSTEM, CLEARANCE,

5517
03:51:45,776 --> 03:51:47,945
BUT, WOULDN'T THERE ALSO BE A

5518
03:51:47,945 --> 03:51:48,879
COMPONENT OF PASSIVE TRIEFING

5519
03:51:48,879 --> 03:51:50,948
FOR US BECAUSE PULSATION WOULD

5520
03:51:50,948 --> 03:51:53,016
PUSH THOSE BIGGER, NOT

5521
03:51:53,016 --> 03:51:54,318
NECESSARILY BIG ARTERIES TO KIND

5522
03:51:54,318 --> 03:51:57,287
OF PUSH THE LYMPHATIC

5523
03:51:57,287 --> 03:51:58,255
PERIVASCULAR FLUID FORWARD IS

5524
03:51:58,255 --> 03:52:00,357
THAT MORE IMPORTANT OR CAPILLARY

5525
03:52:00,357 --> 03:52:03,060
PATHOGEN MUSCLE IS BIGGER

5526
03:52:03,060 --> 03:52:05,362
COMPONENT FOR THAT?

5527
03:52:05,362 --> 03:52:08,198
>> SO THE CAPILLARIES NO
LONGER

5528
03:52:08,198 --> 03:52:10,234
HAVE A VASCULAR SPACE, SO THERE,

5529
03:52:10,234 --> 03:52:12,870
THEFULLIA SPEAKS TO THE VESSEL

5530
03:52:12,870 --> 03:52:13,203
WALL.

5531
03:52:13,203 --> 03:52:14,538
AND NOBODY'S HONE THAT THESE CAN

5532
03:52:14,538 --> 03:52:15,806
GO THROUGH THERE, THAT'S 1 OF

5533
03:52:15,806 --> 03:52:17,975
THE MAJOR PROBLEMS WITH THE

5534
03:52:17,975 --> 03:52:19,276
LYMPHATIC SYSTEM, ALL RIGHT, HOW

5535
03:52:19,276 --> 03:52:23,013
DID THE STUFF GET TO THE VAINS,

5536
03:52:23,013 --> 03:52:23,480
RIGHT?

5537
03:52:23,480 --> 03:52:26,216
WHICH IS NOT CONSISTENT WITH

5538
03:52:26,216 --> 03:52:29,386
THE, ALSO WITH THE CAA BEING

5539
03:52:29,386 --> 03:52:30,454
[INDISCERNIBLE] DISEASE AS

5540
03:52:30,454 --> 03:52:32,256
OPPOSE TO VENUE LA, IT THINKS

5541
03:52:32,256 --> 03:52:33,156
WE'RE STICKING ON THE VAINS

5542
03:52:33,156 --> 03:52:35,125
BECAUSE IT WAS A SLOWING DOWN

5543
03:52:35,125 --> 03:52:37,394
THEN YOU WOULD HAVE VENUE LA CAA

5544
03:52:37,394 --> 03:52:39,830
WHICH IS VERY RARE, 3 OUR

5545
03:52:39,830 --> 03:52:40,998
4 PERCENT OF THE VESSELS ARE

5546
03:52:40,998 --> 03:52:43,533
VAINS AND SO ON, SO IT'S VERY

5547
03:52:43,533 --> 03:52:45,168
MUCH--NOW AS FAR AS THE DRIVING

5548
03:52:45,168 --> 03:52:47,604
FORCES, YOU KNOW ANYBODY'S GOT

5549
03:52:47,604 --> 03:52:49,406
THEIR OWN--SOME PEOPLE A IT'S

5550
03:52:49,406 --> 03:52:53,477
BREATHING AND SOME PEOPLE SAY,

5551
03:52:53,477 --> 03:52:57,180
IS THE PATHWAY OF THE VESSEL AND

5552
03:52:57,180 --> 03:52:58,982
THE PRESSURE WAVE MOVES INTO THE

5553
03:52:58,982 --> 03:53:01,251
BRAIN, ALL RIGHT, I WAS ANN

5554
03:53:01,251 --> 03:53:02,286
TERIOR GRADE PRESSURE WAVE IS

5555
03:53:02,286 --> 03:53:06,456
GOING IT MOVE THINGS BACKWARD

5556
03:53:06,456 --> 03:53:09,059
AGAIN, YOU KNOW, NO 1 KNOWS

5557
03:53:09,059 --> 03:53:10,727
EXACTLY, THE DYNAMICS OF CSF,

5558
03:53:10,727 --> 03:53:12,596
YOU KNOW ISF IS VERY, VERY

5559
03:53:12,596 --> 03:53:14,698
DIFFICULT TO APPROACH, EVEN WITH

5560
03:53:14,698 --> 03:53:16,099
MRI BASED TECHNIQUES, CAN YOU

5561
03:53:16,099 --> 03:53:17,768
SEE THINGS KIND OF SHAT

5562
03:53:17,768 --> 03:53:19,002
SHADOWING BACK AND FORTH, BUT

5563
03:53:19,002 --> 03:53:21,672
YOU NEVER SEE A CLEAR MOVEMENT,

5564
03:53:21,672 --> 03:53:23,573
YOU KNOW RETROGRADE OR

5565
03:53:23,573 --> 03:53:24,007
ANTIRETROGRADE.

5566
03:53:24,007 --> 03:53:25,275
YOU KNOW NOT TO ME, YOU KNOW I

5567
03:53:25,275 --> 03:53:28,278
THINK 1 OF THE BEST EVIDENT WILL

5568
03:53:28,278 --> 03:53:30,314
PROVIDE BY THIS IN THE NEURON

5569
03:53:30,314 --> 03:53:32,549
PAPER WHERE THEY MADE A LITTLE

5570
03:53:32,549 --> 03:53:36,787
MICROHOLE IN THE BLOOD VESSEL,

5571
03:53:36,787 --> 03:53:39,156
THAT'S SEALED ITSELF AND THEY

5572
03:53:39,156 --> 03:53:42,826
TART TO GO BACKWARD, SO THE

5573
03:53:42,826 --> 03:53:43,460
[INDISCERNIBLE] GO BACK.

5574
03:53:43,460 --> 03:53:45,696
SO IN MY BOOK IT'S VERY, VERY

5575
03:53:45,696 --> 03:53:48,198
SOLID EVIDENT THAT THINGS MAY BE

5576
03:53:48,198 --> 03:53:50,600
GOING BACKWARD ACTUALLY IS

5577
03:53:50,600 --> 03:53:56,540
INFLUENCED BY VASCULAR COUPLING.

5578
03:53:56,540 --> 03:53:57,741
>> THANK YOU.

5579
03:53:57,741 --> 03:53:59,276
CLINT IN NTHE DATA FOR KNOCK OUT

5580
03:53:59,276 --> 03:54:00,944
IS INTERESTING, I MAY BE WONDER

5581
03:54:00,944 --> 03:54:03,780
ABOUT IF YOU PUT IN DIFFERENT

5582
03:54:03,780 --> 03:54:08,418
FORMS OF APOE, AND HOW WHAT AND

5583
03:54:08,418 --> 03:54:09,619
WHAT YOU WOULD SEE AND ALSO

5584
03:54:09,619 --> 03:54:12,055
THINKING OF THE LOWER RISK,

5585
03:54:12,055 --> 03:54:14,891
PROTECTIVE 1S BUT APOE 2.

5586
03:54:14,891 --> 03:54:16,760
NGREAT POINT.

5587
03:54:16,760 --> 03:54:19,096
WE HAVE APOE 3 AS A CONTROL.

5588
03:54:19,096 --> 03:54:21,465
APOE 2 IS NOT GOOD FOR VASCULAR

5589
03:54:21,465 --> 03:54:25,969
STUDIES BECAUSE THEY HAVE EARLY

5590
03:54:25,969 --> 03:54:26,903
LIPIDEMIA, AND SUSCEPTIBILITY TO

5591
03:54:26,903 --> 03:54:28,605
HEMORRHAGE SO IT'S NOT A

5592
03:54:28,605 --> 03:54:34,745
FREIGHT--WE SEE ALL THE VASCULAR

5593
03:54:34,745 --> 03:54:38,915
TESTS SAY STAY AWAY FROM APOE2,

5594
03:54:38,915 --> 03:54:40,484
BUT APUNISHING OE 3 IS NEUTRAL,

5595
03:54:40,484 --> 03:54:41,918
BUT WE CONTINUE TO DO IT BECAUSE

5596
03:54:41,918 --> 03:54:44,421
WITH THIS MOUSE, NOW, YOU CAN

5597
03:54:44,421 --> 03:54:47,924
CHANGE THE APOE STATUS OF THE

5598
03:54:47,924 --> 03:54:51,828
[INDISCERNIBLE] PRETTY EASILY.

5599
03:54:51,828 --> 03:54:53,030
>> THANK YOU NSHORT
QUESTION,

5600
03:54:53,030 --> 03:54:55,699
THE FESTER QUESTION ABOUT

5601
03:54:55,699 --> 03:54:57,467
MACROPHAGES THEY ARE RANGING

5602
03:54:57,467 --> 03:54:59,236
EXACTLY PROOD, FROM MONOCYTES

5603
03:54:59,236 --> 03:55:02,873
THEY'RE ENTERING AND THE I HAVE

5604
03:55:02,873 --> 03:55:04,207
KD--SALLIA ALL THAT ANY CHANGE

5605
03:55:04,207 --> 03:55:11,882
IN THE MONOCYTES AND COULD BE

5606
03:55:11,882 --> 03:55:14,918
USED LIKE IMMUNOTHERAPY FOR THE

5607
03:55:14,918 --> 03:55:16,420
AMYLOID CLEARANCE LIKE THE GOAL

5608
03:55:16,420 --> 03:55:18,922
FOR THE CANCER THERAPY?

5609
03:55:18,922 --> 03:55:20,190
SO THIS IS FIRST QUESTION.

5610
03:55:20,190 --> 03:55:23,693
>> YEAH, THAT'S
INTERESTING

5611
03:55:23,693 --> 03:55:26,029
QUESTION, SO UNFORTUNATELY FOR

5612
03:55:26,029 --> 03:55:28,065
THE--PUBLISHED WANT TO GET--IF

5613
03:55:28,065 --> 03:55:29,800
YOU WANT TO REPLACE BRAIN

5614
03:55:29,800 --> 03:55:33,703
MACROPHAGES YOU HAVE TO DO BONE

5615
03:55:33,703 --> 03:55:35,338
MARROW TRANSPLANT.

5616
03:55:35,338 --> 03:55:35,739
N[INDISCERNIBLE].

5617
03:55:35,739 --> 03:55:37,841
>> YOU HAVE TO KILL THE
EXISTING

5618
03:55:37,841 --> 03:55:38,942
[INDISCERNIBLE] AND THEN OPEN

5619
03:55:38,942 --> 03:55:40,744
THE BLOOD BRAIN BARRIER AND LET

5620
03:55:40,744 --> 03:55:41,411
THE MONOCYTES GO IN.

5621
03:55:41,411 --> 03:55:44,314
YOU KNOW IN THE STORAGE DECS,

5622
03:55:44,314 --> 03:55:45,949
CAUSED BY ENZYMATIC LACK OF

5623
03:55:45,949 --> 03:55:47,984
CERTAIN INN SWROIMS, THEY DO

5624
03:55:47,984 --> 03:55:50,387
BONE MARROW TRANSPLANTS TO BRING

5625
03:55:50,387 --> 03:55:52,089
THE STUFF IN WITH THE

5626
03:55:52,089 --> 03:55:54,191
MACROPHAGES THAT STAY THERE AND

5627
03:55:54,191 --> 03:55:55,025
GENERATE THE ENZYME, SO IT'S

5628
03:55:55,025 --> 03:55:57,794
DIFFICULT IT USE THAT, TO KIND

5629
03:55:57,794 --> 03:56:01,298
OF MODIFY THEM USING A KIND OF

5630
03:56:01,298 --> 03:56:02,699
CELL REPLACEMENT APPROACH, BUT

5631
03:56:02,699 --> 03:56:05,502
WHAT YOU COULD DO IS PLOK

5632
03:56:05,502 --> 03:56:07,204
SELECTIVE IMMUNE RECEPTORS LIKE

5633
03:56:07,204 --> 03:56:09,940
WE DID ON THE SURFACE, IT CANNOT

5634
03:56:09,940 --> 03:56:13,343
SOMEHOW BLOCK THE MECHANISM THAT

5635
03:56:13,343 --> 03:56:14,544
TRIGGERS THE ACTIVATION.

5636
03:56:14,544 --> 03:56:18,448
>> BUT CD36 IT'S NOT ON
THE

5637
03:56:18,448 --> 03:56:21,885
RESIDENTIAL MACROPHAGES ON THE

5638
03:56:21,885 --> 03:56:22,185
MICRODPLIA?

5639
03:56:22,185 --> 03:56:24,754
DIFFERENT REGION FROM FECAL

5640
03:56:24,754 --> 03:56:25,122
[INDISCERNIBLE]

5641
03:56:25,122 --> 03:56:29,292
>> CD36 IS ON THE RESIDENT

5642
03:56:29,292 --> 03:56:29,593
MACROPHAGES.

5643
03:56:29,593 --> 03:56:32,262
>> BUT NOT MICRODPLIA.

5644
03:56:32,262 --> 03:56:36,466
>> [SPEAKING AT ONCE ]

5645
03:56:36,466 --> 03:56:38,835
NSO THE HIGHEST LEVEL IS THE

5646
03:56:38,835 --> 03:56:40,770
MICROPHAGES NAND I HAVE A

5647
03:56:40,770 --> 03:56:43,106
QUESTION ABOUT THE PHAGOCYTOSIS,

5648
03:56:43,106 --> 03:56:46,243
ANY HINT ABOUT POSSIBLE RECEPTOR

5649
03:56:46,243 --> 03:56:50,113
WHAT COULD HELP TO DO

5650
03:56:50,113 --> 03:56:51,314
PHAGOCYTOSIS TO UPTAKE

5651
03:56:51,314 --> 03:56:52,082
ENDOTHELIAL CELLS.

5652
03:56:52,082 --> 03:56:53,783
QUESTION FOR YOU NSORRY I COULD

5653
03:56:53,783 --> 03:56:54,718
NONAPOPTOTIC THE HEAR YOU.

5654
03:56:54,718 --> 03:56:59,156
NSORRY, IT'S A QUESTION ABOUT

5655
03:56:59,156 --> 03:57:03,326
PHAGOCYTOSIS, VERY COMPELLING,

5656
03:57:03,326 --> 03:57:06,463
THE PICTURES THERE, ANY HINT

5657
03:57:06,463 --> 03:57:15,639
ABOUT POSSIBLE UPTAKE MECHANISM,

5658
03:57:15,639 --> 03:57:16,239
RECEPTOR OPTIMIZATION,

5659
03:57:16,239 --> 03:57:20,944
[INDISCERNIBLE] WHAT COULD BE

5660
03:57:20,944 --> 03:57:24,281
MECHANISM OF UPTAKE?

5661
03:57:24,281 --> 03:57:27,551
>> YEAH, CD47 EXPRESSION
BY RED

5662
03:57:27,551 --> 03:57:28,852
BLOOD CELLS THE TERM THAT IS

5663
03:57:28,852 --> 03:57:33,223
USED IN THE LITERATURE IS THE

5664
03:57:33,223 --> 03:57:38,195
DON'T EAT ME SIGNAL GENERATED BY

5665
03:57:38,195 --> 03:57:38,395
CD47.

5666
03:57:38,395 --> 03:57:40,163
SO CD47 EXPRESSION BY THE RED

5667
03:57:40,163 --> 03:57:46,069
BLOOD CELL IS A KEY ELEMENT IN

5668
03:57:46,069 --> 03:57:48,104
THE RED BLOOD CELL ENDOTHELIAL

5669
03:57:48,104 --> 03:57:50,407
INTERACTION AND KEY PLAYER IN

5670
03:57:50,407 --> 03:57:51,575
THE PHAGOCYTOSIS.

5671
03:57:51,575 --> 03:57:52,275
>> OKAY, THANK YOU.

5672
03:57:52,275 --> 03:57:53,877
NETWORK OKAY, I THINK WE BETTER

5673
03:57:53,877 --> 03:57:54,311
STOP THERE.

5674
03:57:54,311 --> 03:57:57,347
WE WILL BE TARTING AGAIN AT

5675
03:57:57,347 --> 03:57:57,647
1:15.

5676
03:57:57,647 --> 03:58:00,517
SO PLEASE GO AHEAD AND FIND

5677
03:58:00,517 --> 03:58:06,659
SOMETHING TO EAT.

5678
03:58:06,659 --> 03:58:07,927
OKAY GOOD AFTERNOON

5679
03:58:07,927 --> 03:58:08,194
EVERYBODY.

5680
03:58:08,194 --> 03:58:14,667
HOPE YOU HAD A GOOD LUNCH AND

5681
03:58:14,667 --> 03:58:19,939
REFRESHED FOR THE AFTERNOON.

5682
03:58:19,939 --> 03:58:27,330
I UPON ANYTHING TO TALK ABOUT

5683
03:58:27,330 --> 03:58:31,000
WORK IN THE EARLY 2000S AND THEN

5684
03:58:31,000 --> 03:58:31,768
WE STARTED IMMUNOTHERAPY AND

5685
03:58:31,768 --> 03:58:33,536
THEN WE TART THE IMEAN, SO NOW

5686
03:58:33,536 --> 03:58:34,804
WE'RE DOING NEW STUDIES ON THIS.

5687
03:58:34,804 --> 03:58:45,248
CAN WE GET THE SLIDES UP.

5688
03:58:49,285 --> 03:58:49,586
OKAY.

5689
03:58:49,586 --> 03:58:53,323
SO AGAIN THANKS TO NINDS FOR THE

5690
03:58:53,323 --> 03:58:55,525
INVITATION TO SPEAK AND I JUST

5691
03:58:55,525 --> 03:58:56,926
WANTED TO HIGHLIGHT SOME OF THE

5692
03:58:56,926 --> 03:58:59,729
REALLY EARLY WORK THAT WAS DONE

5693
03:58:59,729 --> 03:59:01,864
AND REALLY THE FIRST

5694
03:59:01,864 --> 03:59:05,301
DESCRIPTIONS OF MICROHEMORRHAGES

5695
03:59:05,301 --> 03:59:15,845
AS A RESULT OF ABASHING AIMIEWP

5696
03:59:18,615 --> 03:59:23,319
O THR ACTIVITIES AND PROJECTSY

5697
03:59:23,319 --> 03:59:26,456
AND THEY SAW AN INCREASED

5698
03:59:26,456 --> 03:59:27,123
INDENSE OF MICROBLEEDS.

5699
03:59:27,123 --> 03:59:28,858
THAT WAS FOLLOWED BY A PAPER I

5700
03:59:28,858 --> 03:59:31,861
PUBLISHED WITH DAVE MORGAN IN

5701
03:59:31,861 --> 03:59:35,064
2004, WHERE WE DID A TIME COURSE

5702
03:59:35,064 --> 03:59:38,601
OF IMMUNIZATION AND THAT, WELL,

5703
03:59:38,601 --> 03:59:39,068
IMMUNIZATION, PASSIVE

5704
03:59:39,068 --> 03:59:43,006
IMMUNIZATION SO THESE ARE

5705
03:59:43,006 --> 03:59:45,308
PASSIVE IMMUNO THERAPY AND WE

5706
03:59:45,308 --> 03:59:47,277
SAW THESE TIME COURSE FOR THESE

5707
03:59:47,277 --> 03:59:49,746
WEEKLY DOINGS OF TCG2576 MICE

5708
03:59:49,746 --> 03:59:51,214
AND YOU CAN SEE IT'S REALLY

5709
03:59:51,214 --> 03:59:53,249
BETWEEN THE 1 AND 2 MONTHS OF

5710
03:59:53,249 --> 03:59:56,085
ADMINITRATION WHERE WE STARTED

5711
03:59:56,085 --> 04:00:02,325
TO SEE THESE MICROPLEADS.

5712
04:00:02,325 --> 04:00:03,059
INCIDENTALLY, IT ALINES

5713
04:00:03,059 --> 04:00:05,361
PERFECTLY WHERE WE SEE THE PEEK

5714
04:00:05,361 --> 04:00:08,164
OF ARIA PATIENTS OF OUR

5715
04:00:08,164 --> 04:00:12,101
REPORTING AS ALSO AND THEN WE

5716
04:00:12,101 --> 04:00:13,903
SAW A STEADY INCREASE AS WE LOOK

5717
04:00:13,903 --> 04:00:15,705
AT THE 3, 4 AND 5 MONTHS OF

5718
04:00:15,705 --> 04:00:16,105
TREATMENT.

5719
04:00:16,105 --> 04:00:22,312
ASSOCIATED WITH THAT WE SAW A

5720
04:00:22,312 --> 04:00:23,746
LOT OF PERIVASC LIEU REACTIVITY

5721
04:00:23,746 --> 04:00:26,049
AND THIS IS JUST AN EXAMPLE OF 1

5722
04:00:26,049 --> 04:00:27,550
OF THE MICROPLEADS WE SAW IN THE

5723
04:00:27,550 --> 04:00:27,784
MICE.

5724
04:00:27,784 --> 04:00:29,319
SO FOLLOWING ON FROM THAT, JUST

5725
04:00:29,319 --> 04:00:32,588
A FEW MONTHS AFTER WE PUBLISHED

5726
04:00:32,588 --> 04:00:35,358
THAT PAPER, PEGGY RACK FROM THE

5727
04:00:35,358 --> 04:00:39,929
GROUP AT LILLY ALSO SHOWED

5728
04:00:39,929 --> 04:00:41,297
MICROHEMORRHAGE INDUCTION IN

5729
04:00:41,297 --> 04:00:43,533
THEIR 3D 6 ANTIBODY WHICH IS THE

5730
04:00:43,533 --> 04:00:46,169
END TERMINAL ANTIBODY AND THE PD

5731
04:00:46,169 --> 04:00:50,273
APUNISHING P NOWS, SO THESE ARE

5732
04:00:50,273 --> 04:00:54,544
ALL DIFFERENT MONOCLONAL

5733
04:00:54,544 --> 04:00:54,844
ANTIBODIES.

5734
04:00:54,844 --> 04:00:56,245
THEY ARE ALSO DIFFERENT MOUSE

5735
04:00:56,245 --> 04:00:57,747
MODELS, THESE WERE ALL DONE IN

5736
04:00:57,747 --> 04:00:59,349
MICE THAT WERE AT A VERY

5737
04:00:59,349 --> 04:01:01,084
ADVANCED AGE WHERE THEY HAD A

5738
04:01:01,084 --> 04:01:07,223
LOT OF EXISTING PATHOLOGY

5739
04:01:07,223 --> 04:01:09,525
INCLUDING CAA AND THEY HAD CAA,

5740
04:01:09,525 --> 04:01:10,660
THEY ALSO HAD ASSOCIATED WITH

5741
04:01:10,660 --> 04:01:12,095
THE CAA BECAUSE IT WAS QUITE

5742
04:01:12,095 --> 04:01:14,297
MATURE AT THAT TIME, THEY DID

5743
04:01:14,297 --> 04:01:19,469
HAVE ASSOCIATED PERIVASCULAR

5744
04:01:19,469 --> 04:01:19,969
INFLAMMATION.

5745
04:01:19,969 --> 04:01:30,346
SO, I'VE STARTED TO GO

5746
04:01:34,250 --> 04:01:34,851
BACK--IT'S NOT ADVANCING.

5747
04:01:34,851 --> 04:01:37,286
OKAY, SO I WENT BACK TO OLD

5748
04:01:37,286 --> 04:01:39,188
TODAYS TO ASK IF THERE ARE NEW

5749
04:01:39,188 --> 04:01:40,390
INSIGHTS WE BEING GAIN FROM NOW,

5750
04:01:40,390 --> 04:01:41,958
FROM THE OLDER STUDIES, SO THIS

5751
04:01:41,958 --> 04:01:49,165
WAS A STUDY WE DID IN 2004-5

5752
04:01:49,165 --> 04:01:51,401
WHERE WE DEFLI COLSIS COSALATED

5753
04:01:51,401 --> 04:01:53,936
THE ASPECT BODY, IT

5754
04:01:53,936 --> 04:01:55,638
SIGNIFICANTLY REDUCES THE

5755
04:01:55,638 --> 04:01:57,440
IGGAFFINNITY FOR THE FC

5756
04:01:57,440 --> 04:01:57,774
RECEPTORS.

5757
04:01:57,774 --> 04:02:00,309
SO YOU CAN SEE IN THE TOP RIGHT

5758
04:02:00,309 --> 04:02:02,779
IS THE RELATIVE AFFINITY OF THE

5759
04:02:02,779 --> 04:02:04,080
INTACT ANTIBODY WHICH IN THIS

5760
04:02:04,080 --> 04:02:06,582
CASE IS CALLED 2 H 6, AND THE

5761
04:02:06,582 --> 04:02:08,351
DEMRI COSALATED ANTIBODY WHICH

5762
04:02:08,351 --> 04:02:09,552
IS THE D2 H6.

5763
04:02:09,552 --> 04:02:13,456
SO THE AFFINITY OF EACH ANTIBODY

5764
04:02:13,456 --> 04:02:15,057
FOR ABETTA IS COMPARABLE BUT THE

5765
04:02:15,057 --> 04:02:17,260
AFFINITY FOR THE VARIOUS FC

5766
04:02:17,260 --> 04:02:18,694
RECEPTOR SYSTEM SIGNIFICANTLY

5767
04:02:18,694 --> 04:02:23,433
REDUCEDENTIOUS SPECIALENTIALLY

5768
04:02:23,433 --> 04:02:24,667
FC GAMMA RECEPTOR 1.

5769
04:02:24,667 --> 04:02:27,570
AND FC GAMMA RECEPTOR 3, AS WELL

5770
04:02:27,570 --> 04:02:29,005
AS C1 Q BINDING.

5771
04:02:29,005 --> 04:02:30,406
AND SO WHAT WE FOUND THERE WAS

5772
04:02:30,406 --> 04:02:31,974
THAT ACTUALLY BOTH OF THESE

5773
04:02:31,974 --> 04:02:33,109
ANTIBODIES WHETHER IT WAS INTACT

5774
04:02:33,109 --> 04:02:36,446
OR WHETHER IT WAS THE

5775
04:02:36,446 --> 04:02:38,214
DEGLYCOSYLATEDDED VERSION, WE

5776
04:02:38,214 --> 04:02:40,349
SIGNIFICANTLY REDUCED TOTAL BETA

5777
04:02:40,349 --> 04:02:41,517
AMYLOID DEPOSITION.

5778
04:02:41,517 --> 04:02:43,052
BEAR IN MIND THAT MOST OF THE

5779
04:02:43,052 --> 04:02:45,054
AMYLOID DEPRIVATION NITION IN

5780
04:02:45,054 --> 04:02:47,723
THESE MICE IS IN THE DIFFUSE

5781
04:02:47,723 --> 04:02:50,359
FORM, NOT IN THE COMPACT FIEB

5782
04:02:50,359 --> 04:02:52,094
RULE FORM, SO WHAT WE FOUND WHEN

5783
04:02:52,094 --> 04:02:54,931
HE LOOKED AT THE DEPOSITS WAS

5784
04:02:54,931 --> 04:03:03,606
THAT WE HAD A REDUCTION IN TOTAL

5785
04:03:03,606 --> 04:03:05,608
COMBOPHILIC MATERIAL BUT THE

5786
04:03:05,608 --> 04:03:14,350
INTAKE ANTIBODY ACTUALLY ALMOST

5787
04:03:14,350 --> 04:03:17,220
COMPLETELY ELIMINATED PATHWAY

5788
04:03:17,220 --> 04:03:27,797
GIVES RENCH MALDEPOSITS.DEPOSIT.

5789
04:03:37,440 --> 04:03:39,242
SO A--ASSOCIATED WITH THAT WAS

5790
04:03:39,242 --> 04:03:41,978
AN AMELIORATION OF THE

5791
04:03:41,978 --> 04:03:42,645
MICROHEMORRHAGE INCIDENTS.

5792
04:03:42,645 --> 04:03:46,249
SO YOU CAN SEE THE 2 H6 INDUCED

5793
04:03:46,249 --> 04:03:47,517
MICROBLEEDS WHICH WAS WHAT

5794
04:03:47,517 --> 04:03:50,753
SOMETHING WE REPORTED 2 YEARS

5795
04:03:50,753 --> 04:03:52,955
BEFORE WITH THE SAME ANTIBODY

5796
04:03:52,955 --> 04:03:55,825
BUT WHEN THE ANTIBODY WAS

5797
04:03:55,825 --> 04:03:56,792
DEGLYCOSYLATEDDED IT WAS

5798
04:03:56,792 --> 04:03:58,261
SIGNIFICANT LE,A 10UATEED SO

5799
04:03:58,261 --> 04:04:00,897
THIS INDICATES AT LEAST, IN THE

5800
04:04:00,897 --> 04:04:02,732
MOUSE MODELS AND WITH THIS

5801
04:04:02,732 --> 04:04:03,766
PARTICULAR ANTIBODY, I DON'T

5802
04:04:03,766 --> 04:04:05,768
WANT TO OVERSTATE IN GENERALIZE

5803
04:04:05,768 --> 04:04:09,872
THIS, BUT IT DID SEEM LIKE FC

5804
04:04:09,872 --> 04:04:11,073
GAMMA RECEPTOR ENGAGEMENT AND

5805
04:04:11,073 --> 04:04:14,210
EFFECTOR CELL FUNCTION IS

5806
04:04:14,210 --> 04:04:16,712
CRITICAL TO THE MICROHEMORRHAGE

5807
04:04:16,712 --> 04:04:18,681
INDUCTION.

5808
04:04:18,681 --> 04:04:21,083
SO WE ASKED OUR MADERIX PROTEIN

5809
04:04:21,083 --> 04:04:24,353
ACES TO PLAIM FOR THIS, WE KNOW

5810
04:04:24,353 --> 04:04:27,924
THAT MMPs IN PARTICULAR, MPP

5811
04:04:27,924 --> 04:04:31,394
2, AND MPP 9 HAVE BEEN HEAVILY

5812
04:04:31,394 --> 04:04:32,862
IMPLICATED IN HEMORRHAGIC

5813
04:04:32,862 --> 04:04:34,063
TRANSFORMATION AFTER STROKE AS

5814
04:04:34,063 --> 04:04:36,799
WELL AS OTHER HEM RAMMINGIC

5815
04:04:36,799 --> 04:04:39,335
EVENTS AND SO, WE WENT BACK,

5816
04:04:39,335 --> 04:04:43,506
THIS WAS ABOUT 6 YEARS LATER IT

5817
04:04:43,506 --> 04:04:45,474
WAS AMAZING, I CALLED DAVEED

5818
04:04:45,474 --> 04:04:47,777
MORGAN AND I SAID DO YOU STILL

5819
04:04:47,777 --> 04:04:49,579
HAVE SOME OF MY TISSUE FROZEN

5820
04:04:49,579 --> 04:04:53,349
AND WE WENT IN AND LOOKEDDA THE

5821
04:04:53,349 --> 04:04:53,549
THIS.

5822
04:04:53,549 --> 04:04:56,886
AND THERE'S 2 PATHWAYS, MMP 9

5823
04:04:56,886 --> 04:04:58,588
AND AMERICA PP 2 AND MPP 9 IS

5824
04:04:58,588 --> 04:05:02,858
DRIVEN A LOT BY PROINFLAMMATORY

5825
04:05:02,858 --> 04:05:07,797
CYTOKINES LIKE IL1, TNF, MPP 2,

5826
04:05:07,797 --> 04:05:10,866
IS DRIVEN BY FURIN AND PLASMA

5827
04:05:10,866 --> 04:05:12,735
AND OTHER FACERS, ALL OF THESE

5828
04:05:12,735 --> 04:05:13,803
RELEASED IN A PROFORM AND THEY

5829
04:05:13,803 --> 04:05:16,072
HAVE TO BE CLEAVED IN ORDER TO

5830
04:05:16,072 --> 04:05:19,008
BE ACTIVE, SO, IT'S A COMPLEX

5831
04:05:19,008 --> 04:05:21,777
SYSTEM, BUT WHAT WE FOUND WHEN

5832
04:05:21,777 --> 04:05:25,815
WE LOOKED AT OUR TIME COURSE,

5833
04:05:25,815 --> 04:05:26,882
ACTUALLY IT'S THE NEXT SLIDE,

5834
04:05:26,882 --> 04:05:30,252
THIS LIED IS SHOWING THAT YOU IF

5835
04:05:30,252 --> 04:05:32,855
WE INCUBATE BB2 MICRODPLEEL

5836
04:05:32,855 --> 04:05:33,456
CELLS THEY'RE COMPLETELY

5837
04:05:33,456 --> 04:05:34,590
IMPERFECT BUT THIS WAS A FIRST

5838
04:05:34,590 --> 04:05:37,727
STEP IN THE STUDY.

5839
04:05:37,727 --> 04:05:40,396
WE INCUBATED THEM WITH EITHER

5840
04:05:40,396 --> 04:05:43,366
ABETTA ALONE OR ABETTA THAT HAD

5841
04:05:43,366 --> 04:05:45,668
BEEN COMBINED WITH ANTIBODY TO

5842
04:05:45,668 --> 04:05:48,437
MAKE IMMUNE COMPLEXES OR TAU AND

5843
04:05:48,437 --> 04:05:55,111
THEN TAU COMBINED WITH TAU

5844
04:05:55,111 --> 04:05:58,147
ANTIBODIES AND YOU CAN SEE WITH

5845
04:05:58,147 --> 04:05:59,749
THE IMMUNE COMPLEX, WHICHEVER

5846
04:05:59,749 --> 04:06:04,820
COMPLEX IT WAS, WE INDUCED

5847
04:06:04,820 --> 04:06:06,522
COMPONENTS OF BOTH THE MMP 2

5848
04:06:06,522 --> 04:06:09,492
PATHWAY AND THE MAMERICA P 9

5849
04:06:09,492 --> 04:06:09,759
PATHWAY.

5850
04:06:09,759 --> 04:06:13,729
AND SO, WE WENT AND LOOKED AT

5851
04:06:13,729 --> 04:06:14,730
OUR PASSIVE IMMUNOTHERAPY MICE,

5852
04:06:14,730 --> 04:06:16,599
WHILE WE HAVE THE TIME COURSE OF

5853
04:06:16,599 --> 04:06:17,767
1, 2, 32 ASK 3 MONTHS OF DOSING

5854
04:06:17,767 --> 04:06:21,637
AND WHAT YOU CAN SEE IS THAT

5855
04:06:21,637 --> 04:06:26,842
MPP2, AND MMP 9 ARE BOTH

5856
04:06:26,842 --> 04:06:28,044
SIGNIFICANTLY ELEVATED, MMP2 WAS

5857
04:06:28,044 --> 04:06:28,944
ELEVATED WITH 1 MONTH OF

5858
04:06:28,944 --> 04:06:30,980
DOATSING AND IT AT AD ELEVATEDDA

5859
04:06:30,980 --> 04:06:32,581
THE 2 AND 3 MONTHS.

5860
04:06:32,581 --> 04:06:34,884
MPP 9 CAME UP BETWEEN THE 1 AND

5861
04:06:34,884 --> 04:06:37,086
2 MONTH TIME POINT AND THEN

5862
04:06:37,086 --> 04:06:38,187
ELEVATED AT THE 3 MONTH TIME

5863
04:06:38,187 --> 04:06:41,724
POINT AND I THINK THIS YOU KNOW

5864
04:06:41,724 --> 04:06:43,426
REALLY DOES .. TO A POTENTIAL

5865
04:06:43,426 --> 04:06:46,295
MECHANISM BY WHICH THE BLOOD

5866
04:06:46,295 --> 04:06:48,631
BRAIN BARRIER IS BREAKING DOWN.

5867
04:06:48,631 --> 04:06:52,268
WE HAVE SINCE ABOUT 2012 WE'VE

5868
04:06:52,268 --> 04:06:53,869
BEEN WORKING WITH A MODEL OF

5869
04:06:53,869 --> 04:06:56,539
SMALL VESSEL DISEASE WHERE WE

5870
04:06:56,539 --> 04:07:01,377
INDUCE HYPE OR HOMER ASSIST

5871
04:07:01,377 --> 04:07:05,314
NEMIA IN WILD-TYPE MICE, THERE'S

5872
04:07:05,314 --> 04:07:07,283
NO APP INVOLVED HERE EMPLOY WE

5873
04:07:07,283 --> 04:07:08,884
SEE MICROPLEADS.

5874
04:07:08,884 --> 04:07:11,487
WE SEE COGNITIVE DEFINITES.

5875
04:07:11,487 --> 04:07:13,389
WE SEE HYPOTRANSFUSION, BUT WE

5876
04:07:13,389 --> 04:07:15,124
SEE AN INFLAMMATORY REPONS AND

5877
04:07:15,124 --> 04:07:17,860
WE ALSO SEE PMMP 9 ACTIVATIONFUL

5878
04:07:17,860 --> 04:07:19,328
SO ANOTHER PLACE, ANOTHER MODEL,

5879
04:07:19,328 --> 04:07:20,896
WHERE WE HAVE BLOOD BRAIN

5880
04:07:20,896 --> 04:07:22,498
BARRIER BRAKE DOWN, WE HAVE

5881
04:07:22,498 --> 04:07:27,903
MICROPLEADS, WE HAVE THIS MMP9

5882
04:07:27,903 --> 04:07:28,604
INDUCTION.

5883
04:07:28,604 --> 04:07:31,273
SO COMING TO PRESENT DAY, WE ARE

5884
04:07:31,273 --> 04:07:33,409
TRYING TO GO BACK TO SOME OF THE

5885
04:07:33,409 --> 04:07:36,212
REAL FUNDAMENTAL STUDIES THAT

5886
04:07:36,212 --> 04:07:38,514
WERE DONE 15 YEARS AGO NOW AND

5887
04:07:38,514 --> 04:07:41,650
USING OUR NEW TOOLS LIKE SINGLE

5888
04:07:41,650 --> 04:07:44,687
CELL TRANSCRIPT OHMIC ANDS

5889
04:07:44,687 --> 04:07:45,488
DINLITTAL SPATIAL PROFILES TART

5890
04:07:45,488 --> 04:07:47,289
TO ASK THE QUESTIONS ABOUT WHAT

5891
04:07:47,289 --> 04:07:48,991
ON A SINGLE CELL LEVEL WHAT

5892
04:07:48,991 --> 04:07:52,428
CHANGES ARE BEING INDUCED BY A

5893
04:07:52,428 --> 04:07:52,995
BETA ANTIBODIES.

5894
04:07:52,995 --> 04:07:56,232
SO IN THIS CASE, THIS IS A TODAY

5895
04:07:56,232 --> 04:07:59,068
BY MY POST DOC IN THE LABICATE

5896
04:07:59,068 --> 04:08:07,376
FOLEY AND WE LOOKED AT WILD-TYPE

5897
04:08:07,376 --> 04:08:09,845
AND TG2576 MICE, 14 MONTHS OF

5898
04:08:09,845 --> 04:08:13,315
AGE, WE DID A IGGOR SE10

5899
04:08:13,315 --> 04:08:13,783
ANTIBODY.

5900
04:08:13,783 --> 04:08:15,885
AND WE THEN EUTHANIZED THEM AT

5901
04:08:15,885 --> 04:08:18,521
24 HOURS OR 3 DAYS AFTER AND WE

5902
04:08:18,521 --> 04:08:21,257
DID SINGLE CELL ANALYSIS AND

5903
04:08:21,257 --> 04:08:25,027
SOME DINLITTAL SPATIAL PROFILES

5904
04:08:25,027 --> 04:08:27,329
ON THE TISSUE AND WE WERE

5905
04:08:27,329 --> 04:08:29,298
PRIMARILY INTERESTED IN THE

5906
04:08:29,298 --> 04:08:30,900
MICRODPLEEL RESPONSES.

5907
04:08:30,900 --> 04:08:32,268
WHAT ARE THE MICROFLI COLSISSA

5908
04:08:32,268 --> 04:08:32,468
DOING.

5909
04:08:32,468 --> 04:08:35,137
SO FIRST I'M GOING TO TALK ABOUT

5910
04:08:35,137 --> 04:08:40,576
THE SINGLE CELL DATA THAT KATE

5911
04:08:40,576 --> 04:08:51,020
GENERATED AND LET'S SEE- 

5912
04:09:18,414 --> 04:09:20,082
-OKAY SO TO SUMMARIZE THE SLIDE

5913
04:09:20,082 --> 04:09:22,017
YOU BARELY SAW, WE IDENTIFIED

5914
04:09:22,017 --> 04:09:23,586
CELLS OF CLUSTERS OF MICROGLIA

5915
04:09:23,586 --> 04:09:26,155
AND WE LOOKED AT EACH CLUSTER

5916
04:09:26,155 --> 04:09:28,657
AND HOW EACH OF THOSE 3 CAN HOW

5917
04:09:28,657 --> 04:09:30,893
THEY CHANGED IN THE PRESENCE OF

5918
04:09:30,893 --> 04:09:33,662
ANTIBETTA ASPECT BODY AS OPPOSE

5919
04:09:33,662 --> 04:09:34,964
TO CONTROL ANTIBODY.

5920
04:09:34,964 --> 04:09:38,567
SO THE CONTROL ANTIBODY

5921
04:09:38,567 --> 04:09:39,668
PRESUMABLY HAS NONSPECIFIC

5922
04:09:39,668 --> 04:09:40,469
IGASHING GASHING RESPONSES WHAT

5923
04:09:40,469 --> 04:09:44,073
WE'RE GOD IN IS WHAT THAT

5924
04:09:44,073 --> 04:09:46,041
SPECIFIC ABETTA RESPONSE IS SO

5925
04:09:46,041 --> 04:09:50,212
WE SAW A DOWN REGULATION OF THE

5926
04:09:50,212 --> 04:09:52,081
NUMBER OF CELLS AND CLUSTER 0,

5927
04:09:52,081 --> 04:09:54,516
SO THE JEEPS THAT WERE PRIMARILY

5928
04:09:54,516 --> 04:09:57,253
DOWN REGULATED WERE ASSOCIATED

5929
04:09:57,253 --> 04:10:01,924
WITH CELLULAR RES PIRRATION

5930
04:10:01,924 --> 04:10:06,595
AEROBIC RESPIRATION,

5931
04:10:06,595 --> 04:10:07,296
METABOLISM,OXIDATIVE

5932
04:10:07,296 --> 04:10:08,731
PHOSPHORYLATION, GENES THAT WERE

5933
04:10:08,731 --> 04:10:11,967
UPREGULATED IN THIS GROUP,

5934
04:10:11,967 --> 04:10:12,601
LYMPHOCYTE ACTIVATION, CYTOKINE

5935
04:10:12,601 --> 04:10:17,273
PRODUCK, IMMUNE RESPONSE

5936
04:10:17,273 --> 04:10:17,573
REGULATION.

5937
04:10:17,573 --> 04:10:19,842
SO IN THIS CLUSTER, AT THE 24

5938
04:10:19,842 --> 04:10:20,943
TIME POINT THERE WAS A DECREASE

5939
04:10:20,943 --> 04:10:26,048
IN THE NUMBER OF CELLS IN IN

5940
04:10:26,048 --> 04:10:28,517
CLUSTER, IN CLUSTER 1--OH, THAT

5941
04:10:28,517 --> 04:10:30,185
TEXT DOES NOT LOOK GOOD DOES IT.

5942
04:10:30,185 --> 04:10:33,255
IT LOOKED IMRAIT ON THE SLIDE

5943
04:10:33,255 --> 04:10:33,622
YESTERDAY.

5944
04:10:33,622 --> 04:10:36,725
YEAH, I DON'T KNOW IF THAT'S

5945
04:10:36,725 --> 04:10:40,229
CLINGON OR WHAT THAT IS.

5946
04:10:40,229 --> 04:10:42,798
SO CLUSTER 1 THERE WAS AGAIN A

5947
04:10:42,798 --> 04:10:46,902
DECREASE IN THE NUMBER OF CELLS

5948
04:10:46,902 --> 04:10:48,971
IN CLUSTER 1 AND I COULD TELL

5949
04:10:48,971 --> 04:10:51,073
YOU ANYTHING ABOUT THOSE GRAPHS

5950
04:10:51,073 --> 04:10:52,441
NOW BUT ACTUALLY, THEY MIRROR A

5951
04:10:52,441 --> 04:10:54,410
LOT OF THE SAME PROCESSES THAT

5952
04:10:54,410 --> 04:10:56,111
WERE IN CLUSTER WHERE ARE EMPLOY

5953
04:10:56,111 --> 04:10:58,047
THE INTERESTING CLUSTER, CLUSTER

5954
04:10:58,047 --> 04:11:00,316
2, IS WHERE WE SAW A BIG

5955
04:11:00,316 --> 04:11:04,586
UPREGULATION IN THE NUMBER OF

5956
04:11:04,586 --> 04:11:05,654
CELLS FALLING INTO THIS CLUSTER

5957
04:11:05,654 --> 04:11:07,523
AT 24 HOURS AND IN THIS CLUSTER

5958
04:11:07,523 --> 04:11:11,126
WHAT YOU CAN SEE IS THERE ARE

5959
04:11:11,126 --> 04:11:14,129
DOWN--THIS CLUSTER HAS DOWN

5960
04:11:14,129 --> 04:11:18,767
REGULATION OF CELL MIGRATION,

5961
04:11:18,767 --> 04:11:20,469
CELL MOTILITY, LEUKOCYTE

5962
04:11:20,469 --> 04:11:24,907
DIFFERENTIATION, AND THEN

5963
04:11:24,907 --> 04:11:28,110
UPREGULATION OF METABOLISM,

5964
04:11:28,110 --> 04:11:29,211
ENERGY PRODUCTION, RESPIRATION,

5965
04:11:29,211 --> 04:11:30,913
SO THERE'S THIS QUITE DRAMATIC

5966
04:11:30,913 --> 04:11:32,982
SHIFT IN THE MICRODPLIA VERY

5967
04:11:32,982 --> 04:11:35,584
QUICKLY IN RESPONSE TO A BETA

5968
04:11:35,584 --> 04:11:38,754
EABT BODIES THAT IS A DOWN

5969
04:11:38,754 --> 04:11:41,357
REGULATION OF METABOLISM AND

5970
04:11:41,357 --> 04:11:49,698
SYNTHESIS AND  RESPIRATION, SO

5971
04:11:49,698 --> 04:11:54,903
THIS DOES HAPPEN QUITE QUICKLY.

5972
04:11:54,903 --> 04:11:58,407
AND THEN, FLEEL CELLS

5973
04:11:58,407 --> 04:12:05,914
RESPONDING, LET ME START AGAIN

5974
04:12:05,914 --> 04:12:09,084
WE WANTED TO LOOK AT HOW THEY'RE

5975
04:12:09,084 --> 04:12:11,086
RESPONDING AFTER THE A-BETA

5976
04:12:11,086 --> 04:12:13,222
DEPOSITS AFTER THE ANTIBODY, SO

5977
04:12:13,222 --> 04:12:14,289
THOSE WHO ARE NOT FAMILIAR WITH

5978
04:12:14,289 --> 04:12:20,295
THIS, WE ARE USING PARAFFIN

5979
04:12:20,295 --> 04:12:22,831
TISSUE SECTIONS AND WE CAN LABEL

5980
04:12:22,831 --> 04:12:26,602
THOSE WITH MARKERS ERS.

5981
04:12:26,602 --> 04:12:29,905
SO IN THIS CASE WE HAVE GFAPP IN

5982
04:12:29,905 --> 04:12:32,975
GREEN FOR OUR ASTRO SIGHTS WE

5983
04:12:32,975 --> 04:12:35,744
HAVE IRA 1 IN RED FOR MICROGLIA

5984
04:12:35,744 --> 04:12:40,182
AND THEN WE HAVE A BETA INIOLE -

5985
04:12:40,182 --> 04:12:42,051
-YELLOW AND WE KNOW THAT

5986
04:12:42,051 --> 04:12:43,819
INJECTION SITE IS SITTING RIGHT

5987
04:12:43,819 --> 04:12:50,192
IN THIS AREA HERE AND SO, WE CAN

5988
04:12:50,192 --> 04:12:51,960
THEN DRAW OUR REGIONS OF

5989
04:12:51,960 --> 04:12:53,062
INTEREST,A ROUND THE PLAQUE AT

5990
04:12:53,062 --> 04:12:56,365
THE INYEKS SITE AND SO, WHEN WE

5991
04:12:56,365 --> 04:13:01,236
DID HERE IS WE LOOKED AT A-BETA

5992
04:13:01,236 --> 04:13:02,604
POSITIVE REGIONS THAT WERE CLOSE

5993
04:13:02,604 --> 04:13:04,506
TO WHERE THE ANTIBODY HAD BEEN

5994
04:13:04,506 --> 04:13:07,009
AS OPPOSE TO BEING FAR AWAY FROM

5995
04:13:07,009 --> 04:13:08,977
WHERE AND IT HADN'T BEEN EXPOSED

5996
04:13:08,977 --> 04:13:11,980
TO ANTIBODY AND THEN WE LOOKED

5997
04:13:11,980 --> 04:13:13,182
AT A-BETA NEG5 REGIONS OF

5998
04:13:13,182 --> 04:13:14,516
INTEREST CLOSE TO THE INYEKS

5999
04:13:14,516 --> 04:13:17,319
SITE AND FAR AWAY FROM THE IPT

6000
04:13:17,319 --> 04:13:20,289
GREATER JEKS SITE AND THIS IS

6001
04:13:20,289 --> 04:13:21,190
COMPLETELY UNPUBLISHED, STILL

6002
04:13:21,190 --> 04:13:22,958
WORKING THROUGH THE DATA SO WHAT

6003
04:13:22,958 --> 04:13:25,127
I'M SHOWING YOU IS VERY

6004
04:13:25,127 --> 04:13:26,662
PRELIMINARY SO THERE'S MULTIPLE

6005
04:13:26,662 --> 04:13:37,139
COMPARISONS THAT WE CAN MAKE

6006
04:13:37,840 --> 04:13:37,973
HERE.

6007
04:13:37,973 --> 04:13:41,076
SO I WILL JUST TALK ABOUT THE

6008
04:13:41,076 --> 04:13:41,910
A-BETA EXPOSED THROUGH ANTIBODY

6009
04:13:41,910 --> 04:13:43,412
AND THEN THROUGH THE SOFTWARE WE

6010
04:13:43,412 --> 04:13:45,547
CAN SAY THAT WE WANT TO LOOK AT

6011
04:13:45,547 --> 04:13:46,281
PROTEIN EXPRESSION JUST IN THE

6012
04:13:46,281 --> 04:13:49,351
CELLS THAT ARE POSITIVE FOR

6013
04:13:49,351 --> 04:13:51,019
GREEN, AND THEP JUST IN THE

6014
04:13:51,019 --> 04:13:53,689
CELLS THAT ARE POSITIVE FOR RED.

6015
04:13:53,689 --> 04:13:59,628
SO NOW WE CAN LOOK AT THIS ARRAY

6016
04:13:59,628 --> 04:14:01,196
OF PROTEINS THAT ARE EXPRESSED

6017
04:14:01,196 --> 04:14:04,366
BUT ONLY WHERE THE GREEN CELLS

6018
04:14:04,366 --> 04:14:04,967
ARE.

6019
04:14:04,967 --> 04:14:06,735
SO PRIMARILY THEN ASTRO SIGHTS

6020
04:14:06,735 --> 04:14:07,302
AND MICROFLI COLSISSA.

6021
04:14:07,302 --> 04:14:09,905
AND SO I WILL SHOW YOU THIS 1

6022
04:14:09,905 --> 04:14:12,641
PIECE OF DATA BECAUSE I SAID

6023
04:14:12,641 --> 04:14:15,043
WE'RE STILL CRUNCHING, BUT THIS

6024
04:14:15,043 --> 04:14:18,480
WAS A PARTICULARLY INTERESTING

6025
04:14:18,480 --> 04:14:21,650
MARKER, SPP1, AND SO WHAT WE

6026
04:14:21,650 --> 04:14:26,588
FOUND WAS THAT SPP1 INCREASES IN

6027
04:14:26,588 --> 04:14:36,565
ABETTA ASSOCIATED MICROGLIA, AND

6028
04:14:36,565 --> 04:14:44,706
SPP1 HAS BEEN ASSOCIATED WITH

6029
04:14:44,706 --> 04:14:46,108
MICROGLIA AND PERIVASCULAR

6030
04:14:46,108 --> 04:14:46,708
MACROPHAGES AND INCREASE LIES

6031
04:14:46,708 --> 04:14:49,211
STUDIES OF MULTIPLE ENDOCRINAL

6032
04:14:49,211 --> 04:14:51,313
PATHWAY, AND INCREASE

6033
04:14:51,313 --> 04:14:52,214
PHAGOCYTOSIS AND SYNAPSES.

6034
04:14:52,214 --> 04:15:01,723
SO WE THINK THIS MAY REPRESENT A

6035
04:15:01,723 --> 04:15:04,593
SINGINALLING PATHWAY THAT MAY BE

6036
04:15:04,593 --> 04:15:06,428
A PRECURSOR TO THOSE PROTEINS

6037
04:15:06,428 --> 04:15:06,862
DOWN STREAM.

6038
04:15:06,862 --> 04:15:10,766
SO JUST TO SUMMARIZE, AGAIN,

6039
04:15:10,766 --> 04:15:11,833
VERY PRELIMINARY, WE PROBABLY

6040
04:15:11,833 --> 04:15:13,735
HAVE A FEW MORE MONTHS OF

6041
04:15:13,735 --> 04:15:17,339
CRUNCHING DATA ON THE STUDY BUT

6042
04:15:17,339 --> 04:15:20,776
WE SAW CHANGES IN CELLULAR

6043
04:15:20,776 --> 04:15:22,110
METABOLISM AND INFLAMMATORY

6044
04:15:22,110 --> 04:15:23,412
CYTOKINES WITH A BETA TRANSFER

6045
04:15:23,412 --> 04:15:25,781
INFECTION AND THEN WE SAW THIS

6046
04:15:25,781 --> 04:15:27,683
INCREASE IN SPP 1 WITH MICROGLIA

6047
04:15:27,683 --> 04:15:34,656
CLOSE TO THE INJECTION SITE

6048
04:15:34,656 --> 04:15:35,357
AROUND IT.

6049
04:15:35,357 --> 04:15:37,259
I WANT TO LACK AT THIS PAPER

6050
04:15:37,259 --> 04:15:39,928
THAT CAME OUT ABOUT A WEEK AGO,

6051
04:15:39,928 --> 04:15:42,264
SOME OF YOU MAY NOT HAVE SEEN

6052
04:15:42,264 --> 04:15:44,433
THIS YET WHERE THEY ARE

6053
04:15:44,433 --> 04:15:49,004
PACIFICALLY LOOKING AT ABETTA

6054
04:15:49,004 --> 04:15:49,404
IMMUNOTHERAPY AND

6055
04:15:49,404 --> 04:15:50,105
MICROHEMORRHAGES AND LOOK AT

6056
04:15:50,105 --> 04:15:51,740
WHAT CELLS ARE ASSOCIATE WIDE

6057
04:15:51,740 --> 04:15:55,510
THAT AND WHAT PROCESSES AND SO,

6058
04:15:55,510 --> 04:15:58,347
WHAT THEY FOUND WAS THAT WHERE

6059
04:15:58,347 --> 04:16:01,917
THEY HAD THE MICROBLEEDS IN

6060
04:16:01,917 --> 04:16:04,753
THESE OLDER MICE THAT HAVE BEEN

6061
04:16:04,753 --> 04:16:08,290
IMMUNIZED THEY SAW SIGNIFICANT

6062
04:16:08,290 --> 04:16:14,596
ENGAGEMENT OF PERIVASCULAR

6063
04:16:14,596 --> 04:16:16,365
MACROPHAGES THEY SAW

6064
04:16:16,365 --> 04:16:18,800
UPREGULATION OF CD169 AND THE CO

6065
04:16:18,800 --> 04:16:22,571
LEGALIZATION OF THE CD169 WITH

6066
04:16:22,571 --> 04:16:23,105
THE THIOFLAVORIN S.

6067
04:16:23,105 --> 04:16:24,606
SO THERE'S MORE TO THIS PAPER

6068
04:16:24,606 --> 04:16:29,444
BUT IT DOES SEEM TO HEAVILY

6069
04:16:29,444 --> 04:16:30,545
IMPLICATE THE PERIVASCULAR

6070
04:16:30,545 --> 04:16:31,613
MACROFAINLS IN THE MICROPLEAD

6071
04:16:31,613 --> 04:16:32,614
PROCESS.

6072
04:16:32,614 --> 04:16:37,119
IN THE STUDY, MMP9 CAME UP AS A

6073
04:16:37,119 --> 04:16:38,787
KEY COMPONENT TO THE MICROPLEADS

6074
04:16:38,787 --> 04:16:40,956
AND SO THEY DID A COUPLE OF

6075
04:16:40,956 --> 04:16:41,256
STUDIES.

6076
04:16:41,256 --> 04:16:45,460
THEY DO BONE MARROW DERIVED

6077
04:16:45,460 --> 04:16:48,230
MACROPHAGE STUDIES AND THEN THEY

6078
04:16:48,230 --> 04:16:50,399
ALSO THEN DID

6079
04:16:50,399 --> 04:16:51,199
IMMUNOHISTOCHEMISTRY IN THE

6080
04:16:51,199 --> 04:16:56,805
TISSUE AND WHEN THEY--WHEN THEY

6081
04:16:56,805 --> 04:16:57,606
GREWSED IBGASHING, ANTIBETTA

6082
04:16:57,606 --> 04:16:59,274
IIMRKS GE TO THE MACROPHAGES

6083
04:16:59,274 --> 04:17:01,777
THEY SAW A SIGNIFICANT

6084
04:17:01,777 --> 04:17:04,713
UPREGULATION OF MATRIX

6085
04:17:04,713 --> 04:17:09,818
REMODELING SIGNALING AND MMP 9

6086
04:17:09,818 --> 04:17:10,952
AND [INDISCERNIBLE] ARE BOTH

6087
04:17:10,952 --> 04:17:13,088
EXPRESSED IN THIS PANEL AND

6088
04:17:13,088 --> 04:17:15,190
THEN, AGAIN, DOWN HERE WITH

6089
04:17:15,190 --> 04:17:17,225
INFLAMMATORY SIGNALING, THAT WAS

6090
04:17:17,225 --> 04:17:24,966
THE SECOND MOST ABUNDANT PATHWAY

6091
04:17:24,966 --> 04:17:26,234
THAT WAS CHANGED.

6092
04:17:26,234 --> 04:17:27,903
SO THE MATRIX REMODELING DOES

6093
04:17:27,903 --> 04:17:30,872
SEEM TO BE A KEY MECHANISM FOR

6094
04:17:30,872 --> 04:17:32,574
MICROHEMORRHAGE AND THIS WITH

6095
04:17:32,574 --> 04:17:35,344
BETA IMMUNE THERAPY THEY SAW A

6096
04:17:35,344 --> 04:17:37,612
LOT OF PERIVASCULAR LABELING

6097
04:17:37,612 --> 04:17:40,215
WHERE THEY HAVE MICROBLEEDS WITH

6098
04:17:40,215 --> 04:17:42,951
MMP9 AND THIS SEEMED TO BE

6099
04:17:42,951 --> 04:17:44,286
EXPRESSED BY THE PERIVASCULAR

6100
04:17:44,286 --> 04:17:44,786
MACROPHAGES.

6101
04:17:44,786 --> 04:17:47,255
SO I WANT TO HIGHLIGHT THAT WORK

6102
04:17:47,255 --> 04:17:55,430
BECAUSE I KNEW THEY WEREN'T

6103
04:17:55,430 --> 04:17:56,665
PRECEPTING TODAY EMPLOY AND I'LL

6104
04:17:56,665 --> 04:18:05,006
TAKE ANY QUESTIONS EMPLOY

6105
04:18:05,006 --> 04:18:06,308
AND I THINK WE'RE DOING

6106
04:18:06,308 --> 04:18:16,852
QUESTIONS NOW IF ANYONE HAS ANY.

6107
04:18:19,388 --> 04:18:21,423
WITH THE'MUNE RESPONSE GOING UP

6108
04:18:21,423 --> 04:18:23,759
AND METABOLISM GOING DOWN IS

6109
04:18:23,759 --> 04:18:26,261
THAT IT SEEMS LIKE INNATE

6110
04:18:26,261 --> 04:18:30,999
IMMUNITY IS THAT WHAT YOU

6111
04:18:30,999 --> 04:18:32,501
THINKING MIGHT HAPPEN THAT'S A

6112
04:18:32,501 --> 04:18:35,470
GO QUESTION, WE WERE AGNOSTIC WE

6113
04:18:35,470 --> 04:18:38,173
KNOW FROM PREVIOUS STUDIES THAT

6114
04:18:38,173 --> 04:18:48,717
PRO INFLAMMATORY CYTOKINES DO GO

6115
04:18:51,620 --> 04:18:53,688
UP O WE KNEW THERE WAS A

6116
04:18:53,688 --> 04:18:54,923
MICRODPLEEL REACTION BUT WE

6117
04:18:54,923 --> 04:18:57,559
DIDN'T KNOW WHAT PROCESSES WERE

6118
04:18:57,559 --> 04:18:58,827
GOING ON.

6119
04:18:58,827 --> 04:19:00,328
SO IT'S INTERESTING WE'RE

6120
04:19:00,328 --> 04:19:02,230
DIGGING DOWN DEEPER ON THOSE

6121
04:19:02,230 --> 04:19:06,468
SPECIFIC YEENS EMPLOY

6122
04:19:06,468 --> 04:19:06,935
NFASCINATING.

6123
04:19:06,935 --> 04:19:08,270
SMRKS BEAUTIFUL WORK DONNA.

6124
04:19:08,270 --> 04:19:09,571
YOU'VE BEEN AT THIS FOR A LONG,

6125
04:19:09,571 --> 04:19:18,680
LONG TIME AND I THINK IT'S

6126
04:19:18,680 --> 04:19:20,081
WONDERFUL WHEN YOU DID THE

6127
04:19:20,081 --> 04:19:21,149
CONTROL ANTIBODY, DID YOU LOOK

6128
04:19:21,149 --> 04:19:22,918
AT THE LOCATION WITHIN THE

6129
04:19:22,918 --> 04:19:23,218
TISSUE?

6130
04:19:23,218 --> 04:19:25,454
WERE YOU ABLE TO SEE?

6131
04:19:25,454 --> 04:19:27,289
COULD YOU LABEL THE ANTIBODIES

6132
04:19:27,289 --> 04:19:29,057
SINCE YOU'RE DOG INJECTION YOU

6133
04:19:29,057 --> 04:19:33,628
WOULDN'T HAVE TO WORRY ABOUT THE

6134
04:19:33,628 --> 04:19:35,831
BLOOD BRAIN BARRIER IN YEAH SO

6135
04:19:35,831 --> 04:19:37,432
WE HAVE LABELED ANTIIGG, THERE

6136
04:19:37,432 --> 04:19:39,734
IS NOT MUCH DIFFUSION OF THE

6137
04:19:39,734 --> 04:19:40,502
ANTIBODY SO YOU'RE REALLY

6138
04:19:40,502 --> 04:19:46,708
WORKING IN A PRETTY TIGHT AREA

6139
04:19:46,708 --> 04:19:50,445
THAT HAS BEEN EXPOSE TO THE

6140
04:19:50,445 --> 04:19:52,547
ANTIBODY SO WE ONLY HAVE A DANCE

6141
04:19:52,547 --> 04:19:53,849
OF 200-MICRONS THAT HAS BEEN

6142
04:19:53,849 --> 04:19:54,816
EXPOSED TO ASPECT BODY.

6143
04:19:54,816 --> 04:19:57,118
AND DO YOU SEE THE ANTIBODIES

6144
04:19:57,118 --> 04:20:05,594
BINDING TO VASCULAR AMYLOID?

6145
04:20:05,594 --> 04:20:08,530
NOT IN THAT STUDY BUT WE HAVE

6146
04:20:08,530 --> 04:20:09,297
SEEN IT BEFORE.

6147
04:20:09,297 --> 04:20:12,634
THESE MICE DIDN'T HAVE A LOT OF

6148
04:20:12,634 --> 04:20:18,273
CAA BECAUSE THEY'RE 14 MONTHS.

6149
04:20:18,273 --> 04:20:23,044
>> OKAY, THERE'S AN ONLINE

6150
04:20:23,044 --> 04:20:25,447
QUESTION, FROM

6151
04:20:25,447 --> 04:20:26,047
DR. [INDISCERNIBLE].

6152
04:20:26,047 --> 04:20:29,251
HE ASKED IF YOU MEASURED

6153
04:20:29,251 --> 04:20:30,552
MMP ACTIVITY LEVELS BECAUSE HE'S

6154
04:20:30,552 --> 04:20:34,890
THINKING ABOUT PROFORMS AND HE'S

6155
04:20:34,890 --> 04:20:37,325
ALSO CATEGORY ABOUT HOMOCYSTINE

6156
04:20:37,325 --> 04:20:39,928
POSSIBLY CAUSING SMOOTH MUSCLE

6157
04:20:39,928 --> 04:20:41,096
PROLIFERATION AND FRAGMENTATION?

6158
04:20:41,096 --> 04:20:44,599
>> YEAH, 2 GREAT
QUESTIONS, AND

6159
04:20:44,599 --> 04:20:46,134
THE STUDY THAT I JUST SHOWED

6160
04:20:46,134 --> 04:20:47,769
WITH THE SINGLE CELL ANALYSIS,

6161
04:20:47,769 --> 04:20:50,972
WE HAVE NOT DONE MMP ACTIVITY

6162
04:20:50,972 --> 04:20:53,174
YET, IN THE PAPER WE PUBLISHED

6163
04:20:53,174 --> 04:20:54,910
IN 2011, WE DID ACTUALLY DO AN

6164
04:20:54,910 --> 04:20:56,378
ACTIVITY ASSAY WITH A DESIGN O

6165
04:20:56,378 --> 04:20:59,948
GRAM AND WE SHOWED THAT MPP 2

6166
04:20:59,948 --> 04:21:05,687
AND AMERICA MP 9 ACTIVITY WAS

6167
04:21:05,687 --> 04:21:08,857
INCREASED AS WELL AS PROTEIN.

6168
04:21:08,857 --> 04:21:13,762
THE SECOND QUESTION? 

6169
04:21:13,762 --> 04:21:15,263
>> SMOOTH MUSCLE
NHOMOCYSTINE,

6170
04:21:15,263 --> 04:21:17,432
IS QUITE POTENTOX DENT AND SO

6171
04:21:17,432 --> 04:21:20,735
THE MECHANISM THAT WE HAVE BEEN

6172
04:21:20,735 --> 04:21:22,837
WORKING THROUGH IS THAT THIS IS

6173
04:21:22,837 --> 04:21:27,909
A PRIMARILY AN

6174
04:21:27,909 --> 04:21:28,977
ENDOTHELIALOXIDATIVE STRESS,

6175
04:21:28,977 --> 04:21:30,345
PROBABLY SMOOTH MUSCLE CELLS AND

6176
04:21:30,345 --> 04:21:32,781
THIS LEADS TO PERIVASCULAR

6177
04:21:32,781 --> 04:21:34,482
INFLAMMATORY RESPONSE WE SEE AND

6178
04:21:34,482 --> 04:21:35,216
ULTIMATELY THE LEAKAGE SO WE

6179
04:21:35,216 --> 04:21:41,890
HAVE  NOT CAREFULLY LOOKED AT

6180
04:21:41,890 --> 04:21:43,959
THAT YET BUT I WOULD IMAGINE

6181
04:21:43,959 --> 04:21:47,262
THERE ARE SIGNIFICANT

6182
04:21:47,262 --> 04:21:48,396
DISRUPTIONS.

6183
04:21:48,396 --> 04:21:48,697
>> DOCTOR?

6184
04:21:48,697 --> 04:21:51,232
>> THIS WILL SOUND LOOK A
NAIVE

6185
04:21:51,232 --> 04:21:55,971
QUESTION BECAUSE AS A THIS IS

6186
04:21:55,971 --> 04:22:00,241
ALL CLINGON TO ME BUT HAVE THERE

6187
04:22:00,241 --> 04:22:01,343
BEEN EXPERIMENTS, THIS VERY

6188
04:22:01,343 --> 04:22:05,080
INTERESTING WORK HAS REALLY BEEN

6189
04:22:05,080 --> 04:22:06,181
MANIPULATED ENOUGH THAT YOU

6190
04:22:06,181 --> 04:22:07,515
COULD GET THIS BALANCE OF IMET

6191
04:22:07,515 --> 04:22:10,151
THE CLEARANCE WITHOUT THE

6192
04:22:10,151 --> 04:22:12,020
INFLAMMATION IN DIFFERENT

6193
04:22:12,020 --> 04:22:15,790
ANTIBODIES, IF YOU TRIED THAT?

6194
04:22:15,790 --> 04:22:17,826
NIT'S A GREAT QUESTION, SO THE

6195
04:22:17,826 --> 04:22:19,361
STUDY AT TIME IS WITH THE

6196
04:22:19,361 --> 04:22:25,467
SCIENCES WHO THEN ACQUIRED BY

6197
04:22:25,467 --> 04:22:26,267
PFIZER, MONOCLONAL ANTIBODY THAT

6198
04:22:26,267 --> 04:22:34,242
CAME OUT OF THAT PROGRAM, SO PE

6199
04:22:34,242 --> 04:22:36,845
NEZUMAB, BUT IT WASN'T

6200
04:22:36,845 --> 04:22:37,879
ENZYMATICALLY DISCIPLINARY FLI

6201
04:22:37,879 --> 04:22:38,947
COLSIS COSALATED, IT WAS

6202
04:22:38,947 --> 04:22:40,415
ENGINEERED AND IT LOST ITS

6203
04:22:40,415 --> 04:22:42,283
EFFICACY WHEN THEY INJURED IT,

6204
04:22:42,283 --> 04:22:44,719
BECAUSE WE DID INTRA CRANIAL

6205
04:22:44,719 --> 04:22:46,855
INYEKS AND WE DIDN'T SEE THE

6206
04:22:46,855 --> 04:22:47,155
CLEARANCE.

6207
04:22:47,155 --> 04:22:48,790
IN, IT'S ALSO I THINK IT'S

6208
04:22:48,790 --> 04:22:51,660
EPITOPE IS NOT RIGHT FOR WHAT WE

6209
04:22:51,660 --> 04:22:53,461
KNOW NOW.

6210
04:22:53,461 --> 04:22:56,798
NC-TERMINAL NBUT WITH AN END

6211
04:22:56,798 --> 04:22:57,065
TERMINAL.

6212
04:22:57,065 --> 04:22:58,299
>> YEAH SO WE HAVE NOT
PLAYED

6213
04:22:58,299 --> 04:23:01,069
WITH THE FLI COLSIS COSALATION

6214
04:23:01,069 --> 04:23:03,204
SINCE THAT STUDY BUT I THINK

6215
04:23:03,204 --> 04:23:05,607
IT'S COMING BACK TO IT NOW.

6216
04:23:05,607 --> 04:23:07,008
ALL THE BASIC SCIENCE KIND OF

6217
04:23:07,008 --> 04:23:08,209
SLOWED DOWN BECAUSE WE THOUGHT

6218
04:23:08,209 --> 04:23:11,446
THE DRUG COMPANIES HAD THIS AND

6219
04:23:11,446 --> 04:23:13,381
NOW IT'S COMING BACK BECAUSE WE

6220
04:23:13,381 --> 04:23:14,516
NEED TO UNDERSTAND THESE ARIA,

6221
04:23:14,516 --> 04:23:16,117
SO WE WILL DEFINITELY BEING

6222
04:23:16,117 --> 04:23:26,561
COMING BACK TO THIS WORK.

6223
04:23:28,229 --> 04:23:30,465
>> DO QUESTIONS DID YOU DO

6224
04:23:30,465 --> 04:23:31,800
ADDITIONAL BINDING WHEN YOU

6225
04:23:31,800 --> 04:23:34,469
CHANGED THE FC FRAGMENT IN.

6226
04:23:34,469 --> 04:23:39,240
>> DID I CHECK WHAT
BINDING.

6227
04:23:39,240 --> 04:23:42,877
>> AVIDITY IN.

6228
04:23:42,877 --> 04:23:43,311
>> AFFINITY?

6229
04:23:43,311 --> 04:23:47,082
NWE HAD THE AFFINITY FOR A-BETA

6230
04:23:47,082 --> 04:23:48,683
AND IT WAS COMPARABLE AND THE

6231
04:23:48,683 --> 04:23:56,725
AFFINITY TO THE FC RECEPTORS--

6232
04:23:56,725 --> 04:23:59,327
>> NO, NO, NO, BINDING, DO
YOU

6233
04:23:59,327 --> 04:24:01,296
SEE DIFFERENCES WHEN YOU CHANGE

6234
04:24:01,296 --> 04:24:04,032
ACTIVITY NNO.

6235
04:24:04,032 --> 04:24:05,300
>> OKAY, SECOND QUESTION
WHICH

6236
04:24:05,300 --> 04:24:07,836
IS PROBABLY RELATED TO THE SAME

6237
04:24:07,836 --> 04:24:12,507
QUESTION, DID YOU TRY TO CD6, IF

6238
04:24:12,507 --> 04:24:16,978
I REMEMBER IT'S MIDTERMINAL,

6239
04:24:16,978 --> 04:24:19,180
RIGHT?

6240
04:24:19,180 --> 04:24:20,548
>> WHICH 1?

6241
04:24:20,548 --> 04:24:22,484
>> THREE D6.

6242
04:24:22,484 --> 04:24:25,086
>> 6010 IS N NEND TERMINAL
BUT

6243
04:24:25,086 --> 04:24:28,957
KRRK DECKER 6 IF I--NO.

6244
04:24:28,957 --> 04:24:32,927
>> 3D 6 IS A BETA.

6245
04:24:32,927 --> 04:24:34,562
NIT'S ROOT TERMINAL NETWORK

6246
04:24:34,562 --> 04:24:35,730
MIDTERMINAL NSO WE PROBABLY NEED

6247
04:24:35,730 --> 04:24:36,631
TO STOP.

6248
04:24:36,631 --> 04:24:41,803
>> I AM JUST TRYING TO

6249
04:24:41,803 --> 04:24:42,904
UNDERSTAND IF YOU--

6250
04:24:42,904 --> 04:24:47,208
>> 3D 6 IS END TERMINAL NI
WILL

6251
04:24:47,208 --> 04:24:49,444
TALK TO YOU IN A LITTLE BIT

6252
04:24:49,444 --> 04:24:52,313
MICHAEL, YEAH NI'M SORRYNY NEED

6253
04:24:52,313 --> 04:24:53,081
TO MOVE ON.

6254
04:24:53,081 --> 04:24:56,050
WE ARE REALLY TIGHT ON TIME

6255
04:24:56,050 --> 04:25:06,594
TOGETHER, SORRY GUYS, THANK YOU

6256
04:25:11,466 --> 04:25:12,000
SO MUCH.

6257
04:25:12,000 --> 04:25:15,236
OKAY, SO I WOULD LIKE TO INVITE

6258
04:25:15,236 --> 04:25:25,580
THE PANELISTS UP, .

6259
04:26:17,432 --> 04:26:26,307
>> HI, I'M  LANNIER
HEYBURN, AND

6260
04:26:26,307 --> 04:26:29,444
I WOULD LIKE TO WELCOME OUR

6261
04:26:29,444 --> 04:26:29,711
PANELISTS.

6262
04:26:29,711 --> 04:26:31,746
WE WOULD LIKE FOR TO YOU TALKOT

6263
04:26:31,746 --> 04:26:34,082
BIGGEST GAPS FOR UNDERSTANDING

6264
04:26:34,082 --> 04:26:35,416
THE BASIC MECHIMISMS OF ARIA

6265
04:26:35,416 --> 04:26:44,225
EMPLOY SO WHAT --WE CAN TART WIH

6266
04:26:44,225 --> 04:26:45,293
DR. ROSENBERG EMPLOY NTHANK YOU.

6267
04:26:45,293 --> 04:26:46,394
I APPRECIATE THE OPPORTUNITY TO

6268
04:26:46,394 --> 04:26:49,631
BE HERE, WHAT I'M SORT OF STRUCK

6269
04:26:49,631 --> 04:26:56,971
BY IS THE ABSENCE OF MULTIMODAL

6270
04:26:56,971 --> 04:26:57,605
OR MULTICO-MORBIDITIES IN THE

6271
04:26:57,605 --> 04:27:00,308
WORK THAT WE'VE BEEN DOING IN

6272
04:27:00,308 --> 04:27:03,544
VASCULAR TEASE, AS IT RELATES TO

6273
04:27:03,544 --> 04:27:04,879
DEMENTIA, IT'S PRETTY CLEAR THAT

6274
04:27:04,879 --> 04:27:07,682
WHEN YOU HAVE THE AMYLOID AND

6275
04:27:07,682 --> 04:27:09,651
THE LASKULAR DISEASE, THAT'S

6276
04:27:09,651 --> 04:27:12,387
WHEN THE REAL INFLAMMATION

6277
04:27:12,387 --> 04:27:15,156
BEGINS AND WE HAVE PRETTY GOOD

6278
04:27:15,156 --> 04:27:17,525
PROOF OF THAT THROUGH THE

6279
04:27:17,525 --> 04:27:19,527
BIOMARKERS THAT WE'VE BEEN

6280
04:27:19,527 --> 04:27:26,668
STUDYING THROUGH MARK ECID.

6281
04:27:26,668 --> 04:27:28,436
SO WE'VE BEEN WORKING ON WAYS TO

6282
04:27:28,436 --> 04:27:29,804
CLASSIFY PATIENTS.

6283
04:27:29,804 --> 04:27:32,073
AS A CLINICIAN IT WAS NEVER EASE

6284
04:27:32,073 --> 04:27:35,543
TO DETERMINE WHO HAD THIS OR

6285
04:27:35,543 --> 04:27:38,012
THAT AND WE STARTED OUT STUDYING

6286
04:27:38,012 --> 04:27:48,456
PATIENTS WITH WHITE MATTER

6287
04:27:55,797 --> 04:27:58,733
DISEASE AND THE ALZHEIMER GROUP

6288
04:27:58,733 --> 04:28:04,105
DECIDED THEY WOULD EMILYINATE

6289
04:28:04,105 --> 04:28:06,841
THE VASCULAR ISSUES BUT WHEN

6290
04:28:06,841 --> 04:28:09,711
THEY WENT BACK AND LOOKED, WHEN

6291
04:28:09,711 --> 04:28:12,380
THEY LOOKEDDA THE PATHOLOGY, 70%

6292
04:28:12,380 --> 04:28:13,815
HAD VASCULAR DEC WITH THE

6293
04:28:13,815 --> 04:28:15,383
ALZHEIMERS SO IT WAS CLEAR THE

6294
04:28:15,383 --> 04:28:17,051
MOST IMPORTANT BROWP IS MIXED

6295
04:28:17,051 --> 04:28:21,122
AND SO WE DEVELOPED A WAY TO

6296
04:28:21,122 --> 04:28:28,363
CLUSTER ANALYSIS THAT IDENTIFY

6297
04:28:28,363 --> 04:28:29,364
THE MIXED PATIENTS.

6298
04:28:29,364 --> 04:28:30,832
CAN THAT'S WHAT I'M SORT OF

6299
04:28:30,832 --> 04:28:32,934
MISSING IN THIS MEETING IS WE

6300
04:28:32,934 --> 04:28:33,768
HAVEN'T DISCUSSED THE IMPACT OF

6301
04:28:33,768 --> 04:28:35,203
1 THING ON ANOTHER.

6302
04:28:35,203 --> 04:28:36,504
AND WHAT WE FOUND WHEN WE WERE

6303
04:28:36,504 --> 04:28:37,538
ABLE TO SEPARATE THE PATIENTS

6304
04:28:37,538 --> 04:28:39,974
AND WE CAN DO THAT NOW WITH

6305
04:28:39,974 --> 04:28:42,877
AMYLOID AND THE CSF, AND AMYLOID

6306
04:28:42,877 --> 04:28:50,118
AND TARK U, , WHITE MATTER DISEE

6307
04:28:50,118 --> 04:28:52,086
AND BIOTESTING AND ALL THE

6308
04:28:52,086 --> 04:28:54,856
MARKERS WE COLLECT, WE CAN

6309
04:28:54,856 --> 04:28:59,827
CLEARLY SEPARATE PATIENTS INTO 8

6310
04:28:59,827 --> 04:29:00,995
GROUPS NOW AND 1 OF THEM IS

6311
04:29:00,995 --> 04:29:05,433
MIXED AND OF COURSE THERE'S PURE

6312
04:29:05,433 --> 04:29:07,068
AMILLIO JEIMERS AND PURE

6313
04:29:07,068 --> 04:29:17,445
VASCULAR SO THE QUESTION THAT I

6314
04:29:17,445 --> 04:29:19,047
THINK FROM TD BIOMARKERS TO

6315
04:29:19,047 --> 04:29:22,250
ANTICIPATE WHICH PATIENTS WILL

6316
04:29:22,250 --> 04:29:24,352
BE BEST STUDIED, YOU KNOW

6317
04:29:24,352 --> 04:29:27,055
PARTICULARLY IN NEW MEXICO WHICH

6318
04:29:27,055 --> 04:29:30,324
IS--THEY CALL IT A FRONTIER

6319
04:29:30,324 --> 04:29:34,829
STATE, LARGE LAND MASS AND FEW

6320
04:29:34,829 --> 04:29:35,063
PEOPLE.

6321
04:29:35,063 --> 04:29:37,331
THEY'RE NOT GOING TO BE ABLE TO

6322
04:29:37,331 --> 04:29:41,569
DO PET STUDIES OR CSF VERY

6323
04:29:41,569 --> 04:29:41,803
EASILY.

6324
04:29:41,803 --> 04:29:43,838
SO WE NEED WAYS TO IDENTIFY

6325
04:29:43,838 --> 04:29:46,908
PATIENTS THAT WOULD BENEFIT FROM

6326
04:29:46,908 --> 04:29:48,643
THESE TREATMENTS.

6327
04:29:48,643 --> 04:29:51,612
CAN TO ME, THE KEY, IS ANYTHING

6328
04:29:51,612 --> 04:29:53,948
TO BE THE BLOOD BASED

6329
04:29:53,948 --> 04:29:54,282
BIOMARKERS.

6330
04:29:54,282 --> 04:30:04,459
I JUST GOT BACK FROM VERY CLOSE

6331
04:30:04,459 --> 04:30:05,159
-VASCOG, THAT'S A BIG

6332
04:30:05,159 --> 04:30:05,726
GROUP OF INTEREST.

6333
04:30:05,726 --> 04:30:06,994
THAT'S SOMETHING I WOULD LIKE TO

6334
04:30:06,994 --> 04:30:08,262
HEAR MORE ABOUT, HOW TO USE

6335
04:30:08,262 --> 04:30:15,269
THOSE IN ORDER TO SELECT

6336
04:30:15,269 --> 04:30:17,672
PATIENTS.

6337
04:30:17,672 --> 04:30:18,139
>> OKAY, THANK YOU.

6338
04:30:18,139 --> 04:30:20,908
WOULD YOU LIKE TO SPEAK NEXT?

6339
04:30:20,908 --> 04:30:23,611
>> SO I WOULD LIKE TO ADD
MY

6340
04:30:23,611 --> 04:30:25,113
THANKS FOR BEING HERE AND BEING

6341
04:30:25,113 --> 04:30:27,281
INVITED AND IT'S BEEN A

6342
04:30:27,281 --> 04:30:27,982
FANTASTIC EXPERIENCE LEARNING

6343
04:30:27,982 --> 04:30:31,152
ABOUT THE CLINICAL ASPECTS OF

6344
04:30:31,152 --> 04:30:35,857
THE ARIA PHENOMENON IN SENSE I'M

6345
04:30:35,857 --> 04:30:38,192
A PRECLINICAL RESEARCHER AND I

6346
04:30:38,192 --> 04:30:40,962
LOOK AT THE WORLD FROM THE ALL

6347
04:30:40,962 --> 04:30:42,363
THE ARTICLES FROM THE LYMPHATICS

6348
04:30:42,363 --> 04:30:45,366
SYSTEM IN THE BRAIN SO WHEN I AM

6349
04:30:45,366 --> 04:30:48,136
ASKED ABOUT WHAT I THINK ABOUT

6350
04:30:48,136 --> 04:30:50,238
TALKS THIS MORNING AND WHAT'S MY

6351
04:30:50,238 --> 04:30:53,841
TAKE ON IT, I WOULD SAY I WROTE

6352
04:30:53,841 --> 04:30:56,344
DOWN SOME OF THESE MAJOR

6353
04:30:56,344 --> 04:30:58,012
QUESTIONS I HAVE AND 1 OF THE

6354
04:30:58,012 --> 04:31:01,082
FIRST 1 ACTUALLY IS EXACTLY LIKE

6355
04:31:01,082 --> 04:31:02,150
DR. ROSENBERG WERE MENTIONING, I

6356
04:31:02,150 --> 04:31:03,417
WOULD LIKE TO KNOW THE BASE LINE

6357
04:31:03,417 --> 04:31:05,887
AT THAT TIMEUS OF THE SEVERAL

6358
04:31:05,887 --> 04:31:07,788
SMALL VESSELS TO SEE IN THESE

6359
04:31:07,788 --> 04:31:10,091
PEASHES THAT ARE ACTUALLY

6360
04:31:10,091 --> 04:31:10,992
UNDERGOING TREATMENT FOR MANY

6361
04:31:10,992 --> 04:31:15,196
REASONS BUT ALSO BECAUSE OF THE

6362
04:31:15,196 --> 04:31:17,498
WHOLE CLEARANCE SYSTEM AND THE

6363
04:31:17,498 --> 04:31:18,599
FLUID HOMEOSTASIS PROBLEM THAT I

6364
04:31:18,599 --> 04:31:21,769
THINK YOU ARE SEEING IN ARIA.

6365
04:31:21,769 --> 04:31:24,705
YOU MENTIONED THE DILATED

6366
04:31:24,705 --> 04:31:26,207
PERIVASCULAR SPACES WE HAVE THAT

6367
04:31:26,207 --> 04:31:30,178
IN SEVERAL SMALL VESSEL DISEASE

6368
04:31:30,178 --> 04:31:34,348
AS WELL AS A HALLMARK AND IN

6369
04:31:34,348 --> 04:31:34,582
CAA.

6370
04:31:34,582 --> 04:31:37,185
IT WAS THEN WE MENTIONED THE

6371
04:31:37,185 --> 04:31:39,287
VENTRICLES AND I WAS INTRIGUED

6372
04:31:39,287 --> 04:31:41,556
BY THAT BECAUSE AGAIN IT TELLS

6373
04:31:41,556 --> 04:31:44,392
ME THERE'S A DISREG USE OF FLUID

6374
04:31:44,392 --> 04:31:45,693
HOMEIO AT AIS THAT WE'RE NOT

6375
04:31:45,693 --> 04:31:47,828
LOOKING AT AND WE'RE NOT

6376
04:31:47,828 --> 04:31:53,301
UNDERSTANDING AND SO THIS COULD

6377
04:31:53,301 --> 04:31:56,137
BE ATTRIBUTED TO MANY THINGS AND

6378
04:31:56,137 --> 04:31:57,572
THE DOCTOR MENTIONED THE BLOOD

6379
04:31:57,572 --> 04:31:59,440
BRAIN BARRIER WHICH WE HAVEN'T

6380
04:31:59,440 --> 04:32:00,241
KNOTTEN GOOD QUAWBTITATION, WE

6381
04:32:00,241 --> 04:32:03,277
DON'T REALLY KNOW WHAT THE

6382
04:32:03,277 --> 04:32:05,012
TRENDS ARE IN PARTS OF AREAS SO

6383
04:32:05,012 --> 04:32:06,881
THAT IS A BIG CONCERN IN MY

6384
04:32:06,881 --> 04:32:09,951
BOOK, BUT WE ALSO DON'T KNOW

6385
04:32:09,951 --> 04:32:12,386
ANYTHING ABOUT THE CLEARANCE

6386
04:32:12,386 --> 04:32:15,189
PATHWAY THROUGH THE MENINGIAL

6387
04:32:15,189 --> 04:32:16,490
SYSTEM, THE MENINGIAL LYMPHATICS

6388
04:32:16,490 --> 04:32:23,564
WHICH CAN BE IMAGED IN THE HUMAN

6389
04:32:23,564 --> 04:32:25,499
BRAIN USING BLACK

6390
04:32:25,499 --> 04:32:26,167
[INDISCERNIBLE] IN CONTRAST,

6391
04:32:26,167 --> 04:32:27,835
IT'S NOT DIFFICULT TO DO AND IT

6392
04:32:27,835 --> 04:32:29,170
COULD BE LOOKED AT IN THESE

6393
04:32:29,170 --> 04:32:30,438
PATIENTS AND MAYBE THIS WILL

6394
04:32:30,438 --> 04:32:32,974
ACTUALLY EXPLAIN WHY YOU HAVE

6395
04:32:32,974 --> 04:32:34,442
THIS DIVERSE OR BAND WIDTH OF

6396
04:32:34,442 --> 04:32:37,178
PATIENTS THAT SEEMS TO HAVE A

6397
04:32:37,178 --> 04:32:39,213
LOT OF ARIA WITH PATIENTS THAT

6398
04:32:39,213 --> 04:32:45,219
SEEM TO BE TOLERATING THE

6399
04:32:45,219 --> 04:32:46,887
ANTIBODIES SO THE SYSTEMS CAN BE

6400
04:32:46,887 --> 04:32:47,521
TRACKED CLINICALLY TOO AND I

6401
04:32:47,521 --> 04:32:48,789
THINK THIS IS SOMETHING THAT IS

6402
04:32:48,789 --> 04:32:51,192
LACKING EMPLOY AND AGAIN, I

6403
04:32:51,192 --> 04:32:53,628
ALSO, THE LAST THING WAS THAT

6404
04:32:53,628 --> 04:32:55,896
SOMEBODY MENTIONED THE NATURAL

6405
04:32:55,896 --> 04:32:57,632
HISTORY OF CAA BEING ABLE TO

6406
04:32:57,632 --> 04:33:00,835
ACTUALLY LEARN MORE ABOUT THAT

6407
04:33:00,835 --> 04:33:04,005
FROM PRECLINICAL ANIMAL MODELS

6408
04:33:04,005 --> 04:33:07,341
AND I KNOW DR. VAN NOSTRAND TALK

6409
04:33:07,341 --> 04:33:09,677
ABOUT THAT LATER TODAY BUT THATY

6410
04:33:09,677 --> 04:33:10,911
AN IMPORTANT PART WE DON'T

6411
04:33:10,911 --> 04:33:11,212
UNDERSTAND.

6412
04:33:11,212 --> 04:33:15,516
I 

6413
04:33:15,516 --> 04:33:17,118
I WILL TOP WITH THIS.

6414
04:33:17,118 --> 04:33:17,785
NTHANK YOU.

6415
04:33:17,785 --> 04:33:19,820
SO JUST A QUICK OVERVIEW OF WHAT

6416
04:33:19,820 --> 04:33:21,856
WE HEARD SO FAR, IT'S AS DONNA

6417
04:33:21,856 --> 04:33:26,394
JUST MENTIONED ISSUES THE FIRST

6418
04:33:26,394 --> 04:33:30,498
PAPER IN 2003 BY A GROUP

6419
04:33:30,498 --> 04:33:31,599
DESCRIBING MICROHEMORRHAGE IN

6420
04:33:31,599 --> 04:33:35,036
MICE TREATED WITH 3D 6.

6421
04:33:35,036 --> 04:33:37,004
FROM THERE WHEN WE THINK ABOUT

6422
04:33:37,004 --> 04:33:40,908
IT 20 YEARS AGO, WE'RE TALKING

6423
04:33:40,908 --> 04:33:41,942
ABOUT MICROHEMORRHAGE THAT WAS

6424
04:33:41,942 --> 04:33:46,147
BRAND NEW WHERE ARE WE NOW?

6425
04:33:46,147 --> 04:33:48,316
UNFORTUNATELY, I THINK WE OFTEN

6426
04:33:48,316 --> 04:33:52,520
STILL IN THE RESEARCH FIELD AT

6427
04:33:52,520 --> 04:33:53,688
LEAST QUANTIFY MICROHEMORRHAGE

6428
04:33:53,688 --> 04:33:56,857
AS AN INDICATOR PREDICTOR OF

6429
04:33:56,857 --> 04:34:01,862
WHAT COULD THERAPEUTIC DO IN

6430
04:34:01,862 --> 04:34:02,363
HUMAN.

6431
04:34:02,363 --> 04:34:04,398
MAYBE THAT'S A LIMITATION OF THE

6432
04:34:04,398 --> 04:34:04,632
FIELD.

6433
04:34:04,632 --> 04:34:08,636
I THINK WE NEED TO MOVE BEYOND

6434
04:34:08,636 --> 04:34:10,037
MICROHEMORRHAGE, THIS BEING SAID

6435
04:34:10,037 --> 04:34:15,609
AUTONOT THAT EASY TO DO.

6436
04:34:15,609 --> 04:34:17,511
AND THAT TAKES ME TO THE GAPS IN

6437
04:34:17,511 --> 04:34:28,022
TERMS OF MODEL TO INTERROGATE

6438
04:34:40,434 --> 04:34:41,769
MECHANISM OF ARIA, NOW MRI CAN

6439
04:34:41,769 --> 04:34:43,738
BE DONE IN ANIMAL MODELS, WE

6440
04:34:43,738 --> 04:34:45,406
NEED MAYBE TO REFINE THE MODELS

6441
04:34:45,406 --> 04:34:45,940
WOE USE.

6442
04:34:45,940 --> 04:34:50,878
WE TEND TO FOCUS ON MOUSE MODEL

6443
04:34:50,878 --> 04:34:55,883
AND MORE AND LARRY WILL WALKER

6444
04:34:55,883 --> 04:34:58,152
WILL TALK ABOUT THE NONHUMAN

6445
04:34:58,152 --> 04:35:00,121
PRIMATE MODEL, IS THAT FEASIBLE,

6446
04:35:00,121 --> 04:35:03,791
TOO EXPENSIVE, TOO RESTRICTIVE,

6447
04:35:03,791 --> 04:35:05,793
AND I THINK THE ONLY ANSWER TO

6448
04:35:05,793 --> 04:35:10,731
OUR QUESTION WILL BE COMING FROM

6449
04:35:10,731 --> 04:35:11,465
THE AUTOPSIES CASES EMPLOY WE

6450
04:35:11,465 --> 04:35:14,034
TALKED ABOUT THAT THIS MORNING.

6451
04:35:14,034 --> 04:35:17,271
RIGHT NOW IT'S FAIRLY LIMITED

6452
04:35:17,271 --> 04:35:19,673
AND AND THE FEW CASES WITH THE

6453
04:35:19,673 --> 04:35:20,875
RECENT THEOR PUTTICS, THE FEW

6454
04:35:20,875 --> 04:35:22,610
CASES THAT WERE PUBLISHED WERE

6455
04:35:22,610 --> 04:35:25,112
VERY SEVERE CASES, I WOULD SAY

6456
04:35:25,112 --> 04:35:26,914
SO THERE'S DEFINITELY A SPECTRUM

6457
04:35:26,914 --> 04:35:31,485
BETWEEN THESE CASES AND WHAT IS

6458
04:35:31,485 --> 04:35:32,787
HAPPENING IN THE MAIORITY OF THE

6459
04:35:32,787 --> 04:35:33,220
OTHER CASES.

6460
04:35:33,220 --> 04:35:34,488
THE LAST THING I WOULD LIKE TO

6461
04:35:34,488 --> 04:35:38,492
DO IS I WOULD LIKE TO SAY IS

6462
04:35:38,492 --> 04:35:49,003
THAT WE ALSO MOVE FROM--IN WE

6463
04:35:52,606 --> 04:35:54,675
WERE TALKING ABOUT THE CELLS.

6464
04:35:54,675 --> 04:35:57,278
THE FIELD HAS, VOLVED AND USES

6465
04:35:57,278 --> 04:36:01,348
NEW TECHNIQUES THAT ARE MORE

6466
04:36:01,348 --> 04:36:04,251
ACCURATE, MAYBE THAN 1 WAY USING

6467
04:36:04,251 --> 04:36:07,721
IT ANOTHER TIME AND THESE

6468
04:36:07,721 --> 04:36:10,724
TECHNIQUES ARE CHANGING VERY,

6469
04:36:10,724 --> 04:36:12,960
VERY QUICKLY, WHAT DONNA JUST

6470
04:36:12,960 --> 04:36:14,829
PRESENTED IT TERMS OF GENOMICS

6471
04:36:14,829 --> 04:36:16,797
IS SOMETHING THAT COULD BE

6472
04:36:16,797 --> 04:36:18,032
INFORMATIVE FOR THE FIELD AND

6473
04:36:18,032 --> 04:36:21,602
FINALLY TO CONCLUDE IN TERMS OF

6474
04:36:21,602 --> 04:36:25,105
SPECIFIC MECHANISM OF ARIA, I

6475
04:36:25,105 --> 04:36:26,574
WOULD LIKE TO, INSTEAD OF USING

6476
04:36:26,574 --> 04:36:31,111
THE TERM MECHANISM, ID LIKE TO

6477
04:36:31,111 --> 04:36:31,579
TALK ABOUT MECHANISTIC

6478
04:36:31,579 --> 04:36:33,314
HYPOTHESIS BECAUSE I THINK THERE

6479
04:36:33,314 --> 04:36:34,381
ARE FEW HYPOTHESIS THAT HAVE

6480
04:36:34,381 --> 04:36:39,253
BEEN AND THAT ARE STILL BEING

6481
04:36:39,253 --> 04:36:41,355
USED AND CURRENTLY WE TILL NEED

6482
04:36:41,355 --> 04:36:44,458
LIKE STRONG DIRECT EVIDENCE FOR

6483
04:36:44,458 --> 04:36:47,761
IMPLICATING 1 OF THESE--1 OR THE

6484
04:36:47,761 --> 04:36:49,129
OTHER MECHANISM AND I THINK

6485
04:36:49,129 --> 04:36:50,631
THOSE MECHANISM ARE NOT

6486
04:36:50,631 --> 04:36:56,136
EXCLUSIVE FROM EACH OTHER.

6487
04:36:56,136 --> 04:36:56,871
NTHANK YOU.

6488
04:36:56,871 --> 04:36:59,440
I WANT TO SEE WHAT YOU

6489
04:36:59,440 --> 04:37:00,508
THOUGHT--I HAD A FOLLOW UP

6490
04:37:00,508 --> 04:37:01,408
QUESTION THAT YOU ALREADY

6491
04:37:01,408 --> 04:37:04,011
ANSWERED FOR YOU BUT I WAS

6492
04:37:04,011 --> 04:37:05,379
CURIOUS WHAT YOU THOUGHT ABOUT

6493
04:37:05,379 --> 04:37:09,049
THE PRECLINICAL SIDE OF THIS AND

6494
04:37:09,049 --> 04:37:11,619
USE PRECLINICAL MODELS TO GET AT

6495
04:37:11,619 --> 04:37:12,820
MECHANISTIC THINGS AND LEARN

6496
04:37:12,820 --> 04:37:14,054
MORE ABOUT IT WITHOUT HAVING TO

6497
04:37:14,054 --> 04:37:17,925
GET OUR INFORMATION FROM THE

6498
04:37:17,925 --> 04:37:18,626
CLINICAL TRIALS.

6499
04:37:18,626 --> 04:37:20,361
>> SO I CAN AT LEAST--WE
ARE

6500
04:37:20,361 --> 04:37:22,563
GOING TO HEAR ABOUT THE

6501
04:37:22,563 --> 04:37:26,767
PRECLINICAL MODELS ON CAA THIS

6502
04:37:26,767 --> 04:37:27,868
AFTERNOON AND CERTAINLY WE HAVE

6503
04:37:27,868 --> 04:37:31,438
HEARD A LOT ABOUT THAT TODAY,

6504
04:37:31,438 --> 04:37:33,240
TOO, BUT YES, SOME OF THE

6505
04:37:33,240 --> 04:37:35,476
QUESTIONS THAT I HAVE CAN

6506
04:37:35,476 --> 04:37:39,246
CERTAINLY BE ANSWERED IN THE

6507
04:37:39,246 --> 04:37:40,314
PRECLENICAL MODELS WITH'MUNE O

6508
04:37:40,314 --> 04:37:43,984
THERAPY, YOU SET IT UP EVEN AS A

6509
04:37:43,984 --> 04:37:45,252
LONGITUDINAL TRIAL AND YOU COULD

6510
04:37:45,252 --> 04:37:46,120
LOOK AT CLEARANCE FOR EXAMPLE,

6511
04:37:46,120 --> 04:37:49,590
YOU COULD LOOK AT THE ABILITY TO

6512
04:37:49,590 --> 04:37:51,792
CLEA FOR FSM WHEN YOU TART THE

6513
04:37:51,792 --> 04:37:52,960
THERAPY VERY LATE WHEN THE

6514
04:37:52,960 --> 04:37:57,531
ANIMALS ARE AGED AND WE KNOW

6515
04:37:57,531 --> 04:37:59,166
THAT LIMBS ARE DETERIORATING

6516
04:37:59,166 --> 04:38:01,735
WITH AGE, SO WE COULD SEE HOW

6517
04:38:01,735 --> 04:38:04,738
THAT IMPACTS AND YOU COULD ALSO

6518
04:38:04,738 --> 04:38:06,373
MAYBE BOOST THE SYSTEM, YOU KNOW

6519
04:38:06,373 --> 04:38:10,711
A GAIN OF FUNCTION MODEL WITH A

6520
04:38:10,711 --> 04:38:13,514
VEG F C OR OTHER THINGS IF YOU

6521
04:38:13,514 --> 04:38:15,916
THINK IT'S ADHERENCE PROBLEMS

6522
04:38:15,916 --> 04:38:17,885
THAT'S CAUSING THE BASAL GENIC

6523
04:38:17,885 --> 04:38:21,422
ADEMA IF WE THINK IT'S VASE O

6524
04:38:21,422 --> 04:38:22,790
GENIC ADEMA CONTAINED IN ARIA

6525
04:38:22,790 --> 04:38:25,793
AND WE ALSO HAVE MIXED MODELS

6526
04:38:25,793 --> 04:38:27,127
NOW WITH SEVERAL SMALL VESSELS,

6527
04:38:27,127 --> 04:38:29,530
AS THIS IS MIX WIDE AD WE HAVE

6528
04:38:29,530 --> 04:38:32,766
ALL THESE DIFFERENT MODELS, WE

6529
04:38:32,766 --> 04:38:35,235
CAN BACK CROSS WITH CHRONIC

6530
04:38:35,235 --> 04:38:36,637
HYPER TENSIVE TRAIN SO WE

6531
04:38:36,637 --> 04:38:38,872
HAVE--WE CAN TART TO GET THE

6532
04:38:38,872 --> 04:38:40,874
CO-MORBIDITY IN THERE, AND WE

6533
04:38:40,874 --> 04:38:43,877
CAN ASK, WE CAN ASK THE

6534
04:38:43,877 --> 04:38:45,512
MECHANISTIC QUESTIONS VERY

6535
04:38:45,512 --> 04:38:46,714
ACCURATELY.

6536
04:38:46,714 --> 04:38:47,681
OBVIOUSLY IT'S IN THE RAT OR

6537
04:38:47,681 --> 04:38:50,150
MOUSE BUT WE HAVE TO LEARN A LOT

6538
04:38:50,150 --> 04:38:57,958
FROM THESE MODELS ALREADY.

6539
04:38:57,958 --> 04:38:59,526
>> WE'VE HEARD A LOT ABOUT
THE

6540
04:38:59,526 --> 04:39:00,794
BLOOD BRAIN BARRIER AND THERE'S

6541
04:39:00,794 --> 04:39:03,430
A LOT OF NAIVE THINKING GOING ON

6542
04:39:03,430 --> 04:39:10,537
IN TERMS OF IT'S OPEN OR IT'S

6543
04:39:10,537 --> 04:39:11,772
CLOSED THAT'S NOT TRUE AND WE

6544
04:39:11,772 --> 04:39:12,973
HAVE EXPERS HERE AND I'VE BEEN

6545
04:39:12,973 --> 04:39:14,375
THINKING ABOUT THAT AND WE'VE

6546
04:39:14,375 --> 04:39:17,378
USED, SO I WAS LIKE DR. CLIFFORD

6547
04:39:17,378 --> 04:39:19,346
I CAME AT THIS FROM THE MS POINT

6548
04:39:19,346 --> 04:39:21,048
OF VIEW AND WE DID A LOT OF

6549
04:39:21,048 --> 04:39:24,952
SPINAL FLUID AND WE LOOKED AT

6550
04:39:24,952 --> 04:39:26,687
WHAT WE THOUGHT WAS THE BLOOD

6551
04:39:26,687 --> 04:39:28,956
BRAIN BARRIER WHICH WAS THE

6552
04:39:28,956 --> 04:39:35,396
ALBUT MIN INDEX AND THEN YOU

6553
04:39:35,396 --> 04:39:37,364
MOVED INTO MRI AND CONTRAST AND

6554
04:39:37,364 --> 04:39:40,668
WE'VE DONE HUNDREDS OF THOSE AND

6555
04:39:40,668 --> 04:39:42,202
SO FINALLY, I HAD A GROUP OF

6556
04:39:42,202 --> 04:39:43,737
PATIENTS THAT HAD BOTH THE ALBUT

6557
04:39:43,737 --> 04:39:47,041
MIN INDEX AND THE DYNAMIC

6558
04:39:47,041 --> 04:39:49,343
CONTRAST MRI AND I SAID WHAT'S

6559
04:39:49,343 --> 04:39:51,412
GOING ON, ARE THEY SIMILAR, SO

6560
04:39:51,412 --> 04:39:55,049
IT TURNS OUT THEY'RE MEASURING

6561
04:39:55,049 --> 04:40:01,355
VERY DIFFERENT THINGS.

6562
04:40:01,355 --> 04:40:02,022
UNFORTUNATELY, FROM THE CORE

6563
04:40:02,022 --> 04:40:06,193
VIEW WE HAD THE BIOMARKER PANEL

6564
04:40:06,193 --> 04:40:08,929
WHICH IS CYTOKINES ANGIOGENIC

6565
04:40:08,929 --> 04:40:16,103
FACTORS, SO WE DID A CORRELATION

6566
04:40:16,103 --> 04:40:19,306
WITH BOTH THE DC MRI AND THE

6567
04:40:19,306 --> 04:40:21,108
ALBUT MIN INDEX SO IT TURNS OUT

6568
04:40:21,108 --> 04:40:23,143
AS YOU WILL EXPECT THE ALBUT MIN

6569
04:40:23,143 --> 04:40:25,045
INDEX IS ACTUALLY MEASURING THE

6570
04:40:25,045 --> 04:40:27,681
OPENING OF THE BLOOD BRAIN

6571
04:40:27,681 --> 04:40:30,918
BARRIER TO INFLAMMATION. 

6572
04:40:30,918 --> 04:40:34,755
IT SHOWS UP THE PROTEIN ACES,

6573
04:40:34,755 --> 04:40:37,591
THE CYTOKINES, CERTAIN

6574
04:40:37,591 --> 04:40:39,793
CYTOKINES, AND THE ANGIOGENIC

6575
04:40:39,793 --> 04:40:40,027
FACTORS.

6576
04:40:40,027 --> 04:40:47,935
SO WE KNOW THAT'S A GOOD MARKER

6577
04:40:47,935 --> 04:40:50,003
OF INFLAMMATION BUT THE DCI

6578
04:40:50,003 --> 04:40:52,272
COORDINATE WIDE THE WATER

6579
04:40:52,272 --> 04:40:57,277
MOVEMENT MEASURED BY DIFFUSION

6580
04:40:57,277 --> 04:40:58,445
TENTS OR IMAGING.

6581
04:40:58,445 --> 04:40:59,646
O IT'S LIKE 2 DEFINITE

6582
04:40:59,646 --> 04:41:04,785
MECHANISMS TO GET THROUGH THE

6583
04:41:04,785 --> 04:41:05,786
BLOOD-BRAIN BARRIER.

6584
04:41:05,786 --> 04:41:08,555
I THINK, IN THE MS WORLD I NEVER

6585
04:41:08,555 --> 04:41:11,191
UNDERSTOOD WHY WE WOULD HAVE A

6586
04:41:11,191 --> 04:41:13,360
WIDE OPEN BLOOD BRAIN BARRIER

6587
04:41:13,360 --> 04:41:16,096
AND NO ALBUT MIN IN THE CSF, IT

6588
04:41:16,096 --> 04:41:16,463
WAS A PARADOX.

6589
04:41:16,463 --> 04:41:18,065
BUT I THINK IF YOU GO BACK CAN

6590
04:41:18,065 --> 04:41:22,803
LOOK AT SOME EARLY HYPER TENSIVE

6591
04:41:22,803 --> 04:41:27,307
PAPERS, WHAT THEY SHOWED WAS

6592
04:41:27,307 --> 04:41:28,842
THERE'S PINO SIGNIFYITOSEIS,

6593
04:41:28,842 --> 04:41:29,977
MICROPINO SIGNIFYITOSEIS AND IF

6594
04:41:29,977 --> 04:41:31,478
YOU THINK ABOUT IT WHEN YOU

6595
04:41:31,478 --> 04:41:35,983
BREAK DOWN THE EXTRA CELLULAR

6596
04:41:35,983 --> 04:41:37,584
MATRIX AND OPEN--NOT NECESSARILY

6597
04:41:37,584 --> 04:41:39,253
OPEN THE TIGHT JUNCTIONS BUT

6598
04:41:39,253 --> 04:41:49,763
JUST REMOVE THE LAYER OF EXTRA

6599
04:42:12,886 --> 04:42:14,087
CELLULAR SO THAT'S INVESTMENT

6600
04:42:14,087 --> 04:42:15,722
MARKER SO PEOPLE ARE NOT, SO

6601
04:42:15,722 --> 04:42:26,200
PEOPLE ARE NOT INTERESTED IN

6602
04:42:38,245 --> 04:42:48,689
LUMBAR PUNCTURES AND ALBUT MIN

6603
04:43:13,146 --> 04:43:23,624
IS---OPEN CLOSED WE NEED A MORE

6604
04:43:26,960 --> 04:43:27,194
PRECISE.

6605
04:43:27,194 --> 04:43:30,430
NTHANK YOU SO MUCH FOR BRINGING

6606
04:43:30,430 --> 04:43:36,470
THIS UP, AND THE POINT IS,

6607
04:43:36,470 --> 04:43:38,238
MECHANISMS THROUGH THE BLOOD

6608
04:43:38,238 --> 04:43:41,575
BRAIN BARRIER AND THE ALBUT MIN

6609
04:43:41,575 --> 04:43:49,349
YOU MENTIONED IS TRANSPORTED

6610
04:43:49,349 --> 04:43:51,251
THROUGH TRANSPORT AND IN MS,

6611
04:43:51,251 --> 04:43:55,555
CSF, WHEN WE LOOK AT PROEN TOOS,

6612
04:43:55,555 --> 04:43:59,092
TRAPEZIUS PORTED ON THE

6613
04:43:59,092 --> 04:44:03,730
TRANSPLANT, WITH THE MRI GADDA

6614
04:44:03,730 --> 04:44:05,165
LYNNIUM SO PERHAPS A SUGGESTION

6615
04:44:05,165 --> 04:44:08,068
WOULD BE TO MAYBE EXPAND THE

6616
04:44:08,068 --> 04:44:10,103
BLOOD PROTEINS THAT ARE USED TO

6617
04:44:10,103 --> 04:44:13,740
TEST AS POTENTIAL BIOMARKERS AND

6618
04:44:13,740 --> 04:44:24,284
BIASED PROTEOMEEC STUDIES IN THE

6619
04:44:25,485 --> 04:44:28,188
PSYCHIATRIC DISORDERS AND AND

6620
04:44:28,188 --> 04:44:29,756
DIFFERENT CORLAYINGS KEPENDING,

6621
04:44:29,756 --> 04:44:36,430
AND FIEB RIB O GEN.

6622
04:44:36,430 --> 04:44:38,098
IT WILL NOT BE ENOUGH TO SOLVE

6623
04:44:38,098 --> 04:44:44,705
THE PROBLEM WITH LOOKING INTO A

6624
04:44:44,705 --> 04:44:46,239
SINGLE BLOOD.

6625
04:44:46,239 --> 04:44:46,540
NTHANK YOU.

6626
04:44:46,540 --> 04:44:47,107
NTHANK YOU.

6627
04:44:47,107 --> 04:44:57,617
NANY OTHER QUESTIONS FROM THE

6628
04:45:22,109 --> 04:45:22,342
AUDIENCE.

6629
04:45:22,342 --> 04:45:23,543
>> REALLY IS LEACHING TO
THE

6630
04:45:23,543 --> 04:45:25,212
BLOOD VESSEL THAT CAN COME OUT

6631
04:45:25,212 --> 04:45:27,447
AND HELP US UNDERSTAND IT, YOU

6632
04:45:27,447 --> 04:45:31,084
LOOK AT HOW TO WHETHER THERE'S

6633
04:45:31,084 --> 04:45:34,054
GADA LYNNIUM OR MEASURE BLOOD

6634
04:45:34,054 --> 04:45:34,654
BRAIN BARRIER VALENTINED IDITY

6635
04:45:34,654 --> 04:45:38,992
BUT FOR THE CASE OF EDEMA AREA,

6636
04:45:38,992 --> 04:45:40,727
I THINK WHEN I WAS TALKING TO

6637
04:45:40,727 --> 04:45:41,828
PEOPLE DURING LUNCH, IT WOULD BE

6638
04:45:41,828 --> 04:45:44,364
USEFUL TO UNDERSTAND THIS, WHERE

6639
04:45:44,364 --> 04:45:45,565
DID THIS WATER COME FROM AND

6640
04:45:45,565 --> 04:45:48,001
WHERE DID THEY GO IN DID THEY

6641
04:45:48,001 --> 04:45:49,870
ACCUMULATE IN THE SPACE, HOW

6642
04:45:49,870 --> 04:45:52,239
MUCH IS THAT ACCUMULATED, AND

6643
04:45:52,239 --> 04:45:53,273
CONCENTRATION IN THE CASE

6644
04:45:53,273 --> 04:45:54,708
COMPARED TO A NORMAL CASE

6645
04:45:54,708 --> 04:45:55,876
BECAUSE FOR INITANCE RIGHT NOW

6646
04:45:55,876 --> 04:45:57,878
WE ARE USING FOR INITANCE, THE

6647
04:45:57,878 --> 04:46:01,448
IMAGE TO DETECT HYPER TENSITY IN

6648
04:46:01,448 --> 04:46:03,617
AN AREA EDEMA CASE BUT REALLY

6649
04:46:03,617 --> 04:46:05,685
T-2 IS VERY SENSITIVE TO ALL THE

6650
04:46:05,685 --> 04:46:07,521
CONTENTS SO IF WE NOT HAVE IN

6651
04:46:07,521 --> 04:46:09,456
SORT OF BASIC BIOLOGICAL

6652
04:46:09,456 --> 04:46:10,390
UNDERSTANDING BY THE WATER

6653
04:46:10,390 --> 04:46:12,893
CONTENT IN THE AREA, THAT WILL

6654
04:46:12,893 --> 04:46:15,495
HELP PEOPLE TO DESIGN BETTER AND

6655
04:46:15,495 --> 04:46:18,231
MY PROTOCOL SEQUENCE TO DETECT

6656
04:46:18,231 --> 04:46:21,268
MAYBE QUANTITY OF IT WILL BE

6657
04:46:21,268 --> 04:46:22,436
BETTER WAY TO QUANTIFY THE

6658
04:46:22,436 --> 04:46:25,605
DETECTION, SO I THINK SOME OF

6659
04:46:25,605 --> 04:46:27,307
OUR IN VIVO IMAGING TECHNOLOGY

6660
04:46:27,307 --> 04:46:29,643
WOULD BENEFIT A LOT FROM BETTER

6661
04:46:29,643 --> 04:46:32,913
UNDERSTANDING OF THE MOLECULAR

6662
04:46:32,913 --> 04:46:35,816
AND BIOLOGICAL MECHANISM OF

6663
04:46:35,816 --> 04:46:37,250
THESE ARIA HEMORRHAGE CASES.

6664
04:46:37,250 --> 04:46:41,755
NI JUST WANT TO ADD TO THAT I

6665
04:46:41,755 --> 04:46:43,790
TOTALLY AGREE WITH YOU BUT IN

6666
04:46:43,790 --> 04:46:45,992
TERMS OF THE PRECLINICAL ANIMAL

6667
04:46:45,992 --> 04:46:47,861
MODELS 1 BIG THING, PROBLEM WE

6668
04:46:47,861 --> 04:46:49,763
HAVE WITH SMALL VESSEL DISEASE,

6669
04:46:49,763 --> 04:46:51,465
ANIMAL MODELS AT LEAST IN THE

6670
04:46:51,465 --> 04:46:56,770
RODENT IS THAT WE--WE RARELY

6671
04:46:56,770 --> 04:46:58,038
SEE, WHITE MATTER HYPER

6672
04:46:58,038 --> 04:46:58,638
INTENSITIES FOR EXAMPLE.

6673
04:46:58,638 --> 04:47:00,006
SO IT'S NOT SOMETHING THAT

6674
04:47:00,006 --> 04:47:01,341
NECESSARILY WILL BE ABLE, WE MAY

6675
04:47:01,341 --> 04:47:03,610
NOT BE ABLE TO TEST THAT TYPE OF

6676
04:47:03,610 --> 04:47:05,712
THING AT LEAST FROM THE

6677
04:47:05,712 --> 04:47:08,415
PRECLINICAL ARENA AND WE HAVE

6678
04:47:08,415 --> 04:47:09,816
NEVER UNDERSTOOD WHY, IT'S MAYBE

6679
04:47:09,816 --> 04:47:11,518
BECAUSE THEY HAVE SO LITTLE

6680
04:47:11,518 --> 04:47:13,553
WHITE MATTER, IT COULD BE THAT

6681
04:47:13,553 --> 04:47:15,655
THAT'S WHY SIMPLY WE DON'T SEE

6682
04:47:15,655 --> 04:47:16,923
IT EVEN DILATED IN THE SPACE IS

6683
04:47:16,923 --> 04:47:19,192
NOT SOMETHING THAT WE SEE

6684
04:47:19,192 --> 04:47:21,094
PRECLINICAL, SO IF WE WANT TO

6685
04:47:21,094 --> 04:47:23,897
TART THE MECHANISMS OF LET'S SAY

6686
04:47:23,897 --> 04:47:24,731
ARIA AND IMMUNOTHERAPY WE HAVE

6687
04:47:24,731 --> 04:47:35,208
TO LOOK AT SOME OTHER METRIC

6688
04:47:35,609 --> 04:47:37,344
ANDS THE--

6689
04:47:37,344 --> 04:47:38,378
>> THAT'S INTERESTING FOR
MICE

6690
04:47:38,378 --> 04:47:40,847
AND RATS, IT'S HARD TO DETECT,

6691
04:47:40,847 --> 04:47:42,616
THE PRIMATE MODEL WILL BE BETTER

6692
04:47:42,616 --> 04:47:46,086
MODEL FOR THIS CASE.

6693
04:47:46,086 --> 04:47:48,288
>> WE'VE BEEN USING THIS

6694
04:47:48,288 --> 04:47:49,055
SPONTAKENIOUSLY HYPER TENSIVE

6695
04:47:49,055 --> 04:47:49,422
RAT.

6696
04:47:49,422 --> 04:47:52,792
IF YOU FEED IT A MCDONALD'S

6697
04:47:52,792 --> 04:47:56,596
DIET, LOW PROTEIN, HIGH FAT, IT

6698
04:47:56,596 --> 04:47:58,598
DOESN'T TAKE A YEAR AND A HALF

6699
04:47:58,598 --> 04:48:01,868
TO GET TO AGE THE BRAIN, CAN YOU

6700
04:48:01,868 --> 04:48:11,311
AGE IT IN YOU KNOW 6 WEEKS AND

6701
04:48:11,311 --> 04:48:14,080
WHEN YOU DO THAT YOU DO SEE E

6702
04:48:14,080 --> 04:48:17,150
DEMA IN THE MATTER AND THAT'S

6703
04:48:17,150 --> 04:48:19,553
LOOKING AT A 4 TESLA OR 7, YOU

6704
04:48:19,553 --> 04:48:21,521
BEING GET BETTER ABOUT YOU CAN

6705
04:48:21,521 --> 04:48:25,892
YOU DETECT FLUID MOVEMENT IN

6706
04:48:25,892 --> 04:48:27,327
THE--YOU CAN'T DO IT IN THE

6707
04:48:27,327 --> 04:48:29,229
MOUSE BECAUSE THE MOUSE HAS SUCH

6708
04:48:29,229 --> 04:48:31,231
A TINY AMOUNT OF WHITE MATTER,

6709
04:48:31,231 --> 04:48:33,366
BUT THE RAT HAS SUFFICIENT WHITE

6710
04:48:33,366 --> 04:48:36,269
MATTER TO SEE THAT AND WE'VE

6711
04:48:36,269 --> 04:48:40,140
ACTUALLY, HONE --SHOWN THAT WE

6712
04:48:40,140 --> 04:48:42,609
COULD TREAT THAT WITH MENOPSYCHE

6713
04:48:42,609 --> 04:48:43,877
LYNN AND REDUCE EDEMA AND THERE

6714
04:48:43,877 --> 04:48:53,153
WILL BE OTHER DRUGS, TOO SO I

6715
04:48:53,153 --> 04:48:54,354
WOULDN'T ELIMINATE THAT, SO

6716
04:48:54,354 --> 04:48:56,556
AUTOSHORT LOAD AND YOU CAN GET

6717
04:48:56,556 --> 04:48:58,058
HUGEARS MOUNT OF FLUID

6718
04:48:58,058 --> 04:48:59,159
ACCUMULATING IN THESE BRAINS BUT

6719
04:48:59,159 --> 04:49:01,094
WE HAVE BEEN TRYING TO WORK WITH

6720
04:49:01,094 --> 04:49:02,629
ANIMAL MODELS THAT MIMIC THE

6721
04:49:02,629 --> 04:49:04,497
CLINICAL ARENA NOT THAT PEOPLE

6722
04:49:04,497 --> 04:49:07,601
DON'T EAT HIGH FAT, HIGH SALT

6723
04:49:07,601 --> 04:49:10,937
DIET BUT IN GENERAL TO GET THEM

6724
04:49:10,937 --> 04:49:12,105
TO SPONTANEOUSLY DEVELOP THESE

6725
04:49:12,105 --> 04:49:16,076
SMALLER AREAS OF HYPER

6726
04:49:16,076 --> 04:49:16,910
SENSITIVITY AND VASCULAR SPACES

6727
04:49:16,910 --> 04:49:21,881
AND WE DON'T SEE IT LIKE USING,

6728
04:49:21,881 --> 04:49:23,350
YOU KNOW NORMAL AGING SO I'M

6729
04:49:23,350 --> 04:49:25,252
JUST SAYING YOU NEED THAT TYPE

6730
04:49:25,252 --> 04:49:25,919
OF INTERVENTION THEN, OF COURSE

6731
04:49:25,919 --> 04:49:29,055
YOU CAN LOOK AT THE PATHOLOGY

6732
04:49:29,055 --> 04:49:30,957
ALSO MAYBE NOT SO CLINICALLY

6733
04:49:30,957 --> 04:49:31,224
RELEVANT.

6734
04:49:31,224 --> 04:49:33,526
I DO NOT KNOW.

6735
04:49:33,526 --> 04:49:36,263
NETWORK I WILL JUST MAKE 1 LAST

6736
04:49:36,263 --> 04:49:36,496
COMMENT.

6737
04:49:36,496 --> 04:49:39,499
SO WE HEARD A GOOD EXAMPLE THIS

6738
04:49:39,499 --> 04:49:42,235
MORNING WITH DR. [INDISCERNIBLE]

6739
04:49:42,235 --> 04:49:44,671
ABOUT THE USE OF SPECIFIC MOUSE

6740
04:49:44,671 --> 04:49:47,207
MODEL THAT CAN INTERROGATE A

6741
04:49:47,207 --> 04:49:48,975
SPECIFIC MECHANISTIC QUESTION

6742
04:49:48,975 --> 04:49:50,610
AND IT'S JUST THE COMBINATION OF

6743
04:49:50,610 --> 04:49:54,914
SEVERAL MODEL THAT WE ARK LOW US

6744
04:49:54,914 --> 04:49:56,683
TO MAKE PROGRESS IN THE

6745
04:49:56,683 --> 04:49:57,284
UNDERSTANDING.

6746
04:49:57,284 --> 04:49:59,352
IT'S NOT REALISTIC TO EXPECT

6747
04:49:59,352 --> 04:50:05,825
THAT THE SINGLE MODEL WILL

6748
04:50:05,825 --> 04:50:07,327
RECAPITULATE EVERYTHING.

6749
04:50:07,327 --> 04:50:08,161
THAT IS TRUE.

6750
04:50:08,161 --> 04:50:15,268
>> ALL RIGHT, ANYMORE
QUESTIONS.

6751
04:50:15,268 --> 04:50:17,270
ANY OTHER TOPICS YOU WANT TO

6752
04:50:17,270 --> 04:50:18,305
COVER IN ALL RIGHT.

6753
04:50:18,305 --> 04:50:21,924
WELL, THANK YOU SO MUCH.

6754
04:50:21,924 --> 04:50:25,495
THROUGH THE NEW SESSION. 

6755
04:50:25,495 --> 04:50:30,032
WE WILL TART WITH DR. WILLIAM

6756
04:50:30,032 --> 04:50:32,034
VAN NOSTRAND FROM THE UNIVERSITY

6757
04:50:32,034 --> 04:50:33,002
OF REFRESH YOUR RECOLLECTION

6758
04:50:33,002 --> 04:50:36,272
HEART ATTACK ODE ISLAND, HE IS A

6759
04:50:36,272 --> 04:50:37,507
GREAT PROFESSOR OF IMMUNOLOGY

6760
04:50:37,507 --> 04:50:42,979
AND CORE EXECUTIVE DIRECTOR OF

6761
04:50:42,979 --> 04:50:43,379
NEUROCONSCIENCES.

6762
04:50:43,379 --> 04:50:44,747
HE'S BEEN DEVELOPING MODELS

6763
04:50:44,747 --> 04:50:47,583
INCLUDING THE 1 I TALKED ABOUT

6764
04:50:47,583 --> 04:50:50,119
IN THE MOUSE, AND IT'S ALSO IN

6765
04:50:50,119 --> 04:50:51,754
RAT MODELS SO WHENEVER HE SHOWS

6766
04:50:51,754 --> 04:51:02,064
UP, WE WILL START.

6767
04:51:02,331 --> 04:51:04,100
NETWORK GOOD AFTERNOON, I WOULD

6768
04:51:04,100 --> 04:51:07,069
LIKE TO THANK NINDS FOR INVITING

6769
04:51:07,069 --> 04:51:09,005
ME TO SPEAK TODAY AND I

6770
04:51:09,005 --> 04:51:10,439
APOLOGIZE FOR NOT BEING THERE IN

6771
04:51:10,439 --> 04:51:11,007
PERSON.

6772
04:51:11,007 --> 04:51:17,313
I WAS ASKED TO SUMMARIZE ANIMAL

6773
04:51:17,313 --> 04:51:20,583
MODELS FOR INVESTIGATING CAA AND

6774
04:51:20,583 --> 04:51:21,751
ARIA.

6775
04:51:21,751 --> 04:51:22,618
THIS IS MY DISCLOSURES.

6776
04:51:22,618 --> 04:51:22,985
NEXT SLIDE.

6777
04:51:22,985 --> 04:51:25,521
SO THERE ARE A NUMBER OF SPECIES

6778
04:51:25,521 --> 04:51:27,189
THAT NATURALLY DEVELOP CAA AS

6779
04:51:27,189 --> 04:51:28,190
THEY AGE.

6780
04:51:28,190 --> 04:51:31,494
THIS INCLUDES BEARS, CATS, DOGS

6781
04:51:31,494 --> 04:51:34,196
AND NONHUMAN PRIME'SS IN

6782
04:51:34,196 --> 04:51:34,730
PARTICULAR, MONKEYS.

6783
04:51:34,730 --> 04:51:39,302
AS WE HEARD THROUGH THE PREVIOUS

6784
04:51:39,302 --> 04:51:41,537
PANEL DISCUSSION, THERE ARE

6785
04:51:41,537 --> 04:51:44,073
MODELS TO STUDY CAA, FIRST IT

6786
04:51:44,073 --> 04:51:46,943
COULD BE ETHICAL ISSUES, THERE

6787
04:51:46,943 --> 04:51:48,911
BEING BE EXPENSES AND ALSO THE

6788
04:51:48,911 --> 04:51:51,547
FACT THAT MANY INVESTIGATORS

6789
04:51:51,547 --> 04:51:53,282
DON'T HAVE FACILITIES THAT CAN

6790
04:51:53,282 --> 04:51:55,084
ACTUALLY MAINTAIN LARGE COHORTS

6791
04:51:55,084 --> 04:51:57,853
OF ANIMALS LIKE THIS STUDY

6792
04:51:57,853 --> 04:51:59,689
EMPLOY SO ALSO, THE OTHER

6793
04:51:59,689 --> 04:52:01,157
IMPORTANT POINT OF THIS AS MOST

6794
04:52:01,157 --> 04:52:02,992
OF THESE SPECIES TAKE A DECADE

6795
04:52:02,992 --> 04:52:04,894
FOR CAA TO EMERGE AND SOME CASE

6796
04:52:04,894 --> 04:52:06,128
MULTIPLE DECADES AND WE WILL

6797
04:52:06,128 --> 04:52:09,899
HEAR MORE ABOUT THE SQUIRREL

6798
04:52:09,899 --> 04:52:14,070
MONKEY FROM LARY WALKER IN THE

6799
04:52:14,070 --> 04:52:14,470
NEXT PRESENTATION.

6800
04:52:14,470 --> 04:52:15,638
NEXT SLIDE.

6801
04:52:15,638 --> 04:52:17,640
SO FOR THESENS MOST ACTIONS THAT

6802
04:52:17,640 --> 04:52:20,176
OCCURRED FOR CAA INVOF THE USE

6803
04:52:20,176 --> 04:52:21,510
FOR TRANSGENIC MICE.

6804
04:52:21,510 --> 04:52:24,080
SO HERE ARE THE FEATURES OF THE

6805
04:52:24,080 --> 04:52:25,147
TYPICAL TRANSGENIC MOUSE MODELS

6806
04:52:25,147 --> 04:52:28,017
THAT ARE USED IN THIS CASE,

6807
04:52:28,017 --> 04:52:31,954
THESE ARE APP MOUSE MODELS THAT

6808
04:52:31,954 --> 04:52:36,692
HARBOR A NUMBER OF FAD

6809
04:52:36,692 --> 04:52:39,228
MUTATIONS, SO THEY HAVE DERIVED

6810
04:52:39,228 --> 04:52:41,597
APP THEY HARBOR 1 OR MORE IN THE

6811
04:52:41,597 --> 04:52:42,898
TEAM, AND SOME OF THE COMMON

6812
04:52:42,898 --> 04:52:44,700
MODELS THAT ARE LISTED BELOW AND

6813
04:52:44,700 --> 04:52:48,971
WE HEARD FROM DONNA WILCOCK

6814
04:52:48,971 --> 04:52:53,409
ABOUT THE MOUSE MODEL, THE

6815
04:52:53,409 --> 04:52:55,978
PD-APP AND SOME MODELS

6816
04:52:55,978 --> 04:52:58,481
ADDITIONALLY CONTAIN FAD MUSEUM

6817
04:52:58,481 --> 04:52:59,548
TAIGS AND PRESEN ILLEGALSEN

6818
04:52:59,548 --> 04:53:02,385
ILLEGALSIN PROTEINS AND THESE

6819
04:53:02,385 --> 04:53:06,088
INCLUDE 5 XFAD, AND APP PS1 AND

6820
04:53:06,088 --> 04:53:08,424
THROORKS X TISSUING G THAT

6821
04:53:08,424 --> 04:53:09,558
EXPRESS MUTANT TAU.

6822
04:53:09,558 --> 04:53:13,162
SO THESE OF THESE DEVELOP

6823
04:53:13,162 --> 04:53:15,865
SECONDAR TOW ABUNDANT

6824
04:53:15,865 --> 04:53:16,999
PARENCHYMAL PLAQUES.

6825
04:53:16,999 --> 04:53:17,667
NEXT SLIDE.

6826
04:53:17,667 --> 04:53:20,870
SO HERE ARE 2 MODELS WE HEARD

6827
04:53:20,870 --> 04:53:23,439
EARLIER TO THE 576, AND THE

6828
04:53:23,439 --> 04:53:25,408
MODELS BOTH OF THESE MODELS

6829
04:53:25,408 --> 04:53:31,847
OVEREXPRESS IN THE NEUROWNALLY

6830
04:53:31,847 --> 04:53:33,182
DERIVED MUTANT APP, THIS IS THE

6831
04:53:33,182 --> 04:53:35,184
COMPARISON OF THE PATHOLOGY THAT

6832
04:53:35,184 --> 04:53:36,619
ACCUMULATES IN THESE MODELS AS

6833
04:53:36,619 --> 04:53:38,487
THAT'S AGE, SO GANNA YOU CAN SEE

6834
04:53:38,487 --> 04:53:41,357
AS MICE GET OLDER AND MORE AND

6835
04:53:41,357 --> 04:53:42,158
MORE PLAQUES BUSINESS AND THE

6836
04:53:42,158 --> 04:53:43,859
CASE OF THE MICE, YOU SEE THE

6837
04:53:43,859 --> 04:53:45,628
PLAQUES TEND TO BE LARGER AND

6838
04:53:45,628 --> 04:53:52,868
MORE EXTENSIVE PAN EVEN THE

6839
04:53:52,868 --> 04:53:53,202
TG22576 MICE.

6840
04:53:53,202 --> 04:53:53,502
NEXT SLIDE.

6841
04:53:53,502 --> 04:54:00,142
SO IN ADDITION TO THE SLIDE,

6842
04:54:00,142 --> 04:54:03,646
BOTH OF THESE HAVE AMOUNTS FROM

6843
04:54:03,646 --> 04:54:04,947
TG2576 AS THEY AGE BUT

6844
04:54:04,947 --> 04:54:06,949
PROGRESSION YOU CAN SEE THE

6845
04:54:06,949 --> 04:54:10,419
INCREASE OF CAA AND THE BUY MICE

6846
04:54:10,419 --> 04:54:14,090
AND FROM THE ORIGINAL STUDY FROM

6847
04:54:14,090 --> 04:54:16,959
THE ALHEWN ET ALL, AND THEY SHOW

6848
04:54:16,959 --> 04:54:20,496
PATHOLOGY AND SIGNIFICANT CAA.

6849
04:54:20,496 --> 04:54:22,465
THEY HAD THE NEXT SLIDE, PLEASE.

6850
04:54:22,465 --> 04:54:24,266
SO AS WAS MENTIONED EARLIER, I

6851
04:54:24,266 --> 04:54:26,869
MEAN SOME OF THE ORIGINAL

6852
04:54:26,869 --> 04:54:28,304
IMMUNIZATION TODAYS IN THESE

6853
04:54:28,304 --> 04:54:29,939
MOUSE MODELS ACTUALLY OCCURRED

6854
04:54:29,939 --> 04:54:31,974
OVER 20 CAREERS AGO AND IN THE

6855
04:54:31,974 --> 04:54:34,110
TOP PANELS THEY HEARD THE PURDYS

6856
04:54:34,110 --> 04:54:35,211
PUBLISHED IN SCIENCE AND AGAIN

6857
04:54:35,211 --> 04:54:38,781
IN IN STUDY, THEY PERFORMED

6858
04:54:38,781 --> 04:54:40,483
PASSIVE IMMUNOTHERAPY ON APP 23

6859
04:54:40,483 --> 04:54:42,017
MICE USING AN END TERMINAL

6860
04:54:42,017 --> 04:54:43,586
ANTIBODY TO A BETA AND WHAT THEY

6861
04:54:43,586 --> 04:54:45,588
REPORTED IN THE STUDY IS THAT

6862
04:54:45,588 --> 04:54:50,493
THIS LED TO AN INCREASE IN

6863
04:54:50,493 --> 04:54:51,026
MICROHEMORRHAGES IN THESE

6864
04:54:51,026 --> 04:54:51,260
ANIMALS.

6865
04:54:51,260 --> 04:54:52,762
NOW IN CONTRAST A MORE RECENT

6866
04:54:52,762 --> 04:54:53,996
TODAY USING THE SAME MOUSE

6867
04:54:53,996 --> 04:54:57,299
MODEL, CAN A PASSIVE

6868
04:54:57,299 --> 04:54:58,167
IMMUNIZATION STUDY AND THEY

6869
04:54:58,167 --> 04:55:02,872
FOUND IN THIS STUDY IS THERE

6870
04:55:02,872 --> 04:55:04,807
WERE CLEAR PARENCHYMAL AMYLOID

6871
04:55:04,807 --> 04:55:06,375
BUT THEY FOUND NO CHANGE IN THE

6872
04:55:06,375 --> 04:55:08,244
LOAD USING THIS MODEL THAT THEY

6873
04:55:08,244 --> 04:55:08,644
HAD.

6874
04:55:08,644 --> 04:55:12,481
THEY ALSO FOWN NO INCREASE IN

6875
04:55:12,481 --> 04:55:13,783
MICROHEMORRHAGES WITH THESE APP

6876
04:55:13,783 --> 04:55:14,784
23 MICE.

6877
04:55:14,784 --> 04:55:16,719
SO I THINK THIS HIGHLIGHTS THE

6878
04:55:16,719 --> 04:55:18,420
POINTS THERE MAY BE DIFFERENT

6879
04:55:18,420 --> 04:55:20,656
RESPONSES TO CAA AND ARIA

6880
04:55:20,656 --> 04:55:21,557
RELATED EFFECTS DEPENDENT UPON

6881
04:55:21,557 --> 04:55:26,595
THE ANTIBODY THAT IS USED IN THE

6882
04:55:26,595 --> 04:55:28,931
STUDY.

6883
04:55:28,931 --> 04:55:29,431
NEXT SLIDE.

6884
04:55:29,431 --> 04:55:32,935
SO HERE I WANT TO SUMMARIZE THE

6885
04:55:32,935 --> 04:55:34,937
ADVANTAGES AND THE MODELS FOR

6886
04:55:34,937 --> 04:55:36,505
CAA EMPLOY THESE MODELS HAVE

6887
04:55:36,505 --> 04:55:38,007
BEEN ARK ROUND FOR MORE THAN 20

6888
04:55:38,007 --> 04:55:39,742
YEARS AND THEY'VE BEEN WELL

6889
04:55:39,742 --> 04:55:41,310
CHARACTERIZED BY MANY GROUPS AND

6890
04:55:41,310 --> 04:55:44,113
THERE ARE MAINTAIN LARGE COHORTS

6891
04:55:44,113 --> 04:55:45,314
AND INCREASED BY MODULATING

6892
04:55:45,314 --> 04:55:54,423
OTHER YEENS FOR EXAMPLE, APOE4

6893
04:55:54,423 --> 04:55:59,662
AND CLUSTERREN AND MEDIN.

6894
04:55:59,662 --> 04:56:00,696
BECAUSE OF THE FACT THAT THE

6895
04:56:00,696 --> 04:56:02,598
MOUSE AND THE MOUSE BRAIN AND

6896
04:56:02,598 --> 04:56:05,334
EASY TO,A ASSESSES, ACCESS, THEY

6897
04:56:05,334 --> 04:56:07,837
ARE WELL SUITED FOR MULTIPHOTON

6898
04:56:07,837 --> 04:56:09,738
IMAGING TODAYS.

6899
04:56:09,738 --> 04:56:10,573
NOW CLEARLY DISADVANTAGES OF

6900
04:56:10,573 --> 04:56:15,244
THESE, THEY ARE MICE, THEY ARE

6901
04:56:15,244 --> 04:56:19,548
NOT HUMAN, THE CAA DEVELOPED

6902
04:56:19,548 --> 04:56:21,517
PARENCHYMAL AND SEEREBERAL

6903
04:56:21,517 --> 04:56:22,885
VASCULAR AMYLOID IN THESE MODEL

6904
04:56:22,885 --> 04:56:26,088
ANDS THEY RELY ON

6905
04:56:26,088 --> 04:56:27,223
NONPHYSIOLOGICAL OVEREXPRESSION

6906
04:56:27,223 --> 04:56:28,757
OF ABPP WITH THE FAD MUTATIONS.

6907
04:56:28,757 --> 04:56:30,392
ANOTHER POINT IS THAT THE

6908
04:56:30,392 --> 04:56:31,961
IMMUNOLOGY DEVELOPED FROM A

6909
04:56:31,961 --> 04:56:34,330
NEURONAL SOLE SOURCE PRODUCTION

6910
04:56:34,330 --> 04:56:38,033
OF THE ABETTA IN MY TALK.

6911
04:56:38,033 --> 04:56:39,235
NEXT SLIDE.

6912
04:56:39,235 --> 04:56:40,502
SUBSEQUENTLY SOME MOUSE MODELS

6913
04:56:40,502 --> 04:56:42,004
ARE DEVELOPED AT MORE SPECIFIC

6914
04:56:42,004 --> 04:56:44,640
FOR DEVELOPING CAA IN THE

6915
04:56:44,640 --> 04:56:45,374
ABSENCE OF PARENCHYMAL

6916
04:56:45,374 --> 04:56:48,510
PATHOLOGY, SO IN THE TOP HERE, I

6917
04:56:48,510 --> 04:56:49,612
SHOW THE APPLICATIONS DUTCH

6918
04:56:49,612 --> 04:56:51,747
MOUSE, THIS IS A MODEL THAT

6919
04:56:51,747 --> 04:56:53,582
PRODUCED THE WORKERS LAB, THIS

6920
04:56:53,582 --> 04:56:55,718
IS A MODEL FOR TYPE 2, AS THESE

6921
04:56:55,718 --> 04:56:58,520
MICE GET OLD THEY DEVELOP

6922
04:56:58,520 --> 04:57:03,926
EXTENSIVE CAA TYPE 2, THEY ALSO

6923
04:57:03,926 --> 04:57:05,427
TWEP BLOODS, THIS IS AN ACTIVE

6924
04:57:05,427 --> 04:57:10,900
PLEADS FROM 1 OF THESE MICE AND

6925
04:57:10,900 --> 04:57:13,002
ALSO PERIVASCULAR EVIDENT OF

6926
04:57:13,002 --> 04:57:13,402
MICROHEMORRHAGE.

6927
04:57:13,402 --> 04:57:17,439
NOW IN MY LAB WE HAVE A MODEL

6928
04:57:17,439 --> 04:57:18,874
FOR CAPILLARY CAA TYPE 1, IN

6929
04:57:18,874 --> 04:57:20,943
THIS CASE THEY HARBOR BOTH THE

6930
04:57:20,943 --> 04:57:22,111
DUTCH AND IOWA MUSEUM TAIGS.

6931
04:57:22,111 --> 04:57:24,780
AND YOU CAN SEE HERE, IN THESE

6932
04:57:24,780 --> 04:57:27,950
PANELS THEY DEVELOP EXTENSIVE

6933
04:57:27,950 --> 04:57:29,251
CAPILLARY AMYLOID EMPLOY NOW IN

6934
04:57:29,251 --> 04:57:32,054
OUR HANDS THIS IS NOT BEEN A

6935
04:57:32,054 --> 04:57:34,757
CONSISTENT RELIABLE MODEL FOR

6936
04:57:34,757 --> 04:57:36,625
MICROHEMORRHAGE, AND WE DO FIND

6937
04:57:36,625 --> 04:57:38,127
VERY RARELY AS SHOWN ON THE

6938
04:57:38,127 --> 04:57:38,861
RIGHT THERE, BUT ON THE OTHER

6939
04:57:38,861 --> 04:57:40,296
HEALTH 

6940
04:57:40,296 --> 04:57:41,597
LABS AX ROUND THE WORLD OF THESE

6941
04:57:41,597 --> 04:57:45,868
MICE AND THEY ARE REPORTED MORE

6942
04:57:45,868 --> 04:57:46,635
CONSISTENT MICROHEMORRHAGES BUT

6943
04:57:46,635 --> 04:57:48,404
IN OUR HANDS IT HAS NOT BEEN A

6944
04:57:48,404 --> 04:57:49,638
GOOD MODEL FOR THAT.

6945
04:57:49,638 --> 04:57:53,175
MAY I HAVE THE NEXT SLIDE,

6946
04:57:53,175 --> 04:57:53,409
PLEASE.

6947
04:57:53,409 --> 04:57:56,278
SO SOME OF THE ADVANTAGES OF

6948
04:57:56,278 --> 04:57:58,914
USING THESE MUTANT MODELS TO

6949
04:57:58,914 --> 04:58:00,049
STUDY, AGAIN BOTH OF THESE

6950
04:58:00,049 --> 04:58:01,283
MODELS HAVE BEEN ASH ROUND FOR

6951
04:58:01,283 --> 04:58:03,018
OVER 20 YEAR ANDS WELL

6952
04:58:03,018 --> 04:58:06,588
CHARACTERIZED AND USED MY MANY

6953
04:58:06,588 --> 04:58:06,822
GROUPS.

6954
04:58:06,822 --> 04:58:09,525
THE DUTCH MIGHT PRESENT WITH

6955
04:58:09,525 --> 04:58:10,826
RELATED HEMORRHAGES, AND IT'S A

6956
04:58:10,826 --> 04:58:12,528
SPECIFIC MODEL FOR TYPE 2

6957
04:58:12,528 --> 04:58:15,264
WITHOUT AMYLOID PLAQUES AND THE

6958
04:58:15,264 --> 04:58:17,533
MICE PROVIDES SPECIFIC MODEL FOR

6959
04:58:17,533 --> 04:58:19,601
TYPE 1 WITH AMYLOID PLAQUES.

6960
04:58:19,601 --> 04:58:21,337
NOW IMPORTANTLY BOTH THESE

6961
04:58:21,337 --> 04:58:31,246
MODELS 1 CAN INVESTIGATE 1

6962
04:58:31,246 --> 04:58:32,581
 1 CAA

6963
04:58:32,581 --> 04:58:33,849
AND SOME OF THE DISADVANTAGES

6964
04:58:33,849 --> 04:58:35,818
AGAIN THEY ARE MICE LIKE THE

6965
04:58:35,818 --> 04:58:37,853
OTHER MODELS, THE CAA RESULTS

6966
04:58:37,853 --> 04:58:40,089
FROM THE FAMILIAL MUTATIONS IN

6967
04:58:40,089 --> 04:58:43,759
THE A-BETA PEPTIDE AND THE MICE

6968
04:58:43,759 --> 04:58:44,159
HAVE INCONSISTENT

6969
04:58:44,159 --> 04:58:46,362
MICROHEMORRHAGES AT LEAST IN OUR

6970
04:58:46,362 --> 04:58:46,628
HANDS.

6971
04:58:46,628 --> 04:58:48,464
ANOTHER DISADVANTAGE IT REQUIRES

6972
04:58:48,464 --> 04:58:50,933
EXTENSIVE ANALLING FOR CAA TO

6973
04:58:50,933 --> 04:58:51,967
EMERGE, GREATER THAN 24 MONTHS

6974
04:58:51,967 --> 04:58:57,239
AND AGAIN BOTH OF THESE MODELS

6975
04:58:57,239 --> 04:58:58,607
COME FROM A BETA, A POABT I WILL

6976
04:58:58,607 --> 04:58:59,842
GET TO AT THE END.

6977
04:58:59,842 --> 04:59:10,285
MAY I HAVE THE NEXT SLIDE,

6978
04:59:12,921 --> 04:59:13,188
PLEASE.

6979
04:59:13,188 --> 04:59:15,858
AT FIRST, WE ARE MORE CLOSELY

6980
04:59:15,858 --> 04:59:17,059
RELATED TO HUMANS THAN MICE

6981
04:59:17,059 --> 04:59:19,595
ISSUES AND IN THE DISCUSSION

6982
04:59:19,595 --> 04:59:20,963
PANEL, THE RAT BRAIN IS LARGER

6983
04:59:20,963 --> 04:59:21,830
THAN THE MOUSE BRAIN AND BECAUSE

6984
04:59:21,830 --> 04:59:23,232
OF THIS WE HAVE MORE TISSUE WE

6985
04:59:23,232 --> 04:59:24,199
CAN ANALYZE AND MORE WHITE

6986
04:59:24,199 --> 04:59:26,935
MATTER TO LOOK AT ASK WE CAN

6987
04:59:26,935 --> 04:59:27,970
COLLECT LARGER AMOUNTS OF CSF

6988
04:59:27,970 --> 04:59:35,511
AND ATHAT WILL SIS, EVALUATING

6989
04:59:35,511 --> 04:59:36,378
WHITE MATTER CHANGES.

6990
04:59:36,378 --> 04:59:39,248
NEXT SLIDE, PLEASE.

6991
04:59:39,248 --> 04:59:39,548
COMPREHEND.

6992
04:59:39,548 --> 04:59:41,917
SO THIS A SMALL, AGAIN WE FIRST

6993
04:59:41,917 --> 04:59:44,353
PUBLISHED ABOUT 5 YEARS AGO AND

6994
04:59:44,353 --> 04:59:47,156
MODELING WHAT WE DID WITH THE

6995
04:59:47,156 --> 04:59:48,624
MOUSE WITH THE CIRCUMSTANCE

6996
04:59:48,624 --> 04:59:51,460
WDGI, THIS IS A RAT MODEL FOR

6997
04:59:51,460 --> 04:59:53,195
CON WOAND RELATED INFLAMMATION,

6998
04:59:53,195 --> 04:59:56,131
IN THE UPPER PANEL YOU CAN SEE

6999
04:59:56,131 --> 04:59:59,068
THERE'S EXTENSIVE CAPILLARY IN

7000
04:59:59,068 --> 05:00:02,204
MULTIPLE BRAIN REGIONS AND WITH

7001
05:00:02,204 --> 05:00:05,574
THIS CAPILLARY THIS IS A STRONG

7002
05:00:05,574 --> 05:00:07,042
GLIAL RESPONSE IT, THE ASTRO

7003
05:00:07,042 --> 05:00:10,946
SIGHTS AND WE LOOK AT THE

7004
05:00:10,946 --> 05:00:11,780
PANELOT AMYLOIDOT CAPILLARY

7005
05:00:11,780 --> 05:00:13,015
SHOWN IN PLURIBU, YOU CANEE

7006
05:00:13,015 --> 05:00:14,650
THERE'S A LARGE INCREASE IN

7007
05:00:14,650 --> 05:00:23,192
NUMBER OF ASTRO SIGHTS IN THESE

7008
05:00:23,192 --> 05:00:23,459
RATS.

7009
05:00:23,459 --> 05:00:26,128
SAMEULARLY, WE SEE IN PLURIBU AS

7010
05:00:26,128 --> 05:00:27,162
THE CAPILLARY AMYLOID, CAN YOU

7011
05:00:27,162 --> 05:00:29,998
SEE IT IF GREEN THE MICROFLI

7012
05:00:29,998 --> 05:00:33,836
COLSISSA THERE'S A LARGE NUMBER

7013
05:00:33,836 --> 05:00:39,274
OF MICROGLIA THEY CHANGE FROM A

7014
05:00:39,274 --> 05:00:40,209
RESTINGITATE TO ACTIVATEDITATE.

7015
05:00:40,209 --> 05:00:44,580
SO THIS A STRONG MODEL FOR CAA

7016
05:00:44,580 --> 05:00:45,747
METHYLATION.

7017
05:00:45,747 --> 05:00:48,817
IN THIS RAT MODEL WE'VE SHOWN

7018
05:00:48,817 --> 05:00:50,018
THEY DEVELOP CONSISTENT

7019
05:00:50,018 --> 05:00:51,854
MICROHEMORRHAGES, AND THE

7020
05:00:51,854 --> 05:00:55,891
STAINING, AND THEY ALSO DEVELOP

7021
05:00:55,891 --> 05:00:57,059
CAPILLARY VESSEL OCCLUSIONS.

7022
05:00:57,059 --> 05:00:59,461
NOW THE PANELS BELOW, THESE ARE

7023
05:00:59,461 --> 05:01:01,029
MRI IMAGES THAT THEY CLEBTED

7024
05:01:01,029 --> 05:01:02,531
LOOKING AT A NUMBER OF THESE

7025
05:01:02,531 --> 05:01:06,535
RATS, AND YOU CAN SEE THE

7026
05:01:06,535 --> 05:01:07,336
MICROHEMORRHAGES THAT APPEARED

7027
05:01:07,336 --> 05:01:10,005
NOTED BY THE ARROW HEAD THEIR

7028
05:01:10,005 --> 05:01:11,406
WITHIN THE REGION AND THE PANEL

7029
05:01:11,406 --> 05:01:13,909
AT THE RIGHT, IT'S 3D RECONTRUKS

7030
05:01:13,909 --> 05:01:15,611
WHEN SHE ANALYZED A NUMBER OF

7031
05:01:15,611 --> 05:01:18,213
THESE RATS, SHOWING AGAIN THE

7032
05:01:18,213 --> 05:01:19,448
CLUSTERING OF THESE

7033
05:01:19,448 --> 05:01:20,716
MICROHEMMAGES IN THE AIR,

7034
05:01:20,716 --> 05:01:22,551
THERE'S BEEN AN INTEREST, TO AND

7035
05:01:22,551 --> 05:01:25,787
LOOKINGA THE ROLE OF COMPLEMENT

7036
05:01:25,787 --> 05:01:27,189
ACTIVATION IN ARIA, IN THIS

7037
05:01:27,189 --> 05:01:29,825
MODEL, EVEN IN THE ABSENCE OF

7038
05:01:29,825 --> 05:01:31,527
IMMUNOTHERAPY WE FIND THERE'S AN

7039
05:01:31,527 --> 05:01:33,629
INCREASE IN THE COMPLEMENT

7040
05:01:33,629 --> 05:01:35,364
ACTIVATION AND COAGULATION

7041
05:01:35,364 --> 05:01:38,066
ACTIVATION. 

7042
05:01:38,066 --> 05:01:38,934
NEXT SLIDE, PLEASE.

7043
05:01:38,934 --> 05:01:40,269
SO ANOTHER MODEL WE MORE

7044
05:01:40,269 --> 05:01:43,772
RECENTLY DEVELOPED IS THE RDG

7045
05:01:43,772 --> 05:01:45,974
RAT MODEL FOR TYPE 2.

7046
05:01:45,974 --> 05:01:47,309
THIS ALSO EXPRESSES DUTCH TYPE

7047
05:01:47,309 --> 05:01:49,077
BETA IN BRAIN, THIS IS THE MODEL

7048
05:01:49,077 --> 05:01:52,181
AGAIN WHERE THEY GET SMALL VESES

7049
05:01:52,181 --> 05:01:53,582
EXCEL ARTERIOLE CAA EMPLOY YOU

7050
05:01:53,582 --> 05:01:55,617
SEE THE PANELS IN THE LEFT.

7051
05:01:55,617 --> 05:01:57,986
YOUEE THIS IN THE CORTEX AND

7052
05:01:57,986 --> 05:02:01,657
KNOWN AS SURFACE VESSELS

7053
05:02:01,657 --> 05:02:02,824
PENETRATING ARTERIOLES.

7054
05:02:02,824 --> 05:02:04,626
NOW IN CONTRAST, IN THIS CASE,

7055
05:02:04,626 --> 05:02:07,596
THERE'S A MUCH MORE MUTED

7056
05:02:07,596 --> 05:02:08,363
CELLULAR INFLAMMATORY RESPONSE.

7057
05:02:08,363 --> 05:02:10,432
AND IN THE BOTTOM PANEL YOU SEE

7058
05:02:10,432 --> 05:02:12,267
THE AMYLOID IN PLURIBU WHICH IS

7059
05:02:12,267 --> 05:02:13,435
NOW ENCASED WITH THE VESSEL WALL

7060
05:02:13,435 --> 05:02:16,238
AND IN THIS CASE, YOU SEE MUCH

7061
05:02:16,238 --> 05:02:20,242
MORE RESTRICTED RESPONSE OF

7062
05:02:20,242 --> 05:02:21,210
ASTRO SIGHTS AND MICROGLIA TO

7063
05:02:21,210 --> 05:02:21,810
SEE THIS.

7064
05:02:21,810 --> 05:02:25,647
WE SEE THIS WHEN THEY'RE

7065
05:02:25,647 --> 05:02:27,382
DYSPHORIC AND PENETRATE FROM THE

7066
05:02:27,382 --> 05:02:31,386
VESSEL WALL EMPLOY NEXT SLIDE.

7067
05:02:31,386 --> 05:02:33,288
WE'VE ALSO SHOWN THAT THE RATS

7068
05:02:33,288 --> 05:02:42,030
AND THE BRAIN REGIONS AND ALSO

7069
05:02:42,030 --> 05:02:45,334
WE THE OCCLUSIONS IN THE RIGHT

7070
05:02:45,334 --> 05:02:48,437
PANEL, AND THEY ALSO HAVE

7071
05:02:48,437 --> 05:02:49,338
ACTIVATION BY TRANSCRIPTOMICS

7072
05:02:49,338 --> 05:02:52,474
AND THEY HAVE COMPLEMENT

7073
05:02:52,474 --> 05:02:55,711
COAGULATION PATHWAYS. 

7074
05:02:55,711 --> 05:02:56,878
NEXT LIED, PLEASE.

7075
05:02:56,878 --> 05:02:59,748
SO WE SENT SOME OF THESE SLIDES

7076
05:02:59,748 --> 05:03:02,951
TO [INDISCERNIBLE] AT YALE AND

7077
05:03:02,951 --> 05:03:05,354
SHE PERFORMED AMERICA R STUDYING

7078
05:03:05,354 --> 05:03:08,357
IN THEM, AND I HAD CONTROLLER OF

7079
05:03:08,357 --> 05:03:09,591
BANKED IN THERE, THESE BRAINS

7080
05:03:09,591 --> 05:03:11,093
WERE HARVESTED FROM HER, FIX

7081
05:03:11,093 --> 05:03:13,161
EXCLUDE SENT BACK TO US FOR

7082
05:03:13,161 --> 05:03:14,429
DOING HISTOLOGY, WE THEN

7083
05:03:14,429 --> 05:03:18,433
SECTIONED TO THIS GENERAL REGION

7084
05:03:18,433 --> 05:03:19,501
WHERE SHE HAD THESE GENERAL

7085
05:03:19,501 --> 05:03:20,802
IMAGES, THAT'S SHOWN IN THE

7086
05:03:20,802 --> 05:03:23,905
LOWER SIDE ON RED, WE LOOK AT

7087
05:03:23,905 --> 05:03:25,641
THE INDICATION WE CAN SEE

7088
05:03:25,641 --> 05:03:28,410
THERE'S CAA IN THE RAS, WE CAN

7089
05:03:28,410 --> 05:03:30,212
DETECT IT BY PERIVASCULAR AND

7090
05:03:30,212 --> 05:03:35,317
THERE'S ALSO VESSEL OCCLUSIONS,

7091
05:03:35,317 --> 05:03:38,020
SO THESE RELATED AFFECTS

7092
05:03:38,020 --> 05:03:39,454
REGARDING THIS CAN BE READILY

7093
05:03:39,454 --> 05:03:41,223
DETECTED BY MR IN THESE RATS.

7094
05:03:41,223 --> 05:03:44,626
MAY I HAVE THE NEXT SLIDE,

7095
05:03:44,626 --> 05:03:44,860
PLEASE.

7096
05:03:44,860 --> 05:03:47,162
SO SOME OF THE ADVANTAGES FOR

7097
05:03:47,162 --> 05:03:48,830
USING THESE RAT MODELS, SIMILAR

7098
05:03:48,830 --> 05:03:50,165
TO THE MICE YOU SLEEP APNEA AND

7099
05:03:50,165 --> 05:03:53,535
OBESITYY FOR LARGE COHORTS, THE

7100
05:03:53,535 --> 05:03:55,570
RATS ARE A SPECIFIC MODEL FOR

7101
05:03:55,570 --> 05:04:02,577
CAPILLARY TYPE 1 WITH THE STRONG

7102
05:04:02,577 --> 05:04:03,545
CAA MODEL, THESE ARE STRONG FOR

7103
05:04:03,545 --> 05:04:07,249
TYPE 2 AND HAVE THE MORE MUTED

7104
05:04:07,249 --> 05:04:11,920
CAPILLARY AND OR MUTED CAA

7105
05:04:11,920 --> 05:04:12,454
INFLAMMARRATORY RESPONSE.

7106
05:04:12,454 --> 05:04:13,655
BOTH LARGELY AVOID AMYLOID

7107
05:04:13,655 --> 05:04:15,524
PLAQUES AND BOTH PRESENT WITH

7108
05:04:15,524 --> 05:04:16,425
MICROPLEADS AND VESSEL

7109
05:04:16,425 --> 05:04:18,093
OCCLUSIONS SO AGAIN WITH THESE

7110
05:04:18,093 --> 05:04:19,995
RAT MODELS HERE AGAIN, WE HAVE

7111
05:04:19,995 --> 05:04:21,563
THE OPPORTUNITY TO STUDY IMMUNE

7112
05:04:21,563 --> 05:04:23,131
OR THERAPY AND ARIA RELATED

7113
05:04:23,131 --> 05:04:25,267
EFFECTS IN A MODEL FOR CAPILLARY

7114
05:04:25,267 --> 05:04:29,371
TYPE 1 OR MODEL FOR ARTERIOLE

7115
05:04:29,371 --> 05:04:29,871
AND TYPE 2.

7116
05:04:29,871 --> 05:04:32,741
SO SOME OF THE DISADVANTAGES OF

7117
05:04:32,741 --> 05:04:35,143
THESE RATS, THEY ARE ROTENTS WE

7118
05:04:35,143 --> 05:04:36,311
FEEL THEY'RE BETTER THAN MICE

7119
05:04:36,311 --> 05:04:37,245
BUT TILL RATS.

7120
05:04:37,245 --> 05:04:39,514
TO SEE RESULTS AGAIN FROM

7121
05:04:39,514 --> 05:04:41,850
FAMILIAL MUTATIONS IN THE A-BETA

7122
05:04:41,850 --> 05:04:43,085
PEPTIDE AND COMPARED TO MICE IS

7123
05:04:43,085 --> 05:04:45,354
A MUCH MORE LIMITED RANGE OF

7124
05:04:45,354 --> 05:04:48,990
OTHER RAT MODELS TO COMBINE WITH

7125
05:04:48,990 --> 05:04:50,926
CA RAT MODELS TO LOOK AT OTHER

7126
05:04:50,926 --> 05:04:52,761
YEENS AND DEVELOPMENT WITH THE

7127
05:04:52,761 --> 05:04:55,297
LIMITATION, AND AGAIN, WITH THE

7128
05:04:55,297 --> 05:04:56,865
TRANSGENIC A--BITS ANIMALS TO

7129
05:04:56,865 --> 05:04:58,100
SEE IF PATHOLOGY DEVELOPS AGAIN

7130
05:04:58,100 --> 05:04:59,901
FROM A NEURONAL SOURCE OF

7131
05:04:59,901 --> 05:05:00,569
PRODUCTION FOR BETA.

7132
05:05:00,569 --> 05:05:01,770
WHAT EXACTLY DID IT MEAN.

7133
05:05:01,770 --> 05:05:05,006
ALL THE MODELS THAT I DESCRIBED

7134
05:05:05,006 --> 05:05:08,310
TODAY, AGAIN THE ABETTA IS

7135
05:05:08,310 --> 05:05:08,944
PRIMARILY PRODUCED, EXCLUSIVELY

7136
05:05:08,944 --> 05:05:10,412
PRODUCED FROM NEURONS TO EXPRESS

7137
05:05:10,412 --> 05:05:16,418
THE TRANSYEEN THAT WAS GIIVE TO

7138
05:05:16,418 --> 05:05:17,419
THE ANIMALS.

7139
05:05:17,419 --> 05:05:20,021
IN ALL THESE MODELS CAN PRODUCE

7140
05:05:20,021 --> 05:05:21,923
CAA, BUT THE QUESTION I HAD

7141
05:05:21,923 --> 05:05:23,992
WELL, IS THAT REALLY HOW THE DEC

7142
05:05:23,992 --> 05:05:27,295
UNFOLDS IN HUMANS?

7143
05:05:27,295 --> 05:05:29,097
AND I THINK NOT.

7144
05:05:29,097 --> 05:05:29,398
NEXT SLIDE.

7145
05:05:29,398 --> 05:05:33,402
SO THIS IS AN EXAMPLE HERE FROM

7146
05:05:33,402 --> 05:05:37,873
TOSHIDA ET ALL FROM THE RIKEN

7147
05:05:37,873 --> 05:05:40,475
ENSELITUTE WHERE THEY DEVELOP A

7148
05:05:40,475 --> 05:05:42,778
TRANSGENIC EXPRESS APP AND THEY

7149
05:05:42,778 --> 05:05:43,745
PRODUCE A-BETA PEPTIDE ANDS THEY

7150
05:05:43,745 --> 05:05:46,548
CAN MEASURE THOSE IN BLOOD NOW.

7151
05:05:46,548 --> 05:05:48,817
CAN IN THE PANEL ON THE LEFT

7152
05:05:48,817 --> 05:05:50,786
THOUGH, WHEN YOU LOOK YOU THEY

7153
05:05:50,786 --> 05:05:51,853
DON'T DEVELOP THE PATHOLOGY ON

7154
05:05:51,853 --> 05:05:52,287
THEIR OWN.

7155
05:05:52,287 --> 05:05:54,289
SO WHAT THEY DID IS THEY USE

7156
05:05:54,289 --> 05:05:56,491
ANOTHER MOUSE MODEL, THE

7157
05:05:56,491 --> 05:05:58,860
KNOCK-IN MOUSE MODEL, SO THIS

7158
05:05:58,860 --> 05:06:01,263
APP MODELS KNOCKED IN WITH HUMAN

7159
05:06:01,263 --> 05:06:02,831
SWEDISH BETA DOMAIN AND THAT

7160
05:06:02,831 --> 05:06:05,066
MODEL IN THE MITSD PANEL

7161
05:06:05,066 --> 05:06:07,402
DEVELOPS FROM SMALL DEPOSITS OF

7162
05:06:07,402 --> 05:06:09,237
BETA, BUT WITH THESE 2 MODELS

7163
05:06:09,237 --> 05:06:12,174
ACROSS, YOU HAVE YOU EMERGENCE

7164
05:06:12,174 --> 05:06:14,142
OF EXTENSIVE CAA, SO THIS RAISES

7165
05:06:14,142 --> 05:06:15,844
THE POINT THAT VASCULAR DERIVED

7166
05:06:15,844 --> 05:06:18,880
SEEDS MAY BE IMPORTANT FOR

7167
05:06:18,880 --> 05:06:19,614
DRIVEWAYING CAA UNDER

7168
05:06:19,614 --> 05:06:20,248
PHYSIOLOGICAL CONDITIONS.

7169
05:06:20,248 --> 05:06:23,585
CAN I GO TO THE NEXT SLIDE,

7170
05:06:23,585 --> 05:06:23,819
PLEASE.

7171
05:06:23,819 --> 05:06:26,755
SO AGAIN HERE IS THE SCHEMATIC

7172
05:06:26,755 --> 05:06:27,656
FROM THE NEUROVASCULAR UNIT.

7173
05:06:27,656 --> 05:06:29,424
AGAIN ALL THE TRANSGENIC MODELS

7174
05:06:29,424 --> 05:06:32,260
I TRIBED HERE, THEY ALL PRODUCE

7175
05:06:32,260 --> 05:06:33,762
A APPROXIMATE A-BETA SOLELY FROM

7176
05:06:33,762 --> 05:06:36,331
NEURONS AND WE KNOW THAT MAYBORS

7177
05:06:36,331 --> 05:06:39,067
ASTRO SIGHTS CAN EXPRESS ATP AND

7178
05:06:39,067 --> 05:06:40,669
MAKE MAUL AMOUNTS OF BETA AND

7179
05:06:40,669 --> 05:06:42,904
YOU LOOK IN THE WALL AND

7180
05:06:42,904 --> 05:06:45,407
ENDOTHELIAL CELLS AND THE

7181
05:06:45,407 --> 05:06:47,375
CAPILLARY CAN ALSO PRODUCE

7182
05:06:47,375 --> 05:06:50,178
A-BETA PEPTIDE, AS 1 MOVES UP

7183
05:06:50,178 --> 05:06:52,481
THE VASCULAR TREE, SMOOTH MUSCLE

7184
05:06:52,481 --> 05:06:55,450
CELLS AND FIBROPLAOF THE GET ATP

7185
05:06:55,450 --> 05:06:57,052
AND SO THEY'RE MULTIPLE SOURCES

7186
05:06:57,052 --> 05:07:00,622
GOING ON, NORMALLY THAT PRODUCE

7187
05:07:00,622 --> 05:07:02,057
A-BETA PEPTIDES EVEN THOUGH THEY

7188
05:07:02,057 --> 05:07:05,093
MAY BE THE PRIMARY PRODUCERS AND

7189
05:07:05,093 --> 05:07:06,194
OTHER SOURCE SOURCES MAY BE

7190
05:07:06,194 --> 05:07:07,696
IMPORTANT.

7191
05:07:07,696 --> 05:07:09,364
NEXT SLIDE, PLEASE.

7192
05:07:09,364 --> 05:07:10,398
2-MINUTE WARNING WILLIAM NALMOST

7193
05:07:10,398 --> 05:07:10,966
FINISHED HERE.

7194
05:07:10,966 --> 05:07:12,434
FOR THIS REASON WE'VE NOW

7195
05:07:12,434 --> 05:07:17,472
RECENTLY MOVED ON THORS NEXT

7196
05:07:17,472 --> 05:07:18,173
GENERATION MODELS USING

7197
05:07:18,173 --> 05:07:19,474
GENE-EDITED RATS SO WHAT EYE

7198
05:07:19,474 --> 05:07:23,545
DONE HERE IS SHOW THE RIGHT

7199
05:07:23,545 --> 05:07:25,881
A-BET WITH WE USE GENE EDITING

7200
05:07:25,881 --> 05:07:27,582
TO CONVERT THOSE TO THE HUMAN

7201
05:07:27,582 --> 05:07:29,985
AMINO ARK SIDS SO WE HAVE RATS

7202
05:07:29,985 --> 05:07:32,554
THAT PRODUCE HUMAN A ABOUTETTA

7203
05:07:32,554 --> 05:07:34,155
WITH DUTCH MUTATION OR DUTCH

7204
05:07:34,155 --> 05:07:35,490
ISLAND MUTATION AND JUST BRIEFLY

7205
05:07:35,490 --> 05:07:38,059
WE WERE IN THE PROCESS OF

7206
05:07:38,059 --> 05:07:39,961
CHARACTERIZING THESE ANIMALS BUT

7207
05:07:39,961 --> 05:07:45,967
EXAMPLE BELOW, WE SEE THE

7208
05:07:45,967 --> 05:07:49,871
ANIMALS EXPRESSING THE BETA, IN

7209
05:07:49,871 --> 05:07:51,306
THIS MODEL WE DON'T NORMALLY

7210
05:07:51,306 --> 05:07:54,876
SEE, BUT WE ALSO SEE A DIFFERENT

7211
05:07:54,876 --> 05:07:56,011
ANATOMICAL GRIEWKS, NEXT SLIDE,

7212
05:07:56,011 --> 05:07:56,344
PLEASE.

7213
05:07:56,344 --> 05:07:58,580
>> SO THIS IS SUMMARIZES
AGAIN

7214
05:07:58,580 --> 05:08:00,215
THAT THE AD MOUSE MODELS DEVELOP

7215
05:08:00,215 --> 05:08:03,518
PLAQUE IN THE CAA, THEY

7216
05:08:03,518 --> 05:08:04,452
TRANSGENIC MOUSE SPECIFIC FOR

7217
05:08:04,452 --> 05:08:05,287
SIGHT 1 OR 2.

7218
05:08:05,287 --> 05:08:06,922
WE HAVE RAT MODELS SPECIFIC FOR

7219
05:08:06,922 --> 05:08:11,626
TYPE 1 OR 2 THAT CAN ALSO HAVE A

7220
05:08:11,626 --> 05:08:12,327
STRONG CAA INFLAMMATORY RESPONSE

7221
05:08:12,327 --> 05:08:15,096
AND WE HAVE NEWLY GENERATED RAT

7222
05:08:15,096 --> 05:08:16,531
MODELS THAT WE'RE IN THE PROCESS

7223
05:08:16,531 --> 05:08:18,600
OF CHAISHTIZING AND MAY BE MORE

7224
05:08:18,600 --> 05:08:20,168
RELEVANT TO INVESTIGATE THE

7225
05:08:20,168 --> 05:08:22,203
IMPACTS OF ABETTA AND

7226
05:08:22,203 --> 05:08:27,008
IMMUNOTHERAPY AND CAA .

7227
05:08:27,008 --> 05:08:27,576
LAST SLIDE.

7228
05:08:27,576 --> 05:08:28,610
JUST THANK THE PEOPLE WORKING IN

7229
05:08:28,610 --> 05:08:30,745
THE LAB AND OUR COLLABORATOR

7230
05:08:30,745 --> 05:08:31,880
ANDS FUNDING SOURCES THAT

7231
05:08:31,880 --> 05:08:42,424
GENEROUSLY SUPPORTED THIS WORK.

7232
05:08:42,624 --> 05:08:43,224
THANK YOU.

7233
05:08:43,224 --> 05:08:46,528
>> DO WE HAVE TIME FOR

7234
05:08:46,528 --> 05:08:46,795
QUESTIONS?

7235
05:08:46,795 --> 05:08:47,629
WE HAVE 1 MINUTE OTHERWISE WE

7236
05:08:47,629 --> 05:08:50,632
CAN SAVE IT FOR THE DISCUSSION

7237
05:08:50,632 --> 05:08:51,099
AFTERWARDS.

7238
05:08:51,099 --> 05:08:55,537
ALL RIGHT, THANK YOU.

7239
05:08:55,537 --> 05:08:56,404
>> THANK YOU.

7240
05:08:56,404 --> 05:09:00,842
>> SO WE MOVE TO TO OUR
NEXT

7241
05:09:00,842 --> 05:09:01,309
TALK.

7242
05:09:01,309 --> 05:09:05,580
BY DR. LARY WALKER FROM EMORY,

7243
05:09:05,580 --> 05:09:11,052
THE SNELLING PROFESSOR OF

7244
05:09:11,052 --> 05:09:13,288
NEUROLOGY AND AND HIS TALK WILL

7245
05:09:13,288 --> 05:09:15,890
BE NONHUMAN PRIMATE MODELS OF

7246
05:09:15,890 --> 05:09:26,134
CAA AND ARIA.

7247
05:09:26,334 --> 05:09:26,601
>> THANK YOU.

7248
05:09:26,601 --> 05:09:26,901
WE'RE HERE.

7249
05:09:26,901 --> 05:09:30,639
SO IT'S GOOD TO BE HERE AND I'D

7250
05:09:30,639 --> 05:09:32,707
LIKE TO SHARE WITH YOU IN OF MY

7251
05:09:32,707 --> 05:09:35,310
VIEWS ABOUT HOW THE NONHUMAN

7252
05:09:35,310 --> 05:09:37,112
PRIMATE MODEL MIGHT BE USEFUL IN

7253
05:09:37,112 --> 05:09:39,514
HELPING US TO UNDERSTAND NOT

7254
05:09:39,514 --> 05:09:42,417
ONLY ARIA BUT PERHAPS THE ROLE

7255
05:09:42,417 --> 05:09:45,286
OF VARIOUS AGENTS IN INDUCING

7256
05:09:45,286 --> 05:09:45,487
ARIA.

7257
05:09:45,487 --> 05:09:47,889
SO AS AN OVERVIEW FOR THE

7258
05:09:47,889 --> 05:09:50,492
UNINITIATED I WILL PRESENT JUST

7259
05:09:50,492 --> 05:09:51,693
BRIEFLY SOME OF THE INFORMATION

7260
05:09:51,693 --> 05:09:55,230
WE ARE ON PRIMATE AGING, A BETA

7261
05:09:55,230 --> 05:09:58,400
DEPOSITION IN PRIMATES AND CAA

7262
05:09:58,400 --> 05:10:01,336
IN PARTICULAR, I'LL THEN DISCUSS

7263
05:10:01,336 --> 05:10:03,938
MAINLY, ARIA IN AN AGED SQUIRREL

7264
05:10:03,938 --> 05:10:05,473
MONKEY, BASIC LYE A CASE REPORT

7265
05:10:05,473 --> 05:10:09,177
AND FINALLY I WOULD LIKE TO

7266
05:10:09,177 --> 05:10:10,478
SPEND A LITTLE TIME DESCRIBING

7267
05:10:10,478 --> 05:10:13,715
HOW THIS MODEL MIGHT BE USEFUL

7268
05:10:13,715 --> 05:10:16,851
IN TELLING US MORE ABOUT HOW WE

7269
05:10:16,851 --> 05:10:26,494
CAN MAKE IMMUNOTHERAPY BOTH MORE

7270
05:10:26,494 --> 05:10:27,328
EFFECTIVE AND SAFER.

7271
05:10:27,328 --> 05:10:29,230
SO HUGH MANS LIVE FOR 120 YEARS

7272
05:10:29,230 --> 05:10:30,932
AS A MAXIMUM LIFE SPAN, THE

7273
05:10:30,932 --> 05:10:33,768
MONKEYS I WILL TALK ABOUT ARE

7274
05:10:33,768 --> 05:10:35,970
SQUIRREL MONKEYS, LIVE TO BE A

7275
05:10:35,970 --> 05:10:42,677
MAXIMUM OF 30 YEARS AND RESUSC

7276
05:10:42,677 --> 05:10:44,546
MONKEYS CAN LIVE TO BE 45 YEARS

7277
05:10:44,546 --> 05:10:51,052
OF AGE, AND YOU CAN SEE ON THE

7278
05:10:51,052 --> 05:10:54,589
LEFT THE--THIS ISN'T WANT TO AT

7279
05:10:54,589 --> 05:11:01,129
A THERE, THE RHESUS MONKEY IS

7280
05:11:01,129 --> 05:11:05,233
EVOLUTIONARY CLOSER TO HUMANS

7281
05:11:05,233 --> 05:11:07,669
OTHER THAN SQUIRREL MONKEYS AND

7282
05:11:07,669 --> 05:11:10,305
MAR MA SETS, AND THEY ARE MUCH

7283
05:11:10,305 --> 05:11:12,640
LARGER AND LIVE MUCH LONGER AND

7284
05:11:12,640 --> 05:11:14,442
FOR THIS REASON, SQUIRREL MONKEY

7285
05:11:14,442 --> 05:11:18,546
ANDS OTHER NEW WORLD MONKEYS CAN

7286
05:11:18,546 --> 05:11:20,749
BE ADVANTAGEOUS.

7287
05:11:20,749 --> 05:11:24,252
THE ABETTA PRECURSOR PROTEIN IN

7288
05:11:24,252 --> 05:11:27,188
NONHUMAN PRIMATES IS BASICALLY

7289
05:11:27,188 --> 05:11:30,525
SIMILAR TO ARK BETA PRECURSOR

7290
05:11:30,525 --> 05:11:37,132
PROTEIN IN HUMANS, CERTAINLY

7291
05:11:37,132 --> 05:11:37,899
ABETTA ITSELF COMPLETELY

7292
05:11:37,899 --> 05:11:39,701
IDENTICAL IN ALL PRIMATES THAT

7293
05:11:39,701 --> 05:11:45,173
HAVE BEEN INVESTIGATED SO FAR.

7294
05:11:45,173 --> 05:11:50,912
IF YOU LOOK HISTOLOGICALLY AT

7295
05:11:50,912 --> 05:11:56,184
NONHUMAN PRIMATES IN THE MIDDLE,

7296
05:11:56,184 --> 05:11:59,187
IS THE RHESUS MONKEY ON THE LEFT

7297
05:11:59,187 --> 05:12:01,689
SPIDER MONKEY, THERE CAN BE A

7298
05:12:01,689 --> 05:12:03,992
BETA DEPOSITION IN AMYLOID, AND

7299
05:12:03,992 --> 05:12:06,528
IF WE MEASURE A-BETA LEVELS IN

7300
05:12:06,528 --> 05:12:09,130
NONHUMAN PRIMATES COMPARED TO

7301
05:12:09,130 --> 05:12:11,466
HUMANS BITE ELIZA, CAN YOU SEE

7302
05:12:11,466 --> 05:12:14,435
THAT THE ABSOLUTE AMOUNTS ARE

7303
05:12:14,435 --> 05:12:17,038
SIMILAR IN NOT GREATER IN THE

7304
05:12:17,038 --> 05:12:19,407
NONHUMAN PRIMATES SO A HUMAN

7305
05:12:19,407 --> 05:12:21,376
WITH ALZHEIMER HYMARY DEC IS

7306
05:12:21,376 --> 05:12:22,610
SHOWN HERE, A-BETA 40 IS SHOWN

7307
05:12:22,610 --> 05:12:27,315
IN THE WHITE AND A-BETA 42 IN

7308
05:12:27,315 --> 05:12:32,954
THE GRAY AND THE A-BETA 40, TO

7309
05:12:32,954 --> 05:12:36,124
42 RATIO TENDS TO BE HIGHER IN

7310
05:12:36,124 --> 05:12:37,692
MOST HUMAN PRIMATES AND THERE IS

7311
05:12:37,692 --> 05:12:38,593
OVERLAP IN THAT REGARD BUT IN

7312
05:12:38,593 --> 05:12:40,829
GENERAL AS YOU CAN SEE THERE CAN

7313
05:12:40,829 --> 05:12:45,099
BE WHOPPING AMOUNTS OF ABETTA IN

7314
05:12:45,099 --> 05:12:51,573
THE NONHUMAN PRIMATE BRAIN

7315
05:12:51,573 --> 05:12:52,540
EMPLOY AMYLOID ANGY OPERATING

7316
05:12:52,540 --> 05:12:54,008
GLOBALLYATHY HAS BEEN SEEN IN

7317
05:12:54,008 --> 05:12:55,944
FAIR AMOUNTS IN EVERY PRIMATE

7318
05:12:55,944 --> 05:13:06,621
SPECIES THAT'S BEEN STUDIED AND

7319
05:13:06,621 --> 05:13:10,792
THIS RANGES FROM LEMURS TO

7320
05:13:10,792 --> 05:13:11,359
HUMANS.

7321
05:13:11,359 --> 05:13:13,428
HERE WE HAVE SQUIRREL MONKEYS

7322
05:13:13,428 --> 05:13:18,132
MUCH MORE RELIABLE DEVELOPPA

7323
05:13:18,132 --> 05:13:20,668
ANGIE OPEN MEETINGATHY AND THAN

7324
05:13:20,668 --> 05:13:22,470
RHESUS MONKEY AND BOTH HAVE

7325
05:13:22,470 --> 05:13:25,006
SIMILAR AMOUNTS.

7326
05:13:25,006 --> 05:13:27,876
SO THE SCORE MONKEY MODEL OF CAA

7327
05:13:27,876 --> 05:13:30,144
HAS BEEN ARK ROUND FOR A FEW FEW

7328
05:13:30,144 --> 05:13:32,080
YEARS NOW, AS I MENTION TODAY

7329
05:13:32,080 --> 05:13:33,882
CAN LISTEN UP TO 30 YEARS,

7330
05:13:33,882 --> 05:13:36,651
THEY'RE RATHER SMALL, THEY CAN

7331
05:13:36,651 --> 05:13:39,053
GO UP TO ABOUT A THOUSAND GRAMS

7332
05:13:39,053 --> 05:13:42,690
FOR SOME MALES TYPES A LITTLE

7333
05:13:42,690 --> 05:13:45,326
OVER BUT MOSTLY 500 TO 900-GRAMS

7334
05:13:45,326 --> 05:13:49,631
SO ESSENTIALLY THE SIZE OF VERY

7335
05:13:49,631 --> 05:13:50,598
LARGE RATS.

7336
05:13:50,598 --> 05:13:53,501
THE DEPOSITION OF A-BETA IN THE

7337
05:13:53,501 --> 05:13:54,802
VASCULAR WALL BEGINSA THE AROUND

7338
05:13:54,802 --> 05:13:56,671
13 YEARS OF AGE IN THIS SPECIES

7339
05:13:56,671 --> 05:13:59,274
AND IT'S MODERATE TO SEVERE, BY

7340
05:13:59,274 --> 05:14:00,475
THE TIME THEY'RE 18 YEARS OF

7341
05:14:00,475 --> 05:14:00,675
AGE.

7342
05:14:00,675 --> 05:14:06,414
AND HERE YOU CAN SEE, THERE'S

7343
05:14:06,414 --> 05:14:08,883
AMYLOID DEPOSITION IN THE

7344
05:14:08,883 --> 05:14:10,385
PATHWAY GIVES RENCHEMMA OF THE

7345
05:14:10,385 --> 05:14:13,621
BRAIN ALSO IN THE SOLKUS, 1 OF

7346
05:14:13,621 --> 05:14:18,826
THE CHARACTERISTICS OF THE

7347
05:14:18,826 --> 05:14:22,964
SQUIRREL MORVEGY AMYLOID

7348
05:14:22,964 --> 05:14:23,264
ANGYOAPATHY.

7349
05:14:23,264 --> 05:14:33,708
CAN CAPILLARY CAA IS QUITE

7350
05:14:45,987 --> 05:14:46,254
COMMON.

7351
05:14:46,254 --> 05:14:48,189
--TO THE DEVELOP AM OF CAA AND

7352
05:14:48,189 --> 05:14:51,159
WE WANTED THEM TO INVESTIGATE

7353
05:14:51,159 --> 05:14:55,363
THIS HUOF  HISTOLOGICALLY.

7354
05:14:55,363 --> 05:14:58,700
SO IN THESE MONKEYS 2 OF THEM

7355
05:14:58,700 --> 05:14:59,901
DEVELOPED, BOTH AS 19 YEARS OF

7356
05:14:59,901 --> 05:15:02,303
AGE AS EXECKED THERE WAS LESS IN

7357
05:15:02,303 --> 05:15:02,837
THE YOUNGER ANIMALS.

7358
05:15:02,837 --> 05:15:09,310
THE MONKEY THAT I WILL FOCUS ON

7359
05:15:09,310 --> 05:15:13,214
IS NUMBER 2266. 

7360
05:15:13,214 --> 05:15:17,618
I WAS IN THE MRI SUITE WITH MY

7361
05:15:17,618 --> 05:15:18,619
COLLEAGUE [INDISCERNIBLE] CAN WE

7362
05:15:18,619 --> 05:15:20,488
HAD GONE THROUGH SCANS OF

7363
05:15:20,488 --> 05:15:21,889
SEVERAL MONKEYS IN PERSON, AND

7364
05:15:21,889 --> 05:15:25,193
WE GOT TO THIS PARTICULAR MONKEY

7365
05:15:25,193 --> 05:15:26,761
2266, AND WHEN WE GOT TO THIS

7366
05:15:26,761 --> 05:15:33,334
REGION WHICH WAS IN THE MORE

7367
05:15:33,334 --> 05:15:34,469
CODDAL PARIETAL OCCIPITAL

7368
05:15:34,469 --> 05:15:36,270
REGION, THEY SAID, WOW, THERE'S

7369
05:15:36,270 --> 05:15:36,838
SOMETHING DEFINITE THERE.

7370
05:15:36,838 --> 05:15:41,609
AND AS YOU CAN SEE, IN THIS

7371
05:15:41,609 --> 05:15:44,846
INITANCE, THERE IS BY 2-2

7372
05:15:44,846 --> 05:15:45,780
WEIGHTED IMAGING CONSIDERABLY

7373
05:15:45,780 --> 05:15:48,783
HYPER INTENSITY IN THE WHITE

7374
05:15:48,783 --> 05:15:50,618
MATTER, MA LESS IN THE GRAY

7375
05:15:50,618 --> 05:15:53,021
MATTER, AS WELL, AND YOU CAN SEE

7376
05:15:53,021 --> 05:15:56,758
THAT IT IS BILATERAL IN THIS

7377
05:15:56,758 --> 05:15:57,225
PARTICULAR INSTANCE.

7378
05:15:57,225 --> 05:16:01,896
AND WE DID NOT SEE ANY SUCH MRI

7379
05:16:01,896 --> 05:16:03,531
ABNORMALITIES IN ANY OF THE

7380
05:16:03,531 --> 05:16:04,799
OTHER 3 ANIMALS OR ELSEWHERE IN

7381
05:16:04,799 --> 05:16:06,200
THE BRAIN OF THIS PARTICULAR

7382
05:16:06,200 --> 05:16:06,501
MONKEY.

7383
05:16:06,501 --> 05:16:09,637
IF YOU LOOK AT A SERIES OF

7384
05:16:09,637 --> 05:16:13,074
SCANS, T-1 STRUCTURAL SCAN, T2

7385
05:16:13,074 --> 05:16:15,810
SCAN, THE LESIONS WERE

7386
05:16:15,810 --> 05:16:17,779
BILATERAL, SOMEWHAT ASYMMETRIC

7387
05:16:17,779 --> 05:16:20,615
AND THEY ECTENDED THE DISTANCE

7388
05:16:20,615 --> 05:16:21,516
ABOUT 8-10-MILLIMETERS THROUGH

7389
05:16:21,516 --> 05:16:23,818
THE BREAN AND YOU CAN SEE IF YOU

7390
05:16:23,818 --> 05:16:27,622
LOOK AT AN AREA WHERE THERE'S

7391
05:16:27,622 --> 05:16:30,458
CONSIDERABLE HYPER INTENSITY ON

7392
05:16:30,458 --> 05:16:36,664
THIS SIDE, THERE'S A REDUCTION

7393
05:16:36,664 --> 05:16:38,866
IN THE SIGNAL OF WHITE MATTER IN

7394
05:16:38,866 --> 05:16:44,939
THE T1 STRUCTURAL KAN--KANA. 

7395
05:16:44,939 --> 05:16:46,040
AND THIS WAS SEEN IN THIS

7396
05:16:46,040 --> 05:16:49,544
PARTICULAR CASE EMPLOY WE DID

7397
05:16:49,544 --> 05:16:50,178
SUSEPTIBILITY, WEIGHTED IMAGING

7398
05:16:50,178 --> 05:16:50,812
IN THIS SQUIRREL MONKEY AND

7399
05:16:50,812 --> 05:16:55,716
THERE WERE A NUMBER OF FOR SHALL

7400
05:16:55,716 --> 05:16:57,585
FOCI BUT MOST PROMINENTLY WE SAW

7401
05:16:57,585 --> 05:17:02,590
HERE IN THE PARIETAL SULKUS, A

7402
05:17:02,590 --> 05:17:07,728
STRONG HYPOINTENSE REGION THAT

7403
05:17:07,728 --> 05:17:08,229
OVERLAPPED PARTIALLY BUT

7404
05:17:08,229 --> 05:17:10,531
SIGNIFICANTLY I THINK WITH THE

7405
05:17:10,531 --> 05:17:17,271
EDEMETUS REGION WE SAW IN THE

7406
05:17:17,271 --> 05:17:18,106
T-2 SCAN.

7407
05:17:18,106 --> 05:17:28,583
AS EXPECTED THIS MONKEY HAD

7408
05:17:33,988 --> 05:17:34,422
CONSIDERABLE ANGIOPATHY

7409
05:17:34,422 --> 05:17:35,022
STRONGLY.

7410
05:17:35,022 --> 05:17:38,726
AND AT A MACROSCOPIC LEVEL, YOU

7411
05:17:38,726 --> 05:17:43,131
GD SEE, WITH EVERYBODY'S TO

7412
05:17:43,131 --> 05:17:45,700
ASTRO CITES TO GFAPP AND

7413
05:17:45,700 --> 05:17:46,901
MICRODPLEEL SALES AND

7414
05:17:46,901 --> 05:17:48,536
MACROPHAGES AND IBA 1, CAN YOU

7415
05:17:48,536 --> 05:17:52,440
SEE A DARKENING IN THE PARIETAL

7416
05:17:52,440 --> 05:17:55,309
SULCUS AROUND WHICH WE SAW MOST

7417
05:17:55,309 --> 05:17:59,347
OF THE SIGNALS BY MRI.

7418
05:17:59,347 --> 05:18:01,516
ANDA THE MICROSCOPIC LEVELS

7419
05:18:01,516 --> 05:18:06,220
INCREASE, WE COULD COMPARE THE

7420
05:18:06,220 --> 05:18:14,362
REGIONS THAT SHOWED CONSIDERABLE

7421
05:18:14,362 --> 05:18:15,029
SIGNAL COMPARED IN THE SAME

7422
05:18:15,029 --> 05:18:17,832
SECTION TO THE AREA THAT LACKED

7423
05:18:17,832 --> 05:18:19,567
THE HYPER INTENSE T2 SIGNAL AND

7424
05:18:19,567 --> 05:18:22,637
AS YOU CAN SEE THERE ARE

7425
05:18:22,637 --> 05:18:23,704
HYPOTROAPIC ASTRO SIGHTS IN THE

7426
05:18:23,704 --> 05:18:26,807
AFFECTED REGION AS WELL AS HYPER

7427
05:18:26,807 --> 05:18:28,209
TROAPIC FLEEL CELLS QUITE

7428
05:18:28,209 --> 05:18:31,179
ABUNDANT IN THIS REGION.

7429
05:18:31,179 --> 05:18:35,583
IN ADDITION, BY LOOKING AT THE

7430
05:18:35,583 --> 05:18:38,619
INTEGRITY OF AXONS IN THE

7431
05:18:38,619 --> 05:18:40,454
REGION, USING SMI 31, ANTIBODY,

7432
05:18:40,454 --> 05:18:45,393
YOU CAN SEE CONSIDERABLE LOSS

7433
05:18:45,393 --> 05:18:48,396
OFAXONS DISRUPTION OR DISMORPHIC

7434
05:18:48,396 --> 05:18:50,131
REMAINING AXONS IN THE AFFECTED

7435
05:18:50,131 --> 05:18:52,099
REGION, COMPARED TO THE

7436
05:18:52,099 --> 05:18:54,602
UNAFFECTED REGION AND USING THE

7437
05:18:54,602 --> 05:18:57,138
LFB STAIN, THERE'S A CLEAR

7438
05:18:57,138 --> 05:18:59,106
RAREFACTION OF MILEIN IN THE

7439
05:18:59,106 --> 05:19:02,210
AFFECTED AS OPPOSE TO THE

7440
05:19:02,210 --> 05:19:07,882
UNAFFECTED AREA. 

7441
05:19:07,882 --> 05:19:10,218
SO THAT WAS THE ARIA REGION IN

7442
05:19:10,218 --> 05:19:18,459
THE REGION THAT HAD THE INTENSE

7443
05:19:18,459 --> 05:19:28,970
SIGNAL AT THE PARIETAL FLANUE

7444
05:19:32,073 --> 05:19:33,507
LOAMUS, NUMEROUS TUOF THE

7445
05:19:33,507 --> 05:19:35,142
VESSELS SURROUNDING THIS AREA,

7446
05:19:35,142 --> 05:19:37,078
THESE WERE SEEING PRETTY MUCH

7447
05:19:37,078 --> 05:19:39,714
SOLELY IN ASSOCIATION WITH THIS

7448
05:19:39,714 --> 05:19:41,315
GRANULA MASS AND 1 LOOKED LIKE

7449
05:19:41,315 --> 05:19:44,118
THE REMNANTS OF A PRIOR BLOOD

7450
05:19:44,118 --> 05:19:48,856
SOMEWHERE IN THE BRAIN IN THIS

7451
05:19:48,856 --> 05:19:52,126
PARTICULAR MONKEY. 

7452
05:19:52,126 --> 05:19:54,161
THERE WERE NUMEROUS A-BETA

7453
05:19:54,161 --> 05:19:56,631
IMMUNO REACTIVE BLOOD VESSELS IN

7454
05:19:56,631 --> 05:19:59,567
THE SULCUS AND SURROUNDING

7455
05:19:59,567 --> 05:20:02,403
PARTICULAR TIMES WITHIN THE

7456
05:20:02,403 --> 05:20:04,171
GRANUE LOAMATUS MASS THERE WAS

7457
05:20:04,171 --> 05:20:07,108
CONSIDERABLE ARK MOUNT OF FAIR

7458
05:20:07,108 --> 05:20:08,809
IRON STAINED WITH THE PEARL

7459
05:20:08,809 --> 05:20:09,210
STAIN.

7460
05:20:09,210 --> 05:20:13,714
THERE WERE ALSO NUMEROUS

7461
05:20:13,714 --> 05:20:16,050
MONOSITTIC CELLS SHOWN HERE

7462
05:20:16,050 --> 05:20:18,753
TAINED WITH CD68, MOSTLY, THESE

7463
05:20:18,753 --> 05:20:21,489
AND LYMPHCITES TAINED WITH CD3,

7464
05:20:21,489 --> 05:20:23,724
WERE WITHIN THE GRANUE LOAMATUS

7465
05:20:23,724 --> 05:20:23,924
MASS.

7466
05:20:23,924 --> 05:20:29,530
THERE WERE A FEW OF CELLS IN THE

7467
05:20:29,530 --> 05:20:30,998
AYAISENT, BUT NOT ALL THAT MEAN,

7468
05:20:30,998 --> 05:20:33,534
REALLY SO THAT'S WHAT WE SAW A

7469
05:20:33,534 --> 05:20:34,802
SPONTANEOUS DEVELOPMENT OF WHAT

7470
05:20:34,802 --> 05:20:37,872
I THINK AS YOU SAW THIS MORNING,

7471
05:20:37,872 --> 05:20:40,408
ALMOST CERTAINLY IS AMYLOID

7472
05:20:40,408 --> 05:20:41,208
RELATED IMANNUALING

7473
05:20:41,208 --> 05:20:42,143
ABNORMALITIES IN THE SQUIRREL

7474
05:20:42,143 --> 05:20:44,045
MONKEYS AND I THINK THAT THE

7475
05:20:44,045 --> 05:20:45,546
SQUIRREL MONKEY MODEL MIGHT BE

7476
05:20:45,546 --> 05:20:46,280
USEFUL FOR MODELING BOG SIDE

7477
05:20:46,280 --> 05:20:47,548
CENTER FOR EXCELLENCE ON AGINGS

7478
05:20:47,548 --> 05:20:50,151
AND THE EFFECTS OF

7479
05:20:50,151 --> 05:20:50,484
IMMUNOTHERAPY.

7480
05:20:50,484 --> 05:20:55,423
AND THE ADVANT ANNUALS OF THE

7481
05:20:55,423 --> 05:20:59,026
PRIMATE MODEL FOR OBVIOUS AS ARE

7482
05:20:59,026 --> 05:21:00,961
I THINK THE DISADVANTAGES

7483
05:21:00,961 --> 05:21:02,196
BESIDES THE 1S THAT BILL JUST

7484
05:21:02,196 --> 05:21:02,463
MENTIONED.

7485
05:21:02,463 --> 05:21:04,932
ONE OF THE ISSUES WITH MONKEYS

7486
05:21:04,932 --> 05:21:05,966
ASK WE TILL DON'T QUITE

7487
05:21:05,966 --> 05:21:07,601
UNDERSTAND THIS IS THAT WE

7488
05:21:07,601 --> 05:21:11,639
PREVIOUSLY FOUND WHEN TRYING TO

7489
05:21:11,639 --> 05:21:13,574
DETERMINE THE BINDING OF

7490
05:21:13,574 --> 05:21:16,277
PITTSBURGH COMPOUND B TO A-BETA

7491
05:21:16,277 --> 05:21:17,478
FROM NONHUMAN PRIME'SS COMPARED

7492
05:21:17,478 --> 05:21:20,548
TO HUMANS, THERE IS CONSIDERABLE

7493
05:21:20,548 --> 05:21:23,351
HIGH AFFINITY BINDING OF PIB IN

7494
05:21:23,351 --> 05:21:25,686
HUMANS WITH ALZHEIMER'S DEC BUT

7495
05:21:25,686 --> 05:21:26,987
ESSENTIALLY NO HIGH AFFINITY

7496
05:21:26,987 --> 05:21:28,856
BINDING IN ANY NONHUMAN PRIMATE

7497
05:21:28,856 --> 05:21:32,793
THAT THAT WE'VE LOOKED AT AND WE

7498
05:21:32,793 --> 05:21:34,729
SIMPLY DON'T KNOW WHY THIS IS, I

7499
05:21:34,729 --> 05:21:38,933
CAN SPECULATE BUT I JUST DON'T

7500
05:21:38,933 --> 05:21:44,505
KNOW.

7501
05:21:44,505 --> 05:21:46,073
ANOTHER DISADVANTAGE IS THE LONG

7502
05:21:46,073 --> 05:21:47,541
LIFE AND AVAILABILITY OF THESE,

7503
05:21:47,541 --> 05:21:49,276
THIS PROBLEM MIGHT BE OVERCOME

7504
05:21:49,276 --> 05:21:59,820
BY THE EXPRESSION OF TRANSGENES

7505
05:22:00,388 --> 05:22:03,858
AND THERE HAD BEEN MARMOSET

7506
05:22:03,858 --> 05:22:04,525
MODELS, THEY'RE EVOLUTIONARY

7507
05:22:04,525 --> 05:22:06,994
DANTE FOWLER FROM HUMANS, ABOUT

7508
05:22:06,994 --> 05:22:10,231
WHERE IMIRL MORKYS ARE, THEY'RE

7509
05:22:10,231 --> 05:22:11,298
SMALLER, 4-500-GRAMS THEY GIVE

7510
05:22:11,298 --> 05:22:13,501
BIRTH TO TWINS, THERE ARE

7511
05:22:13,501 --> 05:22:17,004
ADVABTAGES TO THE MARMOSETS AND

7512
05:22:17,004 --> 05:22:19,039
SOME GROUPS ARE DEVELOPING

7513
05:22:19,039 --> 05:22:20,574
TRANSGENIC HARMA SETS BUT NO 1

7514
05:22:20,574 --> 05:22:22,143
HAS REPORTED ON THE PATHOLOGY IN

7515
05:22:22,143 --> 05:22:23,711
THESE ANIMAL ANDS IN FACT THE

7516
05:22:23,711 --> 05:22:25,546
ONLY REPORTED PATHOLOGY IN A

7517
05:22:25,546 --> 05:22:28,516
NONHUMAN PRIMATE THAT'S BASED ON

7518
05:22:28,516 --> 05:22:30,518
AN APP TRANSGENE WAS IN

7519
05:22:30,518 --> 05:22:32,119
COLLABORATION WITH MY COLLEAGUE

7520
05:22:32,119 --> 05:22:37,425
ANTHONY CHAN WHERE WE FOUND THAT

7521
05:22:37,425 --> 05:22:39,994
APP EXPRESSION IN A RECESS

7522
05:22:39,994 --> 05:22:42,930
MONKEY GENERATED A BETA

7523
05:22:42,930 --> 05:22:45,533
DEPOSITION PRIMARILY IN THE

7524
05:22:45,533 --> 05:22:46,400
OCCIPITAL AND PARIETAL REGIONS

7525
05:22:46,400 --> 05:22:48,269
BY THE TIME THIS PARTICULAR

7526
05:22:48,269 --> 05:22:49,570
MONKEY AND WE ONLY HAVE 1 OF 2

7527
05:22:49,570 --> 05:23:00,080
IN WHICH THIS HAPPENED WAS 10

7528
05:23:01,015 --> 05:23:03,551
YEARS OLD AND AS YOU CAN SEE

7529
05:23:03,551 --> 05:23:07,221
THERE'S A FAIR AMOUNT OF AMYLOID

7530
05:23:07,221 --> 05:23:09,924
ANG YOAPATHY IN THESE MODELS.

7531
05:23:09,924 --> 05:23:12,326
THESE MODELS MIGHT BE REALLY

7532
05:23:12,326 --> 05:23:16,730
USEFUL FOR TESTING IMMUNO

7533
05:23:16,730 --> 05:23:19,433
PREVENTION STRATEGIES.

7534
05:23:19,433 --> 05:23:20,034
FOR TESTING MONOCLONAL

7535
05:23:20,034 --> 05:23:22,203
ANTIBODIES AND ALSO THEIR IRPT

7536
05:23:22,203 --> 05:23:25,873
ACTION WITH OTHER AGENTS SUCH AS

7537
05:23:25,873 --> 05:23:27,208
ANTICO AGULATES AND

7538
05:23:27,208 --> 05:23:27,608
ANTITHROMBOTTICS.

7539
05:23:27,608 --> 05:23:29,210
I ALSO THINK WE SHOULDN'T IMIF

7540
05:23:29,210 --> 05:23:33,047
UP ON ACTIVE IMMUNIZATION EMPLOY

7541
05:23:33,047 --> 05:23:34,715
AND NONHUMAN PRIMATES WILL BE

7542
05:23:34,715 --> 05:23:36,684
IDEAL FOR TESTING ACTIVE

7543
05:23:36,684 --> 05:23:38,486
IMMUNIZATION AND DETERMINING IF

7544
05:23:38,486 --> 05:23:40,721
1 IMMUNIZES ANIMALS AT A YOUNG

7545
05:23:40,721 --> 05:23:43,123
AGE, ARE THERE ANY ADVERSE

7546
05:23:43,123 --> 05:23:43,557
EFFECTS.

7547
05:23:43,557 --> 05:23:45,493
AND DOES THIS THEN DELAY THE

7548
05:23:45,493 --> 05:23:46,427
ONSET OF ABETTA DEPOSITION IN

7549
05:23:46,427 --> 05:23:47,261
THE BRAIN.

7550
05:23:47,261 --> 05:23:52,366
AND IN FACT, WE HAVE DONE AN

7551
05:23:52,366 --> 05:23:54,869
UNPUBLISHED PRELIMINARY STUDY

7552
05:23:54,869 --> 05:23:57,571
WHERE WE'VE IMMUNIZED ALL

7553
05:23:57,571 --> 05:23:58,405
SQUIRREL MONKEYS, ACTIVELY

7554
05:23:58,405 --> 05:23:59,907
IMMUNIZE THEM AND MOST OF PEOPLE

7555
05:23:59,907 --> 05:24:02,042
DO DEVELOP A NICE RESPONSE TO

7556
05:24:02,042 --> 05:24:04,445
THE A-BETA ANTIIEN SO THIS IS

7557
05:24:04,445 --> 05:24:05,145
PERFECTLY FEASIBLE, IT'S DOABLE

7558
05:24:05,145 --> 05:24:08,315
AND I THINK IT WILL BE 1 ARENA

7559
05:24:08,315 --> 05:24:10,284
IN WHICH THE NONHUMAN PRIMATE

7560
05:24:10,284 --> 05:24:11,418
MODEL WOULD BE PARTICULARLY

7561
05:24:11,418 --> 05:24:17,925
USEFUL. 

7562
05:24:17,925 --> 05:24:20,961
SO IN CONCLUSION, CAA IS DEFAULT

7563
05:24:20,961 --> 05:24:23,097
NONHUMAN PRIMATES ALL WE LOOKED

7564
05:24:23,097 --> 05:24:25,332
AT DEVELOPED SIGNIFICANT CAA.

7565
05:24:25,332 --> 05:24:27,368
SPONTANEOUS ARIA WE FOUND NOW IN

7566
05:24:27,368 --> 05:24:28,469
1 AGED SQUIRREL MONKEY.

7567
05:24:28,469 --> 05:24:30,571
HOW OFTEN THIS OCCURS IN OTHER

7568
05:24:30,571 --> 05:24:32,072
SQUIRREL MONKEYS OR OTHER

7569
05:24:32,072 --> 05:24:33,841
PRIME'SS IS UMP SIMPLY NOT KNOWN

7570
05:24:33,841 --> 05:24:40,814
AND I THINK THAT THESE COULD

7571
05:24:40,814 --> 05:24:43,050
HAVE VALUE OF TESTING SAFETY AND

7572
05:24:43,050 --> 05:24:44,852
EFFICACY OF THERAPEUTIC

7573
05:24:44,852 --> 05:24:55,396
APPROACHES TO ALZHEIMER'S DEC. 

7574
05:24:57,731 --> 05:24:58,666
THANK YOU.

7575
05:24:58,666 --> 05:25:02,703
>> WE HAVE TIME FOR
QUESTIONS.

7576
05:25:02,703 --> 05:25:08,309
HOW MANY MONKEYS HAVE BEEN

7577
05:25:08,309 --> 05:25:10,144
CHARACTERIZED IN TERMS OF

7578
05:25:10,144 --> 05:25:10,578
[INDISCERNIBLE].

7579
05:25:10,578 --> 05:25:12,580
SO IS THERE A POPULATION YOU CAN

7580
05:25:12,580 --> 05:25:16,116
FALL BACK ON OR JUST YOUR 5 IN.

7581
05:25:16,116 --> 05:25:18,986
>> WE'VE LOOKED IN TERMS
OF THE

7582
05:25:18,986 --> 05:25:20,854
NUMBER OF SQUIRREL MONKEYS, MOST

7583
05:25:20,854 --> 05:25:25,526
OF THESE HAVE BEEN OPPORTUNISTIC

7584
05:25:25,526 --> 05:25:29,296
INITANCES, THE MONKEYS I'VE

7585
05:25:29,296 --> 05:25:30,831
SHOWN I'VE KNOWN ANALS WHICH IS

7586
05:25:30,831 --> 05:25:32,232
UNUSUAL IN MANY PRIMATE TODAYS

7587
05:25:32,232 --> 05:25:34,568
IF THEY WERE CAUGHT IN THE WILD

7588
05:25:34,568 --> 05:25:36,837
EMPLOY MANY SQUIRREL MONKEYS

7589
05:25:36,837 --> 05:25:43,277
HAVE BEEN ANALYZES MANY RHESUS

7590
05:25:43,277 --> 05:25:45,879
MONKEYS HAVE BEEN ANALYZE

7591
05:25:45,879 --> 05:25:48,015
EXCLUDE NOW MORE MARMOSETTA SES

7592
05:25:48,015 --> 05:25:49,984
HAVE BEEN ANALYZED SO THERE IS A

7593
05:25:49,984 --> 05:25:51,919
PRETTY GOOD IDEA WHERE CAA

7594
05:25:51,919 --> 05:25:55,656
STARTS IN THESE SPECIES NO THERE

7595
05:25:55,656 --> 05:26:01,328
IS I NORMATIVE DATA.

7596
05:26:01,328 --> 05:26:02,496
>> THERE IS SMRKS BUT IF
YOU

7597
05:26:02,496 --> 05:26:03,931
HAVE TO WAIT 13 YEARS, THAT WILL

7598
05:26:03,931 --> 05:26:05,099
BE A PROBLEM NYEAH THAT WILL BE

7599
05:26:05,099 --> 05:26:07,601
A PROBLEM AND YOU CAN DO IT IN A

7600
05:26:07,601 --> 05:26:09,203
WILD RAINCHLING COLONY SOMEWHERE

7601
05:26:09,203 --> 05:26:12,940
SUCH AS IN SANTIAGO WHERE

7602
05:26:12,940 --> 05:26:13,641
YOU'MUNIZE THEM WHEN THEY'RE

7603
05:26:13,641 --> 05:26:14,942
YOUNG AND LET THEM DO WHAT THEY

7604
05:26:14,942 --> 05:26:17,311
DO FOR A NUMBER OF YEAR ANDS

7605
05:26:17,311 --> 05:26:21,482
EVALUATE THEM PERIODICALLY FOR

7606
05:26:21,482 --> 05:26:23,417
SIDE EFFECTS.

7607
05:26:23,417 --> 05:26:24,985
NI'M ALMOST EMBARRASSED TO ASK

7608
05:26:24,985 --> 05:26:26,887
THIS QUESTION BUT I WON'T STOP

7609
05:26:26,887 --> 05:26:29,623
IT, DO OLD MONKEYS DEVELOP

7610
05:26:29,623 --> 05:26:30,624
DEMENTIA, IF THEY DEVELOP

7611
05:26:30,624 --> 05:26:32,092
DEMENTIA IS IT A PATHOLOGY THAT

7612
05:26:32,092 --> 05:26:34,561
CORRELATES IN ANY WAY WITH THE

7613
05:26:34,561 --> 05:26:38,565
HUMAN CONDITION?

7614
05:26:38,565 --> 05:26:39,967
>> GOOD QUESTION EMPLOY
THE

7615
05:26:39,967 --> 05:26:42,970
ANSWER IS DEMENTIA NO, IT'S A

7616
05:26:42,970 --> 05:26:44,772
SEVERE LOSS OF COGNITIVE

7617
05:26:44,772 --> 05:26:45,873
FUNCTION THAT INTERFERES WITH

7618
05:26:45,873 --> 05:26:48,108
EVERY DAY LIFE, THEY DO SLOW

7619
05:26:48,108 --> 05:26:50,477
DOWN AND PERFORM MORE POORLY,

7620
05:26:50,477 --> 05:26:55,149
BUT DEMENTIA'S NEVER BEEN SEEN.

7621
05:26:55,149 --> 05:26:57,084
ALZHEIMER LIKE TAU-OP A THY HAS

7622
05:26:57,084 --> 05:26:59,019
NEVER BEEN SEEN IN THESE

7623
05:26:59,019 --> 05:26:59,286
PRIMATES.

7624
05:26:59,286 --> 05:27:01,622
THIS A DIFFERENCE IN THE FOLD IN

7625
05:27:01,622 --> 05:27:02,923
THE BETA OF NONHUMAN PRIMATES

7626
05:27:02,923 --> 05:27:04,158
AND WE HAVE EVIDENT THAT THAT'S

7627
05:27:04,158 --> 05:27:06,860
THE CASE EMPLOY BUT WHY THEY

7628
05:27:06,860 --> 05:27:08,062
DON'T DEVELOPPAL JEIMER SYSTEM A

7629
05:27:08,062 --> 05:27:08,896
REALLY IMPORTANT PROBLEM THAT I

7630
05:27:08,896 --> 05:27:12,566
THINK MIGHT TELL US ABOUT THE

7631
05:27:12,566 --> 05:27:15,736
WAYS WE COULD TREAT OR PREVENT

7632
05:27:15,736 --> 05:27:16,370
ALZHEIMERS IN HUMANS.

7633
05:27:16,370 --> 05:27:26,847
WE WILL ANY TO ONLINE NOW. 

7634
05:27:32,453 --> 05:27:40,928
NTHIS IS FROM BILL, WHERE IT

7635
05:27:40,928 --> 05:27:42,529
COMING FROM.

7636
05:27:42,529 --> 05:27:45,933
>> IT PRIMARILY AGGREGATES

7637
05:27:45,933 --> 05:27:50,204
BETWEEN THE CELLS SO, I MEAN

7638
05:27:50,204 --> 05:27:53,207
IT'S IN THE--IN THE SUBSTANCE

7639
05:27:53,207 --> 05:27:55,909
THAT SURROUNDS THE CAPILLARY.

7640
05:27:55,909 --> 05:27:59,179
THE BASE OF MEMBRANE BASIC LYE

7641
05:27:59,179 --> 05:28:01,582
OR BASAL LAMINA CALLED BY SOME.

7642
05:28:01,582 --> 05:28:02,816
IT'S PRETTY MUCH ALWAYS THERE

7643
05:28:02,816 --> 05:28:07,788
AND OF COURSE, IN SEVERE CASES,

7644
05:28:07,788 --> 05:28:15,763
THE ARTERIES LOSE THEIR SMOOTH

7645
05:28:15,763 --> 05:28:17,631
MUSCLE CELLS.

7646
05:28:17,631 --> 05:28:19,099
NIMRAIT TALK LARY, I JUST WANTED

7647
05:28:19,099 --> 05:28:22,302
TO SAY WE HAVE DONE WORK WITH

7648
05:28:22,302 --> 05:28:24,938
ACT VISATION IN [INDISCERNIBLE],

7649
05:28:24,938 --> 05:28:26,240
WE HAVEN'T PUBLISHED IT BUT IT

7650
05:28:26,240 --> 05:28:28,876
WAS WORK WE PRESENTED AT A

7651
05:28:28,876 --> 05:28:30,477
NUMBER OF MEETINGS SO WE

7652
05:28:30,477 --> 05:28:32,012
IMMUNIZE THIS WAS TOGETHER WITH

7653
05:28:32,012 --> 05:28:34,515
THE YF AND WE IMMUNIZED MONKEYS

7654
05:28:34,515 --> 05:28:38,152
FOR VETS THAT WERE 18 TO I THINK

7655
05:28:38,152 --> 05:28:43,023
24 YEARS OF AGE WITH EITHER

7656
05:28:43,023 --> 05:28:45,959
AM1752, OR A B-CELL EPITOPE

7657
05:28:45,959 --> 05:28:48,028
DENDRITIC CELL RIMERRIC LYSINE

7658
05:28:48,028 --> 05:28:50,464
PEPTIDE TREE CALLED DENDRITIC

7659
05:28:50,464 --> 05:28:51,832
CELL RAMERRIC A-BETA 115 AND WE

7660
05:28:51,832 --> 05:28:54,935
DID SEE PLAQUE LOWERING WITH THE

7661
05:28:54,935 --> 05:28:56,737
1 YEAR IMMUNIZATION STUDY, WE

7662
05:28:56,737 --> 05:28:59,640
DID SEE PLAQUE LOWERING, WE DID

7663
05:28:59,640 --> 05:29:04,411
SEE IMPROVEMENT WITH THE PEPTIDE

7664
05:29:04,411 --> 05:29:06,413
VACCINE ON THE 1 PARTICULAR

7665
05:29:06,413 --> 05:29:06,713
TEST.

7666
05:29:06,713 --> 05:29:10,818
IT'S A CAN TAB TEST AND SO WE

7667
05:29:10,818 --> 05:29:13,687
DID WE COGNITIVE IMPROVEMENT IN

7668
05:29:13,687 --> 05:29:15,823
EXECUTIVE FUNCTION WITH

7669
05:29:15,823 --> 05:29:16,156
IMMUNOTHERAPY.

7670
05:29:16,156 --> 05:29:17,457
WE DID SEE VASCULAR AMYLOID BUT

7671
05:29:17,457 --> 05:29:20,060
WHAT WE HAVEN'T DONE IS A SERIES

7672
05:29:20,060 --> 05:29:21,328
OF [INDISCERNIBLE] STAINS ON

7673
05:29:21,328 --> 05:29:21,662
THOSE ANIMALS.

7674
05:29:21,662 --> 05:29:22,763
WE TILL HAVE THE BRAINS SO I

7675
05:29:22,763 --> 05:29:23,997
THINK IT WILL BE INTERESTING

7676
05:29:23,997 --> 05:29:29,770
NOW, TO GO BACK AND REALLY LOOK

7677
05:29:29,770 --> 05:29:30,704
FURTHER AT HEMOSITTERIN

7678
05:29:30,704 --> 05:29:33,073
EPECIALLY WITH THE TALK WE HEARD

7679
05:29:33,073 --> 05:29:40,214
FROM JAMES NIC OWELL, W

7680
05:29:40,214 --> 05:29:41,815
ELL,--JAIPS NICOLL AND WE DID

7681
05:29:41,815 --> 05:29:45,385
SEE COMPLEMENT IN THOSE ANIMALS

7682
05:29:45,385 --> 05:29:46,787
ANDY FOUND CR1 UPREGULATION OF

7683
05:29:46,787 --> 05:29:49,690
CR1 IN THE LIVER OF THOSE

7684
05:29:49,690 --> 05:29:51,692
ANIMALS AND SO, I THINK ANOTHER

7685
05:29:51,692 --> 05:29:53,527
THING WE MIGHT WANT TO THINK

7686
05:29:53,527 --> 05:29:58,432
ABOUT IS ANOTHER BIOMARKER IS

7687
05:29:58,432 --> 05:30:00,334
CLEARANCE OF THESE COMPLEXES IN

7688
05:30:00,334 --> 05:30:02,603
THE PERIPHERAL SYSTEM, AND SO,

7689
05:30:02,603 --> 05:30:05,672
LIVER WE DEFINITELY SAW THESE

7690
05:30:05,672 --> 05:30:10,177
COMPLEXES, ACTUALLY BEING

7691
05:30:10,177 --> 05:30:12,946
SEQUESTERED NIT'S INTERESTING,

7692
05:30:12,946 --> 05:30:15,883
WE TOO ARE DONE IMMUNIZATION

7693
05:30:15,883 --> 05:30:17,718
STUDIES IN COLLABORATION WITH

7694
05:30:17,718 --> 05:30:22,389
SAM GANDY AND RHESUS MONKEYS AND

7695
05:30:22,389 --> 05:30:24,358
THAT WAS PUBLISHED SOME YEARS

7696
05:30:24,358 --> 05:30:25,692
AGO, NO PLAQUES OR ANYTHING TO

7697
05:30:25,692 --> 05:30:28,328
START WITH BUT IT DID SHOW IT

7698
05:30:28,328 --> 05:30:29,229
WAS SAFE >>  THANK YOU.

7699
05:30:29,229 --> 05:30:38,238
WE WILL MOVE ON TO OUR NEXT

7700
05:30:38,238 --> 05:30:40,407
SPEAKER. 

7701
05:30:40,407 --> 05:30:41,208
DR. KATERINA AKASSOGLOU, SHE A

7702
05:30:41,208 --> 05:30:43,477
PROFESSOR OF NEUROLOGY AT THE

7703
05:30:43,477 --> 05:30:45,345
SENIOR INVESTIGATE AT THE

7704
05:30:45,345 --> 05:30:46,046
GLADSTONE EN--STRATEGIESITUTE

7705
05:30:46,046 --> 05:30:48,415
AND THE FIELD OF HER TALK IS

7706
05:30:48,415 --> 05:30:52,819
STRATEGIES TO PROTECT THE BBB IN

7707
05:30:52,819 --> 05:30:55,155
PERSONS TAKING ANTIAMYLOID AB

7708
05:30:55,155 --> 05:30:55,389
THERAPY.

7709
05:30:55,389 --> 05:30:56,857
NTHANK YOU AND WE WOULD LIKE TO

7710
05:30:56,857 --> 05:31:04,598
THANK THE ORGANIZATIONS  FOR THE

7711
05:31:04,598 --> 05:31:05,966
OPPORTUNITY TO WORK.

7712
05:31:05,966 --> 05:31:10,871
AND TODAY WILL BE DISCUSSING

7713
05:31:10,871 --> 05:31:12,539
MECHANISMS WE HAVE DISCOVERED AT

7714
05:31:12,539 --> 05:31:14,207
THE BLOOD BRAIN IMMUNE INTERFACE

7715
05:31:14,207 --> 05:31:15,375
AND SHARE MY PERSPECTIVE HOW WE

7716
05:31:15,375 --> 05:31:17,511
CAN SHARE AND HARNESS THIS

7717
05:31:17,511 --> 05:31:20,847
INFORMATION FROM THE DEVELOPMENT

7718
05:31:20,847 --> 05:31:22,582
OF NEW POTENTIAL THERAPIES FOR

7719
05:31:22,582 --> 05:31:25,452
ALZHEIMER'S DEC, ALSO FOR

7720
05:31:25,452 --> 05:31:26,153
PROTECTION FROM ARIA.

7721
05:31:26,153 --> 05:31:28,288
THESE ARE MY DISCLOSURES,

7722
05:31:28,288 --> 05:31:35,896
FUNDING FOR THE LAB, I'M THE

7723
05:31:35,896 --> 05:31:40,033
FOUNDER, NSAB, AND PATENT AND

7724
05:31:40,033 --> 05:31:40,968
PATENT REGULATIONS SOME OF WHICH

7725
05:31:40,968 --> 05:31:46,273
ARE RELATED TO TODAY'S

7726
05:31:46,273 --> 05:31:46,606
PRESENTATION.

7727
05:31:46,606 --> 05:31:48,208
THIS IS ALSO THE KACCTIS INIAL

7728
05:31:48,208 --> 05:31:48,942
HIELER'S DISEASE AND HERE YOU

7729
05:31:48,942 --> 05:31:51,445
CAN SEE FROM OUR STUDY TODAY, 2

7730
05:31:51,445 --> 05:31:54,181
DIMENSIONAL LABELING IN THE

7731
05:31:54,181 --> 05:31:55,549
HUMAN, ALZHEIMER'S BRAIN WHERE

7732
05:31:55,549 --> 05:31:59,152
YOU SEE DEPOSITS OF THE BLOOD

7733
05:31:59,152 --> 05:32:01,888
FOR COMPILATION PROTEIN FIEB RIN

7734
05:32:01,888 --> 05:32:04,591
O GEN SURROUNDING BLOOD VESSELS

7735
05:32:04,591 --> 05:32:07,728
AND BIG CHANGES IN BLOOD VESSELS

7736
05:32:07,728 --> 05:32:09,196
CORRELATE WITH WORSE PROGNOSIS

7737
05:32:09,196 --> 05:32:10,430
AND ALZHEIMER'S DEC AND THE

7738
05:32:10,430 --> 05:32:15,435
DRIVEWAYING 

7739
05:32:15,435 --> 05:32:16,403
DRIVEWAYING--DRIVING DISCUSSION

7740
05:32:16,403 --> 05:32:21,274
IS ARE THESE CAUSAL FOR

7741
05:32:21,274 --> 05:32:21,675
NEURODEGENERATION.

7742
05:32:21,675 --> 05:32:24,745
THIS IS NOT IN THE NORMAL CNS

7743
05:32:24,745 --> 05:32:29,149
AND FIEB RIN OIEN IS A PROCESS

7744
05:32:29,149 --> 05:32:39,626
GENNED IN THE BARRIER AND IT

7745
05:32:40,427 --> 05:32:43,130
REQUIRES GETTING INTO THE BRAIN.

7746
05:32:43,130 --> 05:32:45,365
IN THE A. D. BRAIN COMBOYNED

7747
05:32:45,365 --> 05:32:47,734
BETA AND IT CORRELATES WITH

7748
05:32:47,734 --> 05:32:50,604
SITES OF ACTIVATED MICROGLIA AND

7749
05:32:50,604 --> 05:32:51,738
SHOWING PRESENTATIONS SHOW THIS

7750
05:32:51,738 --> 05:32:53,907
MORNING, I WILL ALSO CORRELATE

7751
05:32:53,907 --> 05:32:56,376
WITH SEVERITY OF CAA IS PRESENT

7752
05:32:56,376 --> 05:32:59,813
IN ARIA AND IS INCREASED IN

7753
05:32:59,813 --> 05:33:02,716
PATIENTS WITH THE POLYMORPHISM.

7754
05:33:02,716 --> 05:33:05,519
IN ADDITION TO NEUROPATHOLOGY

7755
05:33:05,519 --> 05:33:07,020
STUDIES BIOMARKER STUDIES HAVE

7756
05:33:07,020 --> 05:33:08,522
IDENTIFIED FIEB RIN O GENERATED

7757
05:33:08,522 --> 05:33:12,359
AS A PLASMA AND BIOMARKER THATP

7758
05:33:12,359 --> 05:33:13,727
CREASED RISK AND ALZHEIMER'S

7759
05:33:13,727 --> 05:33:16,897
DISEASE AS WELL AS INCREASED

7760
05:33:16,897 --> 05:33:18,899
DEMENTIA RISK IN CORRELATING

7761
05:33:18,899 --> 05:33:20,734
WITH THE FOSTER NURSED FOCUSED

7762
05:33:20,734 --> 05:33:27,774
ON-TAU AND RECEPTOR BETA IN A

7763
05:33:27,774 --> 05:33:30,510
APOE4 AD PATIENTS.

7764
05:33:30,510 --> 05:33:34,147
FIEB RIN O GENERATED IS A UNIQUE

7765
05:33:34,147 --> 05:33:44,424
STRUCTURE, AND U

7766
05:33:51,898 --> 05:33:56,369
RE, AND A DRUGGABLE

7767
05:33:56,369 --> 05:33:56,603
TARGET.

7768
05:33:56,603 --> 05:34:00,006
SO WHAT I NOTICED IS THAT

7769
05:34:00,006 --> 05:34:03,410
FIBRINOGEN HAS ANOTHER SITE,

7770
05:34:03,410 --> 05:34:05,011
WITH THE BYPASSING SITE WHICH

7771
05:34:05,011 --> 05:34:06,880
BYPASSEDS TO THE COMPLEMENT OF

7772
05:34:06,880 --> 05:34:08,615
THE CD11 B DOMAIN RECEPTOR.

7773
05:34:08,615 --> 05:34:11,451
AND OF COURSE WE KNOW THAT THIS

7774
05:34:11,451 --> 05:34:12,619
RECEPTOR IS EXPRESSED IN

7775
05:34:12,619 --> 05:34:17,824
MACROPHAGES AND IS A KEY DRIVER,

7776
05:34:17,824 --> 05:34:19,493
SO THE REQUESTY IN MY LAB HAS

7777
05:34:19,493 --> 05:34:20,894
BEEN WHEN THESE PROTEIN ENTER

7778
05:34:20,894 --> 05:34:25,398
THE BRAIN COULD IT BE HIJACKING

7779
05:34:25,398 --> 05:34:26,399
THESE'MUNE RECEPTORS OFF

7780
05:34:26,399 --> 05:34:27,667
MICRODPLIA AND IMMUNE CELLS IN

7781
05:34:27,667 --> 05:34:30,537
THE BRAIN, AND THESE TALKS THE

7782
05:34:30,537 --> 05:34:31,805
COAGULATION AND INFLAMMATORY ARE

7783
05:34:31,805 --> 05:34:34,274
NOT OVERLAPPING COULD WE DEVELOP

7784
05:34:34,274 --> 05:34:35,675
GENETIC AND PHARMAICOLOGGIC

7785
05:34:35,675 --> 05:34:38,044
TOOLS TO BLOCK THE POTENTIAL

7786
05:34:38,044 --> 05:34:38,645
DAMAGINGLY INFLAMMATORY CENTER

7787
05:34:38,645 --> 05:34:40,180
FOR EXCELLENCE ON AGINGS OF FIEB

7788
05:34:40,180 --> 05:34:43,049
RIN WITHOUT AFFECTING BENEFICIAL

7789
05:34:43,049 --> 05:34:47,320
EFFECTS IN NORMAL HEMOSTASIS.

7790
05:34:47,320 --> 05:34:49,556
SO A HYPOTHESIS WAS THE

7791
05:34:49,556 --> 05:34:51,491
KRIEEVERS OF FIEWROLOGICAL

7792
05:34:51,491 --> 05:34:53,059
DISEASES AND EXPERIMENTS WAS

7793
05:34:53,059 --> 05:34:56,062
GENETIC LOSS OF FUNCTION STUDIES

7794
05:34:56,062 --> 05:34:58,131
TO KNOCKOUT MICE TO TEST WHETHER

7795
05:34:58,131 --> 05:35:00,300
BLOOD PROTEINS ARE NECESSARY TO

7796
05:35:00,300 --> 05:35:04,070
DRIVE NEURODEGENERATION IN

7797
05:35:04,070 --> 05:35:06,706
TEASE. 

7798
05:35:06,706 --> 05:35:08,108
AND OVER 20 YEARS AGO WE

7799
05:35:08,108 --> 05:35:09,809
PERFORMED A STUDY FOR THE MOUSE,

7800
05:35:09,809 --> 05:35:13,013
THIS MOUSE HAS ALL BLOOD

7801
05:35:13,013 --> 05:35:14,114
PROTEINS EXCEPT FIBRINOGEN AND

7802
05:35:14,114 --> 05:35:16,149
WE FOUND THIS MOUSE WAS

7803
05:35:16,149 --> 05:35:17,551
PROTECTED ACROSS MANY

7804
05:35:17,551 --> 05:35:19,653
NEUROLOGICAL DISEASES ENCLUING

7805
05:35:19,653 --> 05:35:21,955
MULTIPLE MODELS OF ALZHEIMER'S

7806
05:35:21,955 --> 05:35:24,124
DEC, MODELS OF MS, AND THESE

7807
05:35:24,124 --> 05:35:28,728
MICE WERE USED EXTENSIVELY IN

7808
05:35:28,728 --> 05:35:30,397
THE FIELD AND SHOWED PROTECTION

7809
05:35:30,397 --> 05:35:37,137
IN THE CHEMICAL DEMILENNATION

7810
05:35:37,137 --> 05:35:39,673
AND PERICITE DEFICIENT MICE.

7811
05:35:39,673 --> 05:35:42,242
IT IS NECESSARY TO DRIVE

7812
05:35:42,242 --> 05:35:47,948
NEURODEGENERATION AND DISFUNK IN

7813
05:35:47,948 --> 05:35:51,251
THIS MODELS MUCH IN

7814
05:35:51,251 --> 05:35:51,885
COLLABORATION WITH

7815
05:35:51,885 --> 05:35:54,588
[INDISCERNIBLE] AT UNIVERSITY OF

7816
05:35:54,588 --> 05:35:56,990
CINCINNATI, THEY USE A MUTATION

7817
05:35:56,990 --> 05:35:57,591
BETWEEN THE INPOLICEMANNATORY

7818
05:35:57,591 --> 05:36:02,429
DOPAIN, THESE MICE CAN HAVE NO

7819
05:36:02,429 --> 05:36:04,798
DEFINITES IN CLOTTING, NORMAL

7820
05:36:04,798 --> 05:36:05,765
HEMOSTASIS BUT THEY CANNOT

7821
05:36:05,765 --> 05:36:07,734
ACTIVATE THE IMMUNE SYSTEM, AND

7822
05:36:07,734 --> 05:36:10,503
WE FOUND THESE WERE PROTECTED IN

7823
05:36:10,503 --> 05:36:12,772
THE IMMUNO LONGIC DEC AND THIS

7824
05:36:12,772 --> 05:36:19,813
SIDE WAS CRITICAL FOR THE

7825
05:36:19,813 --> 05:36:21,815
MICROGLIA CELL, THIS BECAME THE

7826
05:36:21,815 --> 05:36:23,116
BASIS FOR THERAPEUTIC ISHT VENS

7827
05:36:23,116 --> 05:36:26,453
AND DEVELOP THE FIRST IN CLAS BY

7828
05:36:26,453 --> 05:36:30,790
TARGETING  IMMUNOTHERAPY AND THE

7829
05:36:30,790 --> 05:36:34,828
PHASE 1 CLINICAL TRIALS IN

7830
05:36:34,828 --> 05:36:36,096
HEALTHY VOLUNTEERS.

7831
05:36:36,096 --> 05:36:38,164
TO IDENTIFY MECHANISMS BETWEEN

7832
05:36:38,164 --> 05:36:41,301
LINKING THE BRAIN BIODISRUPTION

7833
05:36:41,301 --> 05:36:43,069
AND NEURODEGENERATION, WE,A

7834
05:36:43,069 --> 05:36:45,672
PROACH AN HAVE AAN PROACH FOR

7835
05:36:45,672 --> 05:36:47,040
THE PHOTO IMAGING, DEVELOPING

7836
05:36:47,040 --> 05:36:48,642
NEW PROTOCOLS FOR 3 DIMENSIONAL

7837
05:36:48,642 --> 05:36:50,543
LABELING FOR FIEB RIN IN MOUSE

7838
05:36:50,543 --> 05:36:52,312
AND MUSEUM MAN BRAIN AS WELL AS

7839
05:36:52,312 --> 05:36:53,480
BEHAVIORIAL TEST ANDS WE PERFOR

7840
05:36:53,480 --> 05:36:56,082
THE PURPOSED THESE TODAYS IN THE

7841
05:36:56,082 --> 05:37:01,688
5 X AD MODEL OF A. D.

7842
05:37:01,688 --> 05:37:03,023
BY ENDOGENOUS LABELING OF FIEB

7843
05:37:03,023 --> 05:37:06,593
RIN OIEN, WE FOUND THAT SIMILAR

7844
05:37:06,593 --> 05:37:09,829
AMYLOID DEPOSITS IN THE BRAIN

7845
05:37:09,829 --> 05:37:17,604
WERE ALSO SITES OF SYNAPSE LOSS.

7846
05:37:17,604 --> 05:37:19,939
FIEB RIN O BEGIN SEMESTERULAR TO

7847
05:37:19,939 --> 05:37:21,508
AMYLOID CAN INN DUCE SPINE LOSS

7848
05:37:21,508 --> 05:37:22,375
IN THE BREAN, SOPHISTICATEDY

7849
05:37:22,375 --> 05:37:25,812
THIS IS A NEW CULPRIT FOR SPINE

7850
05:37:25,812 --> 05:37:29,883
LOSS IN A. D. MICE.

7851
05:37:29,883 --> 05:37:33,053
TO TEST WHETHER THIS WAS

7852
05:37:33,053 --> 05:37:34,487
REGULATING NEURODEGENERATION, WE

7853
05:37:34,487 --> 05:37:35,622
CROSS THE MODEL WITH THE FIEB

7854
05:37:35,622 --> 05:37:37,490
RIN O GEN WITH THE MOUSE AND

7855
05:37:37,490 --> 05:37:41,227
THIS HAD THE INCREASED NUMBER OF

7856
05:37:41,227 --> 05:37:42,429
SYNAPSES, DECREASED

7857
05:37:42,429 --> 05:37:42,996
NEURODEGENERATION, DECREASED

7858
05:37:42,996 --> 05:37:43,530
LIES STUDIES OF MULTIPLE

7859
05:37:43,530 --> 05:37:45,865
ENDOCRINIA MARKERS AS WELL AS

7860
05:37:45,865 --> 05:37:47,133
ALSO MICRODPLIA.

7861
05:37:47,133 --> 05:37:50,904
WE EMPLOYED STANDARD COGNITIVE

7862
05:37:50,904 --> 05:37:54,741
TEST 

7863
05:37:54,741 --> 05:37:55,909
INCLUDING MEMORY AND THE LINE,

7864
05:37:55,909 --> 05:37:58,044
CAN YOU SEE THE DEFICIT OF THE

7865
05:37:58,044 --> 05:37:59,946
MICE THAT WAS RESCUED WHEN

7866
05:37:59,946 --> 05:38:03,316
SUPERIMPOSED WITH THE MUTATION

7867
05:38:03,316 --> 05:38:04,718
THAT AGAIN THIS MICE MAKE THE

7868
05:38:04,718 --> 05:38:07,253
LEVEL, BUT NOT ACTIVATE

7869
05:38:07,253 --> 05:38:09,989
RECEPTORS HONE ON THE MICRODPLIA

7870
05:38:09,989 --> 05:38:11,958
AND THE CELLS.

7871
05:38:11,958 --> 05:38:13,660
IN COLLABORATION WITH THE FLAD

7872
05:38:13,660 --> 05:38:16,496
STONE INSTITUTE, WE ALSO

7873
05:38:16,496 --> 05:38:19,165
EMPLOYED AN UNBIASED LEARNING

7874
05:38:19,165 --> 05:38:21,101
APPROACH TO ASSESS THE

7875
05:38:21,101 --> 05:38:23,069
BEHAVIORIAL DURATIONS IN

7876
05:38:23,069 --> 05:38:24,537
ALZHEIMER'S MICE.

7877
05:38:24,537 --> 05:38:26,139
WITH THE SHOWN WITH THE MACHINE

7878
05:38:26,139 --> 05:38:30,543
LEARNING IS THEY CAN IDENTIFY

7879
05:38:30,543 --> 05:38:33,613
MOTIF IN THIS, AND SUPER IMPOSE

7880
05:38:33,613 --> 05:38:35,014
THE MUTATION, WHAT WE FOUND IS

7881
05:38:35,014 --> 05:38:36,583
THAT THESE WERE COMPLETELY

7882
05:38:36,583 --> 05:38:40,453
RESCUED OR REDUCE INDEED THE

7883
05:38:40,453 --> 05:38:44,457
ABSENCE OF THE FIEB RIN O GEN,

7884
05:38:44,457 --> 05:38:49,729
THEREFORING THE  MICROGLIA

7885
05:38:49,729 --> 05:38:52,031
SIGNALING WITH ALTER THE AD

7886
05:38:52,031 --> 05:38:54,801
MUTATIONS IN MICE.

7887
05:38:54,801 --> 05:38:57,837
THE STUDY IDENTIFIED SPINAL ELIM

7888
05:38:57,837 --> 05:38:58,638
NATION AND MUSCULAR DAMAGE AND

7889
05:38:58,638 --> 05:38:59,839
SHOWED THIS COULD NOT BE A

7890
05:38:59,839 --> 05:39:02,909
SIGNAL AND FOUND A MECH NIM THIS

7891
05:39:02,909 --> 05:39:05,311
IS INDUCTION OF FOXOXIDATIVE

7892
05:39:05,311 --> 05:39:07,280
STRESS AND REACTIVE OXYGEN

7893
05:39:07,280 --> 05:39:08,681
SPECIES, WE SHOWED THIS

7894
05:39:08,681 --> 05:39:12,085
IMPORTANT INDUCER OF THE

7895
05:39:12,085 --> 05:39:13,219
ACTIVATION AND THESE FINDINGS

7896
05:39:13,219 --> 05:39:17,624
CAN ALSO PRORIDE THE POTENTIAL

7897
05:39:17,624 --> 05:39:18,858
MECHANISTIC EXPLANATION BEHIND

7898
05:39:18,858 --> 05:39:21,194
EMERGING CLINICAL DATA ABOUT THE

7899
05:39:21,194 --> 05:39:22,262
PATHOLOGY EARLY INDEPENDENT

7900
05:39:22,262 --> 05:39:26,533
MECHANISM, THAT CAN DRIVE

7901
05:39:26,533 --> 05:39:27,000
NEURODEGENERATION AND

7902
05:39:27,000 --> 05:39:28,301
[INDISCERNIBLE], AND FIND THIS

7903
05:39:28,301 --> 05:39:31,004
DATA ARE ALSO SUPPORTING THAT

7904
05:39:31,004 --> 05:39:33,440
VASCULAR PATHOLOGY SHOULD BE

7905
05:39:33,440 --> 05:39:35,408
INDEPENDENTLY TARGETED FOR

7906
05:39:35,408 --> 05:39:37,110
MAXIMUM THERAPEUTIC EFFICACY.

7907
05:39:37,110 --> 05:39:41,781
SO WE WITH THAT IN MIND WE

7908
05:39:41,781 --> 05:39:42,348
DEVELOPED FIBROGENIC IMMUNO

7909
05:39:42,348 --> 05:39:42,882
THERAPY AND ACTIVITIES AND

7910
05:39:42,882 --> 05:39:43,616
PROJECTS COMPETENT THE

7911
05:39:43,616 --> 05:39:45,452
CHALLENGES WE HAD TO OVERCOME

7912
05:39:45,452 --> 05:39:48,221
WAS OF COURSE THE POPULATION.

7913
05:39:48,221 --> 05:39:51,157
WE DIDN'T WANT TO INTERFERE WITH

7914
05:39:51,157 --> 05:39:54,127
THE PROTECTIVE EFFECT IN

7915
05:39:54,127 --> 05:39:54,894
HEMOSTASIS.

7916
05:39:54,894 --> 05:39:56,463
SO TO DEVELOP AN ANTIBODY THAT

7917
05:39:56,463 --> 05:39:58,364
COULD TARGET ITS TOXIC

7918
05:39:58,364 --> 05:40:00,800
INFLAMMATORY FUNCTIONS WE

7919
05:40:00,800 --> 05:40:03,403
DEVELOPED A EPITOPE SPECIFIC

7920
05:40:03,403 --> 05:40:05,071
ANTIBODY THAT [INDISCERNIBLE]

7921
05:40:05,071 --> 05:40:06,039
ORGANIZES THE INFLAMMATORY

7922
05:40:06,039 --> 05:40:07,607
DOMAIN OF FIEB RIN.

7923
05:40:07,607 --> 05:40:09,809
THE ANTIBODY CANNOT BIND TO

7924
05:40:09,809 --> 05:40:13,780
SOLUBLE FIBROGEN IN THE BLOOD SO

7925
05:40:13,780 --> 05:40:20,720
IT DOESN'T HAVE A SYNCH EFFECT.

7926
05:40:20,720 --> 05:40:23,523
AND IT HAS SHOWN THERAPEUTIC

7927
05:40:23,523 --> 05:40:26,192
EFFICACY FOR MULTILE MODELS OF

7928
05:40:26,192 --> 05:40:29,162
SCLEROSIS, AS WELL AS UNIVERSAL

7929
05:40:29,162 --> 05:40:31,064
TRIALS FOR ALZHEIMER'S DEC WHERE

7930
05:40:31,064 --> 05:40:32,398
YOU SEE PROTECTION OF NEURONS

7931
05:40:32,398 --> 05:40:35,935
AND EXPRESSION OF INFLAMMATORY

7932
05:40:35,935 --> 05:40:38,771
PATHWAYS FOR HUMAN AD AND THE

7933
05:40:38,771 --> 05:40:40,507
ANTIBODY HAS BEEN HUMANIZED AND

7934
05:40:40,507 --> 05:40:41,474
COMPLETED SAFETY CAN TOXICOLOGY

7935
05:40:41,474 --> 05:40:44,077
AND THE SPECIES AND THE FIRST IN

7936
05:40:44,077 --> 05:40:48,781
HUMAN TRIALS ALREADY IN MAY, AND

7937
05:40:48,781 --> 05:40:49,983
PLANTING ALZHEIMER PATIENT

7938
05:40:49,983 --> 05:40:51,384
JEIMER'S PEASHES IN 2024,

7939
05:40:51,384 --> 05:40:54,821
PROVIDE OF COURSE THAT TO DATE

7940
05:40:54,821 --> 05:41:02,128
THE TRIAL ARE SAFE.

7941
05:41:02,128 --> 05:41:04,130
THREE YEARS AGO WAS THE

7942
05:41:04,130 --> 05:41:07,267
ANNIVERSARY OF THE NATURE

7943
05:41:07,267 --> 05:41:09,202
IMMUNOLOGY WHICH COINCIDED WITH

7944
05:41:09,202 --> 05:41:11,004
THE BIOLOGICS FROM FDA AND THE

7945
05:41:11,004 --> 05:41:13,172
NATURE PUT ON ITS COVER 20

7946
05:41:13,172 --> 05:41:15,275
ANTIABOUT THINGS FOR YEARS, SO

7947
05:41:15,275 --> 05:41:17,143
NATURE IMMUNOLOGY, SO 1 OF THOSE

7948
05:41:17,143 --> 05:41:18,444
FEATURES WAS THE ANTIBODY AND WE

7949
05:41:18,444 --> 05:41:20,079
GOT THE OPPORTUNITY TO DISCUSS

7950
05:41:20,079 --> 05:41:22,949
HOW CONNECKED THE DOTS OF THE

7951
05:41:22,949 --> 05:41:24,684
NEUROVASCULAR INTERPHASE AND HOW

7952
05:41:24,684 --> 05:41:25,518
CURIOSITY ABOUT HOW FIEB RIN

7953
05:41:25,518 --> 05:41:28,521
AFFECTS THE BRAIN AND THE BLOOD

7954
05:41:28,521 --> 05:41:31,658
AFFECTS THE BRAIN LIKE THE

7955
05:41:31,658 --> 05:41:35,962
DORPHY OF THE FIRST PRINCIPLE

7956
05:41:35,962 --> 05:41:38,031
TOOL TO NEUTRALIZE BLOOD

7957
05:41:38,031 --> 05:41:40,133
TOXICITY IN THE

7958
05:41:40,133 --> 05:41:40,900
NEURODEGENERATIVE DISEASES.

7959
05:41:40,900 --> 05:41:45,905
THESE STUDIES OPENED QUESTIONS

7960
05:41:45,905 --> 05:41:47,974
ABOUT HOW THE--WHAT IS THE

7961
05:41:47,974 --> 05:41:49,809
MOLECULAR AND CELLULAR INTERFACE

7962
05:41:49,809 --> 05:41:51,911
THAT BLOOD PROTEIN INTERACT WITH

7963
05:41:51,911 --> 05:41:53,780
THIS SERVOUS SYSTEM CELLS AND

7964
05:41:53,780 --> 05:41:55,515
DURING SELECTIVITY OF BLOOD

7965
05:41:55,515 --> 05:41:57,150
PROTEINS WHEN THEY ENTER THE

7966
05:41:57,150 --> 05:41:58,985
BRAIP TO ACTIVATE THESE IMMUNE

7967
05:41:58,985 --> 05:41:59,352
FUNCTIONS.

7968
05:41:59,352 --> 05:42:03,723
SO THERE'S QUESTIONS WE

7969
05:42:03,723 --> 05:42:06,926
DEVELOPED AND UNBIASED MULTIOMIC

7970
05:42:06,926 --> 05:42:07,961
PIPELINE, COMBINED WITH THE LOSS

7971
05:42:07,961 --> 05:42:10,330
OF FUNCTION STUDIES TO DEFINE

7972
05:42:10,330 --> 05:42:14,867
THE BLOOD IN THE YEARS FOR THE

7973
05:42:14,867 --> 05:42:15,501
FUNCTIONS IN NEURODEGENERATION

7974
05:42:15,501 --> 05:42:20,373
EMPLOY BUT YOU CAN SEE HERE THE

7975
05:42:20,373 --> 05:42:23,009
MICROGLIA BLOOD NETWORK, SHOWING

7976
05:42:23,009 --> 05:42:24,310
EXPOSURE FROM PLASMA TO MICE,

7977
05:42:24,310 --> 05:42:30,316
AND WE FOUND THAT MICROGLIA HAD

7978
05:42:30,316 --> 05:42:32,251
NEURODEGENERATION UPON EXPOSE

7979
05:42:32,251 --> 05:42:34,253
TOWER WILD-TYPE PLASMA.

7980
05:42:34,253 --> 05:42:36,956
SURPRISINGLY WHEN WE OVERLAY THE

7981
05:42:36,956 --> 05:42:38,124
TRANSCRIPTOME OF MICRODPLIA

7982
05:42:38,124 --> 05:42:41,027
EXPOSED TO THE FIBRINOGEN MICE,

7983
05:42:41,027 --> 05:42:43,296
NEIVE% OF THE MICRODPLIA NETWORK

7984
05:42:43,296 --> 05:42:45,431
WAS DOWN REGULATED AS 50% OF

7985
05:42:45,431 --> 05:42:46,332
THESE YEEPS ARE SIGNIFICANT

7986
05:42:46,332 --> 05:42:48,267
SHOWING THIS IS A KEY PROTEIN IN

7987
05:42:48,267 --> 05:42:52,505
THE BLOOD, IN THE ACTIVATION

7988
05:42:52,505 --> 05:42:53,473
EMPLOY TO IDENTIFY THIS CENTER

7989
05:42:53,473 --> 05:42:54,941
FOR EXCELLENCE ON AGINGS WHAT IS

7990
05:42:54,941 --> 05:42:57,043
MEDIATED WE ALSO LIEUS THE

7991
05:42:57,043 --> 05:43:00,546
PLASMA FROM THE MOUSE, THIS

7992
05:43:00,546 --> 05:43:02,248
CLOTS BUT CANNOT ACTIVATE THE

7993
05:43:02,248 --> 05:43:04,050
RECEPTOR IN THE MICROGLIA AND

7994
05:43:04,050 --> 05:43:06,185
HERE CAN YOU SEE SIGNIFICANT

7995
05:43:06,185 --> 05:43:07,320
REDUCTION OF THE YEENS WHEN

7996
05:43:07,320 --> 05:43:09,355
COMPARED TO THE WILD-TYPE

7997
05:43:09,355 --> 05:43:10,790
PLASMA, COMPARED FOR EXAMPLE,

7998
05:43:10,790 --> 05:43:12,325
WITH THE USE OF CONTROL, BUT

7999
05:43:12,325 --> 05:43:15,728
SEEMS TO BE VERY SIMILAR, THE

8000
05:43:15,728 --> 05:43:17,030
TRANSCRIPT OHM OF MICROFLI

8001
05:43:17,030 --> 05:43:22,568
COLSISSA THAT ARE EXPOSED VERSUS

8002
05:43:22,568 --> 05:43:23,870
WILD-TYPE PLASMA, THEY ARE NOT

8003
05:43:23,870 --> 05:43:27,240
ONLY SELECTIVE BUT RECEPTOR

8004
05:43:27,240 --> 05:43:29,008
MEDIATED TRANSCRIPTOMIC PROGRAMS

8005
05:43:29,008 --> 05:43:30,576
IN THE POLYMERIZATION.

8006
05:43:30,576 --> 05:43:33,046
THE RESULTS ARE ALSO WITH THE

8007
05:43:33,046 --> 05:43:34,847
PREVOUS STUDIES THAT THE

8008
05:43:34,847 --> 05:43:37,050
MICRODPLIA BUT ALSO DOWN STREAM

8009
05:43:37,050 --> 05:43:41,120
EVENS OF MICROGLIA WHERE THERE

8010
05:43:41,120 --> 05:43:43,823
IS ALSO REDUCED DENT RIGHT LAW

8011
05:43:43,823 --> 05:43:45,625
ANDS ACTIVATION OF THE

8012
05:43:45,625 --> 05:43:47,126
FIEBERATION OF THE PLASMA IN THE

8013
05:43:47,126 --> 05:43:55,368
BRAIN COMPARED TO WILD-TYPE

8014
05:43:55,368 --> 05:43:55,601
PLASMA.

8015
05:43:55,601 --> 05:43:58,504
TO FIND OUT IF THESE GENES WERE

8016
05:43:58,504 --> 05:44:02,041
IN ALZHEIMER'S MICE, WE

8017
05:44:02,041 --> 05:44:04,577
PERFORMED IN MICROGLIA 5 X AD

8018
05:44:04,577 --> 05:44:06,713
MICE CROSS THE FIEB RIN O GEN

8019
05:44:06,713 --> 05:44:06,913
MOUSE.

8020
05:44:06,913 --> 05:44:09,415
AND HERE WHAT YOU CAN SEE IS THE

8021
05:44:09,415 --> 05:44:13,786
5 X IS THE EXPECTED UPREGULATION

8022
05:44:13,786 --> 05:44:14,220
OF THE

8023
05:44:14,220 --> 05:44:14,754
NEURODEGENERATIVEOXIDATIVE

8024
05:44:14,754 --> 05:44:17,790
STRESS AND THIS IS ASSOCIATED

8025
05:44:17,790 --> 05:44:19,425
MICRODPLIA YEENS AND DOWN

8026
05:44:19,425 --> 05:44:21,461
REGULATION OF THE FAMILIAL

8027
05:44:21,461 --> 05:44:23,796
STATIC SIGNATURE OF THE

8028
05:44:23,796 --> 05:44:27,166
MICROGLIA AND THE MUTATION, THE

8029
05:44:27,166 --> 05:44:29,202
NEURODEGENERATIVE SIGNATURE WAS

8030
05:44:29,202 --> 05:44:31,237
SUPPRESSED AND THE SIGNATURE,

8031
05:44:31,237 --> 05:44:32,939
WITH THE HOMEOSTATIC SIGNATURE

8032
05:44:32,939 --> 05:44:33,506
WAS RHETORRED.

8033
05:44:33,506 --> 05:44:36,175
SHOWING THAT THESE PATHWAYS

8034
05:44:36,175 --> 05:44:39,112
NECESSARY FOR MICROGLIA FOR THE

8035
05:44:39,112 --> 05:44:40,413
STRESS AND DEGENERATIVE GENE

8036
05:44:40,413 --> 05:44:42,181
EXPRESSION IN AD MICE.

8037
05:44:42,181 --> 05:44:43,516
SO OVERALL WHAT THIS STUDY

8038
05:44:43,516 --> 05:44:45,351
SUGGESTS IS THAT THE BLOOD BRAIN

8039
05:44:45,351 --> 05:44:46,252
IS NOT ONLY SECURITIZATION.ARY

8040
05:44:46,252 --> 05:44:48,888
TO IPT GREATER FLAMMATION BUT

8041
05:44:48,888 --> 05:44:51,791
IT'S IN THE DRIVER OF PATHOGENIC

8042
05:44:51,791 --> 05:44:54,260
INNATE IMMUNITY IN THE BRAIN,

8043
05:44:54,260 --> 05:44:56,329
BLOOD PROTEINS ARE NOT

8044
05:44:56,329 --> 05:44:58,297
INTERCHANGEABLE BUT THEY INDUCE

8045
05:44:58,297 --> 05:44:59,732
DISTINCT MEDIATED POLYMERIZATION

8046
05:44:59,732 --> 05:45:01,200
OF MICRODPLIA AND FIEB RIN NOW

8047
05:45:01,200 --> 05:45:03,035
IS A UNIT AMONG BLOOD PROTEINS

8048
05:45:03,035 --> 05:45:06,172
TO BE IN THE PATIENT WHO ARE

8049
05:45:06,172 --> 05:45:08,441
VERY SPECIFIC NEW O DEGENERATIVE

8050
05:45:08,441 --> 05:45:09,041
POLARIZEDDERRIZATION OF THOSE

8051
05:45:09,041 --> 05:45:10,810
CELLS EMPLOY THIS COULD BE VERY

8052
05:45:10,810 --> 05:45:12,178
IMPORTANT FOR THERAPY, SO THIS

8053
05:45:12,178 --> 05:45:18,217
IS AN INDEPENDENT PATHWAY OF

8054
05:45:18,217 --> 05:45:19,118
NEURODEGENERATION AND CAN BE

8055
05:45:19,118 --> 05:45:22,054
DONE IN A SELECTIVE WAY, THIS

8056
05:45:22,054 --> 05:45:24,056
DOESN'T BLOCK OTHER MICROGLIA

8057
05:45:24,056 --> 05:45:26,259
FUNCTIONS BUT NOW CONTRIBUTE TO

8058
05:45:26,259 --> 05:45:27,460
COGNITIVE PROTECTION, ESPECIALLY

8059
05:45:27,460 --> 05:45:35,268
IN PATIENTS POPULATIONS THAT

8060
05:45:35,268 --> 05:45:42,308
HAVE HIGHER BLOOD BRAIN AND

8061
05:45:42,308 --> 05:45:43,676
MOSTFUL, AND POTENTIALLY EMILY

8062
05:45:43,676 --> 05:45:47,213
THE IT FROM THE BRAIN DUE TO

8063
05:45:47,213 --> 05:45:47,680
ARIA.

8064
05:45:47,680 --> 05:45:49,682
AND TO DEVELOPING THE PATHWAY,

8065
05:45:49,682 --> 05:45:53,219
IN THE CLINICAL DEVELOPMENT IS

8066
05:45:53,219 --> 05:45:54,821
IMPORTANT TO THINK ABOUT

8067
05:45:54,821 --> 05:45:58,758
SENSITIVE IMAGING OF BRAIN

8068
05:45:58,758 --> 05:46:00,493
BARRIER, AND THE STUDIES FOR THE

8069
05:46:00,493 --> 05:46:03,196
FIEB RIN OIEN AND THERE ARE WAYS

8070
05:46:03,196 --> 05:46:06,799
TO DEVELOP NONINVASIVE TOOLS TO

8071
05:46:06,799 --> 05:46:13,139
DIRECTLY DETECT IN THE BRAIN

8072
05:46:13,139 --> 05:46:13,406
PATIENTS.

8073
05:46:13,406 --> 05:46:15,441
I WOULD LIKE TO THANK ALL THE

8074
05:46:15,441 --> 05:46:17,510
HIGHLY TALENTED PEOPLE IN MY

8075
05:46:17,510 --> 05:46:18,811
LAB, AND THE ANTIBODY STUDIES

8076
05:46:18,811 --> 05:46:24,784
WERE LED BY JAKE AND

8077
05:46:24,784 --> 05:46:25,318
[INDISCERNIBLE] PERFORMED

8078
05:46:25,318 --> 05:46:25,918
TRANSCREPT ORDER OF MICRONSIC

8079
05:46:25,918 --> 05:46:30,189
WORK AND AS OF MONDAY THE

8080
05:46:30,189 --> 05:46:32,959
PROFESSOR AT UCSD, AND

8081
05:46:32,959 --> 05:46:34,160
PERFORMING THE MICROGLIA

8082
05:46:34,160 --> 05:46:34,393
STUDIES.

8083
05:46:34,393 --> 05:46:40,399
THESE ARE ALL COLLABORATORS AND

8084
05:46:40,399 --> 05:46:42,735
IN PARTICULAR FOR THIS TALK, I

8085
05:46:42,735 --> 05:46:45,738
WANT TO THANK THE FOLLOWING

8086
05:46:45,738 --> 05:46:47,840
PEOPLE:

8087
05:46:47,840 --> 05:46:49,141
AND FINALLY, THANK ALL OUR

8088
05:46:49,141 --> 05:46:50,643
FUNDING FOR THE SUPPORT AND

8089
05:46:50,643 --> 05:47:01,153
THANK YOU FOR YOUR ATTENTION.

8090
05:47:01,988 --> 05:47:03,256
>> SO THE AH SUSMGZ IS
THAT THE

8091
05:47:03,256 --> 05:47:06,292
OPENING OF THE BLOOD BRAIN

8092
05:47:06,292 --> 05:47:07,460
BARRIER IS WHAT HAPPENS FIRST

8093
05:47:07,460 --> 05:47:11,530
AND IT SHOULD BE OF SUFFICIENT,

8094
05:47:11,530 --> 05:47:13,733
YOU KNOW EBTITY TO ALLOW FIEB

8095
05:47:13,733 --> 05:47:15,201
RIN OIEN TO ENTER.

8096
05:47:15,201 --> 05:47:17,436
SO WHAT'S THE EVIDENT THAT

8097
05:47:17,436 --> 05:47:19,171
THAT'S THE CASE.

8098
05:47:19,171 --> 05:47:22,341
YOU KNOW INFLAMMATORY DISEASE IN

8099
05:47:22,341 --> 05:47:23,209
NWELL, I THINK WHAT'S

8100
05:47:23,209 --> 05:47:24,377
INTERESTING IS THAT DESPITE

8101
05:47:24,377 --> 05:47:25,578
THERE CAN BE DIFFERENT STRIGGERS

8102
05:47:25,578 --> 05:47:28,281
THAT OPEN THE BARRIER BECAUSE WE

8103
05:47:28,281 --> 05:47:29,749
SEE THIS PROTECTION WITH

8104
05:47:29,749 --> 05:47:32,685
ALZHEIMER'S DISEASE AND THOSE OF

8105
05:47:32,685 --> 05:47:33,886
MULTIPLE SCLEROSIS, SO TRAUMA IN

8106
05:47:33,886 --> 05:47:37,256
ALL OF THESE CASES WHEN

8107
05:47:37,256 --> 05:47:40,126
FIBRINOGEN IS IN THE BRAIN IT IS

8108
05:47:40,126 --> 05:47:41,060
NECESSARY FOR THE DOWN STREAM

8109
05:47:41,060 --> 05:47:43,963
EVENS OF THE RESPONSE OF THE

8110
05:47:43,963 --> 05:47:45,564
NEURODEGENERATION, SO THE TOOLS

8111
05:47:45,564 --> 05:47:47,600
I SHOWED TODAY IN THE MODELS ARE

8112
05:47:47,600 --> 05:47:50,269
ALSO IN THE MULTIPLE CLEROSEIS

8113
05:47:50,269 --> 05:47:52,038
MODELS AND BRAIN INJURY MODELS.

8114
05:47:52,038 --> 05:47:55,474
SO THIS APPEARS TO BE A COMMON

8115
05:47:55,474 --> 05:47:58,344
THREAD TO SIGNAL TO THE BRAIN'S

8116
05:47:58,344 --> 05:48:00,546
IMMUNE SYSTEM THIS NEUROTOXIC

8117
05:48:00,546 --> 05:48:01,881
ACTIVATION AND THE EFFECTS OF

8118
05:48:01,881 --> 05:48:05,017
COURSE ARE NOT SPECIFIC FOR

8119
05:48:05,017 --> 05:48:06,452
MICROGLIA.

8120
05:48:06,452 --> 05:48:08,421
FIEB RIN ACTIVATES ALSO 11 B

8121
05:48:08,421 --> 05:48:10,156
POSITIVE CELLS, SO THIS IS

8122
05:48:10,156 --> 05:48:12,024
MACROPHAGES AND A KEY PART OF

8123
05:48:12,024 --> 05:48:22,501
THE SIGNATURE AND EXPRESSION OF

8124
05:48:22,501 --> 05:48:24,370
RECRUITMENT AND CHEMOKINE CELLS

8125
05:48:24,370 --> 05:48:24,737
INTO THE BRAIN.

8126
05:48:24,737 --> 05:48:27,073
SO IT'S A DUAL RESPONSE IF THE

8127
05:48:27,073 --> 05:48:29,642
RECRUITMENT AS WELL AS SOCIAL

8128
05:48:29,642 --> 05:48:30,276
[INDISCERNIBLE] AND RESPONSE.

8129
05:48:30,276 --> 05:48:33,512
WHAT I SAID TO  FIBRINOGEN APART

8130
05:48:33,512 --> 05:48:35,081
TO OTHER BLOOD PROTEINS WE

8131
05:48:35,081 --> 05:48:37,750
STUDIED IS IT'S INDUCING BIAS

8132
05:48:37,750 --> 05:48:40,219
OUTSIDE THE SIGNALING SO IT

8133
05:48:40,219 --> 05:48:41,954
ACTIVATES THEOX DACE AND DID NOT

8134
05:48:41,954 --> 05:48:51,497
FIND THIS WITH OTHER LIGANDS, SO

8135
05:48:51,497 --> 05:48:54,000
I THINK THIS CREATES A

8136
05:48:54,000 --> 05:49:01,507
ASSOCIATION WITH BLOOD BRAIN

8137
05:49:01,507 --> 05:49:02,108
BARRIER LEAKS.

8138
05:49:02,108 --> 05:49:04,276
>> I'M CURIOUS YOU FOCUSED
ON

8139
05:49:04,276 --> 05:49:07,313
THE MICRODPLIAL CELL AND SOME OF

8140
05:49:07,313 --> 05:49:08,647
US ARE BECOMING

8141
05:49:08,647 --> 05:49:12,018
ENAMES--NAMESSORRED WITH THE

8142
05:49:12,018 --> 05:49:13,419
ASTRO GLIAL CELLS DOES FIEB RIN

8143
05:49:13,419 --> 05:49:16,188
HAVE THE SAME THING ON THE ASTRO

8144
05:49:16,188 --> 05:49:16,489
DPLIA,.

8145
05:49:16,489 --> 05:49:21,761
>> IT HAS DIRECT AND
INDIRECT

8146
05:49:21,761 --> 05:49:22,728
EACHS ON THIS, THEY ARE

8147
05:49:22,728 --> 05:49:23,763
ACTIVATED AND WHAT WE FOUND IS

8148
05:49:23,763 --> 05:49:27,033
WHEN WE PLOK THE RESPONSES WE

8149
05:49:27,033 --> 05:49:27,900
HAVE ATTENUATE ASTRO SIGHT

8150
05:49:27,900 --> 05:49:31,037
ACTIVATION AND NOW WE HAVE ALSO

8151
05:49:31,037 --> 05:49:32,571
SHOWN THIS THE OMIC DATA THAT

8152
05:49:32,571 --> 05:49:34,807
ARE THERE YET, ABOUT YOU WELL IS

8153
05:49:34,807 --> 05:49:37,810
ALSO A DIRECT EFFECT OF FIEB RIN

8154
05:49:37,810 --> 05:49:40,746
OIEN ABOUT 10% OF THE PLAID IS

8155
05:49:40,746 --> 05:49:42,681
BOWPPED TO LATENT TGFPAYS BETA

8156
05:49:42,681 --> 05:49:44,884
AND WE PUBLISHED NATURE IN THE

8157
05:49:44,884 --> 05:49:48,421
GENERAL SCIENCE BUT 10 YORES AGO

8158
05:49:48,421 --> 05:49:50,322
THAT 1 FIEB RIN O GEN ENTERS THE

8159
05:49:50,322 --> 05:49:51,991
BRAIN, IT'S IMMEDIATE ACTIVATION

8160
05:49:51,991 --> 05:49:55,528
OF VEG F BETA WHICH IS HOW IT IS

8161
05:49:55,528 --> 05:49:58,230
ACTIVATED SO BEFORE THE

8162
05:49:58,230 --> 05:49:59,698
TRANSCRIPTION, THE ACTIVATION OF

8163
05:49:59,698 --> 05:50:01,667
THIS PATHWAY, IT CAN REGULATE

8164
05:50:01,667 --> 05:50:03,469
THE TGF BETA AND THIS WAS ALSO

8165
05:50:03,469 --> 05:50:11,110
REALLY IMPORTANT FOR ACTIVATION

8166
05:50:11,110 --> 05:50:14,914
OF ASTRO SIGHTS IN IN THE BRAIN,

8167
05:50:14,914 --> 05:50:19,151
AND THE REPAIR IS ALSO NEURONAL

8168
05:50:19,151 --> 05:50:21,087
REACH, BUT WAY ASTRO SITTIC

8169
05:50:21,087 --> 05:50:23,489
PHASE CAN THIS MAY BE A WAY OF

8170
05:50:23,489 --> 05:50:25,024
CONTRIBUTION TO FIGHT

8171
05:50:25,024 --> 05:50:26,292
[INDISCERNIBLE] OUTSIDE INJURY.

8172
05:50:26,292 --> 05:50:36,669
NTHANK YOU VERY MUCH.

8173
05:50:37,069 --> 05:50:38,404
SO NOW, IT'S MY GREAT PLEASURE

8174
05:50:38,404 --> 05:50:42,341
TO INTRODUCE OUR NEXT SPEAKER

8175
05:50:42,341 --> 05:50:45,077
JONAS NEHER, HE IS AT THE GERMAN

8176
05:50:45,077 --> 05:50:48,114
CENTER FOR NEURODEN DEGENERATIVE

8177
05:50:48,114 --> 05:50:50,015
DECS IN TUBING EN, AND HE

8178
05:50:50,015 --> 05:50:52,485
FOCUSES ON MEMORY IN THE BRAIN

8179
05:50:52,485 --> 05:50:55,521
AND CONTRIBUTION TO

8180
05:50:55,521 --> 05:50:56,021
NEURODEGENERATIVE DECS.

8181
05:50:56,021 --> 05:51:01,594
WE LOOK FORWARD TO YOUR TALK

8182
05:51:01,594 --> 05:51:01,827
EMPLOY.

8183
05:51:01,827 --> 05:51:02,828
>> OKAY, THANK YOU VERY
MUCH FOR

8184
05:51:02,828 --> 05:51:04,530
THE ORGANIZERS FOR THE

8185
05:51:04,530 --> 05:51:05,831
INVITATION TO SPEAK HERE TODAY.

8186
05:51:05,831 --> 05:51:07,166
I LEARNED A LOT ABOUT ARIA

8187
05:51:07,166 --> 05:51:08,634
ALREADY AND WHAT I WOULD

8188
05:51:08,634 --> 05:51:09,735
LOAMACYIC TO CONTRIBUTE IS OUR

8189
05:51:09,735 --> 05:51:11,971
THOUGHTS ON HOW MEDIA AMYLOID

8190
05:51:11,971 --> 05:51:15,608
COULD BE A TENTATIVE TARGET FOR

8191
05:51:15,608 --> 05:51:21,447
DAMAGE IN THE PATES WITH THE CAA

8192
05:51:21,447 --> 05:51:21,947
AND OTHER CARDIOVASCULAR

8193
05:51:21,947 --> 05:51:22,248
DISEASES.

8194
05:51:22,248 --> 05:51:26,585
SO WE TURNS OUT THAT THE MOST

8195
05:51:26,585 --> 05:51:30,022
COMMON IN AMYLOID IS MEDIN, AND

8196
05:51:30,022 --> 05:51:31,223
IT'S FOUND IN VIRTUALLY

8197
05:51:31,223 --> 05:51:31,991
EVERYBODY OVER FIEOF THE YEARS

8198
05:51:31,991 --> 05:51:38,130
OF AGE AND IN PARTICULAR, AND

8199
05:51:38,130 --> 05:51:48,674
THE MEDIA, AND ALSO BY THE NAME

8200
05:52:00,586 --> 05:52:00,920
MEDIN COMES FROM.

8201
05:52:00,920 --> 05:52:03,389
SOME PATIENTS WE CAN SEE IT IN

8202
05:52:03,389 --> 05:52:06,458
MORE BETWEEN THESE FIBERS IT CAN

8203
05:52:06,458 --> 05:52:09,128
BE QUITE HETEROGENIUS.

8204
05:52:09,128 --> 05:52:11,297
SO DRIEBED ABOUT 50, 25 YEARS

8205
05:52:11,297 --> 05:52:14,767
AGO AS A 50 AMINO ACIDS ON A

8206
05:52:14,767 --> 05:52:17,570
FRAG M-TEBURKEULOSEIS OF A

8207
05:52:17,570 --> 05:52:20,105
PROTEIN AND IT HAD ANY

8208
05:52:20,105 --> 05:52:22,975
PATHOPHYSIOLOGICAL ROLE IN THE

8209
05:52:22,975 --> 05:52:23,275
VASCULATURE.

8210
05:52:23,275 --> 05:52:26,412
SO IN ORDER TO STUDY IN THIS

8211
05:52:26,412 --> 05:52:27,947
DETAIL, WE USED THE MODEL SYSTEM

8212
05:52:27,947 --> 05:52:29,148
AND BECAUSE WE LIKE WORKING WITH

8213
05:52:29,148 --> 05:52:31,917
THE MICE, WE HAD TO LOOK AT THE

8214
05:52:31,917 --> 05:52:33,919
MEDIN SEQUENCE IN MICE, VERSUS

8215
05:52:33,919 --> 05:52:36,055
IN HUMAN AND FOUND THE AMINO

8216
05:52:36,055 --> 05:52:38,724
ACID LEVELS WAS ABOUT 80% SO NOT

8217
05:52:38,724 --> 05:52:41,093
TOO BAD, AND WHEN WE LOOKED AT

8218
05:52:41,093 --> 05:52:42,795
THE AG IMREIGATION PROPENSITY OF

8219
05:52:42,795 --> 05:52:44,096
THE 2 PEPTIDES WE CAN SEE HERE

8220
05:52:44,096 --> 05:52:46,532
BASED ON THE TANGO PREDICTION IS

8221
05:52:46,532 --> 05:52:49,635
THAT THIS IS IN THE BLUE CURVE,

8222
05:52:49,635 --> 05:52:50,803
HAS 3 AGGREGATION AND THIS 1

8223
05:52:50,803 --> 05:52:54,306
HERE WHICH IS THE MOST SOMEWHAT

8224
05:52:54,306 --> 05:53:04,717
REFLECTIVE IN THE MOUSE

8225
05:53:08,153 --> 05:53:08,721
SEQUENCE.

8226
05:53:08,721 --> 05:53:10,656
THIS LEADS TO FIRST OF ALL THE

8227
05:53:10,656 --> 05:53:11,490
ABSENCE OF MEDIN AND

8228
05:53:11,490 --> 05:53:12,358
SECURITIZATION. OF ALL THE

8229
05:53:12,358 --> 05:53:14,627
FUNCTION TO THE KNOCK OUT, THE

8230
05:53:14,627 --> 05:53:16,395
TRUNCATED FORM BEING RETAINED IN

8231
05:53:16,395 --> 05:53:18,330
THE CELL BECAUSE OF THE TRAN

8232
05:53:18,330 --> 05:53:19,732
MEMBRANE DOMAIN WHERE THE

8233
05:53:19,732 --> 05:53:21,000
WILD-TYPE FORM GETS RELEASED

8234
05:53:21,000 --> 05:53:23,068
INTO THE EXTRA CELLULAR SPACE.

8235
05:53:23,068 --> 05:53:27,072
SO WE WANT TON DO MICE MEDIN

8236
05:53:27,072 --> 05:53:28,641
AGGREGATES IN THE VASCULATURE.

8237
05:53:28,641 --> 05:53:31,977
AND BECAUSE THE AUTHOR HAS THE

8238
05:53:31,977 --> 05:53:34,079
MAIN SITES, WE LOOKEDDA THE

8239
05:53:34,079 --> 05:53:34,847
AORTA FIRST.

8240
05:53:34,847 --> 05:53:37,449
THESE ARE SIMPLE BLACK 6 MICE.

8241
05:53:37,449 --> 05:53:38,584
NO GENETIC MODIFICATION EMPLOY

8242
05:53:38,584 --> 05:53:42,855
AS YOU CAN APPRECIATE IN THE

8243
05:53:42,855 --> 05:53:45,624
SLIDE, WE HAVE WHAT AG

8244
05:53:45,624 --> 05:53:47,159
TBREIGATES BY 20 MONTHS OF AGE

8245
05:53:47,159 --> 05:53:47,793
IN THESE ANIMALS.

8246
05:53:47,793 --> 05:53:52,731
THESE ARE  AGGREGATES ARE IN THE

8247
05:53:52,731 --> 05:53:56,669
MHC 2 KNOCK OUTS SO IT LOOKS AS

8248
05:53:56,669 --> 05:53:58,370
IF MEDIN CAN BE IN MICE, SO THIS

8249
05:53:58,370 --> 05:54:02,308
WOULD BE 1 OF OF THE FEWER

8250
05:54:02,308 --> 05:54:03,175
ENDOGENOUS AMYLOIDS FOR MICE IN

8251
05:54:03,175 --> 05:54:03,609
EFFECT.

8252
05:54:03,609 --> 05:54:05,811
BUT TO CONFIRM THIS WAS THE DDM,

8253
05:54:05,811 --> 05:54:14,086
YOU CAN SEE HERE WE DO GET SEE

8254
05:54:14,086 --> 05:54:15,954
MEDIN IN THE SPACE, AFFECTING

8255
05:54:15,954 --> 05:54:17,790
WHAT'S IN HUMAN PATES BUT THE

8256
05:54:17,790 --> 05:54:18,757
STRUCKURE WAS SURPRISING BECAUSE

8257
05:54:18,757 --> 05:54:20,959
WE DIDN'T SEE ANY FIB RULES, SO

8258
05:54:20,959 --> 05:54:23,395
IF YOU LOOK AT AMYLOID, YOU

8259
05:54:23,395 --> 05:54:24,897
WOULD SEE FIB RULES AND THIS WAS

8260
05:54:24,897 --> 05:54:26,065
BT THE CASE IN MICE.

8261
05:54:26,065 --> 05:54:27,399
SO HAVING SAID THAT WE TALK

8262
05:54:27,399 --> 05:54:29,835
ABOUT THE INITTIAIVE ITS FOR THE

8263
05:54:29,835 --> 05:54:31,537
ANALYSIS IN HUMANS AND HE

8264
05:54:31,537 --> 05:54:35,607
CONFIRMED THAT IN HUMANS WE GET

8265
05:54:35,607 --> 05:54:37,176
MORE AMORPHOUS AGGREGATES RATHER

8266
05:54:37,176 --> 05:54:47,619
THAN THE CLASSICAL AMYLOID

8267
05:54:48,053 --> 05:54:50,289
TRUCTURE. 

8268
05:54:50,289 --> 05:54:55,661
WE DID WANT TO DISCUSS THE

8269
05:54:55,661 --> 05:54:56,095
WILD-TYPE.

8270
05:54:56,095 --> 05:54:57,396
SO LOOKING AT THE RIGHT SIDE,

8271
05:54:57,396 --> 05:55:00,966
YOU CAN SEE THAT IN THIS FIRST

8272
05:55:00,966 --> 05:55:02,868
PLANE OF THE WESTERN PLOT, IN

8273
05:55:02,868 --> 05:55:05,337
THE MOUSE WE ARE 2 ISOFORMS OF

8274
05:55:05,337 --> 05:55:07,039
THE FULL LENGTH AND THEY GET

8275
05:55:07,039 --> 05:55:11,844
DEGRADED BY THE PROCEDURE, BUT

8276
05:55:11,844 --> 05:55:13,912
NO MFGIN THE FINAL TRACTION,

8277
05:55:13,912 --> 05:55:14,847
SITUATIONS ARE DIFFERENT THAN

8278
05:55:14,847 --> 05:55:17,349
THOSE FESTER OF ALL WE HAVE

8279
05:55:17,349 --> 05:55:19,585
MASSIVE AMOUNTS OF THESE, WE CAN

8280
05:55:19,585 --> 05:55:21,787
ALSO SEE WHAT LOOKS LIKE AG

8281
05:55:21,787 --> 05:55:23,122
PREIGATE ANDS INCREASED

8282
05:55:23,122 --> 05:55:25,124
FRAGMENTATION WHICH OF COURSE

8283
05:55:25,124 --> 05:55:29,895
UNNECESSARY TO PRODUCE IT.

8284
05:55:29,895 --> 05:55:31,730
WITH THESE PROTEINS WE END UP

8285
05:55:31,730 --> 05:55:34,466
WITH THE 5 KILODALT AN BAND

8286
05:55:34,466 --> 05:55:35,067
WHICH NICE RESILIENCE SPONDY

8287
05:55:35,067 --> 05:55:37,035
LIGHTISES TO THE MASS OF THE

8288
05:55:37,035 --> 05:55:39,405
METER AND AFFECT BY MASS SPECT

8289
05:55:39,405 --> 05:55:41,407
WE COULD CONFIRM THESE MAG

8290
05:55:41,407 --> 05:55:45,511
FRENTS CONTAIN THE MEDIAN

8291
05:55:45,511 --> 05:55:45,911
SEQUENCE.

8292
05:55:45,911 --> 05:55:47,546
SO THEY ARE DEVELOPING MEDIAN AG

8293
05:55:47,546 --> 05:55:48,814
GERONTOLOGYSTS GET--IS OF THESE,

8294
05:55:48,814 --> 05:55:51,083
YOU ASK WHETHER THIS HAS

8295
05:55:51,083 --> 05:55:52,117
CONQUENCE ON VASCULAR FUNCTION

8296
05:55:52,117 --> 05:55:54,019
FOR THAT WE RETURN TO THE BRAIN

8297
05:55:54,019 --> 05:55:55,053
AS OUR FAVORITE ORGAN AND WE

8298
05:55:55,053 --> 05:55:57,589
FIND THAT WITH THE ARTERIES, AND

8299
05:55:57,589 --> 05:56:00,659
WE USED ENVIVO TO PHOTON IMAGING

8300
05:56:00,659 --> 05:56:02,261
AND HYPE AND STIMMULES IMAGING

8301
05:56:02,261 --> 05:56:04,496
THE SENSORY CORTEX AND LOOKING

8302
05:56:04,496 --> 05:56:06,031
AT FUNCTIONAL HYPEREMIA AND THE

8303
05:56:06,031 --> 05:56:08,167
VASCULAR RESPONSE, AND IN ADULT

8304
05:56:08,167 --> 05:56:09,268
ANIMALS WE DIDN'T ACTUALLY SEE

8305
05:56:09,268 --> 05:56:10,669
ANY DIFFERENCE BETWEEN THE

8306
05:56:10,669 --> 05:56:12,271
MEDIAN AND SUFFICIENT AND

8307
05:56:12,271 --> 05:56:13,939
DEFICIENT ANIMALS BUT IN AGED

8308
05:56:13,939 --> 05:56:15,674
ANIMALS WE COULD SEE IT SLOWING

8309
05:56:15,674 --> 05:56:18,110
OFF THE TIME AND THE WILD-TYPE

8310
05:56:18,110 --> 05:56:20,946
ANIMALS, THIS WAS ALMOST

8311
05:56:20,946 --> 05:56:24,983
COMPLETELY THERE AND WERE ABSENT

8312
05:56:24,983 --> 05:56:26,118
INDICATING MEETING AGGREGATES

8313
05:56:26,118 --> 05:56:28,654
REALLY ALSO ARE A DECLINE IN

8314
05:56:28,654 --> 05:56:30,155
VASCULAR FUNCTION IN AGING.

8315
05:56:30,155 --> 05:56:33,859
WE ALSO SAW KIND OF A RESCUE

8316
05:56:33,859 --> 05:56:34,626
EEIVET WITH CONSTRUCTIONS AFTER

8317
05:56:34,626 --> 05:56:36,361
THEY SEE US AND THAT SEEMS TO

8318
05:56:36,361 --> 05:56:38,964
INDICATE WHAT MIGHT BE LOOKING

8319
05:56:38,964 --> 05:56:49,408
AT IS ARTERIOLE STIFFENING

8320
05:56:55,481 --> 05:56:56,682
RATHER THAN OF COURSE WE'RE

8321
05:56:56,682 --> 05:56:59,184
WONDERING WHETHER IT COULD BE

8322
05:56:59,184 --> 05:57:00,586
IRPTACKING WITH AMYLOID IN THE

8323
05:57:00,586 --> 05:57:00,786
BRAIN.

8324
05:57:00,786 --> 05:57:03,155
SO THE FIRST THING WE DID IS WE

8325
05:57:03,155 --> 05:57:06,124
BEING TO A SECTION FROM OUR APP

8326
05:57:06,124 --> 05:57:08,794
MODELS AND TAINED IT WITH THE

8327
05:57:08,794 --> 05:57:14,233
FGHANTIBODY AND YOU CAN SEE

8328
05:57:14,233 --> 05:57:14,900
SUBSTANTIAL IMMUNO REACTIVITY,

8329
05:57:14,900 --> 05:57:18,470
FOR THE PLAQUE, WE SEE IT

8330
05:57:18,470 --> 05:57:19,705
EXPRESSED IN THE ASTRO SIGHTS

8331
05:57:19,705 --> 05:57:21,173
HERE AND WHEN WE CROSS IT IN THE

8332
05:57:21,173 --> 05:57:24,676
KNOCK OUTS WE SEE THE STAINING

8333
05:57:24,676 --> 05:57:26,578
AROUND PLAQUE COMPLETELY

8334
05:57:26,578 --> 05:57:27,446
DISAPPEARS THE TRUNCATED FORM

8335
05:57:27,446 --> 05:57:29,715
STUCK INSIDE THESE CELLS.

8336
05:57:29,715 --> 05:57:32,050
SO DOESN'T HAVE AN IMPACT ON THE

8337
05:57:32,050 --> 05:57:33,085
AGGREGATION, OF COURSE QUESTIONS

8338
05:57:33,085 --> 05:57:34,887
WE WANTED TO WORRY.

8339
05:57:34,887 --> 05:57:38,690
SO WE LOOKED AT THIS AND

8340
05:57:38,690 --> 05:57:40,259
DIFFERENT TRANSGENIC MODELS 1 OF

8341
05:57:40,259 --> 05:57:46,298
THE PP1 S MICE, VERY RAPID, A

8342
05:57:46,298 --> 05:57:50,369
PITA PLAQUE MODEL WHICH THE MICE

8343
05:57:50,369 --> 05:57:54,006
HEARD ABOUT BEFORE, THEY SHOW

8344
05:57:54,006 --> 05:57:57,709
LEVELS AT 6 MONTHS AND 12 MONTHS

8345
05:57:57,709 --> 05:57:58,977
EMPLOY SO LOOKING AT PLAQUE,

8346
05:57:58,977 --> 05:58:00,913
THAT WAS NICE BUT DISAPPOINTING

8347
05:58:00,913 --> 05:58:04,316
AT SAT TIME BECAUSE WE SAW 50%

8348
05:58:04,316 --> 05:58:05,784
LESS PLAQUES BUT BEFORE MONTHS

8349
05:58:05,784 --> 05:58:07,553
OF AGE THIS LEVELS OFF TO

8350
05:58:07,553 --> 05:58:09,521
SIMILAR LEVELS IN THE WILD-TYPE

8351
05:58:09,521 --> 05:58:11,189
AND MEDIAN DEFICIENT ANIMALS.

8352
05:58:11,189 --> 05:58:14,326
VERY SIMILAR IN THE APP 23

8353
05:58:14,326 --> 05:58:22,167
INSHALLLY VERY NICE DECREASE IN

8354
05:58:22,167 --> 05:58:23,001
THE [INDISCERNIBLE] AND SEARCH

8355
05:58:23,001 --> 05:58:24,503
ANIMALS AND NOW AS I SAID, THIS

8356
05:58:24,503 --> 05:58:26,138
WAS A LITTLE BIT DISAPPOINTING

8357
05:58:26,138 --> 05:58:28,840
BUT I WOULD LIKE TO EMPHASIZE

8358
05:58:28,840 --> 05:58:30,709
THAT WHAT WE'RE LOOKINGA THE IS

8359
05:58:30,709 --> 05:58:35,113
THE IMPACT OF ENDOGENOUS MEDIAN

8360
05:58:35,113 --> 05:58:38,250
ON A MASSIVELY OVERPRODUCED

8361
05:58:38,250 --> 05:58:40,586
AMYLOID BETA AND WE CAN TILL SEE

8362
05:58:40,586 --> 05:58:41,987
THESE EFFECT INDICATING THAT IT

8363
05:58:41,987 --> 05:58:45,123
MIGHT BE INTERACTING WITH IT IN

8364
05:58:45,123 --> 05:58:45,724
SOME WAY.

8365
05:58:45,724 --> 05:58:49,728
AND NOW BECAUSE THIS IS AMYLOID,

8366
05:58:49,728 --> 05:58:53,031
AND DESCRIBED AS A VASCULAR

8367
05:58:53,031 --> 05:58:56,802
AMYLOID AND BEFORE THE APP 23 IT

8368
05:58:56,802 --> 05:59:07,312
YOU CAN SEE IT HERE, THEY HAVE

8369
05:59:07,746 --> 05:59:12,250
ANTI-AB HERE AND IT'S ABSENT

8370
05:59:12,250 --> 05:59:15,187
AGAIN IN THE FGE8 HERE, CAN YOU

8371
05:59:15,187 --> 05:59:17,155
SEE THAT IT'S SIGNIFICANTLY

8372
05:59:17,155 --> 05:59:18,423
REDUCED BY 85% BUT THE VARIANCE

8373
05:59:18,423 --> 05:59:19,925
IS VERY HIGH AND THESE ANIMALS

8374
05:59:19,925 --> 05:59:23,562
ARE JUST STARTING TO DEVELOP

8375
05:59:23,562 --> 05:59:25,230
CAA, BUT AT 24 MONTHS OF AGE

8376
05:59:25,230 --> 05:59:26,632
WHERE WE HAVE SEVERE CAA IN

8377
05:59:26,632 --> 05:59:29,101
THESE ANIMALS WE CAN SEE

8378
05:59:29,101 --> 05:59:30,702
REDUCTION BY 65% IN CAA

8379
05:59:30,702 --> 05:59:32,704
INDICATING THAT MEET NOTHING

8380
05:59:32,704 --> 05:59:33,872
SOME WAYS DRIVING THE

8381
05:59:33,872 --> 05:59:35,707
AGGREGATION IN THE ARTERIES OF

8382
05:59:35,707 --> 05:59:36,441
THESE ANIMALS.

8383
05:59:36,441 --> 05:59:37,709
ALSO TO MENTION THIS GOES ALONG

8384
05:59:37,709 --> 05:59:40,112
WITH THE REDUCTION IN

8385
05:59:40,112 --> 05:59:41,580
MICROORIGINS, THIS IS NOT

8386
05:59:41,580 --> 05:59:44,650
SURPRISING BECAUSE OF THE WE

8387
05:59:44,650 --> 05:59:49,488
REDUCE CAA WE EXPECT TO REDUCE

8388
05:59:49,488 --> 05:59:51,089
THE MICROHEMORRHAGES IN MOUSE.

8389
05:59:51,089 --> 05:59:52,491
WHY SUBJECT THAT IMPACT ON THE

8390
05:59:52,491 --> 05:59:54,393
AG DPREIGATION IN THE

8391
05:59:54,393 --> 05:59:54,993
VASCULATURE CONSISTENTLY BUT

8392
05:59:54,993 --> 05:59:59,631
THOT SO MUCH ON PLAQUES?

8393
05:59:59,631 --> 06:00:01,133
THE SIMPLE ANSWER IS BECAUSE

8394
06:00:01,133 --> 06:00:02,601
IT'S NOR VASCULATURE AND IN THIS

8395
06:00:02,601 --> 06:00:05,537
CASE WE HAVE 50 TIMES HIGHER AND

8396
06:00:05,537 --> 06:00:06,538
ISOLATED BLOOD VESSELS IN THE

8397
06:00:06,538 --> 06:00:08,974
MICE COMPARED TO THE TOTAL

8398
06:00:08,974 --> 06:00:10,275
INNATE AND IT IPT GREATER

8399
06:00:10,275 --> 06:00:12,744
CREASES FURTHER BY 10 FOLD, SO

8400
06:00:12,744 --> 06:00:14,279
THIS IS ARRHYTHMIC SCALE GOES UP

8401
06:00:14,279 --> 06:00:17,916
BY 10 FOLD WITH CAA PATHOLOGY IN

8402
06:00:17,916 --> 06:00:21,086
OUR APP 23 MICE INDICATING THAT

8403
06:00:21,086 --> 06:00:23,055
ALSO FGHSMAZE IN SOME WAYS

8404
06:00:23,055 --> 06:00:23,689
RELATED TO PATHOLOGY.

8405
06:00:23,689 --> 06:00:25,323
WHAT ABOUT THE HUMAN BRAIN.

8406
06:00:25,323 --> 06:00:26,758
SO THIS IS WHEN IT GETS

8407
06:00:26,758 --> 06:00:28,293
INTERESTING, SO THIS IS THE

8408
06:00:28,293 --> 06:00:34,666
HUMAN BRAIN, THIS IS THE PATIENT

8409
06:00:34,666 --> 06:00:37,202
WITH CBS CAA, YOU CAN SEE THE

8410
06:00:37,202 --> 06:00:38,804
SUBSTANTIAL IN THE VESSEL OF

8411
06:00:38,804 --> 06:00:41,573
THESE PATES AND IN HUMANS WE SEE

8412
06:00:41,573 --> 06:00:44,142
IT IN PLAQUES AND WE LOCALIZED

8413
06:00:44,142 --> 06:00:47,512
BLOOD VESSELS IN PATIENTS AND

8414
06:00:47,512 --> 06:00:48,313
THAT'S SOME COLOCALIZATION WITH

8415
06:00:48,313 --> 06:00:49,881
THE IT BUT IT'S NOT COMPLETE.

8416
06:00:49,881 --> 06:00:51,917
VERY SIMILAR TO THE MOUSE MODELS

8417
06:00:51,917 --> 06:00:53,618
AGAIN, THAT WAS ABOUT 50 FOLDS

8418
06:00:53,618 --> 06:00:55,787
HIGHER IN THE ISOLATED BLOOD

8419
06:00:55,787 --> 06:00:58,523
VISITSLES, AND COMPARE AGAIN

8420
06:00:58,523 --> 06:00:59,558
WITH PATES WHO OVER

8421
06:00:59,558 --> 06:01:02,294
[INDISCERNIBLE] AGAIN WE CAN SEE

8422
06:01:02,294 --> 06:01:04,162
THIS INCREASE IN MFG 8 LEVELS

8423
06:01:04,162 --> 06:01:05,063
AND REFLECTIVE OF WHAT WE'VE

8424
06:01:05,063 --> 06:01:08,667
SEEN IN THE MOUSE MODELS.

8425
06:01:08,667 --> 06:01:11,303
SO IN HUMANS WE CAN LOOK AT

8426
06:01:11,303 --> 06:01:18,243
BESTERN PLOTS YOU CAN SEE FULL

8427
06:01:18,243 --> 06:01:19,945
LENGTH MFG-E8, AND WE IS SEE IT

8428
06:01:19,945 --> 06:01:22,647
IN PATIENTS WITH CAA, AND AT THE

8429
06:01:22,647 --> 06:01:23,749
VASCULAR LEVEL IT IS INTERESTING

8430
06:01:23,749 --> 06:01:25,317
BECAUSE IN PATES WE DON'T SEE

8431
06:01:25,317 --> 06:01:26,518
JUST WHAT LOOKS LIKE AG

8432
06:01:26,518 --> 06:01:28,787
DPREIGATES UP HERE BUT WE SEE

8433
06:01:28,787 --> 06:01:30,655
INCREASED FRAGMENTATION AND HAD

8434
06:01:30,655 --> 06:01:32,824
IS OF COURSE NECESSARY TO

8435
06:01:32,824 --> 06:01:35,026
PRODUCE MEDIAN, ALSO ON THE

8436
06:01:35,026 --> 06:01:39,097
INSOLUBLE FACTION, WE CAN SEE HA

8437
06:01:39,097 --> 06:01:40,999
LOOKS LOOK A SMEAR ACROSS THE

8438
06:01:40,999 --> 06:01:42,868
ENTIRE RANGE AND AG FREE

8439
06:01:42,868 --> 06:01:43,668
RADICALSIGATES CHARACTERIZE THEM

8440
06:01:43,668 --> 06:01:54,012
IN DETAIL RIGHT NOW.

8441
06:02:01,052 --> 06:02:06,892
WE TURNED IT FROM THE PATIENT

8442
06:02:06,892 --> 06:02:16,101
STUDY, IS THERE INCREASE TO THE

8443
06:02:16,101 --> 06:02:20,539
INTEGRATION, IS THERE MORE MFED8

8444
06:02:20,539 --> 06:02:22,207
AND IS EVIDENT DRIVEN BEN BY THE

8445
06:02:22,207 --> 06:02:25,710
VESTITURE AND THAT IS CALLED

8446
06:02:25,710 --> 06:02:26,878
WEIGHTED CORRELATION, IT GROUPS

8447
06:02:26,878 --> 06:02:29,748
ALL THE YEEPS BY CO EXPRESSION

8448
06:02:29,748 --> 06:02:35,187
BY CO RECOGNIZATION AND WE ONLY

8449
06:02:35,187 --> 06:02:36,588
FOUND 1 GROUP IN THESE PATIENTS

8450
06:02:36,588 --> 06:02:37,823
AND WE TOOK ALL THESE YEENS AND

8451
06:02:37,823 --> 06:02:39,191
ASKED WHETHER THERE ARE ENRICH

8452
06:02:39,191 --> 06:02:40,458
INDEED A PARTICULAR CELL TYPE

8453
06:02:40,458 --> 06:02:43,428
ASK WE ONLY COULD IDENTIFY

8454
06:02:43,428 --> 06:02:44,830
SMOOTH MUSCLE CELLS, AGAIN,

8455
06:02:44,830 --> 06:02:46,898
TAKING THIS INCREASE TO THE

8456
06:02:46,898 --> 06:02:48,567
VASCULATURE IN THESE PATES.

8457
06:02:48,567 --> 06:02:50,569
AND FINALLY, WHAT THE STATE SENT

8458
06:02:50,569 --> 06:02:52,470
US OUT IS TO ASK US WHETHER

8459
06:02:52,470 --> 06:02:54,773
MEDIAN MAY BE INDEPENDENT

8460
06:02:54,773 --> 06:02:55,574
PREDICTER OF COGNITIVE DECLINE

8461
06:02:55,574 --> 06:03:00,045
ASK THAT SOME OF YOU IN THE

8462
06:03:00,045 --> 06:03:02,881
REGRESSION FACTORING IN A PITA

8463
06:03:02,881 --> 06:03:04,149
AND TAU PATHOLOGY AND EVEN THEN

8464
06:03:04,149 --> 06:03:08,720
THE YEEN EXPRESSION OF THE MFGE8

8465
06:03:08,720 --> 06:03:10,255
CONTRIBUTED SIGNIFICANTLY TO

8466
06:03:10,255 --> 06:03:11,857
PREDICTING COGNITIVE DECLINE IN

8467
06:03:11,857 --> 06:03:13,592
THESE PATIENTS INDICATING IT HAS

8468
06:03:13,592 --> 06:03:18,797
A COMPONENT IN ALZHEIMER'S

8469
06:03:18,797 --> 06:03:20,765
DISEASE.

8470
06:03:20,765 --> 06:03:26,137
SO HOW DOES MEDIAN ACCELERATE

8471
06:03:26,137 --> 06:03:28,006
THE DEPOSITION OF THE

8472
06:03:28,006 --> 06:03:36,047
VASCULATURE, AND THE SAME THING

8473
06:03:36,047 --> 06:03:38,049
IS THE MEDIN, AND WHEN WE PUT

8474
06:03:38,049 --> 06:03:40,685
THEM TOGETHER, WE RADIE AND CO

8475
06:03:40,685 --> 06:03:43,121
AGGREGATE INVITRO AND LOOKING AT

8476
06:03:43,121 --> 06:03:44,756
THE THESE YOU CAN SEE BY 2

8477
06:03:44,756 --> 06:03:46,458
DIFFERENT GOALS FOR THE 2

8478
06:03:46,458 --> 06:03:49,227
PEPTIDES THEY ARE LOCALIZED TO

8479
06:03:49,227 --> 06:03:50,996
SINGLE [INDISCERNIBLE]

8480
06:03:50,996 --> 06:03:51,897
INDICATING CO AGGREGATION.

8481
06:03:51,897 --> 06:03:54,132
SO WOO DID A BUNCH OF OTHER

8482
06:03:54,132 --> 06:03:55,367
EXPERIMENTS BUT I WON'T SHOW YOU

8483
06:03:55,367 --> 06:03:57,102
THEM TODAY, I WOULD RATHER SHOW

8484
06:03:57,102 --> 06:04:01,072
YOU EVIDENCE THAT HAS RECENTLY

8485
06:04:01,072 --> 06:04:08,046
EMERGESSED THAT ALSO INICATES

8486
06:04:08,046 --> 06:04:10,649
VASCULAR DISEASE IN THE BRAIN.

8487
06:04:10,649 --> 06:04:12,984
THIS ARE 2 STUDIES WHERE THERE'S

8488
06:04:12,984 --> 06:04:14,853
LOSS OF FUNCTION MOWITATIONS AND

8489
06:04:14,853 --> 06:04:16,888
THEY ARE HIGHLY PROTECTIVE

8490
06:04:16,888 --> 06:04:17,956
AGAINST CARDIOVASCULAR DEC

8491
06:04:17,956 --> 06:04:18,523
INCLUDING DIFFERENT FOR THE

8492
06:04:18,523 --> 06:04:20,558
PURPOSES OF STROKE, AND 1 OF

8493
06:04:20,558 --> 06:04:21,893
THESE MUTATIONS PARTICULARLY

8494
06:04:21,893 --> 06:04:24,162
INTERESTING BECAUSE IT INDUCES

8495
06:04:24,162 --> 06:04:25,363
THE SPLICE SIGHT AND THAT WOULD

8496
06:04:25,363 --> 06:04:27,499
BE PREDICTED TO CUT OFF THE

8497
06:04:27,499 --> 06:04:28,767
MEDIAN SEQUENCE, COMPARED TO

8498
06:04:28,767 --> 06:04:31,503
WHAT WE'VE SEEN IN THE KNOCK OUT

8499
06:04:31,503 --> 06:04:32,904
MODELS AND THAT IS HIGHLY

8500
06:04:32,904 --> 06:04:34,272
PROTECT EVALUATION PROCESS

8501
06:04:34,272 --> 06:04:35,240
AGAINST CARDIOVASCULAR DEC, AND

8502
06:04:35,240 --> 06:04:37,175
ANOTHER STUDY THAT LEADS TO

8503
06:04:37,175 --> 06:04:40,045
VASCULAR PATHOLOGY AND THIS

8504
06:04:40,045 --> 06:04:40,679
PREPRINT HERE WHEREBY

8505
06:04:40,679 --> 06:04:42,881
PROTEOMICS, THE AUTHORS LOOKEDDA

8506
06:04:42,881 --> 06:04:47,652
MORE THAN 300 SAMPLES OF PASHTS,

8507
06:04:47,652 --> 06:04:49,087
WHAT THEY COULD SHOW WAS THERE

8508
06:04:49,087 --> 06:04:51,222
WERE 5 DIFFERENT MOLECULAR

8509
06:04:51,222 --> 06:04:52,424
SUBTYPES OF PATIENT ANDS 1 OF

8510
06:04:52,424 --> 06:04:54,893
THEM HAS WHAT THEY CALL THE

8511
06:04:54,893 --> 06:04:56,661
VASCULAR DAMAGE PROFILE.

8512
06:04:56,661 --> 06:04:59,597
AND IN THIS PROFILE ACTUALLY

8513
06:04:59,597 --> 06:05:01,733
MEETING DECREASED AND POSSIBLY

8514
06:05:01,733 --> 06:05:02,634
REFLECTINGAEGREGATION IN THE

8515
06:05:02,634 --> 06:05:04,703
VASCULATURE OF THESE PATES AND

8516
06:05:04,703 --> 06:05:09,074
AGAIN THINKING IT TO THE

8517
06:05:09,074 --> 06:05:10,709
VASCULAR PATHOLOGY IN AD PATES.

8518
06:05:10,709 --> 06:05:11,910
SO BRIEFLY WHAT WE'VE DONE SINCE

8519
06:05:11,910 --> 06:05:15,814
AND PLANNING TO DO IS WE CREATED

8520
06:05:15,814 --> 06:05:19,517
MODELS THAT HERE OVEREXPRESS

8521
06:05:19,517 --> 06:05:21,519
HUMAN MFEG8 AND IN WITHIN 6

8522
06:05:21,519 --> 06:05:23,221
MONTHS WE GET MEDIAN DEPOSITION

8523
06:05:23,221 --> 06:05:25,190
IN THE PLOT BRAIN OF THESE

8524
06:05:25,190 --> 06:05:25,423
ANIMALS.

8525
06:05:25,423 --> 06:05:27,492
THIS IS WHAT YOU CAN HOPEFUL

8526
06:05:27,492 --> 06:05:32,931
LEAVE APPRECIATE IS THESE AG

8527
06:05:32,931 --> 06:05:37,302
AGGREGATES SEEM TO BE DEPOSITING

8528
06:05:37,302 --> 06:05:39,637
IN THE BASE OF THE BRAIN.

8529
06:05:39,637 --> 06:05:41,039
THE EXCITING DATA IN THE BRAIN

8530
06:05:41,039 --> 06:05:44,175
WE CAN SEE THESE BIND WITH THE

8531
06:05:44,175 --> 06:05:45,577
CLASSICAL AMYLOID BINDING,

8532
06:05:45,577 --> 06:05:47,078
INDICATING THAT NOW, WE'RE

8533
06:05:47,078 --> 06:05:50,849
GENERATING A PATHOLOGY BASE TO

8534
06:05:50,849 --> 06:05:51,850
THE HUMAN SITUATION.

8535
06:05:51,850 --> 06:05:53,551
WITH A FORMAL PARTNER IMENERATED

8536
06:05:53,551 --> 06:05:55,920
ANTIBODIES WITH HIGH AFFINITY

8537
06:05:55,920 --> 06:05:57,522
AND SPECIFICITY FOR MEDIN.

8538
06:05:57,522 --> 06:05:59,958
YOU CAN SEE THIS 1 HERE.

8539
06:05:59,958 --> 06:06:05,330
IT DOESN'T RECOGNIZE MFEG8, IT

8540
06:06:05,330 --> 06:06:14,072
DOESN'T RECOGNIZE ANY LISAITS OF

8541
06:06:14,072 --> 06:06:16,007
SALES, AND WE CHARACTERIZED THEM

8542
06:06:16,007 --> 06:06:18,576
FOR NATURE OF HUMAN SAMPLES AND

8543
06:06:18,576 --> 06:06:19,778
WHAT THESE ANTIBODY ANDS MOUSE

8544
06:06:19,778 --> 06:06:24,549
MODEL WE WANT TO TRY AND TEST

8545
06:06:24,549 --> 06:06:26,317
THAT HYPOTHESIS THAT THROUGH

8546
06:06:26,317 --> 06:06:28,953
PASSIVE IMMUNIZATION CAN REMOVE

8547
06:06:28,953 --> 06:06:30,889
AGGREGATES AND RESTORE FUNCTION

8548
06:06:30,889 --> 06:06:33,958
IN THESE ANIMAL ANDS THEN

8549
06:06:33,958 --> 06:06:37,395
IEWVENTUALLY ABOUT INTO THE CAA

8550
06:06:37,395 --> 06:06:38,897
MODELS AND HAVE IT AGAINST CAA

8551
06:06:38,897 --> 06:06:40,532
EMPLOY AND BECAUSE WE'RE TALKING

8552
06:06:40,532 --> 06:06:47,806
ABOUT ARIA, I THINK IN TERPS OF

8553
06:06:47,806 --> 06:06:50,041
IN TERMS OF MECHANISMS IT WILL

8554
06:06:50,041 --> 06:06:51,242
BE INTERESTING AFTER MODELS AND

8555
06:06:51,242 --> 06:06:55,680
SEE IF WE CAN GET ANYTHING WITH

8556
06:06:55,680 --> 06:06:57,215
ARIA BY REMOVING THIS VASCULAR

8557
06:06:57,215 --> 06:06:58,183
AMYLOID IN THESE ANIMALS AND

8558
06:06:58,183 --> 06:06:59,684
WITH THAT I WANT TO THANK THE

8559
06:06:59,684 --> 06:07:01,252
PEOPLE IN MY LAB, OUR

8560
06:07:01,252 --> 06:07:06,491
COLLABORATION PARTNERS AND

8561
06:07:06,491 --> 06:07:08,259
FUNDERS AND I'M HAPPY TO TAKE

8562
06:07:08,259 --> 06:07:08,526
QUESTIONS.

8563
06:07:08,526 --> 06:07:08,793
THANK YOU.

8564
06:07:08,793 --> 06:07:11,529
>> THANK YOU VERY MUCH.

8565
06:07:11,529 --> 06:07:13,098
WE HAVE TIME MAYBE FOR 1

8566
06:07:13,098 --> 06:07:16,301
QUESTION. 

8567
06:07:16,301 --> 06:07:18,136
YEAH, GO AHEAD.

8568
06:07:18,136 --> 06:07:19,938
NGREAT TALK, REALLY ENJOYED IT,

8569
06:07:19,938 --> 06:07:21,406
DESCROIBING PEOPLE WITH

8570
06:07:21,406 --> 06:07:23,341
HYPERTENSION OR OTHER VASCULAR

8571
06:07:23,341 --> 06:07:25,643
RISK FACTORS WOULD HAVE MORE

8572
06:07:25,643 --> 06:07:27,078
MEDIN IN THEIR ARTERIOLES, BUT I

8573
06:07:27,078 --> 06:07:29,247
NOTICED IN THE CONTROLS YOU

8574
06:07:29,247 --> 06:07:30,748
DIDN'T SEE ANY, SO WERE THE

8575
06:07:30,748 --> 06:07:33,084
CONTROLS THAT YOU LOOKED AT IN

8576
06:07:33,084 --> 06:07:35,153
THE HUMAN BRAIN DID THEY HAVE

8577
06:07:35,153 --> 06:07:36,254
VASCULAR RISK FACTORS AND HAVE

8578
06:07:36,254 --> 06:07:38,823
YOU LOOKED AT PEOPLE WITH SAY

8579
06:07:38,823 --> 06:07:40,925
HYPERTENSION BUT NO DEMENTIA?

8580
06:07:40,925 --> 06:07:43,928
NNO, WE HAVEN'T LOOKED AT

8581
06:07:43,928 --> 06:07:45,597
SPECIFIC CONTROL GROUPS YET.

8582
06:07:45,597 --> 06:07:48,700
WE DO SEE MEDIN IN PRINCIPLE IN

8583
06:07:48,700 --> 06:07:49,634
ANALLED IN THE AGENTED HUMAN

8584
06:07:49,634 --> 06:07:51,669
BRAIN, WE SEE SOME MEDIAN IN THE

8585
06:07:51,669 --> 06:07:53,638
VASCULATURE BUT IT'S MASSIVELY

8586
06:07:53,638 --> 06:07:55,373
INCREASED IN PATIENTS WITH CAA,

8587
06:07:55,373 --> 06:07:57,008
WE HAVEN'T LOOKED THAT SPECIFIC

8588
06:07:57,008 --> 06:08:06,651
SUBGROUPS OF HUMAN CONTROLS YET.

8589
06:08:06,651 --> 06:08:07,118
>> THANK YOU.

8590
06:08:07,118 --> 06:08:09,454
GREAT IF THERE ARE NO OTHER

8591
06:08:09,454 --> 06:08:15,160
QUESTIONS WE SHOULD MOVE TO OUR

8592
06:08:15,160 --> 06:08:15,994
NEXT SPEAKER THE MY DPRAIT

8593
06:08:15,994 --> 06:08:24,869
PLEASURE TO INTRODUCE OUR NEXT

8594
06:08:24,869 --> 06:08:27,805
SPEAKER BERRY ZLOKAVOIRKS C, HE

8595
06:08:27,805 --> 06:08:30,942
IS DEPARTMENT AND CHAIR OF

8596
06:08:30,942 --> 06:08:32,210
IMMUNOLOGY AND SCIENCE AT USC

8597
06:08:32,210 --> 06:08:33,344
EMPLOY HE PILOT PROJECT OR

8598
06:08:33,344 --> 06:08:35,780
NEARED STUDIES IN THE BLOOD

8599
06:08:35,780 --> 06:08:37,448
BRAIN BARRIER AND

8600
06:08:37,448 --> 06:08:40,084
NEURODEGENERATION AND SEVERAL OF

8601
06:08:40,084 --> 06:08:41,553
HIS RESEARCH DOORS CLINICAL

8602
06:08:41,553 --> 06:08:45,356
DEVELOPMENT FOR STROKE AND

8603
06:08:45,356 --> 06:08:45,790
NEUROLOGIC DISEASES.

8604
06:08:45,790 --> 06:08:56,267
WE LOOK FORWARD TO HIS TALK.

8605
06:09:12,083 --> 06:09:12,450
>> THANK YOU.

8606
06:09:12,450 --> 06:09:15,486
CAN YOU HEAR ME?

8607
06:09:15,486 --> 06:09:16,588
>> YES NTHANK YOU VERY
MUCH FOR

8608
06:09:16,588 --> 06:09:18,022
INVITING ME TO THE MEETING IT

8609
06:09:18,022 --> 06:09:20,291
WAS VERY EARLY MY TIME AND I

8610
06:09:20,291 --> 06:09:22,660
ALSO ENJOY THE CAMERA SHOT OF

8611
06:09:22,660 --> 06:09:26,698
AUDWRENS AND PEOPLE WAS SO WELL

8612
06:09:26,698 --> 06:09:27,198
DONE.

8613
06:09:27,198 --> 06:09:29,100
SOPHISTICATED I WILL PRESENT A

8614
06:09:29,100 --> 06:09:32,237
TALK ABOUT HOW WE CAN PROTECT

8615
06:09:32,237 --> 06:09:33,137
ENDOTHELIAL BARRIER IN

8616
06:09:33,137 --> 06:09:35,106
PERISIGHTS WITH ACTIVE PROTEIN C

8617
06:09:35,106 --> 06:09:37,075
MUTANT ACTUALLY IN PHASE 3

8618
06:09:37,075 --> 06:09:38,876
STUDIES THAT WE HAVE DEVELOPED

8619
06:09:38,876 --> 06:09:42,247
AND ALSO HAVING DISCUSSED THE

8620
06:09:42,247 --> 06:09:45,883
EFFECT OF APOE4 GENE.

8621
06:09:45,883 --> 06:09:48,019
SO I'M THE FOUNDER OF THE

8622
06:09:48,019 --> 06:09:49,687
BIOTECH COMPANY TO DEVELOP NEW

8623
06:09:49,687 --> 06:09:51,990
THERAPEUTICS FOR STROKE AND

8624
06:09:51,990 --> 06:09:52,490
NEUROLOGICAL DISORDERS.

8625
06:09:52,490 --> 06:09:55,193
SO JUST A BIT OF BACKGROUND

8626
06:09:55,193 --> 06:09:57,428
ABOUT ACTIVATED PROTEIN C OR

8627
06:09:57,428 --> 06:09:57,595
APC.

8628
06:09:57,595 --> 06:09:58,696
SNR SORRY TO INTERRUPT, YOU'RE

8629
06:09:58,696 --> 06:10:01,633
NOT SHARING YOUR SLIDES.

8630
06:10:01,633 --> 06:10:02,200
>> OH REALLY?

8631
06:10:02,200 --> 06:10:08,940
I CAN SEE IT OVER HERE.

8632
06:10:08,940 --> 06:10:14,412
TO --DO YOU SEE SLIDES?

8633
06:10:14,412 --> 06:10:18,650
I CAN STOP SHARING AND DO 1 MORE

8634
06:10:18,650 --> 06:10:20,451
TIME HOW ABOUT NOW?

8635
06:10:20,451 --> 06:10:21,853
>> IT SAYS YOU ARE SCREEN

8636
06:10:21,853 --> 06:10:32,330
SHARING, THAT'S WHAT I GET.

8637
06:10:38,503 --> 06:10:39,937
>> I THINK IT'S POSSIBLE
THERE

8638
06:10:39,937 --> 06:10:42,907
IS A COMMAND THAT SAYS REMOVE

8639
06:10:42,907 --> 06:10:44,208
SPOTLIGHT, IT IS SUGGIEST THAD

8640
06:10:44,208 --> 06:10:46,411
THIS MIGHT HELP NREMOVE

8641
06:10:46,411 --> 06:10:56,988
SPOTLIGHT, AND TRY AGAIN, MAYBE 

8642
06:11:05,063 --> 06:11:05,963
>> OKAY, STOP SHARING.

8643
06:11:05,963 --> 06:11:09,934
HOW ABOUT NOW?

8644
06:11:09,934 --> 06:11:15,173
>> OKAY EMPLOY NI THINK I
ALSO

8645
06:11:15,173 --> 06:11:17,008
HAVE SEND THIS TALK, I THINK THE

8646
06:11:17,008 --> 06:11:20,311
PEOPLE THERE MAY HAVE THE TALK

8647
06:11:20,311 --> 06:11:21,012
AS WELL.

8648
06:11:21,012 --> 06:11:22,180
OOSE A LITTLE BIT DIFFERENT I

8649
06:11:22,180 --> 06:11:28,019
DON'T KNOW WHAT ELSE I CAN DO

8650
06:11:28,019 --> 06:11:28,219
HERE.

8651
06:11:28,219 --> 06:11:30,321
CAN YOU TRY AGAIN, I THINK IT

8652
06:11:30,321 --> 06:11:32,857
JUST GAVE YOU CO-HOST PRIVILEGES

8653
06:11:32,857 --> 06:11:36,728
SO MAYBE IF YOU TRY AGAIN?

8654
06:11:36,728 --> 06:11:38,629
>> I AM TRYING SHARING
AGAIN.

8655
06:11:38,629 --> 06:11:40,331
>> YES NYOU WERE JUST
ASSIGNED

8656
06:11:40,331 --> 06:11:44,202
AS A CO-HOST SO--NYES THIS CAN

8657
06:11:44,202 --> 06:11:45,603
SEE NOW YOUR PRESENTATION THAT'S

8658
06:11:45,603 --> 06:11:55,913
WHAT IT SAYS HERE.

8659
06:11:56,814 --> 06:11:58,516
>> I THINK I.T. IS TRYING
TO

8660
06:11:58,516 --> 06:12:08,760
FIGURE IT OUT.

8661
06:12:48,733 --> 06:12:48,933
>> OKAY.

8662
06:12:48,933 --> 06:12:50,835
>> YES, WE CAN SEE EMPLOY.

8663
06:12:50,835 --> 06:12:53,204
>> YES, LET ME GO REALLY
QUICK

8664
06:12:53,204 --> 06:12:57,241
LYE THEN LITTLE BIT ABOUT I TO

8665
06:12:57,241 --> 06:12:58,509
TO SEE, CAN I MOVE THEM.

8666
06:12:58,509 --> 06:13:00,778
OKAY, I WANT TO MAKE A

8667
06:13:00,778 --> 06:13:07,652
DISCLOSURE THAT I AM FOUNDER OF

8668
06:13:07,652 --> 06:13:10,021
ZILKHA BIOTECH IT'S DEVELOPING

8669
06:13:10,021 --> 06:13:11,556
THERAPEUTICS FOR STROKE AND

8670
06:13:11,556 --> 06:13:13,057
NEUROLONLICAL DISORDERS AND

8671
06:13:13,057 --> 06:13:16,694
OKAY, SO I WANT TO TELL YOU ALET

8672
06:13:16,694 --> 06:13:18,262
BIT ABOUT ACTIVATED PROTEIN C

8673
06:13:18,262 --> 06:13:20,731
AND BIOLOGY ACTIVATED PROTEIN C.

8674
06:13:20,731 --> 06:13:22,533
SO WE CALL IT APC.

8675
06:13:22,533 --> 06:13:27,171
THIS IS AN ENDOGENOUS PLASMA

8676
06:13:27,171 --> 06:13:31,509
PROTEIN ACE THAT HAS CANNED WHAT

8677
06:13:31,509 --> 06:13:35,012
AND CELL PROTECTING ACTIVITIES.

8678
06:13:35,012 --> 06:13:37,648
THE ANTICOAGULATION IS IN FACTOR

8679
06:13:37,648 --> 06:13:44,889
5 AND 8 A AND THEP CLEAVAGE OF

8680
06:13:44,889 --> 06:13:46,757
APC AND CELL PROTECTION IS MOO

8681
06:13:46,757 --> 06:13:49,293
EDIATED BOO I PROTEIN ACTIVE

8682
06:13:49,293 --> 06:13:59,804
RECEPTOR 1 PART 1 WHICH ALTERS

8683
06:14:04,775 --> 06:14:08,045
YEEN EXPRESSION PROFILE O WE

8684
06:14:08,045 --> 06:14:13,251
GENERATE A MUTANT IN WHICH THE

8685
06:14:13,251 --> 06:14:19,991
APC 3 LIES IN K99 TO 123 AND

8686
06:14:19,991 --> 06:14:21,559
THIS SELECTIVELY ELIMINATES THE

8687
06:14:21,559 --> 06:14:24,829
ACTIVITY BY MORE THAN 90%

8688
06:14:24,829 --> 06:14:27,632
REDUCTION, BUT FULLY PRESERVES

8689
06:14:27,632 --> 06:14:30,067
CELL SIGNALING AND HAS BEEN IN

8690
06:14:30,067 --> 06:14:32,003
STROKE STUDIES COMPLETED PHASE 1

8691
06:14:32,003 --> 06:14:33,771
STUDY, PHASE 2 STROKE STUDY

8692
06:14:33,771 --> 06:14:37,041
COMPLETED AND SPONSORED BY

8693
06:14:37,041 --> 06:14:38,175
NINDS, AND BIOTECH AND THE

8694
06:14:38,175 --> 06:14:41,045
PATIENTS AND RIGHT NOW, IT IS IN

8695
06:14:41,045 --> 06:14:43,514
FACE 2 STROKE STUDY WHICH WE

8696
06:14:43,514 --> 06:14:46,584
EXPECT WILL START RECRUITING IN

8697
06:14:46,584 --> 06:14:48,519
Q1, 2024.

8698
06:14:48,519 --> 06:14:52,523
THIS IS IN THOUSAND 400 STROKE

8699
06:14:52,523 --> 06:14:53,824
PATIENTS, IT'S EFFICACY TRIAL

8700
06:14:53,824 --> 06:14:56,761
AND ALSO LOOKING AT THE

8701
06:14:56,761 --> 06:14:58,763
HEMORRHAGE SUPPORTED BY NINDS

8702
06:14:58,763 --> 06:15:00,932
STROKE NET AND BIOTECH AND WE

8703
06:15:00,932 --> 06:15:04,035
ALSO FINISH PHASE 2 TO THE

8704
06:15:04,035 --> 06:15:07,438
STUDY, NOW WHAT THIS PROVIDES,

8705
06:15:07,438 --> 06:15:09,473
IT'S A MULTIMECHANISM FOR

8706
06:15:09,473 --> 06:15:11,576
CEREBRAL VASCULAR AND BRAIN

8707
06:15:11,576 --> 06:15:14,312
PROTECTION, SO THIS IS QUITE A

8708
06:15:14,312 --> 06:15:15,146
PROTECTIVE AGENT THAT REDUCES

8709
06:15:15,146 --> 06:15:18,416
THE RISK ASSOCIATED WITH THE

8710
06:15:18,416 --> 06:15:20,251
TISSUE POST ACTIVATOR AND

8711
06:15:20,251 --> 06:15:22,787
THROMECTOMYOSINRY AND DRUG

8712
06:15:22,787 --> 06:15:24,822
PATIENTS, DECREASES INFLAMMATION

8713
06:15:24,822 --> 06:15:26,857
AND INHIBIT APOPTOSIS AND

8714
06:15:26,857 --> 06:15:28,759
IMPROVES NEURONS ON IMPROVING

8715
06:15:28,759 --> 06:15:29,093
OUTCOME.

8716
06:15:29,093 --> 06:15:30,294
REGARING VASCULAR DAMAGE, IT

8717
06:15:30,294 --> 06:15:31,762
PROVIDES EBD O THELLIAL

8718
06:15:31,762 --> 06:15:32,964
PROTECTION AND BLOOD BRAIN

8719
06:15:32,964 --> 06:15:35,766
BARRIER REPAIR AND REDUCE RISK

8720
06:15:35,766 --> 06:15:38,703
OF TPN FOR [INDISCERNIBLE].

8721
06:15:38,703 --> 06:15:41,305
ALSO DIRECT NEURONAL PROTECTIVE

8722
06:15:41,305 --> 06:15:43,374
EFFECT AND PROTECTIVE EFFECT OF

8723
06:15:43,374 --> 06:15:46,277
THE CELLS AND ANTIINFLAMMATORY

8724
06:15:46,277 --> 06:15:47,812
DECREASES AT THE INPOLICEMAN

8725
06:15:47,812 --> 06:15:50,915
TOORY RESPONSE AND MICRODPLIA

8726
06:15:50,915 --> 06:15:51,248
ACTIVATION.

8727
06:15:51,248 --> 06:15:52,984
NOW I JUST WOULD LIKE TO MENTION

8728
06:15:52,984 --> 06:15:54,051
A COUPLE THINGS THAT WOULD BE

8729
06:15:54,051 --> 06:15:55,252
REEL KEEPSAKES VABT FOR THE PART

8730
06:15:55,252 --> 06:16:05,062
OF THIS STUDY IN ARIA WELL IT

8731
06:16:05,062 --> 06:16:12,603
HAS BEEN SHOWN THAT IT REDUCES

8732
06:16:12,603 --> 06:16:15,706
BY ABOUT 65% VOLUME OF BRAIN

8733
06:16:15,706 --> 06:16:17,074
HEMORRHAGE AS SHOWN OVER HERE

8734
06:16:17,074 --> 06:16:19,377
BUT MORE INTERESTINGLY IN PHASE

8735
06:16:19,377 --> 06:16:22,113
2 STUDIES AND STROKE PATIENTS

8736
06:16:22,113 --> 06:16:23,547
ACTUALLY THE RESULTS THAT CARRY

8737
06:16:23,547 --> 06:16:26,283
THE STUDY HAVE SHOWN THERE IS

8738
06:16:26,283 --> 06:16:27,652
REDUCTION IN HEMORRHAGE VOLUME

8739
06:16:27,652 --> 06:16:31,555
BY 62% AND REDUCTION IN

8740
06:16:31,555 --> 06:16:37,995
INCIDENCE IN HEMORRHAGES BY 25%.

8741
06:16:37,995 --> 06:16:39,597
SO, SO THAT IS VERY INTERESTING,

8742
06:16:39,597 --> 06:16:41,432
WE TART THINKING HOW IT WOULD BE

8743
06:16:41,432 --> 06:16:43,100
INTERESTING TO DEVELOP SAFETY

8744
06:16:43,100 --> 06:16:47,905
TRIAL IN A. D. PATIENTS THAT ARE

8745
06:16:47,905 --> 06:16:49,674
TREATED WITH AND OTHER ANTIBETTA

8746
06:16:49,674 --> 06:16:52,743
THERAPIES AND WE THINK THIS

8747
06:16:52,743 --> 06:16:55,913
MIGHT BENEFIT THOSE PATIENTS WHO

8748
06:16:55,913 --> 06:16:59,483
ARE E4 CARES BUT THOT NOT

8749
06:16:59,483 --> 06:17:01,118
EXCLUDE E4 NONCARES FOR THE

8750
06:17:01,118 --> 06:17:02,620
MUTATION THAT THE APO YEEN IS

8751
06:17:02,620 --> 06:17:04,221
NOT ALWAYS SO CRITICAL BUT THEN,

8752
06:17:04,221 --> 06:17:06,157
THE IDEA WOULD BE TO PROTECT

8753
06:17:06,157 --> 06:17:08,959
THESE PATIENTS FROM BBB BREAK

8754
06:17:08,959 --> 06:17:16,667
DOWN, VASCULAR LEAKAGES, EDEMA

8755
06:17:16,667 --> 06:17:18,502
AND MICROHEMORRHAGES, BOTH ARIA

8756
06:17:18,502 --> 06:17:24,875
E AND ARIA H, AND ANTI-ABETTA

8757
06:17:24,875 --> 06:17:26,977
TREATMENT GOVERNEM THANKSGIVING

8758
06:17:26,977 --> 06:17:28,679
3 K3 A-APC, INFUSION BEFORE AND

8759
06:17:28,679 --> 06:17:29,613
EAEVER ANTIBODY TREME.

8760
06:17:29,613 --> 06:17:31,015
SO I WILL LIKE TO TELL YOU, WE

8761
06:17:31,015 --> 06:17:35,386
WERE TALKING ABOUT APOY 4 AND

8762
06:17:35,386 --> 06:17:36,754
BBB BRAIN DOWN AND JOHN SHOWED

8763
06:17:36,754 --> 06:17:41,258
IN HIS MORNING PRESENTATION, THE

8764
06:17:41,258 --> 06:17:43,761
DYNAMIC METHOD THAT WE PUBLISHED

8765
06:17:43,761 --> 06:17:45,062
IN NEURON WITH MY POST DOC AT

8766
06:17:45,062 --> 06:17:55,072
THE TIME WHO IS  NOW AN

8767
06:17:55,072 --> 06:18:00,811
INDEPENDENT INVESTIGATOR,

8768
06:18:00,811 --> 06:18:02,613
STUDYING BBB BREAK DOWN, AND WE

8769
06:18:02,613 --> 06:18:06,350
SAW THAT IN CDRSTAGE 0, THERE IS

8770
06:18:06,350 --> 06:18:08,252
ENCROSED BLOOD BRAIN BARRIER

8771
06:18:08,252 --> 06:18:10,888
BREAK DOWN THAT YOU CAN SEE ON

8772
06:18:10,888 --> 06:18:12,256
THE COLOR AND MORE BREAK DOWN

8773
06:18:12,256 --> 06:18:15,793
ASK THIS ACTUALLY CONTINUES AND

8774
06:18:15,793 --> 06:18:19,864
IS MORE ACCELERATED DURING CDR.5

8775
06:18:19,864 --> 06:18:22,266
COGNITIVE IMPAIRMENT TAIJ EMPLOY

8776
06:18:22,266 --> 06:18:24,101
IT'S NOT AFFECTED WITH BETA CSF

8777
06:18:24,101 --> 06:18:34,111
LEVELS AS CAN YOU SEE HERE AND

8778
06:18:34,111 --> 06:18:36,213
THESE SLIDES HERE SO IT'S AN

8779
06:18:36,213 --> 06:18:37,748
INDEPENDENT PATHWAY AND WE

8780
06:18:37,748 --> 06:18:41,418
CONFIRMED THIS BY STIMMULING PET

8781
06:18:41,418 --> 06:18:46,056
AND APOE YEEN IN THE SUBSET OF

8782
06:18:46,056 --> 06:18:47,525
THE 96 TAU PARTICIPANTS AND WE

8783
06:18:47,525 --> 06:18:50,027
SHOWED ALSO THERE IS AN

8784
06:18:50,027 --> 06:18:50,628
INCREASED BLOOD BARRIER BRAIN

8785
06:18:50,628 --> 06:18:52,696
BREAK DOWN IN THE HYPOCATCHUS

8786
06:18:52,696 --> 06:18:54,999
ALSO IN MEDIAL TEMPORAL LOBE,

8787
06:18:54,999 --> 06:18:58,702
MORE RECENT DATA ALSO SHOWED

8788
06:18:58,702 --> 06:19:05,442
THAT THAT THERE ARE PATHWAYS

8789
06:19:05,442 --> 06:19:11,048
SUCH A SINGLE THAT THEY'RE ALSO

8790
06:19:11,048 --> 06:19:12,883
AFFECTING THE BBB BREAK DOWN.

8791
06:19:12,883 --> 06:19:14,518
BUT THE AMYLOID AS SHOWN OVER

8792
06:19:14,518 --> 06:19:17,121
HERE, OR THE AMYLOID INCREASE

8793
06:19:17,121 --> 06:19:17,988
THE FRONTAL CORTEX IN THE

8794
06:19:17,988 --> 06:19:21,325
CARRIER BUT THERE IS NO CHANGE

8795
06:19:21,325 --> 06:19:23,460
IN THE BBB VALUES, SO THAT

8796
06:19:23,460 --> 06:19:25,596
SUGGESTS TO US THAT THESE ARE

8797
06:19:25,596 --> 06:19:27,398
POSSIBLY 2 INDEPENDENT PATHWAYS

8798
06:19:27,398 --> 06:19:30,701
THAT MAY INTERACT TOGETHER AND

8799
06:19:30,701 --> 06:19:33,938
LEADS TO COGNITIVE IMPAIRMENT

8800
06:19:33,938 --> 06:19:36,106
EMPLOY NOW WE HEARD TODAY FROM

8801
06:19:36,106 --> 06:19:39,176
DONNA'S TALK A LOT ABOUT MPPs

8802
06:19:39,176 --> 06:19:41,412
AND MMP9S, WE DID PUBLISH IN

8803
06:19:41,412 --> 06:19:44,114
HUMAN FOR MICE, LONG TIME AGO,

8804
06:19:44,114 --> 06:19:47,852
APPROXIMATE MY FORMER STUDENT

8805
06:19:47,852 --> 06:19:48,686
GRADUATE STUDENT [INDISCERNIBLE]

8806
06:19:48,686 --> 06:19:51,288
THERE IS ACTIVATION OF THE MMP 9

8807
06:19:51,288 --> 06:19:53,290
PATH 

8808
06:19:53,290 --> 06:19:59,663
PATHWAY AND I THINK THIS  IS

8809
06:19:59,663 --> 06:20:01,599
CALLING FOR OUR PAPER IN 2020.

8810
06:20:01,599 --> 06:20:05,069
AND THIS INCLUDES ACTIVATION OF

8811
06:20:05,069 --> 06:20:07,805
PSYCHOTHELIN A WHICH IS A

8812
06:20:07,805 --> 06:20:09,073
PROINFLAMMATORY MOLECULE THAT

8813
06:20:09,073 --> 06:20:11,275
CONTROLS MP9 AND LEADS TO

8814
06:20:11,275 --> 06:20:11,609
DEGRADATION

8815
06:20:11,609 --> 06:20:12,610
GRATES--GRATUEICATION OF THESE

8816
06:20:12,610 --> 06:20:13,711
JURCHGZS BETWEEN THE ENDOTHELIAL

8817
06:20:13,711 --> 06:20:15,279
CELLS SO THAT HAPPENS IN MOUSE

8818
06:20:15,279 --> 06:20:17,514
MODEL BUT IN HUMANS WE ALSO

8819
06:20:17,514 --> 06:20:18,515
PUBLISH YEARS LATER THAT

8820
06:20:18,515 --> 06:20:21,085
ACTUALLY THERE IS INCREASE IN

8821
06:20:21,085 --> 06:20:22,620
PSYCHOTHELLIAL CELLSIN A AND MMP

8822
06:20:22,620 --> 06:20:25,189
9 IN THE CSF.

8823
06:20:25,189 --> 06:20:27,958
THAT IS ACTUALLY DRIVEN FOR THE

8824
06:20:27,958 --> 06:20:30,294
APOE4 COMPARED TO GENE APOE 3,

8825
06:20:30,294 --> 06:20:32,730
SO THERE IS NOT MUCH CHAIMPLED

8826
06:20:32,730 --> 06:20:33,197
IN ARK POE3.

8827
06:20:33,197 --> 06:20:37,201
SO THERE IS A SPECIFIC EFFECT.

8828
06:20:37,201 --> 06:20:38,669
SO, PERISIGHTS KEEP THE BLOOD

8829
06:20:38,669 --> 06:20:40,104
GRAIN INTEGRITY AND I THINK THIS

8830
06:20:40,104 --> 06:20:42,706
IS 1 OF THEIR FUNCTION, AND WE

8831
06:20:42,706 --> 06:20:46,143
HAVE DEVELOPED NEW BIOMARKER

8832
06:20:46,143 --> 06:20:49,046
WHICH IS CALLED TGFBETTA AS A

8833
06:20:49,046 --> 06:20:50,547
MARKER OF THE [INDISCERNIBLE]

8834
06:20:50,547 --> 06:20:53,550
AND NATURALLY AT THE REVISED

8835
06:20:53,550 --> 06:21:04,061
FORMULA SHOULD BE ENCLUEDED AS

8836
06:21:04,962 --> 06:21:07,031
IS VGF MARKER AND IS THIS

8837
06:21:07,031 --> 06:21:08,365
RELATED TO APOE GENETIC

8838
06:21:08,365 --> 06:21:08,832
INCREASED RISK.

8839
06:21:08,832 --> 06:21:11,035
SO THIS IS A TODAY DONE IN 350

8840
06:21:11,035 --> 06:21:13,771
PARTICIPANTS WITH THE MEDIAN

8841
06:21:13,771 --> 06:21:15,205
SPLIT ABOUT 600 NANO GRAMS PER

8842
06:21:15,205 --> 06:21:16,974
MILL, THESE ARE HIGH VALUES

8843
06:21:16,974 --> 06:21:17,808
APPROXIMATES AND BELOW THAT

8844
06:21:17,808 --> 06:21:19,610
THREEZ ARE ALL THE VALUES AND

8845
06:21:19,610 --> 06:21:22,012
SO, THE FIRST STUDY THAT WE DONE

8846
06:21:22,012 --> 06:21:26,417
IN THE CSF, AND REPORTED WHO

8847
06:21:26,417 --> 06:21:28,819
WILL LEAD THE WAS THAT THESE

8848
06:21:28,819 --> 06:21:31,288
PEOPLE WHO HAVE HIGH LEVELS IN

8849
06:21:31,288 --> 06:21:36,760
PLURIBU DEVELOP REALLY PROFOUND

8850
06:21:36,760 --> 06:21:38,329
MENTAL START WITH THE DURATION

8851
06:21:38,329 --> 06:21:41,131
WITH A FOLLOW UP FORWARD OF 4.5

8852
06:21:41,131 --> 06:21:43,600
YEAR ANDS THIS WAS ALSO HONE ON

8853
06:21:43,600 --> 06:21:45,769
THE COGNITIVE DOMAIN WITH 10

8854
06:21:45,769 --> 06:21:47,938
DIFFERENT TESTS EMPLOY BUT THAT

8855
06:21:47,938 --> 06:21:50,541
MENTAL STATUS IS NOT SO MUCH IN

8856
06:21:50,541 --> 06:21:54,278
THE CARRIERS SO IT AGAIN SHOWS

8857
06:21:54,278 --> 06:21:54,712
THE SPECIFIC EFFECT.

8858
06:21:54,712 --> 06:21:57,147
BUT MORE RECENT STUDIES THAT GET

8859
06:21:57,147 --> 06:21:59,450
US EXCITE BECAUSE THIS WAS IN

8860
06:21:59,450 --> 06:22:00,617
PLASMA THAT DR. [INDISCERNIBLE]

8861
06:22:00,617 --> 06:22:02,653
IN OUR GROUP DID, HE REPEATED

8862
06:22:02,653 --> 06:22:08,192
THE SAME THING AND FOWBD THAT

8863
06:22:08,192 --> 06:22:10,194
THIS BETA MARKER HAS BEEN

8864
06:22:10,194 --> 06:22:13,163
CREASED ALSO THAT ARE APOE4

8865
06:22:13,163 --> 06:22:14,331
CARRIERS AND WE PERFOR THE

8866
06:22:14,331 --> 06:22:17,468
PURPOSE DIFFERENT ARK NALGYS AND

8867
06:22:17,468 --> 06:22:19,169
THE REGRESSION ARK NALGYS THAT

8868
06:22:19,169 --> 06:22:25,509
SHOW WHEN YOU CORRECT FOR  AGE,

8869
06:22:25,509 --> 06:22:28,045
SEX, FACTORS THAT THIS TILL

8870
06:22:28,045 --> 06:22:29,780
HOLDS, THIS RELATIONSHIP HOLDS.

8871
06:22:29,780 --> 06:22:31,782
BUT MOST IMPORTANT FOR

8872
06:22:31,782 --> 06:22:33,617
LONGITUDINAL ANALYSIS KREKED FOR

8873
06:22:33,617 --> 06:22:36,353
SEX, AGE, EDUCATION AND VASC LAT

8874
06:22:36,353 --> 06:22:38,956
FACTORS AND P-TAU.

8875
06:22:38,956 --> 06:22:43,460
THE PEOPLE WHO HAVE LOWEST

8876
06:22:43,460 --> 06:22:45,796
TERTILE, OVER 4 YEARS DEVELOPED

8877
06:22:45,796 --> 06:22:47,131
COGNITIVE DECLINE SO THAT THIS

8878
06:22:47,131 --> 06:22:49,666
HIGH LEVEL IS PREDICTIVE

8879
06:22:49,666 --> 06:22:55,172
COGNITIVE DECLINE WHICH WAS NOT

8880
06:22:55,172 --> 06:22:57,508
THE CASE WITH PEOPLE LONGER THAN

8881
06:22:57,508 --> 06:23:01,645
THE NANO GRAMS PER ML.

8882
06:23:01,645 --> 06:23:03,914
NOW WHY WE STAND WITH APC, AND

8883
06:23:03,914 --> 06:23:06,583
WE TRY IT AS A MOLECULE TO

8884
06:23:06,583 --> 06:23:10,154
TARGET AGAIN ARIA.

8885
06:23:10,154 --> 06:23:15,192
WELL, MY FORMER GRADUATE STUDENT

8886
06:23:15,192 --> 06:23:18,996
SHE PUBLISHED THAT APC PROVIDES

8887
06:23:18,996 --> 06:23:20,564
DIRECT VASCULAR PROTECTION,

8888
06:23:20,564 --> 06:23:23,233
NEURONAL PROTECTION AND

8889
06:23:23,233 --> 06:23:24,735
ANTIINFLAMMATORY ACTIVITY IN 5

8890
06:23:24,735 --> 06:23:26,470
FAD MOUSE MODEL BUT WE ALSO

8891
06:23:26,470 --> 06:23:28,906
FOUND IT PARTIALLY PLOKS BASE 1

8892
06:23:28,906 --> 06:23:30,874
PATHWAY AND REDUCES A BETA LLOYD

8893
06:23:30,874 --> 06:23:32,810
AND FAD MICE AND THIS EFFECT WE

8894
06:23:32,810 --> 06:23:35,813
SHOWED IS MEDIATED BY ACTIVATION

8895
06:23:35,813 --> 06:23:39,516
OF 500 RECEPTOR AND TO NF-KAPPAB

8896
06:23:39,516 --> 06:23:40,951
PATHWAY WHICH CONTROLS MRNA FOR

8897
06:23:40,951 --> 06:23:45,522
BASE 1 AND THIS ACTUALLY AFFECTS

8898
06:23:45,522 --> 06:23:46,523
AMYLOID BETA PRODUCTION LEADING

8899
06:23:46,523 --> 06:23:49,827
IN THIS CASE TO INHIBITION OF

8900
06:23:49,827 --> 06:23:50,627
AMYLOID BETA PRODUCTION WHICH

8901
06:23:50,627 --> 06:23:52,362
TOGETHER WITH OTHER EFFECTS

8902
06:23:52,362 --> 06:23:54,965
PROVIDES VERY BENEFICIAL

8903
06:23:54,965 --> 06:23:55,532
POWERFUL TOOL.

8904
06:23:55,532 --> 06:23:57,334
SO NOW THESE ARE UNPUBLISHED

8905
06:23:57,334 --> 06:24:02,473
DATA FROM MY LAB, THAT ACTUALLY

8906
06:24:02,473 --> 06:24:06,977
THEY DID, AND THIS IS EFFECT OF

8907
06:24:06,977 --> 06:24:08,145
APC AND APOE 4 MICE.

8908
06:24:08,145 --> 06:24:11,615
SO THERE IS A BBB PROTECTION AS

8909
06:24:11,615 --> 06:24:13,584
YOU KNOW US AND MANY PEOPLE

8910
06:24:13,584 --> 06:24:15,285
PUBLISH THIS FOR MICE, WE CALL

8911
06:24:15,285 --> 06:24:19,089
IT E4 F HERE, AS BBB BREAK DOWN

8912
06:24:19,089 --> 06:24:25,095
AS SHOWN IN  FIBRINOGEN AS SHOWN

8913
06:24:25,095 --> 06:24:26,864
BY MICE AND THIS HAS IMPROVED

8914
06:24:26,864 --> 06:24:30,167
EAEVER TREATMENT OF APC AND IN

8915
06:24:30,167 --> 06:24:31,168
THIS CASE, .1-MILLIGRAM, DAILY

8916
06:24:31,168 --> 06:24:33,770
INYEKS FOR 10 KAYS.

8917
06:24:33,770 --> 06:24:36,673
ALSO THE COVERAGE, THERE IS

8918
06:24:36,673 --> 06:24:38,275
DEFINITELY PROTECTION OF

8919
06:24:38,275 --> 06:24:41,011
PERISIGHTS BY THIS TREATMENT AND

8920
06:24:41,011 --> 06:24:43,814
THE PERICYTES, THAT MAINTAIN THE

8921
06:24:43,814 --> 06:24:44,548
BBB WILL IMPROVE AND PRESERVE

8922
06:24:44,548 --> 06:24:49,887
DURING THIS TREATMENT WITH APC

8923
06:24:49,887 --> 06:24:52,990
EMPLOY LOOKING INTO THIS AND THE

8924
06:24:52,990 --> 06:24:54,191
PATHWAY, THESE ARE REEMILYINARY

8925
06:24:54,191 --> 06:24:59,630
DATA SO EYE --I WANT TO SHARE

8926
06:24:59,630 --> 06:25:01,598
DATA WITH THE GROUP, WE WERE

8927
06:25:01,598 --> 06:25:05,769
ABLE TO SHOW THAT APC TREATMENT

8928
06:25:05,769 --> 06:25:07,171
REDUCES PROINNAMES--NAMESSATORY,

8929
06:25:07,171 --> 06:25:10,607
AND ACTIVITY IN PERICYTES, AND

8930
06:25:10,607 --> 06:25:13,443
LOGICAL EXPECTED BECAUSE IT'S

8931
06:25:13,443 --> 06:25:15,078
ANTIINFLAMMATORY AGENT AND THIS

8932
06:25:15,078 --> 06:25:17,114
ALSO CONTROLS THE AMERICA

8933
06:25:17,114 --> 06:25:18,949
PUNISHING P9 PATHWAY WHICH IS E

8934
06:25:18,949 --> 06:25:21,051
CUESED AND MAY EXPLAIN PARTIALLY

8935
06:25:21,051 --> 06:25:23,053
THE BBASHING B EFFECT.

8936
06:25:23,053 --> 06:25:26,290
BUT THEN, I THINK MORE THAN

8937
06:25:26,290 --> 06:25:31,528
THAT, WE ACTUALLY SHOWED BY

8938
06:25:31,528 --> 06:25:33,030
TRANSCRIPTOMIC ANALYSIS THAT APC

8939
06:25:33,030 --> 06:25:38,268
TREATMENT WAS ABLE TO DEACTIVATE

8940
06:25:38,268 --> 06:25:39,403
167 UPREGGULED DIFFERENTIALLY

8941
06:25:39,403 --> 06:25:41,338
EXPRESS YEENS, AND THE

8942
06:25:41,338 --> 06:25:43,807
ENDOTHELIUM OUT OF 175 THAT ARE

8943
06:25:43,807 --> 06:25:45,442
ALL UPREGULATED IN E4 F MICE

8944
06:25:45,442 --> 06:25:51,315
COMPARE TO THE MICE.

8945
06:25:51,315 --> 06:25:54,318
SO ALL THESE JEEPS WERE

8946
06:25:54,318 --> 06:25:54,618
NORMALIZED.

8947
06:25:54,618 --> 06:25:57,821
THEY'RE ALL NORMALIZED AND SO

8948
06:25:57,821 --> 06:25:59,756
WHAT WAS ALSO INTERESTING, THEN

8949
06:25:59,756 --> 06:26:02,426
WE EXTENDED THIS STUDY TO THE

8950
06:26:02,426 --> 06:26:04,962
MUTATION OF THE BRAIN

8951
06:26:04,962 --> 06:26:06,363
MICRORESSLE BY MASS

8952
06:26:06,363 --> 06:26:07,331
SPECTROMETRY, AND WITH THE LAB,

8953
06:26:07,331 --> 06:26:11,401
AND AS YOU CAN SEE, THE

8954
06:26:11,401 --> 06:26:13,704
QUANTIFIED ABOUT 5451 PROTEINS

8955
06:26:13,704 --> 06:26:17,274
IN MICROVESSELS. 

8956
06:26:17,274 --> 06:26:19,643
AND ABOUT 18--1008 HELPED 25

8957
06:26:19,643 --> 06:26:23,180
POSSIBLE GUIDES.

8958
06:26:23,180 --> 06:26:25,983
AND SO, WHAT WAS INTERESTING IN

8959
06:26:25,983 --> 06:26:27,050
THIS STUDY, WAS THAT WE WERE

8960
06:26:27,050 --> 06:26:29,953
ABLE TO SHOW THAT APC NORMALIZED

8961
06:26:29,953 --> 06:26:33,390
ABOUT 45% OF PROTEIN LEVELS AND

8962
06:26:33,390 --> 06:26:35,826
ABOUT 75% OF PROTEIN

8963
06:26:35,826 --> 06:26:37,094
PHOSPHORYLATIONS WHICH IS VERY

8964
06:26:37,094 --> 06:26:41,999
IMPORTANT FOR PROTEIN FUNCTION.

8965
06:26:41,999 --> 06:26:43,700
SO THE FUNCTIONAL CATEGORY

8966
06:26:43,700 --> 06:26:45,769
COLLECTED IN APC IN TOTAL

8967
06:26:45,769 --> 06:26:50,240
PROTEIN IN THIS 9-12 MONTH OLD

8968
06:26:50,240 --> 06:26:53,043
MICE, METABOLIC DNA BINDING

8969
06:26:53,043 --> 06:26:55,979
PROTEIN, METHYLTRANSFERASES AND

8970
06:26:55,979 --> 06:26:57,848
ALSO, ADAPTIVE SKELETAL PROTEINS

8971
06:26:57,848 --> 06:27:01,652
AND THE FUNCTIONAL CATEGORIES

8972
06:27:01,652 --> 06:27:03,020
THAT ACTUALLY REMAIN HERE THAT

8973
06:27:03,020 --> 06:27:06,456
ARE CORRECTED WITH THE APC ALSO

8974
06:27:06,456 --> 06:27:08,392
INCLUDE TY YURCHGZ, DATA

8975
06:27:08,392 --> 06:27:10,560
PROTECTIONIVE PROTEINS, CELL

8976
06:27:10,560 --> 06:27:13,230
HEED HESION, CYTOSKELETON ASK

8977
06:27:13,230 --> 06:27:14,731
GPC SIGNALING RNA BINDING BUT

8978
06:27:14,731 --> 06:27:17,100
THEN PIE USING RNA SEQ GUIDED

8979
06:27:17,100 --> 06:27:19,236
CELLS WITH THE ANALYSIS, TO

8980
06:27:19,236 --> 06:27:21,571
ACTUALLY SEPARATE CHANGES IN THE

8981
06:27:21,571 --> 06:27:22,539
ENDOTHELIAL CELLS, AND ASTRO

8982
06:27:22,539 --> 06:27:25,942
SIGHTS, WE ARE ABLE TO SHOW THAT

8983
06:27:25,942 --> 06:27:29,513
OUT OF THE TOTAL 61 PROTEINS,

8984
06:27:29,513 --> 06:27:31,548
REVERT BIDE APC WITH 27 PROTEINS

8985
06:27:31,548 --> 06:27:34,351
AND 7 OF THOSE IN THE

8986
06:27:34,351 --> 06:27:35,686
ENDOTHELIAL CELLS, 18 PERISIGHTS

8987
06:27:35,686 --> 06:27:38,588
AND 16 ASTRO SIGHTS.

8988
06:27:38,588 --> 06:27:40,290
AND WE ALSO IDENTIFIED CHANGES

8989
06:27:40,290 --> 06:27:44,161
IN 249 PROTEINS IN 262 RELATION

8990
06:27:44,161 --> 06:27:49,099
SITES IN THIS E4 ALL, THERE'S

8991
06:27:49,099 --> 06:27:50,534
ALL MICROVESSEL ANDS 72.5% OF

8992
06:27:50,534 --> 06:27:53,904
THE SITES AS I MENTIONED WERE

8993
06:27:53,904 --> 06:27:55,005
REVERTD BY APC.

8994
06:27:55,005 --> 06:27:58,709
AND 54 ASTRO SIGHTS, 86 PC, AND

8995
06:27:58,709 --> 06:28:05,816
REST IF EBD O THELLIAL CELLS.

8996
06:28:05,816 --> 06:28:08,785
SO WE ACTUALLY ARE THINKING TO

8997
06:28:08,785 --> 06:28:15,726
TEST FOR ARIA. 

8998
06:28:15,726 --> 06:28:25,035
AND 1 THING THAT WE ARE WORKING

8999
06:28:25,035 --> 06:28:32,976
ON FOR THE CDR5 STAGE, AND THIS

9000
06:28:32,976 --> 06:28:34,745
IS A-BETA 42 RATIO DECREASED IN

9001
06:28:34,745 --> 06:28:36,613
THESE CARRIERS AND THAT'S THE

9002
06:28:36,613 --> 06:28:38,682
GUY ALSO HOED HERE THAT THERE IS

9003
06:28:38,682 --> 06:28:44,020
AN INN CREASE LEVEL OF SBD WHICH

9004
06:28:44,020 --> 06:28:46,723
SHOWS YOU KNOW A VASCULAR DAMAGE

9005
06:28:46,723 --> 06:28:51,128
IN APOE 4 CARRIER TO CDR.5

9006
06:28:51,128 --> 06:28:51,328
TEANL.

9007
06:28:51,328 --> 06:28:53,330
SO STEP 1 OF THIS PROPOSAL WAS

9008
06:28:53,330 --> 06:28:56,400
TO ASK THE QUESTION DID THE

9009
06:28:56,400 --> 06:28:59,403
TREATMENT ALTER AB BLOOD

9010
06:28:59,403 --> 06:29:02,639
BIOMARKERS SUCH AS ABETTA

9011
06:29:02,639 --> 06:29:05,008
DURATION AND P-TAU 217 IN STROKE

9012
06:29:05,008 --> 06:29:08,545
PATIENTS FROM PHASE 2 TRIAL

9013
06:29:08,545 --> 06:29:09,246
COMPLETE INDEED 2018.

9014
06:29:09,246 --> 06:29:15,085
O WE ARE OBTAINING SAMPLES FROM

9015
06:29:15,085 --> 06:29:21,324
110 PATIENTS AND THIS IS FOR

9016
06:29:21,324 --> 06:29:26,096
DEVELOPMENT OF A STUDY IN

9017
06:29:26,096 --> 06:29:27,030
ANTIGEN STUDY AND SBO IPT

9018
06:29:27,030 --> 06:29:29,366
GREATER VIVO AND WE WILL LOOK AT

9019
06:29:29,366 --> 06:29:32,102
THOSE LEVEL ANDS THERE AN EFFECT

9020
06:29:32,102 --> 06:29:34,538
OF THE APOEYEEN, WE MAY HAVE

9021
06:29:34,538 --> 06:29:35,372
ENOUGH PARTICIPANT FOR ALL OF

9022
06:29:35,372 --> 06:29:36,573
THAT BUT WE WILL TRY.

9023
06:29:36,573 --> 06:29:39,342
ONE OF THE NOTES I WANT TO SAY

9024
06:29:39,342 --> 06:29:40,710
TAKEN--THEY THE APC WAS SHOWN TO

9025
06:29:40,710 --> 06:29:44,748
BE SAFE IN PHASE 2 TRIAL IN AN

9026
06:29:44,748 --> 06:29:49,352
ESTIMATED RATE AROUND 7% AND 540

9027
06:29:49,352 --> 06:29:52,689
MICROGRAM PERKEG, MAX MULL

9028
06:29:52,689 --> 06:29:55,759
TOLERATED DOSE AS THE DOCTOR

9029
06:29:55,759 --> 06:29:57,227
REPORTED IN NEUROLOGY WHICH IS 2

9030
06:29:57,227 --> 06:29:59,162
TYPES HYPER THAN THOSE OF THE

9031
06:29:59,162 --> 06:30:03,633
APC IN PHASE THRESHOLD MODEL

9032
06:30:03,633 --> 06:30:04,634
STROKE TRIAL.

9033
06:30:04,634 --> 06:30:07,304
SO ONCE WE FIND THERE ARE NO

9034
06:30:07,304 --> 06:30:08,939
CHANGES IN THE ADDPAYS

9035
06:30:08,939 --> 06:30:11,041
BIOMARKERS WE WILL GO TO STEP 2

9036
06:30:11,041 --> 06:30:12,209
AND PROCEED WITH SAFETY TRIAL

9037
06:30:12,209 --> 06:30:14,778
AND PERHAPS FOR THE CARRIERS,

9038
06:30:14,778 --> 06:30:17,747
SELECTED BY OUR APOE GENE KREEN

9039
06:30:17,747 --> 06:30:20,717
AND WE WILL INFUSE THEM AND TO

9040
06:30:20,717 --> 06:30:22,152
DETERMINE WHETHER THEY COULD

9041
06:30:22,152 --> 06:30:24,087
ALTER AD BIOMARKERS IN THIS, SO

9042
06:30:24,087 --> 06:30:25,589
THIS IS BASKLY JUST A SAFETY

9043
06:30:25,589 --> 06:30:27,591
TRIAL THAT WE HAVE DISCUSSED

9044
06:30:27,591 --> 06:30:29,893
WITH PAUL AND SOME OTHER FOLKS

9045
06:30:29,893 --> 06:30:30,794
AT USC.

9046
06:30:30,794 --> 06:30:34,130
AND FINALLY, WE WOULD LIKE TO

9047
06:30:34,130 --> 06:30:37,601
DETERMINE THE TREATMENT BEFORE

9048
06:30:37,601 --> 06:30:39,736
AND AFTER HERE ANTIBODY

9049
06:30:39,736 --> 06:30:41,204
TREATMENT REDUCES THE ENDENSE OF

9050
06:30:41,204 --> 06:30:43,373
ARIA E AND ARIA H THAT WE HEARD

9051
06:30:43,373 --> 06:30:46,276
A LOT ABOUT TODAY.

9052
06:30:46,276 --> 06:30:48,478
SO THE KEY POINTS, YOU KNOW TO

9053
06:30:48,478 --> 06:30:50,847
TAKE HOME MESSAGE FROM THIS

9054
06:30:50,847 --> 06:30:53,016
PRESENTATION IS THAT THIS

9055
06:30:53,016 --> 06:30:55,785
MOLECULE PER THE APC PROVIDES

9056
06:30:55,785 --> 06:30:57,721
VASCULAR AND NEURONAL PROTECTION

9057
06:30:57,721 --> 06:30:59,689
BECAUSE THE ANTIIPT GREATER

9058
06:30:59,689 --> 06:31:00,957
FLAMMATORY PROPERTY ANDS

9059
06:31:00,957 --> 06:31:03,226
ANTIBETTA PROPERTIES.

9060
06:31:03,226 --> 06:31:04,895
THE NORMALIZES TRANSCRIPTOMIC

9061
06:31:04,895 --> 06:31:06,129
AND PROTEOMIC AND PROI DON'T

9062
06:31:06,129 --> 06:31:10,667
MEANIC CHANGES IN BRAIN VESSELS,

9063
06:31:10,667 --> 06:31:12,302
MICROVESSELS FOR MICE, AND APC

9064
06:31:12,302 --> 06:31:13,937
BASED THERAPEUTICS MAY HELP

9065
06:31:13,937 --> 06:31:16,339
PRESERVE BLOOD BRAIN BARRIER AND

9066
06:31:16,339 --> 06:31:17,474
NEURONAL FUNCTION AND VERMEN

9067
06:31:17,474 --> 06:31:19,876
INFECTED RERS THE EFFECTS OF THE

9068
06:31:19,876 --> 06:31:20,911
YEEP AND VASCULATURE.

9069
06:31:20,911 --> 06:31:23,847
SO, THIS MOLECULE IS IN PLACE,

9070
06:31:23,847 --> 06:31:26,550
FOR THE TRIAL FOR ESCHEMIC

9071
06:31:26,550 --> 06:31:30,687
STROKE AND RECRUITMENT EXPECTED

9072
06:31:30,687 --> 06:31:31,254
IN Q12,024.

9073
06:31:31,254 --> 06:31:34,124
AND SMALL PHASE LS TRIAL

9074
06:31:34,124 --> 06:31:34,991
COMPLETED DECEMBER 2022.

9075
06:31:34,991 --> 06:31:37,360
SO WHAT IS POTENTIAL FOR AD THAT

9076
06:31:37,360 --> 06:31:40,330
WE THINK I COULD BE EXPLORED.

9077
06:31:40,330 --> 06:31:42,899
WHETHER IT PROTECT AGAINST ARIA,

9078
06:31:42,899 --> 06:31:46,636
WE EXPECT TO SEE TABLIZING

9079
06:31:46,636 --> 06:31:47,270
EFFECT IN ANTIHEMORRHAGIC CENTER

9080
06:31:47,270 --> 06:31:48,572
FOR EXCELLENCE ON AGING BASED ON

9081
06:31:48,572 --> 06:31:49,940
STROKE DATA, STROKE STUDY, PHASE

9082
06:31:49,940 --> 06:31:51,942
2 STUDY AND ALSO ANTIFLAMAR TOW

9083
06:31:51,942 --> 06:31:54,578
ACTIVITIES THAT WERE SHOWN BY

9084
06:31:54,578 --> 06:31:57,147
NUMEROUS, AND ALSO THE DIRECT

9085
06:31:57,147 --> 06:31:59,349
PROTECTIVE EFFECT AGAINST THE

9086
06:31:59,349 --> 06:32:00,984
VASCULAR NEURONAL TOXICITY AND

9087
06:32:00,984 --> 06:32:03,987
ALSO DIRECTING ON THE NEURONAL

9088
06:32:03,987 --> 06:32:04,287
PROTECTION.

9089
06:32:04,287 --> 06:32:05,755
SO THAT'S ALL I WANTED TO SHARE,

9090
06:32:05,755 --> 06:32:16,199
THANK YOU SO MUCH FOR YOUR

9091
06:32:16,666 --> 06:32:17,100
ATTENTION.

9092
06:32:17,100 --> 06:32:19,169
>> ONE QUESTION, IT'S
HELENA, SO

9093
06:32:19,169 --> 06:32:20,937
NICE TO HEAR YOUR TALK IT'S

9094
06:32:20,937 --> 06:32:23,440
BRILLIANT AND I WANTED TO ASK,

9095
06:32:23,440 --> 06:32:26,543
NOW, THE DROP WOULD BE ACTING

9096
06:32:26,543 --> 06:32:29,346
ALL OVER TO PROTECT THE BBB,

9097
06:32:29,346 --> 06:32:29,579
CORRECT?

9098
06:32:29,579 --> 06:32:37,654
AND THE ARIA PATIENTS HAVE

9099
06:32:37,654 --> 06:32:39,789
SPOTLIGHT CHANGES IN AT LEAST IN

9100
06:32:39,789 --> 06:32:43,026
EDEMA WE AT LEAST TALK ABOUT

9101
06:32:43,026 --> 06:32:44,494
IMPARTMENT ABILITY, DO YOU THINK

9102
06:32:44,494 --> 06:32:45,762
THIS GLOBAL EFFECT OF A

9103
06:32:45,762 --> 06:32:47,764
TREATMENT LIKE THIS, WILL BE

9104
06:32:47,764 --> 06:32:50,700
NEEDED OR WHAT'S YOUR CONCERN

9105
06:32:50,700 --> 06:32:51,968
ABOUT GLOBAL VERSUS THE FOCAL

9106
06:32:51,968 --> 06:32:58,575
EFFECTS YOU SEE IN THE  PATIENT?

9107
06:32:58,575 --> 06:33:00,577
>> THANK YOU HELENA THIS
IS A

9108
06:33:00,577 --> 06:33:02,045
GREAT QUESTION, I SHOULD

9109
06:33:02,045 --> 06:33:03,947
PROBABLY ADDRESS WITH WITH MY

9110
06:33:03,947 --> 06:33:07,984
FOAOF THE DOC FELLOW WE ARE

9111
06:33:07,984 --> 06:33:10,120
PUBLISHED PAPER IN JOURNAL

9112
06:33:10,120 --> 06:33:12,856
MEDICINE IN 2022 SHOWING THAT 3

9113
06:33:12,856 --> 06:33:14,257
K3 PC PROTECTS AGAINST WHITE

9114
06:33:14,257 --> 06:33:15,158
MATTER STROKES.

9115
06:33:15,158 --> 06:33:17,360
O PROECTOMYOSIN ITS AGAINST

9116
06:33:17,360 --> 06:33:19,729
STROKES IN THE MIGHT MATTER AND

9117
06:33:19,729 --> 06:33:21,831
I THINK THIS IS HIGHLY RELEVANT

9118
06:33:21,831 --> 06:33:25,001
BECAUSE THIS ARIA AS I

9119
06:33:25,001 --> 06:33:26,169
UNDERSTAND MRI CHANGES HAPPENING

9120
06:33:26,169 --> 06:33:28,271
VERY MUCH ALONG THE WHITE MATTER

9121
06:33:28,271 --> 06:33:29,439
AS WELL.

9122
06:33:29,439 --> 06:33:34,310
SO I BELIEVE THAT WILL BE ALSO 1

9123
06:33:34,310 --> 06:33:35,712
PROTECTION AND IN TERMS OF

9124
06:33:35,712 --> 06:33:38,415
LOCALIZATION, AS I MENTIONED OUR

9125
06:33:38,415 --> 06:33:40,750
MOST RECENT STUDIES AND WE HAVE

9126
06:33:40,750 --> 06:33:41,618
PAPER WE'RE CO-WORKERSING RIGHT

9127
06:33:41,618 --> 06:33:43,586
NOW ASK WORKING TO COMPLETE,

9128
06:33:43,586 --> 06:33:44,954
THAT I PRESENT IF YOU REMEMBER

9129
06:33:44,954 --> 06:33:47,323
IN THE DUKE MEETING A COUPLE

9130
06:33:47,323 --> 06:33:51,127
WEEKS AGO, IS ACTUALLY SHOWING

9131
06:33:51,127 --> 06:33:54,264
THAT THERE ARE MORE ARIAS NOW

9132
06:33:54,264 --> 06:33:55,498
ESPECIALLY WHITE MATTER ATTRACTS

9133
06:33:55,498 --> 06:33:57,867
FOR THE REGION OF THE HYPOCAMPUS

9134
06:33:57,867 --> 06:34:02,672
AND THE CAMPO GYRUS SUCH AS

9135
06:34:02,672 --> 06:34:03,239
[INDISCERNIBLE] AND

9136
06:34:03,239 --> 06:34:04,240
[INDISCERNIBLE] CORTEX SUCH AS

9137
06:34:04,240 --> 06:34:07,544
SINGLE THAT THEY'RE AFFECTED BY

9138
06:34:07,544 --> 06:34:08,178
BBB BREAK DOWN CHANGES.

9139
06:34:08,178 --> 06:34:11,147
AND ALSO THE CHANGES IN REGIONS

9140
06:34:11,147 --> 06:34:13,817
THAT ARE RESPONSIBLE FOR

9141
06:34:13,817 --> 06:34:16,119
ATTENTION AND EXECUTIVE

9142
06:34:16,119 --> 06:34:17,220
FUNCTIONS.

9143
06:34:17,220 --> 06:34:19,522
THEY'RE ALSO AFGHTED NOW BY THIS

9144
06:34:19,522 --> 06:34:20,790
BLOOD BRAIN BARRIER BREAK DOWN

9145
06:34:20,790 --> 06:34:23,426
SO ESPECIALLY IN OUR APOE

9146
06:34:23,426 --> 06:34:25,328
CARRIER BAH ALSO NOT .3 TO A

9147
06:34:25,328 --> 06:34:26,463
LESSER EXTENT SO I BELIEVE THIS

9148
06:34:26,463 --> 06:34:28,898
ACTUALLY IS A MULTIPLE AGENT

9149
06:34:28,898 --> 06:34:30,567
THAT CAN ACT ON A MULTIPLE

9150
06:34:30,567 --> 06:34:32,102
TARGETS AND THAT'S WHAT I

9151
06:34:32,102 --> 06:34:38,708
BELIEVE IS VERY, ATTRACTIVE IN

9152
06:34:38,708 --> 06:34:39,776
THIS APPROACH.

9153
06:34:39,776 --> 06:34:40,577
>> THANK YOU.

9154
06:34:40,577 --> 06:34:42,679
WE HAVE 1 QUESTION ONLINE THAT'S

9155
06:34:42,679 --> 06:34:45,849
A FOLLOW UP FOR DR. WALKER MAYBE

9156
06:34:45,849 --> 06:34:47,217
WE CAN ADDRESS THAT AND MOVE ON

9157
06:34:47,217 --> 06:34:48,251
TO THE PANEL.

9158
06:34:48,251 --> 06:34:50,920
THE QUESTION IS IN MONKEY CAA

9159
06:34:50,920 --> 06:34:56,092
CAPILLARIES THERE LOSS OF

9160
06:34:56,092 --> 06:34:56,493
PARASITES?

9161
06:34:56,493 --> 06:35:02,165
>> YES, THERE WAS A
QUESTION I

9162
06:35:02,165 --> 06:35:03,399
DID ASK, YEAH.

9163
06:35:03,399 --> 06:35:04,100
>> WE DON'T KNOW.

9164
06:35:04,100 --> 06:35:06,302
I'VE SEEN MANY A PARASITE ARK

9165
06:35:06,302 --> 06:35:08,772
ROUND A VESSEL THAT HAS CAA IN

9166
06:35:08,772 --> 06:35:10,673
IT BUT WE HAVEN'T QUANTIFIED

9167
06:35:10,673 --> 06:35:13,777
PARASITES SPECIFICALLY SO I

9168
06:35:13,777 --> 06:35:17,180
DON'T KNOW. 

9169
06:35:17,180 --> 06:35:18,748
>> CAN I ASK A QUESTION,

9170
06:35:18,748 --> 06:35:21,084
REMEMBER WITH YOUR SCHOOL OF

9171
06:35:21,084 --> 06:35:21,818
MONKEYS WE STUDY AMYLOID

9172
06:35:21,818 --> 06:35:23,253
CLEARANCE RIGHT AND WE PUBLISHED

9173
06:35:23,253 --> 06:35:26,389
THAT AND THEN AFTER THAT WAS IN

9174
06:35:26,389 --> 06:35:28,324
HUMANS, DO YOU THINK THAT THE

9175
06:35:28,324 --> 06:35:28,858
AGE MATTERS?

9176
06:35:28,858 --> 06:35:34,531
YOU KNOW IN TERMS OF CLEARANCE

9177
06:35:34,531 --> 06:35:35,799
IN SQUIRREL MONKEY?

9178
06:35:35,799 --> 06:35:38,968
>> AGE, BECAUSE WE FOUND

9179
06:35:38,968 --> 06:35:42,572
DIFFERENCE IN OLD SQUIRREL AND

9180
06:35:42,572 --> 06:35:43,273
YOUNG SQUIRREL?

9181
06:35:43,273 --> 06:35:45,542
>> IS IT MATTER, I IMAGINE
IT

9182
06:35:45,542 --> 06:35:46,509
MAKESSA I BIG DIFFERENCE BUT I

9183
06:35:46,509 --> 06:35:56,986
DON'T KNOW THAT FROM MY OWN

9184
06:35:57,654 --> 06:35:58,221
EXPERIENCE.

9185
06:35:58,221 --> 06:36:02,625
LET'S BRING UP OUR PANELISTS,

9186
06:36:02,625 --> 06:36:13,169
FRANCESCA AND YAWN AND LAWRENCE.

9187
06:36:24,681 --> 06:36:25,181
>> ALL RIGHT, THANKS.

9188
06:36:25,181 --> 06:36:27,183
IT'S A PLEASURE TO WELCOME THE

9189
06:36:27,183 --> 06:36:28,351
PANELISTS FOR THE LAST PANEL

9190
06:36:28,351 --> 06:36:33,456
DISCUSSION OF THE DAY. 

9191
06:36:33,456 --> 06:36:37,560
SO WE HAVE THE DR. MARION

9192
06:36:37,560 --> 06:36:41,631
BUCKWALTER FROM TAN FORD,

9193
06:36:41,631 --> 06:36:47,136
DR. LAWRENCE HONIG FROM

9194
06:36:47,136 --> 06:36:47,503
COLUMBIA--SORRY.

9195
06:36:47,503 --> 06:36:53,676
AND DR. JOHN SIMS FROM

9196
06:36:53,676 --> 06:36:55,778
ELY LILLY.

9197
06:36:55,778 --> 06:36:56,946
THANK YOU SO WITH THAT I WOULD

9198
06:36:56,946 --> 06:37:01,150
LIKE TO GET THE PANELISTS TO

9199
06:37:01,150 --> 06:37:03,853
COMMENT ON THE PREVIOUS SESSION

9200
06:37:03,853 --> 06:37:07,257
ABOUT THESE NEW RESEARCH IDEAS

9201
06:37:07,257 --> 06:37:10,627
FOR IN THE PRECLINICAL SPACE AND

9202
06:37:10,627 --> 06:37:12,028
ALSO I WOULD LIKE TO ASK THEM

9203
06:37:12,028 --> 06:37:14,631
WHAT DO THEY SEE AS GAPS AND

9204
06:37:14,631 --> 06:37:16,232
OPPORTUNITIES THAT YOU COULD

9205
06:37:16,232 --> 06:37:21,571
FURRINGER EXPLORE IN FUTURE

9206
06:37:21,571 --> 06:37:21,871
RESEARCH.

9207
06:37:21,871 --> 06:37:23,606
SO MAYBE--I DON'T WANT TO PUT

9208
06:37:23,606 --> 06:37:25,942
ANYONE ON THE SPOT, SO, I WILL

9209
06:37:25,942 --> 06:37:30,513
ASK FOR A VOLUNTEER TO START.

9210
06:37:30,513 --> 06:37:32,148
SMRKS SO THANK YOU.

9211
06:37:32,148 --> 06:37:33,316
THANKS FOR THE INVITATION, THIS

9212
06:37:33,316 --> 06:37:38,388
IS A VERY IMPORTANT MEETING AND

9213
06:37:38,388 --> 06:37:41,057
I THINK THE GOAL HERE IS TO

9214
06:37:41,057 --> 06:37:41,758
TIMMULATE SCIENTIFIC IDEA ANDS

9215
06:37:41,758 --> 06:37:44,861
COME UP WITH SOLUTIONS AND I'M

9216
06:37:44,861 --> 06:37:45,995
NOT EXACTLY SURE WHERE TO START

9217
06:37:45,995 --> 06:37:48,698
BECAUSE THERE ARE SO MANY LITTLE

9218
06:37:48,698 --> 06:37:52,335
AREAS TO TALK ABOUT BUT I WILL

9219
06:37:52,335 --> 06:37:55,738
START WITH THE FACT THAT WE

9220
06:37:55,738 --> 06:37:57,173
AGREE THERE MEDES A LOT OF

9221
06:37:57,173 --> 06:37:59,175
RESEARCH IN THIS SPACE AND WE

9222
06:37:59,175 --> 06:38:01,577
TARTED A TRIAL CALLED TB6 OF

9223
06:38:01,577 --> 06:38:02,645
SOLELY UNDERSTANDING SOME OF THE

9224
06:38:02,645 --> 06:38:03,079
SCIENCE BEHIND

9225
06:38:03,079 --> 06:38:04,113
ARE--ADMINISTRATIVE RAW DATA AND

9226
06:38:04,113 --> 06:38:06,249
SEEING IF WE COULD UNDERSTAND

9227
06:38:06,249 --> 06:38:07,050
THAT PATHOPIZZA TAVERNIOLOGY A

9228
06:38:07,050 --> 06:38:07,951
LITTLE BIT BETTER THAN WHAT

9229
06:38:07,951 --> 06:38:11,087
WE'VE DON IN THE CURRENT TRIALS.

9230
06:38:11,087 --> 06:38:12,622
AND SO, I MIGHT WALK THROUGH A

9231
06:38:12,622 --> 06:38:14,290
FEW OF THOSE THINGS BECAUSE I'VE

9232
06:38:14,290 --> 06:38:16,125
HEARD A COUPLE OF ASSPECS HERE

9233
06:38:16,125 --> 06:38:18,261
TODAY OF THINGS THAT HAVE BEEN

9234
06:38:18,261 --> 06:38:21,531
KIND OF DISCUSSED AND I WILL

9235
06:38:21,531 --> 06:38:22,432
START WITH--I WILL START WITH

9236
06:38:22,432 --> 06:38:23,266
THE MOST IMMEDIATE THING WE

9237
06:38:23,266 --> 06:38:25,168
MIGHT BE ABLE TO DO FOR PATIENTS

9238
06:38:25,168 --> 06:38:27,270
AND THAT'S TO UNDERSTAND THE

9239
06:38:27,270 --> 06:38:29,105
DOSING PARADIGM TO SEE IF THE

9240
06:38:29,105 --> 06:38:30,373
DOSING PARADIGM MATTERS AT ALL

9241
06:38:30,373 --> 06:38:31,674
OR NOT.

9242
06:38:31,674 --> 06:38:35,311
AND SO, WE'VE HEARD A BIT ABOUT

9243
06:38:35,311 --> 06:38:36,846
CMAX VERSUS AUC, DOES THAT

9244
06:38:36,846 --> 06:38:39,148
MATTER OR IS IT THAT NOT MATTER.

9245
06:38:39,148 --> 06:38:40,783
I THINK SCIENTIFICALLY, IT'S A

9246
06:38:40,783 --> 06:38:42,185
GOOD QUESTION AND MAYBE

9247
06:38:42,185 --> 06:38:43,152
SOMETHING VERY TRACTABLE TO DO

9248
06:38:43,152 --> 06:38:46,990
FOR PATIENTS IF IT MATTERS.

9249
06:38:46,990 --> 06:38:48,658
I THINK GENERALLY SPEAKING I'M

9250
06:38:48,658 --> 06:38:51,294
MOT SO SURE THIS IS WELL PROVEN

9251
06:38:51,294 --> 06:38:53,963
YET FOR OTHER MOLECULES AND SO

9252
06:38:53,963 --> 06:38:55,531
THAT WILL BE 1 ASPECT THAT WE

9253
06:38:55,531 --> 06:38:59,235
WILL BE TESTING IN THE THAT

9254
06:38:59,235 --> 06:39:01,537
TRIAL VERY SYSTEMATICALLY WHERE

9255
06:39:01,537 --> 06:39:06,175
WE CONTROL AUC AND CHANGE C-MAX,

9256
06:39:06,175 --> 06:39:08,578
SO THAT IS SOMETHING THAT CAN BE

9257
06:39:08,578 --> 06:39:11,981
HELPFUL AT LEAST FOR ADUNAMAB,

9258
06:39:11,981 --> 06:39:15,351
AND I THINK REISA SPOKE ABOUT

9259
06:39:15,351 --> 06:39:17,553
[INDISCERNIBLE] BUT DID IT HAVE

9260
06:39:17,553 --> 06:39:19,722
A LOW OF AN ARIA RATE AS WE

9261
06:39:19,722 --> 06:39:20,523
SHOULD EXPECT FROM THERE.

9262
06:39:20,523 --> 06:39:22,625
SO I THINK THAT'S ANOTHER

9263
06:39:22,625 --> 06:39:24,527
SUGGESTION THAT WE NEED TO KIND

9264
06:39:24,527 --> 06:39:27,864
OF EXPLORE THIS MORE AND SEE IF

9265
06:39:27,864 --> 06:39:28,164
IT MATTERS.

9266
06:39:28,164 --> 06:39:29,866
THE OTHER AREA WE HEARD ABOUT IS

9267
06:39:29,866 --> 06:39:31,434
IMAGES AND HOW CAN WE DO IMAGING

9268
06:39:31,434 --> 06:39:33,669
BETTER AND WHAT ARE THE--WHERE

9269
06:39:33,669 --> 06:39:36,305
CAN WE BE MORE SUCCESSFUL THERE

9270
06:39:36,305 --> 06:39:38,341
SO TRADITIONALLY WE DONE MOST OF

9271
06:39:38,341 --> 06:39:41,344
TRIALS WITH A FULL STANDARD SET

9272
06:39:41,344 --> 06:39:42,545
OF IMAGING CRITERIA AND BECAUSE

9273
06:39:42,545 --> 06:39:44,714
OF THE WORK THAT WAS DONE SO

9274
06:39:44,714 --> 06:39:49,085
WELL WITH THE ARIA

9275
06:39:49,085 --> 06:39:52,121
INVESTIGATORS, THE PANEL THAT

9276
06:39:52,121 --> 06:39:54,424
FORMED INITIAL GUIDELINES, IF

9277
06:39:54,424 --> 06:39:55,658
WE'RE DONE ON 1.5 T TESLA

9278
06:39:55,658 --> 06:39:56,993
MACHINES AND SO GENERALLY NOW

9279
06:39:56,993 --> 06:39:59,128
WHEN WE DO THESE TRIALS WE

9280
06:39:59,128 --> 06:40:01,097
KIND'VE DUMB DOWN OUR LEVEL OF

9281
06:40:01,097 --> 06:40:02,832
UNDERSTANDING OF ARIA TO THAT

9282
06:40:02,832 --> 06:40:04,934
OLD CRITERIA OF THE 1 PASSPORT 5

9283
06:40:04,934 --> 06:40:06,903
TESLA SO 1 OF THE THINGS WE'VE

9284
06:40:06,903 --> 06:40:08,304
BEEN DOING IN THIS NEW TRIAL AND

9285
06:40:08,304 --> 06:40:10,339
REQUIRING EVERYONE TO GET A 3

9286
06:40:10,339 --> 06:40:13,843
TESLA, WE ARE TILL USING THE

9287
06:40:13,843 --> 06:40:15,978
DUMBED DOWN CRITERIA TO ENROLL

9288
06:40:15,978 --> 06:40:17,080
SO WE KEEP SOMETHING CALM IN

9289
06:40:17,080 --> 06:40:19,048
THERE BUT THEN WE ARE USING NEW

9290
06:40:19,048 --> 06:40:21,317
SEQUENCES AND USING A HIGHER

9291
06:40:21,317 --> 06:40:25,488
TESLA WHERE I HEARD SOMEONE TALK

9292
06:40:25,488 --> 06:40:26,923
ABOUT SENSITIVE IMAGING ACCIDENT

9293
06:40:26,923 --> 06:40:29,459
WE'VE DONE FOR A WHILE THAT IS

9294
06:40:29,459 --> 06:40:30,827
WAY FORESENSITIVE, WILL THAT

9295
06:40:30,827 --> 06:40:34,097
GIVE US ANYMORE, WE WILL ASK

9296
06:40:34,097 --> 06:40:37,533
THAT QUESTION WHEN WE'RE IN DTI,

9297
06:40:37,533 --> 06:40:40,703
DWI, THRIE DIMENSIONAL IMAGING

9298
06:40:40,703 --> 06:40:43,339
AS WELL AS TACK LOOKING AT

9299
06:40:43,339 --> 06:40:45,541
FUNCTIONAL MRI.

9300
06:40:45,541 --> 06:40:49,245
SO CAN WE SEE CAA IN

9301
06:40:49,245 --> 06:40:52,048
PARTICIPANTS SO THIS IS A REALLY

9302
06:40:52,048 --> 06:40:54,984
HARD CHALLENGE AND SO WE'RE

9303
06:40:54,984 --> 06:40:57,053
USING FUNCTIONAL MRI LOOKING

9304
06:40:57,053 --> 06:40:57,820
WITH VISUAL STIMULATION, ONLY

9305
06:40:57,820 --> 06:41:00,456
WILL THAT SEE THE CAA THAT MIGHT

9306
06:41:00,456 --> 06:41:02,658
BE RELATED TO THE OCCIPITAL

9307
06:41:02,658 --> 06:41:04,227
CORTEX, BUT WE KNOW THAT ARIA

9308
06:41:04,227 --> 06:41:08,464
HAS A TENDENCY TO BE MORE

9309
06:41:08,464 --> 06:41:10,566
POSTERIOR ANYHOW AND WE KNOW

9310
06:41:10,566 --> 06:41:13,836
THAT CAA TENDS TO BE VERY

9311
06:41:13,836 --> 06:41:15,705
POSTERIOR PREDOMINANT ALSO.

9312
06:41:15,705 --> 06:41:17,406
SO I THINK WE HOLD OPTIMISM WE

9313
06:41:17,406 --> 06:41:18,708
MIGHT BE ABLE TO LEVERAGE SOME

9314
06:41:18,708 --> 06:41:21,644
OF THAT AND THEN I'VE ALSO HEARD

9315
06:41:21,644 --> 06:41:22,845
ABOUT BLOOD BASED BIOMARKERS AND

9316
06:41:22,845 --> 06:41:24,914
SO, AS WE'VE GONE OUT AND TRIED

9317
06:41:24,914 --> 06:41:26,749
TO FIND FROM ALL THE EXPERTS AND

9318
06:41:26,749 --> 06:41:28,117
SOME OF THEM ARE SITTING IN THIS

9319
06:41:28,117 --> 06:41:32,121
ROOM, SOME OF THE KEY EXPERTS,

9320
06:41:32,121 --> 06:41:34,023
WE'RE REAL APOSSITY OF BLOOD

9321
06:41:34,023 --> 06:41:35,057
BASED BIOMARKERS FOR THIS SPACE.

9322
06:41:35,057 --> 06:41:37,860
SO 1 THING WE WILL BE DOING IS A

9323
06:41:37,860 --> 06:41:39,695
VERY LARGE FISHING EXPEDITION

9324
06:41:39,695 --> 06:41:41,864
AND HIGH SAMPLING RATES OF BLOOD

9325
06:41:41,864 --> 06:41:42,965
BOTH BEFORE DOSING AND AFTER

9326
06:41:42,965 --> 06:41:45,368
DOSING BECAUSE MAYBE THE SIGNAL

9327
06:41:45,368 --> 06:41:47,270
COMES AS A RESPONSE OHM RATHER

9328
06:41:47,270 --> 06:41:48,571
THAN A PREDICTIVE ELEMENT SO I

9329
06:41:48,571 --> 06:41:51,440
THINK THOSE WILL BE KEY ASSPECS.

9330
06:41:51,440 --> 06:41:53,509
SO MOST OF ALL OF THAT AND I

9331
06:41:53,509 --> 06:41:54,710
WILL STOPAUK TALKING ABOUT

9332
06:41:54,710 --> 06:42:05,254
UNITED STATES I CAN KEEP GOING.

9333
06:42:09,992 --> 06:42:10,159
NSURE.

9334
06:42:10,159 --> 06:42:12,528
>> SO THANKS JOHN AND
NINDS,

9335
06:42:12,528 --> 06:42:16,265
PUTTING IN THE ROOM STROKE CAN

9336
06:42:16,265 --> 06:42:16,866
ALZHEIMERS EXPERTISE.

9337
06:42:16,866 --> 06:42:18,634
I THINK EACH THOUGH IN PEOPLE

9338
06:42:18,634 --> 06:42:20,403
VIEW ME AS STIEPS MORE THAN

9339
06:42:20,403 --> 06:42:23,005
WILLING TO DISCUSS SOMETHING, I

9340
06:42:23,005 --> 06:42:24,874
ALSO LIKE THE COMMONALITY, AND I

9341
06:42:24,874 --> 06:42:25,474
DIDN'T--YOU KNOW THE COMMON

9342
06:42:25,474 --> 06:42:28,244
THINK THIS WE WILL ALL ADPREE,

9343
06:42:28,244 --> 06:42:30,746
WE WOULD ALL AGREE THAT WE WE

9344
06:42:30,746 --> 06:42:32,515
CALL ARIA E AND H AND THOSE

9345
06:42:32,515 --> 06:42:35,685
NAMES SEEM TO BE GOOD ENOUGH

9346
06:42:35,685 --> 06:42:36,352
EXISTS BOTH SPONTANEOUSLY ANDIST

9347
06:42:36,352 --> 06:42:38,821
ANDS IN THE PRESENCE OF DRUG.

9348
06:42:38,821 --> 06:42:42,959
AND THAT AT LEAST FOR ARIA E IT

9349
06:42:42,959 --> 06:42:44,527
CLEARLY IS MARKEDLY INCREASED IN

9350
06:42:44,527 --> 06:42:45,394
THE PRESENCE OF DRUG AS YOU

9351
06:42:45,394 --> 06:42:47,897
HEARD IN THE MORNING

9352
06:42:47,897 --> 06:42:49,565
FORRITEOLATED ARIA H HA IS WHAT

9353
06:42:49,565 --> 06:42:52,468
I LIKE TO CALL MICROHEMES AND

9354
06:42:52,468 --> 06:42:54,837
MOST PEOPLE LIKE TO CALL

9355
06:42:54,837 --> 06:42:56,038
MICROPLEAD ANDS THAT SAYS

9356
06:42:56,038 --> 06:42:57,440
SOMETHING RIGHT THERE, FOR THAT

9357
06:42:57,440 --> 06:42:58,474
IT'S NOT SO CLEAR THAT THE DRUGS

9358
06:42:58,474 --> 06:43:03,045
AND YOU HEARD THAT THIS MORNING

9359
06:43:03,045 --> 06:43:05,948
THAT BOTH FOR THE BIERK OGEN

9360
06:43:05,948 --> 06:43:07,850
COLLEAGUES, I THINK IT'S NOT SO

9361
06:43:07,850 --> 06:43:10,219
CLEAR THAT ISOLATED ARIA H, THAT

9362
06:43:10,219 --> 06:43:12,655
IS THAT THESE MICROHEMES THAT WE

9363
06:43:12,655 --> 06:43:23,165
SEE RELATE SO HEAVILY TO DRUG

9364
06:43:25,301 --> 06:43:25,501
TREATMENT.

9365
06:43:25,501 --> 06:43:26,502
HOWEVER, CLEARLY, THIS WAS

9366
06:43:26,502 --> 06:43:29,305
MENINGED THIS MORNING IS THAT

9367
06:43:29,305 --> 06:43:30,806
EDEMA BEGETS THE BLEEDS.

9368
06:43:30,806 --> 06:43:33,075
SO THERE'S NO QUESTION THAT THIS

9369
06:43:33,075 --> 06:43:34,777
INCREASE IN MICROHEMES IN THE

9370
06:43:34,777 --> 06:43:38,848
SETTING 

9371
06:43:38,848 --> 06:43:39,248
SETTING OF EDEMA.

9372
06:43:39,248 --> 06:43:41,917
SO THOSE ARE THINGS WE WOULD

9373
06:43:41,917 --> 06:43:44,687
AIMREE ON BUT I HOPE AND I THINK

9374
06:43:44,687 --> 06:43:47,623
THIS CAME OUT SO USEFUL

9375
06:43:47,623 --> 06:43:49,759
PARTICULAR LOW THOSE TANTALIZING

9376
06:43:49,759 --> 06:43:50,760
RESULTS WITH THESE RADIATION

9377
06:43:50,760 --> 06:43:54,096
EXPOSURE RAT SIZE MONKEYS AND

9378
06:43:54,096 --> 06:44:04,540
SUCH, I WAS GLAD THEY WERE

9379
06:44:07,276 --> 06:44:07,943
SIMILAR TO RATS.

9380
06:44:07,943 --> 06:44:09,345
YOU HEARD FROM A NUMBER OF

9381
06:44:09,345 --> 06:44:11,247
PEOPLE THAT SORT OF SKIRTED

9382
06:44:11,247 --> 06:44:13,549
AROUND THIS, THERE'S NO

9383
06:44:13,549 --> 06:44:14,583
QUESTION, THERE'S EDEMA THAT'S

9384
06:44:14,583 --> 06:44:16,852
WHY IT'S CALLED THAT EFFUSIONS

9385
06:44:16,852 --> 06:44:18,621
AIDE, THAT THERE'S SWELLING OF

9386
06:44:18,621 --> 06:44:22,124
THE BRAIN, THAT'S RADIO

9387
06:44:22,124 --> 06:44:25,695
GRAPHICALLY EVIDENT, AND NOT

9388
06:44:25,695 --> 06:44:27,330
INFREQUENTLY SYMPTOMATIC TO THE

9389
06:44:27,330 --> 06:44:28,764
PATIENT ANDS PHYSICIANS ALIKE,

9390
06:44:28,764 --> 06:44:30,232
PUBLISHED IT'S NOT CLEAR HOW

9391
06:44:30,232 --> 06:44:32,301
MUCH IS INFLAMMATION AND HOW

9392
06:44:32,301 --> 06:44:33,936
MUCH IS JUST WHAT ARE CHANGES

9393
06:44:33,936 --> 06:44:37,606
AND WE HEARD EARLIER ON THE

9394
06:44:37,606 --> 06:44:39,075
ACQUAPORIN AND SUCH IS QUITE

9395
06:44:39,075 --> 06:44:40,609
FASCINATING I HAVE TO POINT OUT

9396
06:44:40,609 --> 06:44:42,244
THORS AN AUDIENCE THAT HAS A

9397
06:44:42,244 --> 06:44:44,213
MIXTURE OF CLINICIANS AND

9398
06:44:44,213 --> 06:44:45,181
NONCLINICIANS THAT STEROIDS DO

9399
06:44:45,181 --> 06:44:48,317
NOT DECIDE THAT QUESTION.

9400
06:44:48,317 --> 06:44:53,689
STEROIDS AFFECT BOTH EDEMA AND

9401
06:44:53,689 --> 06:44:55,124
INFLAMMATION, AND ARE REALLY

9402
06:44:55,124 --> 06:44:56,726
RATHER AMAZING DRUGS BUT THEY

9403
06:44:56,726 --> 06:44:58,561
DON'T WILL TUS WHETHER SOMETHING

9404
06:44:58,561 --> 06:45:02,965
IS EDEMA OR INFLAMMATION, AND OF

9405
06:45:02,965 --> 06:45:06,335
COURSE THEN 1 COULD HAVE EDEMA

9406
06:45:06,335 --> 06:45:08,003
WITH INFLAMMATION AND 1 COULD

9407
06:45:08,003 --> 06:45:09,905
HAVE INFLAMMATION WITH EDEMA BUT

9408
06:45:09,905 --> 06:45:20,316
1 COULD HAVE PURE EDEMA.

9409
06:45:27,390 --> 06:45:29,091
I HAD THIS CONVERSATION WITH 1

9410
06:45:29,091 --> 06:45:30,860
OF EYE COLLEAGUES AND YOU HEARD

9411
06:45:30,860 --> 06:45:33,662
3 WORS HERE MICROHEMES,

9412
06:45:33,662 --> 06:45:37,333
MICROPLEA ANDS MICROHEMORRHAGES,

9413
06:45:37,333 --> 06:45:39,969
THE FACTA WE'RE NOT SURE IN

9414
06:45:39,969 --> 06:45:41,704
HUMANS WHICH WE DEFINE AS THE

9415
06:45:41,704 --> 06:45:49,078
TINY AREAS OF DECREASED ON SWI

9416
06:45:49,078 --> 06:45:52,214
OR A VARIETY OF SPECIALIZED MRI

9417
06:45:52,214 --> 06:45:54,316
IMAGES BUT WE DETECT THESE

9418
06:45:54,316 --> 06:45:57,319
LITTLE SMALL AREAS OF

9419
06:45:57,319 --> 06:45:58,587
HYPOINTENSITY, WE'RE NOT CERTAIN

9420
06:45:58,587 --> 06:46:00,656
WOULD THEY REALLY REPRESENT A

9421
06:46:00,656 --> 06:46:02,958
PLEAD AT ANY POINT PER SE, TO ME

9422
06:46:02,958 --> 06:46:04,660
AS A NEUROLOGIST AND

9423
06:46:04,660 --> 06:46:05,828
NEUROSCIENTIST A BLOOD

9424
06:46:05,828 --> 06:46:07,663
REPRESENTS BLOOD OUTSIDE OF A

9425
06:46:07,663 --> 06:46:09,331
BLOOD VESSEL AND THAT'S WHAT A

9426
06:46:09,331 --> 06:46:10,466
BLEED BY DEFINITION IS, WE'RE

9427
06:46:10,466 --> 06:46:13,002
FOCUS ON THE CONVINCED NO 1'S

9428
06:46:13,002 --> 06:46:14,703
CAPTURED A MICROBLEED IN ACTION

9429
06:46:14,703 --> 06:46:16,372
WITH A CT FOR EXAMPLE, SHOWING

9430
06:46:16,372 --> 06:46:21,177
CLEARLY BLOOD IN THE PATHWAY

9431
06:46:21,177 --> 06:46:23,345
GIVES RENCHEMMA THAT EVOLVES TO

9432
06:46:23,345 --> 06:46:26,482
THIS AREA OF MICROHEME OR

9433
06:46:26,482 --> 06:46:29,852
HEMOSITTERIN FOR THE

9434
06:46:29,852 --> 06:46:30,953
SUSCEPTIBILITY OF MRIIMAGE AND

9435
06:46:30,953 --> 06:46:32,755
WHAT IS AURIA H AND IS THAT

9436
06:46:32,755 --> 06:46:34,557
SUSCEPTIBLE TO THE ANIMAL PRPTS.

9437
06:46:34,557 --> 06:46:40,763
IS IT A  BLOOD THAT GETS

9438
06:46:40,763 --> 06:46:41,764
MACROPHAGED AND TREATED IF YOU

9439
06:46:41,764 --> 06:46:43,666
WILL AND ENDS UP WITH PRODUCTS

9440
06:46:43,666 --> 06:46:45,901
OR IS IT MORE COMPLICATED GOING

9441
06:46:45,901 --> 06:46:47,636
ON MORE MORE MICROSCOPIC LEVEL

9442
06:46:47,636 --> 06:46:56,278
GOING ON. 

9443
06:46:56,278 --> 06:46:58,614
BUT OBVIOUSLY THE PROCESS USES

9444
06:46:58,614 --> 06:47:00,316
THE PRODUCTS AND THOSE BIG

9445
06:47:00,316 --> 06:47:03,185
QUESTIONS IS WHAT IS ARIA E,

9446
06:47:03,185 --> 06:47:12,094
WHAT IS ARIA H, THE ANIMAL PANEL

9447
06:47:12,094 --> 06:47:13,562
WILL ADDRESS THAT.

9448
06:47:13,562 --> 06:47:15,764
TREATMENT SEEMS ALTERED AND

9449
06:47:15,764 --> 06:47:16,932
CONFOUNDED AND SOMEONE BROUGHT

9450
06:47:16,932 --> 06:47:17,700
UP EARLIER WHETHER TREATMENT

9451
06:47:17,700 --> 06:47:20,169
WOULD BE GOOD OR BAD, FOR XCH IF

9452
06:47:20,169 --> 06:47:21,804
YOU PUT STEROIDS IN SOMEBODY,

9453
06:47:21,804 --> 06:47:23,138
PERHAPS THEY WON'T GET THE

9454
06:47:23,138 --> 06:47:25,040
AMYLOID CLEARING, I THINK WAS

9455
06:47:25,040 --> 06:47:27,877
THE IMPLICATION AND THAT'S A

9456
06:47:27,877 --> 06:47:28,344
POSSIBILITY.

9457
06:47:28,344 --> 06:47:33,516
NONE OF US WANT SYMPTOMATIC

9458
06:47:33,516 --> 06:47:36,485
BRAIN INJURY TO OUR PATES EVEN

9459
06:47:36,485 --> 06:47:38,787
REVERSIBLE AND CERTAINLY NOT

9460
06:47:38,787 --> 06:47:40,122
IRREVERSIBLE, SO THE QUESTION OF

9461
06:47:40,122 --> 06:47:41,891
WHATNYS TO BE TREATED AND WHEN

9462
06:47:41,891 --> 06:47:44,493
IT NEEDS TO BE TREATED AND HOW

9463
06:47:44,493 --> 06:47:46,762
MUCH WE SHOULD TRY TO OBVIATE

9464
06:47:46,762 --> 06:47:47,396
THESE CENTER FOR EXCELLENCE ON

9465
06:47:47,396 --> 06:47:49,198
AGINGS IS LESS CLEAR AND THERE

9466
06:47:49,198 --> 06:47:50,299
WAS SOME EVIDENT ALLUDED TO IT

9467
06:47:50,299 --> 06:47:51,901
BY SOME PEOPLE AND OTHER EVIDENT

9468
06:47:51,901 --> 06:47:53,335
THAT WASN'T ALLUDED TO THAT

9469
06:47:53,335 --> 06:47:55,437
HAVING ARIA E IS A COMP ANNIEED

9470
06:47:55,437 --> 06:47:57,306
BY CLEARANCE OF AMYLOID AND

9471
06:47:57,306 --> 06:47:59,542
RESEARCH SHOWED THAT NICE PLOTTA

9472
06:47:59,542 --> 06:48:01,744
OVERALL IT WAS TRUE IN TERMS OF

9473
06:48:01,744 --> 06:48:03,679
A CIRCLE PLOT, BUT IT'S EVEN

9474
06:48:03,679 --> 06:48:05,548
TRUE IN INDIVIDUAL CASES WHEN

9475
06:48:05,548 --> 06:48:07,249
YOU LOOK TOPOGRAPHICALLY IN

9476
06:48:07,249 --> 06:48:07,550
INDIVIDUALS.

9477
06:48:07,550 --> 06:48:09,552
SO THAT'S WHAT I WOULD SAY IN

9478
06:48:09,552 --> 06:48:10,853
TERMS OF UNKNOWNS, I THINK

9479
06:48:10,853 --> 06:48:11,820
AUTOIMRAIT WE'RE HAVING THIS

9480
06:48:11,820 --> 06:48:13,289
MEETING TO TRY TO SEE HOW SOME

9481
06:48:13,289 --> 06:48:15,291
OF THEM SHOULD BE ARK PROACHABLE

9482
06:48:15,291 --> 06:48:18,160
AND SOME OF THEM COULD BE EASILY

9483
06:48:18,160 --> 06:48:20,829
APPROACHABLE THROUGH ANIMAL

9484
06:48:20,829 --> 06:48:24,300
PRPLTS SO I'M DELIGHTED TO HEAR

9485
06:48:24,300 --> 06:48:25,467
ABOUT POTENTIAL OF SQUIRREL

9486
06:48:25,467 --> 06:48:26,802
MONKEYS AND OTHERS AND FLAD TO

9487
06:48:26,802 --> 06:48:30,606
HEAR IT'S IN BEARS BY THE WAY.

9488
06:48:30,606 --> 06:48:33,876
INITIATIVES GUESS I'M GO NOW SOW

9489
06:48:33,876 --> 06:48:36,345
I'M MERRION BASHING UCKWALTER

9490
06:48:36,345 --> 06:48:40,282
AND I'M A STROKE AND RESEARCH

9491
06:48:40,282 --> 06:48:41,951
SCIENCE DOCTOR, SO I'M COMING

9492
06:48:41,951 --> 06:48:43,185
FROM AN OUTSIDER PERSPECTIVE IN

9493
06:48:43,185 --> 06:48:45,754
SOME WAYS HERE EMPLOY I THINK I

9494
06:48:45,754 --> 06:48:47,456
TOTAL AGREE WITH YOU LARY ABOUT

9495
06:48:47,456 --> 06:48:48,724
UNDERSTANDING MORE ABOUT THE

9496
06:48:48,724 --> 06:48:51,160
CLENICAL SPECTRUM OF ARIA E AND

9497
06:48:51,160 --> 06:48:52,761
ARIA H.

9498
06:48:52,761 --> 06:48:53,829
I THINK--I MADE THE COMMENT

9499
06:48:53,829 --> 06:48:55,264
EARLIER THIS MORNING AND I WANT

9500
06:48:55,264 --> 06:48:56,765
TO REPEAT IT BECAUSE I DON'T

9501
06:48:56,765 --> 06:48:58,067
THINK WE'VE HEARD AN ANSWER TO

9502
06:48:58,067 --> 06:49:02,237
IT YET, WHICH IS THAT PEOPLE

9503
06:49:02,237 --> 06:49:03,205
WITH APOE 4 ALLELES EESPECIALLY

9504
06:49:03,205 --> 06:49:05,741
2 OF THEM BUT EVEN 1 OF THEM ARE

9505
06:49:05,741 --> 06:49:07,476
MORE LIKELY TO HAVE ARIA, BUT

9506
06:49:07,476 --> 06:49:11,814
THEY'RE NOT MORE LIKELY TO HAVE

9507
06:49:11,814 --> 06:49:15,618
SYMPTOMS FROM ARIA, OR ARIA H SO

9508
06:49:15,618 --> 06:49:17,886
IT COULD BE THESE PEOPLE DON'T

9509
06:49:17,886 --> 06:49:18,787
NOTICE THE SYMPTOMS AS MUCH, I

9510
06:49:18,787 --> 06:49:22,391
DON'T KNOW IF WE HAVE THAT DATA

9511
06:49:22,391 --> 06:49:25,961
OF WHETHER THEY--THIS GROUP IS

9512
06:49:25,961 --> 06:49:27,463
MORE COGNITIVELY IMED WHEN THEY

9513
06:49:27,463 --> 06:49:28,964
HAVE THE ARIA, MAYBE THEY JUST

9514
06:49:28,964 --> 06:49:31,400
MISS THEM BUT IT POSSIBLE THE

9515
06:49:31,400 --> 06:49:34,069
ADEMA WE SEE ON SCANS AS ARIA E

9516
06:49:34,069 --> 06:49:35,137
WHICH IS DIFFERENT IN PEOPLE TO

9517
06:49:35,137 --> 06:49:37,272
GET THE DRUGS VERSUS PEOPLE WHO

9518
06:49:37,272 --> 06:49:38,440
DON'T GET THEM, IS IT POSSIBLE

9519
06:49:38,440 --> 06:49:41,877
THAT IT IT IS JUST A SYMPTOM OF

9520
06:49:41,877 --> 06:49:43,178
THE DRUGS WORKING, IS IT DOESN'T

9521
06:49:43,178 --> 06:49:44,680
DISTURB PEOPLE THAT MUCH AND

9522
06:49:44,680 --> 06:49:47,182
PERHAPS IT WAS SUGGESTED BY

9523
06:49:47,182 --> 06:49:48,584
DR. SPERLING THAT THEY'RE DOG

9524
06:49:48,584 --> 06:49:50,853
BETTER COGNITIVELY IF THEY HAVE

9525
06:49:50,853 --> 06:49:51,654
ARIA.

9526
06:49:51,654 --> 06:49:56,892
SO I THINK WE REALLY NEED TO

9527
06:49:56,892 --> 06:49:57,893
LOOK ATA A SCIENTIFIC COMMUNITY

9528
06:49:57,893 --> 06:49:59,495
WE NEED TO HAVE DATA AVAILABLE

9529
06:49:59,495 --> 06:50:02,398
ON HOW PATIENTS DID IN THE

9530
06:50:02,398 --> 06:50:03,499
MULTIPLE TRIAL ANDS WHETHER ARIA

9531
06:50:03,499 --> 06:50:06,168
IS BAD OR NOT.

9532
06:50:06,168 --> 06:50:07,770
SO I THINK SOMETIMES THOSE

9533
06:50:07,770 --> 06:50:09,772
DOCTORS WE REACT TO A VERY SCARY

9534
06:50:09,772 --> 06:50:12,241
LOOKING IMAGE AND THEY ARE

9535
06:50:12,241 --> 06:50:13,542
SCARY, IT WOULDN'T SURPRISE ME

9536
06:50:13,542 --> 06:50:15,844
IF THEY'RE BAD I'M JUST SAYING

9537
06:50:15,844 --> 06:50:17,646
WE NEED TO PROVE THAT IT'S BAD

9538
06:50:17,646 --> 06:50:19,148
IF SOMEONE GETS ARIA E AND WE

9539
06:50:19,148 --> 06:50:20,616
NEED TO FIGURE OUT THE LINK

9540
06:50:20,616 --> 06:50:22,084
BETWEEN THE SYMPTOMS AND THE

9541
06:50:22,084 --> 06:50:25,054
ARIA E AND WHY THERE'S THIS

9542
06:50:25,054 --> 06:50:25,688
DIFFERENTIAL WITH APOE 4 AND I

9543
06:50:25,688 --> 06:50:27,856
THINK SOME OF THE WORK WE JUST

9544
06:50:27,856 --> 06:50:29,124
HEARD ABOUT IN THE HAS DONE AND

9545
06:50:29,124 --> 06:50:33,395
OTHER PEOPLE IN THIS ROOM,

9546
06:50:33,395 --> 06:50:34,897
DR. [INDISCERNIBLE] HAS SHOWN

9547
06:50:34,897 --> 06:50:37,266
THAT APOE 4 DOESN'T DO AS WELL

9548
06:50:37,266 --> 06:50:40,302
WITH RESERVING PERISIGHTS OR

9549
06:50:40,302 --> 06:50:43,472
WITH SUPPRESSING PERIVASCULAR

9550
06:50:43,472 --> 06:50:44,039
MACROPHAGEOXIDATIVE BURSTS.

9551
06:50:44,039 --> 06:50:45,641
SO THERE COULD BE LINKS BUT I

9552
06:50:45,641 --> 06:50:47,342
JUST THINK WE NEED A LOT MORE

9553
06:50:47,342 --> 06:50:49,311
INFORMATION WITH THE CLINICAL

9554
06:50:49,311 --> 06:50:50,145
SPECTRUM OTHERWISE WE'RE GOING

9555
06:50:50,145 --> 06:50:51,513
TO END UP STUDYING SOMETHING

9556
06:50:51,513 --> 06:50:54,983
THAT'S NOT AS IMPORTANT TO

9557
06:50:54,983 --> 06:50:55,250
PATIENTS.

9558
06:50:55,250 --> 06:50:58,620
MIRROR IMAGE SECOND POINT IS I

9559
06:50:58,620 --> 06:51:00,322
THINK THAT A LOT OF EXCITING WO,

9560
06:51:00,322 --> 06:51:03,125
WE HEARD TODAY IS APPLICABLE

9561
06:51:03,125 --> 06:51:05,594
WHETHER OR NOT ARIA E AND H ARE

9562
06:51:05,594 --> 06:51:07,096
A PROBLEM BECAUSE WE KNOW THAT

9563
06:51:07,096 --> 06:51:10,933
CAA IS A PROBLEM AND CAA IS

9564
06:51:10,933 --> 06:51:12,501
RELATED TO CAA PATHOLOGY AND I

9565
06:51:12,501 --> 06:51:19,975
THOUGHT THERE WAS EXCITING WORK

9566
06:51:19,975 --> 06:51:20,309
PRESENTED.

9567
06:51:20,309 --> 06:51:21,677
HOWEVER WE NEED TO THINK ABOUT

9568
06:51:21,677 --> 06:51:25,047
THE FACT THAT ALZHEIMER'S

9569
06:51:25,047 --> 06:51:26,548
DISEASE HAVE MIXED DEMENTIA SO

9570
06:51:26,548 --> 06:51:28,684
WHEN WE LOOK AT ANIMAL MODELS

9571
06:51:28,684 --> 06:51:30,953
THAT LOOK AT PERICITES THAT LOOK

9572
06:51:30,953 --> 06:51:33,255
AT MEDIN FOR EXAMPLE, WE NEED TO

9573
06:51:33,255 --> 06:51:39,595
CONSIDER LOOKINGA THE ANIMAL

9574
06:51:39,595 --> 06:51:41,396
MODELS WITH VASC LORA RODRIGUEZ

9575
06:51:41,396 --> 06:51:50,339
DISEASE AND 70% OR MORE THE

9576
06:51:50,339 --> 06:51:52,407
PATIENTS WHAT'S THE INTEGRITY OF

9577
06:51:52,407 --> 06:51:53,575
A NEUROVASCULAR TREATMENT SO I

9578
06:51:53,575 --> 06:51:59,148
THINK I WILL TOP THERE.

9579
06:51:59,148 --> 06:51:59,681
>> THANK YOU.

9580
06:51:59,681 --> 06:52:01,049
WE WOULD LIKE TO HEAR MORE FROM

9581
06:52:01,049 --> 06:52:02,417
ALL OF YOU ABOUT THE ANIMAL

9582
06:52:02,417 --> 06:52:06,121
MODEL ANDS WHAT DO YOU SEE AS

9583
06:52:06,121 --> 06:52:07,122
MISSING OR WHAT DO YOU SEE

9584
06:52:07,122 --> 06:52:10,225
SOMETHING THAT WOULD BE VALUABLE

9585
06:52:10,225 --> 06:52:16,598
TO INFORM THE CLINICAL TRIALS AT

9586
06:52:16,598 --> 06:52:24,139
THIS POINT OR OPPORTUNITIES FOR

9587
06:52:24,139 --> 06:52:24,573
REVERSE TRANSLATION.

9588
06:52:24,573 --> 06:52:26,341
WOP THING IS A LOT OF ATTENTION

9589
06:52:26,341 --> 06:52:28,777
TO ARIA H AND AS MIGHT HAVE COME

9590
06:52:28,777 --> 06:52:30,179
ACROSS A FEW MOMENTS AGO, IT'S

9591
06:52:30,179 --> 06:52:34,883
NOT SO MUCH A PROBLEM

9592
06:52:34,883 --> 06:52:36,151
CLIPICALLY, AND IS SOMETHING NOT

9593
06:52:36,151 --> 06:52:40,289
AS CLEARLY DRUG RELATED SO I

9594
06:52:40,289 --> 06:52:41,523
THINK WHILE PLEADING IS

9595
06:52:41,523 --> 06:52:44,493
FASCINATING AND TERRIFYING TO

9596
06:52:44,493 --> 06:52:48,397
OUR PATIENTS AND ALSO AN EASY

9597
06:52:48,397 --> 06:52:50,265
THING TO THINK ABOUT I THINK

9598
06:52:50,265 --> 06:52:53,602
IT'S REALLY THE ARIA E OR EDEMA

9599
06:52:53,602 --> 06:52:56,471
WE HAVE TO FOCUS ON BECAUSE THAT

9600
06:52:56,471 --> 06:53:00,008
IS THE SIDE EFFECT OF THE

9601
06:53:00,008 --> 06:53:01,977
MEDICATIONS WE'RE TALKING ABOUT

9602
06:53:01,977 --> 06:53:04,680
HUNDRED FOLD TIMES INCREASE WITH

9603
06:53:04,680 --> 06:53:07,216
MEDICATIONS AND B IT'S CLEARLY

9604
06:53:07,216 --> 06:53:09,484
SOMETHING THAT CAN BE MORE

9605
06:53:09,484 --> 06:53:10,786
EASILY SYMPTOMATIC AND IT'S

9606
06:53:10,786 --> 06:53:14,890
RARE, HAVING THE MICROHEMES AND

9607
06:53:14,890 --> 06:53:17,759
RARELY SYMPTOMATIC AND EVEN

9608
06:53:17,759 --> 06:53:25,567
MACROHEMES AOCCUR OR LARGE

9609
06:53:25,567 --> 06:53:28,103
MEMORY RESPONSE HEMORRHAGES

9610
06:53:28,103 --> 06:53:30,072
OCCUR SO THEY'RE QUITE RARE AND

9611
06:53:30,072 --> 06:53:33,475
IN THOSE CASES IT MAY BE DUE TO

9612
06:53:33,475 --> 06:53:42,351
MEDICAL MISADVENTURE IN SOME OF

9613
06:53:42,351 --> 06:53:44,052
THOSE CASES.

9614
06:53:44,052 --> 06:53:46,121
SO THE HEMORRHAGE IS NOT THE

9615
06:53:46,121 --> 06:53:47,723
BIGGEST CONCERN, I THINK ANIMAL

9616
06:53:47,723 --> 06:53:48,924
MODELS NEED TO FOCUS MORE ON WHY

9617
06:53:48,924 --> 06:53:51,226
WE GET IT, I CAN BE THE BELIEVE

9618
06:53:51,226 --> 06:53:52,995
I DIDN'T SAY APOE IN THE FIRST

9619
06:53:52,995 --> 06:53:55,097
THINK THIS I SAID BUT CLEARLY

9620
06:53:55,097 --> 06:53:57,599
FOR THAT MATTER, IT'S EITHER OF

9621
06:53:57,599 --> 06:54:02,204
THOSE WORDS BUT CLEARLY WE ALL

9622
06:54:02,204 --> 06:54:05,474
ATBREE THAT ARIA E AND H GO TO

9623
06:54:05,474 --> 06:54:06,308
COMMONALITY AND CONSENSUS, WE

9624
06:54:06,308 --> 06:54:08,577
BOTH AGREEN CELLS THAT ARIA E

9625
06:54:08,577 --> 06:54:10,145
AND H RELATE INTRINSICALLY AND

9626
06:54:10,145 --> 06:54:11,914
SIGNATURES MIF CANTILY AS JOHN

9627
06:54:11,914 --> 06:54:15,717
AND MARION BOTH MENTIONED RELATE

9628
06:54:15,717 --> 06:54:16,985
TO AMYLOID ANGIE OPEN

9629
06:54:16,985 --> 06:54:19,855
MEETINGATHY AND SO APOE OF

9630
06:54:19,855 --> 06:54:20,923
COURSE IS VERY IMPORTANT BECAUSE

9631
06:54:20,923 --> 06:54:28,196
WE KNOW HA APOE4 CARRIERSHIP OR

9632
06:54:28,196 --> 06:54:31,533
HOMOZYGOSITY MARKETEDLY IS

9633
06:54:31,533 --> 06:54:33,302
ASSOCIATED WITH AMYLOID ANGIE

9634
06:54:33,302 --> 06:54:34,202
OPERATING GLOBALLYATHY.

9635
06:54:34,202 --> 06:54:36,505
WE KNOW OVERALL HAS YOU HEARD

9636
06:54:36,505 --> 06:54:39,708
FROM DOCTORS THIS MORNING ALMOST

9637
06:54:39,708 --> 06:54:42,878
ALL ALZHEIMER'S PATIENTS ARE

9638
06:54:42,878 --> 06:54:46,014
AMYLOID ANGIOPATHY AND ONLY

9639
06:54:46,014 --> 06:54:50,752
30-OVERLAPPING OHM 67% HAVE 1 OR

9640
06:54:50,752 --> 06:54:51,019
MORE.

9641
06:54:51,019 --> 06:54:54,389
BUT THOSE WHO HAVE NO ALLELES

9642
06:54:54,389 --> 06:54:56,825
THE VAST MAJORITY HAVE AMYLOID

9643
06:54:56,825 --> 06:54:58,093
AND ANGIE OPERATING GLOBALLYATHY

9644
06:54:58,093 --> 06:54:59,461
IS THE SINGLE GRITTEST RISK

9645
06:54:59,461 --> 06:55:02,431
FACTOR THAT THE ONLY CLEAR RISK

9646
06:55:02,431 --> 06:55:04,099
FACTOR AT THIS MOMENT IN TIME

9647
06:55:04,099 --> 06:55:09,538
AND FOR THAT MATTER ARIA H.

9648
06:55:09,538 --> 06:55:11,540
NSO ON THE ANIMAL MODELS WE WILL

9649
06:55:11,540 --> 06:55:13,408
TOUCH ON 2 THINGS.

9650
06:55:13,408 --> 06:55:14,743
ONE WAS INTERESTING CAN TO ME

9651
06:55:14,743 --> 06:55:16,678
IT'S STILL A MYSTERY FROM HUMAN

9652
06:55:16,678 --> 06:55:16,878
DATA.

9653
06:55:16,878 --> 06:55:20,148
I THINK WE'VE SEEN CONSISTENT

9654
06:55:20,148 --> 06:55:23,118
DECREASES IN GP, FAB AND I THINK

9655
06:55:23,118 --> 06:55:25,687
IT'S COUNTER INTUITIVE TO ME

9656
06:55:25,687 --> 06:55:26,722
WITH THESE THERAPY ANDS HOW AND

9657
06:55:26,722 --> 06:55:30,892
WHY IS THAT OCCURRING AND THE

9658
06:55:30,892 --> 06:55:33,628
ROLE OF ASTRO CITE AND THE FOOT

9659
06:55:33,628 --> 06:55:35,831
PLATE AND CAA IS AN INTRIGUING

9660
06:55:35,831 --> 06:55:38,467
MYSTERY I THINK THAT'S WORTHY OF

9661
06:55:38,467 --> 06:55:39,735
SERIOUS INVESTIGATION AND FOR

9662
06:55:39,735 --> 06:55:43,105
ALET BIT ABOUT THIS, THE FOOT

9663
06:55:43,105 --> 06:55:44,373
PLATE AND ITS INTERACTION AND

9664
06:55:44,373 --> 06:55:48,610
PERHAPS CLEARANCE AND MAYBE WE

9665
06:55:48,610 --> 06:55:52,314
ARE RETEABING A BLOOD BRAIN

9666
06:55:52,314 --> 06:55:53,582
BARRIER OR REDUCING IT AND WE

9667
06:55:53,582 --> 06:55:55,083
HAVE TO BE CAUTIOUS WITH WE SEE

9668
06:55:55,083 --> 06:55:56,385
DECREASE THIS IS CONCENTRATION

9669
06:55:56,385 --> 06:55:57,419
BECAUSE WE DON'T YET KNOW

9670
06:55:57,419 --> 06:56:00,856
WHETHER IT'S A PRODUCTION

9671
06:56:00,856 --> 06:56:03,125
PROBLEM, CLEARANCE PROBLEM OR

9672
06:56:03,125 --> 06:56:03,959
VOLUME DISTRIBUTION PROBLEM

9673
06:56:03,959 --> 06:56:06,094
EMPLOY I ACUME IT'S A

9674
06:56:06,094 --> 06:56:08,263
DISTRIBUTION, SORRY PRODUCTION

9675
06:56:08,263 --> 06:56:08,997
AND CLEARANCE, ISSUANCE, SO WE

9676
06:56:08,997 --> 06:56:12,267
HEARD A BIT OF ALSO DISCUSSION

9677
06:56:12,267 --> 06:56:15,103
ABOUT LYMPHATIC ANDS WHETHER WE

9678
06:56:15,103 --> 06:56:17,172
IMPROVE OR OR DECREASE LYMPHATIC

9679
06:56:17,172 --> 06:56:19,141
OUTFLOWS, YOU KNOW SO I THINK

9680
06:56:19,141 --> 06:56:20,208
THERE'S A VERY INTERESTING

9681
06:56:20,208 --> 06:56:23,145
MYSTERY THERE THAT IS DEFINITELY

9682
06:56:23,145 --> 06:56:24,679
LINKED TO HUMAN BIOLOGY THAT

9683
06:56:24,679 --> 06:56:29,117
WE'VE SEEN SO FAR.

9684
06:56:29,117 --> 06:56:31,186
FROM CAA PERSPECTIVE, I THINK

9685
06:56:31,186 --> 06:56:32,721
I'M ALMOST CONVIN THAT THE

9686
06:56:32,721 --> 06:56:35,490
ANIMAL MODELS THAT HAVE TYPE 1

9687
06:56:35,490 --> 06:56:37,225
CAA IS VERY RELEVANT YET TO THE

9688
06:56:37,225 --> 06:56:39,694
TYPE OF PATHOLOGY THAT WE SEE

9689
06:56:39,694 --> 06:56:40,695
FROM THE IMMUNOTHERAPY EMPLOY SO

9690
06:56:40,695 --> 06:56:42,431
I REALLY THINK THE TYPE 2

9691
06:56:42,431 --> 06:56:46,068
PROBABLY A MORE RELEVANT MODEL.

9692
06:56:46,068 --> 06:56:49,071
AND I THINK AGAIN, SORRY

9693
06:56:49,071 --> 06:56:54,209
FORICKING --FOR PICKING ON YOU

9694
06:56:54,209 --> 06:56:56,445
REISA, BUT I'M GOING TO SAY IT

9695
06:56:56,445 --> 06:56:58,480
IS THAT IS THIS I'M NOT CLEAR

9696
06:56:58,480 --> 06:57:00,482
HOW WE'RE MAKING PEOPLE BETTER

9697
06:57:00,482 --> 06:57:01,983
WITH THESE THERAPIES 1 THING I'M

9698
06:57:01,983 --> 06:57:06,354
WONDERING ARE WE IMPROVING THE

9699
06:57:06,354 --> 06:57:07,789
BASAL REACTIVITY BECAUSE WE'RE

9700
06:57:07,789 --> 06:57:10,192
REMOVING THE AMYLOID FROM THE

9701
06:57:10,192 --> 06:57:11,660
VESSELS AND IMPROVE THAT ASPECT

9702
06:57:11,660 --> 06:57:14,830
VERSUS AND OTHER ASPECT AND I

9703
06:57:14,830 --> 06:57:17,933
THINK THAT'S THE UNKNOWN AND I

9704
06:57:17,933 --> 06:57:20,001
KNOW STEVE IN THE PAST HAS DONE

9705
06:57:20,001 --> 06:57:21,903
EXPERIMENTS LOOKING AT YOU KNOW

9706
06:57:21,903 --> 06:57:23,038
BASAL REACTIVITY WITH ANOTHER

9707
06:57:23,038 --> 06:57:25,807
MOLECULE THAT DOESN'T REALLY

9708
06:57:25,807 --> 06:57:27,008
REMOVE AMYLOID BUT 1 ASPECT WE

9709
06:57:27,008 --> 06:57:28,577
HAD DONE IN THE PAST AND AT THE

9710
06:57:28,577 --> 06:57:31,613
HUMAN LEVEL IS THAT THESE--THESE

9711
06:57:31,613 --> 06:57:33,715
TRACERS CAN BE USED FOR

9712
06:57:33,715 --> 06:57:36,351
PROFUSION AS WELL, SO YOU CAN

9713
06:57:36,351 --> 06:57:37,219
GET CEREBRAL BLOOD FLOW.

9714
06:57:37,219 --> 06:57:39,454
CAN YOU GET A 2 FOR 1 TIMES IF

9715
06:57:39,454 --> 06:57:41,957
YOU DO A DYNAMIC SCAN WHEN YOU

9716
06:57:41,957 --> 06:57:43,959
DO THESE AND SO 1 OF THE

9717
06:57:43,959 --> 06:57:46,795
QUESTIONS IS, YOU KNOW, WHAT

9718
06:57:46,795 --> 06:57:49,097
IS--AND HOW IS THE CHANGE OF THE

9719
06:57:49,097 --> 06:57:53,068
PROFUSION OR BLOOD FLOW AFFECTED

9720
06:57:53,068 --> 06:57:53,802
THROUGH THIS REMOVAL OR WHAT IS

9721
06:57:53,802 --> 06:57:57,973
IT THAT WE'RE DOING WITH VESSEL

9722
06:57:57,973 --> 06:57:58,640
AND IT'S BIOLOGY.

9723
06:57:58,640 --> 06:58:01,343
>> I AGREE WITH THAT IN
TERMS OF

9724
06:58:01,343 --> 06:58:02,677
THE ANIMAL MODELS.

9725
06:58:02,677 --> 06:58:04,079
LOOKING AT DYNAMIC BLOOD NO WILL

9726
06:58:04,079 --> 06:58:05,614
BE IMPORTANT AND SEVERAL PEOPLE

9727
06:58:05,614 --> 06:58:09,451
HAD THAT TODAY BUT I FEEL LIKE

9728
06:58:09,451 --> 06:58:11,853
AS A FIELD IN BASIC SCIENCE LABS

9729
06:58:11,853 --> 06:58:14,723
IT REMAINS REALLY EXPENSIVE AND

9730
06:58:14,723 --> 06:58:16,791
CHALLENGING TO LOOK AT VASCULAR

9731
06:58:16,791 --> 06:58:19,294
REACTIVITY IN MICE AND WE COULD

9732
06:58:19,294 --> 06:58:23,431
USE BETTER TECHNIQUES FOR THAT

9733
06:58:23,431 --> 06:58:25,834
AND I THINK THAT ALSO PLAYS IN

9734
06:58:25,834 --> 06:58:28,370
THE COMMON CO-MORBIDITIES OF

9735
06:58:28,370 --> 06:58:30,305
AGING AND ALZHEIMER'S DISEASE

9736
06:58:30,305 --> 06:58:33,375
PHENOTYPE WHICH HYPERTENSION,

9737
06:58:33,375 --> 06:58:35,143
DIABETES, HIGH CHOLESTEROL,

9738
06:58:35,143 --> 06:58:38,213
INFARCTS ARE ALL ASSOCIATE WIDE

9739
06:58:38,213 --> 06:58:43,418
A CLINICAL DIAGNOSIS OF

9740
06:58:43,418 --> 06:58:44,519
ALZHEIMER'S DEC EMPLOY BUT I

9741
06:58:44,519 --> 06:58:46,021
ALSO WANT TO REITERATE WHAT WAS

9742
06:58:46,021 --> 06:58:48,790
SAID TODAY, I DON'T THINK ANY 1

9743
06:58:48,790 --> 06:58:50,392
ANIMAL MODEL WILL RECAPITULATE

9744
06:58:50,392 --> 06:58:51,793
EVERYTHING SO I THINK

9745
06:58:51,793 --> 06:58:53,395
AUTOIMPORTANT TO HAVE REVERSE

9746
06:58:53,395 --> 06:58:54,596
TRANSLATION OR MAYBE

9747
06:58:54,596 --> 06:58:55,697
INTERDEPENDENT TRANSLATION GOING

9748
06:58:55,697 --> 06:58:56,898
BACK AND FORTH BETWEEN ANIMALS

9749
06:58:56,898 --> 06:58:59,467
AND HUMANS TO MAKE SURE THAT THE

9750
06:58:59,467 --> 06:59:00,869
THING YOU'RE STUDYING IS WHAT'S

9751
06:59:00,869 --> 06:59:01,836
HAPPENING IN HUMANS AND I DO

9752
06:59:01,836 --> 06:59:03,638
THINK THAT IS GETTING EASIER TO

9753
06:59:03,638 --> 06:59:05,774
DO WITH MORE MODEL CITIZENERN

9754
06:59:05,774 --> 06:59:10,812
TECHNIQUES BUT IT'S TILL

9755
06:59:10,812 --> 06:59:11,112
CHALLENGING.

9756
06:59:11,112 --> 06:59:11,413
NTHANK YOU.

9757
06:59:11,413 --> 06:59:12,714
ANY COMMENTS OR QUESTIONS FROM

9758
06:59:12,714 --> 06:59:17,519
THE FLOOR, FOR OUR PANEL?

9759
06:59:17,519 --> 06:59:18,286
>> QUICK COMMENT.

9760
06:59:18,286 --> 06:59:20,255
IS THIS ON.

9761
06:59:20,255 --> 06:59:20,522
>> YES.

9762
06:59:20,522 --> 06:59:22,857
>> I DO THINK THE ANIMAL
MODELS

9763
06:59:22,857 --> 06:59:24,826
CAN BE USEFUL FOR HELPING US

9764
06:59:24,826 --> 06:59:26,194
UNDERSTAND WHAT'S HAPPENING WITH

9765
06:59:26,194 --> 06:59:26,695
ARIA E.

9766
06:59:26,695 --> 06:59:28,997
WHEN PATIENTS WHO ARE TREATED

9767
06:59:28,997 --> 06:59:32,334
WITH THE ANTIBODIES DEVELOP ARIA

9768
06:59:32,334 --> 06:59:33,702
E, THAT I HAVE TAKEN OFF THE

9769
06:59:33,702 --> 06:59:34,869
ANTIBODY AND THE LESION IF YOU

9770
06:59:34,869 --> 06:59:36,605
CALL IT THAT SLOWLY RESOLVES THE

9771
06:59:36,605 --> 06:59:38,773
WATER GOES AWAY BUT WE REALLY

9772
06:59:38,773 --> 06:59:40,075
DON'T KNOW WHAT THE LONG-TERM

9773
06:59:40,075 --> 06:59:41,409
EFFECTS OF THE CELLULAR LEVEL

9774
06:59:41,409 --> 06:59:44,879
ARE AND I THINK ANIMAL MODELS

9775
06:59:44,879 --> 06:59:46,581
MIGHT BE ABLE TO GET US TO A

9776
06:59:46,581 --> 06:59:48,516
REALTIME VIEW OF WHAT'S

9777
06:59:48,516 --> 06:59:49,851
HAPPENING PATHOLOGICALLY IN THE

9778
06:59:49,851 --> 06:59:54,556
AREA OF OUR ARIA E AND HOW LONG

9779
06:59:54,556 --> 06:59:55,357
IT LASTS THEREAFTER.

9780
06:59:55,357 --> 06:59:57,826
I AGREE WITH THAT BUT I WOULD

9781
06:59:57,826 --> 06:59:59,828
JUST REITERATE I THINK KNOWING

9782
06:59:59,828 --> 07:00:00,829
THE COGNITIVE OUTCOMES IN THOSE

9783
07:00:00,829 --> 07:00:02,030
PATIENTS AND HOW THEY'RE

9784
07:00:02,030 --> 07:00:02,964
DIFFERENT WOULD BE REALLY

9785
07:00:02,964 --> 07:00:04,499
IMPORTANT IN TERMS OF

9786
07:00:04,499 --> 07:00:05,133
UNDERSTANDING THE CLINICAL

9787
07:00:05,133 --> 07:00:08,303
SIGNIFICANCE TO THE PATIENT.

9788
07:00:08,303 --> 07:00:09,371
WOP QUESTION FOR YAWN, 1

9789
07:00:09,371 --> 07:00:10,972
QUESTION FOR ALL OF YOU, THE

9790
07:00:10,972 --> 07:00:12,741
QUESTION FOR JON IS DID I

9791
07:00:12,741 --> 07:00:13,708
UNDERSTAND CORRECTLY HA IN

9792
07:00:13,708 --> 07:00:16,878
FUTURE TRIALS YOU ARE LOOKING TO

9793
07:00:16,878 --> 07:00:19,514
HAVE 2 SETS OF CRITERIA, 1 FOR

9794
07:00:19,514 --> 07:00:21,249
BREATHER WHICH MAY BE THE DUMBED

9795
07:00:21,249 --> 07:00:22,851
DOWN VERSION BECAUSE IT'S

9796
07:00:22,851 --> 07:00:24,085
CONSISTENT WITH THE TRIALS DONE

9797
07:00:24,085 --> 07:00:25,720
IN THE PAST BUT MAYBE ANOTHER IN

9798
07:00:25,720 --> 07:00:30,091
THAT SAME TRIAL FOR CLINICAL

9799
07:00:30,091 --> 07:00:33,795
MONITORING THAT MAY HAVE USED

9800
07:00:33,795 --> 07:00:36,865
SWI AND MORE ADVANCED TECHNIQUES

9801
07:00:36,865 --> 07:00:38,099
IN DEVELOPMENT NYEAH, SO IN THAT

9802
07:00:38,099 --> 07:00:40,635
STUDY WE'RE LOOKING AT BOTH A

9803
07:00:40,635 --> 07:00:42,370
RISK PREDICTER, CAN WE DO A

9804
07:00:42,370 --> 07:00:44,806
BETTER AT RISK PREDIC, AND CAN

9805
07:00:44,806 --> 07:00:46,708
WE DO BETTER MONITORING, SO BOTH

9806
07:00:46,708 --> 07:00:48,843
OF THOSE VARY SO WE'RE ALSO

9807
07:00:48,843 --> 07:00:49,878
DOING LONGITUDINAL, WE'RE DOING

9808
07:00:49,878 --> 07:00:52,847
SOME OF THOSE SEQUENCES, ALSO

9809
07:00:52,847 --> 07:00:54,883
LONGITUDINALLY TO PROVIDE ANY

9810
07:00:54,883 --> 07:00:56,151
INFORMATION FROM A--FROM A

9811
07:00:56,151 --> 07:00:57,585
MONITORING PERSPECTIVE AS WELL,

9812
07:00:57,585 --> 07:00:58,753
FOR INITANCE DO THEY SEE

9813
07:00:58,753 --> 07:01:00,889
SOMETHING EARLIER THAN THE OLD

9814
07:01:00,889 --> 07:01:01,489
TRADITIONAL MODELS, MREFRESH

9815
07:01:01,489 --> 07:01:02,524
YOUR RECOLLECTION I SEQUENCES

9816
07:01:02,524 --> 07:01:04,526
DO, AND IF YOU WOULD NOTE--IF

9817
07:01:04,526 --> 07:01:08,229
YOU KNEW THAT WOULD YOU BE ABLE

9818
07:01:08,229 --> 07:01:10,432
TO SAY STOP DOSING OR GIVING

9819
07:01:10,432 --> 07:01:11,633
TERROIDS SORE SOMETHING LIKE

9820
07:01:11,633 --> 07:01:11,933
THAT.

9821
07:01:11,933 --> 07:01:13,968
THOSE WILL BE THE ASSPEBTS NTHE

9822
07:01:13,968 --> 07:01:15,403
COROLLARY TO THAT THIS ISN'T THE

9823
07:01:15,403 --> 07:01:17,439
SECOND QUESTION, THROUGHOUT ALL

9824
07:01:17,439 --> 07:01:18,440
OF MEDICINE, CARDIOVASCULAR

9825
07:01:18,440 --> 07:01:19,708
OTHER STUFF, RISK STRATIFICATION

9826
07:01:19,708 --> 07:01:26,614
IS THE KEY WHETHER IT'S ICD

9827
07:01:26,614 --> 07:01:28,183
DEFRIB ILLEGALS 8ORS OR DRUGS ON

9828
07:01:28,183 --> 07:01:29,918
OR SOMETHING FOR HEART FAILURE

9829
07:01:29,918 --> 07:01:32,087
IT'S RISK STRATEGIC PLANISK,

9830
07:01:32,087 --> 07:01:32,921
IT'S INTERESTING YOU JUST SAID

9831
07:01:32,921 --> 07:01:34,022
SOMETHING THAT WE WILL NOT BE

9832
07:01:34,022 --> 07:01:35,724
ABLE TO DO THAT IN BLOOD TESTS

9833
07:01:35,724 --> 07:01:36,925
NECESSARILY BECAUSE IT BEING BE

9834
07:01:36,925 --> 07:01:38,126
A PREDICTER WHICH WOULD BE

9835
07:01:38,126 --> 07:01:40,795
IDEAL, YOU KNOW IN ADVANCE, YOU

9836
07:01:40,795 --> 07:01:43,331
MAY NOT KNOW UNTIL YOU GET--YOU

9837
07:01:43,331 --> 07:01:45,100
TREAT AND THEN GET A RESPONSE

9838
07:01:45,100 --> 07:01:46,735
AND IT IS THE RESPONSE THAT

9839
07:01:46,735 --> 07:01:48,436
MIGHT ACTUALLY BE MORE VALUABLE

9840
07:01:48,436 --> 07:01:51,439
FOR YOUR RISK STRATIFICATION

9841
07:01:51,439 --> 07:01:53,608
THAN ANYTHING YOU COULD PREDICT.

9842
07:01:53,608 --> 07:01:54,309
IS THAT ACCURATE.

9843
07:01:54,309 --> 07:01:56,411
IS THAT WHAT YOU'RE SAYING, OR

9844
07:01:56,411 --> 07:01:58,480
SUGGESTING THAT MAY BE THE CASE?

9845
07:01:58,480 --> 07:02:00,582
>> I HOLD THAT OUT AS A

9846
07:02:00,582 --> 07:02:01,616
HYPOTHESIS THAT YOU MIGHT BE

9847
07:02:01,616 --> 07:02:02,884
ABLE TO PREDICT A LITTLE BIT

9848
07:02:02,884 --> 07:02:04,919
BETTER ON WHO WILL HAVE A BAD

9849
07:02:04,919 --> 07:02:06,254
RESPONSE ACTUALLY AFTER DOSING.

9850
07:02:06,254 --> 07:02:08,556
SO LOOKING AT THE RESPONSE

9851
07:02:08,556 --> 07:02:11,459
ELEMENTS THAT YOU MIGHT SEE IN

9852
07:02:11,459 --> 07:02:13,294
THE BLOOD.

9853
07:02:13,294 --> 07:02:14,863
SO PICK YOUR FAVORITE

9854
07:02:14,863 --> 07:02:15,730
INFLAMMATORY TARGET, RIGHT IN

9855
07:02:15,730 --> 07:02:17,065
LOOK AT A WHOLE PANEL THERE AND

9856
07:02:17,065 --> 07:02:19,300
SEE IF SOMEONE HAS A HIGH

9857
07:02:19,300 --> 07:02:20,535
INTERLEUKIN 1 ARE THEY THE 1S

9858
07:02:20,535 --> 07:02:25,106
MORE LIKELY TO GO ON AND HAVE A

9859
07:02:25,106 --> 07:02:25,740
SUPER ARIA OR SOMETHING LIKE

9860
07:02:25,740 --> 07:02:27,709
THAT, WE WANT TO IDENTIFY FIRST

9861
07:02:27,709 --> 07:02:29,310
BEFORE WE EVEN DOSE IT BUT IF WE

9862
07:02:29,310 --> 07:02:30,945
CAN'T DO IT THEN CAN WE FIND

9863
07:02:30,945 --> 07:02:33,214
SOMETHING THAT AFTER DOSING

9864
07:02:33,214 --> 07:02:39,287
MIGHT ACTUALLY HELP BECAUSE WE

9865
07:02:39,287 --> 07:02:40,922
KNOW THAT GENERALLY WE'VE ALL

9866
07:02:40,922 --> 07:02:43,057
DISCUSSED THAT BUT IT'S NOT

9867
07:02:43,057 --> 07:02:45,360
AFTER FIRST DONE IT'S USUALLY

9868
07:02:45,360 --> 07:02:47,228
BETWEEN FIRST AND SIXTH DOSE, SO

9869
07:02:47,228 --> 07:02:48,663
IT DOES SUGGIEST THAT AFTER THE

9870
07:02:48,663 --> 07:02:50,632
FIRST DOSE MAYBE WE HAVE ANOTHER

9871
07:02:50,632 --> 07:02:52,333
WINDOW OF OPPORTUNITY TO

9872
07:02:52,333 --> 07:02:53,935
INTERVENE HERE.

9873
07:02:53,935 --> 07:02:55,537
NYEAH, OTHER THAN MRIs,.

9874
07:02:55,537 --> 07:02:57,372
>> YEAH, SO--

9875
07:02:57,372 --> 07:02:58,139
>> SORRY, LAWRENCE WERE
YOU

9876
07:02:58,139 --> 07:02:58,907
GOING TO SAY SOMETHING.

9877
07:02:58,907 --> 07:03:01,409
>> I WAS GOING TO SAY THAT
WE

9878
07:03:01,409 --> 07:03:03,244
ALREADY HAVE THE YIEBT RISK

9879
07:03:03,244 --> 07:03:06,347
FACTOR THERE WHICH IS AMYLOID

9880
07:03:06,347 --> 07:03:10,118
ANGIE OPERATING GLOBALLYATHY AS

9881
07:03:10,118 --> 07:03:12,454
MANIFESTED RADIOLOGICALLY BY

9882
07:03:12,454 --> 07:03:19,160
MICROHEME ANDS APOE 4  4 STATUSO

9883
07:03:19,160 --> 07:03:22,630
IT'S 10 TIMES HIGHER RATE OF

9884
07:03:22,630 --> 07:03:26,868
SYMPTOMATIC ARIA E IN PATES WITH

9885
07:03:26,868 --> 07:03:28,636
APOE FOR HOMOSIGNIFY GOSSITY FOR

9886
07:03:28,636 --> 07:03:29,904
WE ALREADY ARE A GIANT RISK

9887
07:03:29,904 --> 07:03:33,408
FACTOR THERE, AND YOU KNOW OF

9888
07:03:33,408 --> 07:03:34,242
COURSE, THAT DOESN'T EFFECT MANY

9889
07:03:34,242 --> 07:03:35,510
PEOPLE FROM ENTERING A DRUG

9890
07:03:35,510 --> 07:03:37,579
TREATMENT RIGHT NOW, AT LEAST 1

9891
07:03:37,579 --> 07:03:40,415
OF THE 3 DRUGS IS WIDELY

9892
07:03:40,415 --> 07:03:43,117
AVAILABLE AND THE OTHER IS

9893
07:03:43,117 --> 07:03:47,322
RELATIVELY AVAILABLE, BOTH FDA

9894
07:03:47,322 --> 07:03:48,756
APPROVED, SO YOU KNOW A LOT OF

9895
07:03:48,756 --> 07:03:52,227
PEOPLE, A LOT OF MY PATIENTS

9896
07:03:52,227 --> 07:03:53,862
PUTTING ON MY CLINICIAN FLASESS

9897
07:03:53,862 --> 07:03:55,997
A LOT OF MY PATIENTS ARE

9898
07:03:55,997 --> 07:03:57,966
PERFECTLY HAPPY TO ENTER A TRIAL

9899
07:03:57,966 --> 07:03:59,601
WHERE THEY HAVE 10 TIMES HIGHER

9900
07:03:59,601 --> 07:04:01,202
RISK OF HAVING ARIA E THAN

9901
07:04:01,202 --> 07:04:03,037
SOMEONE WHO HAS A DIFFERENT GENO

9902
07:04:03,037 --> 07:04:03,438
TYPE FROM THEM.

9903
07:04:03,438 --> 07:04:04,939
THE OTHER WAY TO LOOK AT THAT IS

9904
07:04:04,939 --> 07:04:08,009
IF THEY HAVE A FINISH% CHANCE OF

9905
07:04:08,009 --> 07:04:10,612
NOT HAVING SYMPTOMATIC ARIA E,

9906
07:04:10,612 --> 07:04:12,981
VERSUS A 90% CHANCE OF HAVING

9907
07:04:12,981 --> 07:04:15,250
ARIA E, WHEN YOU FLIP IT SO 90%

9908
07:04:15,250 --> 07:04:17,151
SOUNDS PRETTY GOOD FOR PEOPLE

9909
07:04:17,151 --> 07:04:19,654
AND 90% CHANCE OF NOT HAVING

9910
07:04:19,654 --> 07:04:20,722
SYMPTOMATIC ARIA E.

9911
07:04:20,722 --> 07:04:20,989
NWELL PUT.

9912
07:04:20,989 --> 07:04:25,026
THE QUESTION FOR ALL OF YOU IS: 

9913
07:04:25,026 --> 07:04:30,632
WHAT IS SIGNIFICANT ARIA TODAY

9914
07:04:30,632 --> 07:04:32,600
AT WHATEVER TIME IT IS BECAUSE

9915
07:04:32,600 --> 07:04:33,635
IT KEEPS CHANGING.

9916
07:04:33,635 --> 07:04:38,006
IS IT SYMPTOMATIC ARIA AND

9917
07:04:38,006 --> 07:04:39,707
MACROHEMORRHAGES WITH THE CAVEAT

9918
07:04:39,707 --> 07:04:42,377
THAT MAYBE THIS IS JUST EVIDENT

9919
07:04:42,377 --> 07:04:44,746
THAT THE DRUG IS ACTUALLY

9920
07:04:44,746 --> 07:04:45,013
WORKING?

9921
07:04:45,013 --> 07:04:48,783
REMEMBER WHEN YOU GOT YOUR COVID

9922
07:04:48,783 --> 07:04:48,983
SHOT?

9923
07:04:48,983 --> 07:04:49,617
SOMETHING EVERYONE IS FAMILIAR

9924
07:04:49,617 --> 07:04:51,286
WITH AND YOU WERE REALLY, YOU

9925
07:04:51,286 --> 07:04:52,754
WERE DOWN FOR 12 HOURS, SOMEONE

9926
07:04:52,754 --> 07:04:55,290
ELSE MIGHT HAVE BEEN DOWN FOR 2

9927
07:04:55,290 --> 07:04:56,658
HOURS, ACTUALLY THE PEOPLE WHO

9928
07:04:56,658 --> 07:04:59,327
ARE DOWN FOR 12 HOURS MIGHT HAVE

9929
07:04:59,327 --> 07:05:00,361
ACTUALLY, THAT MIGHT HAVE BEEN A

9930
07:05:00,361 --> 07:05:02,964
GOOD SIGN, THIS WILL PROTECT ME

9931
07:05:02,964 --> 07:05:03,731
BETTER, IT'S SOMING THAT

9932
07:05:03,731 --> 07:05:05,400
EVERYONE CAN UNDERSTAND IN THAT

9933
07:05:05,400 --> 07:05:05,633
RESPECT.

9934
07:05:05,633 --> 07:05:07,802
SO WITH THE CAVEAT THAT MAYBE

9935
07:05:07,802 --> 07:05:09,137
IT'S A GOOD THING, MAYBE IT'S A

9936
07:05:09,137 --> 07:05:11,506
BAD THING, WE DON'T REALLY KNOW,

9937
07:05:11,506 --> 07:05:12,073
WHAT IS SIGNIFICANT ARIA.

9938
07:05:12,073 --> 07:05:18,513
NETWORK I LOVE THAT QUESTION.

9939
07:05:18,513 --> 07:05:19,881
>> I THINK RIGHT NOW WE
DON'T

9940
07:05:19,881 --> 07:05:21,416
KNOW UNTIL WE KNOW HOW IT

9941
07:05:21,416 --> 07:05:23,518
AFFECTS LONGER TERM OUTCOMES BUT

9942
07:05:23,518 --> 07:05:24,686
IT'S PRETTY OUTCOME THAT A GIANT

9943
07:05:24,686 --> 07:05:26,854
PLEAD IN THE BRAIN IS A BAD

9944
07:05:26,854 --> 07:05:28,823
THING OR DYING OF BRAIN EDEMA

9945
07:05:28,823 --> 07:05:31,693
HAS HAS HAPPENED IN THE ACTIVE

9946
07:05:31,693 --> 07:05:33,761
YOU HAD MACHINIZATION TRIALS NI

9947
07:05:33,761 --> 07:05:34,862
WOULD LIKE TO MAKE A COMMENT

9948
07:05:34,862 --> 07:05:39,601
ABOUT ANSWER THAT QUESTION.

9949
07:05:39,601 --> 07:05:42,003
SO I THINK THE MAIN ISSUE THAT

9950
07:05:42,003 --> 07:05:45,173
KAREN RAISED EARLIER IS ARIA IS

9951
07:05:45,173 --> 07:05:46,574
RELATIVELY COMMON, SOME MORE SO

9952
07:05:46,574 --> 07:05:52,013
WITH DRUGS THAN OTHERS, USUALLY

9953
07:05:52,013 --> 07:05:54,349
REVERSIBLE, USUALLY ATOSM

9954
07:05:54,349 --> 07:05:55,817
TOMATIC AND USUALLY QUITE

9955
07:05:55,817 --> 07:05:57,819
MANAGEABLE SO MARION FOR THOSE

9956
07:05:57,819 --> 07:05:59,187
PATIENTS IT'S OKAY AS LONG AS WE

9957
07:05:59,187 --> 07:06:01,923
KEEP A GOOD EYE ON THEM AND

9958
07:06:01,923 --> 07:06:03,191
MONITOR THEM.

9959
07:06:03,191 --> 07:06:04,025
UNFORTUNATELY THERE'S A GROUP OF

9960
07:06:04,025 --> 07:06:06,194
PATIENTS THAT HAVE A MERE SEVERE

9961
07:06:06,194 --> 07:06:07,095
INFLAMMATORY TYPE REACTION WHICH

9962
07:06:07,095 --> 07:06:09,964
CAN BE VERY HARD TO TREEPT AND

9963
07:06:09,964 --> 07:06:10,164
FATAL.

9964
07:06:10,164 --> 07:06:12,233
AND THERE HAVE BEEN FATALITIES

9965
07:06:12,233 --> 07:06:14,135
AND IF WE'RE NOT CAREFUL THERE

9966
07:06:14,135 --> 07:06:15,503
WILL BE MORE FATALITIES.

9967
07:06:15,503 --> 07:06:16,938
I WILL BE TALKING MORE ABOUT

9968
07:06:16,938 --> 07:06:18,539
THAT TOMORROW, HOW TO IDENTIFY

9969
07:06:18,539 --> 07:06:20,541
THOSE PATIENTS AND USE GOOD

9970
07:06:20,541 --> 07:06:24,545
CLENICAL JUDGMENT TO TRY ARK

9971
07:06:24,545 --> 07:06:26,381
VOID THOSE MORE SERIOUS

9972
07:06:26,381 --> 07:06:27,348
OUTCOMES.

9973
07:06:27,348 --> 07:06:30,018
SO WHAT'S SERIOUS--SORRY, SO

9974
07:06:30,018 --> 07:06:33,187
WHAT'S SERIOUS IS WE WANT TO

9975
07:06:33,187 --> 07:06:34,689
AVOID OBVIOUSLY DISABILITY OR

9976
07:06:34,689 --> 07:06:36,924
DEATH, THAT'S SERIOUS.

9977
07:06:36,924 --> 07:06:39,661
THE OTHER 1S WITH CAREFUL MANAGE

9978
07:06:39,661 --> 07:06:41,262
AM ARE CLINICALLY MANAGEABLE AND

9979
07:06:41,262 --> 07:06:43,431
ARE NOT, THEY COULD BE

9980
07:06:43,431 --> 07:06:45,366
TEMPORARILY SERIOUS BUT THEY'RE

9981
07:06:45,366 --> 07:06:51,072
NOT DISABLING OR PERMANENT.

9982
07:06:51,072 --> 07:06:52,874
>> YEAH, AND I AGREE WITH
YOU.

9983
07:06:52,874 --> 07:06:54,409
THE SERIOUS 1S THAT WORRIED ME

9984
07:06:54,409 --> 07:06:56,878
THE MOST AND THEY'RE THE HARDEST

9985
07:06:56,878 --> 07:06:59,213
1S ACTUALLY BECAUSE FIRST OF ALL

9986
07:06:59,213 --> 07:07:01,716
THEY'RE THE LEAST OCCURRING SO

9987
07:07:01,716 --> 07:07:03,051
THAT MAKES THEM ALSO REALLY

9988
07:07:03,051 --> 07:07:05,253
DIFFICULT TO PREDICT BUT THERE

9989
07:07:05,253 --> 07:07:07,855
IS SOME--THERE IS DEFINITELY

9990
07:07:07,855 --> 07:07:10,792
DISCONNECT BETWEEN THE OVERALL

9991
07:07:10,792 --> 07:07:13,261
RISK OF ARIA, WHICH IS THE

9992
07:07:13,261 --> 07:07:14,696
HETEROZYGOUS TO THE NONCARRIERS

9993
07:07:14,696 --> 07:07:15,430
GENERALLY SPEAKING ABOUT YOU

9994
07:07:15,430 --> 07:07:17,832
WHEN WE LOOK AT SERIOUS ARIA IT

9995
07:07:17,832 --> 07:07:19,033
DOESN'T HAVE EXACTLY THE SAME

9996
07:07:19,033 --> 07:07:19,567
PATTERN.

9997
07:07:19,567 --> 07:07:21,536
IT IS MORE EVENTUALLY

9998
07:07:21,536 --> 07:07:22,303
DISTRIBUTED ACROSS THESE WHICH

9999
07:07:22,303 --> 07:07:25,540
IS IT'S A HIGHER IN THE

10000
07:07:25,540 --> 07:07:28,409
HOMOZYGOUS, BUT FOR SOME REASON

10001
07:07:28,409 --> 07:07:31,713
THE NONCARRIERS BECOME WHAT I

10002
07:07:31,713 --> 07:07:32,413
CALL OVERREPRESENTED IN THIS

10003
07:07:32,413 --> 07:07:35,016
AREA AND I DON'T KNOW WHAT'S

10004
07:07:35,016 --> 07:07:35,683
DRIVING THAT.

10005
07:07:35,683 --> 07:07:37,552
THAT'S THE 1 THING THAT WILL BE

10006
07:07:37,552 --> 07:07:39,454
NICE TO HAVE THAT PREDICTER THAT

10007
07:07:39,454 --> 07:07:49,997
WE DON'T YET HAVE FOR SOME OF

10008
07:07:49,997 --> 07:07:50,198
THEM.

10009
07:07:50,198 --> 07:07:55,303
>> AND WHAT WE SEE ARE THE
CAR

10010
07:07:55,303 --> 07:07:56,270
TISSUING CELLS DESIGNED FOR

10011
07:07:56,270 --> 07:07:57,305
CANCER AND WE SEE A LOT OF SIDE

10012
07:07:57,305 --> 07:07:58,272
CENTER FOR EXCELLENCE ON AGINGS

10013
07:07:58,272 --> 07:08:00,808
FROM THAT AND LOOKING AT IMAGE

10014
07:08:00,808 --> 07:08:01,976
ABNORMALITIES WHICH IS ANOTHER

10015
07:08:01,976 --> 07:08:02,510
IMMUNO THR ACTIVITIES AND

10016
07:08:02,510 --> 07:08:03,778
PROJECTSY EMPLOY NETWORK I AM

10017
07:08:03,778 --> 07:08:05,813
FROM NETWORK YRK U EMPLOY I HAVE

10018
07:08:05,813 --> 07:08:09,183
A FEW COMEBTS ON NONHUMAN

10019
07:08:09,183 --> 07:08:10,952
PRIMATES MODEL CITIZEN MODEL SO

10020
07:08:10,952 --> 07:08:12,687
DR. WALKER THANK YOU FOR YOUR

10021
07:08:12,687 --> 07:08:15,757
TALK, AND WE KAN--KANA OVER 30

10022
07:08:15,757 --> 07:08:19,227
ANIMALS WE SERVED THE LESIONS

10023
07:08:19,227 --> 07:08:21,195
MOSTLY, LESS ARIA H, MAYBE IN 8

10024
07:08:21,195 --> 07:08:22,330
OR NIEP ANIMALS.

10025
07:08:22,330 --> 07:08:26,234
WE WERE LUCKY WE ARE ABLE TO

10026
07:08:26,234 --> 07:08:27,568
HISTOLOGICALLY EVALUATE THE

10027
07:08:27,568 --> 07:08:29,737
LESION NOW AND 1 OR 2 MONTHS

10028
07:08:29,737 --> 07:08:30,338
AFTER IMAGING AFTER MREFRESH

10029
07:08:30,338 --> 07:08:32,874
YOUR RECOLLECTION I SCANS, SO,

10030
07:08:32,874 --> 07:08:34,575
HOPEFULLY WE CAN ADDRESS SOME OF

10031
07:08:34,575 --> 07:08:37,545
THOSE QUESTIONS, IS IT

10032
07:08:37,545 --> 07:08:40,581
INFLAMMATION, EDEMA OR BOTH?

10033
07:08:40,581 --> 07:08:42,817
OR DIFFERENT TYPE OF OR IN

10034
07:08:42,817 --> 07:08:44,552
MACROFAINLS IN WHAT DO WE SEE IN

10035
07:08:44,552 --> 07:08:46,053
WHAT IS THE UNDERLYING PATHOLOGY

10036
07:08:46,053 --> 07:08:48,623
IN THAT WAS A COHORT, WE HAVE A

10037
07:08:48,623 --> 07:08:51,592
NEW STUDY WE HOPE TO EVALUATE

10038
07:08:51,592 --> 07:08:53,528
CONSEQUENCES OF ARIA IN MONKEY

10039
07:08:53,528 --> 07:08:55,563
FOR LONGER IN OBSERVE ARIA ANDEE

10040
07:08:55,563 --> 07:08:58,399
IF IT'S TRANSIENT OR IF IT'S

10041
07:08:58,399 --> 07:08:59,801
PROGRESSING.

10042
07:08:59,801 --> 07:09:01,135
WE'VE DONE ALSO IMMUNOTHERAPY

10043
07:09:01,135 --> 07:09:03,938
BUT NOT ACTIVE OR PASSIVE INNATE

10044
07:09:03,938 --> 07:09:04,205
IMMUNITY.

10045
07:09:04,205 --> 07:09:07,341
WE PUBLISHED PAPER WHERE WE

10046
07:09:07,341 --> 07:09:09,210
REDUCED OUR IMMUNOTHERAPY

10047
07:09:09,210 --> 07:09:11,212
REDUCED PATHOLOGY WITHOUT

10048
07:09:11,212 --> 07:09:13,014
INCREASING HEMORRHAGES, WE

10049
07:09:13,014 --> 07:09:14,916
SIMPLY PUBLISHED THAT PAPER SO I

10050
07:09:14,916 --> 07:09:16,450
THINK SQUIRREL MONKEY IS A GREAT

10051
07:09:16,450 --> 07:09:16,717
MODEL.

10052
07:09:16,717 --> 07:09:19,320
I DON'T KNOW MUCH ABOUT

10053
07:09:19,320 --> 07:09:20,721
MARMOSETS BUT I WILL LOOK INTO

10054
07:09:20,721 --> 07:09:26,060
IT AS WELL NTHANK YOU.

10055
07:09:26,060 --> 07:09:26,961
>> THANK YOU.

10056
07:09:26,961 --> 07:09:29,497
>> HI, THIS IS TERESA WITH
THE

10057
07:09:29,497 --> 07:09:31,699
FDA, I HAVE QUESTION ABOUT THE

10058
07:09:31,699 --> 07:09:33,868
DOSING REGIMENS AND TITRATION

10059
07:09:33,868 --> 07:09:36,571
WITH RISK OF ARIA, I KNOW FROM

10060
07:09:36,571 --> 07:09:38,105
DOSE RANGING STUDIES THAT I'VE

10061
07:09:38,105 --> 07:09:40,274
SEEN THAT THERE ARE LOWER RATES

10062
07:09:40,274 --> 07:09:43,244
OF ARIA SEEN USUALLY AT LOWER

10063
07:09:43,244 --> 07:09:45,546
DOSES, BUT THEN I DON'T KNOW HOW

10064
07:09:45,546 --> 07:09:47,882
THAT TRANSLATES, I THINK REISA

10065
07:09:47,882 --> 07:09:49,050
MADE A COMMENT EARLIER THAT ONCE

10066
07:09:49,050 --> 07:09:51,185
YOU GO UP, THE RISK INCREASES AS

10067
07:09:51,185 --> 07:09:53,087
YOU TITRATE UP BUT I HAVE BEEN

10068
07:09:53,087 --> 07:09:54,222
WONDER FIGURE THERE'S MORE WE

10069
07:09:54,222 --> 07:09:57,391
CAN DO WITH THOSE EXPLORATION

10070
07:09:57,391 --> 07:09:59,160
TITRATION EXPLORATION AND

10071
07:09:59,160 --> 07:10:03,464
CONSIDERING ALTERNATE DOSING

10072
07:10:03,464 --> 07:10:03,831
REGIMENS.

10073
07:10:03,831 --> 07:10:06,067
NI COULDN'T AGREE MORE.

10074
07:10:06,067 --> 07:10:07,568
SO WHEN YOU THINK ABOUT

10075
07:10:07,568 --> 07:10:09,971
TITRATION IT BECOMES A SUPER

10076
07:10:09,971 --> 07:10:17,011
COMPLICATED PROBLEM TO SOLVE FOR

10077
07:10:17,011 --> 07:10:18,679
BECAUSE THERE ARE ALMOST

10078
07:10:18,679 --> 07:10:19,580
INFINITE NUMBER OF VALID AND

10079
07:10:19,580 --> 07:10:21,082
RELIABLE YAIGS THERE TO TEST.

10080
07:10:21,082 --> 07:10:23,451
SO WHAT WE APPRECIATE IS FOR

10081
07:10:23,451 --> 07:10:26,153
MOST MOLECULES MOTE DRUG USUALLY

10082
07:10:26,153 --> 07:10:30,825
EQUALS MORE ARIA, FOR ITS

10083
07:10:30,825 --> 07:10:31,826
PARTICULAR PROFILE AND USUALLY

10084
07:10:31,826 --> 07:10:33,694
PROBABLY ALSO MORE AMYLOID

10085
07:10:33,694 --> 07:10:35,429
REMOVAL SO THOSE 2 THINS SEEM TO

10086
07:10:35,429 --> 07:10:36,731
KIND OF MOVE TOGETHER.

10087
07:10:36,731 --> 07:10:38,699
THE REAL QUESTION IS CAN WE

10088
07:10:38,699 --> 07:10:40,668
UNCOUPLE, CAN WE EVER UNCOUPLE

10089
07:10:40,668 --> 07:10:42,503
THIS MOVE AM, RIGHT IN SO I

10090
07:10:42,503 --> 07:10:43,905
THINK WE'VE HEARD 1 HYPOTHESIS

10091
07:10:43,905 --> 07:10:47,108
THAT MAY BE C-MAX IS A WAY TO

10092
07:10:47,108 --> 07:10:47,575
UNCOUPLE HERE.

10093
07:10:47,575 --> 07:10:50,945
SO I THINK WE'RE GOING TO TEST

10094
07:10:50,945 --> 07:10:52,847
THAT QUITE ROBUSTLY IN THAT

10095
07:10:52,847 --> 07:10:54,849
TRAIL BLAZER 6 STUDY, WE WILL

10096
07:10:54,849 --> 07:10:56,083
CONTROL EVERYTHING, EVERYONE'S

10097
07:10:56,083 --> 07:10:57,685
RANDOMIZED AND CONTROLS AND

10098
07:10:57,685 --> 07:10:59,120
WE'LL CONTROL THE CMAX VERSUS

10099
07:10:59,120 --> 07:11:02,323
AUC AND SEE IF THAT REALLY DOES

10100
07:11:02,323 --> 07:11:04,492
BEAR OUT BECAUSE APPROXIMATE IT

10101
07:11:04,492 --> 07:11:05,893
DOES, THAT'S A REALLY TRACTABLE

10102
07:11:05,893 --> 07:11:08,262
PROBLEM WE CAN BRING TO

10103
07:11:08,262 --> 07:11:08,896
PATIENTS.

10104
07:11:08,896 --> 07:11:11,365
I THINK UNDERSTANDING ALL THE

10105
07:11:11,365 --> 07:11:13,467
DOSING AND VARIATIONS THAT 1 CAN

10106
07:11:13,467 --> 07:11:18,539
DO IS A REAL HARD AND BECOMES

10107
07:11:18,539 --> 07:11:19,640
VERY UNTRACTABLE PROBLEM IF YOU

10108
07:11:19,640 --> 07:11:21,542
THINK ABOUT THE POSSIBLE

10109
07:11:21,542 --> 07:11:23,244
TITRATION KEEMS THAT 1 CAN DO

10110
07:11:23,244 --> 07:11:24,345
AND SO, I THINK WE'RE JUST GOING

10111
07:11:24,345 --> 07:11:26,380
TO HAVE TO KIND OF TRY TO DO IT

10112
07:11:26,380 --> 07:11:28,816
AS PRACTICALLY AS WE CAN AND WE

10113
07:11:28,816 --> 07:11:30,184
HAVE MANAGE THAT WORKS CAN WE

10114
07:11:30,184 --> 07:11:31,252
FIND SOMETHING THAT WORKS

10115
07:11:31,252 --> 07:11:32,787
BETTER, I THINK WE SHOULD

10116
07:11:32,787 --> 07:11:35,656
CONTINUE TO EXPLORE THAT.

10117
07:11:35,656 --> 07:11:39,327
>> RIGHT, YEAH, I THINK IT
IS

10118
07:11:39,327 --> 07:11:40,561
CHALLENGING SINCE THE RATES OF

10119
07:11:40,561 --> 07:11:42,997
ARIA SEEM TO TRACK WITH AMYLOID

10120
07:11:42,997 --> 07:11:44,565
REDUCTION BEING YOU HAVE TO FIND

10121
07:11:44,565 --> 07:11:45,633
THAT BALANCE OF WHAT ARE YOU

10122
07:11:45,633 --> 07:11:48,336
WILLING TO ACCEPT FOR ARRAIA

10123
07:11:48,336 --> 07:11:50,137
INCIDENCE VERSUS POTENTIALLY

10124
07:11:50,137 --> 07:11:51,305
DISCIPLINARY LAKING BENEFIT FOR

10125
07:11:51,305 --> 07:11:53,274
BY USING LOWER DOSE.

10126
07:11:53,274 --> 07:11:54,241
>> RIGHT AWAY I WOULD LIKE
TO

10127
07:11:54,241 --> 07:11:55,710
COME BACK TO BE THAT BECAUSE

10128
07:11:55,710 --> 07:11:57,845
THERE ARE OTHER THINGS FROM AN

10129
07:11:57,845 --> 07:11:59,947
ANIMAL MODEL AND HUMANS THAT ARE

10130
07:11:59,947 --> 07:12:00,548
WORTHY OF KIND EXPECTATIONS

10131
07:12:00,548 --> 07:12:01,615
MORING IN THAT AREA.

10132
07:12:01,615 --> 07:12:03,150
NETWORK SO MAYBE SOMETHING WE

10133
07:12:03,150 --> 07:12:07,121
COULD TOUCH BASE TOMORROW WHEN

10134
07:12:07,121 --> 07:12:09,557
WE MAKE THE FINAL

10135
07:12:09,557 --> 07:12:11,125
RECOMMENDATIONS, SO VERY QUICK

10136
07:12:11,125 --> 07:12:11,726
QUESTION, QUICK ANSWER.

10137
07:12:11,726 --> 07:12:14,095
>>  ERROR QUICK QUESTION.

10138
07:12:14,095 --> 07:12:17,331
MA EVE, I HAVE QUESTION ALSO ON

10139
07:12:17,331 --> 07:12:19,867
NAIVE, THERE ARE PEOPLE WHO ARE

10140
07:12:19,867 --> 07:12:22,203
STARTING CLINICAL TRIAL WITH

10141
07:12:22,203 --> 07:12:26,173
ANTIA BETA [INDISCERNIBLE] COULD

10142
07:12:26,173 --> 07:12:27,441
YOU RECOMMEND SOME SOPs SO

10143
07:12:27,441 --> 07:12:31,779
PEOPLE CAN CHECK ARIA H AND E IN

10144
07:12:31,779 --> 07:12:33,381
EVERY WAY SIMULTANEOUSLY IN

10145
07:12:33,381 --> 07:12:37,351
COULD WE BE SURE THAT WE ARE

10146
07:12:37,351 --> 07:12:39,320
READING CORRECTLY WHEN I DON'T

10147
07:12:39,320 --> 07:12:40,554
UNDERSTAND AND THINKING ARIA, SO

10148
07:12:40,554 --> 07:12:43,190
DO YOU HAVE ANY TEAKNIQUE IN

10149
07:12:43,190 --> 07:12:44,625
WHICH 2 DIFFERENT PEOPLE IN

10150
07:12:44,625 --> 07:12:46,460
DIFFERENT COUNTRIES CAN LOOK FOR

10151
07:12:46,460 --> 07:12:49,063
YOUR MRI, AND SAY, YES THIS IS

10152
07:12:49,063 --> 07:12:52,133
ARIA H, THIS IS SEVERE, THIS IS

10153
07:12:52,133 --> 07:12:55,136
MILD, THIS MODERATE ?

10154
07:12:55,136 --> 07:12:58,072
AND THE SAME WITH ARIA E BECAUSE

10155
07:12:58,072 --> 07:13:02,410
I AM NOT SURE WE HAVE THAT.

10156
07:13:02,410 --> 07:13:04,745
IF YOU CAN HELP PEOPLE AND THEY

10157
07:13:04,745 --> 07:13:07,381
HAVE DEVELOPED SOP, IT MAY HELP

10158
07:13:07,381 --> 07:13:09,150
A LOT.

10159
07:13:09,150 --> 07:13:11,852
THAT'S MY QUESTION.

10160
07:13:11,852 --> 07:13:12,586
>> IT'S DEFINITELY--YOU
CAN GET

10161
07:13:12,586 --> 07:13:14,455
PEOPLE TO USE THE SIMILAR KIND

10162
07:13:14,455 --> 07:13:15,856
OF STALES,'RE SCALES THAT HAVE

10163
07:13:15,856 --> 07:13:18,025
BEEN USED OUT THERE AND THEY'RE

10164
07:13:18,025 --> 07:13:20,728
PRETTY TRAINABLE TO GET PEOPLE

10165
07:13:20,728 --> 07:13:23,097
TO HOPEFULLY CALL THE SEAM LEVEL

10166
07:13:23,097 --> 07:13:23,798
OF ARIA, ACROSS.

10167
07:13:23,798 --> 07:13:26,700
BUT IT DOES REQUIRE TEACHING

10168
07:13:26,700 --> 07:13:27,301
EDUCATION.

10169
07:13:27,301 --> 07:13:28,469
>> I AGREE THERE'S VARIOUS
KALE

10170
07:13:28,469 --> 07:13:32,173
ANDS WAYS OF RATING THEM OR

10171
07:13:32,173 --> 07:13:33,074
MICROHEMES ABOUT THOSE

10172
07:13:33,074 --> 07:13:34,675
TECHNIQUES BUT I WILL POINT OUT

10173
07:13:34,675 --> 07:13:36,043
IT DOESN'T MATTER THAT MUCH

10174
07:13:36,043 --> 07:13:38,813
BECAUSE WHETHER THE PEOPLE ARE

10175
07:13:38,813 --> 07:13:39,613
SYMPTOMATIC OR ASYMPTOMATIC AND

10176
07:13:39,613 --> 07:13:41,482
AS WE KNOW WITH MANY OF THESE

10177
07:13:41,482 --> 07:13:43,984
DRUG PEOPLE PEOPLE HAVE BEEN

10178
07:13:43,984 --> 07:13:45,853
DOSED THROUGH ARIA THROUGH MINOR

10179
07:13:45,853 --> 07:13:47,455
ARIA WITHOUT ANY ADVERSE

10180
07:13:47,455 --> 07:13:47,888
EFFECTS.

10181
07:13:47,888 --> 07:13:50,291
AND WITH RESOLUTION OF THAT ARIA

10182
07:13:50,291 --> 07:13:51,892
DESPITE CONTINUED PRESENCE OF

10183
07:13:51,892 --> 07:13:55,062
DRUG IN THEIR BLOOD STREAM AND

10184
07:13:55,062 --> 07:13:57,098
BRAIN EMPLOY SO I THINK WHEN

10185
07:13:57,098 --> 07:13:59,467
THEY GET LOST, MAKE SURE 1 SEES

10186
07:13:59,467 --> 07:14:01,635
THE FOREST AND NOT GET LOST IN

10187
07:14:01,635 --> 07:14:02,036
THE TREES.

10188
07:14:02,036 --> 07:14:04,505
IT'S TBRAIT TO BE ABLE TO

10189
07:14:04,505 --> 07:14:07,475
QUANTIFY THINGS, BUT QUANTISK

10190
07:14:07,475 --> 07:14:09,610
ISN'T ALWAYS EVERYTHING NOKAY,

10191
07:14:09,610 --> 07:14:10,945
SO, WE ARE OVER TIME BUT IF YOU

10192
07:14:10,945 --> 07:14:13,981
WANT TO MAKE A VERY QUICK PLEASE

10193
07:14:13,981 --> 07:14:21,489
DO AND THEN WE WILL INVITE TO

10194
07:14:21,489 --> 07:14:23,224
MAKE THE CLOSING REMARKS OF THE

10195
07:14:23,224 --> 07:14:25,793
DAY NAS MY REMARKS ARE

10196
07:14:25,793 --> 07:14:26,627
TANGENTIAL IT'S DAIRVELGEROUS

10197
07:14:26,627 --> 07:14:30,965
BUT I WAS COMBINING 1 OF MY

10198
07:14:30,965 --> 07:14:33,033
OTHER FEELS FROM EARLY IN MY

10199
07:14:33,033 --> 07:14:34,201
CAREER, I DEVELOPED VARIOUS

10200
07:14:34,201 --> 07:14:36,237
FORMS OF FOCAL MODELS OF EPILEPS

10201
07:14:36,237 --> 07:14:37,905
COMPETENT 1 OF THE EASIEST BEST

10202
07:14:37,905 --> 07:14:39,607
WAYS TO WAS TO GIVE A LITTLE

10203
07:14:39,607 --> 07:14:43,310
INJECTION OF BLOOD IN THE CORTEX

10204
07:14:43,310 --> 07:14:47,448
AND SEEING FERIA TIN AND HEARING

10205
07:14:47,448 --> 07:14:50,084
THAT SOME OF THE BAD EPISODES OF

10206
07:14:50,084 --> 07:14:54,088
ARIA E HAVE HAD SEIZURES AS A

10207
07:14:54,088 --> 07:14:57,858
SERIOUS AND COMPLICATION OF IT,

10208
07:14:57,858 --> 07:14:58,959
I'M WONDERING IF THE DIFFERENCE

10209
07:14:58,959 --> 07:15:01,328
IS WE'RE TRYING TO SAY, WHICH OF

10210
07:15:01,328 --> 07:15:02,163
THE ARIA CEREBELLUMSs THAT

10211
07:15:02,163 --> 07:15:03,831
AREN'T SO BAD WE COULD TREAT

10212
07:15:03,831 --> 07:15:06,066
THROUGH THIS, IT'S NOT SUCH A

10213
07:15:06,066 --> 07:15:08,002
BIG DEAL, DOESN'T SEEM TO BE

10214
07:15:08,002 --> 07:15:10,004
CAUSING PERFECT DAMAGE AND THOSE

10215
07:15:10,004 --> 07:15:13,340
THAT SPIN INTO A TRAGIC OR EVEN

10216
07:15:13,340 --> 07:15:14,975
FATAL OUTCOME, WHETHER THE

10217
07:15:14,975 --> 07:15:17,378
METABOLIC STATUS, WHETHER IN

10218
07:15:17,378 --> 07:15:19,013
FACT, THERE'S SOME MORE

10219
07:15:19,013 --> 07:15:21,482
ACTIVATION THAT'S GOING ON IN

10220
07:15:21,482 --> 07:15:24,418
THE BAD 1S, COULD BE DRIVEN BY

10221
07:15:24,418 --> 07:15:26,654
AN EPILEPTIC OR OTHER EXCITATORY

10222
07:15:26,654 --> 07:15:30,891
MECH NIM THAT'S BEING SET OFF BY

10223
07:15:30,891 --> 07:15:32,726
THE HEME THAT IS PROBABLY

10224
07:15:32,726 --> 07:15:35,663
PRESENT IN THE REAMINGION.

10225
07:15:35,663 --> 07:15:37,831
BUT YOU KNOW MAYBE WE COULD BE

10226
07:15:37,831 --> 07:15:40,834
DOING THE EEGs OR SOME SIMPLE

10227
07:15:40,834 --> 07:15:43,103
PRETTY METABOLIC TESTING OF

10228
07:15:43,103 --> 07:15:45,739
BRAIN ACTIVITY AND SPEC. SCAN ON

10229
07:15:45,739 --> 07:15:47,741
THE--ON THESE ARIA CASES TO SEE

10230
07:15:47,741 --> 07:15:51,078
IF THAT WOULD BE ANOTHER WAY TO

10231
07:15:51,078 --> 07:15:52,513
DIFFERENTIATE THE DANGEROUS 1S

10232
07:15:52,513 --> 07:15:55,749
FROM THE 1S THAT WE CAN LIVE

10233
07:15:55,749 --> 07:15:58,852
WITH NETWORK I THINK THAT'S A

10234
07:15:58,852 --> 07:16:00,588
GOOD IDEA ALTHOUGH OBVIOUSLY

10235
07:16:00,588 --> 07:16:05,826
EEGs DON'T CATCH A LOT OF

10236
07:16:05,826 --> 07:16:08,429
SMALL SEIZURES, I ALSO LIKE THE

10237
07:16:08,429 --> 07:16:10,531
IDEA OF CONSIDERING INFLAMMATION

10238
07:16:10,531 --> 07:16:13,567
AND EDEMA BECAUSE WE KNOW THAT

10239
07:16:13,567 --> 07:16:14,568
BRAIN INFLAMMATION MAKES YOU

10240
07:16:14,568 --> 07:16:15,869
DIZZ COMPETENT GIVES YOU A

10241
07:16:15,869 --> 07:16:17,304
HEADACHE AND MAKES YOU OUT OF IT

10242
07:16:17,304 --> 07:16:19,773
CAN HA THOSE ARE THE SYMPTOMS.

10243
07:16:19,773 --> 07:16:21,075
NWONDERFUL I WOULD LIKE TO THANK

10244
07:16:21,075 --> 07:16:30,417
ALL OF OUR PANELISTS.

10245
07:16:30,417 --> 07:16:31,652
AND DR. WRIGHT ASSOCIATE

10246
07:16:31,652 --> 07:16:33,020
DIRECTOR OF OUR OFFICE OF

10247
07:16:33,020 --> 07:16:35,556
CLINICAL RESEARCH AT NINDS WILL

10248
07:16:35,556 --> 07:16:36,724
DPIF THE CONCLUDING REMARKS FOR

10249
07:16:36,724 --> 07:16:39,660
TODAY AND WE WILL SEE YOU

10250
07:16:39,660 --> 07:16:43,197
TOMORROW AT 8:30.

10251
07:16:43,197 --> 07:16:43,998
THANK YOU.

10252
07:16:43,998 --> 07:16:45,099
>> SURE.

10253
07:16:45,099 --> 07:16:47,668
THIS IS EXACTLY WHAT NIA HAD IN

10254
07:16:47,668 --> 07:16:50,537
MIND TO BRING TOGETHER PEOPLE

10255
07:16:50,537 --> 07:16:52,039
WITH DIVERSE EXPERTISE AND A LOT

10256
07:16:52,039 --> 07:16:53,607
OF DIFFERENT AREAS THAT ARE

10257
07:16:53,607 --> 07:16:57,144
RELEVANT TO THIS FIELD AND PUT

10258
07:16:57,144 --> 07:16:58,646
HEADS TOGETHER AND SO I THINK

10259
07:16:58,646 --> 07:17:02,850
IT'S BEEN A REALLY FANTASTIC

10260
07:17:02,850 --> 07:17:10,257
DAY, AND IF THE OLD SAW ABOUT

10261
07:17:10,257 --> 07:17:11,325
ANDROIDS DREAMING OF ELECTRIC

10262
07:17:11,325 --> 07:17:15,329
SHEEP ARK PLIES TO AMYLOID

10263
07:17:15,329 --> 07:17:16,497
RESEARCHERS AND SUPER VASCULAR

10264
07:17:16,497 --> 07:17:18,866
RESEARCHERS DREAMING OF WAYS TO

10265
07:17:18,866 --> 07:17:20,934
CREATE NEW MODELS AND CREATE

10266
07:17:20,934 --> 07:17:22,303
SYNERGY THEN I HOPE THAT THAT

10267
07:17:22,303 --> 07:17:23,570
WILL CARRY YOU FORWARD INTEREST

10268
07:17:23,570 --> 07:17:25,205
YOUR DREAMS EMPLOY AND THEN

10269
07:17:25,205 --> 07:17:27,675
TOMORROW, WE CAN GET TOGETHER

10270
07:17:27,675 --> 07:17:32,146
AND REALLY THINK OF HOW TO

10271
07:17:32,146 --> 07:17:32,746
ATTACK THIS PROBLEM TOGETHER,

10272
07:17:32,746 --> 07:17:34,281
AND YOU KNOW SET THE TAIJ FOR

10273
07:17:34,281 --> 07:17:38,419
THE WORK  THAT NEEDS TO COME.

10274
07:17:38,419 --> 07:17:39,967
I DON'T HAVE TO  TIME TO DO MUCH

10275
07:17:39,967 --> 07:17:42,975
MORE AS I HAVE TO GET ON A CALL

10276
07:17:42,975 --> 07:17:44,577
BUT I APPRECIATE EVERYONE'S

10277
07:17:44,577 --> 07:17:48,147
EFFORTS TODAY AND SEE YOU
TOMORROW.

10278
07:17:48,147 --> 07:17:58,324