GOOD MORNING EVERYONE I
AM FRANCESCA, BOSETTI, AT
NINDS, AND I WOULD LIKE TO THANK
YOU FOR JOINING US IN THIS
WORKSHOP THAT IS SPONSORED BY
THE NATIONAL INSTITUTES OF
NEUROLONICAL DISORDER AND TROAK,
AND THE NATIONAL INSTITUTE ON
AGING TO ADDRESS CRITICAL AND
EMERGING ISSUE IF THE FIELD OF
ALZHEIMER'S DEC RESEARCH AND
TREATMENT, AMYLOID RELATED
IMAGING ABNORMALITIES OR ARIA, A
RAINCHL OF NEUROLOGICAL IMAGING
THAT APPEAR TO BE SERIOUS SIDE
CENTER FOR EXCELLENCE ON AGINGS
OF ANTIBETTA AMYLOID
IMMUNOTHERAPY EMPLOY ALZHEIMER'S
DISEASE IS A DEVASTATING
NEURODEGENERATIVE DISORDER
CHARACTERIZED BY COGNITIVE
IMPAIRMENT.
FOR YEARS RESEARCHERS FOCUS ON
BETA AMYLOID PLAQUE WHICH
ACCUMULATE IN THE BRAIN OF
ALZHEIMER'S PATIENTS AS A
CENTRAL TARGET FOR POTENTIAL
TREATMENT.
ANTI-BETA-AMYLOID EMUNE O
THERAPY ANDA UPONY IPT GREATER
VOLVE USING ANTIBODIES TO TARGET
AND REMOVE THESE BETA AMYLOID
PLAQUES FROM THE BRAIN AND
EMERGE AS A PROMISING STRATEGY
EMPLOY DATA FROM RECENT TRIALS
IMPLICATE THE AGENTS HAVE THE
FIRST EFFECTIVE DISEASE
MODIFYING THERAPIES AGAINST
ALZHEIMER'S DISEASE AND HAVE LED
TO THE FDA RECENT APPROVAL OF
[INDISCERNIBLE] UNDER AN
ACCELERATED APPROVAL PATHWAY
BASED ON THE FACTS ON THE
SURROGATE END POINTS OF
REDUCTION OF AMYLOID PLAQUE IN
THE BRAIN OF PATIENTS WITH
ALZHEIMER'S DEC.
THE CLINICAL IMPLICATIONS OF
ARIA ARE MULTIFACETED EMPLOY FOR
PATIENTS OCCURRENCE AND SEVERITY
OF ARIA CAN VARY WIDELY BETWEEN
INDIVIDUALS AND CAN LEAD TO
UNEXPECTED ADVERSE EVENTS AND
WORSEN QUALITY OF LIFE.
FOR HEALTHCARE, IT RAISES
QUESTIONS ABOUT COSTS, ACCESS
AND HEALTH DISPARITIES.
FOR CLINICIANS IT POSES A
CHALLENGE IN DETERMINING THE
APPROPRIATE COURSE OF TREATMENT
FOR MANAGING THE COMPLICATIONS.
FOR RESEARCHERS, IT RAISES
IMPORTANT QUESTIONS ABOUT THE
MECHANISMS BEHIND THE
DEVELOPMENT OF ARIA AND METHODS
TO MITIGATE ITS OCCURRENCE.
MANY QUESTIONS REMANY UNANSWERED
EMPLOY HOW CAN WE PREDICT WITH
THE HIGHEST WAYS OF ARIA, ARE
THERE RISKS WHILE MANY TAINING
THERAPEUTIC BENEFITS AND BETTER
AMYLOID IMMUNOTHERAPY.
IN WHAT ARE THE ON LONG-TERM
CONSEQUENCES OF ACTIVE FUNCTION
AND OVERALL HEALTH?
AND WHAT ARE THE BIOLOGICAL
MECHANISMS INVOLVED?
WE ALSO DON'T FULLY APPRECIATE
THE LONG-TERM EFFECTS OF THE
TREATMENT, THE IMPACT OF
CO-MORBIDITIES, CONCOMITANT
THERAPY LIKE ANTICOAGULATION AS
WELL AS THE EFFECT OF AGE,
GENDER AND GENETIC RISK FACTORS.
IN THIS WORKSHOP WE WILL DISCUSS
SCIENTIFIC GAPS AND FUTURE
OPPORTUNITIES WITH LEADERS FROM
ACADEMIA, INDUSTRY, REGULATORY
AND FUNDING EAMTIONS AND
PATIENTS ADVOCACY ORGANIZATIONS
WITH A MULTIDISCIPLINEAR EXPE
COLLABORATIVE SPIRIT FOR THE
BEST POSSIBLE OUTCOMES FOR THOSE
AFFECTED BY THE DISEASE.
FINALLY SOME HOUSEKEEPING NOTES,
WE ASK THE SPEAKERS TO STRICTLY
ADHERE TO THE PRESENTATION WITH
5 MINUES IF ARE QUESTIONS, IT
WILL BE ENFORCED.
A SPECIAL THANKS TO ALL MY NIH
COLLEAGUES AND PARTICULARLY
DR. HAYBERNE, DR. HARK
CIRCUMSTANCE SANI THAT HELPED
WITH THE PLANNING OF THIS
WORKSHOP, AND TO ALL THE NIH
MODERATORS AND EXTERNAL
MODERATOR ANDS TO STEPHANIE
TILLER AND HER TEAM WHO WORKED
VERY HARD AROUND THE CLOCK TO
MAKE THE LOGISTICS OF THIS
WORKSHOP POSSIBLE EMPLOY
STEPHANIE WILL BE AT THE
REGISTRATION TABLE OUTSIDE, IF
YOU HAVE QUESTIONS ABOUT YOUR
TRAVEL OR NEED ANY OTHER
INFORMATION.
ALSO A REMINDER THAT THERE ARE
NO LUNCH OPTIONS WITHIN WALKING
DISTANCE SO IF YOU HAVE NOT
PREORDERED A LUNCH, YOU MAY WANT
TO ASK STEPHANIE AND YOU WILL
HAVE THE OPPORTUNITY TO ADD A
LUNCH UNTIL 9:30 THIS MORNING TO
PREORDER OR OTHERWISE YOU CAN
CONSIDER YOUR OWN FOOD DELIVERY
OPTIONS.
AND WITHOUT FURTHER ADO, IT IS
MY PLEASURE TO NOW WELCOME
DR. WALTER KOROSHETZ, THE
DIRECTOR OF THE NATIONAL
INNSITUTE OF NEUROLOGICAL
DISORDERS AND STROKE FOR THE
OPENING REMARKS, THANK YOU.
>> HEY, THANK YOU FRANCESCA AND
THANKS EVERYBODY FOR COMING.
LETS OF OLD FRIENDS AND
HOPEFULLY MAKE SOME NEW FREBDS
IN THE NEXT FEW DAYS.
REALLY IMPORTANT TOPIC.
JUST TO OFFER A COUPLE OF
OPENING COMMENTS, WHICH YOU CAN
TAKE THEM OR LEAVE THEM.
--AND YOU KNOW ON THE SIDE OF
NEURODEGENERATION FOR YEARS
[INAUDIBLE DUE TO AWAY FROM MIC
]
TRYING TO GET THIS TREATMENT
FORRAL JEIMERS THAT LED US DOWN
A PATHWAY WHICH WE ALL ANYHOW
WAS IMPORTANT WHICH IS TO GET
THE AMYLOID OUT OF THE BRAIN.
WE HAVE THERAPIES THAT GET
AMYLOID OUT OF THE BRAIN BUT
HOUSTON WE HAVE A PROBLEM.
AND THE PROBLEM IS PRETTY
OBVIOUS, IT'S NOT SO STARING YOU
IN THE FACE, WITH A MRI SCAN,
YOU HAVE PLAQUE AREAS
[INDISCERNIBLE]--REAL EASY TO
SEE AND THEN HAVE YOU THE
PROBLEM WITH HEMORRHAGE, THE
EFFECTSOT BRAIN BOTH SHORT-TERM
AND LONG-TERM.
THE BLOODING IS THE FINAL RESULT
OF A LEAKY BLOOD BRAIN BARRIER,
[AUDIO UNCLEAR DUE TO MIC NOT ON
]
--BUT WE'RE HERE TO TRY TO SEE
WHAT WE CAN DO ABOUT THIS
PROBLEM BECAUSE IT'S TANNING IN
FRONT OF US AND PROBABLY NOT
GOING AWAY.
MAYBE WE SHOULD HAVE KNOWN IT
WAS COMING BECAUSE FROM THE
LESSONS LEARNS FROM
[INDISCERNIBLE] GEOGRAPHY AROUND
[INDISCERNIBLE] DOING THESE
EXQUISITE PATHOLOGICAL STUDIES
OF [INDISCERNIBLE] AND THE
DIFFERENT TAIJS IN THE LAST DAY
IF I RECALL CORRECTLY, IT WAS
[INDISCERNIBLE].
--IN HYPER TENSIVE DISEASE BUT
JOHN PAUL [INDISCERNIBLE]
BASICALLY IDENTIFIED IT AS THE
PATHOLOGIC FEATURE THAT'S
RELATED TO THE PLEADING AND
PEOPLE HAVE CEREBRAL ARVELGIO
OPEN MEETINGATHY, BUT WHAT I HAD
FORGOTTEN BUT I WAS REMINDED OF
IT IN THE LAST MEETING IS THE
AREA OF PLEAD, THE AREA OF
NECROSIS BUT THERE'S NO AMYLOID
LEFT, IT'S BEEN CLEARED FROM THE
BLOOD VESSELS SO NOW HERE WE ARE
CLEARING AMYLOID FROM THE BRAIN,
WE DON'T KNOW, IT MAY BE
CLEARING FROM THE BLOOD VESSEL,
WE MAY BE SETTING UP THE SAME
PATHOLOGY THAT YAWN PAUL
DESCRIBED IN SEVERAL ANCHLY
OPERATING GLOBALLYATHY YEARS
AGO, BUT THOSE ARE THE QUESTIONS
WE HAVE TO ANSWER AND HOW WE CAN
INTERVENE IN THOSE MECHANISMS
AND THIS PROBLEM IS AS I SAID
NOT GOING AWAY, THIS PROBLEM
ONLY GETS BIGGER.
RIGHT NOW WE HAVE INITIAL HOW DO
WE TREAT PEOPLE, HOW DO WE
MANAGE PEOPLE WHO HAVE THIS?
THIS IS LIKE JUST THE BEGINNING
THOUGH BECAUSE THE FUTURE IS
REALLY TRYING TO TREAT THIS
DISEASE EARLIER AND EARLIER,
WHICH MEANS PEOPLE--THE
TREATMENT IS SAFER AND SAFER,
THERE'S A GROUP I'M WORKING WITH
THAT ARE LOOKING AT VACCINES AND
IMMUNIZE PEOPLE AGAINST AMYLOID
AS A WAY OF TREATMENT, SO THIS
LOOKING DOWN THE FUTURE, I THINK
THIS ABILITY WE HAVE NOW TO GET
AMYLOID OUT OF THE BRAIN IS ONLY
GOING TO BECOME MORE AND MORE
IMPORTANT AND SO THIS ISSUE OF
THE BLOOD BRAIN BARRIER AS WE
REMOVE AMYLOID BECOMES VERY,
VERY IMPORTANT EMPLOY SO WE NEED
GOOD IDEAS FROM AROUND THE
TABLE, WE HAVE INDUSTRY PEOPLE,
MEDICAL PEOPLE, PERFECT
OPPORTUNITY TO GET IDEAS GOING.
OT OTHER HAND I CAN'T SAY VERY
FREQUENTLY BUT NIH HAS FUNDING
FOR THIS PROJECT.
WE HAVE AT THE AIMING INNSITUTE
AT NINDS, FUNDING, WE HAVE HAD
RFOOTWORK As OUT FOR SIDES IN
THIS AREA WE GOT LIKE 1
APPLICATION OR SOMETHING LIKE
THAT, 2.
SO PEOPLE CAN, YOU KNOW DIDN'T
REALLY REALIZE HOW IMPORTANT IT
IS AND I THINK THOU WE DO AND SO
WE REALLY THINK THIS IS WORTH
THE INVESTMENT FOR A LOT OF
DIFFERENT REASONS AS I MENTION
BUT IT'S NOT A--IT'S PROBABLY
NOT GOING TO BE SIMPLE.
SO WE NEED SOME REALLY, REALLY
GOOD IDEAS, INNOVATIVE IDEAS FOR
THIS STUDY.
SO REALLY LOOKING FORWARD TO THE
NEXT FEW DAYS, I WANT TO THANK
FRANCESCA AND ELIEZER, AND VERY
GOOD AND FRAN CHESK KACCT SHOULD
WE GO NEXT TO THE MODERATORS?
VERY GOOD.
>> SO WHILE PEOPLE SIT, I FORGOT
TO MAKE AN ANNOUNCEMENT THAT THE
WIFI SHOULD BE UP THIS 10
MINUTES OR SO, SO THANKS FOR
YOUR PATIENCE.
>> OKAY, SO WE'RE GOING TO MOVE
RIGHT ALONG TODAY BECAUSE WE
DON'T HAVE A LOT OF EXTRA TIME
EMPLOY WE WANT TO HAVE LOTS OF
TIME FOR DISCUSSION FOR THIS
IMPORTANT TOPEC SO WITHOUT
FURRINGER ADO, I'M JUST GOING TO
ASK THE FIRST SPEAKER--I BETTER
PUT MY GLASSES ON, DR. STEPHEN
SALLOWAY, FIRST SPEAKER NI'M
READING--IT'S DAVID CLIFFORD, SO
SORRY.
TAKE IT AWAY.
NSO I'M KIND OF A NEW FACE IN
THE ROOM FOR ALZHEIMER'S
DISEASE, I FIGURED I WAS INVITED
BECAUSE I WAS A GRAY HAIRED
PERSON THAT HAD BEEN KNOCKED
DOWN IN THE WEEDS OF TREATING
THIS DISEASE.
NOW WHERE ARE MY CONTROLS IN
THERE THEY ARE.
SO I'M REALLY HONORED OF COURSE
TO GET TO KICK THIS OFF AND I
WILL TRY TO GIVE YOU A REALLY
HIGH ALTITUDE VIEW OF THE WAY
I'M SEEING THIS FIELD AND THEN
IN QUESTIONS PERHAPS IT I CAN
DIG INTO WHERE I'VE BEEN WORKING
WHICH IS IN THE DOMAIN NABTLY
INHERIT ALZHEIMER'S FIELD, SO
THIS IS NOT ADVANCING.
SO I'M--I DON'T THINK I HAVE ANY
MAJOR CONFLICTS HERE, BUT YOU
SHOULD BE,A WARE THAT I'VE
WORKED IN THE DIANE TU THAT HAD
SUPPORT FROM PHARMA OF COURSE
THAT'S BEEN VERY KEY.
I THOUGHT THAT I WOULD TART OUT
REALLY WITH THE AMYLOID HIGHWAY
POGHT SIS BECAUSE HERE WE WILL
SPEND A DAY AND HALF WORKING ON,
TALKING ABOUT AMYLOID THERAPIES
AND YOU KNOW AMYLOID HAS BEG
YOUR PARDON MALIGNED AS A TARGET
WITH ALL THE DECADES OFATIVELYY
WE HAD ADDRESSING IT, BUT I JUST
WANTED TO TOP A MINUTE AND
REMIND YOU THAT THIS IS A
TOTALLY NORMAL PROTEIN IN THE
BRAIN.
IT'S SURPRISINGLY DYNAMIC AND I
WAS JUST BLOWN AWAY WHEN RANDY
BRATEMAN SHOWED A TURNOVER OF
AMYLOID OF LESS THAN A DAY AND
THIS IS A PROTEIN THAT'S
CONSTANTLY BEING MADE AND
THROWN,A WAY, AND THAT PROCESS
OF A FLOW OF THIS PROTEIN IS OF
COURSE, A CRITICAL BIOLOGIC
PROCESS AND IT'S DISTURBED WHEN
ALZHEIMER DISEASE DEVELOPS AND
EITHER THERE'S TOO MUCH OR
THERE'S TOO LITTLE OR
INAPPROPRIATE REMOVAL OR IT'S
ACCUMULATING IN THE BRAIN IN IN
TOXIC FORM AND WE HAVE THESE
EXAMPLES THAT ARE VERY DRAMATIC
FROM THE FAMILIAL MUTATIONS THAT
ABSOLUTELY GIVE AN EARLY ONSET
OF THE CLINICAL DISEASE OR IN
DOWNS PATIENT WHO IS HAVE
TRISONWR 21 OF THE APUNISHING
P YEEP, AND THEY CLEARLY LINK AD
TO THE BIOLOGY WE'RE TRYING TO
ADDRESS AND THE WHOLE TECHNOLOGY
TRANSFER WAS REALLY, PUT A
CHERRYOT TOP WHEN THE ISOTOPE
LANDIC VERSION SAW A DIFFERENT
VERSION OF A-P-P, THAT MADE LESS
AMYLOIDOGENIC DISEASE, AND
THERE'S SOMETHING WORTH PURSUING
A DIRECT THERAPY INTERFERING
WITH ITS BIOLOGY.
NOW THE EASY WAYS OF ADDRESSING
THE BETA SINK RATAISS--SYNTH
HAVE BEEN TAUGHT AND HAVE FAILED
AND THAT'S WHY WE'RE WORKING ON
THE NOTION OF THE MONOCLONALS
BEING BUT YOU HAVE TO REALIZE
THERE ARE MULTIPLE TARGETS,
MONOCLONALS ARE VERY SPECIFIC,
THEY CAN BE DESIGNED TO LOOK FOR
A SPECIFIC ENTITY AND WE HAVE
MONITOR MERS, LIGGA MERS AND
PLAQUES AND THERE'S A LOT OF
CONCERN TAKEN--THEY WE DON'T
RULE KNOW THE TOXIC ENTITIES
THAT DRIVE THIS DEC AND WOULD IT
BE GOOD ENOUGH TO PULL OFF THE
THINGS EARLY IN THE MONOMERSTAGE
SO THERE ARE LESS BELLING PLOKS
FOR PLAQUES AND THEIR OLIGMERS
MIGHT BE THE TOXIC DRIVING THE
DEC, WELL, THAT'S AN IMPORTANT
NOTION IS HAS BEEN TESTED AND
SIMILARLY ARE THESE PLAQUES THAT
ARE PATHOLODGEECLY DRAMATIC, ARE
THEY THE ENTITY OR ARE THEY A
SYNCH THAT PROTECTING US FROM
THE TOXICITY OF THAT AGENT.
WELL, WE NOW HAVE MULTIPLE LARGE
CLINICAL TRIAL ANDS IN THE ROOM
AND THIS MEETING ARE MOST OF THE
SENIOR AUTHORS FOR THESE TRIALS.
SO JUST TO RECOGNIZE THAT THIS
INVESTMENT THAT'S MOVED ON TO
PHASE 3 TRIAL SYSTEM WHERE WE
ARE NOW AND I WANT POINT OUT
THAT THE WHOLE FIELD HAS BEEN
DRIVEN AND AIDED BY THE
DEVELOPMENT OF AMYLOID PET
SCANNING SO THAT WE COULD
IDENTIFY IN LIFE, WITH
DEVELOPMENT OF THESE PATHOLOGIC
PLAQUES THAT WE'RE SO CLOSELY
ASSOCIATED WITH THE DISEASE, BUT
THESE TRIALS ARE DONE AT THE
VERY MOST STUPID TIME TO ADDRESS
AN AMYLOID DRIVEN DEC, AT THE
END OF THE DAY WHEN THE DISEASE
IS ALREADY TEABED.
AND I THINK OF COURSE WE ALL
BELIEVE THAT'S BEEN PART OF THE
PROBLEM BUT IT'S BEEN A PROBLEM
BECAUSE WE COULDN'T ACCURATELY
PREDICT EARLIER WHO WOULD GIVE
US A TRIAL THAT WAS DOABLE.
BUT THIS DYNAMIC 20 YEAR PROCESS
IS REALLY INKRE TINS BELIEVE AND
I LOVE TO SHOW THESE PICTURES
THAT CAME OUT OF OUR DOMINANTLY
INHERITED EXPERIENCE AND THE
TIMING OF THIS SHOWS THERE IN
THE PRECLINICAL REGION, THE
BRIGHTER COLORS APPEARING, IF
YOU LOOK AT THE BOTTOM THIS IS 5
YEARS BEFORE THE ONSET OF
DEMENTIA, AND THEN AS THE
[INDISCERNIBLE] ARE GETTING A
BIG AMYLOID DEPOSIT AND WE SEE
IN THE NEXT SCAN AND THE DG
SCAN, AND THEN DAMAGE AS THE
CORTEX BECOMES THIN AS THE DEC
WASTES THE BRAIN.
SO A VERY DRAMATIC DYNAMIC
PROCESS OF RAPIDLY TURNING OVER
PROTEIN IS WHAT WE HAVE TO
ADDRESS BIOLOGICALLY WITH DRUGS.
MOP O CLONAL ANTIBODIES ARE
TERRIBLE DRUGS TO TREAT THE
BRAIN WITH, AREN'T THEY IN AND
WE'RE ONLY STUCK WITH THEM
BECAUSE EVERYTHING ELSE HAS
FAILED BUT HERE WE ARE, AND THE
HAPPY THING IS THAT ALTHOUGH
THERE ARE BIG PROTEINS THAT
DON'T GET THROUGH THE BLOOD
BRAIN BARRIER VERY WELL, ENOUGH
DOES AND IT'S CLEAR WE CAN
ADDRESS IT AND SO WITH A LOT OF
INVESTMENT, WE CAN GIVE ENOUGH
KRUG TO MATTER IN THE BRAIN AND
THEN WE HAVE TO PICK THE TARGET
AND SO WE HAVE THIS ARRAY OF
POSSIBLE TARGETS.
WOULD IT BE BETTER TO HIT EARLY
PARTS AND EMPTY THE SINK OF THE
COMPONENTS OF AMYLOID BEFORE IT
FORMS FIEB RULES.
WELL THAT'S A GOOD HYPOTHESIS
AND SOME COULD BEING TARGETED
THERE, AND THAT'S A GOOD
MECHANISM BUT ARE THE PLAQUES
THEMSELVES A CRITICAL TARGET AND
I WOULD PONENT OUT THAT
ANTIBODIES DON'T CLEAR PLAQUES.
THEY HAVE TO ENGAGE THE
MICROFLEEL SYSTEM AND THAT'S
WHAT CLEARS THE PLAQUES AND SO
THAT'S THE MECHANISM BY WHICH
BIOLOGICALLY THESE DRUGS ARE
WORKING AND THEN OF COURSE IF
YOU ARE GIVEN THIS PROTEIN, YOU
CAN'T SWALLOW THE PILLS BECAUSE
YOU JUST [INDISCERNIBLE], SO YOU
HAVE TO GIVE IV OR SUBCUE AND
THAT'S VERY INCONVENIENT AND
TROUBLESOME AND EXPENSIVE AND
IT'S ONLY MADE POSSIBLE BECAUSE
ONCE THEY'RE IN THE BLOOD
STREAM, THEY LAST FOR QUITE A
WHILE AND SO YOU HAVE LONG HALF
LIVES.
SO THESE ARE THE TARGETS AND IT
TURNS OUT THAT THE TARGETS THAT
FAILED TO DIRECTLY ADDRESS THE
AMYLOID PLAQUE HAVE BEEN
SOLANEZUMAB, AND CRENEZUMAB, AND
THATY BECAUSE IT'S AN IGD EABT
BODY, THE REST OF THEM DO
ADDRESS PLAQUES WITH THE LATEST
BREATHER IN THE FIELD, DONANEMAB
MOST DIRECTLY CAN EXCLUSIVELY AN
ANTIPLAQUE ANTIBODY SO IF YOU
HAD THE NOTION THAT ALL THE
DISEASE WAS DRIVEN BY TOXIC
FORMS, THIS MIGHT NOT WORK AT
ALL BUT WHAT WE'VE SEEN OF
COURSE IS THAT IN FACT
CORRELATED WITH SUCCESS IN
LOCKING THE PROGRESSION OF
COGNITIVE LOSS AND FUNCTIONAL
LOSS IN THE DEC IS MOST TIGHTLY
CORRELATED WITH THE ABILITY TO
CLEAR THE EVIDENCE AMYLOID
PLAQUES IN THE BRAINS OF
PATIENTS IN THESE LARGE CLINICAL
TRIALS.
THE DRUGS THAT FAILED TO CLEAR
PLAQUES SUFFICIENTLY,
SOLANEZUMAB, CHENEZUMAB, ALL
REALLY FAIL TO PROTECT AS YOU
SEE THE PROGRESSION OF THE DEC
REFLECTED FOR INITANCE IN THE
CDR, SOME OF BOX SCORE WHICH IS
A MEASURE THAT IS WEIGHTED
TOWARD COGNITIVE DECLEAN BUT
ALSO INCLUDES LIFE FUNCTIONAL
DECLINE.
IN CONTRAST, AS THE AGENTS HAVE
BECOME MORE SUCCESSFUL AT
ADDRESSING PLAQUES, THEY'VE
BEGUN TO SHOW EFFICACY AND
[INDISCERNIBLE] HAD THE
EXPERIENCE OF HAVING THE TRIALS
SHORTENED BY A FUTILITY ANALYSIS
THAT WAS PREMATURE AND RESULTING
IN A HUNG URIE BASICALLY WITH
THE CLINICAL RESULTS OF THE 2
LARGE TRIALS, BUT VERY CLEAR
EVIDENCE THAT IT WAS MAKING A
SIGNIFICANT IMPACT ON AMYLOID ON
THE BRAIN OF THE PARTICIPANTS AS
WELL AS A REAL IMPACT ON
PERFORMANCE AND SO, THE LATEST
OF THESE TRIALS, REALLY REPORT
SIGNIFICANT CHANGE IN THIS
DECLINING COURSE OF FUNCTIONAL
IMPAIRMENT WHERE THE PLACEBO
CURVES JUST HAVE THIS STEADY
ONGOING COURSE OF DECLINE OVER A
YEAR AND A HALF OF SO OF STUDY
ASK DOUBLE PLIENDED CONTROL
EXPERIMENTS, THE DRUGS ARE
CLEARLY BENDING THAT CURVE
ALTHOUGH NOT MAKING IT FLAT IN
ALL CASES BUT ON AVERAGE A VERY
SIGNIFICANT CHANGE THAT I THINK
WE ALL BELIEVE IS CLINICALLY
IMPACTFUL, SO THIS HAS BEEN
DONE, THERE'S THIS CORRELATION
AND IT APPEARS TO BE RELATED TO
THE ABILITY TO CLEAR PLAQUE FROM
THE BRAIN AND IN FACT, THE
STRATEGY THAT WAS USED IN
DEVELOPING LECANEMAB, WAS A
CAREFUL STUDY TO SELECT A DOSE
THAT WOULD OPTIMALLY BE
TOLERATED AND CLEAR THE AMYLOID
PLAQUE IN A SOMEWHAT DIFFICULT
BI-WEEKLY ADMINITRATION SCHEME
WAS USED TO OPTIMALLY DRIVE THE
TARGET AND IT RESULTED IN
EXACTLY WHAT WAS PREDICTED IN
THE PHASE 3 TRIAL AND IN THE
CLINICAL RESULTS THAT WERE
REALLY SOUGHT AND A VERY SIMILAR
PATTERN PERHAPS WITH AN EACH
MORE AGGRESSIVE CLEARANCE, IS
DEMON TRAITED WITH THE
DONANEMAB, WHICH IS EXCLUSIVE TO
PLAQUES AND RESULTED IN AN 80%
CLEARANCE OF THE PET EVIDENT
AMYLOID IN THE PARTICIPANTS IN
THIS TRIAL AND A NOTABLE SLOWING
OF THE PROGRESSION OF THE REAL
DISABILITY THAT COMES ON IN THE
COURSE OF ALZHEIMER DISEASE, SO
THE PRICE OF THIS IS WHAT THIS
MEETING IS LARGELY ARIA AND SO
ARIA AND FAIL TO CLEAR BUT
ASSOCIATED WITH THIS PROCESS
CRITICAL EFFICACY OF THIS DRIVES
ASK THE PROCESS IS THESE IMAGING
ABNORMALITIES WHICH ARE SEEN ON
MRI SCANS AND THEY COME IN 2
FLAVORS, 1 IS THE EDEMA AND YOU
CAN SEE ON THE TOP ROW HERE, I
AM NOT SURE IF I CAN--HOW DO I
DID THAT, I CAN'T POINT VERY
WELL, BUT IN THE TOP ROW OF
SCANS, YOU CAN SEE IN THE
OCCIPITAL REGION OF THE BRAIN,
THE DEVELOPMENT OF BRIGHT FLARE
POSITIVE REGIONS THAT SHOW
GREATERUAR ER WATER IN TISSUE IE
FOCAL AREAS OF THE BRAIN AND IF
YOU LOOK AT THE BOTTOM, YOU CAN
SEE THAT THE BRIGHT COLORS THAT
SHOW THE DEPOSIT OF AMYLOID IN
THE BRAINS OF THESE PATIENTS
BEFORE THAT ARE NOTABLILY IN THE
SAME REGIONS THAT DEVELOP THIS
AMYLOID IMAGING, AND THE OTHER 1
IS THE DEPOSITS THAT ARE OFTEN
CLUSTERED IN THE REGION OF THE
ARIA E BUT ALSO CAN OCCUR
RANDOMLY, INDEPENDENTLY IN OTHER
AREAS OF THE BRAIN AND WE
BELIEVE HAVE TO DO WITH PERHAPS
THE AMYLOID IN BLOOD VESSEL
WALLS, BEING CHANGED,
DESTABILIZED, INFLAMED AND
CAUSING THESE LEAKAGES WHICH ARE
USUALLY ASYMPTOMATIC.
THE ARIA E REMARKABLY IS USUALLY
ASIMPLE TOMATIC AND THEREFORE
CAN BE PICKED UP MOST COMMONLY
WITH COSTLY MRI SCANS THROUGH
THE TRIAL AND AS YOU SEE IN THE
TOP ROW IMEAN IF YOU STOP THE
AMYLOID AGENT, TYPICALLY THE
PATHOLOGIC APPEARANCE IN THE
SCAN REVERSES ESSENTIALLY
COMPLETELY TO MY EYE SO IT'S A
REMARKABLE THING.
WHEN YOU COMPARE THESE DIFFERENT
AGENTS, IT'S A VERY DIFFICULT
COMPARISON BECAUSE THE
POPULATIONS THAT WERE PUT INTO
THE STUDIES OR DEFINITE IN THE
DEGREE TO WHICH THE DISEASE HAS
PROGRESSED AND APOE4 IS CLEARLY
A RISK FACTOR AND THE NUMBER OF
APOE CARRIERS AND THE WAY THEY
WERE MANAGED IN DIFFERENT IN THE
TRIALS.
SO IT'S HARD TO HAVE A TO HAVE A
HEAD-TO-HEAD COMPARISON, IS IT
THE ANTIBODIES THE WAY THEY WERE
GIVEN OR THE POPPULESS BUT
THAT'S CLEARLY AN IMPORTANT
QUESTION THAT WE HAVE TO
ADDRESS.
BEYOND ARIA, WE HAVE
SURPRISINGLY FEW COMPLICATIONS
WITH USING THESE DRUGS.
THERE ARE MODEST INFUSION
REACTIONS THAT ARE PRETTY
TOLERABLE AND MANAGEABLE AND
WHEN YOU LOOK AT THE TBLOABAL
SAFETY POPULATION OF THESE
STUDIES, IT ACTUALLY IS VERY
GOOD WITH A GOOD BALANCE BETWEEN
THE PLACEBO AND THE TREATED
PATIENTS, SO IT SEEMS LAKE
THERE'S NOT A HEAVY BURDEN OF
SERIOUS TOXICITY IN SAEs OR IN
DEATHS, BUT THE DEATHS THAT WE
HAVE SEEN IN THE TRIALS HAVE
OFTEN BEEN RELATED TO HEMORRHAGE
AND PREDICTERS OF A GREATER
HEMOGGAGIC TENDENCY INCLUDING
TPA OR PREEXISTING EVIDENT OF
AMYLOID ANCHLY OPERATING
GLOBALLYATHY.
SO WE'RE AT AN EXCITING TIME.
THE BUSINESS OF GETTING THESE
DRUGS INTO USE SO THEY CAN
REALLY MAKERS AND A DIFFERENCE
IN THE WORLD IS GOING TO VERY
HEAVILY TALK ABOUT THE TIME
THEY'RE USED AND IT MAY BE--I
TRULY BELIEVE THAT EARLIER USE
WILL BE MUCH SAFER THAN LATER
USE AND WILL HOPE THAT PANS OUT.
WE'VE GOT TO GET THE PRACTICAL
BUSINESS OF HOW DO YOU SELECT
THE RIGHT POPULATION?
YOU CAN BE THE USE AN
ANTIAMYLOID THERAPY IF THERE'S
NOT AMYLOID IN THE BRAIN.
WE HAVE TO PROVE THAT IF WE ASK
AND SUGCREST TO PEOPLE THAT THEY
TAKE THIS RISK, AND SO MOVING ON
TO PRACTICAL MEASURES TO SCREEN
LARGE NUMBERS OF PEOPLE AND
REALLY RELIABLY KNOW THE AMYLOID
AT THAT TIMEUS IN THEIR BRAIN
AND CRITICAL, AS IS TO REALLY
FULLY UNDERSTAND AS MUCH OF THE
RISKS THAT DRIVE THE DANGER SIDE
FOR USING THESE THERAPIES.
AND THEN A PRACTICAL STRATEGY,
YOU KNOW WE JUST CAN'T HAVE
PEOPLE COMING IN EVERY 2 WEEKS
FOR THE REST OF THEIR LIVES FOR
IV INFUSIONS.
SO ONCE WE'VE CLEARED PLAQUES
WHAT DO WE DO WITH THEM?
HOW DO WE MAKE SURE THAT WHAT
BENEFITS WE ACCRUED WILL BE LONG
LASTING AND SO THAT'S A CRITICAL
PART THAT WE'VE REALLY GOT TO
EXPLORE AND FIGURE OUT EMPLOY SO
I WAS PROBABLY INVITED BECAUSE
I'M NAIVE TO THE FIELD AND I AM
PRETTY NAIVE BUT I'M MOT TOTAL
NAIVE AND YOU 2 I'M SURE ARE NOT
BUT JUST A REMINDER THAT
ADDRESSING ALZHEIMER'S DISEASE
WILL NOT BE JUST ABOUT TREATING
AMYLOID, WE HAVE TO DEAL WITH
THE ENTIRE LIFE CYCLE.
WE HAVE TO DEAL WITH TAU AND
WHAT'S ANYTHING ON WITH THAT, WE
HAVE TO DEAL WITH THE
INFLAMMATORY FACTOR ISSUES THE
GOOD PARTS OF IT AND THE BAD
PARTS OF IT AND UNDERSTAND THAT
AND MAXIMIZE, THE OUTCOMES AND I
THINK WE CAN--WE'RE ON OUR WAY
TO TREATING A DREADFUL, DREADFUL
DISEASE VERY EFFECTIVELY AND
THAT'S EXCITING.
SO I WILL END WITH THAT THANKING
THE PEOPLE AT WASH-U THAT
MENTORED ME AND ESPECIALLY MY
TUTORS AS I HAVE COME IN CAN
MONITORING ARIA THERE, RANDY
BATEMAN GAVE ME MY FIRST TUTOR,
SO VERY HONORED TO BE WITH YOU
TODAY.
NWONDERFUL TALK AND WE'LL HAVE
TIME DURING THE DISCUSSION
PERIOD.
WE WILL CONTINUE NOW TO KEEP ON
TIME.
DR. REISA SPERLING MASSACHUSETTS
GENERAL HOSPITAL.
>> THANK YOU.
SO I THINK I WAS INVITED BECAUSE
I AM IN THE WEEDS SO THANK YOU
FOR THIS SO I CAN ACTUALLY SEE
YOU GUYS WHILE I SPEAK AND
THANKS SO MUCH FOR THE
INVITATION TO COME TO THIS.
I WORKED A LOT ON ARIA 10 OR 12
YEARS AGO AS I WILL SHOW YOU AND
THEN I SOMEWHAT STOPPED BECAUSE
I'M WORKING ON GOING EARLIER IN
PREVENTION TRIALS BUT I NOW SEE
THAT ARIA'S IN THE WAKE OF MY
BEING ABLE TO GIVE THIS TO 50
AND 60 YEARS AROUND THE WORLD.
SO COMING BACK.
ALL RIGHT, LET ME FIRST--HERE
ARE MY DISCLOSURES AND I WANT TO
ACKNOWLEDGE THE FUNDING.
SO I'M GOING START WITH ACTUALLY
SHOWING YOU SOME IMANNUALS
AGAIN, TO REMIND YOU OF WHAT
THIS LOOKS LIKE IN THE BRAIN AND
ESPECIALLY THE INCREDIBLE
SPECTRUM OF WHAT ARIA CAN LOOK
LOOK AND I'M GOING TO GEF YOU A
BRIEF HISTORY ON IN MY CASE A
HERSTORY, ON ARIA PARTLY BECAUSE
IT WAS REALLY HELPFUL TO GO BACK
AND SEE WHERE WE'VE BEEN AND
WHERE WE'RE GOING.
SO I ACTUALLY THINK THE STORY
STARTS BACK IN FIRST VACCINE IN
1982 WHERE MENINETWORK
GOENCEPHALITIS IN 6%, THIS WAS
ONLY BAH THE C-TERMINUS IS
ACTIVATING T-CELLS SO WE DON'T
HAVE TO WORRY ABOUT THIS GOING
FORWARD AND I DO THINK THAT
ANTIBODIES ARE QUITE DIFFERENT
THAN A VACCINE WITH AN ADYU VENT
BUT I THINK THERE'S AN OVERLAP
IN WHAT ACTUALLY OCCURS IN THE
BRAIN AS WE'RE REMOVING AMYLOID
AND THESE MREFRESH YOUR
RECOLLECTION I CHANGES WHICH I
WILL SHOW YOU IN A MOMENT WERE
OBSERVED IN THE SETTING OF
CLINICAL SYMPTOMS AND
IMPORTANTLY THOUGH, THERE WAS
QUITE A LOT OF CELLS IN THE CSF
SO IT WAS CLEARLY AN
INFLAMMATORY PROCESS, SO WE
THOUGHT, OKAY, WE'RE GOING PAST
THAT.
WE WILL FIX THIS, WE WILL GO
ABOUT THE MOP O CLON AT ASPECT
BODY, FOCUSED MORE ON THE END
TERMINUS AND WE STARTED STUDIES
ON BAPINEUZUMAB, AND 3 OUT OF 10
INDIVIDUALS DEVELOPED ARIA AND I
KNOW THOSE WELL BECAUSE I WAS
THE SITE P. I. AND 2 OF THE 3
HAD SUBTLE SYMPTOMS BUT WE KEPT
GOING, WE SAID OKAY, WE WILL GO
TO A LOWER DOSE AND WE MOVED
INTO PHASE 2, I WAS THRILLED TO
BE ABLE TO WORK ON THIS WITH
STEVE SALLOWAY AND OTHER TEAMS
IN FACE 2 AND WE STARTED TO SEE
MULTIPLE CASES EVEN AT THE MITSD
DOSE, BUT THE MIDDLE DOZE AND A
FEW PEOPLE GOT CSF AND IT WAS
INFLAMMATORY AND THE MORE SEVERE
CASES BUT NOT IN EVERYONE, THERE
ARE PEOPLE IN SYMPTOMS WITH NO
CELLS.
AND IMPORTANTLY WALTER WE DID DO
GADA LYNNIUM, BUT WE DID DO GAD
IN QUITE A PEW INDIVIDUALS.
AT THIS POINT THE FDA SENT A
LETTER TO ALL THE SPONSORS AND
THE ALZHEIMER'S ASSOCIATION
CALLED UP MARIA AND SHE
CONVOANED A WORK GROUP ACROSS
ACADEMICS, THE FDA, CUTCHES, AND
I HAVE TO SAY, TO THIS DAY, THIS
COMMITTEE REMAINS THE MOST
USEFUL COMMITTEE I'VE EVER BEEN
ON BECAUSE IT ACTUALLY CHANGED
POLARIZEDEE AND SO SHOUT OUT TO
THE REGULATORS, THIS WAS BACK IN
THE RUSTY CATS DAYS ABOUT YOU IT
SHOWED ME WHAT ALL WORKING
TOGETHER CAN REALLY DO TO SOLVE
THESE PROBLEMS.
SO IT'S THRILLING TO BE HERE AND
WE HAVE TO KEEP WORKING ON IT.
NOW I FOR THE PAST 10IERS OR SO
HAVE BEEN ACCUSED OF NAMING ARIA
SOMETHING BEAUTIFUL BECAUSE TO
MAKE PEOPLE NOT THINK ABOUT IT
AS BEING WORSE BUT I DO WANT TO
MENTION THAT THE ALTERNATIVE
PROPOSED BY CLIFF JACK WAS
FLIRP, WHICH IS SOMETHING ABOUT
FLUID RETENTION RECOVERY PULSES,
SO ARIA WON.
OKAY.
SO HERE TO SHOW YOU IMAGES ON
THE LEFT, SO HAD IS THE VERY IPT
GREATER FLAMMATORY SIDE OF ARIA,
BUT SHOWING RIGHT FROM IMAGES
FROM TEEF SALIBRARY LOWAY'S
PAPER AND MY PAPERS AND I THINK
WHEN IT LOOKS LEAK IN THE BRAIN
CAN OVERLAP AND I THINK THERE'S
REALLY A SPECTRUM OF WHAT AN
INFLAMMATORY AND CLEARANCE OF
WHAT AMYLOID CAN LOOK LEAK IN
THE BRAIN, ALTHOUGH CERTAINLY
THE ACTIVE IMMUNIZATION WAS MUCH
MORE CLEAR.
I ALSO LOOKED BACK TO SAY WHAT
DO WE THINK THEN AND WHAT DO WE
KNOW NOW?
AND I HAVE TO SAY THIS HAS NOT
CHAIRVELGED VERY MUCH SO THE 2
BIG RISK FACTORS FOR ARIA E,
ANYWAY ARE THE DOSE, THE C-MAX
OF THE ANTIBODY INFUSION SEEMS
TO BE ASSOCIATED AND WHETHER YOU
ARE IN APOE 4 CARRIER AND HERE'S
DATA AND DAVID ALREADY SHOWED
YOU SOME NICE DATA ON THIS BUT
THERE REALLY IS A STEP-WISE
RELATIONSHIP BETWEEN THE NUMBER
OF APOE4 ALLELES AND THE RISK OF
ARIA AND THIS IS PRETTY MUCH
TRUE ACROSS ALL ANTIBODIES, ALL
THAT MOVE AMYLOID.
ALL RIGHT, SO HERE'S ANOTHER
TABLE, THIS 1 ACTUALLY CAME FROM
CHRIS VAN DIEK AND I KEEP
UPDATING IT, VERY SIMILAR TO
WHAT DAVID KINDLY SHOWED YOU BUT
I DO WANT TO MAKERS AND A COUPLE
OF MINOR POINTS ON THIS, 1 IS
THAT IT DID SEEM TO MATTER ATH
BIT WHETHER AUTOIIMRKS 1 OR 4 IN
TERMS OF THAT, BUT I THINK 1 OF
THE BIGGEST THING SYSTEM WHETHR
THEY CAN ACTIVATE MICROTBLIA TO
SEE THE CONFIRMATION THAT'S
STICKING OUT AND ACCESSIBLE.
I THINK THIS IS IMPORTANT, IMEN
I HIGHLIGHTED HERE, IN PLURIBU,
WHERE THE RELATIONSHIP BETWEEN
THE--BEING ABLE TO SEE THE FIBER
IN PARTICULAR IN THAT
CONFIRMATION OR STICKING OUT AND
I WILL ALSO POINT OUT AND I
CAN'T WAIT TO HEAR TEEF GREEN
BERG TALK MORE ABOUT THIS BUT IT
BARGAINED ME ABOUT WHY ARE WE
GOING AFTER TO VESSELS AS WELL
AS TRAINING IT FOR POLITICALS
BUT THE CONFIRMATION IN VESSELS,
YOU CAN SEE THE SAME STUFF AND
CONFIRMATION STICKING OUT AND I
THINK THAT'S IMPORTANT.
SO 1 OF THE IMPORTANT THING THAT
I THINK WE'VE LEARNED IS THAT
ARIA IS ASSOCIATE WIDE AMYLOID
CLEARANCE AND WE FIRST KNEW THIS
BACK IF 2012 WHERE WE COULD SEE
VERY FOCAL AT TIMES CLEARANCE OF
AMYLOID IN THE SETTING WHERE YOU
GET ARIA E AND LATER OFTEN ARIA
H, SO THIS IS 1 EXAMPLE THAT I
THINK WAS USEFUL SO YOU CAN SEE
THAT THERE PERSON'S GOT A LOT OF
FRONTAL AMYLOID AT 6 WEEKS WHICH
IS TYPICAL, VERY EARLY, AFTER
THE SECTION INN FUSION OF THIS
ASPECT BODY, YOU CAN SEE THE
CHANGES ON FLAIR, AND THEN YOU
SEE THIS RESOLVE AS YOU HEARD BY
THE COUPLE SCANS LATER BUT YOU
CAN SEE PRETTY FOCAL CLEARANCE
IN THIS CASE WHERE THE ARIA WAS
OCCURRING AND I HOPE CAN YOU SEE
THESE TRAIN TRACKS OF HEMEAT
SITTEROSEIS WHICH WE REFER TO AS
ARIA H, AND WE SEE CASES LIKE
THIS WHERE YOU GET THE FOCAL
CLEARANCE RELATED TO WHERE THE
ARIA IS.
SO I THINK WE'VE SINCE THEN
LEARNED THAT IMRAITER AMYLOID
PET REDUCTION IS ASSOCIATE WIDE
A HIGHER RISK OF ARIA E BUT I
WILL BRING OUT 2 POTENTIAL
OUTLIERS THAT I THINK ARE
ILLUSTRATIVE.
SO THE DOCTOR MENTIONED
GANTENERUMAB, AND THIS WAS
INTERESTING BECAUSE THEY USED
SUBCUE FORMULES WHICH IN THEORY
MIGHT TBIF YOU LESS ARIA AND
THEY DID A SLOW TITRATION OVER
TIME WHICH I THINK RESULTED IN
LESS AMYLOID REMOVAL THAN THEY
HOPED.
THEY HAD A PRETTY HIGH RATE OF
ARIA, THOUGH THAT OCCURRED IN
THE SAME PATTERN AS WE EXPECTED
ACROSS APOE CARRIERS AND THE
EVENTS HERE WERE DESCROWBTED
MORE OVER THE COURSE OF A TRIAL.
NIGHT RIGHT AFTER EACH INFUSION.
SO IT WAS DIFFERENT THAN THE
C-MAX LOOK AND IT HAD LES THAN I
WILL SAY EXPECTED AMYLOID PET
REDUCTION BECAUSE IT WAS A 2
YEAR TRIAL AND ON AVERAGE THEY
ONLY HAVE 53 CENTILLOIDS, 10
MEGS, AND HAD SIMILAR RATES THAT
ARE DISTRIBUTED ACROSS CARRIER
ANDS THOSE ARE CARRIERS AND NONE
CARRIERS ARE IN THAT STEP, BUT
IT SAYS THEE WEEKS WHICH SHOULD
BE 3 MONTHS, SORRY ABOUT ALL OF
THAT, ALMOST ALL THE EVENTS
OCCURRED AFTER THE FESTER COUPLE
OF INFUSIONS ASK LITERALLY ALL
OF THEM BEFORE ABOUT 3 MONTHS.
SO AND HERE I WILL SAY SLIGHTLY
GRADER THAN REMOVAL, THIS IS
WHAT [INDISCERNIBLE] EXPECTED
BUT SLIGHTLY MORE THAN I
EXPECTED GIVEN IT'S GOING AFTER
PROTOFIEB RULES, BUT IT'S
CLEARING PLAQUE AS WELL AND THEY
HAD A 59 CENTILLOID IN 18
MONTHS.
I WILL TALK ABOUT THIS BECAUSE
STEVE AND I TALKED ABOUT THIS
BEFORE IS ARIA ACTUALLY A MARKER
OF POTENTIAL TREATMENT RESPONSE
IN SO OVERALL TOTALLY WE NEED TO
MANAGE THIS AND HOPEFUL WILY GET
RID OF IT BUT IT DOES SEEM TO BE
ASSOCIATED WITH IMRAITER
RESPONSE.
I WILL SAY THERE'S MIXED EVIDENT
ABOUT WHETHER IT'S ASSOCIATED
WITH GREATER RATES OF ATROPHY OR
NEURODEGENERATION, SO EVEN IN
THE FIRST SPHENE 92 TRIAL IT WAS
NOTICED THERE WAS THIS EXPANSION
OF THE VENTRICLES AND GRAY
MATTER ATROPHY AS NICK FOX SAID
THIS CAUSES HYDROKEVA LIAISONS,
I THINK THIS STILL EXISTS THAT
THIS RAPID CLEARANCE IS SOC WIDE
BLOCKAGE OF THE ARACHNOID VILLI
AND THAT MAY RELATE TO ECPANGZ
BUT YOU DO SEE GREAT MATTER
ATROPHY AS WELL.
BUT INTERESTINGLY, IT'S IN MOST
OF THE CORTEX WHERE THE AMYLOID
SITTING IN YOU SEE LESS
HYPOCAMPAL ARK TROPHY OR AT
LEAST THERE'S LOTS OF LESS
AMYLOID WHICH MAY BE A CLUE TO
WHAT THIS ATROPHY MIGHT BE.
AND RECENTLY THERE'S BEEN
REPORTS OF REDUCTION IN G-FAB,
NFL AND PLAZ MIDS THAT TAU, THIS
WAS BACK IN THE BAPI DAYS WE
COULD SEE THAT ARIA WAS
ASSOCIATED WITH MORE OF A
REDUCTION IN P-TARK U.
THIS IS DOING SOMETHING
POTENTIALLY GOOD AND THE
NEURODEGENERATION SIDE WHILE
IT'S MOVING THE AMYLOID.
YOU ALREADY SAW THIS DATA FROM
DAVID BUT ALSO WE HAVE BEEN
WORKING ON WHAT IS THE LINE
BETWEEN AMYLOID REMOVAL AND
COGNITIVE OR CLINICAL BENEFIT.
THERE'S LOTS OF GRAPHICS LIKE
THIS BUT THERE IS A RELATIONSHIP
AGAIN BETWEEN THE REMOVAL AND
THE COGNITIVE DECLINE AND THE
RELATIONSHIP OF LIKELIHOOD OF
DEVELOPING ARIA.
NOW I WILL ESPOUSE 1
CONTROVERSIAL THEORY ABOUT THIS
BECAUSE IT HASN'T GO AWAY FOR
ME, WHICH IS THAT WHEN YOU
DISRUPT THE BLOOD BRAIN BARRIER
AND POTENTIALLY ALLOW MORE
THINGS TO CROSS, YOU ALLOW
ANTIBODIES TO CROSS AND THERE'S
DATA FROM WAY BACK IN 2013 THAT
IN AN ANIMAL MODEL OF ARIA, YOU
SAW MORE ANTIBODIES BIENING AND
MORE MICROFLI COLSISSA
ACTIVATION AROUND PLAQUE AND
IMPORTANTLY, I WAS TALKING TO
OTHER COLLEAGUES HERE, CHANGING
THE VESSELS, BEING ABLE TO CLEAR
THE AMYLOID OUT OF THE VESSELS,
I THINK HELPED THE VASCULATURE
IN CLEARANCE OF MULTIPLE OP A
THIES, POTENTIALLY, I THINK
MAKING THE VESSELS WORK BETTER
MIGHT HELP US IN CLEARING NOT
JUST AMYLOID BUT OTHER PROTEINS
AS WELL, I TALKED ABOUT ARIA E
BUT I WILL TURN TO TALK ABOUT
ARIA H AND THIS IS MORE
CHALLENGING, I THINK TO STUDY
BECAUSE IT DID OCCUR IN THE
NATURAL HISTORY OF ALZHEIMER'S
DEC, THIS IS A CASE FROM THE
MAYO CLINIC AND APOE 33 CARRIER
WHO HAD SPONTANIOUS ARIA H AND
YOU CAN SEE THE MULTIPLE
MICROHEMMAGES HERE AND AGAIN,
THIS HAS A PET SCAN SHOWING THIS
IS A PERSON WHO HAD VERY--WHO
ARE AMYLOID POSITIVE EVEN BEFORE
THEY HAVE SYMPTOMS.
WE'VE ALREADY TALKED ABOUT AND I
THINK THIS WILL BE IMPORTANT,
HEMASID RIN DEPOSIT IS ARK ROUND
HERE, THIS TO BE IS A RISK
FACTOR FOR MACROHEMORRHAGE LATER
AND I'M SURE TEEF OR OTHERS WILL
TALK ABOUT THIS AND OF COURSE
UNFORTUNATELY WHAT WE ALL WANT
TO AVOID WHICH IS MULTIPLE
HEMORRHAGES WHERE THIS BECOMES
REALLY A SERIOUS MEDICAL ISSUE.
SO I DO THINK THERE'S A STRONG
RELATIONSHIP BETWEEN APOE AND
ARIA E AND ARIA H AND I WILL SAY
THAT I WILL GO FURTHER AND SAY,
I THINK THEY ARE THE SAME
TECHNOLOGY TRANSFER.
I THINK THEY SHARE A
PATHOPHYSIOLOGY THAT ARIA E IS
JUST A LEAKAGE OF THE FLUID
WHICH IS TRAN YEBT ON FLAIR AND
IT GOES AWAY BECAUSE IT ABSORBS
OR DISSIPATES AND I THINK ARIA
IS THE LEAKAGE OF RED BLOOD
CELLS SO THAT THE HEMEAT O SIT
RIN IS THERE AND UNLIKE FLAIR
SEQUENCES LOOKING AT ARIA E, THE
ARIA H THE ECHO YOU WILL HAVE IT
FOR LIFE, CAN YOU SEE THIS FOR
YEARS AND YEARS MAYBE DECADES
LATER AND SO IT'S THERE.
THEY ARE OFTEN CO LOCALIZED AS A
SHOWED YOU BUT NOT ALWAYS WHICH
IS REALLY INTERESTING, SO OFTEN
YOU WILL SEE THIS AND ARIA H IN
THAT AREA AS I SHOWED THE
EXAMPLE OF THE TREAN TRACKS BUT
TIMES THEY ARE IN VERY DIFFERENT
PARTS OF THE PREAP XI THINK
THAT'S JUST BECAUSE WE MISSED
THE AREFRESH YOUR RECOLLECTION
IA E AND I'VE COME TO THINK
THERE'S ARIA H THERE WAS ONCE A
PUFF OF ARIA E BUT WE MISSED IT
BECAUSE IT'S TRANSIENT.
THE RISK FACTORS PANE ARE QUITE
SIMILAR ALTHOUGH SOME OF
THE--AND I WILL SHOW YOU THE
DATA SOME OF THESE SHOW LOTS OF
RISK WITH TREATMENT AND DON'T SO
MUCH DIFFERENCES IN ARIA H AND
IT'S HARDER TO TRACK THE
SYMPTOMS AND THE ARIA H BECAUSE
AGAIN, THE ONSET IS SOMETIMES
HARD TO SEAND HARD TO PINPOINT
ANYWAY TO GIVE YOU TEMPORAL
ASSOCIATIONS.
SO HERE ARE 2 I WILL JUST
HIGHLIGHT THE [INDISCERNIBLE]
AND [INDISCERNIBLE].
I HAVE JUST 1 MORE SLIDE.
I HAVE SHOWN HERE YOU HERE,
DONANEMAB IS HIGHER, AND I WANT
TO SEE IF THE RATES PERMONTH
DECREASED BECAUSE I THINK 1 OF
THE QUESTIONS IS: IS THIS
RELATED TO THE RAPIDITY OF
AMYLOID REMOVAL OR IS THIS
RELATED TO THE TARGETING
SYSTEMYS BECAUSE AGAIN DONAEMAB
IS GOING AFTER THE PROTOFIEB
RULES, IT DEVELOPMENTAL
ENDOCRINOLOGY FIT LE PULLS DOWN
FIEB RULES AND I DON'T KNOW IF
OR SOMEONE ELSE WILL TALK ABOUT
THIS BUT THIS PARTICULAR
ANTIBODY WENT AFTER THE ARTIC
MUTATION WHICH IS AN INTERESTING
AUTOSOMAL DOMINANT MUTATION THAT
DOESN'T SHOW A LOT OF FIBULAR
PLAQUE WHEN THEY DIE BUT THEY DO
SO C.ASM A. AND THIS IS BACK
SHOWN BACK IN NORBERG'S PAPER OF
15 YEARS AGO SO THERE IS
SOMETHING ABOUT THIS PARTICULAR
PROTOFIEB RULE THAT MIGHT BE
DIFFERENT IN HOW IT TREATS
PLAQUE AND VASCULAR AMYLOID.
AND THEN THE RECOLLECT
TECHNOLOGY TRANSFER I WANT TO
PONENT OUT IS THIS, THAT WHEN
YOU LOOK AT ISOLATED ARIA H,
MEANING NOT WHERE THERE'SATTIA E
IN THE CASE, YOU ACTUALLY SEE A
VERY SIMILAR RELATIONSHIP
BETWEEN PLACEBO, RATES AND
PLACEBO AND THE ANTIBODY.
AGAIN, SUGGESTING THAT ARIA H OR
MEEK ROUGH ATOM HEMMAGES ARE
OCCURRING IN THE NATURAL HISTORY
OF DISEASE AND AGAIN IT'S REALLY
WHEN WE SEE THE ARIA E, AND ARIA
H TOGETHER THAT IT'S MORE OF A
TREATMENT RELATEDAT ROUGH
ATOMIENIC C. A. A.
OKAY, THERE ARE 2 MAIN YEARS AND
STEVE AND I HAVE BEEN TALKING
ABOUT THIS FOR ARIA FOR A LONG
TIME, THIS IS A RESPONSE TO
AMYLOID THAT'S MOVING FROM THE
PLAQUES INTO THE PERIVASCULAR
SPACE PERHAPS, I WAS TALKING TO
SOMEONE ABOUT THE ROLE OF
APUNISHING OE IN THAT, AND THIS
IS SUPPORTED, I THINK BY SOME
WORK IN HERE TOMORROW ARK ROUND
THE C. A. A. R. I. SYNDROMES
WHERE YOU SEE IT INFLAMMATION
AND A DISCIPLINARY BEFORE PEOPLE
GET ARIA AND SYMPTOMS THEIR
ANTIBODIES RISE.
BUT I HAVE TO SAY THAT THE
TIMING OF ARIA E IN THE ASPECT
BODY TRIALS HAS ALWAYS BOTHERED
ME FOR THIS BEING THE PRIMARY
TECHNOLOGY TRANSFER BECAUSE THE
ARIA E OCCURS EARLY, IT OCCURS
VERY EARLY WHEN PEOPLE GETTICISM
TOPS DPG FOR A WEBBING OR 2,
THEY HAVEN'T MOVED ALL THAT MUCH
AMYLOID YET AND WE DOSE THEM
AGAIN IN THE PHASE 2 STUDIES OF
BAPI, WE DOSED A LOT OF PEOPLE
THROUGH ARIA, AND IT GOT LESS
OVERTIME EVEN THOUGH WE WERE
GIVING MORE AND MORE AND MORE
ANTIBODIES TO REF UP THE
INFLAMMATORY PROCESS, AND ALSO
THE TIMING OF THE AMYLOID
REDUCTION, ALTHOUGH IT'S EARLY
AUTOTILL CONTINUING WHEN THE
ARIA IS GONE EMPLOY SO AGAIN,
THERE'S NOT A PERFECT MATCH
BETWEEN THE INFLAMMATORY AND
ACTIVATION AND THE TIMING.
THE OTHER POSSIBILITY IS THAT
WE'RE REALLY ACTUALLY CHANGING
THE VESSEL STRUCTURE WHERE WE'RE
PULLING THE AMYLOID OUT OF THE
SMOOTH VESSELS MUCH I THINK THIS
IS LESS LIKELY ALTHOUGH THAT
KRRK-MAX, THE FACT THAT YOU GET
THIS VERY EARLY AND IT'S RELATED
TO HOW MUCH ANTIBODY YOU'RE
PUTTING IN THE BLOOD STREAM AND
IT IS THE CASE EVEN THOUGH IT'S
HARD TO MOBILIZE, I GUESS THE
AMYLOID OUT OF THE VESSELS THAT
YOU'RE SEEING, THOSE ANTIBODIES
ARE SEEING THAT END TERPINOUS
STICKING OUT OF THE VESSEL AS
WELL.
AND THIS IS DPEAN SUPPORTED BY
THE TIMING.
ALTHOUGH I HAVE TO SAY THIS
THEORY WAS COMPLETELY DISCOUNTED
IN MY THINKING BY THIS NEXT
REPORT WHICH IS ELECTOR REPORTED
TREM2 CAUSING AMYLOID, SO HERE
ARE 2 CASES AT A HAD.
I WAS PROBABLY THE ONLY 1 IN THE
WORLD THAT WAS THRILLED THIS
CAUSED ARIA BECAUSE IT WILL ITS
US ABOUT MECH INFORM, I'M SURE,
ELECTRA WAS NOT HAPPY AND
UNFORTUNATELY DID HAVE TO CHANGE
DOSING IN THEIR APOE CARRIERS
BUT I THINK IT'S IMPORTANT ABOUT
AM, AND THIS BODY IS NOT SEEING
THIS IN THE VESSELS AND I HAVE
TO SAY I'M MAKING A DICHOTOMY
HERE BUT CERTAINLY IT'S SOME OF
EACH BECAUSE AGAIN IF YOU
DISRUPT THE VESSEL WALL AND YOU
GET MORE ANTIBODY CROSSING,
SETTING UP MORE OF A MICRODPLEEL
OR INFLA AMATORY RESPONSE, THAT
WILL BE SOMEWHAT
SELF-PERPETUATING.
SO WHAT DO WE NOT YET KNOW ABOUT
ARIA SO 1 OF THE BIGGEST THINGS
WE NEED TO UNDERSTAND IS WHAT IS
THE RISK FOR RELATIVELY RARE
CASES?
IN GENERAL THEY LACK OVER ALL
SAME RISK FACTORS MORE LIKELY
CERTAINLY--CERTAINLY 4 CARRIERS,
MORE LIKELY WITH HIGH DOSE BUT
THERE'S A REALLY POOR
CORRESPONDENCE BETWEEN HOW BAD
THE MRI LOOKS AND THE SYMPTOMS,
SO PEOPLE CAN GET VERY
SYMPTOMATIC AND VICE VERSA, SOME
OF THOSE MRs I SHOWED YOU WITH
RIP ROARING, DEMA THOSE PEOPLE
ARE LARGELY ASYMPTOMATIC.
I SUSPECT THOUGH THAT MORE
INFLATION ASSOCIATED WITH
IMRAITER SYMPTOMS SO WOE
DEFINITELY NEED BETTER
PERRIFFERAL BIOMARKERS MUCH IS
IT DONE?
OKAY, NEED TO TALK ABOUT THE
RISK FOR H CASES AND ESPECIALLY
TRY TO DECREASE THE RISK AND
I'LL END THERE BY SAYING I THINK
I TOTALLY ARK FREE WITH 1 OF
THE--AGREE WITH 1 OF THE WAYS TO
DECREASE THIS RISK IS TO GO
EARLIER AND PEOPLE WHO DON'T YET
HAVE AMYLOID THOUGHT INTO L
VESESYS SO WE CAN PREVENT
AMYLOID ARK KIEWMULATION BEFORE
IT ENDS XI WANT TO EPPED WITH
GRATITUDE FOR THE GREAT PEOPLE
I'VE WORKED WITH ON THIS FOR SO
LONG.
THANK YOU.
>> OKAY, THANK YOU SO MUCH
REFRESH YOUR RECOLLECTION EISA,
THAT WAS TERRIFIC.
THE NEXT SPEAKER IS STEVE
GREENBERG FROM MGH, HE'S AN
EXPERT IN CAA, AND CAA-RELATED
INFLAMMATION AND I THINK SOME OF
OUR MORE SERIOUS CASES WITH ARIA
ARE A TYPE OF ANGIEITEIS THAT
RESEMBLE CAA.
SO WE'RE LOOKING FORWARD TO
THIS.
>> I THINK I KNOW EVERYBODY IN
THE AUDIENCE, THERE WAS 1 OTHER
ALTERNATIVE, 1 OTHER ALTERNATIVE
TO ARIA, IT'S REGIONAL SEN
ILLEGALSEN SEVERE MITRAL LO
PATHIC IT'S TURNED OUT REISA
TERM, AND SHE DIDN'T GO FOR
THAT.
SO THESE ARE MY DISCLOSURES AND
I SHOULD MEPGZ PRIOR TO THE 2
YEAR WINDOW I DID SAFETY
MONITORING FOR [INDISCERNIBLE]
AND [INDISCERNIBLE] SO I'VE BEEN
INVOLVE MOSTLY AS A SAFETY
MONITOR IN IN FIELD.
I WANT TO GIVE 1 AREA IN
BACKGROUND INTO CAA, HAD IS
OBVIOUSLY BEEN PART OF A LOT OF
THE DISCUSSION AND WILL TYPESET
TO BE, AND THEN FOCUS ON THIS
QUESTION THAT INTRODUCE THE
RELATIONSHIP BETWEEN
INFLAMMATORY SITUATION ASK ARIA,
AND STARTING WITH THE PATHOLOGIC
FRAMEWORK, HERE I WILL TALK
THANK JUST A SUBSET OF MANY
PEOPLE ININVOLVED WITH THE WORK
WE'VE DONE OVER THE YEARS IN
CAA, AND COLLABORATION IN PEOPE
STUDYING THE DUTCH TIME OF CAA,
WHICH HAS BEEN INFORMATIVE IN
THE FAMILIAL ALZHEIMER'S BEEN
ABOUT THE PATHOGENIC TEPS IN A.
D.
SO THIS IS A BACKGROUND PEEL
WILL BE FAMILIAR WITH.
AND WALTER MENINGED HIS TEACHER
AND MY TEACHER IN THIS AREA WAS
JOHN PAUL [INDISCERNIBLE] WHO IS
RESPONSIBLE FOR ALL THE
PATHOLOGIC IMAGES YOU SEE HERE,
O THIS IS REALLY 1 OF JUST, I
WOULD ARGUE 2 COMMON ANAL
RELATED SMALL VESSEL
PATHOLOGIES, ALONG WITH
SCLEROSIS, AND WOP META,A
MALSIS, AND APPROXIMATELY 80% OF
THAL JEIMERS BREANS AND MODERATE
TO SEVERE CAARK THE LEVEL THAT
WE THINK WITH BE CAUSAATIVE OF
SYMPTOMS IN 50% SO IT'S QUITE,
QUITE HIGH OVERLAP, THE
PATHOLOGIC IMAGES SHOWN HERE
DEMON TRAIT THE PROGRESSION FROM
THE FIRST DEPOSITS IN THE OUTER
PART OF THE MEDIA LIKELY BECAUE
OF THE PERIVASCULAR DEPARTMENT
IS LOCATED AND REPLACING SMOOTH
MUSCLE CELLS AND THE LEADING TO
THE NECROSIS STAGES AND I WILL
COME BACK TO THE POINTS THAT
WALTER RAISED ABOUT THE ROLE OF
ACTIVE ENFLAMMA ARE TOY STEP IN
REMOVING AMYLOID IN SPON SPONTAS
CAA, AND MENTIONED FOR TOXIC
PROTEINS SO HEMORRHAGIC LESIONS
HAVE BEEN THE HALLMARK OF
DIAGNOSTIC FACTOR FOR CAA AND
RECENT MENTION THE LARGE
HEMORRHAGES AND MICROPLEADS BUT
ALSO THE CORTICALE SUPERFICIAL
CLEROSEIS WHICH IS A HEMORRHAGIC
MANIFESTATION OF CARK A, AND
THEN A WIDE RANGE OF
NONHEMORRHAGIC LESIONS, WHITE
MATTER, HYPER TENSITYS,
DIFFUSION DENSER CHANGES,
MICROINFARCTS AND THEN THE LARM
PERIVASCULAR SPACES IN THE
SEMESTERIOLE VALLEY THAT ARE
REFLEKS OF THAT ALTERED VASCULAR
PHYSIOLOGY AND ALTERED CLEARANCE
OF AMYLOID AND IN FACT, THIS HAS
BEEN INCORPORATED IN THE MOST
RECENT UPDATING OF THE BOSTON
CRITERIA ARK HAL SIS LED BY
ANDREAS, AND THE COLLABORATION
THAT EXTENDED THE DIAGNOSTIC
FEATURES, THAT INCLUDE NOT JUST
THE HEMORRHAGIC MARKERS THAT
HAVE BEEN THE HALLMARK FOR
DIGITEXTING KRRK ARKANSAS PAYS
BUT TO INCLUDE NONSIMILAR
HEMORRHAGIC MARKERS IN THIS
MULTISPOT PATTERN OF WHITE
MATTER HYPER DENSITIES AND
IMPROVING BOTH THE SENSITIVITY
OR IMPROVING SENSITIVITY WITHOUT
COMPROMISING THE SPECIFICITY OF
THE DIAGNOSTIC CRITERIA.
AS CAN YOU SEE ON THE RIGHT THAT
IN THE POOLED AWPS BASED
ANALYSIS THIS IS QUITE SENSITIVE
AND SPECIFIC FOR HEMORRHAGIC
PRESENTATIONS ABOUT YOU FOR
PEOPLE WHO DON'T HAVE
MACROHEDGEERAGES, THE
SENSITIVITY IS LOWER MEANING
WE'RE STILL NOT CAPTURING THE
STILL PATHOLOGICALLY ADVANCED
BUT NOT YET GROSSLY HEMORRHAGIC
STAGES OF CACE AND THERE'S TILL
A LOT WE'RE NOT DIAGNOSING AND
THIS COMES UP IN THE ROLE OF
UPDIAGNOSED CAA AS A POTENTIAL
TRIGGER FORRIA, AND THEN THE
PATHOGENIC FRAMEWORK IS BASED ON
STUDIES PRIMARILY OF THE DUTCH
TYPE HEREDITARY CAA.
AND THIS IS MEANT TO BE
ACONDITION TO OUR UNDERSTANDING
FOR THE PRESYMPTOMATIC TAIJS OF
ALZHEIMER'S DISEASE WHERE
THERE'S INITIAL AMYLOID
DEPOSITION IN THE DUTCH TYPE
HEREDITARY CAA HAPPENS ON THE
ORDER OF 3 DECADES BEFORE FIRST
HEMORRHAGE, CAN YOU MEASURE 2
DECADES BEFORE HEMORRHAGE,
ALTERED VASCULAR PHYSIOLOGY,
VASCULAR REACTIVITY TO
PHYSIOLOGIC STIMULATION AND THEN
A DECADE BEFORE IT CAN ALREADY
MEASURE NONHEMORRHAGIC CHANGES
AND THE INDIVIDUAL LEVEL DATA
SHOWN ON THE RIGHT, THE--WE
DON'T MAKE MUCH OUT OF WHERE THE
LINES CROSS BECAUSE THAT JUST
REFLECTS THE STANDARD DEVIATION,
BUT THE CLEAR PROGRESSION OF
FIRST AMYLOID DEPOSITION AND
VASCULAR REACTIVITY IMAGES AND
THEN WHITE YOUR AND AT ITS MOST
ADVANCED TAIJ IS HEMORRHAGE.
AND FOCUSING ON THE HEMORRHAGE
STAGE AND THIS IS THE POINT THAT
WALTER ALLUDED TO IN HIS
INTRODUCTION, IT'S BEAUTIFUL
WORK BY COLLEAGUES USING EXVF O
IMAGING OF TO IDENTIFY
MICROPLEADS AND THEN LOOK AT THE
PATHOLOGY ASSOCIATED WITH
MICROBLOODING AND AS IS SHOWN IN
THE LEFT, THERE'S THIS
INTERESTING VASCULAR REMODELING,
LIKE REMODELING YOUR BATHROOM
BUT IN FACT, IT'S THIS--THE
VESSELS THAT ARE MOST CLOSELY
ASSOCIATED WITH MICROPLEADS ARE
DEVOID OF AMYLOID, THEY'RE NOT
AT ALL DEVOID OF MUSCLES BUT YOU
CAN SEE THEM REPLACED WITH FIEB
RIN O GEN AND OTHER JUNK THAT
HAS NOW INFILTRATED INTO THE
VESSEL WALL AND THE PARTNERSHIP
ON THE RIGHT YOU WILL SEE THAT
AROUND THESE GRADE 4 VESSELS,
THE 1S THAT HAVE THE VUSESLE
REMODELING THERE'S INCREASED
GFAPP, INCREASED CD68 STAINING,
FOR ASTRO SIGNIFYITOSEIS AND
MICROFLEEL, I'M NOT SHOWING HERE
BUT IN MARROW STUDY THERE'S
INCREASED ITG STAINING IN THE
BRAIN AROUND THE VESSELS ARGUING
FOR SOME LEVEL OF BLOOD BRAIN
BARRIER BREAK DOWN.
SO THIS RAISES THE IDEA THAT
THERE'S A KIND OF INFLAMMATORY
COMPONENT TO, AND THIS IS ALL
SPONTANEOUSLY OCCURRING, NOT
PART OF AN ANTIBODY TRIAL.
SO TO SUMMARIZE WHAT I SAID SO
FAR, IT'S LIKELY THIS CAA LIKE
A. D. IS A DECADES LOPPING
PROCESS THAT WE HAPPENING IS
DRIVEN BY THE FAILURE OF
PERIVASCULAR AMYLOID CLEARANCE.
IF THE STEP IS INVOLVED FROM
HEMORRHAGIC TO TO THE BRAIN
INJURY AND SUGGESTION THAT EVEN
IN WHAT'S APPARENTLY
NONINFLAMMATORY CAA, MAY HAVE AN
INFLAMMATORY COMPOENT.
NOW TURNING TO CAI AND ARIA,
THESE HAVE BECOME FAMILIAR IN
THE CA COMMUNITY AND A NUMBER OF
NEUROLOGISTS AND IMAGES THAT
WILL TRIKE PEOPLE INVOLVED IN
THE TRIALS AND IT'S LOOK BEING
LIKE ARIA AND THAT'S THE POINT
OF MY TALK AND THESE ARE
SYNDROMES WHERE PEOPLE--OF
COURSE WE DON'T SEE THE ARK
SYMPTOMATIC PEOPLE UNLESS WE
HAPPEN TO CATCH THEM BUT PEOPLE
ARE PRESENTING SYMPTOMATICALLY
WITH MORE RAPID COGNITIVE
DECLINE THAN THEIR BASE LINE
SEIZURE, HEADACHES, THE CSF IS
ALMOST ALWAYS CHOSE ELERATED
PROTEIN ALTHOUGH OFTEN A NORMAL
CELL COUNT AND INTERESTING POINT
THAT WAS ALLUDED TO IN THE
DIFFERENT CSF FORMULA IN THE
AMFEIGN 92 CASES.
MRI WITH THE VASE O GENIC EDEMA,
BUT MANY OF THESE PEOPLE WERE
BIOPSIED ESPECIALLY WHEN THE
DIAGNOSE WAS DIFFICULT TO MAKE
BY IMAGING ALONE AND THE TYPICAL
PATTERNS AS SHOWN HERE WAS THE
INFILTRATION, NOT SO MUCH WITHIN
THE VESSEL WALL BUT AROUND THE
VESSEL WALL BUT TRIECTLY AROUND
THE AMYLOID CONTAINING SEGMENTS
SO C AA, IS A PATCHY PATHOLOGY,
YOU WOULD NOT SEE THIS AROUND
VESSEL SEGMENTS BUT AROUND THE
AMYLOID VESSEL SEGMENTS.
A LOT OF VISUAL EVIDENT THIS IS
AN AUTOIMMUNE RESPONSE TO
AMYLOID SUCH AS MULTINUCLEATED
CELLS THAT HAD AMYLOID TAPING
THAT HAD BEEN UNGULFED INTO THE
MULTINUCLEATED GIANT CELL.
SO TO YOUR EYE THIS LOOKS LIKA
AN ANTIAMYLOID INFLAMMATORY SIN
TROAM.
[INDISCERNIBLE] WAS, WOOING
BOSTON PROPOSED THIS CRITERIA
FOR PROBABLY CAA RELATED
INFLAMMATION AND IT'S BEST TO
SEE IT ESPECIALLY IN THE IDEA IS
THAT IF YOU SEE THE PATTERN YOU
DON'T HAVE TO PERFORM A BIOPSY,
IT'S GOOD FOR THE PATIENTS IT'S
ACTUALLY BAD PER SCIENCE BECAUSE
WE NO LONGER REGULARLY GET
TISSUE FROM PEOPLE WHERE THE
DIAGNOSIS IS RELATIVELY CLEAR
CUT.
AND THEN I WILL MAKE THE ARGUE
AM AND REISA RAISED THIS
QUESTION, BUT THERE'S A LOT TO
SAY THAT CARKANSAS RELATED
INFLAMMATION ISI 85ULENT OF THE
SPONTANEOUS VERSION OF--WE WANT
TO MAKE THE DIAGNOSIS OUTSIDE
AND THE PATTERN WITH THE
VASO-GENIC AND THE SURROUNDING
AREA, AROUNDLET EDEMA LOOKING
ARE VERY MUCH LIKE WHAT REISA
SHOWED IN THE PREVIOUS STUDY AND
I WILL NOT TAKE AWAY FROM THE
TALK TOMORROW BUT JUST TO SHOW A
COUPLE, I HOPE YOU WILL FORGIVE
ME OF HIS WORK, YOU KNOW REALLY
STRENGTHENING THIS TIE, THE
FINDING OF AUTOANTIBODY IN
SPINAL FLUID OF PEOPLE WITH
ACTIVE PHASE OF THE A. P. OF
CAARK-RELATED INFLAMMATION AND
HOSE PET IS IT THES USING THE
MARKER FOR MICROFLI COLSISSA
SHOWING A PARTIAL OVERLAP OF
BASIC EDEMA AND MICROGLIAL
ACCUMULATION EMPLOY SO AGAIN TO
MAKE THIS ARGUE AM, THERE'S BOTH
SYNDROMES SHOW INCREASED,
OVERREPRESENT EGG OF E4,
PARTICULARLY HOMOWRIEG OATS, SO,
SHOWN AT THE TOP WAS A SERIES
THAT ROBBIE [INDISCERNIBLE]
PUBLISHED A COUPLE YEARS AGO AND
AT THE BOTTOM THIS IS FROM THE
STUDY ASK SIMILAR RESULTS OF
COURSE IN OTHER ANTIBODY STUDIES
SHOWING AN OVERREPRESENTATION OF
E4 CARRIERS IN PARTICULAR, E4
HYM O ZYGOTES, SHARED RISK
FACTOR PREEXISTING MIKE ON
BLEEDS, THE LOCATION OF THE
EDEMA AND THE ROLE OF AUTO,
EITHER EXOGENOUS OR ENDOGENOUS
ANTIBODIES TO AMYLOID, AND JUST
TO MENTION A LITTLE BIT ABOUT
THE CLINICAL SYNDROME SO THIS IS
AN IMPERRIC IMMUNOSUPPRESSIVE
REGIMEN THAT WE USE AT OUR
HOSPITAL, THERE ARE NO
RANDOMIZED DATA OR ANYTHING
CLOSE TO RANDOMIZED DAILY BASIS
THEA IN THIS FIELD BUT IN THIS
PAPER PRACTICES ROBBIE REGENHART
PUBLISHED IN OUR GROUP, SOME
PEOPLE DO GET BETTER SO IT'S NOT
COMPLETE GIVEN THAT TREATMENT IS
REQUIRED BUT THERE IS AMONG
PEOPLE IN THE NONRANDOMMIZED
BSKSAL STUDY WHO RECEIVED IMMUNO
SUPPRESS OF TREATMENT BY THIS
PROTOCOL HAD BOTH CLINICAL AND
RADIO GRAPHIC IMPROVEMENT THAT
APPEARED TO BE IN RESPONSE TO
THIS, DOESN'T SEEM TO BE JUST
REGRESSION TO THE MEAN BUT
RESPONSE TO THE
IMMUNOSUPPRESSION.
AND JUST AN INTERESTING
OBSERVATION WHERE I DON'T KNOW
HOW TO PLACE THE
INPOLICEMANNATION SYNDROME THAT
THERE WAS A LOWER RISK OF
OCCURRENCE, FOR MANY PEOPLE,
PARTICULARLY THE UNTREATED
PEOPLE WOULD SPONTANEOUSLY GET
BETTER AND SHOW A REPEATED
FLAIR, THE REPEATED PLAYERS OF
THE CAA RELATED INFORMATION WERE
IN THE BRAIN LOCATIONS SINCE THE
INITIAL PRESENTATION AND AGAIN
IS QUITE--I THINK BIOLOGICALLY
QUITE INTERESTING BUT THE PEOPLE
WHO RECEIVED IMMUNOSUPPRESSION
WERE LESS LIKELY, NOT--MORE
LIKELY TO SHOW SHORT-TERM I
IMPROVEMENT AND LESS LIKELY TO
HAVE RECURRENCE OVERTIME AND
THIS IS AN ARGUMENT THAT COMES
UP TIMES ABOUT WHETHER TO TREAT
SOMEBODY WITH MINIMAL SYMPTOM
ANDS CAARK-RELATED
INFLAMMATION
IN TREATS PEOPLE WITH SYMPTOMS.
AND TO COMMENT ON THE NEXT FEW
SLIDES ON THE BLEEDING
RELATIONSHIPS.
I THINK IT'S IMPORTANT TO SAY
THAT ARIA H AND E ARE IMPOSSIBLE
TO BUILD MATILY LNK EXCLUDE THIS
IS PRESUMABLILY SEPARATE FOR THE
APPEARANCE OF MICROBLEEDS AS
REISA ALLUDED TO BUT
MICROBLEEDING AND QUITE COMMON.
HEMORRHAGE IN THE THERE IS RARE,
BUT OTHERS HAD AS WELL, BUT IT'S
AN UNCOMMON FEATURE AND RAISES
INTERESTING QUESTIONS ABOUT WHY
A BLEED IS A MICROBLEED RATHER
THAN A MACROBLEED.
I THINK SHERRY IS PRESENTING ON
THIS SO I WON'T STEP ON THAT,
BUT IN THE SETTING OF TP
A TREATMENT HAD MULTIFOCAL
MACROBLEEDING SO EVEN THOUGH
IT'S A RELATIVELY MINOR PART OF
THE SPONTAKENIOUS SYNDROME, IT
RAISES IMPORTANT CLINICAL
QUESTIONS.
SO I WILL CONCLUDE HERE SO THAT
I WILL MAKE THE ARGUMENT TO THE
FIRST APPROXIMATION THAT
ARE--ADMINISTRATIVE RAW DATA IS
THE KRRK AA-REFRESH YOUR
RECOLLECTION I AND ARIA
INPOLICEMANNATION, SHORT-TERM
AND LONG-TERM RESPONSE TO
IMMUNOSUPPRESSION, I THINK THIS
WILL REGENERALLIZE ARIA, WHETHER
THIS IS PREVENTING THE
GENERATION OF ASPECT BODIES IN
WHICH CASE IT WON'T HELP IN
TRIAL RELATED ARIA TREATMENT,
RELATED ARIA OR IF IT'S REDUCING
THE RESPONSE AND WE DON'T HAVE A
GOOD WAY TO KNOW THAT FROM THE
SPONTAKENIOUS SYNDROME AND THEN
SYMPTOMATIC ICH IS RARE BUT
RAISES CONCERNS ABOUT
ANTITHROMBOTTICS AND I JUST
SHOWED HERE 1 OF MANY STUDIES
SHOWING THAT ANTICO AGULATE
RELATED HEMORRHAGE IS 1 OF THE
MOST DEADLY DISEASES IN
MEDICINE, IT'S SHORT-TERM
MORTALITY, 50% ARE NOT THAT MANY
DISEASES HA HAVE A SHORT-TERM
MORTALITY OF 50%.
SO AND CONSIDERATION IN
PARTICULAR OF ANTICO AGULATES OR
THROMBO LYTICS IN THE SEEING OF
ARIA RAISES WHAT CAN BE A TRULY
DIRE COMPLICATIONS AND WITH THAT
I THANK YOU VERY MUCH.
>> THANK YOU, THE FLOOR IS OPEN.
WE HAVE A COUPLE OF MINUTES FOR
QUESTIONS MUCH
QUESTIONS.
PLEASE COME TO THE MIKE AND
BRUCE WROWRS AND ASK QUUR
QUESTION SPHRKS I AM LIAA FROM
UNIVERSITY, THE ENLARGEMENT OF
THE VENTRICLES YOU ARE DRIEBING,
DO YOU THINK THIS IS A SIGN OF
IMPAIRED PLURIBU EDUCATIONAL
HOMEIO STASES OR REFLECTING
ATROPHY?
>> SO I DON'T WE THINK WE KNOW
EMPLOY NICK FOX AND OTHERS THINK
IT WAS A TRANSIENT INCREASE IN
A-BETA IN THE CSF WHEN YOU GET
THE ANTIBODIES OR THE VACCINE.
WHETHER THAT'S CHANGING IT
BECAUSE IT'S ONLY OUT OF
PROPORTION TO THE GRAY MATTER
LOSS.
BEAUTIFUL TODAYS OF THIS, THE
VENTRICULAR ENLARGEMENTS EARLIER
AND EARLIER THAN THE GRAY MATTER
LOSS SO PROBABLY SOME OF EACH.
>> THE SECOND QUESTION I HAVE
QUICKLY IS HOW DO THE PRACTICING
MENTORSHIP SKILLS ONCE THEY ARE
EATEN UP OR UNGULFED WITH
ANTIBODY TREATMENTS, HOW DID
THEY DISAPPEAR?
>> THEY GO IN THE KIDNEY, THAT
MUCH I KNOW.
>> DO WE NEED THE
[INDISCERNIBLE] DISRUPTIONS TO
GET RID OF THEM NYES, I GUESS
THAT'S ANOTHER QUESTION, MAYBE
OTHERS CAN ANSWER THAT IN NI
THINK WE'RE FIGURE--WE'RE MOW
GETTING INTO THE TERRITORY WHERE
WE SHOULD MOVE ON TO THE NEXT
TALK AND CONTINUE THE
DISCUSSION, WE JUST HAD TIME FOR
LIKE 1 QUESTION.
SORRY ABOUT THAT SO DR. JAMES
NIERK KRRK CORRELATED
LL UNIVERSITY OF SOUTH HAMPTON.
>> HI, HELLO THERE, HOPEFULLY
YOU CAN HEAR ME.
YES, I AM VIRTUAL, YEAH.
MANY APOLOGIES THAT I CAN'T YOIN
YOU IN PERSON TO DISCUSS THIS
IMPORTANT TOPIC.
I WILL GIVE MY TALK ON ZOOM BY
SHARING MY KREEN IF THAT WILL
WORK.
IT'S TELLING ME I CAN'T SHARE MY
SCREEN BECAUSE ANOTHER
PARTICIPANT IS SHARING SHARING.
LET ME JUST TRY THAT AGAIN.
YEP, HOPEFULLY YOU CAN SEE MY
SHIED THERE AND HEAR ME.
I WANT TO DO MY SCREEN SHARING
SO THAT YOU CAN SEE MY POINTS SO
I CAN POINT AROUND VARIOUS
THINGS I WANT TO SHOW.
SO THIS IS THE TITLE I'VE BEEN
GIVEN BE TO TALK TO.
NEUROPATHOLOGY OF ARIA IN
PATIENTS GIVEN ANTIBETTA
ANTIBODIES.
HERE ARE DISCLOSURES.
>> YAIMS WAIT FOR JUST A
SECURITIZATION., I THINK YOUR
SLIDES AREN'T SHOWING YET,
SOMEONE WILL FIGURE IT OUT.
>> OKAY.
SORRY, IS THAT BETTER?
NYOU'RE GREAT TO GO.
>> YOU CAN SEE THAT ALL RIGHT
IN.
>> YES NWE LOST YOU BUT WE GOT
THE SLIDES.
SO THIS IS THE TIELTS I'VE BEEN
GIVEN NEUROPATHOLOGY PATIENTS
WITH ARIA.
'RE GIVEN ANTIBETTA ANTIBODIES.
THE PROBLEM IS WE DON'T HAVE ANY
NEUROPATHOLOGY OF ARIA IN PEASHS
WHO HAVE HAD PASSIVE IMMUNIZE
WITH ANTIBODY THERAPY AS LEAST
AS FAR AS I'M AWARE AND I THINK
THAT'S AN IMPORTANT POINT TO
MAKE EMPLOY WE NEED SOME TISSUE
STUDIES IN PATE WHO IS HAD THESE
PASSIVE VACCINES AND HAD ARIA,
BUT I WILL ARGUE THERE ARE CLOSE
SIMILARITIES WITH THE SIDE
EFFECTS EXPERIENCED 1792 WHICH
AT THE TIME WAS TERMED MENING
OENCEPHALITIS.
THIS IS THE FIRST TODAY AND
IMMUNOTHERAPY IN ALZHEIMER'S
TEASE SO IN SPHENE 92 WAS
IMMUNIZATION WITH FULL LENGTH,
PEPTIDE ANDS ADJUVANT CAN THIS
FIRST STUDY WAS A SMALL STUDY OF
80 PATIENTS; MILD TO MODERATE
ALZHEIMER'S DEC.
AND WE'VE BEEN FOLLOWING UP WITH
PATIENTS IN THAT FIRST STUDY
OVER MANY YEARS AND WE'VE SEEN
THE BRAINS OF 22 OF THE 80
PATIENTS WHO WERE IN THAT
INITIAL STUDY SO THESE ARE
HISTOLOGICAL SECTIONS OF
SEEREBERAL HEMISPHERE, THE BLACK
STAINING HERE IS IMMUNO
CHEMISTRY, SHOWING WHERE THE
PLOTS ARE IN THE CORTEX.
FIVE PATIENTS STARTED TO HAVE
VERY SENSITIVE PLOT CLEARANCE,
NO PLAQUES IN THE BRAIN, OTHERS
HAD LARGE PATCHES OR SMALLER
PATCHES OF PLAQUE REMOVAL.
THIS IS SOME QUALIFICATION OF
AB LOAD IN THE IMMUNIZED
ALZHEIMER GROUP AND THE GROUP OF
UPTREATED ALZHEIMER'S DEC, ABOUT
YOU IN CONTRAST TO THE PLAQUE
REMOVAL, IT WAS A VERY
SUBSTANTIAL INKRES IN THE
SEVERITY OF THE CAA WHEN WE
QUANTIFY THE CAA.
SO BOTTOM ROW OF IMAGES HERE IS
TRYING TO SHOW IN EFFECT A TIME
SEQUENCE OF WHAT'S HAPPENING
HERE.
SO UNTREATED ALZHEIMER'S
DISEASE, HERE ON THE LEFT IS ARE
THE PLOTS, THEN AFTER TREATMENT
THEY DISAGGREGATE IN THE WALLS.
AT THE LATER STAGE THE PLAQUES
HAVE GONE BUT A LOT OF SEVERE
CARK A, OF THE BLOOD VESSELS AND
THEN IN THE LATER CASES
SUGIETION THAT AT A LATER STAGE
THE PLAQUES HAVE GONE AND CAA,
HAVE GONE FROM THE
[INDISCERNIBLE] AS WELL.
SO WE'VE LONG KNOWN ABOUT THE
CONCENTRICS OF THIS AND HOW THE
APPEARANCE ARISES THAT IT'S
DEPOSITED IN THE VESSEL AND THE
MEDIA HERE AND SO THE SEVERE
CARK A, THE ABETTA FIBERALS
DESTROY THE SMOOTH MUSCLE CELLS
IN THE MEDIA OF THE BLOOD VESSEL
AND THEN THE AMYLOID IS REMOVED
FROM THE VESSEL WALL, LEAVING
THE SPACE WHERE THE MEDIA SMOOTH
MUSCLE CELLS HAD BEEN, SO THIS
IS A VERY WELL KNOWN FEATURE OF
PATIENTS WITH SEVERE CAA.
AND SO, WHEN WE QUANTIFIED THIS
SPECIFIC FEATURE IN THE
IMMUNIZED AD CASES THERE WAS
MORE OF IT, MORE CONCENTRICS FOR
THE WALL IN THE UNTREATED
ALZHEIMER CASES.
SO REFLECTING SEVERE CARK A, AND
THEN REMOVAL OF A-BETA PRACTICES
THE VESSEL WALLS.
THERE WERE ALSO MICROBLEEDS, YOU
CAN SEE HERE STAINING THE
SHOWING CLUSTERS OF OF IRON
CLICKS, THIS IS THE NUMBER OF
MICROPLEADS AND QUITE VARIABLE,
CAN YOU SEE THE CASES HAVE QUITE
A LARGE NUMBER OF MICROBLEEDS
COMPARED TO UNTREATED
ALZHEIMER'S DEC DOWN HERE.
THERE WERE ALSO OTHER LESIONS
THAT DIDN'T OBVIOUSLY CONTAIN
IRON PIGAMENT, HE'S
MICROVASCULAR LESIONS ARE NOT
ENTEARLY CLER WHETHER THEY WERE
MICROPLEADS IN WHICH THE PIGMENT
HAD BEEN CLEARED OR WHETHER THEY
WERE MICROINFARCTS BUT THEY WERE
ALSO PRESENT.
SO THESE ARE IMANNUALS FROM THE
1 OUT OF THE 22 CASES THAT WE
COULD STUDY THE NEUROPATHOLOGY
OF WHO HAD ARE--ADMINISTRATIVE
KRAMER, I THINK WE COULD CALL
THIS ARIA NOW.
SO THIS WAS THE MRI KAN--KANA
DURING LIFE, SO CAN YOU SEE THIS
FOCAL WHITE MATTER SIGNAL CHANGE
IN THE OCCIPITAL LOBE HERE,
POSTMORTEM OCCIPITAL LOBE SHOWS
STAINING FOR MILEIN, AND WHITE
MATTER AND HIGH POWER SHOWS
AGAIN MILEN TAINING AND SOME
ENLARGED PERIVASCULAR SPACES
WHICH HAS TEEF MENTIONED CAN BE
ASSOCIATE WIDE SEVERE CARK A,
AND THE UNDERLYING CORTEX AND
MEN I THINKIS, SO THIS IS HIGHER
POWER HAVE VIEWS OF THAT CASE,E
CAA, WITH ABSENCE OF SURROUNDING
PLOTS AND CORTEX, OVER HERE TOP
LEFT, YOU CAN SEE THIS IS
CONCENTRIC, POLITTING OF THE
VESSEL WALL WHICH I THINK
REFLECTS AMYLOID REMOVAL, SOME
INPOLICEMANNATORY CELLS,
CLUSTERED AROUND WHICH CHEMISTRY
SHOWS T-HISM O SIGHTS AND THE
WHITE MATTER, THIS IS THE
REFLECTION OF WHITE MATTER AND
HERE'S A MICROPLEAD IN THE
CORTEX.
THAT 11 CASE IF OUR SERIES, THE
SEBS QUENT CLINICAL TRIAL THAT
WAS DONE SO THIS IS DESCRIBED BY
[INDISCERNIBLE] AND LIKEWISE
SHOWS PALLET OF MILEIN STAINING
IN THE WHITE MATTER HERE
ASSOCIATE WIDE SEVERE KRRK ARK
A, AND INFLATION SORB WIDE THE
ABNORMAL BLOOD VESSELS.
SO AS FAR AS I'M AWARE, THESE
ARE THE 2 CASES WHERE THEY'RE
THERE, AND BOTH WITHIN 1592 AND
THE VACCINE AND WE REALLY NEED
SOME TOPOLOGY OF ARIA IN PASSIVE
IMMUNOTHERAPY TO SEE WHAT
SIMILARITIES AND DIFFERENCES
THEY MAY BE.
SO ON THE BASIS OF THOSE 2 CASES
AND BACKGROUND BIOLOGICAL
THINKING, SOME YEARS AGO, WE
DEVISED THIS SCHEME.
WE DEVISED THIS AS A
PATHOLOGICAL SYSTEM FOR ARIA.
SO HERE'S A PLAQUE IN THE CORTEX
OF SOMEBODY WITH ALZHEIMER'S
DISEASE, SO ANTIBETTA ANTIBODIES
ENTER THE BRAIN BEHIND THE
PLAQUE AND DISRUPT THE PLAQUE
THIS RESULTS IN INCREASED
SOLUBLE WHICH TRACKS TO THE
VASCULATURE RESULNOTHING
INCREASE IN SEVERITY OF CAA, THE
ANTIBETTA ANTIABOUT BODIES MAY
BE BIEBDING DIRECTLY TO THE
VESSEL WALLS AND THERE MAY BE AN
IPT GREATER FLAMMATORY REACTION
ASSOCIATED WITH THESE CHANGES IN
THE BLOOD VESSELS AND ALTOGETHER
THESE CHANGES ARE TOGETHER IN
THE MICROPLEAD ANDS ALSO IN THE
WHITE MATTER AND THE MOUSE IN
THE UNDERLYING WHITE MATTER WHY
THE PLAQUES ARE BEING REMOVED.
SO WE SUGGIESTED AT THE TIME
THIS WAS AN PATHOLOGICAL PROCESS
AND THAT THIS WOULD LIKELY BE
RELEVANT TO MOST PROT COLS, MOST
THERAPEUTIC PROTOCOLS THAT
RESULTED IN REMOVAL OF PLAQUES
FROM THE SEEREBERAL CORTEX AND
IT HAS PROVED TO BE.
SO THESE ARE JUST SOME MORE
IMAGES FROM OUR SINGLE CASE FROM
THE 1792, AT LOW POWER SO CAN
YOU SEE THE CORRELATE THAT WITH
THE CARTOON AND SOME OF THE MRI
SCANS THEY'RE SEEING YOU CAN SEE
WILL PLOT ABSENT FROM THE CORTEX
HAVE BEEN REMOVED HERE AND YET
THE SEVERE CAARK IN THE
MENINGIES AND CORTEX, THERE ARE
PERIVASCULAR SPACES IN THE
UNDERLYING WHITE MATTER AND THIS
IS CORRESPONDING HD SECTIONS
AGAIN, HERE'S CONTEXT, OVERLYING
MENINGIAL VESSELS AND
INFLAMMATORY CELLS AND
LYMPHOCYTES ASSOCIATE WIDE THOSE
CAA INFECTED BLOOD VESSELS, AND
IN THE CORTEX HERE AND THE WHITE
MATTER CHANGES AFFECTED BY THE
PACES HERE.
O OF COURSE, THESE ARE THE
ARTERIES TURNED THRAW A RIGHT
ANGLE AND THEY PENETRATE THE
CEREBRAL CORTEX AND THEY GO ON
TO SUPPLY THE UNDERLYING WHITE
MATTER SO THESE ARE ALL THE SAME
BLOOD VESSELS HERE THAT ARE
AFFECTED.
SO THIS IS SOME NICE IMAGING AND
HISTOLOGY CORRELATION DONE ON
THIS COHORT BY SUSAN KD--SALLY
WAAND COLLEAGUES IN BOSTON.
THESE MREFRESH YOUR RECOLLECTION
I SCANS OF BRAIP SLICES, THAT
ARE BEEN DONE IN IMMUNIZED CASES
AND UNTREATED ALZHEIMER'S STEEZ
AND THE DIFFERENCE BETWEEN CASES
AND CONTROLS OF THESE BANDS AND
THESE CORTEX, AND I THINK YOU
WILL CALL THIS SUPERFICIAL
[INDISCERNIBLE] ON THE IMAGING
SO NOT PRESENT IN THE CONTROLS.
THIS IS THE CORRELATION OF THE
IMAGING WITH THE HISTOLOGY SO
THIS HAS BEEN SHOWN THAT WHERE
THESE SIGNAL CHANGE IN THE
CORTEX, THE PIGMENT ALSO OTHER
CALCIUM, ACCUMULATION AND THIS
IS ALL ASSOCIATE WIDE SEVERE
CAA.
A HIGHER POWER IT WAS POSSIBLE
TO SEE THAT THIS IRON PIGMENT IN
THE SUPERFICIAL CEREBRAL CORTEX,
IS A OCCURRING PARTICULARLY IN
AREAS WHERE THERE IS NO ABETTA,
I PRESUME THE ABETTA HAS BEG
YOUR PARDON CLEARED IN THESE
AREAS WHERE THE IRON PIGMENT IS
ACCUMULATE AND THE QUANTITATIVE
ANALYSIS SUGGESTS THAT BUT THERE
WAS AT LEAST ABETTA HAS CLEARED
AND THE IRON DEPOSITS ARE
APPEARING IN THOSE REGIONS
PARTICULARLY.
SO THAT'S ARIA H, ARIA E IS
EXTRA CELLULAR ACCUMULATION OF
WATER.
WE KNOW THE WATER OF TRANSPORT
IN THE CNS IS AQUA PORIN 4, IT
IS RAPIDLY IN THE BRAIN, AND WE
KNOW THE CAA IS IN THE DISEASE
AND IT IS IN POSITION OF AH
QUAPORIN 4 COULD OFFER UP A
POTENTIAL LINK TO THE CHEANKS
FOLLOWING IMMUNIZATION AND THE
DEVELOP AM OF ARIA E.
SO THIS IS A NICE STUDY DONE BY
[INDISCERNIBLE] AND COLLEAGUES
HERE TO LAMB PHARMACEUTICALS SO
THIS IS MICE WHO HAVE GIVEN
ANTIBODY.
AND THAT INDEED FOUND INCREASE
IN CAPILLARY CAA IN THESE MICE
AND THEY LOOK THAT THE WHICH YOU
CAN SEE AROUND CAPILLARIES HERE
AND THIS IS AQUAPORIN 4, THIS IS
ARK ROUND THE WALLS OF THE
AQUAPORIN 4 WAS FROM THE END
FEET.
THEY DID IN NICE ELECTRON
MICROSCOPY, SO THIS IS CROSS
SECTION HERE.
THIS IS AN ASTRO SIGHT INTO THE
CAPILLARY AND THE AMYLOID
FIBERALS DISPLACING THE ASTRO
SIGHT AWAY FROM THE CAPILLARY.
SO WE'VE TRIED AS WELL AS WE
COULD TO LOOK AT CAPILLARY CAA
AND AQUAPORIN 4 IN OUR PATIENTS
IN 1992, SO THIS IS ABETTA
AND/OR IMMEDIATE AYAISENT TO THE
WALLS, SO IT'S CAPILLARY ANCHLIO
PATHY, AND THE IMMUNIZED CASES,
ALL THESE HAVE BEEN ASSOCIATION
OF CAPILLARIES AND NO PLAQUES
AROUND IT.
QUANTICTION SHOWED SIGNIFICANT
LE MORE CAPILLARY ANGIE
OPERATING GLOBALLY RAGHTY AND IN
THE ALZHEIMER'S DEC AND CLOSE TO
SIGNIFICANT RELATIONSHIP WITH
HIP WITH POSSESSION OF E4.
--WITH WE QUANTIFY THE AQUAPORIN
4 WE COULDN'T REALLY DETECT THE
DIFFERENCE BETWEEN THEPUNIZED
AND UNTREATED ALZHEIMER HEMER'S
CASES BUT THEN OBVIOUSLY A
DRAWBACK HERE IS THAT MRI
IMAGING IN NAINITIAL TRIAL
WASN'T PERFORMED SYSTEMAT
BEINGLY SO WE DON'T REALLY HAVE
ANY IDEA HOW MANY OF THE PEASHTS
MIGHT OR MAY MOT HAVE HAD
ARE--ADMINISTRATIVE RAAND AT
WHAT STAGE IN RELATION TO THE
[INDISCERNIBLE] WHO HAD ARIA.
SO TEEF MENTIONED THE CONDITION
OF SPONTANEOUS CAA RELATED
INFLATION AND I ARK TBREE VERY
MUCH THIS IS A VERY USEFUL
COMPARITTOR OR MODEL FOR WHAT'S
HAPPENING IN THE TREATED
ALZHEIMER PATIENTS, SO ABETTA
ANTIBODIES SEVERE CAA,
INFLAMMATION ASSOCIATE WIDE THE
VASCULATURE AND ARIA E LIKE
FEATURES.
SO TEEF --TEEF SAID THIS WAS AN
AUTOIMMUNE REACTION, SO IN TERMS
HERE OF STUDYING PATHOPHYSIOLOGY
AND AT TIMES IN PATIENTS
BIOPSIES ARE PERFORMED MRI SCANS
MORE OR LESS AT THE SAME TIME,
SO TISSUES AVAILABLE FOR STUDY,
AND I WILL SUGGEST THAT
CERTAINLY IN CASES THAT I SEE,
THAT THE SORT OF MORPHOLOGICAL
HISTOLOGICAL PAT E-PRESCRIBINGS
OF ABETTA IMMUNO CHEMISTRY IN
THIS CONDITION VVERY CLOSE
PARALLELS WITH WHAT WE SAW IN
THE IMMUNIZED A. D. PASHS IN
1972 AND I THINK EFFECT UFLY
THESE PATES WHO ARE IMMUNIZING
THEMSELVES AGAIN ABETTA AND
REMOVING PLAQUES SO THIS IS
CERTAINLY A USEFUL MODEL I WOULD
A
AGREE FOR STUDY OF ARIA.
SO HERE ARE CONCLUSIONS.
SO ARIA IS DID YOU TO DYNAMIC
CHANGES IN THE ABETTA.
THERE'S A SHIFT FROM PLAQUES TO
THE WALLS OF BLOOD VESSELS
INCREASING SEVERITY OF CAA AT
LEAST DURING THE PROCESS OF
PLAQUE REMOVAL AND THEN A
SUBSEQUENT PHASE OF MORE
CLEARANCE OF ABETTA FROM THE
VESSEL WALLS OR REDUCTION IN CAA
IN THE LONGER TERM.
SO THE ABETTA REMOVAL FROM THE
VESSEL WALLS COULD BE HAPPENING
AT THE SAME TIME AS THE
DEPOSITION OF ABETTA IN VESSEL
WALLS.
SO REALLY DYNAMIC PICTURE.
ASSOCIATED INFLAMM EGG, WHICH I
ATBRE, WE DON'T KNOW FOR SURE
YET WITH THE INPRELIMINARIATORY
REACTION IS A NECESSARY
COMPONENT OF THE PATHOPHYSIOLOGY
OR WHETHER JUST THIS SHIFTING OF
ABETTA IS ENOUGH PRODUCE THE
ARIA LIKE CHANGES.
SIMPLE COMMENTS THAT ARE KIND OF
OBVIOUS REALLY BUT THEY'RE WORTH
JUSTITATING SO ARIA H IS LAKELY
DO YOU TO INTEGRITY OF THE WALLS
OF SMALL ARTERIES AND
ARE--ADMINISTRATIVE TERIOLE ANDS
THE CORTEX, ARIA E LIKELY DUE TO
FAILURE TO CONTROL WATER FLUX OF
THE BLOOD BRAIN BARRIER,
POTENTIAL ROLE FOR CAPILLARY
CAA, OR IN 4, AMONG OTHER
[INDISCERNIBLE].
RISK FACTORS WE KNOW POSSESSION
OF E4, POTENTIALLY IF THE SEVERE
CAA IS PART OF THE PATIENT'SAL
JEIMER PROCESS THAT MIGHT BE
IMPORTANT BUT QUITE DIFFICULT TO
GET A HANDLE ON.
LIMITATIONS THERE'S LITTLE
TISSUE AVAILABLE TO STUDY EMPLOY
AS I SAY, I THINK I'M RIGHT IN
AT AING THERE'S NO STUDIES YET
OF ARIA PATHOLOGY IN PATIENTS
WHO HAVE AN AB ANTIABOUTS AND WE
NEED TO TODAY IT AND FIND OUT
WHAT'S GOING ON AND THAT'S
COMPOUNDED OR GO TOGETHER WITH
THE DIFFICULTIES IN IMAGING THE
SPECIFIC CAA AND INFLAMMATION IN
LIVE PATIENTS.
AND ANALOGY WITH THE CAA RELATED
INFLAMMATION IS VERY IMPORTANT
AND THERE'S TISSUE AVAILABILITY
IN THIS CONDITION AND I'M SURE
THERE ARE SEVERAL GROUPS THAT
ARE TODAYING IN CONDITION QUITE
INTENSIVELY, NOTE THAT IN THE UK
WE ARE WORKING WITH OUR UK
NETWORK TO GATHER TOGETHER A
COHORT OF AS MANY CASES AS WE
CAN FOR THIS CONDITION FOR THIS
INTENSIVE STUDY AND I MATE SAY
THE WORD FUNDING WAS MENTIONED,
I MIGHT SAY WE DON'T HAVE THAT
STAGE FOR THESE STUDIES WHICH I
THINK ARE IMPORTANT THINGS TO DO
EMPLOY PASSIVE IMMUNOTHERAPY
PROTOCOLS, ROWBSLY THAT PERMIT
ANDS IT CONTRASTS, MODULATE THE
THERAPY BY IMAGING
[INDISCERNIBLE] ARIA AND THE
FINAL POINT I ARE THAT I NEED TO
EMPHASIS, IF EVIDENT THAT IS
SUPPORTED ACTIVE AB IMMUNIZATION
FOR PREVENTION OF AD, BEFORE THE
BRAIN CONTAINS SIGNIFICANT AB,
IT SEEMS LIKE ARIA WOULD NOT
OCCUR, SO THAT'S AN IMPORTANT
POINT TO BEAR IN MIND, I THINK
AND SO JUST FINALLY SOME OF THE
MAN COLLABORATORS WHO WORKED ON
THESE STUDIES OVER THE YEARS.
SO THANK YOU VERY MUCH FOR YOUR
ATTENTION.
>> THANK YOU YAIMS, IT WAS VERY
INTERESTING.
NEXT UP IS JOHN DETRE WHO WILL
TALK ABOUT ADVANCED METHODS IN
BBB IMAGING EMPLOY NTHANK YOU
FOR THE OPPORTUNITY TO
PARTICIPATE.
THIS IS SO FAR A REALLY
INFORMATIVE WORKSHOP AND I
DIDN'T PREPARE A DISCLOSURE
SLIDE, I GRATEFULLY ACKNOWLEDGE
SUPPORT FROM SEVERAL NETWORK IH
INSTITUTES INCLUDING NINDS AND
NIA BUT ACTUALLY NONE OF IT
RELATES TO ARIA OR BLOOD BRAIN
BARRIER IMAGING SO WHAT I'M
GOING TO SHOW TODAY IS VERY
OBJECTIVE SUMMARY OF THE TOPIC
AND I JUST ADDED MRI TO THE
TOPIC BECAUSE THERE'S ALREADY A
PLAN TO DO SERIAL MRI SCREENING
TO TO THE EXTENT THIS MIGHT BE A
HYBRID BETWEEN AN OVERVIEW AND A
CLINICAL RESEARCH IDEA
PRESENTATION I WANTED TO FOCUS
ON MRI METHODS.
LET'S SEE.
SO WE'VE HEARD THIS A COUPLE
TIMES ALREADY TODAY BUT TO
BRIEFLY SUMMARIZE THE
HYPOTHESIZED MECHANISMS OF ARIA,
YOU KNOW THERE'S THE LOSS OF
VESSEL WALL INTEGRITY ISSUE THE
BLOOD BRAIN BARRIER BREAK DOWN
WHICH ACTUALLY THERE ISN'T
REALLY A LOT OF OBJECTIVE
EVIDENT FOR, IT'S REALLY A
HYPOTHESIS, THE IDEA TAKEN--THEY
ANTIBODY MEDIATED INFLAMMATION
MAY CAUSE OR EXACERBATE THAT AS
WELL AS AN IDEA OF DISRUPTED
PERIVASCULAR FLOW AND KIND OF
CLEARANCE.
AND THE POINT ABOUT CAA RI BEING
A MODEL IS ALSO BEEN MENTIONED.
OKAY, WELL I BLEW PAST THE
NORMAL IMAGE HERE, I CAN GO
BACK, SO JUST TO BRIEFLY
SUMMARIZE AGAIN A LOT OF THIS
HAS BEEN COVERED ALREADY BUT
THIS IS A FIGURE FROM A REVIEW
ON IMAGING BLOOD BRAIN BIRRIER
SURFACESSIER ABNORMALITIES IN
ALZHEIMER'S DEC AND THE CELLULAR
COMPONENTS HERE ARE THE TIGHT
YUNKZ PROTEINS THAT SEAL EBD O
THELLIAL CELLS TOGETHER AND FORM
1 PART OF THE BLOOD BRAIN BEAR
IMRER AND THEN THE ASTRO SITTIC
INFEED WHERE THE AQUAPORIN 4
CHANNELS ARE LOCATED, THE
FUNCTION OF THE PLAID BRAIN
BARRIER ALLOWS PASSIVE DIFFUSION
OF SOME COMPOUNDS, ACTIVE
TRANSPORT OF OTHERS AND IN
PARTICULAR WATER EXCHANGE IS
THOUGHT TO OCCUR BY BOTH
MECHANISMS.
AND THE BLOOD BRAIN BARRIER HAS
BEEN PHYSIOLOGICALLY LINKED NOW
TO THE LYMPHATIC SYSTEM WITH THE
IDEA THAT PERIVASCULAR SPACES
ARE CONDUITS FOR CLEARANCE.
THE NEXT IMANNUAL SHOWS THE SAME
CARTOON IN ALZHEIMER'S DEC
SHOWING THAT MANY OF THESE COP
OPPOSITE BEHAVIORIAL
PHENOTYPENTS ARE KNOWN TO BE
AFFECTED AND HIGHLIGHTS SOME OF
THE METHODS I'M GOING TO BE
DISCUSSING.
SO BLOOD BRAIN BARRIER LEAKAGE
CAN BE QUANTIFIED USING CONTRAST
MRI AND BLOOD BRAIN BARRIER,
WATER EXCHANGE CAN ALSO BE ISSUE
MEASURED BY VARIATIONS OF THE
ARE--ADMINISTRATIVE TERIOLE
SPINDLING EXPERIMENT AND THEN
FINALLY MICROHEMORRHAGE IS
ANOTHER PORM OF BLOOD BRAIN
BARRIER LEAKAGE WHERE SOME BLOOD
HAS LEAKED OUT OF THE VESSELS.
WELL IS SURPRISINGLY LITTLE
PUBLISHED DATA ON EVEN CONTRAST
ENHANCED MRI IN
ARE--ADMINISTRATIVE RAW DATA, SO
REISA MENTIONED SOMETHING FROM
YEARS AGO, BUT YOU KNOW I BEING
ONLY FIND 2 REPORTS, 1 OF THEM
TALKED ABOUT PROMINENCE OF
CORTICALE VASCULAR LEAKAGE WHICH
ISN'T REALLY BLOOD BRAIN
BARRIER, LECCAGE, AND THEN 1
OTHER SLIGHT ENHANCE AM THAT WAS
NOT IMPRESSIVE HOWEVER IN ANGIO
AMYLOIDITEIS THERE HAVE BEEN
REPORTS OF BLOOD BARRIER
DISRUPTION, NOW SOME AMERICA RI
HAS CONTRASTED IMAGES SO IT
WOULD BE INTERESTING TO ELECTRIC
AT THOSE.
THERE IS A PAPER OUT IN MOUSE
MODEL THAT ACTUALLY SHOWED YOU
KNOW TBROSES BLOOD BRAIN BARRIER
DADA LIDIUM EPIHANSMENT IN
ASSOCIATION WITH PATHOLOGICAL
EVIDENCE OF MICROHEMORRHAGE AND
THIS OCCURRED IN THE TREATED
MICE SO THIS WAS A PRECLENICAL
STUDY.
SO THAT THE WAY TO QUANTIFY
BLOOD BRAIN BARRIER,
PERMEABILITY WITH CONTRAST MRI,
USING A DYNAMIC IMAGING PROTOCOL
THOO ISN'T USED TYPICALLY
CLINICALLY SO A CLINICAL BLOOD
BRAIN BARRIER DISRUPTION IS
LOOKING AT THE SCAN BEFORE AND
AFTER CONTRAST TO SEE
APPROXIMATE ANYTHING ENHANCED.
BUT IT'S ALSO POSSIBLE ALTHOUGH
SOMEWHAT TIME CONSUMING TO DO
SERIAL IMANNUALING APPROXIMATE
CAN TO MODEL THIS PARAMETER
T-TRANSWHICH IS THE RATE OF
TRANSFER OF DAILY BASISSEDDA
LYNNIUM ACROSS THE BROOD BRAIN
BARRIER, THERE'S SIMPLE AND MORE
COMP LEICATEED MODELS, MOST
STUDIES USE THIS SIMPLIFIED
MODEL WHICH MODELS 2 PARAMETERS,
THE K-TRANSAND THEVILLEUME HAD
INTO WHICH THE GADDA LIBRARY
FOUNDATIONIUM HAS PERMEATED AND
THAT HAS BEEN STUDIED A BIT IN
AGING AND DIMENSIONIA AND THIS
IS A WELL KNOWN PAPER THAT
APPLIED THIS GADDA LYNNIUM BASED
DYNAMIC IMANNUALING TO THE BRAIN
IN AGING AND THEY FOUND THAT
THERE WAS AN INCREASED
PERMIABILITY IN AGING THAT WAS
FURTHER INCREASED IN MCI
PRIMARILY IN THE REAMION OF THE
HYPOCAMPUS.
WHICH IS AN AREA AFFECTED BY
ARIA BUT AS REISA MENTIONED IN
HER TALK IT'S NOT AN AREA THAT
HAS TYPICALLY THE MOST OF
AMYLOID IN IT.
THERE WAS 1 PAPER THAT SUGGEST
THAD PERMEABILITY MAY ALSO BE
INCREASED IN PATIENTS WITH
CEREBRAL SMALL VESSEL DES BUT
THE DAILY BASIS THEA WERE NOT
VERY CONVINCING.
SO THE OTHER APPROACH IS
ARE--ADMINISTRATIVE TERIOLE SPIN
LABELING WHICH IS AN AREA I DO
WORK IN AND IN
ARE--ADMINISTRATIVE TERIOLE SPIN
LABELING WE DID NOT ADMINISTER
EXOGENOUS TRACER BUT RATHER AN
ENDOGENOUS TRACER, OUR
ARE--ADMINISTRATIVE TERIOLE
BLOOD WATER IS ON ITS WAY TO THE
BRAIN.
AND AT 3 TESLA, YOU CAN EXCHANGE
ABOUT 1% OF THE BRAIN WATER WITH
ARE--ADMINISTRATIVE TERIOLE SPIN
LABELING THAT'S NOT EASY TO SEE
BUT THERE ARE WAYS TO SUPPRESS
THE STATIC SIGNATURES UNTIL AND
SO CAN YOU ACTUALLY GET A FAIRY
DESCENT LOOKING THROW OUT OF
THIS.
NOW THE BASIC MODELING OF THIS
BLOOD FLOW MAP DID NOT CONSIDER
THERE'S LIMITATION TO BLOOD
BRAIP BARRIER PERMEABILITY AND I
WOULD SAY THE TEACHING THAT I
GOT IN SAY MEDICAL SCHOOL WAS
THAT THE BLOOD BRAIN BARRIER IS
FULLY PERMEABLE TO WATER BUT IT
TURNS OUT IT ISN'T FULLY
PERMEABLE TO WATER SO THERE ARE
WAYS TO MODEL THE INTERCOM
PARTMENTAL EXCHANGE OF THIS SPEN
LABEL EMPLOY SO CAN YOU THEN TRY
TO QUANTIFY THIS PERMEABILITY.
NOW HERE YOU'RE TRYING TO FIT A
VERY MUCH MORE COMPLEX MODEL TO
THIS TINY 1% SIGNAL AND SO YOUR
NOT GOING TO GET QUITE AS NICE
OF AN IMAGE, THIS IS AN EXAMPLE
OF WHAT A WATER PERMEABILITY MAP
LOOKS LIKE.
THERE'S A FEW DIFFERENT WAYS TO
DIFFERENTIATE THE INTRA RASCULAR
AND KRAMER VASCULAR SIGNAL IS
WHICH IS WHAT YOU NEED TO DO SO
THE VARIATION ON THIS EXPERIMENT
DOES AN ASL EXPERIMENT WITH OR
WITHOUT SUPPRESSION OF 1 OF
THESE COMPART UPONS AND THE 1
THAT'S BEEN TODAYS MOST WAS
INITIATED BY DANNY WANG WHO WAS
IN MY LAB AT THE TIME THAT USES
A PSEUDODIFFUSION EFFECTS OR
VASCULAR CRUSHING.
THIS 1'S AN EXAMPLE OF 1 OF
THOSE EMPLOY SO THAT'S BEEN MOST
STUDIED AND I WILL BRIEFLY
SUMMARIZE SOME OF THAT.
SO HERE'S AN EXAMPLE OF THESE
PROFUSION IMAGES YIERED WITH AND
WITHOUT VASCULAR CRUSHING SO
THESE ARE THE B-VALUES AND THIS
IS HAS BEEN APPLIED TO MULTIPLE
KIND OF CONVENIENT SAMPLES AND
IT EXPLOITS THE DIFFERENCE IN
DIFFUSION COENTIOUS FICIENT
BETWEEN BRAIN TISSUE AND
CAPILLARY FLOWING BLOOD, WATER
AND WHAT THEY FOUND IS THAT THIS
PERMEABILITY ACTUALLY UNLIKE
WHAT WAS FOUND WITH CONTRAST,
THAT THE WATER PERMEABILITY
ACTUALLY DECREASES WITH AGE AND
IT ALSO SEEMS TO DECREASE WITH
VASCULAR RISK FACTORS AND
FURTHER DECREASE WITH AMYLOID
ARK KIEWMULATION, SO IF
ANYTHING, YOU KNOW WATER
PERMEABILITY IS GOING IN THE
OPPOSITE DIRECTION OF WHAT
PEOPLE FOUND, LIMITED KNOWLEDGE
WE HAVE OF BLOOD BRAIN BARRIER
PERMEABILITY TO GD CONTRAST.
SO TO COMPARE THESE 2 METHODS 1
BIG DIFFERENCE IS THE TRACER
SIZE, WATER IS A TINY MOLECULE,
GD COMPLEXES ARE BIGGER
MOLECULES, AND SO 1 IDEA IS THAT
YOU KNOW WATER PERMEABILITY WILL
BE MORE SENSITIVE BECAUSE IT'S A
LITTLE MOLECULE AND IT WILL TAKE
EARLIER LEAK BUT I'M NOT SURE
THAT'S SUPPORTED BY THE FINDINGS
WHICH ARE KIND OF IN THE
OPPOSITE DIRECTION EMPLOY SO,
BUT YOU MODEL A VERY SIMILAR
PARAMETER THAT YOU KNOW THE TIME
CONSTANT OR RATE CONSTANT THE
CONTRAST MODELING TAKES ABOUT 15
MINUTES OR MORE OF DATA AND IT'S
HARD TO MEASURE 1 OF THESE KW
MAPS WITH LESS THAN ABOUT 8 TO
10 MINUTES OF DAILY BASIS THEA
AND THE MECHANISM IS PROBABLY
DIFFERENT THAT THEY'RE SAMPLING
WHICH COULD BE USEFUL WHEN
APPLIED TO SOME OF THE
HYPOTHESIS THAT PEOPLE HAVE
ABOUT MECH INFORMS OF ARIA.
ONE CONCERN I WOULD HAVE ABOUT
BOTH OF THESE METHODS IS THAT
THESE PARAMETRIC IMAGES ARE KIND
OF LOW QUALITY AND IN TERMS OF
CLINICALLY RELATED KREENING
MIGHT BE HARD TO PICK UP.
AND MIGHT BE MORE SENSITIVE AND
THIS IS REALLY VERY NEW, BUT,
DAVE'S LAB AND HARVARD, CAME UP
WITH AN ALTERNATIVE WATER
EXCHANGE MODEL THAT INSTEAD OF
TRYING TO WORK WITH THAT TINY 1%
OF BLOOD WATER THAT COMES FROM
ARTERIES INSTEAD LOOKS AND ALL
THE WATER, THE BRAIN TISSUE, AND
THE BLOOD WATER IN THE BRAIN AND
LOOKING AT EXCHAIVENL BETWEEN
THAT AND INTERTITTIAL FLUID OR
KRRK SF SPACES.
AND SO THAT 1, PRODUCES ABOUT A
HUNDRED FOLD SIGNAL INCREASE
BECAUSE, YOU KNOW YOU'RE NOT
STARTING WITH 1% OF THE SIGNAL,
YOU CAN GET THIS IS AN IMAGE IN
A SINGLE PERSON THAT IS MAYBE
BORDERING ON INTERPRETABLE, SO
THIS APPROACH AS PROMISE BUT IS
VERY NEW.
I WOULD ALSO LIKE TO HIGHLIGHT A
METHOD THAT WAS REPORTED BY HANZ
[INDISCERNIBLE]'S LAB A FEW
YEARS AGO THAT DOESN'T EXACTLY
TRY TO MEASURE THE PERMEABILITY
OF WATER FROM BLOOD TO BRAIN BUT
RATHER LOOKS AT HOW MUCH BLOOD
REMAINS IN THE SAGITTAL SINUS
AFTER IT PASSES THROUGH THE
BRAIN, SO IT'S KIND OF LOOKING
AT THE OTHER HALF OF THIS
CERTAINLY--CERTAINLY QUAIGZ,
WHAT IS NOT EXTRACTED AND SO
THAT, YOU KNOW THAT DOESN'T TRY
TO SPATIALLY LOCALIZE THE
EXCHANGE.
IT DRIVES A SINGLE MEASURE FOR
THE WHOLE BRAIN BUT TO THE
EXTENT THAT SOME OF THESE CENTER
FOR EXCELLENCE ON AGINGS IN
ARE--ADMINISTRATIVE RAMAY BE
RATHER DIFFUSE, THIS COULD BE AN
APPROACH THAT IS SENSITIVE AND
HIS LAB, HAS SHOWN THAT IT'S
REPRODUCIBLE, PLUS SCANNER
PLATFORM ANDS SO THE
ACQUISITIONS RELATIVELY HOTTER
SO THIS MIGHT BE A NICE METHOD
TO TRY TO APPLY.
MOVING BEYOND THIS IDEA OF
STRICTLY LOOKING AT THINGS
EXCHANGED ACROSS THE BLOOD BRAIN
BARRIER, ANOTHER POTENTIALLY
USEFUL METHOD FOR THIS IS TO USE
ADVANCED IMAGING STRATEGIES TO
TRY TO QUANTIFY PERIVASCULAR
SPACE VOLUMES.
THESE ARE READILY VISIBLE,
PARTICULARLY IN ULTRA HIGH
RESOLUTION MREFRESH YOUR
RECOLLECTION I, THERE ARE WAYS
OF ENHANCING THEIR
[INDISCERNIBLE] LIKE USING LONG
ECHO TIME ANDS THEN THERE ARE A
NUMBER OF SIGNAL PROCESSING
EITHER STANDARD FILTERING SHOWN
HERE LIKE A FRANG I FILTERING
HERE FROM A GROUP AT USC OR
USING DEEP LEARNING METHODS THAT
COULD ALLOW VOLUMES TO BE
QUANTIFY AND THAT IS SOMETHING
THAT COULD BE MONITORED THROUGH
THE COURSE OF ANTIAMYLOID
THERAPY.
ANOTHER METHOD THAT MIGHT BEAC
PLIBBABLE IS DIFFUSION BASED
WATER IMAGING AND THE WAY WE SEE
ON T2 WEIGHTED MREFRESH YOUR
RECOLLECTION I IS FROM FREE
WATER, THAT'S WHAT HAS THE
LONGEST T2 BUT IT'S HARD TO
QUANTIFY THE AMOUNT OF FREE
WATER AND SO POTENTIALLY 1 OF
THESE DTI MODELS THAT ACTUALLY
SPECIFICALLY MODELS FREE WATER,
LIKE THIS NODDI MODEL COULD
PROVIDE A FREE WATER MAP THAT'S
SUFFICIENT TO QUANTIFY AND
DETECT CHANGES IN WATER
COMPARTMENTALIZATION.
YOU KNOW MICROHEMORRHAGES ARE
EVIDENCE POTENTIALLY OF BLOOD
BRAIN BARRIER BREAK DOWN AND I
JUST WANTED TO POINT OUT THIS IS
VERY CUTTING EDGE BUT MOST OF
THE CLINICAL TRIALS LOOK AT THE
GRADIENT ECHO IMAGE WHICH IS NOT
QUITE AS SENSITIVE AS
SUSCEPTIBILITY WEIGHTED IMAGE, I
THINK CLENICALLY THE
RECOMMENDATION IS TO STICK WITH
THE IMAGE, BUT IT WILL BT BE
HARD TO ADD A MORE SENSITIVE
IMAGE OF MICROHEMORRHAGE THAT
YOU CAN SEE THE SAME PATIENT YOU
CAN SEE HOW MUCH MORE
CONSPECUOUS AND MOW MANY MORE
MICROHEMORRHAGES ARE EVIDENT
WITH THIS FANCIER IMANNUALING
TECHNIQUE THAT ENHANCES THE
SUSCEPTIBILITY LESIONS BY
COMBINING BOTH MAGNITUDE DATA.
SO IN CONCLUSION THERE ARE A
NUMBER OF MRI METHODS THAT CAN
PROBE THE BLOOD BRAIN BARRIER IN
RELATED PHYSIOLOGY, I THINK
REALLY THIS GD ATRANSAND
ASLK ARE MEASURING TYPES OF
PERMEABILITY IN THE BLOOD BRAIN
BARRIER BUT THEY COULD BE USED
TO TEST SPECIFIC HYPOTHESIS IN
ARIA.
NEITHER OF THESE ARE EERK DEAL
FOR CLINICAL MONITORING, BAKELY
BECAUSE THEY ARE LONG
ACQUISITION TIME AND POOR IMAGE
QUALITY AND RESOLUTION.
THERE'S STILL APPLICABLE TO
COHORT STUDIES, IT'S POSSIBLE A
WHOLE BRAIN MEASURE LIKE THIS
WEBCAST TECHNIQUE TAKEN--THEY
JUST LOOKS THE WATER EXTRACTION
OVERALL COULD BE ARK PLIBBABLE.
THIS WHOLE FIELD OF IMANNUALING
FLUID EXCHANGE IN THE BRAIN IS
VERY NEW AND THERE'S A VERY
DYNAMIC AND I THINK THERE'S
GOING TO BE NEWER BETTER AND
MORE SENSITIVE METHODS COMING
DOWN THE PIKE AND THIS WILL BE
AN EXCITING, YOU KNOW TO THE
EXTENT THAT THEY'RE A HAMMER,
ARIA IS A NAIL AND I THINK
THERE'S A LOT OF FOR DOING
USEFUL AND INFORMATIVE RESEARCH
ON THIS AREA.
THANK YOU.
NTHANK YOU, THANK YOU VERY MUCH
JOHN, HOLD UP QUESTIONS FOR YAWN
AND INVITUP THE NEXT SPEAKER AND
WE MODIFIED THE PROGRAM A BIT
AND THERE WILL BE 15 MINUTES
FORA I DISCUSSION WITH THE
SPEAKERS AFTER THIS SESSION, SO
THE NEXT SPEAKER IS KAREN
SMIRNAKE S FROM BIOGEN WHO SHE
HAS A LOT OF ARIA AND OVERSIGHT
AND SHE WILL TALK ABOUT
IDENTIFYING AND MANAGING PEOPLE
AT RISK FOR ADVERSE EEIVETS DUE
TO ARIA.
>> THANK YOU.
IT'S A PLEASURE TO BE HERE IT
SEE SOME IN PERSON AND
COLLEAGUES FROM SEVERAL DECADES
AGO SO IT'S A PRIVILEGE TO BE
PART OF THIS BOTH TO THE
SCIENTIFIC ASPECTS OF IT, THE
ETIOLOGY AS WELL AS THE
MANAGEMENT.
AND AS SOMEONE WHO'S SPENT A
NUMBER OF YEARS IN PRACTICE AND
THEN WORKING IN THE DRUG SAFETY
PART OF INDUSTRY, THIS IS A
TRULY FASCINATING TIME BECAUSE
TYPICALLY WHEN YOU HAVE A NEW
ADVERSE DRUG REACTION, THE
COMMUNITY UNDERSTANDS WHAT THE
REACTION IS, WHAT'S NOVEL IS
THAT THAT DRUG CAUSES THE
REACTION EMPLOY AND IN THIS
CASE, THE REACTION ITSELF IS
NOVEL AND WE'RE STILL TRYING TO
UNDERSTAND IT, AND WE THOUGHT
COMES ANOTHER OBLIGATIONS
LIAISON GIGZ THAT WE WILL TOUCH
ON BROAFLY AND THAT IS HOW DO
WOE DRIEB THIS ON PATIENTS, HOW
DO WE INSURE THAT THE KIAG
KI--DIAGNOSTIC ABILITY IS THERE
THROUGHOUT THROUGHOUT THE HELT
CARE SYSTEM, IT'S A CHALLENGING
PROBLEM BUT ALSO A VERY EXCITING
OPPORTUNITY TO THINK ABOUT THE
SCIENCE AND THE CLINICAL
PRACTICE.
I WANT TO NOTE MY DISCLOSURES
AND I AM AN EMPLOYEE AND SHARE
HOLDER OF BIOGEN, AND I WILL BE
SHARING MY OWN VIEWS AND NOT
THOSE OF BIOGEN.
SO WHEN I WAS ASKED TO TALK
ABOUT THIS I THOUGHT ABOUT THE
TITLE.
WHAT HAVE WE LEARNED ABOUT
PATIENTS AT RISK FOR ADVERSE
EVENTS RELATED TO ARIA, WHAT DID
WE MEAN BY ADVERSE EVENTS
RELATED TO ORIA, AND I THINK
WHEN WE THINK ABOUT THAT WHAT
WE'RE MOST INTERESTED IN
PREVENTING ARE THE MORE SERIES
SYMPTOMS OF ARIA.
ARIA IS AN ADVERSE EVENT OF
SPECIAL INTEREST SO WHETHER IT
IS SYMPTOMATIC OR ASYMPTOMATIC
IT'S CAPTURED AS AN ADVERSE
EVENT.
AND IT'S CAPTURED IN CLINICAL
TRIAL POPULATION THAT HAVE
INCLUSION AND EXCLUSION CRITERIA
THAT HAVE BEEN INFOR THE
PURPOSED BY PRIOR WORK IN THIS
SPACE TO EXCLUDE PATIENTS WHO
HAVE SIGNIFICANT RISK FACTORS
FOR ARIA OR WHOM THEY HAVE
EVIDENCE OF CEREBRAL AMYLOID
ANGOPEN MEETINGATHY.
THE DATA ON THIS SLIDE IS FROM
THE PHASE 3 ENGEAJ AND EMERGE
TRIALS AND THE OVERALL WHETHER
IT'S ARIA E OR ARIA H ABOUT 41%
OF TRIAL PARTICIPANTS HAD ARIA
EMPLOY AND ONLY 10% OF
PARTICIPANTS HAD SYMPTOMS OF
ARIA AND THOSE WERE MOST
COMMONLY TECHNOLOGY TRANSFERS
LIKE HEADACHE, DIZZINESS ISSUES
NAUSEA AND GAIT DISTURBANCE BUT
THERE WAS A MAUL NUMBER OF
PATIENTS WHO HAD SERIOUS
SYMPTOMS OF ARIA, SO 0.3% IN
THESE TRIALS, AND THOSE INCLUDED
SEIZURES AND STATUS EPILEPTICS.
AND WHEN YOU ELECTRIC AT THESE
NUMBERS, YOU CAN SEE WHAT THE
CHALLENGE IS FOR CLINICAL
TRIALS.
WHAT WE ARE MOST INTERESTED IN
PREVENTING IS NOT VERY COMMON
EMPLOY APPROXIMATE SO WE THEN
HAVE TO SAY ARE THERE OTHER
THINGS WE CAN LEARN IN THE
TRIALS THAT HELP US TO CORRELATE
WHAT THE MRI FINDINGS MAY BE,
WHAT THE LESS SIGNIFICANT
SYMPTOMS MAY BE AND WHAT THE
SERIOUS SYMPTOMS MAY BE SO WE
CAN IESHES DENTIFY MEANS TO
MINIMIZE THESE SERIOUS
CONSEQUENCES.
THIS HAS BEEN CLASSIFIED VERY
WELL, BUT REALLY THOUGHT TO BE
DUE TO THE EPITOPE THAT IS
TARGETED, THE FORM OF THE
AMYLOID THAT IS TARGETED.
THIS IS DATA ALSO FROM THE
ADUCANUMAB ENGAGE AND EMERGE AND
IN THE FIRST COLUMN HERE ARE THE
APOE4 HOMOZYGOTES, SO THOSE
REPRESENT 15% OF THE CLINICAL
TRIAL PARTICIPANTS.
THE MITSD COLUMN ARE THE
HETEROZYGOTES AND THE THIRD IS A
NONCARRIER.
SO ABOUT A THIRD WERE NONCARRIER
ANDS IF WE LOOK AT THE FIRST
ROW, THERE'S A MARKET
ASSOCIATION FOR ARIA E SO 66% IN
THE HOMOZYGOUS PATIENTS, ABOUT
36% IN THE HETEROZYGOUS AND 20%
IN THE NONCARRIERS.
AND WE SEE A SIMILAR
RELATIONSHIP BETWEEN APOE AND
ARIA H, SO 60% FOR BOTH
MICROHEMORRHAGE AND HOMOZYGOTES,
AND 26% IN HETEROZYGOTES AND IN
ABOUT 18% AND NONCARRIERS AND
CORRESPONDING TO THIS, ARE
HIGHER RATES OF DISTINNATION DUE
TO ARIA WHICH ARE LARGELY
PROTOCOL MANDATED.
IN THIS RESK FACTOR IS
CONSISTENT ACROSS THE STUDIES,
THE TOP PART OF THAL IS FROM A
RECENT REVIEW BY COLLEAGUES THAT
2 TODAYS OF KD--SALLY XA
HOMOZYGOUS APOE 4 GENO TYPE IS
ABOUT 7.2 FOLD COMPARED TO 6.2
FOLD FOR THE HETEROGENEOUS ORY
SWROIGOUS, AND EVEN A MORE
SIGNIFICANT RELATIONSHIP FOR
ARIA H.
SO APOE 4 STATUS IS SOMETHING
THAT'S CONSISTENT ACROSS THE
CLASS.
THE OTHER THING THAT CONSIST
EXTENT THIS HAS BEEN DISCUSSED
EARLIER IS THE TIMING OF ARIA,
SO THIS IS A FIGURE OF THE
PROBABILITY OF FIRST ARIA E WITH
TIME ON STUDY FOR ADJUSTICE
ACCESS KAN--KANAA MAB AND IN
THAT TOP LINE IS THE APOE4
HOMOZYGOUS PATIENT.
THE BOTTOM IN PLURIBU ARE
NONCARRIER ANDS THEN THE DARK
GREEN ARE THE HETEROZYGOUS
CARRIERS AND THIS' ALSO A ROLE
FOR TOTAL CARRIERS AND TOTAL
ARIA, TOTAL POPULATION.
SO WHAT YOU CAN SEE ARE A COUPLE
OF HINGS SO FIRST OF ALL
OVERTIME THAT INCIDENCE GOES
DOWN.
SECONDLY MOST OF THE INCREASE
OCCURS AT THE TIME WHEN THERE'S
AN MREFRESH YOUR RECOLLECTION I,
SO YOU SEE THERE'S BIG STEPS UP
AT THE TIME OF THE MRI, SO THAT
WILL ITS US VERY LITTLE IS
DETEBBED BY THE IN, REFRESH YOUR
RECOLLECTION I EVEN IN THE
SETTING OF CLINICAL TRIAL.
AND IN WE LOOK AT WHAT WE'VE
SEEN SO FAR, THE RELATIONSHIP
WITH APOE 4 AT THAT TIMEUS, THE
RELATIONSHIP WITH TIME ON STUDY,
AND THE RELATIONSHIP TO DOSE
WHICH HAS BEEN PREVIOUSLY
DISCUSSED, THERE'S A VERY GOOD
HYPOTHESIS THAT ARIA IS RELATED
TO THE AMYLOID BURDEN, WHETHER
THAT IS OVERALL OR IN SPECIFIC
AREAS, AND OR TO THE RATE OF
REMOVAL OF THAT AMYLOID.
THIS IS A QUESTION THAT HAS BEEN
DIFFICULT TO SHOW IN CLINICAL
TRIALS, WHETHER THERE IS SUCH A
RELATIONSHIP IN THE PET SUBSTUDY
OF ENGAGE AND EMERGE THERE, IS
NOT AN ASSOCIATION FOUND BETWEEN
THE PET SUV OR IN PEASHS WITH OR
WITHOUT ARIA, LOOKINGA THE BASE
LINE PET CORE.
SIMILARLY THERE IS NOT A
RELATIONSHIP FOUND AND NOT SHOWN
ON THE SLIDE BETWEEN THE
REDUCTION IN PET SUVR AND THE
APOE4 4 GENO TYPE AND THERE IS
ANALYSIS, I THINK YOU MENTIONED
DR. PERLING WHERE YOU LOOK AT
ENTERVALENTINEDS OF REDUCTION IN
HOTTER INTERVALS AND THE
INCIDENCE OF ARIA EMPLOY SO 1
LIMITATION IS THAT THE TIMES OF
THE PET SUVR DURING THE STUDY IS
TYPICALLY AT ABOUT 6 MONTHS AND
A YEAR AND 18 MONTHS.
WHEREAS THE ARIAS EARLY SO WE
DON'T HAVE GREAT TEMPORAL
CORRELATION THERE AND THOSE
MEASURES.
AND THE OTHER TECHNOLOGY
TRANSFER IS THAT THIS IS A
FLOABAL SCORE AND WE'VE SEEN IN
SOME OF THE DATA THAT'S BEEN
PRESENTED THAT THERE MAY BE
REALLY GOOD CORRELATIONS BETWEEN
LOCAL AMYLOID LOAD AND THE
INCIDENCE AND RISK OF ARIA.
SO MOVING NOW TO ONCE PATIENTS
HAVE ARIA, IN THE CLINICAL
TRIALS, WHAT ARE THE
CHEARKTISTICS OF THAT ARIA AND
CAN WE LIMITED PARTNERSHIP
ANYTHING ABOUT RISK FACTORS FOR
CLINICALLY SIGNIFICANT ARIA.
AND THE FIRST POABT I WANT TO
MAKE IS THAT DURING TRIALS, THE
CHARACTERIZATION OF ARIA IS VERY
DETAILED IT'S 1 OF THE THINGS
THAT MAKING COMMUNICATION ABOUT
1 OF THE TECHNOLOGY TRANSFERS
ABOUT THE DIFFICULT SOMETIMES
EMPLOY SO EVERY EVENT IS
CHARACTERIZED BY THE RADIO
GRAPHIC SEVERITY AND SO FOR ARIA
E THAT'S SIZE AND NUMBER OF
AREAS OF EDEMA AND FOR ARIA H
IT'S THE NUMBER OF AREAS OF
MICROHEMORRHAGE OR SUPERFICIAL
SITTEROSEIS AND THOSE ARE ON A
SPECIFIC GRE AND THAT DEFINITION
WAS MADE USING THE PROTOCOLS WE
USE IN THOSE TRIALS EMPLOY
SYMPTOMS ARE ALSO RATED ON
SEVERITY.
THERE ARE A SERIES OF TRIALS
THAT ARE ON THE DEVELOPMENTAL
ENDOCRINOLOGY NEGZ OF THE
SERIOUS ADVERSE EVENTS MIGHT BE
THE ADVERSE EVENT OF ARIA OR IT
MIGHT BE THE CLINICAL EVENT.
AND SO, WHEN YOU HEAR A
PARTICULAR CASE OF ARIA, YOU MAY
ARE A PATIENT WITH MODERATE ARIA
E, MILD RAIA H AND HAD A SERIES
EVENT AND TERMINOLOGY CAN BE
KIND OF COMPLEX.
--SO THIS TABLE IS ALSO SET UP
THE SAME WAY WITH HOMOZYGOTES ON
THE LEFT AND NONCARRIERS AND THE
NUMBERS ON THE TOP OF THE
NUMBERS WOE HAVE SEEN BEFORE.
SO WHEN WE LOOK AT THE NUMBER OF
THE MRI SEVERITY IN PATIENTS WHO
ARE APOE 4 HOMOZYGOUS, WE SEE
23% ARE MILD, 62% ARE MODERATE
AND ABOUT 15% ARE SEVERE.
AND WITH WITHOUT READING EVERY
COLUMN, YOU CAN SEE REGARDLESS
OF THE APOE 4 AT THAT TIMEUS,
MOST OF THE ARIA IS MILD OR
MODERATE AND THE PERCENT AMILLIO
THAT IS SEVERE RAINCHLING
BETWEEN 11 AND 15%.
HOWEVER, THAT'S A PERCENTAGE OF
THE ARIA, SO IT IS ALSO TRUE
THAT THOSE 16 SEVERE CASES ON
MRI, ARE 16 OUT OF 159
HOMOZYGOTES, SO FOR HOMOZYGOUS
PATIENTS THAT ARE ENTERING THESE
TRIALS APPROXIMATELY 10% HAD A
SEVERE RADIO GRAPHIC ARIA E
COMPARED TO 4% FOR HETEROZYGOUS
AND 2% FOR NONCARRIERS SO IT DID
APPEAR THAT ONCE A PARTICIPANT
HAS ARIA, LARGELY IT'S THE
SIMILAR, NOW THERE ARE GOING TO
BE INDIVIDUAL CASE EXCEPTIONS
THAT WE'LL TALK ABOUT BUT OVER
ALL THAT RISK IS HIGHER FOR THE
HOMOZYGOTES.
AND THEN IN THE BOTTOM WE LOOK
AT THE SYMPTOMATIC STATUS AND WE
DON'T SEE OVERALL ANY
SIGNIFICANT DIFFERENCES IN THE
PERCENTAGE OF PATIENTS WHO HAVE
SYMPTOMS SEESHTED WITH ARIA,
REGARDLESS OF THE APOE4 GENO
TYPE.
SO THE NEXT QUESTION IS OKAY,
GENO TYPE HAS NOT GIVEN US A
HUGE LINK TO THE MRI SEVERITY
AND TO THE SYMPTOMATIC STATUS,
WHAT ABOUT A CORRELATION BETWEEN
THE MRI FINDING ITSELF AND THE
SYMPTOMS, IS THERE A CORRELATION
BETWEEN A GREATER MRI SEVERITY
AND A GREATER PERCENTAGE OF
PATIENTS WHO HAVE SYMPTOMS.
SO HAD IS THE TABLE, THIS IS THE
ADUCANUMAB ON THE RIGHT AND
PLACENTA SEEB ON THE LEFT.
THIS LOOKS AT EACH SECTION FOR
MILD ARIA, AND MILD ARIA, THIS
IS ALL ARIA, E AND H.
AND THE FIRST NRVEGZ IS THAT
MOST OF THESE EVENTS ARE
ASYMPTOMATIC REGARDLESS OF THE
MRI SEVERITY AND MAYBE SOME
EXPECTED OF THE MRIs, BUT WELL
IS A SLATE INCREASE IN THE
PERCENTAGE THAT ARE SYMPTOMATIC
AND SEVERE ON MRI.
BUT GENERATED, THERE ARE SO FEW
SERIOUS SYMPTOMS WHICH IS WHAT
WE'RE REALLY INTERESTED IN, THAT
THAT IS SOMETHING ON AN
AGGREGATE LEVEL THAT WE REALLY
ARE NOT ABLE TO ANALYZE FROM THE
CLINICAL TRIAL DATA.
SO MOVING TO ISOLATED
ARE--ADMINISTRATIVE KRAMER H
ISSUE ASK IN THIS SLOOD WE LOOK
AT BOTH IN THE FIRST 2 ROWS ASK
HERE CARRIERS ARE DEFINED AS
HETEROZYGOUS AND HOMEIO ZYGOUS,
WE DISCUSS THE HIGHER INCIDENCES
OF EACH.
NOW THE INTERESTING TECHNOLOGY
TRANSFER ABOUT ARIA H IS IF YOU
BREAK IT DOWN BY ARIA H THAT'S
CONCURRENT WITH ARIA E, MEANING
THERE IS SOME TEMPORAL OVERLAP,
IT'S EITHER DIAGNOSED ON THE
SAME MRI THAT THE ARIA E WAS
DIGITEXTED OR IT'S DIAGNOSED
BEFORE THE ARIA E RESULT AND
THIS IS THE THIRD ROW FROM THE
BOTTOM.
SO 21% OF THE ADUCANUMAB, AND
HOWEVER THE INCIDENCE OF
ISOLATED ARIA H WITHOUT ANY IS
VERY SIMILAR AND THIS IS
PHENOCROSS TRIAL ANDS THE OTHER
TECHNOLOGY TRANSFER THAT IS NOT
ON THE SIDE IS THE TIMING OF
THAT.
THIS IS ALSO BEEN MENTIONED
EARLIER TODAY--IN THE INTEREST
OF TIME I WON'T DISCUSS
RECURRENT ARIA, ABOUT CONTINUE%
OF PATES DID HAVE RECURRENT
ARE--ADMINISTRATIVE KRAMER, THE
PERCENTAGE WITH RECURRENCE IS
ALSO HIGHER IN HOMOZYGOUS
COMPARED TO HETEROWROIGOUS
COMPARED TO NONCARRIERS.
AND IN GENERAL, THOSE NEXT ARIA
EVENTS DO TEND TO BE LESS RADIO
GRAPHICALLY SEVERE AND LESS
SYMPTOMATIC SUGGIESTING MAYBE
AGAIN A CORRELATION WITH THE
AMYLOID LOAD BUT THERE ARE
NOTABLE EXCEPTIONS ON INDIVIDUAL
CASES.
AS DISCUSSED, THIS IS A
SUPPLEMENTARY FIGURE THAT A
COLLEAGUE AND I AND OTHERS CO
AUTHORED AND THIS LOOKS AT A
PROPORTIONAL RISK HAZARDS MODEL
FOR THE RISKS OF ARIA EMPLOY SO
WE DISCUSSED THE APOE 4 RISK
FACTOR, ADDITION THE PRESENCE OF
BASE LINE MICROHEMORRHAGES WAS A
RISK FACTOR FOR ARIA E AND IN
THE PAPER THERE'S A SIMILAR
SLIDE WITH CONCURRENT ARIA E AND
SO WE SEE THE SAME THING, APOE 4
STATUS AND BASE LINE
MICROHEMORRHAGES ARE RISK
FACTORS.
WE DID NOT FIND A CORRELATION
THAT BETWEEN AIM, GENDER, BASE
LINE DISEASE STATE OR
ANTITHROMBOTTIC MEDICATION
DURING THE STUDY NOTE THAGOREAN
IN NEEZ STUDIES ASPIRIN UP TO
325-MILLIGRAMS WAS PERMITTED AND
THERE'S VERY LITTLE EXPOSURE TO
ANTITHROMBOTTIC MEDICATIONS.
WHEREAS FOR ISOLATED ARIA H
ISSUES THE ONLY SIGNIFICANT RISK
IN THIS MODEL WAS AGE, SO A
SMALL INCROSE IN RISK WITH AGE,
SO AGAIN ADDITIONAL EVIDENT FROM
THE TRIALS THAT THESE ARE MA
DIFFERENT PRESENTATIONS, PERHAPS
OF SOMETHING SIMILAR, UNDERNEATH
BUT I THINK THAT REQUIRES SOME
ADDITIONAL WORK.
NOW YOU HEARD ME MENTION
INDIVIDUAL CASES A COUPLE OF
TIMES AND I THINK THIS IS WHERE
THE LIMITATIONS ARE OF THE
CLINICAL TRIAL DATA AND AS A
SAFETY PHYSICIAN, OFTEN WILL
TELL PEOPLE THAT WHEN YOU
ELECTRIC AT SAFETY, WE LEARN A
LOT FROM SMALL NUMBERS, RIGHT IN
SO WE'RE NOT GOING TO HAVE A
PATIENT COME IN AND GET
ANAPHYLAXIS RIGHT AFTER A DRUG,
AND SAY, OHS IT'S NOT
STATISTICALLY SIGNIFICANT.
SO COMPARE TO THE EFFICACY END
POINTS WE WILL LOOK AT EACH OF
THOSE INDIVIDUAL CASES.
AND THE CONCLUSION THAT SEIZURE
INCLUDING AT THAT TIMEUS
EPILEPTICUS CAN BE A SYMPTOM OF
ARIA WAS A RESULT OF THAT KIND
OF ANALYSIS SO OVERALL THE
SEIZURES OCCURRED EVEN MORE
COMMONLY IN THE PLACEBO COMPARE
TO THE ADUCANUMAB GROUP BUT WHEN
WE LOOKED AT PATES WITH ARIA E,
THAT WAS .7 OR .8.
AND IF YOU WERE LOOKING AT
NUMBERS YOU WOULD SAY MM-NOT SO
SURE EMPLOY BUT WHEN YOU LOOK AT
THE INDIVIDUAL DATA YOU CAN SEE
THEREYA A TEMPORAL CORRELATION
BETWEEN ARIA E AND THE SEIZURES
AND WE DEVELOP CONFIDENCE IN A
SMALL NUMBER OF CASES THAT CAN
YOU HAVE SEIZURE AS A MORE
SERIOUS SYMPTOM OF ARIA E AND I
THINK THIS IS IMPORTANT AND I
WOULD ENCOURAGE THOSE OF YOU
SEEING PATES IN CLINIC, THE MORE
DATA YOU CAN SHARE WITH THE
SPONSORS ISSUES THE BETTER WOOER
GOING TO BE ABLE TO DO THIS, YOU
DO STILL HAVE VERY DETAILED DATA
COLLECTION FOR ALL OF THESE
CASES.
SO MANAGE AM, THIS IS REALLY
IMPORTANT CAN CLINICAL TRIALS
ONLY GIVE US SO MUCH INFORMATION
ABOUT MANAGEMENT.
NOW THE GOOD NEWS AGAIN IS THAT
MOST OF THE EVENT IN THE
CLINICAL TRIALS USING THE MANAGE
NLT IN THE CLINICAL TRIALS,
WHICH WAS DOSE SUSEXCEPTION FOR
MODERATE OR SEVERE RADIO GRAPHIC
ARIA WHETHER THAT WAS E OR H,
AND DOSE DISCONTINUATION FOR
SERIOUS EVENTS FOR SEER
ARE--ADMINISTRATIVE KRAMER H AND
ONGOING MRI MONITORING THOSE ARE
CARRIED FORWARD AND THOSE ARE
IMPORTANT.
THEY'RE NOT RAPID
LOAMACYYACKING.
THESE ARE DRUGS THAT HAVE A LONG
HALF LIFE SO TEMPORARILY DOSE
CESS PENDING THAT CONCENTRATION
IS GOING TO GO DOWN OVER TIME
EMPLOY BUT NONETHELESS, THE
PROFILE IS STILL REASONABLY
FAVORABLE WITH THESE.
WE HAD VERY LITTLE EXPERIENCE IN
THE TRIALS OF STEROID USE, SO
THERE WAS TOO LITTLE EXPOSURE TO
STEROIDS WHICH WAS NOT PROTOCOL
MANDATED BUT SOME INVESTIGATORS
DID USE STEROIDS FOR US TO BE
ABLE TO DETECT WHETHER IT MADE A
DIFFERENCE OR NOT.
AND THIS IS AGAIN WHERE CLINICAL
YMENT, WE KNOW THAT THAT IT HAS
BEEN USED.
THE APPROPRIATE USE
RECOMMENDATIONS NOTE THE USE OF
STEROIDS.
THERE'S SOME REASON WHERE IT MAY
BE HELPFUL BUT THIS WAS NOT DONE
IN THE TRIAL ANDS YOU KNOW I
THINK LIKELY NOT NECESSARY FOR
THE MAIORITY OF ARIA CASES BUT
DO RECOGNIZE THERE ARE SOME
PARTICULAR SITUATIONS WHERE THAT
MAY BE TRUE AND I THINK AS WE
LEARN MORE ABOUT THE MECHANISM
OF ARIA, YOU KNOW OUR
UNDERSTANDING OF WHAT TREATMENT
MAY BE, WILL EVOLVE.
IN THE LAST COUPLE OF MINUTES I
WANT TO SAY WHAT WE WILL
CONTINUE TO LEARN.
SO EMBARK IS A UNIQUE TRIAL WHEN
THE ADUCANUMAB TRIALS WERE
PAUSED, PATIENTS WERE ALLOWED TO
THEN LATER WHO HAD BEEN IN THOSE
IS ITS ENROLL IN THE EMBARK
TRIAL, SOME OF THOSE WERE ON MA
SEEB O, SOME HAD BEEN ON LOWER
DOSES, SOME HAD BEEN ON HIGHER
DOSES AND THIS IS A STUDY TO
LOOK AT THE LONG-TERM SAFETY ASK
TOLERABILITY OF THOSE PASHTS.
WE WILL HAVE DATA TO BE ABLE TO
SHARE AT CTAD AND WE WILL BE
ABLE INTERESTING THINGS THAT
DATA SET ALONE CAN TEACH US SO
WHAT IS THE RISK OF ARIA IF YOU
REDICE AFTER A POWS, LONGER TERM
USE, SOME OF THOSE PATES HAD
MORE ADVANCED ALZHEIMER'S
DISEASE BY THE TIME THEY WERE IN
THIS TRIAL.
AND IS THERE A DIFFERENCE IN
PATE BHOS HAD HIGHER EXPOSURES,
I LOWER EXPOSURES, HIGHER ARIA,
THERE ARE A NUMBER OF ONGOING
TRIALS IN THE FIELD BUT FOR A
NUMBER OF MOLECULES AND WE WILL
LEARN A LOT SO THE CMAX
HYPOTHESIS, THE SUBQ IMPACT
ARIA, STAGE OF DOZE, CAN WE
CORRELATE STEAJ OF STEEZ WITH
AMYLOID LOAD AND IS THE
IMANNUALING GETTING BETTER IN
WILL WE BE ABLE TO GET MORE
SPECIFIC AND IMAGE PARTS OF THE
BRAIN WHERE THERE MIGHT BE ARIA
AND A LOCAL AMYLOID LOAD.
IN THE REAL WORLD WE HAVE
REGISTRY DATA ONGOING POST
MARKETING SURVEILLANCE AND I
HAVE TO GIVE A SHOUT OUT BECAUSE
I THINK IT'S SO IMPORTANT AS WE
FOCUS ON THE SCIENCE, WE NEED TO
EDUCATE THE HEALTHCARE SYSTEM,
RADIOLOGISTS WHO MAY NOT BE
FAMILIAR WITH THIS, PRIMARY
PHYSICIANS AND ER DOCKS WHO ARE
GOING TO SEE PATES ON THIS
THERAPY AND THEN THERE'S ANOTHER
INTERESTING PART IS THAT IS WORK
ON THE BEST WAY TO EXPLAIN
BENEFIT RISK ON IT A PATIENT
POPULATION IN AREAS BEYOND THE
SCIENCE.
SO WITH THEY WILL CONCLUDE AND
THANK YOU FOR THE OPPORTUNITY.
NTHANKS.
THANKS, KAREN.
I DOPE KNOW IF THAT'S ON.
LET'S HAVE THE SPEAKERS CUM AND
CAN THE LIGHTS COME UP AT ALL
WHERE WE CAN HAVE 15 MINUTES FOR
QUESTIONS AND ANSWERS.
PLEASE USE THE MIC, SO IF THE
SPEAKERS FROM THE SESSION COULD
ALL COME UP.
OKAY, GO ARK HEAD, NICE
PRESENTATIONS, LARRY WALKER FROM
EMORY UNIVERSITY.
SO I HAVE A--IN MY LIMITED
EXPERIENCE, CAPILLARY AMYLOID
ANCHL OPERATING GLOBALLYATHY IS
IN SEVERE CAPILLARY ONCHIOPATHY
AND MODERATE TO SEVERE OVERALL
ANGIO OPERATING GLOBALLYATHY
OCCURS IN 40-50%.
TO WHAT EXTENT MIGHT THE RISK OF
ARIA E IN PARTICULAR BE RELATED
TO THE PRESENCE OF CAPILLARY
AMYLOID ANGIE OPERATING
GLOBALLYATHY IN THESE INITANCES.
MWRAIMS, SAVE US, YES.
NYAIMS YOU HAVE--COULD YOU HEAR
THE QUESTION NYES, I DID.
YEAH.
YES I, GREE THAT IT CAN OCCUR IN
ALZHEIMER'S DEC AS PART OF THE
PATTERN OF ACCUMULATION THAT'S
FAIR LYE UNCOMMON AND OBVIOUSLY
IT'S USUALLY SURROUNDED BY THE
PLAQUES AND THE LARGERRESSLES
THE ARTERIOLES CONTAINING
ABETTA, AND I MENTIONED THE
AQUAPORIN 4 AND THE
[INDISCERNIBLE] WHICH
PARTICULARLY ARE RELATED TO THE
CAPILLARIES AND THE CAPILLARY
WAS QUITE PROMINENT IN SOME
AREAS THAT SEEM TO BE CLEARED OF
PLAQUES BY THE IMMUNOTHERAPY SO
YES, I AGREE THAT AND WHERE WE
QUAWPTIFIED IT, THE CAPILLARY
WAS INCREASED IN THE IMMUNIZED
PEASHTS FOR THE ALZHEIMER'S
DISEASE, AND SO IT'S MORE
PROMINENT AFTER TREATMENT.
AND I WOULD ADPREE, POTENTIALLY
MECH NIM FOR FOR GENERATION OF
ARIA E MEDIATED BY THE ASTRO
SIGHT AND CANNED WHAT IN
AQUAFORIN 4 NTO THE EXTENT THAT
CARI IS A GOOD MODEL OF ARIA, IF
IN FACT IT IS WHERE WE HAVE MORE
PATHOLOGY IN THE ACTIVE PHASE,
NOT REALLY ARK ROUND CAPE
ILLEGALSARYS IF OUR BIOPSY
SPECIMEN, SO AT LEAST YOU CAN
GET SOMETHING THAT LOOKS A LOT
LIKE ARIA WITHOUT CAPILLARIES
BEING THE MAIN SOURCE BUT IT'S A
REALLY GOOD THOUGHT THOUGH.
>> CAN YOU HEAR ME?
>> I THINK THE MIC'S NOT
WORKING.
NTHIS SOUNDS LIKE IT'S ON,
MARRIAN BUCK WALTER FROM
STANFORD, GREAT TALKS, I HAVE
LOTS OF QUESTIONS BUT
DR. SMIRNAKIS, IF THE OTHER
FINDING ARE CLEARLY RELATED TO,
POE 4 AND THE SYMPTOM ANDS SIDE
CENTER FOR EXCELLENCE ON AGINGS
ARE NOT, IS IT POSSIBLE THAT WE
NEED TO REALLY RETHINK WHAT
WE'RE EVALUATING?
ARE WE LOOKING AT SOMETHING ON
AN MREFRESH YOUR RECOLLECTION I
AS TO THE ANTIBODIES CLEARING
AMYLOID BUT NOT THE THING THAT'S
RESPONSIBLE FOR SYMPTOMS, IF
WE'RE NOT LOOKING AT THE THING
RESPONSIBLE FOR SYMPTOMS WHAT
MIGHT THAT BE, I WOULD LOVE TO
HEAR YOUR THOUGHTS ON THAT ASK
OTHER PEOPLE'S THOUGHTS.
NI CAN TART AND MAYBE ASK OTHERS
THAT HAVE SEEN IN OF THESE
PATIENTS IN CLINICS, TO COMMENT
AS WELL.
I THINK THE CHALLENGE IS THAT IT
IS SO SELDOM ASSOCIATED WITH
SIGNIFICANT SYMPTOMS THAT WE'RE
NOT ABLE TO DETECT IT IN THE
CLINICAL TRIAL DATA WHICH IS NOT
THE SAME THING AS SAYING THAT
THERE'S NOT A RELATIONSHIP.
IT MAY NOT BE A SIGNIFICANT OR A
STRONG RELATIONSHIP BUT I WOULD
BE INTERESTED, AND I THINK IT
WAS MAYBE DR. SPERLING WHO NOTE
THAD SOME OF THESE PEASH RS MORE
SIGNIFICANT MREFRESH YOUR
RECOLLECTION I FINDINGS THAN YOU
WOULD EXPECT FOR THEIR SYMPTOMS
AND SO, I THINK WHETHER IT'S THE
RESOLUTION OF IT OR THE--YEAH,
IEP NOT SURE.
>> I WILL JUST SAY THAT I DO
THINK THERE'S SOMETIMES A
MISMATCH.
I'M MORE CONVINCED THAT THE
SYMPTOMS ARE RELATED TO A
POTENTIAL IPT GREATER FLAMMA
TORRATORY COMPONENT.
WHERE SOMETIMES THERE'S A RIP
ROARING EDEMA AND YOU SLEEP
APNEA AND OBESITYY THAT IN
PREGNANT WOMEN AND OTHER THINGS
WHERE THERE'S TERRIBLE IMANNUAL
XG A MILD HEADACHE BUT I THINK
THE INFLAMM EGG IS KEY AND I
DON'T THINK ANYONE'S TALKED
ABOUT INPOLICEMANNATORY IMAGING,
THE LIGANDS ARE NOT THERE YET
BUT IT WOULD BE SUPER HELPFUL
HERE NYEAH, EVEN WITH PRESS,
NORMALLY WHAT WE SEE ON THE SCAN
IS RELATED TO THE PATIENTS
SYMPTOMS.
>> I WILL BE OBSERVINGAL ABOUT
THIS.
FIRST OF ALL I HATE TO THROW OUT
THESE IMAGES THAT ARE SO
DRAMATIC LOAMACYY OPPOSITE
ALTHOUGH IT WOULD BE IDEAL FOR
THE FIELD THAT WE DIDN'T EVEN
NEED TO BE BOTHER TO BE LOOKING.
I'VE PLAYED IN A LOT OF PLAY
PINS AND SO, BRINGING THE
EXPERIENCE I HAVE FOR MULTIPLE
SCLEROSIS, SO HERE'S A DEC WHEN
I WAS BORN IN DISP FIRST LEARNED
IT, DOESN'T HAVE MR SCANNERS AT
ALL AND WE THOUGHT, PEOPLE HAD
EXACKER BAGS 1S ONCE A YEAR, 1
EVERY OTHER YEAR, SOMETHING LIKE
THAT, AND THEN, I GOT INVOLVED
VERY EARLY WITH REPEATED MRI
SCANS AND LOW AND BEHOLD, THERE
WERE HUNDREDS OF ASYMPTOMATIC
QUITE DISTINCT INPOLICEMANNATORY
LESIONS.
AUTOIMMUNE INFLAMMATION IN THE
BRAIN THAT WAS ABSOLUTELY
OBVIOUS AND YOU COULD RUN A
WHOLE CLINICAL TRIAL JUST
SUPPRESSING THAT DARN STUFF, AND
THAT DID EVENTUALLY MATTER IN
THE COURSE OF THIS DEC, SO I
THINK YOU KNOW FIRST OF ALL
THESE ARE IMPORTANT.
THE SAME THING.
THE OTHER THING IS IN OUR
CLINICAL TRIALS I HAD 1 VERY
SERIOUS CASE WHERE THERE WAS
CLEAR CORRELATION OF THE
LOCALIZATION, SO THAT YOU KNOW
THE PATHOLOGY IS CAUSING THE
SYMPTOMS WHEN THERE IS CLEAR
CORRELATION AND THERE'S A VERY
HEAVY OCCIPITAL PREDOMINANCE OF
THIS INFLAMMATION, AND YOU KNOW
I HAD A PATIENT, SUDDEN
CORTICALE PLIENDNESS AND GAVE
STEROID ANDS THAT REVERSE
FEDERAL A MATTER OF A FEW DAYS
AND YOU KNOW THERE WAS NO
QUESTION THIS NEW PATHOLOGY I
SAW IN THE SCAN WAS RELATED TO
THE CLINICAL PICTURE.
SO YOU KNOW THESE ARE RELATED.
I GUARANTEE WE SHOULDN'T SPEND A
LOT OF TIME THINKING THEY
AREN'T.
TEMPERATURE.
>> YEAH, I MEAN I GUESS I WAS
BEING A LITTLE BIT DELIBERATELY
PROVOCATIVE WITH MY QUESTION BUT
I DO THINK IT'S IMPORTANT ABOUT
MIGHT THERE BE A SECOND HIT LIKE
THERE'S EDEMA AND DR. SPERLING
JUST SAID, I THINK CLINICALLY IT
MIGHT BE THAT WITH BETTER MORE
CAREFUL NEUROLOGIC EXAMS, WE
MIGHT SEE SYMPTOMS LIKE YOU
MIGHT SUGGIEST THAT THAT MIGHT
BE REALLY IMPORTANT BECAUSE IT
STILL IS VERY STRIKING TO ME,
YOU COULD HAVE THESE IMAGING
ABNORMALITY ANDS BE QUOTE
ASYMPTOMATIC AND IT MAKES YOU
WONDER.
NI WANT TO BRENG UP AGAIN WE
HAVE PEOPLE WHO HAVE SUBSTANTIAL
MEMORY IMPAIRMENT TO REPORT ON
THIS AND PEOPLE DO I THINK, YOU
KNOW AGAIN THESE ARE MILD
PATIENTS BUT I STILL THINK
THEY--WE BRING THEM IN, SEE AN
MRI AND WE'RE LIKE WHAT HAPPENED
IN THE PAST WEEK AND THAT'S
HARD.
BUT ANOTHER REASON TO TREAT
EARLIER BECAUSE WE MAY BE ABLE
TO GET, BUT, I ABRAE WITH YOU
AND 1 THING I DIDN'T SAY THAT I
DON'T KNOW IF OTHER PEOPLE ARE
DATA BUT I DON'T THINK WE'VE HAD
A GOOD LOOK AT ASYMPTOMATIC ARIA
AND WHETHER IT CHANGES ANYTHING
ON COG NIG, OUR COGNITIVE TESTS
ARE NOT SUPER ENSELLATIVE AND WE
DO OFFER THEM 3 OR 6 MONTHS BUT
THAT'S SOMETHING I HAVE WONDERED
BECAUSE AGAIN, I THINK THERE ARE
GOOD THINGS THAT MIGHT
IMPROVEMENT IS THERE A TRANSIENT
DIP IF WE LOOKED HARD ENOUGH, I
DON'T KNOW.
NWE'VE BEEN LOOKING IF ARE THAT
BECAUSE I HAVE EXPERIENCE WITH
ASYMPTOMATIC THERAPY FOR THE
LAST DECADE NOW, AND WE'VE HAD
MULTIPLE CASES OF ARIA IN THE
DIAN-TISSUING U GROUP, IT'S
TRIKINGLY SIMILAR AND WE'VE HAD
THE OPPORTUNITY TO LOOK AT
DETERIORATION IN THEIR PERFOR
THE PURPOSANCE ON QUANTITATIVE
MEASURES SUBSEQUENT TO CASES OF
ARIA AND WE INFACT DON'T SEE A
SYSTEMATIC LOSS OF FUNCTION IN,
YOU KNOW A SMALL NUMBER OF
CASES, BUT IT'S A VERY CRITICAL
QUESTION AND WE HAVE BEEN
LOOKING AND WE'LL CONTINUE TO
LOOK EMPLOY O I THINK THAT IS AN
IMPORTANT ISSUE.
NYAISON [INDISCERNIBLE]--WE HAVE
A KEEP MOVING, BIEG LYNN UP
THERE, MICHAEL NHI, MIKE FROM
ARIZONA, I WANT TO FOLLOW UP ON
DR. NIERK COLL, AND HIGHLIGHT
THAT WITHIN THE PROGRAM THERE
HAD BEEN THRESHOLD PATHOLOGICAL
REPORTS WITH CONCURRENT ARIA.
SO 1 DR. SARK WELL, LOWAY KNOWS
WELL WITH INTERCEREBRAL
HEMORRHAGE ON THE PATHOLOGY, IT
SHOWED SUBACUTE ISHT CEREBRAL
HEM RANL, MILD CAA, MILD CAA,
THE TPA CASE THAT WAS REPORTED
HAS BEEN PUBLISHED IN THE NEW
ENGLAND YOWRNAL AND ALSO IN
ANOTHER PUBLICATION OF MULTIPLE
ABOUTS CEREBRAL HEMORRHAGES
TREATMENT IN THE APOE HYM O
ZYGOTE IN THE SETTING VERY SOON
AFTER RECEIVING TPA, AND THAT
PATHOLOGY HAD HONE AS WELL A
HISTOSIDIC VASCULITIS,
SUPPORTING IN OF THESE SEVERE
CASES MAY BE CAA, ARIA IN
APPEARANCE AND THEN THE THIRD
CASE WAS ANOTHER HOMOZYGOTE WITH
SEVERE ARIA E AND ALSO MULTIPLE
MICROHEMORRHAGES AND ASSOCIATION
WITH THAT, THAT ALSO PATHOLOGY
SIMILARLY SHOWED SEVERE CAA AND
EFTHIMIOSIO SIDIC TYPE OF
VASCULITIS SO THESE CASES THOUGH
VERY UNCOMMON DO SUPPORT THAT IN
SOME CASES THERE MAY BE AN
INFLAMMATORY COMPONENT NTHANK
YOU MICHAEL FOR SAYING THAT AND
LET ME MACK A PLUG, KAREN'S
HEARD THIS FROM ME FOR A WHILE
THAT THESE CASES, THESE REALLY
SEVERE OR FATAL CASES ARE NOT
THAT COMMON BUT THEY'RE SO
INFORMATIVE AND SO I JUF WANT TO
ENCOURAGE ALL TO REPORT THESE
CASES SO WE CAN LEARN FROM THEM.
THEY'RE CRITICAL.
AMERICA YEAH, TERMS OF THE
DOUBLE EDGED SWORD OF THE BLOOD
VESSEL FUNCTION WHAT HAPPENED TO
THE AMYLOID PET SCANS AND PEOPLE
WHO GOT TREATED WITH IMMUNE
SUPPRESSION?
NYOU KNOW THE AMYLOID PET HAS
NOT BEEN USED CLIPICALLY AND SO,
THERE SHOULD BE NO SYSTEMATIC
CLINICAL AMYLOID PET IN THOSE
GUYS.
I THINK THE QUESTION ABOUT
WHETHER IS INFLAMMATION OR NT,
AUTOIMMUNE RESPONSE GOOD OR BAD
FOR YOU, I THINK IT'S HARD TO
SAY.
I DIDN'T HOE IT BUT THE AIM OF
ARIA PRESENTATION EARLIER IS
ABOUT 5 YEARS EARLIER THAN THE
AVERAGE AGE OF FIRST HEMORRHAGE
AMONG OUR PATIENTS SO I THINK
IT'S AN EARLY TRIP WIRE.
NI'M TALKING ABOUT THE PEOPLE IN
THE TRIAL WHO GOD TREATED WITH
PREDNISONE NYEAH, SO FOR
ADUCANUMAB, I DON'T THINK WE
HAVE THAT.
MOST PATIENTS TREATED WERE A
SMALL NUMBER AND I'M MOT SURE IF
THEY'RE THE SAME 1S IN THE
SUBSTUDY, BUT I'LL GO BACK AND
LOOK NTHE REASON I MENTIONED
CASES THERE WAS 1 CASE REPORT,
THAT'S WHY IT'S SO IMPORTANT TO
HAVE THESE CASES IN THE
LITERATURE OF A PATIENT TREATED
IN OPEN LABEL ADUCANUMAB, A
NEUROLOGIST WHO HAD SUBSEQUENT
PET IMAGING, HAD CORTICALE
STEROIDS, HAD PET INLAGING WITH
AMYLOID LOWERING IN THE AREAS OF
ARIA, IT'S A SING CASE, WE DON'T
HAVE A SYSTEMATIC.
>> WALTERIME FLAD YOU BROUGHT IT
UP BECAUSE I KEPT THINKING ABOUT
IMMUNO THERAPY AND ACTIVITIES
AND PROJECTS COMPETENT CANCER
AND WHEN WE GIVE STEROIDS,
BECAUSE YOU HAVE TO DAMPEN IT
DOWN, YOU HAVE CAN STILL SEE A
RESPONSE BUT IF YOU GIVE SO MUCH
STEROIDS YOU OVERIT CAN THOSE
PEOPLE DON'T DO AS WELL LONG
E-PRESCRIBING TERM SO IT'S AN
IMPORTANT QUESTION NIN TERMS OF
TIMING WHETHER OR NOT YOU COULD
DO SOMETHING EARLY BEFORE YOU
HIT THEM WITH THE ANTIBODY, NOW
IF IT CLEARS THE ANTIBODY, YOU
DEFEAT YOUR PURPOSE BUT YEAH
EMPLOY NYEAH, LAST QUESTION.
>> SORRY.
NMARK FISHER FROM IRVINE,
QUESTION: WITH ALL THE STUDIES
OF INFLAMMATION CAN CAA, I AM
WONDERING IF YOU CAN COMMENT ON
A CELL TYPE THAT HASN'T RECEIVED
A WHOLE LOT ATTENTION WHICH IS
THE MASS CELL MASS CELLS HAVE
PREDILECTION FOR MENING EEL
LOCALIZATION WHICH IS WHERE A
LOT OF THE ACTION IS IN CAA SO
WONDERING IF YOU CAN COMMENT ON
MASS CELL ACTIVATION AND MASS
CELL CONTRIBUTION TO CAA POGHT O
PHYSIOLOGY?
>> I DEFINITELY CAN, I HAVEN'T
TAINED IT, JAMES YOU HAVE A
COMMENT?
>> YEAH, WELL WE LOOKED AT MASS
CELLS SPECIFICALLY IN THE
CONTEXT OF MULTIPLE SCLEROSIS,
ACTUALLY AND THERE ARE VERY FEW
MASS CELLS IN THE BRAIN OR IN
THE MENENG ES, AND HAVEN'T
LOOKED IN CAA.
DON'T THINK THERE ARE MANY
THERE.
>> WELL I WANT TO THANK THE
SPEAKERS FOR AN EXCELLENT
KICKOFF. THANK YOU.
ALL RIGHT, WE'RE GETTING
STARTED, I AM CLINT WRIGHT I'M
DIRECTOR OF THE DIRECTOR OF THE
RESEARCH AT NE NDS AND I WILL
RECEIVE THE CLENICAL TRIAL
NETWORKS AND ALSO ADVISE THE
IPSITUTE ON CLINICAL RESEARCH
PROBLEMS AND THIS IS A CLINICAL
RESEARCH PROBLEM.
THAT WE HAVE TO SORT OUT.
VERY NICE TO SEE SUCH AN
INGAUGED GROUP THIS MORNING WITH
A WONDERFUL SESSION.
SO WE'RE GOING TO FOLLOW IT UP
WITH A PANEL DISCUSSION AND WE
HAVE A NUMBER OF AND WE ARE A
NUMBER OF EXCELLENT PANELISTS
HERE XI WILL BRIEFLY, I WILL NOT
DO EXTENSIVE INTRODUCTIONS,
PEOPLE CAN KIND OF INTRODUCE
THEMSELVES BUT WE HAVE
DR. VISWANATISSUING HAN HERE
FROM HARVARD MEDICAL SCHOOL,
SUSAN CATALANNOR PRACTICES
BIOTHERAPEUTIC ANDS MICHAEL
IRISWRRK AREFRESH YOUR
RECOLLECTION REFRESH YOUR
RECOLLECTION Y, WITH SHEART
ATTACK ARI WITH CMS EMPLOY WE
WILL TALK ABOUT GAPS IN THIS
KRAIR SO THAT NETWORK INDS CAN
THINK ABOUT HOW WE MOVE FORWARD.
I WANTED TO MENTION THAT IN THE
WAKE OF THE MOST RECENT TRIALS
THAT HAVE SHOWN SOME EFFICACY IN
ANTIAMYLOID THERAPY, THERE ARE A
NUMBER OF INCLUSION AND
EXCLUSION CRITERIA THAT WERE
OBVIOUSLY APPLIED AND SO NOW
THAT PATIENTS ARE GOING TO BE
COMING IN AND ASKING FOR THIS
THERAPY, THERE ARE A NUMBER OF
AREAS AND ORDER ZONE AREAS WHERE
WE'RE GOING TO BE HAVING A LOT
OF QUESTIONS ABOUT WHO BENEFIT
ANDS WHO COULD BE HARMED BY IT
AND SO THERE'S A LOT OF--AS
EVERYONE IN THIS ROOM KNOWS
WELL, THERE'S AN ENORMOUS AMOUNT
OF CO-MORBIDITY.
AND THERE'S A LOT OF VASCULAR
DAMAGE THAT UNDERLIES OR THAT IS
COMORBID WITH ALZHEIMER'S
PATHOLOGY, A SUBSTANTIAL NUMBER
OF LOUIS BODY PATHOLOGY AS WELL,
SO HOW DO THOSE CO FACTORS
RELATE TO THIS POTENTIAL THERAPY
AND ARIA SPECIFICALLY.
SO WE HAVE ASH PROVAL TO RUN
TRIALS IN THIS AREA ASK WE NODE
TO UNDERSTAND THE GAPS AND
OPPORTUNITIES IN BEDDING WHO MAY
BE AT RISK.
SO THANK YOU I'M GOING TO START
BY ASKING THE PANELISTS STARTING
MAYBE RIGHT HERE,
DR. VISWANATHAN, SPEAK A BIT
ABOUT YOUR TAKE ON THE LAST
SESSION, YOUR TAKE ON THIS
SUBJECT AND MAYBE THINK ABOUT
SOME RESEARCH, GAPS AND
OPPORTUNITIES TO IDENTIFY AND
TALK ABOUT TOMORROW WHEN WE ARE
OUR BREAK OUT SESSIONS.
>> GREAT.
THANKS, FOR ORGANIZING THIS
MEETING, I FIND THAT THE LESS
AMG TO BE QUITE INTERESTING AND
QUITE PROVOCATIVE IN SOME OF THE
QUESTIONS THAT WERE RAISED ABOUT
INMEDICARE AND MEDICAIDATION
THERAPY AND I'M A STROKE
NEUROLOGIST AND DEMENTIA
SPECIALIST AND YOU KNOW OUR
GROUP AND IN HIS TALK WE FOCUS
ON AMYLOID ANGIE OPERATING
GLOBALLYATHY AND THESE OTHER
PATHOLOGIES AND SO OUR EMPHASIS
OVER THE LAST DECADE OR SO, IT'S
BEG YOUR PARDON REALLY TO
INVESTIGATE THE CARI MECHANISM
AS A POTENTIAL MODEL OR AS A
POTENTIAL OVERLAP WITH THE
ALZHEIMER'S DEC APPLICATION OF
IMMUNOTHERAPY INVESTIGATING
FURTER AREAS ASSOCIATED WITH
CARI AND ALSO THE OTHER ASPECT
OF CAA RELATED IMMUNOTHERAPY FOR
CAA PATES ON THEIR OWN COULD BE
POTENTIAL AREA THAT WE WOULD
LIKE TO SEE GO FORWARD A LITTLE
BIT MORE AS MANY OF YOU MAY KNOW
THAT THERE HAS BEEN A TRIAL OF
IMMUNOTHERAPY AND AMYLOID ANG
IOPATHY, BUT NOT POSITIVE IN THE
SMALL TRIAL THAT WAS CONDUCTED.
IT DID OPEN AN AVENUE FOR
TREATMENT OF ANGASHING IOPATHY
ON ITS OWN BUT AS CLINT POINT
THES OUT MORE IN MY OPINION, THE
OVERLAP IN ANG IOPATHY AND
ALZHEIMER'S DEC WHICH REPRESENTS
A LARGE NUMBER OF PATES WE STUDY
IN OUR CENTER, SO GOING IN THIS
DIRECTION OF THESE OVERLAPPING
PATHOLOGIES AND HOW TO INCLUDE
THE MOST NUMBER OF INDIVIDUALS
WHO COULD BENEFIT FROM THERAPY
WOULD BE SOMETHING THAT I WILL
BE PARTICULARLY INTERESTED IN
PURSUING.
NTHANKS.
YOU KNOW IT DOESN'T ESCAPE
NOTICE AND LOOK AT PRINCIPLES
THAT ARE PRETTY WIDE AND
INDICATES QUITE A BIT OF
VARIABILITY, SO WHAT IS
EXPLAINING THAT VARIABILITY AND
I GUESS 1 THING THAT COMES TO
MIND, YOU'RE A STROKE
MIEWROLOGYIST, WHAT DO YOU THINK
ABOUT THE UNDERLYING HEALTH OF
THE VESSEL, NOT NECESSARILY FROM
AN AMYLOID ANG IOPATHY TANNED
POINT BUT FROM LET'S SAY SOME
OTHER LIPO HIELENOSEIS, OTHER
RISK FACTORS THAT MAY CONTRIBUTE
TO SMALL VESSEL DISEASE?
HAVE YOU THOUGHT ABOUT IT?
>> AND IN RELATION TO THE WHOLE
COGNITIVE PICTURE OR IN NIN
TERMS OF THE REACTION TO THE
ANTIAMYLOID THERAPY.
NTHAT'S A GOOD THOUGHT.
THAT HASN'T REALLY BEEN
INVESTIGATED TOO MUCH AT LEAST
YET, I THINK WE NEED TO TRAIN
MORE PEOPLE LIKE STEVE AND
OTHERS WHO DO BOTH THAT'S KIND
OF REALLY BEEN QUITE SILOS IN
MANY WAYS.
WE'VE GOT INTO THIS AND WE'VE
TRAINED MORE THAN A FEW
COLLEAGUES NOW OVER THE YEARS
WHO ARE INTERESTED IN THIS SMALL
VESSEL DEC PATH OLDER PEOPLE BUT
THUS FAR THE PATHOLOGY HAS
REMAIN--THE FIELD HAS REMANIED
ISOLATED FROM ALZHEIMER'S
DISEASE AND AS CLINT POINTS OUT
IT COULD BE AN AREA TO
INVESTIGATE WITH INDIVIDUALS
WITH EXTENSIVE MAUL VESSEL
DISEASE AS CHARACTERIZED BY MRI
AND THE VARIETY OF DIFFERENT
IMAGES AND IMAGING MODALITIES
WE'VE SHOWN COULD THERE BE A
HIGHER RISK GROUP WHO MAY HAVE
ADVERSE SIDE EVENS ASSOCIATED
WITH THE THERAPY.
CERTAIN LE SOMETHING TO THINK
ABOUT.
>> THANK YOU.
NI WANT TO CLARIFY MY CURRENT
AFFIL YAIG IS WITH CAP
EDUCATIONALLA BIOTHERAPEUTICS,
IT'S GREAT TO BE HERE, GREAT
SESSIONS THIS MORNING AND ALSO
TO COME AND I THINK REALLY IS
RAISES THE QUESTION FOR ME TO
COME AND STUDY THE POPULATION
SPECIFICALLY SO I THINK WE KNOW
ENOUGH ABOUT THE MOLECULAR
MECHANISMS TO REALLY ACTUALLY
ARK PROACH THAT.
THE CURRENT TREATMENT OPTIONS,
THE MONOCLONAL ANTIBODIES
CLEARLY INTERACT WAAMYLOID AND
DO SO IN THE VASCULATURE.
TO A CERTAIN EXTENT WE'RE
ALREADY TESTING THIS IN ONGOING
TRIALS.
SO THEN THE QUESTION BECOMES DO
WE REALLY WANT TO ENROLL THOSE
AMYLOID PET NEGATIVE CAA
POSITIVE PATES THAT ARE NOT
CURRENTLY BEING STUDIED AND YOU
KNOW IF WE WERE TO DO SO, DO YOU
WANT TO EXCLUDE THE FOLKS WITH
THE HEAVY CAA LOAD OR THE FOLKS
AT LIFIC FROM ARIA, CERTAINLY
THAT WILL BE THE CASE THAT WOULD
SUGREST YOUR STUDYING FOLKS
EARLIER IN THE DISEASE, HA'S A
PREVENTION CONPARTICULAR.
THIS SUGGIESTS COST, STUDY, AND
DO WOE KNOW ENOUGH ABOUT THE
HISTORY TO MONITOR CHANGING AT
THE MOLECULAR LEVEL AND THE
PATHOLOGY AND CLINICAL
MEANINGFULNESS AND I THINK WE
MADE TREMENDOUS PROGRESS TO BE
ABLE TO DO THAT EMPLOY SO I
THINK THE ANSWER IS YES AND
CERTAINLY HAVING THAT
THERAPEUTIC SHOULD IT BE
IMPACTFUL GOES A LONG WAY
TOWARDS VALIDATING THOSE
CLINICAL MEASURES AS WELL, SO I
THINK IT'S--WE'RE GOING TO HEAR
MORE, I THINK TO COME IN THIS
SESSION ABOUT HOW TO CLINICALLY
MANAGE THE PATES WHO ARE AT RISK
FOR THESE ADVERSE EVENTS AND THE
VERY RARE SERIES ADVERSE EVENTS.
SO I THINK THAT THE KNOWLEDGE IS
THERE TO ACTUALLY START TO ASK
THESE QUESTIONS CLINICALLY.
NTHANK YOU, BEFORE WE MOVE ON, I
THINK YOU HAVE A TAKE ON LOUIS
BODY AND SINCE IT IS SO COMORBID
WITH ALZHEIMERS, I AM WONDERING
IF YOU HAVE ANY THOUGHTS ABOUT
THAT ESPECIALLY IN THE REALM OF
INFLAMMATION, WHETHER THAT COULD
HAVE ANYTHING TO DO WITH
REACTIONS THAT WE'RE SEEING.
IT HASN'T BEEN LOOKEDDA THE VERY
MUCH.
THERE'S NO QUESTION WHERE WE
LOOK, WE SEE INFLAMMATION.
AND THAT'S GOING TO BE A MAJOR
COMPONENT OF ANY CLINICAL
PROTOCOL THAT YOU WOULD ACTUALLY
CONSIDER IN TREATING THIS
POPULATION, DLB PATIENTS, YOU
KNOW ALZHEIMER'S PATIENTS.
SO I THINK IMETTING THAT RIGHT
OR UNDERSTANDING THAT CAN BE
TOUGH TO MODEL IN VASCULAR DES
EMPLOY IT'S A LITTLE TOUGH TO
GET A PKPD MODEL IN THE
CAPILLARY DEC VERSUS LARGER
VESSELS SO IT'S--SOME ASPECTS OF
THAT ARE CHALLENGING.
BUT AT THE END OF THE DAY, I
THINK, YOU KNOW THIS IS A
SERIOUS DISEASE, IT'S AN UNMET
MAJOR HEALTH NEED?
I THINK WE KNOW ENOUGH TO SAFELY
TART TO ASK IF THESE THERAPIES
ARE GOING TO BE EFFECTIVE IN A
VARIETY OF CONTEXTS.
>> SO AS WE MOVE FORWARD IN
BIOMARKERS AND LOUIS BODY SEIZES
IT WILL HELP.
>> THERE'S NO QUESTION.
BIOMARKERS ACROSS THE BOARD,
IMAGING BIOMARKERS WILL BE
USEFUL.
>> THAIRNGS.
THAT WAS A GREAT TRANSITION
BECAUSE IN TERMS OF RESEARCH
OPPORTUNITIES I WAS THINKING OF
BIOMARKERS SPECIFICALLY FOR CAA
AND ARIA.
AND AT BIOMARKERS FOR SEVERAL
ROLES FOR THAT, SO 1 IS
BIOMARKERS OF CAA RISK THAT MAY
BE ABLE TO STRATIFY EVEN FURTHER
BEYOND THE CURRENT MRI SIGNALS
OR APOE GENO TYPE.
ALSO RECOGNIZING THAT THE
AMYLOID PET SCANS WE'RE GETTING
CAN DIFFERENTIATE CAA FROM
PATHWAY GIVES RENCH MALAREA, SO
THIS MAY REFLECT SEVERE CAA.
AND THEN MARKERS OF ACTIVE ARIA,
SO IF WE THINK THAT THERE'S VASE
O GENIC EDEMA, BREAK DOWN OF THE
BLOOD BRAIN BARRIER, WE MAY
EXPECT PROTEINS TO LEAK OUT FROM
THE BRAIN OR CONVERSELY PROTEINS
FROM PERIPHERY FIGURE INTO THE
BRAIN, SO THAT WOULD BE IF WE'RE
THINKING ABOUT NOW WHETHER TESTS
CAN REPLACE SCANS OR MAY BE IN
TERMS OF DETECTING ARIA AND
WOULD ALLOW MONITORING AS WELL.
AND THEN, MARKERS OF OUTCOME, SO
WE FEEL LIKE LOOKING AT THIS IN
THE COURSE OF A CLINICAL TRIAL
IN BOTH UNBIASED AND SPECIFIC
WAYS TO TRY TO SAFELY IDENTIFY
BY O MARKERS THAT CAN HELP WITH
THE RISK DIAGNOSIS AND
MANAGEMENT.
YEAH, DR. KOROSSHES CHETZ'S
QUESTION WAS REALLY WILL PEOPLE
STILL BENEFIT IF YOU HAVE TO
IMMUNO SUPPRESS THEM TO GET THEM
THROUGH THIS PHASE AND IT WOULD
BE GRAND IF THERE'S DATA THERE
AND WE NEED TO LOOK AT IT, I
THINK.
THE OTHER THING BABESSED ON THE
DISCUSSION THIS MORNING AND WHAT
YOU JUST RAISED IS THE
INTERACTION BETWEEN THE CENTRAL,
AND THE PERIPHERAL IMMUNE
SYSTEM, SO THINKING ABOUT ARIA
RELATED TO MICROFLEEL
ACTIVATION, THAT'S THE
REMODELING WITHIN THE CENTRAL
NERVOUS SYSTEM, RERSUS SOME OF
THESE CASES OF CAA RI WHICH INN
VOFFED T-CELLS AND THE
PERIPHERAL NERVOUS SYSTEM,
UNDERSTANDING THOSE INTERACTIONS
WILL BE VERY IMPORTANT.
>> THANK YOU VERY MUCH.
DR. LING WOULD YOU LIKE TO
PROVIDE A TAKE?
>> SURE.
AND I WOULD LIKE TO ADD TO THE
OPPORTUNITY TO THANK EVERYBODY
AND BEING A PART OF THIS PANEL.
AS FAR AS THE CMS PERSPECTIVE,
CMS ACTUALLY FOLLOWING THE
STATUTORY AUTHORITY WHICH MEANS
THE COVERAGE AND PAYMENT
PRINCIPLES REALLY ALIGN WITH
WHAT IS REASONABLE IS NECESSARY
TO TO MEET THE HEALTHCARE NEEDS
OF THE PEOPLE WHO ARE RECEIVING
THE BENEFIT, THAT IS A MEDICARE
BENEFICIARY POPULATION, SO WHY
THAT IS REALLY IMPORTANT, IT
ACTUALLY GETS BACK TO SOME OF
THE REMARKS MADE BY DR. CLIFFORD
THIS MORNING AND REFLECTED IN
THE THINKING OF THE DOCTOR'S
QUESTION IS THAT THE POPULATION
OF PEOPLE WHO WE ARE SERVING IS
COMFLEX.
SO IF YOU THINK ABOUT AND
KNOWING THE PROPORTION OF PEOPLE
WHO ACTUALLY DEVELOP ARIA IS A
SUBSET OF PEOPLE WHO HAVE
DEMENTIA OR DEVELOP DEMENTIA AND
IN THE MEDICARE POPULATION LESS
THAN 5% WILL HAVE ONLY DEMENTIA.
SO WHAT YOU MENTIONED EARLIER
CLINTON WITH THE CO-MORBIDITIES,
IT'S--IT IS A REAL OPPORTUNITY
AND A CHALLENGE AT THE SAME
TIME.
BUT SINCE THE PEOPLE WHO YOU
WILL BE STUDYING AND THE
OBLIGATION IS TO STUDY PEOPLE
WHO LOOK LIKE THE MEDICARE
BENEFICIARY POPULATION IF WE ARE
TO TRANSLATE THE EVIDENT BO
POLICIES OF COVERAGE AND
PAYMENT, THEN YOU KNOW THEREIN I
THINK IS BOTH A CHALLENGE AND AN
OPPORTUNITY.
EACH 1 OF OUR BENEFICIARIES WHO
ISHT FACES WITH THE HEALTHCARE
SYSTEM ALSO HAS A REFLECTION OF
THAT INTERACTION IN THE
ADMACHINE TRAITIVE CLAIMS EMPLOY
SO I THINK THAT IS AN
OPPORTUNITY TO BE ABLE TO
DELINEATE THE PHENOTYPE THAT
GOES WITH THE OUTCOMES THAT
YOU'RE INTERESTED IN LOOKING AT
AND FOR US ULTIMATELY THE
QUESTION IS WHAT IS THE EVIDENT
THAT WILL HELP CARE TO TIP THE
BALANCE IN FAVOR OF MORE BENEFIT
AND LESS RISK OVER TIME AND WHAT
IS MEANINGFUL TO IMPROVE IS THAT
THE THERAPY HAS TO BE USEFUL IN
THE CARE CAN KEEPING OF THE
PEOPLE WHO WE SERVE.
IT SEEMS SO EASY TO SAY AND YET
HARD TO DO.
SO WHEN IT COMES TO THINKING
ABOUT WHAT SOME OF THE
OPPORTUNITIES ARE YOU KNOW CMS
DID PUBLISH A NATIONAL COVERAGE
DECISION THAT UNDER THE RUBRIC
OF COVERAGE WITH EVIDENCE
DEVELOPMENT AND THERE'S RIGHT
NOW THERE ARE 2 APPROVED TRIALS
UNDER THAT RUBIC BUT 1 OF THE
TRIALS ACTUALLY IS TREATMENT
PERCEIVES BUT IS COVERABLE WITH
PARTICIPATION IN A REGISTRY.
BUT THE CED TEAM REPRESENTED
HERE BY DR.IO HUTTER WHO IS 1 OF
OUR SENIOR MEDICAL OFFICERS AND
THE PROGRAM, THE POLICY IS AN
OPPORTUNITY THAT I THINK WITH
THE ADDRESSING THE QUESTIONS
THAT REALLY ALIGN AROUND RISKS
AND BENEFITS IN AT WHICH TIME
AND TIMING MATTERS, IF THOSE ARE
ADDRESSED THAT CAN BE A VEHICLE
TO COME IN UNDER CED THAT CAN
REALLY BENEFIT BOTH THE SCIENCE
BUT ULTIMATELY THE PEOPLE WHO WE
SERVE.
>> YEAH, THANK YOU.
YEAH, I THINK THERE'S QUESTIONS
THAT CAN BE ANSWERED IN TRIAL
CANS THEN THERE WILL BE A LOT OF
QUESTIONS WHERE IT'S GOING TO BE
DIFFICULT TO ANSWER THEM IN
TRIALS BECAUSE THEY'RE NOT GOING
TO BE VERY COMMON AND THE
REGISTRIES ARE ANYTHING TO HAVE
TO HELP US IN THAT REGARD AS
WELL AND SO I THINK IT'S IT'S
INTERESTING TO HEAR THAT
PERSPECTIVE AND REMEMBER THAT
THAT WE HAVE DIFFERENT SHOTS ON
GOAL, RIGHT AND SO THERE ARE
THESE TRIALS GOING ON.
THERE ARE PERHAPS NIH AND NINDS
TRIALS IN THE COMORBID AREAS,
NIA TRIALS PROBABLY AND THEN
THERE ARE THESE REG TREES AND
THEN THERE ARE CO-MORBIDITIES
THAT ARE VERY UNCOMMON, I MEAN,
WE ARE CONCERNED ABOUT
HEMORRHAGE RISK, THERE ARE
PEOPLE WITH PARTICULAR ARK
NATIONAL LIBRARY OF
MEDICINALLYS, VASCULAR ANOMALIES
THAT MAYBE SOME OF THEM WANT TO
GET TREATMENT CAN THEY WON'T
KNOW WHETHER IT'S SAFE TO DO
THAT AND WE PROBABLY WON'T BE
ABLE TO ANSWER THAT WITH TRIALS
RIGHT, WE WILL NEED REG TREES TO
ANSWER THOSE THINGS, I'M DONE,
YOU KNOW AVMs AND.
>> YEAH, WELL, THANKS FOR
EVERYBODY'S SORT OF TAKE ON THE
MORNING AND I THINK WE SHOULD
OPEN IT UP TO THE LARGER FROWP
AND HAVE A BACK AND FORTH
DISCUSSION, ARE THERE QUESTIONS
FOR PEOPLE ON THE PANEL IN
QUESTIONS FOR OTHERS REISA?
>> BUT I GUESS I'M WONDERING
GIVEN THE COMMENTS IS THERE A
PHASE WHERE THERE IS EVER PET
NEGATIVITY BUT CAA POSITIVITY,
MEANING YOU DON'T HAVE ANY
AMYLOID OR AT LEAST IN THE
DISTRIBUTION, SO WHAT--GOOD
CATCH.
>> WHAT IS KNOWN ABOUT THAT IN
THE EVOLUTION WHERE YOU'RE
FOLLOWING PEOPLE, I EMBASSY THIS
IS ALSO IN THE RARE DUTCH
MUTATION STUFF.
>> SO I THINK CERTAINLY, THEY
CAN OCCUR SO EXTENSIVELY THAT
IT'S, IT CAN BE CHALLENGING BUT
THERE ARE CASES, YOU KNOW THAT
WE KNOW OF WHERE WE DON'T HAVE
THAT.
HAVE WE LOOKED AT THEM
SPECIFICALLY AND SYSTEMATIC
LOAMACYY WITH THE AMYLOID PET,
DO WOE HAVE ENOUGH EXAMPLES OF
THAT TO BE CONFIDENT IN I THINK
THAT'S A GOOD QUESTION.
>> AND REISA'S QUESTION IS
INTERESTING AS SUSAN POINTS OUT
FOR ANOTHER REASON, KIND OF
ANOTHER NUANCE AROUND CAA AND
CAA NATURAL HISTORY.
SO, WE'VE THOUGHT THESE PATIENTS
FOR A LONG TIME ON THE STROKE
SIDE, SO THAT'S HOW THESE CASES
WERE INITIALLY KRIEBED AS CAA
PEASHES WITH HEMORRHAGE BUT
THERE'S A WHOLE GROUP OF
PATIENTS WE STUDIED IN THE LAST
DECADE OR SO THAT DON'T EVER
DEVELOP STROKES SO THEY JUST
COME TO--COME TO OUR AMILLIO
JEIMER'S CLINICS OR OUR DEMENTIA
CLINICS ISSUE PATIENTS WITH
EITHER MILD COGNITIVE,
IMPAIRMENT OR FULL PLOAN DEMENT
RAW DATA AND WE CAM PAIR THESE
GROUPS IN CAA PATIENTS BOTH
HAVING MODERATE TO SEVERE CAA.
AND WHILST THE IMAGING FINDINGS
AND PATHOLOGIES SEEMS TO BE
LARGELY NONDISTINGUISHABLE, THE
[INDISCERNIBLE] IS TOTALLY
VARIED AND DIFFERENT.
SO TREATING THOSE CAA PATIENT
WHO IS DEVELOP STROKES WITH
ANTIAMYLOID THERAPY MAY NOT BE
IDEAL FOR OBTAINING COGNITIVE
OUTCOME AND THEN TREATING THE
DEMENTIA PATES FOR THINGS THAT
AREN'T RELATED TO STROKE, ALSO
SIMILARLY, WE MAY BE MISSING THE
BOAT, SO I THINK THE--1 OF THE
THINGS TO THINK ABOUT AROUND CAA
IS WHO ARE THE CAA PATIENTS,
WHAT TYPE OF CAA IT IS.
WE'RE NOT CAPABLE OF
DISTINGUISHING THAT YET, EARLY
AND OF COURSE, WHICH DIRECTION
THEY GO, BUT MAYBE DEVELOPING
BIOMARKERS TO TRY TO SEE THAT,
TOEE IF THEY'RE MORE OF--AND
THIS MAY BE KIND OF A MORE OF AN
AMYLOID OR A TAU IMAGING TYPE
APPROACH THAT WE'VE DONE IN
SMALL EPIDEMIOLOGIC TODAYS TO
DISTINGUISH THAT GROUP THAT WE
CAN CHARACTERIZE THEM WELL
ENOUGH TO TREAT AS REISA POINTS
OUT.
NI BEING ALSO FOLLOWING UP ON
STEVE'S PATHOLOGIC TODAYING OF
CAA, THE AMYLOID DEFINITION OF
VESSELS APPEARS TO OCCUR 20 OR
30 YEARS BEFORE THE
MICROHEDGEERAGE, SO FOLLOWING OF
COURSE, AND TEASING OUT MAYBE
CHALLENGING IN EMERGING ITS OF
TIME COURSE.
>> DR. CLIFFORD?
>> SO TO STIMULATE THE
DISCUSSION AND MICHAEL'S COMMENT
THE TIME COURSE OF DEPOSITION
DOESN'T SEEM TO CLOSELY LINK
WITH WHEN ARIA'S OCCURRING
EMPLOY I WANT TO BRING 1 OF THE
BEAUTIFUL THINGS ABOUT STUDYING
PREDOMINANTLY INHERIT THED
ALZHEIMER'S POPULATION IS THAT
IT GIVES US MAGIC GOGGLES MUCH
MORE PRECISELY WHERE IN THE
COURSE OF THIS DEC WE ARE
WORKING AND AS I'VE WATCHED THIS
POPULATION BEING TITRATED WITH
GRADUALLY INCREASING DOSES OF
EITHER THAT DIDN'T CAUSE THIS
PROBLEM AT ALL, OR WITH
GRADUALLY INCREASING DOSES OF
[INDISCERNIBLE] THAT CLEARLY CAN
CAUSE IT, WHAT IS VERY OBVIOUS
TO A GRAY HAIRED CLINICIAN AND
DOESN'T REQUIRE MACHINE LEARNING
IS THAT THE NEARNESS TO THE YEAR
OF ONSET OF DEMENTIA IS A VERY
IMPORTANT PARAMETER AND
INTERESTING THING IS THAT THE
DOMINANTLY INHERITED POPULATION,
THE YEAR OF ONSET IS NOT DRIVEN
BY APOE4, A FASCINATING THING,
YOU THINK IT WOULD BE BUT
WE'VE--WE'VE BASICALLY THROWN
OUT APOE BEFORE AS AN
INTERESTING PARAMETER TO GOVERN
THESE FOLKS BECAUSE IT DOESN'T
GOVERN WHEN THE DEC WILL FAN
FEST ITSELF AND YET, YEAR OF
ONSET IS VERY CRITICAL SO
WHAT--YOU KNOW I THINK WE NEED
TO BE THINKING THIS IS PART OF
THE DOWN STREAM BUSINESS THAT'S
DRIVING THE ONSET OF COGNITIVE
DETERIORATION RATHER THAN THE
AMYLOID ITSELF, THE SAME
MISTHINKING OF CHANGING AMYLOID
IS THE WAY TO FIX THIS DISEASEO
WHAT OTHER DOWN TREME STUFF
HAPPENS YOU GET NEUROFIBULARY
TANGLES, WE'VE HAD AMYLOID
PHOSPHORYLATION CHANGES
THROUGHOUT THE DEC BUT AT THE
TIME THAT COGNITION CHANGES,
THAT'S WHEN WE GET THESE TANGLES
FORMING.
THERE'S MANAGE DOWN STREAM AND I
THINK CRITICALLY DESIGNING THE
TRIALS SO WE'RE LOOKING FOR
THOSE DOWN STREAM MARKERS IS
GOING TO BE THE MOST USEFUL WAY
AND IT'S REALLY DRIVE BY THIS
NOTION, IT'S NOT EVERYBODY WITH
THESE DOMINANTLY INHERITED
MUSEUM TAIGS AS AMYLOID DEPOSITS
FOR DECADES AND WE ARE NOT
SEEING ARIA EVEN WITH VERY HIGH
DOSES OF [INDISCERNIBLE] UNTIL
YOU GET NEAR OR PAST THE YEAR OF
ONSET, SO I THINK IT--I THINK
THERE ARE CRITICAL DOWN TREME
PARTS OF THE DEC THAT WE NEED TO
PAY VERY CLOSE ATTENTION TO.
>> THANK YOU.
>> I AM CURIOUS ABOUT THE
PANEL'S THINKING ABOUT THESE
REMARKS.
NOT ONLY--WHAT'S HAPPENING DOWN
STREAM BUT WE'RE ACUMING THINGS
ARE JUST LINEARLY PROGRESSING SO
THE QUESTION AND I'M SAYING
THIS, FROM A CLINICAL
PERSPECTIVE, WE SEE PEOPLE WHO
HAVE THE ABILITY TO COMPENSATE
ISSUES RIGHT?
AND SO TO--AND TO ADAPT, SO,
WHAT MIGHT BE AND WE KNOW
EDUCATION IS PART OF THAT
SIGNAL, BUT ARE THERE ALSO
SIGNALS AND INTERVENTIONS THAT
MIGHT HELP IN THAT SPACE AS WELL
AS WE'RE TRYING TO THINK ABOUT,
SO WHAT DID THIS MEAN AND WHAT
DO WE DO ABOUT IT?
IT'S A QUESTION THAT WE GET IN
THE CLINIC EVERY WEEK.
>> SO WHAT IS RESILIENCE?
NWHAT IS REJILLIENCE AND WHAT
WOULD PREDICT AND FOSTER THAT,
REGARDLESS OR DESPITE
PROGRESSION OF AMYLOID LOAD OR
WHATEVER LOAD THERE IS AND WE
SEE A LOT OF MICROVASCULAR DEC
THAT IS YET TO BE CLASSIFIED AND
I WISH THERE WERE A WAY FOR US
TO BE ABLE TO DETECT WHO IS AT
RISK BEFORE THEY COME INTO
CLINIC WITH MULTIPLE STROKES.
BUT THAT'S A DIFFERENT QUESTION,
SO CURIOUS ABOUT THAT.
THANK YOU.
>> OTHER DOWN STREAM TARGETS,
TAU MAY BE 1 ANGLE, DAMAGE TO
THE VASCULAR TREE IN OTHER
REGARDS.
>> AS CLINTON RAISED BEFORE CAN
WE SURVEY THE HEALTH OF THE
SMALL BLOOD VESSELS OR THE LARGE
BLOOD VESSELS IN THE BRAIN,
SHERRY SAYS TO PREDICT THESE
PATIENTS THAT HAVE DEVELOPED
STROKES COULD THAT BE AN OPTION,
HAD IS MORE A QUESTION AROUND
RESILIENCE IS THAT THERE MAY BE
BIOMARKERS OF RESILIENCE AND WE
CAN ALL HUNT THOSE DOWN BUT
PATIENTS BRING RESILIENCE TO THE
CLINIC SO THEY'RE RESILIENT,
IT'S SOMETHING ALSO TO REMEMBER.
>> SPEAKING, I AM NOT M. D.
I AM IMMUNOLOGIST, I WORK WITH
VACCINE FOR 23 YEARS SO DOWN
STREAM PROCESSING, IT'S
OBVIOUSLY TAU, OBVIOUSLY
INFLAMMATION, WHAT WE KNOW, BUT
I WILL LIKE TO JUST REMIND YOU
THAT MRI AND PET SCAN YOU SEE AG
IMREIGATED MOLECULES.
TODAY, WE KNOW THAT IT'S NOT
MAJOR PROBLEM.
THERE ARE TONS OF DATA SHOWING
THAT AGGREGATED SMALL MOLECULES
AND MUCH MORE IMPORTANT AND THEY
ARE IN THE BLOOD MARKEDLY YOU
CAN SEE IT IN THE PET SCAN SO
THAT'S SOME MAJOR POINT, WHAT
YOU ARE TARGETING AT WHAT TIME
AND TODAY SOMEONE SAID THAT WE
NEED TO USE A VACCINE BEFORE YOU
GET AGGREGATION SO YOU WILL NOT
HAVE ANY PROBLEM WITH THAT,
UNLIKELY YOU WILL HAVE ARIA
BECAUSE THERE IS NOTHING TO
TARGET AND AT THE SAME TIME YOU
CAN DELAY PEL MERRIZATION OF
AMYLOID AND TAU AND YOU WILL
HAVE 20 YEARS EARLIER WHERE YOU
WILL [INDISCERNIBLE] DEMENTIA
FOR MANY YEARS.
AND THAT IS WHY IT'S VERY
IMPORTANT THIS MONOCLONAL
ANTIBODY.
THIS WORK IS EXTREMELY
INTERESTING.
YOU KNOW THESE 20 YORES WHICH WE
ARE, THANKS TO FRANK HAVING THIS
IMMUNOTHERAPY, IT'S REALLY BIG
THING.
WE CAN SEE THAT IT'S WORKING.
YES WE DO HAVE A PROBLEM THAT WE
NEED TO CLEAR THE PROBLEM, AND
THEN WE HAVE A BIOMARKERS TODAY
WHICH IS DEFINITELY IN THE
BLOOD, BECAUSE THAT'S WHAT I
THINK MY INPUT CAN THINK TO LOOK
AT THAT AND TART IMMUNOTHERAPY
AS SOON AS POSSIBLE.
BEFORE INFLAMMATION AND EVEN
BEFORE THE TAU.
SO THAT I THINK ARE WHAT
IMMUNOTHERAPY SHOULD TART WITH.
THANK YOU .
>> I THINK THAT ECHOES WHAT MANY
OF US ARE THINKING THAT
PREVENTION CONTEXT IS PROBABLY,
YOU KNOW THE MOST EFFECTIVE
TREATMENT THAT YOU CAN REALLY
CONSIDER JUST IN TERMS OF THE
MAGNITUDE OF TREATMENT OPTION
EMPLOY SO I THINK THAT'S VERY
MUCH WHERE THE COMMUNITY'S
THINKING HAS BEEN IN THE LAST
FEW YEARS AND HAS BEEN THE BASIS
FOR YOU KNOW THE LARGE
INITIATIVES WE'VE SEEN FROM NIH
TO SUPPORT THAT.
THOSE ARE EXTREMELY EXPENSIVE
TRIALS, AND THEY'RE NOT
SOMETHING THAT INDUSTRY ENGAGES
IN WITHOUT SOME KIND OF SUPPORT.
THEY'RE VERY CHALLENGING TO
EFFECTIVE LIE IMPLEMENT AND DO
WELL.
SO IT'S A CONSIDERABLE CHALLENGE
AND IT'S A CONSIDERABLE HEALTH
PROBLEM AS A RESULT OF THAT,
STILL.
>> OKAY, WE HAVE 1 MORE QUESTION
AND THEN WE NEED TO MOVE ON TO
THE NEXT, WE HAVE A WONDERFUL
BASIC NECKANISMS OVERVIEW, JUST
REINFORCE WHAT SUSAN JUST SAID
AS A CLINICIAN, THERE'S NO
DISEASE IN MEDICINE THAT DOESN'T
RESPOND TO THERAPY BETTER, THE
EARLIER YOU TREAT IT, AS A DRUG
DEVELOPER, PREVENTION TRIALS IN
IMPOSSIBLE TO DO, AND AS YOU
JUST SAID, FOR DEMENTIA, IT'S
VIRTUALLY IMPOSSIBLE TO DO
BECAUSE WE HAVE NO PREDICTION
ABOUT WHO'S GOING TO DEVELOP THE
DEMENTIA NO MATTER WHAT
BIOMARKER YOU CHOOSE, SO I
NOTICED THIS MORNING EVERYONE'RE
EVERYBODY KEEPS KIND OF
DEFALLING TO THE PREVENTION
PIECE, I THINK THAT'S A
DANGEROUS PLACE FOR US TO BE
TALKING ABOUT BECAUSE IT'S AN
IRRATIONAL GOAL.
OUR GOAL NEEDS TO TREAT THE
PROBLEM WE HAVE WHICH A PATIENT
SHOWS UP WITH DEMENTIA, WE TREAT
THEM, LET'S GET THEM BETTER,
LET'S NOT WORRY ABOUT A PROBLEM
WE CAN SOLVE IN 30 YEARS.
>> DISAGREE TOTALLY, WE CAN
PREVENT ALL SORTS OF DECS WITH
VACCINES, WE CAN DO THE SAME
FORRAL JEIMER'S IF WE DO IT
RIGHT.
>> SO WE CAN DO BOTH AND
PREVENTION TRIALS ARE FEASIBLE,
THERE ARE ONGOING PREVENTION
TRIALS WITH [INDISCERNIBLE],
THERE IS THE ABILITY TO IDENTIFY
PEOPLE WITH ELEVATED AMYLOID
BEFORE THEY HAVE THE ONSET OF
SYMPTOMS OR COGNITIVELY IPT
GREATER TACT.
INITIALLY THAT WAS DONE
WITH--THAT'S DONE WITH PET SCANS
AND--AND CSF BUT INCREASINGLY
BLOOD-BASED BIOMARKERS THOSE
PEOPLE ARE AT RISK AND IF
THERE'S PREVENTAATIVE TREATMENT
INITIATED LIKE A STATIN, IT
WON'T BE AS EASY AS A STATIN BUT
I THINK THAT'S WHERE THE FIELD
IS GOING.
IT IS IMPORTANT TO TREAT THE
PATIENT WITH SYMPTOMS BUT WITH
ALL THESE TREATMENTS, THE
EARLIER YOU TREAT, THE EARLIER
YOU PREVENT THAT NERVE CELL LOSS
THAT IS IRREVERSIBLE.
>> DID YOU WANT TO A SOMETHING
DR. LING?
>> JUST TO SAY THAT DON'T THINK
OF THE PREVENTION AS PRIMARY
PREVEPGZ, I THINK THERE'S EVERY
OPPORTUNITY WE CAN TAKE TO
MITIGATE THE PROGRESSION OF THE
DISEASE, THE ABILITY TO
COMPENSATE DESPITE THE PRESENCE
OF ONGOING DEC EMPLOY I THINK,
YOU KNOW YOU HAVE A VERY NEW
AREA OF STUDY HERE, SO, MAKE
FRIEND, THINK NEW THOUGHTS, I
THINK THIS IS REALLY A
TREMENDOUS OPPORTUNITY TO
UNDERSTAND THE PROCESSES AND
WHAT MIGHT HELP THE PEOPLE WHO
LIVE WITH THESE PROCESSES IN
THEIR MINDS, SO THANK YOU SO
MUCH, WALTER.
NWELL THAT'S A GREAT PLACE TO
STOP.
I WILL LIKE TO THANK THE
PANELISTS VERY MUCH AND PEOPLE
WHO HAVE QUESTIONS AND WE WILL
NOW MOVE ON TO BASIC MECHANISMS
OVERVIEW AND IT'LL BE MODERATED
BY DR. MARK FISHER, AND
DR. DONNA WILCOCK AND I THINK
WE'RE DOING THIS RIGHT AWAY,
RIGHT IN AND THEN WE WILL TAKE
THE BREAK AFTER THAT?
OKAY, SEEMS LIKE WE WOULD TAKE A
BREAK NOW.
>> ALL RIGHT, THANK, EVERYBODY
FOR STICKING AROUND EMPLOY WE
WILL SWITCH GEAR ANDS TALK IN
BASIC MECHANISMS NOW, SO IT'S MY
PLEASURE TO INTRODUCE MY CO
MODERATOR DR. MARK FISHER FROM
UC IRVINE.
THANKS MARK.
RESPIRATORY
>> THANK YOU DONNA AND I WANT TO
THANK FRANCESCA AND NINDS FOR
THE INVITATION TO SPEAK TODAY.
AS I WAS DECIDING ON A TITLE OF
THIS PRESENTATION, I CONSIDERED
CALLING IT CEREBRAL AMYLOID
ANETWORK GASHING IOPATHY, VIEW
FROM THE WEST COAST BECAUSE IT'S
JUST ABOUT IMPOSSIBLE TO ESCAPE
THE LONG SHADOW OF ALL THE GREAT
WORK DONE BY THE BOSTON GROUP ON
CAA.
HOWEVER, I WILL SHARE WITH YOU
OUR TAKE.
O WE RECENTLY HAD THE
OPPORTUNITY TO REVIEW SEVERAL
MICROVASCULAR DEC IN A
RELATIVELY COMPREHENSIVE
FASHION.
WE LOOKED AT AGING,
HYPERTENSION, CHRONIC KIDNEY
DISEASE, CAROUSEL,
[INDISCERNIBLE]
[INDISCERNIBLE] DISEASE AND
OTHERS.
WAWE CONCLUDED WAS THAT SEVERAL
MICROVASCULAR DEC MANAGE THE
PARADOX AND THE PARADOCK IS THAT
THE BRAIN PAIREN CHIMAL VASCULAR
DEC ARE RELATIVELY LIMITED AND
THESE CONSIST OF
[INDISCERNIBLE], DEMILEINATION,
MICROHEMORRHAGE,OT 1 HAND.
ON THE OTHER HAND THERE IS A
WIDE VARIETY OF
ARE--ADMINISTRATIVE TERIOLEAR
ABNORMALITIES THAT ARE
RELATIVELY DISTINCTIVE FOR EACH
PATHOLOGIC AND CLINICAL
PATHOLOGIC ENTITY SUGGESTING
THAT IT IS THE
ARE--ADMINISTRATIVE TERIOLE
ACTING AS FINAL COMMON PATHWAY,
SOURCE AND MEDIATOR OF THE
PAIREN CHIMAL INJURIES MANIFEST
IN SEVERAL MICROVASCULAR DEC SO
I WILL MAKE SURE MY COLLEAGUE
KERRY [INDISCERNIBLE] HAS COINED
THE TERM CEREBRAL ANGIO MIRROR
MYOPATHY
IN WHICH THESE ARE SO ARE SO
HIGHLY PREVALENT.
WE KNOW THIS IS NOT THE AREAS
THAT PARTICULARLY PROMINENT,
IT'S THE MEDIA WHERE ALL OR MOST
OF THE ACTION IS.
AND THIS IS WHERE WE SEE
PROGRESSIVE LOSS OF SMOOTH
MUSCLE CELLS, REPLACEMENT BY
BETA AMYLOID AND EVENTUALLY LOSS
OF BETA AMYLOID FROM THE VESSEL
WALL ITSELF PRECEDING DEVELOP AM
OF SERIES POINTSEBERAL
MICROHEMORRHAGES AND
MICROPLEADS.
SO SPEAKING OF MICROPLEADS WHAT
CAN WE SAY ABOUT SEVERAL
MICROPLEADS AND CEREBRAL
MICROHEMORRHAGE.
IN 2014 I ATTEMPTED TO COME UP
WITH A CLASISK SCHEME OF
MICROPLEAD ANDS MICROHEMORRHAGES
AND CAME UP WITH 3 DIFFERENT
CATEGORIES.
THE FIRST WAS WHAT I CALL
PRIMARY MICROPLEADS OR
MICROHEMORRHAGE AND THIS IS
WHERE THE INITIAL PRIMARY YOUR
IS TO THE VESSEL WALL, BOTH AT
THE ARTERIOLE, ARTERIOLEAR LEVEL
AND CAPILLARY LEVEL AND
CAPILLARY DERIVED MICROHOM
RAMMINGS ARE PROMINENT IN
VARIOUS ANIMAL MODELS OF SEVERAL
MICROHEMORRHAGE.
IN ADDITION THERE WERE FAIRLY
SPECULATIVE AT THE TIME CALLED
PSEUDOMICROPLEADS.
THE IDEA HERE IS THAT PERHAPS
MICROPLEADS OR MICROHEMORRHAGES
COULD DEVELOP WITHOUT FRANK
DISRUPTION OF THE VESSEL WALL
AND THIS WAS INSPIRED BY SEVERAL
OBSERVATIONS BY BY JAN WAY AND
COLLEAGUES SHOWING RELEASE OF
IRON FROM OLIGO DENDRITIC CELL O
SIGHT TORES INDUCE BY ESCHEMIA,
AND THEN THERE'S 1 BY COLLEAGUES
DESCRIBING A PROCESS REFERRED TO
AS ANGY OFAGEY, SO CLOTS FROM
THE MICROVASCULATURE SO WHAT I
WILL LIKE TO DO NOW IS TRY TO
UPDATE THIS CLASS IIVES SCHEME
AND SO HOW IT MAY BE REEL
KEEPSAKES VABT TO--RELEVANT TO
OUR CEREBRAL ANGIO OPERATING
GLOBALLY RAGHTY.
SO THE NOTION IT IS ARTERIOLE
RUPTURE THAT RESULTS IN
MICROPLEADS OR HEMORRHAGES WAS
REPORTED EARLY ON AND WELL
ACCEPTED, IN TERMS OF CARK A,
THIS AN EXAMPLE OF A BEAUTIFUL
PAPER FROM THE BOSTON GROUP IN
WHICH THE VESSELS THAT YOU SEE
ARE GREEN, FLOURESCENTLY LABELED
AND THEN THERE IS AN IMMUNOSTAIN
OF FIEB RIN O GEN, THAT'S THE
RED STAIN AND IT SEEMS TO THAT
THE FIEB RIN ISACKING AS A
BRANCH AT THE POINT OF THE
ARTERIOLES.
THIS A STRONG SUGGIEST THAT
WE'RE DEALING WITH A PRIMARY
MICROHEMORRHAGIC PROCESS DUE TO
INJURY TO THE BLOOD VESSEL WALL.
WHAT ABOUT SECONDARY
MICROBLEEDS?
WE SEE INFARCTION AND
SUSCEPTIBILITY WEIGHTED IMAGING
AND THE MITTED PANEL, YOU SEE
THE MICROPLEAD WHICH IS
CONGRUENT WITH THE--WITH THE
INFARCTION.
HER'S ANOTHER EXAMPLE OF A BRAIN
STEM INFARCT AND A--AND A
MICROPLEAD SEEN ON
SUSCEPTIBILITY WEIGHTED IMAGING,
AGAIN, THESE CO LOCALIZE AND
THESE STRONGLY SUGGIEST A
MICROHEMORRHAGIC MICROINFARCTION
OR A HEMORRHAGIC INFARCTION.
NOW SECONDARY MICROBLEEDS HAVE
NOT BEEN TODAYED EXTENSIVELY IN
CAA BUT 1 PAPER THAT LOOKEDDA
THE THIS CAREFULLY WAS A STUDY
OUT OF FINLAND LOOKING AT 300
AUTOPSIES BRAINS AND ABOUT A
THIRD OF THEM EXHIBITED A
COMBINATION OF MICROHEMORRHAGE
AND IMMUNOSTAINING FOR CAA AND
WHAT THEY WERE PORTED WAS IN 40%
OF ALL THE MICROHEMORRHAGES
THERE WAS SOME ASSOCIATION WITH
CORTICAL MICROINFARCTION OR
INFARCTION BUT BEINGLY AMONG THE
LARGER MICROHEMORRHAGES, THAT
WAS 5 OR MORE SIDECKER ERPHAGES,
THERE WAS MORE THAN 40% CO
LOCALIZED WITH MICROINFARCTION
ANDS INFARCTIONS AND OF COURSE
THIS IS LIMITED DATA BUT IT DID
SUGGEST THAT SECONDARY
MICROPLEADS AND SECONDARY
MICROHEMORRHAGES MAY BE A NOT
UNCOMMON FEATURE OF CAA EMPLOY
BUT WHAT ABOUT
PSEUDOMICROBLEEDS.
WE GOT INTERESTED IN THIS WITH
OBSERVATIONS.
HERE IS AN EM VIEW OF A BRAIN
CAPILLARY.
WE SEE THE TIGHT YUNKZ POINTED
ON UTR BY THE REDAR OS AND THEN
YOU SEE--RED ARROWS AND THEN YOU
SEE THESE PLEASE TBROBBULES.
AND TURNS OUT THESE BLACK
GLOBULES ARE IRON AT THE BLOOD
BRAIN BARRIER EMPLOY WE DON'T
SEE THIS COMMONLY BUT WE DO IS
OCCASIONALLY.
WE SAW IT IN THIS PAPER, LATER
MORE RECENT PAPER LOOKING AT
CATISOL BRAINS WITH
[INDISCERNIBLE] AND
[INDISCERNIBLE].
WE ENCOUNTERED THIS AGAIN.
SO THE QUESTION THAT OCCURRED IS
HOW DOES IRON GET BO THE
PERI-SITE.
SO WE CONSIDERED THE POSSIBILITY
THAT MAYBE THE PERI-SITE IS
EXHIBITING ENDOTHELIAL,
EXHIBITING ARITHROPHAGOCYTOSIS.
SO WE LOOKED AT INTENSITY AND IN
PACT WHEN COCULTURING PERICITES
WITH FLUORESCENTLY LABELED BLOOD
LABELS THERE WAS A MODEST UPTAKE
BY THE PERCYTES.
WE WANTED TO HAVE A CONTROL FOR
THESE PERICYTES, AND IT TURNS
OUT IT WAS THE ENDOTHELIAL CELLS
THAT SHOWED A MARKED UPTAKE OF
THE RED BLOOD CELL FRAGMENTS.
MORE THAN 25 FOLD INCREASE
AND'MUNE FLUORESCENT INTENSITY,
SO THAT GOD OUR ATTENTION AND
FINALLY MY FORMER POST DOC
PICKED UP ON THIS AND BEGONE IN
A SERIES OF PAPERS WHICH I WILL
WALK YOU THROUGH, THIS IS A
AGAIN A COCULTURE WITH MOUSE
BRAIN ENDOTHELIAL CELLS AT THE
BOTTOM OF THE WELL ADDING RED
BLOOD CELLS OR RED BLOOD CELLS
THAT WERE TREATED WITH TBHP,
THAT'S TERRA BEAUTAL
HYDROPEROXIDE, PRODUCING
EXPOSURE AND TRESES OF SERIES
POINTSINE FROM THE RED CELL
MEMBRANE CAN REDUCING RED BLOOD
CELL DEFORMABILITY.
AND WHEN YOU COMPARE THOSE RED
BLOOD CELLS WHAT YOU SLEEP APNEA
AND OBESITYY IS THAT AGE RED
BLOOD CELLS IS THE PEROXIDE IS A
BIOCHEMICAL ANALLING PROCESS, SO
THESE BLOOD CELLS SHOW A MARKED
MARKED
INCREASE COMPARED TO THE TREATED
BLOOD CELLS ANDOT RIGHT YOUEE
THIS ISA TIGHT 2 GFP MOUSE WITH
GREEN FLOURESCENTLY LABELED
VESSELS AND RED ARITHROCYTES IN
THE TREATED CELLS, YOU SEE THAT
THESE RED BLOOD CELLS ARE INTRA
VASCULAR, WHEREAS WITH THE TBHP
YOU YOU BEBIN TOEE AS THE ARROWS
POINT OUT, EXTRUSION OF RED
BLOOD CELLS, AND RED BLOOD CELL
FRAGMENTS.
SO THIS WAS FOLLOWED UP WITH
ANOTHER INVESTIGATION IN WHICH
THE AGED RED BLOOD CELLS WERE
INYECTED INTO THE MOUSE AND WHAT
WE SAW WAS A SUBITANTIAL
INCREASE IN MICROHEMORRHAGE LOBE
MANIFEST BY INCREASED PLURIBU
STAINING IN THE MICE THAT WERE
RECEIVING THE AGED RED BLOOD
CELLS AND IN A LATER PAPER THIS
IS STEM CELL DERIVED HUMAN
MICROVASCULAR BRAIN ENDOTHELIUM
AND YOU CAN SEE INCORPORATION OF
THE ARITHROCYTES INTO THE
ENDOTHELIAL CELLS.
WELL LET ME BRENG --BRING YOU UO
DATE WITH CURRENT
INVESTIGATIONS.
THIS IS WORK DONE WITH
COLLEAGUES AND OTHERS.
AND IN THESE STUDIES, WHAT WE
DID WAS WE ONCE AGAIN TOOK RED
BLOOD CELLS, TREATED THISEM WITH
TBHB, SO BIOCHEMICALLY ANALLING
THESE, INYECTING THEM INTO THE
MOUSE AND SUBYEKING THE MOUSE TO
1 WEEK OF INTRA VITAL MICROSCOPY
USING 2-PHOTON IMAGING ALONG
WITH POSTMORTEM ANALYSIS.
AND WHAT YOU SEE ON THE TOP IS
NORMAL RED BLOOD CELL TRANSIT
THROUGH THE CAPILLARIES AND THE
PBS TREATED RED BLOOD CELLS, AND
IN PANEL C YOU BEBIN TO SEE WHAT
ARE CALLED RED BLOOD CELL STALLS
IN THE CAPILLARIES AND IF YOU
PLOT THIS OUT IN THE D-PANEL YOU
SEE THAT WITHIN THE FIRST 24
HOURS, FOLLOWING INYEKS OF THE
AGE RED BLOOD CELLS, THERE'S A
SUBSTANTIAL INCREASE IN RED
BLOOD CELL STALLS IN THE BRAIN
CAPILLARIES.
NCAN WE HAVE A BIT OF HELP FROM
THE TEAM WHAT WE SAW IN THE
EXVIVO STUDIES WAS EXCLUSION OF
RED BLOOD CELLS AND FRAGMENTS
FROM THE MICROVASCULATURE AND
THESE ARE THE AGED RED BLOOD
CELLS, WE ALSO SAW THE BEGINNING
OF AN CORRELATED CLIEWGZ OF THE
CAPILLARY NETWORK HERE WITH THE
AGE PLAID CELLS, SHOWING
ACTIVATION IN THE FIRST 24 HOURS
AND EXTENDING OVER THE 7 DAY
EXPERIMENT.
NOW WHEN WOE DID IMMUNOSTAINING
WE SAW FOE INTRA VASCULAR FIEB
RIN AND NO EXCESS EXTRA VASCULAR
FINE RIN O GENERATED SUGGIESTING
THERE'S NO CLOCK FORMATION IN
THE INTRA VASCULATURE AND ALSO
SUGGIESTING THERE WERE NO MAJOR
DISRUPTIONS OF THE BLOOD BRAIN
BAIPIER AND IMPORTANTLY IN THE
LAST PANEL ONCE AGAIN WE SEE A
VERY SUBITANTIAL INCREASE IN
MICROHEMORRHAGE AND MANIFEST
WITH PRESSURE PLURIBU STAINING.
I WILL TRY TO SHOW YOU WHAT THIS
LOOKS LIKE IN REALTIME.
AND I WILL NEED HELP FROM MY
FRIENDS IN THE BACK OF ROOM.
IF YOU CLICK ON HERE YOU SHOULD
BE ABLE TO--THERE YOU GO, OKAY.
O THIS IS ABOUT AN HOUR AFTER
INYEKS OF THE PBS TREATED RED
BLOOD CELLS, CAN YOU DO THAT FOR
THE BOTTOM IN THIS IS 24 HOURS,
SO THIS IS NORMAL TRANSIT OF THE
RED BLOOD CELLS, THROUGH THE
MICE, THROUGH THE MOUSE
MICROVASCULAR.
OF THE SLUGGISH FLOW THIS IS
WITHIN AT THE BOTTOM, PLEASE
GO,A HEAD, THAT'S SOME
IMPROVEMENT BY 24 HOURS.
ANOTHER EXAMPLE, NO, NO, CAN WE
GO BACK 1 MORE SLIDE.
I THINK WE MISSED A SLIDE.
YEAH, LET'S GO HERE.
AND WHAT YOU SEE HERE, ON THE
RIGHT IS FLOW--WE ALSO SAW
SUBSTANTIAL MICROGLIAL
ACTIVATION THAT WAS SUSTAINED
OVER THE 7 DAY EXPERIMENT, AND
IMPORTANTLY THERE WAS
PROGRESSIVE DEVELOPMENT OF
PUNISHING RUSSIAN BLUE LESIONS
NOTABLE PARTICULARLY AT DAY 7
AND THE SUGGESTION IS THAT THESE
PROCESSES ARE PERHAPS TIED
TOGETHER BY ENDOTHELIAL ARK RYTH
ROUGH ATOM PHAGOCYTOSIS.
SO WHAT DOES THIS HAVE TO DO
WITH CAA?
WELL RED BLOOD CELL
ABNORMALITIES HAVE NOT BEEN
HAVING THE IN CAA, BUT THEY HAVE
BEEN LOOKEDDA THE QUITE
EXTENSIVE IN THE ALZHEIMER'S LIT
RAWR, IN FACT THERE'S MORE THAN
600 PAPERS WHO LOOK AT THIS, A
DEC OF WHICH OF COURSE CAA IS A
PROBLEM, THESE ARE BIOMARKERS OF
ALZHEIMER'S DISEASE BUT THERE
ARE A FEW INVESTIGATION THAT
EMPHASIZED THAT THE RED BLOOD
CELL ABNORMALITIES, REDUCED
DENORMABILITY ITSELF MAY
CONTRIBUTE TO THE PROGRESSION OF
ALZHEIMER'S PATHOLOGY AS YOU SEE
IN THIS RECENT PAPER.
SO TO SUMMARIZE, SEVERAL
MICROVASCULAR DISEASE IS
CHARACTERIZED BY A HIGHLY
VARIABLE ARTERIOLE PATHOLOGY
WITH PROMINENT SMOOTH MUSCLE
CELL CHANGES COMBINED WITH A
LIMITED VARIETY OF PAIREN CHIMAL
INJURIES, AND CAA FITS WELL INTO
THIS SPECTRUM OF MICROVASCULAR
AND ANCHLIO MY O PATHIC
DISORDERS.
ON THE MICROBLEED SIDE WE CAN
CATEGORIZE MICROBLEEDS OR
MICROHEMMAGES AS PRIMARY,
SECONDARY AND PSEUDOMICROPLEADS.
AND THE IDEA OF A
MICROHEMORRHAGES HAPPENING IN
THE PRIMARY MUSCLE WALL, THESE
ARE WELL TEABED FOR CAA AND
BASED ON LIMITED DATA SECONDARY
MICROBLEEDS MAY WELL BE A COMMON
FEATURE OF CAA, THE ROLE OF
PSEUDOMICROPLEADS, BRAIN
CAPILLARY INTERACTIONS AND BRAIN
ENDOTHELIAL PHAGOCYTOSIS IN THE
ANGIOPATHY AND NTHANK YOU FOR
GIVING ME THE OPPORTUNITY TO
TALK TO YOU TODAY ABOUT THE
FOLLOWING ISSUES, YOU KNOW ASK
WHEN WE TALK ABOUT THE EFFECT OF
CAA IN APOE 4 IN NEUROVASCULAR
REGULATION AND THE ROLE OF
MACROPHAGES WHICH SOMEONE MAY
NOT BE VERY FAMILIAR WITH, IN
THIS PROCESSES, AND FINALLY,
WITH THE IMPLICATIONS OF THESE
CONSIDERATION MIGHT BE FOR
IMMUNOTHERAPY AND ALZHEIMERS AND
CAA IN ARIA.
SO AS YOU KNOW THE BLOOD VESSEL
OF THE BRAIN IS MORE THAN FEED
THE BRAIN WITHOXIEN AND
DPLUICOSE, THEY ON DO A LOT OF
OTHER THINGS WE'RE NOT FAMILIAR
WITH AND JUST NOW ARE BECOMING
TO BE MORE APPRECIATED.
SO WE KNOW THAT THE VESSELS OF
THE BRAIN COUPLE NEURAL ACTIVITY
WITH SEVERE BLOOD FLOW AND THE
PHENOMENAL CALLED COUPLING AND
THESE ARE CRITICAL FOR MAKING
FLOW REGULATION AND THEY DO THE
BLOOD BRAIN BARRIER AND ALL THAT
STUFF BUT THE VESSELS IN THE
BRAIN GET RID OF THE JUNK THAT
THE BRAIN GENERATES
CONTINUOUSLY, WE ARE TALKING
ABOUT THE BETA, TAU, AND IT IS
DONE BY A NUMBER OF MECHANO
PATHWAYS WHICH ARE NOT VERY WELL
UNDERSTOOD AND I THINK THE
EPPEDICATION OF THAT IS THAT
THERE ARE MORE REVIEWS ON IT,
THAN THE ORIGINAL PAPERS.
O THIS IS ALWAYS VERY CLEAR
INDICATION OF THE STRENGTH OF
THE INFORMATION MUCH SO 1 IS SO
CALLED LYMPHATIC PROBLEM, WHICH
THINGS GO FORWARD, THEN THERE IS
A PERIVASCULAR RETROGRADE
PATHWAY, WHICH THINGS GO
BACKWARD AND THEN THE SIMPLE
PAN, SIMPLE WOMAN APPROACH, OF
MIXING BETWEEN THE CSF AND THE
INTERSTITIAL FLUID.
NOW THE BOTTOM IS LINE IS THAT
HOWEVER, WHATEVER THESE THINGS
DO, THEY RELY ON THE HEALTH OF
THE BLOOD VESSELS.
SO THE VESSELS DIFFER, IF THE
VESSEL DOES NOT RELAX OR
CONTRACT, THESE THINGS WILL NOT
WORK, WHATEVER THEY ARE.
ALL RIGHT?
SO THESE ARE CRITICALLY LINKED
TO THE HEALTH OF THE BLOOD
VESSEL.
SO IT'S NOT SURPRISING THAT IF
YOU HAVE THINGS THAT SCREW UP
THE BLOOD VESSELS, YOU ARE GOING
TO GET ALL KIND OF ALTASD
RAYINGS INVOLVING NOT ONLY THE
FEEDING OF THE BRAIN BUT THE
TRADITIONAL VIEW OF STARVATION
IS PILOT PROJECT POXIA,
STARVATION BUT YOU WANT TO
EFFECT IMMUNE REGULATION, YOU
WILL AFFECT THE BLOOD BRAIN
BARRIER, ABILITY OF THE BRAIN TO
CLEAR THESE FACTORS AND TODAY WE
WILL TALK ABOUT YOU KNOW THE
ROLE OF CAA IN THE APOE 4 IN
THIS MECHANISMS.
YOU KNOW SO THAT'S--THE VASCULAR
REGULATION IN THE CAA SO IN THIS
PAPER, THEY LOOKED AT THE TYPE
OF CAA CAN THEY FOUND USING A
FUNCTIONAL [INDISCERNIBLE], SO
ACTIVATING THE BRAIN VISUAL
CORTEX USING IMMUNO CHECKER
BOARD AND THEN THE BOLD OKAY,
THIS GOOD ENOUGH FOR CLINICAL
STUDIES AT LEAST AND WHAT YOU
PUT, WHAT THEY FOUND WAS
ATTENUATION OF THIS DYNAMIC
RESPONSE DURING FUNCTIONAL
ACTIVATION.
AND WHEN DEPLAYED WITH THE
PATIENTS WITH SYMPTOMATIC AND
ASYMPTOMATIC PATIENTS, BEINGLY,
THE SYMPTOMATICS ALREADY HAD
NEURODYSFUNCTION, SO USING THIS
DISEASE AND WORK BY THE TEEF AND
COLLEAGUES HAS SHOWN THAT MAYBE
A VERY GOOD BIOMARKER OF CAA.
THOU THE QUESTION IS WHAT
MEDIATES THIS, SO WEB CONNECTED
WENT TO A MOUSE MODEL, WE WILL
HEAR FROM HIM IN AFTERNOON.
HE WILL TALK.
THIS IS A DUTCH-SWEDISH MUTATION
IN MOUSE, AND THIS
[INDISCERNIBLE] CAA, SO DR. PARK
IN OUR GROUP STUDIED THESE MICE
IN DIFFERENT ANALS BECAUSE YOU
KNOW ON THE ASSUMPTION THE
DISEASE MAY BE PROGRESSIVE,
RIGHT IN SO WE LOOK AT 3 MONTHS,
18 MONTHS, 24 MONTHS LOOKING AT
ALL THE CLASSICAL MECHANISMS,
REGULATING THE CIRCULATION,
NEURAL ACTIVITY, ENDOTHELIAL,
THE SMOOTH MUSCLE, WHICH IS THE
BUSINESS END OF THE VESSEL, YOU
HEARD ABOUT CAA AND THE SMOOTH
MUSCLE, YOU WILL HEAR MORE HERE
AND FINALLY [INDISCERNIBLE] 1 OF
THE MOST POWERFUL DILATORS IN
THE BRAIN AND WE FOUND THERE WAS
A PROGRESSIVE ACTINNUATION OF
THESE FACTORS WHICH REALLY WAS
MAXIMAL AT 24 MONTHS WHERE AT
THE TIME WHEN WE DID THE DATA
MEASUREMENT AND SO ON, WE FOUND
OUT THERE WAS MAXED OUT IN THE
BRAIN, 2 MONTHS OF AMYLOID AND
CAPILLARIES, AND THERE WAS ALSO
PERICITE LOSS SO THE VESSEL IS
FALLING APART AND WHAT YOU HEARD
BEFORE WAS FRAGMENTATION OF
SMOOTH MUSCLE CELLS.
SO ESSENTIA WILY THE VASCULAR
WALL WAS FALLING, THE VASCULAR
WALL WAS MEDIATING THE
REACTIVITY OF THE IT WAS
FOLLOWING APART.
RIGHT EMPLOY NOW THE NEXT
QUESTION IS WHAT IS CAUSING THE
EFFECTS.
PREVIOUS STUDIES HAVE SHOWN THAT
THIS VASCULAR EEIVETS THROUGH
FREE RADICALS BY
PRODUCINGOXIDATIVE STRESS THIS
IS BY IMMUNE RECEPTORS ON THE
BLOOD VESSELS AS WE WILL SEE IN
THE MACROPHAGE POPULATION AND
THIS IS THEACIVATION OF A REALLY
A VERY IMMUNOLOGY ENZYME, NOW,
WHICH IS A MAINLIOR SOURCE
OFOXIDATIVE STRESS IN
MACROPHAGES.
THAT'S WHAT THEY DO, THEY MAKE
RADICALS TO KILL CELLS AND SO
ON, AND THIS LEADS TO INFLATION
AND DISTRESS IN THE LUSKULAR
DYSFUNCTION.
SOPHISTICATED THE QUESTION IS IN
THE CAA MODEL DID RADICALS PLAY
A ROLE IN SO WE MEASURED FREE
RADICALS RADICAL PRODUCTION AND
THE BLOOD VESSELS OF THESE MICE
AND WE FOUND THERE WAS AN
INCREASE IN THIS PRODUCTION,
THEN WE FOWBD THAT BY APPLYING
ON THE BRAIN ITSELF, THE FREE
RAD CALIFORNIAS, FORMATION, AT
THE SAME TIME, WE SAW A RESCUE
OF THE NEUROVASCULAR
DYSFUNCTION, FOR EXAMPLE IN 3
MONTHS WE SAW A RESCUE.
HOWEVER AT 18 MONTHS WE DID NOT
SEE IT ANYMORE.
AND WE DIDN'T SEE MUCH CHANGE IN
THE MUSCLE REACTIVITY, WHY?
BECAUSE THE SMOOTH MUSCLE CELL
WAS NO LONGER THERE.
OR IF IT WAS THERE IT WAS IN
SPECS, SO AT THE TIME THE BOTTOM
LINE HERE IS THAT IF YOU WANT TO
MAKE THINGS BETTER, YOU HAVE TO
DO BEFORE THE PATHOGEN MUSCLE
FALLS APART OTHERWISE THAT WILL
NOT HELP REMARKABLILY WELL.
NOW, WHAT ARE THE SOURCES OF
THIS RADICAL [INDISCERNIBLE]
WHICH ARE SO BAD FOR THE BLOOD
VESSELS, WHETHER THE SOURCE IS A
CELL CALLED THE [INDISCERNIBLE]
MACROPHAGE IN PARTICULAR THE
PERIVASCULAR MACROPHAGES THAT
ARE ASSOCIATED WITH RESISTANCE
VESSELS IN THE BRAIN.
THESE CELLS COME FROM
ARITHROADWAY PRECURSORS IN THE
DEVELOPMENT AND THEY GO ALL OVER
THE BODY, GIVE RISE TO THE SOLE
CALLED TISSUE RESIDENT
MACROPAGES.
IN THE BRAIN TISSUE RESIDENT
MACROPHAGES ARE THE MICROFLI
COLSISSA THAT WE LOVE AND HATE
AT THE SAME TIME.
WE ALL HAVE THE PERIVASCULAR
MACROPHAGES HERE.
AND THEN THE MENENG ES, WHERE
THE VESSELS ARE, VERY, VERY
IMPORTANT FOR CO REGULATION, AND
UNLIKE THE OTHER 3 CLASSES ARE
IN EXCHANGE WITH BONE MARROW
DERIVED MONOCYTES.
WE HAVE THE MICROGLIA IN THE
MACROFAJS ARE LOCKED INTO THE
BRAIN AND THEY HAVE A CAPACITY
OF SELF-RENEWAL ALL RIGHT?
SO THEY RENEW AT A VERY, VERY
SMALL RATE.
NOW THESE CELLS IF YOU LOOK AT
THEM SO IT'S LIKE HAVING A BOMB
TOUCHING THE VESSEL READ TO
EXPLODE ANYTIME YOU IMET ANY
IMMUNE SIGNAL THAT GETS TO THE
MACROPAGE, AND 1 OF THESE IMMUNE
IS A BETA WHICH I TOLD YOU
ACTIVATES THE CD36 RECEPTOR.
SO WE TESTED THIS HYPOTHESIS,
WHETHER IT'S THE RESIPTOR ON THE
MACROPHAGES ON THE TRIGGER
SETTING OFF THE BOMB TO GET THE
RADICALS GOING.
AND WE DID AN EXPERIMENT IN THE
DIFFERENT MODEL WHICH IS THE
BOTH IN BRACKS AND IN THE CAA SO
IF YOU WAIT UNTIL THEY GOT 15
MONTHS OLD, YOU HAVE A BEAUTIFUL
CAA DEVELOPING IN THE BRAIN OF
THESE MICE, PRETTY MUCH LIKE YOU
SEE IN THE PATIENTS EMPLOY AND
THEN WE FOUND THAT A BONE MARROW
BASED STRATEGY WHO DELETE CD36
SELECTIVELY FROM THE
MACROPHAGES.
FROM THE PERIVASCULAR
MACROFAINLS AND THE RESULTS ARE
SHOWN HERE SO THE NEGATIVE
MACROPHAGE IN THE BIO6 MICE LED
TO COMPLETE RESCUE OF THE
NEUROVASCULAR DYSFUNCTION,
IMPROVEMENT OF THE BEHAVIOR,
ALSO BY DIFFERENT KIND OF
BEHAVIORIAL PARADIGM.
SO AT LEAST, YOU KNOW THE BEST
WORK BETTER, THE MOUSE THINKING
BETTER, AS MUCH AS A MOUSE CAN
DO THINKING.
BUT WHAT ABOUT THE PATHOLOGY?
SO WHAT WE FOUND THAT THERE WAS
A REMARKABLE SUPPRESSION OF CAA,
SHOWN BY REDUCTION CAA BURDEN,
LOSS OF SMOOTH MUSCLE
SEGMENTATION, SO THE SMOOTH
MUSCLES WERE HOLING UP BETTER
AND THERE WAS NO CHANGE IN THE
PLAQUES, ALL RIGHT?
NOW THIS SUGGESTS THAT THEAC IS
IN THE BLOOD VESSEL.
WHATEVER THIS BUSINESS IS DOING
IS SOMEHOW PREVENTING A BETA
ACCUMULATION IN THE VASCULAR
WALL AND THIS LED US TO LOOK AT
THE CLEARANCE MECHANISMS PER B36
ON THE MACROPAGE ALLOW PERHAPS
THE BETA TO TICK TO THE
MACROPHAGE--TO VESSEL BECAUSE
[INDISCERNIBLE] LOSS FUNCTION TO
MAKE THE VESSEL LESS PRONE TO BE
ABLE TO GET RID OF THIS STUFF.
SO ALL RIGHT IN SO THIS IS NOT A
GREAT EXPERIMENT, IT'S A
PRELIMINARY EXPERIMENT BECAUSE
WE USE TOTAL XOK OUT MICE BUT WE
FOUND WAS THAT IF WE INYECT A
BETA INTO THE CORTECH, ALL RIGHT
IN AND THEN WE LOOK HOW MUCH OF
THAT IS RETAINED INTO THE
CORTEX, BY SAMPLING IT AND
MEASURING IT, ALL RIGHT AND AT
THE SAME TIME LOOK AT BETA AM
CANNING OUT OF THE SUPERIOR
SIDE, WHICH DRAINS THE CORTEX
WHERE WE INYEKED ALL RIGHT CAN
WE LOOK AT THE, AND INCLUDING
BLOOD, YOU SEE THE CD36 XOK OUT
MOUSE AND ABLE TO EMANATE BETTER
BECAUSE IT IS LESS THAN STICKS
IN THE BRAIN AND MORE IN
CIRCULATION.
WE DON'T KNOW IF THIS IS A
MICROPHAGE MEDIATED PHENOMENON,
WE ARE LOOKINGA THE IT NOW, BUT
IT WAS A GOOD SUGGESTION IN THE
CD36 IN THE MACROPHAGES, LOSS OF
DYSFUNCTION TO THE PRERADICALS
REDUCES BETA ADHERENCE AND
PROMOTES ACCUMULATION OF THE
ENDOVASCULAR WALL EMPLOY NOW CAA
IS ALSO A MAJOR PROBLEM HERE.
HOW AM I DOING, NOT SO BAD, THIS
IS ANOTHER RISK FACTOR FOR CAA
ANY ALSO AS WE HEARD
EXTENSIVELYAR ARIA.
SO WHAT IS THE ROLE ON APOE4 ON
THE BLOOD VESSEL TO AFFAIRS TEAM
LEADERRER THIS FUNCTIONS?
SO A FEW YEARS AGO WE MEASURE
BLOOD FLOW IN THE BRAIN THAT WE
HEARD FROM YAWN AND WE FOUND IT
WAS REDUCTION IN APOE 4 MICE, SO
NOW IT'S MICE WHICH WERE CREATED
BY INSERTING THE HUMAN APOE INTO
A MOUSE BUT THE EXPRESSION WAS
CONTROLLED BY THE MOUSE
PROMOTER.
SO APOE TBOT TO THE RIGHT PLACE
BUT WAS HUMAN APOE, OPPOSED TO
THE MOUSE APOE, AND WE FOUND
THERE WAS A REDUCTION, ARRESTING
PLOA AND ALTERATION IN ALL THE
FACTORS REGULATING THE
CIRCULATION, PRETTY MUCH LIKE A
BETA DID, EXACTLY LIKE AT LEAST
THE FUNCTIONAL LEVEL, AS A BETA
DID, BUT THE QUESTION IS WHERE
IS APOE COMING FROM IN YOU KNOW?
AND TO INTIEWS THIS ALSO FREE
RADICALS RADICAL PRODUCK THAT WE
DEMON TRAITED BY USING INHIBITOR
OF AN NADP H OXIDASE AND
PREVENTING VASCULAR DYSFUNCTION.
SO APOE 4 USES THIS AS VASCULAR
FUNCTION THROUGH FREE RADICAL
PRODUCTION.
NOW WHERE IS THE APOE 4 COMING
FROM TO MEDIATE.
SO BEING TO A RECENT MOUSE WHO
JUST DEVELOPED AND THIS PAPER IS
STILL [INDISCERNIBLE] WE WERE
ABLE TO TARGET THIS MACROPHAGES,
INCLUDING THE PERIVASCULAR
MICROPHAGES THEN WE CROSS THIS
MOUSE WITH A MOUSE WITH THE FLOX
APOE 4 AND WE WERE ABLE TO
SELECT UFLY DELETE APOE 4 FROM
THE PERIVASCULAR MICROPHAGES,
WHERE THE REST OF THE BRAIN WAS
APOE 4 POSITIVE ARE ALL RIGHT
ONLY THE MACROPHAGES ACTIVATED
APOE 4, BY ELIMINATING APOE 4
FROM THE BORDER OF THE
MACROPAGES.
SO THE DATA THEN SUGGESTS THAT
THE BRAIN MACROPHAGES,
PARTICULARLY, MENENG EALL, AND
THE SIDE, THE CONVERGENCE OF
THESE SIGNALS MEDIATING
THISOXIDATIVE STRESS AND THEP
NEUROVASCULAR DISFUNCTION EMPLOY
SO APOE 4 PRESUMABLY TO LRP TYPE
RECEPTOR, ACTIVATES PRERADICAL
PRODUCTION, A BETA TO THE CD36
RECEPTOR I'VE SHOWN YOU BEFORE
ACTIVATES THESE FREE RADICAL
PRACTICES DUKS, MOW THIS IMPAIRS
NEUROVASCULAR FUNCTION, FUNCTION
OF WHICH IS GETTING RID OF THIS
ASH BETA.
AND IN THIS THEN MOST LIKELY
LEAD TO THIS ARK KIEWMULATION,
BECAUSE THE VESSEL CANNOT GET
RID OF IT, ALL RIGHT.
NOW WHAT DOES THIS MEAN FOR CAA
AND FOR ARIA EMPLOY WELL, WE
HAVE HEARD BEFORE LIKE IN THIS
CASE, OF THIS PATIENT, THAT DIED
AFTER [INDISCERNIBLE], YOU CAN
SEE THERE IS A VERY EFFECTIVE
CLEARANCE OF PLAQUES BUT CAA IS
TILL THERE, AND THAT'S WHAT WE
HEARD BEFORE, FROM DR. NIERK
COLLs, IT'S EVEN WORSE.
SO MOST LIKELY HERE WE HAVE A
PROBLEM WITH ACCUMULATION OF
ABETTA PRESUMABLILY RESULTING
FROM THIS MACROPHAGE MEDIATED
ACCUMULATION DUE TO THE FACT
THAT THE VESSEL DOESN'T WORK
ANYMORE EMPLOY OKAY, NOW WHAT
ABOUT THE MACROPHAGES?
YOU CAN SEE IT'S ALL THERE.
REMARKABLILY IN THE CAN I HAVE
YEAR-OLD WITHIN APUNISHING OE4
POS 55, HOMOZYGOUS WHO DIED
AFTER STROKE AND TISSUING
PUNISHINGA AND HAD BEEN TREATED,
APPROXIMATE YOU CAN SEE THAT
THERE WAS CD8 163 POSITIVE
MACROPHAGES SURROUNDING AMYLOID
RIDDEN VESSELS SO CD163 IS
MACROPHAGES AS YOU KNOW IN MICE
YOU BEING SEE THERE IS A
MACROPHAGE DRIVEN RESPONSE
SURROUNDING BETA ACCUMULATION IN
MOST LIKELY PLAYS A ROLE IN THIS
ALTERATION OF THE VASCULATURE
INFLAMMATION THAT LEADS TO ARIA
IN ACCUMULATION OF A BETA.
SO I SHOWED YOU BET IN APOE 4
REGULATION CAUSING PROGRESSIVE
DAMAGE, SO IF YOU WANT TO DO
ANYTHING, DO IT EARLY, ALL RIGHT
IN WHICH IS MEDIATED BY
OCIDATIVE TRESES TO REDUCE NADP
H TO ENZYME AND THEN THE BORDER
WITH THE MACROFEAJS ARE REALLY
THE CRITICAL CELL THAT MAKE THIS
RADICAL, SO THEY TOUCH THE
VESSEL READY TO GO OFF WITH
THERE IS AN IMMUNOLOGY SIGNAL
FOR THE PERIVASCULAR SPACE AND
WE'VE SEEN OUR A-BETA AND APOE
ARE ABLE TO DO THAT.
THIS MAY PLAY A ROLE IN THAT, SO
PERHAPS TARGETING THE IMMUNE
RECEPTORS ON THESE MACROPHAGES
MAY BE BENEFICIAL IN THE ALSO IN
THE COMPLICATION OF A BETA
IMMUNOTHERAPY.
THANK YOU VERY MUCH.
TO WE TAKE QUESTIONS?
>> OKAY, SOPHISTICATEDY WE WILL
TAKE SOME QUESTIONS FOR THE
FIRST 2 SPEAKERS.
NI HAVE A QUESTION, GREAT TALK
AS ALWAYS, THIS IS TO CONSTANTIN
O, SO WHEN YOU HAVE THE
PRODUCTION OF SUPEROXIDE
ANDSOXIDATIVE STRESS FROM THESE
CELLS DO YOU THINK IT'S REALLY
AFFECTING THE PERISIGHTS AND THE
SMOOTH MUSCLE CELLS AND CAUSING
DEKRESSED CONTRACTTILITY AND
PULSATILITY, OR DO YOU THINK
IT'S AFFECTING THE
ENDOTHEY'LLIAL CELLS, WHICH ARE
OBVIOUS LE ON THE OTHER SIDE OR
BOTH, IF YOU HAVE ANY EVIDENCE.
>> YES, BIOLOGICAL ANSWER, ALL
RIGHT, SO THE TRESES WORKS IN
MULTIPLE WAYS.
I DON'T THINK THAT THE SMOOTH
MUSCLE CELL ARE THE PRIMARY
TARGETTA THE VERY BEGINNING, YOU
HAVE TO KILL THE SMOOTH MUSCLE
CELLS SO YOU NEED A LOT OF
RADICALS SO PRESUMABLY AT THE
BEGINNING THERE IS NO
DYSFUNCTION, NO DISTRACTION, ALL
RIGHT, SO WHAT YOU GET, A RAICAL
DO, THEY GET RID OF
[INDISCERNIBLE] IT WAS MADE BY
THE ENDOTHELIUM AND COMING FROM
THE NEURONS, ALL RIGHT,
ACTIVATED, RADICALS GET RID OF
THAT.
THEY ARE VERY, VERY WELL KNOWN,
THEY ARE A DEPLETER, ALL RIGHT,
THAT'S HOW YOU GET IN THE
ENDOTHELIAL DYSFUNCTION AND THE
NEUROVASCULAR UNCOUPLING, IF YOU
LET THIS THING GO ON AND ON, YOU
WILL GET THE SMOOTH MUSCLE CELLS
TO DIE, IN WHICH CASE NOTHING
WORKS, ALL RIGHT?
BECAUSE THEY--AS YOU CAN SEE, IN
THEN MODEL THEY FALL INTO
PIECES, SO JUST A GRADUAL VERY
NUANCED PROCESS, YEAH.
AMERICA REALLY GREAT TALKS BY
THE EAST COAST BY AND THE WEST
COAST GUY.
QUESTION ACTUALLY FOR THE WEST
COAST GUY, THE ENDOTHELIAL
ENGULFMENT OF AGED RED BLOOD
CELLS REALLY INTRIGUING CENTER
FOR EFFECT.
I'M SPECULATING GETTING BACK TO
THE ANCHLIO MYOPATHY
TERMINOLOGY, ANY REASON TO THINK
THE HEALTH OF THE MEDIA HAS ANY
ROLE TO PLAY IN THE MECHANISM OR
COMPLETELY INDEPENDENT OF WHAT'S
GOING ON IN THE REST OF THE
VESSEL OUTSIDE THE ENDOTHELIUM.
>> YEAH, REFERRING TO THE
ARITHROUGH ATOM PHAGOCYTOSIS?
>> YEAH, WHAT WE'RE SEEING IS
PRETTY WELL IMITTED TO THE
ENDOTHELIUM AND THE ARITHROUGH
ATOM PHAGOCYTOSIS LOOKS LIKE
IT'S--IT REALLY DOES LOOK LIKE
IT'S LIMITED TO THE EBD O
THELIUM.
THE ENDOTHELIUM WAS ORIGINALLY
DESCRIBED IN 2008 BY
[INDISCERNIBLE] AND COLLEAGUES,
ACTUAL 3 THERE'S SOME SIMILARITY
ANDS SOME DIFFERENCES WITH WHAT
WE UNDERSTAND TO BE ANCHLIO
PHAGE COMPETENT IT'S INREGGING
COMPARISONS BUT THE PHAGOCYTOSIS
BY ENDOTHELIAL CELL HAS BEEN
WELL DESCRIBED BUT I'M NOT AWARE
OF THIS BEING DRIEBED FOR SMOOTH
MUSCLE CELLS NSO IT'S DRIVEN BY
PRIMARILY AIMING RED BLOOD CELLS
BUT NOT BY ANY PARTICULAR
PATHOLOGY.
>> IT'S JUST DRIVEN PRIMARILY BY
ANALLING OF THE ARITHROCYTES AND
NOT PARTICULARLY BY ANYTHING
GOING ON, ANY AGING OF THE
VESSEL.
>> WELL THAT'S A GREAT QUESTION
AND THAT'S AN ISSUE THAT NEEDS
TO BE ADDRESSED.
HOW THE PHAGOCYTOSIS PROCESS IS
AFFECTED BY AGE, 1 WILL EXPECT
THAT THE LOGICAL HYPOTHESIS IS
THIS IS--THIS DECLINES WITH AGE
AND SOME OF [INDISCERNIBLE]
OBSERVATIONS SUGGEST THAT AGING
DID IMPACT NEGATIVELY ANGIE
OPHAGEY SO 1 WOULD EXPECT THAT
WITH AGING, NOT ONLY THE RED
BLOOD CELL IS AFFECTED BUT THE
CAPACITY TO CLEAR CAPILLARIES
MAY ALSO BE IMPAIR PERIOD WHAT
THE CURRENT CHIMAL CONSEQUENCES
OF THAT ARE, YOU KNOW THAT'S
WIDE OPEN.
>> WEE TAKE 1 ONLINE QUESTION
AND WE WILL TAKE YOUR QUESTION,
TOO, 1 SECOND.
FOR DR. FISHER.
MY QUESTION IS WHAT YOU MEAN BY
AGE RED BLOOD CELL, RED BLOOD
CELL CYCLE EVERY 60 DAYS, CO YOU
MEAN RED BLOOD CELLS OBTAINED
FROM YOUNG VERSUS OLD SUBYEBS IN
SO DO YOU MEAN AGED IN TERMS OF
CYCLE OR DO YOU MEAN AGE THAT
IT'S COMING FROM OLDER
INDIVIDUALS?
NTHESE EXPERIMENTS WERE DONE
WITH BIOCHEMICALLY AGED RED
BLOOD CELLS, THIS IS A WELL
TEABED MODEL OF RED BLOOD CELLS
BY INDUCINGOXIDATIVE TRESES WITH
ATHP, AND IT DOES RESULT IN
EXPOSURE TO THE MEMBRANE
MARKEDLY REDUCED RED BLOOD CELL
FORMABILITY SO IT'S A
BIOCHEMICAL MODEL OF ANALLING.
THANK YOU DR. IN.
>> I'M AFRAID OF PULLING THIS
DOWN.
CONSTANTIN O, AWESOME TALK AND
BEAUTIFUL DATA NCAN YOU MOVE IT
MORE NWITHOUT IT FALLING IN
NYEAH, GREAT.
>> I WILL TRY.
BEAUTIFUL TALK EMPLOY NEW DATA
REALLY NICE.
I'M TRYING TO UNDERSTAND, YOU
KNOW WE WORK A LOT ON COMPLEMENT
SOIME TRYING TO FIGURE OUT YOU
KNOW YOU TALKED ABOUT INNATE
IMMUNITY AND WHERE COMPLEMENT
MIGHT FIT IN YOUR MODEL SO HAVE
YOU LOOKED AT ALLENTIOUS
SPECIALLY IN THE CD36 KNOCKOUT
MICE HAVE YOU LOOKED TO SEE?
>> THERE IS A RECENT PAPER FOR
IMMUNO COMPLEXES IN THE ARIA, IN
THE MODEL OF ARIA, YOU KNOW, IN
OTHER WORDS HAVE YOU A BETA
COMPLEXING WITH THE ANTIBODY,
NOW WHETHER THIS IMMUNE COMPLEX
COME PREFORM EXCLUDE THEN THEY
GET TO THE VESSEL AND THEY CAUSE
INFLAMMATION OR WHETHER THE
ANTIBODY BIEBDS TO THE BETA ON
THE VESSEL REMAINS TO BE
DETERMINED BUT THERE IS A
COMPLEMENT MEDIATED PHENOMENON
ACCORDING IN THAT MODEL THAT IF
WE SEE THE RECEPTOR MEDIATED SO
THERE IS SOMETHING GOING ON
ALONG THOSE LINES, YEAH IN.
>> YEAH, YEAH, I THINK THERE'S
COMPLEMENT ACTIVATION IN CAA TO
BE BEGIN WITH, AND THEN WHEN YOU
ADD AN ANTIBODY THAT'S FINDING
FIBULARY AMYLOID BUT NOT OTHERS,
HAS TO BE BINDING, TO ME THAT'S
EVIDENT THAT THE ANTIBODIES ARE
PROBABLY BINDING THE VASCULAR
AMYLOID AND THEN INDUCING THIS
COMPLEMENT REACTION OF CLASSICAL
CONFIDENCE.
THANK YOU.
>> THANK YOU .
>> IN YOUR TALK YOU ECHICIZE THE
ROLE OF SMOOTH MUSCLE CELL IN
THE DRIVING FORCE FOR SORT OF
THE LYMPHATIC SYSTEM, CLEARANCE,
BUT, WOULDN'T THERE ALSO BE A
COMPONENT OF PASSIVE TRIEFING
FOR US BECAUSE PULSATION WOULD
PUSH THOSE BIGGER, NOT
NECESSARILY BIG ARTERIES TO KIND
OF PUSH THE LYMPHATIC
PERIVASCULAR FLUID FORWARD IS
THAT MORE IMPORTANT OR CAPILLARY
PATHOGEN MUSCLE IS BIGGER
COMPONENT FOR THAT?
>> SO THE CAPILLARIES NO LONGER
HAVE A VASCULAR SPACE, SO THERE,
THEFULLIA SPEAKS TO THE VESSEL
WALL.
AND NOBODY'S HONE THAT THESE CAN
GO THROUGH THERE, THAT'S 1 OF
THE MAJOR PROBLEMS WITH THE
LYMPHATIC SYSTEM, ALL RIGHT, HOW
DID THE STUFF GET TO THE VAINS,
RIGHT?
WHICH IS NOT CONSISTENT WITH
THE, ALSO WITH THE CAA BEING
[INDISCERNIBLE] DISEASE AS
OPPOSE TO VENUE LA, IT THINKS
WE'RE STICKING ON THE VAINS
BECAUSE IT WAS A SLOWING DOWN
THEN YOU WOULD HAVE VENUE LA CAA
WHICH IS VERY RARE, 3 OUR
4 PERCENT OF THE VESSELS ARE
VAINS AND SO ON, SO IT'S VERY
MUCH--NOW AS FAR AS THE DRIVING
FORCES, YOU KNOW ANYBODY'S GOT
THEIR OWN--SOME PEOPLE A IT'S
BREATHING AND SOME PEOPLE SAY,
IS THE PATHWAY OF THE VESSEL AND
THE PRESSURE WAVE MOVES INTO THE
BRAIN, ALL RIGHT, I WAS ANN
TERIOR GRADE PRESSURE WAVE IS
GOING IT MOVE THINGS BACKWARD
AGAIN, YOU KNOW, NO 1 KNOWS
EXACTLY, THE DYNAMICS OF CSF,
YOU KNOW ISF IS VERY, VERY
DIFFICULT TO APPROACH, EVEN WITH
MRI BASED TECHNIQUES, CAN YOU
SEE THINGS KIND OF SHAT
SHADOWING BACK AND FORTH, BUT
YOU NEVER SEE A CLEAR MOVEMENT,
YOU KNOW RETROGRADE OR
ANTIRETROGRADE.
YOU KNOW NOT TO ME, YOU KNOW I
THINK 1 OF THE BEST EVIDENT WILL
PROVIDE BY THIS IN THE NEURON
PAPER WHERE THEY MADE A LITTLE
MICROHOLE IN THE BLOOD VESSEL,
THAT'S SEALED ITSELF AND THEY
TART TO GO BACKWARD, SO THE
[INDISCERNIBLE] GO BACK.
SO IN MY BOOK IT'S VERY, VERY
SOLID EVIDENT THAT THINGS MAY BE
GOING BACKWARD ACTUALLY IS
INFLUENCED BY VASCULAR COUPLING.
>> THANK YOU.
CLINT IN NTHE DATA FOR KNOCK OUT
IS INTERESTING, I MAY BE WONDER
ABOUT IF YOU PUT IN DIFFERENT
FORMS OF APOE, AND HOW WHAT AND
WHAT YOU WOULD SEE AND ALSO
THINKING OF THE LOWER RISK,
PROTECTIVE 1S BUT APOE 2.
NGREAT POINT.
WE HAVE APOE 3 AS A CONTROL.
APOE 2 IS NOT GOOD FOR VASCULAR
STUDIES BECAUSE THEY HAVE EARLY
LIPIDEMIA, AND SUSCEPTIBILITY TO
HEMORRHAGE SO IT'S NOT A
FREIGHT--WE SEE ALL THE VASCULAR
TESTS SAY STAY AWAY FROM APOE2,
BUT APUNISHING OE 3 IS NEUTRAL,
BUT WE CONTINUE TO DO IT BECAUSE
WITH THIS MOUSE, NOW, YOU CAN
CHANGE THE APOE STATUS OF THE
[INDISCERNIBLE] PRETTY EASILY.
>> THANK YOU NSHORT QUESTION,
THE FESTER QUESTION ABOUT
MACROPHAGES THEY ARE RANGING
EXACTLY PROOD, FROM MONOCYTES
THEY'RE ENTERING AND THE I HAVE
KD--SALLIA ALL THAT ANY CHANGE
IN THE MONOCYTES AND COULD BE
USED LIKE IMMUNOTHERAPY FOR THE
AMYLOID CLEARANCE LIKE THE GOAL
FOR THE CANCER THERAPY?
SO THIS IS FIRST QUESTION.
>> YEAH, THAT'S INTERESTING
QUESTION, SO UNFORTUNATELY FOR
THE--PUBLISHED WANT TO GET--IF
YOU WANT TO REPLACE BRAIN
MACROPHAGES YOU HAVE TO DO BONE
MARROW TRANSPLANT.
N[INDISCERNIBLE].
>> YOU HAVE TO KILL THE EXISTING
[INDISCERNIBLE] AND THEN OPEN
THE BLOOD BRAIN BARRIER AND LET
THE MONOCYTES GO IN.
YOU KNOW IN THE STORAGE DECS,
CAUSED BY ENZYMATIC LACK OF
CERTAIN INN SWROIMS, THEY DO
BONE MARROW TRANSPLANTS TO BRING
THE STUFF IN WITH THE
MACROPHAGES THAT STAY THERE AND
GENERATE THE ENZYME, SO IT'S
DIFFICULT IT USE THAT, TO KIND
OF MODIFY THEM USING A KIND OF
CELL REPLACEMENT APPROACH, BUT
WHAT YOU COULD DO IS PLOK
SELECTIVE IMMUNE RECEPTORS LIKE
WE DID ON THE SURFACE, IT CANNOT
SOMEHOW BLOCK THE MECHANISM THAT
TRIGGERS THE ACTIVATION.
>> BUT CD36 IT'S NOT ON THE
RESIDENTIAL MACROPHAGES ON THE
MICRODPLIA?
DIFFERENT REGION FROM FECAL
[INDISCERNIBLE]
>> CD36 IS ON THE RESIDENT
MACROPHAGES.
>> BUT NOT MICRODPLIA.
>> [SPEAKING AT ONCE ]
NSO THE HIGHEST LEVEL IS THE
MICROPHAGES NAND I HAVE A
QUESTION ABOUT THE PHAGOCYTOSIS,
ANY HINT ABOUT POSSIBLE RECEPTOR
WHAT COULD HELP TO DO
PHAGOCYTOSIS TO UPTAKE
ENDOTHELIAL CELLS.
QUESTION FOR YOU NSORRY I COULD
NONAPOPTOTIC THE HEAR YOU.
NSORRY, IT'S A QUESTION ABOUT
PHAGOCYTOSIS, VERY COMPELLING,
THE PICTURES THERE, ANY HINT
ABOUT POSSIBLE UPTAKE MECHANISM,
RECEPTOR OPTIMIZATION,
[INDISCERNIBLE] WHAT COULD BE
MECHANISM OF UPTAKE?
>> YEAH, CD47 EXPRESSION BY RED
BLOOD CELLS THE TERM THAT IS
USED IN THE LITERATURE IS THE
DON'T EAT ME SIGNAL GENERATED BY
CD47.
SO CD47 EXPRESSION BY THE RED
BLOOD CELL IS A KEY ELEMENT IN
THE RED BLOOD CELL ENDOTHELIAL
INTERACTION AND KEY PLAYER IN
THE PHAGOCYTOSIS.
>> OKAY, THANK YOU.
NETWORK OKAY, I THINK WE BETTER
STOP THERE.
WE WILL BE TARTING AGAIN AT
1:15.
SO PLEASE GO AHEAD AND FIND
SOMETHING TO EAT.
OKAY GOOD AFTERNOON
EVERYBODY.
HOPE YOU HAD A GOOD LUNCH AND
REFRESHED FOR THE AFTERNOON.
I UPON ANYTHING TO TALK ABOUT
WORK IN THE EARLY 2000S AND THEN
WE STARTED IMMUNOTHERAPY AND
THEN WE TART THE IMEAN, SO NOW
WE'RE DOING NEW STUDIES ON THIS.
CAN WE GET THE SLIDES UP.
OKAY.
SO AGAIN THANKS TO NINDS FOR THE
INVITATION TO SPEAK AND I JUST
WANTED TO HIGHLIGHT SOME OF THE
REALLY EARLY WORK THAT WAS DONE
AND REALLY THE FIRST
DESCRIPTIONS OF MICROHEMORRHAGES
AS A RESULT OF ABASHING AIMIEWP
O THR ACTIVITIES AND PROJECTSY
AND THEY SAW AN INCREASED
INDENSE OF MICROBLEEDS.
THAT WAS FOLLOWED BY A PAPER I
PUBLISHED WITH DAVE MORGAN IN
2004, WHERE WE DID A TIME COURSE
OF IMMUNIZATION AND THAT, WELL,
IMMUNIZATION, PASSIVE
IMMUNIZATION SO THESE ARE
PASSIVE IMMUNO THERAPY AND WE
SAW THESE TIME COURSE FOR THESE
WEEKLY DOINGS OF TCG2576 MICE
AND YOU CAN SEE IT'S REALLY
BETWEEN THE 1 AND 2 MONTHS OF
ADMINITRATION WHERE WE STARTED
TO SEE THESE MICROPLEADS.
INCIDENTALLY, IT ALINES
PERFECTLY WHERE WE SEE THE PEEK
OF ARIA PATIENTS OF OUR
REPORTING AS ALSO AND THEN WE
SAW A STEADY INCREASE AS WE LOOK
AT THE 3, 4 AND 5 MONTHS OF
TREATMENT.
ASSOCIATED WITH THAT WE SAW A
LOT OF PERIVASC LIEU REACTIVITY
AND THIS IS JUST AN EXAMPLE OF 1
OF THE MICROPLEADS WE SAW IN THE
MICE.
SO FOLLOWING ON FROM THAT, JUST
A FEW MONTHS AFTER WE PUBLISHED
THAT PAPER, PEGGY RACK FROM THE
GROUP AT LILLY ALSO SHOWED
MICROHEMORRHAGE INDUCTION IN
THEIR 3D 6 ANTIBODY WHICH IS THE
END TERMINAL ANTIBODY AND THE PD
APUNISHING P NOWS, SO THESE ARE
ALL DIFFERENT MONOCLONAL
ANTIBODIES.
THEY ARE ALSO DIFFERENT MOUSE
MODELS, THESE WERE ALL DONE IN
MICE THAT WERE AT A VERY
ADVANCED AGE WHERE THEY HAD A
LOT OF EXISTING PATHOLOGY
INCLUDING CAA AND THEY HAD CAA,
THEY ALSO HAD ASSOCIATED WITH
THE CAA BECAUSE IT WAS QUITE
MATURE AT THAT TIME, THEY DID
HAVE ASSOCIATED PERIVASCULAR
INFLAMMATION.
SO, I'VE STARTED TO GO
BACK--IT'S NOT ADVANCING.
OKAY, SO I WENT BACK TO OLD
TODAYS TO ASK IF THERE ARE NEW
INSIGHTS WE BEING GAIN FROM NOW,
FROM THE OLDER STUDIES, SO THIS
WAS A STUDY WE DID IN 2004-5
WHERE WE DEFLI COLSIS COSALATED
THE ASPECT BODY, IT
SIGNIFICANTLY REDUCES THE
IGGAFFINNITY FOR THE FC
RECEPTORS.
SO YOU CAN SEE IN THE TOP RIGHT
IS THE RELATIVE AFFINITY OF THE
INTACT ANTIBODY WHICH IN THIS
CASE IS CALLED 2 H 6, AND THE
DEMRI COSALATED ANTIBODY WHICH
IS THE D2 H6.
SO THE AFFINITY OF EACH ANTIBODY
FOR ABETTA IS COMPARABLE BUT THE
AFFINITY FOR THE VARIOUS FC
RECEPTOR SYSTEM SIGNIFICANTLY
REDUCEDENTIOUS SPECIALENTIALLY
FC GAMMA RECEPTOR 1.
AND FC GAMMA RECEPTOR 3, AS WELL
AS C1 Q BINDING.
AND SO WHAT WE FOUND THERE WAS
THAT ACTUALLY BOTH OF THESE
ANTIBODIES WHETHER IT WAS INTACT
OR WHETHER IT WAS THE
DEGLYCOSYLATEDDED VERSION, WE
SIGNIFICANTLY REDUCED TOTAL BETA
AMYLOID DEPOSITION.
BEAR IN MIND THAT MOST OF THE
AMYLOID DEPRIVATION NITION IN
THESE MICE IS IN THE DIFFUSE
FORM, NOT IN THE COMPACT FIEB
RULE FORM, SO WHAT WE FOUND WHEN
HE LOOKED AT THE DEPOSITS WAS
THAT WE HAD A REDUCTION IN TOTAL
COMBOPHILIC MATERIAL BUT THE
INTAKE ANTIBODY ACTUALLY ALMOST
COMPLETELY ELIMINATED PATHWAY
GIVES RENCH MALDEPOSITS.DEPOSIT.
SO A--ASSOCIATED WITH THAT WAS
AN AMELIORATION OF THE
MICROHEMORRHAGE INCIDENTS.
SO YOU CAN SEE THE 2 H6 INDUCED
MICROBLEEDS WHICH WAS WHAT
SOMETHING WE REPORTED 2 YEARS
BEFORE WITH THE SAME ANTIBODY
BUT WHEN THE ANTIBODY WAS
DEGLYCOSYLATEDDED IT WAS
SIGNIFICANT LE,A 10UATEED SO
THIS INDICATES AT LEAST, IN THE
MOUSE MODELS AND WITH THIS
PARTICULAR ANTIBODY, I DON'T
WANT TO OVERSTATE IN GENERALIZE
THIS, BUT IT DID SEEM LIKE FC
GAMMA RECEPTOR ENGAGEMENT AND
EFFECTOR CELL FUNCTION IS
CRITICAL TO THE MICROHEMORRHAGE
INDUCTION.
SO WE ASKED OUR MADERIX PROTEIN
ACES TO PLAIM FOR THIS, WE KNOW
THAT MMPs IN PARTICULAR, MPP
2, AND MPP 9 HAVE BEEN HEAVILY
IMPLICATED IN HEMORRHAGIC
TRANSFORMATION AFTER STROKE AS
WELL AS OTHER HEM RAMMINGIC
EVENTS AND SO, WE WENT BACK,
THIS WAS ABOUT 6 YEARS LATER IT
WAS AMAZING, I CALLED DAVEED
MORGAN AND I SAID DO YOU STILL
HAVE SOME OF MY TISSUE FROZEN
AND WE WENT IN AND LOOKEDDA THE
THIS.
AND THERE'S 2 PATHWAYS, MMP 9
AND AMERICA PP 2 AND MPP 9 IS
DRIVEN A LOT BY PROINFLAMMATORY
CYTOKINES LIKE IL1, TNF, MPP 2,
IS DRIVEN BY FURIN AND PLASMA
AND OTHER FACERS, ALL OF THESE
RELEASED IN A PROFORM AND THEY
HAVE TO BE CLEAVED IN ORDER TO
BE ACTIVE, SO, IT'S A COMPLEX
SYSTEM, BUT WHAT WE FOUND WHEN
WE LOOKED AT OUR TIME COURSE,
ACTUALLY IT'S THE NEXT SLIDE,
THIS LIED IS SHOWING THAT YOU IF
WE INCUBATE BB2 MICRODPLEEL
CELLS THEY'RE COMPLETELY
IMPERFECT BUT THIS WAS A FIRST
STEP IN THE STUDY.
WE INCUBATED THEM WITH EITHER
ABETTA ALONE OR ABETTA THAT HAD
BEEN COMBINED WITH ANTIBODY TO
MAKE IMMUNE COMPLEXES OR TAU AND
THEN TAU COMBINED WITH TAU
ANTIBODIES AND YOU CAN SEE WITH
THE IMMUNE COMPLEX, WHICHEVER
COMPLEX IT WAS, WE INDUCED
COMPONENTS OF BOTH THE MMP 2
PATHWAY AND THE MAMERICA P 9
PATHWAY.
AND SO, WE WENT AND LOOKED AT
OUR PASSIVE IMMUNOTHERAPY MICE,
WHILE WE HAVE THE TIME COURSE OF
1, 2, 32 ASK 3 MONTHS OF DOSING
AND WHAT YOU CAN SEE IS THAT
MPP2, AND MMP 9 ARE BOTH
SIGNIFICANTLY ELEVATED, MMP2 WAS
ELEVATED WITH 1 MONTH OF
DOATSING AND IT AT AD ELEVATEDDA
THE 2 AND 3 MONTHS.
MPP 9 CAME UP BETWEEN THE 1 AND
2 MONTH TIME POINT AND THEN
ELEVATED AT THE 3 MONTH TIME
POINT AND I THINK THIS YOU KNOW
REALLY DOES .. TO A POTENTIAL
MECHANISM BY WHICH THE BLOOD
BRAIN BARRIER IS BREAKING DOWN.
WE HAVE SINCE ABOUT 2012 WE'VE
BEEN WORKING WITH A MODEL OF
SMALL VESSEL DISEASE WHERE WE
INDUCE HYPE OR HOMER ASSIST
NEMIA IN WILD-TYPE MICE, THERE'S
NO APP INVOLVED HERE EMPLOY WE
SEE MICROPLEADS.
WE SEE COGNITIVE DEFINITES.
WE SEE HYPOTRANSFUSION, BUT WE
SEE AN INFLAMMATORY REPONS AND
WE ALSO SEE PMMP 9 ACTIVATIONFUL
SO ANOTHER PLACE, ANOTHER MODEL,
WHERE WE HAVE BLOOD BRAIN
BARRIER BRAKE DOWN, WE HAVE
MICROPLEADS, WE HAVE THIS MMP9
INDUCTION.
SO COMING TO PRESENT DAY, WE ARE
TRYING TO GO BACK TO SOME OF THE
REAL FUNDAMENTAL STUDIES THAT
WERE DONE 15 YEARS AGO NOW AND
USING OUR NEW TOOLS LIKE SINGLE
CELL TRANSCRIPT OHMIC ANDS
DINLITTAL SPATIAL PROFILES TART
TO ASK THE QUESTIONS ABOUT WHAT
ON A SINGLE CELL LEVEL WHAT
CHANGES ARE BEING INDUCED BY A
BETA ANTIBODIES.
SO IN THIS CASE, THIS IS A TODAY
BY MY POST DOC IN THE LABICATE
FOLEY AND WE LOOKED AT WILD-TYPE
AND TG2576 MICE, 14 MONTHS OF
AGE, WE DID A IGGOR SE10
ANTIBODY.
AND WE THEN EUTHANIZED THEM AT
24 HOURS OR 3 DAYS AFTER AND WE
DID SINGLE CELL ANALYSIS AND
SOME DINLITTAL SPATIAL PROFILES
ON THE TISSUE AND WE WERE
PRIMARILY INTERESTED IN THE
MICRODPLEEL RESPONSES.
WHAT ARE THE MICROFLI COLSISSA
DOING.
SO FIRST I'M GOING TO TALK ABOUT
THE SINGLE CELL DATA THAT KATE
GENERATED AND LET'S SEE-
-OKAY SO TO SUMMARIZE THE SLIDE
YOU BARELY SAW, WE IDENTIFIED
CELLS OF CLUSTERS OF MICROGLIA
AND WE LOOKED AT EACH CLUSTER
AND HOW EACH OF THOSE 3 CAN HOW
THEY CHANGED IN THE PRESENCE OF
ANTIBETTA ASPECT BODY AS OPPOSE
TO CONTROL ANTIBODY.
SO THE CONTROL ANTIBODY
PRESUMABLY HAS NONSPECIFIC
IGASHING GASHING RESPONSES WHAT
WE'RE GOD IN IS WHAT THAT
SPECIFIC ABETTA RESPONSE IS SO
WE SAW A DOWN REGULATION OF THE
NUMBER OF CELLS AND CLUSTER 0,
SO THE JEEPS THAT WERE PRIMARILY
DOWN REGULATED WERE ASSOCIATED
WITH CELLULAR RES PIRRATION
AEROBIC RESPIRATION,
METABOLISM,OXIDATIVE
PHOSPHORYLATION, GENES THAT WERE
UPREGULATED IN THIS GROUP,
LYMPHOCYTE ACTIVATION, CYTOKINE
PRODUCK, IMMUNE RESPONSE
REGULATION.
SO IN THIS CLUSTER, AT THE 24
TIME POINT THERE WAS A DECREASE
IN THE NUMBER OF CELLS IN IN
CLUSTER, IN CLUSTER 1--OH, THAT
TEXT DOES NOT LOOK GOOD DOES IT.
IT LOOKED IMRAIT ON THE SLIDE
YESTERDAY.
YEAH, I DON'T KNOW IF THAT'S
CLINGON OR WHAT THAT IS.
SO CLUSTER 1 THERE WAS AGAIN A
DECREASE IN THE NUMBER OF CELLS
IN CLUSTER 1 AND I COULD TELL
YOU ANYTHING ABOUT THOSE GRAPHS
NOW BUT ACTUALLY, THEY MIRROR A
LOT OF THE SAME PROCESSES THAT
WERE IN CLUSTER WHERE ARE EMPLOY
THE INTERESTING CLUSTER, CLUSTER
2, IS WHERE WE SAW A BIG
UPREGULATION IN THE NUMBER OF
CELLS FALLING INTO THIS CLUSTER
AT 24 HOURS AND IN THIS CLUSTER
WHAT YOU CAN SEE IS THERE ARE
DOWN--THIS CLUSTER HAS DOWN
REGULATION OF CELL MIGRATION,
CELL MOTILITY, LEUKOCYTE
DIFFERENTIATION, AND THEN
UPREGULATION OF METABOLISM,
ENERGY PRODUCTION, RESPIRATION,
SO THERE'S THIS QUITE DRAMATIC
SHIFT IN THE MICRODPLIA VERY
QUICKLY IN RESPONSE TO A BETA
EABT BODIES THAT IS A DOWN
REGULATION OF METABOLISM AND
SYNTHESIS AND RESPIRATION, SO
THIS DOES HAPPEN QUITE QUICKLY.
AND THEN, FLEEL CELLS
RESPONDING, LET ME START AGAIN
WE WANTED TO LOOK AT HOW THEY'RE
RESPONDING AFTER THE A-BETA
DEPOSITS AFTER THE ANTIBODY, SO
THOSE WHO ARE NOT FAMILIAR WITH
THIS, WE ARE USING PARAFFIN
TISSUE SECTIONS AND WE CAN LABEL
THOSE WITH MARKERS ERS.
SO IN THIS CASE WE HAVE GFAPP IN
GREEN FOR OUR ASTRO SIGHTS WE
HAVE IRA 1 IN RED FOR MICROGLIA
AND THEN WE HAVE A BETA INIOLE -
-YELLOW AND WE KNOW THAT
INJECTION SITE IS SITTING RIGHT
IN THIS AREA HERE AND SO, WE CAN
THEN DRAW OUR REGIONS OF
INTEREST,A ROUND THE PLAQUE AT
THE INYEKS SITE AND SO, WHEN WE
DID HERE IS WE LOOKED AT A-BETA
POSITIVE REGIONS THAT WERE CLOSE
TO WHERE THE ANTIBODY HAD BEEN
AS OPPOSE TO BEING FAR AWAY FROM
WHERE AND IT HADN'T BEEN EXPOSED
TO ANTIBODY AND THEN WE LOOKED
AT A-BETA NEG5 REGIONS OF
INTEREST CLOSE TO THE INYEKS
SITE AND FAR AWAY FROM THE IPT
GREATER JEKS SITE AND THIS IS
COMPLETELY UNPUBLISHED, STILL
WORKING THROUGH THE DATA SO WHAT
I'M SHOWING YOU IS VERY
PRELIMINARY SO THERE'S MULTIPLE
COMPARISONS THAT WE CAN MAKE
HERE.
SO I WILL JUST TALK ABOUT THE
A-BETA EXPOSED THROUGH ANTIBODY
AND THEN THROUGH THE SOFTWARE WE
CAN SAY THAT WE WANT TO LOOK AT
PROTEIN EXPRESSION JUST IN THE
CELLS THAT ARE POSITIVE FOR
GREEN, AND THEP JUST IN THE
CELLS THAT ARE POSITIVE FOR RED.
SO NOW WE CAN LOOK AT THIS ARRAY
OF PROTEINS THAT ARE EXPRESSED
BUT ONLY WHERE THE GREEN CELLS
ARE.
SO PRIMARILY THEN ASTRO SIGHTS
AND MICROFLI COLSISSA.
AND SO I WILL SHOW YOU THIS 1
PIECE OF DATA BECAUSE I SAID
WE'RE STILL CRUNCHING, BUT THIS
WAS A PARTICULARLY INTERESTING
MARKER, SPP1, AND SO WHAT WE
FOUND WAS THAT SPP1 INCREASES IN
ABETTA ASSOCIATED MICROGLIA, AND
SPP1 HAS BEEN ASSOCIATED WITH
MICROGLIA AND PERIVASCULAR
MACROPHAGES AND INCREASE LIES
STUDIES OF MULTIPLE ENDOCRINAL
PATHWAY, AND INCREASE
PHAGOCYTOSIS AND SYNAPSES.
SO WE THINK THIS MAY REPRESENT A
SINGINALLING PATHWAY THAT MAY BE
A PRECURSOR TO THOSE PROTEINS
DOWN STREAM.
SO JUST TO SUMMARIZE, AGAIN,
VERY PRELIMINARY, WE PROBABLY
HAVE A FEW MORE MONTHS OF
CRUNCHING DATA ON THE STUDY BUT
WE SAW CHANGES IN CELLULAR
METABOLISM AND INFLAMMATORY
CYTOKINES WITH A BETA TRANSFER
INFECTION AND THEN WE SAW THIS
INCREASE IN SPP 1 WITH MICROGLIA
CLOSE TO THE INJECTION SITE
AROUND IT.
I WANT TO LACK AT THIS PAPER
THAT CAME OUT ABOUT A WEEK AGO,
SOME OF YOU MAY NOT HAVE SEEN
THIS YET WHERE THEY ARE
PACIFICALLY LOOKING AT ABETTA
IMMUNOTHERAPY AND
MICROHEMORRHAGES AND LOOK AT
WHAT CELLS ARE ASSOCIATE WIDE
THAT AND WHAT PROCESSES AND SO,
WHAT THEY FOUND WAS THAT WHERE
THEY HAD THE MICROBLEEDS IN
THESE OLDER MICE THAT HAVE BEEN
IMMUNIZED THEY SAW SIGNIFICANT
ENGAGEMENT OF PERIVASCULAR
MACROPHAGES THEY SAW
UPREGULATION OF CD169 AND THE CO
LEGALIZATION OF THE CD169 WITH
THE THIOFLAVORIN S.
SO THERE'S MORE TO THIS PAPER
BUT IT DOES SEEM TO HEAVILY
IMPLICATE THE PERIVASCULAR
MACROFAINLS IN THE MICROPLEAD
PROCESS.
IN THE STUDY, MMP9 CAME UP AS A
KEY COMPONENT TO THE MICROPLEADS
AND SO THEY DID A COUPLE OF
STUDIES.
THEY DO BONE MARROW DERIVED
MACROPHAGE STUDIES AND THEN THEY
ALSO THEN DID
IMMUNOHISTOCHEMISTRY IN THE
TISSUE AND WHEN THEY--WHEN THEY
GREWSED IBGASHING, ANTIBETTA
IIMRKS GE TO THE MACROPHAGES
THEY SAW A SIGNIFICANT
UPREGULATION OF MATRIX
REMODELING SIGNALING AND MMP 9
AND [INDISCERNIBLE] ARE BOTH
EXPRESSED IN THIS PANEL AND
THEN, AGAIN, DOWN HERE WITH
INFLAMMATORY SIGNALING, THAT WAS
THE SECOND MOST ABUNDANT PATHWAY
THAT WAS CHANGED.
SO THE MATRIX REMODELING DOES
SEEM TO BE A KEY MECHANISM FOR
MICROHEMORRHAGE AND THIS WITH
BETA IMMUNE THERAPY THEY SAW A
LOT OF PERIVASCULAR LABELING
WHERE THEY HAVE MICROBLEEDS WITH
MMP9 AND THIS SEEMED TO BE
EXPRESSED BY THE PERIVASCULAR
MACROPHAGES.
SO I WANT TO HIGHLIGHT THAT WORK
BECAUSE I KNEW THEY WEREN'T
PRECEPTING TODAY EMPLOY AND I'LL
TAKE ANY QUESTIONS EMPLOY
AND I THINK WE'RE DOING
QUESTIONS NOW IF ANYONE HAS ANY.
WITH THE'MUNE RESPONSE GOING UP
AND METABOLISM GOING DOWN IS
THAT IT SEEMS LIKE INNATE
IMMUNITY IS THAT WHAT YOU
THINKING MIGHT HAPPEN THAT'S A
GO QUESTION, WE WERE AGNOSTIC WE
KNOW FROM PREVIOUS STUDIES THAT
PRO INFLAMMATORY CYTOKINES DO GO
UP O WE KNEW THERE WAS A
MICRODPLEEL REACTION BUT WE
DIDN'T KNOW WHAT PROCESSES WERE
GOING ON.
SO IT'S INTERESTING WE'RE
DIGGING DOWN DEEPER ON THOSE
SPECIFIC YEENS EMPLOY
NFASCINATING.
SMRKS BEAUTIFUL WORK DONNA.
YOU'VE BEEN AT THIS FOR A LONG,
LONG TIME AND I THINK IT'S
WONDERFUL WHEN YOU DID THE
CONTROL ANTIBODY, DID YOU LOOK
AT THE LOCATION WITHIN THE
TISSUE?
WERE YOU ABLE TO SEE?
COULD YOU LABEL THE ANTIBODIES
SINCE YOU'RE DOG INJECTION YOU
WOULDN'T HAVE TO WORRY ABOUT THE
BLOOD BRAIN BARRIER IN YEAH SO
WE HAVE LABELED ANTIIGG, THERE
IS NOT MUCH DIFFUSION OF THE
ANTIBODY SO YOU'RE REALLY
WORKING IN A PRETTY TIGHT AREA
THAT HAS BEEN EXPOSE TO THE
ANTIBODY SO WE ONLY HAVE A DANCE
OF 200-MICRONS THAT HAS BEEN
EXPOSED TO ASPECT BODY.
AND DO YOU SEE THE ANTIBODIES
BINDING TO VASCULAR AMYLOID?
NOT IN THAT STUDY BUT WE HAVE
SEEN IT BEFORE.
THESE MICE DIDN'T HAVE A LOT OF
CAA BECAUSE THEY'RE 14 MONTHS.
>> OKAY, THERE'S AN ONLINE
QUESTION, FROM
DR. [INDISCERNIBLE].
HE ASKED IF YOU MEASURED
MMP ACTIVITY LEVELS BECAUSE HE'S
THINKING ABOUT PROFORMS AND HE'S
ALSO CATEGORY ABOUT HOMOCYSTINE
POSSIBLY CAUSING SMOOTH MUSCLE
PROLIFERATION AND FRAGMENTATION?
>> YEAH, 2 GREAT QUESTIONS, AND
THE STUDY THAT I JUST SHOWED
WITH THE SINGLE CELL ANALYSIS,
WE HAVE NOT DONE MMP ACTIVITY
YET, IN THE PAPER WE PUBLISHED
IN 2011, WE DID ACTUALLY DO AN
ACTIVITY ASSAY WITH A DESIGN O
GRAM AND WE SHOWED THAT MPP 2
AND AMERICA MP 9 ACTIVITY WAS
INCREASED AS WELL AS PROTEIN.
THE SECOND QUESTION?
>> SMOOTH MUSCLE NHOMOCYSTINE,
IS QUITE POTENTOX DENT AND SO
THE MECHANISM THAT WE HAVE BEEN
WORKING THROUGH IS THAT THIS IS
A PRIMARILY AN
ENDOTHELIALOXIDATIVE STRESS,
PROBABLY SMOOTH MUSCLE CELLS AND
THIS LEADS TO PERIVASCULAR
INFLAMMATORY RESPONSE WE SEE AND
ULTIMATELY THE LEAKAGE SO WE
HAVE NOT CAREFULLY LOOKED AT
THAT YET BUT I WOULD IMAGINE
THERE ARE SIGNIFICANT
DISRUPTIONS.
>> DOCTOR?
>> THIS WILL SOUND LOOK A NAIVE
QUESTION BECAUSE AS A THIS IS
ALL CLINGON TO ME BUT HAVE THERE
BEEN EXPERIMENTS, THIS VERY
INTERESTING WORK HAS REALLY BEEN
MANIPULATED ENOUGH THAT YOU
COULD GET THIS BALANCE OF IMET
THE CLEARANCE WITHOUT THE
INFLAMMATION IN DIFFERENT
ANTIBODIES, IF YOU TRIED THAT?
NIT'S A GREAT QUESTION, SO THE
STUDY AT TIME IS WITH THE
SCIENCES WHO THEN ACQUIRED BY
PFIZER, MONOCLONAL ANTIBODY THAT
CAME OUT OF THAT PROGRAM, SO PE
NEZUMAB, BUT IT WASN'T
ENZYMATICALLY DISCIPLINARY FLI
COLSIS COSALATED, IT WAS
ENGINEERED AND IT LOST ITS
EFFICACY WHEN THEY INJURED IT,
BECAUSE WE DID INTRA CRANIAL
INYEKS AND WE DIDN'T SEE THE
CLEARANCE.
IN, IT'S ALSO I THINK IT'S
EPITOPE IS NOT RIGHT FOR WHAT WE
KNOW NOW.
NC-TERMINAL NBUT WITH AN END
TERMINAL.
>> YEAH SO WE HAVE NOT PLAYED
WITH THE FLI COLSIS COSALATION
SINCE THAT STUDY BUT I THINK
IT'S COMING BACK TO IT NOW.
ALL THE BASIC SCIENCE KIND OF
SLOWED DOWN BECAUSE WE THOUGHT
THE DRUG COMPANIES HAD THIS AND
NOW IT'S COMING BACK BECAUSE WE
NEED TO UNDERSTAND THESE ARIA,
SO WE WILL DEFINITELY BEING
COMING BACK TO THIS WORK.
>> DO QUESTIONS DID YOU DO
ADDITIONAL BINDING WHEN YOU
CHANGED THE FC FRAGMENT IN.
>> DID I CHECK WHAT BINDING.
>> AVIDITY IN.
>> AFFINITY?
NWE HAD THE AFFINITY FOR A-BETA
AND IT WAS COMPARABLE AND THE
AFFINITY TO THE FC RECEPTORS--
>> NO, NO, NO, BINDING, DO YOU
SEE DIFFERENCES WHEN YOU CHANGE
ACTIVITY NNO.
>> OKAY, SECOND QUESTION WHICH
IS PROBABLY RELATED TO THE SAME
QUESTION, DID YOU TRY TO CD6, IF
I REMEMBER IT'S MIDTERMINAL,
RIGHT?
>> WHICH 1?
>> THREE D6.
>> 6010 IS N NEND TERMINAL BUT
KRRK DECKER 6 IF I--NO.
>> 3D 6 IS A BETA.
NIT'S ROOT TERMINAL NETWORK
MIDTERMINAL NSO WE PROBABLY NEED
TO STOP.
>> I AM JUST TRYING TO
UNDERSTAND IF YOU--
>> 3D 6 IS END TERMINAL NI WILL
TALK TO YOU IN A LITTLE BIT
MICHAEL, YEAH NI'M SORRYNY NEED
TO MOVE ON.
WE ARE REALLY TIGHT ON TIME
TOGETHER, SORRY GUYS, THANK YOU
SO MUCH.
OKAY, SO I WOULD LIKE TO INVITE
THE PANELISTS UP, .
>> HI, I'M LANNIER HEYBURN, AND
I WOULD LIKE TO WELCOME OUR
PANELISTS.
WE WOULD LIKE FOR TO YOU TALKOT
BIGGEST GAPS FOR UNDERSTANDING
THE BASIC MECHIMISMS OF ARIA
EMPLOY SO WHAT --WE CAN TART WIH
DR. ROSENBERG EMPLOY NTHANK YOU.
I APPRECIATE THE OPPORTUNITY TO
BE HERE, WHAT I'M SORT OF STRUCK
BY IS THE ABSENCE OF MULTIMODAL
OR MULTICO-MORBIDITIES IN THE
WORK THAT WE'VE BEEN DOING IN
VASCULAR TEASE, AS IT RELATES TO
DEMENTIA, IT'S PRETTY CLEAR THAT
WHEN YOU HAVE THE AMYLOID AND
THE LASKULAR DISEASE, THAT'S
WHEN THE REAL INFLAMMATION
BEGINS AND WE HAVE PRETTY GOOD
PROOF OF THAT THROUGH THE
BIOMARKERS THAT WE'VE BEEN
STUDYING THROUGH MARK ECID.
SO WE'VE BEEN WORKING ON WAYS TO
CLASSIFY PATIENTS.
AS A CLINICIAN IT WAS NEVER EASE
TO DETERMINE WHO HAD THIS OR
THAT AND WE STARTED OUT STUDYING
PATIENTS WITH WHITE MATTER
DISEASE AND THE ALZHEIMER GROUP
DECIDED THEY WOULD EMILYINATE
THE VASCULAR ISSUES BUT WHEN
THEY WENT BACK AND LOOKED, WHEN
THEY LOOKEDDA THE PATHOLOGY, 70%
HAD VASCULAR DEC WITH THE
ALZHEIMERS SO IT WAS CLEAR THE
MOST IMPORTANT BROWP IS MIXED
AND SO WE DEVELOPED A WAY TO
CLUSTER ANALYSIS THAT IDENTIFY
THE MIXED PATIENTS.
CAN THAT'S WHAT I'M SORT OF
MISSING IN THIS MEETING IS WE
HAVEN'T DISCUSSED THE IMPACT OF
1 THING ON ANOTHER.
AND WHAT WE FOUND WHEN WE WERE
ABLE TO SEPARATE THE PATIENTS
AND WE CAN DO THAT NOW WITH
AMYLOID AND THE CSF, AND AMYLOID
AND TARK U, , WHITE MATTER DISEE
AND BIOTESTING AND ALL THE
MARKERS WE COLLECT, WE CAN
CLEARLY SEPARATE PATIENTS INTO 8
GROUPS NOW AND 1 OF THEM IS
MIXED AND OF COURSE THERE'S PURE
AMILLIO JEIMERS AND PURE
VASCULAR SO THE QUESTION THAT I
THINK FROM TD BIOMARKERS TO
ANTICIPATE WHICH PATIENTS WILL
BE BEST STUDIED, YOU KNOW
PARTICULARLY IN NEW MEXICO WHICH
IS--THEY CALL IT A FRONTIER
STATE, LARGE LAND MASS AND FEW
PEOPLE.
THEY'RE NOT GOING TO BE ABLE TO
DO PET STUDIES OR CSF VERY
EASILY.
SO WE NEED WAYS TO IDENTIFY
PATIENTS THAT WOULD BENEFIT FROM
THESE TREATMENTS.
CAN TO ME, THE KEY, IS ANYTHING
TO BE THE BLOOD BASED
BIOMARKERS.
I JUST GOT BACK FROM VERY CLOSE
-VASCOG, THAT'S A BIG
GROUP OF INTEREST.
THAT'S SOMETHING I WOULD LIKE TO
HEAR MORE ABOUT, HOW TO USE
THOSE IN ORDER TO SELECT
PATIENTS.
>> OKAY, THANK YOU.
WOULD YOU LIKE TO SPEAK NEXT?
>> SO I WOULD LIKE TO ADD MY
THANKS FOR BEING HERE AND BEING
INVITED AND IT'S BEEN A
FANTASTIC EXPERIENCE LEARNING
ABOUT THE CLINICAL ASPECTS OF
THE ARIA PHENOMENON IN SENSE I'M
A PRECLINICAL RESEARCHER AND I
LOOK AT THE WORLD FROM THE ALL
THE ARTICLES FROM THE LYMPHATICS
SYSTEM IN THE BRAIN SO WHEN I AM
ASKED ABOUT WHAT I THINK ABOUT
TALKS THIS MORNING AND WHAT'S MY
TAKE ON IT, I WOULD SAY I WROTE
DOWN SOME OF THESE MAJOR
QUESTIONS I HAVE AND 1 OF THE
FIRST 1 ACTUALLY IS EXACTLY LIKE
DR. ROSENBERG WERE MENTIONING, I
WOULD LIKE TO KNOW THE BASE LINE
AT THAT TIMEUS OF THE SEVERAL
SMALL VESSELS TO SEE IN THESE
PEASHES THAT ARE ACTUALLY
UNDERGOING TREATMENT FOR MANY
REASONS BUT ALSO BECAUSE OF THE
WHOLE CLEARANCE SYSTEM AND THE
FLUID HOMEOSTASIS PROBLEM THAT I
THINK YOU ARE SEEING IN ARIA.
YOU MENTIONED THE DILATED
PERIVASCULAR SPACES WE HAVE THAT
IN SEVERAL SMALL VESSEL DISEASE
AS WELL AS A HALLMARK AND IN
CAA.
IT WAS THEN WE MENTIONED THE
VENTRICLES AND I WAS INTRIGUED
BY THAT BECAUSE AGAIN IT TELLS
ME THERE'S A DISREG USE OF FLUID
HOMEIO AT AIS THAT WE'RE NOT
LOOKING AT AND WE'RE NOT
UNDERSTANDING AND SO THIS COULD
BE ATTRIBUTED TO MANY THINGS AND
THE DOCTOR MENTIONED THE BLOOD
BRAIN BARRIER WHICH WE HAVEN'T
KNOTTEN GOOD QUAWBTITATION, WE
DON'T REALLY KNOW WHAT THE
TRENDS ARE IN PARTS OF AREAS SO
THAT IS A BIG CONCERN IN MY
BOOK, BUT WE ALSO DON'T KNOW
ANYTHING ABOUT THE CLEARANCE
PATHWAY THROUGH THE MENINGIAL
SYSTEM, THE MENINGIAL LYMPHATICS
WHICH CAN BE IMAGED IN THE HUMAN
BRAIN USING BLACK
[INDISCERNIBLE] IN CONTRAST,
IT'S NOT DIFFICULT TO DO AND IT
COULD BE LOOKED AT IN THESE
PATIENTS AND MAYBE THIS WILL
ACTUALLY EXPLAIN WHY YOU HAVE
THIS DIVERSE OR BAND WIDTH OF
PATIENTS THAT SEEMS TO HAVE A
LOT OF ARIA WITH PATIENTS THAT
SEEM TO BE TOLERATING THE
ANTIBODIES SO THE SYSTEMS CAN BE
TRACKED CLINICALLY TOO AND I
THINK THIS IS SOMETHING THAT IS
LACKING EMPLOY AND AGAIN, I
ALSO, THE LAST THING WAS THAT
SOMEBODY MENTIONED THE NATURAL
HISTORY OF CAA BEING ABLE TO
ACTUALLY LEARN MORE ABOUT THAT
FROM PRECLINICAL ANIMAL MODELS
AND I KNOW DR. VAN NOSTRAND TALK
ABOUT THAT LATER TODAY BUT THATY
AN IMPORTANT PART WE DON'T
UNDERSTAND.
I
I WILL TOP WITH THIS.
NTHANK YOU.
SO JUST A QUICK OVERVIEW OF WHAT
WE HEARD SO FAR, IT'S AS DONNA
JUST MENTIONED ISSUES THE FIRST
PAPER IN 2003 BY A GROUP
DESCRIBING MICROHEMORRHAGE IN
MICE TREATED WITH 3D 6.
FROM THERE WHEN WE THINK ABOUT
IT 20 YEARS AGO, WE'RE TALKING
ABOUT MICROHEMORRHAGE THAT WAS
BRAND NEW WHERE ARE WE NOW?
UNFORTUNATELY, I THINK WE OFTEN
STILL IN THE RESEARCH FIELD AT
LEAST QUANTIFY MICROHEMORRHAGE
AS AN INDICATOR PREDICTOR OF
WHAT COULD THERAPEUTIC DO IN
HUMAN.
MAYBE THAT'S A LIMITATION OF THE
FIELD.
I THINK WE NEED TO MOVE BEYOND
MICROHEMORRHAGE, THIS BEING SAID
AUTONOT THAT EASY TO DO.
AND THAT TAKES ME TO THE GAPS IN
TERMS OF MODEL TO INTERROGATE
MECHANISM OF ARIA, NOW MRI CAN
BE DONE IN ANIMAL MODELS, WE
NEED MAYBE TO REFINE THE MODELS
WOE USE.
WE TEND TO FOCUS ON MOUSE MODEL
AND MORE AND LARRY WILL WALKER
WILL TALK ABOUT THE NONHUMAN
PRIMATE MODEL, IS THAT FEASIBLE,
TOO EXPENSIVE, TOO RESTRICTIVE,
AND I THINK THE ONLY ANSWER TO
OUR QUESTION WILL BE COMING FROM
THE AUTOPSIES CASES EMPLOY WE
TALKED ABOUT THAT THIS MORNING.
RIGHT NOW IT'S FAIRLY LIMITED
AND AND THE FEW CASES WITH THE
RECENT THEOR PUTTICS, THE FEW
CASES THAT WERE PUBLISHED WERE
VERY SEVERE CASES, I WOULD SAY
SO THERE'S DEFINITELY A SPECTRUM
BETWEEN THESE CASES AND WHAT IS
HAPPENING IN THE MAIORITY OF THE
OTHER CASES.
THE LAST THING I WOULD LIKE TO
DO IS I WOULD LIKE TO SAY IS
THAT WE ALSO MOVE FROM--IN WE
WERE TALKING ABOUT THE CELLS.
THE FIELD HAS, VOLVED AND USES
NEW TECHNIQUES THAT ARE MORE
ACCURATE, MAYBE THAN 1 WAY USING
IT ANOTHER TIME AND THESE
TECHNIQUES ARE CHANGING VERY,
VERY QUICKLY, WHAT DONNA JUST
PRESENTED IT TERMS OF GENOMICS
IS SOMETHING THAT COULD BE
INFORMATIVE FOR THE FIELD AND
FINALLY TO CONCLUDE IN TERMS OF
SPECIFIC MECHANISM OF ARIA, I
WOULD LIKE TO, INSTEAD OF USING
THE TERM MECHANISM, ID LIKE TO
TALK ABOUT MECHANISTIC
HYPOTHESIS BECAUSE I THINK THERE
ARE FEW HYPOTHESIS THAT HAVE
BEEN AND THAT ARE STILL BEING
USED AND CURRENTLY WE TILL NEED
LIKE STRONG DIRECT EVIDENCE FOR
IMPLICATING 1 OF THESE--1 OR THE
OTHER MECHANISM AND I THINK
THOSE MECHANISM ARE NOT
EXCLUSIVE FROM EACH OTHER.
NTHANK YOU.
I WANT TO SEE WHAT YOU
THOUGHT--I HAD A FOLLOW UP
QUESTION THAT YOU ALREADY
ANSWERED FOR YOU BUT I WAS
CURIOUS WHAT YOU THOUGHT ABOUT
THE PRECLINICAL SIDE OF THIS AND
USE PRECLINICAL MODELS TO GET AT
MECHANISTIC THINGS AND LEARN
MORE ABOUT IT WITHOUT HAVING TO
GET OUR INFORMATION FROM THE
CLINICAL TRIALS.
>> SO I CAN AT LEAST--WE ARE
GOING TO HEAR ABOUT THE
PRECLINICAL MODELS ON CAA THIS
AFTERNOON AND CERTAINLY WE HAVE
HEARD A LOT ABOUT THAT TODAY,
TOO, BUT YES, SOME OF THE
QUESTIONS THAT I HAVE CAN
CERTAINLY BE ANSWERED IN THE
PRECLENICAL MODELS WITH'MUNE O
THERAPY, YOU SET IT UP EVEN AS A
LONGITUDINAL TRIAL AND YOU COULD
LOOK AT CLEARANCE FOR EXAMPLE,
YOU COULD LOOK AT THE ABILITY TO
CLEA FOR FSM WHEN YOU TART THE
THERAPY VERY LATE WHEN THE
ANIMALS ARE AGED AND WE KNOW
THAT LIMBS ARE DETERIORATING
WITH AGE, SO WE COULD SEE HOW
THAT IMPACTS AND YOU COULD ALSO
MAYBE BOOST THE SYSTEM, YOU KNOW
A GAIN OF FUNCTION MODEL WITH A
VEG F C OR OTHER THINGS IF YOU
THINK IT'S ADHERENCE PROBLEMS
THAT'S CAUSING THE BASAL GENIC
ADEMA IF WE THINK IT'S VASE O
GENIC ADEMA CONTAINED IN ARIA
AND WE ALSO HAVE MIXED MODELS
NOW WITH SEVERAL SMALL VESSELS,
AS THIS IS MIX WIDE AD WE HAVE
ALL THESE DIFFERENT MODELS, WE
CAN BACK CROSS WITH CHRONIC
HYPER TENSIVE TRAIN SO WE
HAVE--WE CAN TART TO GET THE
CO-MORBIDITY IN THERE, AND WE
CAN ASK, WE CAN ASK THE
MECHANISTIC QUESTIONS VERY
ACCURATELY.
OBVIOUSLY IT'S IN THE RAT OR
MOUSE BUT WE HAVE TO LEARN A LOT
FROM THESE MODELS ALREADY.
>> WE'VE HEARD A LOT ABOUT THE
BLOOD BRAIN BARRIER AND THERE'S
A LOT OF NAIVE THINKING GOING ON
IN TERMS OF IT'S OPEN OR IT'S
CLOSED THAT'S NOT TRUE AND WE
HAVE EXPERS HERE AND I'VE BEEN
THINKING ABOUT THAT AND WE'VE
USED, SO I WAS LIKE DR. CLIFFORD
I CAME AT THIS FROM THE MS POINT
OF VIEW AND WE DID A LOT OF
SPINAL FLUID AND WE LOOKED AT
WHAT WE THOUGHT WAS THE BLOOD
BRAIN BARRIER WHICH WAS THE
ALBUT MIN INDEX AND THEN YOU
MOVED INTO MRI AND CONTRAST AND
WE'VE DONE HUNDREDS OF THOSE AND
SO FINALLY, I HAD A GROUP OF
PATIENTS THAT HAD BOTH THE ALBUT
MIN INDEX AND THE DYNAMIC
CONTRAST MRI AND I SAID WHAT'S
GOING ON, ARE THEY SIMILAR, SO
IT TURNS OUT THEY'RE MEASURING
VERY DIFFERENT THINGS.
UNFORTUNATELY, FROM THE CORE
VIEW WE HAD THE BIOMARKER PANEL
WHICH IS CYTOKINES ANGIOGENIC
FACTORS, SO WE DID A CORRELATION
WITH BOTH THE DC MRI AND THE
ALBUT MIN INDEX SO IT TURNS OUT
AS YOU WILL EXPECT THE ALBUT MIN
INDEX IS ACTUALLY MEASURING THE
OPENING OF THE BLOOD BRAIN
BARRIER TO INFLAMMATION.
IT SHOWS UP THE PROTEIN ACES,
THE CYTOKINES, CERTAIN
CYTOKINES, AND THE ANGIOGENIC
FACTORS.
SO WE KNOW THAT'S A GOOD MARKER
OF INFLAMMATION BUT THE DCI
COORDINATE WIDE THE WATER
MOVEMENT MEASURED BY DIFFUSION
TENTS OR IMAGING.
O IT'S LIKE 2 DEFINITE
MECHANISMS TO GET THROUGH THE
BLOOD-BRAIN BARRIER.
I THINK, IN THE MS WORLD I NEVER
UNDERSTOOD WHY WE WOULD HAVE A
WIDE OPEN BLOOD BRAIN BARRIER
AND NO ALBUT MIN IN THE CSF, IT
WAS A PARADOX.
BUT I THINK IF YOU GO BACK CAN
LOOK AT SOME EARLY HYPER TENSIVE
PAPERS, WHAT THEY SHOWED WAS
THERE'S PINO SIGNIFYITOSEIS,
MICROPINO SIGNIFYITOSEIS AND IF
YOU THINK ABOUT IT WHEN YOU
BREAK DOWN THE EXTRA CELLULAR
MATRIX AND OPEN--NOT NECESSARILY
OPEN THE TIGHT JUNCTIONS BUT
JUST REMOVE THE LAYER OF EXTRA
CELLULAR SO THAT'S INVESTMENT
MARKER SO PEOPLE ARE NOT, SO
PEOPLE ARE NOT INTERESTED IN
LUMBAR PUNCTURES AND ALBUT MIN
IS---OPEN CLOSED WE NEED A MORE
PRECISE.
NTHANK YOU SO MUCH FOR BRINGING
THIS UP, AND THE POINT IS,
MECHANISMS THROUGH THE BLOOD
BRAIN BARRIER AND THE ALBUT MIN
YOU MENTIONED IS TRANSPORTED
THROUGH TRANSPORT AND IN MS,
CSF, WHEN WE LOOK AT PROEN TOOS,
TRAPEZIUS PORTED ON THE
TRANSPLANT, WITH THE MRI GADDA
LYNNIUM SO PERHAPS A SUGGESTION
WOULD BE TO MAYBE EXPAND THE
BLOOD PROTEINS THAT ARE USED TO
TEST AS POTENTIAL BIOMARKERS AND
BIASED PROTEOMEEC STUDIES IN THE
PSYCHIATRIC DISORDERS AND AND
DIFFERENT CORLAYINGS KEPENDING,
AND FIEB RIB O GEN.
IT WILL NOT BE ENOUGH TO SOLVE
THE PROBLEM WITH LOOKING INTO A
SINGLE BLOOD.
NTHANK YOU.
NANY OTHER QUESTIONS FROM THE
AUDIENCE.
>> REALLY IS LEACHING TO THE
BLOOD VESSEL THAT CAN COME OUT
AND HELP US UNDERSTAND IT, YOU
LOOK AT HOW TO WHETHER THERE'S
GADA LYNNIUM OR MEASURE BLOOD
BRAIN BARRIER VALENTINED IDITY
BUT FOR THE CASE OF EDEMA AREA,
I THINK WHEN I WAS TALKING TO
PEOPLE DURING LUNCH, IT WOULD BE
USEFUL TO UNDERSTAND THIS, WHERE
DID THIS WATER COME FROM AND
WHERE DID THEY GO IN DID THEY
ACCUMULATE IN THE SPACE, HOW
MUCH IS THAT ACCUMULATED, AND
CONCENTRATION IN THE CASE
COMPARED TO A NORMAL CASE
BECAUSE FOR INITANCE RIGHT NOW
WE ARE USING FOR INITANCE, THE
IMAGE TO DETECT HYPER TENSITY IN
AN AREA EDEMA CASE BUT REALLY
T-2 IS VERY SENSITIVE TO ALL THE
CONTENTS SO IF WE NOT HAVE IN
SORT OF BASIC BIOLOGICAL
UNDERSTANDING BY THE WATER
CONTENT IN THE AREA, THAT WILL
HELP PEOPLE TO DESIGN BETTER AND
MY PROTOCOL SEQUENCE TO DETECT
MAYBE QUANTITY OF IT WILL BE
BETTER WAY TO QUANTIFY THE
DETECTION, SO I THINK SOME OF
OUR IN VIVO IMAGING TECHNOLOGY
WOULD BENEFIT A LOT FROM BETTER
UNDERSTANDING OF THE MOLECULAR
AND BIOLOGICAL MECHANISM OF
THESE ARIA HEMORRHAGE CASES.
NI JUST WANT TO ADD TO THAT I
TOTALLY AGREE WITH YOU BUT IN
TERMS OF THE PRECLINICAL ANIMAL
MODELS 1 BIG THING, PROBLEM WE
HAVE WITH SMALL VESSEL DISEASE,
ANIMAL MODELS AT LEAST IN THE
RODENT IS THAT WE--WE RARELY
SEE, WHITE MATTER HYPER
INTENSITIES FOR EXAMPLE.
SO IT'S NOT SOMETHING THAT
NECESSARILY WILL BE ABLE, WE MAY
NOT BE ABLE TO TEST THAT TYPE OF
THING AT LEAST FROM THE
PRECLINICAL ARENA AND WE HAVE
NEVER UNDERSTOOD WHY, IT'S MAYBE
BECAUSE THEY HAVE SO LITTLE
WHITE MATTER, IT COULD BE THAT
THAT'S WHY SIMPLY WE DON'T SEE
IT EVEN DILATED IN THE SPACE IS
NOT SOMETHING THAT WE SEE
PRECLINICAL, SO IF WE WANT TO
TART THE MECHANISMS OF LET'S SAY
ARIA AND IMMUNOTHERAPY WE HAVE
TO LOOK AT SOME OTHER METRIC
ANDS THE--
>> THAT'S INTERESTING FOR MICE
AND RATS, IT'S HARD TO DETECT,
THE PRIMATE MODEL WILL BE BETTER
MODEL FOR THIS CASE.
>> WE'VE BEEN USING THIS
SPONTAKENIOUSLY HYPER TENSIVE
RAT.
IF YOU FEED IT A MCDONALD'S
DIET, LOW PROTEIN, HIGH FAT, IT
DOESN'T TAKE A YEAR AND A HALF
TO GET TO AGE THE BRAIN, CAN YOU
AGE IT IN YOU KNOW 6 WEEKS AND
WHEN YOU DO THAT YOU DO SEE E
DEMA IN THE MATTER AND THAT'S
LOOKING AT A 4 TESLA OR 7, YOU
BEING GET BETTER ABOUT YOU CAN
YOU DETECT FLUID MOVEMENT IN
THE--YOU CAN'T DO IT IN THE
MOUSE BECAUSE THE MOUSE HAS SUCH
A TINY AMOUNT OF WHITE MATTER,
BUT THE RAT HAS SUFFICIENT WHITE
MATTER TO SEE THAT AND WE'VE
ACTUALLY, HONE --SHOWN THAT WE
COULD TREAT THAT WITH MENOPSYCHE
LYNN AND REDUCE EDEMA AND THERE
WILL BE OTHER DRUGS, TOO SO I
WOULDN'T ELIMINATE THAT, SO
AUTOSHORT LOAD AND YOU CAN GET
HUGEARS MOUNT OF FLUID
ACCUMULATING IN THESE BRAINS BUT
WE HAVE BEEN TRYING TO WORK WITH
ANIMAL MODELS THAT MIMIC THE
CLINICAL ARENA NOT THAT PEOPLE
DON'T EAT HIGH FAT, HIGH SALT
DIET BUT IN GENERAL TO GET THEM
TO SPONTANEOUSLY DEVELOP THESE
SMALLER AREAS OF HYPER
SENSITIVITY AND VASCULAR SPACES
AND WE DON'T SEE IT LIKE USING,
YOU KNOW NORMAL AGING SO I'M
JUST SAYING YOU NEED THAT TYPE
OF INTERVENTION THEN, OF COURSE
YOU CAN LOOK AT THE PATHOLOGY
ALSO MAYBE NOT SO CLINICALLY
RELEVANT.
I DO NOT KNOW.
NETWORK I WILL JUST MAKE 1 LAST
COMMENT.
SO WE HEARD A GOOD EXAMPLE THIS
MORNING WITH DR. [INDISCERNIBLE]
ABOUT THE USE OF SPECIFIC MOUSE
MODEL THAT CAN INTERROGATE A
SPECIFIC MECHANISTIC QUESTION
AND IT'S JUST THE COMBINATION OF
SEVERAL MODEL THAT WE ARK LOW US
TO MAKE PROGRESS IN THE
UNDERSTANDING.
IT'S NOT REALISTIC TO EXPECT
THAT THE SINGLE MODEL WILL
RECAPITULATE EVERYTHING.
THAT IS TRUE.
>> ALL RIGHT, ANYMORE QUESTIONS.
ANY OTHER TOPICS YOU WANT TO
COVER IN ALL RIGHT.
WELL, THANK YOU SO MUCH.
THROUGH THE NEW SESSION.
WE WILL TART WITH DR. WILLIAM
VAN NOSTRAND FROM THE UNIVERSITY
OF REFRESH YOUR RECOLLECTION
HEART ATTACK ODE ISLAND, HE IS A
GREAT PROFESSOR OF IMMUNOLOGY
AND CORE EXECUTIVE DIRECTOR OF
NEUROCONSCIENCES.
HE'S BEEN DEVELOPING MODELS
INCLUDING THE 1 I TALKED ABOUT
IN THE MOUSE, AND IT'S ALSO IN
RAT MODELS SO WHENEVER HE SHOWS
UP, WE WILL START.
NETWORK GOOD AFTERNOON, I WOULD
LIKE TO THANK NINDS FOR INVITING
ME TO SPEAK TODAY AND I
APOLOGIZE FOR NOT BEING THERE IN
PERSON.
I WAS ASKED TO SUMMARIZE ANIMAL
MODELS FOR INVESTIGATING CAA AND
ARIA.
THIS IS MY DISCLOSURES.
NEXT SLIDE.
SO THERE ARE A NUMBER OF SPECIES
THAT NATURALLY DEVELOP CAA AS
THEY AGE.
THIS INCLUDES BEARS, CATS, DOGS
AND NONHUMAN PRIME'SS IN
PARTICULAR, MONKEYS.
AS WE HEARD THROUGH THE PREVIOUS
PANEL DISCUSSION, THERE ARE
MODELS TO STUDY CAA, FIRST IT
COULD BE ETHICAL ISSUES, THERE
BEING BE EXPENSES AND ALSO THE
FACT THAT MANY INVESTIGATORS
DON'T HAVE FACILITIES THAT CAN
ACTUALLY MAINTAIN LARGE COHORTS
OF ANIMALS LIKE THIS STUDY
EMPLOY SO ALSO, THE OTHER
IMPORTANT POINT OF THIS AS MOST
OF THESE SPECIES TAKE A DECADE
FOR CAA TO EMERGE AND SOME CASE
MULTIPLE DECADES AND WE WILL
HEAR MORE ABOUT THE SQUIRREL
MONKEY FROM LARY WALKER IN THE
NEXT PRESENTATION.
NEXT SLIDE.
SO FOR THESENS MOST ACTIONS THAT
OCCURRED FOR CAA INVOF THE USE
FOR TRANSGENIC MICE.
SO HERE ARE THE FEATURES OF THE
TYPICAL TRANSGENIC MOUSE MODELS
THAT ARE USED IN THIS CASE,
THESE ARE APP MOUSE MODELS THAT
HARBOR A NUMBER OF FAD
MUTATIONS, SO THEY HAVE DERIVED
APP THEY HARBOR 1 OR MORE IN THE
TEAM, AND SOME OF THE COMMON
MODELS THAT ARE LISTED BELOW AND
WE HEARD FROM DONNA WILCOCK
ABOUT THE MOUSE MODEL, THE
PD-APP AND SOME MODELS
ADDITIONALLY CONTAIN FAD MUSEUM
TAIGS AND PRESEN ILLEGALSEN
ILLEGALSIN PROTEINS AND THESE
INCLUDE 5 XFAD, AND APP PS1 AND
THROORKS X TISSUING G THAT
EXPRESS MUTANT TAU.
SO THESE OF THESE DEVELOP
SECONDAR TOW ABUNDANT
PARENCHYMAL PLAQUES.
NEXT SLIDE.
SO HERE ARE 2 MODELS WE HEARD
EARLIER TO THE 576, AND THE
MODELS BOTH OF THESE MODELS
OVEREXPRESS IN THE NEUROWNALLY
DERIVED MUTANT APP, THIS IS THE
COMPARISON OF THE PATHOLOGY THAT
ACCUMULATES IN THESE MODELS AS
THAT'S AGE, SO GANNA YOU CAN SEE
AS MICE GET OLDER AND MORE AND
MORE PLAQUES BUSINESS AND THE
CASE OF THE MICE, YOU SEE THE
PLAQUES TEND TO BE LARGER AND
MORE EXTENSIVE PAN EVEN THE
TG22576 MICE.
NEXT SLIDE.
SO IN ADDITION TO THE SLIDE,
BOTH OF THESE HAVE AMOUNTS FROM
TG2576 AS THEY AGE BUT
PROGRESSION YOU CAN SEE THE
INCREASE OF CAA AND THE BUY MICE
AND FROM THE ORIGINAL STUDY FROM
THE ALHEWN ET ALL, AND THEY SHOW
PATHOLOGY AND SIGNIFICANT CAA.
THEY HAD THE NEXT SLIDE, PLEASE.
SO AS WAS MENTIONED EARLIER, I
MEAN SOME OF THE ORIGINAL
IMMUNIZATION TODAYS IN THESE
MOUSE MODELS ACTUALLY OCCURRED
OVER 20 CAREERS AGO AND IN THE
TOP PANELS THEY HEARD THE PURDYS
PUBLISHED IN SCIENCE AND AGAIN
IN IN STUDY, THEY PERFORMED
PASSIVE IMMUNOTHERAPY ON APP 23
MICE USING AN END TERMINAL
ANTIBODY TO A BETA AND WHAT THEY
REPORTED IN THE STUDY IS THAT
THIS LED TO AN INCREASE IN
MICROHEMORRHAGES IN THESE
ANIMALS.
NOW IN CONTRAST A MORE RECENT
TODAY USING THE SAME MOUSE
MODEL, CAN A PASSIVE
IMMUNIZATION STUDY AND THEY
FOUND IN THIS STUDY IS THERE
WERE CLEAR PARENCHYMAL AMYLOID
BUT THEY FOUND NO CHANGE IN THE
LOAD USING THIS MODEL THAT THEY
HAD.
THEY ALSO FOWN NO INCREASE IN
MICROHEMORRHAGES WITH THESE APP
23 MICE.
SO I THINK THIS HIGHLIGHTS THE
POINTS THERE MAY BE DIFFERENT
RESPONSES TO CAA AND ARIA
RELATED EFFECTS DEPENDENT UPON
THE ANTIBODY THAT IS USED IN THE
STUDY.
NEXT SLIDE.
SO HERE I WANT TO SUMMARIZE THE
ADVANTAGES AND THE MODELS FOR
CAA EMPLOY THESE MODELS HAVE
BEEN ARK ROUND FOR MORE THAN 20
YEARS AND THEY'VE BEEN WELL
CHARACTERIZED BY MANY GROUPS AND
THERE ARE MAINTAIN LARGE COHORTS
AND INCREASED BY MODULATING
OTHER YEENS FOR EXAMPLE, APOE4
AND CLUSTERREN AND MEDIN.
BECAUSE OF THE FACT THAT THE
MOUSE AND THE MOUSE BRAIN AND
EASY TO,A ASSESSES, ACCESS, THEY
ARE WELL SUITED FOR MULTIPHOTON
IMAGING TODAYS.
NOW CLEARLY DISADVANTAGES OF
THESE, THEY ARE MICE, THEY ARE
NOT HUMAN, THE CAA DEVELOPED
PARENCHYMAL AND SEEREBERAL
VASCULAR AMYLOID IN THESE MODEL
ANDS THEY RELY ON
NONPHYSIOLOGICAL OVEREXPRESSION
OF ABPP WITH THE FAD MUTATIONS.
ANOTHER POINT IS THAT THE
IMMUNOLOGY DEVELOPED FROM A
NEURONAL SOLE SOURCE PRODUCTION
OF THE ABETTA IN MY TALK.
NEXT SLIDE.
SUBSEQUENTLY SOME MOUSE MODELS
ARE DEVELOPED AT MORE SPECIFIC
FOR DEVELOPING CAA IN THE
ABSENCE OF PARENCHYMAL
PATHOLOGY, SO IN THE TOP HERE, I
SHOW THE APPLICATIONS DUTCH
MOUSE, THIS IS A MODEL THAT
PRODUCED THE WORKERS LAB, THIS
IS A MODEL FOR TYPE 2, AS THESE
MICE GET OLD THEY DEVELOP
EXTENSIVE CAA TYPE 2, THEY ALSO
TWEP BLOODS, THIS IS AN ACTIVE
PLEADS FROM 1 OF THESE MICE AND
ALSO PERIVASCULAR EVIDENT OF
MICROHEMORRHAGE.
NOW IN MY LAB WE HAVE A MODEL
FOR CAPILLARY CAA TYPE 1, IN
THIS CASE THEY HARBOR BOTH THE
DUTCH AND IOWA MUSEUM TAIGS.
AND YOU CAN SEE HERE, IN THESE
PANELS THEY DEVELOP EXTENSIVE
CAPILLARY AMYLOID EMPLOY NOW IN
OUR HANDS THIS IS NOT BEEN A
CONSISTENT RELIABLE MODEL FOR
MICROHEMORRHAGE, AND WE DO FIND
VERY RARELY AS SHOWN ON THE
RIGHT THERE, BUT ON THE OTHER
HEALTH
LABS AX ROUND THE WORLD OF THESE
MICE AND THEY ARE REPORTED MORE
CONSISTENT MICROHEMORRHAGES BUT
IN OUR HANDS IT HAS NOT BEEN A
GOOD MODEL FOR THAT.
MAY I HAVE THE NEXT SLIDE,
PLEASE.
SO SOME OF THE ADVANTAGES OF
USING THESE MUTANT MODELS TO
STUDY, AGAIN BOTH OF THESE
MODELS HAVE BEEN ASH ROUND FOR
OVER 20 YEAR ANDS WELL
CHARACTERIZED AND USED MY MANY
GROUPS.
THE DUTCH MIGHT PRESENT WITH
RELATED HEMORRHAGES, AND IT'S A
SPECIFIC MODEL FOR TYPE 2
WITHOUT AMYLOID PLAQUES AND THE
MICE PROVIDES SPECIFIC MODEL FOR
TYPE 1 WITH AMYLOID PLAQUES.
NOW IMPORTANTLY BOTH THESE
MODELS 1 CAN INVESTIGATE 1
1 CAA
AND SOME OF THE DISADVANTAGES
AGAIN THEY ARE MICE LIKE THE
OTHER MODELS, THE CAA RESULTS
FROM THE FAMILIAL MUTATIONS IN
THE A-BETA PEPTIDE AND THE MICE
HAVE INCONSISTENT
MICROHEMORRHAGES AT LEAST IN OUR
HANDS.
ANOTHER DISADVANTAGE IT REQUIRES
EXTENSIVE ANALLING FOR CAA TO
EMERGE, GREATER THAN 24 MONTHS
AND AGAIN BOTH OF THESE MODELS
COME FROM A BETA, A POABT I WILL
GET TO AT THE END.
MAY I HAVE THE NEXT SLIDE,
PLEASE.
AT FIRST, WE ARE MORE CLOSELY
RELATED TO HUMANS THAN MICE
ISSUES AND IN THE DISCUSSION
PANEL, THE RAT BRAIN IS LARGER
THAN THE MOUSE BRAIN AND BECAUSE
OF THIS WE HAVE MORE TISSUE WE
CAN ANALYZE AND MORE WHITE
MATTER TO LOOK AT ASK WE CAN
COLLECT LARGER AMOUNTS OF CSF
AND ATHAT WILL SIS, EVALUATING
WHITE MATTER CHANGES.
NEXT SLIDE, PLEASE.
COMPREHEND.
SO THIS A SMALL, AGAIN WE FIRST
PUBLISHED ABOUT 5 YEARS AGO AND
MODELING WHAT WE DID WITH THE
MOUSE WITH THE CIRCUMSTANCE
WDGI, THIS IS A RAT MODEL FOR
CON WOAND RELATED INFLAMMATION,
IN THE UPPER PANEL YOU CAN SEE
THERE'S EXTENSIVE CAPILLARY IN
MULTIPLE BRAIN REGIONS AND WITH
THIS CAPILLARY THIS IS A STRONG
GLIAL RESPONSE IT, THE ASTRO
SIGHTS AND WE LOOK AT THE
PANELOT AMYLOIDOT CAPILLARY
SHOWN IN PLURIBU, YOU CANEE
THERE'S A LARGE INCREASE IN
NUMBER OF ASTRO SIGHTS IN THESE
RATS.
SAMEULARLY, WE SEE IN PLURIBU AS
THE CAPILLARY AMYLOID, CAN YOU
SEE IT IF GREEN THE MICROFLI
COLSISSA THERE'S A LARGE NUMBER
OF MICROGLIA THEY CHANGE FROM A
RESTINGITATE TO ACTIVATEDITATE.
SO THIS A STRONG MODEL FOR CAA
METHYLATION.
IN THIS RAT MODEL WE'VE SHOWN
THEY DEVELOP CONSISTENT
MICROHEMORRHAGES, AND THE
STAINING, AND THEY ALSO DEVELOP
CAPILLARY VESSEL OCCLUSIONS.
NOW THE PANELS BELOW, THESE ARE
MRI IMAGES THAT THEY CLEBTED
LOOKING AT A NUMBER OF THESE
RATS, AND YOU CAN SEE THE
MICROHEMORRHAGES THAT APPEARED
NOTED BY THE ARROW HEAD THEIR
WITHIN THE REGION AND THE PANEL
AT THE RIGHT, IT'S 3D RECONTRUKS
WHEN SHE ANALYZED A NUMBER OF
THESE RATS, SHOWING AGAIN THE
CLUSTERING OF THESE
MICROHEMMAGES IN THE AIR,
THERE'S BEEN AN INTEREST, TO AND
LOOKINGA THE ROLE OF COMPLEMENT
ACTIVATION IN ARIA, IN THIS
MODEL, EVEN IN THE ABSENCE OF
IMMUNOTHERAPY WE FIND THERE'S AN
INCREASE IN THE COMPLEMENT
ACTIVATION AND COAGULATION
ACTIVATION.
NEXT SLIDE, PLEASE.
SO ANOTHER MODEL WE MORE
RECENTLY DEVELOPED IS THE RDG
RAT MODEL FOR TYPE 2.
THIS ALSO EXPRESSES DUTCH TYPE
BETA IN BRAIN, THIS IS THE MODEL
AGAIN WHERE THEY GET SMALL VESES
EXCEL ARTERIOLE CAA EMPLOY YOU
SEE THE PANELS IN THE LEFT.
YOUEE THIS IN THE CORTEX AND
KNOWN AS SURFACE VESSELS
PENETRATING ARTERIOLES.
NOW IN CONTRAST, IN THIS CASE,
THERE'S A MUCH MORE MUTED
CELLULAR INFLAMMATORY RESPONSE.
AND IN THE BOTTOM PANEL YOU SEE
THE AMYLOID IN PLURIBU WHICH IS
NOW ENCASED WITH THE VESSEL WALL
AND IN THIS CASE, YOU SEE MUCH
MORE RESTRICTED RESPONSE OF
ASTRO SIGHTS AND MICROGLIA TO
SEE THIS.
WE SEE THIS WHEN THEY'RE
DYSPHORIC AND PENETRATE FROM THE
VESSEL WALL EMPLOY NEXT SLIDE.
WE'VE ALSO SHOWN THAT THE RATS
AND THE BRAIN REGIONS AND ALSO
WE THE OCCLUSIONS IN THE RIGHT
PANEL, AND THEY ALSO HAVE
ACTIVATION BY TRANSCRIPTOMICS
AND THEY HAVE COMPLEMENT
COAGULATION PATHWAYS.
NEXT LIED, PLEASE.
SO WE SENT SOME OF THESE SLIDES
TO [INDISCERNIBLE] AT YALE AND
SHE PERFORMED AMERICA R STUDYING
IN THEM, AND I HAD CONTROLLER OF
BANKED IN THERE, THESE BRAINS
WERE HARVESTED FROM HER, FIX
EXCLUDE SENT BACK TO US FOR
DOING HISTOLOGY, WE THEN
SECTIONED TO THIS GENERAL REGION
WHERE SHE HAD THESE GENERAL
IMAGES, THAT'S SHOWN IN THE
LOWER SIDE ON RED, WE LOOK AT
THE INDICATION WE CAN SEE
THERE'S CAA IN THE RAS, WE CAN
DETECT IT BY PERIVASCULAR AND
THERE'S ALSO VESSEL OCCLUSIONS,
SO THESE RELATED AFFECTS
REGARDING THIS CAN BE READILY
DETECTED BY MR IN THESE RATS.
MAY I HAVE THE NEXT SLIDE,
PLEASE.
SO SOME OF THE ADVANTAGES FOR
USING THESE RAT MODELS, SIMILAR
TO THE MICE YOU SLEEP APNEA AND
OBESITYY FOR LARGE COHORTS, THE
RATS ARE A SPECIFIC MODEL FOR
CAPILLARY TYPE 1 WITH THE STRONG
CAA MODEL, THESE ARE STRONG FOR
TYPE 2 AND HAVE THE MORE MUTED
CAPILLARY AND OR MUTED CAA
INFLAMMARRATORY RESPONSE.
BOTH LARGELY AVOID AMYLOID
PLAQUES AND BOTH PRESENT WITH
MICROPLEADS AND VESSEL
OCCLUSIONS SO AGAIN WITH THESE
RAT MODELS HERE AGAIN, WE HAVE
THE OPPORTUNITY TO STUDY IMMUNE
OR THERAPY AND ARIA RELATED
EFFECTS IN A MODEL FOR CAPILLARY
TYPE 1 OR MODEL FOR ARTERIOLE
AND TYPE 2.
SO SOME OF THE DISADVANTAGES OF
THESE RATS, THEY ARE ROTENTS WE
FEEL THEY'RE BETTER THAN MICE
BUT TILL RATS.
TO SEE RESULTS AGAIN FROM
FAMILIAL MUTATIONS IN THE A-BETA
PEPTIDE AND COMPARED TO MICE IS
A MUCH MORE LIMITED RANGE OF
OTHER RAT MODELS TO COMBINE WITH
CA RAT MODELS TO LOOK AT OTHER
YEENS AND DEVELOPMENT WITH THE
LIMITATION, AND AGAIN, WITH THE
TRANSGENIC A--BITS ANIMALS TO
SEE IF PATHOLOGY DEVELOPS AGAIN
FROM A NEURONAL SOURCE OF
PRODUCTION FOR BETA.
WHAT EXACTLY DID IT MEAN.
ALL THE MODELS THAT I DESCRIBED
TODAY, AGAIN THE ABETTA IS
PRIMARILY PRODUCED, EXCLUSIVELY
PRODUCED FROM NEURONS TO EXPRESS
THE TRANSYEEN THAT WAS GIIVE TO
THE ANIMALS.
IN ALL THESE MODELS CAN PRODUCE
CAA, BUT THE QUESTION I HAD
WELL, IS THAT REALLY HOW THE DEC
UNFOLDS IN HUMANS?
AND I THINK NOT.
NEXT SLIDE.
SO THIS IS AN EXAMPLE HERE FROM
TOSHIDA ET ALL FROM THE RIKEN
ENSELITUTE WHERE THEY DEVELOP A
TRANSGENIC EXPRESS APP AND THEY
PRODUCE A-BETA PEPTIDE ANDS THEY
CAN MEASURE THOSE IN BLOOD NOW.
CAN IN THE PANEL ON THE LEFT
THOUGH, WHEN YOU LOOK YOU THEY
DON'T DEVELOP THE PATHOLOGY ON
THEIR OWN.
SO WHAT THEY DID IS THEY USE
ANOTHER MOUSE MODEL, THE
KNOCK-IN MOUSE MODEL, SO THIS
APP MODELS KNOCKED IN WITH HUMAN
SWEDISH BETA DOMAIN AND THAT
MODEL IN THE MITSD PANEL
DEVELOPS FROM SMALL DEPOSITS OF
BETA, BUT WITH THESE 2 MODELS
ACROSS, YOU HAVE YOU EMERGENCE
OF EXTENSIVE CAA, SO THIS RAISES
THE POINT THAT VASCULAR DERIVED
SEEDS MAY BE IMPORTANT FOR
DRIVEWAYING CAA UNDER
PHYSIOLOGICAL CONDITIONS.
CAN I GO TO THE NEXT SLIDE,
PLEASE.
SO AGAIN HERE IS THE SCHEMATIC
FROM THE NEUROVASCULAR UNIT.
AGAIN ALL THE TRANSGENIC MODELS
I TRIBED HERE, THEY ALL PRODUCE
A APPROXIMATE A-BETA SOLELY FROM
NEURONS AND WE KNOW THAT MAYBORS
ASTRO SIGHTS CAN EXPRESS ATP AND
MAKE MAUL AMOUNTS OF BETA AND
YOU LOOK IN THE WALL AND
ENDOTHELIAL CELLS AND THE
CAPILLARY CAN ALSO PRODUCE
A-BETA PEPTIDE, AS 1 MOVES UP
THE VASCULAR TREE, SMOOTH MUSCLE
CELLS AND FIBROPLAOF THE GET ATP
AND SO THEY'RE MULTIPLE SOURCES
GOING ON, NORMALLY THAT PRODUCE
A-BETA PEPTIDES EVEN THOUGH THEY
MAY BE THE PRIMARY PRODUCERS AND
OTHER SOURCE SOURCES MAY BE
IMPORTANT.
NEXT SLIDE, PLEASE.
2-MINUTE WARNING WILLIAM NALMOST
FINISHED HERE.
FOR THIS REASON WE'VE NOW
RECENTLY MOVED ON THORS NEXT
GENERATION MODELS USING
GENE-EDITED RATS SO WHAT EYE
DONE HERE IS SHOW THE RIGHT
A-BET WITH WE USE GENE EDITING
TO CONVERT THOSE TO THE HUMAN
AMINO ARK SIDS SO WE HAVE RATS
THAT PRODUCE HUMAN A ABOUTETTA
WITH DUTCH MUTATION OR DUTCH
ISLAND MUTATION AND JUST BRIEFLY
WE WERE IN THE PROCESS OF
CHARACTERIZING THESE ANIMALS BUT
EXAMPLE BELOW, WE SEE THE
ANIMALS EXPRESSING THE BETA, IN
THIS MODEL WE DON'T NORMALLY
SEE, BUT WE ALSO SEE A DIFFERENT
ANATOMICAL GRIEWKS, NEXT SLIDE,
PLEASE.
>> SO THIS IS SUMMARIZES AGAIN
THAT THE AD MOUSE MODELS DEVELOP
PLAQUE IN THE CAA, THEY
TRANSGENIC MOUSE SPECIFIC FOR
SIGHT 1 OR 2.
WE HAVE RAT MODELS SPECIFIC FOR
TYPE 1 OR 2 THAT CAN ALSO HAVE A
STRONG CAA INFLAMMATORY RESPONSE
AND WE HAVE NEWLY GENERATED RAT
MODELS THAT WE'RE IN THE PROCESS
OF CHAISHTIZING AND MAY BE MORE
RELEVANT TO INVESTIGATE THE
IMPACTS OF ABETTA AND
IMMUNOTHERAPY AND CAA .
LAST SLIDE.
JUST THANK THE PEOPLE WORKING IN
THE LAB AND OUR COLLABORATOR
ANDS FUNDING SOURCES THAT
GENEROUSLY SUPPORTED THIS WORK.
THANK YOU.
>> DO WE HAVE TIME FOR
QUESTIONS?
WE HAVE 1 MINUTE OTHERWISE WE
CAN SAVE IT FOR THE DISCUSSION
AFTERWARDS.
ALL RIGHT, THANK YOU.
>> THANK YOU.
>> SO WE MOVE TO TO OUR NEXT
TALK.
BY DR. LARY WALKER FROM EMORY,
THE SNELLING PROFESSOR OF
NEUROLOGY AND AND HIS TALK WILL
BE NONHUMAN PRIMATE MODELS OF
CAA AND ARIA.
>> THANK YOU.
WE'RE HERE.
SO IT'S GOOD TO BE HERE AND I'D
LIKE TO SHARE WITH YOU IN OF MY
VIEWS ABOUT HOW THE NONHUMAN
PRIMATE MODEL MIGHT BE USEFUL IN
HELPING US TO UNDERSTAND NOT
ONLY ARIA BUT PERHAPS THE ROLE
OF VARIOUS AGENTS IN INDUCING
ARIA.
SO AS AN OVERVIEW FOR THE
UNINITIATED I WILL PRESENT JUST
BRIEFLY SOME OF THE INFORMATION
WE ARE ON PRIMATE AGING, A BETA
DEPOSITION IN PRIMATES AND CAA
IN PARTICULAR, I'LL THEN DISCUSS
MAINLY, ARIA IN AN AGED SQUIRREL
MONKEY, BASIC LYE A CASE REPORT
AND FINALLY I WOULD LIKE TO
SPEND A LITTLE TIME DESCRIBING
HOW THIS MODEL MIGHT BE USEFUL
IN TELLING US MORE ABOUT HOW WE
CAN MAKE IMMUNOTHERAPY BOTH MORE
EFFECTIVE AND SAFER.
SO HUGH MANS LIVE FOR 120 YEARS
AS A MAXIMUM LIFE SPAN, THE
MONKEYS I WILL TALK ABOUT ARE
SQUIRREL MONKEYS, LIVE TO BE A
MAXIMUM OF 30 YEARS AND RESUSC
MONKEYS CAN LIVE TO BE 45 YEARS
OF AGE, AND YOU CAN SEE ON THE
LEFT THE--THIS ISN'T WANT TO AT
A THERE, THE RHESUS MONKEY IS
EVOLUTIONARY CLOSER TO HUMANS
OTHER THAN SQUIRREL MONKEYS AND
MAR MA SETS, AND THEY ARE MUCH
LARGER AND LIVE MUCH LONGER AND
FOR THIS REASON, SQUIRREL MONKEY
ANDS OTHER NEW WORLD MONKEYS CAN
BE ADVANTAGEOUS.
THE ABETTA PRECURSOR PROTEIN IN
NONHUMAN PRIMATES IS BASICALLY
SIMILAR TO ARK BETA PRECURSOR
PROTEIN IN HUMANS, CERTAINLY
ABETTA ITSELF COMPLETELY
IDENTICAL IN ALL PRIMATES THAT
HAVE BEEN INVESTIGATED SO FAR.
IF YOU LOOK HISTOLOGICALLY AT
NONHUMAN PRIMATES IN THE MIDDLE,
IS THE RHESUS MONKEY ON THE LEFT
SPIDER MONKEY, THERE CAN BE A
BETA DEPOSITION IN AMYLOID, AND
IF WE MEASURE A-BETA LEVELS IN
NONHUMAN PRIMATES COMPARED TO
HUMANS BITE ELIZA, CAN YOU SEE
THAT THE ABSOLUTE AMOUNTS ARE
SIMILAR IN NOT GREATER IN THE
NONHUMAN PRIMATES SO A HUMAN
WITH ALZHEIMER HYMARY DEC IS
SHOWN HERE, A-BETA 40 IS SHOWN
IN THE WHITE AND A-BETA 42 IN
THE GRAY AND THE A-BETA 40, TO
42 RATIO TENDS TO BE HIGHER IN
MOST HUMAN PRIMATES AND THERE IS
OVERLAP IN THAT REGARD BUT IN
GENERAL AS YOU CAN SEE THERE CAN
BE WHOPPING AMOUNTS OF ABETTA IN
THE NONHUMAN PRIMATE BRAIN
EMPLOY AMYLOID ANGY OPERATING
GLOBALLYATHY HAS BEEN SEEN IN
FAIR AMOUNTS IN EVERY PRIMATE
SPECIES THAT'S BEEN STUDIED AND
THIS RANGES FROM LEMURS TO
HUMANS.
HERE WE HAVE SQUIRREL MONKEYS
MUCH MORE RELIABLE DEVELOPPA
ANGIE OPEN MEETINGATHY AND THAN
RHESUS MONKEY AND BOTH HAVE
SIMILAR AMOUNTS.
SO THE SCORE MONKEY MODEL OF CAA
HAS BEEN ARK ROUND FOR A FEW FEW
YEARS NOW, AS I MENTION TODAY
CAN LISTEN UP TO 30 YEARS,
THEY'RE RATHER SMALL, THEY CAN
GO UP TO ABOUT A THOUSAND GRAMS
FOR SOME MALES TYPES A LITTLE
OVER BUT MOSTLY 500 TO 900-GRAMS
SO ESSENTIALLY THE SIZE OF VERY
LARGE RATS.
THE DEPOSITION OF A-BETA IN THE
VASCULAR WALL BEGINSA THE AROUND
13 YEARS OF AGE IN THIS SPECIES
AND IT'S MODERATE TO SEVERE, BY
THE TIME THEY'RE 18 YEARS OF
AGE.
AND HERE YOU CAN SEE, THERE'S
AMYLOID DEPOSITION IN THE
PATHWAY GIVES RENCHEMMA OF THE
BRAIN ALSO IN THE SOLKUS, 1 OF
THE CHARACTERISTICS OF THE
SQUIRREL MORVEGY AMYLOID
ANGYOAPATHY.
CAN CAPILLARY CAA IS QUITE
COMMON.
--TO THE DEVELOP AM OF CAA AND
WE WANTED THEM TO INVESTIGATE
THIS HUOF HISTOLOGICALLY.
SO IN THESE MONKEYS 2 OF THEM
DEVELOPED, BOTH AS 19 YEARS OF
AGE AS EXECKED THERE WAS LESS IN
THE YOUNGER ANIMALS.
THE MONKEY THAT I WILL FOCUS ON
IS NUMBER 2266.
I WAS IN THE MRI SUITE WITH MY
COLLEAGUE [INDISCERNIBLE] CAN WE
HAD GONE THROUGH SCANS OF
SEVERAL MONKEYS IN PERSON, AND
WE GOT TO THIS PARTICULAR MONKEY
2266, AND WHEN WE GOT TO THIS
REGION WHICH WAS IN THE MORE
CODDAL PARIETAL OCCIPITAL
REGION, THEY SAID, WOW, THERE'S
SOMETHING DEFINITE THERE.
AND AS YOU CAN SEE, IN THIS
INITANCE, THERE IS BY 2-2
WEIGHTED IMAGING CONSIDERABLY
HYPER INTENSITY IN THE WHITE
MATTER, MA LESS IN THE GRAY
MATTER, AS WELL, AND YOU CAN SEE
THAT IT IS BILATERAL IN THIS
PARTICULAR INSTANCE.
AND WE DID NOT SEE ANY SUCH MRI
ABNORMALITIES IN ANY OF THE
OTHER 3 ANIMALS OR ELSEWHERE IN
THE BRAIN OF THIS PARTICULAR
MONKEY.
IF YOU LOOK AT A SERIES OF
SCANS, T-1 STRUCTURAL SCAN, T2
SCAN, THE LESIONS WERE
BILATERAL, SOMEWHAT ASYMMETRIC
AND THEY ECTENDED THE DISTANCE
ABOUT 8-10-MILLIMETERS THROUGH
THE BREAN AND YOU CAN SEE IF YOU
LOOK AT AN AREA WHERE THERE'S
CONSIDERABLE HYPER INTENSITY ON
THIS SIDE, THERE'S A REDUCTION
IN THE SIGNAL OF WHITE MATTER IN
THE T1 STRUCTURAL KAN--KANA.
AND THIS WAS SEEN IN THIS
PARTICULAR CASE EMPLOY WE DID
SUSEPTIBILITY, WEIGHTED IMAGING
IN THIS SQUIRREL MONKEY AND
THERE WERE A NUMBER OF FOR SHALL
FOCI BUT MOST PROMINENTLY WE SAW
HERE IN THE PARIETAL SULKUS, A
STRONG HYPOINTENSE REGION THAT
OVERLAPPED PARTIALLY BUT
SIGNIFICANTLY I THINK WITH THE
EDEMETUS REGION WE SAW IN THE
T-2 SCAN.
AS EXPECTED THIS MONKEY HAD
CONSIDERABLE ANGIOPATHY
STRONGLY.
AND AT A MACROSCOPIC LEVEL, YOU
GD SEE, WITH EVERYBODY'S TO
ASTRO CITES TO GFAPP AND
MICRODPLEEL SALES AND
MACROPHAGES AND IBA 1, CAN YOU
SEE A DARKENING IN THE PARIETAL
SULCUS AROUND WHICH WE SAW MOST
OF THE SIGNALS BY MRI.
ANDA THE MICROSCOPIC LEVELS
INCREASE, WE COULD COMPARE THE
REGIONS THAT SHOWED CONSIDERABLE
SIGNAL COMPARED IN THE SAME
SECTION TO THE AREA THAT LACKED
THE HYPER INTENSE T2 SIGNAL AND
AS YOU CAN SEE THERE ARE
HYPOTROAPIC ASTRO SIGHTS IN THE
AFFECTED REGION AS WELL AS HYPER
TROAPIC FLEEL CELLS QUITE
ABUNDANT IN THIS REGION.
IN ADDITION, BY LOOKING AT THE
INTEGRITY OF AXONS IN THE
REGION, USING SMI 31, ANTIBODY,
YOU CAN SEE CONSIDERABLE LOSS
OFAXONS DISRUPTION OR DISMORPHIC
REMAINING AXONS IN THE AFFECTED
REGION, COMPARED TO THE
UNAFFECTED REGION AND USING THE
LFB STAIN, THERE'S A CLEAR
RAREFACTION OF MILEIN IN THE
AFFECTED AS OPPOSE TO THE
UNAFFECTED AREA.
SO THAT WAS THE ARIA REGION IN
THE REGION THAT HAD THE INTENSE
SIGNAL AT THE PARIETAL FLANUE
LOAMUS, NUMEROUS TUOF THE
VESSELS SURROUNDING THIS AREA,
THESE WERE SEEING PRETTY MUCH
SOLELY IN ASSOCIATION WITH THIS
GRANULA MASS AND 1 LOOKED LIKE
THE REMNANTS OF A PRIOR BLOOD
SOMEWHERE IN THE BRAIN IN THIS
PARTICULAR MONKEY.
THERE WERE NUMEROUS A-BETA
IMMUNO REACTIVE BLOOD VESSELS IN
THE SULCUS AND SURROUNDING
PARTICULAR TIMES WITHIN THE
GRANUE LOAMATUS MASS THERE WAS
CONSIDERABLE ARK MOUNT OF FAIR
IRON STAINED WITH THE PEARL
STAIN.
THERE WERE ALSO NUMEROUS
MONOSITTIC CELLS SHOWN HERE
TAINED WITH CD68, MOSTLY, THESE
AND LYMPHCITES TAINED WITH CD3,
WERE WITHIN THE GRANUE LOAMATUS
MASS.
THERE WERE A FEW OF CELLS IN THE
AYAISENT, BUT NOT ALL THAT MEAN,
REALLY SO THAT'S WHAT WE SAW A
SPONTANEOUS DEVELOPMENT OF WHAT
I THINK AS YOU SAW THIS MORNING,
ALMOST CERTAINLY IS AMYLOID
RELATED IMANNUALING
ABNORMALITIES IN THE SQUIRREL
MONKEYS AND I THINK THAT THE
SQUIRREL MONKEY MODEL MIGHT BE
USEFUL FOR MODELING BOG SIDE
CENTER FOR EXCELLENCE ON AGINGS
AND THE EFFECTS OF
IMMUNOTHERAPY.
AND THE ADVANT ANNUALS OF THE
PRIMATE MODEL FOR OBVIOUS AS ARE
I THINK THE DISADVANTAGES
BESIDES THE 1S THAT BILL JUST
MENTIONED.
ONE OF THE ISSUES WITH MONKEYS
ASK WE TILL DON'T QUITE
UNDERSTAND THIS IS THAT WE
PREVIOUSLY FOUND WHEN TRYING TO
DETERMINE THE BINDING OF
PITTSBURGH COMPOUND B TO A-BETA
FROM NONHUMAN PRIME'SS COMPARED
TO HUMANS, THERE IS CONSIDERABLE
HIGH AFFINITY BINDING OF PIB IN
HUMANS WITH ALZHEIMER'S DEC BUT
ESSENTIALLY NO HIGH AFFINITY
BINDING IN ANY NONHUMAN PRIMATE
THAT THAT WE'VE LOOKED AT AND WE
SIMPLY DON'T KNOW WHY THIS IS, I
CAN SPECULATE BUT I JUST DON'T
KNOW.
ANOTHER DISADVANTAGE IS THE LONG
LIFE AND AVAILABILITY OF THESE,
THIS PROBLEM MIGHT BE OVERCOME
BY THE EXPRESSION OF TRANSGENES
AND THERE HAD BEEN MARMOSET
MODELS, THEY'RE EVOLUTIONARY
DANTE FOWLER FROM HUMANS, ABOUT
WHERE IMIRL MORKYS ARE, THEY'RE
SMALLER, 4-500-GRAMS THEY GIVE
BIRTH TO TWINS, THERE ARE
ADVABTAGES TO THE MARMOSETS AND
SOME GROUPS ARE DEVELOPING
TRANSGENIC HARMA SETS BUT NO 1
HAS REPORTED ON THE PATHOLOGY IN
THESE ANIMAL ANDS IN FACT THE
ONLY REPORTED PATHOLOGY IN A
NONHUMAN PRIMATE THAT'S BASED ON
AN APP TRANSGENE WAS IN
COLLABORATION WITH MY COLLEAGUE
ANTHONY CHAN WHERE WE FOUND THAT
APP EXPRESSION IN A RECESS
MONKEY GENERATED A BETA
DEPOSITION PRIMARILY IN THE
OCCIPITAL AND PARIETAL REGIONS
BY THE TIME THIS PARTICULAR
MONKEY AND WE ONLY HAVE 1 OF 2
IN WHICH THIS HAPPENED WAS 10
YEARS OLD AND AS YOU CAN SEE
THERE'S A FAIR AMOUNT OF AMYLOID
ANG YOAPATHY IN THESE MODELS.
THESE MODELS MIGHT BE REALLY
USEFUL FOR TESTING IMMUNO
PREVENTION STRATEGIES.
FOR TESTING MONOCLONAL
ANTIBODIES AND ALSO THEIR IRPT
ACTION WITH OTHER AGENTS SUCH AS
ANTICO AGULATES AND
ANTITHROMBOTTICS.
I ALSO THINK WE SHOULDN'T IMIF
UP ON ACTIVE IMMUNIZATION EMPLOY
AND NONHUMAN PRIMATES WILL BE
IDEAL FOR TESTING ACTIVE
IMMUNIZATION AND DETERMINING IF
1 IMMUNIZES ANIMALS AT A YOUNG
AGE, ARE THERE ANY ADVERSE
EFFECTS.
AND DOES THIS THEN DELAY THE
ONSET OF ABETTA DEPOSITION IN
THE BRAIN.
AND IN FACT, WE HAVE DONE AN
UNPUBLISHED PRELIMINARY STUDY
WHERE WE'VE IMMUNIZED ALL
SQUIRREL MONKEYS, ACTIVELY
IMMUNIZE THEM AND MOST OF PEOPLE
DO DEVELOP A NICE RESPONSE TO
THE A-BETA ANTIIEN SO THIS IS
PERFECTLY FEASIBLE, IT'S DOABLE
AND I THINK IT WILL BE 1 ARENA
IN WHICH THE NONHUMAN PRIMATE
MODEL WOULD BE PARTICULARLY
USEFUL.
SO IN CONCLUSION, CAA IS DEFAULT
NONHUMAN PRIMATES ALL WE LOOKED
AT DEVELOPED SIGNIFICANT CAA.
SPONTANEOUS ARIA WE FOUND NOW IN
1 AGED SQUIRREL MONKEY.
HOW OFTEN THIS OCCURS IN OTHER
SQUIRREL MONKEYS OR OTHER
PRIME'SS IS UMP SIMPLY NOT KNOWN
AND I THINK THAT THESE COULD
HAVE VALUE OF TESTING SAFETY AND
EFFICACY OF THERAPEUTIC
APPROACHES TO ALZHEIMER'S DEC.
THANK YOU.
>> WE HAVE TIME FOR QUESTIONS.
HOW MANY MONKEYS HAVE BEEN
CHARACTERIZED IN TERMS OF
[INDISCERNIBLE].
SO IS THERE A POPULATION YOU CAN
FALL BACK ON OR JUST YOUR 5 IN.
>> WE'VE LOOKED IN TERMS OF THE
NUMBER OF SQUIRREL MONKEYS, MOST
OF THESE HAVE BEEN OPPORTUNISTIC
INITANCES, THE MONKEYS I'VE
SHOWN I'VE KNOWN ANALS WHICH IS
UNUSUAL IN MANY PRIMATE TODAYS
IF THEY WERE CAUGHT IN THE WILD
EMPLOY MANY SQUIRREL MONKEYS
HAVE BEEN ANALYZES MANY RHESUS
MONKEYS HAVE BEEN ANALYZE
EXCLUDE NOW MORE MARMOSETTA SES
HAVE BEEN ANALYZED SO THERE IS A
PRETTY GOOD IDEA WHERE CAA
STARTS IN THESE SPECIES NO THERE
IS I NORMATIVE DATA.
>> THERE IS SMRKS BUT IF YOU
HAVE TO WAIT 13 YEARS, THAT WILL
BE A PROBLEM NYEAH THAT WILL BE
A PROBLEM AND YOU CAN DO IT IN A
WILD RAINCHLING COLONY SOMEWHERE
SUCH AS IN SANTIAGO WHERE
YOU'MUNIZE THEM WHEN THEY'RE
YOUNG AND LET THEM DO WHAT THEY
DO FOR A NUMBER OF YEAR ANDS
EVALUATE THEM PERIODICALLY FOR
SIDE EFFECTS.
NI'M ALMOST EMBARRASSED TO ASK
THIS QUESTION BUT I WON'T STOP
IT, DO OLD MONKEYS DEVELOP
DEMENTIA, IF THEY DEVELOP
DEMENTIA IS IT A PATHOLOGY THAT
CORRELATES IN ANY WAY WITH THE
HUMAN CONDITION?
>> GOOD QUESTION EMPLOY THE
ANSWER IS DEMENTIA NO, IT'S A
SEVERE LOSS OF COGNITIVE
FUNCTION THAT INTERFERES WITH
EVERY DAY LIFE, THEY DO SLOW
DOWN AND PERFORM MORE POORLY,
BUT DEMENTIA'S NEVER BEEN SEEN.
ALZHEIMER LIKE TAU-OP A THY HAS
NEVER BEEN SEEN IN THESE
PRIMATES.
THIS A DIFFERENCE IN THE FOLD IN
THE BETA OF NONHUMAN PRIMATES
AND WE HAVE EVIDENT THAT THAT'S
THE CASE EMPLOY BUT WHY THEY
DON'T DEVELOPPAL JEIMER SYSTEM A
REALLY IMPORTANT PROBLEM THAT I
THINK MIGHT TELL US ABOUT THE
WAYS WE COULD TREAT OR PREVENT
ALZHEIMERS IN HUMANS.
WE WILL ANY TO ONLINE NOW.
NTHIS IS FROM BILL, WHERE IT
COMING FROM.
>> IT PRIMARILY AGGREGATES
BETWEEN THE CELLS SO, I MEAN
IT'S IN THE--IN THE SUBSTANCE
THAT SURROUNDS THE CAPILLARY.
THE BASE OF MEMBRANE BASIC LYE
OR BASAL LAMINA CALLED BY SOME.
IT'S PRETTY MUCH ALWAYS THERE
AND OF COURSE, IN SEVERE CASES,
THE ARTERIES LOSE THEIR SMOOTH
MUSCLE CELLS.
NIMRAIT TALK LARY, I JUST WANTED
TO SAY WE HAVE DONE WORK WITH
ACT VISATION IN [INDISCERNIBLE],
WE HAVEN'T PUBLISHED IT BUT IT
WAS WORK WE PRESENTED AT A
NUMBER OF MEETINGS SO WE
IMMUNIZE THIS WAS TOGETHER WITH
THE YF AND WE IMMUNIZED MONKEYS
FOR VETS THAT WERE 18 TO I THINK
24 YEARS OF AGE WITH EITHER
AM1752, OR A B-CELL EPITOPE
DENDRITIC CELL RIMERRIC LYSINE
PEPTIDE TREE CALLED DENDRITIC
CELL RAMERRIC A-BETA 115 AND WE
DID SEE PLAQUE LOWERING WITH THE
1 YEAR IMMUNIZATION STUDY, WE
DID SEE PLAQUE LOWERING, WE DID
SEE IMPROVEMENT WITH THE PEPTIDE
VACCINE ON THE 1 PARTICULAR
TEST.
IT'S A CAN TAB TEST AND SO WE
DID WE COGNITIVE IMPROVEMENT IN
EXECUTIVE FUNCTION WITH
IMMUNOTHERAPY.
WE DID SEE VASCULAR AMYLOID BUT
WHAT WE HAVEN'T DONE IS A SERIES
OF [INDISCERNIBLE] STAINS ON
THOSE ANIMALS.
WE TILL HAVE THE BRAINS SO I
THINK IT WILL BE INTERESTING
NOW, TO GO BACK AND REALLY LOOK
FURTHER AT HEMOSITTERIN
EPECIALLY WITH THE TALK WE HEARD
FROM JAMES NIC OWELL, W
ELL,--JAIPS NICOLL AND WE DID
SEE COMPLEMENT IN THOSE ANIMALS
ANDY FOUND CR1 UPREGULATION OF
CR1 IN THE LIVER OF THOSE
ANIMALS AND SO, I THINK ANOTHER
THING WE MIGHT WANT TO THINK
ABOUT IS ANOTHER BIOMARKER IS
CLEARANCE OF THESE COMPLEXES IN
THE PERIPHERAL SYSTEM, AND SO,
LIVER WE DEFINITELY SAW THESE
COMPLEXES, ACTUALLY BEING
SEQUESTERED NIT'S INTERESTING,
WE TOO ARE DONE IMMUNIZATION
STUDIES IN COLLABORATION WITH
SAM GANDY AND RHESUS MONKEYS AND
THAT WAS PUBLISHED SOME YEARS
AGO, NO PLAQUES OR ANYTHING TO
START WITH BUT IT DID SHOW IT
WAS SAFE >> THANK YOU.
WE WILL MOVE ON TO OUR NEXT
SPEAKER.
DR. KATERINA AKASSOGLOU, SHE A
PROFESSOR OF NEUROLOGY AT THE
SENIOR INVESTIGATE AT THE
GLADSTONE EN--STRATEGIESITUTE
AND THE FIELD OF HER TALK IS
STRATEGIES TO PROTECT THE BBB IN
PERSONS TAKING ANTIAMYLOID AB
THERAPY.
NTHANK YOU AND WE WOULD LIKE TO
THANK THE ORGANIZATIONS FOR THE
OPPORTUNITY TO WORK.
AND TODAY WILL BE DISCUSSING
MECHANISMS WE HAVE DISCOVERED AT
THE BLOOD BRAIN IMMUNE INTERFACE
AND SHARE MY PERSPECTIVE HOW WE
CAN SHARE AND HARNESS THIS
INFORMATION FROM THE DEVELOPMENT
OF NEW POTENTIAL THERAPIES FOR
ALZHEIMER'S DEC, ALSO FOR
PROTECTION FROM ARIA.
THESE ARE MY DISCLOSURES,
FUNDING FOR THE LAB, I'M THE
FOUNDER, NSAB, AND PATENT AND
PATENT REGULATIONS SOME OF WHICH
ARE RELATED TO TODAY'S
PRESENTATION.
THIS IS ALSO THE KACCTIS INIAL
HIELER'S DISEASE AND HERE YOU
CAN SEE FROM OUR STUDY TODAY, 2
DIMENSIONAL LABELING IN THE
HUMAN, ALZHEIMER'S BRAIN WHERE
YOU SEE DEPOSITS OF THE BLOOD
FOR COMPILATION PROTEIN FIEB RIN
O GEN SURROUNDING BLOOD VESSELS
AND BIG CHANGES IN BLOOD VESSELS
CORRELATE WITH WORSE PROGNOSIS
AND ALZHEIMER'S DEC AND THE
DRIVEWAYING
DRIVEWAYING--DRIVING DISCUSSION
IS ARE THESE CAUSAL FOR
NEURODEGENERATION.
THIS IS NOT IN THE NORMAL CNS
AND FIEB RIN OIEN IS A PROCESS
GENNED IN THE BARRIER AND IT
REQUIRES GETTING INTO THE BRAIN.
IN THE A. D. BRAIN COMBOYNED
BETA AND IT CORRELATES WITH
SITES OF ACTIVATED MICROGLIA AND
SHOWING PRESENTATIONS SHOW THIS
MORNING, I WILL ALSO CORRELATE
WITH SEVERITY OF CAA IS PRESENT
IN ARIA AND IS INCREASED IN
PATIENTS WITH THE POLYMORPHISM.
IN ADDITION TO NEUROPATHOLOGY
STUDIES BIOMARKER STUDIES HAVE
IDENTIFIED FIEB RIN O GENERATED
AS A PLASMA AND BIOMARKER THATP
CREASED RISK AND ALZHEIMER'S
DISEASE AS WELL AS INCREASED
DEMENTIA RISK IN CORRELATING
WITH THE FOSTER NURSED FOCUSED
ON-TAU AND RECEPTOR BETA IN A
APOE4 AD PATIENTS.
FIEB RIN O GENERATED IS A UNIQUE
STRUCTURE, AND U
RE, AND A DRUGGABLE
TARGET.
SO WHAT I NOTICED IS THAT
FIBRINOGEN HAS ANOTHER SITE,
WITH THE BYPASSING SITE WHICH
BYPASSEDS TO THE COMPLEMENT OF
THE CD11 B DOMAIN RECEPTOR.
AND OF COURSE WE KNOW THAT THIS
RECEPTOR IS EXPRESSED IN
MACROPHAGES AND IS A KEY DRIVER,
SO THE REQUESTY IN MY LAB HAS
BEEN WHEN THESE PROTEIN ENTER
THE BRAIN COULD IT BE HIJACKING
THESE'MUNE RECEPTORS OFF
MICRODPLIA AND IMMUNE CELLS IN
THE BRAIN, AND THESE TALKS THE
COAGULATION AND INFLAMMATORY ARE
NOT OVERLAPPING COULD WE DEVELOP
GENETIC AND PHARMAICOLOGGIC
TOOLS TO BLOCK THE POTENTIAL
DAMAGINGLY INFLAMMATORY CENTER
FOR EXCELLENCE ON AGINGS OF FIEB
RIN WITHOUT AFFECTING BENEFICIAL
EFFECTS IN NORMAL HEMOSTASIS.
SO A HYPOTHESIS WAS THE
KRIEEVERS OF FIEWROLOGICAL
DISEASES AND EXPERIMENTS WAS
GENETIC LOSS OF FUNCTION STUDIES
TO KNOCKOUT MICE TO TEST WHETHER
BLOOD PROTEINS ARE NECESSARY TO
DRIVE NEURODEGENERATION IN
TEASE.
AND OVER 20 YEARS AGO WE
PERFORMED A STUDY FOR THE MOUSE,
THIS MOUSE HAS ALL BLOOD
PROTEINS EXCEPT FIBRINOGEN AND
WE FOUND THIS MOUSE WAS
PROTECTED ACROSS MANY
NEUROLOGICAL DISEASES ENCLUING
MULTIPLE MODELS OF ALZHEIMER'S
DEC, MODELS OF MS, AND THESE
MICE WERE USED EXTENSIVELY IN
THE FIELD AND SHOWED PROTECTION
IN THE CHEMICAL DEMILENNATION
AND PERICITE DEFICIENT MICE.
IT IS NECESSARY TO DRIVE
NEURODEGENERATION AND DISFUNK IN
THIS MODELS MUCH IN
COLLABORATION WITH
[INDISCERNIBLE] AT UNIVERSITY OF
CINCINNATI, THEY USE A MUTATION
BETWEEN THE INPOLICEMANNATORY
DOPAIN, THESE MICE CAN HAVE NO
DEFINITES IN CLOTTING, NORMAL
HEMOSTASIS BUT THEY CANNOT
ACTIVATE THE IMMUNE SYSTEM, AND
WE FOUND THESE WERE PROTECTED IN
THE IMMUNO LONGIC DEC AND THIS
SIDE WAS CRITICAL FOR THE
MICROGLIA CELL, THIS BECAME THE
BASIS FOR THERAPEUTIC ISHT VENS
AND DEVELOP THE FIRST IN CLAS BY
TARGETING IMMUNOTHERAPY AND THE
PHASE 1 CLINICAL TRIALS IN
HEALTHY VOLUNTEERS.
TO IDENTIFY MECHANISMS BETWEEN
LINKING THE BRAIN BIODISRUPTION
AND NEURODEGENERATION, WE,A
PROACH AN HAVE AAN PROACH FOR
THE PHOTO IMAGING, DEVELOPING
NEW PROTOCOLS FOR 3 DIMENSIONAL
LABELING FOR FIEB RIN IN MOUSE
AND MUSEUM MAN BRAIN AS WELL AS
BEHAVIORIAL TEST ANDS WE PERFOR
THE PURPOSED THESE TODAYS IN THE
5 X AD MODEL OF A. D.
BY ENDOGENOUS LABELING OF FIEB
RIN OIEN, WE FOUND THAT SIMILAR
AMYLOID DEPOSITS IN THE BRAIN
WERE ALSO SITES OF SYNAPSE LOSS.
FIEB RIN O BEGIN SEMESTERULAR TO
AMYLOID CAN INN DUCE SPINE LOSS
IN THE BREAN, SOPHISTICATEDY
THIS IS A NEW CULPRIT FOR SPINE
LOSS IN A. D. MICE.
TO TEST WHETHER THIS WAS
REGULATING NEURODEGENERATION, WE
CROSS THE MODEL WITH THE FIEB
RIN O GEN WITH THE MOUSE AND
THIS HAD THE INCREASED NUMBER OF
SYNAPSES, DECREASED
NEURODEGENERATION, DECREASED
LIES STUDIES OF MULTIPLE
ENDOCRINIA MARKERS AS WELL AS
ALSO MICRODPLIA.
WE EMPLOYED STANDARD COGNITIVE
TEST
INCLUDING MEMORY AND THE LINE,
CAN YOU SEE THE DEFICIT OF THE
MICE THAT WAS RESCUED WHEN
SUPERIMPOSED WITH THE MUTATION
THAT AGAIN THIS MICE MAKE THE
LEVEL, BUT NOT ACTIVATE
RECEPTORS HONE ON THE MICRODPLIA
AND THE CELLS.
IN COLLABORATION WITH THE FLAD
STONE INSTITUTE, WE ALSO
EMPLOYED AN UNBIASED LEARNING
APPROACH TO ASSESS THE
BEHAVIORIAL DURATIONS IN
ALZHEIMER'S MICE.
WITH THE SHOWN WITH THE MACHINE
LEARNING IS THEY CAN IDENTIFY
MOTIF IN THIS, AND SUPER IMPOSE
THE MUTATION, WHAT WE FOUND IS
THAT THESE WERE COMPLETELY
RESCUED OR REDUCE INDEED THE
ABSENCE OF THE FIEB RIN O GEN,
THEREFORING THE MICROGLIA
SIGNALING WITH ALTER THE AD
MUTATIONS IN MICE.
THE STUDY IDENTIFIED SPINAL ELIM
NATION AND MUSCULAR DAMAGE AND
SHOWED THIS COULD NOT BE A
SIGNAL AND FOUND A MECH NIM THIS
IS INDUCTION OF FOXOXIDATIVE
STRESS AND REACTIVE OXYGEN
SPECIES, WE SHOWED THIS
IMPORTANT INDUCER OF THE
ACTIVATION AND THESE FINDINGS
CAN ALSO PRORIDE THE POTENTIAL
MECHANISTIC EXPLANATION BEHIND
EMERGING CLINICAL DATA ABOUT THE
PATHOLOGY EARLY INDEPENDENT
MECHANISM, THAT CAN DRIVE
NEURODEGENERATION AND
[INDISCERNIBLE], AND FIND THIS
DATA ARE ALSO SUPPORTING THAT
VASCULAR PATHOLOGY SHOULD BE
INDEPENDENTLY TARGETED FOR
MAXIMUM THERAPEUTIC EFFICACY.
SO WE WITH THAT IN MIND WE
DEVELOPED FIBROGENIC IMMUNO
THERAPY AND ACTIVITIES AND
PROJECTS COMPETENT THE
CHALLENGES WE HAD TO OVERCOME
WAS OF COURSE THE POPULATION.
WE DIDN'T WANT TO INTERFERE WITH
THE PROTECTIVE EFFECT IN
HEMOSTASIS.
SO TO DEVELOP AN ANTIBODY THAT
COULD TARGET ITS TOXIC
INFLAMMATORY FUNCTIONS WE
DEVELOPED A EPITOPE SPECIFIC
ANTIBODY THAT [INDISCERNIBLE]
ORGANIZES THE INFLAMMATORY
DOMAIN OF FIEB RIN.
THE ANTIBODY CANNOT BIND TO
SOLUBLE FIBROGEN IN THE BLOOD SO
IT DOESN'T HAVE A SYNCH EFFECT.
AND IT HAS SHOWN THERAPEUTIC
EFFICACY FOR MULTILE MODELS OF
SCLEROSIS, AS WELL AS UNIVERSAL
TRIALS FOR ALZHEIMER'S DEC WHERE
YOU SEE PROTECTION OF NEURONS
AND EXPRESSION OF INFLAMMATORY
PATHWAYS FOR HUMAN AD AND THE
ANTIBODY HAS BEEN HUMANIZED AND
COMPLETED SAFETY CAN TOXICOLOGY
AND THE SPECIES AND THE FIRST IN
HUMAN TRIALS ALREADY IN MAY, AND
PLANTING ALZHEIMER PATIENT
JEIMER'S PEASHES IN 2024,
PROVIDE OF COURSE THAT TO DATE
THE TRIAL ARE SAFE.
THREE YEARS AGO WAS THE
ANNIVERSARY OF THE NATURE
IMMUNOLOGY WHICH COINCIDED WITH
THE BIOLOGICS FROM FDA AND THE
NATURE PUT ON ITS COVER 20
ANTIABOUT THINGS FOR YEARS, SO
NATURE IMMUNOLOGY, SO 1 OF THOSE
FEATURES WAS THE ANTIBODY AND WE
GOT THE OPPORTUNITY TO DISCUSS
HOW CONNECKED THE DOTS OF THE
NEUROVASCULAR INTERPHASE AND HOW
CURIOSITY ABOUT HOW FIEB RIN
AFFECTS THE BRAIN AND THE BLOOD
AFFECTS THE BRAIN LIKE THE
DORPHY OF THE FIRST PRINCIPLE
TOOL TO NEUTRALIZE BLOOD
TOXICITY IN THE
NEURODEGENERATIVE DISEASES.
THESE STUDIES OPENED QUESTIONS
ABOUT HOW THE--WHAT IS THE
MOLECULAR AND CELLULAR INTERFACE
THAT BLOOD PROTEIN INTERACT WITH
THIS SERVOUS SYSTEM CELLS AND
DURING SELECTIVITY OF BLOOD
PROTEINS WHEN THEY ENTER THE
BRAIP TO ACTIVATE THESE IMMUNE
FUNCTIONS.
SO THERE'S QUESTIONS WE
DEVELOPED AND UNBIASED MULTIOMIC
PIPELINE, COMBINED WITH THE LOSS
OF FUNCTION STUDIES TO DEFINE
THE BLOOD IN THE YEARS FOR THE
FUNCTIONS IN NEURODEGENERATION
EMPLOY BUT YOU CAN SEE HERE THE
MICROGLIA BLOOD NETWORK, SHOWING
EXPOSURE FROM PLASMA TO MICE,
AND WE FOUND THAT MICROGLIA HAD
NEURODEGENERATION UPON EXPOSE
TOWER WILD-TYPE PLASMA.
SURPRISINGLY WHEN WE OVERLAY THE
TRANSCRIPTOME OF MICRODPLIA
EXPOSED TO THE FIBRINOGEN MICE,
NEIVE% OF THE MICRODPLIA NETWORK
WAS DOWN REGULATED AS 50% OF
THESE YEEPS ARE SIGNIFICANT
SHOWING THIS IS A KEY PROTEIN IN
THE BLOOD, IN THE ACTIVATION
EMPLOY TO IDENTIFY THIS CENTER
FOR EXCELLENCE ON AGINGS WHAT IS
MEDIATED WE ALSO LIEUS THE
PLASMA FROM THE MOUSE, THIS
CLOTS BUT CANNOT ACTIVATE THE
RECEPTOR IN THE MICROGLIA AND
HERE CAN YOU SEE SIGNIFICANT
REDUCTION OF THE YEENS WHEN
COMPARED TO THE WILD-TYPE
PLASMA, COMPARED FOR EXAMPLE,
WITH THE USE OF CONTROL, BUT
SEEMS TO BE VERY SIMILAR, THE
TRANSCRIPT OHM OF MICROFLI
COLSISSA THAT ARE EXPOSED VERSUS
WILD-TYPE PLASMA, THEY ARE NOT
ONLY SELECTIVE BUT RECEPTOR
MEDIATED TRANSCRIPTOMIC PROGRAMS
IN THE POLYMERIZATION.
THE RESULTS ARE ALSO WITH THE
PREVOUS STUDIES THAT THE
MICRODPLIA BUT ALSO DOWN STREAM
EVENS OF MICROGLIA WHERE THERE
IS ALSO REDUCED DENT RIGHT LAW
ANDS ACTIVATION OF THE
FIEBERATION OF THE PLASMA IN THE
BRAIN COMPARED TO WILD-TYPE
PLASMA.
TO FIND OUT IF THESE GENES WERE
IN ALZHEIMER'S MICE, WE
PERFORMED IN MICROGLIA 5 X AD
MICE CROSS THE FIEB RIN O GEN
MOUSE.
AND HERE WHAT YOU CAN SEE IS THE
5 X IS THE EXPECTED UPREGULATION
OF THE
NEURODEGENERATIVEOXIDATIVE
STRESS AND THIS IS ASSOCIATED
MICRODPLIA YEENS AND DOWN
REGULATION OF THE FAMILIAL
STATIC SIGNATURE OF THE
MICROGLIA AND THE MUTATION, THE
NEURODEGENERATIVE SIGNATURE WAS
SUPPRESSED AND THE SIGNATURE,
WITH THE HOMEOSTATIC SIGNATURE
WAS RHETORRED.
SHOWING THAT THESE PATHWAYS
NECESSARY FOR MICROGLIA FOR THE
STRESS AND DEGENERATIVE GENE
EXPRESSION IN AD MICE.
SO OVERALL WHAT THIS STUDY
SUGGESTS IS THAT THE BLOOD BRAIN
IS NOT ONLY SECURITIZATION.ARY
TO IPT GREATER FLAMMATION BUT
IT'S IN THE DRIVER OF PATHOGENIC
INNATE IMMUNITY IN THE BRAIN,
BLOOD PROTEINS ARE NOT
INTERCHANGEABLE BUT THEY INDUCE
DISTINCT MEDIATED POLYMERIZATION
OF MICRODPLIA AND FIEB RIN NOW
IS A UNIT AMONG BLOOD PROTEINS
TO BE IN THE PATIENT WHO ARE
VERY SPECIFIC NEW O DEGENERATIVE
POLARIZEDDERRIZATION OF THOSE
CELLS EMPLOY THIS COULD BE VERY
IMPORTANT FOR THERAPY, SO THIS
IS AN INDEPENDENT PATHWAY OF
NEURODEGENERATION AND CAN BE
DONE IN A SELECTIVE WAY, THIS
DOESN'T BLOCK OTHER MICROGLIA
FUNCTIONS BUT NOW CONTRIBUTE TO
COGNITIVE PROTECTION, ESPECIALLY
IN PATIENTS POPULATIONS THAT
HAVE HIGHER BLOOD BRAIN AND
MOSTFUL, AND POTENTIALLY EMILY
THE IT FROM THE BRAIN DUE TO
ARIA.
AND TO DEVELOPING THE PATHWAY,
IN THE CLINICAL DEVELOPMENT IS
IMPORTANT TO THINK ABOUT
SENSITIVE IMAGING OF BRAIN
BARRIER, AND THE STUDIES FOR THE
FIEB RIN OIEN AND THERE ARE WAYS
TO DEVELOP NONINVASIVE TOOLS TO
DIRECTLY DETECT IN THE BRAIN
PATIENTS.
I WOULD LIKE TO THANK ALL THE
HIGHLY TALENTED PEOPLE IN MY
LAB, AND THE ANTIBODY STUDIES
WERE LED BY JAKE AND
[INDISCERNIBLE] PERFORMED
TRANSCREPT ORDER OF MICRONSIC
WORK AND AS OF MONDAY THE
PROFESSOR AT UCSD, AND
PERFORMING THE MICROGLIA
STUDIES.
THESE ARE ALL COLLABORATORS AND
IN PARTICULAR FOR THIS TALK, I
WANT TO THANK THE FOLLOWING
PEOPLE:
AND FINALLY, THANK ALL OUR
FUNDING FOR THE SUPPORT AND
THANK YOU FOR YOUR ATTENTION.
>> SO THE AH SUSMGZ IS THAT THE
OPENING OF THE BLOOD BRAIN
BARRIER IS WHAT HAPPENS FIRST
AND IT SHOULD BE OF SUFFICIENT,
YOU KNOW EBTITY TO ALLOW FIEB
RIN OIEN TO ENTER.
SO WHAT'S THE EVIDENT THAT
THAT'S THE CASE.
YOU KNOW INFLAMMATORY DISEASE IN
NWELL, I THINK WHAT'S
INTERESTING IS THAT DESPITE
THERE CAN BE DIFFERENT STRIGGERS
THAT OPEN THE BARRIER BECAUSE WE
SEE THIS PROTECTION WITH
ALZHEIMER'S DISEASE AND THOSE OF
MULTIPLE SCLEROSIS, SO TRAUMA IN
ALL OF THESE CASES WHEN
FIBRINOGEN IS IN THE BRAIN IT IS
NECESSARY FOR THE DOWN STREAM
EVENS OF THE RESPONSE OF THE
NEURODEGENERATION, SO THE TOOLS
I SHOWED TODAY IN THE MODELS ARE
ALSO IN THE MULTIPLE CLEROSEIS
MODELS AND BRAIN INJURY MODELS.
SO THIS APPEARS TO BE A COMMON
THREAD TO SIGNAL TO THE BRAIN'S
IMMUNE SYSTEM THIS NEUROTOXIC
ACTIVATION AND THE EFFECTS OF
COURSE ARE NOT SPECIFIC FOR
MICROGLIA.
FIEB RIN ACTIVATES ALSO 11 B
POSITIVE CELLS, SO THIS IS
MACROPHAGES AND A KEY PART OF
THE SIGNATURE AND EXPRESSION OF
RECRUITMENT AND CHEMOKINE CELLS
INTO THE BRAIN.
SO IT'S A DUAL RESPONSE IF THE
RECRUITMENT AS WELL AS SOCIAL
[INDISCERNIBLE] AND RESPONSE.
WHAT I SAID TO FIBRINOGEN APART
TO OTHER BLOOD PROTEINS WE
STUDIED IS IT'S INDUCING BIAS
OUTSIDE THE SIGNALING SO IT
ACTIVATES THEOX DACE AND DID NOT
FIND THIS WITH OTHER LIGANDS, SO
I THINK THIS CREATES A
ASSOCIATION WITH BLOOD BRAIN
BARRIER LEAKS.
>> I'M CURIOUS YOU FOCUSED ON
THE MICRODPLIAL CELL AND SOME OF
US ARE BECOMING
ENAMES--NAMESSORRED WITH THE
ASTRO GLIAL CELLS DOES FIEB RIN
HAVE THE SAME THING ON THE ASTRO
DPLIA,.
>> IT HAS DIRECT AND INDIRECT
EACHS ON THIS, THEY ARE
ACTIVATED AND WHAT WE FOUND IS
WHEN WE PLOK THE RESPONSES WE
HAVE ATTENUATE ASTRO SIGHT
ACTIVATION AND NOW WE HAVE ALSO
SHOWN THIS THE OMIC DATA THAT
ARE THERE YET, ABOUT YOU WELL IS
ALSO A DIRECT EFFECT OF FIEB RIN
OIEN ABOUT 10% OF THE PLAID IS
BOWPPED TO LATENT TGFPAYS BETA
AND WE PUBLISHED NATURE IN THE
GENERAL SCIENCE BUT 10 YORES AGO
THAT 1 FIEB RIN O GEN ENTERS THE
BRAIN, IT'S IMMEDIATE ACTIVATION
OF VEG F BETA WHICH IS HOW IT IS
ACTIVATED SO BEFORE THE
TRANSCRIPTION, THE ACTIVATION OF
THIS PATHWAY, IT CAN REGULATE
THE TGF BETA AND THIS WAS ALSO
REALLY IMPORTANT FOR ACTIVATION
OF ASTRO SIGHTS IN IN THE BRAIN,
AND THE REPAIR IS ALSO NEURONAL
REACH, BUT WAY ASTRO SITTIC
PHASE CAN THIS MAY BE A WAY OF
CONTRIBUTION TO FIGHT
[INDISCERNIBLE] OUTSIDE INJURY.
NTHANK YOU VERY MUCH.
SO NOW, IT'S MY GREAT PLEASURE
TO INTRODUCE OUR NEXT SPEAKER
JONAS NEHER, HE IS AT THE GERMAN
CENTER FOR NEURODEN DEGENERATIVE
DECS IN TUBING EN, AND HE
FOCUSES ON MEMORY IN THE BRAIN
AND CONTRIBUTION TO
NEURODEGENERATIVE DECS.
WE LOOK FORWARD TO YOUR TALK
EMPLOY.
>> OKAY, THANK YOU VERY MUCH FOR
THE ORGANIZERS FOR THE
INVITATION TO SPEAK HERE TODAY.
I LEARNED A LOT ABOUT ARIA
ALREADY AND WHAT I WOULD
LOAMACYIC TO CONTRIBUTE IS OUR
THOUGHTS ON HOW MEDIA AMYLOID
COULD BE A TENTATIVE TARGET FOR
DAMAGE IN THE PATES WITH THE CAA
AND OTHER CARDIOVASCULAR
DISEASES.
SO WE TURNS OUT THAT THE MOST
COMMON IN AMYLOID IS MEDIN, AND
IT'S FOUND IN VIRTUALLY
EVERYBODY OVER FIEOF THE YEARS
OF AGE AND IN PARTICULAR, AND
THE MEDIA, AND ALSO BY THE NAME
MEDIN COMES FROM.
SOME PATIENTS WE CAN SEE IT IN
MORE BETWEEN THESE FIBERS IT CAN
BE QUITE HETEROGENIUS.
SO DRIEBED ABOUT 50, 25 YEARS
AGO AS A 50 AMINO ACIDS ON A
FRAG M-TEBURKEULOSEIS OF A
PROTEIN AND IT HAD ANY
PATHOPHYSIOLOGICAL ROLE IN THE
VASCULATURE.
SO IN ORDER TO STUDY IN THIS
DETAIL, WE USED THE MODEL SYSTEM
AND BECAUSE WE LIKE WORKING WITH
THE MICE, WE HAD TO LOOK AT THE
MEDIN SEQUENCE IN MICE, VERSUS
IN HUMAN AND FOUND THE AMINO
ACID LEVELS WAS ABOUT 80% SO NOT
TOO BAD, AND WHEN WE LOOKED AT
THE AG IMREIGATION PROPENSITY OF
THE 2 PEPTIDES WE CAN SEE HERE
BASED ON THE TANGO PREDICTION IS
THAT THIS IS IN THE BLUE CURVE,
HAS 3 AGGREGATION AND THIS 1
HERE WHICH IS THE MOST SOMEWHAT
REFLECTIVE IN THE MOUSE
SEQUENCE.
THIS LEADS TO FIRST OF ALL THE
ABSENCE OF MEDIN AND
SECURITIZATION. OF ALL THE
FUNCTION TO THE KNOCK OUT, THE
TRUNCATED FORM BEING RETAINED IN
THE CELL BECAUSE OF THE TRAN
MEMBRANE DOMAIN WHERE THE
WILD-TYPE FORM GETS RELEASED
INTO THE EXTRA CELLULAR SPACE.
SO WE WANT TON DO MICE MEDIN
AGGREGATES IN THE VASCULATURE.
AND BECAUSE THE AUTHOR HAS THE
MAIN SITES, WE LOOKEDDA THE
AORTA FIRST.
THESE ARE SIMPLE BLACK 6 MICE.
NO GENETIC MODIFICATION EMPLOY
AS YOU CAN APPRECIATE IN THE
SLIDE, WE HAVE WHAT AG
TBREIGATES BY 20 MONTHS OF AGE
IN THESE ANIMALS.
THESE ARE AGGREGATES ARE IN THE
MHC 2 KNOCK OUTS SO IT LOOKS AS
IF MEDIN CAN BE IN MICE, SO THIS
WOULD BE 1 OF OF THE FEWER
ENDOGENOUS AMYLOIDS FOR MICE IN
EFFECT.
BUT TO CONFIRM THIS WAS THE DDM,
YOU CAN SEE HERE WE DO GET SEE
MEDIN IN THE SPACE, AFFECTING
WHAT'S IN HUMAN PATES BUT THE
STRUCKURE WAS SURPRISING BECAUSE
WE DIDN'T SEE ANY FIB RULES, SO
IF YOU LOOK AT AMYLOID, YOU
WOULD SEE FIB RULES AND THIS WAS
BT THE CASE IN MICE.
SO HAVING SAID THAT WE TALK
ABOUT THE INITTIAIVE ITS FOR THE
ANALYSIS IN HUMANS AND HE
CONFIRMED THAT IN HUMANS WE GET
MORE AMORPHOUS AGGREGATES RATHER
THAN THE CLASSICAL AMYLOID
TRUCTURE.
WE DID WANT TO DISCUSS THE
WILD-TYPE.
SO LOOKING AT THE RIGHT SIDE,
YOU CAN SEE THAT IN THIS FIRST
PLANE OF THE WESTERN PLOT, IN
THE MOUSE WE ARE 2 ISOFORMS OF
THE FULL LENGTH AND THEY GET
DEGRADED BY THE PROCEDURE, BUT
NO MFGIN THE FINAL TRACTION,
SITUATIONS ARE DIFFERENT THAN
THOSE FESTER OF ALL WE HAVE
MASSIVE AMOUNTS OF THESE, WE CAN
ALSO SEE WHAT LOOKS LIKE AG
PREIGATE ANDS INCREASED
FRAGMENTATION WHICH OF COURSE
UNNECESSARY TO PRODUCE IT.
WITH THESE PROTEINS WE END UP
WITH THE 5 KILODALT AN BAND
WHICH NICE RESILIENCE SPONDY
LIGHTISES TO THE MASS OF THE
METER AND AFFECT BY MASS SPECT
WE COULD CONFIRM THESE MAG
FRENTS CONTAIN THE MEDIAN
SEQUENCE.
SO THEY ARE DEVELOPING MEDIAN AG
GERONTOLOGYSTS GET--IS OF THESE,
YOU ASK WHETHER THIS HAS
CONQUENCE ON VASCULAR FUNCTION
FOR THAT WE RETURN TO THE BRAIN
AS OUR FAVORITE ORGAN AND WE
FIND THAT WITH THE ARTERIES, AND
WE USED ENVIVO TO PHOTON IMAGING
AND HYPE AND STIMMULES IMAGING
THE SENSORY CORTEX AND LOOKING
AT FUNCTIONAL HYPEREMIA AND THE
VASCULAR RESPONSE, AND IN ADULT
ANIMALS WE DIDN'T ACTUALLY SEE
ANY DIFFERENCE BETWEEN THE
MEDIAN AND SUFFICIENT AND
DEFICIENT ANIMALS BUT IN AGED
ANIMALS WE COULD SEE IT SLOWING
OFF THE TIME AND THE WILD-TYPE
ANIMALS, THIS WAS ALMOST
COMPLETELY THERE AND WERE ABSENT
INDICATING MEETING AGGREGATES
REALLY ALSO ARE A DECLINE IN
VASCULAR FUNCTION IN AGING.
WE ALSO SAW KIND OF A RESCUE
EEIVET WITH CONSTRUCTIONS AFTER
THEY SEE US AND THAT SEEMS TO
INDICATE WHAT MIGHT BE LOOKING
AT IS ARTERIOLE STIFFENING
RATHER THAN OF COURSE WE'RE
WONDERING WHETHER IT COULD BE
IRPTACKING WITH AMYLOID IN THE
BRAIN.
SO THE FIRST THING WE DID IS WE
BEING TO A SECTION FROM OUR APP
MODELS AND TAINED IT WITH THE
FGHANTIBODY AND YOU CAN SEE
SUBSTANTIAL IMMUNO REACTIVITY,
FOR THE PLAQUE, WE SEE IT
EXPRESSED IN THE ASTRO SIGHTS
HERE AND WHEN WE CROSS IT IN THE
KNOCK OUTS WE SEE THE STAINING
AROUND PLAQUE COMPLETELY
DISAPPEARS THE TRUNCATED FORM
STUCK INSIDE THESE CELLS.
SO DOESN'T HAVE AN IMPACT ON THE
AGGREGATION, OF COURSE QUESTIONS
WE WANTED TO WORRY.
SO WE LOOKED AT THIS AND
DIFFERENT TRANSGENIC MODELS 1 OF
THE PP1 S MICE, VERY RAPID, A
PITA PLAQUE MODEL WHICH THE MICE
HEARD ABOUT BEFORE, THEY SHOW
LEVELS AT 6 MONTHS AND 12 MONTHS
EMPLOY SO LOOKING AT PLAQUE,
THAT WAS NICE BUT DISAPPOINTING
AT SAT TIME BECAUSE WE SAW 50%
LESS PLAQUES BUT BEFORE MONTHS
OF AGE THIS LEVELS OFF TO
SIMILAR LEVELS IN THE WILD-TYPE
AND MEDIAN DEFICIENT ANIMALS.
VERY SIMILAR IN THE APP 23
INSHALLLY VERY NICE DECREASE IN
THE [INDISCERNIBLE] AND SEARCH
ANIMALS AND NOW AS I SAID, THIS
WAS A LITTLE BIT DISAPPOINTING
BUT I WOULD LIKE TO EMPHASIZE
THAT WHAT WE'RE LOOKINGA THE IS
THE IMPACT OF ENDOGENOUS MEDIAN
ON A MASSIVELY OVERPRODUCED
AMYLOID BETA AND WE CAN TILL SEE
THESE EFFECT INDICATING THAT IT
MIGHT BE INTERACTING WITH IT IN
SOME WAY.
AND NOW BECAUSE THIS IS AMYLOID,
AND DESCRIBED AS A VASCULAR
AMYLOID AND BEFORE THE APP 23 IT
YOU CAN SEE IT HERE, THEY HAVE
ANTI-AB HERE AND IT'S ABSENT
AGAIN IN THE FGE8 HERE, CAN YOU
SEE THAT IT'S SIGNIFICANTLY
REDUCED BY 85% BUT THE VARIANCE
IS VERY HIGH AND THESE ANIMALS
ARE JUST STARTING TO DEVELOP
CAA, BUT AT 24 MONTHS OF AGE
WHERE WE HAVE SEVERE CAA IN
THESE ANIMALS WE CAN SEE
REDUCTION BY 65% IN CAA
INDICATING THAT MEET NOTHING
SOME WAYS DRIVING THE
AGGREGATION IN THE ARTERIES OF
THESE ANIMALS.
ALSO TO MENTION THIS GOES ALONG
WITH THE REDUCTION IN
MICROORIGINS, THIS IS NOT
SURPRISING BECAUSE OF THE WE
REDUCE CAA WE EXPECT TO REDUCE
THE MICROHEMORRHAGES IN MOUSE.
WHY SUBJECT THAT IMPACT ON THE
AG DPREIGATION IN THE
VASCULATURE CONSISTENTLY BUT
THOT SO MUCH ON PLAQUES?
THE SIMPLE ANSWER IS BECAUSE
IT'S NOR VASCULATURE AND IN THIS
CASE WE HAVE 50 TIMES HIGHER AND
ISOLATED BLOOD VESSELS IN THE
MICE COMPARED TO THE TOTAL
INNATE AND IT IPT GREATER
CREASES FURTHER BY 10 FOLD, SO
THIS IS ARRHYTHMIC SCALE GOES UP
BY 10 FOLD WITH CAA PATHOLOGY IN
OUR APP 23 MICE INDICATING THAT
ALSO FGHSMAZE IN SOME WAYS
RELATED TO PATHOLOGY.
WHAT ABOUT THE HUMAN BRAIN.
SO THIS IS WHEN IT GETS
INTERESTING, SO THIS IS THE
HUMAN BRAIN, THIS IS THE PATIENT
WITH CBS CAA, YOU CAN SEE THE
SUBSTANTIAL IN THE VESSEL OF
THESE PATES AND IN HUMANS WE SEE
IT IN PLAQUES AND WE LOCALIZED
BLOOD VESSELS IN PATIENTS AND
THAT'S SOME COLOCALIZATION WITH
THE IT BUT IT'S NOT COMPLETE.
VERY SIMILAR TO THE MOUSE MODELS
AGAIN, THAT WAS ABOUT 50 FOLDS
HIGHER IN THE ISOLATED BLOOD
VISITSLES, AND COMPARE AGAIN
WITH PATES WHO OVER
[INDISCERNIBLE] AGAIN WE CAN SEE
THIS INCREASE IN MFG 8 LEVELS
AND REFLECTIVE OF WHAT WE'VE
SEEN IN THE MOUSE MODELS.
SO IN HUMANS WE CAN LOOK AT
BESTERN PLOTS YOU CAN SEE FULL
LENGTH MFG-E8, AND WE IS SEE IT
IN PATIENTS WITH CAA, AND AT THE
VASCULAR LEVEL IT IS INTERESTING
BECAUSE IN PATES WE DON'T SEE
JUST WHAT LOOKS LIKE AG
DPREIGATES UP HERE BUT WE SEE
INCREASED FRAGMENTATION AND HAD
IS OF COURSE NECESSARY TO
PRODUCE MEDIAN, ALSO ON THE
INSOLUBLE FACTION, WE CAN SEE HA
LOOKS LOOK A SMEAR ACROSS THE
ENTIRE RANGE AND AG FREE
RADICALSIGATES CHARACTERIZE THEM
IN DETAIL RIGHT NOW.
WE TURNED IT FROM THE PATIENT
STUDY, IS THERE INCREASE TO THE
INTEGRATION, IS THERE MORE MFED8
AND IS EVIDENT DRIVEN BEN BY THE
VESTITURE AND THAT IS CALLED
WEIGHTED CORRELATION, IT GROUPS
ALL THE YEEPS BY CO EXPRESSION
BY CO RECOGNIZATION AND WE ONLY
FOUND 1 GROUP IN THESE PATIENTS
AND WE TOOK ALL THESE YEENS AND
ASKED WHETHER THERE ARE ENRICH
INDEED A PARTICULAR CELL TYPE
ASK WE ONLY COULD IDENTIFY
SMOOTH MUSCLE CELLS, AGAIN,
TAKING THIS INCREASE TO THE
VASCULATURE IN THESE PATES.
AND FINALLY, WHAT THE STATE SENT
US OUT IS TO ASK US WHETHER
MEDIAN MAY BE INDEPENDENT
PREDICTER OF COGNITIVE DECLINE
ASK THAT SOME OF YOU IN THE
REGRESSION FACTORING IN A PITA
AND TAU PATHOLOGY AND EVEN THEN
THE YEEN EXPRESSION OF THE MFGE8
CONTRIBUTED SIGNIFICANTLY TO
PREDICTING COGNITIVE DECLINE IN
THESE PATIENTS INDICATING IT HAS
A COMPONENT IN ALZHEIMER'S
DISEASE.
SO HOW DOES MEDIAN ACCELERATE
THE DEPOSITION OF THE
VASCULATURE, AND THE SAME THING
IS THE MEDIN, AND WHEN WE PUT
THEM TOGETHER, WE RADIE AND CO
AGGREGATE INVITRO AND LOOKING AT
THE THESE YOU CAN SEE BY 2
DIFFERENT GOALS FOR THE 2
PEPTIDES THEY ARE LOCALIZED TO
SINGLE [INDISCERNIBLE]
INDICATING CO AGGREGATION.
SO WOO DID A BUNCH OF OTHER
EXPERIMENTS BUT I WON'T SHOW YOU
THEM TODAY, I WOULD RATHER SHOW
YOU EVIDENCE THAT HAS RECENTLY
EMERGESSED THAT ALSO INICATES
VASCULAR DISEASE IN THE BRAIN.
THIS ARE 2 STUDIES WHERE THERE'S
LOSS OF FUNCTION MOWITATIONS AND
THEY ARE HIGHLY PROTECTIVE
AGAINST CARDIOVASCULAR DEC
INCLUDING DIFFERENT FOR THE
PURPOSES OF STROKE, AND 1 OF
THESE MUTATIONS PARTICULARLY
INTERESTING BECAUSE IT INDUCES
THE SPLICE SIGHT AND THAT WOULD
BE PREDICTED TO CUT OFF THE
MEDIAN SEQUENCE, COMPARED TO
WHAT WE'VE SEEN IN THE KNOCK OUT
MODELS AND THAT IS HIGHLY
PROTECT EVALUATION PROCESS
AGAINST CARDIOVASCULAR DEC, AND
ANOTHER STUDY THAT LEADS TO
VASCULAR PATHOLOGY AND THIS
PREPRINT HERE WHEREBY
PROTEOMICS, THE AUTHORS LOOKEDDA
MORE THAN 300 SAMPLES OF PASHTS,
WHAT THEY COULD SHOW WAS THERE
WERE 5 DIFFERENT MOLECULAR
SUBTYPES OF PATIENT ANDS 1 OF
THEM HAS WHAT THEY CALL THE
VASCULAR DAMAGE PROFILE.
AND IN THIS PROFILE ACTUALLY
MEETING DECREASED AND POSSIBLY
REFLECTINGAEGREGATION IN THE
VASCULATURE OF THESE PATES AND
AGAIN THINKING IT TO THE
VASCULAR PATHOLOGY IN AD PATES.
SO BRIEFLY WHAT WE'VE DONE SINCE
AND PLANNING TO DO IS WE CREATED
MODELS THAT HERE OVEREXPRESS
HUMAN MFEG8 AND IN WITHIN 6
MONTHS WE GET MEDIAN DEPOSITION
IN THE PLOT BRAIN OF THESE
ANIMALS.
THIS IS WHAT YOU CAN HOPEFUL
LEAVE APPRECIATE IS THESE AG
AGGREGATES SEEM TO BE DEPOSITING
IN THE BASE OF THE BRAIN.
THE EXCITING DATA IN THE BRAIN
WE CAN SEE THESE BIND WITH THE
CLASSICAL AMYLOID BINDING,
INDICATING THAT NOW, WE'RE
GENERATING A PATHOLOGY BASE TO
THE HUMAN SITUATION.
WITH A FORMAL PARTNER IMENERATED
ANTIBODIES WITH HIGH AFFINITY
AND SPECIFICITY FOR MEDIN.
YOU CAN SEE THIS 1 HERE.
IT DOESN'T RECOGNIZE MFEG8, IT
DOESN'T RECOGNIZE ANY LISAITS OF
SALES, AND WE CHARACTERIZED THEM
FOR NATURE OF HUMAN SAMPLES AND
WHAT THESE ANTIBODY ANDS MOUSE
MODEL WE WANT TO TRY AND TEST
THAT HYPOTHESIS THAT THROUGH
PASSIVE IMMUNIZATION CAN REMOVE
AGGREGATES AND RESTORE FUNCTION
IN THESE ANIMAL ANDS THEN
IEWVENTUALLY ABOUT INTO THE CAA
MODELS AND HAVE IT AGAINST CAA
EMPLOY AND BECAUSE WE'RE TALKING
ABOUT ARIA, I THINK IN TERPS OF
IN TERMS OF MECHANISMS IT WILL
BE INTERESTING AFTER MODELS AND
SEE IF WE CAN GET ANYTHING WITH
ARIA BY REMOVING THIS VASCULAR
AMYLOID IN THESE ANIMALS AND
WITH THAT I WANT TO THANK THE
PEOPLE IN MY LAB, OUR
COLLABORATION PARTNERS AND
FUNDERS AND I'M HAPPY TO TAKE
QUESTIONS.
THANK YOU.
>> THANK YOU VERY MUCH.
WE HAVE TIME MAYBE FOR 1
QUESTION.
YEAH, GO AHEAD.
NGREAT TALK, REALLY ENJOYED IT,
DESCROIBING PEOPLE WITH
HYPERTENSION OR OTHER VASCULAR
RISK FACTORS WOULD HAVE MORE
MEDIN IN THEIR ARTERIOLES, BUT I
NOTICED IN THE CONTROLS YOU
DIDN'T SEE ANY, SO WERE THE
CONTROLS THAT YOU LOOKED AT IN
THE HUMAN BRAIN DID THEY HAVE
VASCULAR RISK FACTORS AND HAVE
YOU LOOKED AT PEOPLE WITH SAY
HYPERTENSION BUT NO DEMENTIA?
NNO, WE HAVEN'T LOOKED AT
SPECIFIC CONTROL GROUPS YET.
WE DO SEE MEDIN IN PRINCIPLE IN
ANALLED IN THE AGENTED HUMAN
BRAIN, WE SEE SOME MEDIAN IN THE
VASCULATURE BUT IT'S MASSIVELY
INCREASED IN PATIENTS WITH CAA,
WE HAVEN'T LOOKED THAT SPECIFIC
SUBGROUPS OF HUMAN CONTROLS YET.
>> THANK YOU.
GREAT IF THERE ARE NO OTHER
QUESTIONS WE SHOULD MOVE TO OUR
NEXT SPEAKER THE MY DPRAIT
PLEASURE TO INTRODUCE OUR NEXT
SPEAKER BERRY ZLOKAVOIRKS C, HE
IS DEPARTMENT AND CHAIR OF
IMMUNOLOGY AND SCIENCE AT USC
EMPLOY HE PILOT PROJECT OR
NEARED STUDIES IN THE BLOOD
BRAIN BARRIER AND
NEURODEGENERATION AND SEVERAL OF
HIS RESEARCH DOORS CLINICAL
DEVELOPMENT FOR STROKE AND
NEUROLOGIC DISEASES.
WE LOOK FORWARD TO HIS TALK.
>> THANK YOU.
CAN YOU HEAR ME?
>> YES NTHANK YOU VERY MUCH FOR
INVITING ME TO THE MEETING IT
WAS VERY EARLY MY TIME AND I
ALSO ENJOY THE CAMERA SHOT OF
AUDWRENS AND PEOPLE WAS SO WELL
DONE.
SOPHISTICATED I WILL PRESENT A
TALK ABOUT HOW WE CAN PROTECT
ENDOTHELIAL BARRIER IN
PERISIGHTS WITH ACTIVE PROTEIN C
MUTANT ACTUALLY IN PHASE 3
STUDIES THAT WE HAVE DEVELOPED
AND ALSO HAVING DISCUSSED THE
EFFECT OF APOE4 GENE.
SO I'M THE FOUNDER OF THE
BIOTECH COMPANY TO DEVELOP NEW
THERAPEUTICS FOR STROKE AND
NEUROLOGICAL DISORDERS.
SO JUST A BIT OF BACKGROUND
ABOUT ACTIVATED PROTEIN C OR
APC.
SNR SORRY TO INTERRUPT, YOU'RE
NOT SHARING YOUR SLIDES.
>> OH REALLY?
I CAN SEE IT OVER HERE.
TO --DO YOU SEE SLIDES?
I CAN STOP SHARING AND DO 1 MORE
TIME HOW ABOUT NOW?
>> IT SAYS YOU ARE SCREEN
SHARING, THAT'S WHAT I GET.
>> I THINK IT'S POSSIBLE THERE
IS A COMMAND THAT SAYS REMOVE
SPOTLIGHT, IT IS SUGGIEST THAD
THIS MIGHT HELP NREMOVE
SPOTLIGHT, AND TRY AGAIN, MAYBE
>> OKAY, STOP SHARING.
HOW ABOUT NOW?
>> OKAY EMPLOY NI THINK I ALSO
HAVE SEND THIS TALK, I THINK THE
PEOPLE THERE MAY HAVE THE TALK
AS WELL.
OOSE A LITTLE BIT DIFFERENT I
DON'T KNOW WHAT ELSE I CAN DO
HERE.
CAN YOU TRY AGAIN, I THINK IT
JUST GAVE YOU CO-HOST PRIVILEGES
SO MAYBE IF YOU TRY AGAIN?
>> I AM TRYING SHARING AGAIN.
>> YES NYOU WERE JUST ASSIGNED
AS A CO-HOST SO--NYES THIS CAN
SEE NOW YOUR PRESENTATION THAT'S
WHAT IT SAYS HERE.
>> I THINK I.T. IS TRYING TO
FIGURE IT OUT.
>> OKAY.
>> YES, WE CAN SEE EMPLOY.
>> YES, LET ME GO REALLY QUICK
LYE THEN LITTLE BIT ABOUT I TO
TO SEE, CAN I MOVE THEM.
OKAY, I WANT TO MAKE A
DISCLOSURE THAT I AM FOUNDER OF
ZILKHA BIOTECH IT'S DEVELOPING
THERAPEUTICS FOR STROKE AND
NEUROLONLICAL DISORDERS AND
OKAY, SO I WANT TO TELL YOU ALET
BIT ABOUT ACTIVATED PROTEIN C
AND BIOLOGY ACTIVATED PROTEIN C.
SO WE CALL IT APC.
THIS IS AN ENDOGENOUS PLASMA
PROTEIN ACE THAT HAS CANNED WHAT
AND CELL PROTECTING ACTIVITIES.
THE ANTICOAGULATION IS IN FACTOR
5 AND 8 A AND THEP CLEAVAGE OF
APC AND CELL PROTECTION IS MOO
EDIATED BOO I PROTEIN ACTIVE
RECEPTOR 1 PART 1 WHICH ALTERS
YEEN EXPRESSION PROFILE O WE
GENERATE A MUTANT IN WHICH THE
APC 3 LIES IN K99 TO 123 AND
THIS SELECTIVELY ELIMINATES THE
ACTIVITY BY MORE THAN 90%
REDUCTION, BUT FULLY PRESERVES
CELL SIGNALING AND HAS BEEN IN
STROKE STUDIES COMPLETED PHASE 1
STUDY, PHASE 2 STROKE STUDY
COMPLETED AND SPONSORED BY
NINDS, AND BIOTECH AND THE
PATIENTS AND RIGHT NOW, IT IS IN
FACE 2 STROKE STUDY WHICH WE
EXPECT WILL START RECRUITING IN
Q1, 2024.
THIS IS IN THOUSAND 400 STROKE
PATIENTS, IT'S EFFICACY TRIAL
AND ALSO LOOKING AT THE
HEMORRHAGE SUPPORTED BY NINDS
STROKE NET AND BIOTECH AND WE
ALSO FINISH PHASE 2 TO THE
STUDY, NOW WHAT THIS PROVIDES,
IT'S A MULTIMECHANISM FOR
CEREBRAL VASCULAR AND BRAIN
PROTECTION, SO THIS IS QUITE A
PROTECTIVE AGENT THAT REDUCES
THE RISK ASSOCIATED WITH THE
TISSUE POST ACTIVATOR AND
THROMECTOMYOSINRY AND DRUG
PATIENTS, DECREASES INFLAMMATION
AND INHIBIT APOPTOSIS AND
IMPROVES NEURONS ON IMPROVING
OUTCOME.
REGARING VASCULAR DAMAGE, IT
PROVIDES EBD O THELLIAL
PROTECTION AND BLOOD BRAIN
BARRIER REPAIR AND REDUCE RISK
OF TPN FOR [INDISCERNIBLE].
ALSO DIRECT NEURONAL PROTECTIVE
EFFECT AND PROTECTIVE EFFECT OF
THE CELLS AND ANTIINFLAMMATORY
DECREASES AT THE INPOLICEMAN
TOORY RESPONSE AND MICRODPLIA
ACTIVATION.
NOW I JUST WOULD LIKE TO MENTION
A COUPLE THINGS THAT WOULD BE
REEL KEEPSAKES VABT FOR THE PART
OF THIS STUDY IN ARIA WELL IT
HAS BEEN SHOWN THAT IT REDUCES
BY ABOUT 65% VOLUME OF BRAIN
HEMORRHAGE AS SHOWN OVER HERE
BUT MORE INTERESTINGLY IN PHASE
2 STUDIES AND STROKE PATIENTS
ACTUALLY THE RESULTS THAT CARRY
THE STUDY HAVE SHOWN THERE IS
REDUCTION IN HEMORRHAGE VOLUME
BY 62% AND REDUCTION IN
INCIDENCE IN HEMORRHAGES BY 25%.
SO, SO THAT IS VERY INTERESTING,
WE TART THINKING HOW IT WOULD BE
INTERESTING TO DEVELOP SAFETY
TRIAL IN A. D. PATIENTS THAT ARE
TREATED WITH AND OTHER ANTIBETTA
THERAPIES AND WE THINK THIS
MIGHT BENEFIT THOSE PATIENTS WHO
ARE E4 CARES BUT THOT NOT
EXCLUDE E4 NONCARES FOR THE
MUTATION THAT THE APO YEEN IS
NOT ALWAYS SO CRITICAL BUT THEN,
THE IDEA WOULD BE TO PROTECT
THESE PATIENTS FROM BBB BREAK
DOWN, VASCULAR LEAKAGES, EDEMA
AND MICROHEMORRHAGES, BOTH ARIA
E AND ARIA H, AND ANTI-ABETTA
TREATMENT GOVERNEM THANKSGIVING
3 K3 A-APC, INFUSION BEFORE AND
EAEVER ANTIBODY TREME.
SO I WILL LIKE TO TELL YOU, WE
WERE TALKING ABOUT APOY 4 AND
BBB BRAIN DOWN AND JOHN SHOWED
IN HIS MORNING PRESENTATION, THE
DYNAMIC METHOD THAT WE PUBLISHED
IN NEURON WITH MY POST DOC AT
THE TIME WHO IS NOW AN
INDEPENDENT INVESTIGATOR,
STUDYING BBB BREAK DOWN, AND WE
SAW THAT IN CDRSTAGE 0, THERE IS
ENCROSED BLOOD BRAIN BARRIER
BREAK DOWN THAT YOU CAN SEE ON
THE COLOR AND MORE BREAK DOWN
ASK THIS ACTUALLY CONTINUES AND
IS MORE ACCELERATED DURING CDR.5
COGNITIVE IMPAIRMENT TAIJ EMPLOY
IT'S NOT AFFECTED WITH BETA CSF
LEVELS AS CAN YOU SEE HERE AND
THESE SLIDES HERE SO IT'S AN
INDEPENDENT PATHWAY AND WE
CONFIRMED THIS BY STIMMULING PET
AND APOE YEEN IN THE SUBSET OF
THE 96 TAU PARTICIPANTS AND WE
SHOWED ALSO THERE IS AN
INCREASED BLOOD BARRIER BRAIN
BREAK DOWN IN THE HYPOCATCHUS
ALSO IN MEDIAL TEMPORAL LOBE,
MORE RECENT DATA ALSO SHOWED
THAT THAT THERE ARE PATHWAYS
SUCH A SINGLE THAT THEY'RE ALSO
AFFECTING THE BBB BREAK DOWN.
BUT THE AMYLOID AS SHOWN OVER
HERE, OR THE AMYLOID INCREASE
THE FRONTAL CORTEX IN THE
CARRIER BUT THERE IS NO CHANGE
IN THE BBB VALUES, SO THAT
SUGGESTS TO US THAT THESE ARE
POSSIBLY 2 INDEPENDENT PATHWAYS
THAT MAY INTERACT TOGETHER AND
LEADS TO COGNITIVE IMPAIRMENT
EMPLOY NOW WE HEARD TODAY FROM
DONNA'S TALK A LOT ABOUT MPPs
AND MMP9S, WE DID PUBLISH IN
HUMAN FOR MICE, LONG TIME AGO,
APPROXIMATE MY FORMER STUDENT
GRADUATE STUDENT [INDISCERNIBLE]
THERE IS ACTIVATION OF THE MMP 9
PATH
PATHWAY AND I THINK THIS IS
CALLING FOR OUR PAPER IN 2020.
AND THIS INCLUDES ACTIVATION OF
PSYCHOTHELIN A WHICH IS A
PROINFLAMMATORY MOLECULE THAT
CONTROLS MP9 AND LEADS TO
DEGRADATION
GRATES--GRATUEICATION OF THESE
JURCHGZS BETWEEN THE ENDOTHELIAL
CELLS SO THAT HAPPENS IN MOUSE
MODEL BUT IN HUMANS WE ALSO
PUBLISH YEARS LATER THAT
ACTUALLY THERE IS INCREASE IN
PSYCHOTHELLIAL CELLSIN A AND MMP
9 IN THE CSF.
THAT IS ACTUALLY DRIVEN FOR THE
APOE4 COMPARED TO GENE APOE 3,
SO THERE IS NOT MUCH CHAIMPLED
IN ARK POE3.
SO THERE IS A SPECIFIC EFFECT.
SO, PERISIGHTS KEEP THE BLOOD
GRAIN INTEGRITY AND I THINK THIS
IS 1 OF THEIR FUNCTION, AND WE
HAVE DEVELOPED NEW BIOMARKER
WHICH IS CALLED TGFBETTA AS A
MARKER OF THE [INDISCERNIBLE]
AND NATURALLY AT THE REVISED
FORMULA SHOULD BE ENCLUEDED AS
IS VGF MARKER AND IS THIS
RELATED TO APOE GENETIC
INCREASED RISK.
SO THIS IS A TODAY DONE IN 350
PARTICIPANTS WITH THE MEDIAN
SPLIT ABOUT 600 NANO GRAMS PER
MILL, THESE ARE HIGH VALUES
APPROXIMATES AND BELOW THAT
THREEZ ARE ALL THE VALUES AND
SO, THE FIRST STUDY THAT WE DONE
IN THE CSF, AND REPORTED WHO
WILL LEAD THE WAS THAT THESE
PEOPLE WHO HAVE HIGH LEVELS IN
PLURIBU DEVELOP REALLY PROFOUND
MENTAL START WITH THE DURATION
WITH A FOLLOW UP FORWARD OF 4.5
YEAR ANDS THIS WAS ALSO HONE ON
THE COGNITIVE DOMAIN WITH 10
DIFFERENT TESTS EMPLOY BUT THAT
MENTAL STATUS IS NOT SO MUCH IN
THE CARRIERS SO IT AGAIN SHOWS
THE SPECIFIC EFFECT.
BUT MORE RECENT STUDIES THAT GET
US EXCITE BECAUSE THIS WAS IN
PLASMA THAT DR. [INDISCERNIBLE]
IN OUR GROUP DID, HE REPEATED
THE SAME THING AND FOWBD THAT
THIS BETA MARKER HAS BEEN
CREASED ALSO THAT ARE APOE4
CARRIERS AND WE PERFOR THE
PURPOSE DIFFERENT ARK NALGYS AND
THE REGRESSION ARK NALGYS THAT
SHOW WHEN YOU CORRECT FOR AGE,
SEX, FACTORS THAT THIS TILL
HOLDS, THIS RELATIONSHIP HOLDS.
BUT MOST IMPORTANT FOR
LONGITUDINAL ANALYSIS KREKED FOR
SEX, AGE, EDUCATION AND VASC LAT
FACTORS AND P-TAU.
THE PEOPLE WHO HAVE LOWEST
TERTILE, OVER 4 YEARS DEVELOPED
COGNITIVE DECLINE SO THAT THIS
HIGH LEVEL IS PREDICTIVE
COGNITIVE DECLINE WHICH WAS NOT
THE CASE WITH PEOPLE LONGER THAN
THE NANO GRAMS PER ML.
NOW WHY WE STAND WITH APC, AND
WE TRY IT AS A MOLECULE TO
TARGET AGAIN ARIA.
WELL, MY FORMER GRADUATE STUDENT
SHE PUBLISHED THAT APC PROVIDES
DIRECT VASCULAR PROTECTION,
NEURONAL PROTECTION AND
ANTIINFLAMMATORY ACTIVITY IN 5
FAD MOUSE MODEL BUT WE ALSO
FOUND IT PARTIALLY PLOKS BASE 1
PATHWAY AND REDUCES A BETA LLOYD
AND FAD MICE AND THIS EFFECT WE
SHOWED IS MEDIATED BY ACTIVATION
OF 500 RECEPTOR AND TO NF-KAPPAB
PATHWAY WHICH CONTROLS MRNA FOR
BASE 1 AND THIS ACTUALLY AFFECTS
AMYLOID BETA PRODUCTION LEADING
IN THIS CASE TO INHIBITION OF
AMYLOID BETA PRODUCTION WHICH
TOGETHER WITH OTHER EFFECTS
PROVIDES VERY BENEFICIAL
POWERFUL TOOL.
SO NOW THESE ARE UNPUBLISHED
DATA FROM MY LAB, THAT ACTUALLY
THEY DID, AND THIS IS EFFECT OF
APC AND APOE 4 MICE.
SO THERE IS A BBB PROTECTION AS
YOU KNOW US AND MANY PEOPLE
PUBLISH THIS FOR MICE, WE CALL
IT E4 F HERE, AS BBB BREAK DOWN
AS SHOWN IN FIBRINOGEN AS SHOWN
BY MICE AND THIS HAS IMPROVED
EAEVER TREATMENT OF APC AND IN
THIS CASE, .1-MILLIGRAM, DAILY
INYEKS FOR 10 KAYS.
ALSO THE COVERAGE, THERE IS
DEFINITELY PROTECTION OF
PERISIGHTS BY THIS TREATMENT AND
THE PERICYTES, THAT MAINTAIN THE
BBB WILL IMPROVE AND PRESERVE
DURING THIS TREATMENT WITH APC
EMPLOY LOOKING INTO THIS AND THE
PATHWAY, THESE ARE REEMILYINARY
DATA SO EYE --I WANT TO SHARE
DATA WITH THE GROUP, WE WERE
ABLE TO SHOW THAT APC TREATMENT
REDUCES PROINNAMES--NAMESSATORY,
AND ACTIVITY IN PERICYTES, AND
LOGICAL EXPECTED BECAUSE IT'S
ANTIINFLAMMATORY AGENT AND THIS
ALSO CONTROLS THE AMERICA
PUNISHING P9 PATHWAY WHICH IS E
CUESED AND MAY EXPLAIN PARTIALLY
THE BBASHING B EFFECT.
BUT THEN, I THINK MORE THAN
THAT, WE ACTUALLY SHOWED BY
TRANSCRIPTOMIC ANALYSIS THAT APC
TREATMENT WAS ABLE TO DEACTIVATE
167 UPREGGULED DIFFERENTIALLY
EXPRESS YEENS, AND THE
ENDOTHELIUM OUT OF 175 THAT ARE
ALL UPREGULATED IN E4 F MICE
COMPARE TO THE MICE.
SO ALL THESE JEEPS WERE
NORMALIZED.
THEY'RE ALL NORMALIZED AND SO
WHAT WAS ALSO INTERESTING, THEN
WE EXTENDED THIS STUDY TO THE
MUTATION OF THE BRAIN
MICRORESSLE BY MASS
SPECTROMETRY, AND WITH THE LAB,
AND AS YOU CAN SEE, THE
QUANTIFIED ABOUT 5451 PROTEINS
IN MICROVESSELS.
AND ABOUT 18--1008 HELPED 25
POSSIBLE GUIDES.
AND SO, WHAT WAS INTERESTING IN
THIS STUDY, WAS THAT WE WERE
ABLE TO SHOW THAT APC NORMALIZED
ABOUT 45% OF PROTEIN LEVELS AND
ABOUT 75% OF PROTEIN
PHOSPHORYLATIONS WHICH IS VERY
IMPORTANT FOR PROTEIN FUNCTION.
SO THE FUNCTIONAL CATEGORY
COLLECTED IN APC IN TOTAL
PROTEIN IN THIS 9-12 MONTH OLD
MICE, METABOLIC DNA BINDING
PROTEIN, METHYLTRANSFERASES AND
ALSO, ADAPTIVE SKELETAL PROTEINS
AND THE FUNCTIONAL CATEGORIES
THAT ACTUALLY REMAIN HERE THAT
ARE CORRECTED WITH THE APC ALSO
INCLUDE TY YURCHGZ, DATA
PROTECTIONIVE PROTEINS, CELL
HEED HESION, CYTOSKELETON ASK
GPC SIGNALING RNA BINDING BUT
THEN PIE USING RNA SEQ GUIDED
CELLS WITH THE ANALYSIS, TO
ACTUALLY SEPARATE CHANGES IN THE
ENDOTHELIAL CELLS, AND ASTRO
SIGHTS, WE ARE ABLE TO SHOW THAT
OUT OF THE TOTAL 61 PROTEINS,
REVERT BIDE APC WITH 27 PROTEINS
AND 7 OF THOSE IN THE
ENDOTHELIAL CELLS, 18 PERISIGHTS
AND 16 ASTRO SIGHTS.
AND WE ALSO IDENTIFIED CHANGES
IN 249 PROTEINS IN 262 RELATION
SITES IN THIS E4 ALL, THERE'S
ALL MICROVESSEL ANDS 72.5% OF
THE SITES AS I MENTIONED WERE
REVERTD BY APC.
AND 54 ASTRO SIGHTS, 86 PC, AND
REST IF EBD O THELLIAL CELLS.
SO WE ACTUALLY ARE THINKING TO
TEST FOR ARIA.
AND 1 THING THAT WE ARE WORKING
ON FOR THE CDR5 STAGE, AND THIS
IS A-BETA 42 RATIO DECREASED IN
THESE CARRIERS AND THAT'S THE
GUY ALSO HOED HERE THAT THERE IS
AN INN CREASE LEVEL OF SBD WHICH
SHOWS YOU KNOW A VASCULAR DAMAGE
IN APOE 4 CARRIER TO CDR.5
TEANL.
SO STEP 1 OF THIS PROPOSAL WAS
TO ASK THE QUESTION DID THE
TREATMENT ALTER AB BLOOD
BIOMARKERS SUCH AS ABETTA
DURATION AND P-TAU 217 IN STROKE
PATIENTS FROM PHASE 2 TRIAL
COMPLETE INDEED 2018.
O WE ARE OBTAINING SAMPLES FROM
110 PATIENTS AND THIS IS FOR
DEVELOPMENT OF A STUDY IN
ANTIGEN STUDY AND SBO IPT
GREATER VIVO AND WE WILL LOOK AT
THOSE LEVEL ANDS THERE AN EFFECT
OF THE APOEYEEN, WE MAY HAVE
ENOUGH PARTICIPANT FOR ALL OF
THAT BUT WE WILL TRY.
ONE OF THE NOTES I WANT TO SAY
TAKEN--THEY THE APC WAS SHOWN TO
BE SAFE IN PHASE 2 TRIAL IN AN
ESTIMATED RATE AROUND 7% AND 540
MICROGRAM PERKEG, MAX MULL
TOLERATED DOSE AS THE DOCTOR
REPORTED IN NEUROLOGY WHICH IS 2
TYPES HYPER THAN THOSE OF THE
APC IN PHASE THRESHOLD MODEL
STROKE TRIAL.
SO ONCE WE FIND THERE ARE NO
CHANGES IN THE ADDPAYS
BIOMARKERS WE WILL GO TO STEP 2
AND PROCEED WITH SAFETY TRIAL
AND PERHAPS FOR THE CARRIERS,
SELECTED BY OUR APOE GENE KREEN
AND WE WILL INFUSE THEM AND TO
DETERMINE WHETHER THEY COULD
ALTER AD BIOMARKERS IN THIS, SO
THIS IS BASKLY JUST A SAFETY
TRIAL THAT WE HAVE DISCUSSED
WITH PAUL AND SOME OTHER FOLKS
AT USC.
AND FINALLY, WE WOULD LIKE TO
DETERMINE THE TREATMENT BEFORE
AND AFTER HERE ANTIBODY
TREATMENT REDUCES THE ENDENSE OF
ARIA E AND ARIA H THAT WE HEARD
A LOT ABOUT TODAY.
SO THE KEY POINTS, YOU KNOW TO
TAKE HOME MESSAGE FROM THIS
PRESENTATION IS THAT THIS
MOLECULE PER THE APC PROVIDES
VASCULAR AND NEURONAL PROTECTION
BECAUSE THE ANTIIPT GREATER
FLAMMATORY PROPERTY ANDS
ANTIBETTA PROPERTIES.
THE NORMALIZES TRANSCRIPTOMIC
AND PROTEOMIC AND PROI DON'T
MEANIC CHANGES IN BRAIN VESSELS,
MICROVESSELS FOR MICE, AND APC
BASED THERAPEUTICS MAY HELP
PRESERVE BLOOD BRAIN BARRIER AND
NEURONAL FUNCTION AND VERMEN
INFECTED RERS THE EFFECTS OF THE
YEEP AND VASCULATURE.
SO, THIS MOLECULE IS IN PLACE,
FOR THE TRIAL FOR ESCHEMIC
STROKE AND RECRUITMENT EXPECTED
IN Q12,024.
AND SMALL PHASE LS TRIAL
COMPLETED DECEMBER 2022.
SO WHAT IS POTENTIAL FOR AD THAT
WE THINK I COULD BE EXPLORED.
WHETHER IT PROTECT AGAINST ARIA,
WE EXPECT TO SEE TABLIZING
EFFECT IN ANTIHEMORRHAGIC CENTER
FOR EXCELLENCE ON AGING BASED ON
STROKE DATA, STROKE STUDY, PHASE
2 STUDY AND ALSO ANTIFLAMAR TOW
ACTIVITIES THAT WERE SHOWN BY
NUMEROUS, AND ALSO THE DIRECT
PROTECTIVE EFFECT AGAINST THE
VASCULAR NEURONAL TOXICITY AND
ALSO DIRECTING ON THE NEURONAL
PROTECTION.
SO THAT'S ALL I WANTED TO SHARE,
THANK YOU SO MUCH FOR YOUR
ATTENTION.
>> ONE QUESTION, IT'S HELENA, SO
NICE TO HEAR YOUR TALK IT'S
BRILLIANT AND I WANTED TO ASK,
NOW, THE DROP WOULD BE ACTING
ALL OVER TO PROTECT THE BBB,
CORRECT?
AND THE ARIA PATIENTS HAVE
SPOTLIGHT CHANGES IN AT LEAST IN
EDEMA WE AT LEAST TALK ABOUT
IMPARTMENT ABILITY, DO YOU THINK
THIS GLOBAL EFFECT OF A
TREATMENT LIKE THIS, WILL BE
NEEDED OR WHAT'S YOUR CONCERN
ABOUT GLOBAL VERSUS THE FOCAL
EFFECTS YOU SEE IN THE PATIENT?
>> THANK YOU HELENA THIS IS A
GREAT QUESTION, I SHOULD
PROBABLY ADDRESS WITH WITH MY
FOAOF THE DOC FELLOW WE ARE
PUBLISHED PAPER IN JOURNAL
MEDICINE IN 2022 SHOWING THAT 3
K3 PC PROTECTS AGAINST WHITE
MATTER STROKES.
O PROECTOMYOSIN ITS AGAINST
STROKES IN THE MIGHT MATTER AND
I THINK THIS IS HIGHLY RELEVANT
BECAUSE THIS ARIA AS I
UNDERSTAND MRI CHANGES HAPPENING
VERY MUCH ALONG THE WHITE MATTER
AS WELL.
SO I BELIEVE THAT WILL BE ALSO 1
PROTECTION AND IN TERMS OF
LOCALIZATION, AS I MENTIONED OUR
MOST RECENT STUDIES AND WE HAVE
PAPER WE'RE CO-WORKERSING RIGHT
NOW ASK WORKING TO COMPLETE,
THAT I PRESENT IF YOU REMEMBER
IN THE DUKE MEETING A COUPLE
WEEKS AGO, IS ACTUALLY SHOWING
THAT THERE ARE MORE ARIAS NOW
ESPECIALLY WHITE MATTER ATTRACTS
FOR THE REGION OF THE HYPOCAMPUS
AND THE CAMPO GYRUS SUCH AS
[INDISCERNIBLE] AND
[INDISCERNIBLE] CORTEX SUCH AS
SINGLE THAT THEY'RE AFFECTED BY
BBB BREAK DOWN CHANGES.
AND ALSO THE CHANGES IN REGIONS
THAT ARE RESPONSIBLE FOR
ATTENTION AND EXECUTIVE
FUNCTIONS.
THEY'RE ALSO AFGHTED NOW BY THIS
BLOOD BRAIN BARRIER BREAK DOWN
SO ESPECIALLY IN OUR APOE
CARRIER BAH ALSO NOT .3 TO A
LESSER EXTENT SO I BELIEVE THIS
ACTUALLY IS A MULTIPLE AGENT
THAT CAN ACT ON A MULTIPLE
TARGETS AND THAT'S WHAT I
BELIEVE IS VERY, ATTRACTIVE IN
THIS APPROACH.
>> THANK YOU.
WE HAVE 1 QUESTION ONLINE THAT'S
A FOLLOW UP FOR DR. WALKER MAYBE
WE CAN ADDRESS THAT AND MOVE ON
TO THE PANEL.
THE QUESTION IS IN MONKEY CAA
CAPILLARIES THERE LOSS OF
PARASITES?
>> YES, THERE WAS A QUESTION I
DID ASK, YEAH.
>> WE DON'T KNOW.
I'VE SEEN MANY A PARASITE ARK
ROUND A VESSEL THAT HAS CAA IN
IT BUT WE HAVEN'T QUANTIFIED
PARASITES SPECIFICALLY SO I
DON'T KNOW.
>> CAN I ASK A QUESTION,
REMEMBER WITH YOUR SCHOOL OF
MONKEYS WE STUDY AMYLOID
CLEARANCE RIGHT AND WE PUBLISHED
THAT AND THEN AFTER THAT WAS IN
HUMANS, DO YOU THINK THAT THE
AGE MATTERS?
YOU KNOW IN TERMS OF CLEARANCE
IN SQUIRREL MONKEY?
>> AGE, BECAUSE WE FOUND
DIFFERENCE IN OLD SQUIRREL AND
YOUNG SQUIRREL?
>> IS IT MATTER, I IMAGINE IT
MAKESSA I BIG DIFFERENCE BUT I
DON'T KNOW THAT FROM MY OWN
EXPERIENCE.
LET'S BRING UP OUR PANELISTS,
FRANCESCA AND YAWN AND LAWRENCE.
>> ALL RIGHT, THANKS.
IT'S A PLEASURE TO WELCOME THE
PANELISTS FOR THE LAST PANEL
DISCUSSION OF THE DAY.
SO WE HAVE THE DR. MARION
BUCKWALTER FROM TAN FORD,
DR. LAWRENCE HONIG FROM
COLUMBIA--SORRY.
AND DR. JOHN SIMS FROM
ELY LILLY.
THANK YOU SO WITH THAT I WOULD
LIKE TO GET THE PANELISTS TO
COMMENT ON THE PREVIOUS SESSION
ABOUT THESE NEW RESEARCH IDEAS
FOR IN THE PRECLINICAL SPACE AND
ALSO I WOULD LIKE TO ASK THEM
WHAT DO THEY SEE AS GAPS AND
OPPORTUNITIES THAT YOU COULD
FURRINGER EXPLORE IN FUTURE
RESEARCH.
SO MAYBE--I DON'T WANT TO PUT
ANYONE ON THE SPOT, SO, I WILL
ASK FOR A VOLUNTEER TO START.
SMRKS SO THANK YOU.
THANKS FOR THE INVITATION, THIS
IS A VERY IMPORTANT MEETING AND
I THINK THE GOAL HERE IS TO
TIMMULATE SCIENTIFIC IDEA ANDS
COME UP WITH SOLUTIONS AND I'M
NOT EXACTLY SURE WHERE TO START
BECAUSE THERE ARE SO MANY LITTLE
AREAS TO TALK ABOUT BUT I WILL
START WITH THE FACT THAT WE
AGREE THERE MEDES A LOT OF
RESEARCH IN THIS SPACE AND WE
TARTED A TRIAL CALLED TB6 OF
SOLELY UNDERSTANDING SOME OF THE
SCIENCE BEHIND
ARE--ADMINISTRATIVE RAW DATA AND
SEEING IF WE COULD UNDERSTAND
THAT PATHOPIZZA TAVERNIOLOGY A
LITTLE BIT BETTER THAN WHAT
WE'VE DON IN THE CURRENT TRIALS.
AND SO, I MIGHT WALK THROUGH A
FEW OF THOSE THINGS BECAUSE I'VE
HEARD A COUPLE OF ASSPECS HERE
TODAY OF THINGS THAT HAVE BEEN
KIND OF DISCUSSED AND I WILL
START WITH--I WILL START WITH
THE MOST IMMEDIATE THING WE
MIGHT BE ABLE TO DO FOR PATIENTS
AND THAT'S TO UNDERSTAND THE
DOSING PARADIGM TO SEE IF THE
DOSING PARADIGM MATTERS AT ALL
OR NOT.
AND SO, WE'VE HEARD A BIT ABOUT
CMAX VERSUS AUC, DOES THAT
MATTER OR IS IT THAT NOT MATTER.
I THINK SCIENTIFICALLY, IT'S A
GOOD QUESTION AND MAYBE
SOMETHING VERY TRACTABLE TO DO
FOR PATIENTS IF IT MATTERS.
I THINK GENERALLY SPEAKING I'M
MOT SO SURE THIS IS WELL PROVEN
YET FOR OTHER MOLECULES AND SO
THAT WILL BE 1 ASPECT THAT WE
WILL BE TESTING IN THE THAT
TRIAL VERY SYSTEMATICALLY WHERE
WE CONTROL AUC AND CHANGE C-MAX,
SO THAT IS SOMETHING THAT CAN BE
HELPFUL AT LEAST FOR ADUNAMAB,
AND I THINK REISA SPOKE ABOUT
[INDISCERNIBLE] BUT DID IT HAVE
A LOW OF AN ARIA RATE AS WE
SHOULD EXPECT FROM THERE.
SO I THINK THAT'S ANOTHER
SUGGESTION THAT WE NEED TO KIND
OF EXPLORE THIS MORE AND SEE IF
IT MATTERS.
THE OTHER AREA WE HEARD ABOUT IS
IMAGES AND HOW CAN WE DO IMAGING
BETTER AND WHAT ARE THE--WHERE
CAN WE BE MORE SUCCESSFUL THERE
SO TRADITIONALLY WE DONE MOST OF
TRIALS WITH A FULL STANDARD SET
OF IMAGING CRITERIA AND BECAUSE
OF THE WORK THAT WAS DONE SO
WELL WITH THE ARIA
INVESTIGATORS, THE PANEL THAT
FORMED INITIAL GUIDELINES, IF
WE'RE DONE ON 1.5 T TESLA
MACHINES AND SO GENERALLY NOW
WHEN WE DO THESE TRIALS WE
KIND'VE DUMB DOWN OUR LEVEL OF
UNDERSTANDING OF ARIA TO THAT
OLD CRITERIA OF THE 1 PASSPORT 5
TESLA SO 1 OF THE THINGS WE'VE
BEEN DOING IN THIS NEW TRIAL AND
REQUIRING EVERYONE TO GET A 3
TESLA, WE ARE TILL USING THE
DUMBED DOWN CRITERIA TO ENROLL
SO WE KEEP SOMETHING CALM IN
THERE BUT THEN WE ARE USING NEW
SEQUENCES AND USING A HIGHER
TESLA WHERE I HEARD SOMEONE TALK
ABOUT SENSITIVE IMAGING ACCIDENT
WE'VE DONE FOR A WHILE THAT IS
WAY FORESENSITIVE, WILL THAT
GIVE US ANYMORE, WE WILL ASK
THAT QUESTION WHEN WE'RE IN DTI,
DWI, THRIE DIMENSIONAL IMAGING
AS WELL AS TACK LOOKING AT
FUNCTIONAL MRI.
SO CAN WE SEE CAA IN
PARTICIPANTS SO THIS IS A REALLY
HARD CHALLENGE AND SO WE'RE
USING FUNCTIONAL MRI LOOKING
WITH VISUAL STIMULATION, ONLY
WILL THAT SEE THE CAA THAT MIGHT
BE RELATED TO THE OCCIPITAL
CORTEX, BUT WE KNOW THAT ARIA
HAS A TENDENCY TO BE MORE
POSTERIOR ANYHOW AND WE KNOW
THAT CAA TENDS TO BE VERY
POSTERIOR PREDOMINANT ALSO.
SO I THINK WE HOLD OPTIMISM WE
MIGHT BE ABLE TO LEVERAGE SOME
OF THAT AND THEN I'VE ALSO HEARD
ABOUT BLOOD BASED BIOMARKERS AND
SO, AS WE'VE GONE OUT AND TRIED
TO FIND FROM ALL THE EXPERTS AND
SOME OF THEM ARE SITTING IN THIS
ROOM, SOME OF THE KEY EXPERTS,
WE'RE REAL APOSSITY OF BLOOD
BASED BIOMARKERS FOR THIS SPACE.
SO 1 THING WE WILL BE DOING IS A
VERY LARGE FISHING EXPEDITION
AND HIGH SAMPLING RATES OF BLOOD
BOTH BEFORE DOSING AND AFTER
DOSING BECAUSE MAYBE THE SIGNAL
COMES AS A RESPONSE OHM RATHER
THAN A PREDICTIVE ELEMENT SO I
THINK THOSE WILL BE KEY ASSPECS.
SO MOST OF ALL OF THAT AND I
WILL STOPAUK TALKING ABOUT
UNITED STATES I CAN KEEP GOING.
NSURE.
>> SO THANKS JOHN AND NINDS,
PUTTING IN THE ROOM STROKE CAN
ALZHEIMERS EXPERTISE.
I THINK EACH THOUGH IN PEOPLE
VIEW ME AS STIEPS MORE THAN
WILLING TO DISCUSS SOMETHING, I
ALSO LIKE THE COMMONALITY, AND I
DIDN'T--YOU KNOW THE COMMON
THINK THIS WE WILL ALL ADPREE,
WE WOULD ALL AGREE THAT WE WE
CALL ARIA E AND H AND THOSE
NAMES SEEM TO BE GOOD ENOUGH
EXISTS BOTH SPONTANEOUSLY ANDIST
ANDS IN THE PRESENCE OF DRUG.
AND THAT AT LEAST FOR ARIA E IT
CLEARLY IS MARKEDLY INCREASED IN
THE PRESENCE OF DRUG AS YOU
HEARD IN THE MORNING
FORRITEOLATED ARIA H HA IS WHAT
I LIKE TO CALL MICROHEMES AND
MOST PEOPLE LIKE TO CALL
MICROPLEAD ANDS THAT SAYS
SOMETHING RIGHT THERE, FOR THAT
IT'S NOT SO CLEAR THAT THE DRUGS
AND YOU HEARD THAT THIS MORNING
THAT BOTH FOR THE BIERK OGEN
COLLEAGUES, I THINK IT'S NOT SO
CLEAR THAT ISOLATED ARIA H, THAT
IS THAT THESE MICROHEMES THAT WE
SEE RELATE SO HEAVILY TO DRUG
TREATMENT.
HOWEVER, CLEARLY, THIS WAS
MENINGED THIS MORNING IS THAT
EDEMA BEGETS THE BLEEDS.
SO THERE'S NO QUESTION THAT THIS
INCREASE IN MICROHEMES IN THE
SETTING
SETTING OF EDEMA.
SO THOSE ARE THINGS WE WOULD
AIMREE ON BUT I HOPE AND I THINK
THIS CAME OUT SO USEFUL
PARTICULAR LOW THOSE TANTALIZING
RESULTS WITH THESE RADIATION
EXPOSURE RAT SIZE MONKEYS AND
SUCH, I WAS GLAD THEY WERE
SIMILAR TO RATS.
YOU HEARD FROM A NUMBER OF
PEOPLE THAT SORT OF SKIRTED
AROUND THIS, THERE'S NO
QUESTION, THERE'S EDEMA THAT'S
WHY IT'S CALLED THAT EFFUSIONS
AIDE, THAT THERE'S SWELLING OF
THE BRAIN, THAT'S RADIO
GRAPHICALLY EVIDENT, AND NOT
INFREQUENTLY SYMPTOMATIC TO THE
PATIENT ANDS PHYSICIANS ALIKE,
PUBLISHED IT'S NOT CLEAR HOW
MUCH IS INFLAMMATION AND HOW
MUCH IS JUST WHAT ARE CHANGES
AND WE HEARD EARLIER ON THE
ACQUAPORIN AND SUCH IS QUITE
FASCINATING I HAVE TO POINT OUT
THORS AN AUDIENCE THAT HAS A
MIXTURE OF CLINICIANS AND
NONCLINICIANS THAT STEROIDS DO
NOT DECIDE THAT QUESTION.
STEROIDS AFFECT BOTH EDEMA AND
INFLAMMATION, AND ARE REALLY
RATHER AMAZING DRUGS BUT THEY
DON'T WILL TUS WHETHER SOMETHING
IS EDEMA OR INFLAMMATION, AND OF
COURSE THEN 1 COULD HAVE EDEMA
WITH INFLAMMATION AND 1 COULD
HAVE INFLAMMATION WITH EDEMA BUT
1 COULD HAVE PURE EDEMA.
I HAD THIS CONVERSATION WITH 1
OF EYE COLLEAGUES AND YOU HEARD
3 WORS HERE MICROHEMES,
MICROPLEA ANDS MICROHEMORRHAGES,
THE FACTA WE'RE NOT SURE IN
HUMANS WHICH WE DEFINE AS THE
TINY AREAS OF DECREASED ON SWI
OR A VARIETY OF SPECIALIZED MRI
IMAGES BUT WE DETECT THESE
LITTLE SMALL AREAS OF
HYPOINTENSITY, WE'RE NOT CERTAIN
WOULD THEY REALLY REPRESENT A
PLEAD AT ANY POINT PER SE, TO ME
AS A NEUROLOGIST AND
NEUROSCIENTIST A BLOOD
REPRESENTS BLOOD OUTSIDE OF A
BLOOD VESSEL AND THAT'S WHAT A
BLEED BY DEFINITION IS, WE'RE
FOCUS ON THE CONVINCED NO 1'S
CAPTURED A MICROBLEED IN ACTION
WITH A CT FOR EXAMPLE, SHOWING
CLEARLY BLOOD IN THE PATHWAY
GIVES RENCHEMMA THAT EVOLVES TO
THIS AREA OF MICROHEME OR
HEMOSITTERIN FOR THE
SUSCEPTIBILITY OF MRIIMAGE AND
WHAT IS AURIA H AND IS THAT
SUSCEPTIBLE TO THE ANIMAL PRPTS.
IS IT A BLOOD THAT GETS
MACROPHAGED AND TREATED IF YOU
WILL AND ENDS UP WITH PRODUCTS
OR IS IT MORE COMPLICATED GOING
ON MORE MORE MICROSCOPIC LEVEL
GOING ON.
BUT OBVIOUSLY THE PROCESS USES
THE PRODUCTS AND THOSE BIG
QUESTIONS IS WHAT IS ARIA E,
WHAT IS ARIA H, THE ANIMAL PANEL
WILL ADDRESS THAT.
TREATMENT SEEMS ALTERED AND
CONFOUNDED AND SOMEONE BROUGHT
UP EARLIER WHETHER TREATMENT
WOULD BE GOOD OR BAD, FOR XCH IF
YOU PUT STEROIDS IN SOMEBODY,
PERHAPS THEY WON'T GET THE
AMYLOID CLEARING, I THINK WAS
THE IMPLICATION AND THAT'S A
POSSIBILITY.
NONE OF US WANT SYMPTOMATIC
BRAIN INJURY TO OUR PATES EVEN
REVERSIBLE AND CERTAINLY NOT
IRREVERSIBLE, SO THE QUESTION OF
WHATNYS TO BE TREATED AND WHEN
IT NEEDS TO BE TREATED AND HOW
MUCH WE SHOULD TRY TO OBVIATE
THESE CENTER FOR EXCELLENCE ON
AGINGS IS LESS CLEAR AND THERE
WAS SOME EVIDENT ALLUDED TO IT
BY SOME PEOPLE AND OTHER EVIDENT
THAT WASN'T ALLUDED TO THAT
HAVING ARIA E IS A COMP ANNIEED
BY CLEARANCE OF AMYLOID AND
RESEARCH SHOWED THAT NICE PLOTTA
OVERALL IT WAS TRUE IN TERMS OF
A CIRCLE PLOT, BUT IT'S EVEN
TRUE IN INDIVIDUAL CASES WHEN
YOU LOOK TOPOGRAPHICALLY IN
INDIVIDUALS.
SO THAT'S WHAT I WOULD SAY IN
TERMS OF UNKNOWNS, I THINK
AUTOIMRAIT WE'RE HAVING THIS
MEETING TO TRY TO SEE HOW SOME
OF THEM SHOULD BE ARK PROACHABLE
AND SOME OF THEM COULD BE EASILY
APPROACHABLE THROUGH ANIMAL
PRPLTS SO I'M DELIGHTED TO HEAR
ABOUT POTENTIAL OF SQUIRREL
MONKEYS AND OTHERS AND FLAD TO
HEAR IT'S IN BEARS BY THE WAY.
INITIATIVES GUESS I'M GO NOW SOW
I'M MERRION BASHING UCKWALTER
AND I'M A STROKE AND RESEARCH
SCIENCE DOCTOR, SO I'M COMING
FROM AN OUTSIDER PERSPECTIVE IN
SOME WAYS HERE EMPLOY I THINK I
TOTAL AGREE WITH YOU LARY ABOUT
UNDERSTANDING MORE ABOUT THE
CLENICAL SPECTRUM OF ARIA E AND
ARIA H.
I THINK--I MADE THE COMMENT
EARLIER THIS MORNING AND I WANT
TO REPEAT IT BECAUSE I DON'T
THINK WE'VE HEARD AN ANSWER TO
IT YET, WHICH IS THAT PEOPLE
WITH APOE 4 ALLELES EESPECIALLY
2 OF THEM BUT EVEN 1 OF THEM ARE
MORE LIKELY TO HAVE ARIA, BUT
THEY'RE NOT MORE LIKELY TO HAVE
SYMPTOMS FROM ARIA, OR ARIA H SO
IT COULD BE THESE PEOPLE DON'T
NOTICE THE SYMPTOMS AS MUCH, I
DON'T KNOW IF WE HAVE THAT DATA
OF WHETHER THEY--THIS GROUP IS
MORE COGNITIVELY IMED WHEN THEY
HAVE THE ARIA, MAYBE THEY JUST
MISS THEM BUT IT POSSIBLE THE
ADEMA WE SEE ON SCANS AS ARIA E
WHICH IS DIFFERENT IN PEOPLE TO
GET THE DRUGS VERSUS PEOPLE WHO
DON'T GET THEM, IS IT POSSIBLE
THAT IT IT IS JUST A SYMPTOM OF
THE DRUGS WORKING, IS IT DOESN'T
DISTURB PEOPLE THAT MUCH AND
PERHAPS IT WAS SUGGESTED BY
DR. SPERLING THAT THEY'RE DOG
BETTER COGNITIVELY IF THEY HAVE
ARIA.
SO I THINK WE REALLY NEED TO
LOOK ATA A SCIENTIFIC COMMUNITY
WE NEED TO HAVE DATA AVAILABLE
ON HOW PATIENTS DID IN THE
MULTIPLE TRIAL ANDS WHETHER ARIA
IS BAD OR NOT.
SO I THINK SOMETIMES THOSE
DOCTORS WE REACT TO A VERY SCARY
LOOKING IMAGE AND THEY ARE
SCARY, IT WOULDN'T SURPRISE ME
IF THEY'RE BAD I'M JUST SAYING
WE NEED TO PROVE THAT IT'S BAD
IF SOMEONE GETS ARIA E AND WE
NEED TO FIGURE OUT THE LINK
BETWEEN THE SYMPTOMS AND THE
ARIA E AND WHY THERE'S THIS
DIFFERENTIAL WITH APOE 4 AND I
THINK SOME OF THE WORK WE JUST
HEARD ABOUT IN THE HAS DONE AND
OTHER PEOPLE IN THIS ROOM,
DR. [INDISCERNIBLE] HAS SHOWN
THAT APOE 4 DOESN'T DO AS WELL
WITH RESERVING PERISIGHTS OR
WITH SUPPRESSING PERIVASCULAR
MACROPHAGEOXIDATIVE BURSTS.
SO THERE COULD BE LINKS BUT I
JUST THINK WE NEED A LOT MORE
INFORMATION WITH THE CLINICAL
SPECTRUM OTHERWISE WE'RE GOING
TO END UP STUDYING SOMETHING
THAT'S NOT AS IMPORTANT TO
PATIENTS.
MIRROR IMAGE SECOND POINT IS I
THINK THAT A LOT OF EXCITING WO,
WE HEARD TODAY IS APPLICABLE
WHETHER OR NOT ARIA E AND H ARE
A PROBLEM BECAUSE WE KNOW THAT
CAA IS A PROBLEM AND CAA IS
RELATED TO CAA PATHOLOGY AND I
THOUGHT THERE WAS EXCITING WORK
PRESENTED.
HOWEVER WE NEED TO THINK ABOUT
THE FACT THAT ALZHEIMER'S
DISEASE HAVE MIXED DEMENTIA SO
WHEN WE LOOK AT ANIMAL MODELS
THAT LOOK AT PERICITES THAT LOOK
AT MEDIN FOR EXAMPLE, WE NEED TO
CONSIDER LOOKINGA THE ANIMAL
MODELS WITH VASC LORA RODRIGUEZ
DISEASE AND 70% OR MORE THE
PATIENTS WHAT'S THE INTEGRITY OF
A NEUROVASCULAR TREATMENT SO I
THINK I WILL TOP THERE.
>> THANK YOU.
WE WOULD LIKE TO HEAR MORE FROM
ALL OF YOU ABOUT THE ANIMAL
MODEL ANDS WHAT DO YOU SEE AS
MISSING OR WHAT DO YOU SEE
SOMETHING THAT WOULD BE VALUABLE
TO INFORM THE CLINICAL TRIALS AT
THIS POINT OR OPPORTUNITIES FOR
REVERSE TRANSLATION.
WOP THING IS A LOT OF ATTENTION
TO ARIA H AND AS MIGHT HAVE COME
ACROSS A FEW MOMENTS AGO, IT'S
NOT SO MUCH A PROBLEM
CLIPICALLY, AND IS SOMETHING NOT
AS CLEARLY DRUG RELATED SO I
THINK WHILE PLEADING IS
FASCINATING AND TERRIFYING TO
OUR PATIENTS AND ALSO AN EASY
THING TO THINK ABOUT I THINK
IT'S REALLY THE ARIA E OR EDEMA
WE HAVE TO FOCUS ON BECAUSE THAT
IS THE SIDE EFFECT OF THE
MEDICATIONS WE'RE TALKING ABOUT
HUNDRED FOLD TIMES INCREASE WITH
MEDICATIONS AND B IT'S CLEARLY
SOMETHING THAT CAN BE MORE
EASILY SYMPTOMATIC AND IT'S
RARE, HAVING THE MICROHEMES AND
RARELY SYMPTOMATIC AND EVEN
MACROHEMES AOCCUR OR LARGE
MEMORY RESPONSE HEMORRHAGES
OCCUR SO THEY'RE QUITE RARE AND
IN THOSE CASES IT MAY BE DUE TO
MEDICAL MISADVENTURE IN SOME OF
THOSE CASES.
SO THE HEMORRHAGE IS NOT THE
BIGGEST CONCERN, I THINK ANIMAL
MODELS NEED TO FOCUS MORE ON WHY
WE GET IT, I CAN BE THE BELIEVE
I DIDN'T SAY APOE IN THE FIRST
THINK THIS I SAID BUT CLEARLY
FOR THAT MATTER, IT'S EITHER OF
THOSE WORDS BUT CLEARLY WE ALL
ATBREE THAT ARIA E AND H GO TO
COMMONALITY AND CONSENSUS, WE
BOTH AGREEN CELLS THAT ARIA E
AND H RELATE INTRINSICALLY AND
SIGNATURES MIF CANTILY AS JOHN
AND MARION BOTH MENTIONED RELATE
TO AMYLOID ANGIE OPEN
MEETINGATHY AND SO APOE OF
COURSE IS VERY IMPORTANT BECAUSE
WE KNOW HA APOE4 CARRIERSHIP OR
HOMOZYGOSITY MARKETEDLY IS
ASSOCIATED WITH AMYLOID ANGIE
OPERATING GLOBALLYATHY.
WE KNOW OVERALL HAS YOU HEARD
FROM DOCTORS THIS MORNING ALMOST
ALL ALZHEIMER'S PATIENTS ARE
AMYLOID ANGIOPATHY AND ONLY
30-OVERLAPPING OHM 67% HAVE 1 OR
MORE.
BUT THOSE WHO HAVE NO ALLELES
THE VAST MAJORITY HAVE AMYLOID
AND ANGIE OPERATING GLOBALLYATHY
IS THE SINGLE GRITTEST RISK
FACTOR THAT THE ONLY CLEAR RISK
FACTOR AT THIS MOMENT IN TIME
AND FOR THAT MATTER ARIA H.
NSO ON THE ANIMAL MODELS WE WILL
TOUCH ON 2 THINGS.
ONE WAS INTERESTING CAN TO ME
IT'S STILL A MYSTERY FROM HUMAN
DATA.
I THINK WE'VE SEEN CONSISTENT
DECREASES IN GP, FAB AND I THINK
IT'S COUNTER INTUITIVE TO ME
WITH THESE THERAPY ANDS HOW AND
WHY IS THAT OCCURRING AND THE
ROLE OF ASTRO CITE AND THE FOOT
PLATE AND CAA IS AN INTRIGUING
MYSTERY I THINK THAT'S WORTHY OF
SERIOUS INVESTIGATION AND FOR
ALET BIT ABOUT THIS, THE FOOT
PLATE AND ITS INTERACTION AND
PERHAPS CLEARANCE AND MAYBE WE
ARE RETEABING A BLOOD BRAIN
BARRIER OR REDUCING IT AND WE
HAVE TO BE CAUTIOUS WITH WE SEE
DECREASE THIS IS CONCENTRATION
BECAUSE WE DON'T YET KNOW
WHETHER IT'S A PRODUCTION
PROBLEM, CLEARANCE PROBLEM OR
VOLUME DISTRIBUTION PROBLEM
EMPLOY I ACUME IT'S A
DISTRIBUTION, SORRY PRODUCTION
AND CLEARANCE, ISSUANCE, SO WE
HEARD A BIT OF ALSO DISCUSSION
ABOUT LYMPHATIC ANDS WHETHER WE
IMPROVE OR OR DECREASE LYMPHATIC
OUTFLOWS, YOU KNOW SO I THINK
THERE'S A VERY INTERESTING
MYSTERY THERE THAT IS DEFINITELY
LINKED TO HUMAN BIOLOGY THAT
WE'VE SEEN SO FAR.
FROM CAA PERSPECTIVE, I THINK
I'M ALMOST CONVIN THAT THE
ANIMAL MODELS THAT HAVE TYPE 1
CAA IS VERY RELEVANT YET TO THE
TYPE OF PATHOLOGY THAT WE SEE
FROM THE IMMUNOTHERAPY EMPLOY SO
I REALLY THINK THE TYPE 2
PROBABLY A MORE RELEVANT MODEL.
AND I THINK AGAIN, SORRY
FORICKING --FOR PICKING ON YOU
REISA, BUT I'M GOING TO SAY IT
IS THAT IS THIS I'M NOT CLEAR
HOW WE'RE MAKING PEOPLE BETTER
WITH THESE THERAPIES 1 THING I'M
WONDERING ARE WE IMPROVING THE
BASAL REACTIVITY BECAUSE WE'RE
REMOVING THE AMYLOID FROM THE
VESSELS AND IMPROVE THAT ASPECT
VERSUS AND OTHER ASPECT AND I
THINK THAT'S THE UNKNOWN AND I
KNOW STEVE IN THE PAST HAS DONE
EXPERIMENTS LOOKING AT YOU KNOW
BASAL REACTIVITY WITH ANOTHER
MOLECULE THAT DOESN'T REALLY
REMOVE AMYLOID BUT 1 ASPECT WE
HAD DONE IN THE PAST AND AT THE
HUMAN LEVEL IS THAT THESE--THESE
TRACERS CAN BE USED FOR
PROFUSION AS WELL, SO YOU CAN
GET CEREBRAL BLOOD FLOW.
CAN YOU GET A 2 FOR 1 TIMES IF
YOU DO A DYNAMIC SCAN WHEN YOU
DO THESE AND SO 1 OF THE
QUESTIONS IS, YOU KNOW, WHAT
IS--AND HOW IS THE CHANGE OF THE
PROFUSION OR BLOOD FLOW AFFECTED
THROUGH THIS REMOVAL OR WHAT IS
IT THAT WE'RE DOING WITH VESSEL
AND IT'S BIOLOGY.
>> I AGREE WITH THAT IN TERMS OF
THE ANIMAL MODELS.
LOOKING AT DYNAMIC BLOOD NO WILL
BE IMPORTANT AND SEVERAL PEOPLE
HAD THAT TODAY BUT I FEEL LIKE
AS A FIELD IN BASIC SCIENCE LABS
IT REMAINS REALLY EXPENSIVE AND
CHALLENGING TO LOOK AT VASCULAR
REACTIVITY IN MICE AND WE COULD
USE BETTER TECHNIQUES FOR THAT
AND I THINK THAT ALSO PLAYS IN
THE COMMON CO-MORBIDITIES OF
AGING AND ALZHEIMER'S DISEASE
PHENOTYPE WHICH HYPERTENSION,
DIABETES, HIGH CHOLESTEROL,
INFARCTS ARE ALL ASSOCIATE WIDE
A CLINICAL DIAGNOSIS OF
ALZHEIMER'S DEC EMPLOY BUT I
ALSO WANT TO REITERATE WHAT WAS
SAID TODAY, I DON'T THINK ANY 1
ANIMAL MODEL WILL RECAPITULATE
EVERYTHING SO I THINK
AUTOIMPORTANT TO HAVE REVERSE
TRANSLATION OR MAYBE
INTERDEPENDENT TRANSLATION GOING
BACK AND FORTH BETWEEN ANIMALS
AND HUMANS TO MAKE SURE THAT THE
THING YOU'RE STUDYING IS WHAT'S
HAPPENING IN HUMANS AND I DO
THINK THAT IS GETTING EASIER TO
DO WITH MORE MODEL CITIZENERN
TECHNIQUES BUT IT'S TILL
CHALLENGING.
NTHANK YOU.
ANY COMMENTS OR QUESTIONS FROM
THE FLOOR, FOR OUR PANEL?
>> QUICK COMMENT.
IS THIS ON.
>> YES.
>> I DO THINK THE ANIMAL MODELS
CAN BE USEFUL FOR HELPING US
UNDERSTAND WHAT'S HAPPENING WITH
ARIA E.
WHEN PATIENTS WHO ARE TREATED
WITH THE ANTIBODIES DEVELOP ARIA
E, THAT I HAVE TAKEN OFF THE
ANTIBODY AND THE LESION IF YOU
CALL IT THAT SLOWLY RESOLVES THE
WATER GOES AWAY BUT WE REALLY
DON'T KNOW WHAT THE LONG-TERM
EFFECTS OF THE CELLULAR LEVEL
ARE AND I THINK ANIMAL MODELS
MIGHT BE ABLE TO GET US TO A
REALTIME VIEW OF WHAT'S
HAPPENING PATHOLOGICALLY IN THE
AREA OF OUR ARIA E AND HOW LONG
IT LASTS THEREAFTER.
I AGREE WITH THAT BUT I WOULD
JUST REITERATE I THINK KNOWING
THE COGNITIVE OUTCOMES IN THOSE
PATIENTS AND HOW THEY'RE
DIFFERENT WOULD BE REALLY
IMPORTANT IN TERMS OF
UNDERSTANDING THE CLINICAL
SIGNIFICANCE TO THE PATIENT.
WOP QUESTION FOR YAWN, 1
QUESTION FOR ALL OF YOU, THE
QUESTION FOR JON IS DID I
UNDERSTAND CORRECTLY HA IN
FUTURE TRIALS YOU ARE LOOKING TO
HAVE 2 SETS OF CRITERIA, 1 FOR
BREATHER WHICH MAY BE THE DUMBED
DOWN VERSION BECAUSE IT'S
CONSISTENT WITH THE TRIALS DONE
IN THE PAST BUT MAYBE ANOTHER IN
THAT SAME TRIAL FOR CLINICAL
MONITORING THAT MAY HAVE USED
SWI AND MORE ADVANCED TECHNIQUES
IN DEVELOPMENT NYEAH, SO IN THAT
STUDY WE'RE LOOKING AT BOTH A
RISK PREDICTER, CAN WE DO A
BETTER AT RISK PREDIC, AND CAN
WE DO BETTER MONITORING, SO BOTH
OF THOSE VARY SO WE'RE ALSO
DOING LONGITUDINAL, WE'RE DOING
SOME OF THOSE SEQUENCES, ALSO
LONGITUDINALLY TO PROVIDE ANY
INFORMATION FROM A--FROM A
MONITORING PERSPECTIVE AS WELL,
FOR INITANCE DO THEY SEE
SOMETHING EARLIER THAN THE OLD
TRADITIONAL MODELS, MREFRESH
YOUR RECOLLECTION I SEQUENCES
DO, AND IF YOU WOULD NOTE--IF
YOU KNEW THAT WOULD YOU BE ABLE
TO SAY STOP DOSING OR GIVING
TERROIDS SORE SOMETHING LIKE
THAT.
THOSE WILL BE THE ASSPEBTS NTHE
COROLLARY TO THAT THIS ISN'T THE
SECOND QUESTION, THROUGHOUT ALL
OF MEDICINE, CARDIOVASCULAR
OTHER STUFF, RISK STRATIFICATION
IS THE KEY WHETHER IT'S ICD
DEFRIB ILLEGALS 8ORS OR DRUGS ON
OR SOMETHING FOR HEART FAILURE
IT'S RISK STRATEGIC PLANISK,
IT'S INTERESTING YOU JUST SAID
SOMETHING THAT WE WILL NOT BE
ABLE TO DO THAT IN BLOOD TESTS
NECESSARILY BECAUSE IT BEING BE
A PREDICTER WHICH WOULD BE
IDEAL, YOU KNOW IN ADVANCE, YOU
MAY NOT KNOW UNTIL YOU GET--YOU
TREAT AND THEN GET A RESPONSE
AND IT IS THE RESPONSE THAT
MIGHT ACTUALLY BE MORE VALUABLE
FOR YOUR RISK STRATIFICATION
THAN ANYTHING YOU COULD PREDICT.
IS THAT ACCURATE.
IS THAT WHAT YOU'RE SAYING, OR
SUGGESTING THAT MAY BE THE CASE?
>> I HOLD THAT OUT AS A
HYPOTHESIS THAT YOU MIGHT BE
ABLE TO PREDICT A LITTLE BIT
BETTER ON WHO WILL HAVE A BAD
RESPONSE ACTUALLY AFTER DOSING.
SO LOOKING AT THE RESPONSE
ELEMENTS THAT YOU MIGHT SEE IN
THE BLOOD.
SO PICK YOUR FAVORITE
INFLAMMATORY TARGET, RIGHT IN
LOOK AT A WHOLE PANEL THERE AND
SEE IF SOMEONE HAS A HIGH
INTERLEUKIN 1 ARE THEY THE 1S
MORE LIKELY TO GO ON AND HAVE A
SUPER ARIA OR SOMETHING LIKE
THAT, WE WANT TO IDENTIFY FIRST
BEFORE WE EVEN DOSE IT BUT IF WE
CAN'T DO IT THEN CAN WE FIND
SOMETHING THAT AFTER DOSING
MIGHT ACTUALLY HELP BECAUSE WE
KNOW THAT GENERALLY WE'VE ALL
DISCUSSED THAT BUT IT'S NOT
AFTER FIRST DONE IT'S USUALLY
BETWEEN FIRST AND SIXTH DOSE, SO
IT DOES SUGGIEST THAT AFTER THE
FIRST DOSE MAYBE WE HAVE ANOTHER
WINDOW OF OPPORTUNITY TO
INTERVENE HERE.
NYEAH, OTHER THAN MRIs,.
>> YEAH, SO--
>> SORRY, LAWRENCE WERE YOU
GOING TO SAY SOMETHING.
>> I WAS GOING TO SAY THAT WE
ALREADY HAVE THE YIEBT RISK
FACTOR THERE WHICH IS AMYLOID
ANGIE OPERATING GLOBALLYATHY AS
MANIFESTED RADIOLOGICALLY BY
MICROHEME ANDS APOE 4 4 STATUSO
IT'S 10 TIMES HIGHER RATE OF
SYMPTOMATIC ARIA E IN PATES WITH
APOE FOR HOMOSIGNIFY GOSSITY FOR
WE ALREADY ARE A GIANT RISK
FACTOR THERE, AND YOU KNOW OF
COURSE, THAT DOESN'T EFFECT MANY
PEOPLE FROM ENTERING A DRUG
TREATMENT RIGHT NOW, AT LEAST 1
OF THE 3 DRUGS IS WIDELY
AVAILABLE AND THE OTHER IS
RELATIVELY AVAILABLE, BOTH FDA
APPROVED, SO YOU KNOW A LOT OF
PEOPLE, A LOT OF MY PATIENTS
PUTTING ON MY CLINICIAN FLASESS
A LOT OF MY PATIENTS ARE
PERFECTLY HAPPY TO ENTER A TRIAL
WHERE THEY HAVE 10 TIMES HIGHER
RISK OF HAVING ARIA E THAN
SOMEONE WHO HAS A DIFFERENT GENO
TYPE FROM THEM.
THE OTHER WAY TO LOOK AT THAT IS
IF THEY HAVE A FINISH% CHANCE OF
NOT HAVING SYMPTOMATIC ARIA E,
VERSUS A 90% CHANCE OF HAVING
ARIA E, WHEN YOU FLIP IT SO 90%
SOUNDS PRETTY GOOD FOR PEOPLE
AND 90% CHANCE OF NOT HAVING
SYMPTOMATIC ARIA E.
NWELL PUT.
THE QUESTION FOR ALL OF YOU IS:
WHAT IS SIGNIFICANT ARIA TODAY
AT WHATEVER TIME IT IS BECAUSE
IT KEEPS CHANGING.
IS IT SYMPTOMATIC ARIA AND
MACROHEMORRHAGES WITH THE CAVEAT
THAT MAYBE THIS IS JUST EVIDENT
THAT THE DRUG IS ACTUALLY
WORKING?
REMEMBER WHEN YOU GOT YOUR COVID
SHOT?
SOMETHING EVERYONE IS FAMILIAR
WITH AND YOU WERE REALLY, YOU
WERE DOWN FOR 12 HOURS, SOMEONE
ELSE MIGHT HAVE BEEN DOWN FOR 2
HOURS, ACTUALLY THE PEOPLE WHO
ARE DOWN FOR 12 HOURS MIGHT HAVE
ACTUALLY, THAT MIGHT HAVE BEEN A
GOOD SIGN, THIS WILL PROTECT ME
BETTER, IT'S SOMING THAT
EVERYONE CAN UNDERSTAND IN THAT
RESPECT.
SO WITH THE CAVEAT THAT MAYBE
IT'S A GOOD THING, MAYBE IT'S A
BAD THING, WE DON'T REALLY KNOW,
WHAT IS SIGNIFICANT ARIA.
NETWORK I LOVE THAT QUESTION.
>> I THINK RIGHT NOW WE DON'T
KNOW UNTIL WE KNOW HOW IT
AFFECTS LONGER TERM OUTCOMES BUT
IT'S PRETTY OUTCOME THAT A GIANT
PLEAD IN THE BRAIN IS A BAD
THING OR DYING OF BRAIN EDEMA
HAS HAS HAPPENED IN THE ACTIVE
YOU HAD MACHINIZATION TRIALS NI
WOULD LIKE TO MAKE A COMMENT
ABOUT ANSWER THAT QUESTION.
SO I THINK THE MAIN ISSUE THAT
KAREN RAISED EARLIER IS ARIA IS
RELATIVELY COMMON, SOME MORE SO
WITH DRUGS THAN OTHERS, USUALLY
REVERSIBLE, USUALLY ATOSM
TOMATIC AND USUALLY QUITE
MANAGEABLE SO MARION FOR THOSE
PATIENTS IT'S OKAY AS LONG AS WE
KEEP A GOOD EYE ON THEM AND
MONITOR THEM.
UNFORTUNATELY THERE'S A GROUP OF
PATIENTS THAT HAVE A MERE SEVERE
INFLAMMATORY TYPE REACTION WHICH
CAN BE VERY HARD TO TREEPT AND
FATAL.
AND THERE HAVE BEEN FATALITIES
AND IF WE'RE NOT CAREFUL THERE
WILL BE MORE FATALITIES.
I WILL BE TALKING MORE ABOUT
THAT TOMORROW, HOW TO IDENTIFY
THOSE PATIENTS AND USE GOOD
CLENICAL JUDGMENT TO TRY ARK
VOID THOSE MORE SERIOUS
OUTCOMES.
SO WHAT'S SERIOUS--SORRY, SO
WHAT'S SERIOUS IS WE WANT TO
AVOID OBVIOUSLY DISABILITY OR
DEATH, THAT'S SERIOUS.
THE OTHER 1S WITH CAREFUL MANAGE
AM ARE CLINICALLY MANAGEABLE AND
ARE NOT, THEY COULD BE
TEMPORARILY SERIOUS BUT THEY'RE
NOT DISABLING OR PERMANENT.
>> YEAH, AND I AGREE WITH YOU.
THE SERIOUS 1S THAT WORRIED ME
THE MOST AND THEY'RE THE HARDEST
1S ACTUALLY BECAUSE FIRST OF ALL
THEY'RE THE LEAST OCCURRING SO
THAT MAKES THEM ALSO REALLY
DIFFICULT TO PREDICT BUT THERE
IS SOME--THERE IS DEFINITELY
DISCONNECT BETWEEN THE OVERALL
RISK OF ARIA, WHICH IS THE
HETEROZYGOUS TO THE NONCARRIERS
GENERALLY SPEAKING ABOUT YOU
WHEN WE LOOK AT SERIOUS ARIA IT
DOESN'T HAVE EXACTLY THE SAME
PATTERN.
IT IS MORE EVENTUALLY
DISTRIBUTED ACROSS THESE WHICH
IS IT'S A HIGHER IN THE
HOMOZYGOUS, BUT FOR SOME REASON
THE NONCARRIERS BECOME WHAT I
CALL OVERREPRESENTED IN THIS
AREA AND I DON'T KNOW WHAT'S
DRIVING THAT.
THAT'S THE 1 THING THAT WILL BE
NICE TO HAVE THAT PREDICTER THAT
WE DON'T YET HAVE FOR SOME OF
THEM.
>> AND WHAT WE SEE ARE THE CAR
TISSUING CELLS DESIGNED FOR
CANCER AND WE SEE A LOT OF SIDE
CENTER FOR EXCELLENCE ON AGINGS
FROM THAT AND LOOKING AT IMAGE
ABNORMALITIES WHICH IS ANOTHER
IMMUNO THR ACTIVITIES AND
PROJECTSY EMPLOY NETWORK I AM
FROM NETWORK YRK U EMPLOY I HAVE
A FEW COMEBTS ON NONHUMAN
PRIMATES MODEL CITIZEN MODEL SO
DR. WALKER THANK YOU FOR YOUR
TALK, AND WE KAN--KANA OVER 30
ANIMALS WE SERVED THE LESIONS
MOSTLY, LESS ARIA H, MAYBE IN 8
OR NIEP ANIMALS.
WE WERE LUCKY WE ARE ABLE TO
HISTOLOGICALLY EVALUATE THE
LESION NOW AND 1 OR 2 MONTHS
AFTER IMAGING AFTER MREFRESH
YOUR RECOLLECTION I SCANS, SO,
HOPEFULLY WE CAN ADDRESS SOME OF
THOSE QUESTIONS, IS IT
INFLAMMATION, EDEMA OR BOTH?
OR DIFFERENT TYPE OF OR IN
MACROFAINLS IN WHAT DO WE SEE IN
WHAT IS THE UNDERLYING PATHOLOGY
IN THAT WAS A COHORT, WE HAVE A
NEW STUDY WE HOPE TO EVALUATE
CONSEQUENCES OF ARIA IN MONKEY
FOR LONGER IN OBSERVE ARIA ANDEE
IF IT'S TRANSIENT OR IF IT'S
PROGRESSING.
WE'VE DONE ALSO IMMUNOTHERAPY
BUT NOT ACTIVE OR PASSIVE INNATE
IMMUNITY.
WE PUBLISHED PAPER WHERE WE
REDUCED OUR IMMUNOTHERAPY
REDUCED PATHOLOGY WITHOUT
INCREASING HEMORRHAGES, WE
SIMPLY PUBLISHED THAT PAPER SO I
THINK SQUIRREL MONKEY IS A GREAT
MODEL.
I DON'T KNOW MUCH ABOUT
MARMOSETS BUT I WILL LOOK INTO
IT AS WELL NTHANK YOU.
>> THANK YOU.
>> HI, THIS IS TERESA WITH THE
FDA, I HAVE QUESTION ABOUT THE
DOSING REGIMENS AND TITRATION
WITH RISK OF ARIA, I KNOW FROM
DOSE RANGING STUDIES THAT I'VE
SEEN THAT THERE ARE LOWER RATES
OF ARIA SEEN USUALLY AT LOWER
DOSES, BUT THEN I DON'T KNOW HOW
THAT TRANSLATES, I THINK REISA
MADE A COMMENT EARLIER THAT ONCE
YOU GO UP, THE RISK INCREASES AS
YOU TITRATE UP BUT I HAVE BEEN
WONDER FIGURE THERE'S MORE WE
CAN DO WITH THOSE EXPLORATION
TITRATION EXPLORATION AND
CONSIDERING ALTERNATE DOSING
REGIMENS.
NI COULDN'T AGREE MORE.
SO WHEN YOU THINK ABOUT
TITRATION IT BECOMES A SUPER
COMPLICATED PROBLEM TO SOLVE FOR
BECAUSE THERE ARE ALMOST
INFINITE NUMBER OF VALID AND
RELIABLE YAIGS THERE TO TEST.
SO WHAT WE APPRECIATE IS FOR
MOST MOLECULES MOTE DRUG USUALLY
EQUALS MORE ARIA, FOR ITS
PARTICULAR PROFILE AND USUALLY
PROBABLY ALSO MORE AMYLOID
REMOVAL SO THOSE 2 THINS SEEM TO
KIND OF MOVE TOGETHER.
THE REAL QUESTION IS CAN WE
UNCOUPLE, CAN WE EVER UNCOUPLE
THIS MOVE AM, RIGHT IN SO I
THINK WE'VE HEARD 1 HYPOTHESIS
THAT MAY BE C-MAX IS A WAY TO
UNCOUPLE HERE.
SO I THINK WE'RE GOING TO TEST
THAT QUITE ROBUSTLY IN THAT
TRAIL BLAZER 6 STUDY, WE WILL
CONTROL EVERYTHING, EVERYONE'S
RANDOMIZED AND CONTROLS AND
WE'LL CONTROL THE CMAX VERSUS
AUC AND SEE IF THAT REALLY DOES
BEAR OUT BECAUSE APPROXIMATE IT
DOES, THAT'S A REALLY TRACTABLE
PROBLEM WE CAN BRING TO
PATIENTS.
I THINK UNDERSTANDING ALL THE
DOSING AND VARIATIONS THAT 1 CAN
DO IS A REAL HARD AND BECOMES
VERY UNTRACTABLE PROBLEM IF YOU
THINK ABOUT THE POSSIBLE
TITRATION KEEMS THAT 1 CAN DO
AND SO, I THINK WE'RE JUST GOING
TO HAVE TO KIND OF TRY TO DO IT
AS PRACTICALLY AS WE CAN AND WE
HAVE MANAGE THAT WORKS CAN WE
FIND SOMETHING THAT WORKS
BETTER, I THINK WE SHOULD
CONTINUE TO EXPLORE THAT.
>> RIGHT, YEAH, I THINK IT IS
CHALLENGING SINCE THE RATES OF
ARIA SEEM TO TRACK WITH AMYLOID
REDUCTION BEING YOU HAVE TO FIND
THAT BALANCE OF WHAT ARE YOU
WILLING TO ACCEPT FOR ARRAIA
INCIDENCE VERSUS POTENTIALLY
DISCIPLINARY LAKING BENEFIT FOR
BY USING LOWER DOSE.
>> RIGHT AWAY I WOULD LIKE TO
COME BACK TO BE THAT BECAUSE
THERE ARE OTHER THINGS FROM AN
ANIMAL MODEL AND HUMANS THAT ARE
WORTHY OF KIND EXPECTATIONS
MORING IN THAT AREA.
NETWORK SO MAYBE SOMETHING WE
COULD TOUCH BASE TOMORROW WHEN
WE MAKE THE FINAL
RECOMMENDATIONS, SO VERY QUICK
QUESTION, QUICK ANSWER.
>> ERROR QUICK QUESTION.
MA EVE, I HAVE QUESTION ALSO ON
NAIVE, THERE ARE PEOPLE WHO ARE
STARTING CLINICAL TRIAL WITH
ANTIA BETA [INDISCERNIBLE] COULD
YOU RECOMMEND SOME SOPs SO
PEOPLE CAN CHECK ARIA H AND E IN
EVERY WAY SIMULTANEOUSLY IN
COULD WE BE SURE THAT WE ARE
READING CORRECTLY WHEN I DON'T
UNDERSTAND AND THINKING ARIA, SO
DO YOU HAVE ANY TEAKNIQUE IN
WHICH 2 DIFFERENT PEOPLE IN
DIFFERENT COUNTRIES CAN LOOK FOR
YOUR MRI, AND SAY, YES THIS IS
ARIA H, THIS IS SEVERE, THIS IS
MILD, THIS MODERATE ?
AND THE SAME WITH ARIA E BECAUSE
I AM NOT SURE WE HAVE THAT.
IF YOU CAN HELP PEOPLE AND THEY
HAVE DEVELOPED SOP, IT MAY HELP
A LOT.
THAT'S MY QUESTION.
>> IT'S DEFINITELY--YOU CAN GET
PEOPLE TO USE THE SIMILAR KIND
OF STALES,'RE SCALES THAT HAVE
BEEN USED OUT THERE AND THEY'RE
PRETTY TRAINABLE TO GET PEOPLE
TO HOPEFULLY CALL THE SEAM LEVEL
OF ARIA, ACROSS.
BUT IT DOES REQUIRE TEACHING
EDUCATION.
>> I AGREE THERE'S VARIOUS KALE
ANDS WAYS OF RATING THEM OR
MICROHEMES ABOUT THOSE
TECHNIQUES BUT I WILL POINT OUT
IT DOESN'T MATTER THAT MUCH
BECAUSE WHETHER THE PEOPLE ARE
SYMPTOMATIC OR ASYMPTOMATIC AND
AS WE KNOW WITH MANY OF THESE
DRUG PEOPLE PEOPLE HAVE BEEN
DOSED THROUGH ARIA THROUGH MINOR
ARIA WITHOUT ANY ADVERSE
EFFECTS.
AND WITH RESOLUTION OF THAT ARIA
DESPITE CONTINUED PRESENCE OF
DRUG IN THEIR BLOOD STREAM AND
BRAIN EMPLOY SO I THINK WHEN
THEY GET LOST, MAKE SURE 1 SEES
THE FOREST AND NOT GET LOST IN
THE TREES.
IT'S TBRAIT TO BE ABLE TO
QUANTIFY THINGS, BUT QUANTISK
ISN'T ALWAYS EVERYTHING NOKAY,
SO, WE ARE OVER TIME BUT IF YOU
WANT TO MAKE A VERY QUICK PLEASE
DO AND THEN WE WILL INVITE TO
MAKE THE CLOSING REMARKS OF THE
DAY NAS MY REMARKS ARE
TANGENTIAL IT'S DAIRVELGEROUS
BUT I WAS COMBINING 1 OF MY
OTHER FEELS FROM EARLY IN MY
CAREER, I DEVELOPED VARIOUS
FORMS OF FOCAL MODELS OF EPILEPS
COMPETENT 1 OF THE EASIEST BEST
WAYS TO WAS TO GIVE A LITTLE
INJECTION OF BLOOD IN THE CORTEX
AND SEEING FERIA TIN AND HEARING
THAT SOME OF THE BAD EPISODES OF
ARIA E HAVE HAD SEIZURES AS A
SERIOUS AND COMPLICATION OF IT,
I'M WONDERING IF THE DIFFERENCE
IS WE'RE TRYING TO SAY, WHICH OF
THE ARIA CEREBELLUMSs THAT
AREN'T SO BAD WE COULD TREAT
THROUGH THIS, IT'S NOT SUCH A
BIG DEAL, DOESN'T SEEM TO BE
CAUSING PERFECT DAMAGE AND THOSE
THAT SPIN INTO A TRAGIC OR EVEN
FATAL OUTCOME, WHETHER THE
METABOLIC STATUS, WHETHER IN
FACT, THERE'S SOME MORE
ACTIVATION THAT'S GOING ON IN
THE BAD 1S, COULD BE DRIVEN BY
AN EPILEPTIC OR OTHER EXCITATORY
MECH NIM THAT'S BEING SET OFF BY
THE HEME THAT IS PROBABLY
PRESENT IN THE REAMINGION.
BUT YOU KNOW MAYBE WE COULD BE
DOING THE EEGs OR SOME SIMPLE
PRETTY METABOLIC TESTING OF
BRAIN ACTIVITY AND SPEC. SCAN ON
THE--ON THESE ARIA CASES TO SEE
IF THAT WOULD BE ANOTHER WAY TO
DIFFERENTIATE THE DANGEROUS 1S
FROM THE 1S THAT WE CAN LIVE
WITH NETWORK I THINK THAT'S A
GOOD IDEA ALTHOUGH OBVIOUSLY
EEGs DON'T CATCH A LOT OF
SMALL SEIZURES, I ALSO LIKE THE
IDEA OF CONSIDERING INFLAMMATION
AND EDEMA BECAUSE WE KNOW THAT
BRAIN INFLAMMATION MAKES YOU
DIZZ COMPETENT GIVES YOU A
HEADACHE AND MAKES YOU OUT OF IT
CAN HA THOSE ARE THE SYMPTOMS.
NWONDERFUL I WOULD LIKE TO THANK
ALL OF OUR PANELISTS.
AND DR. WRIGHT ASSOCIATE
DIRECTOR OF OUR OFFICE OF
CLINICAL RESEARCH AT NINDS WILL
DPIF THE CONCLUDING REMARKS FOR
TODAY AND WE WILL SEE YOU
TOMORROW AT 8:30.
THANK YOU.
>> SURE.
THIS IS EXACTLY WHAT NIA HAD IN
MIND TO BRING TOGETHER PEOPLE
WITH DIVERSE EXPERTISE AND A LOT
OF DIFFERENT AREAS THAT ARE
RELEVANT TO THIS FIELD AND PUT
HEADS TOGETHER AND SO I THINK
IT'S BEEN A REALLY FANTASTIC
DAY, AND IF THE OLD SAW ABOUT
ANDROIDS DREAMING OF ELECTRIC
SHEEP ARK PLIES TO AMYLOID
RESEARCHERS AND SUPER VASCULAR
RESEARCHERS DREAMING OF WAYS TO
CREATE NEW MODELS AND CREATE
SYNERGY THEN I HOPE THAT THAT
WILL CARRY YOU FORWARD INTEREST
YOUR DREAMS EMPLOY AND THEN
TOMORROW, WE CAN GET TOGETHER
AND REALLY THINK OF HOW TO
ATTACK THIS PROBLEM TOGETHER,
AND YOU KNOW SET THE TAIJ FOR
THE WORK THAT NEEDS TO COME.
I DON'T HAVE TO TIME TO DO MUCH
MORE AS I HAVE TO GET ON A CALL
BUT I APPRECIATE EVERYONE'S
EFFORTS TODAY AND SEE YOU TOMORROW.