>> DR. IADECOLA: HI. THIS IS
CONSTANTINO IADECOLA. CAN I
HAVE MY FIRST SLIDE?
I AM A NEUROLOGIST FROM WEILL
CORNELL MEDICAL COLLEGE IN NEW
YORK AND HAVE NO DISCLOSURES,
AND I AM HONORED TO BE PART OF
THIS DISTINGUISHED GROUP, AND
PROVIDE SOME INPUT INTO THIS
VERY IMPORTANT MEDICAL ISSUES
THAT WE ARE FACING.
NEXT SLIDE.
OKAY SO THIS IS THE
RECOMMENDATION WHICH HAVE TO DO
WITH THE BASIC MECHANISMS AND
THE RECOMMENDATION TO ADVANCE
BASIC RESEARCH AND EXPERIMENTAL
MODELS ON SINGLE, MULTIPLE
INTERACTIVE MECHANISMS DRIVING
MIXED PATHOLOGY, INCLUDING
COMORBIDITIES ACROSS TEXAS,
WITH EMPHASIS ON THE VALIDATION
OF HUMAN DATA SET AND
IDENTIFICATION OF THERAPEUTIC
TARGETS.
SO PARTICULARLY WE NEED TO
DEVELOP NEW MODELS OF MIXED
PATHOLOGY TAKING INTO ACCOUNT
THE COURSE OF THE DISEASES, THE
INTERACTION OF THE DIFFERENT
PATHOLOGIES, CRITICAL
CHECKPOINT FOR THE IMPACT OF
THESE PATHOLOGIES, AND OVER THE
LIFE COURSE THE THERAPEUTIC
WINDOWS THAT MAY BE AVAILABLE
AND NEEDED.
CONSIDER THE IMPACT OF SEX, AGE
AND COMORBIDITY, AT THIS POINT
DR. KOROSHETZ EMPHASIZE THE
IMPORTANCE OF AGING IN THE
EMERGENCE OF MIXED PATHOLOGIES.
THAT IS GOING TO BE VERY, VERY
IMPORTANT ASPECT TO BE
CONSIDERED.
AND ALSO TO IDENTIFY WHAT ARE
THE KEY DRIVERS OF THIS
PATHOLOGY. AND WHAT ARE THE
ULTIMATE FACTORS.
TO THIS UNDERSTANDING OF THIS
INTERACTION, WE MAY BE ABLE TO
FIGURE OUT NEW THERAPEUTIC
INTERVENTION THAT MAY BE
EFFECTIVE.
AS EMPHASIZED BY DR. ERTEKIN
TANER'S REPORT FROM THE
NATIONAL ACADEMY REPORT, WE
NEED TO HAVE METABOLIC RESEARCH
TO APPLY IN THE DIFFERENT
MULTIDISCIPLINARY TEAMS
NECESSARY TO CRACK THIS VERY
COMPLEX PROBLEM OF THIS
MULTIPLE PATHOLOGIES.
WE NEED AN OPEN ACCESS
REPOSITORIES. THERE ARE A LOT
OF EXISTING REPOSITORIES. WE
NEED TO ADD HARMONIZATION, AND
WE NEED EVERYTHING TO BE EASY
TO BE ACCESSIBLE AND SEARCHABLE
AN UP ONLINE SO THAT PROTOCOLS
CAN BE REPRODUCED, AND METHODS
CAN BE ESTABLISHED AND SO ON.
AND FINALLY WE NEED TO
EMPHASIZE THE PUBLIC PRIVATE
PARTNERSHIP AND RAPIDLY REACH A
CONSENSUS ABOUT THERAPEUTIC
TARGETS AND MODEL INTERVENTIONS
SO THIS NEW DISCOVERIES CAN BE
RAPIDLY TRANSLATED INTO THE
CLINIC.
NEXT SLIDE.
THERE IS A VERY UNIQUE AND
COMPLEX FRAMEWORK IN MULTIPLE
DEMENTIAS, HAS TO DO WITH THE
IMPACT OF MULTIPLE THERAPIES.
AND THIS CAN BE CONSIDERED IN
DIFFERENT WAYS.
FOR EXAMPLE YOU MAY HAVE A
MULTIPLE INDEPENDENT
PATHOLOGIST, LIKE 1, 2 AND 3 IN
DIFFERENT REGIONS AND EACH ONE
LEADING TO CERTAIN ASPECTS OF
COGNITIVE IMPAIRMENT. YOU MAY
HAVE DIFFERENT COGNITIVE
DOMAINS BEING AFFECTED BY EACH
INDEPENDENT PATHOLOGY.
ESSENTIALLY THE IMPACT WOULD BE
ADDITIVE, ONE TO THE OTHER.
NEXT SLIDE.
IN THESE SCENARIOS THERE IS A
DRIVING PATHOLOGY RESPONSIBLE
FOR DOWNSTREAM PATHOLOGIES AS
SHOWN HERE.
FOR EXAMPLE IN THE DOMINANT
ALZHEIMER'S DISEASE YOU HAVE A
PATHOLOGY DRIVING -- YOU HAVE A
SITUATION WHERE A PATHOLOGY
DRIVES THE OTHERS AND THE
COGNITIVE IMPAIRMENT-- NEXT
SLIDE -- THE COGNITIVE
IMPAIRMENT IS A RESULT OF THIS
ADDITIVE PATHOLOGIES THAT MAY
OCCUR.
NEXT SLIDE.
ONE OF THE COMPLEXITIES OF THIS
ISSUE IS UNDERLINED BY THE FACT
THAT THESE PATHOLOGIES MAY BE
INTERACTING. SO FOR EXAMPLE
(INDISCERNIBLE) MAY LEAD TO
(INDISCERNIBLE) PATHOLOGY IN
THEM INTERACT RECIPROCALLY, AND
AMPLIFYING THE COGNITIVE
IMPACT. AND THESE PATHOLOGIES
MAY BE LOCATED IN DIFFERENT
BRAIN REGIONS AND MAY BE
CONNECTED TO PATHWAYS WHICH MAY
LEAD TO THE PATHOLOGY
DEVELOPING IN A DIFFERENT BRAIN
REGION. LIKE WE DISCOVERED FOR
(INDISCERNIBLE) WHERE THERE IS
A SPREAD OF THE PATHOLOGY IN
DIFFERENT BRAIN REGIONS.
SO CLEARLY WE NEED TO
UNDERSTAND ALL OF THESE
INTERACTIONS TO REALLY COME UP
WITH EFFECTIVE SOLUTIONS.
NEXT SLIDE.
WHAT WE REALLY NEED -- NEXT --
WOULD BE TO AGAIN DEVELOP
MODELS THAT REFLECT THE
COMPLEXITY OF THIS MULTI
DEMENTIA, WE MAY REFLECT THE
COMPLICITY OF DIFFERENT
PATHOLOGIES, AGAIN THE ROLE OF
SEX AND COMORBIDITY IS GOING TO
BE CRITICAL, IDENTIFYING
HUMAN-BASED METHODS SUCH AS IP
CELLS AND ORGANOIDS AND SOMEONE
THAT MAY LEAD TO A BETTER
TRANSLATION INTO THE HUMAN.
AND DEVELOP DATA REPOSITORIES
IN AN OPEN AND EASILY
ACCESSIBLE, AND MOVE TOWARDS
TRANSLATION.
BECAUSE ONE OF THE KEY ELEMENTS
IS GOING TO BE TO DETERMINE
WHAT IS THE PATHOLOGY THAT IS
MOST PREVAILING FOR AFFECTING
THE KIND OF IMPACT OF THE
PATHOLOGY?
SOME OF THIS MIGHT BE BASED
STANDARDS; SOME MAY BE MORE
DIRECTED TOWARDS THE COGNITIVE
IMPAIRMENT.
I AM DONE I THINK, AHEAD OF
TIME.
>> THANK YOU.
>> DR. FARDO: THANK YOU DR.
IADECOLA. I AM DAVID FARDO,
BIOSTATISTICIAN AND STATISTICAL
GENETICIST FROM THE UNIVERSITY
OF KENTUCKY. I AM HAPPY TO
PRESENT THIS ON BEHALF OF THE
NINDS WORKING GROUP AND THE
SPECTRUM FROM BASIC
TRANSLATIONAL AND CLINICAL
RESEARCH AND DATA
STANDARDIZATION, HARMONIZATION,
AND INTEGRATION. I HAVE NO
DISCLOSURES.
NEXT SLIDE.
THIS DATA RECOMMENDATION IS
SUPPORTING MULTIPLE ETIOLOGY
DEMENTIAS FAIRLY BROAD IN
SCOPE INTENDED TO SUPPORT A
BROAD SPECTRUM OF RESEARCH WITH
TARGETED EFFORTS TO
STANDARDIZE, HARMONIZE, AND
INTEGRATE MULTIPLE ETIOLOGY
DATA FROM NEW AND EXISTING
MODALITIES INCLUDING THAT FROM
NOVEL CLINICAL AND BIOMARKER
COLLECTION APPROACHES.
SPECIFICALLY WE ARE ENDORSING
THE DEVELOPMENT OF DIGITAL
IMAGING, AND AI DRIVEN
APPROACHES TO HARMONIZE DATA
SETS ACROSS THE STATE
PLATFORMS, AS WELL AS
OPEN-SOURCE PLATFORMS FOR
STORAGE, ANALYSIS,
VISUALIZATION, AND INTEGRATION
OF BOTH EXISTING AND NEW DATA
WITH HARMONIZED AND IDEALLY
CONSENSUS OF STANDARDIZED
CONVENTIONS OF NED.
AND EMPHASIZE EFFORTS FOR DRUG
DEVELOPMENT REPURPOSING AND
SHARED ANALYTICAL PRACTICES AND
COMMON NED CODING TO PROMOTE
HARMONIZED INTEGRATION ACROSS
EMRS IN MULTIGROUP EFFORTS.
WE ALSO RECOMMEND TO CREATE
CONSENSUS QUALITY METRICS TO
SUPPORT DATA INTEGRATION ACROSS
BIOMARKER PLATFORMS AND COHORTS
FOR CROSS STUDY COMPARISON AND
AGGREGATION, AS WELL AS
COOPERATION AMONG DATABASE
GROUP SO THAT NED-SPECIFIC DATA
CAN BE MOST PROBABLY,
RESPONSIBLY AND SAFELY BE
INTERCHANGED, AGGREGATED AND
COMPARED.
FINALLY, WE RECOMMEND
SUPPORTING BY REPOSITORIES
ACROSS ORGANIZATION TABS
INCLUDING PUBLIC/PRIVATE
PARTNERSHIPS TO ACHIEVE THIS
RESEARCH SUPPORT.
NEXT SLIDE.
THIS RECOMMENDATION IS
MOTIVATED BY THE FOUNDATIONAL
ROLE THAT QUALITY DATA PLAYS IN
MULTIPLE ETIOLOGY DEMENTIA
RESEARCH AND WE HAVE TO HAVE
COMMON DEFINITIONS AND
NOMENCLATURE REGARDING THIS.
RECOMMENDING EFFORTS TO
MAXIMIZE UTILITY IMPACT
PREVIOUSLY COLLECTED DATA TO
HONOR BOTH FINANCIAL AND HUMAN
INVESTMENTS INCLUDING THAT OF
OUR COMMITTED AND PASSIONATE
RESEARCH VOLUNTEERS, BY
INTEGRATING EXISTING AND NEW
SOURCES OF DATA IN THE MOST
EVER BE RESPONSIBLE AND
EFFICIENT WAY POSSIBLE WE CAN
MAXIMIZE STATISTICAL POWER AND
OUR ABILITY TO MAKE
STATISTICALLY RIGOROUS
INFERENCES AND ADVANCES IN OUR
UNDERSTANDING OF NED.
ADDITIONALLY WITH A BACKDROP OF
STRONG DATA PROTECTIONS
ESPECIALLY FOR HUMAN SUBJECTS
DATA, WE CAN DEMOCRATIZE AND
DATA ACCESS FOR QUALIFIED
RESEARCHERS, THUS PROVIDING
OPPORTUNITY FOR MORE
INVESTIGATION AND MORE
ADVANCED.
NEXT SLIDE.
THIS IS THE DEPICTION OF DATA
COLLECTION AND PROCESSING FOR
DIGITAL HISTOPATHOLOGY, GOING
FROM RESEARCH VOLUNTEERS'
DONATIONS OF THE RANGE THROUGH
AUTOPSY, THROUGH STAGES OF
PREPARATION AND ANALYSIS.
WE RECOMMEND EFFORTS FOR OPEN
SOURCE DIGITAL IMAGING,
FOCUSING ON THE ABILITY TO
RECOGNIZE DIFFERENCES IN
APPROACHES HERE DEPICTED BY
SINGLE NOTES, AND SUBSEQUENTLY
HARMONIZED ACROSS THEM WITH THE
GOAL OF SHARING AND INTEGRATING
ACROSS COHORTS AND PLATFORMS.
AND THEN DISSEMINATING TO
INVESTIGATORS AS ROUNDLY AS
POSSIBLE.
NEXT SLIDE.
THESE RESULTS ARE FROM AN
EXAMPLE HARMONIZATION FOR
MULTI-ETIOLOGY DEMENTIAS FOR
NEURO- PATHOLOGICAL EVALUATIONS
AND SO THE FIGURE ON THE LEFT
SHOWS THE EXTENT TO WHICH THE
PROTEINOPTHYS LIKE DR. CARLSSON
DISPLAYED EARLIER OF TAO, --
AND TDP 43 FROM PARTICIPANTS IN
SEVERAL COHORTS EACH ROW
REPRESENTS A PATTERN OF
MISCODED PROTEINS WITH RED
INDICATOR PRESENCE AND GREY
ABSENT.
IN THE STATE OF THE FIRST ROAD
INDICATES THAT THAT 384 OF THE
-- BRAIN HAD AUTOPSIES. THE
MAJORITY OF BRAINS EXHIBIT
MULTIPLE PROTEIN OPATHIES
SHOWING THE AGE EXCEPTION OF
INDIVIDUALS AND THIS POINTED
MULTIPLE TIMES ON THE SUMMIT
AND UNDERWRITE THE CORRELATION
BETWEEN THOSE FOUR MISS FOLDER
PROTEINS AN ADDITIONAL NEURO-
PATHOLOGIC AND PHENOTYPES, AND
THIS SHOWS INTERRELATEDNESS
BETWEEN DISTINCT PHENOTYPES,
AND IT ECHOES THE IMPORTANCE OF
IDENTIFYING SPECIFIC DISEASE
SUBTYPES THAT CAN BE TARGETED
THERAPEUTICALLY.
NEXT SLIDE.
THIS FINAL SLIDE, HIGHLIGHT TO
EXISTING AND RELATED EFFORTS
FOR RELATING DATA ACROSS
STUDIES AND DATA TYPES AND WE
ADVOCATE FOR THE EXPLICIT
INCORPORATION OF NED.
THE ALZHEIMER'S DISEASE
SEQUENCE PROJECT PHENOTYPE
HARMONIZATION PROJECT BRINGS
TOGETHER DATA FROM MULTIPLE
MODALITIES INCLUDING
LONGITUDINAL, COGNITIVE EXAMS,
IMAGING BIOMARKERS AND
NEUROPATHOLOGY.
AND ON THE RIGHT -- AGGREGATES
GENETIC AND RELATED PHENOTYPIC
DATA FROM MANY STUDIES AND
MAKES THESE DATA AVAILABLE FOR
QUALIFIED INVESTIGATORS.
SIMILAR EFFORT SPECIFIC TO
MULTI-ETIOLOGY DEMENTIA AND
OTHER FOCUS GROUPS IS
RECOMMENDED IN THE SUMMIT IN
THE REPORT, NEEDED TO
EFFICIENTLY ADVANCE DRUG AND
CLINICAL TRIAL DEVELOPMENT AND
PRECISION MEDICINE. THANK YOU.
I WOULD NOT TURN IT OVER TO DR.
CAITLIN LATIMER.
>> THANK YOU SO MUCH MY NAME IS
CAITLIN LATIMER, A PATHOLOGIST
AND ASSISTANT PROFESSOR AT THE
UNIVERSITY OF WASHINGTON
SEATTLE. APPRECIATE THE
PRIVILEGE TO CONTRIBUTE TO THIS
WORKGROUP. I'M GOING TO BE
TALKING ABOUT RECOMMENDATION 4,
BUILDING A MULTIPLE ETIOLOGY
DEMENTIA COMPETENT WORKFORCE.
AND I HAVE NOTHING TO DISCLOSE.
NEXT SLIDE.
THE FIRST THREE RECOGNITIONS
ARE REALLY FOCUSED ON DISCOVERY
AND ADVANCEMENT AND DIAGNOSTIC
AND THERAPEUTIC STRATEGIES FOR
NEDTHIS COMMISSION EMPHASIZES
THE NEED TO DEVELOP A WORKFORCE
THAT UNDERSTANDS AND RECOGNIZES
THE CONCEPT OF MULTIPLE
ETIOLOGY DEMENTIA, TO IMPROVE
HOW WE STUDY, DIAGNOSE AND
MANAGE INDIVIDUAL MULTIPLE
DEGENERATIVE PATHOLOGIES.
TO ACCOMPLISH THIS WE UNDERLINE
SEVERAL KEY POINTS EMPHASIZE.
THE DEVELOPER WORKFORCE WE
REALLY NEED TRAINING PROGRAMS
THAT INTEGRATE MULTIPLE
ETIOLOGY DEMENTIA PRINCIPLES
AND THIS INCLUDES BASIC SCIENCE
RESEARCHERS, CLINICIANS,
CLINICAL CORNERS AND WE NEED
EVERYONE INVOLVED IN DEMENTIA
RESEARCH AND CARE TEAM EFFORT
AND WE NEED TO INVEST IN
IMPLEMENTATION SCIENCE RESEARCH
TO REACH A BROADER SWATH OF
INVESTIGATORS AND CLINICIANS
WHO ARE ENCOUNTERING
INDIVIDUALS WITH MULTIPLE
ETIOLOGY DEMENTIA ON A DAILY
BASIS.
THE IMPLEMENTATION OF SCIENCE
CAN IN TURN HELP INFORM HOW TO
INTEGRATE PRACTICAL TRAINING
METHODS BACK INTO THOSE
TRAINING PROGRAMS, TO
FACILITATE THE ADOPTION OF MED
CONCEPTS. AND ENSURE THAT NEW
AND EVOLVING MED TOOLS ARE
INTEGRATED IN RESEARCH STUDY
DESIGN, AND PATIENT MANAGEMENT
APPROACHES.
AND FINALLY, PROMOTING
EDUCATION ON THE USE OF NOVEL
DIAGNOSTIC TOOLS TO MORE
EFFECTIVELY AND EFFICIENTLY
IDENTIFY MULTIPLE ETIOLOGY
DEMENTIA, AND COMMUNICATE THOSE
FINDINGS WITH PATIENTS AND
THEIR FAMILIES.
NEXT SLIDE.
CURRENTLY THERE ARE MULTIPLE
CHALLENGES FACING THE DEMENTIA
WORKFORCE.
THESE REALLY BEGIN WITH
AWARENESS. AS WE HEARD TODAY
ALTHOUGH THE NEUROPATHOLOGY HAS
SHOWN IS THAT MULTIPLE ETIOLOGY
DEMENTIA IS A RULE NOT THE
EXCEPTION, ON A DAILY BASIS
MOST INDIVIDUALS ARE STILL PUT
INTO EIGHT SINGULAR DIAGNOSTIC
BUCKET. THAT IS THE ATTEMPT.
AND INCREASED AWARENESS OF THE
PERVASIVENESS OF MULTIPLE
ETIOLOGY DEMENTIA AND ITS
POTENTIAL FOR DIAGNOSIS AND
IMPACT , INPATIENT MANAGEMENT
AS NEEDED BUT HAVING ACCESS TO
EDUCATION AND HOW TO USE NOVEL
TESTS FOR MULTIPLE ETIOLOGY
EFFECTIVELY.
AND THIS CAN LEAD TO DELAYED
DIAGNOSIS AND POOR MITIGATION
OR PERCEIVED POOR COMMUNICATION
WITH PATIENTS AND FAMILIES
WHICH LEADS TO FRUSTRATING
ABOUT SIDES.
AND UNDER BASIC SCIENCE AND
CLINICAL TRIAL SITE
INVESTIGATORS NEED TO BE AWARE
OF THE POTENTIAL COMPOUNDS ON
MULTIPLE IDEOLOGY DEMENTIA.
FOR EXAMPLE IF YOU HAVE
MULTIPLE PATHOLOGY TRIALS, THE
TRIAL MAY FAIL BECAUSE IT HAS
NOTHING TO DO WITH EFFECTIVE
TREATMENT AGAINST ALZHEIMER'S.
NEXT SLIDE.
THIS RECOMMENDATION AIMS TO
ADDRESS THESE CHALLENGES IN TWO
MAIN WAYS.
THE FIRST IS PROMOTING TRAINING
PROGRAMS THAT PROVIDE CLINICAL
TRIAL INVESTIGATORS,
TRANSLATIONAL RESEARCHERS, AND
BASIC SCIENTISTS WITH SKILL
SETS TO INTEGRATE MULTIPLE
ETIOLOGY DEMENTIA PRINCIPLES
INTO RESEARCH STUDY DESIGN.
AND SO AGAIN THINKING ABOUT THE
UNDERLYING PATHOLOGIES OF THE
STUDY POPULATION, WHETHER THAT
IS IN CLINICAL TRIAL DESIGN,
TRANSLATIONAL STUDIES, OR BASIC
SCIENCE TO ENSURE THAT MODELS
OF MULTIPLE PATHOLOGIES ARE
INCORPORATED RATHER THAN
INDIVIDUAL PATHOLOGIES FOR
STUDY.
ALSO THE NEURAL PATHOLOGICAL
FOR CHARACTERIZATION, ENSURING
THE PATHOLOGISTS ARE PERFORMING
COMPLETE ASSESSMENT AND
DOCUMENTING AND COMMUNICATING
THE PRESENT MULTIPLE ETIOLOGIES
TO INFORM THE USE OF BY
SPECIMENS FROM BIOLOGICALLY
DIVERSE PARTICIPANTS.
FOR EXAMPLE OFTEN FIELD
REQUESTS FOR BY SPECIMENS FROM
DONORS AND THE REQUESTED THAT
HAVE ALZHEIMER'S OR DON'T HAVE
IT AND WHEN I MEET WITH
INVESTORS AND ASKED WHAT
PATHOLOGIES THAT WANT TO
INCLUDE OR EXCLUDE, THE CONCEPT
OF MULTIPLE ETIOLOGY DOESN'T
EVEN ENTER THE PICTURE.
AND SO FINALLY INFORMATICS TO
LEVERAGE THE COMPLEX COVERT AND
MODELING APPROACHES TO BETTER
UNDERSTAND HOW THEY RELATE TO
ONE ANOTHER AND THE CLINICAL
PRESENTATION.
NEXT SLIDE.
THE OTHER CLINICAL EMPHASIS IS
IMPLEMENTATION OF SCIENCE. IN
ORDER TO BUILD A MULTIPLE
ETIOLOGY-COMPETENT WORKFORCE WE
NEED TO UNDERSTAND WHAT THE
CHALLENGES ARE FOR IMPLEMENTING
NOVEL TESTS, AND APPROPRIATELY
INTERPRETING, AND USING THOSE
RESULTS.
WE ALSO NEED TO UNDERSTAND WHAT
THE MOST EFFECTIVE APPROACHES
ARE, TAKING INTO ACCOUNT THE
SETTING AND THE EDUCATIONAL
GOALS.
AND FINALLY LEARN HOW TO
INCREASE THE REACH OF THESE
EFFORTS TO GENERATE BROADER
ENGAGEMENT BOTH ON THE RESEARCH
AND CLINICAL SIDE.
>> TWO MINUTES.
>> ULTIMATELY THESE EFFORTS
WILL ADDRESS THOSE CHALLENGES
CURRENTLY FACING THE DEMENTIA
WORKFORCE AND WILL BE ASSESSED
BASED ON OUTCOMES RELATED TO
BOTH THE PATIENTS AS WELL AS
CLINICIANS AND RESEARCHERS.
SHORTER TIME TO DIAGNOSIS,
IMPROVED COMMUNICATION WITH
PATIENTS AND FAMILIES AND
ULTIMATELY BETTER PATIENT
EDUCATION AND SUPPORT.
THAT IS ALL I HAVE.
THANK YOU.
>> THANK YOU SO MUCH APPRECIATE
ALL THE MEMBERS FOR THEIR
CONTRIBUTIONS AND TO DR.
LATIMER, DR. FARDO AND DR.
IADECOLA FOR THE PRESENTATIONS.
>> THANK YOU. THE FIRST Q&A
SESSION FOR THE SESSIONS TODAY,
I WANT TO ENCOURAGE EVERYONE
WHO IS ON THE COMMITTEE TO GO
AHEAD AND TURN ON YOUR CAMERAS,
SO WE CAN SEE WHO ALL IS HERE.
FOR ANYONE ON THE COMMITTEE
SHOULD HAVE THE ABILITY TO USE
YOUR MICROPHONE AND CAMERA
UNDER YOUR CONTROL. THANK YOU.
>> FIRST BEFORE WE BEGIN OUR
DISCUSSION, AS WAS DONE
YESTERDAY, WE WANT TO WELCOME
TWO OF OUR COMMITTEE MEMBERS.
MR. AND MS. KAREN AND LARRY
SQUIRES (PHONETIC),
PARTICIPANTS WITH LIVED
EXPERIENCE WHO HAVE SHAPED THE
RECOGNITIONS OF OUR COMMITTEE.
I WILL TURN IT OVER TO KAREN
AND LARRY TO SHARE THEIR
EXPERIENCE. WELCOME AND THANK
YOU.
>> THANK YOU.
I HAVE A FEW COMMENTS. PLEASE
IF YOU HAVE WRITTEN THEM DOWN
BECAUSE I STRUGGLE WITH WORD
FINDING AND I DON'T WANT TO
MISS ANYTHING THAT IS
IMPORTANT, OR THAT I FEEL IS
IMPORTANT.
FIRST I WOULD LIKE TO THANK OUR
FELLOW MEMBERS OF THE COMMITTEE
FOR ALLOWING US TO PROVIDE
INPUT, AND CERTAINLY MAKING US
FEEL WELCOME. THANK YOU.
I HAD A 3-4 YEAR PATH TO MY
PROBABLE DIAGNOSIS THAT WAS
FILLED WITH MORE OBSTACLES THAN
ONE WOULD EXPECT, AND ANXIETY.
IT WAS DIFFICULT TO FIND
CLINICIANS WE FELT WERE
KNOWLEDGEABLE AND BECAUSE OF MY
ATYPICAL PRESENTATION. WE WORRY
FOR THOSE WE JUST DON'T KNOW
JUST HOW TO ADVOCATE FOR
THEMSELVES. AND I WAS LUCKY TO
HAVE KAREN WHO DID A WONDERFUL
JOB TO ADVOCATE AND RESEARCH.
KNOWING SOMETHING IS WRONG WITH
YOUR BRAIN, AND NOT HAVING
ANSWERS CREATES A TREMENDOUS
AMOUNT OF FEAR AND ANXIETY IN
YOUR LIFE. AND SIMPLY HAVING A
DIAGNOSIS OR A PROBABLE
DIAGNOSIS, RELIEVES SOME OF
THAT ISSUE. THAT IS PRETTY
MUCH IT FOR ME.
THANK YOU.
>> HE WOULD KEEP TALKING. I AM
CUTTING YOU OFF.
WE TALKED ABOUT THIS. WE CANNOT
COME UP WITH ANY OTHER MEDICAL
ISSUES WHERE YOUR DOCTOR SAYS
TO YOU, ALWAYS THINK YOU
PROBABLY HAVE THIS.
SO, YOUR WORK IS REALLY
CRITICALLY IMPORTANT TO BOTH
DEMENTIA PATIENTS AND THEIR
FAMILIES. WE JUST ASK THAT AS
YOU MOVE FORWARD WITH RESEARCH,
THAT YOU ALWAYS KEEP A CLEAR
VISION OF THE IMPACT YOUR
RESEARCH IS GOING TO HAVE ON
THOSE PATIENTS.
WILL IT EASE THE TIME AND
ACCURACY OF THE DIAGNOSIS?
WOULD REVERSE THE SITUATION?
HAVING RELIABLE BIOMARKERS
INDICATE THE PRESENCE OF
MULTIPLE ETIOLOGY IS CRITICAL.
AUTOPSY IS TOO LATE TO BE ABLE
TO DEAL WITH PATIENTS LIKE
THIS. AND TOO MANY CLINICIANS
STOP AT ALZHEIMER'S.
WE REALLY NEED ACCESS TO EASY
BRAIN DONATION AND
ENCOURAGEMENT FOR DONATION.
WE EVEN THOUGHT TODAY AS WE
WERE LISTENING TO EVERYBODY,
HEY, HE HAS HAD LOTS OF SCANS
AND LOTS OF TESTS DONE. WHAT
IS THE OPPORTUNITY FOR THOSE
WHO DON'T WANT TO DONATE THEIR
BRAIN TO BE ABLE TO GRANT
ACCESS TO THEIR SCANS AND TESTS?
TO PUT INTO THE RESEARCH.
>> MY OPINION IS THAT EVERYONE
SHOULD BE ASKED.
>> SO WE REALLY THANK YOU FOR
YOUR DEDICATION TO THIS
RESEARCH. AND AGAIN THANK YOU
FOR LETTING US PARTICIPATE.
>> DR. IADECOLA: IT IS OUR
PLEASURE AND PRIVILEGE TO WORK
WITH YOU. AND YOUR INPUT WAS
VERY IMPORTANT IN SHAPING,
KEEPING US FOCUSED. BECAUSE
PEOPLE (INDISCERNIBLE) WILL GO
IN VERY DIFFERENT DIRECTIONS
AND YOU KEPT US GROUNDED AND
YOU GIVE US AN IDEA OF WHAT WE
SHOULD BE SHOOTING UP FOR.
THANK YOU VERY MUCH FOR THAT.
>> BEFORE WE GO TO THE
QUESTIONS, IF I COULD MAKE A
COMMENT TOO. IT IS SUCH AN
HONOR TO BE ABLE TO SERVE HERE;
WE FOCUS ON RESEARCH BUT ALSO
WE ARE CONNECTED WITH AT LEAST
600,000 PEOPLE ACROSS THE US
AND SO AS CONSTANTINO SAID,
KEEPING YOU IN MIND WITH
EVERYTHING AND WANTING IT WOULD
LIKE TO EMPHASIZE IS WITH
MULTIPLE ETIOLOGY WE HAD IT
WRITTEN IN OUR TEXT BUT WE DID
NOT VERBALLY EMPHASIZE THAT WE
NEED TO GET THE FDA AND OTHER
REGULATORY BODIES INVOLVED TO
SOMEHOW TRY TO ACCELERATE
TREATMENTS AND PREVENTIONS.
RIGHT?
BECAUSE RIGHT NOW IF YOU DEAL
WITH EACH ONE OF THESE FOUR OR
MORE BIOMARKERS AT A TIME IT
WILL BE LIKE 20-30 YEARS BEFORE
YOU TRY TO PUT ALL
ACCOMMODATIONS TOGETHER. SO IF
YOU CAN BRING THE FDA AND OTHER
REVELATORY BODIES IN TO TRY TO
ACCELERATE GETTING NEW
TREATMENTS TO THE CLINIC, THAT
WILL HELP AFFECTED FAMILIES.
>> SHALL WE GO TO THE QUESTIONS
CINDY?
>> CINDY YOU ARE MUTED.
>> DR. CARLSSON: SORRY ANY
QUESTIONS OR COMMENTS?
>> WE HAVE SYLVIA-- ASKING A
QUESTION. SYLVIA, GO AHEAD.
>> THANK YOU.
THANK YOU THIS WAS A GREAT
SESSION. AND AS YOU ALL
SHOWED, AND HIS I WILL
REITERATE IN THE BCIB SESSION,
THE GREAT MAJORITY OF DEMENTIA
IS A COMBINATION OF ALZHEIMER'S
AND VASCULAR PATHOLOGY.
I WAS WONDERING IF WE SHOULD
INTENSIFY EVEN MORE IN THE
RECOMMENDATIONS, THAT IS VERY
IMPORTANT TO STUDY ALZHEIMER'S,
NOT IN ISOLATION AND VASCULAR
PATHOLOGY, NOT IN ISOLATION BUT
A COMBINATION OF THESE TWO
PATHOLOGIES IN PARTICULAR.
>> WELL, YOU ARE PREACHING TO
THE CHOIR.
>> NOTED.
>> DR. IADECOLA: OBVIOUSLY,
VASCULAR PATHOLOGY FOUND ITS
WAY IN ALL KINDS OF COGNITIVE
IMPAIRMENT. IT WOULD BE VERY
IMPORTANT BEING THE MOST
PREVALENT CONDITION. AND THE
INTERACTION BETWEEN YOUR
RECOMMENDATION AND OURS IS
GOING TO TELL US WHAT TO DO AND
HOW TO MOVE FORWARD.
>> EXACTLY AND WE WANT TO TELL
THE NIH THAT THIS PARTICULAR
COMBINATION IS REALLY
IMPORTANT.
>> YEAH.
>> AND IF I COULD MAKE A
COMMENT, THE EYE IS AN
EXTENSION OF THE BRAIN AND
REALLY GOOD WINDOW TO THE BRAIN
AND USING THE EYE TO DIAGNOSE
FASTER AND CHEAPER-- IT IS A
LOT CHEAPER WITH THE
FIVE-MINUTE SCAN, THEN GOING
FOR A REALLY EXPENSIVE BRAIN
SCAN. SO TALKING ABOUT THE
CROSSOVER, LET'S BRING THE EYES
IN AS WELL.
>> NICOLE DO YOU WANT TO GO
FORWARD?
>> YES HI I'M A NAME IS
NICOLE-- FROM THE ASSOCIATION
OF (INDISCERNIBLE) NOT SURE
THIS IS THE RIGHT GROUP BUT I
AM WONDERING IF THERE IS
THINKING ABOUT THE TRAINING OF
POTENTIAL PEOPLE WORKING IN
THIS AREA AND ACROSS RELATED
DEMENTIAS LOOKING AT BEST
PRACTICES FOR CARE REALLY
UNDERSTANDING STATISTICALLY, IS
THIS MEANINGFUL?
IS THIS BENEFICIAL?
AND PROVIDING QUALITY OF LIFE
AND WELL-BEING ASSESSMENTS FOR
THESE PEOPLE AND CAREGIVERS.
ESPECIALLY WHO ARE SUFFERING
FROM THESE DEMENTIAS.
IS THERE A PLACE IN EITHER THIS
GROUP OR OTHERS WE CAN
HIGHLIGHT I GUESS STUDYING OF
WELL-BEING FOR THESE DEMENTIAS?
>> INTERACT DIRECTLY WITH HOW
OUR COMMITTEE, AND THE
EDUCATION ELEMENT GOES INTO THE
COMMITTEE THAT WE SAW
YESTERDAY.
>> AND NOTING THIS. THANK YOU
VERY MUCH NICOLE. I THIS IS
SOMETHING WE CAN LOOK TO
INCORPORATE IN THE MED
IMPLEMENTATION SESSION THAT WAS
PRESENTED YESTERDAY, WHICH HAS
A RECOMMENDATION ON CARE.
AND WE WILL SEE IF THIS CAN FIT
INTO THE TRAINING
RECOMMENDATION HERE. THANK YOU
FOR THAT IMPORTANT COMMENT.
CAITLIN, ANYTHING TO ADD?
>> NOTHING SPECIFIC I THINK
THAT WE NEED TO-- INTEGRATING
YESTERDAY'S AND TODAY'S, IN HOW
WE ARE TREATING PATIENTS AND
MAKING SURE THAT THERE IS GOOD
COMMUNICATION I THINK ACROSS
BOTH SIDES FROM BENCH TO
BEDSIDE IS GOING TO BE REALLY
IMPORTANT.
>> BETSY?
DO YOU WANT TO GO AHEAD?
>> YES THANK YOU SO MUCH, TO
THE DEGREE THAT WE CONSIDER
PCPS AS PART OF THE DEMENTIA
WORKFORCE, HOW CAN WE NORMALIZE
SIMPLE, NONINVASIVE SCREENINGS,
COGNITIVE SCREENINGS AS PART OF
WELLNESS EXAMS IN MUCH THE SAME
WAY THAT WE NORMALIZE NOW COLON
CANCER SCREENINGS AFTER A
CERTAIN AGE, TO DIFFUSE THE
FEAR OF THE GENERAL POPULATION
AND JUST TO CAPTURE PEOPLE AT A
MUCH EARLIER STAGE AND
IMPORTANTLY, I'M WONDERING FROM
THE MEDICAL PERSPECTIVE, FROM
THE PCP PERSPECTIVE, IS VERY
CONCERNED ABOUT HOW THESE WOULD
BE BILLED, ANY CONCERN ABOUT
THE PCP COMMUNITY THEY MAY HAVE
TROUBLE GETTING REIMBURSED FOR
THE SERVICES UNDER MEDICARE AND
COMMERCIAL CARRIERS CATCH UP TO
THE IDEA THAT WE SHOULD BE
DOING THESE SCREENINGS.
>> THANK YOU (INDISCERNIBLE).
>> THANK YOU SO MUCH. I
APPRECIATE THAT. I ALSO READ
YOUR COMMENT AND EMAIL
YESTERDAY ABOUT THIS. BY THE
WAY WE READ EVERY SINGLE THING
YOU SENT TO US. THANK YOU SO
MUCH FOR THIS COMMENT.
THIS IS ESSENTIAL TO THE
RECOMMENDATION ON DIAGNOSIS
FROM THE MED IMPLEMENTATION
COMMITTEE YESTERDAY. BUT I
APPRECIATE SOME OF THE LANGUAGE
THAT YOU OFFERED AROUND
NORMALIZING THIS FOR PCPS. AND
ALSO THE FOCUS ON BILLING.
WE ARE GOING TO THINK ABOUT
YOUR COMMENTS AS WE REVISE THAT
RECOMMENDATION.
>> THANK YOU.
>> I WAS GOING TO ADD, I THINK
ONE OF THE OTHER CONSIDERATIONS
THAT PEOPLE HAVE, IS SUCH
VARIED BACKGROUNDS AND
EDUCATION. WE NEED TO MAKE SURE
WE DON'T OVER DIAGNOSE.
SOMETIMES HARD TO COMMUNICATE
INTO BUSY, PRIMARY CARE
PRACTICES. NOT BEING ABLE TO
STICK WITH THE COGNITIVE POINT,
HOPEFULLY A COMBINATION OF
BIOMARKERS AND TRAINING AND
COGNITIVE SCREENING TO BE
COMBINED, AND NOT OVERDIAGNOSED
AND LABEL SOMEONE, AND
APPROPRIATE TO MOVE THEM
FORWARD.
>> I WILL ADD TOO THAT WITH THE
ID CONSORTIUM FUNDED BY THE
NINDS, WE ARE DOING RESEARCH
EVALUATE PATIENTS FOR THE BRAIN
HEALTH WHEN THERE IS A CONCERN,
RATHER THAN SCREENING
EVERYBODY. WE ARE TRYING
PATHWAYS WE ARE ASKING IF THERE
IS A CONCERN IN A SYSTEMATIC
WAY. BUT NOT ADVOCATING AT THIS
POINT FOR DOING A FULL
EVALUATION ON EVERY PERSON OF
OLDER AGE. BECAUSE THERE ARE
CONCERNS ABOUT FALSE POSITIVES,
AND RESOURCES AND PRIMARY CARE
TO PUSH FORWARD AT THIS TIME.
IT IS SOMETHING WE ARE ALWAYS
THINKING ABOUT. AND THE
PRACTICE AND RECOMMENDATIONS ON
THAT MAY CHANGE IN THE FUTURE.
ESPECIALLY AS BETTER TREATMENTS
ARE AVAILABLE.
>> BEN?
>> YES. HI, THANK YOU. AND
GREETINGS FROM DRESSLER
UNIVERSITY.
YESTERDAY WE HEARD A LOT ABOUT
BIOCHEMICAL MARKERS, ABOUT
TECHNOLOGIES AND BRAIN IMAGING.
I'M WONDERING WHY WE HAVE NOT
HEARD SO MUCH ABOUT HUMAN
MOVEMENT, OR MOBILITY AND
BIOMECHANICS.
>> I GUESS DAVID SHOULD ADDRESS
THAT, MAYBE?
>> DR. FARDO: YES SURE. I OUR
RECOMMENDATION IS BROADLY FOR
BIOMARKER, BRINGING IN
BIOMARKERS NOT NECESSARILY FROM
A SPECIFIC DOMAIN. SO, IT'S ...
OPEN TO THE FLAVOR OF
BIOMARKER, THE CRUX FROM THE
DATA PERSPECTIVE IS WE CAN DO
THINGS THAT ARE SHARED ACROSS
DIFFERENT GROUPS IN A WAY THAT
WE HAVE APPLES TO APPLES; AND
CAN GARNER MORE RESOURCES
ACROSS INSTITUTIONS, SO THAT WE
CAN BETTER POWER OUR STUDIES.
>> DR. IADECOLA: AND I THINK
CORRELATING THE TRADITIONAL
BIOMARKER WITH MOVEMENT,
BIOMECHANICAL BIOMARKERS, HAS
REALLY PANNED OUT. BECAUSE
SLOWING OF THE MOVEMENT IS
RELATED TO WHITE MATTER DISEASE
FOR EXAMPLE. SO WE ARE ALREADY
ON THAT TRACK, AND I WE SHOULD
EMPHASIZE THAT MOVING FORWARD.
SO THANK YOU VERY MUCH FOR THE
COMMENT.
>> DR. CARLSSON: WE TRY TO
CAPTURE THAT SO WE INITIALLY
HAD A LOT OF DIFFERENT TYPES OF
BIOMARKERS. AND SO WE GROUPED
THEM UNDER NEUROPHYSIOLOGICAL.
YOUR COMMENTS ARE WELL TAKEN
AND THERE WILL BE NEW MARKERS
PROMISING TO CAPTURE NEW ASPECT
WE HAVEN'T BEFORE. THANK YOU
FOR THAT.
>> JULIE?
>> JULIETTE -- THANK YOU.
ONE STUDY OF ALZHEIMER'S
DISEASE IN THE BRAIN BUT ALSO
IN THE EYE, THE LENS AND
RETINA, I ENDORSE WHAT DIANE
SAID ABOUT THE EYE. IT IS A
WINDOW INTO THE BRAIN AND CAN
BE CHEAPER AND EASIER ACCESS TO
ACCESS THE BRAIN FOR PATIENTS.
ONE POINT BEFORE DIANE EVEN
SAID THAT IS I WANT IS A BUSY
BIOLOGIST TO GET MORE INTO IPAC
CELLS MENTIONED AS MODELS, TO
STUDY THESE MEDS.
WHAT ABOUT MICE MODELS?
EXPANDING MODEL AD, THAT IS
MORE RELEVANT MOUSE MODELS,
WILL THAT BE EXPANDED TO BRING
DIFFERENT PATHOLOGIES TO
DIFFERENT MOUSE MODELS?
>> DR. IADECOLA: ABSOLUTELY ONE
STANDARD WAY OF DOING IT. ONE
INTERESTING ASPECT IS THAT
MODELS OF PATHOLOGIES, COMING
FROM DIFFERENT COMMUNITIES
WHICH DO NOT NECESSARILY TALK
TO EACH OTHER. FOR EXAMPLE AS
YOU WILL SEE THERE IS A LOT OF
VASCULAR PATHOLOGY BEING
DEVELOPED IN MICE THAT WOULD BE
WORTH CROSSING WITH MOUSE WITH
MORE NEURODEGENERATIVE
PATHOLOGY. AND WE NEED
INCENTIVES TO FACILITATE THOSE
INTERACTIONS, STARTING WITH
EXISTING MODELS, AND MOVING
THAT TO THE NEW MODELS AND SO
ON. VERY IMPORTANT POINT. THANK
YOU.
>> WE HAVE TIME FOR ONE LAST
QUESTION, WE ARE TECHNICALLY
OUT OF TIME.
I ENCOURAGE ANYBODY ELSE TO
PLEASE BRING YOUR QUESTIONS AND
COMMENTS FOR FURTHER PUBLIC
TIME THIS AFTERNOON.
>> THANK YOU AMBER.
>> CAN YOU HEAR ME?
MY NAME IS PEPAN CANN
(PHONETIC), WORKING THIS MODEL
IN THIS COMPANY, DEVELOPING
AI-BASED (INDISCERNIBLE)
TECHNOLOGY AND WORKING
PREVIOUSLY AT THE ROCKEFELLER
INSTITUTE (INDISCERNIBLE).
MY QUESTION IS, WILL YOU
CORRELATE ALL THESE BIOMARKERS?
BLOOD TESTS, SKIN TESTS, WITH
MULTIPLE ETIOLOGY OF DEMENTIA?
>> DR. IADECOLA: LOOKS LIKE
DAVID'S NAME IS WRITTEN ON THAT
ONE.
>> THAT IS WHERE YOU COME IN.
>> DR. FARDO: WE ARE ADVOCATING
FOR FUNDING FOR THOSE EFFORTS.
IT IS NOT TRIVIAL.
I THINK OF THINGS IN CAUSAL
DIAGRAMS AND DR. IADECOLA
PRESENTED ONE ABOUT MULTIPLE
PATHOLOGIES EFFECTIVE COGNITIVE
DECLINE, POTENTIALLY GOING
BACK.
THOSE ARE ADVANCED STATISTICAL
METHODOLOGIES THAT ARE REQUIRED
TO BE ABLE TO ANSWER THOSE
SPECIFIC QUESTIONS.
AND SO THE ABILITY FOR US TO
EVEN ENTERTAIN THOSE IS
DEPENDENT ON A COMMON
CLASSIFICATION OR CONSENSUS
CLASSIFICATION SO WE CAN AGAIN
COMPARE APPLES TO APPLES. AT
LEAST READ APPLES AND GREEN
APPLES, RATHER THAN APPLES TO
ORANGES.
>> DR. ERTEKIN TANER:
SORRY FOR MIGHT ADD TO THAT
BEFORE YOU RESPOND. I THIS IS
WHERE IS A NONPROFIT FUNDER WE
TO GET AS MANY FUNDERS
TOGETHER, PUBLIC/ PRIVATE
PARTNERSHIPS AND MOVE TOWARDS
GUARANTORS FUNDING THESE.
>> USED TO SAY
(INDISCERNIBLE)... WE
(INDISCERNIBLE) AT THE
ROCKEFELLER INSTITUTE IN 2006.
WE DON'T HAVE THAT MUCH
MULTIPLE ETIOLOGY. WE HAVE
AROUND (INDISCERNIBLE)... WHAT
WE ARE DOING IN SMALL
BUSINESSES AND SMALL COMPANIES,
NOT CURRENT. OKAY, THIS IS FOR
ALZHEIMER'S DISEASE, WE ONLY
HAVE (INDISCERNIBLE). THE REST
IS MIXED DEMENTIA.
BRAIN IMAGING AND
(INDISCERNIBLE) DIFFERENT
REGIONS. SPECIFIC TO DIFFERENT
DISEASES FOR EXAMPLE VASCULAR
DEMENTIA, ALZHEIMER'S OR LOU
GEHRIG'S DISEASE.
OR WHAT SPECIFIC AGE OF
ETIOLOGY (INDISCERNIBLE)....
PARTICULAR PATHOLOGY.
WE ARE WORKING ON THAT DATA
SET.
>> THANK YOU.
>> IS THAT CORRECT OR NOT?
(INDISCERNIBLE)
HOW DO WE GO FOR MOLECULES?
>> I THINK WE DEFINITELY HEAR
YOUR QUESTION.
AND REALLY APPRECIATE YOUR
QUESTIONS AND THINKING. I THINK
EVERYONE AGREES THAT IS A
RESEARCH QUESTION THAT IS
ACTIVELY PURSUED. WE WILL GO TO
LUNCH RIGHT NOW AND COME BACK
FOR AN ON-TIME START AT 12:40 EASTERN TIME.
SO RACHEL, WE HAVE THE SLIDES FOR LUNCH BREAK? THANK YOU.
>> WE ARE BACK.
DO WE HAVE OUR FIRST SESSION 6
PRESENTERS ONLINE?
>> YES WE COULD HEAR SOMEBODY.
>> I BELIEVE DR. GALVIN IS UP
FIRST.
>> DR. GALVIN: OKAY SHOULD I
START?
>> YES. I THINK IT IS SLOW TO
LOAD ON MY SIDE. I AM GOOD.
WELCOME BACK EVERYBODY.
>> DR. GALVIN: MY NAME IS DR.
JIM GALVIN, A NEUROLOGIST AT
THE MIAMI UNIVERSITY SCHOOL OF
MEDICINE AND I AM GLAD TO
CULTURE LIVES WITH KATHLEEN
POSTON.
I HAVE A BRIEF INTRODUCTION AND
I WANT TO INTRODUCE THE
COMMITTEE.
NEXT SLIDE.
WONDERFUL GROUP OF TALENTED
PEOPLE WHO HAVE MET OVER THE
PAST SEVERAL MONTHS TO CREATE
THIS PRESENTATION.
I WANT TO THANK NIH AND NINDS
FOR THE OPPORTUNITY TO PRESENT
THESE RECOMMENDATIONS AND
PRIORITIES FOR LEWY BODY
DEMENTIA.
TODAY WILL COVER FOUR
RECOMMENDATIONS AND TWO
PRESENTERS WILL DISCUSS TWO
PRIORITIES EACH.
JUANTOLEDO ATUCHA WILL TALK
ABOUT LBD CLINICAL TRIALS AND
ELIZABETH MORMINO WILL TALK
ABOUT BIOMARKERS, AND BRITTANY
DUGGER WILL TALK ABOUT GENOMIC
AND MULTI-OMICS AND ALICE
CHEN-PLOTKIN WILL TIE ALL THIS
TOGETHER.
WHAT IS IMPORTANT IS WE TRY TO
TAKE AS MUCH INFORMATION AS WE
COULD, AND ORGANIZES INASMUCH
OF ALOGICAL SET OF
ACCOMMODATIONS AND PRIORITIES
WITH ACTION PLANS, WITH
INTERMEDIATE AND FUTURE
LONG-TERM GOALS.
I WILL LIKE TO TURN HER OVER TO
DR. JUANTOLEDO ATUCHA, WHO WILL
LEAD US TO THE FIRST SERIES OF
RECOMMENDATIONS.
>> DR. TOLEDO ATUCHA: CAN I
HAVE MY SLIDES?
NEXT SLIDE.
I WANT TO THANK ALL THE
COMMITTEE MEMBERS FOR THE
PARTICIPATION, THOUGHTFUL IDEAS
AND THE NIH FOR GIVING US THE
OPPORTUNITY TO PRESENT THIS.
ALL THE VIEWS THAT WE PRESENT
HERE ARE FROM THE COMMITTEE
MEMBERS AND DO NOT REFLECT THE
OFFICIAL POLICY OF NATIONAL
INSTITUE OF NEUROLOIGCAL
DISORDERS AND OR THE NIH.
I WILL TALK WITH THE FIRST AND
SECOND RECOMMENDATIONS OF THE
LEVY BODY DEMENTIA GROUP.
THE FIRST WILL DEAL WITH
CLINICAL TRIALS. THE MAIN
RECOMMENDATION IS TO EXPAND THE
LEVY BODY DEMENTIA CLINICAL
TRIAL INFRASTRUCTURE AND
PERFORM TRIALS THAT ALLOWS TO
(INDISCERNIBLE) EITHER DELAYING
OR PREVENTING THE ONSET OF
SYMPTOMS. BUT WE AGREE IT IS
IMPORTANT TO HAVE MEDICATIONS
ALLEVIATED CLINICAL SYMPTOMS,
EVEN IF THEY ARE NOT DISEASE
MODIFYING.
NEXT SLIDE.
NEXT. I THOUGHT WE TOOK OUT THE
ANIMATION. SORRY; HERE WHAT WE
ARE SEEING ARE (INDISCERNIBLE),
SUMMARIZING ALL THE CLINICAL
TRIALS PERFORMED AND LEVY BODY
DEMENTIA.
THERE HAS BEEN AN INCREASE IN
2022, HERE IS THE UPDATED GRAPH
FOR 2025 SO YOU CAN SEE IN
BLACK INK THE CURRENT NEW
CLINICAL TRIALS FOR LEVY BODY
DEMENTIA. AND GREY ARE THE ONES
THAT WERE STARTED BEFORE AND
ARE STILL ONGOING.
THE ONES I CIRCLE HERE ARE THE
ONES THAT RECENTLY WE READ. AND
WE CAN SEE ON THE NEXT SLIDE
THE RESULTS. IN THESE
PRE-CLINIC TRIALS READ THE
RESULTS AT THE INTERNATIONAL
LEVY BODY DEMENTIA CONFERENCE
IN AMSTERDAM IN JANUARY.
WE ARE PLEASED THE THREE OF
THEM SHOW POSITIVE SIGNALS, TO
DIFFERENT DEGREES, AFFECTING
SYMPTOMS THAT WERE MOTOR,
BEHAVIORAL AND COGNITIVE.
THESE WERE TRACED TO AN OVERALL
IDEA THAT IT WILL MOVE TO
(INDISCERNIBLE) FOR MEDICATION.
NEXT SLIDE.
THERE HAS BEEN ALSO AN EFFORT
TO INCREASE ON THE LEFT-HAND
SIDE YOU SEE IMPACT IDEA, THIS
IS A COMBINED EFFORT OF THE NIH
AND THE ALZHEIMER'S ASSOCIATION
TO TRAIN AN INCREASE IN THE
GENERATION OF CLINICAL TRIALS,
RESEARCH COORDINATORS AND BRING
SMALL COMPANIES INTO CLINICAL
TRIALS, AND ALSO THE LEVY BODY
DEMENTIA ASSOCIATION INCREASING
A NETWORK OF RESEARCH CENTERS
OF EXCELLENCE ACROSS THE UNITED
STATES TO OFFER A CLINICAL CARE
AND ACCESS TO CLINICAL TRIALS
TO PEOPLE WHO ARE LIVING WITH
LEVY BODY DEMENTIAS.
NEXT SLIDE.
BUT WE STILL ...NEXT... NEXT...
SO WE IDENTIFIED THERE ARE
STILL SEVERAL GAPS.
ONE IS THE LIMITED NUMBER OF
LEVY BODY DEMENTIA CLINICAL
TRIALS.
YOU REMEMBER THE ONES IN BLACK
WITH THE ACTIVE CLINICAL TRIALS
AND YOU CAN COMPARE THESE TO
THE SAME RESULTS FOR-- FOR THE
SAME ACTIVE TRIALS FOR
ALZHEIMER'S DISEASE AND
PARKINSON'S DISEASE. YOU CAN
SEE THERE ARE MANY MORE. AND
THERE ARE LIMITED
(INDISCERNIBLE) OF LEVY BODY
DEMENTIA INTO CLINICAL TRIALS
AND WE ARE LACKING LBD SPECIFIC
CLINICAL SCALES AS PREVIOUS
PRESENTATIONS WE NEED
HARMONIZATION OF CLINICAL
MEASURES, AND THERE IS A
LIMITED INFRASTRUCTURE.
NEXT SLIDE.
BASED ON THESE COMMENTS WE FELT
WE NEEDED TO PROMOTE LEVY BODY
CLINICAL TRIALS AND EXPAND THE
FOOTPRINT AND SCOPE. THE
SUBJECT WILL LIKELY COME FROM
THE MIL. 5-8 AND SECOND WE WILL
HAVE THE DESIGN AND SELECTIONS
BASED ON THE CLINICAL TRIALS
AND WE WANT TO PROMOTE UPLOAD
SELECTION OF CLINICAL TRIAL
PARTICIPANTS ACROSS DIFFERENT
STAGES, AND PRESENTATIONS FOR
AT RISK GROUPS.
BY 2029 WE LOOK FORWARD TO
HAVING AT LEAST ONE ADDITIONAL
AGENT TARGETING THESE
MODIFICATIONS AT LEAST ONE PER
PURPOSE TRACK. WE SHOULD HAVE
REACHED TWO ADDITIONAL AGENTS
OF DISEASE QUALIFICATIONS AND
SYMPTOMATICAL TREATMENT
ENTERING CLINICAL TRIALS.
TO ACHIEVE THIS WE NEED TO
ENHANCE THE CLINICAL
INFRASTRUCTURE SUPPORTING LEVY
BODY DEMENTIA TRACK
DEVELOPMENT. THIS WOULD PUT AT
THE PHASE 0 CLINICAL TRIAL
STAGE, GET THOSE FACILITIES AND
PERSONNEL BUT BRINGING NEW
PEOPLE, SO WE NEED TO BRING
INTO THE FIELD RESEARCHERS INTO
LEVY BODY DEMENTIA.
THERE ARE NOT THAT MANY
VALIDATED SCALES FOR LEVY BODY
SPECIFICALLY AND WE NEED TO
REFINE THEM TO HAVE THE MOST
ACCURATE CLINICAL TRIAL OUTCOME
MEASURES. SO WE NEED THESE
SPECIFIC SCALES THAT CAPTURE
ALL THE SIGNS AND SYMPTOMS THAT
ARE PRESENT IN LEVY BODY
DEMENTIA.
WE ALSO NEED TO-- THIS IS
(INDISCERNIBLE) ENHANCE OPEN
SOURCE INFRASTRUCTURE TO AID IN
STREAMLINING THE SHARING OF
DATA AND SAMPLES COLLECTED IN
CLINICAL TRIALS.
WE NEED TO HARMONIZE AND HAVE
GENERALIZABLE MEASURES ACROSS
THE LBD CLINICAL TRIAL SO WE
CAN COMPARE APPLES TO APPLES
THE RESULTS.
NEXT SLIDE.
SO HERE WE ARE GOING TO BE
MOVING TO THE LBD COHORTS.
HERE THE RECOMMENDATIONS ARE TO
EXPAND AND DEVELOP CLINICALLY,
BIOLOGICALLY AND GENETICALLY
PHENOTYPE COHORTS. AS WE SAW IN
PRE-IS PRESENTATIONS THESE ARE
COMPLEX PROBLEMS THAT NEED TO
BE TACKLED FROM MULTIPLE
ANGLES. REFILL THESE BOARDS
WOULD REPRESENT THE USE
POPULATION OF INDIVIDUALS WILL
HAVE LEVY BODY DEMENTIA. AND
THIS FRAMES ON THE
PRE-SYMPTOMATICALLY STAGES TO
AUTOPSY.
NEXT SLIDE.
THERE ARE SEVERAL COVERT
LOOKING AT THIS FROM DIFFERENT
ANGLES. ALWAYS SHOW THE RESULTS
OF THE US LEVY BODY DEMENTIA
CONSORTIUM SPONSORED BY NINDS.
THERE ARE ADDITIONAL COHORTS
LOOKING AT PARKINSON'S DISEASE;
AND THEY ARE ADEQUATE LEGAL
STATUS SO NINDS IS SUPPORTING
NAPS LOOKING AT BRAIN DISORDER
SLEEPING BEHAVIOR, WHICH IS A
CLINICAL STAGE FOR PARKINSON'S
AND LEVY BODY DEMENTIA. AND
PPMI IS LOOKING AT MULTIPLE
STAGES OF PARKINSON'S DISEASE,
AT THE (INDISCERNIBLE), GENETIC
COHORT SPEARHEADED BY THE --
FOUNDATION AND THERE WILL BE
ADDITIONAL COHORTS THROUGH THE
CENTERS OF EXCELLENCE NETWORK
AND WE WILL SHOW SOME DATA
ABOUT THAT LATER.
THERE ARE SOME OF THE STUDIES
OR COHORTS ABOUT MORE SPECIFIC
ACTS. -- LOOKING AT THE
BIOMARKERS AND FITS FOR MANY OF
THE COHORTS WE TALKED TODAY TO
OFFER -- (INDISCERNIBLE) AND
GP2 IS FOCUSING ON THE GENETICS
IN THEIR EFFORTS TO HARMONIZE
WITH EUROPEAN COHORTS AND OTHER
COLLEAGUES TO GET COMMON
ELEMENTS. THIS HAS BEEN DONE IN
THE INTERNATIONAL LEVY BODY
DEMENTIA CONFERENCE, 2019,
2022, 2025.
NEXT SLIDE.
HERE I'M PRESENTING SOME
RESULTS OF NAPS, THE
(INDISCERNIBLE) COHORT. THE
RECENTLY PRESENTED THE BASELINE
DATA AND THEY ALSO SHOWED HOW
THEY WERE ABLE TO VALIDATE AN
RPD SPECIFIC SKILL THAT CAN BE
USED IN CLINICAL TRIALS AND
CLINICAL PRACTICE ALSO THE
PPMI, HAS BEEN A RECENT
IMPLEMENTATION OF SOME
BIOMARKERS THAT WILL BE
PRESENTED LATER THAT HELP WITH
THE BIOLOGICAL DEFINITIONS OF
LEVY BODY DISEASE ALTHOUGH WE
ARE FINDING THAT THERE ARE SOME
CLINICAL SYMPTOMS OF DISEASE
WILL HOW THE INTERACTION
ANALOGIES THAT AFFECT
CORRELATION WITH BIOMARKERS AND
THE OVERALL RESULTS.
NEXT SLIDE.
AND THE US LBD CONSORTIUM WILL
EVALUATE THE (INDISCERNIBLE),
AND HOW PREVALENT THE
BIOMARKERS ARE. AND WE KNOW
THEY AFFECT THE CLINICAL
PROGRESSION AND IT WILL BE
IMPORTANT FOR THE DESIGN OF
CLINICAL TRIALS IN DLB FOR HALF
OF THE PEOPLE THEY EVALUATE THE
BIOLOGICAL DEFINITION OF
BIOMARKERS...
>> TWO MINUTES..
>> DR. TOLEDO ATUCHA: THANK
YOU. WE RECEIVED OVER 6000
PEOPLE WERE EVALUATED FOR
DIFFERENT DEMENTIAS. 500 OF
THEM HAVE LEVY BODY DEMENTIA,
BUT FROM THIS GROUP LESSON 1/4
HAD LDB SKILLS.
CLINICAL SCALES. WE NEED THESE
COHORT SO THEY CAN FEED THE
NEXT RECOMMENDATIONS THAT WILL
BE PRESENTED.
NEXT SLIDE.
SO, OUR RECOMMENDATIONS TO
EXPAND AND DEVELOP A COHORT
THAT ENCOMPASSES ALL THE STAGES.
WE WANT MORE FREQUENT
ASSESSMENT. AND WE ALSO THINK
THE DIGITAL TOOLS AND BIO FLUID
COLLECTION WILL BE HELPFUL TO
GET MORE TESTING, THIS WILL
HELP THE RECOMMENDATIONS 3-5.
WE THINK THAT THIS PARTICIPANT
IN THE STUDY SHOULD BROADLY
REPRESENT US INDIVIDUALS LIVING
WITH (INDISCERNIBLE).
NEXT SLIDE.
WE WILL NEED PHENOTYPING OF
CRITICAL MEASURES. BUT WE ALSO
WANT TO INCLUDE MEASURES THAT
INCLUDE (INDISCERNIBLE),
COMORBIDITY CONDITIONS AND
CO-PATHOLOGIES AND DIGITAL BIO
MARKERS, WE NEED TO TRAIN
WORKFORCE WITH THE DIFFERENT
SKILLS AND EXPAND THE SCOPE OF
RESEARCH ON THE PROBLEM THAT IS
AVAILABLE THAT WE HAVE SHOWN IS
VERY REDUCED.
AND THE COMMON TOPIC TODAY,
HARMONIZATION OF DATA IS
NECESSARY ACROSS THE COHORT.
WE NEED TO DEVELOP GUIDELINES
TO HARMONIZE STUDIES AND
FACILITATE COMPARISONS.
NEXT I WILL GIVE THE PODIUM TO
DR. MORMINO TO TALK ABOUT
BIOMARKERS.
>> DR. MORMINO: THANK YOU I AM
FROM THE COMMITTEE THAT DO NOT
REFLECT THE POLICY OF THE
NATIONAL INSTITUE OF
NEUROLOIGCAL DISORDERS AND
STROKE OR NIH.
IN THE SPACE BIOMARKERS THAT
CAPTURE HALLMARK DISEASE
PATHOLOGIES AND THE PROGRESSION
OF THESE PATHOLOGIES HAVE BEEN
CRITICAL FOR OUR UNDERSTANDING
OF THE NATURAL HISTORY OF
ALZHEIMER'S DISEASE.
THIS BIOMARKER WORK HAS ALSO
BEEN CRITICAL FOR CLINICAL
TRIAL DESIGN IN THE AD SPACE.
THIS INCLUDES BOTH ENROLLMENT
OF INDIVIDUALS INTO TRIALS,
STRATIFICATION OF ANALYSES, AND
ALSO ASSESSMENT OF DISEASE
MODIFICATION.
AND VERY RECENTLY IN THE AD
SPACE WE ARE SEEING THESE
BIOMARKERS USED IN THE ACTUAL
CLINICAL CONTEXT FOR DECISIONS
SURROUNDING ANTI-AMYLOID
THERAPIES.
NEXT SLIDE.
YEAH, IN PARALLEL TO THESE AD
EFFORTS MULTIPLE RECENT
FRAMEWORKS HAVE BEEN PROPOSED
IN THE LEVY BODY SPACE
HIGHLIGHTING OPPORTUNITIES TO
LEVERAGE BOTH DISEASE SPECIFIC
BIOMARKERS AND BIOMARKERS OF
PROGRESSION TO UNDERSTAND LEVY
BODY PROGRESSION AND CLINICAL
DESIGN IN RESEARCH CONTEXT.
THIS FORMS THE BACKGROUND FOR
THE TWO RECOGNITIONS I'M GOING
TO GO OVER. RECOMMENDATION 3 IS
FOCUSED ON DIAGNOSTIC
BIOMARKERS, DISEASE SPECIFIC TO
REFINE AND VALIDATE EXISTING
BIOMARKERS IN THIS CONTEXT AND
ALSO DEVELOP NEW BIOMARKERS
RELATED TO ACTUAL LEVY BODY
PATHOLOGY.
AND ALSO APPLY THESE BIOMARKERS
IN THE CONTEXT OF MULTIPLE
ETIOLOGY DEMENTIA.
NEXT SLIDE.
SO WE HAVE SEEN TRULY
REMARKABLE BREAKTHROUGHS
RECENTLY IN THE FIELD, WITH THE
SUCCESS OF ROBUST BIOMARKERS
MEASURING ALPHA (PHONETIC)
NUCLEI PATHOLOGY IN VIVO,
AVAILABLE FOR SPINAL FLUID AND
SKIN BIOPSIES HIGHLY SPECIFIC
INITIAL VERY GOOD SENSITIVITY
TO UNDERLYING PATHOLOGY.
PAVING THE WAY FOR IMMEDIATE
OPPORTUNITIES RELATED TO
DIFFERENTIAL DIAGNOSIS AND
EARLY DETECTION OF THESE
PATHOLOGIES IN VIVO.
NEXT SLIDE.
SO THIS LEADS DIRECTLY INTO OUR
RECOMMENDATION. WE ARE VERY
EXCITED ABOUT THESE CURRENT
BIOMARKERS.
ONE OF THE MAIN LIMITATIONS IS
THAT THEY PROVIDE ONLY A BINARY
READOUT, YES/NO MEASURE FOR THE
MOST PART. SO THAT IS ONE
RECOMMENDATION, TO BE ABLE TO
GET MORE OF A CONTINUUM OF
DISEASE, RELATED TO ALPHA
NUCLEUS DEPOSITION.
AND THESE BIOMARKERS OBVIOUSLY
DO NOT TELL US WHERE IN THE
BRAIN THE A-SYNUCLEIN IS
DEPOSIT AND THEY ARE CURRENTLY
MULTIPLE EFFORTS UNDERWAY WE
ARE SEEING EXCITING PROGRESS,
NEURAL A-SYNUCLEIN INCLUSIONS
AND ANOTHER RECOGNITION RELATED
TO THESE RECENT ADVANCEMENTS
ARE DISCLOSURE PROTOCOLS
THEMSELVES. THE ABILITY TO
ACTUALLY COMMUNICATE THESE
RESULTS, THESE A-SYNUCLEIN
POSITIVE RESULTS BACK TO OUR
RESEARCH PARTICIPANTS. AND SO
THIS IS A NEW OPPORTUNITY IN
THESE PROTOCOLS. THEY NEEDED TO
BE DEVELOPED AND BETTER
UNDERSTOOD IN TERMS OF THE
RESEARCH PROTOCOLS THAT WE HAVE
THESE BINARY OPS AVAILABLE TO
US.
NEXT SLIDE.
TO MOVING ON TO RECOMMENDATION
NUMBER 4.
SO HERE WE ARE FOCUSED ON OTHER
PROCESSES AND MECHANISMS THAT
ARE RELEVANT FOR LEVY BODY
PROGRESSION BEYOND THESE
BIOMARKER READOUTS OF THE
DISEASE ITSELF.
AND THIS IS CENTERED AROUND THE
DEVELOPMENT OR REFINEMENT OF
BIOMARKERS RELATED TO MANY
DIFFERENT PROCESSES THAT WE
FEEL ARE IMPORTANT AND THIS
INCLUDES NEURAL INJURY AND
NEURO TRANSMITTERS AND
NEURODEGENERATION, THAT ARE
BOTH PREDICTIVE AND PROGNOSTIC
OF THE DISEASE, IMPORTANTLY
PROVIDE MONITORING TO TRACK THE
ACTUAL PROGRESSION OF THE
DISEASE.
THESE BIOMARKERS WILL ALSO
ALLOW US TO BETTER IDENTIFY
WHETHER TARGETING ENGAGEMENT IS
HAPPENING IN THE CONTEXT OF
THERAPEUTIC INTERVENTIONS AS
WELL.
NEXT SLIDE.
SO HERE-- THIS IS A VERY BROAD
RECOMMENDATION, AND REALLY
CRITICAL. THERE IS A LOT OF
WORK TO BE DONE SO WE HAVE A
FAIR AMOUNT OF DETAILED
RECOMMENDATIONS TO FILL THIS
GOAL.
I'M GOING TO GO THROUGH THEM
ONE AT A TIME HERE.
SO AS I SAID, WE HAVE THESE
REALLY GREAT MARKERS FOR
A-SYNUCLEIN RIGHT NOW, BUT THE
OTHER PROCESSES THAT NEED TO BE
MEASURED IN TERMS OF
BIOMARKERS, SO WE NEED TO
IDENTIFY A NUMBER OF PATHWAYS
HERE, SYNAPTIC, LYSOSOMAL,
MITOCHONDRIAL, IMMUNOLOGIC AND
OTHER PROCESSES RELATED TO
A-SYNUCLEIN PATHOLOGY,
DIFFERENT THAN THE PATHOLOGICAL
CONCLUSION THEMSELVES.
THERE'S A LOT OF WORK IN THE
NEUROTRANSMITTER SPACE, AND
THESE TOOLS ARE OPPORTUNITIES
TO FURTHER REFINE THEM AND
IMPROVE UPON THEM. THIS IS
SOMETHING THAT HAS BEEN WIDELY
IMPLEMENTED IN THE LEVY BODY
SPACE AND THERE IS ALSO
INTEREST IN DEGENERATIVE
CHANGES AND THESE CAN BE
MEASURED WITH BIO FLUIDS AND
ALSO MR TOOLS LOOKING FOR
INSTANCE AT MELANIN, MRI, AND
ION SENSITIVE MRI.
WE WANTED TO HIGHLIGHT THAT THE
SORT OF DISCOVERY OF NEW
BIOMARKERS SHOULD INCLUDE A
BROAD TYPES OF POTENTIAL
SAMPLES. AND SO BLOOD, CSS,
SKIN, COLON, IMAGING FRONT,
DIFFERENT MODALITIES AND WE ARE
IN THE SPACE WE WANT TO EXPLORE
THE FULL RANGE OF POSSIBILITIES
HERE.
THERE SHOULD ALSO BE THESE
BIOMARKERS, THEY REALLY SHOULD
BE A CONNECTION BETWEEN BOTH
THE HUMAN WORK AND ALSO MODEL
SYSTEMS.
WE THINK THAT CONNECTION IS
QUITE IMPORTANT FOR THESE NOVEL
DISCOVERIES.
THERE'S ALSO IMPERILED TO THESE
BIOLOGICAL MARKERS, A LOT OF
INTEREST IN THESE MORE DIGITAL
APPROACHES AS WELL.
NEUROPHYSIOLOGICAL. LOTS OF
IDEAS AROUND THIS. HERE WE ARE
LISTING SOMEWHAT OF A LAUNDRY
LIST OF THESE POTENTIAL
PATHWAYS, WEARABLES, TSG,
COMPUTERIZED TESTING INVERSE
APPROACHES TO HOME-BASED
MONITORING TO CAPTURE
ECOLOGICALLY VALID MEASUREMENTS
ON OUR PARTICIPANTS. WITH ALL
OF THESE THERE NEEDS TO BE
ATTENTION TO SCALABILITY AND
ACCESSIBILITY AS WE VALIDATE
THESE.
GIVEN THE SCOPE OF THIS FEEL
THERE SHOULD BE WORKSHOPS AND
COORDINATED EFFORTS TO ADDRESS
FEASIBILITY, AND IMPLEMENTATION
OF THESE TOOLS AND ALSO DATA
SHARING AS WELL.
NEXT SLIDE.
A FEW MORE RECOMMENDATIONS
HERE. SO FOR ALL THE BIOMARKERS
I JUST MENTIONED, THE CONTEXT
OF USE IS QUITE IMPORTANT SO
THESE BIOMARKERS, WILL THEY BE
USED TO DEFINE FUTURE
PROGRESSION AND RISK?
WILL THERE BE USED TO MONITOR
SYMPTOMS IN THE CONTEXT OF
CLINICAL TRIALS?
FOCUS IS IMPORTANT TO KEEP IN
MIND FOR BIOMARKER DISCOVERY
IMPORTANTLY THESE BIOMARKERS
WILL BE CRITICAL TO ESTABLISH
THAT THEY ARE ASSOCIATED WITH
CLINICALLY MEANINGFUL SIGNS AND
SYMPTOMS THAT WE ARE INTERESTED
IN IN THE CONTEXT OF LBD. THERE
IS A GENERAL SENTIMENT THAT
DISTAL DISCOVERY MIGHT BENEFIT
FROM COORDINATING MULTISITE BIO
MARKER STUDIES WITH A BROAD
RANGE OF EXPERTISE INCLUDED IN
THESE STUDIES, SPANNING
CLINICAL BIOMARKER,
NEUROPATHIC, STATISTICAL
EXPERTISE.
AND WHAT SOMETHING LIKE THIS
WOULD DO IT WOULD ALLOW US TO
BUILD BIGGER COHORTS AND WE
HEARD ABOUT THAT IN THE LAST
SET OF RECOMMENDATIONS. IT WILL
ALLOW US TO COLLECT HARMONIZED
DATA ACROSS THE LARGER COHORTS,
AND SYNCHRONIZE THOSE EFFORTS.
IT WILL ALSO REALLY PROMOTE
BROADER DATA SHARING. THERE
WAS A FEELING THAT IF SOMETHING
LIKE THIS WERE TO TAKE PLACE,
DIGITAL MARKERS SHOULD ALSO BE
INCLUDED. BUT INDEPENDENT OF
THIS THERE IS ALSO A FAIR
AMOUNT OF DATA THAT IS ALREADY
OUT THERE. AND ALSO APPROACHES
TO TAKE ADVANTAGE OF THIS DATA
THAT ALREADY EXISTS, USING
POSTACQUISITION HARMONIZATION
PROTOCOLS. AND HERE IS THE
EXAMPLE OF ...
>> TWO MINUTES...
>> THIS IS AN EXAMPLE OF A
STUDY THAT COULD BE
IMPLEMENTED, MULTIPLE PET
SCANS, PERHAPS MRI SEQUENCE TO
GET AT THESE BRAIN STEM CHANGES
IN OF COURSE IN BIO FLUID DATA
AS WELL.
NEXT SLIDE.
SO SOME COMMON NEEDS ACROSS
BOTH, RECOMMENDATIONS I
DISCUSSED SO THE COHORTS ARE
REALLY CRITICAL FOR THIS. I
JUST TALKED ABOUT SPECIFICALLY
THE MULTISITE STUDY, BUT THERE
ARE DIFFERENT FLAVORS WHERE
EXISTING OR NEW COHORTS COULD
BE ESTABLISHED INTEGRATE THESE
DIFFERENT BIOMARKERS.
AND THERE SHOULD BE A DOCTOR
DOOLITTLE COMPONENT TO LOOK AT
THE PROGRESSION OF THE DISEASE.
THE OPPORTUNITY TO LOOK AT
POSTMORTEM COMPARISONS, ALSO
ESSENTIAL TO VALIDATE THESE
BIOMARKERS. AND THE ABILITY TO
ALSO LOOK AT THESE BIOMARKERS
IN THE CONTEXT OF MIXED
PATHOLOGIES ARE ALSO IMPORTANT.
THERE IS ALSO A GENERAL
CONSENSUS THAT WE SHOULD BE
TARGETING ALL STAGES OF THE
DISEASE. THE DISEASE INCLUDES
MULTIPLE CLINICAL PHASES,
STARTING WITH ASYMPTOMATIC
PHASE. BY TRANSITIONING INTO
SYMPTOMATIC AND THESE
BIOMARKERS WILL LIKELY HAVE
DIFFERENT ROLES AND MEANING AT
DIFFERENT STAGES OF THE
DISEASE. IT WILL BE IMPORTANT
TO INCLUDE THE BROAD RANGE OF
ACTUAL STAGES WITH THE DISEASE.
AND OF COURSE MANY OF THE
MARKERS I MENTIONED, THEY ARE
NOT THE MOST SCALABLE THEY USED
TO BE AN EYE ON MEASURES THAT
ARE NONINVASIVE AND SCALABLE AS
WELL.
I'M GOING TO PASS IT OVER TO
DR. DUGGER FOR THE NEXT SET OF
MILESTONES. THANK YOU.
>> DR. DUGGER: THANK YOU ALL.
CAN YOU HEAR ME OKAY?
OKAY THANK YOU ALL FOR TAKING
YOUR TIME. YOU TOOK TIME OUT
OF YOUR BUSY SCHEDULE TO ATTEND
TODAY, AND TO PROVIDE THIS
CRITICAL FEEDBACK ON THESE
PROPOSED RECOMMENDATIONS AND
PRIORITIES.
NEXT SLIDE.
EVEN THOUGH YOU SEE MY FACE I
WILL BE PRESENTING ON THE
GENETICS OR OMICS OF THE LEVY
BODY DISEASE AND PINCHHITTING
TODAY FOR DOCTOR SONJA SCHOLZ,
AND THESE ARE THE DISCLAIMERS.
THESE ARE THE REGULATIONS
RELATED TO THE OMICS ASPECT AND
THE FUNCTIONAL GENOMICS OF THE
LEVY BODY DISEASE CONTRIBUTING
TO THE ONSET AND PROGRESSION OF
LEVY BODY DISEASE USING
CHARACTERIZATION AND ANALYSIS
TO SUPPORT DRUG DISCOVERY.
NEXT SLIDE.
SO, WITH THIS SLIDE, THIS IS
KIND OF SHOWING GENETICS ALONG
WITH BROADER MULTI-OMICS
TECHNOLOGIES AND THEY HAVE
PROVIDED UNPRECEDENTED
OPPORTUNITIES TO DECODE LEVY
BODY DEMENTIA AND THIS IS JUST
A BRIEF HISTORY OF WHERE WE ARE
AT TODAY.
IS VERY EXCITING TO SEE THESE
ADVANCES FOR OUR ABILITY TO
TACKLE THIS CHALLENGING
DISEASE.
NEXT SLIDE.
IN RECOMMENDATION NUMBER 5, WE
ARE PARTICULARLY EMPHASIZING
WITH THIS RECENT PROGRESS HOW
COMPLEX THINGS ARE. SO WE HAVE
THE STRUCTURAL VARIANTS. THERE
HAS BEEN A X-CHROMOSOMAL
VARIANCE AS WELL AS EPIGENETICS
AND TRANSCRIPTOMICS, IMPORTANT
TO MEET THIS DISEASE.
IN THE ANALYSIS ASPECT WE ARE
IN THE AGE OF BIG DATA AND
COMPUTATIONAL ANALYSIS FOR
NOVEL INSIGHTS ON THESE
DISEASES. AND AGAIN THESE ARE
JUST BRIEF, BRIEF OUTLINES. THE
HAS BEEN SO MUCH WORK IN THE
SPACE AND AGAIN TRYING TO
HIGHLIGHT SOME OF THAT.
NEXT SLIDE.
AND WHEN IT COMES TO DATA AND
BIO SPECIMEN PLATFORMS, THERE
HAVE BEEN A LOT OF GREAT
PLATFORMS THAT ARE OUT IN THE
FIELD. AND YOU CAN SEE HERE
WITH NICRA AND PD, BP AND SOME
OTHERS THAT HAVE GREATLY
ADVANCE THE FIELD.
NEXT SLIDE.
EVEN THOUGH THERE HAS BEEN
THESE GREAT ADVANCES, AND I
KNOW I WANT TO SO MUCH WORK IN
SUCH A BRIEF AMOUNT OF TIME, WE
ARE STILL MISSING HERITABILITY,
MULTI-OMICS AND ENVIRONMENTAL
DATA INTEGRATION EXTEND RISK OF
MULTIGENERATIONAL GENETIC
RISKS, AS WELL AS CELL TYPE IN
TISSUE SPECIFIC CONTEXT OF
GENETIC RISK.
LARGELY DEEP PHENOTYPE COHORTS
WITH MULTI-OMIC DATA AS WELL AS
GENOMIC DATA FROM COHORTS
REPRESENTATIVE OF THE BROADER
US POPULATION. AND A LOT OF
THESE THEMES IF YOU HAVE BEEN
ATTENDING MULTIPLE SESSIONS
HAVE BEEN THROUGHOUT A LOT OF
THESE SESSIONS.
NEXT SLIDE.
SO BASED ON THESE GAPS, AGAIN
OUR RECOMMENDATION 5, IS TO
INTEGRATE FUNCTIONAL GENOMICS
OF LEVY BODY DISEASE BY THE
GENETIC -- CONTRARY TO THE
ONSET PROGRESSION OF LEVY BODY
DISEASE AND SUPPORTING DRUG
DISCOVERY, AND THE ANIMATIONS.
NEXT SLIDE.
SO WE WANTED TO DISCOVER AND
REPLICATE GENETIC AND
ENVIRONMENTAL RISK FACTORS.
NEXT SLIDE.
WE ALSO WANT TO INTEGRATE
GENOMICS IN DEEPLY PHENOTYPE
COHORTS.
FUNCTIONALIZED THESE RISK
VARIANCE INTO MECHANISMS,
TARGETS AND BIOMARKERS. AGAIN
THIS IS JUST REPEATING A LOT OF
THE STUFF, MAKING SURE THAT THE
MESSAGE IS GETTING ACROSS OF
OUR RECOMMENDATIONS INVESTING
IN MOLECULAR HETEROGENEITY
ACROSS LEVY BODY DISEASE AND
RELATED DISORDERS, PRIORITIZING
INNOVATIVE ANALYTICS DATA
PLATFORMS.
NEXT SLIDE.
SO NOW I'M GOING TO BE MOVING
INTO THE NEUROPATHIC PORTION IN
THESE ARE MY DISCLOSURES AND
DISCLAIMERS.
NEXT SLIDE.
THIS IS RECOMMENDATION NUMBER
6. WE WANT TO HARMONIZE
TECHNIQUES NOT STANDARDIZE,
BECAUSE A LOT OF COHORTS AND
RESOURCES ALREADY EXIST, WE
DON'T WANT TO NEGATE THOSE FOR
THE NEURAL PATHOLOGICAL
CHARACTERIZATION OF LEVY BODY
DISEASE WERE USING WELL
CHARACTERIZED REPRESENTATIVE
LEVY BODY COHORTS AND YOU CAN
SEE THE DESCRIPTION BENEATH,
TRYING TO HAVE MORE DETAILS.
NEXT SLIDE.
AND SO WITH RESPECT TO RECENT
PROGRESS, IT IS ALWAYS GOOD TO
KIND OF BENCHMARK. AND SO HERE
ARE SOME OF THE DISEASES WE ARE
COVERING IN THIS SUMMIT.
YOU CAN SEE ALZHEIMER'S
DISEASE, BASIC JUST USING THE
SEARCH TERM "NEUROPATHOLOGY,"
AND THEN THE SPECIFIC TERMS
EITHER LEVY BODY , DISEASE
ALZHEIMER'S, CEREBROVASCULAR,
TDP-43.
WITHOUT A SURPRISE YOU CAN
SEEALZHEIMER'S DISEASE
NEUROPATHOLOGY WINS BY FAR. NOW
ALMOST 700 APPLICATIONS
(CORRECTION) PUBLICATIONS A
YEAR AND THAT FAR OUTWEIGHS TDP
AND LEVY BODY SHOWN HERE DOWN
ON THIS GRAPH, IT VERY MUCH
REMAINS CONSTANT. PRETTY MUCH
ON PAR WITH TDP-43
NEUROPATHOLOGY.
NEXT SLIDE.
AND SO SOME OF THE PROGRESS
THAT HAS BEEN MADE AND AGAIN
EVEN THOUGH WE WERE TALKING IN
THE DECISIONS ABOUT BIOMARKERS,
A LOT OF THOSE BIOMARKERS
CANNOT HAPPEN WITHOUT THE
NEUROPATHOLOGY SO THE TITLE OF
THE SLIDE IS, RECENT PROGRESS
THAT LBD YOUR PATHOLOGY
INFORMING BIOMARKER STUDIES,
AND THESE ARE SOME OF THE
PAPERS THAT HAVE BEEN PUBLISHED
SINCE THE LAST SUMMIT.
AS WELL AS THERE HAVE BEEN
EFFORTS IN HARMONIZATION,
ESPECIALLY WITH THE 12 MEASURES
ACROSS SIX COMMUNITY-BASED
AUTOPSY COHORTS OF DEMENTIA.
NEXT SLIDE.
ONE STUDY TO HIGHLIGHT EVEN
THOUGH I KNOW THERE HAS BEEN A
LOT OF OTHER SLIDES, IS THE
RECENT CENTER WITHOUT WALLS FOR
LEVY BODY DEMENTIA. AND THANK
YOU TO DR. PAM MACLEAN FOR
PROVIDING THE BASIS FOR THIS
SLIDE.
THIS IS VERY NICE BECAUSE
NEUROPATHOLOGY IS AT THE HEART
OF THIS GRANT, AND USING THE
NEUROPATHOLOGY AND WORKING IN
THE OMICS ASPECTS IN THE
FUNCTIONAL PRESENCE USING THESE
RESOURCES. I AM VERY EXCITED
FOR THESE PROJECTS.
NEXT SLIDE.
ALTHOUGH THERE HAS BEEN AGAIN
RECENT PROGRESS, THERE ARE
STILL GAPS. AND THESE TEAMS
HAVE BEEN THROUGHOUT THIS NINDS
SUMMIT ABOUT HARMONIZING
TECHNIQUES; LOOPING SCIENTIST
TO SAMPLES AND DATA IN
USER-FRIENDLY PORTALS AS WELL
AS DIGITAL AND IMAGE ANALYSIS
AND THE LEARNING TECHNIQUES AND
LAST BUT NOT LEAST IS
INCREASING THE NUMBER OF DEEPLY
PHENOTYPE AUTOPSY COHORTS
FOCUSED ON LBD.
AND WHEN I SAY FOCUSED ON LEVY
BODY, ALLOW THE DATA THAT WE
SEE COMING OUT SPECIALLY THANK
YOU TO DOCTOR TOLEDO PRESENTING
FOR SOME OF THE THINGS OF THE
LEVY BODY COHORTS BUT A LOT OF
THE WORK BEING DONE IS BASED ON
ALZHEIMER'S DISEASE CENTER
COHORTS THERE IS NOT A LOT OF
SPECIFIC LEVY BODY COHORTS AND
PLEASE FORGIVE MY LANGUAGE, IT
IS ALMOST LIKE AN AFTERTHOUGHT
OR CAPITALIZATION SOME OF THE
EXISTING COHORTS RELATED TO
WORK ON THE BODY DISEASE. I SAY
THAT VERY LIKELY NOT TO BE
PROVOCATIVE, BUT TO MAKE PEOPLE
AWARE OF THE SITUATION.
NEXT SLIDE.
AND SO, WITH THOSE GAPS-- AND
IF YOU CAN MAYBE HIT A WHOLE
BUNCH BECAUSE THE ANIMATIONS ON
THIS GOT A LITTLE JUMBLED.
THANK YOU. HIT A WHOLE BUNCH
UNTIL EVERYTHING POPS UP AND I
WILL LET YOU KNOW.
YEAH IT GOT A LITTLE JUMBLED.
THANK YOU FOR YOUR PATIENCE.
STOP THERE. THANK YOU.
A RECOMMENDATION IS TO ENHANCE
AND HARMONIZE THE TECHNIQUES
FOR NEURAL PATHOLOGICAL
CHARACTERIZATION OF LEVY BODY
DISEASE AND USE OF LEVY BODY
PATHOLOGY COHORTS AND THE
ENHANCED PRACTICE FOR YOUR
PATHOLOGICAL VALUATION AND
DEVELOP SCALABLE METHODS FOR
ASSESSING LEVY BODY ASSOCIATED
PATHOLOGY AND CAPITALIZING ON
THOSE EXISTING HUMAN TISSUE
RESOURCES.
INCREASING AUTOPSIES OF PERSONS
WHO MAY DEVELOP OR ALREADY HAVE
DEVELOPED LEVY BODY DISEASE AND
ENHANCE INFRASTRUCTURE-- AND I
LOVE THE COMMENT ABOUT THE EYES
IN THE PREVIOUS SECTION AND SO
THIS PERIPHERAL TISSUE SAMPLES,
BECAUSE THE BRAIN IS CONNECTED
TO THE BODY AND SOMETIMES
THAT'S SKULL IS VERY HARD TO
GET TO.
I APPRECIATE THE COMMENTS IN
PRIOR SESSIONS RELATED TO THAT.
AND LAST BUT NOT LEAST IS A
PORTAL LINKING TISSUE
RESOURCES, MOLECULAR, CLINICAL,
IMAGING AND BIOMARKER DATA. AND
I THINK THAT IS IT. THANK YOU.
>> SO, ... MY NAME IS ALICE
CHEN-PLOTKIN, PHYSICIAN
SCIENTIST AT THE UNIVERSITY OF
PENNSYLVANIA.
I WILL BE ROUNDING OUT THE LAST
TWO RECOMMENDATION FROM A
WORKGROUP. THESE ARE THE
DISCLAIMERS AND DISCLOSURES.
NOT MUCH EXCITING THERE.
NEXT SLIDE.
SO, I'M JUST BEGINNING BY
COMING RIGHT TO THE
RECOMMENDATIONS. RECOMMENDATION
7, PRIORITY 1, , TO DEVELOP
MODELS PATHOGENESIS AND
MECHANISMS OF TOXICITY, AND
NORMAL MOLECULAR AND CELLULAR
FUNCTIONS OF A-SYNUCLEIN WITH
THE AIM OF SUPPORTING DRUG
DISCOVERY.
THE RECOMMENDATION I WILL COVER
IS NUMBER 8, WHICH WE ASSIGN
PRIORITY 4.
TO IDENTIFY THEM MULTIPLE
ETIOLOGY MECHANISMS OF
SELECTIVE VULNERABILITY,
DISEASE HETEROGENEITY, DISEASE
SPREAD/ PROPAGATION, AND
INTERACTION WITH OTHER
AGE-RELATED PATHOLOGIES AS
THERAPEUTIC TARGETS.
NEXT SLIDE.
SO I WILL BEGIN BY KIND OF
COVERING THE PROGRESS SINCE THE
LAST SUMMIT IN 2022.
I WILL DIVIDE THIS INTO WHAT WE
HAVE LEARNED ABOUT A-SYNUCLEIN
WHICH IS A LOT. I CANNOT
EMPHASIZE HOW MUCH-- I AM NOT
COVERING THAT HAS BEEN DONE
SINCE 2022, THE BASIS FOR OUR
RECOMMENDATIONS AND 11 HAS ONE
THING, WHICH IS THIS IS A VERY
EXCITING TIME FOR THE LEVY
BODY DISEASES, AND SUPPORT OF
THESE RESEARCH EFFORTS IS VERY
IMPORTANT.
NEXT SLIDE.
SO IF YOU THINK THAT HAVE BEEN
LEARNED. IN 2022-- AND THIS IS
HAPPENING ALL THE TIME--
(INDISCERNIBLE) SHOWING US THAT
THERE MAY BE DIFFERENT
CONFIRMATION SHAPES IN LEVY
BODY DEMENTIA IN LEVY BODY
DISEASE AND PARKINSON'S
DISEASE, VERSUS MULTIPLE
SYSTEMS ATROPHY WHICH IS ALSO
IS SYSTEMS ATROPHY FOR
INCLUSION DATA.
NEXT SLIDE.
THIS IS THE BASIS, THE
DIFFERENCE IN CONFIRMATION AND
MAY BE THE BASIS FOR WHAT
SUBSEQUENT DEVELOPMENT WHICH IS
A BIOMARKER TEST THAT HAS BEEN
SHOWN IN PREVIOUS SLIDES. AND
SO THIS IS THE PAPER FROM
NATURE 2020, THAT ESSENTIALLY
SHOWS THAT IN THE ABILITY TO
SEE IMPLICATION IN A-SYNUCLEIN,
IN SAMPLES OF PARKINSON’S
DISEASE SAMPLES, RELATED TO THE
CONFIRMATION OF A-SYNUCLEIN.
THIS HAS ALREADY BEEN
TRANSLATED IN THIS PERIOD OF
TIME INTO AN FDA AVAILABLE
CLINICAL TESTS. THIS IS THE
TECHNOLOGY RECORDED IN 2020 AND
NOW SHOWN AND THIS IS THE SAME
SEED AMPLIFICATION ASSAY SHOWN
IN PREVIOUS SLIDES THAT LOOKED
AT HOW THE SEED AMPLIFICATION
ASSAY PERFORMED IN MANY
PATIENTS.
AND AS YOU CAN SEE DEPENDING ON
HOW YOU DEFINE PARKINSON'S
DISEASE, DIFFERENT GENETIC
MUTATIONS, THE SENSITIVITIES
ARE VERY, VERY HIGH. WHICH IS
BASICALLY WHY THIS IS NOW A
DIAGNOSTIC TEST THAT A DOCTOR
CAN ORDER IN THE CLINIC.
NEXT SLIDE.
SO EVEN THOUGH WE LEARNED A LOT
ABOUT THE CONFIRMATIONS,
THERE'S A LOT MORE TO LEARN SO
I'M HIGHLIGHTING A FEW THINGS.
IT TURNS OUT THAT WORK FROM --
AND OTHERS SHOW THE
POST-TRANSLATIONAL
MODIFICATIONS IN A-SYNUCLEIN,
WORK DONE IN MSA LBD IN NORMAL
BRAINS AS WELL AND YOU CAN SEE
WITH THE DIFFERENTIATE THAT THE
POST TRANSLATION MODIFICATIONS
ARE LITTLE BIT DIFFERENT
DEPENDING ON THE STUDY.
NEXT SLIDE.
AND THE OTHER THING IS THAT ONE
PHOSPHORYLATION ON SERIN 129
WHICH IS LONG BEEN FOUND TO BE
A HALLMARK OF LEVY BODY
PATHOLOGY IS WHAT WE FIND IN
THE BRAINS OF PEOPLE WITH LEVY
BODY DISEASE AND IT TURNS OUT
IF YOU LOOK AT THE PAPER ONE
THING THAT IS INTERESTING IS
THAT THIS PHOSPHORYLATION IS
FOUND IN NORMAL PEOPLE. AND
PROVOCATIVE WORK FROM -- LAB,
SHOWED THAT MAYBE THIS
PHOSPHORYLATION HAS A
PHYSIOLOGICAL FUNCTION.
NEXT SLIDE.
ANOTHER THING THAT BASICALLY I
WANT TO EMPHASIZE IS THAT THE
REASON THAT THESE DISEASES
CHANGE OVER TIME, THE REASON
PATIENTS PROGRESS OVER TIME IS
THE PATHOLOGY SHOWING THAT IT
SPREADS FROM ONE AREA OF THE
BRAIN TO ANOTHER PART OF THE
BRAIN LIKE IN PARKINSON'S
DISEASE AT START OF THE TREMOR
AND THEN IT STARTS TO DEVELOP
OTHER DISEASES, AND THE SPREAD
OF PATHOLOGY FROM CELL TO CELL.
OTHER THINGS BESIDE THE
NUCLEON, BUT THIS IS AT LEAST
ONE CORE FEATURE.
NEXT SLIDE.
THIS IS WORK FROM OUR LAB THAT
BASICALLY HAS BEEN TRYING TO
UNDERSTAND WHAT ARE THE
DETERMINANTS OF THE SPREAD FROM
CELL TO CELL PATHOLOGY.
IT TURNS OUT THAT ONE OF THE
GENES THAT CAME OUT OF THESE
BIG GENOMICS PARKINSON DISEASE
-- BELONGS TO A GENE CALLED
GPNMB.
IT APPEARS THAT NEURONS CAN NO
LONGER TAKE UP THIS
PATHOLOGICAL NUCLEON, MAY BE
KEY TO THE SPREAD.
NEXT SLIDE.
SO, ANOTHER THING WE WANTED TO
EMPHASIZE IN THIS CAN HAPPEN
MULTIPLE SESSIONS BEFORE.
EVEN THOUGH I BEEN TALKING
ABOUT A-SYNUCLEIN, AND WHAT WE
HAVE LEARNED ABOUT A-SYNUCLEIN,
IN THE BRAIN A-SYNUCLEIN IS NOT
BY ITSELF. AND SO WE WILL SHOW
YOU THE CLINICAL CASES FROM A
LIVE STUDY. AND WHAT YOU CAN
SEE IS THAT YELLOW PART -- THE
RED PART IS JUST LEVY BODY
DISEASE AND THOSE BRAINS. THE
RED PLUS ORANGES LEVY BODY
DISEASE PATHOLOGY PLUS A NORMAL
CHANGES YOU EXPECT WITH AGING.
THE YELLOW AND THE -- IS
BASICALLY NEURODEGENERATIVE
DISEASE, LEVY BODY DISEASES IN
AGING IN ANOTHER PATHOLOGY. YOU
CAN SEE THAT ABOUT ONE THIRD OF
CLINICAL LBD CASES HAVE
ADDITIONAL PATHOLOGIES.
NEXT SLIDE.
IT TURNS OUT THAT THE PATTERNS
OF CO-PATHOLOGY, THE OTHER
TYPES OF PATHOLOGY PROTEINS IN
THE BRAIN WITH THE LEVY BODIES
MAY RELATE TO THIS ORDER OF
SPREAD OF REGIONS AFFECTED BY
A-SYNUCLEIN PATHOLOGY.
SO THESE ARE BASED ON KIND OF
THINGS WE HAVE LEARNED, AND
WHAT WE STILL NEED TO KNOW.
THE FIRST THING IS, DO ALL
MEDICAL PARKINSON'S DISEASE
EXISTS WITH DEMENTIA, AND THEY
HAVE PATHOLOGY
(INDISCERNIBLE), NOT ABOUT WAYS
WE CAN DETECT A-SYNUCLEIN, AND
YOU CAN SEE IT DOES. THE ASSAY
IS NOT 100% SENSITIVE, BECAUSE
THE ASSAY IS NOT SENSITIVE
ENOUGH OR NOT ALL PATIENTS HAVE
A-SYNUCLEIN?
A-SYNUCLEIN CONFIRMATIONS ARE
THE SAME OR DIFFERENT ACROSS
INDIVIDUALS?
ACROSS CLINICALLY IMPORTANT
SUBTYPES?
I SHOW YOU SOME WORK THAT THERE
MAY BE OTHER NORMAL FUNCTIONS
OF ASYN. AND WE WONDER WHAT
DOCTORS GATHERED ABOUT THE
DIFFERENT BEHAVIORS OF ASYN IN
PHYSIOLOGICAL DISEASE
CONDITIONS.
AND THERE IS A LOT OF OTHER
PATHOLOGY. HOW DOES ASYN
INTERACT WITH OTHER
PATHOLOGICAL PROTEINS IN
DISEASE PATHOGENESIS?
WHAT NON-ASYN- RELATED
MECHANISM LEAD TO OR EXACERBATE
DISEASE PATHOGENESIS?
RECOMMENDATION 7, WHICH ARE
RATHER THE BEGINNING IS TO
DEVELOP MODELS TO UNDERSTAND
PATHOGENESIS MECHANISMS OF
TOXICITY IN NORMAL MOLECULAR
AND CELLULAR FUNCTIONS OF
A-SYNUCLEIN.
AND YOU CAN SEE THAT WE HAVE
DETAILS AND THEY WILL BE MORE
DETAILS IN OUR REPORT AND HOW
WE THINK THIS CAN KIND OF BE
WELL PURSUED.
NEXT SLIDE.
RECOMMENDATION 8, IS TO
IDENTIFY MULTIPLE ETIOLOGY
MECHANISMS OF SELECTED
VULNERABILITY, DISEASE
HETEROGENEITY, DISEASE
SPREADING COMPETITION AND
DIRECTION WITH OTHER
AGE-RELATED PATHOLOGIES AS
CLEAR TARGETS. AND THIS IS TO
LOOK AT MIXED PATHOLOGY AND
WHAT THE IMPACT IS AND TO
UNDERSTAND OTHER FACTORS THAT
LEAD TO NEURODEGENERATION.
WITH THE IDEA THAT THESE MAY BE
DISTINCT FROM THE MECHANISM. IS
WHAT MAKES NEURODEGENERATION
LOSS OF NEURONS, BE DIFFERENT
FROM THE (INDISCERNIBLE)
PATHOLOGY.
BECAUSE WE THINK THE OTHER
PROTEINS IN THE MIX WE WANT TO
DEVELOP LBD MODELS THAT ARE
NONEXCLUSIVE LEAD BASED ON
A-SYNUCLEIN.
AND WANT TO CONSIDER THE IMPACT
OF DEMOGRAPHICS, AGE AND SEX
FOR EXAMPLE ON LBD
PATHOPHYSIOLOGY AND TOXIC
MECHANISMS UNDERLYING DISEASE.
>> THANK YOU EVERYONE SO MUCH.
THAT WAS A REALLY WONDERFUL
PRESENTATION FROM ALL OF OUR
SESSION GROUP AND NOW WE OPEN
IT UP TO QUESTIONS FROM THE
PUBLIC.
AND I WILL MODERATE AND ASSIGN
QUESTIONS TO THE PANELISTS. IF
YOU DON'T MIND TURNING THE
CAMERA YOURSELF.
>> EVERYONE ON THE PANEL IS
WELCOME TO TURN ON THEIR
CAMERAS SO YOU CAN POP UP ON
THE SCREEN.
THANK YOU.
>> I SEE HELEN. YOUR HAND IS
RAISED. PLEASE UNMUTE YOURSELF
WITH YOUR QUESTION.
>> CAN YOU HEAR ME?
>> YES WE CAN THANK YOU.
>> THANK YOU DR. POSSTON.
THANK YOU FOR THIS INCREDIBLE
ANALYSIS OF ACROSS THE BROAD
SPECTRUM OF SCIENCE. IS VERY,
VERY IMPORTANT TO ME AS MANY
OTHER PEOPLE ON BOARD HERE
TODAY, I HAVE OVER 35 YEARS IN
THE TRENCHES WITH THIS DISEASE
DUE TO MULTIPLE GENERATIONS IN
MY FAMILY.
IS A LOOK FORWARD TO THE FUTURE
OF MY FAMILY IN THE NEXT
GENERATIONS I AM VERY, VERY
CONCERNED ABOUT SATURDAY THE
LACK OF FUNDING. AND SO
HOPEFULLY THAT CAN BE PUSHED
FORWARD.
BECAUSE AT THIS POINT, I HAVE
BEEN DIRECTLY INVOLVED IN
RESEARCH NOW AS A PARTICIPANT
FOR OVER 18 YEARS. AND OF
COURSE THAT STARTED WITH JUST
BEING PART OF PARKINSON'S
STUDY. THERE WAS NO DLB STUDIES
GOING ON.
BUT AGAIN IT IS ME GOING OUT TO
FIND WHAT IS GOING TO BE
RELEVANT-- AND THE MOST RECENT
I AM NOW PART OF NAPPS.
BUT THAT CONCERNS ME THAT THERE
ISN'T AN INTERCONNECTEDNESS
CONSISTENT ACROSS ALL
INSTITUTES. IS THERE ANY WAY
THAT WE CAN HARMONIZE AND
DE-SILO SOME OF THESE-- SO THE
COHORTS CAN EXPAND SHARING OF
INDIVIDUAL BASIC INFORMATION
INCLUDING IT IN THE CONSENT
WHEN THEY ARE SIGNING THE
CONSENT FORM YOU HAVE
PERMISSION TO SHARE WITH OTHER
INSTITUTIONS, PURSUING SIMILAR
SAMPLING. ALL RELATIVE STUDIES.
SO WE CAN GET THIS EXPANDED
MORE RAPIDLY.
>> THANK YOU FOR THAT
OUTSTANDING QUESTION.
I'M GOING TO MAKE A COMMENT,
AND THEN PASS IT OVER TO DR.
MORMINO WHO HAS DONE SOME HAVE
THIS TYPE OF WORK WITHIN THE
IMAGING SPACE WHICH MAY BE
RELEVANT BROADLY.
BUT I AGREE THAT ALL SAMPLES,
THE SHARING OF THE SAMPLES AND
SHARING OF DATA BROADLY IS
REALLY AT THE HEART OF MULTIPLE
RECOMMENDATIONS.
AND I ALSO THINK-- I REALLY
APPRECIATE YOUR COMMENT THERE
ABOUT IT BEING ADDRESSED AT THE
LEVEL OF THE CONSENT FORM. I
HAVE ALSO FOUND THAT IF IT IS
NOT ON THE CONSENT FORM, THERE
IS VERY LITTLE WE CAN DO DOWN
THE ROAD. AND BEING VERY
PROACTIVE ABOUT THIS, MOVING
FORWARD.
AND THAT IS ACTUALLY-- I DON'T
THINK WE DIRECT THE ADDRESSED
THAT IN OUR RECOMMENDATION SO
THAT IS A GREAT WANT FOR US TO
UPDATE AS WE MOVE FORWARD.
ANY COMMENT FROM THE IMAGING
PERSPECTIVE WITH THIS REGARD,
OTHER WORK YOU HAVE DONE HERE?
>> THIS IS A PROBLEM ACROSS ALL
STUDIES THAT WE DO. NOT
SPECIFIC TO LEVY BODY DEMENTIA.
IS CERTAINLY HARDER GOING
BACKWARDS, COMBINING DATA
BECAUSE OF THIS ISSUE YOU'RE
BRINGING UP. BECAUSE OF THE
CONSENT. BUT THERE ARE SOME
CLEAR EXAMPLES OF SUCCESS IN
THE SPACE. LIKE THE AT ME
(PHONETIC) STUDY, SHARING DATA
BROADLY IN THE CONTEXT OF
ALZHEIMER'S DISEASE. AND STUDY
DESIGNS, PUTTING THIS LAND
WITHIN THE CONTENT IS CRITICAL
FOR BROAD DATA SHARING.
AND FROM THE IMAGING SIDE THERE
ARE CONCERNED NOT JUST WITH
IMAGING, BUT ALL THE DATA WE
COLLECT. THERE ARE ISSUES WITH
THE IDENTIFICATION OF THE DATA.
AND THAT IS A CONCERN BALANCING
THE TWO SIDES ARE PROTECTING
RESEARCH PARTICIPANTS IN TERMS
OF IDENTIFICATION. BUT WE ARE
HEARING MORE AND MORE FROM
PARTICIPANTS HOW IMPORTANT IT
IS THAT THE DATA IS SHARED.
AND IN THE CONSENT, WE MAKE
THESE RISKS STATED IN THE
PARTICIPANTS NEED TO BE AWARE
OF THESE RISKS AND MAKE A
CHOICE OF WHETHER OR NOT THEY
WANT TO PARTICIPATE IN THIS
STUDY, AND THIS BROAD DATA
SHARING.
ONE SPECIFIC ISSUE WITH THE
IMAGING DATA FOR INSTANCES YOU
CAN IDENTIFY THE FACE FROM SOME
OF THE IMAGES THAT ARE
COLLECTED. AND THAT REQUIRES
ADDITIONAL PROTECTION MEASURES
TO BE PLACED ON THAT IMAGING
MODALITY IN PARTICULAR.
I ABSOLUTELY AGREE WITH YOU I
WE SHOULD HAVE THIS IN OUR
CONSENTS. AND PARTICIPANT
SHOULD BE AWARE AND THEY SHOULD
BE A MOVE TOWARDS BROAD DATA
SHARING ACROSS THESE DIFFERENT
STUDIES WHEN AT ALL POSSIBLE.
>> DR. CHEN?
>> DR. CHEN-PLOTKIN: THE ONE I
KNOW THE MOST ABOUT IS THE
PARKINSON'S IS BIOMARKER
PROGRAM MORE PDP EXISTENCES
2012. YOU MAY HAVE ENROLLED IN
THE STUDY THROUHG A SITE, FOR
THE CONSENT IS BROUGHT IN THE
REASON I KNOW THAT IS BECAUSE
I'M A USER OF MANY OF THE
SAMPLES AND SO I DO THINK THAT
THERE IS AWARENESS AT THE LEVEL
OF BIO SAMPLES ORGANIZED IN THE
(INDISCERNIBLE) LEVEL, HAVING
CONSENT FOR BROAD SHARING AND
ESSENTIALLY HAVING A COMMITTEE
OF PEOPLE WHO LOOK AT REQUESTS
TO SEE THE REQUESTS A
REASONABLE AND THEN SHARE OUT
THE SAMPLES.
THAT IS DEFINITELY HAPPENING.
MY LAB FOR EXAMPLE HAS
BENEFITED GREATLY FROM THAT.
>> THANK YOU.
>> VIKI, YOUR HAND IS UP IF YOU
DON'T MIND AND MUTING HERSELF
AND ASKING A QUESTION OR
COMMENT.
>> HI. MY MOTHER HAS BEEN
DIAGNOSED -- WELL, ACTUALLY SHE
REALLY HASN'T BEEN DIAGNOSED
WITH ANYTHING. THAT IS MY
QUESTION.
AT FIRST, SHE DID GET A
DIAGNOSIS OF ... MILD COGNITIVE
IMPAIRMENT. AND NOW IT SAYS ON
HER CHART, "MAJOR
NEUROMUSCULAR, OR
NEURODEGENERATIVE" SOMETHING.
ANYWAY I WAS WONDERING WHAT
KIND OF TESTS SHOULD I INSIST
UPON OR DO I EVEN HAVE THE
RIGHT TO TRY TO FIND OUT A MORE
DEFINITIVE DIAGNOSIS? I GUESS.
>> DR. -- WHICH LIKE TO ADDRESS
THIS ISSUE? OR DR. TOLEDO, TO
TALK ABOUT WHERE WE ARE AT THIS
POINT TO ONE OF THE CHALLENGES
IS THE BALANCE OF THE
BIOMARKERS FROM THE PERSPECTIVE
OF THE RESEARCH USE VERSUS
WHERE WE ARE IN CLINICAL
IMPLEMENTATION AND THERE IS A
DISTINCTION THERE. IF YOU TWO
WOULD NOT MIND COMMENTING ON
THAT.
>> THANK YOU FOR YOUR QUESTION.
IT IS AN IMPORTANT ONE, AND
ONE THAT WE HEAR FROM OFTEN.
IS A CHANCE TO IDENTIFY A
CLINICIAN WHO HAS KNOWLEDGE IN
THIS AREA. AND IF YOU HAPPEN TO
NOT BE FORTUNATE TO MEET WITH A
KNOWLEDGEABLE CLINICIAN
INITIALLY, SEEK INPUT TO MEET
WITH SOMEONE ELSE AND THERE ARE
AMPLE DIAGNOSTIC TESTS
AVAILABLE.
AND THE CLINICIAN FOR WHATEVER
REASON DOESN'T HAPPEN TO KNOW
ABOUT THEM HONESTLY THEY WON'T
BE USED. I SHOULD POINT OUT
THAT THAT THE -- CENTER FOR
EXCELLENCE PROGRAM THERE ARE
OVER TWO DOZEN SPREAD ACROSS
COUNTRY AND THAT NETWORK BUT
DESIGNED FOR CLINICIANS WHO DO
THIS FOR A LIVING.
AND SO IF YOU HAPPEN TO LIVE
FAR FROM ONE OF THE CENTERS,
THAT DOES CREATE SOME
CHALLENGES. BUT HOPEFULLY THAT
IS AT LEAST PARTIALLY HELPFUL.
>> OKAY THANK YOU. I APPRECIATE
THAT.
>> ADDITIONAL QUESTIONS FOR
PANELISTS?
I SEE ... MIKE LEE. WOULD YOU
MIND UNMUTING YOURSELF? YOU
SHOULD BE ABLE TO.
>> OKAY THANK YOU.
>> I CAN HEAR YOUR GO AHEAD.
>> REALLY WONDERFUL
PRESENTATIONS. I REALLY
APPRECIATE IT. I LOVE THE
ACTION ITEMS.
ONE THING THAT I DID WANT TO
MENTION IS THAT AS YOU ALL KNOW
LEVY BODY DEMENTIA UNLIKE
ALZHEIMER'S DISEASE IS
ASSOCIATED WITH VERY LITTLE
NEURODEGENERATION AT LEAST IN
THE LIMBIC AREA.
AND I WE NEED TO MAYBE PUT MORE
EMPHASIS ON WHAT NUCLEON
PATHOLOGY DOES AT THE CELLULAR
LEVEL AND CIRCUIT LEVEL. THERE
IS THE OPPORTUNITY THERE TO
UNDERSTAND THE PATHOBIOLOGY AS
A CERTAIN LEVEL WHAT YOU HAVE
DEMENTIA IN LEVY BODY DEMENTIA.
WE ARE IN ALZHEIMER'S,
OBVIOUSLY YOU ARE LOSING
NEURONS. THAT IS NOT SURPRISING
THAT I WAS SURPRISED THAT THERE
WAS NOT AS MUCH OF THAT FOCUS.
AND I THINK WE REALLY NEED TO
HAVE A BETTER UNDERSTANDING OF
WHAT IS GOING ON WITH THE
NEURONS.
>> GREAT QUESTION. DR.
CHEN-PLOTKIN?
>> DR. CHEN-PLOTKIN: YOU IF YOU
KNOW THE TWOS REGULATIONS I
HAVE, ONE FOCUSED ON
A-SYNUCLEIN. THAT WAS ACTUALLY
A BOLD MOVE FROM A COMMITTEE TO
KIND OF PUT A LOT OF EMPHASIS
ON A-SYNUCLEIN, AND
UNDERSTANDING THE FUNCTIONS
A-SYNUCLEIN HAS IN NEURONS. AND
SPREAD THE CONFIRMATIONS.
THE REASON THERE IS EMPHASIS ON
THAT IN THE COMMITTEE IS THAT
SO MUCH HAS BEEN LEARNED ABOUT
A-SYNUCLEIN. AND AS I SAID IT
IS NOW IN CLINICAL TESTING. SO
WE REALLY NEED TO UNDERSTAND
THIS. OKAY?
AT THE SAME TIME, THE 8TH
RECOMMENDATIONS ABOUT BASICALLY
THE DIRECTION OF OTHER THINGS
WITH A-SYNUCLEIN.
WE COMPLETELY AGREE WITH YOU.
WHY IS IT THAT IN SOME PEOPLE
SOME CIRCUITS ARE MORE
VULNERABLE? RIGHT?
IS IT RELATED TO THE
ALZHEIMER'S DISEASE PATHOLOGY
THAT OCCURS IN SOME PEOPLE
VERSUS NOT, WHICH ONE STUDY
SUGGESTS IS THE CASE.
IS THAT RELATED TO OTHER
FACTORS?
GENETIC, GENOMIC, BIOMARKER
ENVIRONMENTAL FACTORS?
THAT IS CAPTURED IN 8. WHAT
YOU ARE RIGHT WE NEED TO
UNDERSTAND THIS BETTER.
>> I WANT TO FOLLOW UP ON THAT
BECAUSE I UNDERSTAND YOUR
PERSPECTIVE IN TERMS OF HOW IT
IS GREAT IN THE CIRCUIT FASHION.
THAT IS A PATHOLOGY.
I'M TALKING MORE ABOUT ACTUALLY
AT A FUNCTIONAL LEVEL. WE HAVE
A VERY, VERY LIMITED
UNDERSTANDING OF HOW THE
NUCLEON PATHOLOGY, WHY IS IT
NOT DEAD?
CORTICAL NEURONS, THEY DON'T
DIE WHEN YOU HAVE NUCLEON
PATHOLOGY, BUT WE HAVE VERY
LITTLE UNDERSTANDING OF HOW
THAT AFFECTS THE NEURAL
FUNCTION AND HOW THAT NEURON IN
THAT CONTEXT AFFECTS THE
CIRCUIT, WHICH IS VERY, VERY
SIGNIFICANT THING IN TERMS OF
HOW HUMANS ACTUALLY BEHAVE.
THAT IS SOMETHING WE NEED TO
HAVE A BETTER UNDERSTANDING.
>> DR. CHEN-PLOTKIN: WE AGREE
WITH YOU AND I APOLOGIZE IF I
WAS NOT CLEAR ENOUGH. THAT WAS
A DECISION WAS TRYING TO MAKE
BETWEEN FACTORS OF NEURAL
PATHOLOGY VERSUS
NEURODEGENERATION. THEY ARE
RELATED TO EACH OTHER BUT THEY
ARE NOT THE SAME.
>> THANK YOU FOR THE COMMENT.
WE HAVE A FEW HANDS HERE. I
APOLOGIZE. NUMBER ONE, ... IF
YOU WOULDN'T MIND UNMUTING.
>> (CLARIFY THE PRONUNCIATION)
(INDISCERNIBLE).
I WANTED TO ASK THE QUESTION
CONCERNING LEVY BODY DEMENTIA
IN 21 CHROMOSOME TRISOMICS
(PHONETIC).
QUICK QUESTION.
>> IF YOU COULD REPEAT THAT. I
DID NOT QUITE UNDERSTAND.
>> THE QUESTION IS ABOUT LEVY
BODY DEMENTIA, IT HAS
A-SYNUCLEIN NEUROPATHY IN 21
CHROMOSOME TRISOMICS IN DOWN
SYNDROME.
THAT WAS NOT COVERED.
>> NO. THAT WAS NOT.
MY GENERAL UNDERSTANDING, NOT
BEING THE GENETICIST ON THIS
PANEL, IS THAT WHILE
ALZHEIMER'S-ASSOCIATED
PATHOLOGY AND DEMENTIA IS
HEAVILY ASSOCIATED WITH TRISOMY
21 DOWN SYNDROME AND LEVY BODY
DEMENTIA PATHOLOGY IS LESS
LIKELY ASSOCIATED. DOCTOR-- IF
YOU COULD CLARIFY THIS PERMIT
PATHOLOGICAL PERSPECTIVE, THAT
WE DO NOT SEE LEVY BODY
PATHOLOGY?
>> I HAVE NOT SEEN MANY DOWN
SYNDROME BRAINS. I WISH I COULD
KNOW THE LITERATURE. FEEL FREE
TO EMAIL ME AND I CAN GET BACK
TO YOU, TO MAKE SURE IT IS
ANSWERED. THIS IS BEING
RECORDED. SO WE WILL HAVE THIS
RECORDED.
>> DR. TOLEDO?
>> DR. TOLEDO ATUCHA: ACTUALLY
IT IS PRETTY PREVALENT. THE
LEVY BODY IS ACTING IN
(INDISCERNIBLE) PATHOLOGY AND
WE NEED SOME CORE SYMPTOMS
PEOPLE WHO HAVE TRISOMIC
PATHOLOGY -- THINK THAT IS VERY
COMPLEX BECAUSE AS YOU SAW IN
THE PREVIOUS TALK, THE NORM IS
HAVING MULTIPLE CO-PATHOLOGIES.
BUT WE ACKNOWLEDGE THAT THOSE
PEOPLE WITH DEMENTIA THEY HAVE
PEOPLE WITH ALZHEIMER'S DISEASE
WITH (INDISCERNIBLE) PATHOLOGY.
>> THAT IS PART OF WHAT THE
PREVIOUS SESSION WAS TRYING TO
ADDRESS. HOW DO WE THINK ABOUT
THESE MIXED ETIOLOGY SITUATIONS
IN A MORE COMPREHENSIVE WAY?
AND GENETICALLY DEFINED
NEURODEGENERATIVE DISORDERS
REALLY DO FALL UNDER THAT. SOME
OF THEM ARE ONE PATHOLOGY,
OTHERS HAVE A MIXED PICTURE FOR
THE CLINICAL PRESENTATION IS
NOT TYPICAL FOR THE CLASSIC
PHENOTYPE.
I BELIEVE THAT IS ACTUALLY
SOMETHING THAT VERY MUCH NEEDS
TO BE ADDRESSED. THANK YOU FOR
BRINGING THAT UP.
>> WE ARE AT THE END OF TIME.
WE ENCOURAGE PEOPLE TO BRING
THEIR REMAINING QUESTIONS TO
THE FURTHER PUBLIC INPUT
SESSION SCHEDULED TO START AT
2:50 THIS AFTERNOON.
>> THANK YOU TO ALL THE
PRESENTERS.
>> THANK YOU EVERYONE.
>> WE WILL HAVE A SHORT BREAK
WHILE WE GET THE NEXT SESSION
SET UP, AND THEN GO STRAIGHT
INTO THE LAST SESSION OF TODAY.
WE WILL BE BACK IN 3 MINUTES. THANK YOU.
>> IS THE SESSION READY TO GET
STARTED?
>> DR. FOSSATI: I AM CAN YOU
HEAR ME?
>> I CAN.
>> DR. FOSSATI: IT WAS REALLY
AN HONOR AND A PLEASURE TO
COCHAIR THE SESSION TOGETHER
WITH HANZHANG LU.
AND SO I WILL GIVE YOU A BRIEF
INTRODUCTION ON VCID MECHANISMS
AND THEN GO AHEAD AND GIVE YOU
LIKE THE FIRST TWO
RECOMMENDATIONS THAT ARE ON THE
BASIC MECHANISMS.
WHAT IS VCID?
THESE ARE MY VIEWS AND I DON'T
HAVE ANY DISCLOSURES.
NEXT SLIDE.
WHAT IS VCID?
VASCULAR CONTRIBUTIONS TO
COGNITIVE IMPAIRMENT AND
DEMENTIA?
THE SCIENCE OF VCID IS
SIGNIFICANT COGNITIVE
IMPAIRMENT, RESULTING IN BRAIN
LESION, LIKE MICRO INFARCT,
ARTERIOSCLEROSIS, SYSTEMIC
ATTACKS AND SEVERAL OTHERS.
VCID IS NOT ONLY A BRAIN ISSUE
BUT IS IMPORTANT SYSTEMIC
COMPONENTS, VERY COMMON WITH
AGING.
AND WE ALL KNOW THAT IT IS AT
LEAST IN PART PREVENTABLE.
SO, THE COGNITIVE OUTCOMES
ASSOCIATED WITH VCID CAN VARY
IN TERMS OF LIKE HOW SERIOUS
THESE INJURIES ARE. BUT ALSO IN
ANATOMICAL LOCATION OF THE
INJURY, COMORBIDITIES IN
VASCULAR RISK FACTORS AND
SEVERAL OTHER FACTORS.
NEXT SLIDE.
OF COURSE WE HAVE TO KEEP IN
MIND THAT VCID DOESN'T EXIST IN
ISOLATION, BUT IN MANY CASES IT
HAPPENS TOGETHER WITH
ALZHEIMER'S DISEASE PATHOLOGY
SO AMYLOID -- PATHOLOGY.
WE HAVE TO CONSIDER ALL OF
THESE TOGETHER AND WE KNOW
RIGHT NOW AS MANY OF THE
COMMITTEE MEMBERS HAVE
HIGHLIGHTED IT MAKES THE
PATHOLOGY DEMENTIA THE MOST
COMMON FORM, AND VASCULAR-- OF
THE MOST FREQUENT COMBINATION.
WE HAVE TO HIGHLIGHT THAT THE
SCIENCE OF VCID IS VERY MUCH
MULTIDISCIPLINARY. IT HAS TO
ACCOUNT VASCULAR PATHOLOGY AND
RISK FACTORS, AND A LOT OF
THINGS THAT HAPPENED LIKE HYPER
PERFUSION, BLOOD BRAIN BARRIER
PROBLEMS, FLOW ISSUES,
CLEARANCE ISSUES, ETC.
NEXT SLIDE.
SO IF WE TAKE INTO ACCOUNT IN
THOSE FAMOUS BIOMARKER CURVES
THE VASCULAR BIOMARKERS IF WE
ASSUME THAT THESE ARE
IRRESPECTIVE OF HISTOLOGIC
PROCESSES WE CAN SEE IN THE
LIGHT BROWN CURVE IS THE
VASCULAR BIOMARKERS. AND
VASCULAR DISREGULATION MAY BE
EARLY SIGNS OF BRAIN FACTOR,
ASSOCIATED WITH ALZHEIMER'S
DISEASE DEVELOPMENT.
NEXT SLIDE.
WE TALK ABOUT VCID, WE REALLY
HAVE TO TALK ABOUT THE
NEUROVASCULAR UNIT AND THE
CEREBRAL VASCULAR SYSTEM WE CAN
ACCOMPLISH UNIT OF CELLS THAT
SURROUND AND INCLUDE THE
CEREBRAL VESSELS. AND THESE
CHANGES VARY DEPENDING ON THE
SIZE OF THE VESSELS,
MICROVASCULAR VESSELS, BIG
VESSELS. BUT ALSO WHERE IN THE
BRAIN WE ARE. THE BRAIN
LOCALIZATION, HIPPOCAMPUS
VERSUS CORTEX.
AND WE HAVE TO REMEMBER THAT
THE CONTROL OF CEREBROVASCULAR
FUNCTION DOES NOT ONLY DEPEND
ON BRAIN FACTORS, SOCIAL
NEUROVASCULAR COUPLING, BUT
ALSO ON PERIPHERAL SYSTEMIC
FACTORS SUCH AS BLOOD PRESSURE,
PRESSURE OF CO2 AND OTHERS.
NEXT SLIDE.
AND VCID OF COURSE AS MANY RISK
FACTORS. A LOT OF THEM ARE
SHARED WITH CARDIOVASCULAR
DISEASES.
WE HAVE NONMODIFIABLE RISK
FACTORS LIKE AGE, SEX, AND
GENETICS. BEHAVIORAL AND
LIFESTYLE RISK FACTORS, BUT
ALSO PSYCHOSOCIAL,
SOCIOECONOMIC AND OTHER RISK
FACTORS.
WANTED A REALLY IMPORTANT TO
FOCUS ON OUR METABOLIC RISK
FACTORS SUCH AS OBESITY,
DIABETES, HYPERTENSION, AND
MANY OTHERS.
NEXT SLIDE.
AND SO, THESE RECEPTORS
TOGETHER CAN PROMOTE DEMENTIA
PATHOLOGY.
AND WE LOOK AT THE RISK FACTORS
DEPENDING ON SEX, ACTUALLY THE
RISK FACTORS MAY HAVE A
DIFFERENT IMPACT IN MEN VERSUS
WOMEN FOR EXAMPLE HEART DISEASE
IS MORE OF A FACTOR IN MEN AND
HYPERTENSION IS MORE OF A
FACTOR FOR WOMEN.
NEXT SLIDE.
SO TO FINISH THIS INTRODUCTION,
I REALLY WANT TO THANK ALL THE
COMMITTEE MEMBERS. THIS WAS AN
INCREDIBLY COHESIVE AND
COLLABORATIVE PROCESS. AND
ESPECIALLY I WANT TO THANK --
THAT HELP TOGETHER AND ORGANIZE
THIS COMMITTEE. COULD NOT HAVE
DONE THIS WITHOUT THEM.
NEXT SLIDE.
SO I'LL GO NOW INTO THE BASIC
SCIENCE RECOMMENDATIONS.
THE FIRST ONE PRIORITY ONE IS
TO UNDERSTAND MECHANISMS OF
VASCULAR DISEASE ONSET AND
PROGRESSION, SPECIFIC CELL
TYPES AND INTERACTIONS IN THE
CONTEXT OF COGNITIVE DECLINE.
AND SO FOCUSING ON SPECIFIC
SYMPTOMS AND THEIR INTERACTIONS
AND THIS SHOULD INCLUDE CELLS
OF OF THE CEREBRAL POPULAR
SYSTEM INCLUDING ENDOTHELIAL
CELLS, ASTROCYTES, MICROGLIA
AND OTHERS.
IF YOU LOOK AT THE
(INDISCERNIBLE) FOR SPECIFIC
CELL TYPES OF THE NEUROVASCULAR
UNIT YOU SEE THERE IS A GROWING
NUMBER OF CITATIONS WITH 60
RESULTS IN 2024. BUT OF COURSE
WE NEED TO DO MORE.
THIS ALSO ALLOWED THE
DEVELOPMENT OF NEW TECHNOLOGIES
THAT GAVE US THE POSSIBILITY TO
DO SINGLE CELL RNA SEQUENCING
OR SINGLE CELL ANALYSIS IN
CELLS OF THE HUMAN BRAIN
VASCULATURE ACROSS DISEASE AND
IN ALZHEIMER'S DISEASE AND
VASCULAR DYSFUNCTION IN
PARTICULAR.
NEXT SLIDE.
AND ALSO THANKS TO THESE RNA
SEQUENCING STUDIES WE HAVE BEEN
ABLE TO PINPOINT WHERE
IMPORTANT PATHWAYS AND
MECHANISMS.
WE KNOW THAT THE STUDY SHOULD
CLARIFY ALL THESE MECHANISMS
INCLUDING LOSS OF BLOOD BRAIN
BARRIER INTEGRITY,
ANGIOGENESIS, AND HOW THE LAWS
OF BLOOD BARRIER INTEGRITY
AFFECTS BRAIN BIOMARKERS, AND
WE HAVE TO DO MORE INTERESTED
IN HOW THESE PATHWAYS CHANGE
AND HOW THESE CELLS INTERACT IN
DETERMINING THE CHANGES.
NEXT SLIDE.
AND, OF COURSE, AB PATHOLOGY IS
INVOLVED IN THIS MECHANISMS AS
WELL.
WE KNOW THAT -- DEPOSITS IN THE
VESSELS, CAA IN PARTICULAR BUT
RECENT STUDIES HAVE SHOWN THAT
TAU ACCUMULATING THE BRAIN
VASCULATURE. WE ARE STARTING TO
UNDERSTAND THE TAU EFFECTS OF
THE BLOOD BRAIN BARRIER THAT
AFFECTS ENDOTHELIAL CELLS
REDUCING PYRAMID ABILITY. THIS
SHOULD ALSO BE STUDIED.
NEXT SLIDE.
WE WANT TO IMPROVE THE
UNDERSTANDING OF THE EFFECTS OF
THE CID ON THE INTERACTION
BETWEEN DIFFERENT CELL TYPES AS
WELL AS ON THE MOVEMENT AND
CLEARANCE OF MOLECULES ACROSS
THE PERIVASCULAR SPACE, CSF AND
BLOOD-BRAIN BARRIER. AND MANY
MECHANISMS HAVE BEEN POINTED
OUT SUCH AS INTRAMURAL
DRAINAGE, LYMPHATIC DRAINAGE,
MENINGEAL LYMPHATIC CLEARANCE
AND PERIVASCULAR LEARN
MICROPHAGES. THIS MOVEMENT
AFFECT THE MOVEMENT AND
CLEARANCE OF MOLECULES AND HOW
THEY INTERACT WITH EACH OTHER
IS A VERY IMPORTANT QUESTION.
NEXT SLIDE.
AND WE SHOULD ALSO CONSIDER
VASCULAR PATHOLOGY SUCH AS
CEREBRAL ANGIOGRAPHY, CEREBRAL
ARTERIAL SCLEROSIS, AND HOW WE
CAN PREVENT DISEASES FOR
EXAMPLE CARDIOVASCULAR DISEASE,
DEMENTIA IN A DIFFERENT WAY WE
SHOULD CONSIDER ALL OF THEM
TOGETHER OR IN COMBINATION.
NEXT SLIDE.
SO, IN ADDITION TO COGNITIVE
DECLINE WE SHOULD ALSO CONSIDER
OUTCOMES THAT ARE RELATED TO
COGNITIVE DECLINE, BUT MORE
VASCULAR SPECIFICS SUCH AS
MARKER HEMORRHAGES, WHITE
MATTER (INDISCERNIBLE) IN LARGE
PERIVASCULAR SPACES AND LYPO
PERFUSION. AND THERE ARE SOME
NICE ANIMAL MODELS, FOR EXAMPLE
MARKER HEMORRHAGES ON THE LEFT
SIDE, AND YOU CAN SEE A RAT
MODEL WHICH ALLOWS US TO SEE
WHITE MATTER ISSUES BETTER THAN
MOUSE MODELS.
AND ON THE RIGHT SIDE, YOU CAN
SEE HOW THE NOVEL TECHNOLOGIES
ALLOW US TO MONITOR CEREBRAL
BLOOD FLOW FOR EXAMPLE IN MICE
THAT ARE ALIVE AND AWAKE AND WE
CAN SEE CAPILLARY STALL IN THE
RECENT PAPER WE PUBLISHED.
NEXT SLIDE.
SO THE NEXT RECOMMENDATION, THE
SECOND RECOMMENDATION PRIORITY
2, IS TO DISCOVER VCID
MECHANISMS AND POTENTIAL
TARGETS BY LEVERAGING DATA AND
BY ESTABLISHING, REFINING AND
UTILIZING HUMAN, ANIMAL, AND
CELL-BASED EXPERIMENTERS MODELS
AND TECHNOLOGIES.
NEXT SLIDE. THESE MODELS SHOULD
INCLUDE ALSO SYSTEMIC AND
CHRONIC PERIVASCULAR DISEASES,
FOR EXAMPLE HYPERTENSION AND
HEART CARDIAC FAILURE, AND TRY
TO MODEL THEM.
HERE UNLESS YOU SEE A RAT MODEL
THAT INCLUDES A SET OF THE
SMALL VESSEL DISEASE IN THE
PRESENCE OF MANY OF THESE
CARDIOVASCULAR RISK FACTORS
SUCH AS HYPERTENSION, AGING,
AND CEREBRAL LIPO PERFUSION AND
WHEN YOU PUT THEM ALTOGETHER
YOU HAVE AN INCREDIBLE LOSS OF
CEREBRAL BLOOD FLOW.
AND WE MODEL TWO OF THESE
VASCULAR PATHOLOGY SUCH AS CAA,
AND HYPER HOMO STEMIA
(PHONETIC), THERE IS AN
EFFECTIVE LOSS OF FUNCTION
PROCESS AND THE CORRESPONDING
ANIMAL MODEL THAT GIVES US THE
SAME RESULTS ON BLOOD-BRAIN
BARRIER PERMEABILITY.
NEXT SLIDE.
AND THE STUDY SHOULD CLARIFY
THE MECHANISMS AND MOLECULAR
TARGETS OF VASCULAR DISEASE AND
OTHER KEEP PATHOGENIC PROCESSES
RESULTING IN COGNITIVE
IMPAIRMENT. FOR EXAMPLE MICRO
HEMORRHAGES IN MANY OF THE
OTHER ONES WE TALK ABOUT.
THERE MANY ANIMAL MODELS
ALREADY DEVELOPED FOR EXAMPLE
FOR CAA, IN MANY OF THESE
PATHOLOGIES SUCH AS THIS ONE, ,
AND SEVERAL OTHER ANIMAL MODELS
BUT SOME PRIVATE MODELS ARE
COMING UP...
>> TWO MINUTES.
>> DR. FOSSATI: FOR EXAMPLE,
THE SQUIRREL MONKEYS THAT
DEVELOP CAA THAT DEVELOPS
SPONTANEOUSLY WITH AGE.
NEXT SLIDE.
WE SHOULD GIVE ATTENTION TO
LIFESTYLE VASCULAR AND
METABOLIC FACTORS ASSOCIATED
WITH NORMAL AGING AND CHRONIC
CONDITION, IN ADDITION TO
(INDISCERNIBLE) PATHOLOGY.
AND SO THE RISK FACTORS INCLUDE
OF COURSE VASCULAR RISK
FACTORS, TRAUMATIC BRAIN
INJURY, MENOPAUSE FOR WOMEN,
AND WE CAN HAVE THINGS SUCH AS
(INDISCERNIBLE) SIZE THAT CAN
HELP PREVENT VASCULAR RISK
FACTORS.
HERE IS A NICE IMAGE TO SHOW
FOR EXAMPLE IMMUNE REGULATION
IS CHANGING AT DIFFERENT TIMES
DURING AND AFTER TRAUMATIC RAIN
INJURY. (CORRECTION) TRAUMATIC
BRAIN INJURY.
NEXT SLIDE.
WHICH ALSO CONSIDER USING 3D
AND PSC MODELS TO INCORPORATE
FLOW TO HAVE A MORE
PERSONALIZED MEDICINE CREATE
DIFFERENT CELL TYPES AND 3D
CHIP MODELS WILL INCORPORATE
THE FLOW.
AND WE CAN TAKE SOME OF THESE
FROM THE CARDIOVASCULAR FIELD.
OF COURSE WE HAVE TO INCLUDE
ALL THE OTHER CELLS OF THE
NEUROVASCULAR UNIT. THERE ARE
3D ORGANOIDS THAT ARE BEING
DEVELOPED EVEN THOUGH THEY ARE
NOT YET FUNCTIONAL AND 3D CHIPS
THAT CAN HELP US RECAPITULATE
THE NEUROVASCULAR UNIT REALLY
HELPFUL AS WELL.
NEXT SLIDE.
WE SHOULD ALSO CONSIDER THE
SEX-LINK BIOLOGY AND MENOPAUSE
IN THE INTERACTIONS. WOMEN ARE
AT HIGHER RISK OF VCID, AND THE
MENOPAUSE TRANSITION IS
IMPORTANT TO UNDERSTAND THIS
RISK. WE SHOULD LOOK AT THE
RELATIVE CONSIDERATION OF
THEIRS MECHANISMS AND MANY OF
THESE CLEARANCE MECHANISMS HAVE
BEEN CLARIFIED IN THE LAST FEW
YEARS. BUT WE REALLY NEED TO
UNDERSTAND BETTER THEIR
INTERACTIONS.
THANK YOU.
NEXT SLIDE.
I WILL KNOW LEAVE THE
MICROPHONE TO GARETH HOWELL
PULLED RECOMMENDATIONS.
>> WAS A PLEASURE TO BE PART OF
THIS PANEL.
NEXT SLIDE.
I HAVE, THESE ARE MY
DISCLAIMERS AND DISCLOSURES I
AM GARETH HOWELL, PROFESSOR AT
THE -- CHAIR AND LABORATORY.
I'M GOING TO COVER
RECOMMENDATIONS 3 AND 4.
RECOMMENDATION 3, PRIORITY OF
4,
CROSS VALIDATE THE MECHANISMS
OF ANIMAL MODELS AND HUMAN
STUDIES TO ENSURE PHASE AND
CONSTRUCT VALIDITY INCLUDING
MIX PATHOLOGIES, NORMAL
VASCULAR AGING AND COMMUNITY
BASED COHORT.
UNDERLINING THIS ONE OF THE
FIRST BULLET OF THIS IS TO WORK
TRANSLATIONALLY TO CHARACTERIZE
THE INTERRELATIONSHIPS OF
VASCULAR RISK FACTORS AND AD
MECHANISMS DISCOVERED IN CELL
AND ANIMAL MODELS TO BIOMARKERS
OF CEREBROVASCULAR DISEASE.
BOTH RECOMMENDATIONS HOW DID
THE NEED TO IMPROVE THE
TRANSLATION BETWEEN MODELS AND
THE CLINICAL DISEASE.
AND SO IN A WAY WE THINK ABOUT
EXAMPLES OF VCID AS WAS
DESCRIBED PREVIOUSLY, WITH
THINK ABOUT CEREBRAL AMYLOID,
AND CEREBRAL MICROBLEEDS.
THERE IS A NEED HERE TO REALLY
POTENTIALLY REDEFINE THE
BIOLOGICAL ASPECTS OF VCID
OBSERVED IN THE CLINIC.
SIMPLY OBSERVING THE PATHOLOGY
FOR INSTANCE IN THE MASS MODEL
DOES NOT NECESSARILY MEAN IT IS
DRIVEN BY THE SAME FACTORS THAT
WOULD BE SEEN IN THE CLINIC.
WE NEED TO WORK HARDER TO
UNDERSTAND THESE BOTH IN THE
HUMAN CONDITIONS, BUT ALSO IN
OUR MODELS.
NEXT SLIDE.
ANOTHER IMPORTANT COMPONENT OF
THIS RECOMMENDATION IS TO
EVALUATE THE MECHANISMS LEADING
TO AMYLOID RELATED IMAGING
ABNORMALITIES ASSOCIATED WITH
THESE AMYLOID IMMUNOTHERAPIES
AND USING THE HUMAN AND
EXPERIMENTAL MODELS, IMPORTANT
TO RECOGNIZE THAT MODELS HAVE A
HARD TIME IN THIS PATIENT WAS
SHOWN MORE THAN 20 YEARS AGO
THAT YOU WOULD BE ABLE TO CLEAR
AMYLOID FROM RAINS AND EVEN
LEAD TO ARIA-LIKE PATHOLOGIES.
IT WAS NOT CALLED ARIA BACK
THEN.
IT CAN BE MORE PREDICTABLE AS
WE THINK ABOUT IMPROVING
THERAPIES FOR THINGS LIKE
ALZHEIMER'S DISEASE AND RELATED
DIMENSIONS IN THE VCID SPACE.
AND THE SQUIRREL MONKEYS SYLVIA
POINTED TO, WE NEED TO THINK
ABOUT EXPANDING NOT JUST IN THE
CELL SPACE BUT ALSO IN THE
ANIMAL MODEL SPACE.
NEXT SLIDE.
AND I WHEN WE THINK ABOUT
IMPROVING OUR MODEL COLLECTION,
AND AS WE BUILD TO CROSS
VALIDATE ASSETS, WE NEED TO
THINK ABOUT ALL THE DIFFERENT
FACTORS THAT ARE OBSERVED IN
THE CLINIC INCLUDING SEX AND
AGE AS BIOLOGICAL BARRIERS,
EXPERIMENTAL APPROACHES SHOULD
INCLUDE ANIMAL MODELS AND THE
EXTENT OF DIVERSITY IN THIS IS
PARTICULARLY IMPORTANT WHEN WE
THINK ABOUT THE ENVIRONMENTAL
RISK FACTORS AS WAS DESCRIBED
BEFORE, AS WELL AS THE GENETICS
PRESENT IN HUMAN POPULATIONS.
AND THERE'S A REAL FEELING THAT
SOMETIMES WE DO THE QUICK AND
EASY EXPERIMENT IN THE MASS
MODELS, OR EVEN ANY ANIMAL
MODEL DESPITE THE FACT THAT
THERE IS A WEALTH OF RESOURCES
THAT CAN BE ACCESSED THAT HAVE
BEEN SHOWN TO BE REALLY
IMPORTANT IN IMPROVING THE
TRANSLATION BETWEEN HUMANS AND
MICE.
I AM SHOWING HERE ON THE
LEFT-HAND SIDE THAT WE COMMONLY
USE C57 BLACK 6. BUT THERE'S A
WHOLE ARRAY OF OTHER THINGS
LISTED HERE ESSENTIALLY
INCORPORATING AS MUCH GENETIC
VARIATION AS YOU CAN SEE IN
THE HUMAN POPULATION AND YOU
CAN GET QUITE DIFFERENT RESULTS
IF YOU TRY AND DRIVE A HUMAN
RELEVANT PATHOLOGY DEPENDING ON
THE STRAIN.
ON THE LEFT-HAND SIDE I AM
SHOWING A PHOTOGRAPH OF
CEREBRAL AMYLOID -- TAKING BY
OLIVIA-- IN MY LAB AND
HIGHLIGHTS THAT THE B STRAIN
CARRIES THE GENETIC THAT MAKES
MICE MORE SUSCEPTIBLE TO CAA.
SO I WE NEED TO DO BETTER IN
INCORPORATING AND LEVERAGING
ALL OF THE MASS GENETIC
RESOURCES THAT WE HAVE
AVAILABLE.
NEXT SLIDE.
SO WE RECOMMEND 4, PRIORITY 3.
DEVELOP AND ADVANCE ESSENTIAL
NEW THERAPEUTICS AND SELL AN
ANIMAL MODEL TO PREVENT OR
TREAT VCID. TO TARGET
PREVENTION OR TREATMENT OF
VCID-RELATED COGNITIVE DECLINE
WORKING TOWARDS OPTIMIZING
TRANSLATION FROM CELL AND
ANIMAL MODELS TO CLINICAL
TRIALS.
THIS DIAGRAM HAS BEEN SHOWN
BEFORE, ABOUT WHERE WE ARE WITH
ALZHEIMER'S DISEASE. AND I
REALLY DON'T NEED TO SEE ALL
THE DETAILS OF THIS. YOU CAN
SEE THAT THERE IS A LARGE
NUMBER OF CLINICAL TRIALS THAT
ARE AT DIFFERENT PHASES FOR
ALZHEIMER'S DISEASE. AND THE
MECHANISMS OF ACTION ARE VARIED
SO A LOT OF AMYLOID BUT ALSO
EMERGING IN OTHER AREAS SUCH AS
NEURAL INFLAMMATION, EPIGENETIC
REGULATIONS, MITOCHONDRIAL
HEALTH, ETC.
BOTH OF THESE CATEGORIES YOU
NOTICE THERE AREN'T REALLY ANY
SPECIFICALLY TARGETING OR
IMPROVING THE HEALTH OF
CEREBRAL VASCULAR AND LYMPHATIC
CELLS, WHICH WE SHOULD BE
TARGETING POTENTIALLY
UNDERLYING MECHANISMS SO WE
REALLY WANT TO SEE THIS CHANGE
MOVING FORWARD.
NEXT SLIDE.
THIS WAS BROUGHT UP EARLIER
ABOUT MODEL AD.
IN THE ALZHEIMER'S SPACE WE
ALREADY DEVELOPED NEW WAYS OF
DEVELOPING MASS MODELS THAT ARE
MUCH MORE HUMAN RELEVANT,
ENSURING THAT WE START WITH
CLINICAL DATA, AND BUILDING
MODELS BASED ON CLINICAL DATA,
PARTICULARLY THE GENETIC
INFORMATION THAT IS AVAILABLE.
GENETIC IN COMBINATION WITH
ENVIRONMENTAL MONEY RELATION
SUCH AS HIGH-FAT DIET AND TOXIC
METALS, THAT IMPROVE THE
VALIDITY OF THOSE MASS MODELS
AND THE TRANSLATABLE METHOD
SUCH AS FLUID -- AND WE DO THE
CLINICAL SCREENINGS SUCH AS
DRUG TESTING YOU KNOW THESE
MODELS HAVE BEEN ALIGNED TO THE
CLINICAL DISEASE THAT YOU ARE
ACTUALLY STARTING.
NEXT SLIDE.
AND THEN FINALLY UNLESS
RECOMMENDATION THERAPEUTICS
PREVENTION OF PRECISION MEDS
APPROACHES SHOULD ADDRESS ARIA
COMPONENT WHICH IS AN IMPORTANT
COMPONENT AS IT INVOLVES
VCID-RELATED ABNORMALITIES.
THE KEY POINT I WANT TO MAKE
YOUR THAT AS WE THINK ABOUT
DEVELOPING THERAPIES THERE MAY
NOT BE A SINGLE TREATMENT BUT
MORE MORE THESE ARE GOING TO BE
COMBINATORIAL THERAPIES, EVEN
IN COMBINATION WITH HEALTHIER
LIVING RECOMMENDATIONS. IS
GOING TO BE VERY DIFFICULT JUST
IN THE HUMAN SPACE, OR EVEN IN
THE CELL SPACE TO UNDERSTAND
HOW THE COMBINATION OF
THERAPIES ARE GOING TO REFLECT
THE BRAIN AND THE REST OF THE
BODY IF YOU THINK ABOUT VCID
AND ADIDS, AS A WHOLE BODY
DISEASE SO WE NEED TO MAKE SURE
WE IMPROVE CLINICAL STUDIES IN
ORDER TO FEED THAT INFORMATION
INTO MORE APPROPRIATE CLINICAL
TRIALS AND OBSOLETE A RESULT OF
THOSE CAN GET FED BACK TO
IMPROVE CLINICAL STUDIES.
WITHOUT A WILL STOP.
>> THANK YOU. AGAIN A PRIVILEGE
TO BE PART OF THIS GROUP.
THESE ARE MY DISCLOSURES.
>> DR. SESHADRI: I WILL BE
ADDRESSING HUMAN STUDY
RECOMMENDATIONS 5 AND 6.
IN RECOMMENDATION 5, WE
ADVOCATE FOR ADVANCING
INTERVENTIONS AND PREVENTION TO
REDUCE VASCULAR DISEASE BY
VASCULAR BRAIN INJURY IN
POPULATIONS AT INCREASED RISK
FOR VCID.
THIS IS PRIORITY 2.
SO WE ENCOURAGE PHASES 1-4 IN
PRIMARY CLINICAL TRIALS OF VCID
TESTING INTERVENTIONS SHOWN TO
BE EFFICACIOUS IN REDUCING
HEART ATTACKS AND STROKE. THIS
INCLUDES THINGS LIKE MANAGING
BLOOD PRESSURES, DIABETES,
OPTIMIZING DIET AND EXERCISE
AND SLEEP ENVIRONMENT AND
BEHAVIOR. AND THIS IS THE STAGE
OF SOMEBODY WHO HAS NO REST
BRAIN INJURY DETECTABLE,
DRIVING PREVENTION IS PERHAPS
SOMEBODY WHO HAS ALREADY HAD A
STROKE. AND AGAIN EMPHASIZING
TRIALS AS WELL THAT IMPROVE
QUALITY OF LIFE.
FOR EXAMPLE IN PHYSICAL THERAPY
INTERVENTION TO IMPROVE
MUSCULAR STRENGTH, GATE AND
BALANCE.
WE ARE PRIORITIZING WHICH
INTERVENTION SHOULD GO TO TRIAL
CAN BE STRENGTHENED BY USING
MEDICAL RELEVANT COHORTS THAT
ARE NOW EXISTING. FOR EXAMPLE
LOOKING AT COGNITION TWO YEARS
AFTER AN ACUTE STROKE AND EVERY
AND SEEING THE PREDICTORS, AND
CONSEQUENCES AND PROGRESSION OF
WHITE MATTER HYPER INTENSITY IN
VCID.
NEXT SLIDE.
THE RATIONALE FOR THIS
RECOGNITION OF THE FACT THAT
OVER THE LAST SEVERAL DECADES,
WE HAVE A LOT OF OBSERVATIONAL
DATA, ESPECIALLY FOCUSING ON
COGNITIVE IMPAIRMENT AND
DEMENTIA. NOT WHAT WE HOPE THEM
PERHAPS TODAY THE MOST HOPEFUL
ONE INTENSIVE BLOOD PRESSURE
CONTROL IS SEEN
(INDISCERNIBLE), IN PEOPLE WHO
ARE ALREADY AT HIGH RISK.
AND SO WE ARE RECOGNIZING
THINGS LIKE, HOW EFFECT OF THE
INTERVENTION?
WHAT IS THE STAGE OF THE
DISEASE?
WHAT IS THE AGE OF THE PEOPLE
WHO ARE IN THE STUDY?
WHAT IS THE TYPE OF
INTERVENTION?
WHAT ARE THE MOLECULAR PATHWAYS
THAT UNDERLIE AN EFFECTIVE OR
INEFFECTIVE INTERVENTION?
AND SO THE HEART AND BRAIN ARE
DIFFERENT TARGETS.
WHAT ARE THE SUBJECTS LIKE
SPECIFIC CHARACTERISTIC LIKE
GENETICS, AND ENVIRONMENT?
WHAT IS THE COMBINATION OF
THESE INTERVENTIONS THAT MAY BE
SYNERGISTIC OR NOT?
ONE MAY ALSO NOT JUST LOOK AT
THINGS LIKE BLOOD PRESSURE THAT
WE ARE CURRENTLY SEEING CLINIC
BUT FURTHER UPSTREAM. THINGS
LIKE ARTERIAL STIFFNESS THAT
HAVE A LONG-TERM EFFECT ON
DEMENTIA RISK. BUT PROCEED
EVEN DETECTABLE HIGHER BLOOD
PRESSURE.
NEXT SLIDE.
SO, WHEN ONE THINKS ABOUT WHAT
TO PRIORITIZE, THERE ARE THE
VARIOUS MODIFIABLE RISK
FACTORS, AS HIGHLIGHTED BY THE
LANCET (PHONETIC) POPULATION
THAT HAVE SIGNIFICANT A
POPULATION AT RISK OR
HIGHLIGHTED BY THE AHA AND
THESE SEEM TO HAVE THE MAXIMUM
IMPACT IN MIDLIFE.
AND SO THE BENEFITS ARE NOT
MAYBE DETECTABLE AS MUCH AS 20
YEARS OR GREATER LATER. AND AS
YOU HEARD THROUGHOUT THIS,
THESE RISK FACTORS MAY NOT ONLY
BE ACTING THROUGH TRADITIONAL
VASCULAR MECHANISMS, BUT TO
THEIR IMPACT ON VARIOUS
(INDISCERNIBLE) AND OTHER
THINGS.
NEXT SLIDE.
SO KEEPING THESE IN MIND, ONE
DOES HAVE, HOWEVER, A LOT OF
DATA TO MINE. FOR EXAMPLE THIS
NIH WEBSITE, YOU SEE THE
VARIOUS LEGITIMATE DATA FROM
AGE 10-100. THE STUDY IS IN
BLUE THAT ARE NEARLY
OBSERVATIONAL, AS WELL AS ONES
IN GREAY, INTERVENE TO CHANGE
DIABETES RISK. THEN THE
DIFFERENCES BETWEEN THE HEART
AND THE BRAIN FOR EXAMPLE FOR
HEART DISEASE ONE MAY NEED AT
LEAST 30 MINUTES OF MODERATE TO
AGGRESSIVE ACTIVITY TO REMOVE
(INDISCERNIBLE).
WHEN WE COMBINE THESE DATA SETS
WITH BIOMARKERS THAT ARE ABLE
TO BE SEEN IN AN AGNOSTIC
MANNER YOU FIND THAT
(INDISCERNIBLE) HIGHLIGHT NOVEL
PATHWAYS LIKE CHANGES IN
GLUTAMINE LEVELS.
NEXT SLIDE.
NEXT.
IN FACT, THERE ARE A LOT OF
LARGE NUMBER OF-- EVEN IF YOU
CONSIDER ONE MODALITY OF
EXERCISE, A LARGE NUMBER OF
(INDISCERNIBLE) THE RELEASE
THAT HAVE AN EFFECT ON
NEUROGENESIS AND ANGIOGENESIS,
BUT THIS AFFECTS
PERSON-TO-PERSON FOR EXAMPLE
THE IMPACT OF PHYSICAL ACTIVITY
ON MOOD OR COGNITION SEEMS TO
VARY IN , ACUTE OR MORE CHRONIC
SETTINGS BASED ON WHETHER THE
PERSON IS HOMOZYGOTES OR
(INDISCERNIBLE) CARRIER.
NEXT SLIDE.
ONE THING TO MULTIPLE
INTERVENTIONS AGAIN SOME OF
THESE LIKE IMPACTING OMEGA-3
FATTY ACIDS, OR BLOOD PRESSURE
CONTROL WERE NOT AFFECTED WITH
-- EFFECTIVE FOR BLOOD PRESSURE
CONTROL BUT NOT MUCH ADDITIONAL
VALUE AND SO STUDIES ARE
EXTENDING WHAT WAS DONE IN A
SWEETIE SETTING TO A LARGE
NUMBER OF HEALTH SYSTEMS AND
PATIENT POPULATION TO SEE WHAT
THE BENEFIT MIGHT BE.
NEXT SLIDE.
RECOMMENDATION 6 THEREFORE
EMPHASIZES LOOKING AT THE
HETEROGENEITY, UNDERSTANDING
THE IMPACT OF SPECIFIC, SMALL
VESSEL DISEASE PATHOLOGIES AND
VASCULAR RISK FACTORS OF
COGNITIVE CHANGE DECLINE.
RECOGNIZING THAT THESE
HETEROGENEOUS PATHOLOGIES MAY
CO-AUTHOR, MAY IMPACT THE
POPULATION DEPENDING ON WHAT IS
HAPPENING IN THE VASCULAR
SETTING.
AND WE WANT TO REALLY INTERVENE
AT THE PRECLINICAL STAGE, WHEN
THESE PATHOLOGIES ARE THERE BUT
THEY ARE NOT HAVING ANY
DISCERNIBLE EFFECT ON
COGNITION. ANALOGOUS TO THE
PRECLINICAL AMYLOID ARGUMENT
ADDED IN AN ASSET WAS
EMPHASIZED WE HAVE FEW NOVEL
TARGETS EMPHASIZING THE VALUE
ON THE BRAIN IN PARTICULAR.
NEXT SLIDE.
AND SO HOW CAN WE PERHAPS GET
AROUND THAT?
YOU HAVE ALREADY HEARD THAT
CATEGORIZING THE DIFFERENT
SUBTYPES DEPENDS ON LOOKING AT
THE STATUS OF THE HEART, THE
BLOOD VESSELS, THE BLOOD-BRAIN
BARRIER, LOW MRI MEASURES AND
WHITE MATTER HYPER INTENSITY
AND PERIVASCULAR SPACES.
BUT AS WE GET MORE SENSITIVE
BIOMARKERS WHICH WILL HEAR
ABOUT LATER WE ALSO HAVE THE
QUESTION ABOUT WHAT IS THERE.
NEXT SLIDE.
AND THERE ARE INTERACTIONS WITH
THE, FOR EXAMPLE,
POSTMENOPAUSAL STATUS, SO
VASCULAR AND AMYLOID
SYNERGISTICALLY ACT ON TAU
ACCUMULATING THIS IN TURN
MEDIATES THE COGNITIVE DECLINE.
NEXT SLIDE.
SO, WHEN ONE TAKES A LUMPING
APPROACH TO MAXIMIZE THE
ABILITY TO FIND SMALL EFFECTS,
ONE FINDS NEW BIOLOGICAL
PATHWAYS. ONE CAN UNDERSTAND
THE CONTEXT IN BOTH THE
CELLULAR AND -- LAST SLIDE
PLEASE -- BOTH CELL AND
SPATIAL LEVEL USING SINGLE CELL
AND SPATIAL MIX.
NEXT SLIDE.
WE CONSIDER HOMOGENEOUS HYPER
INTENSITY AS WELL, WHEN WE TAKE
(INDISCERNIBLE) WE FIND THERE
IS HETEROGENEITY OF BIOLOGY FOR
EXAMPLE PERIVENTRIC OF
SUBCORTICAL.
CAN LEAD TO THE DETECTION OF
NEW BIOLOGICAL PATHWAYS.
NEXT SLIDE.
WHAT IS THE VALUE OF THIS?
FOR EXAMPLE WE TALKED ABOUT NOT
HAVING SPECIFIC TARGET FOR THE
LYMPHATIC SYSTEM WHEN ONE TAKES
PERIVASCULAR SPACES, IDENTIFIED
UNDERLYING GENETICS, AND
CORRELATES AND SEES WHAT ARE
THE GENES WHOSE LEVELS ARE
IMPACTED BY AVAILABLE,
REPURPOSABLE DRUGS, THIS MAY
LEAD TO NEW TARGETS FOR THE
HUMAN TRACKS.
THANK YOU.
NEXT.
>> DR. LU: THANK YOU VERY MUCH.
CAN YOU HEAR ME?
>> YES WE CAN.
NOW WE CANNOT.
>> WE LOST YOU.
>> I COULD HEAR YOU BEFORE. IF
YOU ARE SPEAKING NOW, WE CANNOT
HEAR YOU.
>> THE SCREEN IS BLACK.
>> YOU MAY HAVE TO LEAVE AND
OCME BACK.
>> I THINK HE LEFT.
WE WILL SEE HIM AGAIN SHORTLY.
HE'S BACK.
>> DR. LU: VERY SORRY ABOUT
THAT.
>> YEAH WE HAVE YOU BACK.
>> DR. LU: OKAY SORRY.
>> THANK YOU.
>> DR. LU: NEXT.
I HAVE NOTHING TO DISCLOSE.
NEXT.
SO, THE COMMITTEE MADE TO
RECOMMENDATIONS RELATED TO
BIOMARKERS OF VCID.
RECOMMENDATIONS 7 AND 8.
THE DIFFERENCE BETWEEN THESE
TWO LIES IN THE STAGE OF THE
DEVELOPING PROCESS OF THE
BIOMARKERS. I WANT TO NOTE THAT
HERE, BY DIFFERENT STAGE AT ALL
MEAN DISEASE SEVERITY STAGE. I
MEAN INSTEAD DEVELOPMENT STAGE
OF THE BIOMARKER PROCESS.
SO RECOMMENDATION 7 IS TO
DEVELOP AND VALIDATE CANDIDATE
BIOMARKERS OF VCID IN
PRECLINICAL MODELS AND
HIGH-RISK POPULATIONS THAT SPAN
THE TYPES OF BIOMARKERS
ENCOMPASSING IMAGING, BIO
FLUID, MULTI-OMIC, DIGITAL, AI,
AND IN OTHER NOVEL BIOMARKERS,
INCLUDING IN THE MOST COMMON
SCENARIO WHERE VCID IS
ACCOMPANIED BY BETA AMYLOID
PLAQUES AND TAU TANGLES.
NEXT SLIDE.
THERE ARE NO CURRENT VALIDATED
BIOMARKERS FOR VCID.
THE COMMITTEE RECOMMENDS THAT
THE PROCESS TO DEVELOP VCID
BIOMARKERS SPANS ACROSS THE
RANGE OF STEPS AND PHASES.
THIS RECOMMENDATION SUPPORT THE
DISCOVERY AND EARLY STAGE OF
IMPLEMENTING THE VALIDATION OF
VCID BIOMARKERS.
NX1
NEXT SLIDE.
ONE CONSIDERATION IN THIS
RECOMMENDATION IS THAT THE
COMMITTEE WOULD LIKE TO
LEVERAGE FINDINGS FROM
PRECLINICAL AND (INDISCERNIBLE)
TO DEVELOP THE NEW BIOMARKERS.
PRECLINICAL AND BASE STUDIES
ACKNOWLEDGE THE MECHANISM OF
VCID; SOME OF THEM IF THEY CAN
BE MEASURED IN NONINVASIVE OR
MINIMALLY INVASIVE CAN
POTENTIALLY BE TRANSLATED TO
BECOME BIOMARKERS.
FOR EXAMPLE IN THIS PARTICULAR
EXAMPLE WE MEASURE THE COVERAGE
OF PARASITES, IMPORTANT TO THE
ELEMENT OF NEUROVASCULAR UNIT.
THEY SHOW THAT THIS PARASITE
MEASUREMENT CAN BE STRONGLY
CORRELATED TO SERUM BASED
(INDISCERNIBLE), POTENTIAL
(INDISCERNIBLE) FOR BIOMARKERS
FOR VCID.
NEXT SLIDE.
SO, ANOTHER ASPECT THAT THE
COMMITTEE CONSIDERED IS THEY
WANT TO HAVE BIOMARKERS
SPECIFIC TO CERTAIN TYPE OF
SMALL VESSEL PATHOLOGY.
AS WE JUST HEARD A
(INDISCERNIBLE) COMMON IN ADID.
ACTUALLY VCID IS NOT ONE
DISEASE. PATIENTS WHO HAVE
DIFFERENT VASCULAR PATHOLOGIES,
SO IS DESIRABLE FOR BIOMARKERS
TO HAVE A SPECIFIC RELATIONSHIP
TO A TYPE OF VASCULAR
PATHOLOGY.
AND THE PATHOLOGY, EXAMPLE SUCH
AS -- ARTERIAL SCLEROSIS-- IN
THIS EXAMPLE WE COULD
POTENTIALLY SEE THAT AB 42 -
ONE RATIO BETWEEN AB 42 AND
BEETA IS A MEASURE OF CSF CAN
BE USED FOR THE PATHOLOGY OF
THE A B PATHOLOGY MARKER.
NEXT SLIDE.
SO FAR, I WILL GIVE YOU
EXAMPLES OF BIO FLUID WITH THE
COMMITTEE ALSO RECOGNIZE WE
SHOULD USE THE FULL SPECTRUM OF
BIOMARKER TECHNOLOGY AVAILABLE
TO US.
ONE EXAMPLE IS IMAGING. IN
THIS PARTICULAR EXAMPLE YOU CAN
SEE THAT THESE INVESTIGATOR USE
MI TO MEASURE (INDISCERNIBLE),
AND THIS CAN PROVIDE A
PHYSIOLOGICAL ASSESSMENT OF THE
LESION AND DAMAGE IN VCID
PATIENTS.
NEXT SLIDE.
SIMILARLY, THERE HAS BEEN
TREMENDOUS PROGRESS IN
MULTI-OMIC TECHNOLOGY, AND SOME
OF THIS IF THEY CAN BE
(INDISCERNIBLE) TO THE
INDIVIDUAL LEVEL THAT CAN BE
LEVERAGED TO DO BE DEVELOPED AS
A BIOMARKER FOR VCID.
FOR EXAMPLE IN THIS REGULAR
EXAMPLE INVESTING SHOW THAT
TRANS MULTI-OMIC DATA CAN BE
USED IN THE CELL PERI VASCULAR
SPACE, SO THIS TECHNOLOGY CAN
BE QUITE USEFUL FOR FUTURE
DEVELOPMENT OF BIOMARKERS IN
VCID.
NEXT SLIDE.
FINALLY THE COMMITTEE
RECOGNIZED THAT THERE HAS BEEN
TREMENDOUS PROGRESS IN
ARTIFICIAL INTELLIGENCE AND
MACHINE LEARNING. THEREFORE
THEY RECOMMEND TO USE AI
MACHINE LEARNING IN ADVANCED
MATHEMATICAL MODELING
TECHNIQUES FOR ADVANCING THE
BIOMARKERS IN THE VCID SPACE.
AND THE GOAL IS TO HAVE MINIMAL
EXPERIMENTAL DATA TO ACHIEVE
THE HIGHEST SENSITIVITY AND
SPECIFICITY FOR PATIENT
BIOMARKER APPLICATION.
IN THIS PARTICULAR EXAMPLE
INVESTING IT IS USED A SMALL
SIMPLE MI IMAGE TO USE MACHINE
LEARNING AND SHOW THE VASCULAR
DEMENTIA OR DISEASE REFLECT THE
REASONS FOR DEMENTIA OR DISEASE
PRIMARILY AFFECT THE
HIPPOCAMPAL REGION.
NEXT SLIDE.
LET'S MOVE ON TO RECOMMENDATION
8. TO CONDUCT STUDIES OF
BIOMARKERS IN LATE STAGE OF
DEVELOPMENT IN INSTRUMENTAL
CLINICAL VALIDATION, DEFINING
THE BIOMARKER CATEGORIES IN THE
CONTEXT OF USE INCLUDING FOR
EXAMPLE INTEGRATIVE ACTIVITIES
OF DAILY LIVING, QUALITY OF
LIFE METRICS WITH THE ULTIMATE
GOAL OF REGULATORY APPROVAL.
THIS IS PRIORITY NUMBER 1.
NEXT SLIDE.
SO WHAT IS THE RATIONALE HERE?
THERE ARE A NUMBER OF PROMISING
CANDIDATE VCID BIOMARKERS. BUT
FEW IF ANY HAVE REACHED THE
LEVEL OF REGULAR TREE
(CORRECTION) REGULATORY
APPROVAL.
WE KNOW THAT REGULATORY
APPROVAL IS IMPORTANT. IT IS
DESIRABLE TO HAVE ONE OR MORE
OF THESE BIOMARKERS OF VCID TO
CROSS THE FINISH LINE OF THE
FDA APPROVAL OR QUALIFICATION.
AND ONCE AGAIN BORROWING FROM
THE EXPERIENCE FROM -- IN THE
AD FIELD, THE FIRST DEVELOPED
AMYLOID AND TALL BIOMARKERS
USED TO ACCELERATE THE
TREATMENT. ONE OF THESE VCID
BIOMARKERS CAN BE VALIDATED OR
APPROVED THAT CAN HELP TO
DEVELOP IN THE FUTURE LESS
EXTENSIVE AND MORE ACCESSIBLE
BIOMARKERS. IN THE AD SPACE, WE
CAN SEE NEW PLASMA MARKERS THAT
CAN BE DEVELOPED AND APPROVED
USING THE EARLIER PET MARKER--
AS LONG AS WE CAN ONE OR MORE
TRULY VALIDATED AND QUALIFIED
APPROVED BIOMARKERS.
NEXT SLIDE.
ONE PURSUIT OF THIS AT THIS
LATE STAGE, ONE HAS TO HAVE
CLINICAL VALIDATION OF THESE
BIOMARKERS. AND THERE ARE A
FEW METRICS ONE CAN ASK IF YOU
HAVE TWO RESEARCHERS TO PERFORM
THE SAME ASSAY, ON THE SAME
PATIENT SAMPLES, DO THEY GET
THE SAME RESULTS?
AND IT WOULD COME BACK AFTER A
SHORT INTERVAL YOU CAN SEE
WHETHER THE MEASURE IS
COMPATIBLE OR CONSISTENT.
SIMILARLY, IF YOU CAN DO MI
MEASUREMENTS ON TWO DIFFERENT
-- YOU CAN SEE WHETHER THE DATA
YOU OBTAIN IS REPRODUCIBLE.
CALLED INTER VENDOR
REPRODUCIBILITY.
AND SHOWS INSTRUMENTAL
VALIDATION. AND IT SHOWS THE
SCATTER PATTERN IS HOPEFULLY TO
SHOW THE RESULT ON THE SAME
LINE WITH LITTLE VARIATION IN
THE SPACE TO MOVE TO FOR THE
VALIDATION STEPS.
THE COMMITTEE NOTED THAT THE
FDA AND MH HAVE SOME GUIDELINES
FOR BIOMARKER DEVELOPMENT AND
THEY JOINTLY DEVELOP THESE
BIOMARKERS END POINTS AND OTHER
TOOLS.
AND UNDER THIS FRAMEWORK THE
DEFINED THE DIFFERENT
CATEGORIES FOR BIOMARKERS. AND
THERE ARE SEVEN POSSIBLE
CATEGORIES. ACCESSIBILITY RISK,
DIAGNOSTIC, MONITORING,
PROGNOSTIC, PREDICTIVE,
PHARMACODYNAMIC, AND SAFETY.
SO WHEN YOU HAVE A BIOMARKER
FOR CONSIDERATION AND EVENTUAL
APPROVAL BY THE REGULATORY
AGENCIES, YOU WANT TO PUT THIS
CATEGORY IN MIND.
SIMILARLY YOU HAVE TO OPPOSE
EACH BIOMARKER AND HAVE AT
LEAST ONE IF NOT MORE CONTENT
USE. CONSIDER INCLUSION,
EXCLUSION CRITERIA IN THE TRIAL
OR EVALUATING TREATMENT
RESPONSE.
NEXT SLIDE.
AND THE COMMITTEE NOTED THAT
MOST OF THE CURRENT BIOMARKERS
HAVE BEEN BASED ON
OBSERVATIONAL STUDIES. AND WE
FELT IT WOULD BE USEFUL-- --
THE VALIDATION OF THE BIOMARKER
IF THE BIOMARKER CAN ALSO BE
TACIT IN SOME INTERVENTIONAL
STUDIES.
IN THIS PARTICULAR EXAMPLE,
INVESTIGATORS USED VASCULAR
ACTIVITY -- AS THE PRIMARY
OUTCOME BIOMARKER MEASURE TO
EVALUATE A SUITE OF CLASSES OF
HYPERTENSIVE DRUGS.
NEXT SLIDE.
AND FINALLY, MOST OF THE
VALIDATION WORK OF BIOMARKERS
ABUSE CONTENT MEASURES,
CLINICAL DIMENSION READING OR
DIAGNOSTIC CATEGORIES.
WE FELT IT WOULD BE USEFUL TO
ALSO CONSIDER THINGS SUCH AS
ACTIVITIES OF DAILY LIVING,
QUALITY OF LIFE METRICS.
SO THESE METRICS HAVE BEEN
INCLUDED IN THE NEW UDS OF THE
SORT OF PROTOCOL. AND THEY HAVE
SOMETHING CALLED "FUNCTIONAL
ASSESSMENT SCALE," FAS.
AND THE BENEFIT IS TO ACTIVATE
-- (INDISCERNIBLE) THE
SPECIFIC TASKS IN OUR DAILY
LIFE. WHETHER THEY ARE
FUNCTIONING PROPERLY WHEN YOU
PERFORM THESE DAILY LIFE
FUNCTIONAL WORK.
>> TWO MINUTES.
>> DR. LU: THIS MEASURE
REQUIRES LESS SKILLS AND
TRAINING TO ADMINISTER.
NEXT SLIDE.
SO SHOWN HERIS AN ILLUSTRATION
OF THE NACC UDS FAS FORM AND
THEY ASKED SPECIFIC QUESTION,
YOU CAN PREPARE A BALANCED MEAL
AND WHETHER (INDISCERNIBLE) SO
THIS PERFORMANCE IS REALLY WHAT
MATTERS TO OUR PATIENTS.
THEREFORE IT IS USEFUL TO
VALIDATE THE VCID BIOMARKER IN
THE CONTEXT OF THESE DAILY LIFE
PERFORMANCE MEASURES.
NEXT SLIDE.
SO, WE HAVE THE OPPORTUNITY TO
SHOW COMMITTEE MEMBERS THEY
WORK REALLY HARD AND MADE
IMPORTANT CONTRIBUTIONS DO THIS
WORK AND I WOULD LIKE TO
ACKNOWLEDGE THEM ONE MORE TIME.
NEXT SLIDE.
TO SUMMARIZE THESE AS THE
RECOMMENDATIONS THAT THE VCID
COMMITTEE CAME UP WITH AS A
REMINDER THEY ARE CATEGORIZED
INTO FOUR DIFFERENT CATEGORIES.
RECOMMENDATIONS 1 AND 2,
INVOLVING MAGNETIC STUDIES OF
VCID AND RECOMMENDATION 4 MOVE
TO TRANSLATION AND EXPANDING
THE MECHANISM AND 5 AND 6, DEAL
WITH HUMAN RELATED STUDIES SUCH
AS INTERVENTION, TREATMENT AND
THE DISEASE FROM THE HUMAN
POINT OF VIEW.
FINALLY RECOMMENDATIONS 7 AND 8
DEAL WITH BIOMARKER DEVELOPMENT
FROM EARLY-STAGE TO LATER STAGE
EVENTUALLY HOPEFULLY TOWARDS
REGULATORY APPROVAL.
THANK YOU VERY MUCH.
>> THANK YOU WILL GO TO
QUESTIONS AND COMMENTS. I
ENCOURAGE EVERYONE ON THE
COMMITTEE FOR THE VCID SESSION
TO TURN ON YOUR CAMERAS.
THE MICROPHONE SHOULD BE UNDER
YOUR CONTROL TO TURN ON OR OFF.
>> THE FIRST QUESTION. THE
FIRST IS FROM HELEN.
>> HELLO, YES, I WAS ACTUALLY
GOING TO LOOK AT WHEN WE LOOK
AT CONTRIBUTIONS TO YOU KNOW,
NOT JUST VASCULAR
CONTRIBUTIONS BUT TO GENERAL
DEMENTIA, ONE OF THE BEST
PHRASES I HEARD FROM A
CLINICIAN WHAT IN THE
INDIVIDUAL NOT ONLY PHYSICALLY
ENGAGED, OBVIOUSLY INTRODUCE
EXERCISE. BUT SOCIALLY ENGAGED.
AND IN MY WORK IN THE FIELD, I
FIND THAT ISOLATION AND LACK OF
SOCIAL ENGAGEMENT IS A HUGE
CONTRIBUTOR.
SO I AM CURIOUS AS TO WHETHER
THAT IS BEING LOOKED INTO, WHEN
WE LOOK AT ALL OF THE FACTORS
THAT MAY BE CONTRIBUTING.
>> YEAH ABSOLUTELY.
>> DR. FOSSATI: YOU WANT TO
COMMENT ON THIS?
>> THANK YOU HELEN FOR ALL YOUR
INSIGHTFUL COMMENTS IN YOUR
ABSOLUTE RIGHT.
BOTH THE DENSITY OF SOCIAL
NETWORKS, AS WELL AS PERCEIVED
LONELINESS SEEM TO HAVE AN
IMPACT ON VASCULAR RISK, STROKE
RISK, DEMENTIA RISK, AND GIVEN
AN AMOUNT OF BRAIN INJURY, THE
COGNITIVE FUNCTION. SO THE
FUNCTIONAL LINK AS WELL AND
THAT IS SOMETHING VERY
IMPORTANT AND YOU CORRECTED
POINTED OUT THAT THAT SHOULD BE
MENTIONED AS SOMETHING TO TAKE
INTO DIFFERENT PHASES OF
TRIALS, AS WELL AS PRAGMATIC
TRIALS.
>> GREAT.
THANK YOU SUDHA.
>> WE HAVE ANOTHER?
I DON'T SEE ANOTHER.
IF YOU HAVE A QUESTION PLEASE
UNMUTE YOURSELF.
>> PRESS STAR 6. TO ASK A
QUESTION. GIVE IT A TRY.
>> I HAVE A QUESTION ABOUT THE
NEURON ITSELF.
AND WHO ARE (CORRECTION)
THROUGH THE PRESENTATIONS
YESTERDAY AND TODAY WE ARE
TALKING ABOUT VARIOUS PROTEINS.
YOU HAVE TAU AND YOU HAVE THE
TDP 43 AND SO FORTH.
AND WE TALKED ABOUT A-SYNUCLEIN
TODAY. ARE ALL OF THESE
PROTEINS CURLED UP AND PACKED
INTO THE NUCLEUS?
I KNOW THE TAU MOLECULE IS VERY
LONG. IT CAN GET WRAPPED UP
AGAINST ITSELF. WHEN IT DOES
THAT IT SCREWS UP THE NEURON TO
BE ABLE TO COMMUNICATE WITH
OTHER NEURONS.
AND THEN IT GETS WORRIED. IT
THINK SOMETHING IS WRONG AND IT
COMMITS SUICIDE. AND YOU GET A
WHOLE BUNCH OF THOSE HAPPENING.
AND THEN YOU HAVE ... THE
PROBLEMS THAT WE'RE DEALING
WITH.
ARE ALL OF THESE PROTEINS WE
ARE TALKING ABOUT WRAPPED UP IN
THE NUCLEUS ITSELF OF THE
NEURON?
>> I CAN TAKE THIS IF YOU WANT.
SO YES THAT IS A GREAT
QUESTION.
WE ARE TALKING ABOUT MULTIPLE
PATHOLOGIES. RIGHT?
WE ARE AFFECTING THE NEURONS
FROM MULTIPLE SIDES AND ALL OF
THESE PATHOLOGIES COME IN
DIFFERENT FLAVORS WE CAN SAY.
SO WE HAVE TAU, YES, A PROTEIN
THAT (INDISCERNIBLE) AN ESCAPE
FROM THE NEURON. TRANSFERS FROM
CELL TO CELL AND GOES TO OTHER
CELLS.
AMYLOID BETA MOSTLY PRODUCED
FROM INSIDE THE (INDISCERNIBLE)
IT GOES OUT IN THE BRAIN AND
FORMS PLAQUES IN THE MATRIX, IN
THE BRAIN, IN THE EXTRACELLULAR
SPACES.
WE ARE TALKING IN OUR CASES OF
VASCULAR PATHOLOGY. VERY
IMPORTANT FOR NEURON FUNCTION.
WE HAVE TO CONSIDER THAT WE
LOSE BLOOD FLOW. THAT IS WHAT
GIVES NEURONS THE OXYGEN, THE
GLUCOSE, ALL THE FUNCTIONAL
SUBSTANCES TO MAKE THEM LIVE
AND SURVIVE AND THRIVE.
AND SO ALL OF THESE
PATHOLOGIES ACTING DIFFERENT
WAYS INSIDE OR OUTSIDE THE
NEURONS. BUT SOMEHOW THEY WILL
AFFECT THEM. THAT IS WHY WE END
UP WITH DEMENTIA.
AND WE HAVE TO UNDERSTAND HOW
EACH PATHOLOGY SPECIFICALLY
AFFECTED NEURON. THAT IS VERY
IMPORTANT.
>> WELL IT CERTAINLY FOLLOWS
THE ... EXAMPLE THAT IS
SOMETIMES GIVEN. BLIND PEOPLE
LOOKING AT AN ELEPHANT, GETTING
ONE PIECE TO LOOK AT AND THEN
ANOTHER PIECE, AND DESCRIBE
WHAT THEY SEE.
NOW THIS IS REALLY TINY STUFF
YOU ARE LOOKING AT. I DID NOT
UNDERSTAND THAT TAU FOR EXAMPLE
MIGRATE OUT OF THE NEURON,
FLOATING AROUND AMONGST THE
MICROGLIA CELLS AND SO FORTH.
ALL I CAN SAY IS WOW, TRYING TO
TRACK ALL THAT STUFF IS MIND
BLOWING. I AM JUST A REGULAR
GUY.
I WANT TO SAY I REALLY
APPRECIATE WHAT YOU HAVE DONE.
AND MS. MCCARTHY, THANK YOU FOR
FIXING ME UP, SO AT LEAST I CAN
ASK A QUESTION OF THESE FOLKS.
BECAUSE RIGHT NOW MY ...
COMMUNICATION SYSTEM ISN'T SO
GOOD.
THANK YOU SO MUCH.
>> HI, THANK YOU. PERFECT
SESSION. APOLOGIES IF I MISSED
THIS.
WONDERING WHERE IN THE
RECOGNITION WE WOULD FIND
(INDISCERNIBLE) ISSUES,
PARTICULARLY THINKING OF TWO
EXAMPLES. MAYBE THIS IS NOT
COUNT AS EXPOSURE BECAUSE IT IS
IN AN INDIVIDUAL LEVEL,
EXPOSURE COLLECT SOME STRESS
AND A VARIETY OF ISMS, AND THE
OTHER IS MORE ON COVID.
>> DR. FOSSATI: THERE IS A
WHOLE SESSION IN JUNE THAT
FOCUSES ON EXPOSURE. AS YOU
KNOW TWO YEARS AGO THERE WAS A
WHOLE SESSION ON COVID AND I
NOW INFECTIONS INCLUDING
SARS-COVID-2 AND INFORMATION
AND (INDISCERNIBLE) RESPONSES
WOVEN INTO THIS AND WILL BE
PART OF THE EXPOSURE SESSION.
>> BUT I HAVE TO SAY THAT YEAH,
WE PROBABLY HAVE TO COORDINATE
WITH THE EXPOSURE SESSION TO
MAKE SURE WE ALSO INCLUDE THESE
RECOMMENDATIONS FOR THAT EFFECT
SPECIFICALLY ON VCID. YEAH,
THAT IS SOMETHING TO NOTE.
>> I WILL ADD THAT WE THINK
ABOUT BUILDING MORE COMPLEX
MODELS THAT MORE TRULY REFLECT
THE COMPLEXITY OF THE HUMAN
CONDITION, YOU WANT TO START
WITH GENETICS. THE ALSO WANT
TO COMBINE GENETICS WITH
ENVIRONMENTAL EXPOSURES. AND
BY DOING THAT BY UNDERSTANDING
HOW YOU BUILD THEM, YOU
UNDERSTAND HOW YOU MIGHT BE
ABLE TO FIX THEM. AND WHAT THE
MECHANISMS ARE. THE
CONTRIBUTIONS OF THE EXPOSEM
(PHONETIC), IT IS A CRITICAL
COMPONENT IN MANY CASES AND YOU
MAKE A GENETIC MANY RELATION IN
THE MODEL AND IT DOES NOT GO
FAR ENOUGH. BUT INCREASES
SUSCEPTIBILITY WHEN YOU COMBINE
THAT WITH A HIGH-FAT DIET, AND
EXPOSURE TO STRESS. YOU CAN
PUSH THE PHENOTYPE MORE TOWARDS
THE DISEASE.
TICKLY AS WE THINK ABOUT IN A
MULTI-OMICS APPROACH YEAR, IF
YOU CAN ALIGN YOUR MODELS NOT
SO MUCH DOES IT HAVE A
PATHOLOGY YES OR NO, WHAT ARE
THE MOLECULAR CHANGES?
WE HAVE MULTI-OMICS, AND
THERE'S A LOT MORE WE CAN DO IN
CREATING BETTER MODELS AND
ALIGNING THEM AT THE LEVEL OF
PROTEIN GENES AND THE METABOLIC
CHANGES.
>> I APPRECIATE THE REMINDER
THAT WE HAVE A SESSION IN JUNE.
WHICH FEELS LIKE A LONG WAY
AWAY ABOUT EXPOSUM. (PHONETIC).
I WOULD ENCOURAGE YOUR
WORKGROUP AND EACH OF THE OTHER
DISEASE SPECIFIC WORK GROUPS TO
THINK ABOUT EMBEDDING LANGUAGE
TO SPECIFIC RISK FACTORS, AND
NOT LEADING TO THE CROSSCUTTING
ALONG. I WORRY THAT IN THE
ENVIRONMENT THAT NIH IS FACING
IN THE MONTH YEARS AHEAD IT
COULD BE LOST. AND IT COULD BE
BETTER IF IT WERE IN THREE OR
FOUR PLACES RATHER THAN JUST
ONE.
>> A LOT OF THE RISK FACTORS
AND EXPOSURES, FOR EXAMPLE
SLEEP-DISORDERED SO
ENVIRONMENTAL FACTORS CAN
AFFECT VASCULAR DISEASE. AND
VASCULAR DISEASE AFFECTS VCID.
SO THEY ARE ALL LINKED
TOGETHER, DEFINITELY.
>> LET'S MOVE ON TO -- NAPHALI?
>> YES, I HEARD WHEN THE
COMMENTS ABOUT THE
PROTEINOPATHY TO BE THE CORE OF
DEMENTIA-CAUSING DISEASES. IN
REFERENCE TO THAT I WANTED TO
ADD MY COMMENT. SO IN
ALZHEIMER'S DISEASE PATHOLOGY,
WHEN WE TAKE A SECTION OF THE
BRAIN AFFECTED BY ALZHEIMER'S
DISEASE, WE NOT ONLY SEE THE
PLAQUES THAT ARE FORMED WITHIN
THE CORTEX BUT WE SEEN THEM
ALSO ON THE VESSELS. WHICH IS
SOMETHING THAT COULD BE AN
EVIDENCE THAT ONE MORE
EVIDENCE, SHOWING THAT THIS
COULD BE ALSO A VASCULAR
PATHOLOGY.
MAYBE PLAQUE MAYBE THE
PROTEINOPATHY IS TOUCHING ONE
ELEMENT AND MISSING THE REST. I
WANTED TO ADD THIS.
>> TOTALLY RIGHT WHICH IS--
WHAT YOU DESCRIBE THE POSITION
AROUND THE VESSELS IS ONE OF
THE MAIN PATHOLOGICAL FEATURES
OF VCID. IT IS ONE OF THE MAIN
FOCUSES OF OUR MECHANISTIC
STUDIES, TOGETHER WITH OTHER
VASCULAR PATHOLOGIES. THANK
YOU.
>> ANOTHER PART OF THE BLIND
METAPHOR SO YOU MENTIONED
MULTIPLE PATHOLOGIES. YOU PUT
(INDISCERNIBLE) YOU INCREASE
THE AMOUNT OF CAA AND SOME ALSO
FOLLOWING THE ELEPHANT ANALOGY,
WE HAVE TO LOOK AT THE WHOLE
ELEPHANT.
>> NEXT WE HAVE --.
GREG?
>> FANTASTIC. REPRESENTATIONS
AND GREAT SUMMARIES. NICE TO
SEE SOME OF YOU THAT HAVE NOT
SEEN SO LONG AND OTHERS I HAVE
SEEN MORE RECENTLY.
YOU KNOW ONE OF THE CONCEPTS
AND PLEASE THROW VIRTUAL
TOMATOES AT ME IF I MISSED
THIS.
ONE OF THE ISSUES WE REALLY
STRUGGLED WITH ARE THESE
MULTIPLE ETIOLOGIES OFTEN
AFFECTING DIFFERENT REGIONS OF
THE BRAIN SO A LOT OF VASCULAR
DISEASE BURDEN IS FOUND
SUBCORTICALLY (INDISCERNIBLE)
-- BUT BEGINNING TO BRING
TOGETHER HOW DO THESE DISEASES
INTERACT WHEN THEY ARE
REGIONALLY IN DIFFERENT AREAS?
AND REALLY BEGINNING TO
INVESTIGATE THAT. I REALLY SEE
SOMETHING THAT IS REALLY
IMPORTANT.
WE TALK ABOUT VASCULAR DISEASE
BURDEN AS IF IT WERE EQUIVALENT
THROUGHOUT ALL AREAS OF THE
BRAIN. WE KNOW THAT IS VERY
DIFFERENT, THE SAME AS WITH
TDP-43, A-SYNUCLEIN, TAU AND/OR
AMYLOID.
AND TELL ME WHEN YOU'RE WORKING
GROUP HOW MUCH DISCUSSION, AND
IS THAT BUILDING TO ANY OF YOUR
RECOMMENDATIONS?
>> DR. LU: THANK YOU VERY MUCH
FOR THIS QUESTION. SO THE
COMMITTEE DID TALK ABOUT USING
MULTIPLE TECHNOLOGIES,
ESPECIALLY TECHNOLOGY LOOKING
AT ALL ASPECTS OF THE DISEASE
BIOLOGY AND ALSO CONSIDERING
(INDISCERNIBLE), AND OTHER
TYPES OF PROTEIN OPPOSITE IN
THIS REGARD I FEEL IMAGING
BIOMARKER CAN PLAY PARTICULARLY
USEFUL ROLE IN THE SENSE THAT
YOU CAN LOOK AT THE ENTIRE
BRAIN AND BIO FLUID AND LOOK AT
THE ENTIRE BRAIN AND LOCALIZE
FOR INSTANCE FRONTAL LOBE
VERSUS CAA WHICH IS MORE
OCCIPITAL LOBE AND BIO MATTER
IS MORE CLASSICAL VASCULAR
DISEASE SO THAT DEEP NUCLEUS.
SO BRINGING TOGETHER THIS
IMAGING TECHNOLOGY CAN
POTENTIALLY TEASE APART THE
MIXED CONTRIBUTION OF DIFFERENT
PATHOLOGIES TO THE PARTICULAR
PERSON.
>> I WONDER IF DAVID WANTS TO
ADD SOMETHING TO THAT?
THAT IS DEFINITELY AN AREA HE
HIGHLIGHTS IN A GREAT EMAIL
EARLIER TODAY.
>> I WILL ADD WHILE DAVID, IF
YOU WANT TO SAY SOMETHING IN A
MOMENT -- I WONDER IF THIS IS
GOING TO REFLECT THE EXPANSION
OF AI CAPABILITIES. I IT WILL
HELP A LOT HERE TAKING THESE
DATA SETS AND -- HAS
EXPERIENCED MACHINE LEARNING
AND APPLYING THOSE TO LOOK AT
MORE REGIONAL CHANGES. CLEARLY
AN IMPORTANT AREA TO STUDY.
>> IF I COULD CHIME IN JUST
QUICKLY. THAT WAS A GREAT POINT
ABOUT LOOKING AT MANY REGIONS
THROUGHOUT THE BRAIN. AND I
THINK THERE'S A LOT OF
TECHNOLOGIES THAT ARE COMING TO
THE POINT THAT THEY COULD BE
USEFUL.
MY CONCERN GOING FORWARD IS WE
HAVE GOOD MOLECULAR MARKERS,
WHICH MEANS WE HAVE GOOD
FLORESCENT DIES OR DIES THAT
HAVE CONTRAST UNDER ULTRASOUND.
AND THIS SHOULD ALLOW US TO DO
LONGITUDINAL STUDIES ON THE
PROGRESSION OF DISEASE. MORE
SO, ALLOW US TO PROBE
MODULATORY REGIONS AND MIDRANGE
REGIONS FUNDAMENTAL FOR FACIAL
ACTIONS, DAILY LIFE.
I THE TECHNOLOGY FROM THE POINT
OF VIEW OF MARKERS AND FROM
INSTRUMENTATION HAS BEEN
SHOOTING UP IN THE LAST FEW
YEARS. THIS COULD HAVE A BIG
IMPACT ON VCID MEASUREMENTS AND
MODELS.
>> I CAN ADD TO THAT.
THE REGIONALITY IS SUCH AN
IMPORTANT ASPECT OF SMALL
VESSEL DISEASE. CAA AFFECT
DIFFERENT REGIONS OF THE BRAIN
COMPARED TO ARTERIOSCLEROSIS,
AND SO WE LOOK AT DIFFERENT
REGIONS OF THE BRAIN, WE CAN
ACTUALLY PARSE OUT UNDERLYING
ETIOLOGIES. IN FACT WE HAVE
USED MACHINE LEARNING TO DO
CLUSTERING ALGORITHMS TO TRY TO
DISTINGUISH PATTERNS OF LIGHT,
OR HYPER INTENSITIES RAISED IN
THE UNDERLYING ETIOLOGY. THAT
IS BEEN A PRODUCTIVE APPROACH
TO PHENOTYPING WHITE MATTER
HYPER INTENSITIES. GREAT
QUESTION. THANKS.
>> THERE IS ONE MORE QUESTION.
GABE?
>> YEAH DR. SESHADRI MENTIONED
ARTERIAL STIFFNESS AND
HYPERTENSION -- IS THAT
SOMETHING THAT NEEDS TO BE
CONCENTRATED ASIDE FROM THESE
STRUCTURAL BELLS AND WHISTLES,
THE FUNCTIONAL PART OF WHAT IS
CONTROLLING A WHAT BECOMES
INTERRUPTED THAT CAUSES THE
DILATION-- CAUSES THE BLOOD
PRESSURE TO GO UP WHICH IS
DEFINITELY LINK TO THE SYSTEMIC
CARDIOVASCULAR DISEASE,
DEMENTIA AND DEATH.
CAN YOU TALK ABOUT THAT PLEASE?
>> I CAN TAKE THAT.
SO IN THE MOCK VCID STUDY THAT
I HAPPEN TO BE INVOLVED WITH,
WE ARE MEASURING THIS DILATION
CAPACITY AND IN THIS CASE WE
USED COMMON DIOXIDE AS A BASAL
STIMULUS. AND WE MEASURE HOW TO
EXTEND (INDISCERNIBLE) AND
DILATE. THIS IS SOMETHING WE
ARE ACTUALLY PURSUING. THANK
YOU VERY MUCH FOR THIS QUESTION.
>> YES, DAVID?
>> DR. FARDO: IF I COULD ADD TO
THAT IT IS A GREAT QUESTION.
GOING BACK TO THE 1980S, THERE
WAS THIS SORT OF HYPOTHESIS
THAT BASICALLY WHAT VESSELS ,
ARE DILATING AS YOU POINT OUT
THEY ARE NATURALLY DILATING DUE
TO VASAL MOTION, ALMOST A 20%
DILATION ABOUT ONCE EVERY 20
SECONDS, IN ADDITION TO
DILATION THAT CAN HAPPEN WITH
INCREASED SENSORY STIMULUS.
AND ... (AUDIO CUTTING OUT)...
YOU HAVE STICKY BLOOD VESSELS.
IN FACT YOU WILL BE ABLE TO
EXTRUDE PROTEINS FROM THE BRAIN
THESE ARE CALLED MIXTURE MODELS
EARLY ON. IF YOU WANT TO THINK
OF IT OF SORT OF A WASHING
MACHINE, NOT THAT FAR FROM THE
PHYSICAL TRUTH.
AND THE POINT YOU BRING UP IS
VERY IMPORTANT. AND AGAIN THIS
IS SOMETHING WE CAN GET A
BETTER HANDLE ON WITH NOT --
WITH MINIMALLY INVASIVE,
LONGITUDINAL MEASUREMENTS AND
POST MARKERS.
>> ALSO, WHAT INTERVENTIONS CAN
IMPROVE VASODILATION?
>> DR. FARDO: MAYBE. MAYBE.
>> LIKE BLOCKING ANGIO TENSION
-- PART OF MY LIFE.
>> DR. FARDO: SOME OF THE
HYPERTENSIVE DRUGS HAVE
INTENSIVE, AND I SUPPOSE THEY
WILL IMPROVE THE VASAL
REACTIVITY.
>> EXPLAINS WHY THE MUCUS
LOWERING DRUGS SEEM TO BE
HAVING AN IMPROVED EFFECT ON
REDUCING DEMENTIA?
STIRS INFORMATION
(INDISCERNIBLE) ... FIBROSIS
CARRIES VASAL DILATION.
>> I THAT IS VERY COMPLEX THOSE
DRUGS INTERACT IN MANY
DIFFERENT WAYS. THAT COULD BE
ONE OF THEM.
WE HAVE TO GET THE PIPELINE
GOING. WE HAVE A LOT OF DRUGS
IN THE PRECLINICAL STAGE AND I
CAN TELL YOU IN MY LAP FOR
EXAMPLE THE DO EXACTLY THAT THE
IMPROVE HYPERACTIVITY TOGETHER
WITH OTHER THINGS SUCH AS
IMPROVING METABOLIC AND
MITOCHONDRIAL FUNCTION AND WE
HAVE TO GET INTO THE CLINICAL
STAGE.
SO THE TRANSLATIONAL
RECOMMENDATIONS EXACTLY SAY
THAT. TO KIND OF FACILITATE
THAT TRANSITION.
>> SO IT IS REALLY
MULTI-ELASTICAL?
THANK YOU.
>> WE ARE OUT OF TIME FOR
QUESTIONS FOR THIS SESSION.
SO WE WILL MOVE STRAIGHT INTO
THE NEXT SESSION WHICH IS THE
FURTHER PUBLIC INPUT.
WE THANKED THIS COMMITTEE.
WE HAVE A SLOW START TO THE
NEXT SESSION BECAUSE, ANYBODY
NEEDS TO GET UP AND STRETCH AND
THEN COME BACK, WE WILL BE HERE
FOR THE NEXT HOUR WITH OPEN
MICROPHONE FOR ANYONE WHO WOULD
LIKE TO SAY SOMETHING.
AND DAVID, I SEE YOUR HAND.
>> NO, NO. MY HAND IS NOT UP. I
WAS THANKING MY COLLEAGUES FOR
A GREAT PRESENTATION.
>> FOR THE SESSION WE ONLY HAVE
ONLY 25 OPEN CAMERAS. RIGHT?
SHOULD WE ...
>> WE WILL LET EVERYBODY, SO
ALL THE SPEAKERS FOR THE LAST
TWO DAYS ARE SETTING UP SO YOUR
CAMERA AND MICROPHONE ARE UNDER
YOUR CONTROL SO THERE ENABLED
WHETHER YOU JOIN AS A PRESENTER
OR AN ATTENDEE TODAY. WE WILL
BE ACTIVELY TRYING TO SPOTLIGHT
PEOPLE ON THE SCREEN SO THE
SPEAKERS ARE POPPING UP TO THE
FRONT, BUT THERE ARE LIMITS. WE
CAN ONLY SPOTLIGHT SEVEN AT A
TIME. FEEL FREE TO USE YOUR
MICROPHONE AND CAMERA.
AND I THINK WE HAVE THAT ALL
SET UP ALREADY.
>> WHAT A GREAT JOB HAVE DONE
ON MAKING THIS VIRTUAL SESSION
FEEL SO REAL AND PRODUCTIVE.
>> THANK YOU SO MUCH FOR THAT
FEEDBACK.
IT IS A BIG TEAM.
I'M GOING TO ... HAND IT OVER
TO KATE POSSIN.
>> DR. POSSIN: I HOPE EVERYBODY
HAD A GENESIS STRETCH AS WE GOT
INTO THE LAST SESSION TODAY BUT
BEFORE WE START I WANT TO MAKE
SURE EVERYONE IS AWARE THERE IS
A THIRD DAY OF THE SUMMIT.
GOING TO BE ON JUNE 2. TODAY WE
WANT TO HEAR YOUR COMMENTS BUT
IF YOU DO NOT TELL US YOUR
COMMENTS TODAY OR SOMETHING
OCCURS LATER, THERE IS ANOTHER
CHANCE. PLEASE JOIN US ON JUNE
2 AND PROVIDE INPUT THERE.
I HAVE A QUESTION FOR AMBER
MCCARTNEY.
IS THERE A WAY FOR PEOPLE TO
EMAIL FEEDBACK BETWEEN THE
MEETINGS?
>> THERE WILL NOT BE A LIVE
FEEDBACK BUTTON ACTIVE IN
BETWEEN BUT YOU CAN EMAIL ...
QUESTIONS TO ME.
I CAN HELP YOU FIND THE RIGHT
PERSON FIVE NOT THE RIGHT
PERSON TO ASK. FEEL FREE TO
REACH OUT TO ME. MY EMAIL
ADDRESS IS
AMBER.MCCARTNEY@NIH.GOV.
WE WILL FOLLOW-UP WITH EVERYONE
WHO ATTENDED TODAY WITH A LINK
TO JOIN THE MEETING HOW THE
SECOND, AND THE UPDATED AGENDA
AND PROGRAM BOOK.
>> THANK YOU THAT IS VERY
HELPFUL AND I SEE WE HAVE OUR
FIRST QUESTION.
SO I AM NOT-- I CANNOT SEE YOU
NEVER WOULD YOU UNMUTE YOURSELF?
IS YOUR NAME DEBBIE YELPS?
(PHONETIC)
>> NO.
>> I SEE MARICE FIRST.
>> I AM NEUROSCIENTIST. THIS IS
A QUESTION AS I HAVE BEEN
TRACKING YOUR PRESENTATIONS
WHICH I THOROUGHLY ENJOYED.
WHEN YOU TALK ABOUT
MULTI-ETIOLOGY, I'M WONDERING
IF WE ARE TALKING ABOUT
ULTIMATE OR PROXIMATE. ARE WE
TALKING ABOUT TAU VS. AMYLOID
VS. LEVY BODIES?
I WOULD TALK ABOUT HEART
FAILURE OR MAYBE OBESITY?
MAYBE BECAUSE I AM NOT A
CLINICIAN BUT I DON'T KNOW WHAT
IT MEANS TO HAVE MULTIPLE
ETIOLOGY.
>> THIS IS SUDHA, I LIKE TO
PASS IT TO YOU.
>> DR. SESHADRI: WHEN WE USED
TO MAKE A CLINICAL DIAGNOSIS
BASED ON THE PREPONDERANCE OF
THE CLINICAL EVIDENCE, A LOT OF
THE TIME WHEN WE COMPARE THAT
WITH WHAT WE SEE AT THE BRAIN
(INDISCERNIBLE), AS YOU SAID WE
ARE SEEING THINGS THAT MIGHT BE
SUFFICIENT IN THEMSELVES TO
CAUSE THE SYMPTOMS.
I DON'T KNOW THAT WE HAVE A
FULL PROOF WAY TO KNOW THAT
YOUR SYMPTOMS ARE BECAUSE OF
THIS OR THAT.
IF SOMEBODY HAS AMYLOID, TAU,
(INDISCERNIBLE) AND ALL OF THE
ABOVE SO WE ARE TALKING ABOUT
PATHOLOGIES THAT WE THINK EACH
CAN LEAD TO COGNITIVE
IMPAIRMENT AND DEMENTIA. AND
THE COEXISTENCE OF THESE.
BASED ON THE WAY WE CAME WE CAN
SOMETIMES SAY OKAY, YOU HAVE
HALLUCINATIONS, WE THINK THIS
WAS PERHAPS RESPONSIBLE FOR
THIS BUT IF SOMEBODY HAS
DIFFICULTY WITH PLANNING AND
EXECUTION, WAS IT BECAUSE OF
THE TAU?
WAS IT BECAUSE OF THE
A-SYNUCLEIN?
THAT CAN BE CHALLENGING.
>> THAT IS SUPER HELPFUL. THANK
YOU SO MUCH.
>> ALL RIGHT.
DEBBIE?
>> IS THERE ANYONE ELSE WHO
WANTS TO ADDRESS THE QUESTION?
>> HI EVERYBODY, SUDHA I LOVE
YOUR ANSWER. MY VOICE IS NOT
TOO GREAT BUT OVER TIME IT HAS
BEEN AS SUDHA SAID, RECOGNIZE
THAT THERE ARE MULTIPLE
PATHOLOGIES THAT MAY CONTRIBUTE
TO DEMENTIA.
AND I A LITTLE BIT OF THE
CHALLENGE, OF KNOWING WHAT TO
SAY IS THAT WE'RE ON THE PATH
TO CERTAINTY OF WHICH OF THOSE
PATHOLOGIES ARE ACTUALLY
CAUSAL.
OR WHETHER IT IS SOMETHING THAT
IS UPSTREAM OF THE PATHOLOGY
THAT IS CAUSAL. AND WHEN YOU
HAVE-- AND THOSE THREE
DIFFERENT PATHOLOGIES IN THE
BRAIN ALL OF WHICH MAY BE
CONTRIBUTING, BUT ALSO ALL OF
WHICH MIGHT BE KIND OF ALONG
FOR THE RIDE, OR DOWNSTREAM. IT
GETS VERY HARD TO KNOW WHAT TO
SAY. IF THAT MAKES SENSE.
SO A MIXED-ETIOLOGY DEMENTIA,
WE ARE REFERRED TO IS A BIT OF
AN OBLIQUE WAY OF ACKNOWLEDGING
THERE IS A LOT WE DON'T KNOW.
AND THAT INCLUDES OUR
UNDERSTANDING OF CAUSES.
>> AND IF I MIGHT JUST ASK,
WOULD YOU SAY THINGS LIKE, "I
DON'T KNOW BLOOD BRAIN BARRIER
INTEGRITY, NEURO-
INFLAMMATION." YOU DON'T KNOW
YET IF THEY ARE UPSTREAM,
CAUSAL, ETC.?
>> YEAH. I WOULD SAY IT LIKE
THEY ARE CERTAINLY IN THE
PICTURE. THEY ARE LIKELY TO BE
IMPORTANT. BUT IN TERMS OF
HARD-BOILED, RIGOROUS PROOF,
THAT IS WHAT PUTS US IN THIS
SPACE OF SAYING THINGS LIKE
MULTIPLE ETIOLOGY.
I MIGHT REPHRASE IT AND SAY,
MULTIPLE PATHOLOGY DEMENTIA.
MY PERSPECTIVE WHAT THAT COME
FROM IS THAT WHEN PEOPLE SEE
MULTIPLE PATHOLOGIES IN
ABSTAINING THAT IS WHAT IS
RECOGNIZE BUT THAT IS MY TWO
BITS.
>> AND IF I CAN ADD SOMETHING
TO WHAT DAVE BEAUTIFULLY SAID,
WE DO NOT KNOW WHAT IS CAUSAL.
BUT IN ADDITION TO THAT THINGS
MAY BE CAUSAL TO EACH OTHER IN
A FEET-FORWARD LOOK. FOR
EXAMPLE VERY PER MOBILITY AND
INFLAMMATION CAN BE CAUSAL TO
COGNITIVE FUNCTION BUT ALSO
(INDISCERNIBLE), SO IS A LITTLE
BIT OF A (INDISCERNIBLE).
>> ALICE, IF YOU WANT TO
COMMENT ON THIS?
OR SOMETHING ELSE?
>> YEAH I WANTED TO SAY I DO
LIKE QUESTION VERY MUCH.
BECAUSE I IT GET TO THE FACT
THAT WE ARE SPEAKING ON TWO
LEVELS. RIGHT?
WE ARE SPEAKING ON THE CLINICAL
LEVEL AND ALSO SPEAKING AT A
MECHANISTIC SCIENTIFIC LEVEL.
AT A CLINICAL LEVEL WHOM WE ARE
TALKING TO PATIENT WE ARE
THINKING ABOUT THE HEAD INJURY.
YOU KNOW?
BASICALLY THE LITTLE STROKE.
THOSE ARE THE THINGS WE ARE
TALKING ABOUT AS ETIOLOGIES.
BUT WHEN WE ARE THINKING ABOUT
THIS MECHANISTICALLY-- AND WE
HAVE TO THINK ABOUT
MECHANISTICALLY IF WE ARE
TRYING TO TARGET AND DEVELOP
THERAPIES-- INFERRING THAT
CAUSE, THE STROKE, THE HEAD
INJURY MAY LEAD TO SOMETHING.
ESSENTIALLY IN THE CASE OF THE
HEAD INJURY MAY BE TAU.
SOMETHING LIKE THAT.
AND THAT I IS THE FIRST THING.
THE WAY ETIOLOGIES HAVE BEEN
USED IN TWO DIFFERENT WAYS
ACROSS DIFFERENT PRESENTATIONS.
FROM THE PERSPECTIVE OF TRYING
TO INTERRUPT THEM WE HAVE TO
THINK LIKE SCIENTISTS, THINKING
ABOUT THE MECHANISTIC PIECES.
AND I DO THINK SOME OF THE
CAUSALITY CAN BE HELPED BY THE
FACT THAT THERE IS A LOT OF
GENETICS AND GENOMICS TOO.
THAT INFERS A CERTAIN AMOUNT OF
CAUSALITY THERE.
>> DEBBIE?
PLEASE UNMUTE AND ASK YOUR
QUESTION OR COMMENT.
>> CAN YOU HEAR ME OKAY?
>> YES.
>> SO THANK YOU SO MUCH FOR
THIS WONDERFUL UPDATE ON ALL
THE WORK STREAMS THAT HAVE BEEN
HAPPENING.
IT REALLY IS HEARTENING,
ESPECIALLY TO HEAR THE PEOPLE
WHO PRESENTED WHAT HAS EMERGED
IN THE LAST THREE YEARS, SINCE
THE LAST SUMMIT.
I LOST MY HUSBAND TO A GENERIC
(INDISCERNIBLE) DISEASE IN THE
RIVERS AND FAMILIES WHO HAVE
LOST LOVED ONES TO SPORADIC AND
GENETIC.
ONE THING I DID NOT HEAR IN THE
RECOMMENDATIONS IN THE
PRIORITIES IN THE WORK TEAMS,
IS REPRESENTATION OF PREOM
(PHONETIC) DISEASE AND WHEN WE
ARE LOOKING TO RUB TOGETHER SO
MUCH IS HAPPENING IN SO MANY
DIFFERENT DIMENSIONS, TO ME
THAT FEELS LIKE A LOSS.
SO MY COMMENT IS, COULD THAT BE
CONSIDERED AS YOU PROCEED WITH
THESE RECOMMENDATIONS?
>> THANK YOU DEBBIE. THAT WAS
VERY WELL SAID.
AMBER, I KNOW THERE HAS BEEN
SOME HISTORY ABOUT INCLUDING
PREON HERE. SO IMPORTANT.
DO YOU HAVE A COMMENT ON THAT
FROM A POLICY SIDE?
>> I DON'T THINK IT IS A POLICY
QUESTION IN TERMS OF INCLUDING
PREONS UNDER THE UMBRELLA OF
ADRD.
THAT IS A SCIENTIFIC QUESTION
INCLUDED TALKING RIGHT NOW TO
FIGURE OUT IF I COULD JUST ASK
A QUESTION ABOUT REPRESENTATION
OF PRION.
WE ARE NOTING IT AND WE WILL
FOLLOW-UP.
>> DOES ANYBODY ELSE WANT TO?
>> THIS IS DIANE --, I DON'T
KNOW IF MY CAMERA IS WORKING
HERE, BUT ANYWAYS YOU CAN HEAR
ME. MORE AND MORE PEOPLE ARE
SHOWING ALZHEIMER'S DISEASE AND
RELATED DEMENTIA. AND THE
INFECTIONS. THERE IS A RECENT
PAPER FROM SOME EUROPEANS AND
SOMEONE IN THE US SHOWED THAT
SHINGLES VACCINE CAN REDUCE THE
INCIDENCE AT LEAST.
AND SO I MEAN I THINK THAT
PRION DISEASE SHOULD ALSO BE
INCLUDED IN THIS.
>> YEAH AND IF I MAY ADD-- THIS
IS CONSTANTINO -- THE PRION
MECHANISM HAS BEEN INVOLVED IN
TAU PROPAGATION.
AND SO WE WE TALK ABOUT
SOMETHING LIKE MAD COW DISEASE,
THE MECHANISM IS SOMETHING THAT
NEEDS TO BE APPLIED AND IF
THERE IS ONE CONDITION WHERE
THIS IS GOING TO BE HIGHLY
RELEVANT, IS MULTI ETIOLOGY
DEMENTIA.
IN THE CONTEXT OF VASCULAR
INSUFFICIENCY OFTEN, THERE ARE
CONDITIONS THAT WILL PROMOTE
THE PRION MECHANISM WHICH IS
CERTAINLY HIGHLY RELEVANT TO
THIS. ALTHOUGH IT MAY BE A PURE
PRION DISEASE, BUT THE
MECHANISM IS HIGHLY RELEVANT.
WALTER CAN SAY SOMETHING ABOUT
THAT TOO.
>> YEAH. A LITTLE BIT OF A
(INDISCERNIBLE) TOPIC HERE. I
GUESS, THERE ARE REALLY TWO
ANSWERS TO YOUR POINT.
THE ANSWER TO AT NINDS, PRION
DISEASE IS REALLY IMPORTANT.
WE ARE FUNDING RESEARCH IN
PRION DISEASE, PUTTING
POTENTIAL TREATMENTS FOR PRION
DISEASE.
WHEN FUNDING CAME FROM CONGRESS
FOR ALZHEIMER'S AND
ALZHEIMER'S-RELATED DEMENTIAS,
THEY DO NOT INCLUDE ALL
DEMENTIAS IN THE FUNDING
APPROPRIATION.
THERE ARE A NUMBER OF OTHER
FORMS OF DEMENTIA THAT ARE NOT
INCLUDED IN THE FUNDING THAT IS
PARTICULARLY COMING FROM
CONGRESS FOR THAT PURPOSE.
SO I GUESS THERE ARE TWO
THINGS. ONE IS, AS COS
MENTIONED, MECHANISM BY WHICH
PRION SPREADS IS SO RELEVANT TO
THE OTHER GENERATIONS THAT WERE
LISTED. WHICH ARE LEVY BODY
DEMENTIA, CARDIOVASCULAR
IMPAIRMENT -- AND
FRONTOTEMPORAL DEMENTIA. THERE
IT IS RELEVANT TO USE THOSE
FUNDS.
BUT OTHERWISE WE USE REGULAR
NINDS FUNDS FOR STUDYING PEOPLE
WITH PRION DISEASE. I KNOW IT
IS A TECHNICAL THING. BUT WE
HAVE TO ABIDE BY THE
APPROPRIATION LANGUAGE THAT
CONGRESS GIVES US.
>> CAN I SAY-- I KNOW WALTER-
CAN I ASK A QUESTION YOU DON'T
HAVE TO ANSWER THIS.
WHATEVER CONDITIONS THAT ARE
NOT CONGRESSIONALLY MANDATED,
CAN THAT BE INCLUDED IN THE
REPORT AS A REFERENCE?
FOR OTHERS.
>> DR. KOROSHETZ: YEAH,
WHATEVER YOU THINK IS IMPORTANT
THAT IS WHAT GOES INTO THE
REPORT. NOT A POLITICAL
DOCUMENT.
>> GREAT. BECAUSE AS I WAS
TRYING TO SAY, THIS IS WHERE
PRIVATE FUNDERS -- AND
INTERNATIONAL FUNDERS WOULD
COME IN AND PARTNER OR DO
THINGS INTERNATIONALLY. AND SO
IT IS GREAT. I WANT TO HAVE
THIS DOCUMENT BE A SHINING
EXAMPLE ON THE HILL, WHATEVER
YOU WANT TO CALL IT; THE
DEFINITIVE RECOMMENDATION TO GO
INTO THE NATIONAL PLAN. THANK
YOU.
>> ALL RIGHT THANK YOU.
LET' SEE.
TRYING TO SEE THE NAME. I
CANNOT SEE THE WHOLE NAME. ERIC
-- I THINK YOU ARE NEXT.
>> CAN YOU HEAR ME?
(INDISCERNIBLE).
ALL RIGHT. SO -- I WANTED TO
THANK YOU ALL FOR THE GREAT
PRESENTATIONS OVER THE PAST TWO
DAYS. I THINK IT IS BEEN VERY,
VERY INFORMATIVE FOR ME.
SO I HAVE ... THREE QUESTIONS.
THREE POINTS I WANTED TO MAKE.
I GUESS I WOULD DO ONE AT A
TIME.
THE FIRST ONE IS A NEURO-
INFLAMMATION. IF WE LOOK AT
ALL OF THIS NEURO-GENETIC
DISORDER, SPREADING
PROGRESSION, INFORMATION IS
INVOLVED IN ALL OF THEM. SEEMS
TO BE THE DRIVER.
IN TERMS OF PRIORITIZATION BY
THIS COMMITTEE, HOW
(INDISCERNIBLE) FROM THIS?
IN TERMS OF EMPHASIS ON THE
IMPORTANCE, WHERE DO YOU RANK
NEURO- INFLAMMATION?
EXPECTING TO SEE BIO MATICS
(PHONETIC).
>> THANK YOU THAT IS A
COST-CUTTING TOPIC. I'M
WONDERING IF SOMEBODY FROM THE
MED BASIC AND CLINICAL
COMMITTEE MIGHT BE WILLING TO
TAKE THIS QUESTION ABOUT NEURO-
INFLAMMATION, AND HOW IT IS
BEING CONSIDERED AND IF IT IS
BEING GIVEN ADEQUATE PRIORITY.
OR ANYONE ELSE.
>> SO INFLAMMATION HAS WORKED
ITS WAY IN ALL KINDS OF ACUTE
AND CHRONIC DISEASES, INCLUDING
NEURO- GENETIC DISEASES.
THERE'S A TREMENDOUS EFFORT TO
UNDERSTAND THE ROLE OF IMMUNE
CELLS WITHIN THE BRAIN WHICH
RECENTLY HAVE BEEN IDENTIFIED
AND THEY WERE NOT KNOWN
PREVIOUSLY TO BE SO MUCH
INVOLVED BECAUSE OF THE LACK OF
PROPER MARKERS AND SO ON.
AND SO NOW THERE IS A GREAT
EFFORT TO UNDERSTAND THE ROLE
OF MICROGLIA IN BOTH IN THE
CONTEXT OF VASCULAR DISEASE
AND IN THE CONTEXT OF TAU, TDP
43, AMYLOID AND SO ON.
THERE IS AN EMERGING ROLE OF
THE MILO SALES ASSOCIATE WITH
THE BORDER OF THE BRAIN MOTOR
ASSOCIATED MACROPHAGES, WHICH
ARE THE CONSTANT CAUSES OF THE
MICROGLIA INVOLVED IN AN NUMBER
OF CRITICAL FUNCTIONS RELEVANT
TO DEMENTIA. FOR EXAMPLE
CLEARANCE OF AMYLOID AND TAU.
THERE IS ALSO AN EMERGING ROLE
OF T CELLS. BOTH THE INNATE
KIND LIKE THE DTP 17 AND GAMMA
DELTA T CELLS THAT PRODUCE
TOXIC CYTOKINES WHICH ARE
INVOLVED IN THE MECHANISMS OF
DEMENTIA.
SO I THE NEURO-INFLAMMATION IS
KIND OF AN ESSENTIAL COMPONENT
OF THIS THAT CONSTITUTES THE
DEMENTIA FIELD. PARTICULARLY
MULTI- (INDISCERNIBLE)
DEMENTIA, WHERE ALL THE
PATHOGENIC FACTORS INTO
CONVERGENT CAUSE NEURO-
INFLAMMATION.
>> I AM THINKING MORE ALONG THE
LINES OF IF THERE IS A
PARTICULAR ORDER OF
PRIORITIZATION OR RANK. IS
THERE ANY FUNDING OR RESOURCES,
DIRECTIONAL RESOURCES?
THAT IS WHY I AM CURIOUS.
ANOTHER WAS A TALK, SOME ITEMS
WERE PRIORITIZED AS 1, 2, 3...
>> OFF THE TOP OF MY HEAD THERE
ARE A NUMBER OF OTHER PHASES
FOCUSING ON THE INFORMATION IS
ONE OF THE MECHANISMS INVOLVED
IN BRAIN DISEASES AND SOMEONE
FROM DNH MAY BE MORE QUALIFIED
TO ADDRESS SPECIFICALLY THE
FUNDS. ALLOTTED TO THAT.
>> I CAN ALSO MAKE SURE WE NOTE
THIS. AND AS WE REVIEW THE
RECOMMENDATIONS, WE CAN MAKE
SURE THAT INFORMATION IS AT AN
APPROPRIATELY HIGH-PRIORITY.
CAN YOU MOVE TO YOUR NEXT
QUESTION BECAUSE YOU SAID YOU
HAD THREE QUESTIONS?
>> YES, THE NEXT ONE, BIOMARKER
IMAGING.
I KNOW CURRENTLY,
(INDISCERNIBLE) HAVE PROVIDED
SO MUCH ADDITIONAL INFORMATION
AND UNDERSTANDING OF THE
DISEASE.
BUT ACCESS TO PET IS DIFFICULT.
COST. WE ALL KNOW. IN TERMS OF
(INDISCERNIBLE), IS THERE SOME
PRIORITIZATION OF ALL THE
IMAGING TECHNOLOGIES OF PET FOR
ADRD LOOKING AT?
HOW DO THEY RANK?
HIGH RISK, HIGH REWARD FOR ALL
THE IMAGING TECHNOLOGIES OTHER
THAN PET?
>> WOULD YOU TAKE THAT?
>> HAPPY TO TAKE THAT.
THAT IS A REALLY, REALLY GREAT
QUESTION AND SOMETHING THAT
WITHIN THE LEVY BODY DEMENTIA
SESSION WE DISCUSSED IN THE
CONTEXT OF USE AND WHY THESE
DIFFERENT BIOMARKERS NEED TO BE
DEVELOPED AND BALANCING BETWEEN
THESE VERY HIGHLY DETAILED
BIOMARKERS.
FOR INSTANCE THE PET IMAGING
GIVES US THE SPATIAL RESOLUTION
THAT COULD BE VERY IMPORTANT
FOR MOVING CERTAIN THERAPIES--
LET'S SAY FROM ASSAYS TO PHASES
-- OR FROM PHASE 1 TO 2. TO
GIVE YOU A SPECIALIST REGIONAL
PROTEINS.
ARE GOING BACK TO A PRIOR
COMMENT WHETHER OR NOT CERTAIN
PROTEINS IN CERTAIN REGIONS OF
THE BRAIN DO OR DO NOT HAVE AN
INFLUENCE ON THE CLINICAL
PICTURE. RIGHT?
SO THAT IS WHERE THOSE CAN COME
INTO IMPORTANCE. THEY MAY NOT
BE REALLY THE ONES THAT YOU
WANT TO PUSH FORWARD ON A
SCALABLE LEVEL FOR USE IN BROAD
CLINICAL USE.
>>
(AUDIO LOST)
>> ... COULD BE DONE AT SCALE
ACROSS MULTIPLE DIFFERENT
SECTORS BOTH ACADEMIC AND NOT.
I THINK THE KEY HERE IS FOR ALL
THE RECOMMENDATIONS TO REALLY
THINK ABOUT NOT JUST IMAGING,
BUT WE NEED IMAGING OF WHAT,
FOR WHAT AND IN WHAT CONTEXT TO
USE. THAT IS A REALLY CRITICAL
PART. YOU HAVE TO BALANCE THOSE
WITH THE PRIORITIES. YOU NEED
THEM BOTH BUT IN DIFFERENT
SITUATIONS FROM MY PERSPECTIVE.
>> IF I MAY ALSO COMMENT, YOU
RAISE A REALLY GOOD QUESTION.
DEPENDING ON WHAT YOU WANT TO
MEASURE, I THINK YOU REALLY SEE
A LOT OF PET WORK AND NOVEL
TRACES AND MODALITIES.
SO IT IS VERY IMPORTANT
QUESTION TO ADDRESS DEPENDING
ON WHAT KIND OF QUESTION YOU
WANT TO SORT OF ADDRESS WHETHER
PROTEIN MEASUREMENT, OR YOUR
INTEREST IS MORE OF
PHYSIOLOGICAL MEASUREMENT.
>> AND AS WE THINK ABOUT EARLY
DIAGNOSES, BRAIN IMAGING IS NOT
WIDELY ACCESSIBLE ACROSS ALL OF
THE UNITED STATES OTHER THAN IN
MAINE. LARGE SWATHES OF RURAL
MAINE DON'T EVEN HAVE ACCESS TO
PET CT OR EVEN MRI.
AND SO THAT IS WHAT WE THINK
ABOUT RARE DANCING AND THE NEED
TO FILTER PATIENTS WE USED TO
THINK PURELY ON COGNITION AND
NOW WE ARE THINKING IMAGING.
AND HIGHLIGHT THE BLOOD-BRAIN
BIOMARKERS WE DISCUSSED.
>> IF I MAY ADD THE PROGRESS
MADE IN BIOMARKERS HAS BEEN
AMAZING. THERE WAS A RECENT
STUDY FROM BRAIN
(INDISCERNIBLE), SHOWING THAT
THE SECURITY LEVELS OF A
PARTICULAR FORM OF
PHOSPHORYLATED TAU IS AS GOOD
AS PET PLEA DIAGNOSIS. IS
GOING TO BE CHEAPER AND BETTER
FOR SCREENING, FOR LARGE, HIGH
THROUGHPUT APPROACHES.
AND I ESPECIALLY FOR LOCATIONS
WHERE IMAGING IS OTHERWISE
AVAILABLE, VERY COSTLY AND
REQUIRE SPECIALIZED PEOPLE.
IT WOULD BE GREAT TO ALSO CROSS
THE BLOOD BARRIER MARKER.
UNFORTUNATELY FOR THE VASCULAR
COMPONENT OF DEMENTIA THERE IS
MUCH GOING ON PROMISING.
SOMETHING IS PROMISING BUT NOT
AS STRONG AS IT IS FOR THE
ALZHEIMER'S DEMENTIA ASPECTS.
>> CAN I JUMP IN QUICKLY?
I APPRECIATE THE REALLY
IMPORTANT RESEARCH AND SCALING
THAT DR. POSTIN MADE.
WE DON'T WANT TO BE DEPENDENT
ON ANY IMAGING MODALITIES IN
THE INCREDIBLY VALUABLE AND WE
NEED TO PURSUE THAT SCIENCE FOR
ADVANCING TO THE CLINICAL
STATION WE WILL ALWAYS NEED FOR
SOME CASES IN CLINICAL
EVALUATION. IT WISHERS ABOUT
SCALING NOT JUST DOMESTICALLY
WHERE IMAGING IS MINIMALLY
ACCESSIBLE AT ALL, BUT
GLOBALLY WILL HAVE TO INVEST ON
THE RESEARCH TO DEVELOP
CLINICAL MODALITY TESTING THAT
CAN BE PROVIDED THROUGHOUT BOTH
OF IN THE GLOBAL MORE THAN
GLOBAL SOUTH.
BUT AS OTHERS HAVE SAID
HOPEFULLY ENVISION-- ULTIMATELY
IT WILL BE SALIVA AND OTHER
MORE READILY ACCESSIBLE AND
ANALYZABLE FLUIDS.
SO IT IS A CONTINUUM. WE ARE
NEVER GOING TO BE ABLE TO JUST
SKIP ANYTHING. BUT WHERE WE ARE
IN BALANCE PUT OUR FOCUS FOR
CLINICAL APPLICATION IN THE
GLOBAL CONTEXT, 90% OF THE
CASES OF COGNITIVE IMPAIRMENT
ARE NOT IN ADVANCED, WESTERN
ECONOMIES. WE ARE GOING TO HAVE
TO GET THOSE OTHER MODALITIES
OF PROTECTION AND DIAGNOSIS,
BOTH CLINICAL OBSERVATION BUT
IN A MORE SENSITIVE AND
SPECIFIC WAY. BUT ALSO FLUID
SAMPLES THAT ARE EASILY
ANALYZED WITH AGAIN HIGH
SPECIFICITY AND SENSITIVITY.
>> THANK YOU.
>> MY FINAL CONTRIBUTION,
QUESTION OR COMMENT. SLEEP
DEFICIT AND OLFACTORY DEFICITS.
CURRENTLY MY UNDERSTANDING IS
THAT, FOR A PATIENT TO BE
REFERRED TO RECEIVE A PET SCAN
FOR AMYLOID THEY MUST HAVE GONE
THROUGH AN ELEMENTAL EXAM.
PROBABLY (INDISCERNIBLE) WHEN
THE PATIENT IS REFERRED TO GET
A PET SCAN.
IS THAT CORRECT?
IT IS ALSO NOW COMMON IN THIS
SMALL ANIMAL MODELS, THAT SLEEP
DEFICIT AND OLFACTORY DEFICIT
... THEY MAY COME REALLY EARLY
WHEN THE DISEASE IS IN THE
EARLY STAGES BEFORE IT GETS
INTO THE COGNITIVE IMPAIRMENT.
AND THERE ARE BIG
CONSIDERATIONS IN THIS
COMMITTEE, THINKING ABOUT MAYBE
RANKING, PUTTING THE SLEEP
DISORDERS COMMITTEE, OLFACTORY
DEFICITS AS APPOINTED WE SHOULD
RAISE FOR AN INDIVIDUAL TO GET
A PET SCAN. ACCOMPANIED BY THE
(INDISCERNIBLE) BIOMARKERS, AND
WE HAVE A COMBINATION OF
(INDISCERNIBLE) BIOMARKERS IN
ANY OF THESE DEFICITS.
IS THERE A POINT WHERE YOU
START THINKING ABOUT A PET SCAN?
>> ALICE IT LOOKS LIKE YOU
MIGHT HAVE A THOUGHT.
>> I WANTED TO ADDRESS WHAT IAN
SAID PREVIOUS TO THIS ALSO WHAT
ERIC SAID RIGHT NOW.
AND SO TO THE FIRST COMMENT, I
THINK THAT WE HAVE TO REMEMBER
THAT AT THIS MOMENT FOR THESE
DISORDERS WE HAVE MINIMAL
DISEASE MODIFYING THERAPIES. SO
WHAT WE ARE TRYING TO DO RIGHT
NOW IS NOT ONLY KIND OF DEVELOP
DIAGNOSTICS BUT ALSO TRYING TO
ENABLE TRIALS THAT WOULD THEN
ENABLE DISEASE MODIFYING
THERAPIES TO BE DEVELOPED.
IF YOU THINK ABOUT THE HISTORY
OF ALZHEIMER'S DISEASE, WITHOUT
THE BASIC AMYLOID DIES, JOE
STRAUSS WOULD NOT HAVE BEEN
ABLE TO GO THE WAY THEY DID. I
AM NOT ORDERING AMYLOID STAINS
ON MY PATIENTS AND SO THERE ARE
THINGS THAT ENABLE TRIALS SO WE
CAN DEVELOP THERAPIES AND WE
HAVE TO WORK ON THOSE. BECAUSE
WE DON'T HAVE THERAPIES AND AT
THE SAME TIME WE HAVE TO THINK
ABOUT HOW WE TRANSLATE THESE
BIOMARKERS IN ALZHEIMER'S, FOR
THE CSF, TAU AND AB MARKERS.
THAT GIVES US A LITTLE
BLUEPRINT FOR HOW TO DEAL WITH
OTHER DISEASES.
AND WITH RESPECT TO ERIC'S
QUESTION, THIS IS THE MOST
RELEVANT, OLFACTORY AND SLEEP
DEFICIT FOR THE BODY DISORDERS.
YOU BOTH HYPOSMIA ARE AT
INCREASED RISK FOR LEVY BODY
DEMENTIA DISORDERS AND PEOPLE
WITH (INDISCERNIBLE) AND I
WOULD SAY THAT I KNOW THAT WHEN
DR. TOLEDO SPELL BEFORE HE
TALKED ABOUT THE COHORT, THERE
IS THAT COHORT OF PEOPLE WITH
SLEEP DISORDERS. AND MANY OF
THE OTHER COHORTS WE TALK
ABOUT, PPMI COHORT AND
PARKINSON'S PROGRESSION MARKER
INITIATIVE COHORT, THEY
INCORPORATE HYPOSMIA, OLFACTORY
TESTING.
I WANTED TO REASSURE YOU, THAT
IS NOT BEING MISSED RIGHT NOW.
>> THANK YOU SO MUCH ERIC FOR
THOSE POINTS.
I'M GOING TO TURN IT OVER TO
DALE DINA (PHONETIC).
WE CAN HEAR YOU JUST YET.
>> GIVE IT A TRY AGAIN WITH
STAR SIX.
>> HOW IS THAT?
>> PERFECT WE CAN HEAR YOU.
>> GOOD. FIRST I WANT TO HAND
OUT A BEAUTIFUL BOUQUET OF
FLOWERS TO EACH OF YOU. FROM
WAY... I HAVE BEEN
PARTICIPATING IN THESE PROGRAMS
NOW FIVE OR SIX YEARS AND I
WOULD LIKE TO SAY THAT AND THE
EVOLUTION OF THESE SESSIONS HAS
BEEN SPECTACULAR.
ONE OF THE FIRST SESSIONS AND
SO FORTH WAS DIFFICULTY FROM
UNIVERSITY RESEARCH TO ANOTHER
UNIVERSITY RESEARCH, THE
VERNACULAR WAS FOR THE SAME
THING VERY DIFFERENT.
AND SO THE DIFFICULTY REALLY
UNDERSTANDING ONE ANOTHER, LET
ALONE A GUY LIKE ME OFF THE
STREET.
EARLY ON THIS IS A COMMITTEE TO
STANDARDIZE THE VERNACULAR. AND
THAT HAS BEEN DONE AND WE DON'T
EVEN HAVE TO THINK ABOUT IT
ANYMORE. OR EARLY START IS WHAT
IT APPEARS LIKE TO ME.
ALSO THE PROCEDURE OF SETTING
UP GOALS AND STUFF FOR
ACCOMPLISHING THOSE GOALS AND
SO FORTH, THAT WAS AN EVOLUTION
FROM WAY BACK THEN. JUSTICE
PARTICULAR PROCESS AND LOOK AT
IT NOW EACH OF YOU HAS AT ANY
TO STANDARDIZE AND IN A WAY
THAT I IS A SPECTACULAR.
NOW BACK IN 2000 WE HAD A GOAL.
NIH SAID THAT WITHIN FIVE YEARS
WE WOULD HAVE CURED ONE OF THE
DEMENTIAS. WELL WE HAVEN'T, BUT
WE ARE WORKING ON IT.
THE FIRST PART OF MY QUESTION
IS, WHICH ONE OF THE DEMENTIAS
IS THE BEST CANDIDATE IN YOUR
VIEW?
MY FIRST QUESTION.
>> I LOVE THAT QUESTION. WHO
WANTS TO TAKE IT?
>> WELL, IT'S...IT MIGHT NOT BE
ANSWERABLE.
>> NOT SURE HE IS HERE, HE
MIGHT HAVE A GOOD ANSWER BUT
WHO CAN SPEAK TO THIS IMPORTANT
QUESTION?
>> CONSTANTINO MIGHT. I SEE HIM
SMILING AND SHAKING HIS HEAD.
>> EVERYONE ON THE CALL WANTS
TO ANSWER.
GREAT PINT.
>> DR. IADECOLA: WE CAN GIVE
YOU OUR TAKE OUR PERSONAL...
>> I AM INTERESTED IN YOURS.
>> DR. IADECOLA: I THINK THE
MAJOR ADVANCE THAT YOU HAVE
SEEN TODAY, AND WE HOPE THAT
THIS IS GOING GO BACK TO THE
OVERALL MEDICAL COMMUNITY WHICH
IS NOT THE CASE IS THAT
DEMENTIA OF AGE IS NOT REALLY
ONE DISEASE.
SO IF WE WERE ABLE TO GET THE
GENERAL PRACTITIONERS AND
NEUROLOGISTS AND EVERYBODY ELSE
TO UNDERSTAND THAT, THAT WILL
BE A GREAT SUCCESS.
BECAUSE WE KNOW HOW TO PREVENT
AND PARTIALLY TREAT SOME
ASPECTS OF THIS DEMENTIA
PROCESS.
FOR EXAMPLE THE VASCULAR
PROCESS. WE HAVE MADE
TREMENDOUS PROGRESS IN
TREATING, AND PREVENTING
STROKES FOR EXAMPLE. THE
MORTALITY FOR STROKE SINCE THE
1960S IS REDUCED BY 60%.
BUT WHEN IT COMES TO DEMENTIA,
IT IS A LITTLE BIT MORE
COMPLICATED. WHY?
BECAUSE THERE ARE MULTIPLE
THINGS GOING ON. AND SO I THINK
IT IS NOT GOOD TO BE A SILVER
BULLET THAT EVERYBODY LIKES.
ALL RIGHT?
IF YOU WANT TO PUBLISH IN
NATURE, YOU HAVE TO PROPOSED A
SINGLE BULLET. BUT LIFE DOES
NOT WORK LET WAY.
I THINK THAT IT IS GOING TO BE
A COMBINATION OF PREVENTION,
VASO PROTECTIVE APPROACHES LIKE
STATINS AND GOP'S WHATEVER YOU
WANT. MAYBE AMYLOID IN ONE
CASE, TAU AND OTHERS. AND THAT
IS WHY WE ARE STRUGGLING SO
MUCH WITH THESE BIOMARKERS.
WE KNOW FOR EXAMPLE HOW TO
DECREASE AMYLOID LEVELS NOT
SPECTACULAR. WHY?
BECAUSE OF THE FIVE OR SIX
THINGS GOING ON THAT WE ARE NOT
ABLE TO ADDRESS SO MY ANSWER IS
A COMBINATION APPROACH, AND
PREVENTION BEING ONE OF THEM.
AND VASO PROTECTION IS ONE OF
THE MAJOR FEATURES.
>> THANK YOU VERY MUCH
CONSTANTINO. THAT IS EASY FOR
ME TO FOLLOW. AND THE
VERNACULAR FOR ME, FOR EACH
INDIVIDUAL, FOR ALL THE
DIFFERENT VARIETIES AND SO
FORTH AND DIFFERENT MIXES OF
THOSE VARIETIES ALMOST HAVE TO
WHIP UP A COCKTAIL FOR EACH ONE
OF PEOPLE THAT HAS A PROBLEM.
BALANCING IN SUCH A WAY THAT IT
WILL TREAT EACH ONE OF THOSE
PIECES. I KNOW THAT IS A BIG,
TALL ORDER.
I KNOW YOU GUYS ARE WORKING ON
IT. AND IS ONE MEMBER OF THE
PUBLIC ARE JUST WANT TO SAY
THANK YOU VERY MUCH.
BACK WHEN WE STARTED, WE HAD
THE TECHNOLOGICAL PEOPLE
TALKING, ONCE THEY GOT THE
NOMENCLATURE STANDARDIZED.
BUT THERE WAS LITTLE MENTION OF
THE CAREGIVER. AND THE
TECHNOLOGICAL DISCUSSION AND SO
FORTH WAS AMONGST THE
RESEARCHERS WHO DO THAT WORK.
AND, YOU'VE GOT A WAY OF
COMMUNICATING WITH ONE ANOTHER.
LATIN, GREEK AND SO FORTH. THE
COMMON GUY OFF THE STREET DOES
NOT UNDERSTAND.
YOU HAVE TRIED TO...I REALLY
APPRECIATE YOU HAVE MADE THE
EFFORT IN A VERY GOOD ONE TO
RESOLVE THAT SO GUYS LIKE ME
CAN UNDERSTAND WHAT IT IS. WE
ARE ALL SPEAKING ENGLISH BUT
THEN THERE'S ALL DIFFERENT
KINDS OF ENGLISH.
I WOULD LIKE TO SAY A QUESTION
ON THE NEURON WALL. I JUST
LEARNED FROM MY PREVIOUS
QUESTION THAT TAU MIGHT MIGRATE
SOMEWHERE IN AND OUT OF THE
NEURON.
HOW DOES IT DO THAT?
IS THE NEURON WALL SEMI
PERMEABLE?
>> WHO WOULD LIKE TO TAKE?
>> I CAN TAKE IT IF YOU WANT.
>> THANK YOU THAT WILL BE
WONDERFUL.
>> SO THERE ARE MANY MECHANISMS
BY WHICH TAU CAN MIGRATE FROM
ONE CELL TO THE OTHER. SOME OF
THEM INVOLVE FORMING LITTLE
VESICLES IN THE CELL MEMBRANE
AND THESE LITTLE VESICLES THEY
PUT TAU OUTSIDE OF THE CELL
MEMBRANE. AND THE NEXT CELL
PICKED IT UP IN A LITTLE
VESICLE AND INCLUDED IN ITSELF.
THERE ARE ALSO RECEPTORS IN THE
NEURAL MECHANISM. THERE ARE
SOME RECEPTORS THAT CAN
RECOGNIZE TAU, USUALLY NOT
SPECIFICALLY TAU BUT THEY CAN
RECOGNIZE TAU AND BRING IT INTO
THE OTHER CELL.
SO THERE ARE MANY MECHANISMS
THAT COORDINATE THIS
TRANSMISSION AND IS INTERESTING
BECAUSE NOW WE SEE THAT TAU IS
ALSO NOT JUST INSIDE THE NEURON
BUT ALSO OUTSIDE THE
VASCULATURE, LIKE IN THE
ENDOTHELIAL CELLS. SO THERE'S A
LOT OF PROGRESS IN THAT FIELD
RIGHT NOW.
>> SO YOU THINK ABOUT IT LIKE
FOOTBALL, THEY CAN PICK TAU,
ENDED HAND IT OFF WANT TO
ANOTHER IN A WAY.
>> THAT IS HOW TAU IS SPREAD IN
THE BRAIN FROM ONE AREA TO THE
OTHER.
>> MY LAST COMMENT.
YOU FOLKS ARE PROBABLY FAMILIAR
WITH THE KIPLINGER LETTER WHICH
COMES TO YOUR MAIL BOX EVERY
WEEK.
THIS WEEK IT SAYS AI HAS
UNCOVERED 200 MILLION PROTEIN
STRUCTURES, FAR MORE THAN THE
200,000 THAT WERE KNOWN IN THE
YEAR 2020. RESEARCHERS AT
STANFORD HAVE CREATED A VIRTUAL
LAB WITH AI MODELS TRAINED ON
SPECIFIC MEDICAL KNOWLEDGE TO
COORDINATE NEW DRUGS.
WELL, WHAT DO YOU KNOW ABOUT
THAT?
IS THIS A COMMON KIND OF THING
OF USING AI?
IS IT DEPENDABLE ENOUGH FOR YOU
TO WORK WITH?
BECAUSE I KNOW IT CAN GIVE YOU
MISLEADING ANSWERS.
IS A TOOL THAT YOU ARE USING?
I GUESS THAT IS THE QUESTION.
>> THANK YOU. I THINK THIS IS
A CROSSCUTTING THEME. I MANY OF
US ACROSS ALL OF THE COMMITTEES
ARE THINKING ABOUT HOW TO USE
AI TO ADVANCE OUR SCIENTIFIC
WORK. AND SO WE ARE GOING TO
NOTE THIS AND DISCUSS THIS WHEN
WE COME TOGETHER.
>> OKAY.
>> THANK YOU AND GOING TO TRY
TO MOVE ON BECAUSE WE HAVE A
FEW OTHER HANDS RAISED IN ONLY
FIVE MORE MINUTES LEFT FOR THE
DISCUSSION.
THANK YOU SO MUCH FOR THOSE
POINTS.
I'M GOING TO GO TO STEPHEN --
WHO IS THE NEXT PERSON.
>> THANKS CAN YOU HEAR ME ALL
RIGHT?
YESTERDAY I ASKED THE QUESTION
ABOUT DRUG DELIVERY TO THE
BRAIN WHICH IS KNOWN TO BE A
MAJOR BARRIER TO TREATING ALL
OF THE DEMENTIAS TALK ABOUT
TODAY AND YESTERDAY AND I GOT
AN ANSWER ABOUT ENDOTHELIAL
CELLS, ETC., BEING INCLUDED IN
SOME OF THESE STUDIES AS A
POTENTIAL DRIVER FOR THE
DISEASE AND THOSE EXPERIMENTERS
ARE DISTINCT FROM THOSE THAT
REVEAL HOW TRANSPORT WORKS
ACROSS THE BLOOD BRAIN BARRIER
IN DIFFERENT CONTEXTS,
INCLUDING A HEALTHY CONTEXT.
PREVENTING DEMENTIA AND HOW TO
POTENTIALLY LEVERAGE THAT FOR
DRUG DELIVERY WHICH MAY HAVE A
LARGE IMPACT ON OUR ABILITY TO
TREAT ALL OF THE DISEASES.
WHY DON'T THE RECOMMENDATIONS
MENTIONED EXPLICITLY THIS
EFFORT TO DEVELOP DRUGS THAT
CROSS THE BLOOD BRAIN BARRIER
MORE EFFICIENTLY AND
SELECTIVELY?
>> WHO CAN TAKE THAT?
>> I CAN TRY.
I MEAN IT IS A VERY IMPORTANT
QUESTION. AND A VERY IMPORTANT
ISSUE FOR THE FIELD.
FOR PART OF THIS IN ALZHEIMER'S
AND OTHER DEMENTIAS IS MADE A
LITTLE BIT EASIER BY THE FACT
THAT THE BLOOD BARRIER BRAIN IS
ALREADY LEAKING IN SOME OF
THESE CASES. SOME OF THE DRUGS
CAN PASS A LITTLE BIT BETTER
BECAUSE OF THAT, BUT STILL I IT
HAS TO BE A QUESTION THAT IS ON
THE SPECIFIC CLINICAL TRIAL.
AND THE SPECIFIC PRECLINICAL
STUDY ON THAT SPECIFIC DRUG.
OF COURSE THIS DRUG WILL ONLY
WORK IF IT IS A DRUG THAT
TARGETS NEURONS, IF IT IS ABLE
TO PASS THE BLOOD BRAIN
BARRIER. AND SO AT THE
TRANSLATIONAL LEVEL, WE HAVE TO
BE ABLE TO CREATE DRUGS-- THE
SPECIFIC DRUG THAT YOU WANT TO
ANALYZE TO MAKE IT A MOLECULE
THAT IS ABLE TO PASS THE BLOOD
BRAIN BARRIER. AND ONLY IF IT
CAN DO THAT, THEN WE CAN MOVE
TO THE CLINICAL LEVEL AND STUDY
IT IN HUMANS.
AND SO I THINK THE NIH IS
CREATING SYSTEMS LIKE THAT AND
MAYBE WALTER WANT TO TALK ABOUT
IT. BUT THEY ARE KIND OF LIKE
MEDIATED BY STEPS.
AND WE CAN DO A PRECLINICAL
STEP WHEN WE MAKE SURE THE DRUG
WILL PASS THE BLOOD BRAIN
BARRIER AND THEN WE CAN MOVE ON
TO THE CLINICAL STEP.
>> THANK YOU FOR THAT ANSWER.
GO AHEAD, PLEASE.
>> IF I MAY, THERE IS ALREADY A
LOT OF INTEREST IN DEVELOPING
(INDISCERNIBLE). FOR EXAMPLE
ROCHE HAS A TRIAL SHOWN TO
REDUCE THE AMYLOID YOU HAVE TO
HAVE A GOOD DRUG FIRST, AND
THEN YOU HAVE TO FIGURE OUT FOR
EXAMPLE THE BRAIN SHUTTLE USES
A TRANSFERENCE REFLECTOR HIGHLY
BROUGHT INTO THE BRAIN. AND
THINGS ARE ALREADY ONGOING AND
WE NEED THE DRUG AND THEN WILL
BE READY TO GO.
>> I HAVE TO ADD TO THE POINT.
THERE'S A LOT OF EFFORTS GOING
UNNECESSARY LISTED AS ADRD OR
IRRELEVANT TO ADRD, MECHANISMS
DELIVER THINGS TO DIFFERENT
TISSUES, SPECIFICITY AND THE
BRAIN IS INCLUDED IN SOME OF
THOSE CONSORTIUMS. MAY BE ABLE
WHOSE IS TO INCLUDE IT IN THE
RECOMMENDATIONS TO LOOK
OUTWARDS ABOUT HOW THESE DRUGS,
THOSE TYPES OF DRUG DELIVERY
MECHANISMS-- WE DON'T WANT TO
BE REINVENTING ANYTHING.
>> THANKS. THAT MAKES A LOT OF
SENSE AND I WILL GENTLY SUGGEST
THAT TRANSFERRING RECEPTORS ARE
IMPERFECT AND THE EFFICIENCIES
WILL BE LOW AND DRUGS ARE
GETTING TO OTHER ORGANS AND I
WOULD ALSO SAY THAT I WILL BE
INTERESTED IN FINDING SOMETHING
BETTER THAN TRANSFERRING
RECEPTOR OR ANTIBODY TARGETING
IT BEFORE KNOWING WHICH DRUG
WAS GOING TO DELIVER. MIGHT
EVEN SUGGEST THE DRUGS
TARGETING ANY OF THESE
DEMENTIAS CAN BE APPENDED TO
SUCH A SHUTTLE SO IT CAN BE A
GENERAL WITH BROADER CAPABILITY
TO ALL OF THESE IMAGES.
>> THANK YOU FOR THAT.
>> ONE MORE THING IMPORTANT THE
PERIPHERAL IMMUNE CELLS
MENTIONED IN MANY OF THESE
DEMENTIAS, CELLS ARE MAKING IT
INTO THE BRAIN FROM THE BLOOD
SYSTEM FROM THE BONE MARROW,
SOME ENABLING THOSE CELLS IN
ORDER TO PRODUCE WHATEVER MIGHT
BE HELPFUL IS ALSO AN AREA THAT
IS HUGELY UNDERSTUDIED. IT WE
CAN LEVERAGE WHAT IS ALREADY
HAPPENING IN THE DISEASE
THROUGH IPS TECHNOLOGIES AND
GENETICS, THAT IS A HUGE AREA
THAT NEEDS TO BE THOUGHT ABOUT.
>> SO WE HAVE JUST A COUPLE OF
MINUTES. I WOULD LOVE IT IF WE
COULD HEAR FROM HOLLAND MESKER
(PHONETIC) AND JULIE SCHNEIDER
TO CLOSE IS OUT OF THE PUBLIC
COMMENT.
SESSION GO AHEAD PLEASE HELEN.
>> I WILL KEEP IT BRIEF AND
THERE'S A LOT OF THINGS I
WANTED TO GIVE. BUT THAT CAN
WAIT.
WE LOOK AT A VARIETY OF
DISEASES TO DATE AND PUSHING
FORWARD PARTICULARLY IN LEVY
BODY'S REALM, WE ARE LOOKING AT
GENETIC CODES AND LOOKING AT
ALMOST EXCLUSIVELY THE HIGH
PENETRANCE MUTATIONS, VERSUS
ALSO BEING INCLUSIVE OF THOSE
VARIANCE WE KNOW OUR
CONTRIBUTORY.
AND SO I AM WONDERING WHY WE
DON'T LOOK TO ACCELERATE THE
SCIENCES ACROSS A BROADER
SPECTRUM AND ENGAGE A LARGER
COHORT. WHY WE AREN'T DOING
CONCURRENT STUDIES IN
WELL-KNOWN CONTRIBUTORY
VARIANTS.
>> I OPEN IT UP TO MY
COLLEAGUES TO ANSWER.
>> I THAT IS STARTING TO
HAPPEN, YOU KNOW?
I YOU ARE ABSOLUTELY RIGHT IN
THESE DISEASES BASICALLY THE
TARGETED ELEMENT WAS BASED ON
THE SIGNATURE NEUROPATHOLOGIES
AND THE HIGH PENETRANCE GENETIC
MUTATIONS. BUT WE ARE SEEING
THAT THEY ARE BEING
FUNCTIONALIZED, MEANING THAT IS
ONE OF THE -- CERTAINLY THE
LBD-- ONE OF THE
RECOMMENDATIONS WAS TO
FUNCTIONALIZED THESE GENETIC
VARIANTS. THE THOUGHT IS WE
SHOULD BE KIND OF LIKE USING
THAT DATA TO IDENTIFY MORE
TARGETS. RIGHT?
>> THANK YOU.
>> JULIE, COULD YOU OFFER SOME
CLOSING COMMENTS?
>> I ACTUALLY HAD A THANK YOU.
WONDERFUL TO HEAR EVERYBODY,
ALL THE DISCUSSION.
MINE WAS KIND OF QUICK. MY
COMMENT IN QUESTION WAS FOR THE
LEVY BODY GROUP, DISCUSSED THAT
LEVY BODIES ARE COMMON OF MIXED
PATHOLOGY EXHIBITING SPECIFIC
CLINICAL SYMPTOMS BUT IN MY
VIEW AND I WOULD LIKE TO HEAR
THEIR THOUGHTS, WHY NOT OPEN IT
UP?
WE KNOW THAT IN THE GENERAL
POPULATION 15-20% OF PEOPLE
HAVE LEVY BODIES OR MORE. AND
MAY HAVE HALLUCINATION,
FLUCTUATIONS, ETC.
IT IS A PROBLEM AND I DON'T
KNOW IF IT WAS EXACTLY BEING
ADDRESSED.
>> THANK YOU SO MUCH FOR THAT
COMMENT JULIE, SO WE ARE
SPECIFICALLY USING LANGUAGE
THAT TALK ABOUT INDIVIDUALS
FROM THE PRESENT THEMATIC,
NONSPECIFIC SYMPTOMATIC,
CLASSICS AND THEMATIC ALL THE
WAY THROUGH AUTOPSY IN ORDER TO
ADDRESS THAT ISSUE.
BECAUSE WE KNOW THAT A LOT OF
INDIVIDUALS WILL DEVELOP A LEVY
BODY TYPE OF SYNDROME GO
THROUGH A VERY NONSPECIFIC TIME
FROM WHERE THEY DON'T HAVE
THOSE CLASSIC SYMPTOMS. WE ALSO
KNOW THERE ARE OTHERS WHO NEVER
DEVELOPED THE CLASSIC LEVY BODY
SYMPTOMS THAT MAY HAVE
IMPORTANT CONTRIBUTIONS TO
THEIR LEVY BODY PATHOLOGY AND
THAT WAS BAKED INTO THE COHORTS
RECOMMENDATIONS AS WELL AS INTO
THE BIOMARKERS PIECE OF IT. AND
ALSO ON THE PATHOLOGY SIDE OF
THINGS IN ORDER TO HAVE THAT
HARMONIZATION ACROSS MULTIPLE
DIFFERENT COHORT TO MAKE SURE
LEVY BODIES ARE BEING LOOKED AT
IN A SYSTEMATIC WAY REGARDLESS
OF HOW SOMEBODY WAS RECRUITED
INTO THAT PATHOLOGICAL STUDY.
SUPER IMPORTANT IMPORTANT THANK
YOU SO MUCH FOR MENTIONING IT.
AND WE WILL MAKE SURE THAT OUR
REVISED RECOMMENDATIONS INCLUDE
THAT.
>> THANK YOU SO MUCH.
>> THIS CONCLUDES OUR OPEN
INPUT PERIOD.
I WANT TO REMIND YOU THAT YOU
CAN STILL PROVIDE YOUR WRITTEN
FEEDBACK TODAY, AND JOIN US
ALSO ON JUNE 2, WHERE WE WILL
HAVE MORE PERIODS FOR YOUR
INPUT.
I WOULD LIKE FOR OUR
CONTRACTORS TO SHARE MY SLIDES,
AS I WILL DO MY BEST TO
SUMMARIZE SOME OF THE REALLY
IMPORTANT INPUT THAT WE HAVE.
GATHERED DURING THESE TWO DAYS
AND WE WILL USED TO REVISE THE
RECOMMENDATIONS.
NEXT SLIDE.
>> DR. POSSIN: SO I WANT TO
START BY SAYING THANK YOU FOR
YOUR PARTICIPATION AND INPUT.
THESE RECOMMENDATIONS THAT WE
THOUGHT ABOUT OVER THE LAST
COUPLE OF DAYS HAVE BEEN
DRAFTED BY NINE COMMITTEES WITH
135 MANY MEMBERS, MOST OF WHOM
ARE SCIENTISTS, BUT ALSO PEOPLE
WOULD LIVED EXPERIENCE AND
PEOPLE WHO WORK IN GOVERNMENT
AND POLICY.
I AM SO GRATEFUL TO OUR
COMMITTEE MEMBERS WHO WERE
FLEXIBLE AND GENEROUS WITH OUR
MOVE FROM THE IN PERSON MEETING
IN MARCH TO THIS VIRTUAL
MEETING AND THE CHANGE OF DATE.
ESPECIALLY DURING THE TIME THAT
HAS BEEN OFTEN CHALLENGING FOR
SCIENTISTS. SO THANK YOU FOR
THE AMENDMENT TO THIS PROCESS.
IT HAS BEEN INSPIRING AND WE
HAVE 2100 PEOPLE REGISTER FOR
THE MEETING AS OF THIS MORNING
AND THERE MAY BE MORE AND
ACROSS THE TEAMS MEETING IN
VIDEOCAST WE HAD UP TO 1000
PEOPLE ADDING ONE TIME, SO
RECORD ENGAGEMENT.
WE HAD EIGHT LIVE PUBLIC INPUT
SESSIONS WITH MORE TO COME AND
SOME WONDERFUL AND INSIGHTFUL
EMAIL FEEDBACK.
NEXT SLIDE.
I WILL REVIEW SOME OF THE
OVERARCHING THEMES THAT I HEARD
AT THE SUMMIT.
THE FIRST IS THAT THERE HAS
BEEN AN INCREDIBLE PROGRESS IN
THE ADRD RESEARCH FIELD EVEN
JUST SINCE THE 2022 SUMMIT AND
YET THERE IS AN URGENCY TO KEEP
MOVING FORWARD.
THERE IS AN APPRECIATION
EXPRESS FOR NIH'S INVESTMENT IN
THE SCIENTIFIC PROGRESS; THE
MASSIVE REPORT WE HEARD THIS
MORNING HIGHLIGHTED THE
SIGNIFICANT CONTINUED
INVESTMENT IN PRIORITY RESEARCH
AND IT MUST CONTINUE.
AND WE HEARD THAT WHEN CHOOSING
RESEARCH PRIORITIES, PLEASE
KEEP THE PATIENTS AND FAMILIES
OF THE TOP OF MIND. WE HEARD
THAT FROM SOMEBODY FROM LIVED
EXPENSES.
DEMENTIA IS NOT POLITICAL. IT
AFFECTS ALL OF US IT IS A
BIPARTISAN ISSUE.
RACE COMPLEXITY WAS ANOTHER
THING. WE KNOW ANYTHING DISCUSS
THE DIAGNOSIS OF ADRD IS NOT A
YES/NO SITUATION. IT IS CAUSED
BY MULTIFACETED INTERPLAY OF
BIOLOGIC, GENETIC,
ENVIRONMENTAL SOCIAL BEHAVIOR
ELEMENTS AND TO UNDERSTAND
THESE DISEASES WELL WE NEED TO
INTEGRATE DATA SOURCES,
PERSPECTIVES AND METHODS.
MOST PATIENTS HAVE MIXED
ETIOLOGIES CALCIUM THEIR
DEMENTIA AND THE PATHOLOGICAL
OVERLAP IN THE DISEASES THAT WE
STUDIED.
I REALLY ENJOYED THE DISCUSSION
ABOUT HOW POST-TDI IS TRULY AN
MED.
WE HAVE TO RAISE THIS
COMPLEXITY AND THERE WERE
COMMENTS MADE ABOUT IMPROVING
MED CODING IN THE ELECTRONIC
HEALTH RECORDS TO IMPROVE CARE
AND IMPROVE DATA HARMONIZATION
OPPORTUNITIES. AND ALSO
ADVANCING AND APPLYING
ARTIFICIAL INTELLIGENCE METHODS
TO UNDERSTAND AND ACCOMMODATE
FOR THE COMPLEXITY THAT WE ARE
STUDYING.
NEXT SLIDE.
THEME 3, COLLABORATIVE
APPROACHES ARE NEEDED AT
MULTIPLE LEVELS.
ACROSS EVERY SESSION IT WAS
MENTIONED THAT WE NEED TO KEEP
IMPROVING OUR APPROACHES FOR
HARMONIZATION, AND MOVING
TOWARDS BROAD DATA SHARING.
WE NEED EXTENSIVE BIOMARKERS
THAT CAN BE WIDELY COLLECTED IN
STANDARD WAYS. WE NEED TO
LEVERAGE PRIVATE/ PUBLIC
PARTNERSHIPS IN DATA
REPOSITORIES AND WE NEED COMMON
DEFINITIONS AND NOMENCLATURE TO
SUPPORT DATA HARMONIZATION FOR
EXAMPLE AROUND FTLD DIAGNOSIS.
WE NEED TO ENGAGE A VARIETY OF
STAKEHOLDERS IN ALL STEPS OF
RESEARCH, INCLUDING PEOPLE WITH
LIVED EXPERIENCE.
WE WANT TO CONTINUE OUR
PARTNERSHIPS ACROSS FEDERAL
AGENCIES THAT HAVE BEEN CRUCIAL
FOR THE PROBLEMS THAT WE HAVE
SEEN DURING THIS SUMMIT.
AND PRIVATE/ PUBLIC
PARTNERSHIPS AND CRUCIAL AS
WELL FOR ADVANCING TIMES AND WE
HEARD THAT NIH SUPPORT IS
CRITICAL FOR THESE PARTNERSHIPS
TO CONTINUE ESPECIALLY IN AN
FTD AREA THAT WAS DISCUSSED IN
MULTIDISCIPLINARY RESEARCH TO
TACKLE THESE COMBOS PROBLEMS
HIGHLIGHTED BY NASEM AND ALSO
NEED COLLABORATION IN OUR CARE
PATHWAYS AND AS WE TRY TO
IMPROVE ACCESS TO CARE.
NEXT SLIDE.
BIOMARKERS!
WE MADE SO MUCH PROGRESS IN THE
LAST THREE YEARS AND MORE, BUT
THERE IS SO MUCH MORE PROGRESS
THAT IS NEEDED BECAUSE THE
AIKIDO DISENTANGLING CLINICAL,
PATHOLOGICAL, HETEROGENEITY AND
NAD.
WE NEED THEM FOR DIAGNOSIS FOR
EXAMPLE WE HEARD HOW LATE IS
ONLY DIAGNOSED AT AUTOPSY AND
WE NEED BETTER BIOMARKERS FOR
MED, POST-TBI, WHERE WE CAN SEE
SO MANY DIFFERENT ETIOLOGIES
PRESENT IN THE PATIENTS. TDP-43
BIOMARKER IS PARTICULARLY
NEEDED. AND AS POINTED OUT BY
KAREN AND LARRY, HAVING
RELIABLE BIOMARKERS IS CRITICAL
AN AUTOPSY IS TOO LATE. WE
CANNOT JUST HAVE BIOMARKERS FOR
AD.
IT IS CRITICAL FOR MONITORING
ESPECIALLY FOR MONITORING
AGENTS AND ACCESS TO BIOMARKERS
AS PART OF THE SCALABLE,
DIAGNOSTIC PATHWAYS.
NEXT SLIDE.
I THINK THIS IS MY LAST
OVERARCHING THEME. FOSTERING
INCLUSIVE RESEARCH AND ACCESS
TO CARE. WE NEED TO STUDY THE
POPULATIONS MOST AT RISK. IT
WAS SUGGESTED THAT RIGOROUS
SCIENCE REQUIRES ADDRESSING
HEALTH EQUITY AND WE SHOULD
THINK ABOUT USING THE RIGHT,
CLEAR, DECISIVE LANGUAGE ON
THIS IN ADVANCE RESEARCH THAT
WILL HELP THE MOST VULNERABLE
AND UNDERSERVED PATIENTS IT IS
SO IMPORTANT AND WE NEED
GENOMIC DATA THAT IS
REPRESENTATIVE OF THE US
POPULATION.
NEXT SLIDE.
SO I HAVE TAKEN CAREFUL NOTE OF
THE INPUT WE RECEIVED IN THESE
SESSIONS THAT YOU HAVE BEEN A
PART OF. AND ALSO THE WRITTEN
FEEDBACK THAT I RECEIVED FROM
YESTERDAY. HAVE NOT GOTTEN
THROUGH THE WRITTEN FEEDBACK WE
GOT TODAY, BUT I'M VERY EXCITED
TO DO SO AND I AM SUMMARIZING
THOSE IN THE SESSION AND I WILL
HIGHLIGHT A FEW THINGS.
IN THE FIRST SESSION WHICH WAS
ON RESEARCH AND IMPLEMENTATION
OF DISCOVERIES INTO PRACTICE,
THERE WAS FEEDBACK THAT THAT
WHEN LOOKING AT DIAGNOSIS IN
PRIMARY CARE NEED TO MAKE SURE
THAT LESS TYPICAL SYMPTOMS ARE
NOT MISSED.
WE NEED TO NORMALIZE BRAIN
HEALTH EVALUATIONS.
AND WE NEED TO PRIORITIZE
RESEARCH ON CULTURALLY
COMPETENT COMMUNICATION OF
BRAIN HEALTH INFORMATION.
CARE APPROACHES NEED TO THINK
ABOUT NONPHARMACOLOGICAL
APPROACHES TO NEUROPSYCHIATRIC
SYMPTOMS. AND FOCUS ON
WELL-BEING AS A KEY OUTCOME.
ACCESS TO CARE SHOULD CONSIDER
FINANCIAL AND SYSTEMIC
BARRIERS. AND SUPPORT AXIS TWO
SUPPORTS AND SERVICES FOR
PEOPLE WHO LIVE ALONE.
WE ALSO NEED TO THINK ABOUT
PEOPLE IN RURAL AREAS, AND HOW
THEY CAN ACCESS QUALITY CARE.
THERE WAS A COMMENT I RECEIVED
VIA EMAIL THAT SAID "AN OUNCE
OF PREVENTION IS WORTH A POUND
OF CURE."
SHOULD PREVENTION BE A HIGHER
PRIORITY? IS CURRENTLY RANKED
AT NUMBER 4.
WE WILL CONSIDER THAT AS A
STEERING COMMITTEE.
AND ALSO AS A SUGGESTION TO
PARTNER WITH CELEBRITY ADVOCATE
TO GET OUR MESSAGES OUT.
NEXT SLIDE.
IN THE FTD SESSION IT WAS
HIGHLIGHTED THAT THE HIGHEST
PRIORITY IS RESEARCH TO IMPROVE
DIAGNOSIS AND TREATMENT. THIS
WAS REALLY GUIDED BY SOMEONE
WITH LIVED EXPERIENCE. AND
THERE WAS AN IMPORTANT
DISCUSSION ABOUT POTENTIAL
THERAPEUTIC TARGETS.
WE NEED TREATMENTS WITH MORE
THAN A MODEST EFFECT THAT CAN
WORK FOR PATIENTS AT DIFFERENT
STAGES OF DISEASE.
PUBLIC/ PRIVATE PARTNERSHIPS
ARE ESSENTIAL. AND THERE WAS A
SENSE OF URGENCY AT THIS
SESSION.
ONE QUOTE I RECEIVED VIA EMAIL
FROM THE VIDEOCAST WAS, "FTD IS
UNIQUELY CRUEL BECAUSE IT OFTEN
AFFECTS A PERSON IN THE PRIME
OF THEIR CAREER AND THE COST OF
LOST PRODUCTIVITY IS HUGELY
IMPACTFUL FOR FAMILIES. OFTEN
BOTH THE PATIENT AND THE
CAREGIVER ARE FORCED TO LEAVE
THEIR CAREERS AND ARE STUCK IN
THIS SITUATION FOR MANY
TORTURERS, AND DISABLED YEARS.
NIH PLEASE HELP US END FTD."
I THINK WE FEEL THIS URGENCY.
NEXT SLIDE.
FTD POST TDI, WE NEED TO THINK
ILLICITLY AND COLLABORATE WITH
THE BROADER FIELD BECAUSE TDI
IS TRULY AN MED.
LOOK FOR OPPORTUNITIES TO LEARN
MORE ABOUT THE IMPACTS OF
DOMESTIC PARTNER VIOLENCE AND
UNDERSTAND HOW TBI IN LATE LIFE
INTERACT WITH OTHER
NEURODEGENERATIVE PROCESSES,
AND COLLABORATE WITH
INTERNATIONAL RESEARCH
COMMUNITIES ESPECIALLY WITH
COUNTRIES WITH EXTENSIVE
HISTORY OF COMBAT RELATED TBIS.
MED - LATE.
WE GOT SOME HELPFUL COMMENTS
FROM SOME OF WE LIVED
EXPERIENCE WITH SAID IT WAS A
GAME CHANGER TO FIND OUT THE
ACTUAL DIAGNOSIS, GETTING THE
WORD OUT IS EVERYTHING.
WE NEED TO EDUCATE FAMILIES
ABOUT WHAT TO EXPECT. EDUCATE
CLINICIANS INCLUDING PRIMARY
CARE, AND DEVELOP CARE
GUIDELINES AND WE NEED
BIOMARKERS FOR LATE.
DEFINITIVE DIAGNOSIS IS ONLY
POSSIBLE AT AUTOPSY. THIS IS A
HUGE BARRIER FOR CLINICAL
TRIALS AND FOR DIAGNOSIS. BUT
IT ALSO AFFECTS OUR STUDY OF
OTHER PATHOLOGIES.
FOR EXAMPLE WE NEED TO RULE OUT
TDP-43 WHEN WE ARE SELECTING
PATIENTS FOR AN AD TREATMENT
TRIAL.
WE ALSO NEED TO ADDRESS
CONSISTENCIES AND DIAGNOSIS OF
HIPPOCAMPAL SCLEROSIS, AND
ADVANCED RESEARCH TO IDENTIFY
THE CHARACTERISTIC SIGNATURES
OF LATE WITH OR WITHOUT AD
CO-PATHOLOGY USING
RETROSPECTIVE STUDIES.
NEXT SLIDE.
IN THE CLINICAL AND BASIC
SCIENCE SESSION, WE HEARD INPUT
THAT WE NEED TO REALLY FOCUS ON
THAT COMBINATION OF AD AND
VASCULAR.
WE NEED RESEARCH ON THE
RELATIVE CONTRIBUTIONS OF EACH
ETIOLOGY, IN A WAY THAT WILL
HELP PATIENTS AND FAMILIES.
FOR BIOMARKERS WE NEED TO MAKE
SURE WE ARE RECOMMENDING
RESEARCH THAT IS BROAD ENOUGH.
AND THERE WAS EMPHASIS ON
COLLECTING BIOMARKERS IN A
STANDARDIZED WAY TO SUPPORT
HARMONIZATION.
AI AND ADVANCED STATISTICAL
METHODS ARE NEEDED, BUT FOR
THESE TO WORK WELL WE NEED THAT
COMMON CLASSIFICATION.
THE EYE IS A WINDOW TO THE
BRAIN AND THERE WAS TALK OF
EXPANDING MODELS.
NEXT SLIDE.
AND LBD. WE TALKED ABOUT
HARMONIZING DATA SETS AND
SAMPLES ACROSS COHORTS. AND
BETTER UNDERSTANDING AT A
FUNCTIONAL LEVEL WHY THERE IS
CELLULAR DYSFUNCTION IN
DEMENTIA WITHOUT
NEURODEGENERATION.
AND FINALLY WANT TO THINK ABOUT
RESEARCH ON A-SYNUCLEIN CO
PATHOLOGY IN PEOPLE WITH DOWN
SYNDROME AND AD.
NEXT SLIDE.
AND IT IS IMPORTANT FOR
PATIENTS TO ENGAGE PHYSICALLY
BUT ALSO SOCIALLY SO WE NEED TO
CONSIDER THIS IN OUR
RECOMMENDATIONS. CONSIDER THE
EXPOZOME AND THEIR EFFECTS ON
VCID. AND SEE ABOUT HOW DO THE
MEDS INTERACT WITH THEIR IN
DIFFERENT REGIONS OF THE BRAIN
AND LASTLY MAKE SURE TO THINK
ABOUT VASODILATION AND CCA IN
OUR RESEARCH.
IN THE CLOSING SESSION WE HAD
REALLY FANTASTIC INPUT AND I
HAVE TAKEN NOTE OF ALL OF IT
AND NOT GOING TO REVIEWED HERE
BECAUSE YOU WERE JUST THERE.
BUT WILL CONSIDER ALL THE GREAT
INPUT WE GOT IN THAT SESSION.
NEXT SLIDE.
SO IN CLOSING, I WANT TO
EXPRESS MY GRATITUDE TO OUR
COLLEAGUES AT NINDS AND ALS AT
NIH FOR MAKING SOME IT
HAPPENED.
OVER THESE LAST FEW MONTHS MANY
OF OUR COLLEAGUES AT NIH AND AT
SOME OF THE FEDERAL AGENCIES
HAVE FACED UNANTICIPATED
CHALLENGES. CHANGES IN THE
RULES COVERING THEIR WORK AND
IN DOWNSIZING THEIR TEAMS.
WHETHER WE AGREE WITH THE
CHANGES ARE NOT, THEY HAVE
ADDED EXTRA CHALLENGES FOR OUR
NIH COLLEAGUES IN PREPARING
THIS SUMMIT.
FOR EXAMPLE, SOME OF THE NIH
LEADS AND STAFF WHO WERE
WORKING ON THE SUMMIT WHEN WE
STARTED ARE NO LONGER EMPLOYED
AT NIH.
AND ALSO, CHALLENGES WERE FACED
IN SETTING THE SUMMIT DATES,
AND GETTING THEM APPROVED AND
AS WE SHIFT FROM IMPERSONAL
MEETING TO VIRTUAL, FINDING A
TECHNOLOGY PROBLEM THAT WILL
WORK FOR THIS MEETING AND ALSO
WAS ALLOWABLE. THAT WAS A
CHALLENGE.
AND SO THIS SUMMIT WOULD NOT
HAVE HAPPENED IF NOT FOR THE
PERSISTENCE, CREATIVITY AND THE
DEDICATION OF OUR NIH
COLLEAGUES.
I WANT TO THANK THE NIH STAFF
TO WORK ON THE SUMMIT AND THE
LOGISTICS CONTRACTOR AND I WANT
TO SPECIFICALLY THANK AMBER
MCCARTNEY FOR HER LEADERSHIP.
SHE HAS WORKED TERRIBLY WITH A
HUMBLE SPIRIT AND NEVER GAVE UP
ON OUR GOAL TO HOST THIS SUMMIT
NO MATTER THE CHALLENGES.
I ALSO WANT TO SPECIFICALLY
THANK ROD -- WHO LED THE PRIOR
ADRD SUMMITS AND I WANT TO WISH
HIM WELL ON HIS NEXT STEPS
GUIDING ADRD WORK.
WITH JOIN ME BY USING THE REACT
FEATURE AT THE TOP OF YOUR
BROWSER, IN OFFERING GRATITUDE
FOR THE WORK AND DEDICATION OF
OUR COLLEAGUES AT NIH.
>> THANK YOU SO MUCH FOR THOSE
KIND WORDS.
IT IS REALLY AN HONOR TO BE
ABLE TO DO THIS AND LEAD THIS
SUMMIT. IT IS REALLY AN
IMPORTANT EVENT.
WE WILL ALWAYS BE GRATEFUL FOR
ALL THE INPUT FROM PEOPLE THAT
WE RECEIVED IN THE COMMITTEE
SENT TO THE LAST TWO DAYS.
AND WE ARE NOT DONE. WE'RE
GOING TO HAVE A THIRD DAY ON
JUNE 2.
>> DR. POSSIN: NEXT SLIDE WHILE
AMBER IS TALKING.
>> PERFECT. THANK YOU.
>> DR. POSSIN: ALL RIGHT WELL
THANK YOU. AND YES THANK YOU
ALL FOR BEING HERE AND WE
REALLY LOOK FORWARD TO A
WONDERFUL THIRD DAY THE SUMMIT.
SEE YOU THEN.