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>>I'M HONORED TO INTRODUCE
OUR SPEAKER DR. REBECCA
GOTTESMAN, THE STROKE BRANCH
CHIEF AND SENIOR INVESTIGATOR OF
THE STROKE COGNITION AND
NEUROEPIDEMIOLOGIC SESSION AT
THE NINDS INTRAMURAL RESEARCH
PROGRAM.
SHE COMPLETED HER DEGREES AT
COLUMBIA UNIVERSITY AND
INTERNSHIP AND NEUROLOGY
RESIDENCY AT JOHNS HOPKINS.
SHE COMPLETED Ph.D. AND
CLINICAL INVESTIGATION AT THE
JOHNS HOPKINS BLOOMBERG SCHOOL
OF PUBLIC HEALTH, ON FACULTY AT
THE JOHNS HOPKINS DEPARTMENT OF
NEUROLOGY AND EPIDEMIOLOGY AS
WELL AS CORE FACULTY MEMBER AT
JOHNS HOPKINS UNTIL 2021 WHEN
SHE JOINED THE NINDS.
RESEARCH IS ON DEMENTIA,
ALZHEIMER'S DISEASE, AS WELL AS
CEREBRAL SMALL VESSEL DISEASE
AND POST STROKE DEMENTIA, USING
NEURAL IMAGING TO EVALUATE
RESEARCH QUESTIONS.
SHE STUDIES DISPARITIES IN
STROKE, DEMENTIA, POST-STROKE
COGNITIVE IMPAIRMENT.
DR. GOTTESMAN IS BOARD CERTIFIED
IN NEUROLOGY AND VASCULAR
NEUROLOGY BY THE AMERICAN BOARD
OF PSYCHIATRY AND NEUROLOGY.
SHE'S A FORMER ASSOCIATE EDITOR
FOR JOURNAL OF NEUROLOGY, 2019
OUTSTANDING STROKE RESEARCH
AWARD AMERICAN HEART
ASSOCIATION, AUTHORED OVER
CO-AUTHORED OVER 350
PUBLICATIONS, MENTORING OVER 40
STUDENTS, RESIDENTS, FELLOWS.
SHE HOLDS NUMEROUS LEADERSHIP
POSITIONS
ELECTED MEMBER OF THE AMERICAN
SOCIETY FOR CLINICAL
INVESTIGATION, MEMBER OF THE
INTRAMURAL CLINICAL NEUROSCIENCE
WORKSHOP PLANNING COMMITTEE,
NINDS HEALTH DISPARITIES
WORKSHOP, NINDS CLINICAL TRIALS
NETWORK EVALUATION WORKING
GROUP, NINDS EXECUTIVE ADVISORY
COMMITTEE.
DR. GOTTESMAN IS CO-CHAIR AND
PANELIST FOR NINDS AMERICAN
NEUROLOGICAL ASSOCIATION
SPONSORED INTERACTIVE WEBINAR
SERIES CREATING A SUCCESSFUL
PROGRAM, BUILDING A DIVERSE AND
INCLUSIVE RESEARCH ENVIRONMENT.
SHE'S ALSO THE ANNUAL PROGRAM
CHAIR FOR AMERICAN NEUROLOGICAL
ASSOCIATION.
TODAY THE TITLE OF THE
PRESENTATION IS "IS
CEREBROVASCULAR VASCULAR DISEASE
EVER SILENT.
JOIN ME IN WELCOMING DR. GOTTESMAN.
THANK YOU FOR THE OPPORTUNITY TO
SPEAK, DELIGHTED TO TALK ABOUT
MY WORK AND THE WORK OF THE MANY
PEOPLE I WORKED WITH OVER THE
YEARS.
THE TITLE OF MY TALK IS TRYING
TO GET AT THIS THIS ISSUE OF
SO-CALLED SILENT CEREBROVASCULAR
DISEASE.
HERE IS MY DISCLOSURES.
I THINK THE DEFINITIONS WILL BE
REALLY IMPORTANT TO MAKE SURE
WE'RE ON THE SAME PAGE, I'LL
APPROACH WHETHER WE SHOULD THINK
OF SMALL VESSEL DISEASE IN LUMP
OR SMALL MANNER AND WHY THEY
AREN'T SO SILENT IN TERMS OF
IMPACT ON STROKE AND POST-STROKE
OUTCOME AND ALSO ON IMPACT ON
COGNITION AND COGNITIVE DECLINE
AND DEMENTIA.
FINALLY WE'LL TOUCH ON
MECHANISMS AND THINK ABOUT SMALL
VESSELS BEYOND THE BRAIN BEFORE
WRAPPING UP WITH FUTURE
DIRECTIONS.
WHEN WE TALK ABOUT SILENCE,
WE'RE TALKING ABOUT A NUMBER OF
CHANGES SEEN IN THE BRAIN OF
INDIVIDUALS THAT IN THEORY ARE
ASYMPTOMATIC, AND I'M SAYING IN
THEORY, OBVIOUSLY I'M PREPARING
YOU FOR THE FACT I DON'T THINK
THESE ARE FULLY ASYMPTOMATIC BUT
THESE ARE IMAGING CHANGES
FREQUENTLY SEEN ON CLINICAL
SCANS OR RESEARCH SCANS,
INCIDENTAL FINDINGS, SO NOT
UNCOMMON IN A CLINICAL READ OF
MRI FOR THERE TO BE A NOTE MADE
OF MICROHEMORRHAGE, WHITE MATTER
HYPERINTENSITIES, INFARCTS NOT
ASSOCIATED WITH STROKE-LIKE
SYMPTOMS, SOFTEN CALL SILENT AND
COVERT CHANGES, A LOT OF
SYNONYMS, BUT THE REALITY IS
THEY ARE OFTEN WHAT IS SUBMERGED
BELOW THE WATER AND CLINICAL
STROKE IS REALLY WHAT WE KNOW OF
MORE CLEARLY HAS CLINICAL
IMPLICATIONS.
I'M GOING TO TALK MORE ABOUT
RISK FACTORS AND PROTECTIVE
FACTORS THROUGHOUT THE TALK BUT
I WANTED TO USE THIS GRAPHIC TO
EMPHASIZE CHANGES LURKING
BENEATH THE WATER, PROBABLY MORE
CLINICALLY APPARENT THAN WE
THINK.
GENERALLY WHEN WE THINK ABOUT
STROKE WE THINK ABOUT STROKE
THAT CAUSES SYMPTOMS AND
INFARCTS THAT DON'T NECESSARILY
CAUSE SYMPTOMS.
SO, THIS SORT OF REWORKING OF
STROKE DEFINITIONS PUBLISHED NOW
TEN YEARS AGO REALLY FOCUSES ON
WHETHER SYMPTOMS OCCUR OR DON'T
TO DETERMINE IF SOMETHING IS A
STROKE, CLINICAL STROKE, OR IF
THERE ARE NO SYMPTOMS IT'S OFTEN
CALLED, AGAIN, A SILENT CEREBRAL
INFARCTION OR CNS INFARCTION.
THIS IS AN EXAMPLE OF SOMETHING
THAT COULD BE SILENT BUT
CERTAINLY COULD HAVE HAD
SYMPTOMS AS WELL.
I DON'T KNOW BY LOOKING AT THE
SCAN, DIFFUSION WEIGHTED MRI
WITH A RIGHT ACUTE INFARCT,
SHOWS BRIGHT LESIONS OR ACUTE
EVENTS THAT OCCUR, WHICH COULD
HAVE HAPPENED INCIDENTALLY IN
SOMEONE AND NOT CAUSED SYMPTOMS
OR MAY HAVE CAUSED SYMPTOMS AND
THAT MIGHT LEAD TO DIFFERENTIAL
BETWEEN STROKES OR SILENT
INFARCTION.
WHAT ARE THESE CHANGES BELOW THE
WATER, THE TYPE OF THE ICEBERG?
ONE VERY COMMON FINDING, AGAIN
AS PEOPLE GET OLDER ALL OF THESE
FINDINGS OCCUR MORE FREQUENTLY,
AND THEY ARE VERY COMMON AS
INCIDENTAL FINDINGS ON MRI
SCANS.
AS MRI TECHNOLOGY IMPROVES,
SEQUENCES IMPROVE, THE FREQUENCY
AND ABILITY TO SEE THESE
SUBCLINICAL OR SILENT LESIONS
GETS EVEN BETTER.
WHITE MATTER HYPER INTENSITY ARE
CHANGES WE SEE FREQUENTLY IN
PEOPLE PARTICULARLY AS THEY AGE.
THE TINY CAVITATIONS HERE
LECUNES MIGHT LOOK LIKE A SMALL
VESSEL LECUNAR INFARCT BUT
DIDN'T NECESSARILY HAVE
SYMPTOMS, EVEN IN LARGE
PERIVASCULAR SPACES, MICROBLEEDS
ARE SMALL HEMORRHAGES THAT
OCCURRED IN THE PAST, NOT
NECESSARILY CAUSING SYMPTOMS.
HERE IS AN EXAMPLE OF A NEW
LOOKING INFARCT ON A SCAN BUT
DIDN'T NECESSARILY CAUSE
SYMPTOMS.
BRAIN ATROPHY CAN EVEN BE A
DOWNSTREAM CHANGE OF SOME OF
THESE OTHER VASCULAR CHANGES,
AND CORTICAL MICROINFARCTS,
THERE'S MORE CONTROVERSY ON WHAT
STRENGTH MAGNET CAN IDENTIFY
THESE ON MRI BUT THESE SMALL
INFARCTS ARE DESCRIBED
PATHOLOGICALLY.
ALL OF THESE GO UP WITH AGE,
HERE IS A GRAPHIC SHOWING
SHOWING LACUNEAR, AND THE
PREVALENCE IN A NUMBER OF COHORT
STUDIES GOES UP, PROBABLY SMALL,
BUT THE TOP OF THE Y-AXIS IS
40%.
SO SOME ESTIMATES HERE AS PEOPLE
GET TO AGE 90, OVER A THIRD OF
PEOPLE MAY HAVE SOME OF THESE
LACUNAR INFARCT, AND WHITE
MATTER HYPERINTENSITIES EVEN
MORE COMMON.
WE CATEGORIZE THESE INTO SMALL
VESSEL DISEASE.
WHEN YOU IDENTIFY ON MRI, YOU
DON'T KNOW WHAT THE ETIOLOGY
WAS.
SO WHEN WE THINK ABOUT ACUTE
STROKE SOMEONE COMES IN WITH
SYMPTOMS, WE SCAN THEM, SEE
ACUTE CHANGES ON THIS DIFFUSION
MRI, DWI MRI.
WE CAN USE OUR INTUITION ABOUT
WHAT THE INFARCTS LOOK LIKE BUT
IMPORTANTLY WE DO OTHER STUDIES
TO HELP US EVALUATE PROBABLE
ETIOLOGY, WE MIGHT SEE THE
LECUNAR AS WELL AS HYPERTENSION
DIABETES, DETERMINING ETIOLOGY
BETTER FOR ACUTE STROKES WITH
SEVERAL CLASSIFICATION SYSTEMS.
THE COMBINATION OF IMAGING PLUS
THE WORKUP.
SILENT CHANGES, INCIDENTAL
FINDINGS ON MRI, WE DON'T KNOW
WHAT UNDERLYING ETIOLOGY WAS AND
TEND TO GROUP THESE TOGETHER AS
FORMS OF SMALL VESSEL DISEASE
BASED ON WHERE THEY ARE, WHAT WE
KNOW THEY ARE ASSOCIATED WITH
BUT THE REALITY IS WE DON'T
REALLY KNOW FOR SURE WHAT THE
UNDERLYING ETIOLOGY IS.
IT'S PLAUSIBLE THAT A CARDIO
EMBOLIC STROKE CAN LEAVE
APPEARANCE LIKE SMALLER LECUNAR
STROKE OVER TIME.
I WANT TO MAKE THAT CAVEAT
BECAUSE I'M GOING TO MAKE
ASSUMPTIONS THAT WE THINK WHEN
WE SEE THESE CHRONIC CHANGES ON
MRI THAT WE CAN GUESS SOME MIGHT
BE FORMS OF SMALL VESSEL DISEASE
BUT WE DON'T ABSOLUTELY KNOW
THAT FOR SURE FOR THESE KINDS OF
CHANGES.
SO, CLASSIFYING SMALL VESSEL
DISEASE SUBTYPES IS SOMETHING
THERE'S MORE OF AN EMPHASIS ON
IN THE LAST TEN YEARS.
SO THIS STRIVE CONSORTIUM WAS A
GROUP IN 2013 THAT PUBLISHED AN
IMPORTANT PAPER, DEFINING FORMS
OF CEREBRAL SMALL VESSEL
DISEASE, WHICH OF THESE WE THINK
ARE INDICATIVE OF DISEASE OF THE
ARTERIAL SMALLER BLOOD VESSELS
IN THE BRAIN.
JUST LAST WEEK THEY RELEASED AN
UPDATE TO THE STRIVE CONSORTIUM,
STRIVE 2, AGAIN FOCUSING ON THE
SAME LESIONS, THESE ARE THINGS
I'VE SHOWN, RECENT SUBCORTICAL
INFARCT IN A LOCATION THAT MIGHT
BE SEEN FOR A LECUNE OR THAT
CAUSED SYMPTOMS, AND WHITE
MATTER HYPERINTENSITIES ENLARGE
THE SPACE.
IN THIS STRIVE-2 UPDATE I MAKE A
POINT OF SAYING THAT THERE ARE
DIFFERENCES WHEN WE SEE THESE AS
SYMPTOMATIC VERSUS SILENT OR
COVERT EVENTS, MAKING STATEMENTS
DESCRIBING WHAT GENERALLY LEADS
TO SOMETHING TO CAUSE SYMPTOMS
VERSUS WHAT DOESN'T, BUT THESE
ARE NOT UNIFORM RULES.
CERTAINLY SOMEONE COULD HAVE
VERY SMALL INFARCT THAT CAUSES
SYMPTOMS, DEPENDING ON WHERE IT
IS, OR SLIGHTLY BIGGER ONE THAT
DOESN'T CAUSE SYMPTOMS.
IN GENERAL, THEIR POINT IS THAT
INFARCTS THAT OCCUR OUTSIDE THE
PRIMARY MOTOR TRACKS OR SENSORY
TRACKS MAY MORE LIKELY BE
SYMPTOMATIC AND VICE VERSA FOR
THE IMPORTANT REGIONS N STRIVE-2
THEY DIFFERENTIATE BETWEEN ACUTE
VERSUS CHRONIC, EMPHASIZING HOW
THINGS LOOK DIFFERENT AT THE
TIME, AND YOU MAY BE ABLE TO
MORE CONFIDENTLY SAY WHAT IS
ACUTE AND WHAT THE ETIOLOGY IS
AS OPPOSED TO MORE CHRONIC SMALL
VESSEL CHANGES ON SCANS THAT ARE
INCIDENTAL FINDINGS.
SO NOW THAT I'M DESCRIBING
DIFFERENT TYPES OF SMALL VESSEL
DISEASE AND GIVEN CAVEATS
ACUTELY VERSUS CHRONICALLY MAY
MAKE A DIFFERENT IN THE
CONFIDENCE OF ETIOLOGY, IN
ADDITION THAT THERE ARE
DIFFERENT FORMS OF SMALL VESSEL
DISEASE, AND WE SEE THEM AGAIN
IN A LOT OF THESE SCANS BUT SOME
OCCUR MORE FREQUENTLY THAN
OTHERS.
ONE IMPORTANT CONSIDERATION
SHOULD WE CATEGORIZE ALL THESE
FORMS TOGETHER OR REALLY SHOULD
WE THINK OF THEM AS DISTINCT
ENTITIES?
AND THE REASON IT MIGHT BE
IMPORTANT TO CONSIDER THEM
TOGETHER IS BECAUSE IT MIGHT
HELP US UNDERSTAND MORE ABOUT
THEIR ETIOLOGY AND IMPORTANTLY
THEIR OUTCOME AND ULTIMATELY IF
THERE'S A WAY TO PREVENT THESE.
THIS IS A VENN DIAGRAM FAR FROM
COMPREHENSIVE BUT WHICH GIVES A
SENSE OF HOW MUCH OVERLAP THERE
IS IN SHARED RISK FACTORS.
STROKE IS ONE END OF THE
SPECTRUM, WE HAVE A GOOD SENSE
OF WHAT THAT LOOKS LIKE, EVEN
THOUGH THERE'S MANY TYPES OF
STROKE.
SILENT LACUNES OR SMALL VESSEL
TYPE CHANGES, LECUNAR INFARCTS
PRESUMABLY SILENT OR SUBCLINICAL
AT THE TIME.
MICROBLEEDS, HEMORRHAGES THAT
DIDN'T NECESSARILY CAUSE
SYMPTOMS.
AND WHITE MATTER
HYPERINTENSITIES.
THERE'S SO MUCH OVERLAP IN RISK
FACTORS.
HYPERTENSION IS A RISK FACTOR.
SOME RISK FACTORS NOT IN CERTAIN
OVERLAP BECAUSE THEY HAVEN'T
BEEN STUDIED OR BECAUSE THOSE
OUTCOMES ARE LESS FREQUENT AND
HARDER TO STUDY BUT REALLY WANT
TO MAKE THE POINT IF WE'RE
TRYING TO DECIDE IF WE SHOULD
LUMP OR SPLIT THESE SMALL VESSEL
DISEASE TYPES IT'S USEFUL TO
THINK HOW THEY HAVE SHARED RISK
FACTORS, AGAIN IT MAY BE
INFORMATIVE TO STUDY THEM
TOGETHER IF THEY HAVE VERY
SIMILAR RISK FACTORS FOR PEOPLE
THAT GET ONE TYPE VERSUS
ANOTHER.
IN ADDITION TO THE RISK FACTORS
BEING SIMILAR,
HISTOPATHOLOGICALLY WE SEE MANY
SIMILARITIES BETWEEN THESE
DIFFERENT TYPES OF SMALL VESSEL
DISEASE CHANGES.
SO WHITE MATTER HYPERINTENSITIES
AND SILENT LECUNAR INFARCTS ARE
ARTERIAL CHANGES WE SEE ON
PATHOLOGY FURTHER EVIDENCE THEY
MIGHT GO TOGETHER.
PEOPLE WITH LECUNAR STROKES ARE
MORE ENLARGED PERIVASCULAR
SPACES AND MORE WHITE MATTER
HYPERINTENSITIES, IN ADDITION
PEOPLE WHO HAVE LACUNES, ALMOST
HALF ALSO HAVE MICROHEMORRHAGES.
MONOGENIC DISORDERS, ALL OF
THESE ARE DESCRIBED TOGETHER,
SUCH AS CADASIL.
IN ADDITION, WE'LL TALK MORE
ABOUT THIS LATER, OUTCOMES TEND
TO BE SIMILAR WITH STROKE AND
SMALL VESSEL DISEASE TYPES.
SO WE KNOW YOU HAVE MICROBLEEDS,
MIGHT HAVE THE SAME EFFECT ON
OUTCOME AS IF YOU HAD WHITE
MATTER INTENSITIES OR SOME
COMBINATION.
THERE'S MORE TO BE DONE IN THIS
AREA, THERE'S SOME EVIDENCE
PREVENTION EFFORTS HAVE WORKED
IN A SIMILAR WAY TO REDUCE
PROGRESSION OF SEVERAL FORMS OF
SMALL VESSEL DISEASE, THE MOST
EVIDENCE IS FOR STROKE AND WHITE
MATTER HYPERINTENSITIES WITH
BLOOD PRESSURE CONTROL,
SPRINT-MIND RANDOMIZED PEOPLE TO
MORE PROGRESSIVE BLOOD PRESSURE
CONTROL, STOPPED EARLY FOR
CARDIOVASCULAR BENEFIT AS MANY
OF YOU KNOW AND DIDN'T REACH
PRIMARY OUTCOME REDUCING
DEMENTIA, THE PRIMARY GOAL OF
SPRINT-MIND, BUT SHOWED
REDUCTION IN MCI IN MORE
AGGRESSIVE BLOOD PRESSURE
CONTROL GROUP BUT EVIDENCE IT
REDUCES CARDIOVASCULAR DISEASE,
THE MORE AGGRESSIVE BLOOD
PRESSURE CONTROL.
AND THEN AS I SAID I WOULD GET
BACK TO THERE IS SOME EVIDENCE
OF SHARED GENETIC RISK, SO HERE
IS ONE EXAMPLE.
FOX F2 AS PART OF A
META-ANALYSIS I WAS PART OF,
GWAS, CHROMOSOME 6, ASSOCIATED
WITH CLINICAL STROKE AND BURDEN
OF WHITE MATTER
HYPERINTENSITIES, ADDITIONAL
STUDIES FOUND WHEN DELETED TO BE
ASSOCIATED WITH MORE WHITE
MATTER HYPERINTENSITIES BUT
KNOCKOUT MICE ARE MORE
MICROHEMORRHAGE, THESE
PHENOTYPES, GLIOSIS, INFARCTION,
IN ZEBRAFISH MUTANTS DECREASED
PARASITE COVERAGE AND SMOOTH
MUSCLE CELL COVERAGE.
FOXF 2 IS ASSOCIATED WITH
LECUNAR STROKE AND WHITE MATTER
HYPERINTENSITIES IN A SEPARATE
GWAS, ONE EXAMPLE LUMPING MIGHT
BE HELPFUL WITH SHARED GENETIC
RISK.
FURTHERMORE THERE ARE A NUMBER
OF IMPORTANT RISK VARIANTS
IDENTIFIED WITH MULTIPLE SMALL
VESSEL DISEASE PHENOTYPES, AND
THIS IS SORT OF SIMILAR TO MY
RISK FACTOR VENN DIAGRAM WHITE
MATTER HYPERINTENSITIES,
INFARCTS, THESE ARE MEASURES OF
WHITE MATTER INTEGRITY FROM
DIFFUSION TENSOR IMAGING,
INDICATORS OF SMALL VESSEL
DISEASE, IN THE WHITE MATTER,
MICROBLEEDS, HEMORRHAGE, SMALL
VESSEL STROKE, YOU SEE A LOT OF
OVERLAP WITH GENETIC RISK.
SO, I HOPE I PERSUADED YOU IT'S
REASONABLE TO LUMP THESE THINGS
TOGETHER, THERE ARE SUBTLE
DIFFERENCES BUT IF WE'RE TRYING
TO UNDERSTAND WHAT THEY MEAN FOR
OUTCOME AND HOW TO PREVENT THEM
IT'S USEFUL TO THINK OF THEM AS
A COMPOSITE ENTITY OF SMALL
VESSEL DISEASE PHENOTYPES.
TO TELL YOU MORE ABOUT WHY I
THINK THESE CHANGES ARE NOT SO
SILENT I WANT TO GIVE BACKGROUND
FOR THE STUDY WHERE THIS WORK
HAS BEEN DONE, THE
ATHEROSCLEROSIS COHORT STUDY,
16,000 PEOPLE RECRUITED IN
1980s, FOLLOWED INITIALLY WITH
VISITS EVERY FEW YEARS, A BIGGER
GAP BEFORE THE FIFTH IN-PERSON
VISIT, NOW AT TENTH IN-PERSON
VISIT, HALF IN PERSON, SHIFTED
TO A VIRTUAL SETTING.
THEY WERE MIDDLE AGE WHEN THEY
STARTED, NOW 8 0-100, FROM FOUR
U.S. COMMUNITIES.
EARLY VISITS WE ASSESSED
COGNITION AT MULTIPLE VISITS AS
WELL AS SUBSET HAVING BRAIN MRI
OR AMYLOID PET SCANS.
STUDY WAS DESIGNED TO LOOK AT
NATURAL HISTORY OF
ATHEROSCLEROSIS AND RISK
FACTORS, DETAILED VASCULAR RISK
FACTOR AND MICROVASCULAR AND
MACROVASCULAR MARKER INFORMATION
THROUGHOUT THE COHORT FOLLOW-UP.
IN ADDITION TO THESE IN-PERSON
VISITS THERE'S NOW SEMI ANNUAL
PHONE CALLS, ONGOING
SURVEILLANCE OF STROKE,
DEMENTIA, OTHER IMPORTANT
OUTCOMES.
GLEN WYNDHAM, UNIVERSITY OF
MISSISSIPPI, LOOKED AT THE ARIC
COHORT, IMPACT ON STROKE AND
MORTALITY.
PEOPLE WHO CEMENTED TO HAVE
SIGH -- SEEMED TO HAVE SILENT
INFARCTS, INCIDENTAL FINDINGS ON
A RESEARCH MRI SCAN.
SHE FOUND PEOPLE WHO HAD MORE
LACUNES AND MULTIPLE TYPES OF
LACUNES, SMALLER VERSUS BIGGER,
WHICH MAY REFLECT ENLARGED
PERIVASCULAR SPACE ARE GREATER
RISK OF POST-STROKE MORTALITY,
MORE WHITE MATTER
HYPERINTENSITIES AND LACUNES WAS
ASSOCIATED WITH INCREASED RISK
OF STROKE AND STROKE-RELATED
MORTALITY.
PROGRESSION WAS LOOKED AT, TO
UNDERSTAND IF YOU HAVE THEM BUT
THEY CONTINUE TO PROGRESS OVER A
PERIOD OF TIME IS THAT WORSE FOR
OUTCOME?
THE ANSWER IS YES.
PEOPLE WITH MORE INCIDENT
LACUNES
EITHER NON AND DEVELOPED SOME OR
SOME AND DEVELOPED MORE, THIS IS
OVER A 10-YEAR PERIOD OF TIME,
HIGHER RISK OF STROKE IN THE
SUBSEQUENT 12 YEARS.
AGAIN, THESE FINDINGS ARE BAD
FOR RISK OF STROKE AND, AGAIN,
IT'S PROBABLY THIS ISSUE OF IT
BEING TIP OF THE ICEBERG IS
STROKE, WE KNOW THESE ARE
LURKING UNDER THE WATER,
INDICATING YOU'RE AT RISK FOR
HAVING A CLINICAL STROKE.
IF YOU HAVE MORE PROGRESSION
RISK MAY BE GREATER.
WE KNOW PEOPLE WHO HAVE STROKE
BUT AT THE TIME HAVE WORSE SMALL
VESSEL DISEASE, AND WE KNOW MORE
FOR WHITE MATTER
HYPERINTENSITIES, LECUNAR
STROKES, YOU CAN COUNT THEM,
HARDER TO LOOK AT THE WHOLE
SPECTRUM OF SEVERITY OF LECUNAR
STROKES OR MICROCLEATS THAN
WHITE MATTER INTENSITIES WHICH
WE CAN MEASURE AND QUANTIFY.
PEOPLE WHO HAVE STROKE CAN GET
tPA, DO WORSE AFTER STROKE IF
THEY HAD WHITE MATTER
HYPERINTENSITIES TO BEGIN WITH.
IF YOU HAVE A HEMORRHAGE AND
MORE WHITE MATTER
HYPERINTENSITIES, WORSE OUTCOME,
MORE GROWTH OF HEMORRHAGE.
FUNCTIONAL STATUS IS WORSE FOR
PEOPLE WITH MORE WHITE MATTER
HYPERINTENSITY, OUT OF
PROPORTION, THEY DO WORSE AFTER
STROKE.
IN ADDITION, LOOKING AT
HEMISPATIAL NEGLECT, THOSE
PEOPLE INDEPENDENT OF STROKE
SIZE HAD WORSE NEGLECT WITH
WHITE MATTER HYPERINTENSITIES.
A FELLOW AT JOHNS HOPKINS LOOKED
AT COLLATERAL FLOW AND FOUND
PEOPLE WITH WHITE MATTER
HYPERINTENSITIES DEVELOPED
COLLATERALS, VERY IMPORTANT FOR
POST-STROKE OUTCOME, ABILITY TO
RECOVER FROM LARGE VESSEL
OCCLUSION.
IN ADDITION, GAIT IS SOMETHING
THAT'S VERY IMPORTANT AND
AFFECTED BY SMALL VESSEL
DISEASE, STROKE RECURRENCE,
MORTALITY, KEVIN SULLIVAN AT
UNIVERSITY OF MISSISSIPPI
MEDICAL CENTER LOOKED AT THIS IN
THE ARIC COHORT.
PEOPLE WITH MORE WHITE MATTER
HYPERINTENSITY WITH LARGER
INCREASE WITH LARGER VOLUME OF
WHITE MATTER HYPERINTENSITIES
HAD SLOWER GAIT SPEED AND
DECLINED MORE RAPIDLY OVER TIME,
IMPORTANT FOR OUTCOMES.
INDIRECTLY WHITE MATTER
HYPERINTENSITIES AFFECTING GAIT
COULD AFFECT RISK, PARTICULARLY
IN OLDER PEOPLE.
STROKE PATIENTS HAVE WORSE GAIT
WITH A LOT OF SMALL VESSEL
DISEASE, IN GENERAL FUNCTIONAL
OUTCOME BEYOND JUST GAIT APPEARS
TO BE WORSE IN PEOPLE WITH MORE
WHITE MATTER HYPERINTENSITIES,
INDEPENDENT MUCH UNDERLYING RISK
FACTORS.
WHITE MATTER HYPERINTENSITIES
BECAUSE THEY ARE SO COMMON ARE
PROBABLY RELEVANT IN OTHER
NEUROLOGIC DISEASE AS WELL.
EVEN IF THEY ARE NOT DIRECTLY
MECHANISTICALLY PLAYING A ROLE
THEIR PRESENCE MAY WORSEN
OUTCOME RELATED TO THAT DISEASE.
PARKINSON'S PATIENTS WHO ALSO
HAVE SMALL VESSEL DISEASE DO
WORSE.
I'LL EMPHASIZE THESE CHANGES ARE
SO COMMON AS PEOPLE GET OLDER
IT'S INEVITABLE A FAIRLY LARGE
PROPORTION OF PATIENTS WITH A
DISEASE LIKE PARKINSON'S ARE
GOING TO HAVE SMALL VESSEL
DISEASE.
SO THINKING ABOUT PREVENTING
THESE AND THEIR PROGRESSION IS
RELEVANT FOR ALL TYPES OF
OUTCOMES RELATED TO NEUROLOGIC
DISEASE.
IN ADDITION, PEOPLE WITH
TRAUMATIC BRAIN INJURY WITH MORE
SMALL VESSEL DISEASE APPEAR TO
DO WORSE THAN THOSE WHO DIDN'T
HAVE SMALL VESSEL DISEASE TO
BEGIN WITH.
IT'S ASSOCIATED WITH MORE
FRAILTY, AGAIN THIS ISSUE OF
WORSE GAIT, WORSE RISK OF
FALLING, MORE FRAILTY IN
GENERAL.
EMILY JOHNSON AT HOPKINS SHOWED
INCREASED RISK OF LATE-ONSET
EPILEPSY.
IT MIGHT ACTUALLY INFLUENCE THE
DEVELOPMENT OF THE DISEASE
ITSELF, IN THIS CASE LATE-ONSET
EPILEPSY.
WHAT ABOUT COGNITION?
SO, THESE ARE DATA FROM THE
ROTTERDAM STUDY SHOWING CLEARLY
AND CONSISTENTLY NO MATTER WHICH
TYPE OF THESE SMALL VESSELS YOU
LOOK AT, I'VE ARGUED WE SHOULD
THINK OF THEM LUMPED TOGETHER,
THAT COGNITION IS WORSE, THIS IS
ANNUAL CHANGE ON A COGNITIVE
INDEX IN ROTTERDAM.
MORE WHITE MATTER, GREATER
DECLINE, DEPENDING ON
PERIVENTRICULAR OR SUBCORTICAL.
SIMILAR PATTERN FOR BRAIN
INFARCTS, SO-CALLED SILENT
VERSUS THOSE WHO DON'T, HAVE
WORSE COGNITIVE SCORES.
MICROBLEEDS ARE ASSOCIATED WITH
WORSE COGNITION WHEN DEFINED IN
A BINARY WAY AS WELL.
STROKE AS WELL, AGAIN THIS TALK
IS FOCUSING ON SMALL VESSEL
DISEASE BUT IF WE THINK ALONG
THE SPECTRUM, STROKE AS THE MOST
CLINICALLY OBVIOUS FORM OF THESE
SMALL VESSEL DISEASE TYPES, WE
KNOW SMALL VESSEL DISEASE TYPES
ARE ALSO ASSOCIATED WITH RISK OF
STROKE, IT'S IMPORTANT TO THINK
ABOUT WHAT STROKE DOES FOR
COGNITION.
HERE IS DATA FROM THE LEVINE-LED
REGARDS STUDY, AFTER THE TIME OF
STROKE WE SEE DECLINE IN
PEOPLE'S COGNITION AND CONTINUES
TO DECLINE OVER TIME SO THIS IS
LOOKING AT LONGITUDINAL REPEATED
COGNITIVE MEASURES ASSOCIATED
WITH STROKE OF ALL TYPES.
GLEN WYNDHAM LOOKED AT COGNITION
WITH INFARCTS AS WELL AS WHITE
MATTER HYPERINTENSITIES AND SHE
FOUND PEOPLE WHO HAD THE CHANGES
SMALL OR LARGE INFARCTS HAD MORE
COGNITIVE DECLINE THAN NORMAL
POPULATION BUT MOST IMPORTANTLY
IF YOU HAD BOTH YOU HAD STEEPER
DECLINE OVER TIME ON COGNITION
OVER 20 YEARS.
AND WHITE MATTER
HYPERINTENSITIES, THE MORE YOU
HAVE, THE GREATER YOUR COGNITIVE
DECLINE OVER TWO DECADES.
WHAT ABOUT DEMENTIA?
I MENTIONED IN ARIC REPEATED
COGNITIVE MEASURES OVER TIME,
TENDS TO BE LESS CONFOUNDED
OUTCOME THAN LOOKING AT
CROSS-SECTIONAL COGNITIVE
PERFORMANCE OR EVEN DEMENTIA.
DEMENTIA IS MORE UNDERSTANDABLE
TO THE POPULATION AND CERTAINLY
IF WE'RE THINKING ABOUT
IMPORTANT TARGETS FOR
PREVENTION, IMPORTANT PUBLIC
HEALTH MESSAGES ABOUT WHY TO
SCREEN FOR RISK FACTORS, ET
CETERA, IT'S IMPORTANT TO THINK
ABOUT THE IMPACT ON DEMENTIA.
HERE ALSO IN ROTTERDAM WE SEE
HAVING ANY OF THESE CHANGES,
SILENT INFARCTS, WHITE MATTER
HYPERINTENSITIESES ASSOCIATED
WITH INCREASED DEMENTIA, NOT AS
UP FOR SUBCORTICAL CHANGES BUT
PERIVENTRICULAR, AFTER
ADJUSTMENT FOR MRI MEASURES THIS
IS SIGNIFICANCE, INCREASED RISK
OF DEMENTIA, WE SEE THAT FOR
JUST WHITE MATTER
HYPERINTENSITIES IN GENERAL, AND
SIMILAR FOR MICROBLEEDS.
AGAIN, MICROHEMORRHAGES
ASSOCIATED WITH INCREASED RISK
OF DEMENTIA.
SULLIVAN LOOKED AT THIS IN ARIC
AND INFARCTS LATER IN LIFE.
WE TALK ABOUT IMPORTANCE OF
MID-LIFE, RISK FACTORS FOR
COGNITIVE DECLINE AND IMAGING
FACTORS.
I'LL TOUCH ON THAT LATER BUT HE
WANTED TO UNDERSTAND A BIT MORE
ABOUT HOW MRI PRESENCE OF THESE
INFARCTS WHICH WE DON'T HAVE IN
MID-LIFE ON PARTICIPANTS BECAUSE
MRI WAS NOT AVAILABLE WHEN THE
STUDY WAS STARTED, BUT
ASSOCIATED WITH RISK OF DEMENTIA
IN SUBSEQUENT YEARS AND FOUND
WHEN YOU THINK ABOUT THESE
SMALLER VERSUS LARGER
INFARCTION, A LITTLE BIT OF
INRISK WITH BOTH BUT REALLY THIS
BIG JUMP IN THE HAZARD IF YOU
HAD TWO TYPES OF SMALL VESSEL
DISEASE, HIGHER RISK OF DEMENTIA
OVER TIME AFTER THAT IMAGING WAS
DONE.
SO, WHAT ABOUT STROKE?
WHEN WE TALK ABOUT THESE TYPES
WE WANT TO THINK ABOUT STROKE,
GIVEN HOW RELATED THEY ARE TO
EACH OTHER, HOW THEY ARE
ASSOCIATED WITH EACH OTHER,
SYLVIA CATONE LED THIS PAPER,
HOW STROKE RECURRENCE AND
SEVERITY WAS ASSOCIATED WITH
DEMENTIA.
SHE FOUND THAT COMPARED TO
PEOPLE WHO NEVER HAD A STROKE
DURING FOLLOW-UP AND YOU CAN SEE
40 YEARS WORTH OF FOLLOW-UP
BASICALLY, THAT PEOPLE WHO HAD
AT LEAST ONE STROKE WITH GREATER
SEVERITY SCORE, NIH STROKE SCALE
IS A WAY TO MEASURE STROKE
SEVERITY, MORE SEVERE STROKES
HAD GREATER HAD MORE DEMENTIA,
AND BOTH WERE GREATER THAN
PEOPLE WITH NO STROKES.
IF YOU LOOKED AT STROKE
RECURRENCE IN COMBINATION WITH
SEVERITY PEOPLE WHO HAD AT LEAST
TWO STROKES HAD GREATER RISK OF
DEMENTIA, PARTICULARLY IF ONE OF
THE STROKES WAS AT LEAST SEVERE
STROKE.
EVEN IF YOU HAD TWO STROKES AND
THEY WERE MILD YOUR RISK IS
SIMILAR, BUT TWO STROKES WITH
ONE MODERATE TO SEVERE RISK OF
DEMENTIA WENT WAY UP AS YOU CAN
SEE HERE.
GOMEZ, BEFORE I MET HER WAS A
POSTBAC HERE AT NIH, NOW A
MEDICAL STUDENT AT JOHNS
HOPKINS, LOOKED AT SPECIFIC
SYNDROME, THIS IS AN ENTITY
DESCRIBED AS SIMILAR TO MCI BUT
HAS A DISTRICT SET OF FEATURES,
PREDOMINANTLY GAIT INVOLVEMENT,
SLOW GAIT AND SUBJECTIVE
COGNITIVE DECLINE.
PEOPLE WHO HAVE MCR HAVE HIGHER
RISK OF DEMENTIA.
MAY START WITH GAIT DISTURBANCE
AND SUBJECTIVE COMPLAINTS BUT
SHE DEFINED THIS IN THE ARIC
COHORT USING STANDARDIZED
CRITERIA.
WHITE MATTER HYPERINTENSITIESES
IN THE PARTICIPANTS WAS
ASSOCIATED WITH MCI AND MCR BUT
PARTICULARLY MCR.
WE KNOW HOW IMPORTANT IT IS FOR
GAIT, A PARTICULAR PART OF THE
DIAGNOSIS OF MCR.
YOU CAN SEE REALLY BOTH WHITE
MATTER HYPERINTENSITIES VOLUME
BEING MORE IMPORTANT FOR MCR
THAN MCI, IMPORTANT AS WE THINK
ABOUT THE CLINICAL SYNDROME THAT
GOES ALONG WITH WHITE MATTER
HYPERINTENSITIES MAY LOOK
SLIGHTLY DIFFERENT THAN OTHER
CLASSIC PATHWAYS WE'RE USED TO
SEEING BUT REALLY THERE'S
PROBABLY A LOT OF OVERLAP IN
DIFFERENT OUTCOMES IN THESE
PATIENTS.
SO WHAT ABOUT MECHANISMS?
TO TOUCH ON MECHANISM, I WANT TO
PROVIDE CAVEAT I'M AN
EPIDEMIOLOGIST, I'M NOT A BENCH
RESEARCHER AND THERE'S LOTS OF
PEOPLE DOING REALLY EXCITING
WORK IN THIS AREA.
I THINK THAT THIS IS REALLY
EXCITING TO UNDERSTAND WHY THESE
STROKES AND SMALL VESSEL DISEASE
SUBTYPES MAY GROUP TOGETHER,
THINKING ABOUT IMPACT ON
COGNITION AND STROKE RISK.
SO ONE POSSIBILITY IS THAT SMALL
VESSEL DISEASE AS I TOLD YOU IS
ASSOCIATED WITH HIGHER RISK OF
STROKE AND MAY JUST BE THESE
PATIENTS WITH SMALL VESSEL
DISEASE HAVE MORE STROKE, THE
STROKE IS CAUSING THE PROBLEMS
AND LEADS TO A MORE TYPICAL
VASCULAR DEMENTIA PICTURE, BUT
THE PROBLEM IS WE LOOK AT THESE
RELATIONSHIPS AND FIND THEY ARE
STILL THERE EVEN IN PEOPLE WHO
DON'T HAVE CLINICAL STROKE
EVENTS.
IN ADDITION, WE RARELY SEE
REALLY A PERIVASCULAR DEMENTIA.
SOME SITUATIONS WE SEE ONE PURE
NEUROPATHIC ENTITY BUT IN MOST
WE SEE MIXED PATHOLOGY.
IT'S NOT LIKELY TO FULLY EXPLAIN
THE RELATIONSHIPS HERE.
IT'S POSSIBLE, I MENTIONED BRAIN
ATROPHY WAS A DOWNSTREAM MARKER
OF SMALL VESSEL DISEASE.
IT'S POSSIBLE THAT SMALL VESSEL
DISEASE LEADS TO BRAIN ATROPHY,
THAT BRAIN ATROPHY CAN LEAD TO
DECREASE IN FUNCTION OVER TIME,
THAT MAY CONTRIBUTE, I'LL SHOW
YOU EVIDENCE FOR THAT, OR
PERHAPS CONTRIBUTES DIRECTLY
PERHAPS TO ALZHEIMER'S-TIME
CHANGES.
WE SEE MIXED PATHOLOGY, IS IT
POSSIBLE SMALL VESSEL DISEASE
MIGHT EVEN BE DIRECTLY
CONTRIBUTING TO ALZHEIMER'S
PATHOLOGY AND THAT'S WHY MIXED
PATHOLOGY IS COMMON?
IT MAY DUE THIS THROUGH
INCORRECT ROUTES LEADING TO
DECREASED BLOOD-BRAIN BARRIER
FUNCTION, NEUROINFLAMMATION.
I SHOWED COMMON RISK FACTORS, IS
IT A MARKER OF THE UNDERLYING
RISK FACTOR CONTRIBUTING TO
DEMENTIA, MAYBE ALZHEIMER'S
NEUROPATHOLOGY, OR AS OPPOSED TO
BEING A PRIMARY DRIVER OF SOME
CHANGES.
SO, I MENTIONED THE IMPORTANCE
OF THESE SHARED RISK FACTORS
BECAUSE WE THINK THEY MAY HAVE
DIRECT LINKS NOT ONLY TO STROKE
BUT ALSO TO DEMENTIA.
WE KNOW A LOT OF DIFFERENT
IMPORTANT RISK FACTORS ARE
ASSOCIATED WITH A LOT OF THESE
SMALL VESSEL DISEASE SUBTYPES.
HERE IS ACCUSE LACUNAR, WHITE
MATTER HYPERINTENSITIES, ALL
ASSOCIATED WITH IMAGING CHANGES.
WE KNOW PEOPLE WHO HAVE IMAGING
CHANGES ARE MORE LIKELY TO HAVE
ACUTE STROKE, THEY MAY HAVE
ATROPHY, AND THEY MAY HAVE
CHANGES RELATED TO
ALZHEIMER'S-SPECIFIC BIOMARKERS.
I WANT TO GIVE YOU EVIDENCE FOR
THESE DASHED LINES.
WE ALSO KNOW NOT ONLY DO ALL OF
THESE CHANGES CONTRIBUTE TO
DEMENTIA RISK, AMYLOID
CERTAINLY, ALTHOUGH NOT
NECESSARILY THE ONLY PATHWAY OR
LEADING HYPOTHESIS IT'S A MAJOR
PLAYER, I WASN'T GOING TO GET TO
THAT, I WANT TO MAKE SURE YOU
UNDERSTAND I'M NOT DISCUSSING
AMYLOID AS SYNONYMOUS WITH
ALZHEIMER'S DISEASE BUT AN
IMPORTANT PLAYER IN THE
DEVELOPMENT OF ALZHEIMER'S, THE
LEADING CAUSE OF DEMENTIA.
ATROPHY IS ASSOCIATED WITH
DEMENTIA, STROKE IS ASSOCIATED
WITH DEMENTIA.
MANY RISK FACTORS ARE ASSOCIATED
WITH DEMENTIA AS WELL.
I'LL TOUCH ON THAT BRIEFLY.
SO, HERE YOU SEE A LOT OF THESE
RISK FACTORS.
I WANT TO POINT OUT HERE
EMPHASIZING MID-LIFE RISK
FACTORS.
IN ARIC, I'M NOT GETTING INTO
THAT LITERATURE HERE, BUT WE'VE
SHOWN CONSISTENTLY THAT
RELATIONSHIPS ARE STRONGER AND
THIS IS SHOWN IN OTHER STUDIES
AS WELL, IF YOU LOOK AT THEM,
RISK FACTORS FOR MID-LIFE AS
OPPOSED TO LATER LIFE.
IT MAY BE IT TAKES DECADES FOR
HYPERTENSION TO HAVE AN IMPACT
ON COGNITION, FOR EXAMPLE, OY
THERE MATE BE A CRITICAL WINDOW
DURING WHICH YOU HAVE TO BE
EXPOSED TO HYPERTENSION OR A
COMBINATION.
LATE IN LIFE IT'S LESS
INDICATIVE, HYPERTENSION IN
MID-LIFE IS A STRONG RISK FACTOR
FOR FUTURE RISK OF DEMENTIA.
YOU CAN SEE FOR A LOT OF RISK
FACTORS, THERE'S BEEN GOOD
EVIDENCE SHOWING ASSOCIATIONS
WITH SMALL VESSEL DISEASE,
STROKE, DEMENTIA AS WELL.
BUT MORE QUESTIONABLE EVIDENCE
ABOUT RELATIONSHIPS WITH THESE
POTENTIAL MECHANISTIC LINKS.
SOME ASSOCIATED WITH ATROPHY,
SOME WITH AMYLOID.
THREE PLUSES MEANS GOOD STRONG
DATA, SOME IS CLINICAL TRIAL
DATA, AS WE GET TO THE NEGATIVE
IT MEANS THERE MIGHT BE EVEN
DATA SUGGESTING LACK OF
RELATIONSHIP BETWEEN THESE TWO
THINGS, WHEREVER THE NEGATIVE
HAPPENS TO BE, FOR INSTANCE
MID-LIFE PHYSICAL INACTIVITY IS
NOT ASSOCIATED WITH AMYLOID IN
THE ARIC STUDIES, IN BETWEEN ARE
DIFFERENT LEVELS OF EVIDENCE.
THERE'S OVERLAP BETWEEN THESE
AND AS WE THINK ABOUT POTENTIAL
MECHANISTIC LINKS WITH
UNANSWERED QUESTIONS.
ATROPHY IS ONE POTENTIAL LINK.
WE EVALUATED WHETHER PEOPLE WHO
WILL WHITE MATTER
HYPERINTENSITIESES AND INFARCT,
ASSOCIATED WITH SMALL VESSEL
DISEASE, RELATIONSHIP BETWEEN
THOSE CHANGES AND COGNITION,
WHETHER MEDIATED THROUGH VOLUME
LOSS, LOOKED AT BRAIN VOLUME AND
FOUND THAT PART OF THE
RELATIONSHIP WAS MEDIATED
THROUGH VOLUME LOSS, SO WE SAW
STRONG RELATIONSHIP ATTENUATED
WHEN INCLUDING BRAIN VOLUME BUT
NOT FULLY EXPLAINED BY VOLUME
LOSS TO LINK SMALL VESSEL
DISEASE AND COGNITION.
WHAT ABOUT ALZHEIMER'S DISEASE
NEUROPATHOLOGY?
SO IN THIS WORK LED BY WALKER,
NOW TENURE TRACK INVESTIGATOR AT
NIA, WE LOOKED AT AMYLOID PET.
I MENTIONED WE HAD A STUDY
LOOKING WITHIN A SUBSET FROM
THREE ARIC SITES.
YOU CAN SEE HERE HE FOUND THAT
PEOPLE WHO HAD MORE WHITE MATTER
HYPERINTENSITIES,
CROSS-SECTIONAL, HAD MORE BRAIN
AMYLOID INDEPENDENT OF
UNDERLYING VASCULAR RISK
FACTORS, WASN'T JUST A MARKER OF
HYPERTENSION, FOR EXAMPLE.
THE SUGGESTION THIS RELATIONSHIP
MIGHT BE STRONGER IN BLACK
PARTICIPANTS.
DEREK, A POSTBAC IN MY LAB NOW,
LOOKED WITH CEREBRAL MICROBLEEDS
IN THIS PAPER UNDER REVISION.
HE FOUND -- HE WAS TRYING TO
UNDERSTAND WHETHER DIFFERENT
PATTERNS OF MICROBLEEDS, SO I
SHOW WHERE THEY WERE
SUBCORTICAL, WHEN PEOPLE ARE
MORE CORTICAL MICRO BLEEDS THERE
ARE A MARKER, DEEPER BLEEDS ARE
A MARKER OF SMALL VESSEL
DISEASE.
WHAT HAPPENS WHEN YOU HAVE BOTH
BECAUSE WE SEE THAT FREQUENTLY
IN PEOPLE, IN THE
POPULATION-BASED STUDIES CAN WE
UNDERSTAND HOW THE PATTERN OF
MICROBLEEDS MIGHT BE RELATED TO
AMYLOID DEPOSITION?
HE FOUND THAT THE MIXED PATTERN
OF DEEP AND LOW BAR WAS NOT
ASSOCIATED WITH AMYLOID.
AND HAVING DEEP MICROBLEEDS
ALONE, SMALL VESSEL DISEASE
TYPE, IN THIS CASE NOT
ASSOCIATED WITH AMYLOID.
ELEVATED AMYLOID CONSISTENT WITH
ANGIOOPATHY, IT COULD BE
QUIESCENT BUT REPRESENTS A
DIFFERENT ENTITY HERE.
THIS DIDN'T SUPPORT LIKE THE
WHITE MATTER HYPERINTENSITIES
STUDY, SMALL VESSEL DISEASE
MARKER ASSOCIATED WITH AMYLOID
IN DEEP PATTERN, MORE CONSISTENT
WITH SMALL VESSEL DISEASE.
THERE'S SOME OTHER EVIDENCE THAT
AD-SPECIFIC BIOMARKERS HAVE BEEN
ASSOCIATED WITH SMALL VESSEL
DISEASE.
SO TREM-2 RELATED TO WHITE
MATTER HYPERINTENSITY, THIS IS
AN IMPORTANT EVIDENCE OF
MICROGLIAL ACTIVATION.
IN ADDITION WE HAVE INDICATION,
THIS IS REALLY AN EXCITING TIME
FOR THIS FIELD, WE HAVE REALLY
GOOD PLASMA BIOMARKERS OF
ALZHEIMER'S DISEASE CHANGES, AND
SO P-TAU 181 AND 17 WERE
ASSOCIATED WITH HIGHER WHITE
MATTER HYPERINTENSITIES BUT
DIDN'T FIND CONSISTENT
RELATIONSHIPS WITH TAU PET AND
WHITE MATTER HYPERINTENSITIES.
FURTHER INDICATION THAT THERE
MIGHT BE A LINK BETWEEN SMALL
VESSEL DISEASE AND AD-SPECIFIC
BIOMARKERS, REALLY IMPORTANT
CONSIDERATION AS YOU THINK ABOUT
THESE AND THINK ABOUT THE ROLE
SMALL VESSEL DISEASE MAY PLAY IN
A.D. PATHOGENESIS THINKING ABOUT
UNDERLYING RISK FACTORS AND
WHETHER CONFOUNDERS ARE
ADDRESSED.
ANOTHER IMPORTANT QUESTION, HOW
IT CONTRIBUTES TO DEMENTIA, WE
DID HERE IN THE COHORT LOOKED AT
RELATIVE CONTRIBUTIONS EVER
WHITE MATTER HYPERINTENSITIES
AND AMYLOID ON DEMENTIA RISK.
SO IN THE SUBSTUDY THESE ARE
PEOPLE JUST WITHOUT DEMENTIA WE
FOUND THAT WHITE MATTER
HYPERINTENSITIES AND AMYLOID
MEASURED THE UPTAKE VALUE RATIO
WERE BOTH INDEPENDENTLY
ASSOCIATED WITH RISK OF
DEMENTIA.
THEY DID NOT INTERACT WITH EACH
OTHER MEANING IF YOU HAD HIGH
AMYLOID AND WHITE MATTER
HYPERINTENSITIES THERE WAS NO
INCREASED RISK OF DEMENTIA
INDIAN
INDEPENDENT OF RISK FACTORS.
HOWEVER, THE RELATIONSHIP WITH
WHITE MATTER HYPERINTENSITIESES
WENT AWAY, THINKING ABOUT HOW
SMALL VESSEL DISEASE MIGHT BE
ASSOCIATED WITH
ALZHEIMER'S-SPECIFIC MARKERS, WE
NEED TO THINK ABOUT UNDERLYING
POTENTIAL CONFOUNDERS, MOST
STUDIES DON'T HAVE ABILITY TO
LOOK OVER DECADES TO UNDERSTAND
WHAT UNDERLYING VASCULAR RISK
MIGHT HAVE CONTRIBUTED BUT IT'S
IMPORTANT IN UNDERSTANDING
WHETHER WHITE MATTER
HYPERINTENSITIES NO MATTER WHAT
ROLE THEY PLAY IF CAUSAL OR JUST
ASSOCIATIVE THAT THEY MAY BE A
MARKER OF OTHER UNDERLYING RISK.
AGAIN, DIDN'T HAVE EVIDENCE OF
INTERACTION BETWEEN THE RISK
FACTORS AND AMYLOID ON THE RISK
OF DEMENTIA.
YOU CAN SEE THE NUMBERS ARE NOT
SO BIG, THIS LAST LINE HERE,
SMALLEST -- LOWEST LINE WHICH
MEANS THE LEAST DEMENTIA-FREE
SURVIVAL OR MOST DEMENTIA IS
INDIVIDUALS WHO HAD HIGH BLOOD
PRESSURE AND HAD HIGH AMYLOID
LEVEL, AGAIN SUGGESTING THAT
PERHAPS THERE MAY BE SOME
SYNERGISTIC EFFECT WE'RE NOT
ABLE TO CAPTURE WITH INADEQUATE
POWER.
THERE'S SOME EVIDENCE IN THE
WORK BY LOOKING AT SYNERGISTIC
INFLUENCE OF VASCULAR RISK AND
AMYLOID-BETA ON COGNITIVE
DECLINE, SUGGESTING PARTLY
RELATED THROUGH TAU, IF YOU HAVE
HIGH AMYLOID YOU'RE GOING TO
LOOK DIFFERENT IN TERMS OF TAU
LEVELS, FOR EXAMPLE, THAN
SOMEONE WHO DOESN'T HAVE THOSE
HIGH AMYLOID-BETA LEVELS AS
WELL.
SO AGAIN THE JURY IS VERY MUCH
OUT.
WE THINK THAT THERE ARE
IMPORTANT INTERRELATIONSHIPS
BETWEEN THESE.
THE DIFFICULTY IS MEASURES THESE
DIFFERENT A.D.-SPECIFIC
BIOMARKERS, MEASURING FORMS OF
SMALL VESSEL DISEASE,
UNDERSTANDING ABOUT THE
UNDERLYING LONG-TERM VASCULAR
RISK THAT COULD BE CONFOUNDING
SOME RELATIONSHIPS.
WHAT ABOUT SMALL VESSEL DISEASE
BEYOND THE BRAIN?
SO, CERTAINLY I SUSPECT THAT
MANY PEOPLE WHO ATTEND THIS TALK
AND WHO WORK IN THE CLINICAL
CENTER ARE STUDYING SOME FORM OF
SMALL VESSEL DISEASE ELSEWHERE
IN THE BODY.
I'M NOT TOUCHING ON MOST OF
THOSE OTHER FORMS OF SMALL
VESSEL DISEASE BUT I WANT TO
TALK ABOUT THE RETINA BECAUSE
IT'S THE MOST RELEVANT AND
HIGHLY LINKED WITH THESE
CEREBRAL FORMS OF SMALL VESSEL
DISEASE.
MICROVASCULAR CHANGES IN THE
RETINA OCCUR AFTER VASCULAR RISK
FACTOR EVALUATION, AND SOMETIME
BEFORE COGNITIVE DECLINE.
IT'S POSSIBLE THIS COULD MEDIATE
SOME OF THOSE OBSERVED
ASSOCIATIONS THAT WE COULD
UNDERSTAND MORE ABOUT HOW
VASCULAR RISK AFFECTS DEMENTIA
BUT THINKING ABOUT HOW THE
RETINA IS AFFECTED AS WELL.
IT COULD BE A MARKER FOR DISEASE
PRESENCE OR DISEASE PROGRESSION,
CERTAINLY EASY ISSUE -- EASIER
TO LOOK IN THE EYE THAN GET AN
MRI AND CHEAPER.
POTENTIALLY A USEFUL SURROGATE
FOR CLINICAL TRIALS OR MAYBE
EVEN HAVE A ROLE IN ENROLLMENT
OF CLINICAL TRIALS.
SO, WE KNOW IT CO-OCCURS WITH
MICROVASCULAR DISEASE MARKERS IN
THE BRAIN.
WE KNOW THERE'S COMMON GENETIC
RISK FACTORS, IN GENERAL AS WELL
AS RELATIONSHIP WITH COGNITION
AND RELATED OUTCOMES.
WE HAVE RETINAL IMAGING FROM
EARLIER VISITS AND MORE RECENT
VISITS, JUST TO SHOW IN THIS
EARLIER WORK MORE RETINAL
MICROVASCULAR DISEASE VISIT 3
ASSOCIATED CROSS-SECTIONALLY
WITH MORE WHITE MATTER
HYPERINTENSITIES, TOM HANFF
WORKED WITH ME, NOW AT PENN AT A
CARDIOLOGIST, WAS STUDYING
IMPORTANCE OF PROGRESSION OF
RETINAL MICROVASCULAR DISEASE,
I'M SORRY, PROGRESSION OF SMALL
VESSEL DISEASE PREDICTED BY
RETINAL DISEASE, IF YOU HAD MORE
RETINAL DISEASE IT PROGRESSED
MORE.
I'VE TOLD YOU PROGRESSION OF
CHANGES IS AN IMPORTANT RISK
FACTOR FOR WORSE OUTCOME
INCLUDING RECURRENT STROKE.
IN ADDITION WE KNOW IT'S
ASSOCIATED WITH COGNITION SO
PEOPLE WHO ARE ABNORMAL RETINAL
MICROVASCULATURE SIMILAR TO
OTHER CHANGES IN THE BRAIN HAVE
MORE COGNITIVE DECLINE.
PEOPLE WITH RETINOPATHY HAD MORE
DECLINE OVER TEN YEARS IN
COGNITION THAN PEOPLE WITHOUT,
WE SEE LESSER EFFECT SIZES FOR
OTHER MARKERS.
A LOT OF THESE ARE NOT PREVALENT
IN THIS POPULATION RECRUITED AS
A COMMUNITY-BASED COHORT BUT WE
DO SEE THIS CLEAR RELATIONSHIP.
JENNIFER DEAL AT HOPKINS LOOKED
AT LONGER FOLLOW-UP, TWO
DECADES, PEOPLE WHO HAD MORE
RETINOPATHY, MODERATE/SEVERE
VERSUS NONE IN ADJUSTED MODELS
HAD MORE COGNITIVE DECLINE OVER
TWO DECADES.
FURTHER EVIDENCE THIS MIGHT BE
AN IMPORTANT MARKER OF OUTCOME
AND IMPORTANT MARKER OF
CONCURRENT SMALL VESSEL DISEASE
AND MIGHT BE USEFUL TO THINK IF
WE'RE TRYING TO STUDY MECHANISMS
IN SMALL VESSEL DISEASE, ROLE ON
COGNITION.
A POSTDOCTORAL FELLOW WITH ME
HERE AT NINDS IS LOOKING AT THIS
AND HAS A PAPER UNDER REVIEW
LOOKING AT AMYLOID PET AND
RELATIONSHIP WITH RETINAL
DISEASE.
IF WE KNOW IT'S ASSOCIATED WITH
COGNITION WHAT MIGHT THE
MECHANISM BE?
HE EVALUATED PEOPLE WITHOUT
DEMENTIA FROM THREE ARIC SITES,
LOOKING AT RELATIONSHIPS BETWEEN
EARLIER, SO CLOSER TO MID-LIFE
RETINAL DISEASE AS WELL AS LATER
LIFE RETINAL DISEASE, AND LOOKED
AT POSITIVE AMYLOID SCANS, YES
OR NO.
HERE TO SHOW THERE'S NOT THAT
MANY PEOPLE WITH RETINOPATHY,
THAT MADE IT INTO THE MUCH LATER
STUDY OF NON-DEMENTED
INDIVIDUALS, SO CERTAINLY THE
PEOPLE THAT HAD MORE RHETT
INOPATHY HAD MORE DIABETES,
SMALL NUMBERS.
20+ YEARS LATER DIABETES IN THIS
VISIT 3, LATE MID-LIFE, MUCH
LESS PREVALENT NOW 10 OF THE 11
PEOPLE WITH RETINOPATHY AT VISIT
5, WHEN WE DID THE PET SCAN, HAD
RETINOPATHY, HAD DIABETES WITH
HIGH RATES OF HYPERTENSION AS
WELL.
BASICALLY HE FOUND RELATIONSHIPS
WERE NULL, SO PEOPLE WHO HAD
RETINAL SIGNS, MID-LIFE AND LATE
LIFE, VERY SMALL NUMBERS, HAD
ASSOCIATIONS WITH ELEVATED BRAIN
AMYLOID, I'M SORRY, PEOPLE WHO
HAD -- WE DID NOT FIND EVIDENCE
OF RETINAL DISEASE IN MID-LIFE
OR LATE LIFE BEING ASSOCIATED
WITH BRAIN AMYLOID BUT IT MAY
LOOK PROTECTIVE, MEANING IF HAD
YOU RETINOPATHY LESS LIKELY TO
HAVE BRAIN AMYLOID.
THEY WERE A ROBUST GROUP.
NO EVIDENCE HERE THAT RETINAL
SIGNS WERE ASSOCIATED WITH
AMYLOID, EITHER
CROSS-SECTIONALLY OR LOOKING
CROSS-TEMPORALLY OVER TIME.
I WANT TO TOUCH A GAPS AND TALK
ABOUT TREATMENT AND PREVENTION
BECAUSE THIS IS REALLY AN
IMPORTANT AND EXCITING PART OF
THIS.
CERTAINLY IN THE FIELD WE NEED
CLEAR DEFINITIONS, DIAGNOSTIC
CRITERIA, WHEN WE THINK ABOUT
HYPERTENSIVE SMALL VESSEL
DISEASE IT'S HARD TO DEFINE FOR
RESEARCH OR CLINICAL CARE.
THERE'S MORE TO BE DONE,
MECHANISMS OF SMALL VESSEL
DISEASE, COGNITION, DEMENTIA.
REALLY WHAT DOES THIS MEAN FOR
OPPORTUNITIES FOR TREATMENT AND
PREVENTION?
I'LL COME BACK TO THAT IN A
SECOND.
AND ARE THERE OPPORTUNITIES TO
USE SOME OF THESE SURROGATE END
POINTS IN CLINICAL TRIALS FOR
ENROLLMENT OR OUTCOME?
AND THIS IS A REALLY TRICKY AREA
WHEN YOU'RE DESIGNING A TRIAL
BASED ON STROKE, EVERYONE KNOW
WHAT IS A STROKE IS.
YOU CAN SAY HOW TO ENROLL
SOMEONE WITH A STROKE, BUT
SURROGATE ENDPOINT HAS LESS
MEANING FOR THE PUBLIC, ALSO WE
NEED TO MAKE SURE WE HAVE
HOMOGENOUS METHODS FOR DEFINING
SOME OF THESE THINGS.
TREATMENT AND PREVENTION, THE
LONG AND SHORT, WE DON'T KNOW
WHAT TO DO WHEN WE SEE THESE
PATIENTS.
PEOPLE WITH SMALL VESSEL DISEASE
ARE FOUND ALL THE TIME
INCIDENTALLY.
WE DID A SURVEY OF NEUROLOGISTS,
GOT 136 RESPONDENTS, HERE IS A
PATIENT A LOT OF WHITE MATTER
HYPERINTENSITIES HERE.
SHE HAD SOME SYMPTOMS, NO
CLINICAL STROKE THOUGH.
HOW WOULD YOU TREAT HER?
THERE WAS SO MUCH VARIETY IN
WHAT PEOPLE SAID.
SOME PEOPLE SAID THIS IS PRIMARY
PREVENTION, THEY HAVEN'T HAD AN
EVENT, HAVEN'T HAD A STROKE,
THEREFORE WE NEED TO THINK AS
PRIMARY PREVENTION.
A QUARTER SAID WE SEE THIS MUCH
WHITE MATTER HYPERINTENSITY,
COMPARABLE TO HAVING HAD A
STROKE SO THINK OF SECONDARY
PREVENTION, IMPORTANT BECAUSE
DIFFERENT TREATMENT AND
DIFFERENT THERAPIES ARE
DIFFERENT EVIDENCE FOR PRIMARY
VERSUS SECONDARY PREVENTION.
HALF SAID THEY MIGHT USE
ASPIRIN.
A THIRD HAD NO IDEA.
22% SAID WON'T USE ASPIRIN, AND
STATIN.
JUST YESTERDAY THIS WAS
PUBLISHED ONLINE, PRO/CON
CONTROVERSY IN STROKE ARTICLE,
LOOKING AT ANTIPLATELET THERAPY
OR NOT FOR ASYMPTOMATIC LACUNAR,
SHOULD WE PUT THOSE PEOPLE ON
ASPIRIN, FOR EXAMPLE?
PROMINENT PEOPLE SAID YES, AND
NO, AND WE DON'T HAVE A
CONSISTENT MESSAGE OR CONSISTENT
RECOMMENDATION.
AS WE THINK ABOUT PRIMARY AND
SECONDARY PREVENTION, THERE ARE
DIFFERENT QUESTIONS, IF YOU'RE
TRYING TO PREVENT A STROKE, WE
KNOW THAT'S PRIMARY PREVENTION.
IF HAVE YOU SMALL VESSEL DISEASE
AND YOU'RE TRYING TO PREVENT
PROGRESSION OF SMALL VESSEL
DISEASE OR THE STROKE OR TRYING
TO PREVENT COGNITIVE DECLINE
IT'S UNCERTAIN, PART OF WHAT
MAKES IT CONFUSING ABOUT
TREATMENT.
YOU CAN SEE HERE, AGAIN, NOT
VERY CLEAR DATA ABOUT WHAT TO DO
DEPENDING WHAT YOU'RE TRYING TO
PREVENT.
REALITY IS YOU'RE TRYING TO
PREVENT MULTIPLE THINGS.
BUT WE REALLY HAVE SOME
INCONSISTENT EVIDENCE WHICH
MAKES THIS MURKY AND CONFUSE C.
WE NEED BETTER STUDIES.
SMALL VESSEL DISEASE IS VERY
COMMON, PARTICULARLY CERTAIN
FORMS LIKE WHITE MATTER
HYPERINTENSITIES, AND EVEN
THOUGH IT'S CLASSICALLY REFERRED
TO AS SILENT OR COVERT OR
ASYMPTOMATIC, OR INCIDENTAL, IT
CLEARLY HAS CONSEQUENCES AND ITS
PRESENCE AND PROGRESSION CAN
HAVE GREAT IMPACTS ON PEOPLE.
WHEN WE THINK ABOUT THESE
SUBTYPE, IT'S USEFUL TO THINK
ABOUT LUMPING THEM BECAUSE OF
SHARED OUTCOMES, MAKING
RECOMMENDATIONS FOR TREATMENT,
PROGNOSIS AND THINKING ABOUT
CAUSE.
THERE ARE MULTIPLE POTENTIAL
MECHANISMS, SOME I'VE DISCUSSED
AS TO HOW SMALL VESSEL DISEASE
AND STROKE COULD ACT ON DEMENTIA
INCLUDING ATROPHY, AMYLOID
DEPOSITION, WE DON'T SEE CLEAR
EVIDENCE OF MULTI-PLICATIVE
INDICATIONS IN OUR WORK.
THERE'S SO MUCH UNCERTAINTY.
WE SEE THESE INCIDENTAL FINDINGS
ALL THE TIME, AND WHEN PRESENTED
CLINICALLY IT'S UNCLEAR.
IF YOU ARE LOOKING FOR EXCUSE TO
START MEDICATION WE CAN USE
SMALL VESSEL DISEASE BUT WE
DON'T KNOW BEST GUIDANCE.
FUTURE DIRECTION, I'LL CONTINUE
TO UNDERSTAND MORE ABOUT SMALL
VESSEL DISEASE, BETTER
UNDERSTAND HOW TO PHENOTYPE AND
UNDERSTAND MORE ABOUT WHO
PROGRESSES AND WHY, AND
ULTIMATELY HOW WE CAN MAYBE
PREVENT THAT PROGRESSION.
ALSO UNDERSTANDING HOW SMALL
VESSEL DISEASE AFFECTS EARLY
STROKE RECOVERY AND OUTCOME.
IN ADDITION WE THINK OF THE
CONCEPT OF COGNITIVE RESERVE,
THIS IDEA THERE ARE FACTORS THAT
MAKE YOU MORE RESISTANT TO
PATHOLOGIC CHANGES IN YOUR
BRAIN.
WE THINK OF THIS IN ALZHEIMER'S
DISEASE, WHERE WE KNOW PEOPLE
CAN HAVE A LOT OF PATHOLOGY ON
AUTOPSY, BUT COGNITIVELY NORMAL.
COGNITIVE RESEARCH, WHETHER
EDUCATION OR OTHER FACTORS,
PROTECTED YOU FROM THAT
PATHOLOGY, FROM HAVING THE
COGNITION YOU MIGHT BE EXPECTED
TO HAVE.
I THINK IT'S IMPORTANT TO THINK
OF THIS FOR SMALL VESSEL
DISEASE, HOW DOES IT AFFECT YOUR
COGNITIVE PERFORMANCE, IT MAY
DIFFER BECAUSE OF RESERVE
FACTORS, WE ARE EVALUATING,
UNDERSTANDING HOW IT PLAYS A
ROLE IN A.D. PATHOLOGY, TARGETS
FOR PREVENTION, TREATMENT,
BECAUSE THIS IS LIKELY TO HAVE
LARGE IMPACTS ON A POPULATION
SCALE.
BRIEFLY, MY LAST SUBSTANTIVE
SLIDE, THE DISCOVERY COHORT IS
REALLY GOING TO FOCUS ON -- IT'S
A STUDY OF INDIVIDUALS WITH
STROKE BEING RECRUITED FROM 30
SITES ACROSS THE COUNTRY AND
UNDERSTAND THE RELATIONSHIP
BETWEEN STROKE AND POST-STROKE
OUTCOMES IN A DISPARITIES
POPULATION OR DISPARITIES
POPULATIONS BUT FOCUSING ALSO ON
HOW SMALL VESSEL DISEASE AFFECTS
YOUR ABILITY TO RECOVER FROM A
COGNITIVE STANDPOINT AFTER
STROKE.
DISCOVERY IS LED BY CO-P.I.s
AT MASS GENERAL, A LARGE STUDY
FROM 30 SITES, TO STUDY
POST-STROKE COGNITION AND FOCUS
ON DIVERSE POPULATIONS TO
UNDERSTAND DISPARITIES IN THIS
AREA.
THAT'S ONGOING, CLOSE TO 2,000
PEOPLE IN RECRUITMENT, STILL
EARLY DAYS.
FINALLY I'D LIKE TO ACKNOWLEDGE
MANY TREMENDOUS COLLABORATORS,
ALL OF THIS WORK IS VERY MUCH A
TEAM SPORT.
AND SO HERE IS MANY OF THE
PEOPLE INVOLVED IN A LOT OF WORK
I DESCRIBED, PRIOR FUNDING
SOURCES AS WELL AS FUNDING FOR
ARIC IN PARTICULAR, AND HERE WE
ARE MEETING IN ZOOM TIMES AS
WELL AS A COUPLE WEEKS AGO ON
THE SOUTH LAWN OF BUILDING 10,
AND THIS IS THE STROKE BRANCH,
AND THIS IS THE GROUP OF ARIC
INVESTIGATORS YEARS ALLEY.
WITH THAT I'LL STOP AND TAKE
QUESTIONS.
THANK YOU VERY MUCH.
>>THANK YOU FOR SHARING YOUR
WORK AND YOUR DEEP INSIGHTS INTO
THE PRESENCE OF THESE SO-CALLED
SILENT LESIONS OF SMALL VESSEL
DISEASE, ESPECIALLY MARKERS OF
DECLINE IN COGNITION AND
DEMENTIA.
WE DO HAVE A COUPLE QUESTIONS.
FIRST OF ALL, WHY DOES HIGH
CHOLESTEROL PROTECT AGAINST
DEMENTIA?
>>SO, THE CHOLESTEROL ISSUE IS
VERY TRICKY.
WE HAVE EVIDENCE THAT HIGH
CHOLESTEROL IS ASSOCIATED WITH
DEMENTIA RISK, IT'S NOT NEARLY
AS STRONG OF A RISK FACTOR AS IS
HYPERTENSION, FOR EXAMPLE, IN
GENERAL CHOLESTEROL APPEARS TO
BE MORE IMPORTANT FOR THE HEART
AND BLOOD PRESSURE APPEARS TO BE
MORE IMPORTANT FOR THE BRAIN.
THERE IS SOME EVIDENCE GOING
BOTH WAYS THAT STATINS, FOR
EXAMPLE, ARE ASSOCIATED WITH
LOWER DEMENTIA RATES.
BUT ALSO SOME EVIDENCE THAT IT
CAUSES SOME COGNITIVE PROBLEMS
AS WELL.
I THINK IN GENERAL OBVIOUSLY IF
YOU THINK ABOUT MEDICATION USE,
YOU HAVE TO WORRY ABOUT THE
HEALTHY USER EFFECT PEOPLE WHO
TAKE MEDICATIONS ARE DIFFERENT
IN OBSERVATIONAL STUDIES THAN
THOSE WHO DON'T.
IT'S HARD TO KNOW WHAT TO THINK
OF THE STATIN EVIDENCE.
WE SEE HIGHER LEVELS OF MID-LIFE
CHOLESTEROL ARE ASSOCIATED WITH
GREATER RISK OF COGNITIVE
DECLINE BUT IT'S VERY SMALL
AMOUNT OF DECLINE.
IT'S NOT A VERY LARGE EFFECT.
AND, AGAIN, CHOLESTEROL APPEARS
TO BE LESS IMPORTANT IN GENERAL
THAN RISK FACTORS LIKE HIGH
BLOOD PRESSURE.
s.
>>THANK YOU VERY MUCH.
ANOTHER QUESTION HERE.
IT SAYS, THANK YOU FOR SHARING
THE EFFECT OF THE LACK OF
EQUIPOISE IN MANAGEMENT OF THESE
FINDINGS OF SMALL VESSEL
DISEASE, BUT DO YOU YOURSELF
HAVE ANY RECOMMENDATIONS ON HOW
THESE PATIENTS COULD OR SHOULD
BE MANAGED?
>>YEAH, SO I CERTAINLY THINK
ABOUT BLOOD PRESSURE AS THE
FIRST THING WHEN I SEE SOMEONE
WITH A SCAN, WITH SMALL VESSEL
DECEMBER.
WE KNOW BLOOD PRESSURE CONTROL
IS GOING TO BE IMPORTANT FOR
MULTIPLE REASONS.
I PERSONALLY DON'T TREAT PEOPLE
WITH ASPIRIN AT THIS POINT IN
TIME OR ANOTHER ANTIPLATELET
BASED ON HAVING THAT KIND OF
SCAN.
WE KNOW FROM RECENT STUDIES
PRIMARY PREVENTION ASPIRIN
DOESN'T HAVE A CLEAR ROLE.
I THINK ABOUT RISK FACTORS THIS
MIGHT BE ALERTING ME TO.
WHEN I SEE THAT SCAN I LOOK HARD
FOR HIGH BLOOD PRESSURE.
IF IT'S NOT THERE, THAT'S RARE
AND MAKES ME WONDER WHAT ELSE IS
GOING ON IN THIS PERSON BECAUSE
THAT'S USUALLY SUCH A BIG PART
OF THE AMOUNT OF CHANGE WE SEE
IN WHITE MATTER
HYPERINTENSITIES, A LOT IS
DRIVEN BY HIGH BLOOD PRESSURE.
I USE THIS AS INDICATOR I SHOULD
DO SOMETHING ABOUT RISK FACTORS
AND WOULD RECOMMEND TREATMENT OF
THOSE RISK FACTORS BUT
PERSONALLY I DON'T TREAT WITH
ASPIRIN OR ANTIPLATELETS BECAUSE
I DON'T THINK AWAY EVIDENCE,
NEED FOR EQUIPOISE AND MORE
CLINICAL TRIALS.
>>ANOTHER QUESTION, ARE THERE
RISK FACTORS OR BIOMARKERS THAT
COULD BE IDENTIFIED IN YOUNGER
ADULTS THAT MAY PRECEDE OR EVEN
BE PREDICTIVE MUCH SMALL VESSEL
DISEASE FOUND IN OLDER COHORTS
AND POPULATION?
>>YES, THIS IS AN IMPORTANT
AREA THAT WE NEED TO DO MORE
RESEARCH, I DON'T THINK MID-LIFE
IS IMAGINE -- MAGICAL.
THERE'S COHORTS LIKE CARDIA,
WHICH STARTS ELLER, -- EARLIERI
WOULD LOVE TO LINK PEDIATRIC
WITH OLDER, MY SUSPICION IS
HIGHER RATES OF DIABETES,
HYPERTENSION IN ADOLESCENTS WILL
BE A BIG PROBLEM DECADES DOWN
THE ROAD IN TERMS OF SMALL
VESSEL DISEASE AND DEMENTIA.
SO, I WOULD SAY PROBABLY THE
MOST IMPORTANT THING IS
SCREENING BLOOD PRESSURE, AND
THAT'S GOING TO BE IMPORTANT FOR
SMALL VESSEL DISEASE AS WELL AS
FOR -- IT'S ASSOCIATED WITH RISK
OF DEMENTIA AS WELL AND THINGS
LIKE NOT SMOKING, OTHER VASCULAR
HEALTH, BUT IF IN TERMS OF
BIOMARKERS BLOOD PRESSURE
SCREENING AND MANAGEMENT IS
WOULDN'T MOST IMPORTANT EARLY
MARKERS.
>>THAT TAKES US UP TO THE
HOUR.
DR. GOTTESMAN, THANK YOU VERY
MUCH FOR SHARING YOUR WORK AND
YOUR BRILLIANT PRESENTATION.
WE MUCH APPRECIATE IT.
AND TO THE NIH COMMUNITY, THANK
YOU FOR JOINING THIS AFTERNOON
AND HAVE A GOOD DAY.
THANK YOU VERY MUCH.
>>THANKS SO MUCH.