>> ALL RIGHT, WE'RE READY TO
START THIS MORNING.
I JUST WANTED TO SAY A FEW
THINGS BEFORE WE GET
STARTED.
AGAIN, FOR THOSE OF YOU WHO
MAY NOT HAVE BEEN HERE
YESTERDAY, MOLLY WAGSTER ON
THE NATIONAL INSTITUTE OF
AGING AND THERE IS A KEY
CARD UP HERE ON THE PODIUM
SO IF IT BELONGS TO ANY OF
YOU, YOU CAN CLAIM IT LATER.
WE HAVE TWO MORE SESSIONS
TODAY, BOTH EXTREMELY
EXCITING AND AS EXCITING AS
THE ONES WE HAD YESTERDAY
AND SO PLEASED TO SEE ALL OF
YOU BACK.
WE WILL -- THIS SESSION WILL
GO UNTIL ABOUT 10:20 A.M.
AND THEN WE HAVE A FAIRLY
BRIEF BREAK SPECIAL THEN
START WITH THE FINAL SESSION
OF THE SUMMIT.
WE SHOULD BE WINDING UP
AROUND A LITTLE AFTER
1:00 SO I JUST WANTED TO
GIVE Y'ALL THOSE NOTES AND
SORT OF REMINDERS OF HOW THE
DAY IS GOING TO GO TODAY.
AGAIN, WE REALLY APPRECIATE
EVERYONE BEING HERE AGAIN
AND LOOKING FORWARD TO
EXCITING PRESENTATIONS FOR
THE REST OF THE SUMMIT.
THANK YOU.
>> GOOD MORNING, EVERYONE,
WE WELCOME YOU TO SESSION 5,
COMORBIDITIES AND SLEEP
ENVIRONMENT.
WE HAVE SOME TERRIFIC LINEUP
OF SPEAKERS THIS MORNING.
I AM JENNIFER BIZON FROM THE
UNIVERSITY OF FLORIDA, I
SHOULD SAY AND OUR SESSION
THIS MORNING IS GOING TO
START WITH GINA POE TELLING
US ABOUT SLEEP FEATURES AND
HOW AGING INFLUENCES THEM
AND THEN WE'RE GOING TO MOVE
TO KRISTEN OH CONNELL WHO
WILL TALK ABOUT HOW GENETIC
ENVIRONMENT WITH SECTION IS
IMPORTANT IN HER RESEARCH
AND THEN CHRISTINE YAFFE
WILL TALK ABOUT THE
IMPORTANCE OF LIFE COURSE
APPROACH TO AGING AND
MICHELLE MIEIKE WILL TALK
ABOUT THE INFLUENCE OF
ALZHEIMER'S DISEASE ON
BIOMARKERS.
SO I WILL NOT TAKE ANYMORE
TIME AND INTRODUCE THE
SPEAKERS AND START WITH GINA
POE FROM UNIVERSITY OF
CALIFORNIA-LOS ANGELES AND
THE TITLE OF HER TALK IS
SLEEP FEATURES IMPACTED BY
THE AGING ENVIRONMENT.
>> THANK YOU SO MUCH,
JENNIFER, I AM COMING OFF A
RED EYE FLIGHT SO I AM THE
EPITOME OF NOT SLEEPING AND
AGING SO YOU WILL SEE WHAT
THAT DOES.
[LAUGHTER]
ALL RIGHT, SO THIS IS MY
GRANDSON.
HE IS SIX MONTHS OLD AND YOU
CAN SEE AT THIS AGE ON THE
SLIDE THAT THEY ARE SLEEPING
A LOT AND THAT A LOT OF THAT
SLEEP IS RAPID EYE MOVEMENT
SLEEP.
BUT AS WE GET OLDER AND
OLDER, WE GET LESS AND LESS
REM SLEEP AND ALSO AS YOU
CAN SEE WHEN WE GET VERY
MUCH OLDER, WE GET A LOT
LESS SLOWER SLEEP AND WE'LL
TALK WITH THAT.
SO YOU CAN SEE HERE, THE BIG
BLUE IS SLOW E SLEEP AND I
DREW THE EEG ON TOP OF THIS
SO YOU CAN SEE WHAT THIS
LOOKS LIKE.
IS A WE GO FROM WAKEFULNESS
INTO SLEEP AND THEN DEEP
SLOW A STREET AND THAT IS
THE STAGE THAT GETS IMPACTED
AS WE GET OLDER AND I WILL
TELL YOU WHAT THAT WILL DO
TO US AND THEN THE SPINDLES
OF ANY ONE PERSON IS LINKED
TO IQ AND WHERE WE'RE
TRANSFERRING FROM THE HIPPO
CAMPUS TO THE CORTEX AND
THEN THERE IS THE SLOW REM
SLEEP WHICH IS WHAT BABIES
HAVE IN EYE AMOUNTS.
THE HIPPO CAMPUS, IT IS
REALLY BEAUTIFUL AND RELATED
TO WAKEFULNESS AND THEN WE
HAVE THE SLOW A SLEEP THAT
RELATES TO MEMORY.
AND EACH OF THREES HAVE A
DIFFERENT NEUROCHEMICAL
RESPONSE.
DURING THE EARLY STAGES, YOU
HAVE LOTS OF ACETYLCHOLINE
IN YOUR BRAIN, THE REM, NOR
HE HAVE FLYNN AND THEN
SEROTONIN IN THE SLOW A
SLEEP AND YOU REALLY NEED
ACETYLCHOLINE TO GO TO ZERO
IN THE BRAIN TO SET UP THE
SLOW WAVES AND ANIMALS THAT
DON'T SLEEP, THE ONE THING
THAT CHANGES IS THE
ACETYLCHOLINE WHERE IT
CASHES INTO NOTHING.
SO ALL THE TRANSMITTERS I
HAVE HERE ARE DOWN TO ALMOST
NOTHING, AND THIS IS THAT
UNIQUE TIME WHEN THE BRAIN
IS REALLY SHUT OFF TO THE
OUTSIDE WORLD AND
TRANSFERRING MEMORIES FROM
THE HIPPOCAMPUS TO THE
CORTEX AND THEN THERE IS THE
AND THIS IS REALLY IMPORTANT
TO REFRESH OUR BRAINS FOR
THE NEXT DAY.
SO THIS IS NOT MY RESEARCH
BUT THE RESEARCH OF DOZENS
OF RESEARCHERS SO WHAT SLOW
WAVE SLEEP WE KNOW NOW IS
BUILD CONNECTIONS IN TEN
TIMES THE AMOUNT IT DOES IN
WAKEFULNESS.
WE CLEAR THE GARBAGE THROUGH
THE GLMPHATIC SYSTEM AND THE
PROTEINS IN THE EXTRA
CELLULAR SPACE GETS CLEARED
AND THEN WE CONVERT THE
ADENOCINE THAT HAS BUILT UP
WITH THE BREAKDOWN OF ATP,
THE MITOCHONDRIA GET REALLY
BUSY DURING THIS STAGE AND
BREAK DOWN THE ATP MORE THAN
IT DOES IN WAKEFULNESS AND
IT REDUCES ANXIETY.
WE HAVE NO IDEA WHAT THIS IS
YET BUT WE KNOW THAT IS A
REALLY IMPORTANT FUNCTION.
HERE IS A STUDY BY MICHELLE
CRAFT'S LAB, SORRY, I DON'T
HAVE THE REFERENCE ON IT BUT
YOU CAN SEE THE ASSOCIATION
BETWEEN SLOW WAVE SLEEP AND
ANXIETY IS HUGE AND BIGGER
THAN ANYTHING ELSE.
IF ALL YOU CAN DO IS LIGHT
SLEEP AND DOZING, YOU HAVE
MORE ANXIETY BUT IF YOU GET
REALLY BIG JUICY SLOW WAVE
SLEEP, YOUR ANXIETY LEVELS
ARE LOWER THE NEXT DAY.
SO HERE IS THE BOLUS OF OUR
SLEEP, IF WE GO TO BED WHEN
THE MELATONIN LEVELS ARE
ALIGNED IN SLEEP, MEN AND
WOMEN GET A BIG BOLUS OF
GROWTH HORMONE ASSOCIATED
WITH PROTEIN SYNTHESIS ALL
OVER THE BODY BUT ESPECIALLY
THE BRAIN.
HERE IS THIS OLD SLIDE FROM
1990 SHOWING IN SLOW A
STREET AT THE VERY BOTTOM
THERE, THE IMAGE AT THE
BOTTOM IS A CROSS-SECTION OF
A RAT'S BRAIN AND YOU CAN
SEE THAT IS THE TIME WHEN
AMINO ACIDS ARE REALLY
INCORPORATED INTO PROTEIN
WHERE WAKEFULNESS AND REM
SLEEP AT THE TOP ARE NOT
REALLY AS EFFICIENT.
SO HERE IS SLOW WAVE SLEEP
CLEARING THE BRAIN, I LIKEN
IT TO A BILLING PUMP TIME
AND WITH EVERY SLOW WAVE,
THE NEURONS ARE FIRING AND
AT THE TROUGHS, THE NEURONS
ARE NOT FIRING AND IT IS A
ASYNCHRONOUS TIME OF FIRING
AND NOT FIRING AND EVERY
TIME THEY FIRE, THEY EXPAND
THE BRAIN 15 PERCENT AND
THEN WHEN THEY ARE NOT
FIRING, THEY CONTRACT AGAIN
AND I THINK OF THAT AS A
BILLING PUMP.
SO IT HAS BEEN SHOWN TO
CLEAR THE AMALOID BETA FROM
THE BRAIN AND THAT HAPPENS
THROUGH THE GLYMPHATIC AND
THE FIRST AREA TO REALLY
DEGENERATE IS THE LOCUS AND
THE LOW FUNCTIONING IS
ASSOCIATED WITH STRESSFUL
CONDITIONS AND WOULD CAUSE
POOR SLEEP IN A POSITIVE
FEEDBACK LOOP BETWEEN
ANXIETY, STRESS AND POOR
SLEEP AND THEN ALSO THE LACK
OF THE ABILITY TO CLEAR THIS
PROTEIN.
SO DISTURBED SLEEP AND
SMALLER SLOW WAVES REALLY
COULD BE A CAUSATIVE FACTOR
FOR DEMENTIA SO THAT IS
SOMETHING TO KEEP IN MIND.
SO HERE IS AN IMAGE UNLIKE
THE ONE I SHOWED YOU BEFORE
OF A DISTURBED NIGHT SLEEP
AND UNFORTUNATELY, WAY TOO
MANY OF US HAVE A NIGHT
SLEEP LIKE THIS FOR WHATEVER
REASON AND I WILL TALK ABOUT
THOSE REASONS.
SO WHO GETS A POOR NIGHT'S
SLEEP?
A LOT OF PEOPLE.
SO WHAT HAPPENS?
ONE OF THE CORRELATES OF A
POOR NIGHT'S SLEEP IS AGING.
OF COURSE IT IS VARIABLE IN
DIFFERENT PEOPLE WHEN THEY
START -- THE SLEEP STARTS
AGING BUT THIS IS AN IMAGE
ON THE LEFTHAND SIDE OF A
POPULATION OF OLDER
SUBJECTS, AGE 51 TO 85, HALF
OF WHOM ARE FEMALE AND IT
SHOWS THAT IN THE RED, IN
THE FRONT IS BIG BEAUTIFUL
JUICY SLOW WAVES AND THERE
IS NOT VERY MUCH OF THAT
COMPARED IT A YOUNGER
POPULATION AGES 18 TO 23
WHICH YOU CAN SEE HAS A LOT
MORE RED AND BLACK WHICH IS
LARGE AMPLITUDE SLOW WAVES
ON THE FRONTAL CORTEX.
AND THEN ON THE RIGHT END
SIDE, YOU CAN SEE THE PEAK
TO PEAK AMPLITUDE OF THE
SLOW WAVES GOES DOWN.
THE GRAY ONES ARE OLDER
INDIVIDUALS, RED IS FEMALE
AND GRAY IS MALE AND YOU CAN
SEE BOTH FEMALES AND MALES,
THE AMPLITUDE OF OUR SLOW
WAVES DECREASES AS WE AGE.
SO SLOW WAVE SLEEP ALSO IS
MORE FRAGMENTED AND SLOW
WAVES THEMSELVES ARE LESS
DENSE SO ALTOGETHER, THE
QUALITY OF SLOW WAVE SLEEP
GOES DOWN WITH AGING AND IT
IS REALLY ALMOST THE LARGEST
THING THAT CHANGES ABOUT
SLEEP AS WE GET OLDER.
SO HERE IS SHOWING THE
DURATION OF SLOW WAVE SLEEP
ON THE LEFT.
YOU CAN SEE THE YOUNGER
SUBJECTS ARE IN OPEN CIRCLES
AND YOU CAN SEE THAT THEY
HAVE MORE PROBABILITY ON THE
X AXIS AND THEN THE NUMBER
OF SLOW WAVES PER MINUTE
DIMINISHES WITH AGE
SIGNIFICANTLY.
SO WHAT ELSE CAN DISTURB
SLEEP?
WELL, ESTROGEN -- NOT
ESTROGEN, ACTUALLY ESTROGEN
DOES -- OKAY, JUST TALK
THROUGH THIS.
SO THIS IS WHAT A ESTROCYCLE
LOOKS LIKE IN A RAT.
YOU CAN SEE ALL OF THE
HORMONES IN THE SPACE ARE
MUCH HIGHER AND IT IS NOT
UNLIKE A WOMEN'S MENSTRUAL
CYCLE WHEN IT IS A PHASE
WHEN ALL OF OUR HORMONES ARE
HIGH.
IN A RAT, IT IS ONE DAY OF
FOUR AND THEN IN WOMEN,
THERE ARE A COUPLE OF DAYS
WHERE IT RISES, LESS THAN
HALF OF THE CYCLE WHEN OUR
HORMONES ARE HIGH AND
ESTROGEN ITSELF HAS EFFECTS
ON HIPPO
CAMPAL SYNAPTOGENESIS, LTP
AND LEARNING AND WE DID A
STUDY A FEW YEARS AGO WHEN
THE PRO-ESTROUS SPACE, THE
FEMALES HAVE VERY, VERY
LITTLE REM SLEEP IN THE DARK
CYCLE AND WAKEFULNESS
INCREASES AND SLOW WAVE
SLEEP IN PURPLE ON THE
BOTTOM ALSO BOTTOMS OUT SO
THESE ANIMALS ARE GETTING
MUCH LESS SLEEP ON THE
HIGHEST ESTROGEN PHASE,
ESPECIALLY REM AND SLOW WAVE
SLEEP.
BUT THE GOOD NEWS IS THAT
SLEEP, THE LITTLE SLEEP THAT
THEY GET IS ACTUALLY WAY
MORE EFFICIENT.
YOU HAVE MORE SPINDLES PER
MINUTE AND YOU HAVE MUCH
BIGGER SLOW WAVE DELTA
ACTIVITIES, THE SLOW WAVES
OF SLOW WAVE SLEEP AND GAMMA
IS AN COMP FEEING FASTER
FREQUENCY SO DELTA AND GAMMA
BOTH INCREASE DURING THIS
LOW ESTROGEN PHASE OF SLEEP.
SO WHAT HAPPENS WITH ALL THE
OTHER PHASES?
IT IS MUCH LOWER
UNFORTUNATELY.
SO ON THIS YOU CAN SEE MALES
ARE IN THE OPEN CIRCLES AND
YOU CAN SEE DURING THIS
PRO-ESTRUS PHASE IN RED, IT
IS BIGGER THAN ALL THE OTHER
MALES IN THE OTHER PHASES OF
CYCLES SO IT IS EFFICIENT
SLEEP BUT ALL THE OTHER
CYCLES ARE LESS EFFICIENT
AND LESS EFFICIENT THAN
MALES SO THAT IS NOT GOOD
EITHER.
SO WHAT ELSE CAN DISTURB
SLEEP?
NOISY ENVIRONMENTS.
FOR EXAMPLE, LIVING IN THE
UPPER CITY.
HELICOPTER-PATROLLED AREAS
LIKE LOS ANGELES, IT IS THE
MOST HELICOPTER-PATROLLED
CITY IN THE WORLD AND I LIVE
THERE SO I CAN TELL YOU THE
HELICOPTERS DO COME AT ALL
HOURS OF THE NIGHT AND FLY
MUCH LOWER THAN THE
1000-FOOT FAA MINUTE AND
CIRCLE FOR 20 MINUTES AT A
TIME.
AND IT IS DISTURBING AND NOT
ONLY IS IT THE NOISE THAT
DISTURBS YOU BUT ALSO THE
THREAT THAT IT IMPLIES.
SO IT IS NOT A GOOD, NOT
GOOD.
SO ON THE LEFT BOTTOM
ORANGE, THE BIGGEST DARKEST
ORANGE IS LA X SO THAT IS
THE NOISE IF YOU LIVE IN THE
FLIGHT PATH OF LA X AND THAT
ISING GELWOOD, PREDOMINANTLY
BLACK IN SOUTH L.A.
AND IF YOU PLAY A 2 SECOND
NOISE AT THAT LEVEL AND THEN
OVERLAID IN THOSE COLORS ARE
HOW MUCH HELICOPTER CIRCLING
AT 600 TO 1000 FEET, HOW
MUCH NOISE IT WOULD MAKE AND
WHETHER YOU HAVE AN OPEN
WINDOW, SINGLE PANED GLASS
WINDOW THAT IS CLOSED AND A
DOUBLE PANED GLASS WINDOW
THAT IS CLOSED AND I CAN
TELL YOU IN LOS ANGELES IN
THE SUMMERTIME IN YOU DON'T
HAVE AIR CONDITIONING, YOU
HAVE THOSE WINDOWS OPEN.
SO EVEN THAT CAN DISTURB
YOUR SLEEP -- EVEN THAT DEEP
SLOW WAVE SLEEP WHICH IS
USUALLY VERY HARD TO DISTURB
SOMEONE FROM WILL BE
DISTURBED BY THE HELICOPTER.
AT THE BOTTOM RED CIRCLES
AND BLACK, YOU CAN SEE THE
PATTERN OF CIRCLING
HELICOPTERS IN SOUTH L.A.
I AM DOING A STUDY TOGETHER
WITH NICK SHAPIRO TO
ACTUALLY FOIA THE HELICOPTER
FLIGHT PATTERNS AND SEE WHAT
IT IS RELATIVE TO THE
POPULATION AND THE
POPULATION MAKEUP AND IT IS
A DISTURBING PICTURE.
ANOTHER THING THAT DISTURBS
SLEEP ESPECIALLY AS WE GET
OLDER WHICH IS DISRUPTIVE
SLEEP APNEA THAT GOES HIGHER
AND HIGHER AND THAT IS A
WEAKENING OF MUSCLE AS WE
GET OLDER THROUGH THE NASAL
AIRWAYS AND ALSO INCREASING
FLAT PADS THAT PRESS ON THE
AIR I WOULD SO THE TWO
COMBINED TO CLOSE OFF YOUR
AIR WAY SO EVEN IF YOUR DIVE
FEDERAL IS TRYING TO
RESPIRE, YOU HAVE A CLOSED
AIRWAY.
AND FOR IT TO BE OBSTRUCTIVE
SLEEP APNEA, YOU HAVE TO
HAVE FIVE DISRUPTIONS PER
HOUR IN SLEEP AND THAT IS A
LOT OF WAKEFULNESS AND
PEOPLE DON'T REALIZE BECAUSE
THEY ARE SO SLEEPY THAT THEY
ARE WAKING SO OFTEN TO
BREATHE BUT THIS IS
OBSTRUCTIVE SLEEP APNEA THAT
LIKELY INCREASES WITH AGE
AND MEN PRIMARILY GET SLEEP
APNEA BECAUSE THEY HAVE MORE
FATTY TISSUE BUT WOMEN ALSO
GET SLEEP APNEA.
AND GOOD NEWS.
AIR WAVE EXERCISE, SINGING
IN THE SHOWER IS GOOD.
MORE AIR WAVE EXERCISE, MORE
TALKING AND SINGING YOU CAN
DO, THE MORE TIGHTENED YOUR
AIRWAY IS GOING TO BE AT
NIGHT SO DON'T CRITICIZE
ANYONE FOR TALKING OR
SINGING ALL THE TIME.
HUMMING IS A GOOD WAY TO DO
IT ACTUALLY.
AND EVEN PEOPLE THAT HAVE A
LOT OF FAT BUT SING OPERA
BECAUSE THEY ARE PRACTICING
FOUR HOURS A DAY, THEY DO
NOT HAVE SLEEP APNEA.
OR PLAY THE DIDGIERIDOO.
SO PEOPLE GETTING UP AT
NIGHT, NOCTUREA AND YOU CAN
SEE MORE THAN 50 PERCENT OF
THE 55 TO 84-YEAR POPULATION
SAY THEY GET UP AT LEAST
ONCE PER MIGHT TO GO TO THE
BATHROOM AND THAT DISTURBS
THEIR SLEEP MORE THAN
PHYSICAL PAIN OR CAREGIVING,
HEALTH CONCERNS, COUGHING,
WHATEVER IT IS, GOING TO THE
BATHROOM AT NIGHT IS THE
NUMBER ONE CAUSE AND IT
HAPPENS IN WOMEN AND IN MEN
AND ON THE X-AXIS IN DECADES
OF LIFE, YOU CAN SEE IN
WOMEN AND MEN GETTING UP TO
PEE AT NIGHT INCREASES AND
THAT IS IN TWO DIFFERENT
STUDIES.
YEAH, SO MY TIME IS ALMOST
UP BUT WHY WOULD THIS AFFECT
MEMORIES?
REALLY MULTIPLE AROUSE
SALARIES FOR WHATEVER WOMEN
INCREASES THE LOCUS CERILLUS
ACTIVITY, IF IT BECOMING
HYPERACTIVE FOR ANY REASON,
IT IS A POSITIVE FEEDBACK
LOOP AND NOT GOOD.
SO IT CHANGES THE MOLECULAR
AND GLIAL SUPPORTS FOR
LEARNING, YOUR EXTRA
CELLULAR MATRIX, ALL OF THIS
STUFF AND IT IS CONTRIBUTED
TO BY STRESS AND THE
ENVIRONMENT WHICH TWEAKS THE
LOCUS CERILLUA AND WAKES YOU
UP.
SO THE LAST SLAVE IS HOW TO
GET BETTER SLEEP, INCREASE
SLOW WAVE AMPLITUDE BY
GETTING EXERCISE DURING THE
DAY AND AIR WAVE SLEEP, MAKE
SURE YOUR RHYTHMS ARE
ALIGNED THROUGH BRIGHT LIGHT
EXPOSURE IN THE AM AND TRY
TO FIND A WAY TO REDUCE THE
NOISE AND POLLUTION, MAYBE
IT WILL REQUIRE POLICY
CHANGES.
SO I WANT TO THANK THE
LABORATORY AND NIH FOR MY
FUNDING THROUGHOUT THE
YEARS, AND THE LABORATORY,
THANK YOU FOR YOUR
ATTENTION.
[APPLAUSE]
>> THANKS SO MUCH, GINA,
WHAT A GREAT TALK.
SO THE NEXT TALK IS FROM
KRISTEN OH'CONNELL AND THE
TALK IS GENETIC INTERACTIONS
WITH SEX AND ENVIRONMENT
SHAPE SHAPE SLEEP AND
FUNCTION ACROSS THE
LIFESPAN.
>> THANK YOU VERY MUCH,
FIRST I WANT TO THANK THE
ORGANIZERS, ORGANIZING
COMMITTEE, MOLLY WAGSTER AND
THE NIH FOR INVITING ME AND
HAVING ME SPEAK.
THIS IS FANTASTIC, I HAVE
LEARNED A TON AND REALLY
EXCITED TO BE UP HERE
SHARING OUR WORK WITH YOU.
SO HOPEFULLY BY NOW YOU
UNDERSTAND THERE ARE A
VARIETY OF MECHANISMS THAT
INTERACT TO SHAPE THE
COGNITIVE FUNCTION AND THE
RATE IS AN INTERACTION
BETWEEN BOTH YOUR
CHRONOLOGICAL AGE,
ENVIRONMENTAL FACTORS AND
YOUR GENETIC BACKGROUND.
COGNITIVE AGING IS HIGHLY
VARIABLE.
IT CAN BE ATTRIBUTED TO
GENETIC FACTORS, ANYWHERE
FROM 50 TO 80 PERCENT SO
UNDERSTANDING THOSE
INTERACTIONS AND WHAT THOSE
GENETIC FACTORS ARE CAN
POINT THIS IN THE DIRECTION
OF NEW PARGTS OR FUNCTIONS
TO MITIGATE COGNITIVE
DECLINE BUT THERE ARE A
NUMBER OF CHALLENGES BOTH IN
HUMAN POPULATIONS AS WELL AS
IN MOUSE MODEL ORGANISMS.
FOR HUMANS, WE HAVE COMPLEX
GENOMES AND WE HAVE TO THINK
OF THIS AS A FEATURE, NOT A
BUG.
WE ARE INCREDIBLY DIVERSE
AND THE WAY WE RESPOND
ACROSS OUR ENVIRONMENT AND
AGE IS AN IMPORTANT REASON
WHY HUMANKIND IS AS
INCREDIBLE AS IT IS.
WE HAVE LONG LIFESPAN AND AS
A SPECIES, ARE NOTORIOUSLY
DIFFICULT TO ACCURATELY
ASSESS, WHO REMEMBERS OUR
CHILDHOOD?
SO WE RELY ON SELF-REPORT
AND MANY OF THE THINGS
HAPPENING DURING AGING, THE
INFLUENCE WHERE YOU END UP
TOWARD THE END OF YOUR LIFE
ARE OCCURRING IN MIDLIFE AND
AS HUMANS, WE DON'T HAVE
RELIABLE ACCESS TO THAT
TISSUE.
MOUSE MODELS HAVE A SOLUTION
TO.
THIS THEY HAVE A SHORT
LIFESPAN, WE CAN FOLLOW
THEM, THEY LIVE TWO, TWO AND
A HALF YEARS.
WE HAVE TREMENDOUSLY TO US
CONTROL OVER THEIR
ENVIRONMENT, WE CONTROL
EVERYTHING MICE DO AND HAVE
A LOT MORE PRECISION IN
ASSESSMENT AND MEASUREMENT.
AND OF COURSE THEY ARE
RETRACTIBLE, WE DON'T HAVE
CONSENT ISSUES WITH MICE AND
WE CAN ACCESS THEIR BRAIN
TISSUE AT ANY AGE.
HOWEVER THERE IS ONE
DIFFERENCE THAT HAS
INFLUENCED THE DATA DROP
FROM MOUSE MODELS TO HUMAN
IS THAT IS OUR GENETIC
BACKGROUND.
MOST MOUSE MODELS ARE A
SINGLE GENE STRAIN AND MOST
OFTEN MALE.
SO IT IS ONE OF THESE THINGS
THAT IS A MODIFIABLE FACTOR
AND THAT IS THE GENOME OF
MICE AND MOST OF THE WORK I
AM ABOUT TO TELL YOU ABOUT
REPRESENTS A VERY LONG
COLLABORATION WITH THE COSBY
LOUSY LAB WHO WENT OVER THIS
YESTERDAY SO I WON'T GO
THROUGH IT EXCEPT WE HAVE
TAKEN THE PANEL AND EXTENDED
IT TO A F1 PANEL WHICH
INTRODUCES A FEW ADVANTAGES
INCLUDING A CONSIDERABLE
AMOUNT OF VARIATION.
THE BXD PANEL NOW CARRIES
SIX MILLION VARIANTS ACROSS
10 STRAINS, WE HAVE CREATED
60 GIVE OR TAKE AND BY
CREATING A BXD F1 PANEL, WE
HAVE SOME VARIATION IN THE
FREQUENCY.
SO I WON'T GO INTO THE
COGNITIVE FUNCTION OF THE
MICE EXCEPT TO SAY MOST OF
WHAT WE SEE IS PSEUDO
COHORTS, WE CAN ASSESS
COGNITIVE FUNCTION AND WHAT
DOES THIS DO IN THE BXD F1
PANEL?
JUST TO ORIENT YOU ON THIS
PANEL, YOU WILL SEE THIS IN
A NUMBER OF MY SLIDES.
SO WE LOOK AT THE GENETIC
BACKGROUND, MALES AND
FEMALES AND EACH POINT IS A
STRAIN AND THE AVERAGE OF
ALL THE MICE IN THAT STRAIN
PER AGE, FROM 6, 14 AND 22
MONTHS OF AGE THE BOX FACTOR
IS THE POPULATION.
THE BIGGEST DETERMINANT OF
COGNITIVE FUNCTION AT EVERY
AGE IS GENETIC BACK GROUPED.
STRAINS DETERMINE MOST OF
THIS, NOT AGE, NOT SEX.
WE HAVE STRAINS THAT PERFORM
EXCEPTIONALLY WELL AT YOUNG
AGES AND LIFESPANS.
WE ALSO HAVE STRAINS THAT
DON'T FORM WELL EVEN AT
YOUNG AGES AND THIS
PARALLELS THE HUMAN
POPULATION MUCH BETTER THAN
A SINGLE STRAIN DOES.
THE OTHER THING IS THERE IS
A PROFOUND SEX DIFFERENCE
HERE AND WE HEARD THIS A FEW
TIMES YESTERDAY.
OFTEN MALES AND FEMALES
START AT THE SAME PLACE AND
END AT THE SAME PLACE, BUT
IT IS THE TRAJECTORY OF HOW
THEY GET THERE AND THAT IS
TRUE FOR MICE AS WELL.
14 MONTHS IS LATE MIDLIFE IN
MICE AND THEN THEY DECLINE
FROM MIDLIFE TO OLD AGE.
MALES ON THE OTHER HAND
START HIGH, DECLINE IN
MID-AGE AND THEN END UP AT
THE SAME PLACE.
AND LIKE HUMANS, WE HAVE A
SURVIVAL BIAS.
MORE OF OUR FEMALE MICE
SURVIVE TO 22 MONTHS OF AGE
THAN MALE MICE DO SO FEMALE
MICE ARE OVERREPRESENTED AND
WE HAVE STRAINS IN WHICH NO
MALES SURVIVE THE 22 MONTHS
OF AGE.
SO OTHERS HAVE DONE A BETTER
JOB OF EXPLAINING SLEEP AND
COGNITIVE AGING THAN I CAN
BUT THE MAIN THING TO TAKE
AWAY FROM MY TALK IS THERE
ARE INDIVIDUAL DIFFERENCES
IN PHENOTYPE ITSELF THAT
INFLUENCES SLEEP AND COG
ANYTHING.
PATTERNS AND HOW WE ALL
SLEEP CAN BE ATTRIBUTED TO
GENETIC VARIATION.
SO NOW THAT WE HAVE A
VARIATION OF MICE THAT
APPROXIMATE MATES S WHAT WE
SEE IN HUMANS, WHAT DOES
SLEEP LIKE?
AND GENETIC BACKGROUND NOT
SURPRISINGLY IS THE BIGGEST
INFLUENCE.
SO THIS IS TOTAL SLEEP, DARK
CYCLE, LIGHT CYCLE AND WE
REMEMBER MICE ARE NOCTURNAL
SO THEY SLEEP THE MOST WHEN
LIGHTS ARE ON.
EACH ONE OF THESE IS THE
PERCENT SLEEP FOR A GIVEN
STRAIN.
SOME STRAINS WILL SLEEP
ALMOST 70 PERCENT OF THE
TIME IN THE LIGHT CYCLE,
OTHERS LESS THAN 60 PERCENT
OF THEIR TIME IS SPENT
ASLEEP AND WE SEE JUST AS
MUCH OR MORE VARIATION WHERE
SOME STRAINS WILL SPEND
ALMOST 40 PERCENT OF THAT
CYCLE ASLEEP AND OTHERS,
LESS THAN 20 OR 15.
AND JUST SO YOU KNOW, THIS
EQUATES TO TWO AND A HALF
HOURS OF DIFFERENCE ACROSS
THE PANEL.
SO WE HAVE SOME MICE THAT
GENETICALLY TEND TO BE SHORT
SLEEPERS AND SOME THAT TEND
TO BE LONG SLEEPERS.
ONE OF THE OTHER BIG FACTORS
THAT WAS ALLUDED TO IN
GINA'S TALK IS THAT THINGS
LIKE OBESITY AND BODY WEIGHT
INFLUENCE SLEEP.
THEY ALSO INFLUENCE
COGNITION AND UNDERSTANDING
HOW OBESITY AND DIET AND
THESE SORT OF ENVIRONMENTAL
FACTORS AND LIFESTYLE
FACTORS IMPACT NORMAL
FUNCTION AND PLASTICITY HAS
BEEN AN INTEREST OF MY LAP
FOR A LONG TIME.
SO SHORT SLEEP IS ASSOCIATED
WITH INCREASED FOOD INTAKE
AND PREFERENCE FOR HIGHLY
PALATABLE FOODS.
IN ANIMAL MODELS,
CONSUMPTION OF OBESOGENIC
DIETS LEAD TO CIRCADIAN
DISRUPTION AND SLEEP LOSS.
AND HIGH FAT DIET IS
ASSOCIATED WITH UNCOUPLING
OF PERIPHERAL METABOLIC
PATHWAYS FROM THE CIRCADIAN
RHYTHM.
SO HOW DO WE COMBINE ALL OF
THESE FACTORS TO AGE, DIET
AND SLEEP?
SO USING A VERY WELL
VALIDATED MODEL WHERE WE
FEED THE MICE A HIGH FAT
DIET, THE WESTERN DIET,
STARTED AT THREE MONTHS OF
AGE, SO FAIRLY YOUNG AND
THEN MONITOR THEIR BODY
WEIGHT AND PHENOTYPES.
THIS IS A PSEUDO LAUNCH
STUDY.
THESE MICE GET 24 HOURS
CONTINUOUS MONITORING OF
METABOLISM AND BEHAVIOR FROM
WHICH WE CAN EXTRACT SLEEP
AND CIRCADIAN RELATED
BEHAVIORS.
I WILL CONCEDE THIS IS NOT
THE GOLD STANDARD FOR THESE
BEHAVIORS BUT DOES A GOOD
JOB AT EXPLAINING THIS
THROUGH THE INPUT SCREENING
OF THOUSANDS OF MICE.
SO THIS IS PROOF OF CONCEPT.
THIS MODEL WORKS REALLY WELL
AT INDUCING OBESITY
PARTICULARLY IN MALE MICE
WHICH IS THE MODEL FOR WHICH
IT WAS DEVELOPED AND THERE
IS A DIFFERENCE IN BODY SIZE
BUT THE GENETIC BACKGROUND
DICTATES THE SIZE AND MOST
MICE WILL STEADILY BECOME
OBESE.
FOR FEMALES, IT IS A LITTLE
LONGER.
IT TAKES LONGER FOR FEMALE
MICE TO GAIN WEIGHT AND
BECOME OBESE BUT GENETIC
BACKGROUND IS THE BIGGEST
DRIVER HERE, IT IS NOT DIET.
SO IT IS THE RESPONSE TO
INDIVIDUAL VARIATION TO THAT
ENVIRONMENTAL FACTOR THAT
DETERMINES WHETHER AN ANIMAL
WILL BECOME OBESE.
SO WHAT ABOUT SLEEP, WHAT
HAPPENS IF WE LOOK AT SLEEP
ON THESE MICE ON A HIGH FAT
DIET AND OBESE OR NOT.
AND AGAIN, GENETIC VARIATION
PLAINS MOST OF THE
DIFFERENCES WE SEE HERE AND
THIS IS REALLY PROFOUND FOR
THIS TYPE OF PHENOTYPE AND
IN MALE MICE IS EXPLAINS 3/4
OF THE VARIATION.
THERE IS A HUGE SEX
DIFFERENCE AGAIN HOW MALES
AND FEMALES RESPOND TO A
HIGH FAT DIET AND THEIR
SLEEP PATTERNS.
THIS IS ONLY DARK CYCLE
SLEEP BECAUSE THERE WAS NO
EFFECT ON THE LIGHT CYCLE,
ONLY GENETIC BACKGROUND.
THE DARK CYCLE IS MUCH MORE
VARIABLE.
MALE MICE RESPOND TO AGE AND
SEX AND THEY INCREASE IN THE
DARK CYCLE WITH OLD AGE.
FEMALES ARE DIFFERENT.
THERE IS NO EFFECT OF SEX --
OR DIET, BEING ON HIGH FAT
DIET OR BEING OBESE DOESN'T
INFLUENCE THEIR SLEEP AND
THEY RESPOND BY SLEEPING
MORE, NOT LESS.
SO IF YOU WERE TO
ANTHROMORPHIZE ON THIS,
MAYBE THE GREATEST VARIANT
WOULD BE DAYTIME NAPPING.
SO THIS IS CIRCADIAN, WE USE
THIS AS A PROXY FOR
CIRCADIAN DISRUPTION AND
AGAIN TO PROVE THE POINT,
GENETIC BACKGROUND IS THE
BIGGEST DRIVER, GENETIC
VARIATION IS PREDICTIVE OF
OBESITY AND AGAIN IT IS THE
TRAJECTORY THAT IS
DIFFERENT, NOT THE
DESTINATION.
SO WHAT WE'RE REALLY
INTERESTED IN IN MY LAB IS
MAKING THIS LINK OF HOW DO
WE GET FROM THIS GENETIC
VARIATION AND ALL THESE
INTERACTIONS TO THE ULTIMATE
BEHAVIORAL OUTCOME?
AND A LOT IN THE MIDDLE IS
UNKNOWN.
THERE IS A LOT TO FILL IN IN
THIS GAP AND AGAIN, TO KIND
OF REFER BACK TO THE
COMMENTS MADE YESTERDAY
ABOUT HOW MUCH TECHNOLOGY --
HOW FAR IT HAS COME IN THE
LAST TEN YEARS, WOULD HE NOW
HAVE THE ABILITY TO DO VERY
DETAILED OMICS MEASUREMENTS
IN A WAY WE COULDN'T DO EVEN
FIVE YEARS AGO.
SO TAKING ADVANTAGE OF THE
RESOURCES AVAILABLE, WHERE
WE HAVE A REALLY
SOPHISTICATED IMAGING CORE
AND CAN DO MASS SPEC IMAGING
WHICH WE COULDN'T DO FIVE
YEARS AGO.
SO HE PRESS THE BRAIN,
INSTEAD OF USING A
MICROSCOPE, YOU SPRAY IT
WITH A MATRIX AND USE THE
PLATFORM WHICH IS OPTIMIZED
FOR MSI AND CONVERTS THE
SPECTRA IN FEATURES AND AN
KNOW TATE THEM AND ALLOWS US
TO LOOK AT LIPID PEPTIDE AND
SO ARE WHAT DOES IT LOOK
LIKE?
IT DOESN'T LOOK THAT
DIFFERENT FROM THE
MICROSCOPY IMAGE.
SO I WANT TO POINT OUT THERE
IS NO ANATOMICAL OBSTRUCTIVE
INFORMATION IN THIS BRAIN.
THIS IS LIPIDS.
IT LOOKS LIKE A HEAT MAP BUT
IT IS ACTUALLY A HIGH
DIMENSION PCA PLOT.
THE COLORS ARE LIPIDS MOST
SIMILAR TO ONE ANOTHER
COMPARED TO THE OUTER BRAIN.
THE INNER CORTICAL LAYER
MORE SIMILAR TO ITSELF AND
YOU COULD MAKE THAT
COMPARISON TO EVERYTHING.
THIS IS A LEAN LOW FAT DIET
CHILD OR A MOUSE THAT WAS
GIVEN THE HIGH FAT DIET AND
YOU CAN SCAN THESE AT THE
SAME TIME AND MAKE
COMPARISONS AS THEY ARE
NORMALIZED WITH EACH OTHER.
SO THIS IS WITH RESPECT TO
THE COMPOSITION OF THE BRAIN
AND WE CAN DRILL DOWN ON
SPECIFIC REGIONS AND SINCE
WE'RE INTERESTED IN
COGNITION HERE, WE DID THIS
FOR THE DORSAL HIPPO CAMPUS
AND NOW WE'RE LOOKING AT
RELATIVE COMPOSITION
RELATIVE TO THE HIPPOCAMPUS.
AND THIS IS ALL LIPID
ABUNDANCE OF WHICH THERE IS
A TREMENDOUS VARIATION
ACROSS THE HIPPOCAMPUS AND
WE CAN TAKE THIS WITH EVERY
SINGLE FEATURE WE'RE ABLE TO
ACQUIRE AND COLLAPSE IT IN A
SINGLE IMAGE WHICH IS REALLY
HARD TO PROCESS AND
INTERPRET.
SO WE TOOK A FEW OF THOSE
FEATURES, A FEW OF THE NAMED
LIP PIT CLASSES AND WE CAN
NOW SUPER IMPOSE THOSE ON TO
OUR IMAGE, ON THE BRAIN AND
LOOK AT THE SPECIFIC
CLASSES.
THESE ARE THE NINE MOST
PROLIFICALLY ABUNDANT LIPID
CLASSES AND NOW WHAT YOU ARE
LOOKING AT IS THE REAL
DIFFERENCE ACROSS THE BRAIN,
COLORS ARE INDIVIDUAL
PROCESSES OF LIPIDS.
I APOLOGIZE, ONCE YOU GET UP
TO 9, YOU START RUNNING OUT
OF COLORS SO THERE IS A LOT
OF THE SAME COLOR ON HERE
BUT HOPEFULLY IT DRIVES HOME
THE POINT THAT A FEW MONTHS
AFTER EATING A HIGH FAT DIET
THE LIPID CONCENTRATION
THROUGHOUT THE BRAIN HAS
BEGUN TO CHANGE AND THESE
ARE GENETIC MICE SO THIS IS
REALLY A DIET DRIVEN EFFECT.
AND I ALSO WANT TO POINT OUT
YOU MAY NOT BE ABLE TO READ
THIS ON THE SLIDE, THE
LIPIDS I AM SHOWING ARE
IMPORTANT FOR MEMBRANE
STRUCTURE AND FLUIDITY BUT
THERE IS ALSO BIOSIGNALING
WITH THIS.
THESE ARE REALLY IMPORTANT
LIPIDS FOR THE FUNCTION OF
THE BRAIN AND THEY ARE
CHANGING IN RESPONSE TO
DIET.
AND SO JUST TO WRAP UP,
HOPEFULLY I HAVE CONVINCED
YOU BY INCREASING THE
GENETIC DIFFERENCE IN THE
MOUSE MODELS WE CAN DO A
MUCH BETTER JOB OF ALIGNING
THESE MODELS TO THE
VARIATION ACROSS THE HUMAN
POPULATION AND DO A WEIR JOB
BETTER JOB OF CAPTURING
THAT THROUGH GENETICS AND
VERSATILITY AND DO A BETTER
JOB THROUGH THE LIFETIME
EXPOSURES OF HUMANS AND
MODEL THAT TO BETTER
UNDERSTAND WHAT THE
UNDERLYING GENETIC AND
MOLECULAR DRIVERS ARE TO DO
A BETTER JOB OF
UNDERSTANDING HOW WE AGE IN
EVERY FACET.
AND THEN OUR GOAL IS TO NOW
USE THESE ADVANCED
MULTIOMICS TO FILL IN THESE
GAPS.
HOW DO WE GET THE DIVERSITY,
WHAT ARE THE FACTORS AT
LEVELS WE HAVE NOT
PREVIOUSLY BEEN ABLE TO
ASSESS, LIKE LIPIDOME,
METABOLOME AND PEPTIDONE.
SO THERE ARE A LARGE NUMBER
OF MEMBERS IN THE LAB DOING
THIS WORK, AMY DUNN WHO
ORGANIZED THE DATA AND THOSE
OF YOU WORKING WITH BIG
DATASETS, YOU KNOW HOW GOOD
IT IS TO HAVE CLEANING AND
ORGANIZATION OF THE DATA AND
MIKO DID AN EXCEPTIONAL JOB
OF THAT BEFORE SHE WENT TO
GRAD SCHOOL.
AND THEN OF COURSE TO THANK
THE FUNDING AGENCIES WHO
HAVE FUNDED THIS WORK FOR SO
LONG INCLUDING THE NIH, AND
THE KACZOROWSKI LAB AND ALSO
MATHEW WHO IS WORKING ON
THIS.
THANKS VERY MUCH.
>> THANKS SO MUCH, KRISTEN.
THE NEXT TALK WILL BE
KRISTINE YAFFE FROM
UNIVERSITY OF CALIFORNIA-SAN
FRANCISCO AND THE TALK IS
IMPORTANCE OF A LIFE COURSE
APPROACH TO COGNITIVE AND
BRAIN AGE.
>> GOOD MORNING, REALLY
GREAT TO BE HERE, WANT TO
THANK MOLLY IN PARTICULAR
AND IT IS IMPORTANT TO BE
HERE WHICH IS WHAT WE DO,
LEARN FROM ONE ANOTHER AND
MEET NEW FRIENDS AND I LOVE
THE TRANSLATIONAL ASPECT
THAT WE'RE TALKING ABOUT OUR
MINDS AND TALKING ABOUT
PEOPLE.
I AM GOING TO TALK ABOUT
PEOPLE ALTHOUGH IT MAKES ME
THINK FROM PRIOR TALKS MAYBE
I SHOULD SWITCH TO MICE.
[LAUGHTER]
SO I WILL TALK ABOUT TWO
THINGS.
ONE, YOU HAVE HEARD ABOUT
THE LIFE COURSE AND I WILL
TRY TO CONVINCE YOU WHY A
LIFE APPROACH TO COGNITIVE
AGING IS VERY IMPORTANT AND
THEN I WILL TALK ABOUT THE
RESEARCH WORK WE HAVE FROM
THE TRIAL, TRYING TO IMPROVE
COGNITIVE AGING.
WHAT AM I DOING WRONG HERE?
THERE WE GO, OKAY.
WE ALL KNOW THE PHYSIOLOGIC
AND NEUROLOGIC CHANGES THAT
HAPPEN OVER AGE TAKE A LONG
TIME TO DEVELOP AND SO, YOU
KNOW, WITH RISK FACTORS AND
WE KNOW A LOT OF THE CHANGES
THAT LEAD TO AGING SUCH AS
VASCULAR SLEEP, PHYSICAL
ACTIVITY YET MOST OF OUR
WORK IS REALLY FOCUSED ON
OLDER ADULTS, PEOPLE IN
THEIR 60s, 70s AND 80s
AND I WOULD LIKE TO
HYPOTHESIZE THAT WE'RE
MISSING REALLY A CHANCE TO
UNDERSTAND THE WHOLE LIFE
COURSE AND WHAT HAS BEEN
HAPPENING BEFORE, MAYBE EVEN
STARTING IN UTERO.
SO IT IS HARD TO STUDY THIS,
RIGHT?
WE'RE NOT MICE, YOU KNOW AND
IN HUMANS, WE DON'T HAVE
STUDIES THAT GO FOR NIH
CYCLES OF FIVE YEARS AND I
KNOW MOLLY IS WORKING ON
THAT BUT YOU KNOW WE DON'T
HAVE A NIH STUDY THAT IS 80
YEARS OLD.
SO IT IS HARD TO STUDY THIS
AND YET WE'RE MISSING, I
THINK, THIS OPPORTUNITY TO
STUDY PEOPLE FOR DECADES,
THEIR WHOLE LIFE.
WE DON'T HAVE BIRTH
CATEGORIES, SOME COUNTRIES
DO.
THE OTHER THING IS THE RISK
FACTOR IS OFTEN CUMULATIVE
SO YOU MAY HAVE OBESITY OVER
50 YEARS AND THAT IS
DIFFERENT FOR SOMEONE WHO IS
70.
THERE MAY BE CRITICAL
WINDOWS FOR EXAMPLE WITH
HORMONES.
IT MIGHT BE IMPORTANT
WHETHER YOU GET HORMONES IN
PERI MENOPAUSE OR SO MUCH
LATER SO THESE ARE SPECIFIC
REASONS WHY THE LIFESPAN IS
IMPORTANT.
AGAIN, WE DON'T STUDY A LOT
OF THESE.
YOU CAN DO SOME POOLING OF
COHORTS WHICH OTHERS HAVE
DONE, YOU CAN DO ANALYTIC
METHODS, YOU CAN DO LIKE
RANDOMIZATION WHICH IS A
GREAT WAY TO GO, ET CETERA,
BUT I WANT TO SHOW YOU A
STUDY WE HAVE BEEN INVOLVED
WITH CALLED THE CARDIA STUDY
AND THIS IS A REALLY GREAT
STUDY.
I WANT TO INCREASE YOUR
AWARENESS OF THIS BECAUSE I
THINK IT PROVIDES A LOT OF
OPPORTUNITIES, ANHLBI STUDY
WHICH IS REALLY A COOL
STUDY.
THIS IS 5000 MEN AND WOMEN,
HALF BLACK, HALF WHITE,
PRETTY DIVERSE AND WE HAVE
BEEN STUDYING THEM ALMOST 40
YEARS.
THEY STARTED WHEN THEY WERE
IN THEIR 20s SO THE MEAN
AGE IS ABOUT 25 AND I AM
SORRY THIS MAY BE HARD TO
SEE BUT THE BOXES REPRESENT
EACH VISIT AND THAT IS THE
MEAN AGE.
SO THEY STARTED AT 25 AND
THEN WHEN THEY ARE 50, WE
START DOING COGNITIVE AND
BRAIN ASSESSMENTS AND THAT
HAS BEEN MY ROLE WITH SOME
COLLEAGUES.
AND WE'RE NOW COMING UP TO
THE POINT WHERE THEY ARE
ACTUALLY TURNING -- THEY ARE
IN THEIR MID-60s.
SO IT IS A REALLY GREAT
OPPORTUNITY.
I WILL SHOW YOU SOME OF THIS
WORK WE HAVE BEEN WORKING ON
SINCE THEY WERE 50 USING THE
COGNITIVE BRAIN MRI.
AND REALLY OUR GOAL IS TO
TRY TO UNDERSTAND THE LIFE
COURSE APPROACH.
HOW ARE THESE CUMULATIVE OR
LIFE EXPOSURES THAT OFTEN
ARE MODIFIABLE INKHRAOUPBS
COGNITIVE -- INFLUENCE
COGNITIVE LIFE, AS PEOPLE
ARE AGING AND WE HOPE THAT
AS THEY GET OLDER WE CAN
CONTINUE TO STUDY THEM.
WE JUST SUBMITTED A RENEWAL
TO STUDY THEM WHEN THEY ARE
65.
AND I WILL FOCUS ON A COUPLE
OF EXAMPLES JUST TO GIVE YOU
A FLAVOR OF WHY I THINK THIS
CAN BE SO POWERFUL.
OKAY SO THE FIRST EXAMPLE IS
BLOOD PRESSURE.
NOW WE KNOW BLOOD PRESSURE
IS EXTREMELY IMPORTANT FOR
RISK OF COGNITIVE AGING,
DEMENTIA, NOT TO MENTION
STROKE AND MRI, ET CETERA.
THIS IS THE WORK WE DID A
WHILE AGO WHERE WE SAID,
OKAY, WHAT IS THE BLOOD
PRESSURE EXPOSURE TO WHEN
PEOPLE WERE IN THEIR
MID-20s NOW ALL THE WAY TO
THE 50s.
AND THESE WERE NOT PEOPLE
WHO HAD HYPERTENSION.
THEY DID NOT MEET THE
CRITERIA FOR HYPERTENSION,
IT WAS JUST THEIR BLOOD
PRESSURE AND WE LOOKED AT
THIS HISTOLIC BLOOD PRESSURE
AND LOOKED AT THE AUC TO SEE
EXPOSURE AND WHAT YOU CAN
SEE PRETTY CLEARLY, THE
LINES ARE ALL THE COGNITIVE
TEXT, YOU CAN SEE THE
GREATER EXPOSURE IF YOU WILL
TO HIGH NORMAL SYSTOLIC
BLOOD PRESSURE, THE WORSE
PEOPLE DID AT HIGH FUNCTION.
SO IF YOU ARE HIGH NORMAL
FOR MANY YEARS, THIS MIGHT
NOT BE SUCH A GOOD THING AND
WE SAW THIS FOR OTHER
CARDIOVASCULAR RISK FACTORS
AS WELL.
RECENTLY CHRISTINE YITINKA
IN MY GROUP LOOKED AT THIS
PROCESS IN AGING USING THE
TIMELY AVERAGE SO TAKING IT
FROM MID-20s, TO 50, 55
AND WHAT SHE FOUND WAS USING
A MACHINE LEARNING BRAIN
AGING PATTERN THAT MOHAMMED
HAVAS DEVELOPED AND WHAT SHE
FOUND IS IF YOU HAVE SOLID
BLOOD PRESSURE ALL THAT
TIME, YOU HAVE A GREATER
BRAIN AGING.
SO THE RED LINE IS ELEVATED
ABOVE THE CUTOFF AND THE
GREEN IS NORMAL.
SO SHOWING THERE IS
SOMETHING GOING ON WITH THE
BRAIN AGING PATTERN.
THIS IS NOT WHITE MATTER,
JUST AN ATROPHY PATTERN.
AND WE HAVE DONE SOME WORK
ON HAVING THESE PATTERNS,
DIABETES, BLOOD PRESSURE AND
HAVING THIS IN MID-LIFE WAS
ASSOCIATED WITH ACCELERATED
VASCULAR DECLINE SO WE THINK
THE RISK FACTORS ARE VERY
IMPORTANT STARTING IN THE
20s.
SO WHAT ABOUT DEPRESSION?
WHAT IS GOING ON WITH THE
COGNITIVE DECLINE?
SO THIS IS WORK THAT
CHRISTINA HAS ALSO DONE,
DONE THIS DEVELOPMENT TO
LOOK AT THESE PATTERNS AND
AS MOST PEOPLE EXPECT, THERE
ARE NOT A LOT OF DEPRESSIVE
SYMPTOMS BUT SOME PEOPLE ARE
DECLINING, SOME INCREASING
AND SOME PEOPLE WHO STAY
HIGH AND REMAIN HIGH AND
THEN WHAT SHE DID, WHEN SHE
LOOKED AT HOW DID THESE
DIFFERENT PATTERNS RELATE TO
COGNITIVE FUNCTION, AGAIN,
THIS IS MIDDLE-AGE, 55, AND
HOW DID THIS VARY IN TERMS
OF MRI FINDINGS.
COMPARED TO THOSE WHO ARE
ALWAYS LOW, THOSE WHO ARE IN
THE DIFFERENT GROUPS,
HIGHER, ALWAYS HIGH,
INCREASING, DECREASING, HAD
WORSE COGNITIVE FUNCTION,
THIS IS ON A WORSE COGNITIVE
MEASURE AND HAD DIFFERENCES
IN TERMS OFENTORHINAL CORTEX
VOLUME AND AMYGDALA VOLUME.
SO LOOKING FROM THE HIGH
GROUP TO THE LOW GROUP.
AND THEN FROM THE INCREASING
GROUP TO LOW GROUP, THEY
ALSO HAD DIFFERENCES BUT IN
THIS CASE, IT WAS MORE WHITE
MATTER AND TOTAL GRAY
VOLUME.
SO NOW I WILL TURN TO SLEEP,
THE LAST THING I WANT TO
SHOW YOU IS SLEEP WHICH WE
HAVE BEAUTIFULLY HEARD ABOUT
TODAY.
THIS IS SOMETHING THAT ULANG
HAS DONE IN MY GROUP,
BEAUTIFUL WORK LOOKING AT
SLEEP QUALITY WHEN PEOPLE
ARE ABOUT 40 AND THEN
SHOWING THE COGNITIVE
FUNCTION 11 YEARS LATER WAS
MUCH WORSE ON A VARIETY OF
SLEEP PARAMETERS.
WE HEARD ABOUT
FRAGMENTATION, WAKE AFTER
SLEEP ONSET, TOSSING AND
TURNING OR SLEEP APNEA.
AND IN THIS CASE WE HAVE
SLEEP DURATION SHOWING
DIFFERENCES IN SLEEP
DURATION, SHORT SLEEP
DURATION WAS ASSOCIATED WITH
WORSE QUALITY IN TERMS OF
DTI AND ACTUAL WHITE MATTER
VOLUME.
SO I THINK -- I HOPE I HAVE
SHOWN YOU THAT THERE IS REAL
GOOD EVIDENCE THAT LOOKING
AT SOME OF THESE RISK
FACTORS EARLY IN LIFE MIGHT
BE VERY IMPORTANT IN TERMS
OF COGNITIVE FUNCTION IN
MID-LIFE AND I WILL TELL YOU
I THINK THIS SETS US UP.
WE HAVE HEARD A LOT THAT WE
CAN'T PICK OUR PARENTS OR
YOU ARE A GENETICS BUT WE
CAN DO SOMETHING ABOUT THESE
THINGS AND MAYBE WE'RE
STARTING TOO LATE.
I THINK THEY APPRAISAL
REALLY EARLY AND IF WE WANT
TO SET US UP FOR A BETTER
TRAJECTORY OF COGGIVE AGING,
WOULD HE NO HE HAD TO START
THIS EARLIER, PROBABLY TO DO
SOME MULTIDOMAIN RISK AGING,
AND I HAD A CONVERSATION
ABOUT THIS AT BREAKFAST.
SO WHAT IF YOU COULD MOVE
THE NEEDLE ON SOME OF THESE
RISK FACTORS?
WHAT IF YOU COULD MODIFY THE
RISK FACTORS?
THIS IS SOME WORK I DID WITH
BARNES AND SO IF YOU WOULD
MOVE THE NEEDLE, WHAT WOULD
YOU DO?
SO WE LOOKED AT THE RISK
FACTORS, SEVEN OF THEM, SOME
WERE MID-LIFE, OTHERS
LATE-LIFE AND 30 PERCENT OF
THE ATTRIBUTABLE RISK FOR
DEMENTIA AND COGNITIVE AGING
WOULD BE RELATED TO SOME OF
THESE FACTORS.
AND THEN WHAT WOULD HAPPEN
IF YOU COULD REDUCE THEM AND
SEE IN THE RED AND THE BLUE,
THIS IS 10 PERCENT,
20 PERCENT, SO IN OUR THE
EVEN ASKING PEOPLE TO
EXERCISE, LIKE JOIN A
TRIATHALON, YOU ARE JUST
ASKING THEM TO CHANGE THEIR
BEHAVIOR 10 PERCENT,
20 PERCENT AND AS A PUBLIC
HEALTH PERSON, YOU COULD
HAVE A BIG DOWNSTREAM EFFECT
ON DEMENTIA PREVALENCE AND I
WOULD SAY COGNITIVE AGING
ISSUES AS WELL.
SO WE HAVE LOOKED AT THIS
WORK, EXPANDED IT TO 40
VARIANTS.
I AM NOT SURE SOME OF THESE
HAVE BEEN SO CAREFULLY
STUDIED BUT THE IDEA HERE
REMAINS.
THIS IDEA THAT IF YOU CAN
CHANGE SOME OF THESE RISK
FACTORS, YOU ACTUALLY COULD
IMPROVE COGNITION AND REDUCE
DEMENTIA.
SO THIS IS ALL GREAT BUT HOW
DO YOU GET PEOPLE TO CHANGE
THEIR BEHAVIOR?
IT IS NOT SO EASY.
NIH HAS BEEN INTERESTED IN
THIS AND I HAD A GREAT
WORKSHOP WITH THE NATIONAL
ACADEMY OF MEDICINE AND AARP
HAS GOT TEN VERY INTERESTED
IN THIS.
HOW DO YOU GET PEOPLE TO
CHANGE THEIR BEHAVIORS?
I KNOW I SHOULD EXERCISE
MORE AND EAT BETTER AND I AM
NOT BAD AT IT BUT IT IS HARD
TO GET MOTIVATED.
SO WE WERE REALLY
INTERESTED, HOW CAN YOU
MOTIVATE PEOPLE AND GET THEM
TO ENGAGE IN RISK REDUCTION?
SO WE DECIDED TO DO A TRIAL
AND MAKE THIS PERSONALIZED.
ONE OF OUR THEMES OF THIS
CONFERENCE IS PRECISION
MEDICINE.
THIS IS PRECISION MEDICINE
IN TERMS OF REDUCING RISK
POCKET TARS.
SO WE DESIGNED THIS TRIAL,
COURTESY OF NIA, THANK YOU
NIA, WE DID A MULTIRISK
REDUCTION TRIAL AND THIS IS
WITH COLLEAGUES AT KAISER IN
SEATTLE.
WHAT WE FIRST DID WAS SAY
LET'S IDENTIFY PEOPLE WITH
RISK FACTORS.
SO THESE WERE PEOPLE WHO DID
NOT HAVE DEMENTIA, THEY WERE
OLDER, 70 AND ABOVE, BUT WE
WANT TO SEE IF THEY HAVE
COGNITIVE CHANGE OVER TIME.
BUT THEY HAVE TO HAVE AT
LEAST TWO RISK FACTORS, A
LIST OF EIGHT RISK FACTORS
AND THEY HAD TO HAVE AT
LEAST TWO OF THOSE.
OTHERS HAD A PERSONALIZED
INTERVENTION.
THEY GOT TO CHOOSE WHAT THEY
WANTED TO WORK ON.
SO WE TOLD THEM WHAT THE
RISK FACTORS WERE, AND THEY
SAID OKAY I WANT TO WORK ON
PHYSICAL ACTIVITY, I WANT TO
WORK ON MY SLEEP, I WANT TO
WORK ON MY HYPERTENSION AND
SO WE ENGAGED THEM BY THEM
CHOOSING WHAT THEY WANTED TO
WORK ON, WHAT THEY HAD FIRST
OF ALL, RIGHT, AND THEN WHAT
THEY WANTED TO WORK ON AND
HOW THEY WANTED TO WORK ON
IT.
DO YOU WANT TO GO TO THE
GYM?
YOU WANT TO HAVE A FIT BIT,
YOU WANT TO DO CDT FOR
INSOMNIA, WHAT DO YOU WANT
TO DO.
AND THEN OUTCOMES WERE
COGNITIVE FUNCTION OF COURSE
AND LOOKING AT THE RISK
FACTOR CHANGES AND QUALITY
OF LIFE.
WE HAVE HAD MUCH MORE
OUTCOMES BUT THIS HAPPENED,
WE WERE FINISHING ENROLLMENT
IN MARCH 2020 AND THIS WAS
SEATTLE WHICH WAS THE FIRST
CITY TO SHUT DOWN SO, YOU
KNOW, JUST MY LUCK, RIGHT?
SO ANY WAY, IT WAS ALL VERY
INTERESTING BUT IN THE END,
WE ENDED UP GOING ALL REMOTE
WHICH IN SOME WAYS MADE IT
MORE PRACTICAL.
SO THIS IS WHAT WE FOUND.
AFTER TWO YEARS, THE
COGNITIVE COMPOSITE, A
MODIFIED NEUROTEST BATTERY,
VERY SIMILAR TO WHAT WE USED
IN BINGHA AND MUCH TO MY
SURPRISE BECAUSE THIS WAS
DURING COVID, WHAT WE FOUND
IS THE INTERVENTION GROUP
IMPROVED, BOTH GROUPS
IMSKPRAOUFRBD MANY
PREVENTION TRIALS HAVE FOUND
COGNITIVE FUNCTION IMPROVES.
BUT THE INTERVENTION GROUP
IMPROVED MUCH MORE,
80 PERCENT MORE THAN THE
CONTROL GROUP AND YOU CAN
SEE THIS IS PRETTY
SUSTAINED.
THIS IS AN AVERAGE TREATMENT
EFFECT EVER .5 OF DEVIATION,
SIMILAR TO A LOT OF DRUGS,
MAYBE EVEN BETTER THAN SOME
DRUGS SO VERY EXCITED ABOUT
THESE RESULTS.
AND THEN WE LOOKED AT THE
RISK FACTORS, YOU KNOW, DID
THE RISK FACTORS CHANGE,
THIS IS THE SECONDARY
OUTCOME AND YOU SEE THE RISK
FACTORS DID CHANGE.
THE FIRST SIX MONTHS IS WHEN
COVID HIT SO THAT WAS
PROBABLY MID-2020 BUT THE
INTERVENTION GROUP ACTUALLY
STAYED THE SAME AND THE
CONTROL GROUP GOT WORSE AND
THEN YOU CAN SEE THEY SORT
OF REBOUNDED AND THERE WAS A
IMPROVEMENT IN QUALITY OF
LIFE AND AGAIN, SIGNIFICANT
ACROSS THE TWO GROUPS.
SO WE'RE VERY EXCITED ABOUT
THIS.
WE'RE INTERESTED IN TAKING
THIS TO THE NEXT STEP,
PROBABLY DOING A BIGGER
MULTI-SITE TRIAL BUT I ALSO
THINK WE SHOULD BE THINKING
SHOULD WE DO THIS IN
MIDLIFE, SOMETHING WE WERE
TALKING ABOUT THIS MORNING,
IS LATE-LIFE TOO MUCH?
YOU WILL NOT SEE MUCH
COGNITIVE CHANGE BUT YOU
COULD LOOK AT CARDIOVASCULAR
OUTCOMES AS WELL.
I HOPE I HAVE SHOWN YOU THE
IMPORTANCE OF THE LIFE
COURSE, THAT THESE RISK
FACTORS ARE OPERATING OVER
OUR WHOLE LIVES AND PROBABLY
EVEN EARLIER THAN WE CAN
STUDY IN TERMS OF CHILDHOOD
IN UTERO BUT I THINK WE NEED
TO UNDERSTAND THIS MUCH
BETTER, HOW DOES THIS SET US
UP.
I WOULD LOVE TO PARTNER WITH
KRISTEN AND HOW DO YOU
LOOK -- MAYBE USE THE MICE
TO FIND THINGS AND THEN ROLL
IT OUT INTO PEOPLE, I DON'T
KNOW BUT I THINK THERE ARE
SOME REALLY COOL THINGS YOU
CAN DO IN TERMS OF IMPROVING
YOUR COGNITIVE -- THIS IS
ALL WE TALK ABOUT, RISK AND
RESILIENCE REALLY, HOW DO
YOU GET THE BRAIN TO BE
RESILIENT, HOW DO YOU REDUCE
RISK.
I THINK WE NEED MORE
RESEARCH ON DIVERSE
POPULATIONS.
THIS CARDIA IS SOMEWHAT
DIVERSE BUT WE CAN DO MORE.
WE HAVE DONE RESEARCH
LOOKING AT PARTICIPATORY
RESEARCH AND THE RISK FACTOR
PROFILES ARE VERY DIFFERENT
PARTICULARLY WITH RECENT
IMMIGRANTS AND DIFFERENT
PLACES IN THE COUNTRY SO WE
NEED TO PAY ATTENTION TO
THAT.
ULTIMATELY I THINK THESE
PERSONALIZED APPROACHES MUST
BE MORE EFFECTIVE, YOU GET
BUY-IN FROM THE PARTICIPANTS
AND YOU ARE MEETING THEM
WHERE THEY ARE.
BUT FOR NOW WE DO HAVE
RECOMMENDED THINGS WE CAN
OFFER TO PEOPLE, THEY ARE
LOW COST, DON'T HAVE A LOT
OF SIDE EFFECTS, SUCH THINGS
AS CARDIOVASCULAR RISK
MODIFICATION, SLEEP,
HYGIENE, PHYSICAL ACTIVITY,
DEPRESSION OF COURSE
INVOLVES MORE OF A USUAL
PRACTITIONER APPROACH.
SO I WANT TO THANK YOU, THIS
IS MY GROUP AND SOME OF THE
FUNDING I SHOWED TODAY SO
THANK YOU SO MUCH.
[APPLAUSE]
>> THANKS SO MUCH, SUCH
GREAT DATA.
SO OUR LAST SPEAKER IS
MICHELLE MIELKE FROM WAKE
FOREST UNIVERSITY AND THE
TITLE OF HER TALK IS
INTERPRETING BLOOD-BASED
ALZHEIMER'S DISEASE
BIOMARKERS IMPACT
COMORBIDITIES.
>> THANK YOU VERY MUCH,
DOCTOR BIZON, LOVELY TO BE
HERE AND WE'RE ALL IN THIS
COLOR COORDINATED GROUP.
REALLY FUN TO FOLLOW ALL
THESE GREAT WOMEN.
MY TALK MIGHT VEER A LITTLE
BIT, FOCUSED ON BLOOD-BASED
BIOMARKERS AND HOW THEY
IMPACT AGING.
SO THE BLOOD-BASED ALDZ
ALZHEIMER'S BIOMARKERS AND
THERE IS A LOT OF ADVANTAGE
IN TERMS OF RESEARCH, COST
LIMITATIONS AND
ACCESSIBILITY AS WELL AS
INVASIVENESS.
SO THE TECHNOLOGICAL
ADVANCES THAT HAVE LED TO
THE DEVELOPMENT OF BLOOD
BASED BIOMARKERS FOR
ALZHEIMER'S DISEASE REALLY
OVER THE PAST FIVE YEARS
HAVE BEEN AN INCREDIBLE
ACCOMPLISHMENT.
SOME OF THESE MARKERS ARE
NOW AVAILABLE FOR CLINICAL
USE AND IN FACT SOME OF THE
AMINO AS SAYS ARE
REIMBURSABLE THERE CDC CODE.
MOST STUDIES TO DATE HAVE
FOCUSSED ON VERY WELL
CHARACTERIZED INDIVIDUALS IN
CLINICAL POPULATIONS SO
THERE IS STILL THIS OVERALL
LACK OF UNDERSTANDING AS TO
HOW THESE MARKERS WORK IN A
GENERAL POPULATION AS WELL
AS WHAT FACTORS MAY
INTERPRET THEIR LEVELS IN
THE POPULATION.
SO IN THE REST OF THESE
SLIDES, FIRST I WILL TALK
ABOUT THE IMPACT OF
COMORBIDITIES AND MEDICATION
ON A LEVEL OF INTERPRETING
THESE BIOMARKERS AND THEN I
HAVE A COUPLE MORE SLIDES ON
HOW TO ANALYZE THE DATA AND
THINKING ABOUT SOME OF THE
EPIDEMIOLOGICAL STUDIES
WHICH YOU MAY BE WORKING ON.
SO ORIGINALLY WHEN WE WERE
FIRST THING ABOUT HOW TO
INTERPRET THESE MARKERS IN
THE POPULATION, WE WERE
LOOKING IN THE MAYO CLINIC
STUDY OF AGING WHICH IS A
POPULATION-BASED STUDY IN
MINNESOTA AND HERE IN THIS
PARTICULAR SLIDE, WE LOOKED
AT PTAU181 AND PTAU217.
THE RESULTS ARE ESSENTIALLY
THE SAME SO I WILL FOCUS ON
P-TAU217.
THE BLACK IS THE ANALYSIS
AND THE RED IS THE AGING
EFFECTS AND TO GIVE YOU A
BASELINE COMPARISON, YOU SEE
ON THE BOTTOM, THIS IS THE
DIFFERENCE BETWEEN P-TAU
MEASURES BETWEEN THOSE WHO
ARE AMYLOID POSITIVE AND
THOSE WHO ARE AMYLOID
NEGATIVE.
INTERESTINGLY WHEN YOU START
TO SEE CHRONIC MORBIDITY
PARTICULARLY WITH CHRONIC
KIDNEY DISEASE, YOU CAN SEE
IT IS BASICALLY THE SAME AS
SOMEBODY WITHOUT AMYLOID AND
THIS ISN'T DRIVEN BY AMYLOID
POSITIVE BECAUSE EVEN IF WE
EXCLUDE THOSE INDIVIDUALS,
YOU SEE THIS VERY STRIKING
DIFFERENCE.
NOW, WE ALSO SEE LEVELS OF
P-TAU FOR PEOPLE WHEN A
HISTORY OF SMOKE AS WELL AS
MYOCARDIAL FUNCTION.
IN ADDITION, THE DATA, THIS
FIGURE SHOWS YOU AMYLOID
DATA 42-40 RATIO AND AGAIN
IF WE FOCUS ON CKD, WE SEE I
HER LEVELS FOR AMYLOID42 AS
WELL AS 40 BUT WHEN WE LOOK
AT RATIOS, SOME OF THAT IS
DIFFERENTIATED SO WE REALLY
ONLY SEE THAT IN IMPAIRED
GROUPS.
SO THERE HAVE BEEN A LOT OF
EVIDENCE ON THE BIOMARKERS
SINCE THAT STUDY BUT IT IS
IMPORTANT TO POINT OUT THERE
IS A RANGE ACROSS THE KIDNEY
FUNCTION.
SO THAT IS GENERALLY EGFR
LOWER THAN 90 BUT AS YOU CAN
SEE WITH THIS PARTICULAR
STUDY, EVEN THOUGH THERE IS
A VERY SIGNIFICANT
CORRELATION BETWEENGFR, NIL
AND GFAP, PHYSIOLOGICAL
IMPACTING OF THE KIDNEYS
AFFECTS BIOMARKERS.
NOW THERE ARE STUDIES THAT
ADJUST TO CHRONIC KIDNEY
DISEASE AND IT DOESN'T
REALLY MAKE A DIFFERENCE
WHEN YOU ARE LOOKING AT
BIOMARKERS AND COGNITION.
IN A COUPLE OF SLIDES, YOU
WILL TALK MORE ABOUT THAT
AND WHY THAT MIGHT BE.
BUT MOST OF THESE ARE GROUP
STUDIES WHEN ADJUSTING FOR
CKD.
HOW DOES THIS AFFECT
INDIVIDUALS ON A BASIS IN
TERMS OF DIAGNOSIS?
SO THIS REALLY BECAME
APPARENT TO US, WORKING WITH
MELISSA MURRAY AT
JACKSONVILLE WHERE YOU ARE
LOOKING AT THE CORRELATION
BETWEEN THE PLASMA BLOOD
MARKERS AND NEURAL
PATHOLOGY.
SO ESSENTIALLY THESE
INDIVIDUALS THE HIGHEST
P-TAU LEVELS AND WOULD HAVE
BEEN DIAGNOSED WITH
ALZHEIMER'S DISEASE BUT
DIDN'T HAVE SIGNIFICANT
FACTORS IN THE BRAIN.
NEARLY TWO WEEKS BEFORE
THEIR STUDY VISIT, THEY HAD
A CREATININE LEVEL OF 3.7.
SO AGAIN THEY COULD HAVE
BEEN DIAGNOSED WITH
ALZHEIMER'S DISEASE WHEN IN
FACT THEY DIDN'T HAVE THE
PATHOLOGY.
SO THERE HAS BEEN SOME WORK
TRYING TO FIGURE OUT HOW TO
MITIGATE THESE FACTORS FOR
THOSE WHO HAVE CHRONIC
KIDNEY SKIS AND SIMILAR WHEN
YOU USE THE 40 TO 42 RATIO,
SOME OF THAT WAS ATTENUATED
AND WHEN YOU LOOK AT THE
P-TAU RATIO, SOME OF THOSE
EFFECTS ARE MITIGATED AS
WELL.
THIS PARTICULAR STUDY LOOKED
AT MILD CKD PATIENTS SO
THERE IS ONGOING WORK BY
MURRAY AT THE FURMAN
INSTITUTE WHO ARE LOOKING AT
THESE RATIOS AND IN MORE
SEVERE CKD.
SO SHIFTING GEARS A LITTLE
BIT, I SHOWED YOU THIS
FIGURE.
WHAT I DIDN'T HIGHLIGHT WAS
THE ASSOCIATION BETWEEN
THESE MARKERS AND BMI.
SO WITH INCREASING BMI, WE
SEE DECREASING IN THE
MARKERS.
AND IN OTHER STUDIES YOU SEE
THE SAME THING WITH PLASMA
P-TAU AS WELL AS NIL AND
GFAS.
NOW WHAT MIGHT BE THE REASON
FOR THIS EXPLANATION?
THE FIRST WORK THAT REALLY
FOCUSED ON THIS CAME OUT IN
2020 LOOKING AT MS PATIENTS
AND CONTROLS.
AND THEY FOUND THERE WAS AN
INKRERS ASSOCIATION BETWEEN
BODY WEIGHT AND NFL AND THAT
WAS DRIVEN BY CHANGES IN
BLOOD VOLUME.
SO WITH INCREASING OBESITY
THERE IS INCREASING BLOOD
VOLUME AND THIS IS RESULTING
IN LOWER LEVELS OF NFL.
IMPORTANTLY, AGAIN, OBESITY
OR INCREASED BMI IN THESE
PATIENTS DID NOT AFFECT CSF
OR NFL LEVELS SO THIS IS
CERTAINLY A PERIPHERAL
PHENOMENON.
AND I THINK THIS HIGHLIGHTS
EVEN MORE WHAT THE POTENTIAL
EFFECT OF WHAT BMI CAN BE.
SO THIS STUDY BY REVLOS HAD
LOOKED AT P-TAU LEVELS IN
NORMAL PATIENTS AND COMPARED
THEM TO INDIVIDUALS WHO WERE
OVERWEIGHT AND ABOUT TO
UNDERGO BASS STRICK BY PASS
SURGERY.
AND I DON'T THINK I HAVE A
POINTER HERE BUT WHAT YOU
CAN SEE IS THAT INDIVIDUALS
WHO WERE OF NORMAL WEIGHT
HAD HIGHER LEVELS OF NFL
COMPANY PAIRED TO THOSE
INDIVIDUALS WHO WERE OBESE.
HOWEVER INTERESTINGLY, SIX
MONTHS LATER WHEN
INDIVIDUALS WENT FROM
AVERAGE BMI OF 41 TO 9 AT BY
PASS, THE LEVELS ARE NOT
ELEVATED AND THERE IS NO
DIFFERENCE BETWEEN
OVERWEIGHT INDIVIDUALS AND
MILDLY OVERWEIGHT
INDIVIDUALS.
AND I SHOULD SAY I TALKED
WITH SOME IN OUR DEPARTMENT
AND TYPICALLY WITH BY PASS
SURGERY, YOU SEE BETTER
COGNITION SO YOU WOULDN'T
EXPECT TO SEE ADVERSE
CHANGES IN
NEURODEGENERATION.
IN ADDITION, THERE IS ALSO
MORE WORK SUGGESTING THAT
BLOOD AMYLOID MAY BE
AFFECTED BY CARDIAC
CONDITIONS.
WE KNOW IT ACCUMULATES IN
THE HEART OF ALZHEIMER'S
PATIENTS AND SOME RECENT
STUDIES HAVE SHOWN THAT
PLASMA LEVELS OF AMYLOID
DATA, 40 AND 42, HIGH LEVEL,
ARE RISK FACTORS FOR CARDIAC
AND OTHER CONDITIONS.
NOW A RECENT STUDY SHOWED
THAT SACUBITRIL LOWERED THE
42/40 RATIO BUT NOT THE
CSF42/40 RATIO.
SO THIS PARTICULAR
MEDICATION INCREASES THE
42/40 OVER A YEAR BUT THE
RATIO IS SIGNIFICANTLY
INCREASED IN INDIVIDUALS SO
THIS IS A POSSIBILITY WHEN
AN INDIVIDUAL COMES IN AND
YOU NOTICE ELEVATED 42/40 IN
THE BLOOD, THEY MAY HAVE
ALZHEIMER'S ALTHOUGH THE
P-TAU IS A BETTER MARKER
WITH PARTICIPANTS.
I WANTED TO TALK A LITTLE ON
ETHNICITY BECAUSE THINKING
ABOUT BIOMARKERS, THERE HAS
BEEN A LOT OF DISCUSSION IN
THIS.
IF YOU GO BACK AND LOOK AT
THE BIOMARKERS, THERE ARE
STUDIES TO SUGGEST THAT THE
AD FLUID MAY BE LOWER IN
AFRICAN-AMERICANS THAN WHITE
AMERICANS AND THOSE BLACK
AMERICANS WHO ARE ENROLLED
ARE GENERALLY HIGHER
EDUCATED, HEALTHIER AND NOT
THE TYPICAL POPULATION.
IN TERMS OF BLOOD MARKERS,
SOME WE SEE DIFFERENCES AND
SOME WE DON'T.
BUT COMORBIDITY, CHRONIC
KIDNEY DISEASE, CARDIAC
DISEASE, COGNITIVE DISEASE,
THERE IS NOT A BIG
DIFFERENCE IN THE BLACK
VERSUS THE WHITE.
AND SOME REASONS THE STUDIES
SEE THIS AND SOME DO NOT ARE
THE RELEVANCE OF THESE
CHRONIC CONDITIONS.
SO SUMMARY IN TERMS OF THE
COMORBIDITIES, AS I SHOWED,
CHRONIC KIDNEY DISEASE
INCREASES THE ALZHEIMER'S
DISEASE BLOOD BIOMARKERS AND
ON A INDIVIDUAL LEVEL, IT
COULD LEAD TO FALSE
DIAGNOSIS.
THE USE OF RATIOS MAY BE
MORE ACCURATE BUT A LOT MORE
WORK NEEDS TO BE DONE
ESPECIALLY AT SOME OF THE
MORE SEVERE RANGES OF
CHRONIC KIDNEY DISEASE.
INCREASING BMI IS ASSOCIATED
WITH LOWER LEVELS OF
BIOMARKERS.
IT IS REALLY UNCLEAR HOW TO
THINK ABOUT THIS AND I WILL
TALK A LITTLE MORE ABOUT
THIS IN THE NEXT SLIDE SO I
WON'T PREEMPT THAT, WHETHER
IT IS A RISK FACTOR OR
PHYSIOLOGICAL BUT IT MAY BE
OVER TIME LOOKING AT
LONGITUDINAL STUDIES,
ADJUSTING FOR BMI MAY BE
IMPORTANT.
AND IF OLDER ADULTS ARE
GOING ON THESE GOP AGONISTS
THAT COULD LOWER BODY WEIGHT
AS WELL.
THE NEED TO EXAMINE MULTIPLE
CONDITIONS, THE EFFECTS OF
CKD AND CARDIAC AND HIGH BMI
IN THE BLOOD LEVELS, THERE
IS A LOT OF PEOPLE WHO HAVE
OBESITY AND CHRONIC KIDNEY
DISEASE SO HOW DO YOU
INTERPRET THE LEVELS IN
THOSE INDIVIDUALS?
SO ONE THING I REALLY WANT
TO TALK ABOUT IS THAT WHEN
WE THINK ABOUT EXAMINING
BLOOD BIOMARKERS IN
COGNITIVE AGING RESEARCH AND
WHAT I HAVE SHOWN YOU, YES,
THERE ARE A LOT OF FACTORS
THAT MAY AFFECT THESE BLOOD
MARKERS, MORE THAN I HAVE
SHOWN YOU TODAY, BUT THERE
IS A BIG DIFFERENCE BETWEEN
PHYSIOLOGICAL FACTORS VERSUS
RISK FACTORS.
SO SOME FACTORS THAT ARE
RISK FACTORS MAY AFFECT THE
LEVELS JUST BECAUSE THEY ARE
ON A DISEASE PATHWAY.
OTHERS MAY BE PHYSIOLOGICAL
FACTORS AND MAY NOT BE
RELATED TO ALZHEIMER'S
PATHOLOGY BUT MAY HAVE RISK
FACTORS FOR OTHER REASONS.
SO AS AN EXAMPLE, I
MENTIONED WITH CHRONIC
KIDNEY DISEASE, THEY DON'T
SEE ANY DIFFERENCE BETWEEN
THE BIOMARKER LEVELS AND
COGNITION.
WELL, I THINK A PRIMARY
REASON FOR THIS IS THAT IN
THE BRAIN AND KIDNEY DISEASE
STUDY OR THE BRAIN STUDY,
THEY DID NOT FIND AN
ASSOCIATION BETWEEN CHRONIC
KIDNEY DISEASE AND
ALZHEIMER'S PATHOLOGY.
SO THE CONFOUNDER HAS TO BE
ASSOCIATED WITH YOUR RISK
FACTOR AND OUTCOME AND IF IT
IS NOT, THEN IT IS NOT
NECESSARILY THE OUTCOME AND
SO IF YOU ADJUSTOR IT, IT
WILL NOT DOING ANYTHING.
BUT IT CLEARLY AFFECTS THE
LEVELS.
SO IN THIS CASE IT IS BETTER
TO ANALYZE THE DATA
STRATIFYING BY THAT
CONDITION OF INTEREST.
IN CONTRAST, BMI IS
SOMETHING, WELL, WE TALK
ABOUT PHYSIOLOGICAL CHANGES
BUT WE KNOW OBESITY IS
RELATED TO A LOT OF BRAIN
FUNCTION AS HAS BEEN TALKED
ABOUT TODAY.
SO TO BE HONEST, I AM NOT
EXACTLY SURE HOW TO CONSIDER
BMI AND OBESITY AT THIS
POINT BUT DEPENDING WHAT OUR
SPECIFIC QUESTION IS, WE
WILL HAVE TO AN WORK
THROUGH HOW TO ANALYZE THE
VARIOUS LEVELS.
LASTLY, THINKING ABOUT THE
INTERPRETATION OF THE
BIOBLOOD MARKERS.
THE REAL WORLD STUDIES ARE
NOT QUITE CLEAR.
MOST OF THE WORK HAS BEEN
DONE IN A SPECIALIZED MEMORY
CLINIC, HAVEN'T NECESSARILY
BEEN LOOKED AT IN LIGHT OF A
VARIETY OF CHRONIC
CONDITIONS AND OTHER
FACTORS.
IT IS ALSO I THINK IMPORTANT
TO CONSIDER THAT AD PATH
THOSE BEGIN DECADES PRIOR TO
SYMPTOMS AND INCREASE WITH
AGE.
THEREFORE THIS IS A
POSSIBILITY BOTH CLINICAL
AND RESEARCH THAT A POSITIVE
TEST MAY BE INS DENTAL AND
THIS IS PARTICULARLY
IMPORTANT WHEN THINKING
ABOUT COGNITIVE AGING.
SO IT IS OUTSTANDING, WE
HAVE THESE AD BIOMARKERS AND
IN THIS GROUP AS WELL AS
YESTERDAY, THERE IS A WHOLE
LOT OF OTHER MECHANISMS THAT
IMPACT COGNITIVE AGING IN
THE BRAIN AND RISK OF OTHER
NEURODEGENERATIVE PATHOLOGY.
SO EVEN IF WE'RE LOOKING AT
A CUT POINT AND THIS PERSON
MAY BE POSITIVE AND THEY
HAVE COGNITIVE IMPAIRMENT,
THAT MAY NOT BE THE SOLE
DRIVING FORCE OF THAT
COGNITIVE IMPAIRMENT.
THERE ARE LIKELY A LOT OF
OTHER FACTORS PLAYING A ROLE
AS WELL.
SO AGAIN WE NEED TO THINK
ABOUT THIS IN A WHOLE AND IN
CONTEXT AND CONSIDER OTHER
MECHANISMS AS WE'RE DOING
COGNITIVE AGING RESEARCH.
AND IN CLOSING, I WOULD LIKE
TO HIGHLIGHT THE U24 WE
RECENTLY FUNDED, WE CALL IT
THE ADAC ALZHEIMER'S
DIAGNOSIS IN OLDER ADULTS
WITH CHRONIC CONDITIONS AND
THE PURPOSE IS TO BUILD A
NATIONAL NETWORK FOCUSED ON
UNDERSTANDING HOW TO USE
BIOMARKERS FOR OLDER ADULTS
WITH IMPAIRMENT BUT ALSO WHO
HAVE CHRONIC CONDITIONS.
SO AS PART OF THIS NETWORK,
WE HAVE A EXECUTIVE
COMMITTEE, STEERING
COMMITTEE, WE HAVE THREE
PILOT PROJECTS AVAILABLE
EACH YEAR, 150,000 EACH AND
WE HAVE A ANNUAL MEETING.
OUR FIRST WILL BE IN
WINSTON-SALEM APRIL 29-30TH
AND THE FOCUSES WILL BE TO
BRING IN THOSE ON THE FRONT
LINES OF PRIMARY CARE, TO
UNDERSTAND WHAT THEY ARE
LOOKING AT IN TERMS OF
PATIENT QUESTIONS AND WHAT
GUIDELINES THEY NEED IN
TERMS OF GOING FORWARD AND
WHAT WE CAN DO TO HELP THEM
IN THAT SPACE.
WE HAVE A LOT OF WORKING
GROUPS AND LOOK FORWARD TO
ANYBODY THAT IS INTERESTED
IN BEING INVOLVED WITH THAT,
NOT JUST UNDERSTANDING THE
BIOMARKERS BUT THE EFFICACY
AND GUIDELINES SO SORRY, I
AM 25 SECONDS OVER BUT THANK
YOU.
[APPLAUSE]
>> OKAY, GREAT, THANK YOU SO
MUCH, THAT WAS GREAT.
SO WE HAVE -- COME ON UP TO
THE MIC IF YOU HAVE
QUESTIONS FOR THE SPEAKERS
AND I AM GOING TO START OUT
AND ACTUALLY ASK GINA IF YOU
COULD COMMENT ON SLEEP AND
MENOPAUSE.
>> THANK YOU SO MUCH FOR
GIVING ME THAT.
I REALIZED I HAD FORGOTTEN
WHEN I WAS TALKING ABOUT THE
MENSTRUAL CYCLE AND WHY THAT
IS RELATED TO AGING AND THAT
IS BECAUSE OUR CYCLES ARE
LOWER AND THAT MIGHT
CONTRIBUTE TO A POOR QUALITY
OF SLEEP AS WE GET OLDER.
ALSO IT IS POSSIBLE, AND
THERE IS NO RESEARCH ON
EITHER ONE OF THESE
POSSIBILITIES THAT MENSTRUAL
CYCLING SETS YOU UP FOR MORE
SUSCEPTIBILITY TO GETTING
ALZHEIMER'S LATER WHEN YOU
GO THROUGH MENOPAUSE.
THERE NEEDS TO BE RESEARCH
ON THAT.
>> THANK YOU.
>> THANK YOU FOR SUCH AN
INTERESTING SET OF TALKS.
I HAVE TWO QUESTIONS.
SO ONE IS FOR Dr. OH'
CONNELL.
YOU WERE USING S1 CROSSES
AND LIKE TO KNOW A LITTLE
BIT MORE WHY YOU ARE DOING
THAT RATHER THAN THE BXE
THEM AND HE WAS AS
INVESTIGATORS THINK THROUGH
THE PANELS ADDRESSING OTHER
KINDS OF QUESTIONS.
>> THE DECISION TO DO A F1
CROSS, COUPLE OF THINGS.
WE CAN CONTROL THE MATERNAL
ENVIRONMENT.
SO THE PRENATAL, LIKE
GESTATION, POST NATAL, ALL
OF THAT IS THE SAME BECAUSE
THE MATERNAL STRING IS THE
SAME.
A LOT OF THE GENETIC TOOL
STRINGS ARE BUILT ON THE
BACKGROUND SO THAT LIVES US
A WAY TO GET IN AND
MANIPULATE ON THE DOWNSTREAM
SAY FOR EXAMPLE, DISEASE.
SO IT GIVES US A PLATFORM WE
CAN BUILD ON AND BRING IN
CAN IN ADDITIONAL THINGS.
THOSE STRAINS ARE FULLY
INBRED SO THE H1 YOU CAN
HAVE A BLACK SIX.
IT IS NOT ANYMORE
CHALLENGING TO MAKE THAN THE
ORIGINAL BXD'S AND IT HAS
THE SAME LEVEL OF
REPRODUCIBILITY AND WITHIN
EACH STRAINS, THE
INDIVIDUALS ARE ISOGENIC.
SO IT ISN'T ANYMORE
CHALLENGING THAN JUST USING
THE BXD.
>> AND THEN THE OTHER
QUESTION I HAD WAS -- I'M
SORRY, I AM SPACING ON THAT.
>> ABSOLUTELY TERRIFIC
SITUATION, ENJOYED IT.
ENJOYED HEARING ABOUT THE
SLEEP AND CARDIOVASCULAR
RISK FACTORS AND WHAT THEY
MIGHT MEAN FOR DEMENT IS
THAT AND COGNITIVE DECLINE.
SPECIFIC QUESTION FOR
CHRISTINE.
LIKE TO MARRY MORE ABOUT THE
SPART TRIAL AND -- ABOUT
THE SMARRT TRIAL AND HOW YOU
PERSONALIZE THAT
INTERVENTION BEING SCALED IN
A RESEARCH CONTEXT, HOW
EXPENSIVE WOULD THE
INTRODUCTION BE AND HOW
WOULD YOU GO ABOUT DOING
THAT?
>> YES, TOP OF MY MIND.
[LAUGHTER]
SO WE THOUGHT A LOT ABOUT
IT.
WE TRIED TO MAKE THE SMART
TRIAL FAIRLY PRAGMATIC IN
THAT WE USE DHR.
THAT IS WHY I WANTED TO
PARTNER WITH KAISER BECAUSE
THEY HAVE THIS GREAT EHR AND
WE USE THE EHR TO IDENTIFY
RISK FACTORS AND THEN WE
VALIDATED THEM, YOU KNOW, WE
WANTED TO MAKE SURE THEY
REALLY HAD WHAT WE THOUGHT
THEY HAD BUT BY DID GO
SOMETHING QUESTIONNAIRES AND
MEASURES.
SO I THINK YOU COULD DO THAT
AGAIN AND THAT WAY, YOU
KNOW, THE RECRUITMENT IS
VERY EFFICIENT IN TERMS OF
IDENTIFYING PEOPLE AT RISK,
EXCLUDE PEOPLE WITH
DEMENTIA, ET CETERA.
BECAUSE OF COVID, EVERYTHING
ENDED UP GOING ACTUALLY BY
PHONE WHICH IS WHY I WAS
SURPRISED WE FOUND
SOMETHING.
THE OLDER ADULTS, A LOT OF
THEM WEREN'T AS COMFORTABLE
ONLINE AND A LOT OF THIS IS
ON PHONE AT THE END.
SO ACTUALLY COVID MADE THIS
QUITE PRACTICAL AND
PRAGMATIC AND WE'RE NOW
TRYING TO DECIDE NEXT STEPS.
WE HOPE TO DO A REMOTE
MULTI-SITE TRIAL AND I THINK
YOU CAN USE EHR IN A LOT OF
WAYS, YOU CAN EVEN USE EHR
FOR OUTCOMES, RISK FACTOR
CHANGES.
SO WE'RE THINKING ABOUT IT
AND THERE ARE A NUMBER OF
WAYS TO GO.
YOU ALLUDE DO YOU STAY WITH
A PRIMARY CARE MODEL, TRY TO
DO COMMUNITY PARTICIPATORY
RESEARCH, I THINK I DON'T
WANT TO GO WITH MORE OF A
ALZHEIMER'S CENTERED GROUP
BECAUSE I THINK THAT IS NOT
REALLY THE GROUP WE WANT TO
RECRUIT.
YOU KNOW, THESE ARE PEOPLE
AT RISK, NOT REAL COGNITIVE
CHANGES BUT LIKE TO TALK
WITH YOU MORE ABOUT IT.
MORE AHA, THE CDC, PEOPLE
ARE TRYING TO ROLL SOME OF
THESE THINGS OUT IN TERMS OF
PUBLIC POLICY SO I THINK IT
IS A IMPORTANT TIME TO BE
THINKING ABOUT THIS.
>> GREAT, THANK YOU.
[ OFF MIC ]
>> WANT TO HEAR YOUR
THOUGHTS ON EVEN THE LOCAL
OR NATIONAL POLICY LEVEL
TARGETS THAT SOME OF THESE
MIGHT HAVE.
SO WHERE DO YOU THINK THE
OPPORTUNITIES ARE, POLICY
LEVEL AND WHO ARE THE
PARTNERS?
YOU WORKED WITH AARP
SUBSTANTIALLY BUT HOW DO WE
CHANGE THINGS ON THE LOCAL
AND NATIONAL LEVEL WITH SOME
OF THESE FACTORS?
>> YES, THE CDC AND
ALZHEIMER'S ASSOCIATION HAVE
A PARTNERSHIP AND THEY JUST
ROLLED OUT THIS ROAD MAP
WHICH I THINK IS REALLY
EXCITING, TRYING TO ENGAGE
STATE LEVEL PUBLIC HEALTH
OFFICES TO TRY AND TEACH
PEOPLE ABOUT BRAIN HEALTH.
SO I REALLY THINK A LOT OF
THIS IS EDUCATIONAL, THAT
YOU KNOW A LOT OF DOCTORS
DON'T EVEN UNDERSTAND ABOUT
BRAIN HEALTH AND EVEN WHAT
DEMENTIA IS OR HOW YOU
EVALUATE IT.
SO ASKING THE PUBLIC TO
UNDERSTAND SOME OF THIS
STUFF IS NOT REALLY -- IT IS
CHALLENGING.
SO I THINK THERE IS A REALLY
IMPORTANT ROLE FOR PUBLIC
EDUCATION ABOUT WHAT BRAIN
HEALTH IS, WHAT ARE THE RISK
FACTORS, HOW IS THE HEART
CONNECTED TO THE BRAIN, HOW
IS PHYSICAL ACTIVITY THAT
MAY BE HELPFUL, WHY OVER THE
LIFE COURSE THIS MIGHT BE
HELPFUL?
I HAVE A COLLEAGUE IN FRANCE
WHO HAS DONE THIS BEAUTIFUL
VIDEO FOR ELEMENTARY SCHOOL,
CALLED MY BRAIN ROBBIE AND
IT IS A REALLY CUTE VIDEO
AND IT TEACHES ELEMENTARY
SCHOOL KIDS WHY THEY NEED TO
PROTECT THEIR BRAIN, WHETHER
IT IS WEARING A HELMET OR
EXERCISING.
SO I THINK THIS IS A REALLY
EX SOOTHING TIME IN THIS
COUNTRY AND OTHERS TO TRY TO
DO PUBLIC EDUCATION.
>> SCOTLAND HAS A SIMILAR
PROGRAM FOR PRIMARY CHILDREN
CALLED STARS AND IT IS
EXACTLY IDENTIFYING RISK
FACTORS, A HEALTHY DIET AND
SO ON SO HAPPY TO SHARE
THAT AS WELL.
>> THANKS FOR THE GREAT SET
OF TALKS, LIZ NIELSEN, AHEAD
OF THE RESEARCH AT NIA.
JUST FOR AWARENESS, I
TOTALLY RESONATE WITH YOUR
NEED FOR A LIFE COURSE
APPROACH BUT I WANTED YOU TO
BE AWARE WE HAVE TENS OF
THOUSANDS OF INDIVIDUALS
PHENOTYPED PARTICULARLY FOR
THEIR EDUCATIONAL EXPOSURES,
LIFE BLOOD EXPOSURES, BLOOD
BIOMARKERS IN A NUMBER OF
THESE GROUPS, PEOPLE BORN IN
THE 70s AND 80s.
A LONGITUDINAL STUDY FROM
HIGH SCHOOL AND BEYOND AND
THEN PROJECT TALENT WHICH IS
ACTUALLY 300,000 INDIVIDUALS
IN SCHOOL IN THE 60s.
SO THESE STUDIES REPRESENT A
OPPORTUNITY FOR
COLLABORATION IN LOOKING AT
THESE EXPOSURES AND I THINK
SOME MAY BE LESS EXPLORED
BECAUSE THERE IS NOT AS MUCH
AWARENESS IN THIS AREA IS.
AND THEN A SECOND COMMENT
AND SORT OF THE QUESTION
THAT Dr. COE IS TOUCHING
ON, HOW DO YOU TACKLE THESE
EXPOSURES AND THINKING IN
TERMS OF PREVENTION, WHAT
WILL BE POSSIBLE, EVEN IN
TAILORING TO SOMEONE IF THE
SLEEP ENVIRONMENT DOESN'T
MAKE IT POSSIBLE TO ADDRESS
THE SLEEP CHALLENGES FOR
TRANQUIL NIGHT SLEEP.
SO I AM CURIOUS WHERE YOU
SEE YOUR EFFORTS GOING
RELATED TO LOOKING AT THESE
THAT ARE MORE POP LEVEL
THINGS AND WHERE THAT MIGHT
TAKE YOU.
>> YES, THANK YOU SO MUCH
FOR THAT.
I THINK POLICY IS REALLY
IMPORTANT AND JUST ACTUALLY
SINCE A PRESS RELEASE OF THE
EARLY STUDY THAT WE DID
SHOWING THE HELICOPTER
POLICE ACTIVITY, HELICOPTER
POLICE ACTIVITY HAS ALREADY
BEEN REDUCED QUITE A BIT.
MAYBE IT HELPS WE HAVE A NEW
MAYOR AS WELL BUT POLICE
WERE ASKING FOR TEN MORE
HELICOPTERS AND THE CITY
SAID NO.
AND AGAIN, L.A. IS THE MOST
POLICE-SURVEILLED CITY.
WHY?
THERE IS NO NEED FOR THAT.
SO I THINK POLICY
DIFFERENCES AND JUST
BECOMING AWARE.
CITY LIGHTS, STREET LIGHTS,
WINDOWS, DOUBLE PANET, AIR
CONDITIONING, COULD HELP
PEOPLE PRIORITIZE THEIR
SLOPE IN WAYS -- AND
LEARNING ABOUT THE HEALTH
CONSEQUENCES OF POOR SLEEP.
IT HELPS THE CITY, THE
STATE, THE NATION, THE
WORLD, PRIORITIZE QUALITY
SLEEP.
>> JOHN FROM NORTHWEST
UNIVERSITY, I HAVE TWO
QUESTIONS FOR Dr.
O'CONNELL.
FIRST, THIS ISSUE OF MOUSE
DATA TO HUMANS, WOULD YOU
COMMENT ON THE IMPLICATIONS
OF YOUR FINDINGS FOR SUPER
AGER STUDIES?
SO I MEAN I AM SURE YOU HAVE
THOUGHT ABOUT THIS AND --
>> YEAH, THAT IS A GREAT
QUESTION.
ONE OF THE ADVANTAGES OF
MICE BUT EVEN SOMETHING THAT
PEOPLE WHO WORK ON MICE
DON'T DO IS AGE THEIR MICE
LONG ENOUGH.
SO EVEN 22 MONTHS IS -- WE
HAVE MICE THAT WILL KEEP
GOING.
SO IT IS STILL CHALLENGING
TO GENERALIZE TO SUPER I
THINK AR STUDIES BUT THERE'S
STILL A LOT OF, I THINK,
PARALLELLIZATION THAT CAN BE
INFERRED BETWEEN OUR VERY
OLDEST MICE, AS LONG AS WE
AGE THEM OUT LONG ENOUGH AND
IT WILL BE THE FEMALES THAT
MAKE IT THAT FAR.
THE MALE STRAINS OFTEN
DON'T.
BUT YEAH, COMPARISONS WITH
THE SUPER AGER STUDIES,
PARTICULARLY FOR LIFE
COURSE, THAT IS INCREDIBLY
IMPORTANT TO UNDERSTAND WHAT
EARLIER LIFE IMPACT IS ON
THAT VERY, VERY LATE LIFE.
BUT I THINK PEOPLE WHO EVEN
WORK ON MOUSE MODELS, WE
NEED TO BE COGNIZANT OF HOW
OLD WE AGE THEM.
>> AND ALSO THE IMPORTANCE
OF GENES, RIGHT, THE
GENETICS --
>> THE GENETICS ARE WHAT THE
LIFESPAN IS DETERMINED BY
GENETICS.
IT IS NOT EVERY STRAIN THAT
MAKES IT THAT FAR.
IT IS A SELECT SUBSTRAINS
THAT LIVE THAT LONG AND THAT
IS LONGEST DEPENDENT ON
BACKGROUND.
SO IF YOU ARE ONLY STUDYING
A SINGLE STRAIN OF MICE, YOU
CAN'T STUDY INTERACTION IF
YOU DON'T HAVE ANYTHING TO
INTERACT WITH.
>> AND THE OTHER QUESTION IS
IN YOUR -- THE TWO PICTURES
YOU SHOWED OR SLIDES YOU
SHOWED OF FAT MEASUREMENTS,
WAS THERE -- IT LOOKED TO ME
LIKE THE HIPPOCAMPUS IN THE
HIGH-FAT DIET WAS
CONSIDERABLY SMALLER.
IS THAT -- WAS THAT
ACCIDENTAL OR IS THAT WHAT
YOU FIND?
I REALIZE THOSE ARE NOT
HISITOLOGICAL SECTIONS --
>> THEY ARE NOT HYSTOLOGICAL
BUT I THINK IT WOULD BE FUN
TO GO BACK AND DO THAT WITH
MORE ACCURATE HYSTOLOGY.
THERE IS LACK OF ABUNDANCE
OF LIPIDS IN THE HIPPOCAMPUS
SO IT IS NOT A LEAP TO
BELIEVE THAT IS NOT BRINGING
A CHANGE IN THE HIPPOCAMPUS.
AND THE DIFFERENCE IS REALLY
DIFFERENT IN CA1 BUT CA3 AND
THE REST IS NOT AS
DIFFERENT.
YOU KNOW, WE NOTICED THAT
TOO.
SO WHETHER IT IS REAL OR IT
LOOKS -- BECAUSE THERE IS
NO -- IT IS CRAZY BUT THERE
IS NO STRUCTURAL INFORMATION
IN THAT IMAGE, THAT WAS ALL
JUST LIPIDS WHICH IS
STRUCTURE.
>> THANKS.
>> ZOEL ALINA WITH THE
HEALTH INITIATIVE,
DEFINITELY ON THE SAME PAGE
CONCERNING LIFE APPROACH.
THIS QUESTION IS FROM Dr.
[ AUDIO CUTTING OUT ]
-- WHATTIZATION ARE
CONNECTION ARE YOU GIVING TO
OTHER FACTORS SUCH AS
LONELINESS, LIFE CHANGE,
SUPPORT --
>> PEOPLE ALWAYS SAY WHAT IS
THE ONE THING I SHOULD DO
AND OF COURSE WHAT I USUALLY
SAY TONGUE IN CHEEK IS,
WELL, IMPROVE PUBLIC
EDUCATION IN THIS COUNTRY.
YOU KNOW, I SAID THE SAME
THING ABOUT INCOME
INEQUALITY AND THERE IS ONLY
SO MANY WAYS I COULD FIX
THAT.
SO YOUR POINT IS EXTREMELY
WELL TAKEN WHICH IS WHY I
THINK EXPANDING THIS TO, YOU
KNOW, NOT KAISER, IT MIGHT
FOR EXAMPLE BE IMPORTANT
TO -- YOU KNOW, BECAUSE I
THINK THERE ARE A LOT OF
RISK FACTORS THAT VARY BY
INCOME, OF COURSE, AND BY
REGION AND RACE AND
ETHNICITY, EMIGRATION
STATUS.
SO I THINK IT IS REALLY AN
OPEN QUESTION AND REALLY
RICH OPPORTUNITY FOR US TO
TRY AND DO BETTER IN THIS
COUNTRY IN TERMS OF, YOU
KNOW, PUBLIC HEALTH IN
GENERAL ABOUT SOME OF THESE
THINGS IN TERMS OF BRAIN
HEALTH.
IT IS A HARD -- HARD TO SAY
OTHER THAN INTRODUCING
QUALITY IN EDUCATION.
SOCIAL WAS ONE OF OUR RISK
FACTORS AND WE WERE ABLE TO
IMPROVE THAT WHICH WAS TOUGH
BECAUSE OF COVID SO WE HAVE
A PAPER THAT SHOWED COVID
TANKED ALL THE RISK FACTORS,
THE INTERVENTION GROUP THEY
COULDN'T ALL GO TO.
BUT SOCIALIZATION HAS GOT
TEN A LOT OF PRESS OBVIOUSLY
BECAUSE OF SOME OF THE
EMERGING RESEARCH AND THE
SURGEON GENERAL.
YOU KNOW, I THINK IT IS
REALLY INTERESTING AND YOU
KNOW IT GOES WITH OTHER
THINGS, TOO.
SO I THINK THAT
INTERSECTIONALITY OF
SOCIALIZIZATION IS REALLY
IMPORTANT TO LOOK AT.
>> THANKS A LOT FOR A GREAT
SESSION AND TO ALL THE
SPEAKERS.
I HAVE A QUESTION, KRISTEN,
REALLY IMPORTANT WORK.
THE ROLE OF BIOMARKERS WHERE
PEOPLE MIGHT USE IT FOR
SCREENING, PEOPLE MIGHT BE
ACCESSING THEM OR WANTING TO
ACCESS THEM BECAUSE THEY ARE
WORRIED ABOUT THEM IN THE
ABSENCE OF CLEAR CLINICAL
WORK IN THE DIAGNOSIS OF
COGNITIVE IMPAIRMENT.
THAT IS SOMETHING I WORRY
ABOUT ESPECIALLY BECAUSE I
HAVE PATIENTS IN MY CLINIC,
ONE OF WHOM HAS GOT TEN THIS
TEST AND WORRIED THAT THIS
IS BASED ON NORMS FROM A ACT
SUBSTRACT AN ABSTRACT ON
MEDICATION.
AND SO COMMENT ON THAT IF
YOU COULD.
AND THE SECOND QUESTION I
HAVE, THE SLEEP DISTURBA
NCE, EVEN ONE NIGHT, WILL
CHANGE THAT SIGNAL.
SO HOW IMPORTANT IS IT TO
ASCERTAIN HAVE YOU HAD A
GOOD NIGHT SLEEP OR HAVE YOU
BEEN SLEEPING THE LAST WEEK
BEFORE WE GO ON TO INTERPRET
WHAT THE BIOMARKERS ARE
TELLING US?
>> GREAT COMMENTS AND I AM
COMPLETELY IN AGREEMENT WITH
YOU.
YOU HAVE GOT SOME PEOPLE
COMING IN, SAY I HAVE A
SPLIT MARKER AND TELL ME IF
I AM ALZHEIMER'S AND NOT
UNDERSTANDING THERE IS A
DIFFERENCE BETWEEN SYMPTOMS
AND WHAT NOT AND THERE ARE A
LOT OF PEOPLE WALKING IN WHO
HAVE HAD THESE TESTS.
NUMBER ONE, THEY SHOULD NOT
BE USED FOR SCREENING
PURPOSES, EVEN INCLUDING
THOSE WHO MAY HAVE A FAMILY
HISTORY.
SECONDLY, THEY REALLY SHOULD
BE USED IN COMBINATION WITH
A WORKUP SO IT SHOULDN'T
EVEN JUST BE A MOCHA AND A
BLOOD TEST, YOU NEED TO LOOK
AT OTHER POTENTIAL REASONS
FOR THE COGNITIVE IMPAIRMENT
AND WHAT MIGHT BE DRIVING
THAT.
FORTUNATELY, THE DIRECT
CONSUMER TESTS HAVE BEEN
TAKEN OFF THE MARKET SO
THANK GOODNESS FOR THAT
BECAUSE I THINK THAT CAUSED
A LOT OF PROBLEMS.
THE OTHER THING THAT IS VERY
IMPORTANT THAT WE AREN'T
TALKING ABOUT ENOUGH ARE THE
ETHICAL AND POLICY
IMPLICATIONS BECAUSE AS
THESE FOR CLINICAL PURPOSES,
RIGHT DRAW -- WE ARE
STARTING A COUPLE OF PRIMARY
CARE REAL WORLD COHORT
STUDIES BUT WE CALL THEM
RESEARCH EVEN THOUGH THEY
ARE VERY PRAGMATIC AND WE
CAN KEEP THE INFORMATION OUT
OF MEDICAL RECORDS BUT ONCE
THEY ARE IN THE MEDICAL
RECORDS, THEY INVOLVE
LONG-TERM CARE AND OTHER
ISSUES SO WE NEED TO HAVE
THAT DISCUSSION WITH THE
PATIENT TO DISCUSS THOSE AS
WELL.
SORRY, I AM OFF TOPIC A
LITTLE BIT.
I THINK THEY CAN BE USED
APPROPRIATELY BUT WITHIN
LIMITS AND YOU ARE RIGHT, IN
TERMS OF SLEEP, I HAVEN'T
SEEN AS MANY STUDIES THAT
HAVE LOOKED AT SLEEP IN THE
BLOOD MARKERS, LIKE WITH CFS
AND I KNOW THERE ARE A
COUPLE OF STUDIES THAT
LOOKED AT -- OKAY, YOU ARE
DOING IT?
COMING OUT SOON?
BUT THERE ARE SOME STUDIES
THAT LOOKED AT DIET AND
FASTING STATUS AND HAVE SEEN
SOME EFFECTS THERE AND NOT
EXACTLY SURE HOW TO TAKE
THAT TO THE CLINICAL
INTERPRETATION.
>> TO FOLLOW UP ON YOUR
POINT, IT IS SUCH AN
INTERESTING AREA NOW AND
WE'RE AHEAD OF OURSELVES.
CAN YOU SAY MORE ABOUT WHY
YOU DON'T THINK IT SHOULD BE
USED FOR SCREENING?
BECAUSE A LOT OF PEOPLE
THINK IT MIGHT BE USED FOR
SCREENING IN THE SENSE THAT
YOU HAVE SOMEBODY WHO HAS
COGNITIVE COMPLAINTS, YOU DO
A MOCHA OR WHATEVER AND SOME
PEOPLE THINK WELL MAYBE YOU
DO THAT AND THEN IF IT IS
POSITIVE, YOU SEND THEM OFF
TO A SPECIALIST, AND IF NOT,
YOU ARE REASSURED.
>> THANKS FOR THAT QUESTION.
SO WHEN I WAS THINKING ABOUT
SCREENING, I WAS THINKING
THESE BLOOD MARKERS FOR THE
NEXT CHOLESTEROL TEST AS FAR
AS PREVENTION.
SO I WAS THINKING MORE IN
TERMS OF THAT AMONG
ASYMPTOMATIC INDIVIDUALS.
AND THERE IS A SURVEY THAT
HAS GONE OUT, I THINK WE
WILL BE PRESENTING IT AT
AAIC PRIMARY CARE PHYSICIANS
AND A THIRD OF THOSE
SURVEYED STATED THEY WOULD
USE THE BLOOD MARKERS FOR
ASYMPTOMATIC INDIVIDUALS IF
THEY HAD A FAMILY HISTORY OF
ALZHEIMER'S AND WERE WORRIED
ABOUT IT AND IN THOSE CASES,
IT IS NOT APPROPRIATE
BECAUSE WE DON'T KNOW WHAT
THE PROGNOSTIC VALUES OF
THESE BIOMARKERS ARE.
SO IF SOMEONE HAS IMPAIRMENT
AND GET THE TEST, THEN YOU
UNDERSTAND IT AND THAT IS
OKAY.
>> THANKS FOR THE PHENOMENAL
TALKS.
BLOWN AWAY THE LAST COUPLE
OF DAYS.
FROM THE UNIVERSITY OF
FLORIDA AND I HAVE TWO QUICK
QUESTIONS FROM Dr.
O'CONNELL, I AM ALSO A
NUTRITIONAL SCIENTIST AND
GET EXCITED BECAUSE THERE
ARE NOT MANY OF US.
SO THE HIGH FAT HIGH SUGAR
DIET, WHERE WERE THOSE
NUTRIENTS FROM, WERE THEY
PLANT BASED, ANIMAL BASED,
REFINED, NOT REFINED?
>> IT IS PLANT BASED.
THE FAT IS SUGAR, PLANT
BASED.
>> OKAY, AND MY SECOND
QUESTION IS GIVEN THE
GENETIC COMPONENT AND
GROWING EVIDENCE THAT THE
DIET AND NUTRIENTS CAN
INTERACT WITH THE EPIGENOME,
ARE THERE PLANS TO LOOK AT
THAT IN THESE MICE AND THEN
DO YOU THINK KNOWING YOUR
PROJECT, THAT YOU WOULD
ACTUALLY SEE SOME OF THIS
PASSED ON TO THE OFFSPRING
OF THESE ANIMALS?
>> I WOULD LOVE TO DO WHAT
YOU ARE DESCRIBING.
[LAUGHTER]
ACTUALLY THE DESIGN OF THE
BXD PANEL, THE DESIGN OF THE
F1 BXD PANEL WOULD WORK THE
BEST IF THE FATHERS WERE
WHERE THE GENETIC DIVERSITY
COMES FROM.
IF WE SWITCHED IT AND PUT
THE MOTHERS ON DIETS, THAT
IS AN INTERESTING QUESTION
IN AND OF ITSELF THAT BRINGS
IN GENETIC DIVERSITY ON X
WHICH WE DON'T HAVE.
IT IS A REALLY IMPORTANT
QUESTION.
WE DON'T HAVE PLANS TO DO IT
IN THE IMMEDIATE TERM,
LARGELY BECAUSE IT IS SUCH A
BIG STUDY.
I WILL JUST BE UPFRONT WITH
IT, IT IS TOUGH, BUT IT
SHOULD BE DONE AND VERY
TRACTABLE IN MICE, IT IS
EASY TO FOLLOW THEM AND
INTERVENE AND CONTROL THEIR
ENVIRONMENT SO SOMEONE
SHOULD DEFINITELY DO IT AND
I WOULD LOVE TO HELP AND
ADVISE ON HOW TO DEVELOP AND
EXECUTE THAT STUDY.
>> THEN WE NEED TO CHAT
MORE.
>> YEAH.
[OVERLAPPING SPEAKERS]
>> THANK YOU.
>> TO PICK UP ON THE
DISCUSSION ABOUT THE PLASMA
BIOMARKERS BECAUSE I THINK
THIS IS SOME OF THE MOST
IMPORTANT WORK TO DO BECAUSE
IT IS THE TIP OF THE SPEAR
SO TO SPEAK.
THIS IS NOW SOMETHING THAT
FOR A LARGE GROUP OF
INDIVIDUALS HAS A LOT OF
SIGNAL VALUE SO TO SEE THESE
OTHER GROUPS THAT DON'T HAVE
HETEROG ENEITY WITH SIGNAL
VALUE, I WOULD SURMISE THAT
MAYBE THE OTHERS DO BUT WE
DON'T KNOW IT YET.
SO I GUESS MAYBE I DISAGREE
ABOUT SCREENING, THINKING
ABOUT ALL THE CHALLENGES.
SO DO YOU IMAGINE A WORLD TO
MAKE THIS A HIGH SIGNAL
APPTOMASES.
>> I KNOW RACE IS A SOCIAL
CONSTRUCT BUT STILL WE
REALLY NEED TO CONSIDER THE
GENETIC RELATIONSHIP BETWEEN
APOE AND ALZHEIMER'S DISEASE
IS NOT PRESENT IN THE BLACK
POPULATION SO IT MIGHT BE
THAT WE REALLY NEED TO --
WHAT'S THAT?
>> WELL, YEAH, DEPENDING ON
THE --
>> THE OPPOSITE, YEAH.
>> SO QUICK AND COME BACK TO
THAT, THAT IS ONE THING TO
WATCH OUT FOR BECAUSE THERE
ARE CLINICAL TESTS THAT ARE
DEVELOPING ALGORITHMS AND
TAKE INTO ACCOUNT A
GENOTYPE IN THEIR SCORE SO
WOULD NOT SUGGEST USING
THOSE IF WE DON'T KNOW HOW
THEY WORK IN MORE
HETEROGENOUS POPULATIONS.
>> BASED ON YOUR QUESTIONS,
DOWN THE ROAD, YEAH, IDEAL
SITUATIONS, IT WOULD BE
GREAT TO HAVE THOSE AS
MARKERS AND THINK OF THEM AS
A COLLECTORAL TEST.
CERTAINLY THERE ARE THINGS
THAT NEED TO BE DONE BEFORE
THEN.
WOULD HE DO NEED TO KNOW HOW
THEY WORK IN HETEROGENOUS
POPULATIONS.
I WAS TALKING TO MY COWORKER
BEFORE THIS AND IN A LOOK
AHEAD STUDY WHERE THEY ARE
TYPE 2 2 DIABETICS AND
OBESE, WE ARE NOT SEEING
THESE MARKERS AND IN FACT
TAKES IT THE OTHER DIRECTION
SO WE NEED TO LOOK AT WHAT
IS REALLY GOING ON.
IT NEEDS TO BE MORE DIVERSE
TO LOOK AT SOME OF THESE
OTHER FACTORS BUT I THINK
THE QUESTION TOO IS THE
PROGNOSTIC INDIVIDUAL.
SOME INDIVIDUALS DIE WITH
THEIR HEADS FULL OF PLAQUES
AND TANGLES BUT DON'T HAVE
SYMPTOMS NECESSARILY SO HOW
DO WE PUT THAT IN THE LIGHT
AND UNDERSTAND WHAT THAT IS?
THE SECOND THING IS WE NEED
EDUCATION, REALLY ON THE
PART OF THE LAY PUBLIC AND
HEALTHCARE PROVIDERS AND
WHAT NOT BECAUSE, YOU KNOW,
THERE IS THIS IDEA THAT
ALZHEIMER'S PATHOLOGY IS THE
SAME AS ALZHEIMER'S DISEASE
DEMENTIA AND WE NEED TO
CHANGE THAT DISCUSSION
PARTICULARLY IN ASYMPTOMATIC
INDIVIDUALS AS A RISK
FACTOR, IT IS NOT
NECESSARILY A DIAGNOSIS OF
ALZHEIMER'S DISEASE.
AND THEN -- SORRY, I HAD ONE
MORE THING BUT NOW I FORGOT.
BUT YEAH, I DO THINK IT IS
BOTH.
SORRY, AND THE LAST THING
COMES BACK TO ETHICS.
UNTIL WE HAVE THESE POLICIES
IN PLACE THAT PROTECT
PATIENTS, I AM A LITTLE
BIT -- WELL, NOT JUST A
LITTLE BIT BUT I AM VERY
CONCERNED ABOUT
INCORPORATING THESE BLOOD
MARKERS AND ASYMPTOMATIC
INDIVIDUALS.
IF THEY ARE DISTRESSED NOW
AND WE HAVE THESE BLOOD
MARKERS, THEN THEY WILL
REALLY HAVE A LOT OF
PROBLEMS.
>> THANKS FOR THESE
WONDERFUL TALKS.
I AM FROM THE UNIVERSITY OF
MINNESOTA.
Dr. YAFFE, YOU MENTIONED
THE CONTROL GROUP WAS COMMON
IN THE PREVENTION TRIAL BUT
MAYBE YOU COULD COMMENT ON
THE HYPOTHESIZED MECHANISMS
BETWEEN THEM.
>> MOST PEOPLE THINK THAT
SOMEHOW A PRACTICE EFFECT
MAKES SENSE AND BECAUSE OF
THE EDUCATION, MAYBE IT WAS
A BIT OF ACTIVE CONTROL, I
DON'T KNOW.
WE DID SEE THE DIFFERENCE IN
TERMS OF RISK FACTOR CHANGE
BUT IT MAY BE THAT, YOU
KNOW, THEY -- MOST OF THE
CONTROL GROUP WAS ACTUALLY
WORSE.
AGAIN, SOME OF THAT COULD
HAVE BEEN COVID AND IT IS A
LITTLE HARD TO UNTANGLE BUT
MOST TIMES PEOPLE THINK IT
IS FACTOR CHANGE.
I HAVE A LOT OF FRIENDS IN
PSYCHOLOGY HERE AND THEY CAN
WEIGH IN BUT I THINK WE SAW
THAT CERTAINLY IN FINGER AND
A LOT OF THE MULTIDOMAIN
TRIALS AND A LOT OF TIMES
PEOPLE DO GET BETTER.
>> SHANDRA REYNOLDS FROM
UNIVERSITY OF COLORADO.
INTERESTS IN THE BIOMILE BY
MARKERS AND TRYING TO GET A
UNDERSTANDING OF THESE
BIOMARKERS AND PRIOR TO
MIDLIFE.
SEEMS TO ME WITH THE
DISCUSSION OF ETHICS OF
ROLLOUT, I THINK THERE IS A
REAL DEARTH OF INFORMATION
EARLIER IN TERMS OF HOW
THESE BIOMARKERS MIGHT
CHANGE AND WHAT
RECOMMENDATIONS YOU NIGHT
MAKE -- MIGHT MAKE IN TERMS
OF TRYING TO PRIORITIZE THAT
IN THE RESEARCH.
>> YEAH, SO I THINK THAT IS
A GOOD QUESTION.
WE HAVE LOOKED AT THESE
BIOMARKERS FROM BIRTH ON AND
SPECIFICALLY AT THE NFL THAT
HAS A SPECIFIC CUT POINT.
HOW THAT RELATES TO DISEASE
POINT AND COGNITIVE AGING I
DON'T THINK IS FULLY
UNDERSTOOD.
WITH P-TAU, IT DECREASED
WITH AGE, 65 OR 70 BUT ONLY
INCREASED IN INDIVIDUALS
THAT WERE AMYLOID POSITIVE.
SO AGAIN THAT WAS A
PRIMARILY WHITE COHORT AND
WE KNOW ADRD PROCESSES START
EARLIER IN SOME
UNDER-REPRESENTED MINORITIES
AND OTHER COHORTS AS WELL.
SO THERE IS ABSOLUTELY A
NEED IN SOME OF THE MORE
DIVERSE COHORTS HOW THESE
MARKERS CHANGE OVER TIME.
AND THEN WITH THE MORBIDITY,
TOO.
THE EARLY MARKERS, TOO.
I HAVE A COLLEAGUE WHOSE
THOUGHT WAS THE PTAU MAY BE
ELEVATED EARLY IN LIFE, THEN
DROPS DOWN AND INCREASES
AGAIN BUT WE HAVEN'T GOT TEN
A SAMPLE OF THAT TO BE ABLE
TO LOOK AT THAT ACROSS THE
LIFESPAN.
>> CAN YOU COMMENT ABOUT HOW
MUCH OF THE DATA IS COMING
FROM A SINGLE SHOT VERSUS
LONGITUDINAL WORK BECAUSE
THAT IS WHERE I THINK THERE
IS A REAL GAP.
>> I COMPLETELY AGREE WITH
YOU.
THE VAST MAJORITY IS STILL
SINGLE SO WHEN YOU LOOK
LONGITUDINALLY, IT IS
BASELINE AND HOW DOES THAT
CHANGE AND THERE IS STILL
NOT ENOUGH FOCUSES ON THE
INDIVIDUAL VARIABILITY
ACROSS TIME.
>> OKAY, WE ONLY HAVE TIME
FOR ONE MORE QUESTION.
AND THEN HOPEFULLY EVERYBODY
CAN ASK OTHER QUESTIONS AT
THE BREAK.
>> JOHN BRADY WITH A
RESEARCH FOUNDATION BUT MY
DAY JOB IS AS A PHYSICIANS.
I APPRECIATE YOUR LECTURES
TODAY AND SO MANY QUESTIONS
INVOLVING ALL OF THESE BUT
GIVEN THAT YOU ARE FIRST,
DOCTOR POE, I WAS INTERESTED
IN YOUR DESCRIPTION OF SEEP
AND HOW IT IS HEALING.
MY QUESTION IS GIVEN THAT WE
ALSO KNOW MEDITATION INDUCES
SLOW WAVES IN THE BRAIN, CAN
YOU SUBSTITUTE MEDITATION
DURING THE DAY FOR A LITTLE
BIT OF SLEEP AT NIGHT AND
HAS THAT BEEN SHOWN TO BE
REPARATIVE AS WELL?
>> I WOULD SAY I DON'T KNOW
BECAUSE WE HAVE NEVER
MEASURED ACETYLCHOLINE WHILE
WE HAD A RAT MEDITATE.
IT MIGHT BE THAT IS ENOUGH
IF IT LOWERS THE
ACETYLCHOLINE.
BUT YOU COULD ALSO TEACH
THEM TO DO BREATHING
EXERCISES SO AT LEAST GET
THEM TO DO MEDITATION IN
THAT SENSE.
>> THANK YOU.
>> JUST WANT TO SAY THANK
YOU TO ALL OF THE SPEAKERS
FOR THE GREAT TALKS AND THAT
WILL CLOSE OUR SESSION,
THANKS.
[APPLAUSE]
>> THANK YOU.
WE HAVE A BRIEF BREAK THIS
MORNING SO PLEASE BE BACK
AT, I THINK IT'S 10:30 A.M.,
>> THANK YOU AND WELCOME
BACK TO OUR FINAL SESSION.
I SUSPECT SOME PEOPLE WILL
BE WANDERING IN AS I KICK
THIS OFF.
I ALSO WANTED TO -- THE LAST
SESSION OF THIS SYMPOSIUM
TODAY, I WANT TO THANK
MOLLY, JON AND ALSO DAVE FOR
ORGANIZING THIS AND THE
McKNIGHT BRAIN RESEARCH
FOUNDATION FOR BRINGING
TOGETHER SUCH AN
EXTRAORDINARY SET OF
SPEAKERS AND OPPORTUNITY.
AND I THINK WE HAVE BEEN
SEEING THIS PUSH SINCE THE
LAST TIME WE WON ARE SEEING
THIS EXTRAORDINARY SET OF
TECHNOLOGY, THE TESTS, HOW
WE CAN IMPACT THE BRAIN AND
AGING OF INDIVIDUALS IN THE
REAL WORLD AND WE HAVEN'T
DONE ENOUGH.
THERE HAVE BEEN CHALLENGES
AND STARTS AND THINGS THAT
HAVEN'T BEEN GENERALIZED IN
ACADEMIC SETTINGS SO THIS IS
ABOUT WHAT WE CAN DO BETTER,
THE COMPUTATIONAL
STRATEGIES, NEW STUDIES TO
GUIDE STUDIES TO BE MORE
EFFICIENT AND WHAT CAN WE
LEARN FROM TRIALS THAT ARE
ONGOING AND JUST COMPLETED
THAT HAVE HAD SOME
CHALLENGES AND SUCCESSES AND
HOW WE CAN DO BETTER SO WITH
THIS, I WILL CO-CHAIR WITH
RANDY BUCKNER AND MICHAEL
YASSA AND KICK IT OFF WITH
THE FIRST SPEAKER,
ANNE TRELOS HAVE UNIVERSITY
OF MICHIGAN ON MACHINE
LEARNING FOR ADAPTIVE
EXPERIMENTAL DESIGNS.
>> THANK YOU FOR HAVING ME
TODAY AND HELPING ME LEARN A
LOT MORE ABOUT THE
NEUROSTUDY AND I AM AN
ASSISTANT PROFESSOR AND JUST
RECENTLY GOT INTO AGING IN
THE LAST SIX MONTHS AGO AS I
MET KATHERINE KACZOWLOWSKI.
SO HIGH TALK WILL BE ON
MACHINE LEARNING FOR
ADAPTIVE EXPERIMENTAL
DESIGNS.
SO I PUT THREE CATEGORIES OR
EXAMPLES ON THE SLIDE HERE.
SO TENS OF THOUSANDS,
MILLIONS OF NEURONS YOU CAN
RECORD SIMULTANEOUSLY IN THE
BRAINS OF LIVING ANIMALS,
SPATIAL TEMPORAL MEASURES
AND THEN MOVING TOWARDS MORE
NATURALISTIC STIMULI OF
ENVIRONMENTS TO THE
INDIVIDUAL.
AND YOU SEE WE HAVE THIS
TRUE WEALTH OF DATA AND WHEN
WE ADD A TIME VARIABLE TO
ALL OF THIS TO STUDY THINGS
LIKE AGING, YOU INCREASE THE
DIMENSIONALITY OF YOUR DATA.
SO WE WOULD LIKE TO FIRST
MAKE CLAIMS HOW THESE
THOUSANDS OF NEURONS ARE
ACTING TOGETHER WITH COMPLEX
STIMULI THAT MIGHT GUIDE
BEHAVIOR IN THE BRAIN OF THE
INDIVIDUAL.
BUT THE TIME WE HAVE TO DO
EXPERIMENTS CAUSALLY TESTING
HYPOTHESES ALL ARE THE SAME
BECAUSE WE ONLY HAVE 24
HOURS A DAY.
HOW DO WE CHOOSE IN THE
IDEAS WE HAVE SCALING IN
EXPERIMENTS IN HIGH
DIMENSIONAL SPACES IS TO USE
ADAPTIVE ENVIRONMENT
DESIGNS.
IF YOU HAVE PLAYED ONE OF
THESE GAMES SHOWN ON THE
SLIDE, YOU HAVE SHOWN THE
ABILITY TO DO SO.
SO THE FIRST ONE, I THINK OF
A OBJECT AND THEN YOU ASK
QUESTIONS TO TRY TO FIGURE
OUT WHAT THAT IS.
IF I CHOOSE A DUCK, IS IT A
HORSE, SO ON, SO YOU PICK
THE NEXT QUESTION.
BUT WHAT IF I ASK YOU TO
POSE YOUR QUESTIONS IN
ADVANCE, WRITE THEM DOWN AND
HAND THEM TO ME?
YOU WOULD PROBABLY KNOW I
WAS THINKING OF A DUCK BUT
ONLY IF YOU KNEW A SMALLER
SUBSET OF WHAT I WAS
THINKING AHEAD OF TIME.
AND THE REASON THIS IS VERY
WITTABLE FOR YOU IS YOU ARE
ABLE TO LEVERAGE
INFORMATION, DATA AS IT IS
BEING ACQUIRED WHICH ALLOWS
YOU TO GUIDE SELECTION OF
THE NEXT BEST QUESTION TO
ASK AND SO WHAT I AM GOING
TO SHOW YOU IS ADAPTING THE
MACHINE MODEL AND HOW IT CAN
BE PARTICULAR TO MANY
NEUROMICE IN THE STUD DE.
SO FIRST I WILL TALK ABOUT
ITIVE MEASURES AND THEY HAVE
ABILITY TO WORK WITH DIVERSE
FRAME SETS.
THEY NEED THAT DIVERSITY TO
GET THE CROSS SET ACROSS THE
POPULATION.
AND IT ALLOWS US TO TUNE
MODELS TO SPECIFIC
INDIVIDUALS, PERSONALIZE
THEM AND I WILL TALK ABOUT
SOME METHODS THAT ALLOW US
TO DO THAT.
SECONDLY, THESE KIND OF
MODELS ALLOW US TO
IMMEDIATELY LEARN FROM
INTERVENTION RESULTS, WHICH
IS THE GAME OF 20 SECONDS,
SO ADAPTING THE STRATEGY CAN
ALLOW US TO BE MORE
EFFICIENT IN OBTAINING
SOMETHING OF INTEREST AS
WELL AS DESIGNING SOME
OPTIMAL ALLOCATION OF TESTS
WHEN YOU HAVE A LIMITED
NUMBER OF THEM.
AND THEN WE WILL TALK ABOUT
MALADAPTATION.
SO ONE KIND OF VARIATION WE
MIGHT WANT TO THINK ABOUT
INCLUDING IS IN MODELS OF
NEURODYNAMICS.
SO FIRST WE WANT TO DISCOVER
NEW PATTERNS OF NOURISH
ACTIVITY THROUGH TIME SO
IDENTIFY LATENT ITEMS IN OUR
DATA AS WE DEPLOY THE DATA.
SO WE MIGHT SEE BENEATH THE
ORANGE CIRCLE THERE IS A
CURVED GRAY TRAJECTORY, SOME
REPEATED PATTERN YOUR BRAIN
CAN RECOGNIZE BUT THERE IS
SOME VARIATION THERE.
RATHER THAN SEEING EACH OF
THESE CURVES AS A NEW
PATTERN OR FEATURE, WE
INSTEAD TO WANT CHARACTERIZE
THEM AS SOME SINGLE FEATURE
WITH VARIATION AROUND A
MEANS SO WE DEVELOPED A
MODEL INDIVIDUALIZED IN
MORNING THAT USE A GASEOUS
MIXTURE IN MARKUP MODELS AND
CAPTURES VARIATION.
SO WE ULTIMATELY STAY
FLEXIBLE TO THE
IDENTIFICATION OF NEW
PATTERNS AS TIME GOES ON.
AND SO HERE ARE SOME VIDEOS
OF DYNAMICS THAT THE SAME
ALGORITHM IS ABLE TO QUICKLY
LEARN HOW TO MODEL, TUNE FOR
A GIVEN INDIVIDUAL.
YOU CAN SEE WE'RE LOOKING AT
DATASETS, THE TOP FROM A CAT
AND THE BOTTOM FROM A MOUSE
AND IT IS THE SAME ALGORITHM
APPLIED TO EACH OF THESE
DATASETS.
SO CHANGING THE MODEL CAN
ALLOW US TO SEE NEW
INTERESTS AND WE HAVE SEEN
THIS THROUGHOUT THE SUMMIT
OF FINDING NEW LATE TEN
FEATURES.
BUT WHAT YOU CAN ALSO DO IS
USE MACHINE LEARNING DURING
THE ACQUISITION PROCESS AND
IDENTIFY WHICH QUANTITIES OF
INTEREST WE SHOULD BE PAYING
THE MOST ATTENTION TO AND
NOMINATE FOR FUTURE STUDIES.
SO HERE I AM USING DATA FROM
THE PUBLICATION ON THE TOP
RIGHT THAT LOOKS AT
IDENTIFYING WHICH BEHAVIORAL
FEATURES FROM THIS VIDEO OF
A MOUSE ARE FEATURES OF
ONGOING NEUROACTIVITY.
SO RATHER THAN LOOKING AT
PREDEFINING FEATURES OF THE
MOUSE, LIKE PUPIL SIZE, THEY
FIND INFORMATION ACROSS THE
CHEEK THAT ARE MORE
PREDICTIVE OF NEURAL
ACTIVITY SO IT IS NOT
LOOKING AT IT ALL AT ONCE
AND HERE YOU HAVE A
STREAMING FORM THAT SHOWS
VERY SIMILAR RESULTS IN ONLY
A MINUTE OR TWO OF DATA.
SO IF YOU LOOK AT THE BOTTOM
RIGHT, YOU SEE THE CON V
DEFENSE IN ABOUT 60 SECONDS
SO WE'RE ABLE TO IDENTIFY
THE SAME RELEVANT FEATURES
THAT MIGHT HAVE OTHER DEVICE
BE ACQUIRED, TO GO POSTDATE
TO AND THEN A POST TALK
ANALYSIS.
SO STARTING FROM SCRATCH, WE
CAN LOOK AT THESE ONGOING
DATASETS, NEW INFORMATION IN
THE MODEL AND SAY YOU SHOULD
INTERVENE ON THESE.
AND IT MAY BE DIFFERENT FOR
EACH INDIVIDUAL BUT TUNING
IT TO THE INDIVIDUAL IS VERY
POSSIBLE.
SO WHEN I TALK ABOUT HOW WE
CAN USE THESE KIND OF MODELS
THAT UPDATE THEMSELVES IN
RESPONSE TO NEW DATA TO HELP
GUIDE OUR CHOICE OF WHAT AND
WHERE TO MEASURE, WHAT WHAT
KIND OF NEW DATA IS BEST TO
COLLECT, AND THIS IS WORK I
DID AT UNIVERSITY --
[INDISCERNIBLE]
AND HER LAB USES MODELS OF
ZEBRAFISH.
SO WE WANT TO ASK THE
QUESTION HOW DO WE CHOOSE
WHAT IS RELEVANT TO THE
POPULATION.
SO IF YOU LOOK AT THE FIGURE
ON THE LEFT, THIS IS A
MOVING RESOLUTION AT
45 DEGREES.
IT HAS NEURAL FIRING RATES,
EIGHT DIFFERENT DIRECTIONS
OF MOTION.
IF WE HAD LOTS OF TIME, WE
COULD MEASURE THIS AT
15-DEGREE RESOLUTION AND
WHAT YOU FIND IS A NEURON
WHO MIGHT HAVE BEEN
IDENTIFIED AS SELECTIVE TO
THAT RIGHT MOTION IS IN FACT
BIMODALLY STIMULATED SO LEFT
EYE AND RIGHT EYE AND THIS
GIVES YOU A BETTER PICTURE
OF THE NEURAL CIRCUITS AND
UNDERLYING FACTORS.
BUT THEN WHEN WE TRY TO THIS
IN HIGHER DIMENSIONAL SPACE,
EVEN TWO DIMENSIONS, THAT
LEAVES US WITH A PROBLEM.
NOW WE HAVE 600 STIMULI TO
PRESENT TO THOSE FISH.
NOW YOU ARE TALKING TENS OF
THOUSANDS OF THINGS YOU
MIGHT NEED TO MEASURE SO
THIS IS CLEARLY INFEASIBLE.
SO WHAT WE WILL DO INSTEAD
IS USE AN ONLINE
OPTIMIZATION APPROACH.
SO HERE BOTTOM LEFT, WE WILL
BE USING THE IMAGING TO GIVE
US THIS NEURAL ACTIVITY.
WE WILL START BY SHOWING A
PARTICULAR STIMULUS AND
OBSERVING THE NEURAL
RESPONSE.
WE INCORPORATE THIS INTO A
MODEL USING DASH AND
PROCESSES TO THE CURVE AND
THERE YOU SEE THE HEAT MAP.
THEN YOU GET A LOOK AT THE
UNCERTAINTY OF PREDICTIONS
AND THIS IS HOW WE USE WHAT
TO MAXIMIZE NEXT.
AND SO AS WE BASICALLY
CHOOSE THE NEXT SELECTION,
WE OBSERVE A NEW DATA POINT
AND ITERATE TILL WE HAVE A
PARTICULAR CONFIDENCE LEVEL
THAT THE MODEL HAS REACHED.
SO THIS IS JUST A QUICK
VIDEO OF THIS HAPPENING.
YOU CAN SEE NEURAL
RESPONSES, TUNING CURVE,
ESTIMATE GETTING REFINED IN
THE CENTER AND THEN
UNCERTAINTY ON THE FAR RIGHT
GOING TO BLACK WHICH IS
GOING DOWN.
SO WITH UNCERTAINTY, IT GOES
DOWN AND THIS IS WHAT ALLOWS
US TO KNOW WHEN WE CAN STOP
MEASURING AND GO ON TO THE
NEXT NEURON.
WITH UNCERTAINTIES IN MANY
OF THESE MODELS WE CAN
DEPLOY EARLY STOPPING AND
APPLY WHAT WE LEARNED TO
STRATEGIES.
SO WHAT MIGHT TAKE AN HOUR
TAKES ONLY THREE TO FIVE
MINUTES AND AGAIN THESE
METHODS CAN ADAPT THEMSELVES
TO A PARTICULAR INDIVIDUAL
OR IN THIS CASE BRAIN AREA
AUTOMATICALLY.
SO HERE WE SEE THIS IS A
NEURAL POPULATION MAP AND
YOU CAN SEE IT IS CHOOSING
DIFFERENT LOCATIONS
DEPENDING ON THE REGION
WHERE MORE NEURONS ARE
INDEED MORE MOST RESPONSIVE
AND IT CAN DO THIS WITHOUT
ANY HUMOR INTERVENTION SO
THE EXPERIMENTS CAN RAPIDLY
IDENTIFY WHERE IT SHOULD BE
MEASURING BASICALLY
ATOMICALLY.
SO ONE MORE SLIDE TO SHOW
YOU HOW WE DESIGN CAUSAL
EXPERIMENTS THAT CAN SCALE
TO HIGH DIMENSIONAL SPACES.
SO WE DON'T WANT TO LEARN
THIS ON AVERAGE BUT APPLY
THIS TO AN INDIVIDUAL SO WE
WANT TO LEARN THIS
EFFICIENTLY SO WE CAN
IDENTIFY WITH ONE PARTICULAR
ORGANISM.
AGAIN, WE USED ZEBRAFISH AND
WE CAN USE STIMULATION TO
PERTURB THE NEURONS AND
REFRESH SURE RESPONSES OF
ALL THE OTHER NEURONS IN THE
NETWORK.
SO THIS IS A PRETTY TYPICAL
STRAIGHT FRAMEWORK TO DO
THIS.
INTERVENE ONCE, MEASURE
RESPONSES, THEN INTERVENE
AGAIN AND YOU DO THIS FOR
EACH NEURON IN THE NETWORK.
SO FOR 100, IT WILL TAKE YOU
42 MINUTES.
IF YOU DO 1000 NEURONS, IT
WILL TAKE YOU DAYS.
SO WE DO NOT HAVE THIS TIME
OR INTERVENTIONS.
SO WHAT WE DID WAS TURN TO
THE STATISTICAL GROUP
TESTING.
SO HERE WE'RE NOT SELECTING
ONE AT A TIME BUT A GROUP OF
THEM SIGN OBTAIN CROSSLY.
WE CAN LOOK FOR NETWORK
RESPONSES AND MEASURE VERY
RAPIDLY THE FULL STRUCTURE
OF THE NETWORK.
SO NOT ONLY IS THIS FASTER
BECAUSE WE ARE USING
MULTIPLE INTERVENTIONS BUT
WE CAN REWRITE THIS PROBLEM
USING VARIATION AND THAT IS
AT THE BOTTOM AND WHAT THIS
DOES IS ALLOW US TO MEASURE
UNCERTAINTY IN OUR
EXPERIMENTS.
NOW WE DON'T NEED TO CHOOSE
RANDOM INTERVENTIONS BUT
INSTEAD OBSERVE THE
INTERVENTIONS, INCORPORATE
IT IN THE MODEL, SEE WHERE
THE MODEL IS UNSERB AND
CHOOSE THOSE FOR THE NEXT
INTERVENTION.
SO THIS IS AN ADAPTIVE
PROCEDURE SCALED REALLY WELL
FOR LARGE NETWORKS.
IF YOU LOOK AT THE DIAGRAM
ON THE RIGHT IT ALLOWED US
TO EXAMINE 10 TO THE 8TH IN
TWO HOURS.
SO I HOPE I SHOWED YOU A FEW
WAYS IN WHICH INCORPORATING
MACHINE MODELS IN A
EXPERIMENTAL SET AND NOT
JUST USING THEM FOR A TALK
CAN BE EXTREMELY USEFUL FOR
CONSIDERING POWERFUL
EXPERIMENTAL DESIGNS.
THESE CAN BE USED ACROSS
POPULATIONS AND TUNE MODELS
TO SPECIFIC INDIVIDUALS.
THEY ALSO ALLOW US TO
ACCUMULATE DATA AS ACQUIRED
AND EXPONENTIALLY LEARN MORE
EFFICIENTLY WHICH IS VERY
DOABLE SINCE WE HAVE A
LIMITED NUMBER OF TRIALS TO
INTERVENE.
I SHOULD POINT OUT THAT NONE
OF THESE WERE SPECIFIC TO A
PARTICULAR ORGANISM.
WE USED THEM ON MICE, FISH,
APAK, USING OCTOPUS AND
OTHER ORGANISMS AS WELL.
IF YOU WANT MORE INFORMATION
ON HOW YOU CAN INCORPORATE
THIS IN YOUR EXPERIMENTAL
DESIGNS, I WOULD BE MORE
THAN HAPPY TO CHAT WITH YOU
ABOUT IT.
SO WITH THAT I THANK MY LAB,
MY ADVISOR AND MY FUNDING
SOURCES.
THANK YOU.
[APPLAUSE]
>> THANK YOU FOR THAT
SPECTACULAR TALK.
WE WILL CONTINUE WITH Dr.
NATHAN PRICE FROM THORNE
HEALTHCARE WHO WILL BE
SPEAKING ABOUT TAKING
DIGITAL TWIN MODELS OF
COGNITIVE HEALTH IN AGING.
>> THANK YOU, GREAT TO BE
HERE.
REALLY INTERESTING TO HEAR
SO MANY FANTASTIC TALKS.
A LOT OF IDEAS OFF THE LAST
ONE I AM EXCITED ABOUT.
SO I AM GOING TO TALK A
LITTLE BIT TODAY ABOUT
DIGITAL TWIN MODELS OF
COGNITIVE HEALTH IN AGING
AND AT THE END, ESPECIALLY
HOW THIS LEADS US TO A
DIFFERENT WAY OF THINKING
HOW WE MIGHT DESIGN CLINICAL
TRIALS.
SO I WILL START VERY BROADLY
JUST IN TERMS OF MY
BACKGROUND AND PERSPECTIVE.
I AM VERY INTERESTED IN AS
BROADLY ACROSS OUR MEDICAL
AND RESEARCH ENTERPRISE ON
THE IDEA THAT WE INTERVENE
MUCH TOO LATE IN GENERAL AND
SPEND WAY TOO MUCH TIME
STUDYING ONLY LATE-STAGE
DISEASE AND NOT THE EARLIEST
TRANSITION STATES TO IT.
I WROTE A BOOK ON THIS WITH
LEE HOOD THROUGH HARVARD
PRESS CALLED SCIENTIFIC
WELLNESS AND WE HAVE BEEN
DOING THESE LARGE
LONGITUDINAL STUDIES ON
HEALTHY PEOPLE FOR ABOUT A
DECADE WHICH I AM NOT GOING
TO GET INTO TODAY BUT
RELATES TO HOW WE THINK
ABOUT COGNITIVE AGING AND
WHAT WE CAN DO.
WE SAW SOME BEAUTIFUL
EXAMPLES IN THE LAST SESSION
WHICH WAS REALLY FASCINATING
ABOUT HOW OFTEN THINGS THAT
HAPPEN EARLIER IN LIFE CAN
HAVE AN IMPACT LATER.
A REALLY WONDERFUL
PERSPECTIVE.
I CAME UP TO GIVE A LECTURE
AT RPI, DRIVING THROUGH THE
CORE, LISTENING TO A BOOK
WRITTEN 2000 YEARS AGO BY
SENECA AND HE WAS TALKING
ABOUT LONGEST LONG
LONGEVITY AND HAD A QUOTE I
REALLY LIKED AS HE WAS
EXPOSED TO HIS YOUNG
PROTEGE‘, IT MAKES A GREAT
DEAL OF DIFFERENCE IF A MAN
IS LENGTH THING IN HIS LIFE
OR HIS DEATH AND I THOUGHT
THAT A BEAUTIFUL WAY TO PUT
IT.
FOR THOSE OF US IN THE
LONGEVITY OR AGING SPACE,
THE NEXT PIECE OF ADVICE I
FOUND REALLY FASCINATING
BECAUSE HE SAID THE NEXT
CRAZE IS PERIODIC FASTING
AND WE HAVE ADVANCED TO
INTERMITTENT FASTING SO WE
HAVE COME A LONG WAY.
THERE WE GO.
SO OBVIOUSLY IN COGNITIVE
AGING, THIS MAKES A HUGE
DIFFERENCE.
I WROTE A PIECE FOR THE L.A.
TIMES AGAIN WITH LEE LAST
YEAR.
BUT ONE OF THE THINGS THAT
REALLY STRIKES YOU WHEN YOU
LOOK AT SAY ALZHEIMER'S AND
WHAT YOU CAN DO ABOUT IT, IS
WHEN YOU LOOK AT DRUGS, THEY
ARE HIGHLY EXPENSIVE.
WE HAVE SPENT, DEPENDING ON
THE ESTIMATE, 300 BILLION UP
TO SOME ESTIMATES ARE A
TRILLION CUMULATIVELY ON
ANTI-AMYLOID THERAPIES AND
OTHER DRUGS OVER THE DECADES
WITH VERY LIMITED BENEFIT.
HOWEVER IF YOU LOOK AT
PREESSENTIAL, THE
PREVENTION, THE EFFECTS ARE
YEARS AWAY AND THE AFFECT
SIZE MUCH LONGER AND THIS IS
TRUE IN COMMUNITIES AS WELL.
ONE OF THE REALLY STRIKING
FINDINGS, THE HISPANIC
COMMUNITY IN PARTICULAR IS
HIGHLY RESPONSIVE TO THAT.
THE ESTIMATE IS 56 PERCENT
OF ALZHEIMER'S IS AVOIDABLE
OR COULD BE LIMITED THROUGH
HIVE STYLE PREESSENTIAL AND
THAT IS MORE DATA COMING OUT
OF STUDIES.
SO WE KNOW THAT FOCUSING ON
COGNITIVE AGING MAKES A HUGE
DIFFERENCE AND THERE IS A
LOT YOU CAN DO OVER THESE
TRAJECTORIES.
THIS HAS BECOME LESS
CONTROVERSIAL OVER THE LAST
FEW YEARS.
THERE WAS A GREAT STUDY IN
LANCET AROUND ALZHEIMER'S
DISEASE, THAT THERE ARE
THINGS YOU CAN DO TO
MAINTAIN YOUR BRAIN HEALTH
LONGER AND YOU CAN SEE THE
THINGS THERE, MANY ADDRESSED
IN THE MEETINGS WE HAVE HAD
HERE OVER THE LAST COUPLE OF
DAYS.
SO COMING OUT OF DIGITAL
TWINS, A COLLEAGUE OF MINE
TOM PATTERSON MANY YEARS AND
COMING OUT OF SMITH CLINE,
HOW TO MAINTAIN BRAIN HEALTH
SO THIS STARTED OUT AS A
MODEL LOOKING AT ORDINARY
MODELS, THEN ADDING IN
UNCERTAINTY AND YOU ARE ABLE
TO SIMULATE TRAJECTORIES OF
COGNITIVE HEALTH OVER
LIFESPAN.
NOW I WILL NOT GET INTO IT
IN THE INTEREST OF TIME.
THIS HAS GIVEN ME A VERY
DIFFERENT VIEW I HAVE TO SAY
IN WHAT I THINK ARE THE MAIN
DRIVERS OF ALZHEIMER'S
DISEASE BUT ONE OF THE
THINGS THIS REALLY GETS AT
IS HOW DOES THE BRAIN
MAINTAIN ENOUGH ENERGY TO
STAY ALIVE?
20PERCENT OF YOUR BRAIN'S
ENERGY USE, 2 PERCENT
BIOMASS, OXYGENATION OF THE
BRAIN GOES DOWN AS YOU GET
OLDER, SOLVING THOSE GETS
HARDER AND HARDER, TURNS OUT
YOU WANT TO KEEP ASTROCYTES
LOW TO KEEP ENERGY LEVELS
HIGH DURING OXYGEN
DEPRIVATION.
APOE4 TRANSPORTS THE ENERGY
OUT OF THOSE CELLS AND DOES
IT SLOWLY, LESS EFFICIENT,
THEREFORE THEY DIE.
APO2 DOES IT QUICKLY AND
THEY STAY HIGH, YOU CAN
MODEL A LOT OF THESE IN TIME
AND IF YOU WANT TO CHAT
ABOUT THAT, HAPPY TO DO
THAT.
NOW AS MENTIONED, THIS MODEL
STARTS AS A MODEL OF BRAIN
HEALTH, MAINTAINING ENERGY,
TAKING OUT THE TRASH, WHAT
YOU DO A LOT WHEN YOU ARE
ASLEEP WHICH WE HEARD ABOUT
EARLIER.
MICROGLIA FUNCTIONS ALL OF
THOSE KIND OF THINGS IN THE
MODEL.
ONCE WE BUILT THIS MODEL TO
SAY HOW DO YOU MAINTAIN
HEALTH, THEN OF COURSE YOU
CAN LAYER ON TO THAT THE
DIFFERENT ASPECTS OF THE
DRIVERS OF DISEASE, RIGHT?
SO THIS IS JUST KIND OF A
SANITY CHECK.
SO WE DID THIS FOR
ALZHEIMER'S AFTER THE FACT
AND SO HERE THESE ARE KNOWN
EFFECTS OF GENETIC AND
LIFESTYLE RISK FACTORS.
I CAN SEE MY COMPLICATION
THERE IS GENERAL KNOWLEDGE
TO ANYONE IN THE ROOM BUT WE
KNOW APOE4 GIVING YOU HIGH
RISK, APOE2 LOW RISK AND SO
FORTH AND THEN AT THE BOTTOM
LISTED FROM VARIOUS PAPERS
SOME OF THE RISK FACTORS.
SO GLOMULAR FILTRATION RATE,
IF THAT IS HIGHWAY, YOUR
ALZHEIMER'S CONVERSION IS
LOW, VITAMIN D IS LOW, ALD
HYPER'S ALSO LOW.
CORTISOL, STRESS LEVELS ARE
HIGH, HIGH AND SO FORTH.
SO THESE ARE A COMPILATION
OF DATA FROM LOTS OF STUDIES
ON LOTS OF PAPERS ON WHAT WE
KNOW ABOUT THE CONVERSION
RATES AND HAZARD RATIOS TO
ALZHEIMER'S.
SO ONE OF THE THINGS I
BRIEFLY DESCRIBED WAS TO
GENERATE DIGITAL TWINS ON
THAT SO WE HAVE GENERATED
ABOUT 26 MILLION OF THESE ON
TOP OF THIS CORE MODEL.
ONE OF THE QUESTIONS WAS HOW
SIMILAR IS THIS POPULATION
IF YOU SIMULATE ON THESE
DATA AND THERE IS DATA AND
INSIGHTS BEHIND THE MODEL
FROM ABOUT 1200 CARES AND WE
COMPARED IT TO 30 DIFFERENT
CLINICAL RESEARCH STUDIES
AND TRIALS AND THIS IS WHAT
IT LOOKS LIKE.
WHEN YOU EVALUATE THAT
POPULATION, SO THE SOLID
LINES HERE ARE THE DIGITAL
POPULATION, THE FATTER LINES
THE ACTUAL DATA, WHAT YOU
FIND IS THAT POPULATION
LOOKS AN AWFUL LOT LIKE THE
ACTUAL POPULATION.
SO SOME OF THE THINGS I
MENTIONED BEFORE ON THE
EFFECTS OF APOE4 DYNAMICS OR
APOE2 DYNAMICS, BEING ABLE
TO EXPLAIN WHEN PEOPLE TURN
INTO DEMENTIA.
TURNS OUT IF YOU TAKE THE
TWO ENERGY LOWERING
EFFICIENCY BASED ON APOE2
AND APOE4, THIS GIVES YOU
BACK THOSE CURVES AND YOU
CAN CENTER THIS AROUND
KEEPING NEURONS ALIVE FROM A
ENERGETIC LEVEL.
SO WE GET INTO ALL THESE
THINGS AS WE GO THROUGH THIS
SO WE CAN DO SIMULATIONS,
AGAIN OVER TIME, THAT RELATE
MOLEC ULAR LEVEL DETAIL TO
WHAT IS HAPPENING IN
PATIENTS.
SO THIS THEN LEADS TO A
DIGITAL TWIN SIMULATION.
I WILL SHOW A VERSION OF
THIS HERE AND SEE HOW WELL
YOU CAN SEE THAT.
BUT WE TAKE THE RELATABLE
MODIFIABLE RISK FACTORS WE
HAVE DETERMINED, THE NEXT
SLIDE, BASED ON A MAN WHO IS
50 YEARS OLD, HAS TWO COPIES
OF THE APOE4 GREEN, LOW
VITAMIN D, SLEEPING
TERRIBLY, CORTISONE LEVELS
NOT TERRIBLY BAD, YOU CAN
PUT THIS KIND OF INFORMATION
IN, AGAIN QUITE READILY TO
MEASURE AND WHAT YOU GET OUT
OF A MODEL LIKE THIS IS A
PROBABILITY DISTRIBUTION.
SO SHOWN ON THE RIGHT HERE
WHERE YOU SIGH THE HISTOGRAM
IS A PROBABILITY
DISTRIBUTION.
GIVEN THIS PERSON'S DATA,
THE MOST LIKELY ONSET OF AGE
FOR DEMENTIA IN THIS
INDIVIDUAL IS AGE 61 THERE
IS A 99 PERCENT CHANCE THAT
THIS PERSON GETS TO AGE 9
WITHOUT HAVING ALZHEIMER'S
DISEASE.
SO THINK A BIT ABOUT THIS AS
GHOST FOR CHRISTMAS FUTURE,
YOU ARE NOT DOING
INTERVENTION AND WHAT IS THE
EXPECTATION GIVEN WHERE YOU
ARE AT?
NOW AT THE BOTTOM WHAT WE
HAVE IS A SERIES OF
INTERVENTIONS, FOCUSED ON
THINGS VERY SAFE TO DO IN AN
OTHERWISE HEALTHY
INDIVIDUAL, EXERCISE, SLEEP,
DIETARY SUPPLEMENTS,
NUTRITION, THINGS OF THIS
NATURE BUT WHAT YOU CAN SEE
GOING ON AT THE BOTTOM IS
YOU CAN CALCULATE THE
PERCENTILE RESPONDER YOU
EXPECT EACH PERSON TO BE AT
FOR EACH OF THESE AND THE
BENEFIT.
SO IF YOU ARE LOOKING AT THE
BOTTOM THERE, YOU ARE
LOOKING AT THINGS LIKE
B-COMPLEX, GETTING BRAIN
OXYGENATION UP,
PHOSPHATIDYSERINE AND SO
FORTH.
IF YOU DO THESE ONE AT A
TIME WHAT YOU WILL SEE AT
THE BOTTOM IS THE PREDICTION
OF CHANGE IS ZERO.
THERE IS NO PREDICTION OF
CHANGE IN ANY OF THESE CASES
FOR ANY SINGLE INTERVENTION
BUT IF YOU GO TO THE TOP
LINE WHERE IT SAYS AL, ALL
IS JUST TO MAKE THE SLIDE
SHORTER, YOU CAN OPTIMIZE
WHICHEVER ONE YOU WANT AND I
DON'T HAVE TIME TO GO
THROUGH THAT DATA BUT WE
BELIEVE THERE ARE SIX EXTRA
HEALTHY BRAIN YEARS OF LIFE
ON THE TABLE FOR THIS
INDIVIDUAL WHERE YOU CAN
SHIFT THAT.
YOU CAN TELL THEM WHAT THAT
IS AND TELL THEM HOW MUCH
BENEFIT YOU WOULD EXPECT
THEM TO GET.
TO GET A SENSE OF WHERE THIS
CHANGES PERSON TO PERSON, I
WILL RUN THROUGH A VIDEO OR
ANIMATION JUST SO YOU CAN
SEE THIS.
HOPEFULLY THIS WILL RUN --
YES, OKAY.
SO THIS YOU CAN SEE.
I DON'T THINK WITHOUT A
COMPUTER I CAN PAUSE THIS
BUT YOU CAN SEE HOW MUCH
THIS IS JUMPING AROUND OR
HOW DIFFERENT AN
INDIVIDUAL'S PATTERN LOOKS
LIKE.
AND YOU WILL SEE SOME PEOPLE
HAVE QUITE NARROW RANGES,
ONLY A LITTLE BIT ON THE
TABLE, SOME PEOPLE HAVE BIG
RANGES.
NOW THIS RELATE BACK TO
ANNE'S TALK AND ESPECIALLY
WHEN YOU SEE THESE BROAD
RANGES, YOU CAN USE THE
MODEL TO SAY WHAT IS THE
NEXT THING I WOULD LIKE TO
MEASURE TO GET A MORE
FOCUSED PREDICTION ON THIS
INDIVIDUAL AND HOW FAR CAN I
PUSH THIS INTO THE FUTURE.
YOU CAN ALSO DO THIS FOR
DRUGS.
WE HAVE DONE THIS PROACTIVE
SIMULATION OF TRIN2
AGONISTS.
THAT WOULD HAVE A SIX MONTH
BENEFIT FOR PEOPLE AFTER
DIAGNOSIS BUT YOU GET A
CURVE WHERE THERE IS THIS
LONG TAIL AND THERE ARE
DIGITAL TWINS WE WOULD LIKE
AT THAT GET THREE, FOUR,
FIVE YEARS OF BENEFIT, AND
WHEN YOU RUN THE SIMULATION,
YOU CAN PULL BACK AND SAY
WHAT MAKES THEM A SUPER
RESPONDER, WHAT ARE THE
CHARACTERISTICS OF THIS
INDIVIDUAL AND USE THAT
APPROACH WITH DIFFERENT
STRATEGIES TO FIND DIFFERENT
COMBINATIONS FOR PEOPLE WHO
ARE SUPER RESPONDERS.
SO THE MAIN THING I WANT TO
FINISH ON HERE IS HOW THIS
CAN HELP US WITH
PERSONALIZED MEDICINE.
SO DIFFERENT STYLES OF TRIAL
DESIGN.
ONE EXAMPLE, FROM
OBSERVATIONAL STUDIES
ELDERLY PEOPLE WHO ARE LOW
IN VITAMIN D GET ALZHEIMER'S
MUCH SOONER THAN THOSE WHO
DON'T AND THAT IS ONE OF THE
THINGS WE KNOW OF BUT WHEN I
GAVE THE EXAMPLE OF THE
LANCET STUDY, FOR EXAMPLE,
WE DO NOT INCLUDE VITAMIN D
AS A OBSERVATION FOR
ALZHEIMER'S.
SO WHY WOULD WE NOT DO THAT?
WE HAVE DONE A FEW
RANDOMIZED CLINICAL TRIALS
AND VITAMIN D HAS FAILED ON
THOSE CLINICAL TRIALS,
THEREFORE WE CAN CORRELATE
AS WE GENERALLY DO, NO
CAUSATION, WE THROW IT AWAY.
I WOULD SAY WE'RE DOING THIS
TOO MUCH.
THESE ARE MOST OF THE
TRIALS, MOST OF THEM SHORT,
SIX MONTHS TO A YEAR, THE
LONGEST THREE YEARS THAT WAS
DONE ON PEOPLE 67.8 YEARS OF
AGE.
SO TO BE CLEAR WHEN WE DO
THE INTERVENTION, THE KNOWN
MECHANISM FOR VITAMIN D,
ATTEN UNITED STATES THE
VARIABILITY OF THE
CHOLESTEROL PATHWAY OVER A
DECADE OF LIFE.
WHEN WE SIMULATE THAT, IT
GIVES BACK TO US WHAT WE SEE
IN THE OBSERVATIONAL DATA
THAT YEAH, THIS WOULD IN
FACT LOWER THE CONVERSION TO
ALZHEIMER'S SO THAT GIVES ME
SOME CONFIDENCE TO THE MODEL
BUT THAT THE MECHANISM WOULD
BE EXPLANATORY.
NOW WHAT YOU CAN DO IN A
SIMULATION IS SIMULATE THE
EXACT TRIALS THAT WERE RUN.
SO WE WENT BACK, SIMULATED
THE TRIALS, EXACTLY THE
AGES, TRIALS THEY WERE
FOLLOWED AND SO FORTH AND
SAID IN THE SIMULATION GIVEN
THE MECHANISM WAS TOTALLY
EXPLAINABLE FOR WHAT YOU SAW
OR OBSERVED, WOULD WE HAVE
EXPECTED ANY OF THESE TRIALS
TO SHOW US A SIGNAL?
AND THE OWNS IS ANSWER IS
NO.
SO IN MY MIND VITAMIN D HAS
NOT BEEN TESTED AND ALTHOUGH
IT HAS NOT SUCCEEDED, IT HAS
NOT FAILED.
SO IN THE MODELS, THIS IS A
COMPLICATED PLOT AND THERE
ARE JUST A COUPLE OF MINUTES
LEFT BUT BASICALLY THE TIME
IS MUCH TOO SHORT TO HAVE AN
EFFECT.
YOU WOULD NEED TO WATCH TEN
YEARS IN THOSE TRIALS BEFORE
YOU SEE SEPARATION WHEREAS
ON THE RIGHT THE
OBSERVATIONAL TRIALS ARE
LONG ENOUGH.
SO THE BIG POINT I WANT TO
MAKE IN TERMS OF CLINICAL
TRIALS DESIGN IS I THINK THE
WAY WE DO PREVENTIVE
CLINICAL TRIALS IS REALLY
SUBOPTIMAL AND THE THE WAY I
THINK WE DO THIS THAT MAKES
NO SENSE, THE CURRENT
PARADIGM WE TEND TO RUN A
BLIND AND RANDOMIZED
CLINICAL TRIAL, THAT IS
GOOD, BUT WE ONLY TEST ONE
COMPOUND.
AND WHEN YOU DO THE
SIMULATIONS, THE ONE
COMPOUND IS ALMOST NEVER
EFFECTIVE.
YOU ARE DEPENDING ON SHEER
DUMB LUCK THAT THAT ONE
COMPOUND IS A PIECE OF THE
PUZZLE.
SO IT DOESN'T MATTER IF YOU
HAVE IN SUBJECT FOR THE
PATHWAY, IF INFLAMMATION IS
OVER, IT IS NOT ENOUGH, IT
IS A SMALL PIECE OF THE
PUZZLE.
SO WHAT WE FIND THEN IS IF
YOU DO A DIFFERENT METHOD,
INSTEAD OF TESTING A
COMPOUND, WHAT WE WILL TEST
IS THE TWIN MODEL ITSELF,
LIKE THE ALGORITHM.
SO THIS LETS YOU TEST ONE
THING SO YOU ARE NOT GETTING
INTO ALL THE SQUISHINESS OF
THINGS CHANGING ALL THE TIME
AS YOU ARE GOING THROUGH, SO
YOU TEST ONE ELEMENT BUT IT
IS COMPLICATED, A COMPLEX
OBJECT.
AND WHAT THAT MEANS IS YOU
TAKE THE MODEL, TAKE A
PERSON'S INDIVIDUAL DATA AND
EVERY PERSON WILL GET THEIR
OWN INDIVIDUALIZED
COMBINATION.
SO YOU ARE NOT TESTING A
COMPOUND BUT YOU ARE TESTING
IN ESSENCE YOUR ENTIRE
CONCEPTION OF WHAT IS
DRIVING THE DISEASE AND HOW
TO PERMIZE IT AND --
PERSONALIZE IT AND WHAT YOU
ARE DOING.
AGAIN YOU ARE NOT DEPENDING
ON LUCK, YOU ARE GUIDING IT,
YOUR EFFECT SIZE IS HIGHER,
AND WHEN LOOKING AT VITAMIN
D, THIS IS CRUCIAL OR
ANYTHING OUT OF THE PRODUCT
WORLD, YOU ARE NOT TALKING
ABOUT A DRUG THAT WOULD TAKE
BILLIONS OF DOLLARS AND
RUNNING THE TILE THEREFORE
IS INFEASIBLE, NO ONE HAS
EVER DONE IT.
BUT IF YOU RUN IT THIS WAY,
YOU WILL GET MUCH LARGER
EFFECT SIZES, LOWER END,
MODELS THAT ARE FEASIBLE AND
I THINK THIS LETS US GET TO
A STYLE OF CLINICAL TRIAL I
AM EXCITED ABOUT.
AND IN THE INTEREST OF TIME,
I WILL SKIP THAT, THANK YOU,
AND ENTERTAIN QUESTIONS IN
THE BREAK, THANKS.
[APPLAUSE]
>> OKLAHOMA, CONTINUING
ALONG, WE WILL MOVE INTO THE
SECOND PART OF THIS SESSION
WHERE WE HAVE FOUR SPEAKERS
STARTING WITH ROB REINHART
FROM BOSTON UNIVERSITY
TALKING TO US ABOUT BRAIN
STIMULATION.
>> HELLO, THANK YOU, GLAD TO
BE HERE, THIS IS ONE DYNAMIC
CONFERENCE AND A REAL HONOR
TO SPEAK AT THIS' END.
SO I WOULD LIKE TO THANK MY
LAB MEMBERS AND FUNDING
AGENCIES UPFRONT.
THANK YOU OF COURSE TO THE
NIH WITH WHOM I HAVE WORKED
OVER THE YEARS.
SO JUST ONE OF THE OVER
ARCHING GOALS AS WE SEE IT
OF COGNITIVE AGING IS TO
DEVELOP NOVEL PROCEDURES
INCLUDING BRAIN STIMULATION
PROCEDURES TO EFFECTIVELY
SLOW OR THE IDEA IS TO
ARREST OR REVERSE COGNITIVE
DECLINE IN OLDER PEOPLE.
A PARALLEL GOAL FOR US AS
WELL AS IDENTIFY PARAMETERS
OF THOSE DISEASES THAT COULD
POTENTIALLY OPTIMIZE THEM
AND SOME OF THOSE PARAMETERS
THAT ARE EMERGING FROM OUR
LAB'S WORK, I WANT TO
UNDERSCORE THROUGHOUT THE
TALK THAT INVOLVE THE BRAIN
MECHANISM, SOME OF ITS
FEATURES, THE INTERVENTION
ITSELF AND THE STUDIED
POPULATION.
SO THE ROAD MAP FOR THIS
TALK IS TO INTRODUCE YOU TO
OUR THEORETICAL FRAMEWORK,
OUR TECHNICAL APPROACH, SOME
OF OUR CURRENT PROMISING
RESULTS AND FUTURE
DIRECTIONS.
SO THE APPROACH WE TAKE TO
BRAIN STIMULATION,
NEUROMODULATION DESIGNED, IS
GROUNDED IN REALLY DECADES
OF FUNDAMENTAL SYSTEMS
NEUROSCIENCE THAT VIEWS
COGNITION AS ARISING FROM
SYNC NOW IS
ELECTROPHYSIOLOGICAL RHYTHM
OR OSCILLATION.
SO THESE ARE RHYTHMIC
FLUCTUATIONS OVER TIME IN
BRAIN ACTIVITY OR
EXCITABILITY THAT DERIVE
FROM IN INHIBITOR AND
EXCITATORY POST-SYNAPTIC
THAT WILL SHOW UP IN THE
ENCEPHALOPATHY RECORDINGS.
OSCILLATION IS INTERESTING
FUNCTIONALLY BECAUSE THEY
ARE THOUGHT TO FACILITATE
PRECISE BUT FLEXIBLE BRAIN
COMMUNICATION AND
PLASTICITY.
TWO OF THE MOST EXTENSIVELY
STUDIES SYNCHRONIZATION
MOTIFS AS THEY ARE SOMETIMES
CALLED IS THE BETWEEN
FREQUENCY PHASED SING PAYING
SO WHEN TWO NEURONAL
ENSEMBLES ARE COORDINATED
WITH EACH OTHER IN THE BRAIN
SO THIS IS ASPECT OF NEURAL
ACTIVITY.
ANOTHER DOMINANT MOATY IS
BETWEEN FREQUENCY PHASE
AMPLITUDE SYNCHRONIZATION,
SOMETIMES CALLED COUPLING.
THIS IS A MEASURE OF THE
HIERARCHICAL, WHEN THE LOW
FREQUENCY WAVE AMPLITUDES
THE IN SYNC OSCILLATION.
SO WE HAVE TOOLS AS NEURAL
SCIENTISTS THAT CAN CAUSALLY
ISOLATE AND AUGMENT THESE
RHYTHMIC PATTERNS OF BRAIN
ACTIVITY THAT ARE IMPLICATED
IN COGNITIVE FUNCTION AND
DYSFUNCTION.
SO ONE OF THESE TOOLS, IN A
LARGER CLASS OF TOOLS IS
CALLED TRANSCRANIAL
ALTERNATING CURRENT
STIMULATION.
THIS IS A NONINVASIVE
SUBTHRESHOLD NEUROMODULATION
TOOL THAT INVOLVES APPLYING
EXTREMELY WEEK SONUCIDAL
ELECTRODES TO THE SCOPE THAT
INDUCES FIELD GRADIENTS IN
BRAIN REGIONS THAT ARE
IMPLICATED IN COGNITIVE
FUNCTION OR DYSFUNCTION, SO
THIS IS ONE OF THE SAFEST
WAYS TO NONINVASIVELY
STIMULATE MACROSCOPIC BRAIN
WORK DYNAMICS.
15 YEARS OF ANIMAL RESEARCH
SUGGEST THE ACTION
MECHANISMV NEURONAL IN
TRAINMENT AND NEURONAL IN
PLASTICITY.
SO I WANT TO BRIEFLY TAKE
YOU THROUGH A NUMBER OF
YEARS OF COLLECTIONS OF WORK
THAT FALL UNDER THE HEADER
OF STUDY 1.
THE UPSO THE IS WE ARE
FINDING FRONTAL TEMPORAL
HIGH RESOLUTION MULTIFOCAL
TACS MAY IMPROVE VISUAL
WORKING MEMORY IN OLDER
ADULTS AND I WANT TO
IDENTIFY PARAMETERS THAT ARE
IMPORTANT TO OPTIMIZE
STIMULATION PROCEDURES TO
GET BETTER MEMORY BENEFITS.
SO BY HIGHER RESOLUTION, I
AM REFERRING TO A NEWER
TECHNOLOGY THAT PROVIDES US
WITH SMALLER ELECTRODES
SPECIAL MANY MORE OF THEM SO
WE CAN FOLLOW THE CURRENT IN
A HIGH SPATIAL RECOGNITION
MATTER, MULTIFOCAL
STIMULATING REGIONS OF THE
BRAIN SIMULTANEOUSLY SO A
WAY TO MODULATE CONNECTION
WITHIN THE BRAIN.
THERE ARE TWO FLAVORS IN
THIS CONTEXT, THE ANTIPHASE,
DESTRUCTIVELY INTERFERING OR
DESYNCHRONIZING ACS THAT CAN
IMPEDE LONG DISTANCES AND
THE IN-PHASE THAT CAN
FACILITATE NEURONAL
COMMUNICATION BETWEEN
DISTANT BRAIN REGIONS.
AND THEN LASTLY, I HAVE
ACTUALLY PIONEERED THE
PHYSIOLOGY OF PEAK MEMORY.
SO YOU COME INTO THE LAB,
GET A MEMORY TEST, SEE A
OBJECT, THERE IS A MEMORY
DELAY, SEE ANOTHER OBJECT,
TELL US WHAT YOU SEE AND WE
FIND FOR WHAT HAS BEEN
RECOGNIZED OVER THREE
DECADES, THE DELAYED MATCH
TO EXAMINER TASK WITH MEMORY
AND WE PREDICTED THIS WAS
DUE AT LEAST PARTIALLY TO
ATTEN WAGES, SPECIFICALLY
LOW RANGE SYNCHRONIZATION
ACROSS THE TEMPOROFRONTAL
CONTEXT, THIS IS TOP DOWN ON
THE PROCESSING TO THE BACK
OF THE HEAD AS WELL AS THE
ATTEN WAGES, THE THETA-GAMMA
PHASES AMPLITUDE OF ACROSS
COUPLING SYNCHRONIZATION AND
THAT IS THOUGHT TO PLAY A
ROLE IN THE ACTIVE ONGOING
STORAGE AND PROCESSING OF
THE WORKING ITEMS
THEMSELVES.
AND THAT IS WHAT WE TUNED TO
IN 2019.
OLDER PEOPLE WERE REDUCED
IN, AGAIN, LETS ASSAY THERE
IS AMPLITUDE COUPLING IN THE
FRONTAL CORTEX AND THEN THEY
ARE LOSING THAT CONNECTIVITY
IN NEURAL SYNCHRONIZATION IN
THE PREFRONTAL CORTEX.
BUT THEY DID HAVE AN
INTERESTING ASSOCIATION IN
CONNECTIVITY.
SO WE USE THIS TO DESIGN
CROSS FREQUENCY AFS TO THE
MODEL, WE COMBINE EACH
PERSON'S FREQUENCY, THAT
NEURAL CONNECTIVITY MEASURE
IN ORDER TO ACT VIES PEOPLE
TO THE FOX SEE OF THE BRAIN
AND PHASE COUPLING AND
BEHAVIOR COMES ALONG FOR THE
RIDE SO WE CAN BOOST
COGNITIVE PERFORMANCE ON
THIS MEMORY TASK BY
RESURRECTING THESE NEURAL
CODING TECHNOLOGIES BUT
WITHOUT SLOWING PEOPLE DOWN,
RT DIDN'T CHANGE.
SO WE CAN MAKE PEOPLE BETTER
WITHOUT SLOWING THEM DOWN
AND AFTER ONE SHOT, 25
MINUTES FOR THE TEST, IT WAS
STATISTICALLY HIGH FOR BRAIN
MEASURING.
WE ALSO LOOKED AT THE
COUPLING SIGNIFICANCE, THE
BETTER THE COUPLING, THE
BETTER YOUR MEMORY.
AFTER 25 MINUTES OF
STIMULATION, WE CANNOT ONLY
REVISE THESE CODING MOAT
MOTIFFS, NOW WE CAN REVIEW
THEM ON THIS COUPLING LEVEL.
WE APPLY THE ANTIPHASE,
DESTRUCTIVELY ENTER VEERING
ATF AND SEE WE CAN INDUCE
DEFICIT IN MEMORY.
THIS IS SOMETHING WE
OBSERVED SOME YEARS AGO,
THIS BI DIRECTIONAL CONTROL
OF CIRCUITRY OF THE BRAIN
BASED ON WHAT WE'RE PULLING
OUT OF THE SYSTEM.
SO HERE WE LOOK AT HEALTHY
ADULTS BASED ON PHASAL
RELATIONSHIPS WITH THE TACS
AND ALSO OBSERVING IN
LABORATORIES ACROSS THE
WORLD, WE SEARCHERS ARE
WITNESSING A SIMILAR
PATTERN.
THIS IS THE LARGEST
METANALYSIS TO DATE.
WE RECENTLY PUBLISHED
ANOTHER EXPERIMENT WHERE WE
REPLICATED THE EXPERIMENTAL
FINDINGS IN THE COHORT OF
ALL THE PEOPLE AND EXTENDED
THEM, LOOKING AT FACIAL
SPECIFICITY AND BEHAVIORAL
BENEFITS WITH THE
PERSONALIZEDTACS.
THE UPSHOT HERE IS YOU CAN'T
STIMULATE JUST ANY PART OF
THE BRAIN AND SEE THESE
EFFECTS.
YOU HAVE TO AFFECT
SIMULTANEOUSLY FOR DOMAIN,
PARADIGM, STIMULUS, MORE
EVIDENCE TO SUGGEST WE'RE
REALLY LOCKING INTO A
MANIPULATION KIND OF
ACTIVITY.
IN TERMS OF FREQUENCY, YOU
CAN'T JUST CREATE ANY
FREQUENCY OF THE BRAIN NOR
CAN YOU STIMULATE FREQUENCY
OF THE INDIVIDUAL AND
FINDING IT IS PERCEPTUAL.
SO IT CAN IMPROVE VISUAL
WORKING MEMORY IN OLDER
PEOPLE AT LEAST IN THE
CONCEPT STUDY AND
IDENTIFYING PERSONALIZED
DATA TREKS SEE, ZERO DEGREE
LAG AND SPACE LEFT FRONTO
TEMPORAL.
SO HERE IS ANOTHER EXAMPLE
OF EXPERIMENTS, STUDY NUMBER
2 AND WHAT IS EMERGING IS
THE FRONTO AND PROPRIETY
TALL TACS MAY SELECT FOR
IMPROVEMENT IN AUDITORY
VERBAL WORKING MEMORY AND
LONG-TERM MEMORY IN OLDER
ADULTS AND THESE ARE THE
PARAMETERS FOR OPTIMIZING
HERE.
SO WE HAVE KNOWN FOR ALMOST
A CENTURY FROM EXPERIMENTAL
PSYCHOLOGY, IF I READ YOU A
LIST OF WORDS, CAN YOU
RECALL BACK TO ME FOR AS
MANY WORDS AS YOU CAN.
YOU HAVE THE ADVANTAGE OF
THE EARLY EFFECTS BASED ON
THE DUAL PLATFORM NETWORK
AND YOU ALSO HAVE AN
ADVANTAGE LINKED TO WORKING
MEMORY.
WE KNOW QUITE A LOT ABOUT
THE FUNCTIONAL ANATOMY OF
THE POSITIONING CURVE
EFFECTS.
THE LOBULES A PLAYER IN
RECENT MEMORY AND THE
PREFRONTO CORTEX A MAJOR
CONTRIBUTOR BUT WHAT WE
DON'T KNOW IS IF THERE ARE
INDIVIDUAL MECHANISMS WITHIN
THESE BRAIN SECTIONS THAT
CAN PRESERVE FUNCTION AND IF
THERE ARE, AND CAN BE
IDENTIFIED, WE CAN BRING
TACS TO SELECTIVELY AND
INDEPENDENTLY MANIPULATE
THESE MEMORY SYSTEMS AND
THAT IS PRECISELY WHAT WE
SET OUT TO DO IN THIS SERIES
OF EXPERIMENTS HEADED UP BY
THE POST-DOC IN THE LAB NOW,
WE DEFINED TWO PROCEDURES
AND THIS TIME WE WERE
INTERESTED IN SUSTAINING THE
BENEFITS FOR FOUR DAYS IN A
ROW SO WE REPEATED THE TESTS
FOUR TIMES IN A ROW AND WHAT
WE FIND IS THE SPATIAL
COMPONENTS OF THE MECHANISM
ON THE ONE HAND AND THE
MEMORY SYSTEM BEING
MANIPULATED ON THE OTHER
HAND.
IN THE BOTTOM LEFT IN THE
RED BOX, YOU SEE WHEN WE
APPLY LOW FREQUENCY, NOT
HIGH FREQUENCY, ENTRAINMENT
TO PARITAL CORTEX AND NOT
FRONTO TEMPORAL CORTEX, WE
CAN ACHIEVE IMPROVEMENT ON
THE WORKING EFFECT.
ON DAY 2, 3 AND 4, WHEN WE
APPLY THE RETAINMENT, WE
KRAUSE LONG-TERM MEMORY
IMPROVEMENTS.
ON DAY 2, 3 AND 4 AND ONE
MONTH POST.
SO THIS IS THE OUTSET OF THE
DOSE CURATION I WANT TO
UNDERSCORE, HOW MANY DAYS IT
TAKES FOR THE MEMORY TO COME
ONLINE.
WE DID SOMETHING UNIQUE HERE
WHERE WE ACQUIRED
PERFORMANCE DATA WITHIN THE
EXPERIMENT ITSELF WHICH IS
SELDOMLY DONE WHICH ALLOWS
US TO EVALUATE HOW PEOPLE
ARE RESPONDING TO THE MEMORY
BENEFIT AND WE FOUND THAT
THE SEEPER THAT RATE OF
IMPROVEMENT FOR BOTH MEMORY
IMPROVEMENT, THE BIGGER THE
BENEFITS ONE MONTH LATER.
WE ALSO FIND THE BASELINE
GENERAL COGNITIVE
PERFORMANCE MEASURED IN
LOCO, HOW PEOPLE RESPONDED
DURING THE PREDICTION AND
HOW LARGE THE BEN GETS WERE
ONE MONTH AFTER IT WAS OVER.
AND THAT IS WHAT I MEANT BY
COGNITION OF STUDIES AS A
FEATURE.
AT THE SPEED OF MEMORY
LEVEL, WE SEE PROMISING
RESULTS, NORTHERN IRELAND
MODERATE SIZE EFFECTS.
WE THINK THESE ARE BEING
UNDERESTIMATED AS TO THE
POWER OF THIS PROCEDURE
BECAUSE THERE IS A SMALL
NUMBER OF STUDIES TOGETHER
AND THE VAST MAJORITY DON'T
PERSONALIZE THE SIMULATION,
NOT MULTIFOCAL, NOT HIGH
DEFINITION.
SO WE HAVE DEVELOPED THREE
NOVEL HTACS ON INDIVIDUALS
TO IMPROVE LONG, MEDIAN AND
LONG-TERM MEMORY IN THESE
INDIVIDUALS.
OUR SPRAEFRPLS
REPRESENTATIVE IN TERMS OF
RACE, ETHNICITY AND SEX OF
THE GREATER BOSTON AREA
WHICH IS NOT TOO DIFFERENT
THAN LARGER AREAS.
AND THEN THE PARAMETERS FOR
THE ROLE, THE FREQUENCY AND
SPACE, DOSE AND DURATION AND
COGNITIVE STATUS.
THERE ARE A NUMBER OF FUTURE
DIRECTIONS I WOULD LOVE TO
TALK ABOUT.
ONE 'THEM RELATES TO
ALZHEIMER'S DISEASE, A
CLINICAL TRIAL I AM RUNNING
IN MY LAB RIGHT NOW SO I
WILL JUST SHARE SOME OF THE
PRELIMINARY DATA.
IT IS KIND OF AT THIS
TITILLATING AND NEW DATA SO
WE'RE SEEING THESE DRASTIC
MPI AND WITH A 25-MINUTE
DOSE OF THIS STIMULATED
BRAIN RESTORATION, WE CAN GO
A LONG WAY TO RECOVER THE
CAPACITY PARTICULARLY AT
LARGER LOADS WHERE THE
DEFICIT IS THE GREATEST.
THANK YOU.
[APPLAUSE]
>> THANK YOU, ROB,
INTERESTING TALK.
UP NEXT WE HAVE FRANK LIN
WHO JUST CAME DOWN THE
STREET FROM JOHNS HOPKINS
AND WE WILL BE HEARING ABOUT
HEARING INTERVENTION,
COGNITIVE DECLINE AND BRAIN
HEALTH WITH ACHIEVE
RANDOMIZED TRIAL.
>> THANK YOU, DELIGHTED TO
BE HERE AND THANK EVERYONE
FOR INVITING OUT.
SO THIS WILL BE A BROAD
OVERVIEW OF A STUDY FOCUSING
ON THE PRIMARY RESULT AND
HOW IT REALLY DIFFERED AMONG
STUDY POPULATIONS.
AS ALL OF YOU KNOW, SIGNS OF
A TEAM BASED SPORT, FOR A
MULTIPLE TIE GROUP STUDY,
TEN YEARS, WORKING THROUGH
THE GENEROUS SUPPORT OF NIA.
SO BRIEF BACKGROUND, WHAT
HAS BEEN STUDIES AND WHY,
MODIFIABLE RISK FACTORS AND
RELATED TO HEARING LOT MID
TO LATE IN LIFE BASED ON A
FRACTION OF RISK.
THE REASON FOR THIS IS THE
EPIDEMIOLOGICAL LINKING OF
THIS HAVE SHOWN HIGH RISK
RATIOS AND HEARING LOSS IS A
VERY COMMON PREVALENT
CONDITION FOR EVERYONE.
BEGINNING AFTER TEENAGE
YEARS, EVERYONE'S HEARING
SLOWLY DECREASES OVER A
LIFETIME BECAUSE OF
MITOTOXINS, THERE ARE
DIFFERING RATES BUT
EVERYBODY LOSES HEARING OVER
TIME.
SO WE HAVE THESE FEW
MECHANISMS LINKING HEARING
LOSS WITH A INCREASED RISK
WITH COGNITIVE DEMENTIA.
KEEP IN MIND, ALL HEARING
CHANGES THROUGH I THINK A
BUT IT MEANS YOU ARE GETTING
A MORE GARBLES SIGNATORY
CODE TO THE BRAIN SO THE
BRAIN HAS TO WORK HARDER TO
TRANSLATE THAT SIGNAL.
AND THEN THAT COMES AT THE
EXPENSE OF OTHER SYSTEMS.
EITHER THAT OR THE DIRECT
EFFECTS OF HEARING LOSS AND
DIRECT EFFECTS ON BRAIN
STRUCTURE AND FUNCTION,
LOOKING AT EPIDEMIOLOGICAL
ANIMAL STUDIES AND SOCIAL
ISOLATION.
THE REASON IT IS IMPORTANT
IS BECAUSE IT SUGGESTS
THEORETICALLY, IF YOU TREAT
THIS, YOU COULD MODIFY THE
PATHWAYS AND REDUCE THE
COGNITIVE DECLINE AND
DEMENTIA OVER TIME.
SO THIS IS A REALLY SIMPLE
QUESTION.
MAINLY IF WE TREAT HEARING
LOSS IN OLDER ADULTS, CAN WE
INDUCE COGNITIVE DECLINE IN
THREE YEARS, A SHORT PERIOD
OF TIME IN OLDER ADULTS.
SO THE MAIN OUTCOME IS
GLOBAL COGNITIVE DECLINE.
THERE ARE SOME SECONDARY
GLOBAL RESULTS WHEN I WON'T
GO OVER TODAY BUT I WILL
SHOW YOU THE AMYLOID DATA.
SO THE DESIGN PRETTY SIMPLE.
977 OLDER ADULTS, 70 TO 84
YEARS OLD, MILD TO MODERATE
HEARING LOSS, INTACT.
WE STUDIES TWO DISTINCT
POPULATIONS AND THIS IS
IMPORTANT.
A QUARTER OF THE COHORT CAME
FROM AN EXISTING
OBSERVATIONAL HEART HEALTH
STUDY AND THE OTHER THREE
QUARTERS CAME FROM DENOVO,
NEW RELY CRUDE VOLUNTEERS
THROUGH FACEBOOK,
ADVERTISEMENTS, THINGS LIKE
THAT.
THOSE TWO COHORTS ARE THEN
RANDOMIZED, THEN FOLLOWED
ANNUALLY THE NEXT SIX
MONTHS, AND A HOST OF OTHER
EXPLORATORY OUTCOMES AS
WELL.
NOW, I MENTIONED BEFORE, THE
ACHIEVE STUDY, IF ANY OF YOU
HAD TO DO A MULTI-SITE
TRIAL, THEY ARE HARDER TO
GET SET UP SO IF YOU CAN
COMBINE RESOURCES, IT MAKES
IT EASIER.
SO IN OUR CASE WE HAD THE
HELP OF ACHIEVE STUDY.
BASIC WE RE CRUDE 30 YEARS
AGO MID-LIFE ADULTS FROM A
RANDOM POPULATION, VOTER
REGISTRATION POLLS, DRIVER
RECORD POLLS AND RECRUITED
THEM INTO THE STUDY LOOKING
AT MIDLIFE CARDIO RISK
POCKET TORSION AND AGING
DISEASE AND FOLLOWED THEM
FOR MANY YEARS.
SO WE APPLIED THE SCREENS IN
THE STUDY.
THREE QUARTERS OF THE
COHORTS CAME FROM THE SAME
COMMUNITIES BUT NEW
VOLUNTEERS.
LITERALLY PEOPLE RESPONDED
TO FACEBOOK ADS, THINGS
LIKE THAT.
THE INTERVENTION, FIRST
THREE MONTHS OF THE STUDY
THEY GOT HEARING AIDS, HALF
OF THEM, THEN THE OTHER HALF
BASICALLY GOT GENERAL
EDUCATION, COUNSELING ON
HEALTHY AGING TOPICS.
SO EVERY THREE MONTHS, THEN
EVERY SIX MONTHS A FOLLOW UP
BOOSTER SESSION AND THERE
AFTER.
THE COGNITIVE BATTERY, ABOUT
45 MINUTES, ADMINISTERED BY
A --
[INDISCERNIBLE]
, WE GOT ONE GLOBAL
COGNITION SCORE.
SO IF IT IS ZERO, YOU ARE
SMACK DAB IN THE MIDDLE AT
MEAN, BASELINE.
IF YOU ARE .05, YOU ARE HALF
AWAY FROM THAT, LIKEWISE IT
CAN CHANGE OVER TIME,
NECKIVE FIVE OR THREE YEARS
IT DECLINED OVER A THREE
YEAR PERIOD.
YOU CAN ALSO EXTRACT
DOMAINS, LANGUAGE
PRODUCTION, NOT LANGUAGE WE
CEPTION, CATEGORY WITH RUNS
IN SEE, EXECUTIVE FUNCTION
AND MEMORY AND PROBABLY WANT
TO EMPHASIZE EIGHT OF THE
TEN COGNITIVE TESTS ARE NOT
AUDITORY EXCLUSIVE.
SO IF SOMEONE IS NOT DOING
WELL ON A COGNITIVE TEST, I
CAN TELL YOU IT IS NOT
BECAUSE THEY ARE NOT HEARING
WELL.
THESE ARE VISUAL AND
AUDITORY TESTS.
OF THE TWO THAT ARE
AUDITORY, WE VERIFY THEIR
SPEECH UNDERSTANDING AND
WHAT I MEAN IS THEY ARE READ
A LIST OF SENTENCES AND
ASKED TO REPEAT BACK TO
CONFIRM THEY ARE HEARING
WELL.
AND FACE-TO-FACE, IN A QUIET
ROOM, YOU WOULDN'T EXPECT
THAT TO MODIFY TRAJECTORY
OVERALL BUT WE ENSURED IT
WAS STANDARD OVER TIME.
THE RECRUITING PERIOD BEGAN
IN JANUARY 2018.
ALWAYS VERY PROUD OF THE
FACT WE HIT 850 ON TARGET,
TWO WEEKS BEHIND SCHEDULE
AND HIT 850.
BECAUSE OF HOW WELL IT WAS
GOING, WE KEPT IT OPEN A
LITTLE LONGER WITH THE HELP
OF NI A AND NIAH.
AND RIGHT BEFORE THE
PANDEMIC HIT.
FULL WE RE CRUDE, EVERYONE
RECEIVED THEIR PRIMARY
INTERVENTION BEFORE THE
PANDEMIC BEGAN.
THE REASON WHY IT IS
IMPORTANT IS WE STUDIES
THESE FOR THREE YEARS AND
THE BASELINE ALL DONE IN
PERSON SO ATTESTING TO THE
QUALITY STAFF, AFTER THREE
YEARS THROUGH THE PANDEMIC,
COMPLETE UPDATE ON
90 PERCENT OF THE PEOPLE
THREE YEARS LATER.
SO ATTRITION RATE OF
10 PERCENT, SOME PEOPLE DIED
UNFORTUNATELY, SOME MOVED
AWAY.
SO THIS NORMALLY IS A TABLE
I WOULD SHOW STRESS BY
INTERVENTION VERSUS CONTROL.
I CAN SHOW YOU SOME THINGS
ARE EQUAL BECAUSE IT IS
RANDOMIZED BUT WHAT I AM
SHOWING YOU HERE IS THE
BASELINE CHARACTERISTICS
STRATIFIED BY RECRUITMENT
SOURCE.
THE DENOVO HAD FEWER RISK
FACTORS OF DECLINE AND
DEMENTIA THAN THE ARIC
COHORT.
AND YOU SEE THAT STUDY
POPULATION SOURCE BEING
REFLECTED ON THESE
CHARACTERISTICS.
SO THE ARIC COHORT IS
YOUNGER.
BLACK IS INTERESTING BECAUSE
THE REASON THERE IS A SKU IS
ONE QUARTER WAS FULLY BLACK
AMERICAN, SO YOU ARE SEEING
IT THERE WHEREAS DENOVO, YOU
ARE SEEING A COMMUNITY OF
VOLUNTEERS, MORE OF A
DISCREPANCY THERE.
ON AVERAGE, THE DENOVO HAD
HIGHER EDUCATION AND WOULD
BE RANDOMLY DIFFERENT THAN
THE RECRUITMENT OF A RANDOM
POPULATION.
SO RISK FACTORS, DENOVO WITH
A LOWER RATE OF DIABETES,
LESS HYPERTENSION, SEEING
LESS LIVING ALONE IN THE
DENOVO VERSUS THE ARIC
COHORT.
NOW WHAT IS INTERESTING, YOU
LOOK AT THE BASELINE
COGNITION, STANDARDIZED
SCORES, YOU CAN SEE THEY ARE
1.7 ABOVE THE MEANS WHERE
THE ARIC STARTS BELOW THE
MEAN BASED ON THIS AVERAGE
SO A BASELINE OF COGNITION
AMONG A GROUP OF VOLUNTEERS
VERSUS A RANDOM SAMPLE OF
THE POPULATION.
SO I AM GOING TO JUMP TO THE
THREE YEAR COGNITIVE
OUTCOMES.
THIS IS A BUSY STUDY BUT
WHAT YOU ARE SEEING THERE
THE CONTROL GROUP ON AVERAGE
DECLINED BY .202 IN TERMS OF
COGNITION.
IF YOU LOOK AT THE PURE
GROUP, ESSENTIALLY THE SAME.
SO NO DIFFERENCES IN RATES
OF COG DECLINE OVER THREE
YEARS OF THE CONTROL.
SO DISAPPOINTING AT FIRST.
IF YOU LOOK AT THE SECONDARY
OUTCOMES, ALMOST THE SAME
THING.
REALLY NOTHING TO WRITE HOME
ABOUT.
NOW WHAT GETS A LOT MORE
INTERESTING THOUGH IS ONE OF
OUR PRESET BY SENSITIVITY
ANALYSIS OVER FIVE YEARS
WHEN WE DESIGNED THE STUDY,
WE SAID WE WOULD REPLICATE
THE STRATEGY BASED ON
CONVERSATIONS.
WE DIDN'T REALIZE HOW
DIFFERENT THEY WOULD BE BUT
THIS IS WHAT YOU WILL SEE.
SO AMONG THE ARIC COPORT, A
RANDOM SAMPLE OF POPULATION,
SEEING VERY STRONG HEARING
AFFECTS REDUCING COGNITIVE
DECLINE COMPARED TO CONTROL,
SEEING A 48 PERCENT
REDUCTION IN RATES OF
COGNITIVE DECLINE, YOU CAN
SEE THEM AT THE LEFT THERE.
BUT IF YOU LOOK AT THE
DENOVO COHORT, YOU ARE
SEEING IN EFFECTS OF THE
HEARING INTERVENTION ON
SLOWING COGNITIVE DECLINE.
SO WHY?
AND IF YOU LOOK AT THE DATA
MORE CLEARLY, IT BECOMES
MORE CLEAR.
IF YOU LOOK AT THE RATES
AMONG THE CONTROL GROUP OF
3-YEAR COGNITIVE DECLINE IN
THE ARIC, THE .2 CHANGE IN
THREE YEARS AND THE DENOVO
CONTROLS, ONLY 1.51 SO A
THREE-FOLD SLOWER RATE OF
COG CHANGE OVER THE THREE
YEARS AMONG THE DENOVO
CONTROL VERSUS THE ARIC
COHORT.
SO FEWER RISK FACTORS THAN
AVERAGE THAN THE AR IC
COHORT.
SO ONE WAY OF INTERPRETING
THIS IS THAT A HEARING ENTER
VENGE IS PREDICATED ON
REDUCING COGNITIVE DECLINE,
DENOVO, VERY LITTLE
COGNITIVE DECLINE IN TWO
YEARS AND YOU CAN'T SLOW
DOWN SOMETHING THAT ISN'T
THERE TO BEGIN WITH.
SO WITH DENOVO, THERE IS
ROOM TO SLOW THAT DOWN WITH
OBSERVING IN THREE YEARS.
I WILL SHOW YOU EXPLORATORY
EFFECTS LOOKING AT BRAIN
HEALTH AND MRI DATA AND THIS
IS PREDICATED ON THE MAIN
MECHANISM, HEARING,
COGNITIVE DECLINE AND
STRUCTURE.
SO IS IT REDUCING RATES OF
BRAIN ATROPHY, CORTICO
THINNING, THIS IS WITHIN
THREE YEARS.
I WILL JUMP TO THE DATA.
THE HALF SAMPLE HAD MRI AS A
BASELINE AND THEN MRIS THREE
YEARS LATER.
THIS IS CORTICAL THICKNESS
ALL CONSTRUCTED BY CLIFF
JACK'S GROUP AT MAYO IN THE
RESEARCH LABORATORY AND WHAT
YOU SEE HERE AGAIN, THIS
EXPLORATORY DATA, NOT KEY
VALUES BUT THE EXPLORATORY
EFFECTS OF WHAT INTERVENTION
THEY DO.
WHAT WE CLEARLY SEE HERE IS
A CLEAR GENERAL TREND FOR
PROTECTIVE EFFECT ON THE
REDUCED CORTICAL THICKNESS.
SEEING A VERY CLEAR SIGNAL
OF REDUCED CORTICAL
THINNING.
NOW, I WILL SHOW YOU ONE
OTHER FOLLOW UP FIGURE AND
THIS IS INTEREST ANALYSIS
USING THE SAME DATA AS
BEFORE, LOOKING AT CORTICAL
FIXES IN EACH ROI, RED IS
REDUCE OVER THREE YEARS WITH
LESS INTERVENTION AND THE
BLUE TO INCREASE CORTICAL
BUILDING AND WHAT YOU ARE
SEEING HERE IS VERY STRONG
SIGNALS IN CERTAIN AREAS.
THE STRONGEST SIGNAL IS IN
THE FRONTAL LOBE, A CRITICAL
AREA FOR LANGUAGE PROCESSING
SO SEEING A VERY STRONG
SIGNAL.
THIS IS EXPLORATORY, NOT
TESTING FOR THIS BUT CLEARLY
RECEIVING A SIGNAL AND
REDUCED HEARING VERSUS THE
CONTROL GROUP.
SO BRIEF SUMMARY, IN THE
TOTAL COMBINED COHORT, WE'RE
NOT SEEING A CHANGE IN THE
HEARING OVER THREE YEARS.
USING A DIFFERENT POPULATION
IT COULD BE VERY DIFFERENT.
SEEING 48 PERCENT RELATIVE
REDUCTION IN COGNITIVE
DECLINE, .21 VERSUS 4.2 SO
ABOUT A .2 DIFFERENCE OVER
THREE YEARS AND YOU MIGHT
EXTRAPOLATE THE HEARING
INTERVENTION HAD NO EFFECT
ON REDUCING COGNITIVE
DECLINE.
THERE WERE STRONG EFFECTS IN
THE ARIC SUGGESTING THE
HEARING INTERVENTION MIGHT
REDUCE COGNITIVE DECLINE
WITHIN THREE YEARS IN
POPULATIONS AT INCREASED
RISK FOR COGNITIVE DECLINE.
NO EFFECT OBSERVED IN THE
DENOVO LEADING TO SLOW RATE
OF COG CHANGE.
EXPLORATORY MRI.
ERIC WENT OVER AND TESTED
COGNITIVELY EVERY FEW YEARS,
NOT SEEING RATES OF ERROR SO
YOU MAY SEE MORE TRUE RATES
OF CHANGE.
AND THEN YOU MIGHT SEE THIS
FOR DRUG STUDIES, RISK AND
BIOMARKERS BUT LESS IN THE
WAY OF HARD TO REACH
POPULATIONS ARE THE MOST
IMPORTANT TO REACH AND ITCH
OCCASIONS OF COGNITIVE
TESTING PRACTICE EFFECTS
NEEDS TO BE FULLY CONSIDERED
WHEN REDUCING COGNITIVE
DECLINE AS THE PRIMARY
OUTCOME.
>> OKAY, MOVING ALONG, WE
WILL HAVE JULIE WETHERELL,
PH.D. FROM UNIVERSITY OF
CALIFORNIA-SAN DIEGO AND
WILL TALK ABOUT MINDFULNESS
BASED STRESS REDUCTION AND
EXERCISE IN COGNITIVE
FUNCTION IN HEALTHO OLDER
ADULTS.
>> THANK YOU SO MUCH, GLAD
TO BE A PART OF THIS.
SO WHAT WE HAVE DISCUSSED IN
THE PAST, THE COGNITIVE
FUNCTION HAS GOT TEN QUITE A
BIT OF ATTENTION WITH
RESPECT TO COGNITIVE DECLINE
AND THERE ARE A NUMBER OF
MECHANISMS FOR THIS.
IN THE WAY OF EXERCISE,
INTRODUCTIONS AND
INFORMATION, CHANGES IN
OXYGENATION, NEUROTROPHIC
FACTORS, IMPROVED SINCE LYNN
SENSITIVITY THROUGH
EXERCISE, THROUGH
MINDFULNESS MECHANISMS WE
SEE MORE INCREASED ATTENTION
CONTROL, IMPROVED EMOTION
REGULATION AND REDUCED
COURTS SO WILL PRODUCTION.
SO I HAVE BEEN WORKING WITH
UNIVERSITY OF ST. LOUIS WITH
OLDER ADULTS IN PSYCHOLOGY
AND DECIDED TO DO A STUDY TO
LOOK AT OLDER ADULTS WITH
ANXIETY OR DEPRESSION AND
THEIR SUBJECTIVITY TO
COGNITIVE CHANGES AND DID
THIS THROUGH M BS R VERSUS
HEALTH EDUCATION.
RELATIVE TO HEALTH EDUCATION
WE SAW IMPROVED MEMORY
PERFORMANCE SOMEBODY UNITED
WITH STRESS REDUCTION AND
SOME EVIDENCE THAT THE
REDUCTION IN COURTS
CORTISOL MIGHT BE THE
MECHANISM SO THOSE FOLKS WE
SAW AT BASELINE WERE SUBJECT
TO M BS R AND HEALTH
EDUCATION.
SO USING THOSE AS PILOT
DATA, WE DID FUND THROUGH
AMA AND McKNIGHT A LARGER
STUDY WHERE WE ARE LOOKING
AT THE EFFECTS OF STRESS
REDUCTION, MULTICOMPONENT
EXERCISE INTERVENTION, WE
ALSO WERE GOING TO LOOK AT
SOME OF THE PROPOSED
MECHANISMS SO LOOKING AT
CORTISOL TO MEASURE FITNESS,
HYPERACTIVITY.
WE WERE LOOKING DOING BRAIN
IMAGING TO LOOK AT
STRUCTURAL AND FUNCTIONAL
CONNECTIVITY AND THEN
FINALLY THE MOST DISTAL
OUTCOMES, IMPACTS ON
COGNITION, SPECIFICALLY
MEMORY AND COGNITIVE
CONTROL, ALSO KNOWN AS
EXECUTIVE FUNCTION.
SO OUR EXERCISE INTERVENTION
INCLUDING AEROBIC ACTIVITY
KIND OF IN LINE WITH OUR
HYPOTHESIS BUT WE ALSO
INCLUDED BALANCE AND
STRENGTH AND ABILITY
TRAINING BECAUSE THAT IS THE
PACKAGE OF INTERVENTION FOR
OLDER PEOPLE.
INITIALLY FOR THE FIRST SIX
MONTHS, THESE PEOPLE MET IN
GROUPS TWICE A WEEK, A
GROUP OF 15 AND THEN SENT TO
HOME EXERCISE AND TAILORED
WITH PROGRESSIVELY
INCREASING INTENSITY.
SO THEIR INITIAL GOAL WAS
300 MINUTES A WEEK AND THEY
INTENSIFIED THAT THROUGH THE
STUDY.
MIND CONTROL DEMONSTRATION,
YOU MAY BE FAMILIAR WITH
THIS, IT INCLUDES
MEDITATION, YOGA, TAUGHT IN
EIGHT TWO AND A HALF HOUR
WEEKLY CLASSES AND THEN HE
ADDED MONTHLY BOOSTER
SESSIONS OUT TO THE 18-MONTH
DURATION OF THE TRIAL, DAILY
HOME PRACTICE WITH A GOAL OF
UP TO 60 PINS MINUTES BETTER
DAY OF MEDITATIVE PRACTICE
AND THEN WE USED HEALTH
CONTROL AND THIS WAS BASED
ON THE STANFORD HEALTH
BENEFITS PROGRAM WHICH HAS
BEEN THE SUBJECT OF RESEARCH
IN AND OF ITSELF, DESIGNED
TO IMPROVE SELF EFFICACY,
NOT CONDITION AND TALKS
ABOUT MINDFULNESS BUT
DOESN'T TALK ABOUT
PREVENTION.
SO THIS IS SOMEONE WHO MAY
BE TRYING TO CONTROL THEIR
DIET, THEIR BLOOD PRESSURE
AND WE DID IT WITH THE
INTENTION OF MINIMIZING THE
PLACEBO SO WE MATCHED THE M
BS R FOR SETTING TIME BUT
STILL KEPT IT LIMITED.
SO 18 MONTHS TOTAL, PEOPLE
ASSIGNED FOR THE FIRST SIX
MONTHS TO EITHER M BS R
ALONE, EXERCISE ALONE,
COMBINATION OR HEALTH
EDUCATION.
STUDY POPULATION TENDED TO
BE 580 PEOPLE, AGES 65 AND
OLDER, NO DEMENTIA, WE
COMPLETED A VERY LARGE
BATTERY OF TESTS,
NEUROPSYCHOLOGICAL, PEUF AL
BIOMARKERS, METABOLIC,
FITNESS AND PERFORMANCE,
NEUROIMAGING AND BEHAVIORAL
AND FUNCTIONAL AND THE
OUTCOMES I WILL TALK ABOUT
TODAY ARE COGNITIVE SO WHAT
Dr. LIN TALKED ABOUT IN
TERMS OF MEMORY AND
COGNITIVE CONTROL, WE HAD
SOME LIFT IN LEARNING AND
THEN MEASURES FROM THE NIH
TOOL BOX WHICH Dr. LIN
MENTIONED YESTERDAY FOR
COGNITIVE CONTROL AND THEN
OTHER COMPUTER BASED
COGNITIVE CONTROL FUNCTION.
OUR SAMPLE, WE ACTUALLY
RECRUITED A LITTLE BIT WHICH
IS GOOD, VERY MUCH FEMALE,
MAINLY NONHISPANIC WHITE,
NORMAL COGNITION TO START.
HAD SOME COLLEGE, LARGELY
HEALTHY BECAUSE THEY HAD TO
BE HEALTHY ENOUGH TO BE
EXPOSED TO A MILD TO
MODERATE EXERCISE PROGRAM,
THEY DID HAVE MENTAL
ILLNESS, AVERAGE OF THREE, A
THIRD IMPAIRED INSULIN
SENSITIVITY AND OTHER THINGS
AS WELL.
AND BOTTOM LINE IS THIS WAS
A IN RESULTS TRIAL.
WE DID NOT FIND IN OUR STUDY
AT LEAST THAT EITHER
EXERCISE OR MINDFULNESS OR
THE COMBINATION HAVING
IMPACT ON COGNITIVE FUNCTION
OR BRAIN VOLUMES.
WE DID FIND SOME MARGINAL
EFFECTS ON THE FUNCTIONAL
BRAIN WHICH I AM NOT GOING
TO TALK ABOUT BUT IT HAS
BEEN PUBLISHED.
GENERALLY SPEAKING, WE HAD
TO DO A LITTLE DIGGING THEN
TO TRY TO FIGURE OUT WHY
THIS STUDY DID NOT WORK AS
WE INTENDED.
BUT TO PROVIDE A LITTLE DATA
WHAT THIS LOOKS LIKE, ON THE
RIGHT SIDE YOU HAVE PEOPLE
WHO DID OR DID NOT RECEIVE M
BS R, COGNITIVE FUNCTIONING
OVER 18 MONTHS.
YOU MAY SEE SOME IMPROVEMENT
BUT WE DID A NEUROPSYCH
BATTERY WITHIN TWO WEEKS TO
GET OLDERS FOLKS FAMILIAR
WITH SITTING DOWN AT A
COMPUTER AND TAKING THESE
TESTS BUT BASICALLY THEY
APPROVED THE SAME AMOUNT
WITH OR WITHOUT M BS R AND
WITH OR WITHOUT EX SER VICE
AND NO INTERACTION EFFECTS
BUT THE SAME WAS TRUE OVER
18 MONTHS.
COGNITIVE EFFECTS WITH
LITTLE OR NO EXERCISE, THERE
WAS IMPROVEMENT UP TO SIX
MONTHS AND THEN PEOPLE
STABILIZED AFTER.
SO TRYING TO FIGURE OUT WHY
AND THE QUESTION WAS MAYBE
PEOPLE WEREN'T ADHERENT,
DOING THE THINGS WE
RECOMMENDED THEY DO.
SO WE LOOKED AT CLASS
PARTICIPATION, VERY EASY TO
MEASURE AND THE VAST
MAJORITY OF PEOPLE IN ALL
THREE GROUPS ATTENDED AT
LEAST 70 PERCENT OF THE
CLASSES SO YOU KNOW WITH
RESPECT TO CLASS
PARTICIPATION, WE HAD PRETTY
GOOD ADHERENCE WITH THE
STUDY AT THIS TIME.
WE COLLECTED AT-HOME
PRACTICE INFORMATION,
SELF-REPORT EARLY WHILE
FOLKS WERE IN THE EXERCISE
CLASS OR WEEKLY AND MONTHLY
WHERE PEOPLE HAD M BS R.
WE ALSO LOOKED AT
ASSESSMENTS WHERE THREE
TIMES A DAY WE ASKED THEM
ABOUT SLEEP AT HOME, THEIR
PRACTICE SO WE DID GET DATA
THAT WAS A LITTLE MORE
RELIABLE AND THE HISTOGRAMS
SHOW THAT PEOPLE DID REPORT
HOME PRACTICE AND MOST
REPORTED HIGH AMOUNTS OF IT.
SO YOU SEE ON THE LEFT GRAPH
NO DIFFERENCE WITH FOLKS WHO
DID OR DID NOT RECEIVE M BS
R.
ON THE RIGHT, FOLKS WHO
REPORTED HOME PRACTICE ON AT
LEAST 75 PERCENT OF DAYS AND
AGAIN NO PRACTICE BETWEEN
THE TWO GROUPS.
WITH RESPECT TO EXERCISE, NO
DIFFERENCE ON THE LEFT AND
HOME PRACTICE 70 PERCENT SO
SEEING THE SAME SORT OF
THING WITH THE FOLKS WHO
RECEIVED EXERCISE
INTERVENTION AND THOSE WHO
DID NOT.
SO THEN THE NEXT QUESTION TO
ASK IS MAYBE WE DIDN'T
ACHIEVE TARGET, MAYBE THE
EXERCISE WASN'T INTENSE
ENOUGH, MAYBE WE WEREN'T
MAKING A DIFFERENCE IN OUR
INTERVENTION.
SO WE LOOKED AT A LOT OF
DIFFERENT EMPHASES, EXERCISE
INFLUENCED MANY
PHYSIOLOGICAL AND
PERFORMANCE VARIABLE, AND
THOSE WITH INSULIN
SENSITIVITY, AEROBIC
FITNESS, STRENGTH, SLEEP
LATENCY AND TOTAL SLEEP
TIME, EVERYBODY IMPROVED ALL
OF THESE THINGS.
SO LOOKING AT THE MEMORY
COMPOSITE CHANGE IN THE
FOLKS WHO GOT EXERCISE AND
WE'RE COMPARING THE PEOPLE
WHO HAD THE MOST IMPROVEMENT
IN THEIR INSULIN SENSITIVITY
VERSUS THE ONES WHO HAVE THE
LEAST IMPROVEMENT AND AGAIN
NO SIGNIFICANT DIFFERENCES.
SO TARGETING ENGAGEMENT DID
NOT APPEAR TO BE A FACTOR
AND WE LOOKED AT THIS MANY
DIFFERENT WAYS AND I AM JUST
SHOWING YOU AN EXAMPLE HERE.
SO WHEN YOU GET RESULTS LIKE
THIS, OKAY, WAS IT GENUINELY
A NEGATIVE RESULT OR FAILED
TRIAL?
AND I WOULD ARGUE IN SOME
WAYS YOU KNOW I THINK WE
WERE PRETTY SUCCESSFUL BUT
WHEN YOU SAY WHAT ARE THE
OUTCOMES, WE FOUND THE
COGNITIVE RATES HAD GOOD
RELIABILITY AT 28, WHICH IS
REASONABLE.
POOR ADHERENCE, I SHOWED
THOSE DATA ALREADY THAT
PEOPLE WERE PRETTY ADHERENCE
AND THE FOLKS WHO WERE
ADHERENT LOOKED SIMILAR TO
THE FOLKS IN THE OVERALL
SAMPLE.
WERE THE INTERVENTIONS TOO
WEAK?
EXERCISE GROUP DID WHAT
EXERCISE SHOULD DO IN A
GROUP OF SEDENTARY ADULTS IN
TERMS OF THE OUTCOMES YOU
WOULD EXPECT ARE PHYSICAL
HEALTH, NOT SO CLEAR WITH
MINDFULNESS AND AGAIN THOSE
WHO SHOWED OBJECTIVE
EVIDENCE OF IMPROVEMENT BY
EXERCISE HAD SIMILAR
OUTCOMES THAN -- VERSUS
THOSE WHO DID NOT.
SO PERHAPS IT WAS THE WRONG
TIME OF INTERVENTION.
MIGHT HAVE BEEN TOO SOON.
HOPING OLDER ADULTS NOT ON A
TRAJECTORY YET PERHAPS, TOO
LATE, WE HAVE HEARD LOTS OF
STARTING THESE INTERVENTIONS
TILL MIDLIFE OR EARLIER SO
WAITING TILL THEY WERE OLDER
MIGHT HAVE HAD NO IMPACT.
TOO SHORT, HEARING ABOUT
LONGER INTERVENTIONS, IT IS
POSSIBLE THAT WAS AN ISSUE.
TOO LOW INTENSITY?
I DON'T KNOW ABOUT THAT.
WE KIND OF DESIGNED THIS TO
BE WHAT WAS RECOMMENDED IN
TERMS OF EXERCISE AND
STANDARD PROTOCOLS BUT IT IS
POSSIBLE THAT IS NOT ENOUGH
TO IMPROVE COGNITIVE
OUTCOMES IN OLDER PEOPLE.
SO HERE IS ONE OF THE
ISSUES, I THINK, FAILURE OF
RECRUITMENT.
MOST CLEARLY OBVIOUSLY IN
Dr. LIN'S STUDY, THESE
WERE LARGELY HEALTHY
PARTICIPANTS.
THEY WERE REQUIRED TO BE
SEDENTARY AND WE HAD A
NUMBER OF QUESTIONS TO
ELICIT THAT INFORMATION BUT
THEY HAD TO BE RANDOMIZABLE
AND THEY ALSO HAD TO NOT
HAVE DIABETES OR SOME OTHER
CRITERIA.
SO THEY WERE PRETTY HEALTHY.
I REMEMBER A PILOT STUDY
THAT SHOWED EFFECT FOR OLDER
ADULTS WITH ANXIETY OR
DEPRESSION, WE DID NOT
SCREEN THOSE OUT BUT VERY
FEW OF THESE FOLKS HAD
SIGNIFICANT LEVELS OF
ANXIETY OR DEPRESSION.
THESE WERE A VOLUNTEER
SAMPLE, LARGELY AFFLUENT,
HAD GOOD ACCESS TO
HEALTHCARE THROUGH THEIR
LIVES, GOOD NUTRITION, A LOT
OF KIND OF PRIVILEGE FACTORS
BASICALLY THAT MAY HAVE
AFFECTED OUR RESULTS.
AND COGNITIVELY IN FACT TO
START WITH.
SO WE ROUX CRUDE FOR PEOPLE
WHO WERE REPORTING SOME KIND
OF COGNITIVE CHANGE BUT THE
QUESTION IS WHAT DOES THAT
REPRESENT?
SO THERE ARE ALSO ANXIETY
DISORDER AND OFTEN PEOPLE
WHO REPORT COGNITIVE CHANGES
ARE MORE ANXIOUS OR
DEPRESSED AS OPPOSED TO
EARLY STAGES OF DECLINE.
BUT IN THIS CASE WE HAD
FOLKS WHO WERE VERY INTENSE
IN THE WAY OF COGNITION,
TAKING CARE OF THEIR HEALTH,
ACCESS TO GOOD NEWS
ATTRITION.
SO IN CONCLUSION, WE DID NOT
FIND COGNITIVE CHANGES WITH
INTERVENTION, IT DID CAST
DOUBT IN THIS STUDY ON THE
INTERVENTION ON A VOLUNTEER
OLDER HEALTHY SAMPLE.
IN THE FUTURE, I THINK IT
WOULD BENEFIT TO DO TESTS
WITH HEALTHY OLDER ADULTS,
MAYBE WITH INTERVENTION AND
IN MORE VULNERABLE OLDER
ADULTS, WHETHER WE ARE ABLE
TO KEEP THEM COGNITIVELY
HEALTHY LONGER.
SO WITH THAT I WANT TO THANK
THESE HUGE CROWDS OF PEOPLE
IN SAN DIEGO AND ST. LOUIS
WITHOUT WHOM WE COULD NOT
HAVE DONE THIS WORK AND LOOK
FORWARD TO QUESTIONS LATER.
THANK YOU.
[APPLAUSE]
>> OKAY, OUR FINAL SPEAKER.
ARNOLD BAKKER FROM JOHNS
HOPKINS UNIVERSITY AND
TALKING ABOUT TARGETING
INDIVIDUAL DIFFERENCES IN
HIPPO CAMPAL HYPERACTIVITY.
>> Translator: LAKESAL
STUDIES OF NEUROCOGNITIVE
AGING.
>> THANK YOU, HAPPY TO BE
HERE.
SO IF YOU TAKE RATS AND PUT
THEM IN A RINSE, YOU
QUANTIFY THEM AND SEE
DIFFERENCES BETWEEN AGE
GROUPS AND YOUNG ANIMALS
WITH THE AGED SHOWING A
WIDER RANGE OF ABILITY IN
THEIR PERFORMANCE AND THE
INTERESTING OBSERVATION THAT
SOME AGED ANIMALS WILL
PERFORM EQUIVALENT TO THEIR
COUNTERPARTS WHERE SOME
ANIMALS DO NOT AND SHOW
IMPAIRMENT WITH RESPECT TO
THE SAME TASK AS THEIR
YOUNGER COUNTERPARTS AND YOU
CAN USE THIS TO DEFINE THESE
TWO GROUPS.
THIS IS OBVIOUSLY NOT
LIMITED TO RATS.
ON THE RIGHTHAND SIDE AT THE
BOTTOM I AM SHOWING A GRAPH
THAT WAS A MEMORY PARADIGM
ON PRIMATES AND SEEING THE
SAME OR SIMILAR RESULTS AND
THEN I SHOW HUMAN SUBJECTS
WHERE WE KNOW THIS IS A
DIFFERENCE IN TRAJECTORIES
WHICH LEADS US TO ASK WHAT
ARE THE SUCCESSFUL AGENTS
VERSUS NONSUCCESSFUL AGENTS
AND THERE ARE MANY
CONTRIBUTING FACTORS TO
THESE TRAJECTORIES.
IN MY LAB, WE ARE TRYING TO
UNDERSTAND THE MAJOR
CONTRIBUTING FACTORS TO
MEMORY IMPAIRMENT.
SO IF YOU FOCUS ON MEMORY
IMPAIRMENT AND TAKE THOSE
TWO GROUPS OF ANIMALS AND
FOCUS ON THE AGE IMPAIRED
COMPARED TO THE YOUNG AND DO
SINGLE CELL RECORDING IN THE
HIPPO CAMPAL CELLS WHILE
NAVIGATING THROUGH THE
FAMILIAR ENVIRONMENT, AS
SEEN ON THE LEFTHAND SIDE,
WE SEE THE RECORDING WITH
YOUNG ANIMALS THAT IT
RAPIDLY DOES A REVIEW OF THE
NEW ENVIRONMENT AND THEN
REMEMBERS THE OLD
ENVIRONMENT WHEN IT IS PUT
BACK.
BUT IF YOU LOOK AT THE AGED
ANIMALS, THERE IS A FAILURE
TO UP WITH DATE OR REPRESENT
THE NOVEL ENVIRONMENT AS
CLASSIFIED ON THE BOTTOM
RIGHTHAND SIDE AND THIS IS
SPECIFIC TO THE CA3 IMPAIRED
ANIMAL AND DO NOT SEE THAT
IN THE CA1.
WHAT IS SHOWN IN THE FAR
RIGHT, THE FIRING RATE.
WE ARE NOTING A INCREASED
FIRING RATE IN THE AGED IN
BOTH NOVEL AND FAMILIAR
ENVIRONMENTS AND THAT IS
SOMETHING NOT SEEN IN THE
YOUNG ANIMALS.
SO THIS IN ADDITION TO A LOT
OF OTHER DATA LEFT TO A
MODEL OF NEUROCOGNITIVE
AGING PROPOSED BY WILSON AND
COLLEAGUES IN 2006 PROPOSING
LOSS OF INPUT FROM THE
CORTEX INTO THE HYPO CAMPAL
CIRCUITRY AS WELL AS
HYPERACTIVE NEURONS IN CA3
IS THE RESULT OF PROJECTION
AND UNDER CURRENT
COLLATERALS, INBOUNDS OF
THAT ACTIVATION RESULT IN
MEMORY IMPAIRMENT OR
CONTRIBUTE TO MEMORY
IMPAIRMENT IN THE RIGIDITY
OF CA3.
IN HUMAN SUBJECTS, THERE HAS
BEEN SOME EVIDENCE OF THIS
HYPER EXCITABILITY IN THE
HIPPO CAMPUS AS WELL.
HARVARD UNIVERSITY PUBLISHED
A PAPER IN 2005 SHOWING
INDIVIDUALS WITH ISLAND
COGNITIVE IMPAIRMENT SHOWING
IRON ACTIVITY THAT WAS NOT
SEEN IN THE CONTROL
PARTICIPANTS OR THOSE WITH
DEMENT THAT.
THIS STUDY DID NOT HAVE THE
DETAILS TO LOCATE THE
HYPERACTIVITY TO THE
HIPPOCAMPUS, THAT STUDY WAS
DONE A LITTLE LATER.
AND I AM SHOWING IN THE
BOTTOM RIGHTHAND SIDE THAT
THE HYPERACTIVITY CAN BE
LOCALIZED WITH THE SUBFUSION
OF THE HIPPOCAMPUS AND IS
NOT OBSERVED IN THE CA1.
AND BOTTOM RIGHTHAND, THE
RESULTANT CIRCUITRY.
SO THIS RAISES A QUESTION.
DICKERSON SAID THAT IT WAS
COMPENSATORY FOR THE
HIPPOCAMPUS TO MAKE UP FOR
LOSS AND THESE DATA
SUGGESTED IT MIGHT BE
RELATING TO AN IMPAIR
MOUNTLAKE TERRACE THEY ARE
EXPERIENCING.
SO THEN THE HYPOTHESIS DOES
REDUCING ACTIVATION OBSERVED
BENEFIT OR IMPAIR MOUNTLAKE
TERRACE?
IT WOULD MAKE MEMORY WORSE
OR REDUCING IT, IMPAIR
FURTHER THE PARTICIPANTS.
SO THE PRO AT JOHNS HOPKINS
USING LORAZAPAM, A
ANTISEIZURE MEDICATION AND
YOU CAN SEE ON THE BOTTOM
LEFTHAND SIDE, SPECIFIC
DOSES OF LEVETIRACETAM
SIGNIFICANTLY REDUCED THE
EFFECTS SHOWING THEY SPENT
FAR LESS TIME IN THE SALINE
THAN THE IMPAIRED GROUP.
SO THIS IS A TREATMENT FOR
EPILEPSY THAT HAS BEEN
AROUND FOR MANY YEARS AND WE
CAN TEST THIS IN A HUMAN
HYPOTHESIS AT WELL AND THIS
WAS DONE IN AN AGING STUDY
ON RODENTS WITH MCI.
SO HING THE DESIGN OF THE
STUDY ON THE RIGHTHAND SIDE,
TUCKED CROSSOVER STEIN, MCI
PATIENTS WERE INITIALLY
ASSIGNED TO A DRUG
CONDITION, THEY COMPLETED
DRUG TREATMENT FOR TWO
WEEKS.
THOSE WHO NIPPERLY WERE
ASSIGNED DRUGS COMPLETE A
WASHOUT CONDITION, THEN
ANOTHER TWO WEEKS AND THOSE
ASSIGNED TO A PLACEBO WOULD
COMPLETE THE WASHOUT AND
THEN TRANSFER BACK TO THE
PLACEBO GROUP THROUGHOUT THE
DURATION OF THE STUDY.
WE ENROLLED 54 MCI PATIENTS
ACROSS THREE DOSES OF THE
DRUG AND THESE ARE THE
RESULTS OF THAT PROOF OF
CONCEPT STUDY.
SO THE LEFTHAND BAR GRAPH
SHOWING THE DOSE EQUIVALENT
TO THAT IN ANIMALS, IN ALL
THREE CASES YOU SEE THE
LIGHT GRAY BAR THAT REFLECTS
HYPERACTIVITY ACROSS THE
HIPPOCAMPUS AND THAT HAS
BEEN OBSERVED IN A NUMBER OF
STUDIES NOW.
BOTH THE 62.5MG AND THE
125MG DOSE SIGNIFICANTLY
IMPROVED EXCITABILITY IN THE
HIPPOCAMPUS AND RESULTED IN
BETTER MEMORY PERFORMANCE.
BUT THE 250MG DID NOT LOWER
THE EXCITABILITY IN THE
HIPPOCAMPUS AND ALSO DID NOT
HAVE ANY MEMORY BENEFIT.
SO BRINGING THE ANIMAL DATA
BACK ON THE FAR RIGHTHAND
SIDE TO SHOW YOU HOW
COMPARABLE THESE DOSES ARE.
SO OF COURSE THE NEXT STEP
IN TERMS OF TESTING IF THE
HYPOTHESIS WAS SUCCESSFUL,
SHOWING THE HYPER
EXCITABILITY IS NOT
COMPENSATORY BUT PART OF THE
PROBLEM AND RAISES THE
QUESTION COULD THIS DOSE BE
USED IN MILD IMPAIRMENT
WHERE THEY RECOGNIZE IN
ALZHEIMER'S DISEASE
PROGRESSION IN ADDITION TO
HAVING ELEVATED AMYLOID
LEVELS AND TAU, WE SEE THIS
EXCITABILITY FOR A PERIOD OF
TIME IN CONJUNCTION WITH THE
CORTICO ATROPHY.
SO THIS IS SHOWING THE TRIAL
SITES ACROSS THE UNITED
STATES AND CANADA WHO
PARTICIPATED IN THE STUDY,
164 AND UNFORTUNATELY THIS
DOES OCCUR OVER THE PANDEMIC
WITH ALL THE CHANGES THAT
PRESENTED.
THE AVERAGE AGES HERE ON THE
LEFTHAND SIDE.
WE ACHIEVED ALMOST
100 PERCENT MINORITY
PARTICIPATION IN THE STUDY
BUT IT IS A LARGELY HISPANIC
NONWHITE POPULATION THAT
PARTICIPATED IN THE STUDY,
17 PERCENT HISPANIC OR
LATINO AND THE PRIMARY STUDY
WAS 18 MONTHS IN DURATION.
AGB101 IS AN EXTENDED
VERSION OF LOW DOSE
LEVETIRACETAM SO IN THESE
TREATMENTS WE SIMPLIFIED
THAT WITH THE AGB101.
SO WE USED THE PET IMAGING
AND LONGITUDINAL STRUCTURE
MRI AND YOU CAN SEE HERE
REALLY A MODEST
NONSIGNIFICANT IMPROVEMENT
COMPARED TO THE PLACEBO OVER
THE COURSE OF THE TRIAL
WHICH WAS SOMEWHAT
UNEXPECTED AND OBVIOUSLY
THERE IS A POINT THERE.
HOWEVER IN A PRESPECIFIED
SUBGROUP ANALYSIS BASED ON
OUR OLD FRIEND, WE DID A
SUBSEQUENT ANALYSIS AND ON
THE RIGHTHAND BOTTOM SIDE
YOU SEE THE EFFECT IN THE
OVERALL SAMPLE WAS LARGELY
DRIVEN BY THE FOUR CARRIERS
WHO AS EXPECTED WERE ALL
SAMPLED.
THEY SHOWED A RELATIVE --
AGAIN, NONCONSISTENT EFFECT
ON THE TRIAL HOWEVER THE
APOE4 NONCARRIERS, YOU CAN
SEE THERE IS A 40 PERCENT
BENEFIT OVER 18 MONTHS
TREATMENT WITH THIS LOWER IN
THE HIPPOCAMPUS WHICH IS A
VERY MEANINGFUL BUT
NONSIGNIFICANT ON THE
PRIMARY OUTCOME OF THIS
PARTICULAR STUDY.
WE ALSO AS I MENTIONED
SELECTED MRI SCANS AT
BASELINE AND AT THE END OF
STUDY SHOWING PRELIMINARY
DATA HERE FROM A STUDY WE
PREVIOUSLY COMPLETED SHOWING
THE VOLUME CHANGE OR THE
SHAPE CHANGE OF THE CORTEX
OVER A PERIOD OF 24 MONTHS.
FROM THESE STUDIES, WE KNOW
THERE IS A SPECIFIC PATTERN
OF ATROPHY WITH PATIENTS
WITH MILD IMPAIRMENT IN THE
CORTEX.
WITH THE MCI STUDY WE
OBSERVED THE FOLLOWING
RESULTS.
THOSE TREATED WITH THE 101
SHOWED A STATISTICALLY
SIGNIFICANT BENEFIT OF
TREATMENT ON ATROPHY OF THE
CORTEX.
SO ON THE FAR LEFT GRAPH
UNDER A, YOU CAN SEE THE
VOLUME CHANGE IN THE PLACEBO
CONDITION FOR NONCARRIERS IS
APPROXIMATELY 6 PERCENT
CHANGE VOLUME PER YEAR --
SORRY, OVER THE COURSE OF
THE STUDY WHICH IS
CONSISTENT WITH THE
LITERATURE.
THE 101 TREATMENT REDUCES
THAT VOLUME CHANGE DOWN TO
APPROXIMATELY 2 PERCENT OVER
THE COURSE OF THE STUDY AND
IN BA35, THIS IS THE TREND
OF THE CORTEX WITH A SIMILAR
ATROPHY WITH TREATMENT.
SO REDUCING THE
HYPERACTIVITY HERE DOES HAVE
A BENEFIT ON CLINICAL
COGNITIVE OUTCOME AND
IMPORTANT IN THIS CORTEX
WHICH IS CRITICAL TO THE
PROGRESSION OF ALZHEIMER'S
DISEASE/DEMENTIA.
SO THIS IS THE PRIOR RESULT
AND WERE VERY RECENTLY
PUBLISHED IN ALZHEIMER'S AND
DEMENTIA.
I WILL BRING YOU BACK NOW TO
THIS GRAPH I HAVE SHOWN YOU
BEFORE, NOTING THE
DIFFERENCE IN SUCCESSFUL
TRAJECTORIES AND PERFORMANCE
OF THESE RATS, IN THE THEORY
RAT CALL GRAPH, THE PROPOSED
CHANGES HAPPEN OVER TIME AND
YOU CAN NOTE FROM THE GREEN
LINE THERE IS A RELATIVELY
EARLY START OF THAT HYPER
EXCITABILITY AND OF COURSE
THE KEY QUESTION IS WHEN
DOES THIS HYPER EXCITABILITY
START?
THERE HAS BEEN EVIDENCE OUT
THERE SUGGESTING THIS IS NOT
A CONDITION THAT IS
SPECIFICALLY MILD IMPAIRMENT
BUT CAN BE OBSERVED IN ANY
INDIVIDUALS WHO ARE
COGNITIVELY NORMAL.
SO THE QUESTION WOULD ARISE
CAN WE START WITH THIS
TREATMENT BEFORE THE ONSET
AND REDUCE THE
HYPERACTIVITY?
SO TO ADDRESS THIS QUESTION,
WE ENGAGED IN A PILOT STUDY
WITH UNIVERSITY OF WISCONSIN
WITH LI THERE, VERY
INTERESTED IN USING
COGNITIVE FUNCTIONAL IMAGING
TO QUANTIFY THE HIPPO CAMP
PAL NETWORK.
THROUGH LITERATURE WE
UNDERSTAND THIS CHANGE IN
OVER ACTIVITY AND
EXCITABILITY IN THE
INHIBITOR VALVES THE
HIPPOCAMPUS CAN BE OBSERVED
IN MEASURES THAT SHOW AN
INCREASED EXCITABILITY WITH
THE FUNCTION OF THE BRAIN
ASSOCIATED WITH AGING.
SO THE INCREASING AGE IS
ASSOCIATED WITH INCREASED
FUNCTION CONNECTIVITY OF THE
HIPPOCAMPUS WITH THE REST OF
THE BRAIN.
IN THIS PILOT STUDY, A
SAMPLE OF 25 COGNITIVELY
NORMAL OLDER ADULTS WERE
ENROLLED, FUNCTIONAL
CONNECTIVE WAS USED TO
QUANTIFY HIPPOCAMPAL HYPER
CONNECTIVITY WITH THE REST
OF THE BRAIN AND AS YOU CAN
SEE IN THE SAMPLE, AGB101
LOWERED THE EXCITABILITY IN
THE BRAIN.
SO THERE ARE A NUMBER OF
STEPS WE HAVE TO CONSIDER
GOING FORWARD IN THIS
RESEARCH.
WE'RE CURRENTLY PLANNING A
PHASE 3 TRIAL OF AGB101
TESTING THE EFFICACY OF THIS
TREATMENT IN NONCARRIERS AS
A SUCCESSFUL TREATMENT FOR
MCI AND MCS PROGRESSION.
WE ALSO NEED TO UNDERSTAND
MORE THAT THE SIGNAL WE'RE
SEEING IN AGING.
CAN THIS BE SUCCESSFULLY
USED IN SLOW PROGRESSION OF
THOSE ON THE PATH FOR
ALZHEIMER'S DISEASE BY
INTERVENING EARLY IN THIS
TRAJECTORY AND SELECTING
THESE CASES FOR
PARTICIPATION AND THUS FOR
EARLY TREATMENT?
THE THIRD THING WE NEED TO
FOCUS ON IS GOING BACK AND
ESSENTIALLY DOING THE BACK
TRANSLATION OF THE ANIMAL
WORK TO UNDERSTAND WHAT THE
APOE4 IS.
AND OF COURSE THE ANIMAL
IMPROVEMENT AND
UNDERSTANDING BETWEEN THE
TREATMENT AND APOE4 STATUS
WHICH CLEARLY IS IMPORTANT
AS THESE DATA SHOW.
SO WITH THAT, I WOULD LIKE
TO THANK THE PEOPLE IN MY
LAB AND COLLABORATORS MAKING
THIS WORK POSSIBLE AND I
WELCOME ANY QUESTIONS.
[APPLAUSE]
>> SO OUR SPEAKERS WERE
ALTER RISK ALL ALTER RISK
-- AL TERRIFIC.
SO I WANT TO KIND OF NOTE
FROM YOU ALL, GO ROUND
ROBIN, VERY BRIEF, HOW DOES
TRAJECTORY RELATE IN YOUR
WORK, HOW DO YOU NOTE OR
THINK ABOUT IT?
ANYONE CAN TAKE IT AWAY.
>> NATHAN?
>> TO ME TRAJECTORY IS JUST
THE MAPPING OF HEALTH OR
MOVEMENT AWAY FROM IT OVER
TIME AND WHAT WE FOCUS ON
VERY STRINGENTLY IN THE TWIN
MODELS ALTHOUGH I DIDN'T
SHOW IT AND YOU ARE SHOWING
THE TRAJECTORY TOWARD BRAIN
HEALTH, ALZHEIMER'S, ALL
BASED ON STIMULATION.
>> THIS IS NOT NECESSARILY
RELEVANT TO THE WORK I
PRESENTED TODAY BUT I DO A
LOT OF WORK WITH ADULTS WITH
ANXIETY AND DEPRESSION WHICH
IS AN EPISODIC ILLNESS WHERE
PEOPLE ARE DEPRESSED IN SOME
TIMES AND NOT OTHERS WHERE
ANXIETY TENDS TO START EARLY
IN LIFE AND RISE THROUGH THE
THRIVE COURSE SO TRAJECTORY
IS WHEN PEOPLE START OUT
WITH ANXIETY AND HOW DOES
THAT AFFECT THEM THROUGHOUT
LIFE AS OPPOSED TO THOSE WHO
MIGHT DEVELOP DEPRESSION FOR
A SHORT TIME AND HAVE A
POTENTIALLY BETTER OUTCOME.
>> I THINK IN WHAT OUR DATA
SHOWS FROM OUR PARTICULAR
STUDIES FOR CLIP CALL TRIAL,
WE TAKE ENROLLMENT CRITERIA
THAT PERSON HAPPENS TO MEET
AT THAT POINT IN TIME AND
GET ENROLLED IN A 18-24
MONTH TRIAL AND YOU CAN
CLEARLY SEE FROM OUR WORK
THOSE INDIVIDUALS WERE ON A
DIFFERENT PATH OR SLOPE THAN
NONCARRIERS WERE AND I DON'T
THINK IN CLINICAL TRIALS WE
KEEP THAT IN MIND ENOUGH.
WE HAVE THESE ENROLLMENT
CRITERIA, TRY TO ENROLL AS
QUICK AS POSSIBLE AND ASSUME
THAT MEANS WE HAVE A UNIFORM
SAMPLE BUT CLEARLY WE DON'T.
>> ONE OF THE THINGS I THINK
ABOUT TRAJECTORY IS THE
SEQUENCE OF INTERVENTION
THROUGH THE GENETIC PHASE,
HOW THE INTERVENTIONS
APPLIED AT DIFFERENT TIMES
DURING THE SEQUENCES CAN
RESULT IN A DIFFERENT HEALTH
TRAJECTORY.
>> WE HAVE LOTS OF FOLKS
LINED UP AT THE MICROPHONES
SO WE'LL START OVER THERE.
>> THANKS, MITCH HARKINS
FROM THE AMERICAN HEART
ASSOCIATION, ANOTHER
TERRIFIC SESSION, LEARNED A
LOT.
I HAVE A COUPLE OF QUESTIONS
BUT WILL LIMIT MYSELF TO
TWO.
THE FIRST SUN IS IN THE
ACHIEVED MINUTES TRIAL, THE
ONE OVERALL MESSAGE IS
EFFECTS MAY BE GREATER IN
THEME ALREADY EXPERIENCING A
MORE SIGNIFICANT OUTCOME OF
DECLINE THAN PEOPLE EARLIER
IN THE DISEASE COURSE.
AND I AM JUST WONDERING HOW
WE RECONCILE WITH WHAT WE
THINK TO BE THE CASE
GENERALLY, THE FURTHER ALONG
YOU ARE THE LESS LIKELY WE
ARE TO HELP PEOPLE AND IF WE
WANT TO INTERVENE IN
ALZHEIMER'S DISEASE AND SLOW
THEIR DECLINE, WE WANT TO
START EARLIER IN LIFE.
WE HAVE HEARD ABOUT HOW
EARLY IN LIFE INTERVENTIONS
ARE IMPORTANT.
SO WHAT IS GOING ON?
>> I WILL TAKE A STAB AT IT
AND THAT IS A GREAT
QUESTION.
AS SCIENTISTS ARE LIMITED TO
A 5-YEAR GRANT, YOU ARE
LIMITED TO FOLLOWING THAT
FOR A LONGER ACTIVITY.
AND FOR 10, 20 YEARS, THERE
IS A PRAGMATIC AS WELL AS
REALISTIC THING.
IN THE ACHIEVE TRIAL, WE ARE
ACTUALLY -- IF YOU PREHOP,
THE DENOVO CORE WOULD DO
BETTER BECAUSE THEY ARE MORE
LIKELY TO RESPOND TO
INTERVENTION, DOING BETTER
THAN THE AIRC COHORT.
THESE ARE SUPER MOTIVATING
ONES.
THE AIRC, A LITTLE LESS BUT
I THINK THAT EFFECT WAS
TRENCHED BECAUSE THE PRIMARY
OUTCOMES WAS REDUCING
COGNITIVE DECLINE.
SO YOU WANT DETECT THAT
UNLESS YOU HAVE COGNITIVE
DECLINE, RIGHT?
SO I THINK WE'RE ENCOURAGED
TO ACHIEVE TRIALS WITH A
POPULATION -- I SHOULDN'T
SAY INCREASED RISK BUT A
POPULATION WE SAW IN EFFECT
THERE, LATE LIFE WITHIN
THREE YEARS AND THE THING I
DIDN'T GET TO SHOW OF ALL
THE EXPLORATORY OUTCOMES,
VERY PROXIMAL IN COGNITION,
SOCIAL INTERACTION,
LONELINESS, YOU SAW CLEAR
SIGNALS CROSS BOTH COHORTS
BUT ONLY MANIFEST THIS
REDUCING THOSE ADULTS WITH A
COGNITIVE DECLINE.
SO I THINK YOUR POINT THERE
IS WELL TAKEN AND IT IS A
TRADEOFF AS FAR AS THE
TRIALS WHERE YOU GET A
POPULATION THAT IS REALLY
HELPFUL AND EXPERIENCE
INTERVENTION, THEY MAY GET
LESS OUTCOME.
SO SOMETIMES TIME IS HARD TO
MODEL AND PREDICT COMPLETELY
BUT I WISH I HAD A BETTER
ANSWER.
>> TOO SOON OR TOO LATE IN
THAT WE WERE STARTING WITH
THESE PEOPLE WHEN THEY WERE
OLDER BUT HEALTHIER AND
STARTING AT A HIGHER
BASELINE.
WE DON'T HAVE THE DATA TO
SAY WHICH IS WHICH BUT WE
ARE CONTINUING TO FOLLOW SO
WE WILL SEE.
>> THIS IS FOR Dr.
REINHART, THIS IS APPLICABLE
TO YOUR STUDIES BUT THE
BRAIN STIMULATION PARADIGM
AND PERHAPS EFFECTIVE ON
OLDER AGING PEOPLE, MAYBE
LOOK FOR EFFECTS ON YOUNGER
HEALTHY PEOPLE TO
DEMONSTRATE AN IMPROVEMENT
BEYOND NORMAL SO NOT JUST
TALKING ABOUT PREVENTING
DECLINE BUT MAKING PEOPLE
SMARTER, SO FORTH, KIND OF A
NEUROGENIC COS MET TO
M ETOLOGY AS YOU WILL.
IT STRUCK ME STRONGLY YOU
CAN GET A LONG-TERM EFFECT
WITH A SHORT STIMULATION AND
THE ACCESS MIGHT BE FOR
PERFECTLY NORMAL PEOPLE
SEEKING SOME ADVANTAGE, IS
THAT SOMETHING YOU WOULD
CONSIDER?
>> YEAH, I MEAN ONE
EXPERIMENT I DIDN'T MENTION
WAS WE INVITED ALL THE
HEALTHY YOUNG PEOPLE FROM
EXPERIMENT 2 BACK IN THE LAB
AND JUST TESTED THE PEOPLE
FOR COUPLERS WHO HAD BRAIN,
YOU KNOW, RHYTHMS THAT
APPROXIMATED THAT OF THE 60,
70YEAR ~OLD AND SO THERE WAS
MORE ROOM FOR IMPROVEMENT
AND WE WERE ABLE TO APPLY
STIMULATIONS TO SEE MORE
BENEFIT IN THAT SUBGROUP BUT
ACTUALLY MOST OF OUR WORK IS
IN HEALTHY YOUNG DOUBTS AND
YOUNG ADULTS AND YOU CAN SEE
IMPROVEMENT THERE BUT THE
BIGGEST IMPROVEMENT IS IN
OLDER ADULTS.
ACCESS AND EQUITY, I DON'T
THINK OF THAT A LOT BUT
MAYBE STARTUP INDUSTRY FOLKS
TO SPIN-OFF TECHNOLOGIES
AVAILABLE TO THE PUBLIC AND
THEY ARE ALREADY OUT THERE.
THESE ARE DEVICES THAT ARE
EASY TO MAKE YOUR SELF
POTENTIALLY, SO THERE ARE
HOME HOBBYISTS WHO ARE
DESIGNING DIRECT CURRENT
STIMULATION TO MY KNOWLEDGE,
TIN FOIL AND BATTERY AND
WIRE SO I DON'T RECOMMEND
THAT BUT WERE THINGS TO
PROGRESS THROUGH FDA
APPROVAL THROUGH THE STAGES
OF CLINICAL TRIALS AND
BECOME AVAILABLE LIKE P.M.S.
NOW FOR NDD, HOPEFULLY IT
WOULD BE AVAILABLE FOR
EVERYONE.
PERSONALLY MORE LIKE SALK
AND THE POLIO VACCINE, LET
'EM HAVE IT FOR FREE BUT IT
IS KIND OF BEYOND MY
BACKGROUND.
>> SO THE VALIDITY AND
SENSITIVITY OF COGNITIVE
MEASURES BEING MEASURED IN
THESE STUDIES, WE'RE USING
DIFFERENT COGS OF MEASURES,
SOME HAVE A PRACTICED EFFECT
MEANING THEY ARE LESS
PREDICTABLE IN EVERY DAY
EXPERIENCES AND IN OTHER
CASES, EVERY DAY EXPERIENCES
MAY BE CHANGING BUT WE ARE
NOT MEASURING THEM WELL SO I
AM CURIOUS YOUR THOUGHTS
AROUND THIS ISSUE AND WHAT
MIGHT NEED TO ADDRESS IT.
>> SO IN THE FIRST STUDY WE
DID NOT FIND EFFECTS ON
COGNITIVE CONTROL OR
FUNCTION AND WE THOUGHT THAT
WAS BECAUSE IT WAS MORE PEN
AND PAPER AND COMPUTER BASED
CONTROLS MIGHT BE MORE
SENSITIVE BUT I DON'T THINK
NECESSARILY THINK THAT IS
TRUE.
SOME OF WHAT I AM MORE
INTERESTED IN IN THE FUTURE
MAY BE A MORE COGNITIVE
AUDITORY ASSESSMENT, THINGS
THAT COME UP ON YOUR PHONE
THAT YOU CAN PARTICIPATE IN
AND MAKE MEASURES MORE
SENSITIVE BUT WE DIDN'T DO
THAT.
>> OTHER PEOPLE HAVE VIEWS
ON THE SAME QUESTION?
OTHER OPINIONS?
>> I CAN JUST WRAP IT UP
FROM A CLINICAL TRIAL
PERSPECTIVE.
I AGREE MORE WORK NEEDS TO
BE DONE BUT IT IS VERY
DIFFICULT TO DO THAT, RIGHT?
IF YOU DO GET RESULTS IN
CLINICAL TRIALS FOR OLDER
ADULTS, THERE ARE OTHER
RESULTS OUT THERE SO
CHANGING SOMETHING IS VERY
DIFFICULT.
WHERE YOU NEED LONGER
CLINICAL TRIALS, YOU NEED A
PROGRESSION RELIABLE OVER
TIME AND THAT IS VERY
DIFFICULT TO VALIDATE
BECAUSE YOU NEED TO DO
LONG-TERM STUDIES TO
GENERATE ALL THAT DATA.
WE NEED MORE WORK IN THESE
AREAS BUT THEY ARE DIFFICULT
PROBLEMS TO SOLVE SOMETIMES.
>> HI, STAN GOLDMAN,
QUESTION I HAVE FOR JULIE,
YOUR PRESENTATION REALLY
IMPRESSIVE AND AMBITIOUS.
THE THING THAT STOOD OUT FOR
ME IS THIS STUDY WITH
HEALTH, EDUCATION, IMPROVING
SLEEP, DIET AND WEIGHT, THAT
TO ME USING THE ENGAGEMENT
OF PHYSIOLOGICAL ASSESSMENT,
IF YOU HAD TOLD ME YOU WERE
GOING TO DO THOSE
INTERVENTIONS, I WOULD NOT
BE SURPRISED.
DID YOU MEASURE CHANGES IN
PHYSIOLOGICAL MEASURES WITH
THE DD02 IN THE ASSESSMENT
GROUP AS THE CONTROL GROUP?
>> WE DID AND DIDN'T FIND
THEM AND WE WERE PRETTY
CAREFUL ABOUT DRAWING A
BALANCE BETWEEN PEOPLE
SAYING I WANT TO EXERCISE
MORE AND MAYBE MAY HAVE BEEN
WALKING MORE VERSUS OUR
FOLKS IN THE TRIAL WHO IN
OUR CASE HAD MEMBERSHIP AT
THE Y IN ST. LOUIS, ACCESS
TO A GYM THAT WAS RESEARCH
ORIENTED.
SO I TRULY DON'T THINK THEY
WERE GETTING, EVEN THE FOLKS
WHO WANTED TO EXERCISE MORE,
I DON'T THINK THEY WERE
GETTING THE SAME AMOUNT OF
EXERCISE IN THE HEALTH
EDUCATION GROUP BUT THE
CHALLENGE WITH BEHAVIORAL
TRIALS, YOU NEED TO GET
INTERVENTIONS THAT ARE
COMPARABLY CRITICAL AND
EARLIER IN OUR STUDY WE HAD
LOOKED TO SEE THE HEALTH
EDUCATION AND MBR WERE
CREDIBLE.
SO IF YOU HAVE SOMEONE
COMING IN SAYING I HAVE THE
CONTROL OR THIS WON'T HELP,
LIKELY IT WON'T.
SO HOW DO YOU FIND SOMETHING
EQUALLY BELIEVABLE BUT
INERT, SO TO SPEAK.
AND IN RECRUITING, YOU ARE
ABLE TO OFFER SOMETHING TO
EVERYONE.
THESE CLASSES WERE CLEARLY A
VALUE TO PEOPLE AND PEOPLE
ENJOYED THEM AND GOT
SOMETHING OUT OF THEM.
BUT CROSS BENEFITS, I AGREE
WITH YOU NOT A LOT OF PEOPLE
WHO WERE USING EXERCISE WERE
DOING DIFFERENT KINDS OF
THINGS, SETTING GOALS AND
NOT TO THE INTENSITY LEVEL
WE WERE BRINGING THEM ALONG
WITH OUR INTERVENTION.
>> DID YOU SAY YOU DID --
[INDISCERNIBLE]
[ OFF MIC ]
>> YEAH, WE DID.
>> DAVID?
>> I WANT TO MAKE ONE FOLLOW
UP POINT THERE.
WHEN WE WERE BUILDING THE
DIGITAL TWIN MODELS I WAS
TALKING ABOUT, ONE OF THE
THINGS YOU GET INTO IS THERE
IS AN EXPECTATION THAT
EXERCISE WOULD HAVE A HUGE
EFFECT BECAUSE OF THE
IMPORTANCE OF PROFUSION OF
OXYGEN IN THE BRAIN.
THE MOST DETAILED STUDY OF
THIS, ONE OF THE THINGS THAT
COULD HAPPEN IS EXERCISE
COULD CHANGE THE SLOPE OF
THE TRAJECTORY IN AGING FOR
HOW QUICKLY OXYGENATION GOES
DOWN IN THE BRAIN BUT THE
MOST CAREFUL STUDY OF THAT
ACTUALLY DID NOT CHANGE THE
SLOPE BUT WAS AN OFFSET THAT
DELAYED THE ONSET BUT THE
SHOWN WAS THE SAME AFTER
THAT.
SO ONE OF THE BIG SURPRISES
OF THE MODEL IS WHEN WE
SIMULATED THE DETAILED DATA
THAT WAS AVAILABLE, IT
PREDICTED EXERCISE WOULD
HAVE A VERY MODEST EFFECT
AND VERY SURPRISING TO ME
AND I HATED THAT OUTCOME
WITH THE TEAM BUT JUST
SOMETHING THAT MIGHT BE
INTERESTING TO LOOK AT, THAT
IS KIND OF WHEN WE LOOKED AT
THE WHOLE THING, WHAT CAME
OUT.
>> THOSE MODELS LOOKING AT
THE CHANGE IN PLASTICITY AND
EXERCISE DON'T HAVE ANYTHING
TO DO WITH OXYGENATION.
OKLAHOMA GENUINE
OXYGENATION OF THE BRAIN IS
REALLY PRETTY CONSTANT AND
EXERCISE DOESN'T CHANGE MUCH
OF THAT.
IT IS JUST THE FOLK IDEA OF
GETTING MORE OXYGEN TO THE
BRAIN THAT IS BENEFICIAL.
>> YES, WE JUST TAKE THE
EXACT MEASURES THAT ARE
DONE.
>> SO MY QUESTION IS FOR
DOCTOR LIN.
I AM REALLY GLAD YOU ARE
HERE BECAUSE THE T TRIALS
HAVE FUNDAMENTALLY CHANGED
WHAT I THINK ARE POSSIBLE
ABOUT TRIALS TO IMPROVE
COGNITION.
THE FIRST THING IS REALLY
JUST A COMMENT.
YOU DESCRIBED THAT THE
ERRANT COHORT IS A RANDOM
POPULATION SAMPLE BUT THEY
WERE RANDOM IN 1987 WHEN
THEY WERE RECRUITED.
WHAT THEY WERE WHEN YOU
STARTED YOUR TRIAL IS
SOMETHING THAT, YOU KNOW, IS
BASED ON A RANDOM SAMPLE
FROM THOSE CITIES BUT IT IS
NOT NOW.
SO THAT IS JUST A COMMENT, I
THINK, JUST FOR ACCURACY.
THE OTHER PART IS I WILL BE
HONEST WITH EVERYBODY, I
REALLY DON'T UNDERSTAND,
HAVING A HARD TIME
UNDERSTANDING THIS ISSUE
WITH PRACTICE EFFECTS VERSUS
THE POPULATION DECLINE MORE.
SO I UNDERSTAND WHAT YOU ARE
SAYING THAT A COHORT WAS
TESTED OVER SEVERAL TIMES
AND AS A RESULT, THE TESTS
THAT WERE USED IN THE TRIAL
WERE NOT PARTICULARLY NOVEL
FOR THEM SO YOU DIDN'T
NECESSARILY SEE THAT BUMP
UP.
BUT I AM WONDERING IF YOU
CAN SAY MORE ABOUT THE
TRAJECTORIES WITHIN EACH
GROUP, IF YOU TOOK A LOOK AT
THAT, AND HELP US UNDERSTAND
HOW MUCH OF THIS IS PRACTICE
EFFECT OR HOW MUCH OF THIS
IS THE VERY IMPORTANT
CONCLUSION YOU CAME TO WHICH
IS THAT PEOPLE WHO ARE
ESSENTIALLY AT HIGHER RISK
FOR COGNITIVE DECLINE ARE
THE ONES WHERE WE SHOULD BE
FOCUSING OUR TRIALS.
AND THEN I HAVE ONE MORE
THING WHICH I HAD TO LOOK AT
MY PHONE TO REMEMBER BECAUSE
I AM GETTING SO EXCITED.
I AM VAN ROLLING HERE
BECAUSE I HAVE BEEN TALKING
ABOUT YOUR TRIALS A VERY
LONG TIME.
AT THE END AND IN YOUR
ANSWER TO MITCH, YOU
MENTIONED THE REAL MOVERS
WHICH WERE SOCIAL ISOLATION,
DECLINE AND WELL-BEING
INCREASE TO PEOPLE
RANDOMIZED TO THE HEARING
AID.
IS IT POSSIBLE EFFECTS OF
HEAR AIDS WERE INDIRECT
THROUGH THOSE
SOCIAL/WELL-BEING MECHANISMS
AND NOT THROUGH, YOU KNOW,
HEARING IN AND OF ITSELF?
>> THANK YOU SO MUCH MUCH
FOR THOSE PHENOMENAL
QUESTIONS AND I COMPLETELY
AGREE.
THEY REPRESENT ONE POINT IN
A CERTAIN DAY AND ARE
SURVIVORS OF THAT.
BUT THE NEW COHORTS ARE
SURVIVORS OF THE CURRENT
DAY.
SO TRAJECTORY, THE PRACTICE
TEST, THIS IS REALLY
INTERESTING.
THE DATA THAT I SHOWED YOU
WHICH IS WHAT WE PUT IN THE
LANCET TRIAL IS ALL
PREDICATED ON BASELINE AND
YEAR 3 AND NOT ANY
INTERVENING DATA WHICH IS
NOT WHAT WE INTENDED TO DO.
WE INTENDED TO DO A
TRAJECTORY USING YEAR 1 AND
YEAR 2 DATA BUT THE REASON
WE HAD TO THROW THAT OUT,
SOME WAS IN PERSON, SOME ON
THE PHONE AND THAT IS VERY
DIFFERENT.
WE TRIED RENORMALIZING IT,
BUT IN THE END IT WAS
DECIDED BY THE DMSB TO ONLY
BASE IT ON YEAR 3 TO GET A
CLEAN ANALYSIS AND WE KNOW
WHAT WE GOT.
BUT WHAT WE PLAN FOR, IN THE
SUBANALYSIS IF WE HAD NOT
MISSED THAT TO A PERSON,
COULD YOU SEE A BUMP-UP ON
THE EFFECTS OF THAT.
ON THE LONG LAUNDRY LIST OF
EFFECTS, YOU LOOK AT THE
PEOPLE WHO HAD YEAR 1 IN
PERSON, AND DUE IN FACT TO
SEE MORE OF A PRACTICE SET
AMONG THE DENOVOS VERSUS THE
AIRC AND I WOULD THINK WE
WOULD SEE LESS.
SO THAT IS IN THE TEST, WE
JUST HAVEN'T GOT TEN AROUND
TO IT SO THAT IS WHY WE
BASED IT ON YEAR 3 TO GET A
CLEAR STUDY OF IT.
BUT I THINK WE CAN GO BACK
TO STUDY YEAR 1 AND 2 DATA.
SO THE OTHER PART OF YOUR
QUESTION, GOING TO COGNITIVE
ON INSTRUCTION, SOCIAL
ISOLATION, I DON'T THINK IT
WOULD BE JUST ONE, I THINK
IT WOULD BE A COMBINATION OF
ALL THREE.
AND LOOKING AT THE MRI DATA
FUNDED BY AH GRAHAM, WE
DIDN'T THINK WE WOULD SEE
ANYTHING BUT WE SAW IT AS A
SIGNAL.
MAYBE THERE WAS THINNING OF
THE CORTICAL NETWORK BUT YOU
ARE EITHER SEEING
IMPROVEMENT WITH YOUR
INTERVENTION OR RELATIVELY
REDUCED DECLINES.
SO ANOTHER THING IN THE LIST
OF ANALYSIS,.
[INDISCERNIBLE]
INSTEAD OF LOOKING AT
MEDIATION MODELING, WE JUST
HAVEN'T GOT AROUND TO IT BUT
WE WILL.
>> ISN'T IT POSSIBLE THAT
THE BRAIN IMAGING FINDINGS,
CORTICO FITNESS FINDINGS
COULD ALSO BE EXPLAINED BY
THE IMPROVEMENT IN SOCIAL
INTERACTION AND WELL-BEING?
>> YEAH -- NO, ABSOLUTELY.
THE ONLY THING THERE THAT
WAS INTERESTING AND I WILL
SAY IT CAN BE A STRONG PART
OF THE ANALYSIS, ONE OF THE
STRONGEST SIGNALS IS THE
CORTICO METALIS WHICH IS THE
BASE OF LANGUAGE.
SO IN TERMS OF ACCELERATED
HEARING LOSS, THAT IS IN THE
FRONT AL TEMPORAL NODE.
AND AGAIN, HAND WAVING MIGHT
MAKE SENSE BUT HEARING
INTERVENTION IS NOT
REVERSING HEARING LOSS.
IN A WAY IT IS AN UNDER
REGENT, NOT THE AREAS THAT
CAN BE AFFECTED BY AUDITORY
DEGENERATION BUT IT IS IN
EARLY DAYS OF FURTHER AND
ANALYSIS ALL STILL ON THE
TABLE AND WE'LL GET AROUND
TO IT.
THANK YOU.
BACK.
>> CAN YOU HEAR ME?
I HAVE TWO QUICK QUESTIONS.
ONE REGARDING THE AG
BIOMARKERS FOR EXAMPLE YOU
TALKED ABOUT, THE HIGHER
LEVEL IN THE CONTEXT OF
COMORBIDITY, ARE YOU
SUGGESTING THAT IT IS
ABILITY TO ACTUAL PRODUCTION
SEEMS TO BE DIFFERENT BUT
MAYBE ALSO CONTRIBUTING TO
THE QUESTION OF CLEARANCE
AND I AM HAVING A HARD TIME
HAVING THAT CONCLUSION
WITHOUT OTHER ANOMALY
BIOMARKERS AS CONTROL.
SO THAT IS ONE THING IN
TERMS OF THINKING.
AND THEN THE SECOND QUESTION
IS THE GREAT SHROUD WE'RE
PRESENTING AND TO COME UP TO
WHAT YOU WERE SAYING, THE
POPULATION IN JACKSON,.
[INDISCERNIBLE]
IN THE NEW COHORT, DID YOU
STRATIFY -- I MIGHT HAVE
MISSED THAT WHEN YOU
PRESENTED, DID YOU STRATIFY
IN TERMS OF ENROLLMENT IN
THE NEW COHORT?
THAT IS SORT OF MY FIRST
QUESTION, ALLEVIATING
POSSIBLY THE IMBALANCE AND
THEN PERHAPS TRY TO ANALYZE
BY SITE AND FOLLOWING UP ON
JENNIFER'S QUESTION, YOU
WOULD KNOW THE OBJECT OF
HEARING LOSS BECAUSE YOU
WOULD HAVE PREVIOUS
INFORMATION.
SO HOW DID PEOPLE GET THERE
AND THEN THE LAST ONE, IN
ONE SENTENCE, AND SOMETHING
I AM ABOUT TO SAY, THE
BEAUTIFUL WORD PRESENTED BY
THE TRIAL WHICH WAS THERE
WAS NO RESULT.
IT IS NOT A NEGATIVE TRIAL,
YOU KNOW, IT IS THE RESULT.
YOU KNOW THAT BUT I AM JUST
SAYING TO ADD VALUE TO
ACTUALLY IDENTIFY
SUBPOPULATIONS THAT ARE
ACTUALLY JUST LIKE
UNDERESTIMATING YOUR WORTH.
>> SORRY, I LOST THE
QUESTION.
I WILL ANSWER VERY BRIEFLY
AND MAYBE YOU CAN TALK TO ME
AFTER.
THE ERIC COHORT CONCLUDED30
YEARS AGO, 60,000 PEOPLE,
AND HUNDRED PERCENT BLACK
AMERICANS.
OTHER SITES PRIMARILY WHITE
DEPENDING ON THE LOCATION.
SO THE BREAKDOWN OF RACE IN
THE ERIC IS DIFFERENT
BECAUSE OF THAT ORIGINAL
DESIGN.
THE DENOVOS WERE RECRUITED
IN THE SAME EXACT FOUR
COMMUNITIES BUT NOT NEARLY
SEEING THE SAME DEGREE OF
RACIAL SPREAD.
SO THE ANSWER REALLY
QUICKLY, WE DO SUBANALYSIS
BY SITE, RACE, EDUCATION,
THINGS LIKE THAT, WE DIDN'T
REALLY SEE ANYTHING YET.
I MEAN THERE WAS NO SMOKING
GUN PER SE.
EVERY TIME YOU STRATIFY A
LITTLE BIT, THERE ARE STRONG
SIGNALS WHEN YOU GET TO
ANALYSIS.
THE ONE WE THOUGHT WE SAW
WAS PEOPLE WITH A MILD TO
MODERATE HEARING LOSS, WE
WEREN'T SEEING ANY TRENDS
THERE.
WE HAVEN'T PUBLISHED THAT
YET BUT THE PRO NERVE
READOUT YOU ARE NOT SEEING
ANY BIG DIFFERENCES BY SEX,
LEVEL HEARING, EDUCATION,
THINGS LIKE THAT.
ACTUALLY I DON'T KNOW IF WE
HAVE IN-STUDY SITES BUT YOUR
SAMPLE SIZE GETS MORE AND
MORE RESTRICTED AS YOU DO
THAT BUT HAPPY TO CHAT
AFTERWARDS.
>> I HAVE A QUESTION FOR
EVERY SINGLE ONE OF YOU BUT
I WILL ASK THE ONE QUESTION
THAT ENCOMPASSES MOST OF YOU
AND I AM ASKING BECAUSE I
HAVE NEVER DONE HUMAN
STUDIES BEFORE AND I AM
ABOUT TO DO A SURVEY OF
SLEEP IN SOUTH L.A. AND I
DEFINITELY AM AFRAID I WILL
BE WASTING MY TIME BECAUSE
THE ONLY ONES WHO WILL
VOLUNTEER FOR MY STUDY WILL
BE THE AFFLUENT ONES WHO
HAVE THE TIME, YOU KNOW, AND
I WILL NOT GET A SURVEY OF
SLEEP IN SOUTH L.A.
SO HOW CAN YOU DO BETTER AT
REALLY ACTUALLY SAMPLING THE
POPULATION SO THAT WE GET
PEOPLE WHO, YOU KNOW, REALLY
MIGHT BENEFIT FROM THE
INTERVENTION, PEOPLE
MIGHT -- I FEEL LIKE WE'RE
GOING TO WASTE MILLIONS OF
DOLLARS AND YEARS OF TIME IF
WE DON'T GET THE RIGHT
POPULATION.
I AM ASKING ALL OF YOU IN
THE ROOM HOW CAN WE DO
BETTER?
WE KNOW A LOT OF THE
PROBLEMS WITH COMMUNITY
ENGAGEMENT IN CERTAIN
POPULATIONS, PEOPLE DON'T
COME FORWARD BECAUSE THEY
DON'T TRUST US AND PERHAPS
SHOULDN'T OR PERHAPS THEY
SHOULD, THEY DON'T
COMMUNICATE, WE DON'T TELL
THEM THE RESULTS OF THE
STUDY, DON'T GIVE THEM
ANYTHING BACK EXCEPT MAYBE A
GIFT CARD AND THEY DON'T
HAVE THE TIME TO ENGAGE.
HOW DO WE DO BETTER?
ANYBODY?
>> YOU ARE ASKING SOMEONE
WHO WISHES THEY HAD DONE
THAT.
AND WE TRIED TO DO SOME OF
THIS, RECRUITING THROUGH
ORGANIZATIONS OF TRUSTED
GATEKEEPERS FOR EXAMPLE, SO
RELIGIOUS MINISTERS, PASTORS
KIND OF AT THE BEGINNING OF
YOUR PLANNING STAGES AND
THEN YOU MIGHT HAVE BETTER
LUCK IN KIND OF BEING, YOU
KNOW, SEEN AS A SAFE AND
TRUSTED SOURCE OF
ASSISTANCE.
WE PRESENTED AT A LOT OF
HEALTH FAIRS AND SOME OF
THOSE WERE TARGETING
SPECIFIC POPULATIONS.
I THINK YOU KNOW THIS MEANS
YOU ARE NOT GOING TO GET A
RANDOM SAMPLE BUT I THINK
ASKING PEOPLE TO REFER THEIR
FRIENDS AND NEIGHBORS, YOU
KNOW, SORT OF GETTING
COMPLETELY RANDOM WHICH YOU
ARE NOT GOING TO GET FOR AN
INTERVIEW.
BUT YOU SAID A SURVEY SO YOU
MIGHT WANT A LITTLE MORE
RANDOM --
>> YEAH, EVEN IF YOU DO
PHONE CALLS, THE ONLY PEOPLE
ANSWERING THEIR PHONES ARE
THE ONES THAT ARE HOME AND
DON'T HAVE JOBS.
AND TO BUILD THOSE
COMMUNITIES TO TRUST
PARTNERSHIPS TAKES YEARS AND
I AM SURE THESE CHURCH
LEADERS ARE GETTING LOTS AND
LOTS OF REQUESTS NOW SO I
JUST --
>> ACTUALLY IN SOME WAYS,
YOU ACTUALLY ANSWERED YOUR
OWN QUESTION SAYING HERE IS
ALL THE STUFF WE DO, DO THE
APPS OF -- OPPOSITE OF ALL
OF THAT BECAUSE CLEARLY IT
HAS NOT WORKED.
WE HAD ONE LAST YEAR -- YOU
WANT TO WEIGH IN ON THIS?
OKAY, FINE, I AM CHANNELING
Dr. MANLY HERE BUT I THINK
IT DOES TAKE A VERY
CAREFULLY THOUGHT-OUT
APPROACH AND PARTNERSHIP
WITH THE COMMUNITY SO
ORGANIZATION IS PART OF IT
BUT JUST LISTENING, SPENDING
TIME, NOT ASKING FOR
ANYTHING AND TRYING TO
UNDERSTAND THE CHALLENGES
AND WHAT THEY ARE GOING
THROUGH AND THEN TRYING TO
BUILD THEM AS PARTNERS.
>> FROM THE LISTENING
STANDPOINT, I ALSO FEAR THE
QUESTIONS I WILL ASK WITH MY
ECOLOGICAL MOMENTARY
ASSESSMENT AREN'T THE ONES
THAT ARE RELEVANT.
I MEAN THEY ARE VERY
LIMITED, DOING ONE TO
THREE-MINUTE SAMPLES PER DAY
BUT MAYBE I NEED TO LISTEN
TO THE COMMUNITY TO SEE WHAT
THE RIGHT QUESTIONS ARE
BEFORE I FILL OUT THIS
SURVEY OR GIVE THEM A FREE
FORM AREA SO THEY CAN TELL
ME WHAT IS THE PROBLEM
SATURDAY INSTEAD OF
ASSUMING THE ANSWER.
>> OKAY, JAN ICE WILL HELP
ANSWER YOUR QUESTION.
>> I THINK FIRST OF ALL
THERE ARE PEOPLE IN THE
WORLD WHO HAVE EXPERTISE IN
THIS TYPE OF THING AND I
WOULD URGE YOU TO PARTNER
WITH THEM IN A MEANINGFUL
WAY BECAUSE THEY HAVE HAD
SUCCESS AND THEY HAVE TRUST
AND THEY KNOW THE SCIENCE OF
INCLUSION TO WHAT YOU ARE
TALKING ABOUT.
AND WHAT THEY ARE GOING TO
DO IS COMMUNITY ENGAGED
METHODS SO THAT THOSE
QUESTIONS THAT YOU HAVE, YOU
KNOW, IF I WERE TO ASK YOU
THESE QUESTIONS ABOUT SLEEP,
HOW WOULD THAT COME ACROSS
TO YOU?
YOU KNOW, THAT SORT OF
COGNITIVE INTERVIEWING TYPE
OF THING COULD GIVE ONE
APPROACH.
YOU COULD PARTNER WITH A
COMMUNITY TO COME UP WITH
THE QUESTIONS, PEOPLE WHO DO
THAT AS WELL.
THERE ARE A LOT OF OPTIONS
BUT THEY ARE GENERALLY, YOU
KNOW, AND IT TAKES A LOT OF
RESOURCES, IT DOES TAKE TIME
BUT IT IS TIME AND RESOURCES
THAT SHOULD BE BUILT INTO
ANY STUDIES, THAT IS WHAT WE
SHOULD BE EXPECTING FROM
THOSE SEEKING COMMUNITY
PARTICIPATION AND
REPRESENTATIVE
PARTICIPATION.
SO THAT'S JUST A START.
>> I WOULD MAYBE ADD ONE
MORE THING, VERY BRIEFLY AND
I DON'T WANT TO TAKE UP TOO
MUCH SPACE HERE BUT ONE OF
THE PROBLEMS WE DEAL WITH IS
STRUCTURE IN THE WAY OUR
GRANTS AND PROJECTS ARE
DESIGNED, RIGHT?
SO WE DESIGN OUR RESEARCH
QUESTIONS AND THINK THOSE
ARE THE MOST IMPORTANT AND
THEN SAY WE ARE GOING TO GO
COLLECT THE DATA BUT WE'RE
MISSING CODESIGNING THE
RESEARCH QUESTIONS WITH THE
COMMUNITY, ASKING THE RIGHT
QUESTIONS, BEING INFORMED
WITH THIS THEY HAVE SO SAY
BUT THAT IS WHAT WE LEARN AS
WELL AND WE DON'T DO ENOUGH
OF THAT.
>> EVEN JUST TO ADMIT IT IN
THE CV --
>> RIGHT, BUT ALSO JOIN THE
CHAT, GO HAVE A CUP OF
COFFEE.
>> SO I WANT TO ASK Dr.
LIN OR OPEN TO ANYBODY ON
THE PANEL, GIVEN THE
90 PERCENT RETENTION ON THE
LONG-TERM STUDY AND WHY WAS
IT SO SUCCESSFUL?
>> THE STAFF OVER 30 YEARS,
A PHENOMENAL GROUP OF
PROFESSIONALS AND WHAT I
MEAN BY THAT IS THEY
MAINTAINED THAT THROUGHOUT
30 YEARS WHICH WAS REALLY A
LOT OF TLC AND HAND HOLDING.
WE SENT THEM BIRTHDAY CARDS,
PICKED THEM UP IF WE NEEDED
TO, SO THAT WAS IMPORTANT.
THE OTHER THING IS YOU ARE
ALWAYS GETTING SOMETHING,
EITHER THE CURE INTERVENTION
OR REALLY THE REAL PROGRAM,
ONE-ON-ONE HAND HOLDING WITH
A NURSE OR HEALTH EDUCATOR.
USUALLY A NURSE.
SO EVERYBODY GOT SOMETHING
SO THERE REALLY WAS
SOMETHING IN IT FOR THEM AND
THEN SAID AFTER THREE YEARS,
YOU GET THE OTHER
INTERVENTION AS WELL.
SO I THINK IT IS A
COMBINATION OF SITE DESIGN,
COMBINATIONS WERE APPEALING
TO PEOPLE, RIGHT, AND THEN A
CREDIT TO THE STUDY STAFF
THERE FOR MANY YEARS WITH A
HIGH GROUP OF OF
PROFESSIONALS TO TREAT THE
PARTICIPANTS HOW THEY WANT
TO BE TREATED.
REALLY A LOT OF LITTLE
THINGS THAT MATTER THERE.
>> HI, I AM A SENIOR AT --
[INDISCERNIBLE]
AND MY QUESTION IS ABOUT THE
MCI TRIAL.
IT IS VERY INFORMATIVE ABOUT
THE STRATIFICATION OF APOE4
CARRIERS.
I WONDER IF THERE IS ANY
QUANTIFICATION OF THE
HIPPOCAMPUS FLUIDITY IN THIS
SYSTEM, LIKE THE ETIOLOGY OR
MRI AND WOULD IT BE THE CASE
THAT IF YOU STRATIFY WITH
INDIVIDUALS WHO HAVE HYPER
EXCITEMENT VERSUS THOSE WHO
DON'T OR PEOPLE AT THE
HIGHER EXTREME OF IT OR
AGAIN THE LOWER EXTREME OF
IT, WOULD THAT BE BEN
EFFICIENT TO BENEFICIAL FOR
PEOPLE INVOLVED WITH THAT.
>> VERY DIFFICULT TO OBTAIN
A FUNCTIONAL MRI AND
PARTICULARLY THE TYPE OF MRI
TO LOCALIZE THE HIPPO
CAMPAL, VERY DIFFICULT TO DO
AT SITES.
ALSO THE CHASE WAS MADE NOT
TO COLLECT THAT.
WE DID COLLECT PARTICULAR
DATA ON THE SET OF
PARTICIPANTS WHO CAN SO AT
JOHNS HOPKINS BUT THERE IS
NOT ENOUGH SUBJECT TO DO
THERE TO DO THE BREAKDOWN,
PLANNED VERSUS NOT PLANNED.
SO GOING BACK TO THE
HISTORICAL DATA, TRYING TO
UNDERSTAND WHAT THE SOURCE
OF THOSE DIFFERENCES MIGHT
BE.
SO IN ANSWER TO YOUR
QUESTION, CAN YOU LOOK AT
THE EXCITABILITY, THESE ARE
MEASURES OBTAINED AT THE
GROUP LEVEL AND VERY SMALL
SIGNALS YOU GET AT THE GROUP
LEVEL AND UNFORTUNATELY NOT
POSSIBLE AS IDENTIFYING THE
SUBJECT AS HAVING HIPPO
CAMPAL ACTIVITY OR NOT
HAVING THAT ACTIVITY.
BECAUSE THERE IS NO
THRESHOLD TO COMPARE THAT,
NO THRESHOLD TO SAY THIS
PERSON IS POSITIVE OR
NEGATIVE.
SO I AM GOING TO SOLVE THAT
PROBLEM AND THAT IS
SOMETHING WE WILL FOCUS
GOING FORWARD.
>> ONLY GOT A COUPLE OF
MINUTES LEFT, THIS IS THE
BONUS ROUND SO WE WILL GO
WITH QUICK QUESTIONS, QUICK
ANSWERS.
>> FOR SOMEONE WHO SAID
OXYGENATION DOES NOT HAVE
IMPACT ON, EXERCISE, YOU
CAN PUT IN ALL THE OXYGEN IN
THE WORLD AND THE BRAIN
COULDN'T CARELESS.
JULIE YOU MAY HAVE FOUND
75 PERCENT ADHERENCE BUT
DON'T DO ANYTHING ABOUT THE
QUALITY OF THE EXERCISE
BECAUSE IF YOU DON'T QUALIFY
THE EXERCISE, YOU DON'T GET
A TREATMENT EFFECT.
>> THAT'S TRUE EX ISN'T WE
DID IDENTIFY PEOPLE WHO
IMPROVED THEIR STRENGTH AND
WHAT THEY WERE DOING.
>> SOME OF THE STUDIES WE
HAVE DONE, WE FOUND INCREASE
IN BO2 MAX BUT NOTHING ELSE.
>> WITH RESPECT TO FITNESS,
CURIOUS IN THE CONTROL
GROUP, WAS IT ASSESSED THEIR
MINDFULNESS BEFORE, A AND
ALSO HOW DID THEY LIVE THEIR
LIFE, THEIR LIFE STYLE, WHAT
KIND OF STRESSORS DID THEY
HAVE IN THEIR LIFE?
I WOULD BE CURIOUS TO KNOW
COMPARED TO THE OTHER
STRESSORS WITH THE GROUP IN
THEIR LIFE.
>> SO LOOKING AT THIS ACROSS
ALL PARTICIPANTS, IN TERMS
OF STRESSORS, WE DID NOT
ASSESS FOR LIFE STRESSORS
WHICH I THINK IS A GAP IN
THE DATA WE COLLECTED AND IN
TERMS OF THEIR OVERALL
LIFESTYLE, THERE WAS A
SUGGESTION TO LOOK AT DIET
AND SOME OTHER FACTORS BUT
AGAIN, WE WERE ALREADY KIND
OF COLLECTING A LOT OF DATA
FROM FOLKS SO THAT WAS ONE
OF THE THINGS WE DID NOT DO.
IN THE EXTENSION WHICH HAS
GONE THROUGH THE PANDEMIC,
WE HAVE BEEN ASKING ABOUT
STRESSORS SO LOOKING AT
SOCIAL ISOLATION AND
LONELINESS AND SOME OF THAT
AS WELL SO THE IMPACT ON
STRESS AND COGNITIVE
FUNCTION BUT IN THE FIRST
PHASE, UNFORTUNATELY NO.
>> AND MINDFULNESS BEFORE
AND AFTER?
>> CAMS, YEAH.
>> I AM GETTING THE SIGNAL
WE HAVE TO SHUT IT OFF HERE
BUT THIS WAS A GREAT
DISCUSSION, LET'S THANK OUR
SPEAKERS ONE MORE TIME.
[APPLAUSE]
>> AND MOLLY, YOU ARE UP.
>> SO WE'RE AT THE END OF
THE MEETING AND, YOU KNOW, I
ALWAYS LIKE TO SEE A GAUGE
AT A LEVEL OF SUCCESS IN
TERMS OF HOW MANY IDEAS WE
HAVE SEEN THAT ARE GOING TO
BE TURNED IN OR HAVE BEEN
TURNED INTO ACTION OR
RESEARCH.
AND THEY BE TAKING THOSE
ACTIONS INTO IMPLEMENTATION.
SO OVER THE PAST COUPLE OF
DAYS, I HAVE HEARD A LOT OF
ENCOURAGING TALKS THAT WE
ARE MOVING IN THE RIGHT
DIRECTION AND THE KIND OF
DIRECTIONS WE WANT TO MOVE
IN TO BEGIN TO REALLY SORT
OF PIERCE THE ENVELOPE AND
MOVE FORWARD IN A VERY
POSITIVE AND DIFFERENT WAY.
IN A DIFFERENT WAY.
AND INSTEAD OF DOING WHAT WE
HAVE BEEN DOING BUT TO
IMPROVE AND TRY ON NEW
OPPORTUNITIES, NEW
APPROACHES, NEW TECHNOLOGY
TO RELAY FURTHER OUR
KNOWLEDGE.
SO I WOULD LIKE TO RECOGNIZE
AGAIN THE SPEAKERS, THEIR
EFFORTS AND CONTRIBUTIONS
HAVE BEEN EVEN MORE
EXTENSIVE THAN THE SHARING
THE RESEARCH FUNDS OVER THE
LAST COUPLE OF DAYS.
THEY HAVE BEEN WORKING WITH
NIH STAFF FOR WEEKS, MONTHS
REGARDING DISCUSSION,
DEVELOPMENT OF CONTENT AND
CONSIDERATION OF GAPS AND
OPPORTUNITIES IN THE
SCIENTIFIC SPACE, EFFORTS
FOR WHICH THEY HAVE
GENEROUSLY GIVEN THEIR TIME
AND INSIGHTS SO ONE MORE
ROUND OF APPLAUSE FOR OUR
SPEAKERS.
[APPLAUSE]
THOSE WE DON'T SEE BUT WHO
ALLOW US TO SEE AND HEAR
EVERYTHING, MY DEEP THANKS
GOES TO NIH MANAGEMENT THAT
THEY HAVE TAKEN, DAISY CHAIN
OVER ON THE SIDE OF THE
RAIN, THE BETHESDA MARRIOTT
HOTEL, DAVID LOPEZ, NIA
PERSON WHO HAS BEEN WORKING
OVER THE LAST SEVERAL WEEKS
AND RALPH, AN INSTANT WAVE
OF CALM AND CONFIDENCE THAT
SWEEPS OVER ME SO THANK YOU
VERY MUCH TO THOSE WHO
HELPED US SEE AND HEAR THE
CONFERENCE.
[APPLAUSE]
>> FOR NIH, WE HAVE WORKED
CLOSELY A NUMBER OF WEEKS
AND MONTHS WITH MATT SLADER,
WHO IS CORPORATE FOUNDATION
RELATIONS AND APPRECIATE HIS
GUIDANCE AND DIRECTION
THROUGHOUT THE SUMMIT.
AND THEN OF COURSE THERE IS
THE EVENT STAFF WHO HAVE
COORDINATED ALL THE
LOGISTICS TO BRING US HERE
THE LAST FEW DAYS, INCLUDING
MIRA PATEL, MEETING AND
EVENTS.
MATHIA HICKS, JASMINE
BUCHANAN AND THE PRIMARY
MOVER, I ASKED THE STAFF FOR
HER TO COME IN THE ROOM BUT
DON'T KNOW IF SHE IS, THERE
SHE IS, FOR ALL SUMMIT
RELATED LOGISTICS, ASHLEY
SOMERVAL, A MEETING OF THIS
SCALE TAKES A LOT OF THINGS
TO HAPPEN AND SO WANT TO
EXPRESS OUR THANKS.
NOT PRESENT, YOU HAVEN'T
SEEN THEM BUT THEY DID A LOT
FOR WORKING UP TO THIS DAY.
I STILL WANT TO RECOGNIZE
FROM NIA FROM OUR OFFICE OF
COMMUNICATIONS AND PUBLIC
LIAISON, JORDAN BRODERICK
AND KELLY OHAVER WHO HELPED
ADVERTISE THIS MEETING
THROUGH THE WEBSITE AND
OUTER COMMUNICATIONS DISSEM
NATIONS EFFORTS.
AND THEN SPECIAL THANKS TO
THE MEMBERS OF THE SUMMIT
ORGANIZING COMMITTEE WHO
ALSO SERVED AS SESSION
CHAIRS IF YOU DON'T NOTICE
THAT.
THEIR CONTRIBUTIONS HAVE
BEEN ENORMOUS AND THEY
EXTENDED THEIR TIME AND
EXPERTISE OVER THE LAST
SEVERAL MONTHS AND THEN
LATER TODAY, THE EXECUTIVE
SESSION.
SO THANK YOU.
[APPLAUSE]
AND THEN THERE IS THE NIA
FOLKS, LAURA, SO I WANT TO
THANK Dr. JOHN KING AND
Dr. HERALD FROM THE
DIVISION OF BEHAVIORAL AND
SOCIAL RESEARCH, Dr.
FRANKOWSKI FROM THE DIVISION
OF NEURAL SCIENCE.
THEY ROSE TO THE OCCASION
MORE TIMES THAN YOU WOULD
CARE TO COUNT TO MAKE THIS
COHESIVE, EXCITING, BLEEDING
EDGE SO I WILL ASK THEM TO
RISE ONE MORE TIME SO WE CAN
RECOGNIZE THEIR CENTRAL
ROLE.
JOHN AND AARON AND DAVE, IF
YOU COULD STAND?
[APPLAUSE]
AND I AM GOING TO TAKE A
MOMENT TO INDIVIDUALLY
RECOGNIZE DAVE FRANKOWSKI
WHO CHEERFULLY AND
CONSISTENTLY OFFERED HIS
SKILLS AND TIME TO EVERY
ASPECT OF THE THE PLANNING
AND EXECUTION.
THANKS, DAVE.
[APPLAUSE]
BUT MOST IMPORTANTLY, OUR
THANKS GOES TO THE
McKNIGHT BRAIN RESEARCH
FOUNDATION BOARD OF TRUSTEES
FOR HAVING THE
DETERMINATION, COMMITMENT
AND VISION TO PRIORITIZE
THIS.
THIS MARKS THE FOURTH TIME
THE FOUNDATION HAS MADE IT
POSSIBLE TO CONVENE THIS
IMPORTANT MEETING.
ANGELICA, EXECUTIVE DIRECTOR
FOR THE FOUNDATION WORKED
CLOSELY WITH THE SUMMIT
PLANNING COMMITTEE OVER THE
PAST SEVERAL MONTHS SPECIAL
PROVIDED VALUABLE INPUT AND
RESOURCES.
DURING THE PLANNING PHASE,
MET WITH US MULTIPLE TIMES
AND ALL HERE TODAY BECAUSE
OF THE McKNIGHT BRAIN
RESEARCH FOUNDATION.
[APPLAUSE]
AND NOW I WILL TURN IT OVER
TO YOU.
>> THANK YOU ALL VERY MUCH.
NOT ONLY FOR STICKING IT OUT
TO THE END BUT BEING HERE IN
THE FIRST PLACE.
AMAZED THE DISTANCES PEOPLE
HAVE TRAVELED AND TAKING
TIME OUT OF YOUR SCHEDULES
NOT ONLY TO BE HERE BUT
PARTICULARLY THE ORGANIZING
COMMITTEE, GIVING US
WONDERFUL IDEAS THAT ARE NEW
TO ME SO I THANK YOU FOR
THAT.
LET'S SEE, WE WANT TO HAVE A
FEW PUBLIC RELATIONS
COMMENTS HERE, TAKE A
PICTURE OF THAT IF YOU WANT,
OF THE NEW BRAIN WORKS SITE
THAT GOES LIVE TOMORROW AND
WANTING US TO BE A OUTREACH
SO SHARE THAT WITH FRIENDS,
FAMILY, PATIENTS AND THEN
ALSO ON OUR WEBSITE WHILE
YOU ARE THERE, WE HAVE
SEVERAL PARTNERSHIPS WHERE
THERE ARE FUNDING
OPPORTUNITIES SO I KNOW THAT
PEAKS THE INTEREST FOR FOLKS
DOING RESEARCH TO BE SURE TO
CHECK THAT OUT AS WELL.
AND THEN AT THE END I WOULD
JUST THANK YOU ALL FOR THE
GREAT RESEARCH.
I WOULD KIND OF ASK FOR A
LITTLE TWIST BECAUSE WE ARE
LOOKING FOR HOW CAN WE MAKE
A DIFFERENCE SO THEN THE
QUESTION ALWAYS IS HOW CAN
WE APPLY THIS CLINICALLY IN
HUMANS, TO MAKE A
DIFFERENCE, HELP US
SUCCESSFULLY AGE WELL.
AND SO AS LONG AS WE HAVE
THAT LENSE THROUGH WHICH
WE'RE VIEWING EVERYTHING, I
THINK THE WORK MAKES AN EVEN
GREATER SIGNIFICANCE.
SO THANK YOU ALL AGAIN AND
THAT'S IT.
[APPLAUSE]
>> AND THAT CONCLUDES THE
MEETING.
SAFE TRAVELS HOME, EVERYONE.
THANKS AGAIN.
[ END OF SESSION ]