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-Good morning, everyone.

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I'm Natalia Rost,
and I'm Scientific Chair

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of the 2022 ADRD Summit,

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and this is the moment
we've been waiting for

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for 3 years
to get together again,

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and on behalf of our entire
program-planning team,

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it is my great honor
to officially open the summit

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and to introduce our first
speaker, Dr. Walter Koroshetz,

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Director
of the National Institute

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of Neurological Disorders
and Stroke.

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Welcome.

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-Oh, thank you, Natalia.

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Can you hear me all right?

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Very good.

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Yep, well, I want to welcome
everyone who's attending

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and also thank all the people
who put a lot of work

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into what we're going to hear
in the next 2 days.

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This was really the result
of a lot of hard thinking

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and very smart people,

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all dedicated to this common
goal of trying to figure out

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how we can better reduce
the burden of illness

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due to Alzheimer-related
dementias.

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The next slide, please.

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And again, special thanks to
Natalia for leading the group.

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I think it was a good group,

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so it wasn't as hard as
some of the other groups

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I made her
lead in the past.

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Next slide.

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So what we're talking about
is a national priority

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that Congress has spoken about
and actually funded generously

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to try to make a difference
in this problem

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of Alzheimer-disease-related
dementias.

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We're talking about
irreversible,

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right now, irreversible,
progressive brain diseases

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that rob people of the ability
to interact and communicate,

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and eventually many of these
are fatal diseases.

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They slowly destroy
brain function,

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leading to cognitive decline,

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behavioral and psychiatric
disorders and inability

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to even function
and activities of daily

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living and requiring care.

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It's a major public health issue

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affecting the health
and finances,

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but it's really a tragedy
for the individual

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and the family particularly.

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So the NAPA law in 2011
offered historic opportunity

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to address
the Alzheimer's disease issue

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and Alzheimer's
disease-related dementias,

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and we will be talking mostly

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about the Alzheimer's
disease-related dementias

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as opposed to Alzheimer's
as a pure entity.

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That is --
comes under the purview

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of the National Institute
of Aging Summit

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that we intersperse
with our summit.

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But as you'll see, there is
tremendous overlap

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in the Alzheimer's and
the Alzheimer-related dementias,

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and so learning from one really
helps learning in the others.

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Next slide.

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So what we're talking about
in terms of the congressionally

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defined Alzheimer's
disease-related dementias

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are basically the vascular
contributions of dementia,

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so as our brains age,

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our blood vessels
to the brain age.

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This is easily seen
under the microscope,

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but also the contributions
of vascular aging

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and several vascular diseases
are very apparent on MRI scans,

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a very sensitive technique
to pick up these changes,

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and so these are things that are
standing right in front of us,

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easy to identify but tricky
so far to figure out

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how to decrease the contribution
of vascular disease

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and vascular risk factors
for dementia

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although if one looks
at the literature

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in terms of a short-term win,

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all the data points to the fact
that controlling vascular health

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will actually reduce
cognitive impairment as we age

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and also potentially reduce
the risk of developing dementia.

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Lewy body dementia is a term
that's used for conditions

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where there's dementia related

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to what are called
these aggregates of a protein

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called synuclein
inside of neurons,

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also in the neurites themselves,
the processes of the neurons.

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You get these aggregates
of synuclein,

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and that is also the signature
of Parkinson's disease,

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and many patients
with Parkinson's develop

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cognitive impairment over time

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because these Lewy bodies start
to move throughout the brain,

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and there's also a condition
in which the Lewy bodies

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start in the thinking area
of the brain

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and cause dementia first
and then Parkinson's later.

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Frontal temporal dementia

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is also a very common
cause of dementia,

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one of the more common
causes of dementia

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in people who are younger,
in their 50s or 60s,

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and these, again,
are associated with atrophy

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and loss of brain tissue

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in particular areas
of the brain.

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Depending on the area, there
are these certain symptoms,

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frequently troubles
with behavior or language.

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And also, of interest,
we found more recently

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is there's a strong association

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with some of these
frontal dementias

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with amyotrophic
lateral sclerosis,

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which causes progressive
and fatal paralysis

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of all the muscles
in the body

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due to loss of the motor neurons
that control those muscles.

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And finally probably also
incredibly important

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is the discussion of the fact
that when people's brains

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are examined who have dementia
in this elderly space,

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more frequently than not,
there's a combination

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of different
pathologies in the brain,

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so the cause of the dementia,
we think,

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is related to a combination
of the Alzheimer problem,

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the synuclein problem,
the cerebrovascular problem,

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and so we see
those combinations,

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and certainly we're going
to treat Alzheimer's.

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We're going to have to
try to understand

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how each of these contributing
pathologies are best treated.

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Next slide.

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And so the research is focused
right now

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on trying to understand
the biological mechanisms.

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Without understanding those,

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we really can't
develop treatments,

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but there has been a lot
of progress in this space,

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in discovery of targets

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that could be pursued
to develop therapies,

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and also importantly
is the progress

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in developing biomarkers,
so these are measurements

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that one can make
in living individuals

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that will predict
what kind of pathology

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there is going on
in the brain.

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And lastly we want to mention

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that the research
that's being done,

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Alzheimer's disease
and related dementias,

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includes a lot of gaps
in knowledge,

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but there is a lot of research
going on, very basic research

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in how the brain works
and how it organizes

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and how inflammatory cells
interact with the brain,

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both normally and abnormally,
that all kind of come together

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in trying to improve
our understanding

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of Alzheimer's and
Alzheimer's-related dementias.

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Next slide.

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And this is just to tell you

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that we, you know,
it is complicated

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because there are
so many factors

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that go into
the development of dementia.

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It's something that occurs
usually in the,

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you know,
the age of individual,

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and so, so many things have
happened to the brain over time,

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whether it's traumatic
brain injury

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or stroke or vascular disease,

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the development
of these abnormal proteins,

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but we have to
piece this apart...

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piece this together
and identify the pieces

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that are going to be
most potentially important

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as targets for therapies,

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but that's kind of
the just simplistic version

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of what our goal is,

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is to understand the features,
understand how they fit together

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and then develop treatments
that are going to be effective.

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Next slide.

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And there has certainly
been advances over time,

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particularly in
the biomarker space,

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for Alzheimer's, and also,
the Alzheimer-related dementias

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is,
we think, very good now,

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accurate ways
of testing spinal fluid

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or even skin biopsies
to detect the synuclein

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aggregates that are associated
with Parkinson's disease

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and Lewy body disease.

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There are certain
radioactive scans

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that one can do to detect
dopamine loss in people

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who have Lewy body disease,

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separates them
from Alzheimer's disease,

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and there's now
really interesting,

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very predictive studies

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looking at evidence
of Alzheimer pathology in people

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with Lewy body disease
and Parkinson's disease

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that contributes to their
troubles with cognition,

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so we're getting now the ability
to look at living individuals

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and actually get evidence for
what is going on in the brain,

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and as I mentioned before,

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that's the critical thing
to know in determining

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what treatment is going to be
best for what patient,

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and so there was tremendous
progress in this space now.

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Next slide.

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And right, and so,
even on the vascular side,

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I said, yeah, the MRI
is incredibly sensitive

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to picking up changes in
the white matter of the brain,

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which is very common,
associated with hypertension

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and several vascular disease,

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present in probably
80 percent of people

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at some degree
after the age of 80.

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These are kind of things
that we can,

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you know,
follow over time

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and see if therapy affects
their progression over time

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because you're not born
with this,

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but it develops over time,

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and it's easy to see
on the MRI scan.

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Next slide.

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And just important to mention
that we are really doubling down

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in looking to the future
where there are treatments

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to make sure that
those treatments

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are going to be available
for everyone in our society,

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and that is unfortunately
not a trivial task.

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People may present differently
depending on their culture,

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the racial,
ethnic background.

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You don't want to miss...

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If you need to treat early
in the dementia,

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you don't want to miss that

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because there's some inequities
in the system

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in terms of picking it up
in addition

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to being able to make sure

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that all the treatments
are accessible to folks.

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You do a lot of genetic studies
to determine,

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you know,
genetic risk factors.

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I'm sorry to say most of that
genetic work has been done

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on Caucasians
of European descent,

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and we know now that
some things like APOE are --

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may act very different
in African Americans,

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so we really need to think
as we move forward

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so that what we discover
is relevant

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to all segments
of our population.

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They may not all be the same,

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but we need to know
what those differences are.

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So thank you.

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Next slide.

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And I want to just end up
by thanking our partner

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in this effort,

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working hand in hand with
the National Institute of Aging

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for many years.

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We initially started, you know,
putting out the plan

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not realizing that there was
going to be funding coming,

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and with the funding coming,
both NIA, NINDS

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and the other partners
have really put together

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what I think is a really
earth-shattering series

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of research projects

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over the years that really
opening the door

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to therapies
for these diseases now.

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So I want to thank everybody
and looking forward

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to hearing
the recommendations

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coming out of
the different work groups.

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Thank you very much.

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-Thank you.
Good morning.

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Thank you, Dr. Koroshetz.

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My name is Cindy Carlsson.

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I'm a physician in geriatrics

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of University of Wisconsin
in Madison,

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Professor of Medicine there,

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and also with the VA hospital
in Madison, Wisconsin,

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and as Chair of the Advisory
Council on Alzheimer's Research,

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Care and Services,
I'll be speaking next

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just for the next few minutes
to share with you

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all a little bit of perspective
based on the NAPA Council.

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So the National Plan
to Address Alzheimer's Disease

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has already been addressed
by Dr. Koroshetz,

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and we'll hear more
from Dr. Rose, Dr. Corriveau,

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00:13:55,840 --> 00:13:58,200
but again,
the national plan really,

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00:13:58,200 --> 00:14:00,280
really bases a lot of its input

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00:14:00,280 --> 00:14:02,200
from these important
research summits,

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00:14:02,200 --> 00:14:05,640
so again, as you'll see today
and as we'll touch on briefly,

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00:14:05,640 --> 00:14:13,480
these summits really feed
into helping develop these ideas

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00:14:13,480 --> 00:14:16,640
and moving this work forward,
so the NAPA plan,

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00:14:16,640 --> 00:14:19,760
which I'll talk about,
covers clinical care,

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00:14:19,760 --> 00:14:23,000
long-term services
and support and research

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00:14:23,000 --> 00:14:25,320
and has a new goal
of risk reduction,

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00:14:25,320 --> 00:14:28,320
so we have four subcommittees
that really help alter

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the national plan
and move it forward,

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00:14:30,640 --> 00:14:32,520
but these summits
are critically important

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00:14:32,520 --> 00:14:35,600
as we move forward
in these areas.

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Next slide, please.

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00:14:37,760 --> 00:14:40,440
So by way of disclosure, again,
these are my views,

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00:14:40,440 --> 00:14:43,400
not NIH's views or NAPA
or ASPE,

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00:14:43,400 --> 00:14:45,560
and I do receive
funding from NIH,

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00:14:45,560 --> 00:14:49,400
the VA,
NIH/Lilly and NIH/Eisai.

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00:14:49,400 --> 00:14:52,200
Next slide.

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00:14:52,200 --> 00:14:55,200
So then the National Alzheimer's
Project Act was first enacted

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just over 10 years ago in 2011
as Dr. Koroshetz mentioned,

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00:14:59,400 --> 00:15:01,600
and one thing that's
extremely important to note

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00:15:01,600 --> 00:15:04,200
for this meeting is that this...

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00:15:04,200 --> 00:15:06,080
although it's called
the Alzheimer's Act,

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00:15:06,080 --> 00:15:08,840
it's really meant to include
Alzheimer's-related dementias

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00:15:08,840 --> 00:15:11,200
as well,
so again, for brevity's sake,

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00:15:11,200 --> 00:15:12,960
it just says, "Alzheimer's,"
throughout the plan,

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00:15:12,960 --> 00:15:15,400
but it says in introduction
that this is really meant

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00:15:15,400 --> 00:15:18,000
to include all the different
forms of dementias,

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00:15:18,000 --> 00:15:20,560
and so as we speak
about NAPA,

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00:15:20,560 --> 00:15:23,400
it should be whatever the
abbreviation would be pronounced

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00:15:23,400 --> 00:15:26,280
with all
the other dementias included.

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00:15:26,280 --> 00:15:29,720
So again, this is led by the
Assistant Secretary's Offices

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for Planning
and Evaluation,

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00:15:31,200 --> 00:15:33,760
and they became the lead
right after that,

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00:15:33,760 --> 00:15:35,600
and then the first
Advisory Council

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was in September of 2011.

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00:15:38,000 --> 00:15:40,680
The first national plan
was developed

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00:15:40,680 --> 00:15:43,000
and released
just almost 10 years ago,

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00:15:43,000 --> 00:15:46,280
so one thing, I think, that's
important for us to step back

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00:15:46,280 --> 00:15:49,160
and think about is,
as far as perspective,

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00:15:49,160 --> 00:15:50,960
is not only to look
to the future

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00:15:50,960 --> 00:15:53,400
about what areas need
to be evaluated still,

299
00:15:53,400 --> 00:15:55,280
what gaps there are in research

300
00:15:55,280 --> 00:15:57,080
but also for us
to take a step back

301
00:15:57,080 --> 00:15:59,080
and to think about the progress
that's been made

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00:15:59,080 --> 00:16:00,840
in the last 10 years,

303
00:16:00,840 --> 00:16:04,680
so thinking about new, novel
PET-scan tools, biomarker tools

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00:16:04,680 --> 00:16:07,000
that really help us
pinpoint the disease

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00:16:07,000 --> 00:16:09,560
and help us to understand
that many of these dementias

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00:16:09,560 --> 00:16:11,880
are multiple-etiology dementias.

307
00:16:11,880 --> 00:16:14,800
So again, having these factors
can really help us

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00:16:14,800 --> 00:16:16,840
find the commonalities
and the differences

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00:16:16,840 --> 00:16:20,600
between these types of dementias
among many other advances.

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00:16:20,600 --> 00:16:23,680
So in our upcoming NAPA meeting,
we'll be highlighting,

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00:16:23,680 --> 00:16:25,720
having the federal agencies
highlight

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00:16:25,720 --> 00:16:29,000
the accomplishments
over the past 10 years,

313
00:16:29,000 --> 00:16:30,920
so again,
taking a step back to think,

314
00:16:30,920 --> 00:16:32,480
"What have we accomplished
so far,

315
00:16:32,480 --> 00:16:35,760
and how can we use
that momentum to move forward?"

316
00:16:35,760 --> 00:16:38,320
Next slide.

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00:16:38,320 --> 00:16:40,400
So the National Alzheimer's
Project Act

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00:16:40,400 --> 00:16:43,880
required that the Department
of Health and Human Services

319
00:16:43,880 --> 00:16:46,160
establish the following items,

320
00:16:46,160 --> 00:16:48,760
so again, there's two
main products out of this

321
00:16:48,760 --> 00:16:52,920
that have generated a lot
of synergy with these summits,

322
00:16:52,920 --> 00:16:55,520
so for example, to create
and maintain a national plan

323
00:16:55,520 --> 00:16:58,720
to overcome Alzheimer's disease
and related dementias,

324
00:16:58,720 --> 00:17:02,360
to coordinate research and
services across federal agencies

325
00:17:02,360 --> 00:17:04,040
and, again,
not just federal agencies.

326
00:17:04,040 --> 00:17:05,920
This is a national plan,
so again,

327
00:17:05,920 --> 00:17:07,440
to serve as a blueprint
for states,

328
00:17:07,440 --> 00:17:10,880
counties, communities
to really align their work

329
00:17:10,880 --> 00:17:13,360
together
to move things forward,

330
00:17:13,360 --> 00:17:15,880
to accelerate the development
of treatments

331
00:17:15,880 --> 00:17:20,480
that would hopefully prevent,
halt or reverse the disease,

332
00:17:20,480 --> 00:17:23,400
the numerous disease
we'll be talking about today,

333
00:17:23,400 --> 00:17:26,080
improve early diagnosis
in coordination of care

334
00:17:26,080 --> 00:17:27,600
and treatment of the disease,

335
00:17:27,600 --> 00:17:29,600
improve outcomes
for people from racial

336
00:17:29,600 --> 00:17:31,800
and ethnic-diverse
communities

337
00:17:31,800 --> 00:17:33,880
throughout our country
who are at higher risk

338
00:17:33,880 --> 00:17:36,480
in some cases
for developing dementia

339
00:17:36,480 --> 00:17:38,760
and then coordinating with
international bodies as well,

340
00:17:38,760 --> 00:17:41,560
so we really want to make sure
that we're leading the way

341
00:17:41,560 --> 00:17:43,960
globally in these efforts,

342
00:17:43,960 --> 00:17:45,920
and then creating
an advisory council,

343
00:17:45,920 --> 00:17:48,080
which again,
I currently serve as chair,

344
00:17:48,080 --> 00:17:50,280
to review and comment
on the national plan

345
00:17:50,280 --> 00:17:52,000
and its implementation.

346
00:17:52,000 --> 00:17:54,840
Next slide.

347
00:17:54,840 --> 00:17:56,600
So the advisory council, again,

348
00:17:56,600 --> 00:17:59,000
works together
to review the national plan,

349
00:17:59,000 --> 00:18:02,040
to integrate ideas from summits
just like this one

350
00:18:02,040 --> 00:18:03,760
to make sure
that the plan reflects

351
00:18:03,760 --> 00:18:06,280
the current scientific thinking,
clinical care,

352
00:18:06,280 --> 00:18:08,000
policies that are there,

353
00:18:08,000 --> 00:18:12,560
and so the public arm of the
council includes 12 members,

354
00:18:12,560 --> 00:18:13,960
and so these 12 members

355
00:18:13,960 --> 00:18:15,960
come from diverse
backgrounds from...

356
00:18:15,960 --> 00:18:17,640
Some are patient advocates,
again,

357
00:18:17,640 --> 00:18:19,520
including people
who are living with dementia

358
00:18:19,520 --> 00:18:21,440
and mild cognitive impairment.

359
00:18:21,440 --> 00:18:24,080
There's caregivers, providers,
state

360
00:18:24,080 --> 00:18:26,880
and local representatives,
researchers

361
00:18:26,880 --> 00:18:30,400
and then two voluntary health
association representatives.

362
00:18:30,400 --> 00:18:34,440
So again, this input is really
important as we shape the future

363
00:18:34,440 --> 00:18:38,640
of research, clinical care
and long-term support services,

364
00:18:38,640 --> 00:18:41,800
and again, we want people
to continue to provide input,

365
00:18:41,800 --> 00:18:43,160
and as I'll mention
at the end,

366
00:18:43,160 --> 00:18:45,200
there's always room
for public comment,

367
00:18:45,200 --> 00:18:47,520
and so we want the public,
whether it be a researcher,

368
00:18:47,520 --> 00:18:50,640
advocate, a caregiver,
to really speak into these goals

369
00:18:50,640 --> 00:18:54,360
and help shape
this national plan.

370
00:18:54,360 --> 00:18:56,640
We also have colleagues
from our federal --

371
00:18:56,640 --> 00:18:58,160
from the federal government,
so again,

372
00:18:58,160 --> 00:18:59,920
we have colleagues
from the Department of Health

373
00:18:59,920 --> 00:19:02,280
and Human Services,
Veterans Affairs,

374
00:19:02,280 --> 00:19:05,000
Department of Defense,
National Science Foundation,

375
00:19:05,000 --> 00:19:08,560
and you'll see within Health
and Human Services we have:

376
00:19:08,560 --> 00:19:10,720
the Office of
the Assistant Secretary

377
00:19:10,720 --> 00:19:12,240
for Planning
and Evaluation,

378
00:19:12,240 --> 00:19:17,160
or ASPE, Indian Health Service,
NIH, of course,

379
00:19:17,160 --> 00:19:21,280
National Centers for Medicare
and Medicaid Services, CMS,

380
00:19:21,280 --> 00:19:23,600
Agency for Healthcare
Research Equality,

381
00:19:23,600 --> 00:19:25,720
Administration for
Community Living,

382
00:19:25,720 --> 00:19:30,200
Centers for Disease Control,
Health Services Administration

383
00:19:30,200 --> 00:19:32,000
and Food
and Drug Administration.

384
00:19:32,000 --> 00:19:34,480
So you, again, see that
there's this partnership

385
00:19:34,480 --> 00:19:36,600
for the public team
bringing in a perspective

386
00:19:36,600 --> 00:19:38,840
of patients,
caregivers, researchers

387
00:19:38,840 --> 00:19:41,000
and then the federal
partners helping guide

388
00:19:41,000 --> 00:19:43,040
that towards
actionable items.

389
00:19:43,040 --> 00:19:45,760
Next slide.

390
00:19:45,760 --> 00:19:48,080
So here are current members
for both the public

391
00:19:48,080 --> 00:19:51,840
and federal components
of the advisory council,

392
00:19:51,840 --> 00:19:55,000
so again, you'll see
we have four subcommittees.

393
00:19:55,000 --> 00:19:58,440
So Research Subcommittee,
the LTSS stands for Long-Term

394
00:19:58,440 --> 00:20:00,800
Support
Services Subcommittee,

395
00:20:00,800 --> 00:20:04,240
Clinical Subcommittee
and Risk Reduction Subcommittee,

396
00:20:04,240 --> 00:20:05,960
and as we'll discuss,
the risk reduction

397
00:20:05,960 --> 00:20:07,840
is a new goal this year,

398
00:20:07,840 --> 00:20:10,640
and really while
there's always been a goal

399
00:20:10,640 --> 00:20:13,120
to prevent and treat
Alzheimer's disease

400
00:20:13,120 --> 00:20:14,720
and related dementias,

401
00:20:14,720 --> 00:20:16,800
this really helps us move
into the public-health space,

402
00:20:16,800 --> 00:20:20,240
try to reduce risk
in a large-scale effort

403
00:20:20,240 --> 00:20:23,800
as Dr. Koroshetz mentioned
with several of the other --

404
00:20:23,800 --> 00:20:26,480
with numerous agencies
making efforts in,

405
00:20:26,480 --> 00:20:28,600
for example,
reduction of hypertension,

406
00:20:28,600 --> 00:20:32,400
increased exercise
and other areas.

407
00:20:32,400 --> 00:20:35,600
Next slide.

408
00:20:35,600 --> 00:20:38,960
So the national plan focuses
on initially five and now,

409
00:20:38,960 --> 00:20:43,200
again, with a new sixth goal,
so goal one is ambitious,

410
00:20:43,200 --> 00:20:45,760
to prevent and effectively
treat Alzheimer's disease

411
00:20:45,760 --> 00:20:48,080
and related dementias
by 2025,

412
00:20:48,080 --> 00:20:51,120
so again, we're coming up
against that benchmark,

413
00:20:51,120 --> 00:20:53,160
but again, I think it's
important for us to step back

414
00:20:53,160 --> 00:20:56,600
and think where we've come,
so again, there's the first...

415
00:20:56,600 --> 00:20:59,200
While controversial, the first
agent has been approved

416
00:20:59,200 --> 00:21:02,640
by the FDA to treat
Alzheimer's disease,

417
00:21:02,640 --> 00:21:04,760
so the first step
in helping us to think

418
00:21:04,760 --> 00:21:07,280
through what kind of research
needs to be done

419
00:21:07,280 --> 00:21:11,120
to help us focus
disease-modifying therapies

420
00:21:11,120 --> 00:21:13,680
and effective treatment
strategies.

421
00:21:13,680 --> 00:21:15,480
And also, how does our health
care system

422
00:21:15,480 --> 00:21:18,080
respond to these agents
being approved?

423
00:21:18,080 --> 00:21:20,480
Do we have the
infrastructure available

424
00:21:20,480 --> 00:21:23,080
to help monitor safety
for patients?

425
00:21:23,080 --> 00:21:26,080
Do we have clinicians
who are trained in diagnosing

426
00:21:26,080 --> 00:21:29,240
and managing patients
to be able to use

427
00:21:29,240 --> 00:21:30,760
these new, novel therapies?

428
00:21:30,760 --> 00:21:33,960
So again, prevention
and treatment

429
00:21:33,960 --> 00:21:36,080
is one of the first goals.

430
00:21:36,080 --> 00:21:38,920
Second goal, again, to enhance
care, quality and efficiency,

431
00:21:38,920 --> 00:21:41,320
so again, it takes research
to do this as well,

432
00:21:41,320 --> 00:21:44,840
and you'll see today the
multi-etiology dementia group,

433
00:21:44,840 --> 00:21:47,920
that there's discussion about,
how do you initially diagnose,

434
00:21:47,920 --> 00:21:50,720
and how do you make sure
that we have the workforce

435
00:21:50,720 --> 00:21:54,000
to provide good care,
quality and efficiency?

436
00:21:54,000 --> 00:21:55,600
The goal three is to support
people

437
00:21:55,600 --> 00:21:57,840
with Alzheimer's-related
dementias and their families,

438
00:21:57,840 --> 00:22:00,200
so again, there's
a caregiving summit

439
00:22:00,200 --> 00:22:04,080
that occurs every third year
in this summit series,

440
00:22:04,080 --> 00:22:07,160
and that came out of NAPA
goals with the need...

441
00:22:07,160 --> 00:22:08,800
understanding that
we need more research

442
00:22:08,800 --> 00:22:12,240
and how to best support people
with dementia

443
00:22:12,240 --> 00:22:14,600
and their families.

444
00:22:14,600 --> 00:22:17,240
Increasing public awareness
and engagement, so again,

445
00:22:17,240 --> 00:22:19,000
we want people to be
a part of these meetings.

446
00:22:19,000 --> 00:22:21,360
We want people to be
a part of NAPA meetings.

447
00:22:21,360 --> 00:22:23,200
If people aren't aware
of dementia,

448
00:22:23,200 --> 00:22:26,560
then they're not going to get in
to get the care that they need.

449
00:22:26,560 --> 00:22:28,840
They're not going to become
a part of clinical trials.

450
00:22:28,840 --> 00:22:30,800
They're not going to spread
the word among their colleagues

451
00:22:30,800 --> 00:22:33,520
and engage
in risk-reduction activity,

452
00:22:33,520 --> 00:22:37,880
so again, these are
very important areas to promote.

453
00:22:37,880 --> 00:22:40,680
And then improving data
to track progress

454
00:22:40,680 --> 00:22:42,920
so that we can see,
how are we doing now,

455
00:22:42,920 --> 00:22:46,680
and how are we doing in the
future with these initiatives?

456
00:22:46,680 --> 00:22:49,160
So accelerating action
to promote healthy aging

457
00:22:49,160 --> 00:22:50,960
and risk reduction
is our new goal,

458
00:22:50,960 --> 00:22:53,400
so again, moving
into public health space

459
00:22:53,400 --> 00:22:56,600
and reducing risk
for these factors

460
00:22:56,600 --> 00:22:59,440
but also needing research
to make sure that we understand,

461
00:22:59,440 --> 00:23:02,760
what are the most promising
risk-reduction factors?

462
00:23:02,760 --> 00:23:05,600
Next slide.

463
00:23:05,600 --> 00:23:09,200
-Two minutes remaining.
-Thank you.

464
00:23:09,200 --> 00:23:10,800
So the...

465
00:23:10,800 --> 00:23:14,200
Again, the summits really
influence the NIH plan by --

466
00:23:14,200 --> 00:23:16,000
the NAPA plan
by really determining

467
00:23:16,000 --> 00:23:17,800
the highest research questions

468
00:23:17,800 --> 00:23:20,520
that can really drive the field
forward and coordinate efforts

469
00:23:20,520 --> 00:23:23,480
and serve as a blueprint
for not only federal programs

470
00:23:23,480 --> 00:23:26,080
but also national programs
outside of the government,

471
00:23:26,080 --> 00:23:28,840
state programs
and international programs.

472
00:23:28,840 --> 00:23:30,440
Next slide.

473
00:23:33,000 --> 00:23:35,760
So what you'll see today
Dr. Corriveau will go over

474
00:23:35,760 --> 00:23:37,760
in more detail next

475
00:23:37,760 --> 00:23:39,880
is that we have
with the ADRD Summit,

476
00:23:39,880 --> 00:23:41,800
as you'll see listed off
to the right,

477
00:23:41,800 --> 00:23:45,600
there are overarching topics
that really impact

478
00:23:45,600 --> 00:23:48,600
all of the different
phases of dementia

479
00:23:48,600 --> 00:23:50,400
and all the different goals
that are addressed,

480
00:23:50,400 --> 00:23:53,000
so under
multiple-etiology dementia,

481
00:23:53,000 --> 00:23:55,000
as mentioned,
we'll be talking about,

482
00:23:55,000 --> 00:23:57,000
how do you diagnose
Alzheimer's?

483
00:23:57,000 --> 00:23:58,600
How do you diagnose
other dementias?

484
00:23:58,600 --> 00:24:00,680
Do we have
the workforce available

485
00:24:00,680 --> 00:24:02,760
to make these diagnoses?

486
00:24:02,760 --> 00:24:05,040
Are we including people
who are at high risk

487
00:24:05,040 --> 00:24:07,200
for the disease
in our clinical trials?

488
00:24:07,200 --> 00:24:10,000
Are we making sure
that a therapy for developing

489
00:24:10,000 --> 00:24:14,600
are effective in all people
in all communities?

490
00:24:16,840 --> 00:24:19,160
Lewy body disease, are we
helping people

491
00:24:19,160 --> 00:24:21,840
to understand frontal
temporal dementia,

492
00:24:21,840 --> 00:24:24,400
Lewy body disease,
vascular contributions?

493
00:24:24,400 --> 00:24:27,800
Do clinicians understand
how to diagnose these?

494
00:24:27,800 --> 00:24:29,480
Do we have the therapies
needed

495
00:24:29,480 --> 00:24:31,680
to specifically treat
these conditions?

496
00:24:31,680 --> 00:24:33,320
And then you'll see that
we'll be talking about today

497
00:24:33,320 --> 00:24:37,400
about new and arising issues,
such as COVID-19,

498
00:24:37,400 --> 00:24:39,200
newer pathologies that have
been discovered,

499
00:24:39,200 --> 00:24:42,000
TDP-43
and also the impact,

500
00:24:42,000 --> 00:24:44,040
which is important to veterans
who I work with,

501
00:24:44,040 --> 00:24:47,320
on post-traumatic brain injury
in people who are risk

502
00:24:47,320 --> 00:24:49,640
for Alzheimer's
and related dementias.

503
00:24:49,640 --> 00:24:52,000
So you'll see that the summit
today really informs

504
00:24:52,000 --> 00:24:56,880
a lot of the goals
that NAPA covers, so next slide.

505
00:24:56,880 --> 00:25:00,080
So again, I encourage people
to stay involved,

506
00:25:00,080 --> 00:25:02,680
provide public comment,
provide feedback,

507
00:25:02,680 --> 00:25:05,280
and then, again, our next
NAPA meeting will be

508
00:25:05,280 --> 00:25:08,000
May 2nd and 3rd, and we'll
address some of the research

509
00:25:08,000 --> 00:25:09,520
and risk-reduction goals

510
00:25:09,520 --> 00:25:12,120
and also hit the highlights
of the last 10 years

511
00:25:12,120 --> 00:25:14,000
and the progress
that's been made,

512
00:25:14,000 --> 00:25:17,040
so thank you for this chance
to share with you

513
00:25:17,040 --> 00:25:19,600
the integration of NAPA
with the summit.

514
00:25:25,520 --> 00:25:27,000
-Wonderful.

515
00:25:27,000 --> 00:25:29,640
Thank you, Dr. Carlsson,
and I also want to mention

516
00:25:29,640 --> 00:25:33,400
that Dr. Carlsson joins us today
in her capacity

517
00:25:33,400 --> 00:25:35,720
as the Chair
of the NAPA Council.

518
00:25:35,720 --> 00:25:38,080
She's also an endowed professor
in Alzheimer's disease

519
00:25:38,080 --> 00:25:42,800
and the Director of the
Wisconsin Alzheimer's Institute,

520
00:25:42,800 --> 00:25:47,480
and so really appreciate you
helping us frame this meeting.

521
00:25:47,480 --> 00:25:49,080
Next slide, please.

522
00:25:52,000 --> 00:25:57,480
I'm just going to focus on
the last point on this slide,

523
00:25:57,480 --> 00:25:59,160
and that is,
under the National Plan

524
00:25:59,160 --> 00:26:00,560
to Address
Alzheimer's Disease,

525
00:26:00,560 --> 00:26:02,960
there's an action item
to regularly convene

526
00:26:02,960 --> 00:26:06,600
on Alzheimer's
Disease-Related Dementia Summit

527
00:26:06,600 --> 00:26:11,240
to consider progress
and research recommendations

528
00:26:11,240 --> 00:26:13,840
to help drive
the field forward.

529
00:26:13,840 --> 00:26:15,040
That's what we're doing today.

530
00:26:15,040 --> 00:26:16,840
This is the fourth
of these summits,

531
00:26:16,840 --> 00:26:19,560
and we take it
very seriously,

532
00:26:19,560 --> 00:26:21,960
and we really want
your input today.

533
00:26:21,960 --> 00:26:23,560
Next slide, please.

534
00:26:26,680 --> 00:26:30,120
So to also put it in context
of how seriously

535
00:26:30,120 --> 00:26:33,400
and the scope
of what we're doing is,

536
00:26:33,400 --> 00:26:38,040
this is a process that has
involved at least 6 months,

537
00:26:38,040 --> 00:26:41,160
probably more of planning
with more than 120 scientists,

538
00:26:41,160 --> 00:26:43,520
physicians and administrators.

539
00:26:43,520 --> 00:26:47,800
I'm the NINDS lead, and Natalia
Rost is our Scientific Chair.

540
00:26:47,800 --> 00:26:50,640
We have a distinguished
steering committee,

541
00:26:50,640 --> 00:26:53,800
including past chairs
of these summits,

542
00:26:53,800 --> 00:26:57,000
and the session committees
are --

543
00:26:57,000 --> 00:26:58,880
just to review them
quickly once more,

544
00:26:58,880 --> 00:27:00,680
multiple-etiology dementias,

545
00:27:00,680 --> 00:27:04,080
health equity in AD/ADRD,
Lewy body dementias,

546
00:27:04,080 --> 00:27:05,760
frontal temporal dementia,

547
00:27:05,760 --> 00:27:09,000
vascular contributions to
cognitive-impairment dementia.

548
00:27:09,000 --> 00:27:10,480
We also have special topics.

549
00:27:10,480 --> 00:27:13,400
This has been a tradition
in the Alzheimer's

550
00:27:13,400 --> 00:27:16,400
Disease-Related
Dementia Summits.

551
00:27:16,400 --> 00:27:19,600
Impact of COVID-19
on AD/ADRD risk

552
00:27:19,600 --> 00:27:21,840
and outcomes is a new topic.

553
00:27:21,840 --> 00:27:25,720
We're also following up on LATE,
TDP-43 pathology

554
00:27:25,720 --> 00:27:32,280
in common, late-onset dementias
and post TBI AD/ADRD.

555
00:27:32,280 --> 00:27:35,200
The goals of the meeting
are really to present

556
00:27:35,200 --> 00:27:37,840
the rationale for the draft
research recommendations

557
00:27:37,840 --> 00:27:39,320
that you will be seeing,

558
00:27:39,320 --> 00:27:42,200
to encourage discussion
amongst stakeholders.

559
00:27:42,200 --> 00:27:44,760
These are, again,
draft recommendations.

560
00:27:44,760 --> 00:27:46,240
We want your input.

561
00:27:46,240 --> 00:27:48,520
We want these recommendations
to be as strong

562
00:27:48,520 --> 00:27:51,240
and as impactful
as they can possibly be.

563
00:27:51,240 --> 00:27:53,520
So we're soliciting feedback,

564
00:27:53,520 --> 00:27:55,200
and this feedback
will be considered

565
00:27:55,200 --> 00:27:56,720
and considered seriously

566
00:27:56,720 --> 00:27:59,240
when drafting the final
draft recommendations.

567
00:27:59,240 --> 00:28:00,920
Next slide, please.

568
00:28:06,880 --> 00:28:09,560
Over the years, funds available
for Alzheimer's

569
00:28:09,560 --> 00:28:10,800
and Alzheimer's
disease-related

570
00:28:10,800 --> 00:28:14,160
dementia research
have increased.

571
00:28:14,160 --> 00:28:16,080
I won't go over the details
of this slide,

572
00:28:16,080 --> 00:28:18,600
but you can see
that there are now considerable

573
00:28:18,600 --> 00:28:21,760
more funds available

574
00:28:21,760 --> 00:28:26,440
now than there were even
5 or 6 years ago.

575
00:28:26,440 --> 00:28:28,040
Next slide, please.

576
00:28:31,400 --> 00:28:34,800
Through our partnership with
the National Institute on Aging,

577
00:28:34,800 --> 00:28:37,840
which leads the NIH's response
to the National Plan

578
00:28:37,840 --> 00:28:41,840
to Address Alzheimer's Disease,
funds are available,

579
00:28:41,840 --> 00:28:45,320
made available to the NINDS
for research,

580
00:28:45,320 --> 00:28:50,000
and the NINDS uses these funds
for investigator-initiated

581
00:28:50,000 --> 00:28:52,640
research
as well as Alzheimer's disease

582
00:28:52,640 --> 00:28:56,800
and Alzheimer's
disease-related dementias

583
00:28:56,800 --> 00:28:59,080
funding opportunity
announcements

584
00:28:59,080 --> 00:29:01,600
that are directed
at specific areas

585
00:29:01,600 --> 00:29:04,680
that are responsible to the
milestones in the national plan

586
00:29:04,680 --> 00:29:06,920
that come from these summits.

587
00:29:06,920 --> 00:29:08,520
Next slide, please.

588
00:29:11,480 --> 00:29:14,680
To illustrate the level
of activity and responsive,

589
00:29:14,680 --> 00:29:17,600
NINDS led 14 new
funding announcements

590
00:29:17,600 --> 00:29:20,240
in fiscal year 2022,

591
00:29:20,240 --> 00:29:26,080
and there are number of them
that are still open,

592
00:29:26,080 --> 00:29:30,280
and there are 14 new NINDS
funding-announcement concepts

593
00:29:30,280 --> 00:29:32,480
that are planned
for fiscal year 2023.

594
00:29:32,480 --> 00:29:34,000
We have an ongoing process.

595
00:29:34,000 --> 00:29:36,320
We work closely within NINDS

596
00:29:36,320 --> 00:29:38,240
and collaboration
with other institutes,

597
00:29:38,240 --> 00:29:40,440
in particular with the NIA,

598
00:29:40,440 --> 00:29:45,200
and we create funding-
opportunity announcements

599
00:29:45,200 --> 00:29:47,000
that are responsive
to workforce

600
00:29:47,000 --> 00:29:50,560
needs as well as research
needs that are detailed here.

601
00:29:50,560 --> 00:29:52,160
Next slide, please.

602
00:29:57,240 --> 00:30:00,200
So these summits set
national research priorities

603
00:30:00,200 --> 00:30:03,440
for the Alzheimer's
disease-related dementias.

604
00:30:03,440 --> 00:30:06,000
Over the years,
we've had 62 NINDS

605
00:30:06,000 --> 00:30:08,600
Alzheimer's disease-related
funding initiatives

606
00:30:08,600 --> 00:30:12,480
that have resulted in major
ADRD programs and consortia,

607
00:30:12,480 --> 00:30:14,560
and you see some of the logos

608
00:30:14,560 --> 00:30:19,000
for those programs
here on this slide.

609
00:30:19,000 --> 00:30:27,240
And NIH ADRD research funding
has increased from 2015 to 2020

610
00:30:27,240 --> 00:30:32,600
to around 600 million
per year at this point.

611
00:30:32,600 --> 00:30:34,920
I'm going to -
In interest of time,

612
00:30:34,920 --> 00:30:38,680
I'm going to not talk about
these programs specifically.

613
00:30:38,680 --> 00:30:40,560
There's a lot of science
to come today,

614
00:30:40,560 --> 00:30:43,720
and I want to be able to move
on to that, so next slide.

615
00:30:47,920 --> 00:30:50,000
Just to give you a quick guide
to the ADRD

616
00:30:50,000 --> 00:30:52,760
draft recommendations,
next slide, please.

617
00:30:56,840 --> 00:30:59,160
As you're look at - looking
at these recommendations

618
00:30:59,160 --> 00:31:02,080
and as the scientific chair
are presenting them

619
00:31:02,080 --> 00:31:03,520
and you're thinking about them

620
00:31:03,520 --> 00:31:05,880
and thinking about
what your input might be -

621
00:31:05,880 --> 00:31:08,400
And please,
use the open mic time,

622
00:31:08,400 --> 00:31:12,040
the question-and-answer time
in this meeting.

623
00:31:12,040 --> 00:31:14,640
Please use it.
Please provide input.

624
00:31:14,640 --> 00:31:17,560
You know, put your name
in the question-and-answer box

625
00:31:17,560 --> 00:31:20,680
that's down
at the middle of your screen,

626
00:31:20,680 --> 00:31:22,960
and let's have
a lively discussion

627
00:31:22,960 --> 00:31:24,920
during the open mic time.

628
00:31:24,920 --> 00:31:27,640
But you'll see that there's
a recommendation number.

629
00:31:27,640 --> 00:31:29,200
There's a prioritization.

630
00:31:29,200 --> 00:31:33,120
Priority one is the highest
level prioritization.

631
00:31:33,120 --> 00:31:34,960
It goes down, two, three four.

632
00:31:34,960 --> 00:31:39,400
Keep in mind, anything that
is mentioned in this summit

633
00:31:39,400 --> 00:31:43,560
as a recommendation is
a very high priority.

634
00:31:43,560 --> 00:31:45,880
There are many, many things that
could have been written up

635
00:31:45,880 --> 00:31:47,600
as recommendations,

636
00:31:47,600 --> 00:31:53,000
but didn't kind of make the
final list for top priorities.

637
00:31:53,000 --> 00:31:55,520
There are timelines that
indicate the number of years

638
00:31:55,520 --> 00:31:59,680
to complete or make
fully operational a goal,

639
00:32:02,720 --> 00:32:06,400
and so this just, I hope,
helps you orient a little bit

640
00:32:06,400 --> 00:32:09,160
to the recommendations
as they're presented.

641
00:32:09,160 --> 00:32:10,760
Next slide, please.

642
00:32:14,840 --> 00:32:17,400
And I would like to introduce
our scientific chair,

643
00:32:17,400 --> 00:32:19,000
Dr. Natalia Rost.

644
00:32:19,000 --> 00:32:20,000
Thank you.

645
00:32:20,000 --> 00:32:21,760
-Thank you, Rod.

646
00:32:21,760 --> 00:32:23,880
It is my great pleasure
and privilege

647
00:32:23,880 --> 00:32:27,040
to be part of this initiative,
which is, as you know,

648
00:32:27,040 --> 00:32:30,280
critical to
scientific progress in dementia

649
00:32:30,280 --> 00:32:33,280
but more importantly
in translating this science

650
00:32:33,280 --> 00:32:36,960
into clinical practice
of diagnosis, treatment

651
00:32:36,960 --> 00:32:39,040
and most importantly
prevention of dementia

652
00:32:39,040 --> 00:32:43,000
in the U.S. and worldwide,
so next slide.

653
00:32:43,000 --> 00:32:45,600
So these are my disclaimer
and disclosures.

654
00:32:45,600 --> 00:32:47,520
Next slide?

655
00:32:47,520 --> 00:32:50,560
I would like to begin
with a global view

656
00:32:50,560 --> 00:32:53,280
of why our work here
is so important

657
00:32:53,280 --> 00:32:56,320
and remind everyone that
despite the recent advances,

658
00:32:56,320 --> 00:32:58,840
there is certainly
much more to be done,

659
00:32:58,840 --> 00:33:00,800
and I find this
recent map generated

660
00:33:00,800 --> 00:33:03,240
by the Global Burden
of Disease Collaborative

661
00:33:03,240 --> 00:33:05,640
of estimated percent
change of dementia

662
00:33:05,640 --> 00:33:09,040
prevalence to be
a very effective tool

663
00:33:09,040 --> 00:33:11,400
to demonstrate
the ongoing challenge.

664
00:33:11,400 --> 00:33:13,840
Even with some reports of,
so to speak,

665
00:33:13,840 --> 00:33:16,280
flattening the curve
and, in dementia incidents

666
00:33:16,280 --> 00:33:19,240
in some regions of the world,
according to this report,

667
00:33:19,240 --> 00:33:22,040
there is still uniformly
projected growth

668
00:33:22,040 --> 00:33:27,240
in prevalence of dementia cases
expected between 2019 and 2050

669
00:33:27,240 --> 00:33:29,560
with the estimated
percent-change variant

670
00:33:29,560 --> 00:33:31,800
anywhere between 20
to 40-percent increase

671
00:33:31,800 --> 00:33:35,000
as the smallest and up
to 2000-percent increase

672
00:33:35,000 --> 00:33:37,240
in some regions,
with the U.S. projected

673
00:33:37,240 --> 00:33:40,720
to be in 80
to 100-percent increase by 2050.

674
00:33:40,720 --> 00:33:43,360
Next slide.

675
00:33:43,360 --> 00:33:46,920
But despite the need for global
vigilance with this issue,

676
00:33:46,920 --> 00:33:48,360
as clinician-scientists,

677
00:33:48,360 --> 00:33:51,560
our focus is always
on individual patients,

678
00:33:51,560 --> 00:33:53,280
a focus that has always guided

679
00:33:53,280 --> 00:33:55,080
the principles
of dementia science,

680
00:33:55,080 --> 00:33:57,200
our North Star,
so to speak,

681
00:33:57,200 --> 00:34:00,600
from bedside to bench
and back to bedside,

682
00:34:00,600 --> 00:34:04,240
and our patients' questions
like, "What is happening to me?"

683
00:34:04,240 --> 00:34:07,160
lead to development
of cutting-edge diagnostics.

684
00:34:07,160 --> 00:34:10,400
Questions like, "Why is it
happening?" and "Why now?"

685
00:34:10,400 --> 00:34:12,800
lead us to pursue
some deep understanding

686
00:34:12,800 --> 00:34:15,080
of basic mechanisms
of disease.

687
00:34:15,080 --> 00:34:17,400
When patients
and their families ask,

688
00:34:17,400 --> 00:34:19,240
"Where do we go
from here?"

689
00:34:19,240 --> 00:34:22,480
we seek novel interventions,
we test support systems,

690
00:34:22,480 --> 00:34:24,760
and we forge ahead
with clinical trials,

691
00:34:24,760 --> 00:34:28,480
and when our patients ask,
"Am I going to be all right?"

692
00:34:28,480 --> 00:34:30,600
we develop
prognostication tools,

693
00:34:30,600 --> 00:34:33,480
a screening test and employ
robust support systems.

694
00:34:33,480 --> 00:34:35,880
Next slide.

695
00:34:35,880 --> 00:34:38,120
But the task at hand
remains quite complex,

696
00:34:38,120 --> 00:34:39,640
as you know.

697
00:34:39,640 --> 00:34:41,400
There's been a fascinating
evolution of dementia

698
00:34:41,400 --> 00:34:45,040
as a clinical syndrome concept,
especially over the few past

699
00:34:45,040 --> 00:34:47,120
decades with the accumulation
of knowledge

700
00:34:47,120 --> 00:34:50,560
about underlying
disease pathology,

701
00:34:50,560 --> 00:34:52,600
you know, variability
of clinical features,

702
00:34:52,600 --> 00:34:54,040
molecular genetics

703
00:34:54,040 --> 00:34:56,400
and environmental interactions
as well,

704
00:34:56,400 --> 00:34:58,840
and while science
continues to evolve,

705
00:34:58,840 --> 00:35:02,480
prior dogmas, like "One
pathology equals one disease,"

706
00:35:02,480 --> 00:35:05,320
are rapidly changing
and understanding evolves

707
00:35:05,320 --> 00:35:08,760
that multiple pathways may lead
to a clinical dementia syndrome.

708
00:35:08,760 --> 00:35:11,800
Next slide.

709
00:35:11,800 --> 00:35:13,200
Furthermore, we'll learn that,

710
00:35:13,200 --> 00:35:15,320
on the wide spectrum
between brain health

711
00:35:15,320 --> 00:35:17,480
on one end and brain disease

712
00:35:17,480 --> 00:35:19,560
such as AD and ADRD
on the other,

713
00:35:19,560 --> 00:35:21,960
there is literally
a lifetime where,

714
00:35:21,960 --> 00:35:25,240
at every stage of our individual
chronological lifespan,

715
00:35:25,240 --> 00:35:27,200
including influences
that occurred

716
00:35:27,200 --> 00:35:28,800
during brain development,

717
00:35:28,800 --> 00:35:31,680
there are innate as well
as environmental factors

718
00:35:31,680 --> 00:35:33,640
that impact the risk
of developing dementia

719
00:35:33,640 --> 00:35:35,240
at a later stage.

720
00:35:35,240 --> 00:35:37,520
Most of these life stages are,
of course, arbitrary,

721
00:35:37,520 --> 00:35:38,920
and manufactures,

722
00:35:38,920 --> 00:35:42,000
in part, their influence
across their entire life,

723
00:35:42,000 --> 00:35:44,520
of course, including those
that have cumulative effects,

724
00:35:44,520 --> 00:35:45,880
such as health disparities

725
00:35:45,880 --> 00:35:48,600
related to historic
societal structures.

726
00:35:48,600 --> 00:35:50,720
Next slide.

727
00:35:50,720 --> 00:35:54,160
So unsurprisingly, to overcome
the complexities

728
00:35:54,160 --> 00:35:57,280
of AD and ADRD
as a disease process,

729
00:35:57,280 --> 00:36:00,240
our approach to science
has to remain nimble,

730
00:36:00,240 --> 00:36:03,480
robust and informed
by patient experiences,

731
00:36:03,480 --> 00:36:04,840
and to stay on mission,

732
00:36:04,840 --> 00:36:07,400
we must bring together
diverse expertise,

733
00:36:07,400 --> 00:36:10,400
close-cutting science
and the perpetual cycle

734
00:36:10,400 --> 00:36:14,080
of innovation, collaboration
and communication in research,

735
00:36:14,080 --> 00:36:18,240
and this is what 2022
ADRD Summit is all about.

736
00:36:18,240 --> 00:36:20,400
After almost six -
more than 6 months

737
00:36:20,400 --> 00:36:23,240
of intense preparations,
we're excited to present to you

738
00:36:23,240 --> 00:36:25,200
a product
of our scientific workgroups.

739
00:36:25,200 --> 00:36:26,760
Next slide.

740
00:36:26,760 --> 00:36:29,520
So by the way, a brief
introduction, as an example,

741
00:36:29,520 --> 00:36:31,400
the top priorities
to be discussed by

742
00:36:31,400 --> 00:36:33,760
the Health Equity
in AD/ADRD group,

743
00:36:33,760 --> 00:36:36,400
led by Dr. González
and Zissimopoulos,

744
00:36:36,400 --> 00:36:39,320
are to advance equity in AD

745
00:36:39,320 --> 00:36:42,080
and ADRD research
via inclusion science

746
00:36:42,080 --> 00:36:45,120
and to expand the AD and the
ADRD scientific workforce

747
00:36:45,120 --> 00:36:48,040
of persons historically
underrepresented in science.

748
00:36:48,040 --> 00:36:50,160
Next slide.

749
00:36:50,160 --> 00:36:52,000
The Frontotemporal Degeneration
group,

750
00:36:52,000 --> 00:36:55,320
led by Doctors Boxer and Karch
will provide the rationale

751
00:36:55,320 --> 00:36:57,320
for their top-priority
recommendations

752
00:36:57,320 --> 00:37:00,200
of understanding
FTD epidemiology and genetics

753
00:37:00,200 --> 00:37:02,000
in diverse populations

754
00:37:02,000 --> 00:37:04,320
and in advancing
understanding of FTD

755
00:37:04,320 --> 00:37:07,360
with a goal of identifying
therapeutic targets.

756
00:37:07,360 --> 00:37:09,560
Next slide.

757
00:37:09,560 --> 00:37:13,400
VCID group, cochaired
by Doctors Wilcock and Petersen

758
00:37:13,400 --> 00:37:16,200
will present their top
priority recommendations

759
00:37:16,200 --> 00:37:18,800
to establish and refine
experimental models

760
00:37:18,800 --> 00:37:23,040
and technologies to identify
disease-relevant mechanisms

761
00:37:23,040 --> 00:37:25,640
and to develop
and validate markers of VCID

762
00:37:25,640 --> 00:37:27,680
in diverse populations.

763
00:37:27,680 --> 00:37:29,560
Next slide.

764
00:37:29,560 --> 00:37:31,160
Lewy Body Dementias group,

765
00:37:31,160 --> 00:37:33,320
led by Dr. Leverenz
and Kantarci,

766
00:37:33,320 --> 00:37:35,720
will share their top-priority
recommendations

767
00:37:35,720 --> 00:37:38,960
including the need
for clinical trials to alleviate

768
00:37:38,960 --> 00:37:40,960
or slow the course of LBD

769
00:37:40,960 --> 00:37:43,840
while continuing to work
on delineate genetic loci

770
00:37:43,840 --> 00:37:45,200
and their functions
that contribute

771
00:37:45,200 --> 00:37:47,760
to the onset
and progression of LBD.

772
00:37:47,760 --> 00:37:50,200
Next slide.

773
00:37:50,200 --> 00:37:53,760
On day two, the Multiple
Etiology Dementias group,

774
00:37:53,760 --> 00:37:57,400
led by Dr. Possin, continues
its work on high priority

775
00:37:57,400 --> 00:38:01,560
to evaluate pragmatic approaches
to detect cognitive impairment

776
00:38:01,560 --> 00:38:03,520
and moving conducting
clinical studies

777
00:38:03,520 --> 00:38:05,680
on a proofed
or promising interventions

778
00:38:05,680 --> 00:38:08,000
to mitigate
cognitive decline.

779
00:38:08,000 --> 00:38:11,200
Next slide.

780
00:38:11,200 --> 00:38:15,080
In this Special Topics
from the 2019 summit, post-TBI,

781
00:38:15,080 --> 00:38:20,520
AD and ADRD and TDP-43 in Common
Late-Onset Dementias or LATE,

782
00:38:20,520 --> 00:38:22,840
as you will learn
later in day two,

783
00:38:22,840 --> 00:38:24,520
will present
their top priorities

784
00:38:24,520 --> 00:38:26,000
of promoting collaboration

785
00:38:26,000 --> 00:38:28,600
among TBI
and dementia researchers

786
00:38:28,600 --> 00:38:30,440
and defining late classification

787
00:38:30,440 --> 00:38:33,000
and diagnostic boundaries
respectively.

788
00:38:33,000 --> 00:38:36,080
Next slide.

789
00:38:36,080 --> 00:38:38,360
And finally, I wanted to
highlight the topic

790
00:38:38,360 --> 00:38:40,840
that we have been
very anxious to bring forward

791
00:38:40,840 --> 00:38:43,080
for your consideration
at this summit,

792
00:38:43,080 --> 00:38:46,080
and it's the topic that clearly
dominated our discussions

793
00:38:46,080 --> 00:38:47,920
over the past two years:

794
00:38:47,920 --> 00:38:50,480
the impact of COVID-19 pandemic
on risk

795
00:38:50,480 --> 00:38:53,040
and outcomes of AD and ADRD.

796
00:38:53,040 --> 00:38:55,480
Clearly, a topic that
is truly worthy

797
00:38:55,480 --> 00:38:59,280
of an emerging science
topic status in 2022.

798
00:38:59,280 --> 00:39:02,040
Next slide.

799
00:39:02,040 --> 00:39:06,960
As we all know, there are nearly
80 million COVID-19 survivors

800
00:39:06,960 --> 00:39:08,800
in the U.S. alone,

801
00:39:08,800 --> 00:39:12,440
and what we as clinicians learn
from beginning of this pandemic

802
00:39:12,440 --> 00:39:15,480
is that neurological,
neuropsychiatric and cognitive

803
00:39:15,480 --> 00:39:18,200
complaints are common
in those suffering from COVID

804
00:39:18,200 --> 00:39:20,000
and in survivors.

805
00:39:20,000 --> 00:39:23,000
We have learned that
SARS-CoV-2 infection has acute

806
00:39:23,000 --> 00:39:25,160
and long-term effects
on the brain

807
00:39:25,160 --> 00:39:26,800
and that there are
multiple mechanisms

808
00:39:26,800 --> 00:39:29,120
by which the virus
can cause the damage,

809
00:39:29,120 --> 00:39:31,840
including the potential
downstream effects

810
00:39:31,840 --> 00:39:35,160
on neurodegenerative
and vascular injury pathways,

811
00:39:35,160 --> 00:39:39,200
and while the overall impact
on AD and ADRD risk

812
00:39:39,200 --> 00:39:41,800
and outcomes
and is not yet known.

813
00:39:41,800 --> 00:39:45,440
Potential detrimental effects
may include increase

814
00:39:45,440 --> 00:39:50,040
in incidents of cognitive
impairment in dementia cases,

815
00:39:50,040 --> 00:39:52,200
accelerated course
of cognitive decline

816
00:39:52,200 --> 00:39:56,080
among already diagnosed
with AD and ADRD diagnosis,

817
00:39:56,080 --> 00:40:00,200
accelerated neurodegeneration
and vascular pathologies

818
00:40:00,200 --> 00:40:02,840
in the brain
among currently symptomatic,

819
00:40:02,840 --> 00:40:04,720
shift in the population timeline

820
00:40:04,720 --> 00:40:07,040
of cognitive decline
toward younger ages

821
00:40:07,040 --> 00:40:09,800
and increased incidents
of early-onset dementias

822
00:40:09,800 --> 00:40:12,200
and unfortunately,
increased mortality

823
00:40:12,200 --> 00:40:16,040
among those
with advanced dementia.

824
00:40:16,040 --> 00:40:19,440
-One minute remaining.
-At this time, however,

825
00:40:19,440 --> 00:40:23,000
the data is still scarce and
knowledge is rapidly evolving,

826
00:40:23,000 --> 00:40:25,120
but even in this
very early stage,

827
00:40:25,120 --> 00:40:26,920
the impact
of SARS-CoV-2 infection

828
00:40:26,920 --> 00:40:29,920
on the brain can be detected,
as in, for example,

829
00:40:29,920 --> 00:40:33,000
this recent study published
by the UK Biobank on the left,

830
00:40:33,000 --> 00:40:35,280
examining brain MRI
in 400 patients

831
00:40:35,280 --> 00:40:39,360
who tested positive for COVID-19
between their two scans

832
00:40:39,360 --> 00:40:40,960
or the effects
of the pandemic

833
00:40:40,960 --> 00:40:43,640
on the newer psychiatric
symptoms of dementia patients,

834
00:40:43,640 --> 00:40:46,720
and notably their caretakers,
as shown by a recent

835
00:40:46,720 --> 00:40:49,840
international collaboration
on the right.

836
00:40:49,840 --> 00:40:52,400
So we have a lot of questions
to answer in the future

837
00:40:52,400 --> 00:40:54,040
as related
to this special topic,

838
00:40:54,040 --> 00:40:57,280
and I'm delighted that our
newly formed working group,

839
00:40:57,280 --> 00:41:00,200
cochaired with me
by Dr. Sudha Seshadri,

840
00:41:00,200 --> 00:41:03,400
will present to you our initial
set of recommendations tomorrow.

841
00:41:03,400 --> 00:41:05,000
Next slide.

842
00:41:08,720 --> 00:41:10,880
Next slide.

843
00:41:10,880 --> 00:41:13,520
But for now, I would like
to welcome you again

844
00:41:13,520 --> 00:41:16,200
to the 2022 ADRD Summit,

845
00:41:16,200 --> 00:41:17,800
and I hope you
all take advantage

846
00:41:17,800 --> 00:41:20,400
of the open microphone
sessions after each topic

847
00:41:20,400 --> 00:41:22,600
like all of my colleagues
urge you to.

848
00:41:22,600 --> 00:41:24,160
This is, after all,
an open forum,

849
00:41:24,160 --> 00:41:26,840
and we would like
to have a robust dialogue

850
00:41:26,840 --> 00:41:28,600
or as robust as possible,

851
00:41:28,600 --> 00:41:31,200
and thank you in advance
for your contribution.

852
00:41:31,200 --> 00:41:34,680
So we're on time,
and without further ado,

853
00:41:34,680 --> 00:41:37,680
I would like to welcome
Doctors Hector González

854
00:41:37,680 --> 00:41:39,400
and Dr. Julie Zissimopoulos,

855
00:41:39,400 --> 00:41:42,800
cochairs of the Health Equity
in AD and ADRD group,

856
00:41:42,800 --> 00:41:45,240
who will kick off
our scientific session program.

857
00:41:45,240 --> 00:41:48,800
Welcome.

858
00:41:48,800 --> 00:41:50,320
-Thank you.

859
00:41:50,320 --> 00:41:52,920
On behalf of our health
equity panel,

860
00:41:52,920 --> 00:41:55,400
I thank Dr. Koroshetz,
Corriveau

861
00:41:55,400 --> 00:41:57,600
and the organizers
for bringing our topic area

862
00:41:57,600 --> 00:42:01,400
to the forefront of the
2022 Alzheimer's Disease

863
00:42:01,400 --> 00:42:05,000
and Related Dementias Summit.

864
00:42:05,000 --> 00:42:07,840
As a panel, we appreciate
this opportunity

865
00:42:07,840 --> 00:42:10,800
to further scientific attention
and commitment

866
00:42:10,800 --> 00:42:13,640
toward achieving
Alzheimer's disease

867
00:42:13,640 --> 00:42:17,680
and related dementia
health equity through research.

868
00:42:17,680 --> 00:42:21,640
In this health equity model -
Next, please.

869
00:42:21,640 --> 00:42:24,320
Oops, those are my disclosures.

870
00:42:24,320 --> 00:42:25,440
Nothing to report.

871
00:42:25,440 --> 00:42:28,400
In this health equity model,

872
00:42:28,400 --> 00:42:31,480
dementia disparities
are apparent in later life,

873
00:42:31,480 --> 00:42:33,960
but we know this,
and we've known this for years,

874
00:42:33,960 --> 00:42:37,560
as Dr. Rost
had mentioned before.

875
00:42:37,560 --> 00:42:40,280
The big and unanswered
questions are, "Why?

876
00:42:40,280 --> 00:42:44,600
Why do these AD/ADRD
disparities exist,

877
00:42:44,600 --> 00:42:48,680
and when in the life course
did they begin?"

878
00:42:48,680 --> 00:42:50,160
and most importantly,

879
00:42:50,160 --> 00:42:53,360
"How do we resolve
the major public health problems

880
00:42:53,360 --> 00:42:58,160
facing so many underrepresented
minority communities?"

881
00:42:58,160 --> 00:43:01,440
Some key implementation
questions include,

882
00:43:03,600 --> 00:43:08,000
"Does the scientific community
have the tools necessary?

883
00:43:08,000 --> 00:43:10,280
If not, then what
research infrastructure

884
00:43:10,280 --> 00:43:14,440
is needed to achieve
research equity?"

885
00:43:14,440 --> 00:43:15,760
To address these questions,

886
00:43:15,760 --> 00:43:22,560
we recommend moving
beyond disparities

887
00:43:22,560 --> 00:43:25,600
and to seek new
and innovative ways

888
00:43:25,600 --> 00:43:29,200
to achieve health equity
through our research.

889
00:43:29,200 --> 00:43:31,960
Ethnic racial differences
can only tell us

890
00:43:31,960 --> 00:43:35,680
that the disparities exist

891
00:43:35,680 --> 00:43:40,960
but not the means
for achieving health equity.

892
00:43:40,960 --> 00:43:46,280
As this life-course model
suggests, within-group research

893
00:43:46,280 --> 00:43:50,840
can tell us the origins
and sources of the problems

894
00:43:50,840 --> 00:43:56,000
and promising means for
resolving AD/ADRD disparities.

895
00:43:56,000 --> 00:43:57,800
Next slide, please.

896
00:43:59,960 --> 00:44:05,440
As we - We as an ADRD health
equity panel

897
00:44:05,440 --> 00:44:07,320
were tasked
with providing recommendations

898
00:44:07,320 --> 00:44:11,080
for achieving health
equity through research.

899
00:44:11,080 --> 00:44:13,600
Our panelists -
Our health equity panelists

900
00:44:13,600 --> 00:44:16,680
responded to the challenge
by recommending four focus areas

901
00:44:16,680 --> 00:44:21,000
shown in these rectangles
on the slide here.

902
00:44:21,000 --> 00:44:23,280
First and foremost,

903
00:44:23,280 --> 00:44:26,800
our panelists agreed
that growing a diverse

904
00:44:26,800 --> 00:44:29,120
and committed
scientific workforce

905
00:44:29,120 --> 00:44:34,440
is needed for achieving
AD/ADRD health equity.

906
00:44:37,200 --> 00:44:42,000
As shown here, the workforce
encompasses and forms

907
00:44:42,000 --> 00:44:44,120
a basic substrate
for achieving health

908
00:44:44,120 --> 00:44:48,800
equity goals of
the other focus areas within.

909
00:44:51,600 --> 00:44:54,800
Appropriate
assessment tools and data

910
00:44:54,800 --> 00:44:57,400
from underrepresented
minority communities

911
00:44:57,400 --> 00:44:59,800
is still
woefully lacking.

912
00:44:59,800 --> 00:45:02,600
Important data,
for example, genomics,

913
00:45:02,600 --> 00:45:06,320
are largely unavailable,
as it was mentioned before,

914
00:45:06,320 --> 00:45:07,800
which means
that underrepresented

915
00:45:07,800 --> 00:45:09,960
minority communities

916
00:45:09,960 --> 00:45:14,280
have been left out of recent
advances in biomarkers,

917
00:45:14,280 --> 00:45:20,760
genomics, neuroimaging and other
cutting-edge areas of research.

918
00:45:20,760 --> 00:45:24,520
Additionally,
replication studies so important

919
00:45:24,520 --> 00:45:27,800
for scientific rigor
are nearly impossible,

920
00:45:27,800 --> 00:45:31,840
thereby compounding
research inequalities.

921
00:45:31,840 --> 00:45:35,440
Epidemiologic research progress
is hampered

922
00:45:35,440 --> 00:45:39,320
by a lack of basic tools
that are largely nonexistent

923
00:45:39,320 --> 00:45:42,280
for underrepresented
minority communities.

924
00:45:44,320 --> 00:45:46,560
Randomized clinical trials
have been large -

925
00:45:46,560 --> 00:45:47,800
have largely omitted

926
00:45:47,800 --> 00:45:49,480
underrepresented minority
communities

927
00:45:49,480 --> 00:45:54,600
and so are so statistically
underpowered

928
00:45:54,600 --> 00:45:57,800
that inferences
to non-white communities are,

929
00:45:57,800 --> 00:46:01,160
at best, inconclusive.

930
00:46:01,160 --> 00:46:05,080
Ultimately, the inequalities
in available research tools

931
00:46:05,080 --> 00:46:07,600
and data
for underrepresented communities

932
00:46:07,600 --> 00:46:11,000
affects patient
care and quality,

933
00:46:11,000 --> 00:46:14,160
which is compounded by
the inaccessibility of health

934
00:46:14,160 --> 00:46:19,480
care to so many underrepresented
minority communities.

935
00:46:19,480 --> 00:46:25,000
So moving forward, next,
Dr. Luis Medina.

936
00:46:25,000 --> 00:46:26,680
Next slide, please.

937
00:46:26,680 --> 00:46:32,000
Dr. Luis Medina will provide the
workforce panels recommendations

938
00:46:32,000 --> 00:46:34,200
for achieving
Alzheimer's disease

939
00:46:34,200 --> 00:46:37,640
and related dementia
health equity through research.

940
00:46:37,640 --> 00:46:39,240
Thank you very much.

941
00:46:42,520 --> 00:46:43,400
-Hi, everyone.

942
00:46:43,400 --> 00:46:45,840
I'm delighted to be here.

943
00:46:45,840 --> 00:46:48,880
For the next few minutes,
Dr. Medina and myself

944
00:46:48,880 --> 00:46:51,320
will talk about the importance
of a diverse

945
00:46:51,320 --> 00:46:55,840
and inclusive workforce
trained in health equity.

946
00:46:55,840 --> 00:46:58,760
Next slide, please.

947
00:46:58,760 --> 00:47:02,240
As you can see in this slide,
the views that we're expressing

948
00:47:02,240 --> 00:47:06,440
are not those
of the NIH or NINDS,

949
00:47:06,440 --> 00:47:10,040
and we have received funding,
both Dr. Medina and myself,

950
00:47:10,040 --> 00:47:14,080
from the NIH
and the Alzheimer's Association.

951
00:47:14,080 --> 00:47:16,720
Next slide, please.

952
00:47:16,720 --> 00:47:20,520
So workforce diversity
is critical.

953
00:47:20,520 --> 00:47:22,520
It drives innovation.

954
00:47:22,520 --> 00:47:24,920
It helps facilitate
the translation

955
00:47:24,920 --> 00:47:26,920
of scientific findings

956
00:47:26,920 --> 00:47:30,400
and results
into advances in health,

957
00:47:30,400 --> 00:47:33,800
and it prepares the healthcare
professional workforce

958
00:47:33,800 --> 00:47:38,520
to better care for our
increasingly diverse population,

959
00:47:38,520 --> 00:47:41,800
and this includes
the population over age 65,

960
00:47:41,800 --> 00:47:43,800
so the age [Indistinct]

961
00:47:43,800 --> 00:47:47,480
really relevant when we're
discussing AD and ADRD.

962
00:47:47,480 --> 00:47:50,880
Next slide, please?

963
00:47:50,880 --> 00:47:52,800
With that in mind,
I want to describe,

964
00:47:52,800 --> 00:47:57,000
a bit, the current state of
workforce diversity in the U.S.,

965
00:47:57,000 --> 00:47:59,520
and as you can see
in this figure,

966
00:47:59,520 --> 00:48:03,000
the percent of individuals
who identify as Black,

967
00:48:03,000 --> 00:48:06,760
African-American,
Hispanic, Latino,

968
00:48:06,760 --> 00:48:11,600
American Indian or Alaska Native
in science and engineering field

969
00:48:11,600 --> 00:48:13,200
has grown
across all degrees,

970
00:48:13,200 --> 00:48:15,480
so those three lines
with the different degrees,

971
00:48:15,480 --> 00:48:17,800
since 1993.

972
00:48:17,800 --> 00:48:20,520
However, they are
underrepresented

973
00:48:20,520 --> 00:48:22,560
when you look
at the occupations

974
00:48:22,560 --> 00:48:26,280
because they account for only
29 percent of the science

975
00:48:26,280 --> 00:48:28,120
and engineering workforce,

976
00:48:28,120 --> 00:48:34,400
while they represent 52 percent
of U.S. residents above age 21,

977
00:48:34,400 --> 00:48:38,200
and this underrepresentation
also exists when we look at -

978
00:48:38,200 --> 00:48:43,240
through our PIs of R01s
and R01-equivalent awards.

979
00:48:43,240 --> 00:48:48,680
In 2020, only 6.7 percent
of PIs of those types of grants

980
00:48:48,680 --> 00:48:54,200
identified as Hispanic, Latino,
Black or African-American.

981
00:48:54,200 --> 00:48:56,000
This means that the workforce
not only

982
00:48:56,000 --> 00:48:59,000
doesn't reflect
the diversity of the U.S.,

983
00:48:59,000 --> 00:49:01,800
but it also means that the
workforce doesn't reflect

984
00:49:01,800 --> 00:49:05,000
those most affected
by AD and ADRD,

985
00:49:05,000 --> 00:49:09,040
which disproportionately affects
minoritized populations.

986
00:49:09,040 --> 00:49:10,680
Next slide, please.

987
00:49:13,400 --> 00:49:17,480
Though the prior slide focused
on racial and ethnic diversity,

988
00:49:17,480 --> 00:49:19,640
there are many
additional domains to consider

989
00:49:19,640 --> 00:49:22,040
when we're talking
about a diverse workforce,

990
00:49:22,040 --> 00:49:25,800
and that includes but is
not limited to dimensions

991
00:49:25,800 --> 00:49:29,960
such as sex, gender, age,
socioeconomic status

992
00:49:29,960 --> 00:49:31,560
and many other aspects

993
00:49:31,560 --> 00:49:34,920
that affect people's
lived experiences.

994
00:49:34,920 --> 00:49:37,760
An inclusive
and diverse workforce

995
00:49:37,760 --> 00:49:40,080
brings additional perspectives.

996
00:49:40,080 --> 00:49:41,920
It promotes creativity,

997
00:49:41,920 --> 00:49:44,120
and it broadens
the research question -

998
00:49:44,120 --> 00:49:46,560
the research scope by
including more questions

999
00:49:46,560 --> 00:49:49,800
or encouraging more questions

1000
00:49:49,800 --> 00:49:51,920
because it's critical
and essential

1001
00:49:51,920 --> 00:49:55,400
when thinking about
health equity research.

1002
00:49:55,400 --> 00:49:57,480
Studies have found that
diverse groups

1003
00:49:57,480 --> 00:49:58,920
produce more paper

1004
00:49:58,920 --> 00:50:01,520
and that those papers
are cited more often,

1005
00:50:01,520 --> 00:50:04,600
and this is valuable as a proxy
to show that they are -

1006
00:50:04,600 --> 00:50:07,640
There's increasing knowledge
and quality knowledge,

1007
00:50:07,640 --> 00:50:10,160
and this, in turn,
hopefully, is knowledge

1008
00:50:10,160 --> 00:50:13,600
that can be used
to promote health equity.

1009
00:50:13,600 --> 00:50:16,760
In his research, Dr. Scott Page

1010
00:50:16,760 --> 00:50:18,880
stated that diverse
groups of problem

1011
00:50:18,880 --> 00:50:23,520
solvers consistently
outperformed groups of the best

1012
00:50:23,520 --> 00:50:25,400
and the brightest.

1013
00:50:25,400 --> 00:50:27,000
Next slide, please?

1014
00:50:31,520 --> 00:50:34,160
Additionally, a representative
workforce

1015
00:50:34,160 --> 00:50:37,520
that aligns with the diverse
communities is important

1016
00:50:37,520 --> 00:50:39,400
because it facilitates
better commute -

1017
00:50:39,400 --> 00:50:42,800
communication between
researchers and the community.

1018
00:50:42,800 --> 00:50:45,560
It can help mitigate
implicit bias.

1019
00:50:45,560 --> 00:50:49,160
It increases enrollment
and can increase retention.

1020
00:50:49,160 --> 00:50:51,200
Both of those are
really critical.

1021
00:50:51,200 --> 00:50:54,720
It can also lead
to greater validity of data.

1022
00:50:54,720 --> 00:50:56,320
Again, this is really valuable

1023
00:50:56,320 --> 00:50:58,080
because it helps expand
our knowledge,

1024
00:50:58,080 --> 00:51:00,880
enabling us
to promote health equity.

1025
00:51:00,880 --> 00:51:07,160
I now let Dr. Medina take over.
-Next slide, please.

1026
00:51:09,240 --> 00:51:14,720
And so as - Some of the work
that's come out of

1027
00:51:14,720 --> 00:51:16,880
NIH,
some wonderful tool kits,

1028
00:51:16,880 --> 00:51:19,840
as I'll show in one
of the upcoming slides,

1029
00:51:19,840 --> 00:51:22,760
but Dr. Marie Bernard
even cited,

1030
00:51:22,760 --> 00:51:24,400
"As a woman of color
in science,

1031
00:51:24,400 --> 00:51:26,640
I have seen the missed
opportunities to take advantage

1032
00:51:26,640 --> 00:51:29,680
of this full spectrum
of scientific talent.

1033
00:51:29,680 --> 00:51:31,960
It is profoundly important
for all members

1034
00:51:31,960 --> 00:51:34,200
of the biomedical workforce
to feel included,

1035
00:51:34,200 --> 00:51:36,720
welcomed, supported
and that they have a fair

1036
00:51:36,720 --> 00:51:39,000
and equal opportunity
to pursue their passion

1037
00:51:39,000 --> 00:51:41,600
for research
and scientific discovery.

1038
00:51:41,600 --> 00:51:43,080
Our institutions and society

1039
00:51:43,080 --> 00:51:45,240
must take steps
to eliminate threats

1040
00:51:45,240 --> 00:51:47,640
that create barriers
such as structural racism,

1041
00:51:47,640 --> 00:51:50,640
incivility,
harassment and bias."

1042
00:51:50,640 --> 00:51:53,400
Next slide, please.

1043
00:51:53,400 --> 00:51:56,200
And so how do we address
these issues

1044
00:51:56,200 --> 00:51:58,120
and these potential barriers?

1045
00:51:58,120 --> 00:52:02,080
There are several resources
from the NIH,

1046
00:52:02,080 --> 00:52:04,360
as well as outside
the NIH,

1047
00:52:04,360 --> 00:52:07,600
including the Scientific
Workforce Diversity

1048
00:52:07,600 --> 00:52:12,520
Toolkit to help address some
of these workforce disparities.

1049
00:52:12,520 --> 00:52:16,720
There are various
administrative supplements

1050
00:52:16,720 --> 00:52:20,000
and other notices
of special interest

1051
00:52:20,000 --> 00:52:23,400
that have been announced to help
address some of these issues,

1052
00:52:23,400 --> 00:52:26,920
including this one relating
to recognizing excellence

1053
00:52:26,920 --> 00:52:30,440
in diversity, equity, inclusion
and accessibility.

1054
00:52:30,440 --> 00:52:33,360
Various funding opportunities
for individuals

1055
00:52:33,360 --> 00:52:37,520
have various training levels,

1056
00:52:37,520 --> 00:52:46,280
including K99/R00 opportunities
but also F31s,

1057
00:52:46,280 --> 00:52:50,120
F32s for individuals
in their graduate training

1058
00:52:50,120 --> 00:52:52,400
or in their
post-doctoral training,

1059
00:52:52,400 --> 00:52:55,240
as well as the National
Research Mentoring Network

1060
00:52:55,240 --> 00:52:58,880
to help, again, address some
of these workforce disparities.

1061
00:52:58,880 --> 00:53:01,400
Next slide, please.

1062
00:53:01,400 --> 00:53:04,280
And so before I provide
the recommendations

1063
00:53:04,280 --> 00:53:09,480
from our
particular workforce, workgroup,

1064
00:53:09,480 --> 00:53:12,640
we highlight this here, which is
that workforce diversity

1065
00:53:12,640 --> 00:53:15,760
is critical to aspects
of science of AD

1066
00:53:15,760 --> 00:53:18,400
and ADRD,
from neurons to nations,

1067
00:53:18,400 --> 00:53:21,160
as it affects the quality
of the data collected,

1068
00:53:21,160 --> 00:53:22,560
the knowledge accumulated

1069
00:53:22,560 --> 00:53:24,800
and representativeness
of future research

1070
00:53:24,800 --> 00:53:26,840
and the workforce pipeline.

1071
00:53:26,840 --> 00:53:29,920
Next slide, please.

1072
00:53:29,920 --> 00:53:32,600
So with that, our recommendation
to increase

1073
00:53:32,600 --> 00:53:34,320
training support and capacity

1074
00:53:34,320 --> 00:53:36,680
of an AD/ADRD
scientific workforce

1075
00:53:36,680 --> 00:53:38,840
or persons
historically underrepresented

1076
00:53:38,840 --> 00:53:41,920
in biomedical, behavioral
and social sciences;

1077
00:53:41,920 --> 00:53:45,120
suggest that we leverage
existing diverse AD/ADRD

1078
00:53:45,120 --> 00:53:47,920
health equity research
groups and organizations,

1079
00:53:47,920 --> 00:53:50,080
that we partner with
relevant stakeholders

1080
00:53:50,080 --> 00:53:53,600
to invest in promising trainees
early in the pipeline;

1081
00:53:53,600 --> 00:53:56,000
that we enhance existing
systems for tracking

1082
00:53:56,000 --> 00:53:58,320
and monitoring progress
in diversification

1083
00:53:58,320 --> 00:54:01,080
of the AD/ADRD
scientific workforce;

1084
00:54:01,080 --> 00:54:04,080
that we incentivize
mentors and institutions

1085
00:54:04,080 --> 00:54:07,760
to sponsor training awards
for underrepresented scholars,

1086
00:54:07,760 --> 00:54:10,680
target training mechanisms,
writing workshops

1087
00:54:10,680 --> 00:54:12,640
and other
career-development resources

1088
00:54:12,640 --> 00:54:17,400
to support underrepresented
scientists is also recommended.

1089
00:54:17,400 --> 00:54:20,000
Next slide, please.

1090
00:54:20,000 --> 00:54:22,800
In order to promote career
development

1091
00:54:22,800 --> 00:54:25,160
of biomedical, behavioral
and social scientists

1092
00:54:25,160 --> 00:54:28,120
conducting AD/ADRD
health equity research,

1093
00:54:28,120 --> 00:54:31,800
we suggest and recommend
an iterative training framework

1094
00:54:31,800 --> 00:54:36,560
for ADRD health
equity research be used;

1095
00:54:36,560 --> 00:54:38,800
that we retool and expand
the knowledge base

1096
00:54:38,800 --> 00:54:40,480
on conducting
inclusive science

1097
00:54:40,480 --> 00:54:42,600
of mid-career
and senior scientists,

1098
00:54:42,600 --> 00:54:44,800
again, highlighting the need
to address

1099
00:54:44,800 --> 00:54:48,680
these issues across
the training spectrum;

1100
00:54:48,680 --> 00:54:50,400
that we require
training and education

1101
00:54:50,400 --> 00:54:53,240
in health equity
principles for all scholars;

1102
00:54:53,240 --> 00:54:55,000
that provide training
and education

1103
00:54:55,000 --> 00:54:57,560
in health equity research
to all grant reviewers;

1104
00:54:57,560 --> 00:55:01,320
that we increase participation
on study sections of scientists

1105
00:55:01,320 --> 00:55:03,280
with expertise
in health equity research,

1106
00:55:03,280 --> 00:55:04,800
including individuals

1107
00:55:04,800 --> 00:55:07,080
who are members
of underrepresented populations

1108
00:55:07,080 --> 00:55:09,600
and that we increase
opportunities for participation

1109
00:55:09,600 --> 00:55:12,360
in high-level decision-making
committees and opportunities

1110
00:55:12,360 --> 00:55:14,120
for underrepresented
scholars.

1111
00:55:14,120 --> 00:55:16,720
Next slide, please.

1112
00:55:16,720 --> 00:55:21,560
The NIH is already addressing
some of these issues.

1113
00:55:21,560 --> 00:55:24,600
In addition to some of the
resources that I showed earlier,

1114
00:55:24,600 --> 00:55:27,560
we see special calls
for understanding

1115
00:55:27,560 --> 00:55:29,840
and addressing the impact
of structural racism

1116
00:55:29,840 --> 00:55:33,320
and discrimination on minority
health and health disparities,

1117
00:55:33,320 --> 00:55:36,800
this particular R01 opportunity,

1118
00:55:36,800 --> 00:55:39,920
the Health Disparities
Research Institute

1119
00:55:39,920 --> 00:55:42,800
and these administrative
supplements for research

1120
00:55:42,800 --> 00:55:45,480
on sexual and gender
minority populations,

1121
00:55:45,480 --> 00:55:49,120
as well as other opportunities
not listed here.

1122
00:55:49,120 --> 00:55:50,720
Next slide, please?

1123
00:55:53,680 --> 00:55:57,120
Now, I will hand it over
to our moderators.

1124
00:55:57,120 --> 00:55:58,720
Thank you.

1125
00:56:02,480 --> 00:56:04,080
-Yes, next is the assessment

1126
00:56:04,080 --> 00:56:07,440
and data
focus area recommendations

1127
00:56:07,440 --> 00:56:17,400
that I believe Dr. Gottesman
will be presenting.

1128
00:56:17,400 --> 00:56:19,400
-I'll be taking -
I'll be taking over.

1129
00:56:19,400 --> 00:56:20,960
Good morning, all.

1130
00:56:20,960 --> 00:56:23,000
On behalf of my colleagues,
I want to thank the NINDS

1131
00:56:23,000 --> 00:56:24,880
for putting this summit together

1132
00:56:24,880 --> 00:56:27,640
and providing us the opportunity
to share our thoughts

1133
00:56:27,640 --> 00:56:32,160
on how to advance health equity
through AD/ADRD research.

1134
00:56:32,160 --> 00:56:33,840
My name is Wassim Tarraf,

1135
00:56:33,840 --> 00:56:35,480
and I'll be presenting on behalf
of my colleagues in the data

1136
00:56:35,480 --> 00:56:39,120
and assessment focus area,
including Dr. Gottesman,

1137
00:56:39,120 --> 00:56:42,440
Dr. O'Bryant, Dr. Fornage
and Dr. González.

1138
00:56:42,440 --> 00:56:44,360
Next slide, please?

1139
00:56:44,360 --> 00:56:46,040
I have no conflicts to report.

1140
00:56:46,040 --> 00:56:48,040
Next slide, please.

1141
00:56:48,040 --> 00:56:49,840
So over the next few slides,

1142
00:56:49,840 --> 00:56:52,280
I'm going to try to make
a few observations

1143
00:56:52,280 --> 00:56:53,960
to place in context -

1144
00:56:53,960 --> 00:56:57,760
discussions as a group,
leading to our recommendations.

1145
00:56:57,760 --> 00:56:59,480
As you probably know,

1146
00:56:59,480 --> 00:57:02,040
the U.S. population is becoming
increasingly more diverse,

1147
00:57:02,040 --> 00:57:04,400
but ethnic and racial groups
remain underrepresented

1148
00:57:04,400 --> 00:57:07,600
in clinical trials,
which are, as an example,

1149
00:57:07,600 --> 00:57:10,680
the primary pathway for
the development of therapeutics,

1150
00:57:10,680 --> 00:57:13,880
so scientists need
more resources to understand

1151
00:57:13,880 --> 00:57:15,920
and bring down the barriers
to participation

1152
00:57:15,920 --> 00:57:19,600
in clinical trials for these
underrepresented groups.

1153
00:57:19,600 --> 00:57:22,120
We've made progress over time,

1154
00:57:22,120 --> 00:57:24,280
and the rates of participation
for traditionally

1155
00:57:24,280 --> 00:57:26,360
underrepresented groups
have increased,

1156
00:57:26,360 --> 00:57:29,880
but these rates
still do not fully represent

1157
00:57:29,880 --> 00:57:32,400
the overall population
of the United States.

1158
00:57:32,400 --> 00:57:36,240
As you see here, as of 2013,

1159
00:57:36,240 --> 00:57:38,840
72 percent of clinical
trial participants

1160
00:57:38,840 --> 00:57:40,400
were non-Hispanic whites,

1161
00:57:40,400 --> 00:57:42,080
and among ethnic
and racial minorities

1162
00:57:42,080 --> 00:57:44,000
that do participate
in clinical trials,

1163
00:57:44,000 --> 00:57:48,000
the rates vary drastically
by the groups included.

1164
00:57:48,000 --> 00:57:49,280
This lack of representation

1165
00:57:49,280 --> 00:57:51,000
has critical implications
to the health

1166
00:57:51,000 --> 00:57:53,960
and well-being of racial
and ethnic minorities

1167
00:57:53,960 --> 00:58:00,160
but also
the general population.

1168
00:58:00,160 --> 00:58:01,680
A better understanding
of the factors

1169
00:58:01,680 --> 00:58:05,200
that affect these groups
can shed light on novel pathways

1170
00:58:05,200 --> 00:58:09,400
that will have implications
for the overall public health.

1171
00:58:09,400 --> 00:58:12,800
So existing policies
do recognize this as an issue,

1172
00:58:12,800 --> 00:58:14,800
and there are many efforts
to increase

1173
00:58:14,800 --> 00:58:17,800
the representation of minorities
in clinical trials,

1174
00:58:17,800 --> 00:58:20,440
but policy alone
is insufficient to overcome

1175
00:58:20,440 --> 00:58:23,640
some of these existing
barriers to inclusion.

1176
00:58:23,640 --> 00:58:25,360
We believe that the science
of inclusion

1177
00:58:25,360 --> 00:58:27,960
plays a critical role in how
to improve representation,

1178
00:58:27,960 --> 00:58:30,000
and over the next few years,

1179
00:58:30,000 --> 00:58:32,680
we believe that we should
continue to invest in programs

1180
00:58:32,680 --> 00:58:34,680
that increase the awareness
and visibility

1181
00:58:34,680 --> 00:58:36,320
of the science
of recruitment,

1182
00:58:36,320 --> 00:58:38,960
establish AD/ADRD
diversity recruitment

1183
00:58:38,960 --> 00:58:40,480
and retention centers

1184
00:58:40,480 --> 00:58:42,960
and build accountability
mechanisms for recruitment goals

1185
00:58:42,960 --> 00:58:46,160
within existing
NIH-funded networks.

1186
00:58:46,160 --> 00:58:48,520
Establishing these processes
can potentially bring

1187
00:58:48,520 --> 00:58:50,400
about this
meaningful participation

1188
00:58:50,400 --> 00:58:54,160
of all population groups
and yield potential gains

1189
00:58:54,160 --> 00:58:55,720
to improve the public health.

1190
00:58:55,720 --> 00:58:57,400
Next slide, please?

1191
00:58:57,400 --> 00:59:02,160
So the statistics that you seen
on the previous slide

1192
00:59:02,160 --> 00:59:04,600
also extend
to observational data.

1193
00:59:04,600 --> 00:59:06,800
What you see here is a breakdown
of some data

1194
00:59:06,800 --> 00:59:08,360
provided by the NIH

1195
00:59:08,360 --> 00:59:11,840
RCDC Inclusion
Statistics Report.

1196
00:59:11,840 --> 00:59:13,600
These figures, to a large
extent,

1197
00:59:13,600 --> 00:59:15,200
mirror the story that we've -

1198
00:59:15,200 --> 00:59:18,200
was told in
the clinical trials case.

1199
00:59:18,200 --> 00:59:20,000
It is critical to point here

1200
00:59:20,000 --> 00:59:22,760
that there's significant
variability across institutes,

1201
00:59:22,760 --> 00:59:25,920
and all institutes
are making progress,

1202
00:59:25,920 --> 00:59:28,040
but more is needed
to advance the process

1203
00:59:28,040 --> 00:59:30,600
and provide the data
that is required to allow

1204
00:59:30,600 --> 00:59:35,400
appropriate generalizability
to a diversely aging population.

1205
00:59:35,400 --> 00:59:38,200
Next slide, please?

1206
00:59:38,200 --> 00:59:42,200
So moving beyond disparities
and towards equity,

1207
00:59:42,200 --> 00:59:48,400
as the chair of many - and many
other speakers have emphasized -

1208
00:59:48,400 --> 00:59:50,640
And proving participation
for better representation

1209
00:59:50,640 --> 00:59:54,320
has the potential
to yield better data,

1210
00:59:54,320 --> 00:59:56,720
and that can help improve
assessment tools,

1211
00:59:56,720 --> 00:59:59,560
better measures,
better quantification

1212
00:59:59,560 --> 01:00:03,600
and better studies
for pathways to ADRD

1213
01:00:03,600 --> 01:00:05,840
and will enhance
the generalizability

1214
01:00:05,840 --> 01:00:08,480
and equity
of scientific research.

1215
01:00:08,480 --> 01:00:10,360
On the cognitive
assessment front,

1216
01:00:10,360 --> 01:00:13,640
we have ample evidence
from years of studies

1217
01:00:13,640 --> 01:00:16,120
that existing cutoffs
on cognitive tests

1218
01:00:16,120 --> 01:00:18,800
have major shortcomings
for epidemiological estimates

1219
01:00:18,800 --> 01:00:21,280
of disease
across racial and ethnic groups,

1220
01:00:21,280 --> 01:00:23,160
across socioeconomic
status groups,

1221
01:00:23,160 --> 01:00:25,600
particularly across
educational level groups,

1222
01:00:25,600 --> 01:00:27,040
and we have clear calls

1223
01:00:27,040 --> 01:00:29,640
and supportive efforts
to create better tools

1224
01:00:29,640 --> 01:00:32,520
and invest scientific efforts
to identify metrics

1225
01:00:32,520 --> 01:00:34,360
that allow
appropriate generalization.

1226
01:00:34,360 --> 01:00:37,360
So this includes generating
the deep data

1227
01:00:37,360 --> 01:00:39,960
that we need that could enable
stratification by race,

1228
01:00:39,960 --> 01:00:44,320
ethnicity, by education, by SES
and ensure better detection,

1229
01:00:44,320 --> 01:00:46,360
particularly at early stages
of disease,

1230
01:00:46,360 --> 01:00:49,680
example,
mild cognitive impairment,

1231
01:00:49,680 --> 01:00:52,200
but also critically to permit
clear demarcation

1232
01:00:52,200 --> 01:00:56,240
across disease stages
across and within groups.

1233
01:00:56,240 --> 01:01:00,200
Unfortunately, we're not
at that level of data yet.

1234
01:01:00,200 --> 01:01:02,240
The point and our view
is made clear

1235
01:01:02,240 --> 01:01:04,560
by looking at recent reviews
of the evidence,

1236
01:01:04,560 --> 01:01:06,520
which you see
on the slide here,

1237
01:01:06,520 --> 01:01:09,800
that shows that data
for some groups, as an example,

1238
01:01:09,800 --> 01:01:11,880
American Indians
or Alaska Natives

1239
01:01:11,880 --> 01:01:14,400
to note one,
is near nonexistent.

1240
01:01:14,400 --> 01:01:16,560
Data on other groups,
while we have some,

1241
01:01:16,560 --> 01:01:18,000
is potentially insufficient

1242
01:01:18,000 --> 01:01:20,800
to provide precise estimates
of the problem,

1243
01:01:20,800 --> 01:01:24,040
particularly at the earlier
stages of the disease process,

1244
01:01:24,040 --> 01:01:27,280
and this evidence also points
that there's a clear need

1245
01:01:27,280 --> 01:01:29,800
to generate data
that allows disaggregation

1246
01:01:29,800 --> 01:01:31,800
of large
race-ethnic classifications,

1247
01:01:31,800 --> 01:01:35,080
among Asian Americans,
among Black Americans,

1248
01:01:35,080 --> 01:01:36,440
among Hispanic Americans,

1249
01:01:36,440 --> 01:01:38,800
to kind of disentangle
this heterogeneity

1250
01:01:38,800 --> 01:01:44,440
within these large
non-monolithic groups.

1251
01:01:44,440 --> 01:01:46,200
So given the state
of the evidence,

1252
01:01:46,200 --> 01:01:48,840
we recommend a national effort
for developing novel

1253
01:01:48,840 --> 01:01:50,600
and unbiased normative methods

1254
01:01:50,600 --> 01:01:53,200
that will lay the ground
for recommendations,

1255
01:01:53,200 --> 01:01:55,280
for guidelines
and for guidance on how

1256
01:01:55,280 --> 01:01:58,320
and when to use
or not to use race

1257
01:01:58,320 --> 01:02:01,280
or ethnic-based norms
in cognitive data.

1258
01:02:01,280 --> 01:02:02,840
Next slide, please.

1259
01:02:05,440 --> 01:02:09,920
On the biomarkers and
the evidence base

1260
01:02:09,920 --> 01:02:11,360
regarding availability,

1261
01:02:11,360 --> 01:02:14,400
let alone equivalency
of AD/ADRD biomarkers,

1262
01:02:14,400 --> 01:02:17,800
is even much thinner
than what's available

1263
01:02:17,800 --> 01:02:19,200
for cognitive assessment.

1264
01:02:19,200 --> 01:02:22,440
For example, recent study
looking at screening

1265
01:02:22,440 --> 01:02:24,120
and enrollments
in the Alzheimer's Disease

1266
01:02:24,120 --> 01:02:26,160
Neuroimaging Initiative, ADNI,

1267
01:02:26,160 --> 01:02:28,800
shows that of
the enrolled participants

1268
01:02:28,800 --> 01:02:33,800
between 2004 and 2020,
only 11 percent of the data

1269
01:02:33,800 --> 01:02:35,600
came from individuals
that identified

1270
01:02:35,600 --> 01:02:39,200
as being from ethnoculturally
underrepresented populations

1271
01:02:39,200 --> 01:02:41,440
and only 15 percent
from individuals

1272
01:02:41,440 --> 01:02:43,440
with less than
12 years of education.

1273
01:02:43,440 --> 01:02:45,440
Both of these rates
are drastically lower

1274
01:02:45,440 --> 01:02:47,440
than what comparative
census data

1275
01:02:47,440 --> 01:02:49,920
would allow
for these categories.

1276
01:02:49,920 --> 01:02:52,280
Now serious observers
of the field of AD

1277
01:02:52,280 --> 01:02:55,480
and ADRD biomarkers recognize
that this is an exciting time

1278
01:02:55,480 --> 01:02:59,000
to be doing research in AD
and ADRD with,

1279
01:02:59,000 --> 01:03:01,120
you know, potential tools
at our disposal

1280
01:03:01,120 --> 01:03:03,160
that have the promise,
as was mentioned,

1281
01:03:03,160 --> 01:03:05,720
of better understanding
complex pathologies,

1282
01:03:05,720 --> 01:03:07,800
transforming care
and diagnostics

1283
01:03:07,800 --> 01:03:09,840
and even disease monitoring.

1284
01:03:09,840 --> 01:03:13,000
But despite this excitement,
there's also clear recognition

1285
01:03:13,000 --> 01:03:15,600
that there are critical
shortcomings in existing data

1286
01:03:15,600 --> 01:03:16,800
and clear limitations

1287
01:03:16,800 --> 01:03:19,320
in the lack of diversity
of existing data

1288
01:03:19,320 --> 01:03:22,400
which limits the potential
for extending any findings

1289
01:03:22,400 --> 01:03:24,600
to real-world clinical problems.

1290
01:03:24,600 --> 01:03:27,400
So the figure that you see
on this slide

1291
01:03:27,400 --> 01:03:30,160
provides some hints
from existing data.

1292
01:03:30,160 --> 01:03:32,160
These data are largely limited

1293
01:03:32,160 --> 01:03:35,200
in terms of representation
based on small n,

1294
01:03:35,200 --> 01:03:37,080
but they show that biomarkers
of AD

1295
01:03:37,080 --> 01:03:39,840
present in complex ways
across population groups

1296
01:03:39,840 --> 01:03:43,040
and are likely to differ
by race and ethnicity.

1297
01:03:43,040 --> 01:03:46,760
So planning for achieving equity
in AD and ADRD research

1298
01:03:46,760 --> 01:03:50,600
is the only way, in our view,
to avoid neglecting,

1299
01:03:50,600 --> 01:03:53,800
leaving behind, omitting major
sections of the US populations

1300
01:03:53,800 --> 01:03:56,400
and potentially jeopardizing
the public health

1301
01:03:56,400 --> 01:03:58,560
for future generations.

1302
01:03:58,560 --> 01:04:01,400
We recommend developing
resources to address

1303
01:04:01,400 --> 01:04:04,040
the fundamental questions
of biomarker equivalency

1304
01:04:04,040 --> 01:04:06,200
in distinct race
and ethnic groups,

1305
01:04:06,200 --> 01:04:08,200
to explore alternative
frameworks,

1306
01:04:08,200 --> 01:04:10,200
recognizing that
the ATN framework

1307
01:04:10,200 --> 01:04:13,120
may not apply as well in
diverse populations

1308
01:04:13,120 --> 01:04:15,080
given the lack,
as an example,

1309
01:04:15,080 --> 01:04:17,960
for considerations
of cardiovascular disease,

1310
01:04:17,960 --> 01:04:20,800
misdistribution
of the population.

1311
01:04:20,800 --> 01:04:23,800
And biomarkers may have
different meaning and value

1312
01:04:23,800 --> 01:04:25,200
in different groups.

1313
01:04:25,200 --> 01:04:28,520
Next slide, please.

1314
01:04:28,520 --> 01:04:31,160
We think also that
a similar story comes up

1315
01:04:31,160 --> 01:04:34,560
when we look at the evidence
for genetic data.

1316
01:04:34,560 --> 01:04:36,200
So research finding suggest

1317
01:04:36,200 --> 01:04:38,400
that even for relatively
simple links,

1318
01:04:38,400 --> 01:04:41,200
as in the APOE epsilon 4 story,

1319
01:04:41,200 --> 01:04:43,400
when more data
becomes available,

1320
01:04:45,600 --> 01:04:47,200
it shows more complexity.

1321
01:04:47,200 --> 01:04:50,880
And it shows that conclusive
evidence still alludes us

1322
01:04:50,880 --> 01:04:54,320
until more sampling
and higher levels of inclusion

1323
01:04:54,320 --> 01:04:57,720
to clarify the potential of
within group heterogeneities

1324
01:04:57,720 --> 01:04:59,400
and links

1325
01:04:59,400 --> 01:05:03,400
and the synergistic effects
that could happen within groups.

1326
01:05:03,400 --> 01:05:07,400
But also it shows a particular
need for availability of data

1327
01:05:07,400 --> 01:05:10,200
that enables replication.

1328
01:05:10,200 --> 01:05:12,480
We think that better and more
inclusive data

1329
01:05:12,480 --> 01:05:14,080
will open doors for discovery.

1330
01:05:14,080 --> 01:05:16,440
It'll enable newer and more
nuanced ways

1331
01:05:16,440 --> 01:05:19,040
of thinking about the pathways.

1332
01:05:19,040 --> 01:05:21,200
And to get there,
we recommend enhancing

1333
01:05:21,200 --> 01:05:22,600
the availability
of studies

1334
01:05:22,600 --> 01:05:25,080
that better characterize
genetic risk factors,

1335
01:05:25,080 --> 01:05:28,200
particularly in the context
of other nongenetic factors.

1336
01:05:28,200 --> 01:05:30,600
So our view is that any genetic
discovery,

1337
01:05:30,600 --> 01:05:33,360
in order to translate
the real-world benefits,

1338
01:05:33,360 --> 01:05:36,240
need to be examined
in the context of environmental,

1339
01:05:36,240 --> 01:05:38,760
behavioral and socioeconomic
cultural factors

1340
01:05:38,760 --> 01:05:41,000
in order to have
the data necessary

1341
01:05:41,000 --> 01:05:46,080
to allow these kinds
of associations.

1342
01:05:46,080 --> 01:05:48,400
Next slide, please.

1343
01:05:48,400 --> 01:05:54,760
-Two minutes remaining.
-In the interest of time,

1344
01:05:54,760 --> 01:05:59,560
the excitement about the
potential of new technologies

1345
01:05:59,560 --> 01:06:02,400
and their capacities
for collecting rich,

1346
01:06:02,400 --> 01:06:05,720
almost instantaneous data
through digital biomarkers

1347
01:06:05,720 --> 01:06:10,400
to improve the health
of Americans is tremendous.

1348
01:06:10,400 --> 01:06:14,120
The question, however,
in our view is, which Americans?

1349
01:06:14,120 --> 01:06:16,880
And the hope is that we're not
setting ourselves up

1350
01:06:16,880 --> 01:06:18,920
for a new wave
of scientific excitement

1351
01:06:18,920 --> 01:06:22,000
that passes underrepresented
populations.

1352
01:06:22,000 --> 01:06:23,560
I want to thank you
for the opportunity

1353
01:06:23,560 --> 01:06:26,280
to share some of our stats,
and it is now my pleasure

1354
01:06:26,280 --> 01:06:29,520
to pass the baton
to Dr. Khachaturian.

1355
01:06:29,520 --> 01:06:32,400
Thank you.

1356
01:06:32,400 --> 01:06:34,120
-Thank you, Dr. Tarraf.

1357
01:06:34,120 --> 01:06:35,800
Hello, my name
is Ara Khachaturian,

1358
01:06:35,800 --> 01:06:39,600
and I'm representing
the focus area on diagnosis,

1359
01:06:39,600 --> 01:06:41,320
treatment and care.

1360
01:06:41,320 --> 01:06:44,360
These are recommendations
for four and eight.

1361
01:06:44,360 --> 01:06:47,120
Next slide, please.

1362
01:06:47,120 --> 01:06:51,240
These are my disclaimers,
and this is my disclosure.

1363
01:06:51,240 --> 01:06:54,160
Next slide.

1364
01:06:54,160 --> 01:06:57,000
I want to acknowledge
that our focus area

1365
01:06:57,000 --> 01:07:00,680
included
Dr. Julie Zissimopoulos,

1366
01:07:00,680 --> 01:07:05,000
Dr. Erica Littlejohn,
Dr. Alberto Ramos

1367
01:07:05,000 --> 01:07:08,600
and also, Dr. Michael Wolf.

1368
01:07:08,600 --> 01:07:10,360
We really took upon
this question

1369
01:07:10,360 --> 01:07:12,600
of looking at the issues
of diagnosis, treatment

1370
01:07:12,600 --> 01:07:16,240
and care in terms
of really thinking about

1371
01:07:16,240 --> 01:07:18,160
from broadly the patient journey

1372
01:07:18,160 --> 01:07:21,600
when one has Alzheimer's
or a related dementia

1373
01:07:21,600 --> 01:07:23,200
as well as also
thinking about,

1374
01:07:23,200 --> 01:07:26,320
what it's going to take
to have new quote, unquote,

1375
01:07:26,320 --> 01:07:28,160
learning health systems
of the future

1376
01:07:28,160 --> 01:07:30,440
and how are we actually
going to arrive

1377
01:07:30,440 --> 01:07:34,440
at providing equitable
care for individuals,

1378
01:07:34,440 --> 01:07:36,120
particularly from
underrepresented

1379
01:07:36,120 --> 01:07:38,720
and underserved populations.

1380
01:07:38,720 --> 01:07:42,000
Our first recommendation,
recommendation four,

1381
01:07:42,000 --> 01:07:46,680
is to assess the social,
economic, structural impediments

1382
01:07:46,680 --> 01:07:49,680
to equity in Alzheimer's
and Alzheimer's-related

1383
01:07:49,680 --> 01:07:52,280
disorders assessment,
diagnosis and referrals

1384
01:07:52,280 --> 01:07:57,680
and impacts on health
and economic outcomes.

1385
01:07:57,680 --> 01:07:59,960
Within this recommendation,
there's really an opportunity

1386
01:07:59,960 --> 01:08:03,320
to think about several
important research questions,

1387
01:08:03,320 --> 01:08:07,080
public health questions
and public policy questions.

1388
01:08:07,080 --> 01:08:09,760
We're going to take a look
at some of those questions.

1389
01:08:09,760 --> 01:08:12,480
These are not exhaustive,
but really illustrative.

1390
01:08:12,480 --> 01:08:15,640
Next slide, please.

1391
01:08:15,640 --> 01:08:17,880
We think that these questions
are really going to be

1392
01:08:17,880 --> 01:08:21,960
sort of examined more critically
and perhaps even really become

1393
01:08:21,960 --> 01:08:23,280
sort of dominating
the literature

1394
01:08:23,280 --> 01:08:25,920
over the next 3
to 5 years.

1395
01:08:25,920 --> 01:08:27,400
One if these first questions is,

1396
01:08:27,400 --> 01:08:30,440
how does CMS and private
insurance benefit designs,

1397
01:08:30,440 --> 01:08:33,600
payment and reimbursement
policies impact the assessment,

1398
01:08:33,600 --> 01:08:37,920
diagnosis of dementia
in diverse populations?

1399
01:08:37,920 --> 01:08:39,680
We know that there is
an ongoing tension

1400
01:08:39,680 --> 01:08:42,000
in the US health care system

1401
01:08:42,000 --> 01:08:46,000
about how best
to enhance quality care.

1402
01:08:46,000 --> 01:08:49,520
In one way, this question seeks
to pinpoint those opportunities

1403
01:08:49,520 --> 01:08:54,440
to gain efficiencies
in the US health care system.

1404
01:08:54,440 --> 01:08:57,400
Next slide, please.

1405
01:08:57,400 --> 01:09:00,920
Another important question
for supporting

1406
01:09:00,920 --> 01:09:03,880
this recommendation is,
how generalizable are provider

1407
01:09:03,880 --> 01:09:06,240
and specific health
system factors?

1408
01:09:06,240 --> 01:09:10,120
This will include access
to dementia specialists,

1409
01:09:10,120 --> 01:09:13,520
the role of race concordance
and also other providers

1410
01:09:13,520 --> 01:09:15,400
and practice-level
organization factors

1411
01:09:15,400 --> 01:09:18,760
among diverse populations.

1412
01:09:18,760 --> 01:09:20,360
Next slide, please.

1413
01:09:22,960 --> 01:09:28,200
This question, what socio-,
behavioral and environmental

1414
01:09:28,200 --> 01:09:30,040
and economic health
care system factors

1415
01:09:30,040 --> 01:09:34,320
impede equitable assessment
and detection and diagnosis

1416
01:09:34,320 --> 01:09:35,800
and referrals of individuals

1417
01:09:35,800 --> 01:09:39,160
with Alzheimer's
and related disorders?

1418
01:09:39,160 --> 01:09:41,400
Next slide, please.

1419
01:09:41,400 --> 01:09:44,800
And the related question of,
how best to quantify

1420
01:09:44,800 --> 01:09:48,200
the assessment, detection,
diagnosis and referrals

1421
01:09:48,200 --> 01:09:51,520
on health,
social and economic outcomes?

1422
01:09:51,520 --> 01:09:54,680
As Dr. Tarraf had mentioned
in the previous outcome --

1423
01:09:54,680 --> 01:09:56,920
in the previous presentation,

1424
01:09:56,920 --> 01:10:00,200
there is very much an important
need for new data

1425
01:10:00,200 --> 01:10:02,200
and new assessments.

1426
01:10:02,200 --> 01:10:04,200
As our group thought
about these questions,

1427
01:10:04,200 --> 01:10:06,280
we really were thinking
in terms of both

1428
01:10:06,280 --> 01:10:10,320
from how public health
and information sciences

1429
01:10:10,320 --> 01:10:12,000
can come together
to really think

1430
01:10:12,000 --> 01:10:15,440
about looking at these questions
from a complexity point of view,

1431
01:10:15,440 --> 01:10:18,520
thinking about that
there are complex interactions,

1432
01:10:18,520 --> 01:10:20,680
and certainly many
of these related factors

1433
01:10:20,680 --> 01:10:22,320
are not going to be linear.

1434
01:10:22,320 --> 01:10:24,000
In fact, how are we going
to be able to think

1435
01:10:24,000 --> 01:10:26,960
about
modeling nonlinear relationships

1436
01:10:26,960 --> 01:10:28,640
across these various measures.

1437
01:10:28,640 --> 01:10:31,200
And certainly, this is going
to be proved to be

1438
01:10:31,200 --> 01:10:35,160
very important
over the next couple of years.

1439
01:10:35,160 --> 01:10:36,760
Next slide, please.

1440
01:10:39,200 --> 01:10:42,320
So our group sort of went from
asking these questions,

1441
01:10:42,320 --> 01:10:45,000
important questions
of how to really look

1442
01:10:45,000 --> 01:10:48,320
at the issues of diagnosis,
treatment and care

1443
01:10:48,320 --> 01:10:52,040
to really provide better
assurance for health equity,

1444
01:10:52,040 --> 01:10:54,600
to thinking about this
from a structural point of view

1445
01:10:54,600 --> 01:10:57,200
and really looking at
what are going to be

1446
01:10:57,200 --> 01:10:58,960
some of the tools and methods

1447
01:10:58,960 --> 01:11:02,560
that are going to help drive
exploration of these questions.

1448
01:11:02,560 --> 01:11:07,320
So recommendation eight looks at
and makes the recommendation

1449
01:11:07,320 --> 01:11:10,000
that we need to support
infrastructure and policy

1450
01:11:10,000 --> 01:11:13,080
research
to understand individuals,

1451
01:11:13,080 --> 01:11:17,280
community and societal drivers
of inequities

1452
01:11:17,280 --> 01:11:20,560
in cost of and access
to treatments, care

1453
01:11:20,560 --> 01:11:22,640
and the impact on Alzheimer's

1454
01:11:22,640 --> 01:11:26,600
and Alzheimer's-related
disorders outcomes.

1455
01:11:26,600 --> 01:11:28,200
Next slide, please.

1456
01:11:31,320 --> 01:11:33,640
This recommendation really sort
of points

1457
01:11:33,640 --> 01:11:37,760
to what are going to be
some of the specific needs

1458
01:11:37,760 --> 01:11:39,720
that we're going to
have to think about.

1459
01:11:39,720 --> 01:11:42,080
So our group actually started
to think in terms of,

1460
01:11:42,080 --> 01:11:45,000
how can we start to go
from this recommendation stage

1461
01:11:45,000 --> 01:11:47,000
to an implementation?

1462
01:11:47,000 --> 01:11:49,320
One of the ideas was really
in terms of trying

1463
01:11:49,320 --> 01:11:52,960
to define one's concepts.

1464
01:11:52,960 --> 01:11:55,800
Certainly having national
standards for dementia costs

1465
01:11:55,800 --> 01:12:01,600
and health outcomes is going
to be absolutely imperative.

1466
01:12:01,600 --> 01:12:05,120
Dr. González, in his opening
remarks to this session,

1467
01:12:05,120 --> 01:12:07,640
really sort of laid out
the NINDS framework.

1468
01:12:07,640 --> 01:12:11,040
And so, one of the ideas that we
hope that perhaps future

1469
01:12:11,040 --> 01:12:12,480
working groups will look at is,

1470
01:12:12,480 --> 01:12:15,000
how to parameterize
some of these key

1471
01:12:15,000 --> 01:12:20,200
constructs in terms of
looking at how to model better

1472
01:12:20,200 --> 01:12:21,760
and also to think
about inclusion

1473
01:12:21,760 --> 01:12:25,600
into a national data repository.

1474
01:12:25,600 --> 01:12:27,600
And that really leads
to our third point here,

1475
01:12:27,600 --> 01:12:30,880
which is a national database
for dementia equity research

1476
01:12:30,880 --> 01:12:37,360
on social, economic
and health-related factors.

1477
01:12:37,360 --> 01:12:38,960
Next slide, please.

1478
01:12:42,360 --> 01:12:46,040
We also seek to think that
it's going to be very important

1479
01:12:46,040 --> 01:12:50,080
to have measures to look at
inequities in pharmacological,

1480
01:12:50,080 --> 01:12:54,640
non-pharmacological, medical
and social care services,

1481
01:12:54,640 --> 01:13:00,360
with a focus looking at impact
on cost and health outcomes.

1482
01:13:00,360 --> 01:13:03,640
Also, health outcomes and care
quality of managed care

1483
01:13:03,640 --> 01:13:07,000
and associated access
among diverse populations

1484
01:13:07,000 --> 01:13:12,960
is going to be another
important area to examine.

1485
01:13:12,960 --> 01:13:14,560
Next slide, please.

1486
01:13:18,080 --> 01:13:22,000
Looking at this thoroughly from
the health economic perspective,

1487
01:13:22,000 --> 01:13:23,920
supply-side factors
are also going to be

1488
01:13:23,920 --> 01:13:26,040
an important area to measure.

1489
01:13:26,040 --> 01:13:29,280
This is going to require looking
at health system ownership,

1490
01:13:29,280 --> 01:13:31,880
for example,
of physician practices

1491
01:13:31,880 --> 01:13:38,000
and also looking at the equity
of Medicare benefit plans.

1492
01:13:38,000 --> 01:13:40,160
Another idea
that we discussed as well

1493
01:13:40,160 --> 01:13:43,760
is this adoption of something
called the model-base.

1494
01:13:43,760 --> 01:13:45,080
Here, the idea would be

1495
01:13:45,080 --> 01:13:47,920
to actually not
just have data available,

1496
01:13:47,920 --> 01:13:50,440
but really to have
a collection of models,

1497
01:13:50,440 --> 01:13:53,640
health economic models
of pharmacological,

1498
01:13:53,640 --> 01:13:57,160
non-pharmacological
and health care interventions

1499
01:13:57,160 --> 01:14:00,560
that will help measure
and predict access,

1500
01:14:00,560 --> 01:14:03,040
costs and health
care outcomes.

1501
01:14:05,440 --> 01:14:07,960
And next slide, please.

1502
01:14:10,120 --> 01:14:13,600
And finally, we are really
interested in seeing

1503
01:14:13,600 --> 01:14:16,320
what is going to happen
in terms of the examine

1504
01:14:16,320 --> 01:14:20,400
of sociocultural, behavioral,
environmental, health

1505
01:14:20,400 --> 01:14:22,640
and other care system factors

1506
01:14:22,640 --> 01:14:25,520
that will influence
equitable access.

1507
01:14:25,520 --> 01:14:28,000
This is a topic that certainly
is beginning to gain

1508
01:14:28,000 --> 01:14:31,280
a lot of interest
within journals,

1509
01:14:31,280 --> 01:14:33,000
and we really anticipate

1510
01:14:33,000 --> 01:14:35,040
seeing a lot of this research
coming forward

1511
01:14:35,040 --> 01:14:37,800
over perhaps even shorter
than the 5 to 7 years

1512
01:14:37,800 --> 01:14:39,640
that we anticipate.

1513
01:14:39,640 --> 01:14:41,400
And as noted by Dr. Rost

1514
01:14:41,400 --> 01:14:43,960
also at the beginning
of the presentation,

1515
01:14:43,960 --> 01:14:47,200
the impact of COVID in terms
of what that has meant

1516
01:14:47,200 --> 01:14:48,880
to our health care systems
in terms

1517
01:14:48,880 --> 01:14:52,240
of delivering better diagnosis,
treatment and care,

1518
01:14:52,240 --> 01:14:55,720
certainly telemedicine
and mobile health care options

1519
01:14:55,720 --> 01:14:58,280
on reducing
some of the financial burdens

1520
01:14:58,280 --> 01:15:00,360
and some of
the communications problems

1521
01:15:00,360 --> 01:15:02,280
are going to be
absolutely essential.

1522
01:15:04,560 --> 01:15:06,600
Next slide.

1523
01:15:06,600 --> 01:15:10,040
Thank you, and I'd like to now
introduce my colleague,

1524
01:15:10,040 --> 01:15:11,400
Professor Jennifer Weuve

1525
01:15:11,400 --> 01:15:13,560
at Boston University
School of Public Health,

1526
01:15:13,560 --> 01:15:18,520
who's going to be talking about
the focus area on epidemiology.

1527
01:15:18,520 --> 01:15:20,200
-Thank you, Ara.

1528
01:15:20,200 --> 01:15:22,600
I will be summarizing
recommendations

1529
01:15:22,600 --> 01:15:26,800
that address how to use
epidemiology to understand

1530
01:15:26,800 --> 01:15:31,080
and intervene
on health inequities in AD/ADRD.

1531
01:15:31,080 --> 01:15:33,320
Next.

1532
01:15:33,320 --> 01:15:35,400
I have no disclosures to report.

1533
01:15:35,400 --> 01:15:38,000
Next.

1534
01:15:38,000 --> 01:15:42,000
Our first recommendation
concerns the documentation

1535
01:15:42,000 --> 01:15:45,240
of health inequities
in AD/ADRD.

1536
01:15:45,240 --> 01:15:49,200
Specifically, we recommend
applying existing and novel

1537
01:15:49,200 --> 01:15:50,600
surveillance methods

1538
01:15:50,600 --> 01:15:54,200
to assess inequities
in AD/ADRD prevalence,

1539
01:15:54,200 --> 01:15:57,920
incidence, diagnosis,
treatment and care.

1540
01:15:57,920 --> 01:16:01,760
We also advocate attention
to trends in inequities.

1541
01:16:01,760 --> 01:16:04,920
That is, how inequities
might be changing over time,

1542
01:16:04,920 --> 01:16:07,240
whether shrinking
or expanding.

1543
01:16:07,240 --> 01:16:09,560
Next.

1544
01:16:09,560 --> 01:16:12,320
Now, acts of documentation
are integral

1545
01:16:12,320 --> 01:16:16,560
to achieving health
equity in AD/ADRD

1546
01:16:16,560 --> 01:16:18,960
by informing
public health priorities,

1547
01:16:18,960 --> 01:16:22,600
as well as prevention
and treatment strategies.

1548
01:16:22,600 --> 01:16:26,080
Now, some inequities have
already been quantified,

1549
01:16:26,080 --> 01:16:28,320
but many remain unknown.

1550
01:16:28,320 --> 01:16:31,720
For example, numerous studies
have reported declines

1551
01:16:31,720 --> 01:16:33,800
in dementia incidence rates,

1552
01:16:33,800 --> 01:16:35,480
but most of these studies
focused

1553
01:16:35,480 --> 01:16:39,120
on non-Latinx white persons
in the US and Europe.

1554
01:16:39,120 --> 01:16:41,960
Little has been reported
about whether dementia incidence

1555
01:16:41,960 --> 01:16:45,120
has been falling
in underrepresented populations

1556
01:16:45,120 --> 01:16:47,400
or in other
geographic regions.

1557
01:16:47,400 --> 01:16:50,040
Next.

1558
01:16:50,040 --> 01:16:53,160
Now, in addition to more
attention on trends,

1559
01:16:53,160 --> 01:16:55,320
we recommend that inequities
be estimated

1560
01:16:55,320 --> 01:16:58,800
across a range of social
determinants of health,

1561
01:16:58,800 --> 01:17:00,840
such as across racialized group

1562
01:17:00,840 --> 01:17:03,560
or indices of
neighborhood environment,

1563
01:17:03,560 --> 01:17:06,360
and as for explaining
those inequities,

1564
01:17:06,360 --> 01:17:09,560
we directly address this
in our second recommendation.

1565
01:17:09,560 --> 01:17:13,600
Still, the very monitoring
of inequities in AD/ADRD

1566
01:17:13,600 --> 01:17:17,000
can reveal impacts of historic
and contemporary policies

1567
01:17:17,000 --> 01:17:21,320
and events, such as civil rights
policy and pandemics.

1568
01:17:21,320 --> 01:17:24,000
Next.

1569
01:17:24,000 --> 01:17:28,440
Now, I've outlined the nature
of inequities in AD/ADRD

1570
01:17:28,440 --> 01:17:32,360
that we recommend monitoring,
and now to the how.

1571
01:17:32,360 --> 01:17:34,320
Now, valid estimates
of inequities

1572
01:17:34,320 --> 01:17:35,800
should come from samples

1573
01:17:35,800 --> 01:17:38,440
that are representative
of the US population,

1574
01:17:38,440 --> 01:17:41,960
but we can expand
what useful representativeness

1575
01:17:41,960 --> 01:17:43,600
means beyond proportions

1576
01:17:43,600 --> 01:17:46,120
that are consistent
with the US census.

1577
01:17:46,120 --> 01:17:50,600
Many smaller or minoritized
or marginalized groups

1578
01:17:50,600 --> 01:17:54,160
will need to be oversampled
to provide adequate numbers

1579
01:17:54,160 --> 01:17:58,920
for accurate
and precise estimates.

1580
01:17:58,920 --> 01:18:02,080
Historically, cohort studies
of AD/ADRD

1581
01:18:02,080 --> 01:18:05,640
have underincluded specific
communities and populations,

1582
01:18:05,640 --> 01:18:07,000
as you've heard.

1583
01:18:07,000 --> 01:18:09,400
And as a result,
adequately estimating

1584
01:18:09,400 --> 01:18:12,240
the experience of AD/ADRD
in these communities

1585
01:18:12,240 --> 01:18:15,640
may require
establishing new cohorts.

1586
01:18:15,640 --> 01:18:18,240
New cohorts combined
with other methods

1587
01:18:18,240 --> 01:18:20,720
may also be helpful
in shedding light

1588
01:18:20,720 --> 01:18:23,200
on prevalence and incidence
of rare dementias

1589
01:18:23,200 --> 01:18:26,000
in previously
underrepresented groups.

1590
01:18:26,000 --> 01:18:28,480
Next.

1591
01:18:28,480 --> 01:18:31,440
And whether the cohort
is established or new,

1592
01:18:31,440 --> 01:18:35,760
to make it useful for accurately
gauging inequities,

1593
01:18:35,760 --> 01:18:38,840
investigators must identify
and act on determinants

1594
01:18:38,840 --> 01:18:41,240
of underinclusion
in these cohorts...

1595
01:18:41,240 --> 01:18:47,000
[Audio drop]

1596
01:18:47,000 --> 01:18:50,000
-Dr. Weuve,
your microphone is muted.

1597
01:18:50,000 --> 01:18:52,440
-Yeah, I'm not sure
how that happened.

1598
01:18:52,440 --> 01:18:53,920
My apologies.

1599
01:18:53,920 --> 01:18:55,360
I'm going to start here.

1600
01:18:55,360 --> 01:18:57,800
And whether the cohort
is established or new,

1601
01:18:57,800 --> 01:19:01,880
to make it useful for accurately
gauging inequities,

1602
01:19:01,880 --> 01:19:03,920
investigators must identify
and act

1603
01:19:03,920 --> 01:19:06,600
on determinants of
underinclusion in these cohorts,

1604
01:19:06,600 --> 01:19:08,320
as you've heard.

1605
01:19:08,320 --> 01:19:10,880
Now, the levers of inclusion
could involve aspects

1606
01:19:10,880 --> 01:19:14,280
of recruitment
and retention practices,

1607
01:19:14,280 --> 01:19:18,040
economic barriers and stigma,
for example.

1608
01:19:18,040 --> 01:19:20,920
Now, some key levers may lie
outside

1609
01:19:20,920 --> 01:19:24,200
investigator's own experience
and imagination,

1610
01:19:24,200 --> 01:19:27,000
and developing the capacity
to appreciate them and act

1611
01:19:27,000 --> 01:19:30,040
on them may require
intentional acts of partnership

1612
01:19:30,040 --> 01:19:31,840
and engagement
with communities.

1613
01:19:31,840 --> 01:19:34,080
Next.

1614
01:19:34,080 --> 01:19:38,440
Our second recommendation that
uses the tools of epidemiology

1615
01:19:38,440 --> 01:19:43,400
concerns determining how health
inequities in AD/ADRD occur.

1616
01:19:43,400 --> 01:19:47,600
Specifically, we recommend
identifying life course

1617
01:19:47,600 --> 01:19:53,240
and multilevel mechanisms of
pathways to AD/ADRD inequities

1618
01:19:53,240 --> 01:19:56,400
and use the discoveries
to reduce these inequities.

1619
01:19:56,400 --> 01:19:59,320
Next.

1620
01:19:59,320 --> 01:20:02,400
As a foundational act
of that recommendation,

1621
01:20:02,400 --> 01:20:05,280
we encourage researchers
to make a standard practice

1622
01:20:05,280 --> 01:20:09,400
in their research
on inequities in AD/ADRD

1623
01:20:09,400 --> 01:20:13,440
to disclose the conceptual model
that is guiding their work.

1624
01:20:13,440 --> 01:20:17,120
Some broad examples include
race as a social construct

1625
01:20:17,120 --> 01:20:21,160
or even defining age-group
cohorts to specific places,

1626
01:20:21,160 --> 01:20:24,000
times and even policy.

1627
01:20:24,000 --> 01:20:26,080
Now, the absence of such
a disclosure

1628
01:20:26,080 --> 01:20:28,600
can leave open the door
for interpretations

1629
01:20:28,600 --> 01:20:31,400
that veer
toward bioessentialism.

1630
01:20:31,400 --> 01:20:34,000
Next.

1631
01:20:34,000 --> 01:20:38,000
Among populations
facing inequities in AD/ADRD,

1632
01:20:38,000 --> 01:20:42,800
we suggest that putative
risk factors AD/ADRD inequities

1633
01:20:42,800 --> 01:20:47,200
be measured over several
dimensions of time, for example,

1634
01:20:47,200 --> 01:20:50,400
over the life course
across generations

1635
01:20:50,400 --> 01:20:52,640
and specific risk periods,

1636
01:20:52,640 --> 01:20:56,600
and that these risk factors be
assessed in relation to AD/ADRD

1637
01:20:56,600 --> 01:21:02,600
or well-known
determinants of AD/ADRD.

1638
01:21:02,600 --> 01:21:05,320
Next.

1639
01:21:05,320 --> 01:21:07,560
The interplay between social,

1640
01:21:07,560 --> 01:21:09,600
environmental
and biological mechanisms

1641
01:21:09,600 --> 01:21:13,640
in producing AD/ADRD inequities
is multidimensional

1642
01:21:13,640 --> 01:21:18,040
and, as a result,
likely to be complicated.

1643
01:21:18,040 --> 01:21:20,440
This complicated interplay
can be evaluated

1644
01:21:20,440 --> 01:21:24,000
with new intentionally
designed AD/ADRD

1645
01:21:24,000 --> 01:21:26,760
cohorts
for harmonization efforts.

1646
01:21:26,760 --> 01:21:29,320
Next.

1647
01:21:29,320 --> 01:21:30,600
Now, this figure,

1648
01:21:30,600 --> 01:21:32,600
based on the work
of Bailey and colleagues,

1649
01:21:32,600 --> 01:21:35,280
illustrates the potential
complexity of mechanisms

1650
01:21:35,280 --> 01:21:39,080
leading to inequities
in AD/ADRD.

1651
01:21:39,080 --> 01:21:42,400
You can see multiple and
nested mechanistic domains

1652
01:21:42,400 --> 01:21:46,920
represented here, from policy
structures to phenotype.

1653
01:21:46,920 --> 01:21:49,400
And these are all
implicitly embedded

1654
01:21:49,400 --> 01:21:51,800
in various dimensions
of time.

1655
01:21:51,800 --> 01:21:54,720
Next.

1656
01:21:54,720 --> 01:21:57,400
The studies of the mechanisms
of and pathways

1657
01:21:57,400 --> 01:22:01,560
to AD/ADRD inequities
might also examine the extent

1658
01:22:01,560 --> 01:22:05,920
to which excess risk
in AD/ADRD is intersectional,

1659
01:22:05,920 --> 01:22:08,520
for example,
involving combinations of race

1660
01:22:08,520 --> 01:22:11,360
and gender or race
and education.

1661
01:22:11,360 --> 01:22:13,920
This is another line of evidence
that can be generated

1662
01:22:13,920 --> 01:22:18,960
with sufficiency large
or oversampled populations.

1663
01:22:18,960 --> 01:22:21,000
And to the point
of this research,

1664
01:22:21,000 --> 01:22:25,760
we encourage researchers to work
toward translating discoveries

1665
01:22:25,760 --> 01:22:28,520
in this domain
to the underrepresented groups

1666
01:22:28,520 --> 01:22:31,960
and/or regions
from which they are drawn.

1667
01:22:31,960 --> 01:22:35,960
And finally, age-related
disorders, such a AD/ADRD,

1668
01:22:35,960 --> 01:22:38,120
disproportionately affect
those among us

1669
01:22:38,120 --> 01:22:39,440
who may be marginalized,

1670
01:22:39,440 --> 01:22:42,360
stigmatized
and underrepresented.

1671
01:22:42,360 --> 01:22:45,600
So clearly, these disorders
are not agnostic

1672
01:22:45,600 --> 01:22:48,280
to the structures
and cascades of inequity.

1673
01:22:48,280 --> 01:22:51,080
And as long as inequities exist
in our societies,

1674
01:22:51,080 --> 01:22:54,680
it is imperative for researchers
to document them,

1675
01:22:54,680 --> 01:22:58,920
identify the determinants
and strive to resolve them.

1676
01:22:58,920 --> 01:23:00,320
And thank you so much.

1677
01:23:00,320 --> 01:23:03,480
I turn over the platform
to Dr. Zissimopoulos.

1678
01:23:05,800 --> 01:23:06,640
-Oh, thank you so much.

1679
01:23:06,640 --> 01:23:07,840
Thank you to our speakers

1680
01:23:07,840 --> 01:23:09,600
for your excellent
presentations.

1681
01:23:09,600 --> 01:23:10,920
My name is Julie Zissimopoulos.

1682
01:23:10,920 --> 01:23:13,560
I serve as cochair
with Dr. Hector González

1683
01:23:13,560 --> 01:23:15,720
over the Health Equity
in Alzheimer's Disease

1684
01:23:15,720 --> 01:23:18,240
and Alzheimer's Diseased-Related
Dementias Working Group.

1685
01:23:18,240 --> 01:23:21,160
It is my privilege to briefly
summarize

1686
01:23:21,160 --> 01:23:23,000
the recommendations
of the working group

1687
01:23:23,000 --> 01:23:25,760
and present
our priority order.

1688
01:23:25,760 --> 01:23:28,440
Next slide, please.

1689
01:23:28,440 --> 01:23:31,200
The views do not reflect
the official policy of NINDS

1690
01:23:31,200 --> 01:23:32,440
or NIH.

1691
01:23:32,440 --> 01:23:34,120
I receive funding from the NIA

1692
01:23:34,120 --> 01:23:36,960
and no other relevant financial
relationship disclosed.

1693
01:23:36,960 --> 01:23:39,840
Next slide, please.

1694
01:23:39,840 --> 01:23:41,480
In driving final
recommendations,

1695
01:23:41,480 --> 01:23:44,200
we built from prior year
recommendations,

1696
01:23:44,200 --> 01:23:46,920
insights from research
and patient care

1697
01:23:46,920 --> 01:23:48,920
and a framework
for achieving health equity

1698
01:23:48,920 --> 01:23:50,800
that considers life
course health,

1699
01:23:50,800 --> 01:23:54,840
socioeconomic historical policy
and place-based factors,

1700
01:23:54,840 --> 01:23:57,440
that may act as barriers
to or opportunities

1701
01:23:57,440 --> 01:24:00,320
for achieving health equity.

1702
01:24:00,320 --> 01:24:03,760
We identified four focus areas
with distinctive significance

1703
01:24:03,760 --> 01:24:06,000
for health equity
in Alzheimer's Disease

1704
01:24:06,000 --> 01:24:08,800
and Related Dementias
through research, workforce,

1705
01:24:08,800 --> 01:24:12,400
data and assessment,
epidemiology and diagnosis,

1706
01:24:12,400 --> 01:24:14,200
treatment and care.

1707
01:24:14,200 --> 01:24:16,000
You just heard two
recommendations

1708
01:24:16,000 --> 01:24:18,840
aligned with each focus area
from our experts

1709
01:24:18,840 --> 01:24:21,000
from the Health Equity
Working Group.

1710
01:24:21,000 --> 01:24:22,720
I will now present
our prioritization

1711
01:24:22,720 --> 01:24:26,640
of these recommendations
in a summarized form.

1712
01:24:26,640 --> 01:24:28,320
Our priority one recommendation

1713
01:24:28,320 --> 01:24:30,400
is establish
the high importance of actions

1714
01:24:30,400 --> 01:24:33,120
that increase participation
of underrepresented groups

1715
01:24:33,120 --> 01:24:34,840
in clinical trials.

1716
01:24:34,840 --> 01:24:37,120
We also addressed
the significance of a diverse

1717
01:24:37,120 --> 01:24:39,840
workforce for building knowledge
and capability

1718
01:24:39,840 --> 01:24:43,280
to achieve our goal
of health equity.

1719
01:24:43,280 --> 01:24:46,280
Our priority two recommendations
emphasize educating

1720
01:24:46,280 --> 01:24:49,200
and retooling scientists
across the biomedical,

1721
01:24:49,200 --> 01:24:51,400
behavioral
and social science fields,

1722
01:24:51,400 --> 01:24:54,600
for achieving excellence
in health equity research.

1723
01:24:54,600 --> 01:24:57,200
We also recommend new research
into impediments

1724
01:24:57,200 --> 01:25:00,520
to equitable assessments,
diagnosis and referrals,

1725
01:25:00,520 --> 01:25:03,000
as well as the health
and economic consequences

1726
01:25:03,000 --> 01:25:07,000
of inequities in accurate
and timely diagnoses.

1727
01:25:07,000 --> 01:25:08,920
Our priority three
recommendations address

1728
01:25:08,920 --> 01:25:11,600
the need for biomarkers,
assessment tools and methods

1729
01:25:11,600 --> 01:25:14,440
that are applicable to different
racial and ethnic groups

1730
01:25:14,440 --> 01:25:16,640
and how improvements
to them provide opportunities

1731
01:25:16,640 --> 01:25:20,000
for advancing equitable
scientific research.

1732
01:25:20,000 --> 01:25:22,480
Similarly, a second priority
three recommends

1733
01:25:22,480 --> 01:25:24,000
complementing the existing

1734
01:25:24,000 --> 01:25:28,200
but limited surveillance methods
for assessing inequities

1735
01:25:28,200 --> 01:25:30,680
with novel ones
to inform risk reduction,

1736
01:25:30,680 --> 01:25:33,800
prevention and treatment
strategies.

1737
01:25:33,800 --> 01:25:36,520
And finally, our priority
four recommendations focus

1738
01:25:36,520 --> 01:25:39,080
on how inequities occur.

1739
01:25:39,080 --> 01:25:41,800
They propose establishing
conceptual models

1740
01:25:41,800 --> 01:25:45,400
for identifying the health,
socioeconomic historical policy

1741
01:25:45,400 --> 01:25:47,160
in place-based mechanisms

1742
01:25:47,160 --> 01:25:51,520
that are producing inequities
and also in risk

1743
01:25:51,520 --> 01:25:53,960
and also the inequities
in the cost of disease

1744
01:25:53,960 --> 01:25:57,760
and access to care and
social services and treatment.

1745
01:25:57,760 --> 01:25:59,240
They recommend new data

1746
01:25:59,240 --> 01:26:01,480
and improved methods
for quantifying inequities

1747
01:26:01,480 --> 01:26:05,560
and the consequences
of those inequities.

1748
01:26:05,560 --> 01:26:08,400
Before turning to the open
microphone discussion,

1749
01:26:08,400 --> 01:26:11,800
and on behalf of
Dr. Hector González and myself,

1750
01:26:11,800 --> 01:26:14,480
I want to thank
the summit organizers,

1751
01:26:14,480 --> 01:26:17,320
our speakers and all
the working group members

1752
01:26:17,320 --> 01:26:20,560
and the participants here today.

1753
01:26:20,560 --> 01:26:22,680
Now, I invite all Health Equity
Working Group

1754
01:26:22,680 --> 01:26:25,000
panelists to turn
on their cameras

1755
01:26:25,000 --> 01:26:28,440
for the open
microphone discussion.

1756
01:26:28,440 --> 01:26:32,200
Dr. Hector González will
invite participants by name,

1757
01:26:32,200 --> 01:26:35,320
and in the order
that we receive the question,

1758
01:26:35,320 --> 01:26:39,760
to turn on their cameras and
verbally ask their questions.

1759
01:26:39,760 --> 01:26:42,080
Following this, panelists
may indicate their interest

1760
01:26:42,080 --> 01:26:44,520
in responding via the chat
or verbally,

1761
01:26:44,520 --> 01:26:48,360
and Dr. González
will invite you to respond.

1762
01:26:48,360 --> 01:26:52,440
Dr. González, I turn the session
back over to you.

1763
01:26:52,440 --> 01:26:54,800
-Dr. Zissimopoulos,
thank you very much.

1764
01:26:54,800 --> 01:26:58,840
And now we go to the open
mic session,

1765
01:26:58,840 --> 01:27:02,720
and I invite all the panelists
to be on screen

1766
01:27:02,720 --> 01:27:06,200
as we field
these questions.

1767
01:27:06,200 --> 01:27:08,560
We have several in the Q and A,

1768
01:27:08,560 --> 01:27:12,200
and I believe one person
has been invited to speak

1769
01:27:12,200 --> 01:27:15,600
or present
his question verbally.

1770
01:27:15,600 --> 01:27:17,600
And so that might be
the best opportunity

1771
01:27:17,600 --> 01:27:20,280
to go to start there.

1772
01:27:20,280 --> 01:27:22,400
If not, I'll go ahead and read
some questions

1773
01:27:22,400 --> 01:27:26,560
here in the question
and answer chat box.

1774
01:27:26,560 --> 01:27:28,320
-Hi, Doctor.

1775
01:27:28,320 --> 01:27:30,200
Dr. Ellenbogen is ready, so
let's go ahead and move to him.

1776
01:27:30,200 --> 01:27:31,800
-Very good. Thank you.

1777
01:27:35,680 --> 01:27:37,320
-Go ahead, Michael.

1778
01:27:37,320 --> 01:27:41,240
-[Audio drop]

1779
01:27:41,240 --> 01:27:43,960
-Yeah, regrettably, there's
some audio problems.

1780
01:27:43,960 --> 01:27:46,760
-[Audio drop]

1781
01:27:46,760 --> 01:27:48,120
-Yeah.

1782
01:27:48,120 --> 01:27:50,200
-Yeah, Michael,
we're going mute you,

1783
01:27:50,200 --> 01:27:52,400
and you need to toggle
your microphone.

1784
01:27:52,400 --> 01:27:54,080
And we're going to go
ahead do Charlie

1785
01:27:54,080 --> 01:27:56,000
while you get it sorted out,
and we'll come back to you.

1786
01:27:56,000 --> 01:27:57,880
Dr. DeCarli, are you available?

1787
01:27:57,880 --> 01:28:01,480
-Yes.
Can you hear me well enough?

1788
01:28:01,480 --> 01:28:05,080
-Yeah, of course, Charlie.
Thank you.

1789
01:28:05,080 --> 01:28:08,040
-I want to start by saying,
I'm a little bit more optimistic

1790
01:28:08,040 --> 01:28:10,320
about how much work
has been done.

1791
01:28:10,320 --> 01:28:12,800
At the level of
the epidemiology,

1792
01:28:12,800 --> 01:28:14,840
I think that there are members
of this panel

1793
01:28:14,840 --> 01:28:21,600
and others who have been leading
incredibly important studies

1794
01:28:21,600 --> 01:28:23,800
on diverse populations

1795
01:28:23,800 --> 01:28:27,600
and that have resulted
in some really unique findings.

1796
01:28:27,600 --> 01:28:30,920
My question for the group is,

1797
01:28:30,920 --> 01:28:35,040
how do we take those
epidemiological studies

1798
01:28:35,040 --> 01:28:36,640
and dive deeper,

1799
01:28:36,640 --> 01:28:42,000
as we have done with
our European white individuals,

1800
01:28:42,000 --> 01:28:47,200
to really look at these
important mechanisms

1801
01:28:47,200 --> 01:28:52,400
that may differ by life
experience and cultural effects

1802
01:28:52,400 --> 01:28:56,400
and possibly
some minor genetic effects?

1803
01:28:56,400 --> 01:28:58,440
I think about our own ADRC,

1804
01:28:58,440 --> 01:29:04,120
in which we have three different
groups that we look at,

1805
01:29:04,120 --> 01:29:05,560
but that's not enough.

1806
01:29:05,560 --> 01:29:07,120
You know, we're missing
other groups,

1807
01:29:07,120 --> 01:29:10,360
and we need to take the tools
that have been developed

1808
01:29:10,360 --> 01:29:17,120
in the European studies
through core resources

1809
01:29:17,120 --> 01:29:21,200
and extend them
to our diverse communities

1810
01:29:21,200 --> 01:29:25,600
to really start
to understand mechanistic --

1811
01:29:25,600 --> 01:29:29,800
mechanisms of dementia,
and I just would like the panel

1812
01:29:29,800 --> 01:29:34,760
to speak to how they feel
about that digging deeper

1813
01:29:34,760 --> 01:29:40,520
and getting into, you know,
the mechanistic approaches.

1814
01:29:43,600 --> 01:29:45,120
-Thank you, Dr. DeCarli.

1815
01:29:45,120 --> 01:29:48,000
We great appreciate
your question.

1816
01:29:48,000 --> 01:29:54,200
I think I will go ahead
and pass this over

1817
01:29:54,200 --> 01:29:57,360
to Dr. Khachaturian,
who has his hand raised,

1818
01:29:57,360 --> 01:29:59,520
and I believe
wants to field the...

1819
01:29:59,520 --> 01:30:01,960
No, Jennifer.

1820
01:30:04,640 --> 01:30:07,000
-I'll start out here.

1821
01:30:07,000 --> 01:30:10,240
I think, Charlie, you touch
on this aspect

1822
01:30:10,240 --> 01:30:14,560
of the richness and
informativeness of experiences

1823
01:30:14,560 --> 01:30:19,960
that we're missing out
when we aim for cohorts to be

1824
01:30:19,960 --> 01:30:24,240
proportionately representative
of the US population.

1825
01:30:24,240 --> 01:30:27,320
So we miss out on the experience

1826
01:30:27,320 --> 01:30:30,160
of traditionally
underrepresented groups,

1827
01:30:30,160 --> 01:30:34,400
and so I think that is
one of many justifications

1828
01:30:34,400 --> 01:30:36,440
for developing cohorts

1829
01:30:36,440 --> 01:30:42,040
that are composed completely of
groups from specific communities

1830
01:30:42,040 --> 01:30:44,520
that have traditionally
not been represented,

1831
01:30:44,520 --> 01:30:46,360
and that gives us
an opportunity

1832
01:30:46,360 --> 01:30:49,160
to look at the range
of those experiences

1833
01:30:49,160 --> 01:30:50,600
that you were mentioning,

1834
01:30:50,600 --> 01:30:52,800
and I know there's some people
on the panel here

1835
01:30:52,800 --> 01:30:55,400
who, in fact,
are the PIs of such cohorts.

1836
01:30:55,400 --> 01:30:58,840
So that would be one start
into that,

1837
01:30:58,840 --> 01:31:02,680
but I certainly open up
the panel or open up the floor

1838
01:31:02,680 --> 01:31:05,840
to others who have suggestions
and thoughts on this.

1839
01:31:08,400 --> 01:31:10,040
-Yeah. Dr. Weuve I think

1840
01:31:10,040 --> 01:31:14,000
that's something we have been
stressing in this shift

1841
01:31:14,000 --> 01:31:16,200
from health disparities

1842
01:31:16,200 --> 01:31:19,440
to a focus more
on health equities

1843
01:31:19,440 --> 01:31:23,960
and to achieve
such lofty goals,

1844
01:31:23,960 --> 01:31:28,040
I think as you mentioned,
looking within the life

1845
01:31:28,040 --> 01:31:33,920
course of individual
ethnic racial groups

1846
01:31:33,920 --> 01:31:36,600
may be preferred,
if not desirable

1847
01:31:36,600 --> 01:31:39,720
and underscoring
this notion of life course

1848
01:31:39,720 --> 01:31:43,360
and the midlife perspective
in particular

1849
01:31:43,360 --> 01:31:44,600
that seems to be so rich

1850
01:31:44,600 --> 01:31:47,600
in terms of finding
new opportunities

1851
01:31:47,600 --> 01:31:53,280
or risks and resilience
factors for healthy

1852
01:31:53,280 --> 01:31:57,000
or unhealthy
cognitive aging.

1853
01:31:57,000 --> 01:31:59,040
And so perspective
cohort studies,

1854
01:31:59,040 --> 01:32:01,120
beginning earlier in life,

1855
01:32:01,120 --> 01:32:06,200
certainly are of high interest
and seem to be addressing

1856
01:32:06,200 --> 01:32:12,840
what you are suggesting
here in your question.

1857
01:32:12,840 --> 01:32:14,240
-No, I'm going to interrupt.

1858
01:32:14,240 --> 01:32:15,800
I apologize, I'm going to
push back a little.

1859
01:32:15,800 --> 01:32:17,080
-Sure.

1860
01:32:17,080 --> 01:32:20,080
-When I'm talking about
are studies

1861
01:32:20,080 --> 01:32:22,880
where we can follow
these individuals

1862
01:32:22,880 --> 01:32:29,600
and get in depth, biologically
meaningful information,

1863
01:32:29,600 --> 01:32:31,680
that extend beyond...

1864
01:32:31,680 --> 01:32:36,000
the epidemiological studies
are very important,

1865
01:32:36,000 --> 01:32:39,120
critically important
to get perspective.

1866
01:32:39,120 --> 01:32:41,840
But then we need to dig down,
and that includes,

1867
01:32:41,840 --> 01:32:44,600
I mean,
missing from this are --

1868
01:32:44,600 --> 01:32:48,800
has been alluded
to serum plasma,

1869
01:32:48,800 --> 01:32:53,360
CSF biomarkers,
neuropathological materials.

1870
01:32:53,360 --> 01:32:55,960
When you look at
what's out there

1871
01:32:55,960 --> 01:32:59,680
in terms of
neuropathological materials,

1872
01:32:59,680 --> 01:33:01,240
it's very limited,

1873
01:33:01,240 --> 01:33:04,160
and I believe we need to be
moving in that direction,

1874
01:33:04,160 --> 01:33:06,280
just as we've done
in other populations,

1875
01:33:06,280 --> 01:33:09,200
with European
population.

1876
01:33:09,200 --> 01:33:12,800
That's where discovery
occurs, in mechanisms.

1877
01:33:16,200 --> 01:33:17,560
-I think we have
several panelists

1878
01:33:17,560 --> 01:33:20,120
that are also
wishing to respond.

1879
01:33:20,120 --> 01:33:21,640
So...

1880
01:33:21,640 --> 01:33:23,080
-Yeah, can I jump in, Hector,
just to quickly...

1881
01:33:23,080 --> 01:33:24,600
-Yeah, sure, Lisa, please,
Dr. Barnes.

1882
01:33:24,600 --> 01:33:27,960
-Charlie, I think you answered
your own question.

1883
01:33:27,960 --> 01:33:33,280
I do believe we need to move
beyond descriptive epidemiology

1884
01:33:33,280 --> 01:33:37,600
with these minoritized
populations and understand

1885
01:33:37,600 --> 01:33:43,600
some of the barriers to getting
more of the more invasive data,

1886
01:33:43,600 --> 01:33:48,080
you know, like the pathology
data, biomarker data.

1887
01:33:48,080 --> 01:33:50,480
As you know, we at Rush work
very hard

1888
01:33:50,480 --> 01:33:54,120
to get brains
from minoritized populations

1889
01:33:54,120 --> 01:33:58,440
and it takes decades of effort
and relationship building,

1890
01:33:58,440 --> 01:34:01,400
but that is how
we are going to discover

1891
01:34:01,400 --> 01:34:07,240
these underlying mechanisms that
are leading to the disparities,

1892
01:34:07,240 --> 01:34:09,360
but also something
that you said,

1893
01:34:09,360 --> 01:34:12,080
I don't think we should
just take what we've learned

1894
01:34:12,080 --> 01:34:15,200
from the white
homogeneous samples.

1895
01:34:15,200 --> 01:34:18,280
I think we have to work
to understand

1896
01:34:18,280 --> 01:34:22,640
the unique race
or ethnic relevant factors

1897
01:34:22,640 --> 01:34:24,480
in the populations
that we're studying.

1898
01:34:24,480 --> 01:34:25,920
And you cannot get that

1899
01:34:25,920 --> 01:34:27,760
unless you have people
enrolled in the study,

1900
01:34:27,760 --> 01:34:30,720
you build relationships,
and you work to educate them

1901
01:34:30,720 --> 01:34:33,640
on why these types of data
are needed.

1902
01:34:33,640 --> 01:34:37,240
So thank you for that question.

1903
01:34:37,240 --> 01:34:41,480
-Okay, so now we invite
any other speaker to --

1904
01:34:41,480 --> 01:34:44,880
or person with a question
to step up.

1905
01:34:47,160 --> 01:34:49,040
-Well, Sid and Toni,
do you guys want to answer

1906
01:34:49,040 --> 01:34:53,080
that one or can we move on?
-Yes.

1907
01:34:53,080 --> 01:34:55,240
I'd just like to say
a couple of things

1908
01:34:55,240 --> 01:34:58,840
to reiterate
what Dr. Barnes has said,

1909
01:34:58,840 --> 01:35:01,560
and a little bit about
what our group reported on.

1910
01:35:01,560 --> 01:35:06,000
When we said we need to address
issues from neurons

1911
01:35:06,000 --> 01:35:08,600
to neighborhoods,
and that's what we need.

1912
01:35:08,600 --> 01:35:10,640
I mean, it's not
a one-size-fits-all.

1913
01:35:10,640 --> 01:35:13,240
It's not a one approach
fits all.

1914
01:35:13,240 --> 01:35:21,000
It's we need a combination
of multiple perspectives,

1915
01:35:21,000 --> 01:35:23,400
and we need to go wide and deep.

1916
01:35:23,400 --> 01:35:26,800
So we need a within
and a between approach.

1917
01:35:26,800 --> 01:35:31,000
We need life course
cumulative studies.

1918
01:35:31,000 --> 01:35:33,960
We need an accumulation
across studies

1919
01:35:33,960 --> 01:35:40,400
that have perhaps
been more width than breadth.

1920
01:35:40,400 --> 01:35:44,560
So I just want to say
that we need multiple methods.

1921
01:35:44,560 --> 01:35:46,000
We need multiple approaches.

1922
01:35:46,000 --> 01:35:49,240
We need multiple samples,
and we need to understand

1923
01:35:49,240 --> 01:35:54,320
that good science will help us
across a variety of approaches.

1924
01:35:54,320 --> 01:35:56,800
And I think these are words
people will understand.

1925
01:35:56,800 --> 01:35:58,200
I just want to bring it forward

1926
01:35:58,200 --> 01:36:01,240
in addressing the question
that was raised.

1927
01:36:01,240 --> 01:36:02,920
-Thank you, Dr. Antonucci.

1928
01:36:02,920 --> 01:36:08,200
Next up, I'd like to invite
Mr. Dr. Michael Ellenbogen

1929
01:36:08,200 --> 01:36:13,200
to ask --
try his question again, please.

1930
01:36:13,200 --> 01:36:14,960
-Can you hear me?

1931
01:36:14,960 --> 01:36:16,400
-Quite well, thank you.

1932
01:36:16,400 --> 01:36:18,320
-Great, thank you so much.

1933
01:36:18,320 --> 01:36:19,880
First, let me correct you.

1934
01:36:19,880 --> 01:36:22,520
I appreciate being upgraded,
but I'm not a doctor.

1935
01:36:22,520 --> 01:36:26,080
I'm just a patient
living with dementia.

1936
01:36:26,080 --> 01:36:29,080
I would like to thank you all
for what you have done.

1937
01:36:29,080 --> 01:36:32,600
I've been a part of these
summits for many years,

1938
01:36:32,600 --> 01:36:35,880
and every time
I am at one of these,

1939
01:36:35,880 --> 01:36:38,640
you folks always take
my recommendations

1940
01:36:38,640 --> 01:36:40,200
and follow through with them.

1941
01:36:40,200 --> 01:36:43,840
So I thank you so much
for making all this happen.

1942
01:36:43,840 --> 01:36:47,760
I'd like to speak though,
in reference to the health

1943
01:36:47,760 --> 01:36:50,520
equity for people with dementia.

1944
01:36:50,520 --> 01:36:53,520
And I think that is a very
important subject

1945
01:36:53,520 --> 01:36:58,200
because there are
so many places out there,

1946
01:36:58,200 --> 01:37:01,520
like the University
of Pennsylvania,

1947
01:37:01,520 --> 01:37:09,360
who you folks tend to fund
for various clinical trials.

1948
01:37:09,360 --> 01:37:13,040
But some of the problems
we have is, places like that,

1949
01:37:13,040 --> 01:37:17,560
believe it or not, charge money
to get into the clinical trial.

1950
01:37:17,560 --> 01:37:20,920
Most clinical trials you do not
have to pay money for.

1951
01:37:20,920 --> 01:37:25,800
So I think NIH and NIA
needs to find a way

1952
01:37:25,800 --> 01:37:27,880
that when you ask

1953
01:37:27,880 --> 01:37:33,320
for these folks
to do clinical trials for you,

1954
01:37:33,320 --> 01:37:36,200
that you put some kind of
stipulations to make it

1955
01:37:36,200 --> 01:37:38,280
so that it's going to be free.

1956
01:37:38,280 --> 01:37:42,840
Because if it's not, it's going
to hold up for getting people

1957
01:37:42,840 --> 01:37:46,880
who are Hispanics,
African Americans

1958
01:37:46,880 --> 01:37:49,000
to get into these
clinical trials.

1959
01:37:49,000 --> 01:37:51,960
University of Pennsylvania
happens to be

1960
01:37:51,960 --> 01:37:54,440
in a very big minority area,

1961
01:37:54,440 --> 01:37:57,640
yet if you look
at the amount of minorities

1962
01:37:57,640 --> 01:38:00,120
they have included
in their clinical trials,

1963
01:38:00,120 --> 01:38:02,680
you'll see they're not able
to get into them.

1964
01:38:02,680 --> 01:38:06,040
I try to get into it and I
wasn't able to get into it

1965
01:38:06,040 --> 01:38:07,360
because they wanted
to charge money.

1966
01:38:07,360 --> 01:38:10,000
So therefore, I went to
some other place,

1967
01:38:10,000 --> 01:38:11,800
and there's many places
to go to.

1968
01:38:11,800 --> 01:38:13,240
But most people don't have
the luxury

1969
01:38:13,240 --> 01:38:16,280
I have that they can drive
to further places.

1970
01:38:16,280 --> 01:38:18,600
So I would hope you folks
consider

1971
01:38:18,600 --> 01:38:21,000
how you address
this kind of situations

1972
01:38:21,000 --> 01:38:23,760
so more people of minorities
can get into clinical trials,

1973
01:38:23,760 --> 01:38:27,040
because to me, I think they're
the most important people to be

1974
01:38:27,040 --> 01:38:28,800
in the clinical trials.

1975
01:38:31,200 --> 01:38:34,160
-Mr. Ellenbogen, thank you
so much for your comments.

1976
01:38:34,160 --> 01:38:41,120
Greatly appreciate hearing
not PhD or MD's perspective,

1977
01:38:41,120 --> 01:38:43,680
but the patient perspective
of the patient's journey

1978
01:38:43,680 --> 01:38:47,480
through the clinical trials
experiences.

1979
01:38:47,480 --> 01:38:50,680
And you're absolutely right,
as you said at the beginning,

1980
01:38:50,680 --> 01:38:56,360
your recommendations now
that you just voiced will be

1981
01:38:56,360 --> 01:39:01,400
addressed in the final
recommendations that we make.

1982
01:39:01,400 --> 01:39:04,600
I don't have a particular
response for you,

1983
01:39:04,600 --> 01:39:06,440
but I want you
to rest assured

1984
01:39:06,440 --> 01:39:10,040
that we will address your
comment and your recommendation.

1985
01:39:10,040 --> 01:39:13,040
Thank you so much.

1986
01:39:13,040 --> 01:39:17,400
Moving right along, and again,
thank you for your question.

1987
01:39:17,400 --> 01:39:22,840
I believe
Ms. or Dr. Florence Johnson --

1988
01:39:22,840 --> 01:39:28,200
how's that? -- will take the
floor or the mic next please.

1989
01:39:28,200 --> 01:39:30,840
-Good morning, thank you all
for a great presentation.

1990
01:39:30,840 --> 01:39:33,120
I would like to say
to Mr. Ellenburg

1991
01:39:33,120 --> 01:39:36,800
that you're not just a patient
living with dementia.

1992
01:39:36,800 --> 01:39:38,600
You have a strong voice.

1993
01:39:38,600 --> 01:39:42,640
People living with dementia
are definitely teachers for us

1994
01:39:42,640 --> 01:39:45,280
and we need to listen
to your life experiences

1995
01:39:45,280 --> 01:39:49,040
as we continue
with our research.

1996
01:39:49,040 --> 01:39:50,960
I'm a second year student

1997
01:39:50,960 --> 01:39:53,960
in the University of Michigan
School of Nursing,

1998
01:39:53,960 --> 01:39:58,400
and I -- my focus of research
is on family caregivers.

1999
01:39:58,400 --> 01:40:00,560
I would just like some
historical background

2000
01:40:00,560 --> 01:40:06,040
on how we got to the term
Alzheimer's disease

2001
01:40:06,040 --> 01:40:08,200
and related dementias.

2002
01:40:10,320 --> 01:40:11,920
Thank you.

2003
01:40:15,200 --> 01:40:18,920
-I will turn this...

2004
01:40:18,920 --> 01:40:22,960
I don't see anybody volunteering
to respond to this question,

2005
01:40:22,960 --> 01:40:25,240
which I think would be --
so let me give it a shot

2006
01:40:25,240 --> 01:40:30,840
and I'll invite others
to step up and respond as well.

2007
01:40:30,840 --> 01:40:32,760
How did we come to this term,

2008
01:40:32,760 --> 01:40:35,200
Alzheimer's disease
and related dementias?

2009
01:40:35,200 --> 01:40:36,480
And that's an excellent question

2010
01:40:36,480 --> 01:40:38,600
as a second year
nursing student,

2011
01:40:38,600 --> 01:40:40,640
and I certainly wish
you the best

2012
01:40:40,640 --> 01:40:43,040
at one of the great institutions
in our country,

2013
01:40:43,040 --> 01:40:44,800
the University of Michigan.

2014
01:40:44,800 --> 01:40:46,520
Go blue.

2015
01:40:46,520 --> 01:40:48,760
Yes, we got thumbs up
from Dr. Antonucci too,

2016
01:40:48,760 --> 01:40:50,520
who's a Michigan person here.

2017
01:40:50,520 --> 01:40:56,680
So all that said, is that this
started with some seminal work

2018
01:40:56,680 --> 01:41:00,600
over 100 years ago about --
from pathology,

2019
01:41:00,600 --> 01:41:04,200
from a pathological study
by a man named Alzheimer's.

2020
01:41:04,200 --> 01:41:05,920
Now, I'm not going to go into
the full history

2021
01:41:05,920 --> 01:41:08,800
of Alzheimer's
and related dementias,

2022
01:41:08,800 --> 01:41:11,400
but since then we've come
to recognize

2023
01:41:11,400 --> 01:41:17,000
that dementia
has different etiologies.

2024
01:41:17,000 --> 01:41:20,040
Alzheimer's disease
is just one etiology,

2025
01:41:20,040 --> 01:41:21,680
and I think we need
to keep that in mind

2026
01:41:21,680 --> 01:41:24,200
as we look across the field.

2027
01:41:24,200 --> 01:41:27,440
There are other etiologies,
and in particular etiologies

2028
01:41:27,440 --> 01:41:31,600
that we think may impact
people of color

2029
01:41:31,600 --> 01:41:34,960
are vascular dementias
in particular.

2030
01:41:34,960 --> 01:41:37,080
You know, you're probably
learning right now

2031
01:41:37,080 --> 01:41:41,520
about the high rates
of hypertension, diabetes

2032
01:41:41,520 --> 01:41:43,600
and these other terrible,
chronic conditions

2033
01:41:43,600 --> 01:41:47,920
that so disproportionately
affect Latino,

2034
01:41:47,920 --> 01:41:51,800
Black, African American
and other populations.

2035
01:41:51,800 --> 01:41:53,640
We think these are
major contributors

2036
01:41:53,640 --> 01:41:56,600
to dementias among dementias,

2037
01:41:56,600 --> 01:41:59,200
now I'm saying because
we're going to be agnostic

2038
01:41:59,200 --> 01:42:05,440
in terms of the etiology,
dementias that may be drivers.

2039
01:42:05,440 --> 01:42:06,880
But we don't know.

2040
01:42:06,880 --> 01:42:09,600
We need the data,
as has been mentioned before,

2041
01:42:09,600 --> 01:42:13,080
as Dr. Barnes and others
have said we need the data,

2042
01:42:13,080 --> 01:42:16,600
we need to move forward
in gathering this data.

2043
01:42:16,600 --> 01:42:19,640
But we're kind of feeling
around in the dark,

2044
01:42:19,640 --> 01:42:23,080
and until we have the light
of new data, new research,

2045
01:42:23,080 --> 01:42:29,200
I think we will --
there's much work to be done.

2046
01:42:29,200 --> 01:42:32,000
I see there's other people
wishing to respond

2047
01:42:32,000 --> 01:42:34,960
and I'll start
with Dr. Peterson.

2048
01:42:34,960 --> 01:42:37,240
-Thanks very much, Hector.

2049
01:42:37,240 --> 01:42:40,480
I will take some responsibility
for this term,

2050
01:42:40,480 --> 01:42:44,960
going back to the beginning
of the advisory council

2051
01:42:44,960 --> 01:42:47,240
for the national plan.

2052
01:42:47,240 --> 01:42:51,320
And as was outlined initially,
earlier this morning,

2053
01:42:51,320 --> 01:42:54,400
the terminology focused
on Alzheimer's disease,

2054
01:42:54,400 --> 01:42:57,800
but clearly the law,
the NAPA activity,

2055
01:42:57,800 --> 01:42:59,600
wanted to include the other

2056
01:42:59,600 --> 01:43:01,880
major dementic disorders
as well.

2057
01:43:01,880 --> 01:43:04,600
And while it's imperfect,
this was the term

2058
01:43:04,600 --> 01:43:08,760
that was decided upon to capture
these related disorders.

2059
01:43:08,760 --> 01:43:11,160
Now there's a whole nomenclature
initiative

2060
01:43:11,160 --> 01:43:13,840
that has been part
of these summits in the past

2061
01:43:13,840 --> 01:43:15,800
that is addressing this topic.

2062
01:43:15,800 --> 01:43:19,480
But it is a bit confusing,
I will admit that,

2063
01:43:19,480 --> 01:43:22,960
because these disorders
may or may not be related

2064
01:43:22,960 --> 01:43:24,720
to Alzheimer's disease itself,

2065
01:43:24,720 --> 01:43:29,800
but it is sort of
a historical explanation.

2066
01:43:29,800 --> 01:43:31,400
-Thank you.

2067
01:43:31,400 --> 01:43:33,000
-Thank you, Dr. Peterson.

2068
01:43:33,000 --> 01:43:35,320
If you could lower
your hand now, please.

2069
01:43:35,320 --> 01:43:38,600
Next up, I'd like to invite
Dale Lestina,

2070
01:43:38,600 --> 01:43:41,960
and I'm not going to scribe
any titles or honorifics

2071
01:43:41,960 --> 01:43:43,320
to anybody here now,

2072
01:43:43,320 --> 01:43:47,440
just please,
Dale Lestina, if you would.

2073
01:43:47,440 --> 01:43:49,200
-With some apologies,
we're actually having trouble

2074
01:43:49,200 --> 01:43:51,080
getting Dale promoted up.

2075
01:43:51,080 --> 01:43:57,680
So the next one is Rene Anand,
I think you're with us here.

2076
01:43:57,680 --> 01:44:01,000
-Yeah, hi. Good afternoon.

2077
01:44:01,000 --> 01:44:05,600
Thank you, by the way
for this wonderful webinar.

2078
01:44:05,600 --> 01:44:07,600
My question related --
it's a three-part question.

2079
01:44:07,600 --> 01:44:09,960
It relates to how genetics,

2080
01:44:09,960 --> 01:44:12,400
environment and nutrition
interact

2081
01:44:12,400 --> 01:44:17,240
to actually get susceptibility
to clinical disease.

2082
01:44:17,240 --> 01:44:20,880
Just to disclose,
we make brain organoid models

2083
01:44:20,880 --> 01:44:22,200
of Alzheimer's disease,

2084
01:44:22,200 --> 01:44:24,320
so we are very advanced
in our studies

2085
01:44:24,320 --> 01:44:26,760
and they're very replicable.

2086
01:44:26,760 --> 01:44:31,040
What we find, and this is why
I was asking the question is,

2087
01:44:31,040 --> 01:44:35,440
orotic Alzheimer's
also genetic origin.

2088
01:44:35,440 --> 01:44:40,360
What I'm asking actually,
is all Alzheimer's genetic?

2089
01:44:40,360 --> 01:44:43,920
And we find, by making models
of sporadic

2090
01:44:43,920 --> 01:44:46,280
Alzheimer's versus
familiar Alzheimer's

2091
01:44:46,280 --> 01:44:49,560
that in fact there's
a convergent for data sets,

2092
01:44:49,560 --> 01:44:52,320
which leads us to believe --
our samples are small --

2093
01:44:52,320 --> 01:44:56,240
leads us to believe
that in fact the genetic risk

2094
01:44:56,240 --> 01:45:00,080
that exists at birth
for all Alzheimer's,

2095
01:45:00,080 --> 01:45:04,280
however the risk is not
necessarily clinical disease.

2096
01:45:04,280 --> 01:45:06,840
There's a gene
and environmental interactions

2097
01:45:06,840 --> 01:45:10,680
that occur throughout life,
somewhere along the way,

2098
01:45:10,680 --> 01:45:14,200
either at birth
or during childhood

2099
01:45:14,200 --> 01:45:17,200
to take that risk
into disease.

2100
01:45:17,200 --> 01:45:21,200
And the risk that we are finding
are environmental,

2101
01:45:21,200 --> 01:45:24,040
as well as nutritional.

2102
01:45:24,040 --> 01:45:26,120
And so I think it's a game
changer

2103
01:45:26,120 --> 01:45:28,400
in how we think
about Alzheimer's

2104
01:45:28,400 --> 01:45:32,880
because a lot of discussion
about health equity.

2105
01:45:32,880 --> 01:45:34,600
And I think we have the ability

2106
01:45:34,600 --> 01:45:37,000
to begin to answer
this question,

2107
01:45:37,000 --> 01:45:40,000
but however our sample size,
I must admit,

2108
01:45:40,000 --> 01:45:42,000
are rather small at this time.

2109
01:45:42,000 --> 01:45:48,000
So is there any other evidence
from the other types of studies

2110
01:45:48,000 --> 01:45:49,320
that leads us to believe

2111
01:45:49,320 --> 01:45:51,680
that what we are seeing
might be correct?

2112
01:45:56,160 --> 01:46:01,200
-For this one, I think I will
turn it over to Dr. Fornage.

2113
01:46:01,200 --> 01:46:02,800
I was thinking of you, Miriam,

2114
01:46:02,800 --> 01:46:05,600
when Dr. Anand presented
his question.

2115
01:46:05,600 --> 01:46:09,200
So I'll hand it over to you,
please, Dr. Fornage.

2116
01:46:09,200 --> 01:46:11,000
-Yes, so thank you
for the question.

2117
01:46:11,000 --> 01:46:14,720
So Alzheimer's disease,
the sporadic form

2118
01:46:14,720 --> 01:46:18,400
is indeed genetic,
but it's not fully genetic.

2119
01:46:18,400 --> 01:46:21,520
So it's a poster child for
multifactorial disease,

2120
01:46:21,520 --> 01:46:23,080
as you mentioned.

2121
01:46:23,080 --> 01:46:26,280
It is a combination of genes
and the environment.

2122
01:46:26,280 --> 01:46:31,200
And so as geneticists spend
a lot of time looking for genes,

2123
01:46:31,200 --> 01:46:35,720
and in fact, we have identified
quite a number of genetic loci

2124
01:46:35,720 --> 01:46:39,400
across the genome
in human studies,

2125
01:46:39,400 --> 01:46:42,600
including APOE
being the major risk factors --

2126
01:46:42,600 --> 01:46:44,280
genetic risk factor.

2127
01:46:44,280 --> 01:46:47,800
But others, we have probably
around 40 loci at the moment

2128
01:46:47,800 --> 01:46:49,480
for Alzheimer's disease,

2129
01:46:49,480 --> 01:46:53,560
and individually this loci don't
contribute much to the risk,

2130
01:46:53,560 --> 01:46:57,560
but collectively
they do quite a bit.

2131
01:46:57,560 --> 01:47:02,360
And as you mentioned, certainly
the environment is important.

2132
01:47:02,360 --> 01:47:09,360
And it's not -- we haven't done
very in depth studies

2133
01:47:09,360 --> 01:47:14,360
to look at this gene
environment interaction problem

2134
01:47:14,360 --> 01:47:16,440
because this is
a difficult problem

2135
01:47:16,440 --> 01:47:18,640
that requires very,
very large sample size

2136
01:47:18,640 --> 01:47:21,920
and good measures
of environment.

2137
01:47:21,920 --> 01:47:24,640
And so for that,

2138
01:47:24,640 --> 01:47:27,320
we still in the infancy
of these types of studies.

2139
01:47:27,320 --> 01:47:32,000
But as you mentioned, this is
a very critical area of focus

2140
01:47:32,000 --> 01:47:37,160
for us to understand
how genetic behaves

2141
01:47:37,160 --> 01:47:39,600
or the genetic risk
to Alzheimer's disease

2142
01:47:39,600 --> 01:47:41,640
and dementia is modified

2143
01:47:41,640 --> 01:47:45,400
by environment
and environment factors.

2144
01:47:45,400 --> 01:47:48,800
So thank you for the question,
I hope that answered it.

2145
01:47:48,800 --> 01:47:50,280
-Thank you, Dr. Fornage.

2146
01:47:50,280 --> 01:47:52,000
-Yeah, thank you, Myriam.
I just wanted to add --

2147
01:47:52,000 --> 01:47:56,320
I think poverty that leads
to the nutritional deficiencies

2148
01:47:56,320 --> 01:47:58,360
is in fact one of the drivers.

2149
01:47:58,360 --> 01:48:00,560
That's where I'm going
with the question.

2150
01:48:00,560 --> 01:48:04,080
And if it's not addressed,
it just shows up

2151
01:48:04,080 --> 01:48:05,960
much later in life

2152
01:48:05,960 --> 01:48:08,040
in ways that are much harder
to deal with.

2153
01:48:08,040 --> 01:48:09,640
But thank you all.

2154
01:48:11,800 --> 01:48:14,080
-Thank you very much,
Dr. Anand.

2155
01:48:14,080 --> 01:48:16,000
And I think Martine --

2156
01:48:16,000 --> 01:48:20,040
Martin had a response
or a question.

2157
01:48:20,040 --> 01:48:22,560
Or if it's a question,
I'd just like to follow up

2158
01:48:22,560 --> 01:48:24,800
with Dr. Fornage,
what she had to say.

2159
01:48:24,800 --> 01:48:29,240
And I am very curious
and interested

2160
01:48:29,240 --> 01:48:32,480
in some of the work
that's being done with organoids

2161
01:48:32,480 --> 01:48:36,240
and I think it holds
great promise for our science.

2162
01:48:36,240 --> 01:48:39,320
My understanding of the organoid
work that's been done

2163
01:48:39,320 --> 01:48:43,400
is we have a limited
spectrum of patients

2164
01:48:43,400 --> 01:48:48,120
from which organoids
have been derived.

2165
01:48:48,120 --> 01:48:50,160
And I think this is something
that Dr. Turoff

2166
01:48:50,160 --> 01:48:54,560
and his group had alluded to
is that truly we need to expand

2167
01:48:54,560 --> 01:48:59,080
that diversity of people
with dementias

2168
01:48:59,080 --> 01:49:04,800
to include people of different
ethnic racial heritages

2169
01:49:04,800 --> 01:49:08,760
so that we can understand
if there's any variability

2170
01:49:08,760 --> 01:49:12,360
between how those organoids
respond to,

2171
01:49:12,360 --> 01:49:17,520
whether it be shotgun approaches
for therapies or what have you.

2172
01:49:17,520 --> 01:49:22,920
So I just wanted to follow up
with that comment of my own.

2173
01:49:22,920 --> 01:49:24,840
Martin, you had your hand up?

2174
01:49:24,840 --> 01:49:26,960
-Hi, yes. Good morning.

2175
01:49:26,960 --> 01:49:29,080
I'm a program director at NIA,

2176
01:49:29,080 --> 01:49:32,000
but I just wanted
to follow up on a comment

2177
01:49:32,000 --> 01:49:35,720
on the importance
of really trying to understand

2178
01:49:35,720 --> 01:49:39,000
how the environment
also contributes

2179
01:49:39,000 --> 01:49:41,680
and interacts
with the genetics.

2180
01:49:41,680 --> 01:49:45,600
This is particularly important
for health equity research,

2181
01:49:45,600 --> 01:49:48,640
since most of our
minoritized operations

2182
01:49:48,640 --> 01:49:55,000
are often the ones that
are living in an environment

2183
01:49:55,000 --> 01:49:57,520
with the worse
environmental exposures.

2184
01:49:57,520 --> 01:50:00,840
And so I believe that there is
a lot of room

2185
01:50:00,840 --> 01:50:03,760
to do additional work
in this regard

2186
01:50:03,760 --> 01:50:05,080
and really understand it

2187
01:50:05,080 --> 01:50:10,280
and how we measure
environmental exposures,

2188
01:50:10,280 --> 01:50:15,960
how we assess the multiple
sources of exposures

2189
01:50:15,960 --> 01:50:17,640
over a life course

2190
01:50:17,640 --> 01:50:20,880
and how this relates to the
etiology of the disease overall.

2191
01:50:23,240 --> 01:50:26,240
-Thank you very much
for your insights.

2192
01:50:31,040 --> 01:50:37,640
Before we get to the next
question, Milan Fiala...

2193
01:50:41,160 --> 01:50:43,000
...you had your hand raised.

2194
01:50:43,000 --> 01:50:46,560
Well while we're waiting,

2195
01:50:46,560 --> 01:50:51,080
I'd like to invite
Patricia Heyn to the mic please.

2196
01:50:54,560 --> 01:50:56,720
-Thank you so much
for the opportunity.

2197
01:50:56,720 --> 01:50:58,400
This is such a great meeting

2198
01:50:58,400 --> 01:51:02,600
and I'm so excited
to see all the developments.

2199
01:51:02,600 --> 01:51:07,600
And I just made a suggestion to,
as we plan for the workforce

2200
01:51:07,600 --> 01:51:10,200
and for the diversity
and inclusion,

2201
01:51:10,200 --> 01:51:15,000
to also think in the support
of research, mentoring,

2202
01:51:15,000 --> 01:51:19,520
leadership training
through a life span perspective.

2203
01:51:19,520 --> 01:51:23,160
There's so much of work
now in the early career,

2204
01:51:23,160 --> 01:51:31,200
in the stages of the very early
development of your profession,

2205
01:51:31,200 --> 01:51:35,400
but we as professionals,
we also have a life span

2206
01:51:35,400 --> 01:51:38,920
in terms of the different phases
and the different needs.

2207
01:51:38,920 --> 01:51:41,680
And I think we also need
to start to think about

2208
01:51:41,680 --> 01:51:45,000
how we're going to be developing
our research and portfolio,

2209
01:51:45,000 --> 01:51:48,280
that we'll take that
into consideration for us

2210
01:51:48,280 --> 01:51:52,440
to avoid to be
age discriminating

2211
01:51:52,440 --> 01:51:56,240
or maybe career stage
is in discrimination

2212
01:51:56,240 --> 01:51:59,880
because we are not thinking
about this perspective

2213
01:51:59,880 --> 01:52:03,960
of career span development
or the different needs,

2214
01:52:03,960 --> 01:52:05,600
especially for researchers

2215
01:52:05,600 --> 01:52:10,600
that come from underserved
background or minority,

2216
01:52:10,600 --> 01:52:12,600
where they're already
going to be

2217
01:52:12,600 --> 01:52:15,000
in a position
of less privilege

2218
01:52:15,000 --> 01:52:17,960
when they're going to be
starting the development.

2219
01:52:17,960 --> 01:52:20,360
And that contribution
does not only come

2220
01:52:20,360 --> 01:52:24,520
by evaluating the number
of grants of other ones,

2221
01:52:24,520 --> 01:52:28,560
but is also diverse
in terms of the contribution

2222
01:52:28,560 --> 01:52:31,960
that professionals can bring to
their field in different sectors

2223
01:52:31,960 --> 01:52:37,840
that sometimes is not
by grant awards.

2224
01:52:37,840 --> 01:52:39,880
-Thank you for your comments.

2225
01:52:39,880 --> 01:52:46,520
I am going to turn this over
to either Dr. Gilsanz or Medina,

2226
01:52:46,520 --> 01:52:49,240
who may wish to respond.

2227
01:52:49,240 --> 01:52:51,560
But I think yours
is a recommendation

2228
01:52:51,560 --> 01:52:55,200
to enhance workforce
development,

2229
01:52:55,200 --> 01:52:59,480
not only for the new people
coming into the field,

2230
01:52:59,480 --> 01:53:03,840
maybe leaning
towards younger perhaps,

2231
01:53:03,840 --> 01:53:06,320
but also across the life span

2232
01:53:06,320 --> 01:53:11,720
and also to ensure that
workforce development continues

2233
01:53:11,720 --> 01:53:14,640
and is available
throughout the life course.

2234
01:53:14,640 --> 01:53:19,480
There are some efforts, but we
certainly will add the --

2235
01:53:19,480 --> 01:53:22,920
your recommendation or consider
your recommendation

2236
01:53:22,920 --> 01:53:24,400
as we develop --

2237
01:53:24,400 --> 01:53:26,440
as we finalize
our recommendations

2238
01:53:26,440 --> 01:53:29,240
shown here
on the screen right now.

2239
01:53:29,240 --> 01:53:31,520
So thank you very much
for your comments.

2240
01:53:33,680 --> 01:53:38,680
I see Milan Fiala has her hand
raised again,

2241
01:53:38,680 --> 01:53:43,480
would you please try
your mic this time, take two?

2242
01:53:49,240 --> 01:53:50,840
Yeah, you're still muted.

2243
01:53:53,880 --> 01:54:01,680
So, okay, go for it.

2244
01:54:01,680 --> 01:54:05,400
You just need
to unmute yourself.

2245
01:54:05,400 --> 01:54:08,200
-Okay, can you hear me now?

2246
01:54:08,200 --> 01:54:12,200
-Yes, I can.
Yes we can, I hope.

2247
01:54:12,200 --> 01:54:17,600
-This summit has been
about health equity

2248
01:54:17,600 --> 01:54:23,200
and ways to overcome this.

2249
01:54:23,200 --> 01:54:27,720
But on the other hand,
in cardiology the progress

2250
01:54:27,720 --> 01:54:32,720
has been made by identifying
the common factors

2251
01:54:32,720 --> 01:54:39,120
and then showing how each group
deviates from this norm.

2252
01:54:39,120 --> 01:54:45,560
And I think our basic research
in neuroimmunology shows

2253
01:54:45,560 --> 01:54:48,800
that there are common factors,

2254
01:54:48,800 --> 01:54:53,040
a common norm
that should be applied

2255
01:54:53,040 --> 01:54:57,600
and then identify
the diversity.

2256
01:54:57,600 --> 01:55:02,480
And the diversity lies
in the lifestyle

2257
01:55:02,480 --> 01:55:09,400
and especially in the diet,
because the most important thing

2258
01:55:09,400 --> 01:55:15,160
is to identify how the brain
is cleared of amyloid beta

2259
01:55:15,160 --> 01:55:16,960
and flushed with tau.

2260
01:55:16,960 --> 01:55:21,240
Those are the drivers
of the disease.

2261
01:55:21,240 --> 01:55:27,440
And we showed that
the immune system in the brain

2262
01:55:27,440 --> 01:55:35,840
is what the lymphatics are doing
elsewhere in the body

2263
01:55:35,840 --> 01:55:40,680
and there are lymphatic
connections in the brain,

2264
01:55:40,680 --> 01:55:45,720
to the meninges that help
the immune system

2265
01:55:45,720 --> 01:55:47,840
to clean the brain.

2266
01:55:47,840 --> 01:55:53,600
And the problem is that
the immune system does not have

2267
01:55:53,600 --> 01:55:58,360
the energy to do its job,
that's one problem.

2268
01:55:58,360 --> 01:56:05,000
And the other problem is that
the immune system is inhibited

2269
01:56:05,000 --> 01:56:10,360
by accumulation of amyloid
beta in the vessels.

2270
01:56:10,360 --> 01:56:15,840
And so, if we can push forward

2271
01:56:15,840 --> 01:56:19,840
this way of treating
the disease,

2272
01:56:19,840 --> 01:56:24,960
that we needs to have
the right carbohydrate --

2273
01:56:24,960 --> 01:56:27,160
complex carbohydrate,

2274
01:56:27,160 --> 01:56:32,480
and then we have
the right sources of fats,

2275
01:56:32,480 --> 01:56:38,840
energy,
which are plant-based energies,

2276
01:56:38,840 --> 01:56:41,440
then we can then identify

2277
01:56:41,440 --> 01:56:47,600
how each group
deviates from this norm

2278
01:56:47,600 --> 01:56:53,480
and advance changes in the diet
and the lifestyle

2279
01:56:53,480 --> 01:56:58,160
and this will help us
to be more effective.

2280
01:56:58,160 --> 01:57:05,240
As it is now, the diet is driven
by economic interests,

2281
01:57:05,240 --> 01:57:07,760
not by science.

2282
01:57:07,760 --> 01:57:10,800
Thank you.

2283
01:57:10,800 --> 01:57:12,600
-Thank you for your comments.

2284
01:57:15,720 --> 01:57:18,400
I think now we will turn
to the Q and A box.

2285
01:57:18,400 --> 01:57:19,960
How's our time?

2286
01:57:19,960 --> 01:57:22,440
-Hector, we actually managed
to get Dale Lestina,

2287
01:57:22,440 --> 01:57:24,240
so can we go to Dale?

2288
01:57:24,240 --> 01:57:25,960
-Oh, please, I'm sorry.
Thank you.

2289
01:57:25,960 --> 01:57:27,360
-Oh, no problem.

2290
01:57:27,360 --> 01:57:30,680
-Thank you very much.

2291
01:57:30,680 --> 01:57:38,680
I have a recommendation
based on being a caregiver.

2292
01:57:38,680 --> 01:57:40,000
One can --

2293
01:57:40,000 --> 01:57:43,680
there are some cancers
that are curable,

2294
01:57:43,680 --> 01:57:50,720
but Alzheimer's, that is not
curable, it just ends in death.

2295
01:57:50,720 --> 01:57:59,040
And as a former caregiver,
my wife has now passed on,

2296
01:57:59,040 --> 01:58:03,080
the role of a caregiver really,
during this process

2297
01:58:03,080 --> 01:58:08,200
is to keep the person
that they're care giving to

2298
01:58:08,200 --> 01:58:13,480
as calm and stress free
and comfortable as possible

2299
01:58:13,480 --> 01:58:18,400
during the time that they're
going through the journey.

2300
01:58:18,400 --> 01:58:24,120
What happens is that when --
at least in my case,

2301
01:58:24,120 --> 01:58:27,120
and I know it
in the support groups,

2302
01:58:27,120 --> 01:58:30,800
almost without exception

2303
01:58:30,800 --> 01:58:37,000
is that the neurologist
that treats this,

2304
01:58:37,000 --> 01:58:40,760
and that you go to first
in the process,

2305
01:58:40,760 --> 01:58:46,480
won't tell you it's terminal,
will give you a medicine,

2306
01:58:46,480 --> 01:58:49,840
and you do get a little better
for it for a while

2307
01:58:49,840 --> 01:58:51,400
and then it doesn't
work anymore.

2308
01:58:51,400 --> 01:58:55,680
Then you get another medicine,
same kind of result.

2309
01:58:55,680 --> 01:58:58,200
I think that to be four-square

2310
01:58:58,200 --> 01:59:04,160
and to tell the caregiver
offline if necessary...

2311
01:59:13,200 --> 01:59:15,880
-Mr. Lestina, we're firstly,

2312
01:59:15,880 --> 01:59:21,400
my condolences to you
for the loss of your wife.

2313
01:59:21,400 --> 01:59:25,640
But your audio visual
seems to have frozen,

2314
01:59:25,640 --> 01:59:29,240
so regrettably you're unable

2315
01:59:29,240 --> 01:59:33,360
to complete
your important thoughts.

2316
01:59:33,360 --> 01:59:35,560
Okay, I think we're going to
have to move on,

2317
01:59:35,560 --> 01:59:39,680
but certainly, I, again,
want to offer my condolences

2318
01:59:39,680 --> 01:59:42,080
on behalf of the panel.

2319
01:59:42,080 --> 01:59:46,480
And I think that your comments
as a caregiver are very valuable

2320
01:59:46,480 --> 01:59:51,640
and important to the panelists,
and I will certainly --

2321
01:59:51,640 --> 01:59:56,200
we will take note of your
comments about disclosure

2322
01:59:56,200 --> 02:00:00,200
and being open and candid
and transparent

2323
02:00:00,200 --> 02:00:02,360
with the caregivers

2324
02:00:02,360 --> 02:00:08,920
about a loved one's condition
and ultimate fate.

2325
02:00:08,920 --> 02:00:10,160
So thank you very much
for your comments.

2326
02:00:10,160 --> 02:00:12,320
-Well yes.

2327
02:00:12,320 --> 02:00:13,800
-Oh, there you are.

2328
02:00:13,800 --> 02:00:15,880
-I just --
I don't know what happened.

2329
02:00:15,880 --> 02:00:18,880
I didn't touch a thing.

2330
02:00:18,880 --> 02:00:22,600
-It was the gremlins again,
but please proceed.

2331
02:00:22,600 --> 02:00:29,000
-Okay, well this would be good
to know, right up front if --

2332
02:00:29,000 --> 02:00:32,520
that your wife or the person
that you're care giving

2333
02:00:32,520 --> 02:00:38,000
is not going to get better
and that what your role is

2334
02:00:38,000 --> 02:00:41,800
just to help him or her
along through the process

2335
02:00:41,800 --> 02:00:45,720
as stress free as possible,
didn't have that.

2336
02:00:45,720 --> 02:00:49,360
And for my view, that's a pretty
common thing,

2337
02:00:49,360 --> 02:00:52,720
if it's not pervasive
of the medical profession

2338
02:00:52,720 --> 02:00:56,760
not letting a person know where
in the world this is headed.

2339
02:00:56,760 --> 02:00:59,320
That is my recommendation.

2340
02:00:59,320 --> 02:01:01,240
-Yes, thanks again.

2341
02:01:01,240 --> 02:01:03,480
And this is what
the open mic is about,

2342
02:01:03,480 --> 02:01:06,120
to solicit your recommendations
as a caregiver,

2343
02:01:06,120 --> 02:01:10,080
and I'm very grateful to you
for sharing your experience

2344
02:01:10,080 --> 02:01:13,280
but also your recommendation
here in this open forum.

2345
02:01:13,280 --> 02:01:14,600
Thank you very much.

2346
02:01:14,600 --> 02:01:16,200
-You're welcome.

2347
02:01:16,200 --> 02:01:19,000
-You have been heard,
and you will be heard.

2348
02:01:19,000 --> 02:01:21,400
[ Chatter ]

2349
02:01:21,400 --> 02:01:22,680
-So we're going to extend

2350
02:01:22,680 --> 02:01:25,280
for about 4 more minutes
into the break,

2351
02:01:25,280 --> 02:01:28,920
but for everyone that's in line
to ask questions, apologies,

2352
02:01:28,920 --> 02:01:30,400
just like in the live
version of this,

2353
02:01:30,400 --> 02:01:32,520
we're not going to be able
to get to everyone.

2354
02:01:32,520 --> 02:01:35,840
We will open up the chat for
everyone during all the breaks.

2355
02:01:35,840 --> 02:01:37,000
If you want to ask
your questions

2356
02:01:37,000 --> 02:01:38,560
in a less formal way there,

2357
02:01:38,560 --> 02:01:40,600
the panelists may or may not
choose to interact there,

2358
02:01:40,600 --> 02:01:42,280
but again just like
in the live sessions,

2359
02:01:42,280 --> 02:01:43,760
we're not going to be able
to get to everyone.

2360
02:01:43,760 --> 02:01:45,280
So we're going to do our best.

2361
02:01:45,280 --> 02:01:47,320
The next questioner
is Diane Bovenkamp.

2362
02:01:47,320 --> 02:01:51,640
-Thank you, Keith.
Diane Bovenkamp.

2363
02:01:51,640 --> 02:01:54,280
-Yeah, so I'm with
BrightFocus Foundation.

2364
02:01:54,280 --> 02:01:56,960
We fund research for Alzheimer's
and related to dementia,

2365
02:01:56,960 --> 02:01:59,640
glaucoma
and macular degeneration.

2366
02:01:59,640 --> 02:02:01,680
So this has been a wonderful
session.

2367
02:02:01,680 --> 02:02:03,280
Thank you so much to everyone,

2368
02:02:03,280 --> 02:02:06,800
and I'm really excited
about all the recommendations.

2369
02:02:06,800 --> 02:02:08,960
So my question for the panel

2370
02:02:08,960 --> 02:02:12,880
is when considering
health equity and differences

2371
02:02:12,880 --> 02:02:15,360
of underrepresented
and minority communities,

2372
02:02:15,360 --> 02:02:17,600
how can we consider
the whole person,

2373
02:02:17,600 --> 02:02:21,680
not just the brain but perhaps
crossover mechanisms

2374
02:02:21,680 --> 02:02:24,200
with the retina and eye,
right, as well?

2375
02:02:24,200 --> 02:02:27,800
So have the committees here
considered

2376
02:02:27,800 --> 02:02:33,400
bringing in vision researchers,
maybe the National Eye Institute

2377
02:02:33,400 --> 02:02:38,680
when making future plans
for research or trial design,

2378
02:02:38,680 --> 02:02:43,840
perhaps collecting eyes
as well as brains at banks?

2379
02:02:43,840 --> 02:02:45,280
And so the context of that

2380
02:02:45,280 --> 02:02:46,760
is that there are
a lot of biomarkers,

2381
02:02:46,760 --> 02:02:51,160
a lot of genes they're finding
like ApoE, APBB2,

2382
02:02:51,160 --> 02:02:54,640
right that there are risk genes
in African Americans

2383
02:02:54,640 --> 02:02:56,600
different from Caucasians,

2384
02:02:56,600 --> 02:02:59,880
and in many cases
there could be inverse effects

2385
02:02:59,880 --> 02:03:05,480
that increase the risk
of vision versus ADRD,

2386
02:03:05,480 --> 02:03:08,800
and, you know,
also in light of many groups

2387
02:03:08,800 --> 02:03:12,040
using the eye to diagnose
dementia, as well, right?

2388
02:03:12,040 --> 02:03:14,240
So I guess my question is --

2389
02:03:14,240 --> 02:03:15,560
And the other thing
is so perhaps

2390
02:03:15,560 --> 02:03:17,400
there could be
unintended consequences

2391
02:03:17,400 --> 02:03:21,400
for future treatments
in differing groups,

2392
02:03:21,400 --> 02:03:22,640
and so you definitely need to go

2393
02:03:22,640 --> 02:03:25,400
the route of personalized
medicine, right?

2394
02:03:25,400 --> 02:03:28,800
So my question is just to,
you know,

2395
02:03:28,800 --> 02:03:30,480
ask the panel to comment that

2396
02:03:30,480 --> 02:03:33,960
and maybe have you considered,
you know, including vision

2397
02:03:33,960 --> 02:03:38,120
and maybe the NEI and eye
researchers in the plans?

2398
02:03:38,120 --> 02:03:43,400
-Thank you Ms. Bovenkamp,
or Dr. Bovenkamp.

2399
02:03:43,400 --> 02:03:45,680
Anyway, I'm going to turn
this over to Dr. O'Bryant,

2400
02:03:45,680 --> 02:03:48,480
who quickly responded
with a raised hand,

2401
02:03:48,480 --> 02:03:50,480
but before he does,
I do want to say

2402
02:03:50,480 --> 02:03:57,320
that our own ADRC is collecting
other nervous tissue,

2403
02:03:57,320 --> 02:03:59,520
in particular eye,

2404
02:03:59,520 --> 02:04:05,400
and so I think this is
a brilliant recommendation.

2405
02:04:05,400 --> 02:04:08,000
I think it's more of
a recommendation instead

2406
02:04:08,000 --> 02:04:09,320
of a question

2407
02:04:09,320 --> 02:04:13,240
but certainly to gather
additional tissue

2408
02:04:13,240 --> 02:04:17,360
that may be useful,
but first we got to get there.

2409
02:04:17,360 --> 02:04:20,120
I think that's something
that Dr. Barnes has alluded to

2410
02:04:20,120 --> 02:04:27,640
is we do not have the level
of autopsy enrollment

2411
02:04:27,640 --> 02:04:34,520
that is parallel or equal
to that among whites,

2412
02:04:34,520 --> 02:04:37,600
so I think this is something
that as a panel we need

2413
02:04:37,600 --> 02:04:41,360
to bring to the forefront
not only just additional tissue,

2414
02:04:41,360 --> 02:04:43,760
but just getting the tissue
in the first place

2415
02:04:43,760 --> 02:04:45,480
and engaging communities

2416
02:04:45,480 --> 02:04:49,160
to be willing to enroll
in autopsy studies.

2417
02:04:49,160 --> 02:04:51,040
That's a major challenge
facing us.

2418
02:04:51,040 --> 02:04:55,560
Dr. O'Bryant, sorry to steal
your time there, but you're up.

2419
02:04:55,560 --> 02:04:59,000
-That's a great point, Diane,
great question,

2420
02:04:59,000 --> 02:05:01,920
and it actually circles back
to one of our initial comments

2421
02:05:01,920 --> 02:05:05,280
by Charlie of this isn't...

2422
02:05:05,280 --> 02:05:07,200
The eye for example,

2423
02:05:07,200 --> 02:05:09,480
is a great way to get
into additional research

2424
02:05:09,480 --> 02:05:12,800
because there's research showing
different medical comorbidities

2425
02:05:12,800 --> 02:05:15,240
and so the diabetic neuropathy

2426
02:05:15,240 --> 02:05:17,080
may be more common
among certain groups

2427
02:05:17,080 --> 02:05:20,320
which may predispose
to cognitive dysfunction.

2428
02:05:20,320 --> 02:05:22,000
One way I like
to conceptualize this

2429
02:05:22,000 --> 02:05:25,040
and think about
is as scientists,

2430
02:05:25,040 --> 02:05:29,720
we really bear the responsible
of increasing access

2431
02:05:29,720 --> 02:05:32,440
to research methods too.

2432
02:05:32,440 --> 02:05:37,600
These advanced methods
of getting at pathology

2433
02:05:37,600 --> 02:05:40,360
all within
a sociocultural context

2434
02:05:40,360 --> 02:05:42,400
is something that has not
been done enough,

2435
02:05:42,400 --> 02:05:44,960
and so we must increase access

2436
02:05:44,960 --> 02:05:46,720
to these cutting-edge
technologies

2437
02:05:46,720 --> 02:05:48,480
that have been used in research

2438
02:05:48,480 --> 02:05:50,200
among non-Hispanic
white populations

2439
02:05:50,200 --> 02:05:52,080
since they've been invented,

2440
02:05:52,080 --> 02:05:57,840
and so the breadth
of the examinations and methods

2441
02:05:57,840 --> 02:05:59,360
that we do
in diverse communities

2442
02:05:59,360 --> 02:06:01,760
really has to mirror
that among...

2443
02:06:01,760 --> 02:06:03,400
That we've done among
non-Hispanic whites,

2444
02:06:03,400 --> 02:06:06,120
and so I view that
as increasing access

2445
02:06:06,120 --> 02:06:08,720
even to the research
methods themselves

2446
02:06:08,720 --> 02:06:10,520
because we're going
to learn more.

2447
02:06:10,520 --> 02:06:13,440
And the research already coming
out among diverse populations

2448
02:06:13,440 --> 02:06:15,840
says that many
of these markers change,

2449
02:06:15,840 --> 02:06:17,800
so this is of incredible
importance,

2450
02:06:17,800 --> 02:06:20,240
and so it's a great comment.

2451
02:06:20,240 --> 02:06:22,960
-Dr. Khachaturian,
and thank you Dr. O'Bryant.

2452
02:06:22,960 --> 02:06:25,760
-I'll be brief, and thank you,
Diane, for the question.

2453
02:06:25,760 --> 02:06:27,440
I mean, and I really think

2454
02:06:27,440 --> 02:06:29,800
that this topic
around patient journey

2455
02:06:29,800 --> 02:06:32,600
and learning health systems
is going to be something

2456
02:06:32,600 --> 02:06:35,160
that we're really now
going to have to focus on,

2457
02:06:35,160 --> 02:06:38,800
I mean, certainly the decision
by FDA around aducanumab

2458
02:06:38,800 --> 02:06:41,440
certainly opened up
and laid bare

2459
02:06:41,440 --> 02:06:43,880
some of the regulatory issues
that we have to deal with

2460
02:06:43,880 --> 02:06:48,880
in terms of not just
efficacy decisions of drugs

2461
02:06:48,880 --> 02:06:51,880
but also the reimbursement side
of the equation, and I think,

2462
02:06:51,880 --> 02:06:54,360
you know, your concepts
and those of many others

2463
02:06:54,360 --> 02:06:56,920
looking at sort of
this more holistic question

2464
02:06:56,920 --> 02:06:58,640
is really going to have
to figure out

2465
02:06:58,640 --> 02:07:00,280
how we're actually going to pay
for these things

2466
02:07:00,280 --> 02:07:02,400
and how are we going to help
the general practitioners,

2467
02:07:02,400 --> 02:07:07,440
the primary care physicians
be able to manage patients

2468
02:07:07,440 --> 02:07:09,000
particularly from these
underserved

2469
02:07:09,000 --> 02:07:12,360
and underrepresented communities
more holistically.

2470
02:07:12,360 --> 02:07:14,040
And I think it's a great point,

2471
02:07:14,040 --> 02:07:18,000
and I think it's really going to
be sort of an exciting 2022

2472
02:07:18,000 --> 02:07:21,400
as we talk about that further.

2473
02:07:21,400 --> 02:07:23,800
-Thank you, Dr. Khachaturian,
and again thank you, Diane,

2474
02:07:23,800 --> 02:07:28,640
for your insightful
recommendation.

2475
02:07:28,640 --> 02:07:33,880
I think we had Dr. Whitfield --

2476
02:07:33,880 --> 02:07:39,000
as Whitaker has suggested,
we're going to go over 5 minutes

2477
02:07:39,000 --> 02:07:42,040
but now I see
we've gone over 7 minutes.

2478
02:07:42,040 --> 02:07:47,000
I don't know, I'm going to yield
the floor to Dr. Whitaker

2479
02:07:47,000 --> 02:07:48,960
for his guidance
on how to proceed,

2480
02:07:48,960 --> 02:07:51,360
but on behalf of the Health
Equities Committee,

2481
02:07:51,360 --> 02:07:55,600
thank you to all
for your stepping up to the mic

2482
02:07:55,600 --> 02:07:58,160
and also for your comments
in the chat box.

2483
02:07:58,160 --> 02:08:01,880
We will be responding to
those online

2484
02:08:01,880 --> 02:08:05,200
and as I said before, we will --

2485
02:08:05,200 --> 02:08:10,000
are definitely taking your
comments into consideration.

2486
02:08:10,000 --> 02:08:12,480
So thank you for providing
your insights.

2487
02:08:12,480 --> 02:08:14,000
-Our next scientific session

2488
02:08:14,000 --> 02:08:17,000
is dedicated
to frontotemporal degeneration.

2489
02:08:17,000 --> 02:08:19,880
And it's my pleasure to
introduce the session

2490
02:08:19,880 --> 02:08:23,360
cochairs Drs. Adam Boxer
and Celeste Karch.

2491
02:08:23,360 --> 02:08:26,320
Welcome.

2492
02:08:26,320 --> 02:08:27,600
-Hi.
-Thank you.

2493
02:08:27,600 --> 02:08:30,040
-Thank you.

2494
02:08:30,040 --> 02:08:34,120
Hi, I'm Celeste Karch,
and along with Adam Boxer

2495
02:08:34,120 --> 02:08:38,640
we served as cochairs
of this session

2496
02:08:38,640 --> 02:08:43,000
to focus on the priorities
for FTD research.

2497
02:08:43,000 --> 02:08:46,840
And this has been such
an outstanding group to work

2498
02:08:46,840 --> 02:08:52,600
with that has been led
by Thomas Cheever at NINDS

2499
02:08:52,600 --> 02:08:54,400
and really represents

2500
02:08:54,400 --> 02:08:58,000
outstanding investigators
in academia,

2501
02:08:58,000 --> 02:09:03,320
in industry and
from patient advocacy groups.

2502
02:09:03,320 --> 02:09:04,920
Next slide.

2503
02:09:08,640 --> 02:09:11,200
So in this session,
we're hoping to address

2504
02:09:11,200 --> 02:09:14,040
some of the major
accomplishments

2505
02:09:14,040 --> 02:09:19,800
that have come as a result
of the 2019 recommendations,

2506
02:09:19,800 --> 02:09:23,160
and these were really focused
in two main areas,

2507
02:09:23,160 --> 02:09:26,000
clinical science
and basic science

2508
02:09:26,000 --> 02:09:30,680
with a focus
on pathogenesis and toxicity,

2509
02:09:30,680 --> 02:09:36,120
and with the results that have
come in the intervening years,

2510
02:09:36,120 --> 02:09:42,000
we've set a series of eight
major recommendations for 2022,

2511
02:09:42,000 --> 02:09:45,400
and you'll hear
about the first three.

2512
02:09:45,400 --> 02:09:51,000
Adam, do you want to say those,
or should I jump to the fourth?

2513
02:09:51,000 --> 02:09:54,240
-Maybe you can just keep going,
and I'll jump back.

2514
02:09:54,240 --> 02:09:55,480
-Great.

2515
02:09:55,480 --> 02:09:57,880
So you'll hear in just a bit
from Adam

2516
02:09:57,880 --> 02:10:01,200
about recommendations
one through three,

2517
02:10:01,200 --> 02:10:04,640
and throughout this session
you'll hear

2518
02:10:04,640 --> 02:10:10,280
about how these different
recommendations have emerged

2519
02:10:10,280 --> 02:10:12,520
based
on the prior research.

2520
02:10:12,520 --> 02:10:18,720
And so in recommendation four,
we are hoping to identify

2521
02:10:18,720 --> 02:10:21,040
overlapping
pathogenic mechanisms

2522
02:10:21,040 --> 02:10:24,640
between FTD and other
neurodegenerative diseases.

2523
02:10:24,640 --> 02:10:26,840
In recommendation five,

2524
02:10:26,840 --> 02:10:30,320
we hope to advance
the understanding of FTD

2525
02:10:30,320 --> 02:10:34,640
and to identify therapeutic
targets through preclinical

2526
02:10:34,640 --> 02:10:38,760
and translational tools
and resources.

2527
02:10:38,760 --> 02:10:42,560
And in recommendation six to
accelerate preclinical disease

2528
02:10:42,560 --> 02:10:45,800
modifying and somatic
therapeutic development.

2529
02:10:45,800 --> 02:10:49,000
And in recommendation seven
to elucidate

2530
02:10:49,000 --> 02:10:52,440
the mechanisms of cell
type vulnerability

2531
02:10:52,440 --> 02:10:56,560
both cell intrinsic
and cell extrinsic.

2532
02:10:56,560 --> 02:11:01,040
And finally in recommendation
eight to define the genetic

2533
02:11:01,040 --> 02:11:05,240
and molecular modifiers of FTD
with a special emphasis

2534
02:11:05,240 --> 02:11:11,680
on including diverse populations
in these efforts.

2535
02:11:14,360 --> 02:11:15,520
-Great.

2536
02:11:15,520 --> 02:11:17,640
Well, thank you, Celeste,

2537
02:11:17,640 --> 02:11:19,760
and also wanted
to thank the committee

2538
02:11:19,760 --> 02:11:22,800
and I'm going to be
the first speaker,

2539
02:11:22,800 --> 02:11:25,160
and I am going to focus
on recommendations

2540
02:11:25,160 --> 02:11:27,480
one through three.

2541
02:11:27,480 --> 02:11:32,200
And just wanted to highlight
that these recommendations

2542
02:11:32,200 --> 02:11:37,560
really are an evolution of some
of the recommendations in 2019,

2543
02:11:37,560 --> 02:11:39,680
and we've made
really good progress,

2544
02:11:39,680 --> 02:11:41,640
we think,
and so recommendation

2545
02:11:41,640 --> 02:11:45,080
one is to understand
FTD epidemiology

2546
02:11:45,080 --> 02:11:48,800
genetics in diverse populations.

2547
02:11:48,800 --> 02:11:50,680
Our recommendation two is
to develop

2548
02:11:50,680 --> 02:11:52,600
an array of FTD biomarkers

2549
02:11:52,600 --> 02:11:56,480
for diagnosis, prediction
and disease monitoring.

2550
02:11:56,480 --> 02:11:58,640
Recommendation three is
to accelerate

2551
02:11:58,640 --> 02:12:01,000
the evaluation of novel
FTD treatments

2552
02:12:01,000 --> 02:12:03,480
by developing new
clinical trial resources

2553
02:12:03,480 --> 02:12:07,680
and FTD-specific designs
and by conducting new trials,

2554
02:12:07,680 --> 02:12:09,520
and then I'll highlight
some things

2555
02:12:09,520 --> 02:12:11,920
that also influence
recommendation

2556
02:12:11,920 --> 02:12:16,760
eight which is defining genetic
and molecular modifiers of FTD.

2557
02:12:16,760 --> 02:12:18,440
Next slide, please.

2558
02:12:20,600 --> 02:12:21,920
Here are my disclosures.

2559
02:12:21,920 --> 02:12:23,920
There are quite a number
to go through.

2560
02:12:23,920 --> 02:12:25,200
So we'll just skip this.

2561
02:12:25,200 --> 02:12:27,920
Next.

2562
02:12:27,920 --> 02:12:32,800
So first I wanted to highlight
some of the progress that we,

2563
02:12:32,800 --> 02:12:35,000
as the FTD research community,

2564
02:12:35,000 --> 02:12:38,960
have made since
the 2019 recommendations,

2565
02:12:38,960 --> 02:12:43,360
and one is the initiation
of a large clinical research

2566
02:12:43,360 --> 02:12:45,120
network called ALLFTD

2567
02:12:45,120 --> 02:12:49,800
which was the continuation of
two previously funded projects

2568
02:12:49,800 --> 02:12:54,280
called ARTFL and LEFFTDS.
This began in 2019,

2569
02:12:54,280 --> 02:12:56,560
and unfortunately
we were heavily

2570
02:12:56,560 --> 02:12:59,000
impacted by the COVID pandemic,

2571
02:12:59,000 --> 02:13:05,120
but we were able to initiate
23 centers, and next, please.

2572
02:13:05,120 --> 02:13:08,240
This project enrolls
both individuals

2573
02:13:08,240 --> 02:13:10,600
with genetic forms of FTD

2574
02:13:10,600 --> 02:13:13,120
and about 40 percent
of individuals

2575
02:13:13,120 --> 02:13:17,520
have a strong family history
as well as sporadic individuals

2576
02:13:17,520 --> 02:13:21,280
who do not have a clear genetic
or family history of FTD,

2577
02:13:21,280 --> 02:13:25,600
and you can see
the different genetic cohorts

2578
02:13:25,600 --> 02:13:30,040
that we have as well
as the main sporadic cohorts,

2579
02:13:30,040 --> 02:13:33,000
and there are about
1,000 in each, next.

2580
02:13:36,800 --> 02:13:38,400
And this is...

2581
02:13:38,400 --> 02:13:41,920
This ALLFTD network
has really allowed for multiple

2582
02:13:41,920 --> 02:13:45,920
other research projects
to be funded and built

2583
02:13:45,920 --> 02:13:47,920
and this is
a nice infrastructure

2584
02:13:47,920 --> 02:13:49,440
on which we can also work

2585
02:13:49,440 --> 02:13:52,440
with our patient
advocacy group partners

2586
02:13:52,440 --> 02:13:54,760
including the FTD
Disorders Registry

2587
02:13:54,760 --> 02:13:57,520
and the Bluefield Project
which sponsors a project

2588
02:13:57,520 --> 02:14:01,560
to further develop
a plasma neurofilament light

2589
02:14:01,560 --> 02:14:03,560
as a biomarker
through the neurofilament

2590
02:14:03,560 --> 02:14:07,280
light surveillance project
as well as increasingly this

2591
02:14:07,280 --> 02:14:10,760
is serving to promote
clinical trials.

2592
02:14:10,760 --> 02:14:13,600
Next slide.

2593
02:14:13,600 --> 02:14:17,960
So these are some of the studies
that have either been published

2594
02:14:17,960 --> 02:14:21,480
or will be published soon
from the ALLFTD network.

2595
02:14:21,480 --> 02:14:23,400
One is to show...

2596
02:14:23,400 --> 02:14:25,720
Many of them are focusing
on blood biomarkers

2597
02:14:25,720 --> 02:14:27,120
which has really been a focus,

2598
02:14:27,120 --> 02:14:29,000
and you can see that
neurofilament light chain

2599
02:14:29,000 --> 02:14:31,680
is a good predictor
of disease progression

2600
02:14:31,680 --> 02:14:34,040
in genetic forms of FTD
on the left

2601
02:14:34,040 --> 02:14:36,440
and on the right
is also very elevated

2602
02:14:36,440 --> 02:14:38,480
in sporadic forms of FTD,

2603
02:14:38,480 --> 02:14:41,120
and so maybe a good biomarker
for both groups.

2604
02:14:41,120 --> 02:14:42,720
Next.

2605
02:14:45,000 --> 02:14:48,600
We've also put quite a bit
of effort into biomarkers

2606
02:14:48,600 --> 02:14:52,800
that can differentiate
sporadic forms of FTD

2607
02:14:52,800 --> 02:14:56,720
from Alzheimer's disease
because clinically these are

2608
02:14:56,720 --> 02:15:00,480
difficult diseases
to differentiate,

2609
02:15:00,480 --> 02:15:06,200
and here you can see that plasma
phosphorylated forms of tau

2610
02:15:06,200 --> 02:15:07,520
are really very useful

2611
02:15:07,520 --> 02:15:09,800
at differentiating
Alzheimer's disease

2612
02:15:09,800 --> 02:15:13,280
from different
FTD neuropathologies

2613
02:15:13,280 --> 02:15:14,640
and really quite accurate.

2614
02:15:14,640 --> 02:15:17,400
We think this is going
to help clinicians

2615
02:15:17,400 --> 02:15:20,200
to more accurately
diagnose FTD

2616
02:15:20,200 --> 02:15:24,760
but also to enable new
clinical trials of sporadic FTD.

2617
02:15:28,840 --> 02:15:32,560
We've also learned quite
a bit about risk factors

2618
02:15:32,560 --> 02:15:35,800
and potential interventions
that might help individuals

2619
02:15:35,800 --> 02:15:39,200
both with genetic
and sporadic forms of FTD.

2620
02:15:39,200 --> 02:15:43,840
And so on the left you can see
that in mutation carriers,

2621
02:15:43,840 --> 02:15:46,800
that there is now
increasing evidence

2622
02:15:46,800 --> 02:15:51,160
that both physical activity
and cognitive activity

2623
02:15:51,160 --> 02:15:54,200
are associated with slower rates
of disease progression

2624
02:15:54,200 --> 02:15:57,120
and less brain atrophy
over time,

2625
02:15:57,120 --> 02:16:01,440
and we think that this may also
apply to sporadic forms of FTD.

2626
02:16:01,440 --> 02:16:04,000
Next.

2627
02:16:04,000 --> 02:16:06,960
And we've been trying
to harmonize

2628
02:16:06,960 --> 02:16:09,640
the genetic
and sporadic FTD studies,

2629
02:16:09,640 --> 02:16:13,080
and here is an example
showing that brain atrophy

2630
02:16:13,080 --> 02:16:16,200
in genetic forms of FTD
is very similar

2631
02:16:16,200 --> 02:16:20,080
to what you see in sporadic FTD,
and this gives us confidence

2632
02:16:20,080 --> 02:16:23,360
that what we learn
from the genetic forms of FTD

2633
02:16:23,360 --> 02:16:28,240
can be applied to sporadic FTD
and hopefully vice verse.

2634
02:16:28,240 --> 02:16:31,040
Next slide.

2635
02:16:31,040 --> 02:16:33,000
So one of the exciting
developments,

2636
02:16:33,000 --> 02:16:35,600
and this is a study
that's funded by the NIH

2637
02:16:35,600 --> 02:16:37,960
and the Alzheimer's Association,

2638
02:16:37,960 --> 02:16:42,000
is through the ALLFTD network
we can now start to think about

2639
02:16:42,000 --> 02:16:45,760
putting together novel clinical
trials for our patients with,

2640
02:16:45,760 --> 02:16:48,680
in this case sporadic FTD,

2641
02:16:48,680 --> 02:16:52,640
and this is for semantic variant
primary progressive aphasia,

2642
02:16:52,640 --> 02:16:54,200
and you can see in the images

2643
02:16:54,200 --> 02:16:56,160
and on the left side
of the slide

2644
02:16:56,160 --> 02:16:58,840
that in this form
of primary progressive aphasia

2645
02:16:58,840 --> 02:17:00,560
there is very strong evidence

2646
02:17:00,560 --> 02:17:04,000
that inflammation in the brain
plays a big role.

2647
02:17:04,000 --> 02:17:07,000
So there's a PET scan and color
picture on the left

2648
02:17:07,000 --> 02:17:09,800
showing inflammation
in the left temporal lobe,

2649
02:17:09,800 --> 02:17:13,080
and this correlates with where
we see damage by brain atrophy,

2650
02:17:13,080 --> 02:17:15,280
and this is from
one of our sites

2651
02:17:15,280 --> 02:17:17,600
in the ALLFTD
network in Houston.

2652
02:17:17,600 --> 02:17:19,120
And so we think

2653
02:17:19,120 --> 02:17:24,080
that the inflammation
promotes TDP 43 pathology,

2654
02:17:24,080 --> 02:17:27,280
and we will be soon
testing a new drug,

2655
02:17:27,280 --> 02:17:29,040
a myeloperoxidase inhibitor

2656
02:17:29,040 --> 02:17:33,280
that we hope can block
this inflammation in microglia,

2657
02:17:33,280 --> 02:17:35,800
and we hope will slow
the progression

2658
02:17:35,800 --> 02:17:40,680
of primary progressive
aphasia or semantic variant PPA.

2659
02:17:40,680 --> 02:17:43,200
So very excited about this.
Next slide.

2660
02:17:45,720 --> 02:17:47,000
But we've also learned,

2661
02:17:47,000 --> 02:17:48,640
and I think there were
comments earlier,

2662
02:17:48,640 --> 02:17:50,880
that FTD is a very rare disease,

2663
02:17:50,880 --> 02:17:55,880
and it's going to take a global
effort to really prevent FTD

2664
02:17:55,880 --> 02:17:57,640
and to possibly understand it,

2665
02:17:57,640 --> 02:18:02,880
and so in collaboration with
our colleagues around the world

2666
02:18:02,880 --> 02:18:04,480
we formed a new organization

2667
02:18:04,480 --> 02:18:09,560
called the FTD Prevention
Initiative, and next, please.

2668
02:18:09,560 --> 02:18:12,400
This started as a collaboration
between ALLFTD

2669
02:18:12,400 --> 02:18:17,040
and the genetic FTD initiative
in Europe and Canada

2670
02:18:17,040 --> 02:18:21,000
and the UK led by
our colleague John Rohrer,

2671
02:18:21,000 --> 02:18:23,280
and next, we're now...

2672
02:18:23,280 --> 02:18:26,840
And this was supported initially
by our patient advocacy

2673
02:18:26,840 --> 02:18:29,960
group partners, the AFTD
and the Bluefield project

2674
02:18:29,960 --> 02:18:31,600
and the FTD
Disorders Registry.

2675
02:18:31,600 --> 02:18:33,200
Next.

2676
02:18:33,200 --> 02:18:36,560
We're now working to incorporate
other FTD research

2677
02:18:36,560 --> 02:18:37,960
networks around the world,

2678
02:18:37,960 --> 02:18:40,880
so the ReDLat study
funded by the NIH

2679
02:18:40,880 --> 02:18:43,880
led by Augustine Ibanez
in South America

2680
02:18:43,880 --> 02:18:48,200
and the DINAD and FTDGen studies
in Australia and New Zealand,

2681
02:18:48,200 --> 02:18:52,680
next, as well as networks
throughout Asia

2682
02:18:52,680 --> 02:18:55,200
that we're starting
to form links with,

2683
02:18:55,200 --> 02:18:57,560
and the goal is to share data

2684
02:18:57,560 --> 02:19:00,720
to really understand FTD
in diverse populations

2685
02:19:00,720 --> 02:19:04,600
but to plan global FTD
prevention trials as well.

2686
02:19:04,600 --> 02:19:07,400
Next.

2687
02:19:07,400 --> 02:19:09,600
So here I want to show you
an example

2688
02:19:09,600 --> 02:19:11,400
of one of the
collaborative studies

2689
02:19:11,400 --> 02:19:13,440
that has come out
of this global network,

2690
02:19:13,440 --> 02:19:18,400
and this is data
in FTD mutation carriers

2691
02:19:18,400 --> 02:19:21,200
with the three most common FTD
causing mutations

2692
02:19:21,200 --> 02:19:23,280
C9 open reading frame
for granulin

2693
02:19:23,280 --> 02:19:26,600
and tau on the three panels
at the top,

2694
02:19:26,600 --> 02:19:31,960
and this is data from combined
across the USA, Canada,

2695
02:19:31,960 --> 02:19:34,760
Europe and the UK,
and what you can see is that

2696
02:19:34,760 --> 02:19:39,000
we can start to harmonize
the different clinical measures,

2697
02:19:39,000 --> 02:19:41,960
MRI biomarkers
and blood neurofilament levels

2698
02:19:41,960 --> 02:19:45,800
to understand what the earliest
signs of disease

2699
02:19:45,800 --> 02:19:48,080
are prior to the onset
of symptoms

2700
02:19:48,080 --> 02:19:52,120
which is on the X axis
indicated by a zero.

2701
02:19:52,120 --> 02:19:53,800
And hopefully what
you can appreciate

2702
02:19:53,800 --> 02:19:56,360
is that due
to the different mutations

2703
02:19:56,360 --> 02:19:57,920
there are slightly
different patterns

2704
02:19:57,920 --> 02:19:59,960
of presymptomatic changes.

2705
02:19:59,960 --> 02:20:03,000
On the left in C9 open
reading frame mutation carriers,

2706
02:20:03,000 --> 02:20:05,800
you see very early MRI changes,

2707
02:20:05,800 --> 02:20:09,680
whereas in tau mutation
carriers on the right,

2708
02:20:09,680 --> 02:20:13,200
we see a later rise
in purple of neurofilament.

2709
02:20:13,200 --> 02:20:15,160
Next.

2710
02:20:15,160 --> 02:20:18,600
-A few minutes remaining.
-Yep, next.

2711
02:20:18,600 --> 02:20:21,920
And so these are the raw data
on which they're based,

2712
02:20:21,920 --> 02:20:23,280
and you can see
these are harmonized

2713
02:20:23,280 --> 02:20:24,760
across the different networks.

2714
02:20:24,760 --> 02:20:26,480
Next.

2715
02:20:26,480 --> 02:20:28,840
And what we're learning
from looking at all these data

2716
02:20:28,840 --> 02:20:32,400
is that there are bits of noise
you can see prior

2717
02:20:32,400 --> 02:20:34,040
to the onset of symptoms

2718
02:20:34,040 --> 02:20:37,120
that means that really
what we need are new biomarkers

2719
02:20:37,120 --> 02:20:42,000
to detect and measure disease in
the early presymptomatic stage,

2720
02:20:42,000 --> 02:20:45,240
and so this needs to be
a focus of our future research.

2721
02:20:45,240 --> 02:20:47,480
Next.

2722
02:20:47,480 --> 02:20:51,200
And so the new recommendations
really are focused --

2723
02:20:51,200 --> 02:20:54,080
come out of these challenges
in various FTD research.

2724
02:20:54,080 --> 02:20:55,840
Next.

2725
02:20:55,840 --> 02:21:00,600
So first is just --
one back, but this is fine --

2726
02:21:00,600 --> 02:21:04,040
lack of diversity, and really
everything that we know is

2727
02:21:04,040 --> 02:21:06,520
from data in non-Latin
white individuals,

2728
02:21:06,520 --> 02:21:10,120
and despite a lot of efforts
we haven't been very successful

2729
02:21:10,120 --> 02:21:12,800
in including people
from diverse populations

2730
02:21:12,800 --> 02:21:16,000
in FTD studies around the world,
and this needs to be a focus

2731
02:21:16,000 --> 02:21:19,200
because we're learning
that the genetics of FTD

2732
02:21:19,200 --> 02:21:20,960
are different
in different populations.

2733
02:21:20,960 --> 02:21:24,200
So this is not just a diversity,
equity and inclusion issue

2734
02:21:24,200 --> 02:21:29,000
but also a scientific flaw
in our previous work.

2735
02:21:29,000 --> 02:21:32,120
We've heard that FTD diseases
are rare diseases,

2736
02:21:32,120 --> 02:21:34,200
and so to do large
clinical trials

2737
02:21:34,200 --> 02:21:35,800
we're going to need
a global effort.

2738
02:21:35,800 --> 02:21:37,400
Next.

2739
02:21:39,680 --> 02:21:42,600
And as I mentioned,
we have some biomarkers,

2740
02:21:42,600 --> 02:21:45,400
but we need much more
particularly for sporadic

2741
02:21:45,400 --> 02:21:48,520
diseases where late diagnosis
is a real problem

2742
02:21:48,520 --> 02:21:51,200
for testing therapies.

2743
02:21:51,200 --> 02:21:53,960
Next.

2744
02:21:53,960 --> 02:21:56,960
And then we've learned from
COVID that in all these rare

2745
02:21:56,960 --> 02:21:59,400
and geographically
dispersed populations,

2746
02:21:59,400 --> 02:22:00,840
it's very hard for people

2747
02:22:00,840 --> 02:22:03,800
particularly from
underrepresented populations

2748
02:22:03,800 --> 02:22:05,600
to travel
to research centers,

2749
02:22:05,600 --> 02:22:09,360
and so we need to think
about remote assessment tools,

2750
02:22:09,360 --> 02:22:11,520
particularly biomarkers
that we can deploy

2751
02:22:11,520 --> 02:22:14,640
even in third-world countries
where PET scans or MRI

2752
02:22:14,640 --> 02:22:16,240
may not be available.

2753
02:22:16,240 --> 02:22:18,160
Next.

2754
02:22:18,160 --> 02:22:21,600
And so I'm just going to end
that these are the priorities

2755
02:22:21,600 --> 02:22:24,200
that I hopefully
talked to you a bit about

2756
02:22:24,200 --> 02:22:26,880
and that really you'll hear
much more about it

2757
02:22:26,880 --> 02:22:28,800
throughout the future talks,

2758
02:22:28,800 --> 02:22:31,200
and I want to thank you
for your attention

2759
02:22:31,200 --> 02:22:33,800
and now introduce
the next speakers

2760
02:22:33,800 --> 02:22:39,720
who are Anthony Fitzpatrick
and Leonard Petrucelli.

2761
02:22:39,720 --> 02:22:41,400
-Thanks very much, Adam.

2762
02:22:41,400 --> 02:22:43,200
My name is Anthony Fitzpatrick

2763
02:22:43,200 --> 02:22:45,760
from Columbia University
in New York,

2764
02:22:45,760 --> 02:22:50,200
and today Leonard Petrucelli
and I from Mayo Clinic Florida

2765
02:22:50,200 --> 02:22:53,200
will be talking about
recently published work

2766
02:22:53,200 --> 02:22:55,760
that we've been doing on FTD.

2767
02:22:55,760 --> 02:22:58,240
Next slide, please.

2768
02:22:58,240 --> 02:23:00,680
So we have nothing to disclose.

2769
02:23:00,680 --> 02:23:02,720
Next slide, please.

2770
02:23:02,720 --> 02:23:05,760
So my lab primarily is using

2771
02:23:05,760 --> 02:23:08,200
a very powerful
microscopy technique

2772
02:23:08,200 --> 02:23:10,760
known as
cyro-electron microscopy

2773
02:23:10,760 --> 02:23:14,160
to actually study
at the atomic level

2774
02:23:14,160 --> 02:23:16,600
those protein tangles associated

2775
02:23:16,600 --> 02:23:20,000
with many different
neurodegenerative diseases.

2776
02:23:20,000 --> 02:23:23,640
This started in 2017
whenever we solved

2777
02:23:23,640 --> 02:23:26,920
the first structure
of tau filaments

2778
02:23:26,920 --> 02:23:30,520
from Alzheimer's disease
shown here on the right,

2779
02:23:30,520 --> 02:23:32,080
and over the last few years

2780
02:23:32,080 --> 02:23:35,480
we've been systematically
going through other diseases

2781
02:23:35,480 --> 02:23:38,160
such as progressive
supranuclear palsy

2782
02:23:38,160 --> 02:23:42,280
and also CBD and solving
their structures

2783
02:23:42,280 --> 02:23:44,640
at the neuro-atomic level,

2784
02:23:44,640 --> 02:23:47,720
so that we can understand
better what the differences

2785
02:23:47,720 --> 02:23:51,280
are between
the molecular signatures

2786
02:23:51,280 --> 02:23:54,160
of each of these
terrible diseases.

2787
02:23:54,160 --> 02:23:59,600
And what we're finding is
that each different tauopathy

2788
02:23:59,600 --> 02:24:01,800
has a unique
molecular signature.

2789
02:24:01,800 --> 02:24:04,720
So you can see that these
cross sections

2790
02:24:04,720 --> 02:24:08,560
which we're showing here in the
figure look quite different,

2791
02:24:08,560 --> 02:24:10,680
and if we go to
the next slide, please.

2792
02:24:12,840 --> 02:24:14,400
And as a result of that,

2793
02:24:14,400 --> 02:24:17,680
we can actually begin
to understand better

2794
02:24:17,680 --> 02:24:21,040
not only what the differences
are at a molecular level

2795
02:24:21,040 --> 02:24:24,520
between tau filaments in each of
these different diseases

2796
02:24:24,520 --> 02:24:27,640
but also how we can better
design biomarkers

2797
02:24:27,640 --> 02:24:32,720
that bind to each of these tau
filaments in different diseases.

2798
02:24:32,720 --> 02:24:37,040
So what we've shown here is
a kind of cartoon representation

2799
02:24:37,040 --> 02:24:39,440
of the molecules,

2800
02:24:39,440 --> 02:24:43,440
and you can see that
there's a big difference

2801
02:24:43,440 --> 02:24:47,600
between the accessible regions
of the tau molecule.

2802
02:24:47,600 --> 02:24:52,120
So we consider them broken down
into what we call microtubule

2803
02:24:52,120 --> 02:24:55,280
binding repeats
so R1, 2, 3 and 4,

2804
02:24:55,280 --> 02:24:57,280
and looking at those
different colors you can see

2805
02:24:57,280 --> 02:25:01,320
that the actual cross sections
across these different diseases

2806
02:25:01,320 --> 02:25:03,000
are incredibly different.

2807
02:25:03,000 --> 02:25:08,480
So even between CBD and PSP
which are two very closely,

2808
02:25:08,480 --> 02:25:11,120
very difficult
to distinguish tauopathies,

2809
02:25:11,120 --> 02:25:13,000
you can actually see
that there's a great deal

2810
02:25:13,000 --> 02:25:15,480
of difference in terms of
where you could bind,

2811
02:25:15,480 --> 02:25:18,760
say small molecules
or antibodies.

2812
02:25:18,760 --> 02:25:21,000
Next slide, please.

2813
02:25:21,000 --> 02:25:23,800
I think one of the very exciting
findings that we just made

2814
02:25:23,800 --> 02:25:27,000
and just published
in "Cell" a month ago

2815
02:25:27,000 --> 02:25:30,200
is the finding that basically
we were looking along

2816
02:25:30,200 --> 02:25:33,440
with Ian MacKenzie at University
of British Columbia

2817
02:25:33,440 --> 02:25:36,600
and tissue also from
Dennis Dixon at Mayo Clinic,

2818
02:25:36,600 --> 02:25:39,280
Florida the sort of range
of filaments

2819
02:25:39,280 --> 02:25:42,760
that you find in FTLD TDP,

2820
02:25:42,760 --> 02:25:46,520
and so we looked at a range
of different FTLD TDP subtypes,

2821
02:25:46,520 --> 02:25:49,480
A, B and C,
and we found surprisingly

2822
02:25:49,480 --> 02:25:51,560
that there was
a common filament

2823
02:25:51,560 --> 02:25:54,880
that we were finding
in each of these different cases

2824
02:25:54,880 --> 02:25:57,160
that were
phenotypically different

2825
02:25:57,160 --> 02:25:59,400
and also pathologically
distinct,

2826
02:25:59,400 --> 02:26:01,640
and what was surprising
was we also found

2827
02:26:01,640 --> 02:26:05,800
the same filament in PSP
along with tau filaments

2828
02:26:05,800 --> 02:26:08,960
and also in dementia
with Lewy bodies.

2829
02:26:08,960 --> 02:26:12,800
And with the unique
resolving power of cryo-EM,

2830
02:26:12,800 --> 02:26:15,280
we were actually able
to identify

2831
02:26:15,280 --> 02:26:17,280
what these filaments
were composed of

2832
02:26:17,280 --> 02:26:20,640
because we can actually image
right down to the individual

2833
02:26:20,640 --> 02:26:23,440
building blocks
of the filaments themselves.

2834
02:26:23,440 --> 02:26:26,080
Next slide, please.

2835
02:26:26,080 --> 02:26:28,000
So it turned out that actually
these filaments

2836
02:26:28,000 --> 02:26:31,000
are all composed
of a protein

2837
02:26:31,000 --> 02:26:34,760
that we previously did
not know much about,

2838
02:26:34,760 --> 02:26:37,000
TMEM106B which has been known

2839
02:26:37,000 --> 02:26:42,440
since 2012 to be a risk factor
for aging and FTLD TDP,

2840
02:26:42,440 --> 02:26:46,800
but the protein itself was
thought to have an end terminus

2841
02:26:46,800 --> 02:26:50,040
which is associated with
trafficking of lysosomes

2842
02:26:50,040 --> 02:26:53,760
and endosomes but not much
was known about the C terminus,

2843
02:26:53,760 --> 02:26:57,640
and it turns out that this
luminal C terminal fragment

2844
02:26:57,640 --> 02:26:59,840
is extremely aggregation prone

2845
02:26:59,840 --> 02:27:02,200
and when it gets cleaved
can actually go on

2846
02:27:02,200 --> 02:27:05,480
to form these filaments
that we find.

2847
02:27:05,480 --> 02:27:08,440
Next slide, please.

2848
02:27:08,440 --> 02:27:11,600
So I think the really
exciting thing about cryo-EM

2849
02:27:11,600 --> 02:27:15,640
in this regard
is that it can actually identify

2850
02:27:15,640 --> 02:27:20,920
uniquely the actual molecular
constituent and shape

2851
02:27:20,920 --> 02:27:24,320
and form of the molecules
forming these filaments,

2852
02:27:24,320 --> 02:27:28,080
and we really did not expect
to find something

2853
02:27:28,080 --> 02:27:31,680
other than TDP-43 or tau
in these diseases,

2854
02:27:31,680 --> 02:27:34,840
and we've now found
a new fibrillization factor

2855
02:27:34,840 --> 02:27:36,320
and pathway entirely

2856
02:27:36,320 --> 02:27:40,640
from just imaging
postmortem human brain tissue.

2857
02:27:40,640 --> 02:27:44,280
And as you can see here, this is
the highest resolution map

2858
02:27:44,280 --> 02:27:46,560
that we have at 2.7 angstrom,

2859
02:27:46,560 --> 02:27:49,720
and not only can you see
the individual amino acids

2860
02:27:49,720 --> 02:27:51,760
that build up this filament

2861
02:27:51,760 --> 02:27:54,040
and the shape
and form of the filament,

2862
02:27:54,040 --> 02:27:56,800
but you can also see the
post-translation modifications.

2863
02:27:56,800 --> 02:27:59,040
We have a lot of glycosylations.

2864
02:27:59,040 --> 02:28:04,200
We can also see
the disease-associated T185 site

2865
02:28:04,200 --> 02:28:06,600
which we think
is also phosphorylated,

2866
02:28:06,600 --> 02:28:08,360
and so this begins
to tell you more

2867
02:28:08,360 --> 02:28:10,960
about the biology of why
these filaments are forming

2868
02:28:10,960 --> 02:28:13,080
and what
their possible impact could be.

2869
02:28:13,080 --> 02:28:15,600
Next slide, please.

2870
02:28:15,600 --> 02:28:18,120
So it's early days, this was
an unexpected finding

2871
02:28:18,120 --> 02:28:21,320
but given that the TMEM106B
is a lysosomal,

2872
02:28:21,320 --> 02:28:24,880
endosomal protein we feel like

2873
02:28:24,880 --> 02:28:28,000
whenever it gets cleaved
and forms these fibrils,

2874
02:28:28,000 --> 02:28:32,240
this may be associated
with additional lysosomal stress

2875
02:28:32,240 --> 02:28:34,960
and given that the lysosome
is a mechanism

2876
02:28:34,960 --> 02:28:37,800
by which other filaments form
by say tau

2877
02:28:37,800 --> 02:28:40,920
or TDP-43 get degraded,

2878
02:28:40,920 --> 02:28:44,600
it could be that this
fibrillization of TMEM106B

2879
02:28:44,600 --> 02:28:47,160
is actually causing
additional problems

2880
02:28:47,160 --> 02:28:50,320
in terms of getting rid
of those filaments,

2881
02:28:50,320 --> 02:28:54,760
and this could in fact
be leading to wider accumulation

2882
02:28:54,760 --> 02:28:57,200
of more disease-
associated filaments

2883
02:28:57,200 --> 02:29:00,120
such as TDP tau or synuclein.

2884
02:29:00,120 --> 02:29:02,040
And I think with that,
I'll hand over to Len

2885
02:29:02,040 --> 02:29:03,840
who will then talk
about his recent work.

2886
02:29:03,840 --> 02:29:06,440
Thank you.
-Thank you, Anthony.

2887
02:29:06,440 --> 02:29:09,200
Next slide, please.

2888
02:29:09,200 --> 02:29:12,280
So as Dr. Walter Koroshetz
mentioned in the beginning,

2889
02:29:12,280 --> 02:29:15,800
really a lot of the field
has focused their understanding

2890
02:29:15,800 --> 02:29:20,000
on delving into the biologic
mechanism with the intent

2891
02:29:20,000 --> 02:29:25,160
that this will lead to improved
and identification of novel

2892
02:29:25,160 --> 02:29:29,400
therapeutic targets
as well as novel biomarkers,

2893
02:29:29,400 --> 02:29:34,200
and so this is work that,
in collaboration

2894
02:29:34,200 --> 02:29:37,400
with Dr. Aaron Gitler
from Stanford University

2895
02:29:37,400 --> 02:29:41,800
as well as my team
at Mayo Clinic.

2896
02:29:41,800 --> 02:29:45,000
In addition there was a paper
also with our colleagues

2897
02:29:45,000 --> 02:29:51,080
from Dr. Michael Ward from NIH
and Dr. Pietro Fratta from UCL.

2898
02:29:51,080 --> 02:29:53,800
Next slide.

2899
02:29:53,800 --> 02:29:56,680
And what this paper
fundamentally describes

2900
02:29:56,680 --> 02:30:00,680
is a novel
TDP-43 RNA target.

2901
02:30:00,680 --> 02:30:03,640
TDP-43 normally is
within the nucleus

2902
02:30:03,640 --> 02:30:06,600
where it regulates
many DNA and RNA events,

2903
02:30:06,600 --> 02:30:10,720
and as a result of its
mislocalization to the cytoplasm

2904
02:30:10,720 --> 02:30:12,840
there is an apparent
loss of function.

2905
02:30:12,840 --> 02:30:15,880
So work from Dr. Eddy Lee
from UPenn

2906
02:30:15,880 --> 02:30:18,600
took the first approach which
really enabled these studies,

2907
02:30:18,600 --> 02:30:22,800
and that was to fact sort,
to fundamentally separate nuclei

2908
02:30:22,800 --> 02:30:26,200
based on the nuclear levels
of TDP-43,

2909
02:30:26,200 --> 02:30:28,320
and when we mined that data

2910
02:30:28,320 --> 02:30:31,920
looking for potential
alterations in particular

2911
02:30:31,920 --> 02:30:35,200
with cryptic exon events
we noticed

2912
02:30:35,200 --> 02:30:36,600
that there were
numerous targets,

2913
02:30:36,600 --> 02:30:40,280
but one target as denoted
in red really stood out.

2914
02:30:40,280 --> 02:30:41,480
Next slide, please.

2915
02:30:41,480 --> 02:30:43,560
And the reason why
that it stood out

2916
02:30:43,560 --> 02:30:45,640
was because of the fact
that prior work

2917
02:30:45,640 --> 02:30:49,960
had really focused on this gene
called UNC13A,

2918
02:30:49,960 --> 02:30:52,600
a very important
protein that's involved

2919
02:30:52,600 --> 02:30:58,160
in synaptic
neurotransmission release,

2920
02:30:58,160 --> 02:31:03,400
pinpointed that it was a risk
factor for ALS and FTD/ALS,

2921
02:31:03,400 --> 02:31:05,800
and so it really highlighted
the importance

2922
02:31:05,800 --> 02:31:08,160
that perhaps RNA -- excuse me,

2923
02:31:08,160 --> 02:31:13,040
that TDP-43 was involved
in the regulation of UNC13A.

2924
02:31:13,040 --> 02:31:15,600
Next slide.
And so through a series of...

2925
02:31:15,600 --> 02:31:17,560
-Two minutes remaining.

2926
02:31:17,560 --> 02:31:19,400
-...through a series
of cell culture experiments,

2927
02:31:19,400 --> 02:31:23,000
which are not shown here
but really highlighting

2928
02:31:23,000 --> 02:31:25,720
the human postmortem studies
in collaboration

2929
02:31:25,720 --> 02:31:28,160
with Dr. Dennis Dickson
at Mayo Clinic,

2930
02:31:28,160 --> 02:31:33,080
we show that this abnormal
cryptic exon splicing event

2931
02:31:33,080 --> 02:31:36,040
is significantly elevated
in FTD TDP-43,

2932
02:31:36,040 --> 02:31:38,160
as you can see in the tissues,

2933
02:31:38,160 --> 02:31:43,240
which correlate with the amount
of Phospho-TDP-43 burden.

2934
02:31:43,240 --> 02:31:44,840
Next slide.

2935
02:31:47,120 --> 02:31:50,120
And so as we heard
from Dr. Boxer as well as,

2936
02:31:50,120 --> 02:31:51,520
you know,
from our previous speakers,

2937
02:31:51,520 --> 02:31:54,440
really the need for
TDP-43 biomarkers...

2938
02:31:54,440 --> 02:31:56,760
This is just
a typical case report

2939
02:31:56,760 --> 02:31:59,040
that my colleagues
in neurology will see,

2940
02:31:59,040 --> 02:32:02,960
and fundamentally
it's hard to diagnose

2941
02:32:02,960 --> 02:32:07,280
whether or not they have
FTD TDP-43 or an FTD tau.

2942
02:32:07,280 --> 02:32:08,800
Next slide.

2943
02:32:08,800 --> 02:32:12,400
So our approach is to work
towards this capitalizing

2944
02:32:12,400 --> 02:32:14,640
on the TDP-43 function
in collaboration

2945
02:32:14,640 --> 02:32:16,640
with Dr. Michael Ward,

2946
02:32:16,640 --> 02:32:20,160
the intraneural program,
and Dr. Andy Qi.

2947
02:32:20,160 --> 02:32:22,840
We've fostered a collaboration
to really pursue this

2948
02:32:22,840 --> 02:32:25,400
from a proteomic
and amino-based assay.

2949
02:32:25,400 --> 02:32:27,400
Next slide.

2950
02:32:27,400 --> 02:32:31,240
And so we wanted to harness
the cryptic splicing events

2951
02:32:31,240 --> 02:32:35,240
whereby we would be able
to either generate RNA

2952
02:32:35,240 --> 02:32:39,640
or peptide biomarker
candidates.

2953
02:32:39,640 --> 02:32:40,840
Next slide.

2954
02:32:40,840 --> 02:32:44,000
And as you can see here,
in the left,

2955
02:32:44,000 --> 02:32:47,960
an ideal biomarker is one
in which the cryptic exon event

2956
02:32:47,960 --> 02:32:50,880
is actually occurring
within the protein itself,

2957
02:32:50,880 --> 02:32:53,320
generating a novel
fusion protein.

2958
02:32:53,320 --> 02:32:56,560
Other nonideal biomarkers
such as actually UNC13A

2959
02:32:56,560 --> 02:32:59,320
from a protein perspective
or Stathmin-2

2960
02:32:59,320 --> 02:33:00,840
would be less ideal
because of the fact

2961
02:33:00,840 --> 02:33:03,640
that they have
premature termination codon

2962
02:33:03,640 --> 02:33:05,560
or premature poly(A).

2963
02:33:05,560 --> 02:33:07,160
So I'm just going to give you
one such example

2964
02:33:07,160 --> 02:33:09,440
of an RNA target,
next slide,

2965
02:33:09,440 --> 02:33:13,640
that really captures our efforts
from a proteomic-based approach,

2966
02:33:13,640 --> 02:33:17,000
and this just validates a novel
RNA target called MYO18A,

2967
02:33:17,000 --> 02:33:19,600
and you can see that
it's significantly elevated,

2968
02:33:19,600 --> 02:33:21,080
this abnormal
splicing event,

2969
02:33:21,080 --> 02:33:24,760
in iPS neurons
as well as in human brain,

2970
02:33:24,760 --> 02:33:28,120
but using an antibody
against that novel epitope,

2971
02:33:28,120 --> 02:33:32,120
we were able to identify
this protein

2972
02:33:32,120 --> 02:33:36,040
in the iPSCs in which TDP-43
has been knocked down.

2973
02:33:36,040 --> 02:33:38,000
So this is just, you know,
one --

2974
02:33:38,000 --> 02:33:41,080
somewhat of a textbook example,
if you will, in which, you know,

2975
02:33:41,080 --> 02:33:44,720
we are confident that if we can
take a look at TDP-43 targets,

2976
02:33:44,720 --> 02:33:46,880
and there's many of them,
as I had showed you,

2977
02:33:46,880 --> 02:33:49,320
that we might be able
to identify a marker

2978
02:33:49,320 --> 02:33:53,200
or a surrogate marker
of TDP-43 biological activity

2979
02:33:53,200 --> 02:33:54,760
with the intent
that we can discriminate

2980
02:33:54,760 --> 02:33:58,000
FTD tau versus FTD TDP-43,

2981
02:33:58,000 --> 02:34:02,840
and certainly the implications
are clear for ALS.

2982
02:34:02,840 --> 02:34:05,280
And with that, I'll stop
and turn it over

2983
02:34:05,280 --> 02:34:09,560
to Drs. Boxer and Karch.

2984
02:34:12,200 --> 02:34:14,160
-Okay, thank you.

2985
02:34:14,160 --> 02:34:15,880
So my name is Celeste Karch,
again,

2986
02:34:15,880 --> 02:34:19,080
and I'm at Washington University
in St. Louis,

2987
02:34:19,080 --> 02:34:22,560
and here I'll be sharing
some of our advances

2988
02:34:22,560 --> 02:34:25,040
and next steps
for using genetics

2989
02:34:25,040 --> 02:34:28,280
to understand
the biology of disease,

2990
02:34:28,280 --> 02:34:31,400
and this really builds off
of some of the successes

2991
02:34:31,400 --> 02:34:35,280
from the 2019 milestones

2992
02:34:35,280 --> 02:34:38,000
and has led
to the identification

2993
02:34:38,000 --> 02:34:42,640
of some new
recommendations for 2022.

2994
02:34:42,640 --> 02:34:44,360
Next slide.

2995
02:34:44,360 --> 02:34:45,600
I've no disclosures.

2996
02:34:45,600 --> 02:34:47,680
Next slide.

2997
02:34:47,680 --> 02:34:50,800
So ultimately we know
that in FTD

2998
02:34:50,800 --> 02:34:53,440
as well as with other
neurodegenerative diseases,

2999
02:34:53,440 --> 02:34:57,320
the genetic architecture
is quite complex,

3000
02:34:57,320 --> 02:35:01,880
and there's an additional level
of complexity for FTD genetics

3001
02:35:01,880 --> 02:35:05,240
given that FTD
has many subtypes,

3002
02:35:05,240 --> 02:35:09,800
but what we know is that
the exceedingly rare variants

3003
02:35:09,800 --> 02:35:11,360
shown in the upper --

3004
02:35:11,360 --> 02:35:17,640
top upper panel on the left,
such as variants in MAPT,

3005
02:35:17,640 --> 02:35:23,800
in granulin, in VCP expansions
in C9orf72

3006
02:35:23,800 --> 02:35:27,560
and a number of other genes,
that carrying these variants

3007
02:35:27,560 --> 02:35:30,160
is really sufficient
to cause disease,

3008
02:35:30,160 --> 02:35:34,360
and these are typically
termed pathogenic mutations,

3009
02:35:34,360 --> 02:35:36,600
and understanding
the mechanism

3010
02:35:36,600 --> 02:35:40,120
by which these genes
and variants lead to disease,

3011
02:35:40,120 --> 02:35:43,160
cause disease is really
central to understanding

3012
02:35:43,160 --> 02:35:46,560
those events that are central
to disease mechanisms,

3013
02:35:46,560 --> 02:35:53,000
and ultimately these genes,
their resulting protein products

3014
02:35:53,000 --> 02:35:56,800
can be used as biomarkers
and even targeted

3015
02:35:56,800 --> 02:36:02,720
therapeutically with antisense
oligos and other mechanisms.

3016
02:36:02,720 --> 02:36:05,360
But even beyond
the pathogenic mutations,

3017
02:36:05,360 --> 02:36:09,200
there's still a lot we can learn
from sporadic populations

3018
02:36:09,200 --> 02:36:12,200
because really
these rare variants

3019
02:36:12,200 --> 02:36:18,720
that confer risk and resilience
for disease and common variants

3020
02:36:18,720 --> 02:36:22,680
can tell us a lot about
how we can manipulate the system

3021
02:36:22,680 --> 02:36:27,320
to support or protect
against disease,

3022
02:36:27,320 --> 02:36:29,560
and so some of these variants
have been identified

3023
02:36:29,560 --> 02:36:31,760
in genome-wide
association studies

3024
02:36:31,760 --> 02:36:38,480
and in other rare variant
sequencing studies and --

3025
02:36:38,480 --> 02:36:40,160
but ultimately,

3026
02:36:40,160 --> 02:36:43,720
while we know some about
the genetic architecture of FTD,

3027
02:36:43,720 --> 02:36:46,880
there remains a lot
that has been --

3028
02:36:46,880 --> 02:36:48,640
remains unexplained,

3029
02:36:48,640 --> 02:36:52,840
and this is particularly the
case among diverse populations,

3030
02:36:52,840 --> 02:36:58,120
and so that's a major goal
of our recommendations in 2022,

3031
02:36:58,120 --> 02:37:01,240
is to expand these efforts.

3032
02:37:01,240 --> 02:37:03,120
But beyond understanding
the contribution

3033
02:37:03,120 --> 02:37:07,320
of rare variants to disease,
we can also leverage existing

3034
02:37:07,320 --> 02:37:10,800
and emerging
antemortem biomarkers

3035
02:37:10,800 --> 02:37:13,840
in order to understand
how variants across the genome

3036
02:37:13,840 --> 02:37:16,040
may impact these analytes.

3037
02:37:16,040 --> 02:37:18,000
This can be a really
powerful approach

3038
02:37:18,000 --> 02:37:23,200
for understanding
additional cells

3039
02:37:23,200 --> 02:37:29,720
and gene mechanisms that may be
contributing to disease

3040
02:37:29,720 --> 02:37:34,040
and that could be monitored
in therapeutic trials

3041
02:37:34,040 --> 02:37:40,760
and address
in biologic assays,

3042
02:37:40,760 --> 02:37:46,760
and additionally,
one goal for 2022,

3043
02:37:46,760 --> 02:37:52,480
which has also been highlighted
by Dr. Boxer, is that while --

3044
02:37:52,480 --> 02:37:54,680
one really
interesting example in FTD

3045
02:37:54,680 --> 02:37:59,920
are these rare variants
in the MAPT gene that confer --

3046
02:37:59,920 --> 02:38:05,680
that lead to one form
of disease, FTD,

3047
02:38:05,680 --> 02:38:09,440
but beyond these very rare
mutations that cause disease,

3048
02:38:09,440 --> 02:38:12,400
we also know that there's
a number of common variants,

3049
02:38:12,400 --> 02:38:15,800
and you can see this
in the lower right panel,

3050
02:38:15,800 --> 02:38:19,560
common variants in the MAPT gene
that confer risk

3051
02:38:19,560 --> 02:38:22,680
for a number
of different diseases,

3052
02:38:22,680 --> 02:38:26,960
including FTD, PSP, CBD,
and even Parkinson's disease,

3053
02:38:26,960 --> 02:38:30,600
but this region remains
very poorly understood,

3054
02:38:30,600 --> 02:38:35,280
and so additional efforts
to resolve this genetic region

3055
02:38:35,280 --> 02:38:40,000
and to understand
the biologic impact is critical.

3056
02:38:40,000 --> 02:38:44,400
Next set, next slide.

3057
02:38:44,400 --> 02:38:49,480
So here I'm going to highlight
some of the outstanding progress

3058
02:38:49,480 --> 02:38:53,320
that's been made
to resolve the function

3059
02:38:53,320 --> 02:38:58,480
and to develop biomarkers
for using pathogenic mutations,

3060
02:38:58,480 --> 02:39:02,360
risk factors
and protective variants.

3061
02:39:02,360 --> 02:39:04,840
This is just a snapshot,

3062
02:39:04,840 --> 02:39:08,480
and we're leaving out
a number of incredible studies,

3063
02:39:08,480 --> 02:39:12,440
but one really exciting finding
was that VCP,

3064
02:39:12,440 --> 02:39:17,200
which is known to be mutated
and cause FTD, is --

3065
02:39:17,200 --> 02:39:23,320
has been reported to actually
act as a tau disaggregase,

3066
02:39:23,320 --> 02:39:26,560
so it can interfere
with and block

3067
02:39:26,560 --> 02:39:32,400
the aggregation of soluble tau
into fibril --

3068
02:39:32,400 --> 02:39:34,200
tau fibrils and aggregates,

3069
02:39:34,200 --> 02:39:36,440
and so this finding
is really central

3070
02:39:36,440 --> 02:39:39,880
to understanding
the function of VCP,

3071
02:39:39,880 --> 02:39:42,600
to understand the impact
of a mutation

3072
02:39:42,600 --> 02:39:46,600
that may block
this disaggregase function

3073
02:39:46,600 --> 02:39:48,360
and promote aggregation,

3074
02:39:48,360 --> 02:39:51,480
as well as to set up
potential new avenues

3075
02:39:51,480 --> 02:39:56,520
for efforts
in other diseases

3076
02:39:56,520 --> 02:39:59,400
where the tau protein
aggregates.

3077
02:39:59,400 --> 02:40:01,680
Additionally,
in the last few years,

3078
02:40:01,680 --> 02:40:03,200
there's been huge progress
made

3079
02:40:03,200 --> 02:40:08,720
in our understanding
of the expansion of C9orf72

3080
02:40:08,720 --> 02:40:12,680
and how these expansions
can lead to loss of function

3081
02:40:12,680 --> 02:40:17,120
of the C9orf72 protein
and gain of toxic function,

3082
02:40:17,120 --> 02:40:18,560
and these efforts have resolved

3083
02:40:18,560 --> 02:40:20,960
a lot of the biology
underlining --

3084
02:40:20,960 --> 02:40:24,760
underlying the function and
dysfunction of these expansions

3085
02:40:24,760 --> 02:40:25,960
but, really importantly,

3086
02:40:25,960 --> 02:40:28,840
has also led
to new opportunities

3087
02:40:28,840 --> 02:40:35,200
in the development of biomarkers
to monitor some of these DPRs

3088
02:40:35,200 --> 02:40:39,040
and also to consider
therapeutic approaches

3089
02:40:39,040 --> 02:40:42,400
that target
these mechanisms.

3090
02:40:42,400 --> 02:40:44,000
Next slide, please.

3091
02:40:46,840 --> 02:40:51,640
We just heard about UNC13A,
and this is a risk variant

3092
02:40:51,640 --> 02:40:58,880
that's been identified in ALS
and FTD, and importantly,

3093
02:40:58,880 --> 02:41:03,120
the new findings
in these parallel studies,

3094
02:41:03,120 --> 02:41:05,400
that were just published
in "Nature,"

3095
02:41:05,400 --> 02:41:10,360
really highlight
and place UNC13A in the --

3096
02:41:10,360 --> 02:41:13,840
right in the center
of TDP-43 biology,

3097
02:41:13,840 --> 02:41:16,440
and so not only does this
tell us about individuals

3098
02:41:16,440 --> 02:41:18,600
that carry these variants

3099
02:41:18,600 --> 02:41:21,760
but also provides
additional mechanisms

3100
02:41:21,760 --> 02:41:28,760
that we can apply
to TDP-43 proteinopathies.

3101
02:41:28,760 --> 02:41:30,400
Next slide.

3102
02:41:30,400 --> 02:41:32,000
-Two minutes remaining.

3103
02:41:36,520 --> 02:41:42,800
-So we can learn a lot from
these rare pathogenic mutations

3104
02:41:42,800 --> 02:41:44,560
and common risk factors,

3105
02:41:44,560 --> 02:41:47,800
but we can also learn a lot
from these protective variants,

3106
02:41:47,800 --> 02:41:51,520
where we can sort of leverage
the biology of the system

3107
02:41:51,520 --> 02:41:53,840
that's actually
promoting protection,

3108
02:41:53,840 --> 02:41:57,600
and TMEM106B, which you
just heard about, was --

3109
02:41:57,600 --> 02:41:59,240
rare variants
were actually originally --

3110
02:41:59,240 --> 02:42:02,400
or variants were
originally identified

3111
02:42:02,400 --> 02:42:05,200
in genome-wide association
studies of FTD,

3112
02:42:05,200 --> 02:42:07,240
and in fact
it was found that,

3113
02:42:07,240 --> 02:42:12,840
if you carried the minor allele
of a variant in TMEM106B,

3114
02:42:12,840 --> 02:42:14,520
that carrying that allele

3115
02:42:14,520 --> 02:42:18,440
while also carrying a causative
mutation in progranulin

3116
02:42:18,440 --> 02:42:20,960
extended survival.

3117
02:42:20,960 --> 02:42:23,760
And so in fact, TMEM106B

3118
02:42:23,760 --> 02:42:26,280
represents
this very interesting molecule

3119
02:42:26,280 --> 02:42:29,160
that both may confer
protection as well

3120
02:42:29,160 --> 02:42:33,200
as what you heard previously
may play a role in pathogenesis,

3121
02:42:33,200 --> 02:42:40,120
and huge efforts have gone on to
demonstrate a role of TMEM106B

3122
02:42:40,120 --> 02:42:41,920
in lysosomal function

3123
02:42:41,920 --> 02:42:46,560
and in trafficking
of lysosomes through axons

3124
02:42:46,560 --> 02:42:51,200
and both to highlight
the impact of TMEM106B

3125
02:42:51,200 --> 02:42:53,280
in neurons
as well as glia.

3126
02:42:53,280 --> 02:42:54,880
Next slide, please.

3127
02:42:58,600 --> 02:43:01,400
But ultimately I think
we've had a lot of success

3128
02:43:01,400 --> 02:43:06,640
in not only understanding
individual variants in genes

3129
02:43:06,640 --> 02:43:07,920
and their functions
in the cell

3130
02:43:07,920 --> 02:43:12,040
but to use high
throughput genomics

3131
02:43:12,040 --> 02:43:15,480
to identify additional
pathways in genes

3132
02:43:15,480 --> 02:43:19,760
and networks that we can
target therapeutically,

3133
02:43:19,760 --> 02:43:24,400
and one example from 2019
looked at mouse

3134
02:43:24,400 --> 02:43:28,640
and human tissue from FTD
caused by tau mutations

3135
02:43:28,640 --> 02:43:31,200
and FTD caused by
progranulin mutations

3136
02:43:31,200 --> 02:43:33,360
and identified a number
of common genes

3137
02:43:33,360 --> 02:43:34,960
that were dysregulated,

3138
02:43:34,960 --> 02:43:37,600
and among these genes
were a number of microRNAs,

3139
02:43:37,600 --> 02:43:40,680
and using
computational techniques,

3140
02:43:40,680 --> 02:43:44,000
it was identified that there was
a small molecule

3141
02:43:44,000 --> 02:43:48,320
that in fact targeted and
modified a number of the genes

3142
02:43:48,320 --> 02:43:52,080
and microRNAs that were
identified to be dysregulated.

3143
02:43:52,080 --> 02:43:54,800
These could be then taken
into cell in mouse models

3144
02:43:54,800 --> 02:43:59,840
to understand the effectiveness
of these molecules and pathways,

3145
02:43:59,840 --> 02:44:01,800
and more recently
there's been outstanding work

3146
02:44:01,800 --> 02:44:07,600
showing essentially a map of tau
interactomes in human neurons,

3147
02:44:07,600 --> 02:44:12,280
and using a PAX2
in human-induced pluripotent

3148
02:44:12,280 --> 02:44:15,280
stem cells,
it's been shown that tau in fact

3149
02:44:15,280 --> 02:44:18,080
interacts with a number
of mitochondrial proteins,

3150
02:44:18,080 --> 02:44:22,720
and in the context of mutations
in tau that cause FTD,

3151
02:44:22,720 --> 02:44:24,720
these interactions
are disrupted.

3152
02:44:24,720 --> 02:44:27,040
So these findings using
unbiased approaches

3153
02:44:27,040 --> 02:44:28,480
have really highlighted

3154
02:44:28,480 --> 02:44:33,360
a potential role
of bioenergetics in tauopathies

3155
02:44:33,360 --> 02:44:38,800
and FTD tauopathies that
can be further investigated.

3156
02:44:38,800 --> 02:44:40,280
Next slide, please.

3157
02:44:40,280 --> 02:44:41,880
-Your time has expired.

3158
02:44:44,560 --> 02:44:47,480
-And so just with
this remaining,

3159
02:44:47,480 --> 02:44:50,080
we've seen great progress
in organoids

3160
02:44:50,080 --> 02:44:53,600
that are derived from induced
pluripotent stem cells

3161
02:44:53,600 --> 02:44:56,080
that model disease-relevant
phenotypes

3162
02:44:56,080 --> 02:45:00,200
including phospho-tau, autophagy
and glutamatergic loss

3163
02:45:00,200 --> 02:45:04,800
that could be further rescued
upon treatment

3164
02:45:04,800 --> 02:45:07,040
with drugs such as apilimod.

3165
02:45:07,040 --> 02:45:08,640
And final.

3166
02:45:12,960 --> 02:45:16,840
And all of this has really
highlighted the need

3167
02:45:16,840 --> 02:45:21,640
for stem cell models
and somatic cell models

3168
02:45:21,640 --> 02:45:23,640
that are genetically defined

3169
02:45:23,640 --> 02:45:26,400
as well as
from sporadic individuals,

3170
02:45:26,400 --> 02:45:30,840
and moving forward,
additional efforts

3171
02:45:30,840 --> 02:45:34,400
are needed to build
more diverse biorepositories

3172
02:45:34,400 --> 02:45:37,840
and to leverage these lines
to understand therapeutics,

3173
02:45:37,840 --> 02:45:40,400
to understand disease mechanism
and build therapeutics.

3174
02:45:40,400 --> 02:45:42,800
So final slide.

3175
02:45:42,800 --> 02:45:46,440
So just briefly to end here,
this all highlights work

3176
02:45:46,440 --> 02:45:50,640
that has led
to our 2022 recommendations

3177
02:45:50,640 --> 02:45:54,240
to understand FTD genetics
in diverse populations,

3178
02:45:54,240 --> 02:45:58,560
to understand overlapping
pathogenic mechanisms

3179
02:45:58,560 --> 02:46:01,360
and to better elucidate
the mechanisms

3180
02:46:01,360 --> 02:46:04,440
of cell type vulnerability
and to further dissect

3181
02:46:04,440 --> 02:46:08,200
and extend these genetic
and molecular modifiers of FTD.

3182
02:46:08,200 --> 02:46:10,000
So I apologize for going over,

3183
02:46:10,000 --> 02:46:14,960
and I'll next turn it over
to Dr. Frost.

3184
02:46:14,960 --> 02:46:16,280
-Thank you, Dr. Karch.

3185
02:46:16,280 --> 02:46:17,880
So I'm Bess Frost.

3186
02:46:17,880 --> 02:46:20,400
I'm at the University of Texas
Health in San Antonio

3187
02:46:20,400 --> 02:46:23,080
and the Biggs Institute ADRC,

3188
02:46:23,080 --> 02:46:26,040
and I'll be going over
some real successes

3189
02:46:26,040 --> 02:46:30,560
since 2019 that are relevant
to milestones one and two

3190
02:46:30,560 --> 02:46:33,920
and that provide rationale
for recommendations

3191
02:46:33,920 --> 02:46:36,640
number four through seven
about the basic science

3192
02:46:36,640 --> 02:46:39,280
of frontotemporal dementia.

3193
02:46:39,280 --> 02:46:41,560
Next slide.

3194
02:46:41,560 --> 02:46:43,080
I do serve as a consultant

3195
02:46:43,080 --> 02:46:46,200
for the Neurodegeneration
Consortium at MD Anderson,

3196
02:46:46,200 --> 02:46:49,080
and I have a sponsored
research agreement with them

3197
02:46:49,080 --> 02:46:52,000
as well as with
Transposon Therapeutics.

3198
02:46:52,000 --> 02:46:54,440
Next slide.

3199
02:46:54,440 --> 02:46:58,120
So I'll first focus
on milestone one,

3200
02:46:58,120 --> 02:47:01,120
which was really focused
on trying to understand

3201
02:47:01,120 --> 02:47:04,800
the shared mechanisms of disease
among different proteins

3202
02:47:04,800 --> 02:47:08,240
that are known to accumulate
in frontotemporal dementias.

3203
02:47:08,240 --> 02:47:12,400
So tau, TDP-43 and dipeptide
repeats

3204
02:47:12,400 --> 02:47:15,880
originating from C9orf72
expansions

3205
02:47:15,880 --> 02:47:17,200
are some of the proteins

3206
02:47:17,200 --> 02:47:19,680
that accumulate in
frontotemporal dementia.

3207
02:47:19,680 --> 02:47:21,280
This is not comprehensive,

3208
02:47:21,280 --> 02:47:23,400
but I felt that
the most progress

3209
02:47:23,400 --> 02:47:26,200
in terms of shared mechanisms
have come out of work

3210
02:47:26,200 --> 02:47:30,600
focusing on these three
different aspects of FTD.

3211
02:47:30,600 --> 02:47:32,760
Next slide.

3212
02:47:32,760 --> 02:47:35,720
We have really gained
a greater understanding

3213
02:47:35,720 --> 02:47:40,720
of how these proteins affect
overall nuclear architecture

3214
02:47:40,720 --> 02:47:43,360
and what's going on
in the nucleus,

3215
02:47:43,360 --> 02:47:46,280
and importantly, these studies
have ranged from,

3216
02:47:46,280 --> 02:47:52,160
you know, flies to iPSC cultures
to analyzing human brain tissue.

3217
02:47:52,160 --> 02:47:53,800
Next slide.

3218
02:47:53,800 --> 02:47:56,280
For example, we see in the
context of tauopathies

3219
02:47:56,280 --> 02:47:59,480
that there are invaginations
of the nucleus

3220
02:47:59,480 --> 02:48:01,640
deep into the nucleoplasm.

3221
02:48:01,640 --> 02:48:06,200
This also occurs in the context
of TDP-43 toxicity

3222
02:48:06,200 --> 02:48:11,880
and in some models but not
all of C9orf72 expansions.

3223
02:48:11,880 --> 02:48:15,480
In the context of these
proteins, nuclear pore proteins

3224
02:48:15,480 --> 02:48:17,880
have been shown to be depleted
in some contexts

3225
02:48:17,880 --> 02:48:19,760
and even pulled out
of the nucleus

3226
02:48:19,760 --> 02:48:22,120
and accumulate
in the cytoplasm.

3227
02:48:22,120 --> 02:48:26,000
Nucleocytoplasmic transport
deficits have been reported

3228
02:48:26,000 --> 02:48:29,080
in the contexts
of all of these proteins.

3229
02:48:29,080 --> 02:48:32,320
These affect how RNA is
trafficked out of the nucleus.

3230
02:48:32,320 --> 02:48:34,400
For example, in the context
of tauopathy,

3231
02:48:34,400 --> 02:48:36,600
we see that RNA accumulates
within these

3232
02:48:36,600 --> 02:48:41,880
nuclear envelope invaginations
as well as how proteins

3233
02:48:41,880 --> 02:48:44,880
are trafficked in
and out of the nucleus.

3234
02:48:44,880 --> 02:48:47,680
Next slide.

3235
02:48:47,680 --> 02:48:49,800
We've also seen quite a bit
of work

3236
02:48:49,800 --> 02:48:54,360
suggesting that all of these
factors disrupt

3237
02:48:54,360 --> 02:48:57,160
heterochromatin-mediated
gene silencing,

3238
02:48:57,160 --> 02:49:04,480
so the overall structure of how
DNA is localized in the nucleus,

3239
02:49:04,480 --> 02:49:09,520
and the specific type
of epigenetic changes

3240
02:49:09,520 --> 02:49:14,480
that are being seen are a loss
of heterochromatin-mediated

3241
02:49:14,480 --> 02:49:15,560
gene silencing.

3242
02:49:15,560 --> 02:49:18,000
Next slide.

3243
02:49:18,000 --> 02:49:22,400
So we see that tau, TDP-43
and in the context of C9orf72

3244
02:49:22,400 --> 02:49:25,400
expansions that heterochromatin
protein 1,

3245
02:49:25,400 --> 02:49:29,320
which is really important for
maintaining a tight packaging

3246
02:49:29,320 --> 02:49:32,720
of DNA near the centromere,
is becoming disrupted,

3247
02:49:32,720 --> 02:49:35,080
and when this protein
becomes disrupted,

3248
02:49:35,080 --> 02:49:38,600
you see increased
expression, transcription

3249
02:49:38,600 --> 02:49:42,200
of repetitive elements that are
located near the centromere.

3250
02:49:42,200 --> 02:49:45,000
Next slide.

3251
02:49:45,000 --> 02:49:48,720
One of the types of elements
that is silenced by this really,

3252
02:49:48,720 --> 02:49:52,880
really condensed type of DNA
are the transposable elements.

3253
02:49:52,880 --> 02:49:55,040
So these transposable elements

3254
02:49:55,040 --> 02:49:58,120
make up 45 percent
of the human genome.

3255
02:49:58,120 --> 02:50:00,200
They're very similar to --

3256
02:50:00,200 --> 02:50:03,200
They're very similar in sequence
to exogenous viruses,

3257
02:50:03,200 --> 02:50:05,360
and it's thought
that these elements

3258
02:50:05,360 --> 02:50:07,040
got stuck
in the human genome

3259
02:50:07,040 --> 02:50:09,720
due to infection
of the germ line,

3260
02:50:09,720 --> 02:50:12,080
you know,
over the course of evolution,

3261
02:50:12,080 --> 02:50:13,760
and our cells
have developed strategies,

3262
02:50:13,760 --> 02:50:16,720
one of which is silencing
by heterochromatin,

3263
02:50:16,720 --> 02:50:19,200
to keep these elements
silenced.

3264
02:50:19,200 --> 02:50:22,680
However, in the context
of all of these types

3265
02:50:22,680 --> 02:50:24,240
of frontotemporal dementia...

3266
02:50:24,240 --> 02:50:26,560
Next slide --

3267
02:50:26,560 --> 02:50:28,800
we see that these
transposable elements

3268
02:50:28,800 --> 02:50:31,000
are becoming activated,
and in fact,

3269
02:50:31,000 --> 02:50:35,680
the basic mechanistic studies
in the context of tau

3270
02:50:35,680 --> 02:50:40,160
and C9orf have led
to two clinical trials

3271
02:50:40,160 --> 02:50:42,000
that are currently ongoing
for the treatment

3272
02:50:42,000 --> 02:50:43,360
of Alzheimer's disease

3273
02:50:43,360 --> 02:50:47,160
that are leveraging
antiretroviral therapies

3274
02:50:47,160 --> 02:50:49,240
to stop transposable
element activation

3275
02:50:49,240 --> 02:50:51,240
and suppress
neurodegeneration.

3276
02:50:51,240 --> 02:50:55,840
There are also currently trials
enrolling for PSP and ALS/FTD

3277
02:50:55,840 --> 02:50:59,640
associated with
C9orf72 expansion.

3278
02:50:59,640 --> 02:51:02,800
Next slide.

3279
02:51:02,800 --> 02:51:04,600
We also --

3280
02:51:04,600 --> 02:51:07,800
There's a lot of accumulating
work from many different groups

3281
02:51:07,800 --> 02:51:09,600
about the effects
of these proteins

3282
02:51:09,600 --> 02:51:12,400
on splicing
and RNA metabolism.

3283
02:51:12,400 --> 02:51:14,680
You heard from Dr. Petrucelli
and Dr. Karch

3284
02:51:14,680 --> 02:51:20,640
about links between TDP --
effects of TDP-43 on splicing.

3285
02:51:20,640 --> 02:51:22,400
I have to include FUS in here
as well

3286
02:51:22,400 --> 02:51:25,720
because FUS is a well-known
regulator of RNA splicing.

3287
02:51:25,720 --> 02:51:28,400
Next slide.

3288
02:51:28,400 --> 02:51:30,320
So these proteins have either
been shown

3289
02:51:30,320 --> 02:51:32,480
to interact directly
with the spliceosome

3290
02:51:32,480 --> 02:51:35,000
or to affect
spliceosome function.

3291
02:51:35,000 --> 02:51:38,880
We see splicing aberrations
in all of these contexts.

3292
02:51:38,880 --> 02:51:41,800
For example, in the context
of tau pathology,

3293
02:51:41,800 --> 02:51:43,760
there's an increase
in intron retention.

3294
02:51:43,760 --> 02:51:46,680
We heard about cryptic
exon inclusion in TDP-43,

3295
02:51:46,680 --> 02:51:48,080
et cetera,

3296
02:51:48,080 --> 02:51:49,880
and there's
accumulating evidence

3297
02:51:49,880 --> 02:51:54,200
that the overall quality of RNA
is compromised in the context

3298
02:51:54,200 --> 02:51:56,520
of these -- this type of front--

3299
02:51:56,520 --> 02:51:59,240
these types
of frontotemporal dementia.

3300
02:51:59,240 --> 02:52:00,800
Next slide.

3301
02:52:00,800 --> 02:52:07,200
-Two minutes remaining.
-New work reports that tau

3302
02:52:07,200 --> 02:52:11,400
and C9orf72
are associated with senescence.

3303
02:52:11,400 --> 02:52:16,120
So this is a cellular phenotype,
where if the cell is

3304
02:52:16,120 --> 02:52:19,000
replicative,
it stops replicating,

3305
02:52:19,000 --> 02:52:22,400
and it starts to secrete
inflammatory factors

3306
02:52:22,400 --> 02:52:25,480
that are detrimental
for the cells next to it.

3307
02:52:25,480 --> 02:52:28,160
In the context of tauopathy,
we now know that --

3308
02:52:28,160 --> 02:52:31,440
or there is evidence supporting
senescence in neurons,

3309
02:52:31,440 --> 02:52:34,280
which oppose mitotic --
most of which oppose mitotic,

3310
02:52:34,280 --> 02:52:36,600
the vasculature
and in astrocytes,

3311
02:52:36,600 --> 02:52:39,360
and this work has led
to two clinical trials

3312
02:52:39,360 --> 02:52:43,400
now using senolytics for the
purpose of Alzheimer's disease,

3313
02:52:43,400 --> 02:52:47,120
where these drugs
are killing the senescent cells.

3314
02:52:47,120 --> 02:52:48,400
And I realize
that Alzheimer's disease

3315
02:52:48,400 --> 02:52:50,280
is not frontotemporal dementia,

3316
02:52:50,280 --> 02:52:52,640
but because these mechanisms
are tau-based,

3317
02:52:52,640 --> 02:52:54,440
it's possible that
if we see success

3318
02:52:54,440 --> 02:52:56,240
in the Alzheimer's
disease area,

3319
02:52:56,240 --> 02:53:00,920
these trials could also be
relevant for FTD tauopathies

3320
02:53:00,920 --> 02:53:05,200
and C9orf72 expansions,
which is already enrolling.

3321
02:53:05,200 --> 02:53:08,280
Next slide.

3322
02:53:08,280 --> 02:53:11,600
So for milestone two,
this is focused on aggregation

3323
02:53:11,600 --> 02:53:13,800
from 2019, aggregation
and intercellular

3324
02:53:13,800 --> 02:53:16,200
spread of FTD-associated
proteins.

3325
02:53:16,200 --> 02:53:17,760
There's new work
in the tau area,

3326
02:53:17,760 --> 02:53:20,000
really nice work
from Judith Steen

3327
02:53:20,000 --> 02:53:23,240
using her
FLEXITau technology,

3328
02:53:23,240 --> 02:53:26,200
really creating a barcode
of tau phosphorylation,

3329
02:53:26,200 --> 02:53:30,120
acetylation, ubiquitination
and methylation events

3330
02:53:30,120 --> 02:53:32,000
that are associated
with tau aggregation.

3331
02:53:32,000 --> 02:53:34,400
Next slide.

3332
02:53:34,400 --> 02:53:38,160
In terms of tau spread,
we know now that LRP1

3333
02:53:38,160 --> 02:53:41,680
is a major regulator
of cell-to-cell tau spread.

3334
02:53:41,680 --> 02:53:44,000
We know that microglia
are important cell types

3335
02:53:44,000 --> 02:53:46,280
that facilitate the spread
of tau between cells,

3336
02:53:46,280 --> 02:53:49,080
and we now know
that viral capsid proteins

3337
02:53:49,080 --> 02:53:53,280
may be also facilitating
the spread of tau between cells.

3338
02:53:53,280 --> 02:53:55,680
Next slide.

3339
02:53:55,680 --> 02:54:00,360
TDP-43, great work
from the past few years shows

3340
02:54:00,360 --> 02:54:03,960
that S-nitrosylation is
important for TDP-43 aggregation

3341
02:54:03,960 --> 02:54:05,520
and spread.

3342
02:54:05,520 --> 02:54:07,760
Next slide.

3343
02:54:07,760 --> 02:54:11,480
So based on all of these
successes since 2019,

3344
02:54:11,480 --> 02:54:15,280
we thought it was important to
leverage what's really working

3345
02:54:15,280 --> 02:54:17,560
and continue doing that
for the future,

3346
02:54:17,560 --> 02:54:19,520
so recommendations four,
five, six

3347
02:54:19,520 --> 02:54:23,000
and seven are all relevant
to what I spoke about today,

3348
02:54:23,000 --> 02:54:26,040
and you can read more about them
in the meeting materials.

3349
02:54:26,040 --> 02:54:27,640
Thank you.

3350
02:54:31,400 --> 02:54:32,480
-All right.

3351
02:54:32,480 --> 02:54:33,600
Thank you, Dr. Frost.

3352
02:54:33,600 --> 02:54:35,240
So I'm Richard Tsai.

3353
02:54:35,240 --> 02:54:38,200
I'm a Senior Medical Director
at Denali Therapeutics,

3354
02:54:38,200 --> 02:54:41,120
and I've been asked to sort of
give a overview

3355
02:54:41,120 --> 02:54:44,200
of clinical trials in FTD
and all the advances recently

3356
02:54:44,200 --> 02:54:47,120
but also give a perspective
from the industry side

3357
02:54:47,120 --> 02:54:50,360
on developing therapeutics
for FTD

3358
02:54:50,360 --> 02:54:53,000
and, most of all,
talk about what reflect

3359
02:54:53,000 --> 02:54:55,360
2022 recommendations
one through three.

3360
02:54:55,360 --> 02:54:57,360
Next slide.

3361
02:54:57,360 --> 02:54:59,480
These are the disclaimers
and disclosures,

3362
02:54:59,480 --> 02:55:01,840
and go ahead, next slide.

3363
02:55:01,840 --> 02:55:04,480
Okay, so the speakers
before me

3364
02:55:04,480 --> 02:55:07,040
have really illustrated a lot of
the advancements in FTD,

3365
02:55:07,040 --> 02:55:09,040
whether it's genetics,
tau structure,

3366
02:55:09,040 --> 02:55:11,800
protein homeostasis,
cell senescence,

3367
02:55:11,800 --> 02:55:13,760
and really the advancements
in these areas

3368
02:55:13,760 --> 02:55:16,720
have really resulted
in an explosion

3369
02:55:16,720 --> 02:55:18,360
of clinical trials in FTD,

3370
02:55:18,360 --> 02:55:21,720
and really it's such an exciting
time to be in this field.

3371
02:55:21,720 --> 02:55:24,200
If you see on the right there,
this is derived from a recent

3372
02:55:24,200 --> 02:55:26,000
"Lancet Neurology"
review article.

3373
02:55:26,000 --> 02:55:29,360
There's a lot of clinical
trials,

3374
02:55:29,360 --> 02:55:31,960
most of them thought to be
disease-modifying therapy,

3375
02:55:31,960 --> 02:55:35,000
especially in FTD caused by
the granulin gene mutation

3376
02:55:35,000 --> 02:55:37,280
or the C9 mutation
as well,

3377
02:55:37,280 --> 02:55:38,960
but what I want
to point out here

3378
02:55:38,960 --> 02:55:43,080
is that despite the improved
availability of clinical trials,

3379
02:55:43,080 --> 02:55:45,880
more has to be done,
especially if you look here.

3380
02:55:45,880 --> 02:55:50,800
Not a lot is being done in
MAPT mutation or sporadic FTD,

3381
02:55:50,800 --> 02:55:54,000
and really, if you pay
a little more close attention,

3382
02:55:54,000 --> 02:55:56,920
you know, the trials
currently available

3383
02:55:56,920 --> 02:55:58,840
for MAPT mutation
and sporadic FTD

3384
02:55:58,840 --> 02:56:01,640
are actually all
investigator-initiated trials,

3385
02:56:01,640 --> 02:56:04,040
which really emphasizes
sort of the importance

3386
02:56:04,040 --> 02:56:08,720
of NIH-funded,
academia-started,

3387
02:56:08,720 --> 02:56:10,400
investigator-initiated
clinical trials

3388
02:56:10,400 --> 02:56:13,760
and maybe a reflection
on some of the novel

3389
02:56:13,760 --> 02:56:15,240
and risk-taking
measures available

3390
02:56:15,240 --> 02:56:16,920
through that mechanism.

3391
02:56:16,920 --> 02:56:20,120
And finally, also, these are all
pharmacological clinical trials,

3392
02:56:20,120 --> 02:56:23,280
and as I said, most of them are
thought to be disease-modifying,

3393
02:56:23,280 --> 02:56:26,400
but we really shouldn't forget
the importance of drugs

3394
02:56:26,400 --> 02:56:30,400
that could offer symptomatic
benefits to clinical trials,

3395
02:56:30,400 --> 02:56:32,600
as well as
nonpharmacological interventions

3396
02:56:32,600 --> 02:56:33,800
that are not listed here.

3397
02:56:33,800 --> 02:56:36,400
Next slide, please.

3398
02:56:36,400 --> 02:56:42,400
So first, I just want to go over
how really academic consortiums,

3399
02:56:42,400 --> 02:56:45,600
such as ALLFTD that Adam Boxer
mentioned earlier or GENFI

3400
02:56:45,600 --> 02:56:48,400
over in Canada
and parts of Europe,

3401
02:56:48,400 --> 02:56:51,080
have really enabled
drug development.

3402
02:56:51,080 --> 02:56:54,080
These international cohorts
with longitudinal clinical data,

3403
02:56:54,080 --> 02:56:57,000
biomarker collection
and infrastructure

3404
02:56:57,000 --> 02:56:59,560
have really enabled drug
development and trial design.

3405
02:56:59,560 --> 02:57:02,640
So what's maybe not
super obvious here

3406
02:57:02,640 --> 02:57:05,440
is you see both consortiums
have identified

3407
02:57:05,440 --> 02:57:07,000
and are following
a lot of patients,

3408
02:57:07,000 --> 02:57:08,680
collecting a lot of data,

3409
02:57:08,680 --> 02:57:11,080
but what's not so obvious here
is that also they have --

3410
02:57:11,080 --> 02:57:12,400
they're working with sites

3411
02:57:12,400 --> 02:57:15,480
across the U.S.
and Europe and Canada,

3412
02:57:15,480 --> 02:57:17,760
and that's also really important
for drug development

3413
02:57:17,760 --> 02:57:19,120
and clinical trial design

3414
02:57:19,120 --> 02:57:21,760
because this enables
industry folks, like us,

3415
02:57:21,760 --> 02:57:25,800
to really have
sort of a first...

3416
02:57:25,800 --> 02:57:29,040
Not firsthand but a ready
knowledge of which sites

3417
02:57:29,040 --> 02:57:32,240
have the physicians and staff
and infrastructure

3418
02:57:32,240 --> 02:57:34,080
that is already
sort of known

3419
02:57:34,080 --> 02:57:37,400
to be able to handle
a clinical trial for FTD.

3420
02:57:37,400 --> 02:57:40,400
Next slide, please.

3421
02:57:40,400 --> 02:57:42,480
So I want to give a case example

3422
02:57:42,480 --> 02:57:45,760
of how all of this effort
in the past 3 years

3423
02:57:45,760 --> 02:57:49,200
have really helped
developing drugs for FTD,

3424
02:57:49,200 --> 02:57:51,120
and this is the case
example for FTD

3425
02:57:51,120 --> 02:57:52,720
caused by the granulin
gene mutation,

3426
02:57:52,720 --> 02:57:55,560
which we all know results
in haploinsufficiency,

3427
02:57:55,560 --> 02:57:59,480
30 to 50 percent of progranulin
in the CSF peripheral blood,

3428
02:57:59,480 --> 02:58:01,480
which we think, you know, is...

3429
02:58:01,480 --> 02:58:03,720
Progranulin is critical
for lysosomal function,

3430
02:58:03,720 --> 02:58:05,560
so it may lead
to lysosomal dysfunction

3431
02:58:05,560 --> 02:58:08,960
and may ultimately lead
to inflammation, microgliosis,

3432
02:58:08,960 --> 02:58:11,600
TDP-43 pathology
and neurodegeneration,

3433
02:58:11,600 --> 02:58:13,360
as illustrated
by the highly elevated

3434
02:58:13,360 --> 02:58:15,600
NF-L there in the CS set.

3435
02:58:15,600 --> 02:58:17,720
So in this case study, you know,

3436
02:58:17,720 --> 02:58:19,960
we thought
that we would give --

3437
02:58:19,960 --> 02:58:22,320
solve this problem
by giving back progranulin

3438
02:58:22,320 --> 02:58:24,720
using a brain penetrant
progranulin technology.

3439
02:58:24,720 --> 02:58:27,880
Next slide, please.

3440
02:58:27,880 --> 02:58:29,440
But does this really work?

3441
02:58:29,440 --> 02:58:32,000
So next slide.

3442
02:58:32,000 --> 02:58:34,960
What we were able to do
in collaboration with ALLFTD

3443
02:58:34,960 --> 02:58:38,600
is to really use the large
amounts of clinical data

3444
02:58:38,600 --> 02:58:42,920
as well as biofluid samples
in a collaborative study,

3445
02:58:42,920 --> 02:58:46,680
and we used it to identify
a series of abnormal biomarkers

3446
02:58:46,680 --> 02:58:50,600
in patients with FTD caused by
the granulin gene mutation

3447
02:58:50,600 --> 02:58:54,720
that really sort of reflects
the pathophysiology hypothesis

3448
02:58:54,720 --> 02:58:56,200
of lysosomal dysfunction,

3449
02:58:56,200 --> 02:58:58,960
inflammation, gliosis
and neurodegeneration.

3450
02:58:58,960 --> 02:59:02,360
So here you can see on the top
row data from ALLFTD,

3451
02:59:02,360 --> 02:59:04,400
patients with the granulin
gene mutation

3452
02:59:04,400 --> 02:59:05,960
on the right,
orange and dark red,

3453
02:59:05,960 --> 02:59:08,600
and you can see
that asymptomatic carriers

3454
02:59:08,600 --> 02:59:10,320
have elevated
glucosylsphingosine

3455
02:59:10,320 --> 02:59:12,080
or lysosomal biomarker,

3456
02:59:12,080 --> 02:59:14,360
and patients in dark red
are symptomatic FTD

3457
02:59:14,360 --> 02:59:15,840
with a granulin gene mutation

3458
02:59:15,840 --> 02:59:19,680
but even higher
elevated glucosylsphingosine,

3459
02:59:19,680 --> 02:59:22,200
and they also have
elevated YKL-40

3460
02:59:22,200 --> 02:59:24,160
or biomarker
of astrogliosis

3461
02:59:24,160 --> 02:59:25,880
and, of course,
highly elevated NF-L

3462
02:59:25,880 --> 02:59:28,240
when they become
symptomatic.

3463
02:59:28,240 --> 02:59:33,200
So that sort of reflects
the pathophysiology hypothesis,

3464
02:59:33,200 --> 02:59:35,200
but what's nice is that
we were able to find

3465
02:59:35,200 --> 02:59:38,800
the same abnormal biomarkers
in granulin knockout mouse

3466
02:59:38,800 --> 02:59:40,360
and treat them
with this drug,

3467
02:59:40,360 --> 02:59:42,400
this brain penetrant
progranulin,

3468
02:59:42,400 --> 02:59:44,680
and we see a near
dose-responsive

3469
02:59:44,680 --> 02:59:48,400
improvement or correction
of these same biomarkers

3470
02:59:48,400 --> 02:59:51,600
that are abnormal in patients
that are also abnormal in mouse,

3471
02:59:51,600 --> 02:59:54,600
so, you know, improvements
in glucosylsphingosine,

3472
02:59:54,600 --> 02:59:57,440
improvements in YKL-40
and also improvements in NF-L.

3473
02:59:57,440 --> 02:59:59,360
So this really helped accelerate

3474
02:59:59,360 --> 03:00:02,960
a preclinical proof of concept
for drug developers like us

3475
03:00:02,960 --> 03:00:05,200
in order to bring the drug
into the clinic,

3476
03:00:05,200 --> 03:00:08,600
and I'll further add
that all this clinical data

3477
03:00:08,600 --> 03:00:12,080
obtained from ALLFTD and GENFI
has really helped drug companies

3478
03:00:12,080 --> 03:00:16,520
sort of determine the right size
and duration of clinical trials

3479
03:00:16,520 --> 03:00:18,080
to accurately...

3480
03:00:18,080 --> 03:00:19,960
So that we can have
more confidence that we'll see

3481
03:00:19,960 --> 03:00:23,120
the effect size in
these biomarkers that we want.

3482
03:00:23,120 --> 03:00:24,800
Next slide, please.

3483
03:00:24,800 --> 03:00:26,680
-Two minutes remaining.
-Oh, that was quick.

3484
03:00:26,680 --> 03:00:32,200
Okay, so I just want to quickly
go over

3485
03:00:32,200 --> 03:00:33,560
some of the challenges
we're facing.

3486
03:00:33,560 --> 03:00:37,400
I think sample size
estimated at FTD

3487
03:00:37,400 --> 03:00:39,800
you'll need about 200 patients
in the pivotal trial

3488
03:00:39,800 --> 03:00:42,120
to gain a clinical
meaningful effect.

3489
03:00:42,120 --> 03:00:44,800
And on the right there,
we see that, you know,

3490
03:00:44,800 --> 03:00:47,120
as a case study
for FTD progranulin,

3491
03:00:47,120 --> 03:00:49,400
just back-of-the-envelope
calculation

3492
03:00:49,400 --> 03:00:51,600
after taking the prevalence
and estimates

3493
03:00:51,600 --> 03:00:52,880
for the number
of Americans we...

3494
03:00:52,880 --> 03:00:54,720
That's just maybe
400 trial-ready patients,

3495
03:00:54,720 --> 03:00:56,480
meaning patients
with a mutation,

3496
03:00:56,480 --> 03:00:58,600
right stage
of disease severity,

3497
03:00:58,600 --> 03:01:01,600
not just severe
and also not asymptomatic.

3498
03:01:01,600 --> 03:01:03,920
And so, you know, there may not
be enough patients

3499
03:01:03,920 --> 03:01:06,200
to support multiple
investigational efforts for FTD,

3500
03:01:06,200 --> 03:01:07,600
especially for male FTD.

3501
03:01:07,600 --> 03:01:09,560
So to solve this,
we either enhance

3502
03:01:09,560 --> 03:01:10,880
the availability of patients

3503
03:01:10,880 --> 03:01:12,800
or improve clinical
trial efficiency.

3504
03:01:12,800 --> 03:01:15,800
So next slide, please.

3505
03:01:15,800 --> 03:01:18,000
One way, of course,
as many people understand,

3506
03:01:18,000 --> 03:01:19,600
is to gain better understanding

3507
03:01:19,600 --> 03:01:22,520
of underrepresented
diverse populations in FTD.

3508
03:01:22,520 --> 03:01:24,440
And on the left here,
you can see that we know

3509
03:01:24,440 --> 03:01:27,000
quite a bit about FTD
in North America and Europe,

3510
03:01:27,000 --> 03:01:29,400
but very little
in South America, Asia

3511
03:01:29,400 --> 03:01:31,040
and virtually nothing Africa.

3512
03:01:31,040 --> 03:01:34,280
And, you know, I think
by understanding FTD better

3513
03:01:34,280 --> 03:01:35,440
in these populations,

3514
03:01:35,440 --> 03:01:37,160
we sort of enhance
the availability

3515
03:01:37,160 --> 03:01:39,000
to the pool of patients
that we needed,

3516
03:01:39,000 --> 03:01:41,000
we were able to study
and develop drugs

3517
03:01:41,000 --> 03:01:44,840
with because we need better
tools to understand FTD

3518
03:01:44,840 --> 03:01:46,360
in these populations

3519
03:01:46,360 --> 03:01:48,040
and better measurements
for end points as well.

3520
03:01:48,040 --> 03:01:51,120
Next slide, please.

3521
03:01:51,120 --> 03:01:54,120
And just want to illustrate
that other ways to make trials

3522
03:01:54,120 --> 03:01:56,400
more efficient
is through biomarkers,

3523
03:01:56,400 --> 03:01:59,560
and this is data that shows
that NfL really rises

3524
03:01:59,560 --> 03:02:01,600
dramatically
during the conversion stage

3525
03:02:01,600 --> 03:02:04,400
from asymptomatic to symptomatic
on the left here,

3526
03:02:04,400 --> 03:02:08,000
and so that may help us identify
patients that progress rapidly

3527
03:02:08,000 --> 03:02:10,600
and maybe decrease
the sample size.

3528
03:02:10,600 --> 03:02:13,120
And here in the middle is a
paper that shows that baseline

3529
03:02:13,120 --> 03:02:15,520
NfL levels may also
predict disease progression,

3530
03:02:15,520 --> 03:02:17,840
which may also help us
identify patients

3531
03:02:17,840 --> 03:02:20,400
that change more rapidly
during clinical trial.

3532
03:02:20,400 --> 03:02:22,720
And on the right here is a paper
from the ALLFTD group.

3533
03:02:22,720 --> 03:02:25,680
This shows the MRI
atrophy rates differ

3534
03:02:25,680 --> 03:02:28,640
and change in MAPT and granulin
gene mutation carriers,

3535
03:02:28,640 --> 03:02:32,320
but not so much in C9 carriers,
which also helps drug companies

3536
03:02:32,320 --> 03:02:35,520
design sample sizes
and treatment durations

3537
03:02:35,520 --> 03:02:38,280
as we are developing
therapies and clinical trials.

3538
03:02:38,280 --> 03:02:39,880
Next slide, please.

3539
03:02:42,040 --> 03:02:43,880
-We are at time.
-Oh, okay.

3540
03:02:43,880 --> 03:02:46,600
And finally, I just want to end
with, you know,

3541
03:02:46,600 --> 03:02:49,240
novel clinical trial designs
will also really help us.

3542
03:02:49,240 --> 03:02:51,960
On the left, I took a sample
from the HEALEY ALS Platform

3543
03:02:51,960 --> 03:02:55,320
Trial just to emphasize that,
you know, novel trial designs

3544
03:02:55,320 --> 03:02:57,560
can allow us to evaluate
multiple therapies,

3545
03:02:57,560 --> 03:03:00,480
decrease the placebo group
as they share placebo groups,

3546
03:03:00,480 --> 03:03:02,320
but a three
to one randomization.

3547
03:03:02,320 --> 03:03:04,360
And on the right here
is another example of a basket

3548
03:03:04,360 --> 03:03:08,040
trial conducted by UCS,
where we took a single drug

3549
03:03:08,040 --> 03:03:10,040
and evaluated it against
multiple diseases

3550
03:03:10,040 --> 03:03:13,640
in a single trial that all have
tau pathology.

3551
03:03:13,640 --> 03:03:16,160
And this also may increase the
efficiency of clinical trials,

3552
03:03:16,160 --> 03:03:17,800
so thank you for your time.

3553
03:03:23,320 --> 03:03:25,560
-Good afternoon, everyone,
and thank you for being here.

3554
03:03:25,560 --> 03:03:27,800
I'm Chiadi Onyike from Johns
Hopkins University

3555
03:03:27,800 --> 03:03:29,920
and along with Dr. Penny Dacks

3556
03:03:29,920 --> 03:03:31,840
from The Association
for Frontotemporal Dementia.

3557
03:03:31,840 --> 03:03:35,600
It falls on us both essentially
to land this ship.

3558
03:03:35,600 --> 03:03:37,160
We will be summarizing
the objectives

3559
03:03:37,160 --> 03:03:39,280
of our committees'
recommendations.

3560
03:03:39,280 --> 03:03:41,960
May I have the next slide,
please?

3561
03:03:41,960 --> 03:03:43,920
So for transparency,
I will mention

3562
03:03:43,920 --> 03:03:46,560
that I have sponsored research
with Alector

3563
03:03:46,560 --> 03:03:48,600
and conversations
with Transposon and Denali

3564
03:03:48,600 --> 03:03:49,880
about sponsored research,

3565
03:03:49,880 --> 03:03:51,720
and I'm also a consultant
with Alector.

3566
03:03:51,720 --> 03:03:53,840
Dr. Dacks has no disclosures.

3567
03:03:53,840 --> 03:03:56,000
Let's have the next one.

3568
03:03:56,000 --> 03:03:57,160
Thank you.

3569
03:03:57,160 --> 03:03:58,840
Now, the last 15 odd years

3570
03:03:58,840 --> 03:04:02,000
have been an especially
dynamic period for FTD research,

3571
03:04:02,000 --> 03:04:05,360
and the extraordinary leaps
in our knowledge

3572
03:04:05,360 --> 03:04:08,000
have been so well illustrated
in the early presentations,

3573
03:04:08,000 --> 03:04:09,800
as you've seen.

3574
03:04:09,800 --> 03:04:12,440
In saluting this progress then,
I would like to take a moment

3575
03:04:12,440 --> 03:04:14,280
to remember
two important figures

3576
03:04:14,280 --> 03:04:17,760
that we lost in the last year,
Professor John Trojanowski

3577
03:04:17,760 --> 03:04:20,080
and Professor Stuart
Pickering-Brown.

3578
03:04:22,400 --> 03:04:25,400
So their hugely influential
contributions are deeply,

3579
03:04:25,400 --> 03:04:27,960
deeply appreciated.

3580
03:04:27,960 --> 03:04:30,160
The new recommendations
are designed to build

3581
03:04:30,160 --> 03:04:33,240
on the progress since 2019,
and that's been a period

3582
03:04:33,240 --> 03:04:36,440
in which the leveraging of large
international FTD cohorts

3583
03:04:36,440 --> 03:04:42,640
primarily in North America
and Europe and new technologies,

3584
03:04:42,640 --> 03:04:45,720
leveraging the many
penetrating lines of research

3585
03:04:45,720 --> 03:04:48,320
have led to important clinical
and biological discoveries.

3586
03:04:48,320 --> 03:04:50,200
And these have yielded,
as Dr. Tsai

3587
03:04:50,200 --> 03:04:52,960
has just illustrated,
an impressive first wave

3588
03:04:52,960 --> 03:04:56,400
of disease-modifying
opportunities and drugs.

3589
03:04:56,400 --> 03:04:58,240
Now the activities that
are encapsulated

3590
03:04:58,240 --> 03:04:59,800
in any recommendations

3591
03:04:59,800 --> 03:05:02,600
are intended to build
on this momentum by firstly,

3592
03:05:02,600 --> 03:05:06,720
incorporating ethnocultural
and socioeconomic questions

3593
03:05:06,720 --> 03:05:08,280
at the clinical
and preclinical levels.

3594
03:05:08,280 --> 03:05:12,240
And this is explicit
in recommendation one,

3595
03:05:12,240 --> 03:05:13,880
but the recommendation
two speaks to it

3596
03:05:13,880 --> 03:05:16,400
in terms of access
of diagnosis and care,

3597
03:05:16,400 --> 03:05:18,600
and in recommendation
eight in terms

3598
03:05:18,600 --> 03:05:21,760
of linking
this preclinical level.

3599
03:05:21,760 --> 03:05:24,920
Now, we also expect to deepen
and cross-link

3600
03:05:24,920 --> 03:05:26,320
the preclinical lines
of research,

3601
03:05:26,320 --> 03:05:28,760
and this is illustrated
or mentioned

3602
03:05:28,760 --> 03:05:31,040
in recommendations four,
seven and eight.

3603
03:05:31,040 --> 03:05:34,840
There's an explicit emphasis
on preclinical drug development

3604
03:05:34,840 --> 03:05:37,560
activities in recommendations
five and six,

3605
03:05:37,560 --> 03:05:39,160
emphasis on translation
of discoveries

3606
03:05:39,160 --> 03:05:41,640
into buy markets and novel drugs
in recommendations two,

3607
03:05:41,640 --> 03:05:43,520
three, five and six.

3608
03:05:43,520 --> 03:05:46,800
And altogether,
the overarching agenda

3609
03:05:46,800 --> 03:05:50,200
is an expansion of clinical --
or the culminating agenda --

3610
03:05:50,200 --> 03:05:52,000
We expect this to culminate
in an expansion

3611
03:05:52,000 --> 03:05:55,000
of clinical trials
and treatments

3612
03:05:55,000 --> 03:05:57,000
that will arrest progression,

3613
03:05:57,000 --> 03:06:01,560
hopefully also
rehabilitate impairments.

3614
03:06:01,560 --> 03:06:03,200
So our committee has also
recognized

3615
03:06:03,200 --> 03:06:05,480
and sought to make explicit
in its recommendations

3616
03:06:05,480 --> 03:06:08,280
the importance of cross-
disciplinary collaboration

3617
03:06:08,280 --> 03:06:10,800
within and between preclinical
and clinical sciences

3618
03:06:10,800 --> 03:06:15,080
and across neurodegenerative
disease research communities.

3619
03:06:15,080 --> 03:06:17,560
In other words, it is our view
that cross-linking research

3620
03:06:17,560 --> 03:06:20,840
in FTD and ALS, in AD
and other ADRD fields

3621
03:06:20,840 --> 03:06:23,800
to identify biological
commonalities, intersections

3622
03:06:23,800 --> 03:06:27,200
and points of divergence
will accelerate discovery.

3623
03:06:27,200 --> 03:06:30,560
And this is explicitly codified
in recommendation four.

3624
03:06:36,240 --> 03:06:37,800
-Thank you, Dr. Onyike.

3625
03:06:37,800 --> 03:06:40,840
Our colleagues today have
outlined the incredible progress

3626
03:06:40,840 --> 03:06:44,000
in FTD research
over recent years.

3627
03:06:44,000 --> 03:06:46,000
As we all speak together
about the future,

3628
03:06:46,000 --> 03:06:47,880
we have to remember
that the progress to date

3629
03:06:47,880 --> 03:06:49,880
has not yet had
a tangible impact

3630
03:06:49,880 --> 03:06:53,240
on the lives of those
who suffer from FTD --

3631
03:06:53,240 --> 03:06:56,400
struggle with inequity
and access to accurate,

3632
03:06:56,400 --> 03:07:00,280
timely diagnoses --
fatal dementia with no --

3633
03:07:00,280 --> 03:07:02,920
with zero approved treatments
despite profounding

3634
03:07:02,920 --> 03:07:06,600
for both symptomatic
and disease-modifying therapies.

3635
03:07:06,600 --> 03:07:08,520
And despite that
sobering reflection,

3636
03:07:08,520 --> 03:07:10,320
when we look at
those recommendations we know

3637
03:07:10,320 --> 03:07:12,480
that the coming 3 years
will not take us fully

3638
03:07:12,480 --> 03:07:14,160
where we need to go.

3639
03:07:14,160 --> 03:07:17,840
But -- pragmatic, realistic
and incredibly exciting road map

3640
03:07:17,840 --> 03:07:21,400
to getting us closer
to improve peoples' lives.

3641
03:07:21,400 --> 03:07:22,960
Now, I want to make sure
that we have the time

3642
03:07:22,960 --> 03:07:25,280
for really a rich discussion,

3643
03:07:25,280 --> 03:07:27,840
so I'm going to just say
a couple things.

3644
03:07:27,840 --> 03:07:31,440
One is that the need for
more comprehensive understanding

3645
03:07:31,440 --> 03:07:34,120
of FTD in diverse populations
has been really richly,

3646
03:07:34,120 --> 03:07:37,160
eloquently articulated
into the prior session

3647
03:07:37,160 --> 03:07:39,320
and this one --

3648
03:07:39,320 --> 03:07:41,680
still in early stages
of understanding

3649
03:07:41,680 --> 03:07:44,160
how socioeconomic
and ethnocultural status

3650
03:07:44,160 --> 03:07:46,720
can affect disease
risk manifestations

3651
03:07:46,720 --> 03:07:52,040
as well as access to diagnosis,
care and research opportunities.

3652
03:07:52,040 --> 03:07:54,280
An array of biomarkers
to support diagnosis,

3653
03:07:54,280 --> 03:07:57,000
clinical monitoring
and clinical trial design

3654
03:07:57,000 --> 03:07:59,680
going to be foundationally
important to transform

3655
03:07:59,680 --> 03:08:03,320
how we define and treat these
disorders to categorize people

3656
03:08:03,320 --> 03:08:05,000
not only by
the clinical phenotype

3657
03:08:05,000 --> 03:08:06,760
that can be treated
symptomatically

3658
03:08:06,760 --> 03:08:08,480
but by the underlying
pathobiologies

3659
03:08:08,480 --> 03:08:12,200
that can be targeted with
disease-modifying therapies.

3660
03:08:12,200 --> 03:08:13,800
Since we are at time,
I'm going to skip

3661
03:08:13,800 --> 03:08:15,320
some of my remaining comments

3662
03:08:15,320 --> 03:08:18,000
and just say that on behalf
of all the families

3663
03:08:18,000 --> 03:08:19,800
that are out there
needing help,

3664
03:08:19,800 --> 03:08:22,360
thanks to all the researchers,
funders and companies

3665
03:08:22,360 --> 03:08:25,240
that are working on FTD
and the people

3666
03:08:25,240 --> 03:08:27,800
who are volunteering
to participate in research

3667
03:08:27,800 --> 03:08:30,720
and to spread awareness
of FTD and reduce stigma.

3668
03:08:30,720 --> 03:08:32,280
All of us working together
are the key

3669
03:08:32,280 --> 03:08:34,400
to improving peoples' lives.

3670
03:08:35,200 --> 03:08:38,320
-Yeah, Dr. Dacks, apologies
for having to cut you off.

3671
03:08:38,320 --> 03:08:40,760
So we are going to go
to the Q and A.

3672
03:08:40,760 --> 03:08:42,720
The first four people
that are in cue,

3673
03:08:42,720 --> 03:08:46,280
the cue is the Q and A box
at the bottom of your screen.

3674
03:08:46,280 --> 03:08:47,880
We've promoted them
over to panelists.

3675
03:08:47,880 --> 03:08:51,800
They can turn on their cameras
if you wouldn't mind.

3676
03:08:51,800 --> 03:08:55,400
The first question is going
to be from David Pfeifer,

3677
03:08:55,400 --> 03:08:57,040
and I'm going to yield back
to the chairs.

3678
03:08:57,040 --> 03:08:58,640
Thank you.

3679
03:09:00,800 --> 03:09:03,400
-Thank you all so very much.

3680
03:09:03,400 --> 03:09:05,200
I cannot see myself.

3681
03:09:05,200 --> 03:09:08,440
I'm not sure if you can see me,
but my name is David Pfeifer,

3682
03:09:08,440 --> 03:09:14,400
and I am the Board Chair,
the current Board Chair of AFTD.

3683
03:09:14,400 --> 03:09:17,960
I had prepared a few comments
regarding reaching

3684
03:09:17,960 --> 03:09:22,400
all with FTD diagnostic tools
and the need for biomarkers.

3685
03:09:22,400 --> 03:09:24,040
However, these very
thoughtful presentations

3686
03:09:24,040 --> 03:09:26,200
have touched on everything
that I had intended to say,

3687
03:09:26,200 --> 03:09:27,880
so I'm simply going to
include those in the Q and A

3688
03:09:27,880 --> 03:09:29,800
for the record.

3689
03:09:29,800 --> 03:09:31,800
I want to thank you all
for all of your hard work

3690
03:09:31,800 --> 03:09:33,280
on FTD research.

3691
03:09:33,280 --> 03:09:38,880
I lost my wife, Cathy,
in 2016 to FTD and ALS.

3692
03:09:38,880 --> 03:09:42,160
Most of all, I want to express
sincere thanks to the NIH

3693
03:09:42,160 --> 03:09:44,400
for the summit
and for funding this research,

3694
03:09:44,400 --> 03:09:46,360
which is advancing the science

3695
03:09:46,360 --> 03:09:48,120
and providing hope
to our entire community

3696
03:09:48,120 --> 03:09:51,000
that a true understanding
of these diseases

3697
03:09:51,000 --> 03:09:53,760
and effective therapeutics
are on the horizon.

3698
03:09:53,760 --> 03:09:55,800
I'd also like to note
that as was evidence

3699
03:09:55,800 --> 03:09:58,680
in our patient-focused
drug development meeting

3700
03:09:58,680 --> 03:10:00,160
with the FDA last year,

3701
03:10:00,160 --> 03:10:02,880
our community is extremely
energized and eager

3702
03:10:02,880 --> 03:10:04,680
to step up and participate

3703
03:10:04,680 --> 03:10:07,400
in the clinical trials
that are emerging.

3704
03:10:07,400 --> 03:10:12,080
We're ready to do our part once
the drugs reach clinical trials.

3705
03:10:12,080 --> 03:10:13,600
Again, thank you all
so very much

3706
03:10:13,600 --> 03:10:15,280
for all of the work
that you do.

3707
03:10:22,000 --> 03:10:24,680
-Thank you, appreciate it.

3708
03:10:24,680 --> 03:10:26,600
Does anyone on the panel want
to address anything from that,

3709
03:10:26,600 --> 03:10:29,720
or should I go
onto the next question?

3710
03:10:29,720 --> 03:10:31,000
-No, those are great comments.

3711
03:10:31,000 --> 03:10:36,800
Thank you, David,
and maybe the next.

3712
03:10:36,800 --> 03:10:38,640
-Matthew Sharp?

3713
03:10:41,280 --> 03:10:46,000
-Hi. Thanks for the opportunity
to comment today.

3714
03:10:46,000 --> 03:10:50,400
I'm Matt Sharp,
the Advocacy Manager with AFTD.

3715
03:10:50,400 --> 03:10:53,480
And I just want to say thank you
to the FTD working group

3716
03:10:53,480 --> 03:10:55,800
for making
a better understanding

3717
03:10:55,800 --> 03:10:58,200
of the epidemiology, genetics,

3718
03:10:58,200 --> 03:11:03,680
and risk and resilience factors
in FTD a top priority.

3719
03:11:03,680 --> 03:11:06,080
Inequity to access
in diagnostics

3720
03:11:06,080 --> 03:11:09,600
is a fundamental problem in FTD,
and it affects pretty much

3721
03:11:09,600 --> 03:11:12,280
everything from
the lived experience,

3722
03:11:12,280 --> 03:11:14,600
as well as research
participation.

3723
03:11:14,600 --> 03:11:16,400
So trying to understand
it better

3724
03:11:16,400 --> 03:11:19,720
is really the necessary
first step

3725
03:11:19,720 --> 03:11:24,320
in order to make advances
across the board.

3726
03:11:24,320 --> 03:11:25,920
That's all.
Thank you.

3727
03:11:30,080 --> 03:11:33,600
-All right.
Thank you.

3728
03:11:33,600 --> 03:11:35,160
-Thank you for those
great comments.

3729
03:11:35,160 --> 03:11:37,640
And, yes, you know, I just
thought I would comment

3730
03:11:37,640 --> 03:11:41,800
that one of our priorities
is to develop new biomarkers

3731
03:11:41,800 --> 03:11:44,800
and particularly biomarkers
that are more accessible

3732
03:11:44,800 --> 03:11:47,200
to people throughout the world,

3733
03:11:47,200 --> 03:11:52,000
but in different communities
so that we can make it easier

3734
03:11:52,000 --> 03:11:55,480
for an early and accurate
diagnosis of different FTDs.

3735
03:11:55,480 --> 03:11:57,200
So thank you for your comment.

3736
03:12:00,160 --> 03:12:03,360
Should we go onto
the next question?

3737
03:12:03,360 --> 03:12:04,600
-That sounds great.

3738
03:12:04,600 --> 03:12:06,800
The next one
is from Jean Swidler.

3739
03:12:06,800 --> 03:12:08,200
-Yes, hi.

3740
03:12:08,200 --> 03:12:09,200
Thank you all so much
for all the work you do.

3741
03:12:09,200 --> 03:12:10,920
My name is Jean Swidler.

3742
03:12:10,920 --> 03:12:15,320
I'm a leader in the pre-manifest
ALS and FTD genetic community.

3743
03:12:15,320 --> 03:12:17,680
I don't know if this
is fully understood

3744
03:12:17,680 --> 03:12:18,920
by everyone in this summit.

3745
03:12:18,920 --> 03:12:21,000
There are hundreds and thousands
of people

3746
03:12:21,000 --> 03:12:26,000
who are at risk for genetic FTD
in this country and, you know,

3747
03:12:26,000 --> 03:12:28,520
you have that about
half of them will have the gene.

3748
03:12:28,520 --> 03:12:31,800
And then you look at the slides
that Dr. Boxer showed.

3749
03:12:31,800 --> 03:12:34,120
About 30, 40 percent
of those people

3750
03:12:34,120 --> 03:12:36,320
are actively
undergoing neurodegeneration

3751
03:12:36,320 --> 03:12:39,320
as we speak ahead
of major symptoms.

3752
03:12:39,320 --> 03:12:45,000
So I did not see in the very
long page of recommendations

3753
03:12:45,000 --> 03:12:46,960
that was developed, and I'm sure
a lot of work went into that,

3754
03:12:46,960 --> 03:12:48,400
and I thank everyone for it,

3755
03:12:48,400 --> 03:12:51,560
I did not see
the word prevention once.

3756
03:12:51,560 --> 03:12:56,000
We need to be thinking of this
as a crisis

3757
03:12:56,000 --> 03:12:57,320
because it is a crisis.

3758
03:12:57,320 --> 03:13:00,400
If my brain is melting,
that's a problem.

3759
03:13:00,400 --> 03:13:02,880
And we know that there
are hundreds...

3760
03:13:02,880 --> 03:13:05,040
There's probably close
to 100,000 people

3761
03:13:05,040 --> 03:13:07,400
undergoing presymptomatic
neurodegeneration,

3762
03:13:07,400 --> 03:13:11,400
excessive neurodegeneration
in these genetic ALS families

3763
03:13:11,400 --> 03:13:16,680
and genetic FTD families
as we speak.

3764
03:13:16,680 --> 03:13:18,400
NfL is ready to go.

3765
03:13:18,400 --> 03:13:20,480
NfL is a surrogate end point.

3766
03:13:20,480 --> 03:13:23,200
We do not need to wait
for anything else.

3767
03:13:23,200 --> 03:13:27,240
If we should find out
these other ones, that's great.

3768
03:13:27,240 --> 03:13:29,000
That's excellent.

3769
03:13:29,000 --> 03:13:32,080
But we have this powerful tool
to measure neurodegeneration,

3770
03:13:32,080 --> 03:13:33,520
and guess what?

3771
03:13:33,520 --> 03:13:35,800
We can see if neurodegeneration
is modulated

3772
03:13:35,800 --> 03:13:37,520
with interventional therapies.

3773
03:13:37,520 --> 03:13:43,400
It's time, and, you know,
that really will unlock

3774
03:13:43,400 --> 03:13:45,360
the ability to have shorter
clinical trials,

3775
03:13:45,360 --> 03:13:48,080
to have clinical trials
for all these hundreds,

3776
03:13:48,080 --> 03:13:49,280
all these people undergoing

3777
03:13:49,280 --> 03:13:53,080
presymptomatic
neurodegeneration.

3778
03:13:53,080 --> 03:13:55,960
Also, you know,
I know we're not...

3779
03:13:55,960 --> 03:13:58,840
You know, this is NIH-focused,
but somehow we got to figure out

3780
03:13:58,840 --> 03:14:03,640
how to get neurofilament-light
as a commercial test.

3781
03:14:03,640 --> 03:14:06,120
It should not be locked
in research anymore.

3782
03:14:06,120 --> 03:14:09,000
You know, think about what this
could be doing

3783
03:14:09,000 --> 03:14:12,400
for people who are undergoing

3784
03:14:12,400 --> 03:14:16,600
FTD and interacting
with the court system

3785
03:14:16,600 --> 03:14:19,000
or the criminal justice system,

3786
03:14:19,000 --> 03:14:22,160
if people could have
their neurodegeneration measured

3787
03:14:22,160 --> 03:14:27,360
and, you know, show
that what's going on is relevant

3788
03:14:27,360 --> 03:14:31,200
to what's happening
in their life.

3789
03:14:31,200 --> 03:14:33,160
So those are my big things.

3790
03:14:33,160 --> 03:14:35,680
We need to focus on prevention
in addition

3791
03:14:35,680 --> 03:14:37,760
to treating people
with the disease.

3792
03:14:37,760 --> 03:14:41,200
We've got to focus on getting
NfL over the finish line here.

3793
03:14:41,200 --> 03:14:48,560
We've got to focus on, you know,
using the tools that we have.

3794
03:14:48,560 --> 03:14:52,800
Thank you so much.
-Right.

3795
03:14:52,800 --> 03:14:55,000
Those are really
terrific comments,

3796
03:14:55,000 --> 03:15:00,880
and I see that Penny Dacks
on the panel wanted to respond.

3797
03:15:00,880 --> 03:15:02,440
Penny?

3798
03:15:02,440 --> 03:15:03,840
-Yeah, thank you, Dr. Boxer.

3799
03:15:03,840 --> 03:15:07,200
And, Mrs. Swidler, I just wanted
to emphasize

3800
03:15:07,200 --> 03:15:08,840
how important what you said is,

3801
03:15:08,840 --> 03:15:14,840
that it may not be clear enough
in the recommendations

3802
03:15:14,840 --> 03:15:16,880
that prevention is absolutely
one of the main

3803
03:15:16,880 --> 03:15:19,000
focuses of those who are
doing clinical trials,

3804
03:15:19,000 --> 03:15:24,400
to find people who are at
the very stages of conversion

3805
03:15:24,400 --> 03:15:27,200
into symptomatic
manifestation of disease

3806
03:15:27,200 --> 03:15:29,880
so that that's manifestation
can be delayed.

3807
03:15:29,880 --> 03:15:32,000
I think it's a major focus
of all of the researchers,

3808
03:15:32,000 --> 03:15:34,160
and if that's not clear enough
in the recommendations,

3809
03:15:34,160 --> 03:15:36,560
then that's something
we can go back and revise.

3810
03:15:36,560 --> 03:15:38,600
And I hear you, as well,
in terms of neurofilament,

3811
03:15:38,600 --> 03:15:40,120
and I think there's
a lot of energy

3812
03:15:40,120 --> 03:15:42,880
there in trying to get it
validated to the point

3813
03:15:42,880 --> 03:15:44,600
that it can be used
in the clinic.

3814
03:15:44,600 --> 03:15:47,160
We very much are aligned
with your priorities,

3815
03:15:47,160 --> 03:15:50,440
and thank you
for the point about

3816
03:15:50,440 --> 03:15:52,400
how we can all
make it more clear.

3817
03:15:57,040 --> 03:16:02,120
-Any other comments from our
panelists -- responses?

3818
03:16:02,120 --> 03:16:03,480
I would just like to, you know,

3819
03:16:03,480 --> 03:16:07,560
add in thanks, Dr. Dacks,
for your comments.

3820
03:16:07,560 --> 03:16:09,800
Yeah, so, you know, I'm aware

3821
03:16:09,800 --> 03:16:11,440
that there are
a number of efforts

3822
03:16:11,440 --> 03:16:15,160
to qualify a neurofilament
and to bring it into the clinic.

3823
03:16:15,160 --> 03:16:16,680
And, you know, I think it's...

3824
03:16:16,680 --> 03:16:18,360
We hope that within
the next couple of years,

3825
03:16:18,360 --> 03:16:21,800
this will be a much more
clinically available test,

3826
03:16:21,800 --> 03:16:24,600
and completely agree
with Dr. Dacks' comment

3827
03:16:24,600 --> 03:16:28,480
that although we did mention
prevention trials

3828
03:16:28,480 --> 03:16:29,880
in one of our recommendations,

3829
03:16:29,880 --> 03:16:31,680
perhaps we could make
that a bit clearer.

3830
03:16:31,680 --> 03:16:34,160
But the global effort
that I mentioned,

3831
03:16:34,160 --> 03:16:37,280
the FTD Prevention Initiative,
is really targeting

3832
03:16:37,280 --> 03:16:42,200
what the question
was about that really,

3833
03:16:42,200 --> 03:16:44,480
we want to get to the point
where we can prevent

3834
03:16:44,480 --> 03:16:46,920
the onset of disease
and not just treat it.

3835
03:16:46,920 --> 03:16:50,640
So I think we'll move
onto the next question.

3836
03:16:53,360 --> 03:16:55,600
-That would be Esther Kane.

3837
03:16:55,600 --> 03:16:56,720
-Thank you.

3838
03:16:56,720 --> 03:16:58,240
So my name is Esther Kane,

3839
03:16:58,240 --> 03:17:01,600
and I am AFTD's Director
of Support and Education.

3840
03:17:01,600 --> 03:17:04,240
I am a registered nurse who has
spent most of my career

3841
03:17:04,240 --> 03:17:06,000
caring for those living
with dementia

3842
03:17:06,000 --> 03:17:08,520
and supporting
their care partners.

3843
03:17:08,520 --> 03:17:11,600
While progress is being made in
genetics and biomarker research,

3844
03:17:11,600 --> 03:17:15,240
a quick overview of funded
FTD-specific projects in eye

3845
03:17:15,240 --> 03:17:16,960
drop shows

3846
03:17:16,960 --> 03:17:19,320
that the number of projects
in care and services research

3847
03:17:19,320 --> 03:17:21,200
is dwarfed
by the number of projects

3848
03:17:21,200 --> 03:17:24,120
in basic translational
and clinical research.

3849
03:17:24,120 --> 03:17:26,840
In addition, there is already
a large population of people

3850
03:17:26,840 --> 03:17:29,080
with FTD
that are past the point of help

3851
03:17:29,080 --> 03:17:31,280
from disease-modifying
therapies.

3852
03:17:31,280 --> 03:17:33,680
The need for new and better
symptomatic therapies

3853
03:17:33,680 --> 03:17:35,200
is immediate,

3854
03:17:35,200 --> 03:17:37,400
and there are still precious
few medical options

3855
03:17:37,400 --> 03:17:39,000
to help people now.

3856
03:17:39,000 --> 03:17:41,200
We need to increasing funding
in research to assist

3857
03:17:41,200 --> 03:17:43,000
those living
with the disease now,

3858
03:17:43,000 --> 03:17:45,200
in addition to other research
initiatives.

3859
03:17:45,200 --> 03:17:46,800
Thank you.

3860
03:17:50,680 --> 03:17:52,080
-Thank you for that comment.

3861
03:17:52,080 --> 03:17:57,000
Do any of the panelists
want to respond?

3862
03:18:01,400 --> 03:18:04,040
I'll just say
that I completely agree,

3863
03:18:04,040 --> 03:18:07,560
and I think as we build a larger
clinical research population,

3864
03:18:07,560 --> 03:18:10,240
we really need to focus
on these other issues much more.

3865
03:18:10,240 --> 03:18:14,080
So thank you for the comment.

3866
03:18:14,080 --> 03:18:16,880
Maybe we'll move onto
the next question.

3867
03:18:16,880 --> 03:18:19,080
-That would be great.
So Arvind?

3868
03:18:19,080 --> 03:18:22,560
-Yeah. So thank you,
[Indistinct].

3869
03:18:22,560 --> 03:18:25,520
So my question is linked
to diagnostic

3870
03:18:25,520 --> 03:18:27,680
and presymptomatic conditions.

3871
03:18:27,680 --> 03:18:29,840
What the biomarker we have --

3872
03:18:29,840 --> 03:18:31,880
capable enough
to diagnose people

3873
03:18:31,880 --> 03:18:34,880
who have presymptomatic
or asymptomatic situation,

3874
03:18:34,880 --> 03:18:38,880
and if not, then what effort
going on to finding that?

3875
03:18:41,240 --> 03:18:42,880
Thank you.

3876
03:18:42,880 --> 03:18:47,320
-So that's a terrific question,
and I think, you know,

3877
03:18:47,320 --> 03:18:51,240
I'll start, but I'm going to ask
some of the panelists whether,

3878
03:18:51,240 --> 03:18:54,560
you know, you guys would also
want to comment as well.

3879
03:18:54,560 --> 03:18:56,240
So we're very limited.

3880
03:18:56,240 --> 03:18:58,640
We heard about
neurofilament-light chain,

3881
03:18:58,640 --> 03:19:00,760
and I showed a little bit
of data very quickly

3882
03:19:00,760 --> 03:19:02,280
as something
that seems to change

3883
03:19:02,280 --> 03:19:06,320
before the onset of symptoms
in genetic forms of FTD.

3884
03:19:06,320 --> 03:19:10,720
And we also have seen
that brain volume changes occur,

3885
03:19:10,720 --> 03:19:15,320
and yet those are really
the two biomarkers

3886
03:19:15,320 --> 03:19:16,960
that are changing the most.

3887
03:19:16,960 --> 03:19:19,720
And we have very few other
biomarkers that we can use,

3888
03:19:19,720 --> 03:19:22,680
and so in our
international efforts

3889
03:19:22,680 --> 03:19:24,520
to model the onset of disease,

3890
03:19:24,520 --> 03:19:28,680
it seems that we can start
to describe

3891
03:19:28,680 --> 03:19:30,760
what happens
before the onset of symptoms

3892
03:19:30,760 --> 03:19:33,320
but not accurately enough,
we think,

3893
03:19:33,320 --> 03:19:35,600
that we can really effectively

3894
03:19:35,600 --> 03:19:39,280
and in all cases predict exactly
when someone will get sick.

3895
03:19:39,280 --> 03:19:42,600
So there's still a lot
of uncertainty,

3896
03:19:42,600 --> 03:19:46,640
and that's why we think that
even more, you know, biomarkers,

3897
03:19:46,640 --> 03:19:50,040
whether they be biologic,
fluid biomarkers,

3898
03:19:50,040 --> 03:19:52,760
different types of brain scans,
PET scans,

3899
03:19:52,760 --> 03:19:55,520
looking at particular
molecular species,

3900
03:19:55,520 --> 03:19:58,120
but also clinical changes

3901
03:19:58,120 --> 03:20:03,720
and maybe remote monitoring
with movement changes,

3902
03:20:03,720 --> 03:20:06,960
or subtle
behavioral or clinical changes,

3903
03:20:06,960 --> 03:20:08,520
social changes.

3904
03:20:08,520 --> 03:20:10,600
All of these are likely
to be important,

3905
03:20:10,600 --> 03:20:15,040
and we think should be
a focus of future research.

3906
03:20:15,040 --> 03:20:16,800
Other comments?

3907
03:20:16,800 --> 03:20:19,480
Any of the panelists
want to respond?

3908
03:20:24,400 --> 03:20:26,360
-Or if not,
I completely agree,

3909
03:20:26,360 --> 03:20:29,720
and did that answer
your question?

3910
03:20:29,720 --> 03:20:32,000
-Yes, thank you.

3911
03:20:32,000 --> 03:20:36,040
-So maybe we'll move onto
the next question.

3912
03:20:36,040 --> 03:20:39,080
-Kathleen Welsh-Balmer?
-Yeah, hi.

3913
03:20:39,080 --> 03:20:41,800
Kathy Welsh-Balmer here
from Duke University.

3914
03:20:41,800 --> 03:20:43,600
I'm with the Duke Clinical
Research Institute

3915
03:20:43,600 --> 03:20:47,080
in the Duke/UNC ADRC.

3916
03:20:47,080 --> 03:20:49,920
It's tremendous the amount
of progress that's been made

3917
03:20:49,920 --> 03:20:52,680
just since 2019 recommendations.

3918
03:20:52,680 --> 03:20:54,920
So I can't keep up with it,

3919
03:20:54,920 --> 03:20:59,040
and I just applaud
all the panelists in summarizing

3920
03:20:59,040 --> 03:21:02,120
what is an incredible amount
of discovery

3921
03:21:02,120 --> 03:21:05,360
that's occurred
in just several years.

3922
03:21:05,360 --> 03:21:08,040
My comment really echoes
what you were just saying, Adam,

3923
03:21:08,040 --> 03:21:09,680
which is, you know,

3924
03:21:09,680 --> 03:21:12,160
it's incredible the work
that's been done

3925
03:21:12,160 --> 03:21:15,040
and the progress made
in the biomarker area.

3926
03:21:15,040 --> 03:21:16,960
As we move particularly

3927
03:21:16,960 --> 03:21:20,640
into the presymptomatic area
and start to look

3928
03:21:20,640 --> 03:21:23,280
for end points
for clinical trials,

3929
03:21:23,280 --> 03:21:27,200
or even end points for
monitoring patients in practice,

3930
03:21:27,200 --> 03:21:29,120
I think there really
does need to be

3931
03:21:29,120 --> 03:21:30,800
some emphasis on the development

3932
03:21:30,800 --> 03:21:33,160
of novel end points,
the pick-up

3933
03:21:33,160 --> 03:21:38,440
on the clinical expression
of these diverse types of FTDs,

3934
03:21:38,440 --> 03:21:40,960
whether that is
the social end points,

3935
03:21:40,960 --> 03:21:43,720
cognitive functional,
behavioral motor.

3936
03:21:43,720 --> 03:21:45,800
I think there's tremendous
opportunity,

3937
03:21:45,800 --> 03:21:48,760
and I'd love to see
the investment of effort

3938
03:21:48,760 --> 03:21:50,600
in developing those
clinical end points

3939
03:21:50,600 --> 03:21:52,040
similar to what we've done

3940
03:21:52,040 --> 03:21:55,520
with the development
of biological biomarkers.

3941
03:21:55,520 --> 03:21:57,400
Thank you.

3942
03:21:57,400 --> 03:21:59,320
-Yeah, those are great comments.
Thank you.

3943
03:21:59,320 --> 03:22:00,760
And maybe I wanted to ask --

3944
03:22:00,760 --> 03:22:03,400
Oh, it looks like
Dr. Onyike raised his hand.

3945
03:22:03,400 --> 03:22:05,480
So I was just about to call on
you, so, great.

3946
03:22:05,480 --> 03:22:06,880
-Okay, yes.
-Thank you.

3947
03:22:06,880 --> 03:22:08,320
-Thank you.
Thank you, Adam.

3948
03:22:08,320 --> 03:22:10,080
Thank you, Kathleen.

3949
03:22:10,080 --> 03:22:13,240
Yes, we completely agree.

3950
03:22:13,240 --> 03:22:15,280
Adam touched on this earlier,

3951
03:22:15,280 --> 03:22:18,160
and there is actually also work
and already work in the field,

3952
03:22:18,160 --> 03:22:19,840
you know, seeking to
address this question.

3953
03:22:19,840 --> 03:22:23,160
You know, I think one
of the challenges is trying

3954
03:22:23,160 --> 03:22:25,400
to figure out
where the goalpost should lie,

3955
03:22:25,400 --> 03:22:28,120
especially in relation
to clinical trials.

3956
03:22:28,120 --> 03:22:29,640
The earlier you go, of course,

3957
03:22:29,640 --> 03:22:31,880
the more difficult it is
to use clinical indices.

3958
03:22:31,880 --> 03:22:35,760
And so part of the effort
involves, for example,

3959
03:22:35,760 --> 03:22:38,680
linking clinical outcomes
or clinical indices

3960
03:22:38,680 --> 03:22:40,720
to physiological measurements,

3961
03:22:40,720 --> 03:22:42,240
whether they be
electrophysiological,

3962
03:22:42,240 --> 03:22:45,000
which is an interesting
new area...

3963
03:22:45,000 --> 03:22:47,640
Or not so new,
but a re-emphasized area,

3964
03:22:47,640 --> 03:22:50,760
and then also linking it
to other things,

3965
03:22:50,760 --> 03:22:53,040
blood-based biomarkers,
CSF-based biomarkers

3966
03:22:53,040 --> 03:22:56,600
because we have to, you know,

3967
03:22:56,600 --> 03:22:59,640
adjust the goalpost according
to the therapeutic goals.

3968
03:22:59,640 --> 03:23:01,640
And so we're going to need
a multitude

3969
03:23:01,640 --> 03:23:04,040
and the diversity
of what are biomarkers

3970
03:23:04,040 --> 03:23:06,160
to address these objectives,

3971
03:23:06,160 --> 03:23:08,800
and that's implicit
in the recommendations.

3972
03:23:08,800 --> 03:23:10,240
It's unfortunately difficult

3973
03:23:10,240 --> 03:23:13,920
to specify
everything in the documents.

3974
03:23:17,640 --> 03:23:19,080
-Thanks.
Thanks, Dr. Onyike.

3975
03:23:19,080 --> 03:23:22,240
And Dr. Irwin also wanted
to respond, I believe.

3976
03:23:22,240 --> 03:23:25,560
-Yeah, I just wanted
to briefly comment to agree

3977
03:23:25,560 --> 03:23:28,320
on the need for different
objective clinical measures

3978
03:23:28,320 --> 03:23:29,840
and that link to biology

3979
03:23:29,840 --> 03:23:33,280
in a biologically
heterogeneous disorder,

3980
03:23:33,280 --> 03:23:35,280
the importance of brain donation
to try to help link

3981
03:23:35,280 --> 03:23:38,240
some of the clinical physiology
that we see microscopically,

3982
03:23:38,240 --> 03:23:41,400
the antemortem biomarkers,
I think is also important.

3983
03:23:44,640 --> 03:23:46,200
-Great.

3984
03:23:46,200 --> 03:23:48,200
If there are no more comments
from the panelists,

3985
03:23:48,200 --> 03:23:50,920
then maybe we'll move
onto the next question.

3986
03:23:52,560 --> 03:23:55,280
-Mr. Ellenbogen.

3987
03:23:55,280 --> 03:23:58,600
-Can you hear me?
-Sound clear.

3988
03:23:59,920 --> 03:24:05,120
-Over the years, I participated
in about 12 clinical trials.

3989
03:24:05,120 --> 03:24:08,840
At that time,
they thought I had Alzheimer's.

3990
03:24:08,840 --> 03:24:11,480
Since the science
has gotten better,

3991
03:24:11,480 --> 03:24:15,720
they now believe I have semantic
dementia, which falls under FTD.

3992
03:24:15,720 --> 03:24:18,840
Since my second diagnosis,
I have not been able

3993
03:24:18,840 --> 03:24:22,080
to get into
any clinical trials.

3994
03:24:22,080 --> 03:24:24,280
Why must we be placed into a box

3995
03:24:24,280 --> 03:24:26,400
with this specific type
of dementia

3996
03:24:26,400 --> 03:24:30,320
when I actually learned
right here at NIH

3997
03:24:30,320 --> 03:24:35,240
that 50 to 60 percent of those
who had a biopsy after death

3998
03:24:35,240 --> 03:24:39,360
died of three or four types
of dementia?

3999
03:24:39,360 --> 03:24:41,320
On another note,

4000
03:24:41,320 --> 03:24:44,600
I don't want to sound like
a conspiracy theorist,

4001
03:24:44,600 --> 03:24:47,920
but I've been living
with dementia for a long time.

4002
03:24:47,920 --> 03:24:51,640
I would have never said
this in the past,

4003
03:24:51,640 --> 03:24:53,200
but I do believe I found

4004
03:24:53,200 --> 03:24:57,120
a way to address
a way to delay dementia

4005
03:24:57,120 --> 03:24:59,880
by using a cocktail of drugs

4006
03:24:59,880 --> 03:25:02,440
and other habit-changing ways.

4007
03:25:02,440 --> 03:25:05,200
While I cannot say this
with certainty,

4008
03:25:05,200 --> 03:25:07,800
I do have some proof
it's working.

4009
03:25:07,800 --> 03:25:09,720
I'd be happy to speak to anyone

4010
03:25:09,720 --> 03:25:13,000
who may be interested
in chatting with me about this.

4011
03:25:13,000 --> 03:25:16,480
I would sure hate
to just be ignored

4012
03:25:16,480 --> 03:25:19,160
when there may actually
be something here

4013
03:25:19,160 --> 03:25:22,680
that could actually help others.

4014
03:25:22,680 --> 03:25:25,880
Thank you.

4015
03:25:25,880 --> 03:25:28,960
-Well, I wanted to thank you,
Mr. Ellenbogen,

4016
03:25:28,960 --> 03:25:30,560
for your comments.

4017
03:25:30,560 --> 03:25:33,000
And thank you also for
participating in research

4018
03:25:33,000 --> 03:25:34,640
in so many clinical trials,

4019
03:25:34,640 --> 03:25:38,120
and, you know,
I want to say I'm sorry

4020
03:25:38,120 --> 03:25:43,440
that it's taken such a long time
to get an accurate diagnosis.

4021
03:25:43,440 --> 03:25:46,680
I think your points
are very well taken,

4022
03:25:46,680 --> 03:25:50,760
and one of our recommendations
is around

4023
03:25:50,760 --> 03:25:53,360
developing
new clinical trial designs.

4024
03:25:53,360 --> 03:25:57,240
And one idea is that maybe,
you know,

4025
03:25:57,240 --> 03:26:00,200
we could think about different
ways of testing therapies

4026
03:26:00,200 --> 03:26:02,520
or finding what helps people

4027
03:26:02,520 --> 03:26:04,880
so that we're not so exclusive,

4028
03:26:04,880 --> 03:26:08,560
or that anyone who feels --

4029
03:26:08,560 --> 03:26:11,080
who is part of the community
could participate.

4030
03:26:11,080 --> 03:26:15,120
So one idea is called
a pragmatic clinical trial,

4031
03:26:15,120 --> 03:26:18,440
where we would allow many
different people to participate

4032
03:26:18,440 --> 03:26:22,240
and share their experiences,
perhaps, you know, the cocktail

4033
03:26:22,240 --> 03:26:25,280
that you've developed or learned
about that's helping you.

4034
03:26:25,280 --> 03:26:28,400
And we would love to learn
and get more about that as well,

4035
03:26:28,400 --> 03:26:31,760
and so we hope that
through other recommendations

4036
03:26:31,760 --> 03:26:34,480
where we're developing
less expensive

4037
03:26:34,480 --> 03:26:38,240
and easier-deployed biomarkers
and clinical measures,

4038
03:26:38,240 --> 03:26:40,760
that might enable
clinical trials sort of

4039
03:26:40,760 --> 03:26:42,000
like you're suggesting

4040
03:26:42,000 --> 03:26:45,120
that more people
could participate in.

4041
03:26:45,120 --> 03:26:49,680
So I also want to call again
on Dr. Onyike,

4042
03:26:49,680 --> 03:26:51,480
who wanted to comment
as well, I think,

4043
03:26:51,480 --> 03:26:53,680
unless your hand was...

4044
03:26:53,680 --> 03:26:54,920
-Yeah, no.
Thank you, Michael.

4045
03:26:54,920 --> 03:26:56,200
I think in addition

4046
03:26:56,200 --> 03:26:58,240
to what Dr. Boxer
has just gone over,

4047
03:26:58,240 --> 03:27:00,400
you also highlighted the issue

4048
03:27:00,400 --> 03:27:02,240
of delayed, you know,
late diagnosis

4049
03:27:02,240 --> 03:27:05,680
and what that can mean
for access to clinical trials.

4050
03:27:05,680 --> 03:27:09,400
And this is a reason why there's
an explicit emphasis on the...

4051
03:27:09,400 --> 03:27:12,640
And I recall, you mentioned
in the earlier panel the issue,

4052
03:27:12,640 --> 03:27:15,800
how it relates
to diverse communities.

4053
03:27:15,800 --> 03:27:18,800
And so this is a reason
why we have an explicit focus

4054
03:27:18,800 --> 03:27:24,440
on these ethnocultural
and socioeconomic,

4055
03:27:24,440 --> 03:27:27,440
if you will,
factors that influence,

4056
03:27:27,440 --> 03:27:31,160
essentially permeate everything
that we're trying to do here

4057
03:27:31,160 --> 03:27:34,520
including, in particular,
access to care

4058
03:27:34,520 --> 03:27:36,520
and access to timely diagnosis.

4059
03:27:36,520 --> 03:27:37,640
So I just wanted
to thank you again

4060
03:27:37,640 --> 03:27:39,080
for highlighting those issues

4061
03:27:39,080 --> 03:27:41,440
and giving us the opportunity
to speak to them.

4062
03:27:41,440 --> 03:27:43,120
Thank you.

4063
03:27:46,560 --> 03:27:47,960
-Thanks.

4064
03:27:47,960 --> 03:27:49,680
We're close to time.

4065
03:27:49,680 --> 03:27:52,480
Do we have time for one
more question, Keith?

4066
03:27:52,480 --> 03:27:54,240
-We're going to extend
into the break a little bit

4067
03:27:54,240 --> 03:27:55,840
and hope to have a couple more,
actually.

4068
03:27:55,840 --> 03:27:57,560
So, Dr. Niehoff?

4069
03:27:59,760 --> 03:28:02,280
-Thank you.
I'm Debra Niehoff,

4070
03:28:02,280 --> 03:28:06,240
and I'm the Director of Research
and Grants for AFTD.

4071
03:28:06,240 --> 03:28:08,760
And many of the advances

4072
03:28:08,760 --> 03:28:12,440
that we've heard so well
described this afternoon

4073
03:28:12,440 --> 03:28:14,720
are the result
of the increasing wealth

4074
03:28:14,720 --> 03:28:19,480
of genomic, transcriptomic,
epigenomic, proteomic,

4075
03:28:19,480 --> 03:28:21,880
and biomarker data.

4076
03:28:21,880 --> 03:28:25,440
But one type of data that's
still in very short supply

4077
03:28:25,440 --> 03:28:27,160
is quantitative data,

4078
03:28:27,160 --> 03:28:30,240
and that would be information
on parameters

4079
03:28:30,240 --> 03:28:33,760
such as association,
dissociation rates

4080
03:28:33,760 --> 03:28:37,200
for critical
protein-protein interactome,

4081
03:28:37,200 --> 03:28:40,840
binding constants,
catalytic rates.

4082
03:28:40,840 --> 03:28:45,880
And these are data
that could not only reveal

4083
03:28:45,880 --> 03:28:51,280
unknown vulnerabilities in
the Tau or TDP-43 interaction.

4084
03:28:51,280 --> 03:28:54,400
They could also be the starting
point for computational

4085
03:28:54,400 --> 03:28:58,000
and mechanistic modeling
that could generate novel

4086
03:28:58,000 --> 03:29:02,920
hypotheses about disease,
pathogenesis and progression.

4087
03:29:02,920 --> 03:29:04,760
And I'm wondering if the panel

4088
03:29:04,760 --> 03:29:08,960
could please comment
on the lack of quantitative data

4089
03:29:08,960 --> 03:29:12,080
and whether under
recommendation five,

4090
03:29:12,080 --> 03:29:15,520
one of the goals could be to
encourage the acquisition

4091
03:29:15,520 --> 03:29:17,160
of such data.

4092
03:29:27,000 --> 03:29:31,120
-Yes, and I'm going to ask
some of the panelists.

4093
03:29:31,120 --> 03:29:35,200
Anyone want to comment,
since I've been speaking a lot?

4094
03:29:37,880 --> 03:29:42,240
-Yeah. So I think that
I totally agree with you

4095
03:29:42,240 --> 03:29:45,120
that there's going
to be huge value

4096
03:29:45,120 --> 03:29:48,000
to expanding our ability

4097
03:29:48,000 --> 03:29:51,200
to leverage the genomic findings

4098
03:29:51,200 --> 03:29:53,720
and to use
these quantitative traits

4099
03:29:53,720 --> 03:29:57,080
to extend our understanding
of disease,

4100
03:29:57,080 --> 03:30:01,080
both to distinguish between
different FTD subtypes

4101
03:30:01,080 --> 03:30:05,200
and to understand converging
indistinct mechanisms.

4102
03:30:08,960 --> 03:30:10,800
-Thanks.

4103
03:30:13,960 --> 03:30:17,440
So I think we have time
just for a few more comments...

4104
03:30:17,440 --> 03:30:20,400
Oh, I think Anthony
wanted to make a comment.

4105
03:30:20,400 --> 03:30:23,760
-Yeah. I would just add
to what Celeste said.

4106
03:30:23,760 --> 03:30:27,320
With regard to the quantitative
aspect, Deb,

4107
03:30:27,320 --> 03:30:30,160
I think that, you know,
cryo-EM as a tool

4108
03:30:30,160 --> 03:30:31,480
has been very powerful,

4109
03:30:31,480 --> 03:30:33,080
and, you know,
our lab and others

4110
03:30:33,080 --> 03:30:36,560
have really shown the power
of understanding

4111
03:30:36,560 --> 03:30:38,960
the filament structures,
individual filaments

4112
03:30:38,960 --> 03:30:41,680
when we extract them
from postmortem human tissue.

4113
03:30:41,680 --> 03:30:45,160
But I think in the context
of those interactions

4114
03:30:45,160 --> 03:30:47,760
and the interactome,
as you mentioned,

4115
03:30:47,760 --> 03:30:51,640
in think that cryotomography
is going to play a great role

4116
03:30:51,640 --> 03:30:54,040
in the coming years
to understand

4117
03:30:54,040 --> 03:30:58,560
when we directly visualize
the filaments in situ

4118
03:30:58,560 --> 03:31:01,040
and watch the various
interactions happening,

4119
03:31:01,040 --> 03:31:03,320
and what those filaments
are actually doing

4120
03:31:03,320 --> 03:31:04,680
in the context of disease,

4121
03:31:04,680 --> 03:31:06,520
I think that's going to be
very powerful

4122
03:31:06,520 --> 03:31:08,520
for the field moving forward.

4123
03:31:11,080 --> 03:31:14,600
-Great. So maybe just a few
more comments and questions,

4124
03:31:14,600 --> 03:31:16,640
and I think we're going to
the break a little bit,

4125
03:31:16,640 --> 03:31:19,000
but thank you for your patience.

4126
03:31:19,000 --> 03:31:22,200
I believe that Dr. Barnes
had a comment.

4127
03:31:22,200 --> 03:31:25,920
I don't know
if she's still online.

4128
03:31:25,920 --> 03:31:29,760
But, Dr. Barnes,
did you want to discuss

4129
03:31:29,760 --> 03:31:32,160
your comment a little bit more?

4130
03:31:34,040 --> 03:31:37,120
-Oh, hi.
Well, I just --

4131
03:31:37,120 --> 03:31:40,560
My comment was just about
your opening statement,

4132
03:31:40,560 --> 03:31:42,200
and not to call you out,

4133
03:31:42,200 --> 03:31:44,120
because I think
we're all guilty of it,

4134
03:31:44,120 --> 03:31:46,840
but that we often make
this artificial separation

4135
03:31:46,840 --> 03:31:51,080
between recruitment
and rigor of science,

4136
03:31:51,080 --> 03:31:53,520
and I just think
that we need to think

4137
03:31:53,520 --> 03:31:56,400
about diversity, inclusion
and equity

4138
03:31:56,400 --> 03:31:58,960
as integral to everything
we do in research

4139
03:31:58,960 --> 03:32:02,480
because it's going to impact
how we are able to recruit,

4140
03:32:02,480 --> 03:32:04,560
how we're able to keep
people in our studies,

4141
03:32:04,560 --> 03:32:07,280
and the community can tell that
we're looking at these things

4142
03:32:07,280 --> 03:32:09,000
in two different ways.

4143
03:32:09,000 --> 03:32:12,520
So I guess the general point
is that they're not separate

4144
03:32:12,520 --> 03:32:14,040
and that we need to think
about it

4145
03:32:14,040 --> 03:32:19,920
as a key to our scientific
progress in this area.

4146
03:32:19,920 --> 03:32:21,200
-Yeah, and I --

4147
03:32:21,200 --> 03:32:23,480
You know, I apologize
if I misspoke.

4148
03:32:23,480 --> 03:32:25,960
That's sort of the point
that I wanted to make as well,

4149
03:32:25,960 --> 03:32:28,480
but I didn't do it
in a very eloquent way,

4150
03:32:28,480 --> 03:32:31,760
so thank you for clarifying
and emphasizing that point.

4151
03:32:31,760 --> 03:32:34,760
Thank you.

4152
03:32:34,760 --> 03:32:38,160
I think there were two
more comment --

4153
03:32:38,160 --> 03:32:41,600
or maybe we have time
for one more comment.

4154
03:32:41,600 --> 03:32:45,560
-David, you're next in line.
-My apologies.

4155
03:32:45,560 --> 03:32:47,080
I don't have a question.

4156
03:32:47,080 --> 03:32:48,600
I just put my...
-Okay.

4157
03:32:48,600 --> 03:32:50,480
-...those comments, as I had
mentioned in my remarks,

4158
03:32:50,480 --> 03:32:53,080
I think all these thoughtful
presentations had addressed,

4159
03:32:53,080 --> 03:32:56,280
so I don't have
any further follow-up.

4160
03:32:56,280 --> 03:32:58,600
-Thanks, appreciate that.
-Thank you.

4161
03:32:58,600 --> 03:33:00,440
-Zeynep Demir.

4162
03:33:00,440 --> 03:33:02,880
This will be your last question
before we go to lunch.

4163
03:33:02,880 --> 03:33:04,120
-Hey.

4164
03:33:04,120 --> 03:33:05,680
I'm a clinical fellow
at the NIH.

4165
03:33:05,680 --> 03:33:07,960
I have a quick question.

4166
03:33:07,960 --> 03:33:11,120
We are working on developing
early MRI markers,

4167
03:33:11,120 --> 03:33:14,400
and I am curious,
is there any platform specific

4168
03:33:14,400 --> 03:33:18,360
to those imaging markers
and how we can collaborate?

4169
03:33:21,160 --> 03:33:23,000
-I'll take that, and yes.

4170
03:33:23,000 --> 03:33:26,440
So the ALLFTD study
is collecting MRI.

4171
03:33:26,440 --> 03:33:29,400
I'm not sure if your question

4172
03:33:29,400 --> 03:33:32,800
is about
the availability of data or --

4173
03:33:32,800 --> 03:33:34,200
Yeah, so you can apply --

4174
03:33:34,200 --> 03:33:38,040
-Reaching out the patient
as well.

4175
03:33:38,040 --> 03:33:39,440
-I'm sorry.

4176
03:33:39,440 --> 03:33:41,560
I didn't understand that last.
-Oh, sorry.

4177
03:33:41,560 --> 03:33:42,880
We are collecting the data

4178
03:33:42,880 --> 03:33:45,400
as well as reaching out
the patients,

4179
03:33:45,400 --> 03:33:50,880
so testing our markers as well,
so just collaborate as a site.

4180
03:33:50,880 --> 03:33:53,080
-Yeah, so let's discuss
that offline

4181
03:33:53,080 --> 03:33:55,480
if you want to send me
an e-mail, or we could --

4182
03:33:55,480 --> 03:33:57,800
can also contact us
through our website.

4183
03:33:57,800 --> 03:34:02,240
Great.
But definitely happy to discuss.

4184
03:34:02,240 --> 03:34:05,640
Well, I think we're probably
out of time

4185
03:34:05,640 --> 03:34:10,400
and want to thank
all of the panel members

4186
03:34:10,400 --> 03:34:13,520
as well as everyone who made
comments and asked questions,

4187
03:34:13,520 --> 03:34:16,840
and apologies
to those individuals

4188
03:34:16,840 --> 03:34:18,280
who we didn't get to,

4189
03:34:18,280 --> 03:34:20,720
but we will definitely
address your comments

4190
03:34:20,720 --> 03:34:24,960
in the recommendations
and try to do our best offline.

4191
03:34:24,960 --> 03:34:26,360
Thanks again.

4192
03:34:26,360 --> 03:34:28,680
-And it's my pleasure
to introduce to you

4193
03:34:28,680 --> 03:34:32,920
our session cochairs, Drs.
Donna Wilcock and Ron Petersen.

4194
03:34:32,920 --> 03:34:36,360
Welcome.

4195
03:34:36,360 --> 03:34:38,040
-Thank you, Natalia.

4196
03:34:38,040 --> 03:34:42,800
Thank you to the NINDS
for their organization.

4197
03:34:42,800 --> 03:34:48,360
It's my pleasure to open
the VCID session this afternoon,

4198
03:34:48,360 --> 03:34:51,840
and I think we've got
a great session for you.

4199
03:34:51,840 --> 03:34:53,640
We've got a wonderful committee,

4200
03:34:53,640 --> 03:34:57,000
and everybody has worked really
hard on these recommendations,

4201
03:34:57,000 --> 03:35:00,480
so we look forward
to your input at the end.

4202
03:35:00,480 --> 03:35:04,000
Please can we go
to the next slide?

4203
03:35:04,000 --> 03:35:09,600
So my disclosures, I think
you've seen this from everybody.

4204
03:35:09,600 --> 03:35:11,640
So these are my views,

4205
03:35:11,640 --> 03:35:14,520
not necessarily official views
of the NIH,

4206
03:35:14,520 --> 03:35:18,200
and I do not have any financial
disclosures to make.

4207
03:35:18,200 --> 03:35:20,680
Next slide, please.

4208
03:35:20,680 --> 03:35:25,320
So VCID, vascular contributions
to cognitive impairment

4209
03:35:25,320 --> 03:35:27,480
and dementia,

4210
03:35:27,480 --> 03:35:30,000
the science of VCID
really does overlay

4211
03:35:30,000 --> 03:35:34,600
these two clinical syndromes,
clinical stroke where we think

4212
03:35:34,600 --> 03:35:37,680
about cardio
and cerebrovascular disease

4213
03:35:37,680 --> 03:35:40,960
and then the clinical
Alzheimer's and dementia

4214
03:35:40,960 --> 03:35:45,000
where we think more about
cognitive decline and dementia,

4215
03:35:45,000 --> 03:35:46,800
and I love this image,

4216
03:35:46,800 --> 03:35:49,800
and this image
was from Dr. Corriveau.

4217
03:35:49,800 --> 03:35:52,120
Next slide, please.

4218
03:35:52,120 --> 03:35:58,200
Because of this complexity,
the science of VCID

4219
03:35:58,200 --> 03:36:01,640
I think is truly
interdisciplinary.

4220
03:36:01,640 --> 03:36:04,920
When we think about
the science of VCID,

4221
03:36:04,920 --> 03:36:07,280
even just thinking about
the neurovascular unit

4222
03:36:07,280 --> 03:36:10,520
where a lot of the insults
are occurring in the brain,

4223
03:36:10,520 --> 03:36:15,040
you have such a density
of different cell types

4224
03:36:15,040 --> 03:36:20,200
in that area, astrocytes,
neurons, pericytes, microglia,

4225
03:36:20,200 --> 03:36:21,960
capillaries,
smooth muscle cells.

4226
03:36:21,960 --> 03:36:25,440
They all meet in
that neurovascular unit,

4227
03:36:25,440 --> 03:36:29,800
and so there are many
different specialists,

4228
03:36:29,800 --> 03:36:33,120
special areas of focus
to think about,

4229
03:36:33,120 --> 03:36:36,520
cerebrovascular and
cardiovascular, biology.

4230
03:36:36,520 --> 03:36:38,120
We have metabolism.

4231
03:36:38,120 --> 03:36:40,800
We have the different
proteinopathies with dementia,

4232
03:36:40,800 --> 03:36:44,680
which VCID often is comorbid
with some of,

4233
03:36:44,680 --> 03:36:47,080
if not all of,
these proteinopathies,

4234
03:36:47,080 --> 03:36:50,640
and then we also have unique
immune responses.

4235
03:36:50,640 --> 03:36:52,760
Next slide, please.

4236
03:36:52,760 --> 03:36:54,160
And you'll hear about
some of those

4237
03:36:54,160 --> 03:36:57,480
in the presentations
this afternoon.

4238
03:36:57,480 --> 03:37:02,200
VCID also reflects really
an umbrella

4239
03:37:02,200 --> 03:37:04,840
of different
vascular pathologies,

4240
03:37:04,840 --> 03:37:10,080
and so some of these
might be more associated

4241
03:37:10,080 --> 03:37:12,840
with a modest
cognitive impairment

4242
03:37:12,840 --> 03:37:16,000
whereas some may actually
be associated more

4243
03:37:16,000 --> 03:37:19,880
with a full dementia,
and these run on a spectrum

4244
03:37:19,880 --> 03:37:21,280
as you can see there
on the left.

4245
03:37:21,280 --> 03:37:24,400
So we have pathologies
like microinfarcts,

4246
03:37:24,400 --> 03:37:28,960
microbleeds, very common,
very, very focal

4247
03:37:28,960 --> 03:37:32,040
and a lone, a single one,
may not have an impact.

4248
03:37:32,040 --> 03:37:35,320
Multiple, obviously,
the more you accumulate,

4249
03:37:35,320 --> 03:37:39,640
the more likely you are to have
a functional outcome from those,

4250
03:37:39,640 --> 03:37:44,000
and then we move
through silent strokes, TIAs.

4251
03:37:44,000 --> 03:37:48,120
Obviously, CADASIL is
a genetic condition

4252
03:37:48,120 --> 03:37:51,600
that we think about with respect
to small vessel disease,

4253
03:37:51,600 --> 03:37:55,440
and then we start to get into
the larger vessel involvement

4254
03:37:55,440 --> 03:37:58,720
where you have a much larger
area of the brain involved,

4255
03:37:58,720 --> 03:38:02,400
CAA, ischemic stroke,
hemorrhagic stroke,

4256
03:38:02,400 --> 03:38:05,000
and so as a committee,

4257
03:38:05,000 --> 03:38:07,120
we feel that it's really
important to develop

4258
03:38:07,120 --> 03:38:09,200
clinical outcomes,
biomarkers,

4259
03:38:09,200 --> 03:38:11,920
interventions that are
going to match

4260
03:38:11,920 --> 03:38:15,320
these particular vascular
injuries and diseases.

4261
03:38:15,320 --> 03:38:19,160
VCID most certainly will not be
a one-size-fits-all,

4262
03:38:19,160 --> 03:38:20,720
and I think that's why
those of us

4263
03:38:20,720 --> 03:38:24,880
who study it embrace that
heterogeneity that exists there,

4264
03:38:24,880 --> 03:38:28,920
and so for successful
VCID intervention,

4265
03:38:28,920 --> 03:38:30,120
we need mechanisms.

4266
03:38:30,120 --> 03:38:31,640
We need interventions.

4267
03:38:31,640 --> 03:38:33,360
We need biomarkers,
and we need clinical trials,

4268
03:38:33,360 --> 03:38:35,640
and hopefully you'll hear
about plans for all of those

4269
03:38:35,640 --> 03:38:38,920
and where we think
the field should move.

4270
03:38:38,920 --> 03:38:40,880
Next slide, please.

4271
03:38:40,880 --> 03:38:44,800
So I just want to take a second
to thank our committee.

4272
03:38:44,800 --> 03:38:46,640
Everybody, I'm not going
to name everybody,

4273
03:38:46,640 --> 03:38:48,400
but we had
a wonderful committee.

4274
03:38:48,400 --> 03:38:51,040
A lot of work went into this,

4275
03:38:51,040 --> 03:38:56,200
and what you see is a product
of everybody's input.

4276
03:38:56,200 --> 03:38:57,920
Next slide, please.

4277
03:38:57,920 --> 03:39:00,880
So we're going to have three
presentations this afternoon.

4278
03:39:00,880 --> 03:39:04,320
The first is the Focus Area 1.

4279
03:39:04,320 --> 03:39:06,320
So our recommendations
are broken down

4280
03:39:06,320 --> 03:39:08,600
into three focus areas,

4281
03:39:08,600 --> 03:39:12,320
Focus Area 1, basic mechanisms
and experimental models,

4282
03:39:12,320 --> 03:39:17,320
and Dr. Andy Shih
from Seattle Children's Hospital

4283
03:39:17,320 --> 03:39:20,960
is going to speak to you
about those recommendations.

4284
03:39:20,960 --> 03:39:25,080
Focus Area 2 is
three recommendations

4285
03:39:25,080 --> 03:39:29,520
focused around human studies,
and Dr. Prashanthi Vemuri

4286
03:39:29,520 --> 03:39:32,280
will be presenting
those recommendations,

4287
03:39:32,280 --> 03:39:36,760
and she is from the Mayo Clinic,
and then our last focus area,

4288
03:39:36,760 --> 03:39:40,200
we have two recommendations
on translational studies,

4289
03:39:40,200 --> 03:39:43,000
and Dr. Sudha Seshardi
will be presenting those,

4290
03:39:43,000 --> 03:39:45,680
and she is from
the University of Texas

4291
03:39:45,680 --> 03:39:48,320
Health Science Center
in San Antonio.

4292
03:39:48,320 --> 03:39:49,600
So without further ado,

4293
03:39:49,600 --> 03:39:52,400
I will hand over
to Dr. Andy Shih,

4294
03:39:52,400 --> 03:39:57,600
who will present those first
focus area recommendations.

4295
03:39:57,600 --> 03:40:01,080
Thank you, Andy.
>> Thanks, Donna.

4296
03:40:01,080 --> 03:40:04,200
And real honored to speak
on behalf of the committee

4297
03:40:04,200 --> 03:40:06,000
and all that
we've discussed.

4298
03:40:06,000 --> 03:40:07,680
Next slide, please.

4299
03:40:07,680 --> 03:40:10,840
So these are my disclaimers
and disclosures.

4300
03:40:10,840 --> 03:40:13,920
These are my own views,
not of the NIH,

4301
03:40:13,920 --> 03:40:17,520
but they were shaped and guided
by the committee members,

4302
03:40:17,520 --> 03:40:22,720
and I receive funding from the
NIH and NINDS for ADRD research.

4303
03:40:22,720 --> 03:40:25,400
Next slide.

4304
03:40:25,400 --> 03:40:30,640
So what I'm focusing on today
is on the basic mechanism

4305
03:40:30,640 --> 03:40:34,640
and experimental models
that we use to study VCID

4306
03:40:34,640 --> 03:40:36,320
at a preclinical level.

4307
03:40:36,320 --> 03:40:39,680
Now, I want to emphasize how
important animal models are here

4308
03:40:39,680 --> 03:40:42,600
because it is the sandbox,
essentially,

4309
03:40:42,600 --> 03:40:44,880
that we use to study
the different mechanisms

4310
03:40:44,880 --> 03:40:46,680
that might be contributing
to disease

4311
03:40:46,680 --> 03:40:49,960
but also where we start to,
you know,

4312
03:40:49,960 --> 03:40:52,000
test whether the drugs
that we have come up with

4313
03:40:52,000 --> 03:40:55,720
are actually useful
in treating the disease.

4314
03:40:55,720 --> 03:40:58,160
We talked about a lot of things
in these meetings,

4315
03:40:58,160 --> 03:41:01,280
but we have the painful,
you know,

4316
03:41:01,280 --> 03:41:04,240
role of trying to distill down
all these important topics,

4317
03:41:04,240 --> 03:41:05,800
the three recommendations

4318
03:41:05,800 --> 03:41:08,360
that I'm going dig a lot deeper
into in this talk:

4319
03:41:08,360 --> 03:41:11,280
so, first, to establish
and refine experimental models

4320
03:41:11,280 --> 03:41:14,880
and technologies to identify
disease-relevant mechanisms

4321
03:41:14,880 --> 03:41:17,520
that underlie VCID;
second,

4322
03:41:17,520 --> 03:41:20,400
to study the neurovascular
unit structure and function

4323
03:41:20,400 --> 03:41:23,720
and to establish
how it is impacted by VCID;

4324
03:41:23,720 --> 03:41:25,960
and then, three,
to use experimental models

4325
03:41:25,960 --> 03:41:28,120
to investigate
how aging cerebrovascular

4326
03:41:28,120 --> 03:41:30,800
and cardiovascular disease
impacts myelin,

4327
03:41:30,800 --> 03:41:33,800
white matter degeneration
and neurodegeneration.

4328
03:41:33,800 --> 03:41:37,280
Next slide.

4329
03:41:37,280 --> 03:41:39,560
So when we start to think
about modeling VCID,

4330
03:41:39,560 --> 03:41:42,880
we have to appreciate that VCID
is really an umbrella term

4331
03:41:42,880 --> 03:41:44,600
for many different
vascular disease

4332
03:41:44,600 --> 03:41:46,800
processes that are happening
in a human,

4333
03:41:46,800 --> 03:41:48,840
and all these
processes converge down

4334
03:41:48,840 --> 03:41:52,480
to create neurodegeneration
and cognitive decline.

4335
03:41:52,480 --> 03:41:54,160
The vascular problems
can exist

4336
03:41:54,160 --> 03:41:56,200
both extracranially
in the large vessels

4337
03:41:56,200 --> 03:41:59,040
but also in the small vessels
within the brain,

4338
03:41:59,040 --> 03:42:00,960
the arteries,
the small arterioles,

4339
03:42:00,960 --> 03:42:04,600
capillaries and venules,
and various types of pathologies

4340
03:42:04,600 --> 03:42:07,600
occurring at all these different
levels of the vasculature

4341
03:42:07,600 --> 03:42:09,080
can lead to a progressive loss

4342
03:42:09,080 --> 03:42:11,400
of vascular perfusion
and structure,

4343
03:42:11,400 --> 03:42:13,720
and this might involve
occlusion of the vessels,

4344
03:42:13,720 --> 03:42:16,200
partial occlusion
of the vessels,

4345
03:42:16,200 --> 03:42:18,680
impairment of the responsivity
of the vessels,

4346
03:42:18,680 --> 03:42:20,880
damage to the vessel wall
that cause them to leak

4347
03:42:20,880 --> 03:42:23,520
or various types
of inflammatory reactions

4348
03:42:23,520 --> 03:42:26,280
in the vessels
that impair the perfusion.

4349
03:42:26,280 --> 03:42:29,120
Next slide, please.

4350
03:42:29,120 --> 03:42:31,120
So we're tasked with trying
to model

4351
03:42:31,120 --> 03:42:33,840
a constellation of
different disease processes,

4352
03:42:33,840 --> 03:42:35,600
and by looking at this,
you can already imagine

4353
03:42:35,600 --> 03:42:37,280
that there is no magic bullet.

4354
03:42:37,280 --> 03:42:39,440
There's no one model
that captures the complexity

4355
03:42:39,440 --> 03:42:41,400
of what's going on
in the human brain,

4356
03:42:41,400 --> 03:42:43,200
and so therefore,
we have to think about,

4357
03:42:43,200 --> 03:42:44,560
as we develop models,

4358
03:42:44,560 --> 03:42:46,640
a number of fundamental
core concepts

4359
03:42:46,640 --> 03:42:50,120
that we have to keep
with each of the new models

4360
03:42:50,120 --> 03:42:52,800
that we develop,
and they're listed here.

4361
03:42:52,800 --> 03:42:55,280
So, first, they have to
reproduce small vessel disease

4362
03:42:55,280 --> 03:42:57,560
and other key
pathogenic mechanisms

4363
03:42:57,560 --> 03:42:59,760
thought to result
in cognitive impairment

4364
03:42:59,760 --> 03:43:01,960
and that reflect
the human condition.

4365
03:43:01,960 --> 03:43:05,320
Second, they have to
address contributions to damage

4366
03:43:05,320 --> 03:43:07,800
in both the white matter
and the gray matter.

4367
03:43:07,800 --> 03:43:09,640
Three, they have to include
genetic

4368
03:43:09,640 --> 03:43:13,360
and acquired conditions that are
associated with human VCID,

4369
03:43:13,360 --> 03:43:16,200
and three, because aging
is the key risk factor

4370
03:43:16,200 --> 03:43:17,960
that we all can't avoid,

4371
03:43:17,960 --> 03:43:20,520
incorporating aging
as a key factor

4372
03:43:20,520 --> 03:43:23,840
in the disease progression
is going to be very important.

4373
03:43:23,840 --> 03:43:27,440
Next slide.

4374
03:43:27,440 --> 03:43:30,720
So because the pathogenic
diversity of VCID

4375
03:43:30,720 --> 03:43:32,920
is so great,
it's logical for us

4376
03:43:32,920 --> 03:43:35,080
to be creating many
different types of models,

4377
03:43:35,080 --> 03:43:38,120
and each of these models
should recapitulate features

4378
03:43:38,120 --> 03:43:40,440
of the human disease
process.

4379
03:43:40,440 --> 03:43:43,800
So we have many models now
that reproduce different

4380
03:43:43,800 --> 03:43:45,520
clinically
relevant manifestations

4381
03:43:45,520 --> 03:43:48,400
that we see in
the pathology postmortem

4382
03:43:48,400 --> 03:43:50,720
but also using
in vivo MRI,

4383
03:43:50,720 --> 03:43:54,080
and they include topics such
as white matter degeneration,

4384
03:43:54,080 --> 03:43:56,000
lacunar strokes,
cerebral microinfarcts,

4385
03:43:56,000 --> 03:43:58,560
microbleeds,
superficial siderosis,

4386
03:43:58,560 --> 03:44:00,880
dilated perivascular spaces,

4387
03:44:00,880 --> 03:44:05,160
and certainly as we study
these injuries to the vessels,

4388
03:44:05,160 --> 03:44:07,400
we want to understand
how they are contributing

4389
03:44:07,400 --> 03:44:11,200
to neurodegeneration
and the disease progression,

4390
03:44:11,200 --> 03:44:14,080
but we also need to think
earlier in the etiology

4391
03:44:14,080 --> 03:44:15,560
of when these arise.

4392
03:44:15,560 --> 03:44:17,240
We know that these are actually
end points

4393
03:44:17,240 --> 03:44:18,760
of a vascular disease.

4394
03:44:18,760 --> 03:44:21,520
Next slide.

4395
03:44:21,520 --> 03:44:22,840
Or next, yeah.

4396
03:44:22,840 --> 03:44:26,400
And so therefore,
we need to think about --

4397
03:44:26,400 --> 03:44:28,560
In order to really define
therapeutic targets,

4398
03:44:28,560 --> 03:44:31,000
we need to think about
the early microvascular changes

4399
03:44:31,000 --> 03:44:33,600
that are occurring that have
created these manifestations,

4400
03:44:33,600 --> 03:44:35,520
and there's numerous
different types,

4401
03:44:35,520 --> 03:44:37,200
and I've just listed
a few here,

4402
03:44:37,200 --> 03:44:38,720
but I'm certain
that you can all think

4403
03:44:38,720 --> 03:44:41,040
of many different types
of vascular pathologies

4404
03:44:41,040 --> 03:44:44,680
that could lead
to these fundamental outcomes.

4405
03:44:44,680 --> 03:44:47,800
Next slide.

4406
03:44:47,800 --> 03:44:50,200
So when we think about
the models that exist

4407
03:44:50,200 --> 03:44:52,440
in our field right now,
we're actually quite rich.

4408
03:44:52,440 --> 03:44:55,520
We have got many different types
of models to think about,

4409
03:44:55,520 --> 03:44:57,600
ranging from ones
that are induced,

4410
03:44:57,600 --> 03:45:00,880
for example using
a surgical manipulation

4411
03:45:00,880 --> 03:45:04,400
to go and modify the way
that blood flows into the brain

4412
03:45:04,400 --> 03:45:06,200
or to include small vessels.

4413
03:45:06,200 --> 03:45:09,280
We've got dietary strategies
that will mimic comorbid factors

4414
03:45:09,280 --> 03:45:12,400
such as diabetes
and high-fat diet.

4415
03:45:12,400 --> 03:45:16,120
We've got genetic factors,
for example manipulating

4416
03:45:16,120 --> 03:45:18,800
or knocking out genes
that are involved,

4417
03:45:18,800 --> 03:45:20,800
known to be involved
in human VCID,

4418
03:45:20,800 --> 03:45:22,520
and there's a wide variety
of different types

4419
03:45:22,520 --> 03:45:25,040
with different phenotypes.

4420
03:45:25,040 --> 03:45:27,480
Embedded
within these genetic models

4421
03:45:27,480 --> 03:45:32,680
are CAA mice or models
of Alzheimer's disease,

4422
03:45:32,680 --> 03:45:35,880
where they try to overexpress
amyloid beta

4423
03:45:35,880 --> 03:45:39,280
or express amyloid
beta from the human,

4424
03:45:39,280 --> 03:45:42,920
and they sometimes lead
to the aggregation of amyloid

4425
03:45:42,920 --> 03:45:44,680
beta around the outside
of the vessel,

4426
03:45:44,680 --> 03:45:46,480
creating cerebral
amyloid angiopathy,

4427
03:45:46,480 --> 03:45:48,560
or also called CAA.

4428
03:45:48,560 --> 03:45:51,240
So when you think about
the different types of models

4429
03:45:51,240 --> 03:45:52,880
that could be used,

4430
03:45:52,880 --> 03:45:55,520
you have to first dial down
to your research question,

4431
03:45:55,520 --> 03:45:57,240
you know, what is the question
that you're going after,

4432
03:45:57,240 --> 03:46:00,120
and find the right model
that fits that question in order

4433
03:46:00,120 --> 03:46:05,000
to really utilize the tools
that we have at our disposal.

4434
03:46:05,000 --> 03:46:07,600
So for example, if you wanted to
study white matter degeneration,

4435
03:46:07,600 --> 03:46:09,960
you've got to be sure
that these models

4436
03:46:09,960 --> 03:46:12,160
have white matter
degeneration in them.

4437
03:46:12,160 --> 03:46:14,800
Next.

4438
03:46:14,800 --> 03:46:18,320
So this is where we come --
we fall a little bit short.

4439
03:46:18,320 --> 03:46:19,880
We would think that most
of these models

4440
03:46:19,880 --> 03:46:22,200
are actually relatively
undercharacterized

4441
03:46:22,200 --> 03:46:25,320
with respect to the types of
vascular pathologies that exist,

4442
03:46:25,320 --> 03:46:29,720
when they arise and also
that behavioral phenotype

4443
03:46:29,720 --> 03:46:31,440
that might arise
in these animals,

4444
03:46:31,440 --> 03:46:34,600
so we need this information in
order to make critical decisions

4445
03:46:34,600 --> 03:46:36,440
about which models
are appropriate.

4446
03:46:36,440 --> 03:46:39,600
Next.

4447
03:46:39,600 --> 03:46:41,640
And also, we sometimes
take these models

4448
03:46:41,640 --> 03:46:43,040
and mix them
with other models

4449
03:46:43,040 --> 03:46:44,800
in order to study
certain cell types,

4450
03:46:44,800 --> 03:46:48,040
and when we do so,
we mix genetic backgrounds,

4451
03:46:48,040 --> 03:46:49,480
and we now know that depending

4452
03:46:49,480 --> 03:46:51,120
on the genetic background
of the mouse,

4453
03:46:51,120 --> 03:46:53,120
the phenotype of the model
might change significantly,

4454
03:46:53,120 --> 03:46:55,480
so we have to be careful
of that as well.

4455
03:46:55,480 --> 03:46:58,520
Next.

4456
03:46:58,520 --> 03:47:00,200
It also then makes sense
to think

4457
03:47:00,200 --> 03:47:02,000
about adding these
different models together,

4458
03:47:02,000 --> 03:47:04,000
mixing them
and multiplexing them,

4459
03:47:04,000 --> 03:47:05,800
and here are some examples
of what have been.

4460
03:47:05,800 --> 03:47:07,760
You know, models that
are relevant to CAA

4461
03:47:07,760 --> 03:47:10,160
can be mixed
with models of dietary

4462
03:47:10,160 --> 03:47:13,160
or lifestyle-acquired
pathologies,

4463
03:47:13,160 --> 03:47:15,040
and you can imagine
this leads to an explosion

4464
03:47:15,040 --> 03:47:17,760
in the richness of the different
possibilities to explore,

4465
03:47:17,760 --> 03:47:20,560
and it creates additional
features of VCID pathology

4466
03:47:20,560 --> 03:47:22,000
that you can't necessarily see

4467
03:47:22,000 --> 03:47:24,680
with one individual model
on its own.

4468
03:47:24,680 --> 03:47:27,200
Next.

4469
03:47:27,200 --> 03:47:29,760
So here's one example
from Cos and Nicole's lab,

4470
03:47:29,760 --> 03:47:32,960
a really nice
one that shows the ApoE4 mice,

4471
03:47:32,960 --> 03:47:37,720
you know, that express the main
risk factor ApoE4 for AD,

4472
03:47:37,720 --> 03:47:42,600
these animals don't have white
matter hypoperfusion or hypoxia

4473
03:47:42,600 --> 03:47:45,000
until you give them BCAS,

4474
03:47:45,000 --> 03:47:47,440
which is the bilateral
carotid artery stenosis model,

4475
03:47:47,440 --> 03:47:51,320
and you don't see that
with the wild-type or the ApoE3.

4476
03:47:51,320 --> 03:47:53,920
Next.

4477
03:47:53,920 --> 03:47:55,360
But there are some gaps.

4478
03:47:55,360 --> 03:47:56,360
Although we're rich in
the different models,

4479
03:47:56,360 --> 03:47:58,240
most of them are mirroring,

4480
03:47:58,240 --> 03:48:01,000
and we have to think about
higher-order mammals as well.

4481
03:48:01,000 --> 03:48:04,360
The higher-order mammals
will allow us to study more

4482
03:48:04,360 --> 03:48:06,200
because their brains
are larger.

4483
03:48:06,200 --> 03:48:07,800
They can show additional
phenotypes

4484
03:48:07,800 --> 03:48:09,440
or features
of VCID pathology

4485
03:48:09,440 --> 03:48:11,800
that we don't see
in a simple mouse brain.

4486
03:48:11,800 --> 03:48:14,080
Their larger brains
have more white matter,

4487
03:48:14,080 --> 03:48:16,200
and because
they have larger brains,

4488
03:48:16,200 --> 03:48:18,320
the limited
spatial resolution of MRI

4489
03:48:18,320 --> 03:48:22,240
can be used to study the defects
a little bit more closely.

4490
03:48:22,240 --> 03:48:27,400
Further, you can use
these larger animal models

4491
03:48:27,400 --> 03:48:30,560
to do sophisticated
neurocognitive testing.

4492
03:48:30,560 --> 03:48:33,120
Next.

4493
03:48:33,120 --> 03:48:36,640
And so here's one example
from Bill Van Nostrand

4494
03:48:36,640 --> 03:48:38,760
and Helena Benveniste

4495
03:48:38,760 --> 03:48:41,480
recently where they developed
a CAA model of rat

4496
03:48:41,480 --> 03:48:42,880
where the rat brain
is about four

4497
03:48:42,880 --> 03:48:45,240
to five times larger
than the mouse brain,

4498
03:48:45,240 --> 03:48:47,760
and you can see here that there
is white matter degeneration

4499
03:48:47,760 --> 03:48:49,160
occurring within this model,

4500
03:48:49,160 --> 03:48:52,000
and they've been using
this model with MRI

4501
03:48:52,000 --> 03:48:55,720
to very carefully track
white matter degeneration

4502
03:48:55,720 --> 03:49:00,200
using routine MRI clinical
scanning approaches.

4503
03:49:00,200 --> 03:49:03,640
Next.

4504
03:49:03,640 --> 03:49:05,640
We also want to think
about larger mammals

4505
03:49:05,640 --> 03:49:07,360
beyond the rat as well.

4506
03:49:07,360 --> 03:49:09,480
There are important studies
that are being done in canine,

4507
03:49:09,480 --> 03:49:12,720
porcine and nonhuman
primate animals

4508
03:49:12,720 --> 03:49:17,600
that are going to be important
to further study as well.

4509
03:49:17,600 --> 03:49:20,680
Next.

4510
03:49:20,680 --> 03:49:22,240
Now, moving to the other end
of the scale,

4511
03:49:22,240 --> 03:49:26,480
there are also important
developments in the

4512
03:49:26,480 --> 03:49:28,400
in vitro space as well.

4513
03:49:28,400 --> 03:49:33,720
The reductionist methods of in
vitro models are very important,

4514
03:49:33,720 --> 03:49:37,080
not only because this is where
we can do a lot of drug testing

4515
03:49:37,080 --> 03:49:40,200
but also because a lot of times,
the animal model,

4516
03:49:40,200 --> 03:49:41,840
the vasculature
in the animal models

4517
03:49:41,840 --> 03:49:44,000
might not represent what's
going on in the human brain.

4518
03:49:44,000 --> 03:49:46,560
So, therefore, we need to take
human tissues

4519
03:49:46,560 --> 03:49:48,200
and try to culture them.

4520
03:49:48,200 --> 03:49:51,360
So in this space, the inducible
pluripotent stem cells

4521
03:49:51,360 --> 03:49:53,400
from human tissue

4522
03:49:53,400 --> 03:49:55,600
highlighted here
from Li-Huei Tsai's lab

4523
03:49:55,600 --> 03:49:58,640
has been used to differentiate

4524
03:49:58,640 --> 03:50:02,400
into different types
of vessel cell types,

4525
03:50:02,400 --> 03:50:05,720
including endothelial cells
and mural cells and astrocytes,

4526
03:50:05,720 --> 03:50:09,600
that then can be collated back
together again into hydrogels

4527
03:50:09,600 --> 03:50:12,800
and then be developed
into cell culture systems

4528
03:50:12,800 --> 03:50:13,960
that have a human

4529
03:50:13,960 --> 03:50:16,240
blood-brain-barrier-like
phenotype.

4530
03:50:16,240 --> 03:50:18,680
Next slide.

4531
03:50:18,680 --> 03:50:20,400
And so these models are going
to be very important

4532
03:50:20,400 --> 03:50:23,440
for understanding mechanism
but also drug testing as well,

4533
03:50:23,440 --> 03:50:25,640
but care is needed to ensure
that they are reasonably

4534
03:50:25,640 --> 03:50:28,280
modeling in vivo features
of the vascular cell types

4535
03:50:28,280 --> 03:50:31,000
in vivo or in humans.

4536
03:50:31,000 --> 03:50:34,000
Next.

4537
03:50:34,000 --> 03:50:36,000
We've also been very excited
by the development

4538
03:50:36,000 --> 03:50:38,920
and application
of next-generation technologies.

4539
03:50:38,920 --> 03:50:41,040
In particular
in the last 3 years,

4540
03:50:41,040 --> 03:50:43,600
some really exciting techniques
have come about that,

4541
03:50:43,600 --> 03:50:48,480
if applied to VCID research,
can be very, very insightful.

4542
03:50:48,480 --> 03:50:50,840
They include deep
multiphoton microscopy

4543
03:50:50,840 --> 03:50:53,680
to image subcortical
white matter in vivo,

4544
03:50:53,680 --> 03:50:55,960
more sophisticated cognitive
and behavioral

4545
03:50:55,960 --> 03:50:58,400
testing approaches
such as touch screen

4546
03:50:58,400 --> 03:51:00,800
testing for mice and rodents,

4547
03:51:00,800 --> 03:51:03,720
which mimic more what we're
doing in the clinic as well;

4548
03:51:03,720 --> 03:51:07,640
home cage assessments
that look across the clock

4549
03:51:07,640 --> 03:51:10,800
to understand what the animals
are doing in their cages;

4550
03:51:10,800 --> 03:51:14,680
higher resolution MRI
and CT and PET modalities;

4551
03:51:14,680 --> 03:51:17,520
spatial proteomics
and transcriptomic analyses;

4552
03:51:17,520 --> 03:51:20,960
and finally, CRISPR editing,
gene editing approaches

4553
03:51:20,960 --> 03:51:24,080
to create more physiologically
relevant rodent models.

4554
03:51:24,080 --> 03:51:26,040
Next.

4555
03:51:26,040 --> 03:51:28,600
And so just one highlight
from Chris Xu's lab

4556
03:51:28,600 --> 03:51:31,840
where they've used multicolor
three-photon microscopy

4557
03:51:31,840 --> 03:51:34,440
to study the neural
and vascular architecture

4558
03:51:34,440 --> 03:51:37,400
and function of blood vessels
within the white matter,

4559
03:51:37,400 --> 03:51:39,400
so that blue streak
in the middle of that image

4560
03:51:39,400 --> 03:51:41,640
on the left
shows the white matter,

4561
03:51:41,640 --> 03:51:44,000
and now we're able to image
all the way down to that

4562
03:51:44,000 --> 03:51:47,880
in the living brain of an animal
in order to study

4563
03:51:47,880 --> 03:51:50,560
what's going on
to the blood vessels over time

4564
03:51:50,560 --> 03:51:52,480
and also to study
the different cell types

4565
03:51:52,480 --> 03:51:54,120
and the responses
to the blood vessel

4566
03:51:54,120 --> 03:51:55,840
changes that are occurring,

4567
03:51:55,840 --> 03:51:57,800
and we can even image much
deeper beyond the white matter,

4568
03:51:57,800 --> 03:51:59,360
into the hippocampus,

4569
03:51:59,360 --> 03:52:02,000
opening up completely
different types of questions

4570
03:52:02,000 --> 03:52:03,400
to the research field.

4571
03:52:03,400 --> 03:52:06,560
Next.

4572
03:52:06,560 --> 03:52:08,080
We want to continue
investigation

4573
03:52:08,080 --> 03:52:11,200
of how neurovascular
unit contributions

4574
03:52:11,200 --> 03:52:15,400
are regulating neurovascular
coupling and basal blood flow.

4575
03:52:15,400 --> 03:52:17,160
The area of understanding

4576
03:52:17,160 --> 03:52:18,760
how blood flow
is regulated in the brain

4577
03:52:18,760 --> 03:52:21,920
is still an actively
researched area,

4578
03:52:21,920 --> 03:52:25,040
but in order to get at
what is going on

4579
03:52:25,040 --> 03:52:26,400
in the diseased condition,

4580
03:52:26,400 --> 03:52:28,280
we need to understand
the fundamentals

4581
03:52:28,280 --> 03:52:32,200
of blood flow regulation
in the normal brain.

4582
03:52:32,200 --> 03:52:34,360
Next.

4583
03:52:34,360 --> 03:52:38,320
And so one thing that we'd like
to do is encourage researchers

4584
03:52:38,320 --> 03:52:40,200
to think about
the neurovascular unit

4585
03:52:40,200 --> 03:52:42,440
across the different
microvascular zones

4586
03:52:42,440 --> 03:52:44,440
and think about how
VCID pathology

4587
03:52:44,440 --> 03:52:46,760
affects each of these zones.

4588
03:52:46,760 --> 03:52:49,240
The extracranial vessels
in comparison

4589
03:52:49,240 --> 03:52:50,800
to the smaller
intercranial vessels

4590
03:52:50,800 --> 03:52:52,840
are completely different
in their composition,

4591
03:52:52,840 --> 03:52:55,120
in their thickness,
in their dynamics,

4592
03:52:55,120 --> 03:52:58,760
and therefore,
disease mechanisms that act

4593
03:52:58,760 --> 03:53:00,600
on the different zones
of the blood vessels

4594
03:53:00,600 --> 03:53:05,360
might have completely
different underlying bases.

4595
03:53:05,360 --> 03:53:07,880
Not included in this diagram
are also veins.

4596
03:53:07,880 --> 03:53:09,680
All that blood has to come
through the arteries

4597
03:53:09,680 --> 03:53:11,520
and come out
through the veins,

4598
03:53:11,520 --> 03:53:13,480
and we don't really think
about veins very much

4599
03:53:13,480 --> 03:53:16,000
in the context of VCID.

4600
03:53:16,000 --> 03:53:19,560
So it's important to think about
the drainage networks as well.

4601
03:53:19,560 --> 03:53:21,160
Next.

4602
03:53:23,560 --> 03:53:27,080
So some very exciting work
in this area of single-cell

4603
03:53:27,080 --> 03:53:31,200
and spatial technologies
for transcriptomic analysis

4604
03:53:31,200 --> 03:53:34,160
of the cerebrovasculature
has come about

4605
03:53:34,160 --> 03:53:37,560
in the last 5 years or so.

4606
03:53:37,560 --> 03:53:39,240
Pioneering work from
Christopher Bechtel

4607
03:53:39,240 --> 03:53:42,240
has shown that it's possible
to isolate blood vessels

4608
03:53:42,240 --> 03:53:44,800
from the adult mouse brain,
and this has been used

4609
03:53:44,800 --> 03:53:48,760
to study the transcriptional
phenotypes of cells

4610
03:53:48,760 --> 03:53:50,720
across different zones
of the blood vessels

4611
03:53:50,720 --> 03:53:52,600
within the cerebrovasculature.

4612
03:53:52,600 --> 03:53:54,920
Next.

4613
03:53:54,920 --> 03:53:57,960
And -- Next, please.

4614
03:53:57,960 --> 03:53:59,640
Oops, sorry, go back.

4615
03:53:59,640 --> 03:54:01,280
Something didn't pop up here.

4616
03:54:01,280 --> 03:54:02,800
Okay.

4617
03:54:02,800 --> 03:54:04,880
Interestingly, the --

4618
03:54:04,880 --> 03:54:09,440
Even more recently,
just in the last month or so,

4619
03:54:09,440 --> 03:54:11,400
new work has come out from
a number of different groups

4620
03:54:11,400 --> 03:54:15,360
showing that it's also possible
to isolate blood vessels

4621
03:54:15,360 --> 03:54:19,400
from fresh human brain tissue,
and this has led to,

4622
03:54:19,400 --> 03:54:22,280
essentially, a nice correlate
across comparison

4623
03:54:22,280 --> 03:54:24,200
between the animal studies
and the human studies

4624
03:54:24,200 --> 03:54:27,800
that allow us to think about the
cell types of the blood vessels,

4625
03:54:27,800 --> 03:54:31,680
driving the possibility
of exciting new hypotheses

4626
03:54:31,680 --> 03:54:35,720
in the animal research arena
but also to help us think

4627
03:54:35,720 --> 03:54:38,040
about what we might be missing
with animal models

4628
03:54:38,040 --> 03:54:41,480
or what types of differences
are not captured adequately

4629
03:54:41,480 --> 03:54:45,000
between the mouse
and the human brain vasculature,

4630
03:54:45,000 --> 03:54:48,760
and what do we need to do
to make them align better.

4631
03:54:48,760 --> 03:54:50,600
Next.

4632
03:54:50,600 --> 03:54:53,400
-Two minutes remaining.
-Okay.

4633
03:54:53,400 --> 03:54:57,520
We also have to think about
the clearance mechanisms

4634
03:54:57,520 --> 03:54:59,200
of waste from the brain,

4635
03:54:59,200 --> 03:55:04,040
and the vasculature has become
a central focus in this.

4636
03:55:04,040 --> 03:55:05,720
Removal of waste metabolites

4637
03:55:05,720 --> 03:55:08,440
through the blood-brain barrier
along perivascular spaces

4638
03:55:08,440 --> 03:55:12,200
that are filled with CSF or
through phagocytic degradation

4639
03:55:12,200 --> 03:55:14,640
need to be thought
about more carefully.

4640
03:55:14,640 --> 03:55:17,920
Next.

4641
03:55:17,920 --> 03:55:21,520
And in particular,
dilated perivascular spaces,

4642
03:55:21,520 --> 03:55:25,400
which are often seen
as an increased risk factor

4643
03:55:25,400 --> 03:55:29,640
and increased with age and also
with vascular risk factors

4644
03:55:29,640 --> 03:55:32,920
are interesting biomarkers,
perhaps, for VCID,

4645
03:55:32,920 --> 03:55:34,400
but we'd also want to understand

4646
03:55:34,400 --> 03:55:38,200
what this actually means
for brain clearance

4647
03:55:38,200 --> 03:55:40,680
in the context
of human neuroimaging.

4648
03:55:40,680 --> 03:55:42,280
Next.

4649
03:55:44,560 --> 03:55:48,480
So this is where animal models
come back into the spotlight.

4650
03:55:48,480 --> 03:55:50,240
A lot of these questions
are very difficult

4651
03:55:50,240 --> 03:55:51,720
to address
in the human brain,

4652
03:55:51,720 --> 03:55:54,600
but if we could study them
in the rodent brain

4653
03:55:54,600 --> 03:55:55,800
or in the animal brain,

4654
03:55:55,800 --> 03:55:58,480
we can get
much more information,

4655
03:55:58,480 --> 03:56:00,920
and so recent studies
from Macon Utgaard's lab,

4656
03:56:00,920 --> 03:56:04,760
for example, are shown,
the ability to use optical

4657
03:56:04,760 --> 03:56:07,760
imaging to track the movement
of dyes or different small beads

4658
03:56:07,760 --> 03:56:09,960
that have been injected
into the CSF.

4659
03:56:09,960 --> 03:56:13,600
MRI has also been used to watch
the diffusion

4660
03:56:13,600 --> 03:56:20,040
of intercortically injected dyes
within the interstitial space

4661
03:56:20,040 --> 03:56:21,960
to see how they clear
over time.

4662
03:56:21,960 --> 03:56:23,720
Next.

4663
03:56:23,720 --> 03:56:26,000
But also different --
It's becoming more clear

4664
03:56:26,000 --> 03:56:27,960
that different types
of physiological rhythms

4665
03:56:27,960 --> 03:56:30,080
might be involved
in augmenting this clearance

4666
03:56:30,080 --> 03:56:35,440
and driving the clearance of CSF
and metabolic waste as well,

4667
03:56:35,440 --> 03:56:38,920
and this is heartbeat,
breathing,

4668
03:56:38,920 --> 03:56:41,200
vasomotor oscillations
of the blood vessels,

4669
03:56:41,200 --> 03:56:43,400
neural activity, sleep.

4670
03:56:43,400 --> 03:56:45,600
A lot of different factors
might be involved,

4671
03:56:45,600 --> 03:56:49,920
and so animal models can be used
to help disentangle

4672
03:56:49,920 --> 03:56:51,200
some of these complexities.

4673
03:56:51,200 --> 03:56:54,120
Thanks.

4674
03:56:54,120 --> 03:56:56,200
We also want to think
about the cells

4675
03:56:56,200 --> 03:56:58,480
that actually make
the white matter white,

4676
03:56:58,480 --> 03:57:00,160
the oligodendrocytes.

4677
03:57:00,160 --> 03:57:02,360
We know that white matter is
particularly vulnerable in VCID,

4678
03:57:02,360 --> 03:57:03,760
but yet we know very little

4679
03:57:03,760 --> 03:57:06,760
about the pathophysiology
of oligodendrocytes

4680
03:57:06,760 --> 03:57:09,240
and the repair mechanisms
that are involved --

4681
03:57:09,240 --> 03:57:14,200
that they mount in the face of
vascular and neurodegeneration.

4682
03:57:14,200 --> 03:57:15,640
Next.

4683
03:57:15,640 --> 03:57:18,720
And so through in vivo
imaging approaches --

4684
03:57:18,720 --> 03:57:20,080
Next, yeah.

4685
03:57:20,080 --> 03:57:23,400
-Time has expired.
-Oh, okay, very quick.

4686
03:57:23,400 --> 03:57:26,400
Yeah, and so through using
in vivo

4687
03:57:26,400 --> 03:57:28,360
imaging approaches here
from Ethan Hughes Lab,

4688
03:57:28,360 --> 03:57:31,080
you can see that you can
track the remodeling

4689
03:57:31,080 --> 03:57:34,120
and the remyelination
of these cells over time

4690
03:57:34,120 --> 03:57:36,960
in living animals,
and then next.

4691
03:57:36,960 --> 03:57:38,800
My final slide here
is just to say

4692
03:57:38,800 --> 03:57:41,440
that the development
of new tools

4693
03:57:41,440 --> 03:57:45,720
are what lead to major gap
leaps within our insight

4694
03:57:45,720 --> 03:57:47,440
into a disease progression,

4695
03:57:47,440 --> 03:57:49,840
and so we want to encourage
the development of new tools,

4696
03:57:49,840 --> 03:57:53,920
and this is just one slide
showing from [Indistinct] lab

4697
03:57:53,920 --> 03:57:55,440
at University
of Southern California

4698
03:57:55,440 --> 03:57:57,160
that's designed
a new Cre driver

4699
03:57:57,160 --> 03:57:59,480
that allows us to target
a very specific cell type

4700
03:57:59,480 --> 03:58:03,400
within the brain, a pericyte,
that wouldn't have been possible

4701
03:58:03,400 --> 03:58:06,080
without single-cell
transcriptomic analyses

4702
03:58:06,080 --> 03:58:08,360
identifying specific genes

4703
03:58:08,360 --> 03:58:11,640
that allow us to do
this genetic targeting.

4704
03:58:11,640 --> 03:58:13,000
So with that,
I'd like to thank you.

4705
03:58:13,000 --> 03:58:14,520
Sorry for going over
a little bit,

4706
03:58:14,520 --> 03:58:19,120
and I'll pass the baton
onto Prashanthi Vemuri.

4707
03:58:19,120 --> 03:58:20,600
-Thank you, Andy.

4708
03:58:20,600 --> 03:58:22,800
It's an honor to be here
on behalf of the committee

4709
03:58:22,800 --> 03:58:26,000
and represent
the great discussions

4710
03:58:26,000 --> 03:58:28,680
we had coming up
with these recommendations.

4711
03:58:28,680 --> 03:58:29,840
Next, please.

4712
03:58:29,840 --> 03:58:31,240
I have nothing to disclose.

4713
03:58:31,240 --> 03:58:32,800
Next.

4714
03:58:32,800 --> 03:58:36,800
So the recommendations
came through based on three

4715
03:58:36,800 --> 03:58:40,520
guiding principles specific
to human studies.

4716
03:58:40,520 --> 03:58:42,440
VCID is really common.

4717
03:58:42,440 --> 03:58:45,360
It coexists with other
deteriorative pathologies,

4718
03:58:45,360 --> 03:58:49,440
so detection and screening
for these is very important.

4719
03:58:49,440 --> 03:58:51,280
Number two,
on the next slide,

4720
03:58:51,280 --> 03:58:54,000
is that VCID is preventable.

4721
03:58:54,000 --> 03:58:57,760
So there's decreasing prevalence
of raised blood pressure

4722
03:58:57,760 --> 03:59:01,400
because of better blood
control across the globe,

4723
03:59:01,400 --> 03:59:03,720
and this has resulted
in declining incidence rate

4724
03:59:03,720 --> 03:59:07,920
of dementia in Europe and U.S.A.
across seven studies.

4725
03:59:07,920 --> 03:59:11,080
So the fact that VCID
is preventable

4726
03:59:11,080 --> 03:59:12,720
is an important
fact to consider

4727
03:59:12,720 --> 03:59:15,440
when designing
these recommendations.

4728
03:59:15,440 --> 03:59:20,280
The next slide shows
that we understand VCID

4729
03:59:20,280 --> 03:59:22,600
as a heterogeneous
and a broad phenomenon.

4730
03:59:22,600 --> 03:59:26,680
So it captures all forms of
cerebrovascular brain injury,

4731
03:59:26,680 --> 03:59:28,560
not solely stroke.

4732
03:59:28,560 --> 03:59:30,800
Therefore, studying this
in the context

4733
03:59:30,800 --> 03:59:32,320
of mild
cognitive impairment

4734
03:59:32,320 --> 03:59:35,200
or fully developed dementia
is really important,

4735
03:59:35,200 --> 03:59:37,720
and these are the three
guiding principles

4736
03:59:37,720 --> 03:59:40,240
that set us up
for the recommendations,

4737
03:59:40,240 --> 03:59:43,160
and we also wanted to take
into consideration

4738
03:59:43,160 --> 03:59:45,720
the progress
that has been made so far.

4739
03:59:45,720 --> 03:59:48,160
Next slide, please.

4740
03:59:48,160 --> 03:59:49,880
Next.

4741
03:59:49,880 --> 03:59:53,640
There's been tremendous progress
that has been made in VCID,

4742
03:59:53,640 --> 03:59:56,560
like Donna alluded
to right in the beginning,

4743
03:59:56,560 --> 03:59:59,640
but one of the major
improvements in the field

4744
03:59:59,640 --> 04:00:02,000
has been that in the last
couple of decades,

4745
04:00:02,000 --> 04:00:06,280
we really understand the
mechanisms and biology of VCID,

4746
04:00:06,280 --> 04:00:08,200
like Dr. Shih showed.

4747
04:00:08,200 --> 04:00:12,720
Here's an example of studies
across NIH-funded VCID cohorts.

4748
04:00:12,720 --> 04:00:16,160
These are examples of studies,
and we have tried to understand

4749
04:00:16,160 --> 04:00:19,600
how risk factors, lifestyle
as well as genetic variants

4750
04:00:19,600 --> 04:00:22,240
can express and increase
the risk

4751
04:00:22,240 --> 04:00:24,600
for large
and small vessel diseases

4752
04:00:24,600 --> 04:00:28,000
as well as contribute
to the burden of dementia.

4753
04:00:28,000 --> 04:00:29,760
Next.

4754
04:00:29,760 --> 04:00:33,760
We've also gotten really good
with imaging markers of VCID.

4755
04:00:33,760 --> 04:00:35,480
I'd really like to look
at the image

4756
04:00:35,480 --> 04:00:37,440
on the top left in blue,

4757
04:00:37,440 --> 04:00:39,720
which shows some
of the earliest images

4758
04:00:39,720 --> 04:00:41,720
of white matter
hyperintensities,

4759
04:00:41,720 --> 04:00:44,440
which are manifestations
of vascular disease,

4760
04:00:44,440 --> 04:00:47,760
and from then to now, these
are images taken last year.

4761
04:00:47,760 --> 04:00:50,240
You can really see that
on the top panel,

4762
04:00:50,240 --> 04:00:53,120
we have gotten very good
at detecting lesions,

4763
04:00:53,120 --> 04:00:54,680
quantifying them.

4764
04:00:54,680 --> 04:00:57,240
At the bottom panel, you can see
that we have quantitative

4765
04:00:57,240 --> 04:00:59,600
imaging available right now
in human studies

4766
04:00:59,600 --> 04:01:02,480
where we can capture various
aspects of the brain

4767
04:01:02,480 --> 04:01:05,840
as well as measure
vessel structure and function.

4768
04:01:05,840 --> 04:01:08,200
So we made tremendous
progress there.

4769
04:01:08,200 --> 04:01:10,000
Next slide, please.

4770
04:01:10,000 --> 04:01:13,120
We've also been able
to try and understand

4771
04:01:13,120 --> 04:01:15,800
what the clinical implications
of VCID are.

4772
04:01:15,800 --> 04:01:18,360
So if someone has a positive
amyloid scan,

4773
04:01:18,360 --> 04:01:20,720
how do the vascular
disease contributions

4774
04:01:20,720 --> 04:01:24,600
add onto Alzheimer's disease
and cause cognitive impairment,

4775
04:01:24,600 --> 04:01:27,360
which is very similar
over an age range

4776
04:01:27,360 --> 04:01:30,880
of 70 plus or 5 years.

4777
04:01:30,880 --> 04:01:33,600
And on the next slide,
I'll talk about the successes

4778
04:01:33,600 --> 04:01:35,760
that have come through
AD/ADRD summits,

4779
04:01:35,760 --> 04:01:39,080
where there's several
NIH initiatives for VCID.

4780
04:01:39,080 --> 04:01:41,840
MarkVCID, which has been focused
on analyzing,

4781
04:01:41,840 --> 04:01:44,640
optimizing and validating
VCID biomarkers

4782
04:01:44,640 --> 04:01:47,200
and has really brought
into the field of AD/ADRD

4783
04:01:47,200 --> 04:01:52,600
to have tools to be able
to detect vascular disease.

4784
04:01:52,600 --> 04:01:56,200
DISCOVERY Study, which has been
fantastic at bringing together

4785
04:01:56,200 --> 04:01:59,360
and trying to understand
mechanisms of poststroke VCID.

4786
04:01:59,360 --> 04:02:01,840
And the newly funded
DiverseVCID,

4787
04:02:01,840 --> 04:02:04,240
which has been focused
on white matter lesions

4788
04:02:04,240 --> 04:02:06,720
in diverse individuals
across US.

4789
04:02:06,720 --> 04:02:10,040
So we did -- have made
a lot of progress in VCID,

4790
04:02:10,040 --> 04:02:12,760
but when the committee met,
on the next slide,

4791
04:02:12,760 --> 04:02:14,800
we thought that
our recommendations

4792
04:02:14,800 --> 04:02:17,720
should reflect
the common theme

4793
04:02:17,720 --> 04:02:21,280
across all the things
that I've talked about so far

4794
04:02:21,280 --> 04:02:24,960
as well as consider the progress
that we've made so far.

4795
04:02:24,960 --> 04:02:26,280
Next slide.

4796
04:02:26,280 --> 04:02:27,880
Before I get into
the recommendation,

4797
04:02:27,880 --> 04:02:31,400
I wanted to bring this health
equity concept back again

4798
04:02:31,400 --> 04:02:33,320
because in each of
the recommendations

4799
04:02:33,320 --> 04:02:34,920
that we talked about,

4800
04:02:34,920 --> 04:02:38,280
the crosscutting theme
was that specific populations

4801
04:02:38,280 --> 04:02:41,280
with high vascular risk factors,
as well as inequalities,

4802
04:02:41,280 --> 04:02:42,880
are not considered
in the studies

4803
04:02:42,880 --> 04:02:44,680
that we're conducting
right now.

4804
04:02:44,680 --> 04:02:46,680
And this should be a key aspect

4805
04:02:46,680 --> 04:02:48,840
of what we're going
to do in the future.

4806
04:02:50,880 --> 04:02:54,560
After setting up this,
we came up with recommendations,

4807
04:02:54,560 --> 04:02:56,600
and the first recommendation
was developing

4808
04:02:56,600 --> 04:02:59,240
and validating markers of VCID.

4809
04:02:59,240 --> 04:03:01,760
So one might say that they made
a lot of progress.

4810
04:03:01,760 --> 04:03:03,000
We have imaging markers.

4811
04:03:03,000 --> 04:03:04,880
We have emerging plasma markers.

4812
04:03:04,880 --> 04:03:07,320
Why would we need
this recommendation?

4813
04:03:07,320 --> 04:03:09,800
The committee felt that,
on the next slide,

4814
04:03:09,800 --> 04:03:12,760
their could be
cost-effective ways

4815
04:03:12,760 --> 04:03:16,040
to measure the presence
and progression of VCID.

4816
04:03:16,040 --> 04:03:18,440
If you remember the first slide
that I showed,

4817
04:03:18,440 --> 04:03:20,760
VCID is extremely common,

4818
04:03:20,760 --> 04:03:23,280
so we really need
cost-effective ways

4819
04:03:23,280 --> 04:03:25,960
to be able to detect
the presence of VCID

4820
04:03:25,960 --> 04:03:28,200
and track
the progression of VCID.

4821
04:03:28,200 --> 04:03:30,400
There's several ways
you could go about it,

4822
04:03:30,400 --> 04:03:32,240
and I wanted to give you
two examples

4823
04:03:32,240 --> 04:03:33,840
to kind of get us
thinking about,

4824
04:03:33,840 --> 04:03:37,680
what kind of tools would be
optimal to consider this?

4825
04:03:37,680 --> 04:03:39,960
Next slide, please.

4826
04:03:39,960 --> 04:03:42,320
This is a simple example
of how you could look

4827
04:03:42,320 --> 04:03:46,200
at the electronic health care
records and look at the ICD-9,

4828
04:03:46,200 --> 04:03:50,000
10 codes for the patients
in the health care records

4829
04:03:50,000 --> 04:03:51,800
and consider
the seven conditions

4830
04:03:51,800 --> 04:03:55,200
proposed by US Department
of Health and Human Services

4831
04:03:55,200 --> 04:03:59,240
for measuring cardiovascular
metabolic conditions.

4832
04:03:59,240 --> 04:04:00,800
In this particular example,

4833
04:04:00,800 --> 04:04:03,400
what we did was we looked
at individuals

4834
04:04:03,400 --> 04:04:05,600
who had two or more
of these conditions,

4835
04:04:05,600 --> 04:04:07,280
a very simple cutoff,

4836
04:04:07,280 --> 04:04:11,520
and we found that people who had
two or more of these conditions,

4837
04:04:11,520 --> 04:04:13,200
which can be easily obtained,

4838
04:04:13,200 --> 04:04:15,920
are predictable of greater
white matter hyperintensities,

4839
04:04:15,920 --> 04:04:18,200
which is manifestation
of vascular disease,

4840
04:04:18,200 --> 04:04:20,400
as well as greater
progression over time.

4841
04:04:20,400 --> 04:04:23,000
So tools like this
could be very helpful.

4842
04:04:23,000 --> 04:04:24,600
Next slide, please.

4843
04:04:24,600 --> 04:04:27,400
There's another example
that Dr. Eric Smith

4844
04:04:27,400 --> 04:04:28,800
brought up,
which was --

4845
04:04:28,800 --> 04:04:30,960
which elegantly looked
at natural language

4846
04:04:30,960 --> 04:04:32,720
processing in EHR

4847
04:04:32,720 --> 04:04:35,080
and how you could
actually look at MRI

4848
04:04:35,080 --> 04:04:39,760
and CT scans for a non-stroke
indication in EHR

4849
04:04:39,760 --> 04:04:43,000
and come up with ways in which
you can detect people

4850
04:04:43,000 --> 04:04:44,840
who are at greater
risk of dementia

4851
04:04:44,840 --> 04:04:47,240
because of vascular
cognitive contributions

4852
04:04:47,240 --> 04:04:49,000
to impairment and dementia.

4853
04:04:49,000 --> 04:04:50,480
In this particular study,

4854
04:04:50,480 --> 04:04:53,200
they said that when
they looked at CT and MRI,

4855
04:04:53,200 --> 04:04:56,440
they were able to recognize and
identify a group of individuals

4856
04:04:56,440 --> 04:05:00,640
who are at greater risk of
declining over the next 5 years,

4857
04:05:00,640 --> 04:05:03,120
which is a tremendous
progress.

4858
04:05:03,120 --> 04:05:06,040
Next slide.

4859
04:05:06,040 --> 04:05:07,400
We talked about new markers.

4860
04:05:07,400 --> 04:05:09,560
The other thing that
was recurring

4861
04:05:09,560 --> 04:05:11,480
when we talked
about markers was that,

4862
04:05:11,480 --> 04:05:14,600
we need to refine and validate
the markers we have.

4863
04:05:14,600 --> 04:05:18,400
We're doing a really good job
with coming up with markers.

4864
04:05:18,400 --> 04:05:21,240
For example, plasma NfL
is a fantastic marker

4865
04:05:21,240 --> 04:05:22,640
for several vascular disease,

4866
04:05:22,640 --> 04:05:25,440
but we also talk about
being a great marker

4867
04:05:25,440 --> 04:05:27,600
for other neurodegenerative
diseases.

4868
04:05:27,600 --> 04:05:32,000
There is emerging evidence
that plasma NfL values

4869
04:05:32,000 --> 04:05:34,200
are impacted by renal function.

4870
04:05:34,200 --> 04:05:37,520
So considering them
while you're measuring it,

4871
04:05:37,520 --> 04:05:40,640
refining your measurements
will go a long way.

4872
04:05:40,640 --> 04:05:44,400
The other aspect of that, goal
standard is always pathology.

4873
04:05:44,400 --> 04:05:46,200
We can come up with biomarkers.

4874
04:05:46,200 --> 04:05:49,360
We can measure them, but what
do they mean pathologically?

4875
04:05:49,360 --> 04:05:53,560
That meets a better focus
than we have done in the past.

4876
04:05:53,560 --> 04:05:56,160
Next slide, please.

4877
04:05:56,160 --> 04:05:59,240
And the elephant in the room,
or the elephant

4878
04:05:59,240 --> 04:06:03,600
and the six blind men,
is that we have been --

4879
04:06:03,600 --> 04:06:05,200
We understand the concept three,

4880
04:06:05,200 --> 04:06:08,240
which is VCID
is extremely broad.

4881
04:06:08,240 --> 04:06:10,160
When we are measuring
biomarkers,

4882
04:06:10,160 --> 04:06:11,840
we need more specificity,

4883
04:06:11,840 --> 04:06:13,720
and we need to consider
the heterogeneity.

4884
04:06:13,720 --> 04:06:17,600
When we are saying VCID,
what are we exactly measuring,

4885
04:06:17,600 --> 04:06:20,400
and what is the contribution
of our biomarker

4886
04:06:20,400 --> 04:06:22,320
to the measurement
we are making?

4887
04:06:22,320 --> 04:06:23,720
In some certain senses,

4888
04:06:23,720 --> 04:06:25,720
it could be a blood-brain
barrier dysfunction.

4889
04:06:25,720 --> 04:06:28,000
In other cases, it could be
white matter damage

4890
04:06:28,000 --> 04:06:30,920
that Dr. Shir talked
about in his presentation.

4891
04:06:30,920 --> 04:06:32,720
But increasing the specificity

4892
04:06:32,720 --> 04:06:36,000
and understanding the
heterogeneity in the population

4893
04:06:36,000 --> 04:06:38,320
as well as in the ways
it manifests,

4894
04:06:38,320 --> 04:06:41,360
vascular disease manifests,
is very important.

4895
04:06:41,360 --> 04:06:44,000
Next slide.

4896
04:06:44,000 --> 04:06:48,920
So as I said, recommendation
four was focused on biomarkers.

4897
04:06:48,920 --> 04:06:50,400
How do we develop new,

4898
04:06:50,400 --> 04:06:53,240
better biomarkers
as well as refine what we have?

4899
04:06:53,240 --> 04:06:56,400
Recommendation five was given
a priority two,

4900
04:06:56,400 --> 04:06:59,920
and we thought interventions,

4901
04:06:59,920 --> 04:07:03,680
especially given the fact
that VCID is preventable,

4902
04:07:03,680 --> 04:07:06,400
there should be
a focus on interventions.

4903
04:07:06,400 --> 04:07:07,920
Developing and identifying

4904
04:07:07,920 --> 04:07:10,120
as well
as validating interventions,

4905
04:07:10,120 --> 04:07:13,600
testing the efficacy
as well as treatment of VCID

4906
04:07:13,600 --> 04:07:15,160
across spectrum of severity

4907
04:07:15,160 --> 04:07:17,120
as well as
in diverse populations

4908
04:07:17,120 --> 04:07:19,040
is extremely important.

4909
04:07:19,040 --> 04:07:24,840
On the next slide, you'll see
that the committee brought up

4910
04:07:24,840 --> 04:07:26,440
the SPRINT Mind Study,

4911
04:07:26,440 --> 04:07:28,680
where it's been shown
that intensive blood pressure

4912
04:07:28,680 --> 04:07:32,600
controls can reduce
the risk of MCI and dementia.

4913
04:07:32,600 --> 04:07:38,160
So trying to focus back on
what randomized clinical trials

4914
04:07:38,160 --> 04:07:41,360
can we begin
and test the efficacy of?

4915
04:07:41,360 --> 04:07:44,880
There are a wide range
of vascular risk factors

4916
04:07:44,880 --> 04:07:47,560
we could target
and how we could target them.

4917
04:07:47,560 --> 04:07:49,600
But designing them
and optimizing them

4918
04:07:49,600 --> 04:07:51,280
should be a priority,

4919
04:07:51,280 --> 04:07:54,600
so we can translate it
into prevention.

4920
04:07:54,600 --> 04:07:58,200
And we also talked about
incorporating biomarkers

4921
04:07:58,200 --> 04:08:00,200
in our clinical trials.

4922
04:08:00,200 --> 04:08:04,960
When we talked about
the biomarkers for VCID,

4923
04:08:04,960 --> 04:08:07,160
more often than not,
they're not included

4924
04:08:07,160 --> 04:08:10,800
in other AD/ADRD studies
for when you're studying,

4925
04:08:10,800 --> 04:08:13,680
let's say, FTD
or Alzheimer's disease.

4926
04:08:13,680 --> 04:08:16,240
But the point I'd like
to bring across

4927
04:08:16,240 --> 04:08:20,080
is that we thought given that
VCID is manifested along

4928
04:08:20,080 --> 04:08:22,400
with several
neurodegenerative diseases,

4929
04:08:22,400 --> 04:08:24,800
incorporating VCID markers,

4930
04:08:24,800 --> 04:08:27,960
some of them
MarkVCID initiative,

4931
04:08:27,960 --> 04:08:31,520
would be helpful
across all studies.

4932
04:08:31,520 --> 04:08:34,880
Next slide, please.

4933
04:08:34,880 --> 04:08:36,800
At this point, it was brought
forward

4934
04:08:36,800 --> 04:08:39,480
by Dr. Eric Smith
through our discussions,

4935
04:08:39,480 --> 04:08:42,600
and he thought that early
phase clinical trials

4936
04:08:42,600 --> 04:08:44,240
would be very important.

4937
04:08:44,240 --> 04:08:48,800
An example of this is by a study
led by Dr. Joanna Wardlaw.

4938
04:08:48,800 --> 04:08:51,160
Their goal was to see
if they could increase

4939
04:08:51,160 --> 04:08:55,040
cerebrovascular function
using a method called CVR,

4940
04:08:55,040 --> 04:08:57,360
where there's inhalation
of CO2,

4941
04:08:57,360 --> 04:09:00,240
in individuals who had
lacunar ischemic strokes

4942
04:09:00,240 --> 04:09:02,600
and if they could increase
cerebrovascular function

4943
04:09:02,600 --> 04:09:04,320
over an 8-week period.

4944
04:09:04,320 --> 04:09:07,760
And they found that medication
Vascepa, specific medication

4945
04:09:07,760 --> 04:09:09,960
did improve
cerebrovascular function,

4946
04:09:09,960 --> 04:09:13,120
but what really helped them
is the ability to measure

4947
04:09:13,120 --> 04:09:16,880
these early changes
to cerebrovascular function.

4948
04:09:16,880 --> 04:09:20,360
So incorporating surrogate
biomarkers

4949
04:09:20,360 --> 04:09:24,160
to try and improve function
would be really important.

4950
04:09:24,160 --> 04:09:26,680
Next slide.

4951
04:09:26,680 --> 04:09:28,800
Finally, coming to our
last recommendation

4952
04:09:28,800 --> 04:09:30,840
for human studies,
this was a difficult one

4953
04:09:30,840 --> 04:09:33,680
because there are many concepts

4954
04:09:33,680 --> 04:09:35,800
that emerge through
this recommendation,

4955
04:09:35,800 --> 04:09:39,120
which is that we have
a lot of observational data,

4956
04:09:39,120 --> 04:09:41,120
observation study-led data,

4957
04:09:41,120 --> 04:09:43,440
but we need to bring back
the idea

4958
04:09:43,440 --> 04:09:47,440
that we need to study life
course in diverse population,

4959
04:09:47,440 --> 04:09:49,360
and we really need
to consider the fact

4960
04:09:49,360 --> 04:09:53,000
that VCID is complex and broad.

4961
04:09:53,000 --> 04:09:55,720
There's several dementia-related
risk factors

4962
04:09:55,720 --> 04:09:59,880
as well as several biomarkers
of neurodegeneration

4963
04:09:59,880 --> 04:10:02,240
that can be leveraged
to try and understand,

4964
04:10:02,240 --> 04:10:06,560
how does VCID emerge
and change over the life span.

4965
04:10:06,560 --> 04:10:10,440
And this recommendation
on the next slide

4966
04:10:10,440 --> 04:10:12,800
could be used in
the context of hypertension.

4967
04:10:12,800 --> 04:10:16,480
This is an example how you would
go about a life span approach.

4968
04:10:16,480 --> 04:10:18,880
Let's say you're
studying hypertension.

4969
04:10:18,880 --> 04:10:22,680
You could collaborate across
individuals and scientists

4970
04:10:22,680 --> 04:10:25,640
who are studying systemic
health and brain health,

4971
04:10:25,640 --> 04:10:30,480
study extracranial vessel
as well as intercranial health,

4972
04:10:30,480 --> 04:10:34,200
and try to map out
how the disease is progressing,

4973
04:10:34,200 --> 04:10:35,920
how the changes fold in the body

4974
04:10:35,920 --> 04:10:37,600
as well as the brain
are progressing,

4975
04:10:37,600 --> 04:10:41,760
and that could really help us
design and feedback

4976
04:10:41,760 --> 04:10:44,520
into better interventions
in the future.

4977
04:10:44,520 --> 04:10:47,800
On the next slide,
there's a slide

4978
04:10:47,800 --> 04:10:51,160
from Dr. Tim Hughes
from the MESA study,

4979
04:10:51,160 --> 04:10:53,800
and this slide beautifully
makes the point

4980
04:10:53,800 --> 04:10:56,640
that there are
complex pathways involved.

4981
04:10:56,640 --> 04:10:59,040
There are upstream vascular
measures

4982
04:10:59,040 --> 04:11:02,720
that influence the imaging
measurements that we make,

4983
04:11:02,720 --> 04:11:05,600
and they also
impact neuropsychology

4984
04:11:05,600 --> 04:11:07,520
outcomes that we measure.

4985
04:11:07,520 --> 04:11:10,880
So how do we go about modeling
these complex pathways?

4986
04:11:10,880 --> 04:11:14,200
How do we leverage the methods
that we have so far,

4987
04:11:14,200 --> 04:11:18,920
and how do we design studies

4988
04:11:18,920 --> 04:11:22,920
that can better study
the evolution of VCID changes?

4989
04:11:22,920 --> 04:11:25,880
That would be really important
as we go forward.

4990
04:11:25,880 --> 04:11:30,120
On the last slide, I'd like to
close on some of the thoughts

4991
04:11:30,120 --> 04:11:32,640
that we had about study design.

4992
04:11:32,640 --> 04:11:35,800
The group thought that we should
really focus on rigor

4993
04:11:35,800 --> 04:11:37,520
and reproducibility
of our results,

4994
04:11:37,520 --> 04:11:40,760
consider heterogeneity of VCID
in all our studies,

4995
04:11:40,760 --> 04:11:43,440
as well as improve the
generalizability of the samples

4996
04:11:43,440 --> 04:11:46,480
that we are studying
to include diverse population

4997
04:11:46,480 --> 04:11:49,600
as well as move more
towards open science

4998
04:11:49,600 --> 04:11:54,160
so that the whole field benefits
as such while studying VCID.

4999
04:11:54,160 --> 04:11:55,440
With that, I'll stop here

5000
04:11:55,440 --> 04:11:58,000
and pass it on
to Dr. Sudha Seshardi.

5001
04:12:06,720 --> 04:12:10,840
-Hi, I am Sudha from UT
Health San Antonio,

5002
04:12:10,840 --> 04:12:13,400
and again,
it's my honor to present.

5003
04:12:13,400 --> 04:12:15,160
Next slide.

5004
04:12:15,160 --> 04:12:18,760
On behalf of our working group,

5005
04:12:18,760 --> 04:12:21,800
these are my disclaimer
and disclosures.

5006
04:12:21,800 --> 04:12:24,840
Next slide.

5007
04:12:24,840 --> 04:12:30,080
Focus area three, which
is on translational studies.

5008
04:12:30,080 --> 04:12:34,800
As you know, translation
is where we take insights

5009
04:12:34,800 --> 04:12:38,560
from basic science,
like Dr. Shih outlined,

5010
04:12:38,560 --> 04:12:45,440
and assess their applicability
in the design of human trials,

5011
04:12:45,440 --> 04:12:49,720
targeting prevention or
treatment of dementia and MCI,

5012
04:12:49,720 --> 04:12:52,840
so that was
our recommendation seven.

5013
04:12:52,840 --> 04:12:58,240
And recommendation eight
was conversely to look

5014
04:12:58,240 --> 04:13:03,200
at associations,
hypotheses that we can generate

5015
04:13:03,200 --> 04:13:06,800
based on the large
community-based diverse

5016
04:13:06,800 --> 04:13:11,600
human studies,
that Dr. Vemuri outlined,

5017
04:13:11,600 --> 04:13:16,000
and see are these
associations valid?

5018
04:13:16,000 --> 04:13:19,760
What is the biology
underlying these associations?

5019
04:13:19,760 --> 04:13:22,800
So there is a large amount
of biospecimens,

5020
04:13:22,800 --> 04:13:24,880
genetic, biometric imaging,

5021
04:13:24,880 --> 04:13:29,240
longitudinal data
in human studies,

5022
04:13:29,240 --> 04:13:33,280
but only if we understand
the biology of these markers,

5023
04:13:33,280 --> 04:13:35,760
whether it's NfL
or something else,

5024
04:13:35,760 --> 04:13:38,880
can we apply them
appropriately.

5025
04:13:38,880 --> 04:13:42,320
So this reciprocal flow of
information

5026
04:13:42,320 --> 04:13:46,000
between basic science studies
and human studies

5027
04:13:46,000 --> 04:13:50,320
is key to rapidly
advancing our understanding

5028
04:13:50,320 --> 04:13:54,600
and to more successful trials
and interventions.

5029
04:13:54,600 --> 04:13:57,000
I'd like to highlight this,
you know,

5030
04:13:57,000 --> 04:14:01,000
explain what the rationale
for our working group

5031
04:14:01,000 --> 04:14:03,680
was to make
these recommendations

5032
04:14:03,680 --> 04:14:05,840
using about five examples.

5033
04:14:05,840 --> 04:14:08,240
Next slide.

5034
04:14:08,240 --> 04:14:10,680
One of these is something
you've heard about.

5035
04:14:10,680 --> 04:14:14,040
In 2012 in science,
there was this exciting

5036
04:14:14,040 --> 04:14:17,640
finding that the glymphatic
system of the brain

5037
04:14:17,640 --> 04:14:20,320
and the perivascular,
the paravertebral

5038
04:14:20,320 --> 04:14:23,560
and the paravenus pathways
were --

5039
04:14:23,560 --> 04:14:26,120
had a role in clearing
in substances,

5040
04:14:26,120 --> 04:14:27,720
including amyloid,

5041
04:14:27,720 --> 04:14:31,160
and at least in mice
as you can see from that graph,

5042
04:14:31,160 --> 04:14:34,640
where the green line
is the amount of CSF tracer

5043
04:14:34,640 --> 04:14:37,560
on the y-axis removed
during sleep

5044
04:14:37,560 --> 04:14:41,000
and the orange line
during the wake state.

5045
04:14:41,000 --> 04:14:44,520
Sleep seemed to be
more important

5046
04:14:44,520 --> 04:14:49,400
in removing these agents,
these molecules.

5047
04:14:49,400 --> 04:14:51,720
Simultaneously, in human studies

5048
04:14:51,720 --> 04:14:55,120
that put together observations
on MRI,

5049
04:14:55,120 --> 04:14:57,960
observations
whose significance

5050
04:14:57,960 --> 04:15:01,400
we were earlier less clear of
with neuropathology,

5051
04:15:01,400 --> 04:15:07,200
it was seen that these
in perivascular spaces

5052
04:15:07,200 --> 04:15:12,280
corresponded with what was seen
on pathology as enlarged spaces,

5053
04:15:12,280 --> 04:15:17,680
and they were greater
in number in conditions

5054
04:15:17,680 --> 04:15:19,800
where we would experience
the protein clearance

5055
04:15:19,800 --> 04:15:22,720
to be poor,
like in Alzheimer's.

5056
04:15:22,720 --> 04:15:27,000
So here, you had a pathology
in animals

5057
04:15:27,000 --> 04:15:31,520
correlating with a highly
valued outcome in humans,

5058
04:15:31,520 --> 04:15:35,640
which is clearance of
the amyloid, and next slide.

5059
04:15:37,920 --> 04:15:40,920
How could this be incorporated
in clinical trials?

5060
04:15:40,920 --> 04:15:42,800
Clearly, we want
clinical trials

5061
04:15:42,800 --> 04:15:47,400
looking at these modifiable
vascular and metabolic factors,

5062
04:15:47,400 --> 04:15:51,400
so can we use
what we have learned in animals?

5063
04:15:51,400 --> 04:15:56,360
In animal studies, as you see
in the panels below on the left,

5064
04:15:56,360 --> 04:16:00,800
B is obese mice,
and A is control mice.

5065
04:16:00,800 --> 04:16:04,040
And you can see these
enlarged perivascular spaces

5066
04:16:04,040 --> 04:16:08,800
on the animal MRI are more
abundant in the obese mice.

5067
04:16:08,800 --> 04:16:10,800
The next panel shows, in yellow,

5068
04:16:10,800 --> 04:16:14,920
the CSF spaces in control rats
on your left

5069
04:16:14,920 --> 04:16:18,600
and aging spontaneously
hypertensive rats on the right,

5070
04:16:18,600 --> 04:16:21,000
again showing larger spaces.

5071
04:16:21,000 --> 04:16:26,040
So if perhaps in humans as well,
the impact --

5072
04:16:26,040 --> 04:16:28,880
the adverse impact
of vascular risk factors

5073
04:16:28,880 --> 04:16:31,880
on brain cognition and dementia

5074
04:16:31,880 --> 04:16:35,200
is partly mediated
through glymphatic function,

5075
04:16:35,200 --> 04:16:39,000
and MRI enlarged
perivascular spaces

5076
04:16:39,000 --> 04:16:42,840
are a marker
of this glymphatic function,

5077
04:16:42,840 --> 04:16:47,480
we can then assess the success
of the vascular intervention

5078
04:16:47,480 --> 04:16:49,720
using the specific biomarker.

5079
04:16:49,720 --> 04:16:51,800
And going back to
animal studies,

5080
04:16:51,800 --> 04:16:56,440
you can understand better
why this may be so.

5081
04:16:56,440 --> 04:16:59,400
Next slide.

5082
04:16:59,400 --> 04:17:02,160
Some of the unanswered questions
are,

5083
04:17:02,160 --> 04:17:05,960
how important is this pathway
for amyloid clearance

5084
04:17:05,960 --> 04:17:08,400
in the common
Alzheimer's disease?

5085
04:17:08,400 --> 04:17:12,680
How is it modified
by coexisting VCID?

5086
04:17:12,680 --> 04:17:17,200
In humans, how important
is sleep and stage of sleep?

5087
04:17:17,200 --> 04:17:20,920
And of course, how well do these
enlarged perivascular spaces,

5088
04:17:20,920 --> 04:17:25,800
which after all are a static,
structural finding on the MRI,

5089
04:17:25,800 --> 04:17:27,400
how does the volume or location

5090
04:17:27,400 --> 04:17:31,400
of this ePVS reflect
glymphatic clearance?

5091
04:17:31,400 --> 04:17:34,120
Would it be better if we had
a more functional,

5092
04:17:34,120 --> 04:17:37,960
real-time MRI biomarker
for glymphatic clearance,

5093
04:17:37,960 --> 04:17:39,600
and how might we develop that?

5094
04:17:39,600 --> 04:17:41,080
Next.

5095
04:17:41,080 --> 04:17:43,200
As Dr. Shih alluded,

5096
04:17:43,200 --> 04:17:46,400
one way of developing
a human-based technique

5097
04:17:46,400 --> 04:17:49,920
for assessing clearance may be
looking at animal studies.

5098
04:17:49,920 --> 04:17:51,720
Next.

5099
04:17:51,720 --> 04:17:54,800
Professor Van Nostrand,
who is in this panel,

5100
04:17:54,800 --> 04:18:01,280
and others showed in a rat model
of cerebral amyloid angiopathy

5101
04:18:01,280 --> 04:18:05,440
that the movement
of biomolecules across the brain

5102
04:18:05,440 --> 04:18:08,400
and into the neck vessels
could be seen

5103
04:18:08,400 --> 04:18:10,760
using dynamic MRI imaging,

5104
04:18:10,760 --> 04:18:13,640
and our group felt
that developing powerful

5105
04:18:13,640 --> 04:18:16,880
techniques in humans
could be very valuable.

5106
04:18:16,880 --> 04:18:18,760
Next slide.

5107
04:18:18,760 --> 04:18:22,280
We know that cerebral
amyloid angiopathy,

5108
04:18:22,280 --> 04:18:28,360
one of the VCID types
that is seen in people

5109
04:18:28,360 --> 04:18:30,240
with Alzheimer's

5110
04:18:30,240 --> 04:18:34,440
appears to be a risk factor
for what is called ARIA,

5111
04:18:34,440 --> 04:18:38,320
or amyloid-related
imaging abnormalities.

5112
04:18:38,320 --> 04:18:40,480
This is an area
of great interest now

5113
04:18:40,480 --> 04:18:43,760
when the FDA and Medicare
are assessing

5114
04:18:43,760 --> 04:18:49,800
the risk-benefit ratio
of amyloid lowering therapies.

5115
04:18:49,800 --> 04:18:51,680
One of these risks, of course,

5116
04:18:51,680 --> 04:18:56,440
is this edema that you see
in the left two MRI panels

5117
04:18:56,440 --> 04:19:00,720
as those white changes
or the hemorrhages that you see

5118
04:19:00,720 --> 04:19:05,240
in the right two MRI panels
as small black dots.

5119
04:19:05,240 --> 04:19:10,080
The fact that coexisting VCID
increases the risk

5120
04:19:10,080 --> 04:19:14,160
is also an opportunity for
mitigating therapies that could,

5121
04:19:14,160 --> 04:19:18,440
perhaps, be coadministered
with amyloid-lowering agents.

5122
04:19:18,440 --> 04:19:22,040
There also seems to be
an individual propensity

5123
04:19:22,040 --> 04:19:24,640
to develop
these side effects.

5124
04:19:24,640 --> 04:19:28,840
The study showed that
if you were an E4 carrier,

5125
04:19:28,840 --> 04:19:33,720
you had three times the risk
as if you were not an E4 carrier

5126
04:19:33,720 --> 04:19:36,720
of developing
this type of ARIA edema.

5127
04:19:36,720 --> 04:19:39,120
Next.

5128
04:19:39,120 --> 04:19:44,760
How does APOE actually increase
the risk of ARIA, E4?

5129
04:19:44,760 --> 04:19:47,200
Is it only because E4
is associated

5130
04:19:47,200 --> 04:19:51,640
with the greater prevalence
of cerebral amyloid angiopathy?

5131
04:19:51,640 --> 04:19:53,600
What is the mechanism
of the ARIA

5132
04:19:53,600 --> 04:19:56,320
developing in cerebral amyloid
angiopathy?

5133
04:19:56,320 --> 04:20:00,000
You know, in humans,
we have imaging or blood or CSF

5134
04:20:00,000 --> 04:20:02,000
and then pathology,

5135
04:20:02,000 --> 04:20:05,800
but in animals, you can look
at the different stages.

5136
04:20:05,800 --> 04:20:07,920
So clearly, next slide,

5137
04:20:07,920 --> 04:20:10,760
we need better models
of cerebral amyloid

5138
04:20:10,760 --> 04:20:14,280
angiopathy and ARIA,
and we need them now.

5139
04:20:14,280 --> 04:20:19,200
One of the reasons we did
no suspect ARIA in human studies

5140
04:20:19,200 --> 04:20:22,840
is because it is not
very common in mice,

5141
04:20:22,840 --> 04:20:24,600
so we need other models.

5142
04:20:24,600 --> 04:20:27,480
Another question is that
in human studies,

5143
04:20:27,480 --> 04:20:29,200
the ARIA develops.

5144
04:20:29,200 --> 04:20:32,880
You stop the agent, the MRI
apparently returns to normal,

5145
04:20:32,880 --> 04:20:35,880
but people want to know,
is there any lasting,

5146
04:20:35,880 --> 04:20:39,200
long-term injury
or side effects?

5147
04:20:39,200 --> 04:20:43,800
And one larger animal model,
as Dr. Shih referred to,

5148
04:20:43,800 --> 04:20:45,360
is the squirrel monkey.

5149
04:20:45,360 --> 04:20:48,720
These are genetically
predisposed to accumulate

5150
04:20:48,720 --> 04:20:51,000
amyloid
along their blood vessels,

5151
04:20:51,000 --> 04:20:52,960
so a CAA model.

5152
04:20:52,960 --> 04:20:58,000
And as these monkeys age,
they develop ARIA-E-like

5153
04:20:58,000 --> 04:20:59,720
changes on MRI,

5154
04:20:59,720 --> 04:21:02,840
like you can see in the left
panel with those white areas,

5155
04:21:02,840 --> 04:21:05,120
as well as ARIA-H-like changes,

5156
04:21:05,120 --> 04:21:08,800
as you can see with the white
arrows in the middle panel.

5157
04:21:08,800 --> 04:21:11,480
And when these monkeys die,
if you look at the brain,

5158
04:21:11,480 --> 04:21:16,680
the regions that had ARIA-E
have this changes in the myelin

5159
04:21:16,680 --> 04:21:18,720
and structure injury,

5160
04:21:18,720 --> 04:21:22,920
raising concern that ARIA-E,
even if it reverses,

5161
04:21:22,920 --> 04:21:27,440
might leave residual cognitive
or functional deficits.

5162
04:21:27,440 --> 04:21:29,040
Next.

5163
04:21:29,040 --> 04:21:31,040
To go to another example,

5164
04:21:31,040 --> 04:21:33,080
you heard about the SPRINT
MIND study

5165
04:21:33,080 --> 04:21:36,960
that showed that intensive
control of blood pressure

5166
04:21:36,960 --> 04:21:39,840
to 120 millimeters mercury

5167
04:21:39,840 --> 04:21:42,960
reduced white matter
hyperintensity accumulation

5168
04:21:42,960 --> 04:21:48,080
compared to more standard
blood pressure control to 140,

5169
04:21:48,080 --> 04:21:50,040
but white matter hyperintensity

5170
04:21:50,040 --> 04:21:53,120
is something
that accrues over time.

5171
04:21:53,120 --> 04:21:55,840
Can we use a more
sensitive measure

5172
04:21:55,840 --> 04:21:59,200
that reflects
functional changes?

5173
04:21:59,200 --> 04:22:02,800
And one that was discussed
was cerebrovascular reactivity.

5174
04:22:02,800 --> 04:22:05,920
What is this?
Next slide.

5175
04:22:05,920 --> 04:22:11,200
This is something that was also
initially developed in mice,

5176
04:22:11,200 --> 04:22:15,120
like transgenic mice
having Swedish,

5177
04:22:15,120 --> 04:22:18,200
Dutch and Iowa mutations.

5178
04:22:18,200 --> 04:22:22,640
When the concentration of carbon
dioxide is slightly increased,

5179
04:22:22,640 --> 04:22:26,400
there is a real-time response
of vasodilation

5180
04:22:26,400 --> 04:22:27,920
and increased blood flow.

5181
04:22:27,920 --> 04:22:32,000
In the MarkVCID study,
Dr. Hanzhang Lu at Hopkins

5182
04:22:32,000 --> 04:22:37,000
has led the standardization and
application of these to humans,

5183
04:22:37,000 --> 04:22:39,440
and so this could be applied
in a study

5184
04:22:39,440 --> 04:22:41,360
not just like SPRINT or ADNI,

5185
04:22:41,360 --> 04:22:44,400
but even something like
an FTD study.

5186
04:22:44,400 --> 04:22:49,800
And this change in flow is seen
with just an MRI BOLD.

5187
04:22:49,800 --> 04:22:51,400
Next slide.

5188
04:22:53,600 --> 04:22:57,360
Conversely, speaking about
looking at data

5189
04:22:57,360 --> 04:22:59,480
accrued in population studies,

5190
04:22:59,480 --> 04:23:04,600
what can that tell us that could
then be taken to animal studies?

5191
04:23:04,600 --> 04:23:07,600
In the CHARGE Consortium
in about 50,000 people,

5192
04:23:07,600 --> 04:23:11,000
white matter hyperintensity,
a large GWAS,

5193
04:23:11,000 --> 04:23:13,600
we found about 27 loci.

5194
04:23:13,600 --> 04:23:16,240
During a transcriptome-wide
association study,

5195
04:23:16,240 --> 04:23:19,800
there were about 39 genes
at these 27 loci,

5196
04:23:19,800 --> 04:23:23,200
four of them encoding
for drugable targets.

5197
04:23:23,200 --> 04:23:27,000
Interestingly, these genes
were also associated

5198
04:23:27,000 --> 04:23:32,560
with white matter integrity
measured in a sensitive measure,

5199
04:23:32,560 --> 04:23:34,680
diffusion tensor
imaging measure,

5200
04:23:34,680 --> 04:23:36,600
in nearly 2,000 young adults,

5201
04:23:36,600 --> 04:23:40,360
who were college students,
completely healthy.

5202
04:23:40,360 --> 04:23:44,200
And Mendelian randomization
using this composite score

5203
04:23:44,200 --> 04:23:47,080
suggested that white
matter hyperintensity volume

5204
04:23:47,080 --> 04:23:48,840
was associated
with subsequent

5205
04:23:48,840 --> 04:23:53,240
risk of cognitive decline,
dementia and ADRD.

5206
04:23:53,240 --> 04:23:57,520
So if these risk variances
are acting across the life span,

5207
04:23:57,520 --> 04:24:00,600
there is an opportunity
here for prevention,

5208
04:24:00,600 --> 04:24:05,200
but we need to understand their
function through animal studies.

5209
04:24:05,200 --> 04:24:07,440
Next slide.

5210
04:24:07,440 --> 04:24:12,520
Another example of using animal
studies to understand biology

5211
04:24:12,520 --> 04:24:15,720
and develop human biomarkers

5212
04:24:15,720 --> 04:24:19,720
to understand the specific role
of individual cell types,

5213
04:24:19,720 --> 04:24:22,160
like the cell types
in the blood-brain barrier,

5214
04:24:22,160 --> 04:24:24,920
is work from [Indistinct] lab.

5215
04:24:24,920 --> 04:24:29,000
The parasite is part
of the blood-brain barrier,

5216
04:24:29,000 --> 04:24:33,840
and in mice that have
the APP mutation

5217
04:24:33,840 --> 04:24:39,320
that gives them a propensity
to accumulate beta amyloid.

5218
04:24:39,320 --> 04:24:42,760
If you also partially knock
out parasites

5219
04:24:42,760 --> 04:24:45,920
so that they have
dysfunctional parasites,

5220
04:24:45,920 --> 04:24:48,280
you can see, in the second panel
on the right,

5221
04:24:48,280 --> 04:24:50,960
amyloid accrues even faster.

5222
04:24:50,960 --> 04:24:55,600
So this was then extended to
humans by measuring this marker,

5223
04:24:55,600 --> 04:24:58,200
platelet-derived growth factor
receptor-beta,

5224
04:24:58,200 --> 04:25:01,360
which is expressed on
the surface of the parasites.

5225
04:25:01,360 --> 04:25:03,640
Next.

5226
04:25:03,640 --> 04:25:07,920
And you can see that levels
of PDFGR beta

5227
04:25:07,920 --> 04:25:14,000
and the CSF are higher
with worse cognition,

5228
04:25:14,000 --> 04:25:18,120
a Clinical Dementia
Rating scale score of 0.501

5229
04:25:18,120 --> 04:25:22,040
is associated
with higher levels,

5230
04:25:22,040 --> 04:25:25,440
suggesting that here
we have a biomarker for parasite

5231
04:25:25,440 --> 04:25:28,800
to add to biomarkers
like YKL-40 and NfL,

5232
04:25:28,800 --> 04:25:34,280
which are for glia
and neurons.

5233
04:25:34,280 --> 04:25:37,600
Next.

5234
04:25:37,600 --> 04:25:41,320
The gut-brain axis is emerging
as another important factor

5235
04:25:41,320 --> 04:25:43,200
in many neurological disorders,

5236
04:25:43,200 --> 04:25:47,080
and there's a fascinating animal
example that showed us this.

5237
04:25:47,080 --> 04:25:51,600
In mice, next,
that have a KRIT1 mutation,

5238
04:25:51,600 --> 04:25:53,000
there is these development

5239
04:25:53,000 --> 04:25:55,400
of the cerebral
cavernous malformations,

5240
04:25:55,400 --> 04:25:56,960
just like
the ones humans have.

5241
04:25:56,960 --> 04:26:00,520
This KRIT1 gene is associated
with CCM in humans,

5242
04:26:00,520 --> 04:26:03,240
but if you deliver the mice
aseptically through

5243
04:26:03,240 --> 04:26:04,640
Cesarean section

5244
04:26:04,640 --> 04:26:08,360
and have them foster
by germ-free mothers,

5245
04:26:08,360 --> 04:26:10,600
you can see
the eight panels below.

5246
04:26:10,600 --> 04:26:14,800
Most of those nice developed
the cavernous malformations.

5247
04:26:14,800 --> 04:26:17,000
Could this have relevance
for humans?

5248
04:26:17,000 --> 04:26:18,520
Next slide.

5249
04:26:18,520 --> 04:26:21,640
In fact, humans who are
genetically predisposed

5250
04:26:21,640 --> 04:26:24,480
to higher levels
of inflammatory factors,

5251
04:26:24,480 --> 04:26:30,040
like TLR4 or CB14,
were more likely to have

5252
04:26:30,040 --> 04:26:33,200
larger number of cavernous
malformations in the brain

5253
04:26:33,200 --> 04:26:35,720
when they carried
a KRIT1 mutation.

5254
04:26:35,720 --> 04:26:37,160
Next.

5255
04:26:37,160 --> 04:26:40,040
And can this be related
to their microbiome?

5256
04:26:40,040 --> 04:26:42,560
In fact, a recent study showed

5257
04:26:42,560 --> 04:26:45,280
that the fetal microbiota
are different.

5258
04:26:45,280 --> 04:26:49,400
There are those three phyla
in green

5259
04:26:49,400 --> 04:26:54,880
that differed between people
with cerebral cavernous angiomas

5260
04:26:54,880 --> 04:26:57,600
and people without
cavernous angiomas.

5261
04:26:57,600 --> 04:27:01,040
So here, you have a gene
environment interaction,

5262
04:27:01,040 --> 04:27:04,480
an environmental modification
that could really improve

5263
04:27:04,480 --> 04:27:07,120
the clinical picture
in these patients.

5264
04:27:07,120 --> 04:27:09,440
Next.

5265
04:27:09,440 --> 04:27:15,880
A final example comes from
an overlap, next slide,

5266
04:27:15,880 --> 04:27:19,560
of a gene TREM2
discovered about a decade ago

5267
04:27:19,560 --> 04:27:23,000
to be associated
with risk of AD.

5268
04:27:23,000 --> 04:27:26,880
This gene, next, is known to be
expressed not in neurons,

5269
04:27:26,880 --> 04:27:32,600
but microglia and to play a role
in clearance of substances.

5270
04:27:32,600 --> 04:27:35,720
And if you have a TREM2
knockout,

5271
04:27:35,720 --> 04:27:40,960
then a stroke in the mouse model
results in

5272
04:27:40,960 --> 04:27:45,840
a larger infarc, and TREM2
is expressed around vessels.

5273
04:27:45,840 --> 04:27:47,240
Next.

5274
04:27:47,240 --> 04:27:49,800
So we are learning something
about this gene,

5275
04:27:49,800 --> 04:27:51,680
about this marker.

5276
04:27:51,680 --> 04:27:56,040
Soluble TREM2 was found to be
a potential marker

5277
04:27:56,040 --> 04:28:00,240
of cerebrovascular disease
in neurodegenerative disorders

5278
04:28:00,240 --> 04:28:02,520
in some persons
with hemorrhagic stroke,

5279
04:28:02,520 --> 04:28:06,120
who had either
small vessel disease

5280
04:28:06,120 --> 04:28:10,600
because of CAA or small vessel
disease because of hypertension.

5281
04:28:10,600 --> 04:28:13,240
Higher levels of TREM2
were associated

5282
04:28:13,240 --> 04:28:16,200
with greater
white matter hyperintensity,

5283
04:28:16,200 --> 04:28:20,400
and this was also true
as shown in a paper in "Brain."

5284
04:28:20,400 --> 04:28:21,680
When you looked at people

5285
04:28:21,680 --> 04:28:23,640
who had tau pathology
in the brain,

5286
04:28:23,640 --> 04:28:26,000
the red circles
are people with AD,

5287
04:28:26,000 --> 04:28:28,920
and they had higher levels
of soluble TREM2.

5288
04:28:28,920 --> 04:28:31,600
But soluble TREM2
may not be all bad.

5289
04:28:31,600 --> 04:28:33,440
The levels vary over time.

5290
04:28:33,440 --> 04:28:36,560
And if you looked at people
with AD, amyloid positive,

5291
04:28:36,560 --> 04:28:39,960
tau positive, higher levels
of soluble TREM2

5292
04:28:39,960 --> 04:28:42,000
in the plasma
were actually associated

5293
04:28:42,000 --> 04:28:44,480
with better MMSE scores,

5294
04:28:44,480 --> 04:28:47,440
so you see the importance
of understanding

5295
04:28:47,440 --> 04:28:50,400
something that we have
identified as a biomarker

5296
04:28:50,400 --> 04:28:53,080
based on
just genetic association.

5297
04:28:53,080 --> 04:28:58,000
So these were some of the
reasons for the strong

5298
04:28:58,000 --> 04:29:00,800
push on recommendation
seven and eight,

5299
04:29:00,800 --> 04:29:05,520
and I look forward to further
feedback and discussions.

5300
04:29:05,520 --> 04:29:06,960
Thank you.

5301
04:29:06,960 --> 04:29:08,560
Handing back to Donna.

5302
04:29:11,600 --> 04:29:13,760
-Maybe I'll jump in here,
Ron Petersen.

5303
04:29:13,760 --> 04:29:17,200
Thanks very much, Sudha,
for that wonderful,

5304
04:29:17,200 --> 04:29:18,720
kind of tying
everything together.

5305
04:29:18,720 --> 04:29:21,400
And I'd like to thank Andy
and Prashanthi

5306
04:29:21,400 --> 04:29:26,800
also for summarizing the work
of the three work groups

5307
04:29:26,800 --> 04:29:28,080
and very, very nicely.

5308
04:29:28,080 --> 04:29:30,200
I think it's been
an exciting time

5309
04:29:30,200 --> 04:29:34,280
to discuss the possibilities,
and as Prashanthi outlined,

5310
04:29:34,280 --> 04:29:37,440
there has been significant
movement in this area

5311
04:29:37,440 --> 04:29:41,520
funded by NIH
since the 2019 summit.

5312
04:29:41,520 --> 04:29:47,000
MarkVCID, DISCOVERY,
DiverseVCID on the human side

5313
04:29:47,000 --> 04:29:48,640
have all been launched,

5314
04:29:48,640 --> 04:29:51,400
and we've had numerous
animal model studies.

5315
04:29:51,400 --> 04:29:54,000
So again, Andy nicely outlined

5316
04:29:54,000 --> 04:29:58,640
where we are with regard
to the modeling of VCID,

5317
04:29:58,640 --> 04:30:01,040
and he pointed out,
Prashanthi pointed out,

5318
04:30:01,040 --> 04:30:06,320
Sudha pointed out the
complexity of VCID disorders,

5319
04:30:06,320 --> 04:30:08,600
that is the heterogeneity
of them.

5320
04:30:08,600 --> 04:30:14,560
So not only does VCID exist
in a heterogeneous environment

5321
04:30:14,560 --> 04:30:16,800
in the aging human
with amyloid,

5322
04:30:16,800 --> 04:30:23,080
tau, alpha-synuclein, TDP-43,
but within VCID itself,

5323
04:30:23,080 --> 04:30:25,760
it is heterogeneous,
multifactorial.

5324
04:30:25,760 --> 04:30:27,400
That's the tough news.

5325
04:30:27,400 --> 04:30:28,680
The good news is that

5326
04:30:28,680 --> 04:30:31,760
May addressed
some therapeutic options.

5327
04:30:31,760 --> 04:30:35,200
Each of those different
mechanisms that Andy outlined

5328
04:30:35,200 --> 04:30:38,680
could potentially be
amenable to intervention,

5329
04:30:38,680 --> 04:30:43,120
so I think the pathologic
diversity is encouraging,

5330
04:30:43,120 --> 04:30:47,400
and I think what he outlined
was an approach using genetics,

5331
04:30:47,400 --> 04:30:52,200
lifestyle modifications,
looking at age, looking at sex,

5332
04:30:52,200 --> 04:30:56,720
taking into account
the VCID-AD interactions

5333
04:30:56,720 --> 04:31:00,040
that are likely in many,
many situations,

5334
04:31:00,040 --> 04:31:03,760
but I think this does give us
the opportunity to move forward.

5335
04:31:03,760 --> 04:31:07,800
The basic group also focused
on the neurovascular unit,

5336
04:31:07,800 --> 04:31:09,280
so both single-cell,

5337
04:31:09,280 --> 04:31:12,600
cell-specific technologies
are being developed,

5338
04:31:12,600 --> 04:31:14,840
looking at
neurovascular coupling,

5339
04:31:14,840 --> 04:31:17,280
blood-brain barrier integrity,

5340
04:31:17,280 --> 04:31:22,080
clearance of toxic proteins
as Sudha outlined

5341
04:31:22,080 --> 04:31:23,680
and the aging
process itself.

5342
04:31:23,680 --> 04:31:24,760
Aging on top of this.

5343
04:31:24,760 --> 04:31:26,600
Why is it that aging is --

5344
04:31:26,600 --> 04:31:29,520
How is aging contributing
to the increase

5345
04:31:29,520 --> 04:31:31,920
in vascular disease
as we go forward?

5346
04:31:31,920 --> 04:31:33,720
The experimental models then,

5347
04:31:33,720 --> 04:31:35,680
learning from
cardiovascular disease,

5348
04:31:35,680 --> 04:31:37,360
cerebrovascular disease,

5349
04:31:37,360 --> 04:31:41,600
their impact on myelin white
matter and neurodegeneration

5350
04:31:41,600 --> 04:31:47,800
are all becoming more apparent
as these studies continue.

5351
04:31:47,800 --> 04:31:50,400
The human studies group
also looked

5352
04:31:50,400 --> 04:31:54,200
at the diversity of the disease
and, as Prashanthi indicated,

5353
04:31:54,200 --> 04:31:57,600
really focused on biomarkers
because biomarker says --

5354
04:31:57,600 --> 04:31:59,040
We're hearing
throughout this meeting.

5355
04:31:59,040 --> 04:32:00,480
We'll hear it tomorrow.

5356
04:32:00,480 --> 04:32:02,280
Biomarkers are really key
at trying

5357
04:32:02,280 --> 04:32:05,360
to separate out
the individual components

5358
04:32:05,360 --> 04:32:06,920
of these various pathologies,

5359
04:32:06,920 --> 04:32:11,320
so I think that the group
focused on the fact

5360
04:32:11,320 --> 04:32:15,080
that these tools need
to be evaluated

5361
04:32:15,080 --> 04:32:16,800
in diverse communities.

5362
04:32:16,800 --> 04:32:21,640
Among all the ADRDs that we'll
be discussed today and tomorrow,

5363
04:32:21,640 --> 04:32:25,640
perhaps VCID is among
the most important with regard

5364
04:32:25,640 --> 04:32:27,480
to understanding
in diverse communities

5365
04:32:27,480 --> 04:32:30,800
because of increased prevalence
of some of the cardiovascular

5366
04:32:30,800 --> 04:32:33,000
and cerebrovascular
comorbidities,

5367
04:32:33,000 --> 04:32:37,840
so VCID is really in
the crosshairs of this exercise,

5368
04:32:37,840 --> 04:32:40,640
and I think the group
certainly was aware of that

5369
04:32:40,640 --> 04:32:43,600
and focused many
of the recommendations

5370
04:32:43,600 --> 04:32:44,920
in that direction.

5371
04:32:44,920 --> 04:32:47,560
So certainly standardizing
evaluations,

5372
04:32:47,560 --> 04:32:52,240
assessments, behavioral,
functional, noninvasive,

5373
04:32:52,240 --> 04:32:55,040
using some of the digital tools
that are emerging now

5374
04:32:55,040 --> 04:32:59,600
will allow us to evaluate
a variety of populations,

5375
04:32:59,600 --> 04:33:02,160
again, looking at heterogeneity

5376
04:33:02,160 --> 04:33:05,280
and focusing also
on fluid biomarkers,

5377
04:33:05,280 --> 04:33:07,200
exosomes and what
they will tell us

5378
04:33:07,200 --> 04:33:09,480
about the underlying pathology.

5379
04:33:09,480 --> 04:33:11,560
Getting into interventions,
we can talk then

5380
04:33:11,560 --> 04:33:15,360
about either pharmacologic
or lifestyle modifications.

5381
04:33:15,360 --> 04:33:19,080
Lifestyle for vascular disease
right now are very important,

5382
04:33:19,080 --> 04:33:21,560
and we really need
to be concerned.

5383
04:33:21,560 --> 04:33:23,600
This morning, we had heard
about the strategy

5384
04:33:23,600 --> 04:33:27,200
of possibly oversampling
underrepresented groups.

5385
04:33:27,200 --> 04:33:29,080
Maybe that is the strategy
that we use --

5386
04:33:29,080 --> 04:33:32,560
need to use here in VCID
studies as well.

5387
04:33:32,560 --> 04:33:36,720
Of course, harmonization
of data is critical.

5388
04:33:36,720 --> 04:33:40,520
The combination of risk factors
throughout the life course,

5389
04:33:40,520 --> 04:33:43,440
as both Prashanthi
and Sudha mentioned,

5390
04:33:43,440 --> 04:33:45,640
is increasingly important
because we know

5391
04:33:45,640 --> 04:33:48,080
that these diseases
don't develop overnight.

5392
04:33:48,080 --> 04:33:51,000
The pathology evolves
over many, many years.

5393
04:33:51,000 --> 04:33:53,800
So we need to look
at a life-course projection

5394
04:33:53,800 --> 04:33:57,600
not only with age
but with sex, complex pathways.

5395
04:33:57,600 --> 04:34:01,120
But interestingly, the other
side of the coin is --

5396
04:34:01,120 --> 04:34:02,640
Involves resilience.

5397
04:34:02,640 --> 04:34:04,680
That is, there are people
who have these various

5398
04:34:04,680 --> 04:34:06,800
risk factors who do just fine,

5399
04:34:06,800 --> 04:34:09,480
and so while we do this in
the Alzheimer's disease space,

5400
04:34:09,480 --> 04:34:11,800
we need to do it
in the vascular space as well.

5401
04:34:11,800 --> 04:34:14,400
And then Sudha very nicely
put this together.

5402
04:34:14,400 --> 04:34:16,360
What are learning
from the animal models,

5403
04:34:16,360 --> 04:34:19,200
and how in fact
are we going to apply it

5404
04:34:19,200 --> 04:34:21,880
from the animal models
to the human model?

5405
04:34:21,880 --> 04:34:24,320
So again, I want to thank
the entire committee.

5406
04:34:24,320 --> 04:34:27,000
If the committee could turn
on their cameras,

5407
04:34:27,000 --> 04:34:30,200
I please would offer them
the opportunity to comment

5408
04:34:30,200 --> 04:34:32,600
on any of the questions
that are out there,

5409
04:34:32,600 --> 04:34:36,280
and I think we have -- see some
that are posting already,

5410
04:34:36,280 --> 04:34:38,400
so let me start
with Steve Greenberg.

5411
04:34:38,400 --> 04:34:40,800
Steve?
-Hey.

5412
04:34:40,800 --> 04:34:42,440
Really great to see everybody,

5413
04:34:42,440 --> 04:34:45,320
and I know I'm speaking
for a big audience here to say

5414
04:34:45,320 --> 04:34:48,880
those were just spectacular
overviews of the field,

5415
04:34:48,880 --> 04:34:51,080
and the talks were great,
and the field is great.

5416
04:34:51,080 --> 04:34:53,760
I mean, it's really
an exciting time.

5417
04:34:53,760 --> 04:34:57,280
I'm just going to pick up
on one thread that came up.

5418
04:34:57,280 --> 04:35:01,080
The cross-link between vascular
and neurodegenerative disease

5419
04:35:01,080 --> 04:35:02,720
came up in --

5420
04:35:02,720 --> 04:35:07,280
as a recommendation priority
item in multiple sections,

5421
04:35:07,280 --> 04:35:11,440
and really just to continue
the line of sights

5422
04:35:11,440 --> 04:35:13,800
that Sudha showed,

5423
04:35:13,800 --> 04:35:16,200
you know, of all the different
postulated mechanisms

5424
04:35:16,200 --> 04:35:17,880
for the interaction

5425
04:35:17,880 --> 04:35:20,400
between the vascular system
and neurodegenerative,

5426
04:35:20,400 --> 04:35:23,960
probably the one
that's most well substantiated

5427
04:35:23,960 --> 04:35:25,680
is the role
of vascular disease

5428
04:35:25,680 --> 04:35:28,400
in affecting
cardiovascular clearance

5429
04:35:28,400 --> 04:35:29,960
in the lymphatic system.

5430
04:35:29,960 --> 04:35:34,400
That seems to be
a really striking area,

5431
04:35:34,400 --> 04:35:36,720
kind of nexus between
the two processes,

5432
04:35:36,720 --> 04:35:39,320
and it fits into
really well --

5433
04:35:39,320 --> 04:35:40,840
It fits very well
with what we understand

5434
04:35:40,840 --> 04:35:44,920
about amyloid clearance,
and amyloid is an extracellular,

5435
04:35:44,920 --> 04:35:47,920
sort of interstitial
fluid peptide

5436
04:35:47,920 --> 04:35:49,320
that needs to be cleared,

5437
04:35:49,320 --> 04:35:51,000
and if the clearance system
is mucked up,

5438
04:35:51,000 --> 04:35:53,800
that's going to
increase deposition.

5439
04:35:53,800 --> 04:35:55,600
You know, more broadly speaking,
it's hard to believe

5440
04:35:55,600 --> 04:35:59,000
that clearance of the fluid
in the interstitial space

5441
04:35:59,000 --> 04:36:02,200
isn't a much broader
mechanism in disease,

5442
04:36:02,200 --> 04:36:04,160
so even outside
of the amyloid context,

5443
04:36:04,160 --> 04:36:06,920
which maybe, you know,
maybe is the most important one

5444
04:36:06,920 --> 04:36:08,720
from a disease standpoint,

5445
04:36:08,720 --> 04:36:10,720
you know, it's hard to believe
that there aren't other disease

5446
04:36:10,720 --> 04:36:15,000
processes that are affected
by having stuff that does

5447
04:36:15,000 --> 04:36:18,400
or doesn't get cleared out
of the interstitial fluid

5448
04:36:18,400 --> 04:36:21,320
and especially
with the number of ADRDs

5449
04:36:21,320 --> 04:36:25,120
and ther disease that are driven
by protein deposits.

5450
04:36:25,120 --> 04:36:26,440
Not all of them have
this prominent

5451
04:36:26,440 --> 04:36:28,200
extracellular phase
that amyloid does,

5452
04:36:28,200 --> 04:36:31,600
but all of them have some
sort of extracellular phase,

5453
04:36:31,600 --> 04:36:33,160
and, you know,
one of the advantages

5454
04:36:33,160 --> 04:36:34,680
of having an ADRD summit

5455
04:36:34,680 --> 04:36:36,360
is the chance to do
what we don't do very often,

5456
04:36:36,360 --> 04:36:38,520
which is getting together
as an ADRD community

5457
04:36:38,520 --> 04:36:41,360
and thinking in
a very cross-disciplinary way.

5458
04:36:41,360 --> 04:36:45,880
So the question if we could all
sit in the same room together

5459
04:36:45,880 --> 04:36:49,400
or at least virtually would be,
you know, broadly speaking,

5460
04:36:49,400 --> 04:36:53,560
what else do we think that loss
of perivascular clearance

5461
04:36:53,560 --> 04:36:56,600
might be doing to promote
neurodegenerative disease,

5462
04:36:56,600 --> 04:36:59,960
and how would that translate
into either biomarkers?

5463
04:36:59,960 --> 04:37:01,600
And Sudha brought up the,
you know,

5464
04:37:01,600 --> 04:37:07,000
the high position
of lymphatic markers

5465
04:37:07,000 --> 04:37:09,000
on our wish list
for biomarkers

5466
04:37:09,000 --> 04:37:12,200
but how it might move
into trials,

5467
04:37:12,200 --> 04:37:15,480
so anyway,
it's a broad question,

5468
04:37:15,480 --> 04:37:17,080
and it's hard, again,
hard to believe

5469
04:37:17,080 --> 04:37:20,440
it isn't playing a role
in a lot of disease states.

5470
04:37:20,440 --> 04:37:22,120
-Absolutely, Steve.
Thanks very much.

5471
04:37:22,120 --> 04:37:23,640
Comments?

5472
04:37:23,640 --> 04:37:27,960
Sudha, other folks on the panel,
comments for Steve?

5473
04:37:27,960 --> 04:37:31,920
-Completely agree that
it probably plays a role.

5474
04:37:31,920 --> 04:37:34,960
Other molecules that might
be involved in the pathway

5475
04:37:34,960 --> 04:37:36,400
like [Indistinct]

5476
04:37:36,400 --> 04:37:40,680
also potentially valuable
biomarkers completely.

5477
04:37:40,680 --> 04:37:44,360
Thank you for bringing this up
and for the pioneering work

5478
04:37:44,360 --> 04:37:48,440
that MarkVCID and is doing,
for instance,

5479
04:37:48,440 --> 04:37:55,200
to establish these as usable,
pragmatic, biologically

5480
04:37:55,200 --> 04:37:57,760
and technologically
validated biomarkers

5481
04:37:57,760 --> 04:37:59,400
that can then be extended

5482
04:37:59,400 --> 04:38:01,920
the studies
of other neurodegeneration

5483
04:38:01,920 --> 04:38:07,000
as well as of
vascular interventions.

5484
04:38:07,000 --> 04:38:08,200
-All right.
Thank you.

5485
04:38:08,200 --> 04:38:09,640
Couple up.

5486
04:38:09,640 --> 04:38:11,960
Prashanthi, you have your hand
up and then Dave.

5487
04:38:11,960 --> 04:38:14,840
-Quick point, I think
there's emerging evidence

5488
04:38:14,840 --> 04:38:16,400
that it's the same with tau,

5489
04:38:16,400 --> 04:38:18,800
so I think studying
the changes locally

5490
04:38:18,800 --> 04:38:20,600
and globally would be
very important

5491
04:38:20,600 --> 04:38:23,560
to move
this concept forward.

5492
04:38:23,560 --> 04:38:25,080
-Very good.
Dave?

5493
04:38:25,080 --> 04:38:26,640
-In regard to Steve
Greenberg's point,

5494
04:38:26,640 --> 04:38:28,680
I think there's a lot
of emerging evidence

5495
04:38:28,680 --> 04:38:31,600
from labs
like the Cos Iadecola,

5496
04:38:31,600 --> 04:38:34,880
Jony Kipnis' and others
that strongly suggest

5497
04:38:34,880 --> 04:38:37,640
that specific cells
that surround blood vessels,

5498
04:38:37,640 --> 04:38:40,280
such as perivascular
macrophages,

5499
04:38:40,280 --> 04:38:42,880
are really important
in regulating the connection

5500
04:38:42,880 --> 04:38:46,960
between interstitial fluid
flow and lymph --

5501
04:38:46,960 --> 04:38:49,240
ultimately flow out
through the lymphatic system,

5502
04:38:49,240 --> 04:38:51,880
so I think that those could
easily affect not just amyloid

5503
04:38:51,880 --> 04:38:55,040
but lots of other functions,
such as blood-vessel function,

5504
04:38:55,040 --> 04:38:58,240
so I think that's an area that
really needs a lot more study.

5505
04:38:58,240 --> 04:39:00,320
-Yeah, rich area of study.

5506
04:39:00,320 --> 04:39:06,000
Speaking of Cos Iadecola,
Cos, I have you up next.

5507
04:39:06,000 --> 04:39:09,600
-Yeah, I like to make
two points,

5508
04:39:09,600 --> 04:39:14,320
so one is that the focus
of the field,

5509
04:39:14,320 --> 04:39:16,800
you know, very masterfully,
you know,

5510
04:39:16,800 --> 04:39:22,560
described by the speakers
has been of vascular failure

5511
04:39:22,560 --> 04:39:28,120
being linked to starvation of
the brain of oxygen and glucose.

5512
04:39:28,120 --> 04:39:34,440
I think now,
as Dave pointed out,

5513
04:39:34,440 --> 04:39:37,360
the clearance of the blood
vessels is now becoming

5514
04:39:37,360 --> 04:39:40,440
another potential
pathogenic mechanism.

5515
04:39:40,440 --> 04:39:42,400
The blood-brain barrier
has emerged

5516
04:39:42,400 --> 04:39:43,960
as a pathogenic mechanism,

5517
04:39:43,960 --> 04:39:46,880
all right, which are independent
of the delivery of oxygen

5518
04:39:46,880 --> 04:39:48,120
and glucose to the brain,

5519
04:39:48,120 --> 04:39:50,200
which has been
traditionally considered

5520
04:39:50,200 --> 04:39:51,760
the basis
of vascular injury.

5521
04:39:51,760 --> 04:39:52,600
All right?

5522
04:39:52,600 --> 04:39:54,400
But the brain, I mean,

5523
04:39:54,400 --> 04:39:56,800
the vessels of the brain
do more than that.

5524
04:39:56,800 --> 04:39:59,400
They deliver growth factors
to the neurons,

5525
04:39:59,400 --> 04:40:02,200
and that's been very well
described in development.

5526
04:40:02,200 --> 04:40:06,800
And for example, even
in neurogenesis in adult animals

5527
04:40:06,800 --> 04:40:10,800
where the vessels
deliver vital factors,

5528
04:40:10,800 --> 04:40:12,560
including nitric oxide,

5529
04:40:12,560 --> 04:40:16,600
that keeps the neurogenic
niche alive.

5530
04:40:16,600 --> 04:40:19,520
The recent paper in neuron
shows that [Indistinct]

5531
04:40:19,520 --> 04:40:21,240
of the blood vessels
in hippocampus

5532
04:40:21,240 --> 04:40:25,680
is vital for maintaining
the neurogenic niche.

5533
04:40:25,680 --> 04:40:27,760
For example,
the other [Indistinct]

5534
04:40:27,760 --> 04:40:29,400
suggests that, you know,
[Indistinct]

5535
04:40:29,400 --> 04:40:32,080
from the endothelial
is required to maintain

5536
04:40:32,080 --> 04:40:34,480
tau homeostasis in neurons.

5537
04:40:34,480 --> 04:40:35,680
All right?

5538
04:40:35,680 --> 04:40:37,160
So there is a new area
out there,

5539
04:40:37,160 --> 04:40:41,480
and I think that that is
very ripe for [Indistinct]

5540
04:40:41,480 --> 04:40:46,800
that will explore
nonischemia-related aspect

5541
04:40:46,800 --> 04:40:48,040
of vascular function

5542
04:40:48,040 --> 04:40:51,200
which are ever
very important role

5543
04:40:51,200 --> 04:40:53,560
in the maintenance
of brain health.

5544
04:40:53,560 --> 04:40:55,880
All right?
That's really --

5545
04:40:55,880 --> 04:40:57,400
The other point I want to make
is that,

5546
04:40:57,400 --> 04:41:02,600
you know, the diversity
of the brain in VCID

5547
04:41:02,600 --> 04:41:06,320
combines with the diversity
of the mechanism of VCID.

5548
04:41:06,320 --> 04:41:09,560
Now this proposes a number
of issues or problems

5549
04:41:09,560 --> 04:41:11,240
that we need to address.

5550
04:41:11,240 --> 04:41:15,440
One is that there is a diversity
of cell types in the brain,

5551
04:41:15,440 --> 04:41:19,200
so anything that you do in vitro
we used to do with cultured

5552
04:41:19,200 --> 04:41:20,440
and endothelial cells.

5553
04:41:20,440 --> 04:41:21,600
Now we know there are
eight kinds

5554
04:41:21,600 --> 04:41:24,000
of endothelial cells in a brain.

5555
04:41:24,000 --> 04:41:25,560
They all look the same.

5556
04:41:25,560 --> 04:41:27,840
They have completely different
transcriptomic profiles.

5557
04:41:27,840 --> 04:41:31,400
So what kind of cells are we
going to use organoids, right?

5558
04:41:31,400 --> 04:41:32,800
What kind of, you know,

5559
04:41:32,800 --> 04:41:35,000
what kind of parasite
are we going to use?

5560
04:41:35,000 --> 04:41:38,040
There are now three classes
of parasites in humans.

5561
04:41:38,040 --> 04:41:40,080
What kinds of smooth muscle
cells are you going to use?

5562
04:41:40,080 --> 04:41:42,600
So that's a level of complexity.

5563
04:41:42,600 --> 04:41:45,720
The other level of complexity
is regional complexity.

5564
04:41:45,720 --> 04:41:48,240
White-matter regulation
of blood flow

5565
04:41:48,240 --> 04:41:51,000
is different than cortical
regulation of blood flow,

5566
04:41:51,000 --> 04:41:53,000
which has been one
traditionally studied

5567
04:41:53,000 --> 04:41:56,840
because it's there easily for us
to drill a hole in the head

5568
04:41:56,840 --> 04:41:58,040
and look at the cortex.

5569
04:41:58,040 --> 04:41:59,840
All right?
But what about, you know,

5570
04:41:59,840 --> 04:42:02,640
the cerebellum has a completely
different vascular regulation

5571
04:42:02,640 --> 04:42:04,160
than the cortex does?

5572
04:42:04,160 --> 04:42:06,960
Nitrous oxide being responsible
for 100 percent

5573
04:42:06,960 --> 04:42:08,600
on [Indistinct]

5574
04:42:08,600 --> 04:42:12,200
whereas, in the cortex,
it's only 50, 60 percent,

5575
04:42:12,200 --> 04:42:14,200
so there is
regional complexity.

5576
04:42:14,200 --> 04:42:16,800
And finally there is
a mechanistic complexity.

5577
04:42:16,800 --> 04:42:19,120
I've heard, you know, both,
you know,

5578
04:42:19,120 --> 04:42:23,600
Prashanth and Sudha mention,
you know, CO2 reactivity.

5579
04:42:23,600 --> 04:42:26,920
That's only one aspect
of vascular regulation.

5580
04:42:26,920 --> 04:42:28,440
The mechanism of which

5581
04:42:28,440 --> 04:42:30,320
are completely different
from neurovascular coupling,

5582
04:42:30,320 --> 04:42:32,680
for example,
or endothelial function,

5583
04:42:32,680 --> 04:42:36,600
so if you study CO2 reactivity
and it's normal,

5584
04:42:36,600 --> 04:42:40,920
doesn't mean that the vessels of
the brain are working normally

5585
04:42:40,920 --> 04:42:44,080
because, you know,
the endothelial may be failing.

5586
04:42:44,080 --> 04:42:47,200
You know, CO2 is multifactorial
in the brain,

5587
04:42:47,200 --> 04:42:48,640
depends on number of factors

5588
04:42:48,640 --> 04:42:51,000
coming from every single cells
in the brain.

5589
04:42:51,000 --> 04:42:54,200
So we need to kind of also
be aware of that,

5590
04:42:54,200 --> 04:42:57,240
and I grant you that is
very difficult to study,

5591
04:42:57,240 --> 04:42:58,800
you know, neurovascular
coupling versus

5592
04:42:58,800 --> 04:43:01,200
to get the guy
to breathe CO2.

5593
04:43:01,200 --> 04:43:02,400
All right?

5594
04:43:02,400 --> 04:43:03,600
It's very easy to do that.

5595
04:43:03,600 --> 04:43:04,880
That's why people do it.

5596
04:43:04,880 --> 04:43:06,400
All right?
We got to start somewhere,

5597
04:43:06,400 --> 04:43:09,320
and I'm all, you know,
in support of that,

5598
04:43:09,320 --> 04:43:12,200
but I believe that, you know,
we need to kind of be,

5599
04:43:12,200 --> 04:43:14,720
you know,
much more nuanced approach

5600
04:43:14,720 --> 04:43:20,400
when we start to translate
these findings to the humans,

5601
04:43:20,400 --> 04:43:24,640
and thank you for allowing me
to express my thoughts on this.

5602
04:43:24,640 --> 04:43:25,920
-Well, thanks very much, Cos,

5603
04:43:25,920 --> 04:43:27,760
for simplifying
the whole situation,

5604
04:43:27,760 --> 04:43:29,200
making it pretty
straightforward.

5605
04:43:29,200 --> 04:43:31,760
But, Sudha, please comment.

5606
04:43:31,760 --> 04:43:33,200
-Just wanted to --

5607
04:43:33,200 --> 04:43:35,480
Cos, you're obviously
a leader in the field,

5608
04:43:35,480 --> 04:43:39,400
always on the cutting edge,
and couldn't agree more.

5609
04:43:39,400 --> 04:43:46,120
Some of the emerging imaging
technologies like the 7-Tesla

5610
04:43:46,120 --> 04:43:49,240
imaging that may show the
hippocamp or microvasculature

5611
04:43:49,240 --> 04:43:53,240
to a greater extent,
things like C11-FDP PET,

5612
04:43:53,240 --> 04:43:57,360
which we are employing
in a study of rapamycin funded,

5613
04:43:57,360 --> 04:44:02,480
you know, where we can see
different aspects of blood flow

5614
04:44:02,480 --> 04:44:05,360
and things like correlating
the postmortem MRI

5615
04:44:05,360 --> 04:44:06,800
with the kind of [Indistinct]

5616
04:44:06,800 --> 04:44:09,320
study that Andy Shih showed

5617
04:44:09,320 --> 04:44:12,080
where you can actually look
at single-cell omics

5618
04:44:12,080 --> 04:44:16,720
and different perhaps
regions of the brain.

5619
04:44:16,720 --> 04:44:20,320
Yes, it seems like increasing
complexity

5620
04:44:20,320 --> 04:44:25,080
seems inevitable before
we arrive at simplicity,

5621
04:44:25,080 --> 04:44:28,000
but at least
the attention to VCID

5622
04:44:28,000 --> 04:44:33,200
is very exciting as a key factor
in all of ADRD.

5623
04:44:33,200 --> 04:44:34,440
-Okay.
Thanks.

5624
04:44:34,440 --> 04:44:36,040
Let's -- In the interest
of getting to

5625
04:44:36,040 --> 04:44:38,600
as many individuals as we can,
let's turn to Charlie.

5626
04:44:38,600 --> 04:44:40,600
Charlie, your thoughts?

5627
04:44:40,600 --> 04:44:43,520
-Thank you, and first,
I want to say

5628
04:44:43,520 --> 04:44:45,760
this is so exciting
having been in this field

5629
04:44:45,760 --> 04:44:49,080
for such a long time to see how
new innovation is going,

5630
04:44:49,080 --> 04:44:53,120
and I just want to say
shout-out to Dr. Corriveau

5631
04:44:53,120 --> 04:44:57,200
for leading this charge and
supporting this through NINDS.

5632
04:44:57,200 --> 04:44:59,720
I'm very, very grateful.

5633
04:44:59,720 --> 04:45:04,800
My point and question is,
how do we tie this together?

5634
04:45:04,800 --> 04:45:09,360
And my feeling is that vascular
cognitive impairment

5635
04:45:09,360 --> 04:45:11,680
is a systemic disease.

5636
04:45:11,680 --> 04:45:14,720
It involves the endothelial.

5637
04:45:14,720 --> 04:45:16,800
It involves vascular remodeling,

5638
04:45:16,800 --> 04:45:19,560
and it involves disruption
of the blood-brain barrier,

5639
04:45:19,560 --> 04:45:22,800
or subtle dysfunction
might be a better word.

5640
04:45:22,800 --> 04:45:26,880
And I think it's rife,
or the opportunity exists

5641
04:45:26,880 --> 04:45:31,320
to look at that interaction
through cell-cell communication.

5642
04:45:31,320 --> 04:45:34,240
Right now, we're looking
at some exosome signaling,

5643
04:45:34,240 --> 04:45:37,040
but it could be
circulating factors

5644
04:45:37,040 --> 04:45:39,880
and new data
that's coming out suggesting

5645
04:45:39,880 --> 04:45:42,640
that, you know,
placental growth factor

5646
04:45:42,640 --> 04:45:45,640
may be important,
but inflammation --

5647
04:45:45,640 --> 04:45:50,040
And my point here
is that a broader view

5648
04:45:50,040 --> 04:45:53,720
as it's been alluded
to that combines animal models

5649
04:45:53,720 --> 04:45:58,600
with human health injury
and teases apart

5650
04:45:58,600 --> 04:46:01,840
how the system itself
is affecting the brain,

5651
04:46:01,840 --> 04:46:04,440
and I think that
that emphasis is important,

5652
04:46:04,440 --> 04:46:07,640
and I'd love to hear
thoughts on that.

5653
04:46:07,640 --> 04:46:09,760
-Thanks, Charlie.
Comments for him?

5654
04:46:15,080 --> 04:46:17,400
Eric, what do you think?

5655
04:46:17,400 --> 04:46:20,080
Charlie on target here?

5656
04:46:20,080 --> 04:46:21,880
-Yeah, I didn't raise my hand

5657
04:46:21,880 --> 04:46:24,400
because I agree
with Charlie's point.

5658
04:46:24,400 --> 04:46:25,960
I think of putting it
all together.

5659
04:46:25,960 --> 04:46:28,200
I raised my hand and lowered it
before too

5660
04:46:28,200 --> 04:46:30,360
because Sudha made a point,
which is that the extent

5661
04:46:30,360 --> 04:46:34,400
that we can also drive
human biomarkers

5662
04:46:34,400 --> 04:46:37,120
of these processes
to help us link,

5663
04:46:37,120 --> 04:46:39,200
you know, how the complexity
is being unraveled

5664
04:46:39,200 --> 04:46:40,400
in the basic science lab

5665
04:46:40,400 --> 04:46:42,480
and translate it
to human studies

5666
04:46:42,480 --> 04:46:45,080
and then use those as targets
for early phase

5667
04:46:45,080 --> 04:46:46,640
therapeutic trials,

5668
04:46:46,640 --> 04:46:49,600
I think, is something
the field has to be considering.

5669
04:46:49,600 --> 04:46:50,800
Thank you.

5670
04:46:50,800 --> 04:46:52,560
-Very good.
Thanks, Eric.

5671
04:46:52,560 --> 04:46:54,000
Okay.

5672
04:46:54,000 --> 04:46:58,600
Alexandria Early or Alexandria
Linton, comments?

5673
04:46:58,600 --> 04:47:00,000
-Recent name change.

5674
04:47:00,000 --> 04:47:02,400
I just wanted to start by saying
thank you so much

5675
04:47:02,400 --> 04:47:06,280
to all of the speakers for
a very clear and engaging talk.

5676
04:47:06,280 --> 04:47:09,920
Dr. Vemuri, you made a great
point in your conclusion slide

5677
04:47:09,920 --> 04:47:12,600
about prioritizing rigor
and reproducibility,

5678
04:47:12,600 --> 04:47:14,080
but I wanted to actually bring

5679
04:47:14,080 --> 04:47:16,920
that point back
to Dr. Shih's section.

5680
04:47:16,920 --> 04:47:18,280
So, Dr. Shih, you showcased

5681
04:47:18,280 --> 04:47:20,240
many innovative methods
in your section,

5682
04:47:20,240 --> 04:47:23,120
but as a trainee
studying in this area,

5683
04:47:23,120 --> 04:47:26,480
I was wondering how
the committee plans to address

5684
04:47:26,480 --> 04:47:31,000
or prioritize the repeatability
and reproducibility problem

5685
04:47:31,000 --> 04:47:32,880
that we've encountered
as these techniques

5686
04:47:32,880 --> 04:47:35,920
and these methods tend to evolve
and advance so quickly,

5687
04:47:35,920 --> 04:47:38,720
especially in light
of the heterogeneity

5688
04:47:38,720 --> 04:47:40,320
that we recently discussed.

5689
04:47:40,320 --> 04:47:41,400
Thank you.
-Thank you.

5690
04:47:41,400 --> 04:47:43,640
Let me throw that to Rema Raman.

5691
04:47:43,640 --> 04:47:46,440
Rema, you've been the one
who've been pushing us

5692
04:47:46,440 --> 04:47:49,400
on the rigor
and reproducibility.

5693
04:47:49,400 --> 04:47:50,760
Comments?

5694
04:47:50,760 --> 04:47:52,600
-Yeah, that's a great point,
Alexandria.

5695
04:47:52,600 --> 04:47:56,000
I think it's something that
we should all be cognizant of

5696
04:47:56,000 --> 04:48:01,680
as we develop experimental to
make sure that the designs --

5697
04:48:01,680 --> 04:48:04,240
It's a discussion that's had
at the design stage,

5698
04:48:04,240 --> 04:48:07,920
the training of scientists
who are [Indistinct]

5699
04:48:07,920 --> 04:48:10,160
clinical research, you know,

5700
04:48:10,160 --> 04:48:12,880
so sort of addressing
it across the board

5701
04:48:12,880 --> 04:48:16,280
starting with training,
focus on experimental design,

5702
04:48:16,280 --> 04:48:17,880
focus on data collection,

5703
04:48:17,880 --> 04:48:20,560
focus on data quality
that would then --

5704
04:48:20,560 --> 04:48:23,040
and then open science,
sharing these results,

5705
04:48:23,040 --> 04:48:27,760
making sure that everything
is shared at the global level

5706
04:48:27,760 --> 04:48:30,200
so that studies
can be reproduced,

5707
04:48:30,200 --> 04:48:33,720
and so taking that
comprehensive view

5708
04:48:33,720 --> 04:48:37,440
around the need for rigor
and reproducibility

5709
04:48:37,440 --> 04:48:40,720
right from the start
all the way through the end

5710
04:48:40,720 --> 04:48:44,000
and open sharing sort of
will help us get there,

5711
04:48:44,000 --> 04:48:45,400
and that's some
of the discussions

5712
04:48:45,400 --> 04:48:50,960
we've been having as
part of this discussion.

5713
04:48:50,960 --> 04:48:51,920
-Very good.
-Thank you.

5714
04:48:51,920 --> 04:48:53,680
-Thanks, Rema.
Okay.

5715
04:48:53,680 --> 04:48:57,240
Let me turn to
Atticus Hainsworth.

5716
04:48:57,240 --> 04:49:00,640
Question, comments?
-I thank you very much.

5717
04:49:00,640 --> 04:49:02,120
Great to be part of this.

5718
04:49:02,120 --> 04:49:05,640
Atticus Hainsworth
dialing in from London, UK.

5719
04:49:05,640 --> 04:49:09,160
Great to hear about all these
fantastic new biomarkers,

5720
04:49:09,160 --> 04:49:11,280
new models, new targets.

5721
04:49:11,280 --> 04:49:14,200
My question is, what do you rate
as the chances

5722
04:49:14,200 --> 04:49:17,400
of attracting
the drug companies

5723
04:49:17,400 --> 04:49:20,880
back into the space
of brain vascular disease,

5724
04:49:20,880 --> 04:49:23,880
and is it something
you even would want to do?

5725
04:49:26,520 --> 04:49:29,000
-Excellent question,
excellent question.

5726
04:49:29,000 --> 04:49:32,840
There's been a migration away
over the years.

5727
04:49:32,840 --> 04:49:36,000
Let me --
Maybe let me throw --

5728
04:49:36,000 --> 04:49:37,480
You're not
paying attention, Natalia,

5729
04:49:37,480 --> 04:49:39,160
but I'm going to
throw this one to you.

5730
04:49:39,160 --> 04:49:41,880
What do you think about bringing
the pharmaceutical industry

5731
04:49:41,880 --> 04:49:45,040
back into the business here?

5732
04:49:45,040 --> 04:49:48,120
-Well, I think
it's already happening, right?

5733
04:49:48,120 --> 04:49:52,280
So there's already
some interest and...

5734
04:49:58,480 --> 04:50:00,000
-Are you freezing?

5735
04:50:00,000 --> 04:50:01,240
-I think she's frozen.

5736
04:50:01,240 --> 04:50:04,640
-You may have frozen there,
Natalia.

5737
04:50:04,640 --> 04:50:06,040
We'll let you unfreeze.

5738
04:50:06,040 --> 04:50:09,280
Donna, you have a comment.

5739
04:50:09,280 --> 04:50:12,880
Natalia is back?
-No, I apologize.

5740
04:50:12,880 --> 04:50:14,040
I'm sure -- I'm sorry.

5741
04:50:14,040 --> 04:50:19,600
This says, "Zoom quit" --
Oh, no.

5742
04:50:19,600 --> 04:50:21,800
-It did that to me
over our lunch break, Natalia.

5743
04:50:21,800 --> 04:50:25,080
You're just going to have
to sign off, come back in.

5744
04:50:25,080 --> 04:50:26,840
-Okay.
-So, I mean...

5745
04:50:26,840 --> 04:50:28,040
-Donna.

5746
04:50:28,040 --> 04:50:29,760
-...I'll just
give my two cents.

5747
04:50:29,760 --> 04:50:31,640
You know, I think we have
to at some point

5748
04:50:31,640 --> 04:50:33,760
get the drug companies back in.

5749
04:50:33,760 --> 04:50:35,600
I don't think this is something
we can solve...

5750
04:50:35,600 --> 04:50:36,760
-I'm --

5751
04:50:36,760 --> 04:50:39,000
-...just ourselves.
-Yeah.

5752
04:50:39,000 --> 04:50:42,480
Oh.
-That's okay.

5753
04:50:42,480 --> 04:50:46,280
But it takes us to find
the targets, and it takes us to,

5754
04:50:46,280 --> 04:50:49,880
you know, get to mechanism,

5755
04:50:49,880 --> 04:50:52,120
and I think that's where,
Atticus,

5756
04:50:52,120 --> 04:50:55,520
we really need
those mechanistic studies,

5757
04:50:55,520 --> 04:50:57,480
and, you know,

5758
04:50:57,480 --> 04:51:01,200
I think Sudha's presentation
brought it all back together

5759
04:51:01,200 --> 04:51:05,920
where we need that backwards
and forwards translation from,

5760
04:51:05,920 --> 04:51:10,520
you know,
from our animal models to our,

5761
04:51:10,520 --> 04:51:12,480
you know,
our clinical human studies

5762
04:51:12,480 --> 04:51:14,960
and then back to the mice
to see,

5763
04:51:14,960 --> 04:51:16,520
you know,
what we find in the humans.

5764
04:51:16,520 --> 04:51:19,200
What does that
mean mechanistically

5765
04:51:19,200 --> 04:51:21,560
when we manipulate
that system?

5766
04:51:21,560 --> 04:51:25,120
Then you start looking
at targets, you know,

5767
04:51:25,120 --> 04:51:27,000
but there's got to be
a back and forth,

5768
04:51:27,000 --> 04:51:32,200
and for me, I think we need
a metal, you know, mammal.

5769
04:51:32,200 --> 04:51:34,240
You know, mouse-to-human
translation

5770
04:51:34,240 --> 04:51:36,680
has not served as well today

5771
04:51:36,680 --> 04:51:38,320
in the dementia field
as a whole.

5772
04:51:38,320 --> 04:51:41,280
So...
-Thank you.

5773
04:51:41,280 --> 04:51:43,200
Eric, you have your hand up?

5774
04:51:43,200 --> 04:51:46,160
-Yeah, sure, no,
I think Natalia is right.

5775
04:51:46,160 --> 04:51:49,080
There does seem to be
some beginning glimmers

5776
04:51:49,080 --> 04:51:50,880
of interest in this space.

5777
04:51:50,880 --> 04:51:54,000
There has not been a lot
of commercial interest

5778
04:51:54,000 --> 04:51:58,960
in clinical trials
in therapies for VCID.

5779
04:51:58,960 --> 04:52:02,200
I think what's needed are
targets that Donna mentioned,

5780
04:52:02,200 --> 04:52:05,040
you know, like innovative
aspects of the biology

5781
04:52:05,040 --> 04:52:06,960
of the neurovascular unit
that can be exploited

5782
04:52:06,960 --> 04:52:09,760
for a therapeutic benefit
ideally

5783
04:52:09,760 --> 04:52:12,480
where genetic modifiers,
the process can be discovered

5784
04:52:12,480 --> 04:52:14,400
because I think they put
a lot of stock in

5785
04:52:14,400 --> 04:52:16,720
Mendelian randomization
studies to suggest

5786
04:52:16,720 --> 04:52:20,400
that the quantifying target
might improve outcomes,

5787
04:52:20,400 --> 04:52:25,400
and we need standardization
of our methods

5788
04:52:25,400 --> 04:52:27,800
for clinical trials
in this population too,

5789
04:52:27,800 --> 04:52:29,800
and I think MarkVCID, you know,

5790
04:52:29,800 --> 04:52:32,480
has given a package
of biomarkers that can be used,

5791
04:52:32,480 --> 04:52:33,880
but it's also standardization,

5792
04:52:33,880 --> 04:52:36,280
the clinical assessment
on definition

5793
04:52:36,280 --> 04:52:41,040
of who has the disease and how
to measure it on outcomes,

5794
04:52:41,040 --> 04:52:44,120
not only cognitive but
also behavioral and functional.

5795
04:52:44,120 --> 04:52:45,560
I'm part of a group
called Finesse.

5796
04:52:45,560 --> 04:52:47,480
Some others on this call
are part of this too led

5797
04:52:47,480 --> 04:52:50,080
by Hugh Markus
and Martin Dichgans

5798
04:52:50,080 --> 04:52:54,800
to try to provide
some consensus around,

5799
04:52:54,800 --> 04:52:58,120
you know, how a trial
for VCID should be run.

5800
04:52:58,120 --> 04:53:02,080
That hopefully will give
companies more confidence

5801
04:53:02,080 --> 04:53:06,000
that we have achieved
the ability to run a trial

5802
04:53:06,000 --> 04:53:08,160
with high-quality,
standardized methods.

5803
04:53:08,160 --> 04:53:09,160
Thanks.

5804
04:53:09,160 --> 04:53:10,160
-Very good.
Thank you.

5805
04:53:10,160 --> 04:53:11,960
Steve, you had some comments?

5806
04:53:11,960 --> 04:53:15,600
-Just going to add that
although we always want

5807
04:53:15,600 --> 04:53:17,400
a better
mechanistic understanding,

5808
04:53:17,400 --> 04:53:19,160
we certainly want it
for small vessel disease.

5809
04:53:19,160 --> 04:53:23,240
I don't think we have a shortage
of rational targets.

5810
04:53:23,240 --> 04:53:25,720
The issue that, you know,
everyone on this call is aware

5811
04:53:25,720 --> 04:53:29,400
is that VCID is in
a different position from --

5812
04:53:29,400 --> 04:53:33,080
certainly from the FTD or LBD

5813
04:53:33,080 --> 04:53:36,160
in that it's a highly
prevalent pathology.

5814
04:53:36,160 --> 04:53:37,960
Almost everybody has it,

5815
04:53:37,960 --> 04:53:41,320
and it almost never is the sole
cause of cognitive impairment.

5816
04:53:41,320 --> 04:53:46,320
It almost always coexists
with other pathologies.

5817
04:53:46,320 --> 04:53:49,320
So for a highly prevalent,
you know,

5818
04:53:49,320 --> 04:53:53,760
modestly contributing pathology,

5819
04:53:53,760 --> 04:53:56,600
but the overall attributable
risk is extremely high

5820
04:53:56,600 --> 04:53:58,000
because it's so prevalent,

5821
04:53:58,000 --> 04:54:02,240
so we need biomarkers
that can live in a world

5822
04:54:02,240 --> 04:54:06,080
where small vessel disease
or other vascular pathologies

5823
04:54:06,080 --> 04:54:09,600
are coexisting with
neurodegenerative pathologies

5824
04:54:09,600 --> 04:54:12,160
and that we're able
to not use that

5825
04:54:12,160 --> 04:54:14,280
as a reason not to do trials
but as a reason to say,

5826
04:54:14,280 --> 04:54:16,680
"Okay. We need biomarkers
that can at least help select

5827
04:54:16,680 --> 04:54:19,160
out the vascular contribution

5828
04:54:19,160 --> 04:54:20,720
and then make that
the focus of a trial,"

5829
04:54:20,720 --> 04:54:24,400
so I think that that's a concept
that's a little harder

5830
04:54:24,400 --> 04:54:26,800
for drug companies
to get their teeth around

5831
04:54:26,800 --> 04:54:29,200
where they're used to saying,
"Okay. You've got this disease,

5832
04:54:29,200 --> 04:54:32,120
and we're going to give you
this therapy for this disease.

5833
04:54:32,120 --> 04:54:35,080
The mixed world is messier,
but it's also the real world,

5834
04:54:35,080 --> 04:54:36,960
and it's certainly
a big unmet need,

5835
04:54:36,960 --> 04:54:40,640
so, you know, it's a little
self-serving of me to say,

5836
04:54:40,640 --> 04:54:41,960
"Biomarkers are important,"

5837
04:54:41,960 --> 04:54:44,320
but I think that's
going to be the key

5838
04:54:44,320 --> 04:54:46,400
to getting the companies back.

5839
04:54:46,400 --> 04:54:48,200
-I think so too [Indistinct].

5840
04:54:48,200 --> 04:54:49,840
Gareth.

5841
04:54:49,840 --> 04:54:52,120
-Yeah, and I think this is
what Andy mentioned in his talk,

5842
04:54:52,120 --> 04:54:54,200
which is we have
a panel of models,

5843
04:54:54,200 --> 04:54:56,680
but they're not
particularly well defined

5844
04:54:56,680 --> 04:55:01,280
in terms of what they show
and when and in what order,

5845
04:55:01,280 --> 04:55:05,280
and so when companies would look
to the preclinical studies,

5846
04:55:05,280 --> 04:55:09,480
it's hard for them to, you know,
design the next step,

5847
04:55:09,480 --> 04:55:11,960
either preclinical
or even clinical studies,

5848
04:55:11,960 --> 04:55:14,960
and so first step, I think,
would be to better define

5849
04:55:14,960 --> 04:55:18,440
what it is that the models
actually recapitulate

5850
04:55:18,440 --> 04:55:20,640
and also then make the call
as to whether those models

5851
04:55:20,640 --> 04:55:23,280
and the panel of models
is sufficient,

5852
04:55:23,280 --> 04:55:25,360
which then means
we would then need to go back

5853
04:55:25,360 --> 04:55:28,040
and generate better models
that better recreate

5854
04:55:28,040 --> 04:55:32,640
particularly the heterogeneity
of this pretty complex disease.

5855
04:55:32,640 --> 04:55:33,760
-Very good.
Thank you.

5856
04:55:33,760 --> 04:55:35,600
Rod?

5857
04:55:35,600 --> 04:55:38,400
-Thanks, yeah, I just want
to build a bit agreeing

5858
04:55:38,400 --> 04:55:42,920
with Steve and just --
and say it in a slightly --

5859
04:55:42,920 --> 04:55:46,120
or add to it, and that is that
if we're thinking about,

5860
04:55:46,120 --> 04:55:49,680
you know, if we think about VCID
and you think about, you know,

5861
04:55:49,680 --> 04:55:51,640
who will be involved
in the clinical trials,

5862
04:55:51,640 --> 04:55:53,680
biomarkers
are absolutely critical.

5863
04:55:53,680 --> 04:55:55,960
It's also critical for companies

5864
04:55:55,960 --> 04:55:59,200
and actually individuals
to recognize

5865
04:55:59,200 --> 04:56:01,920
and be able to embrace
that concept,

5866
04:56:01,920 --> 04:56:04,800
and right now those companies
and individuals

5867
04:56:04,800 --> 04:56:09,560
for the most part are looking
at clinical Alzheimer's disease.

5868
04:56:09,560 --> 04:56:12,640
That's the biggest space
for VCID clinical trials,

5869
04:56:12,640 --> 04:56:14,800
clinical Alzheimer's disease,

5870
04:56:14,800 --> 04:56:19,520
and connecting those things,
you know,

5871
04:56:19,520 --> 04:56:22,960
in terms of molecular mechanisms
and with biomarkers

5872
04:56:22,960 --> 04:56:26,800
also just with the light bulb
going off and everyone say,

5873
04:56:26,800 --> 04:56:30,000
"Oh, my goodness, yes,
I have clinical Alzheimer's.

5874
04:56:30,000 --> 04:56:34,000
I'm going to enroll
in a clinical trial for VCID,"

5875
04:56:34,000 --> 04:56:37,240
from my perspective
is part of the challenge

5876
04:56:37,240 --> 04:56:42,040
that this field faces.

5877
04:56:42,040 --> 04:56:43,400
-Very good.

5878
04:56:43,400 --> 04:56:45,520
Keith is giving us
5 additional clinics.

5879
04:56:45,520 --> 04:56:46,800
There are a couple
of questions left.

5880
04:56:46,800 --> 04:56:48,680
Dave, you got a quick comment?

5881
04:56:48,680 --> 04:56:51,680
-Just a quick comment
about the --

5882
04:56:51,680 --> 04:56:55,920
developing drugs for VCID,
I think,

5883
04:56:55,920 --> 04:56:58,040
as in Alzheimer's disease,
I think the biggest success

5884
04:56:58,040 --> 04:57:00,920
is going to be prevention
or secondary prevention.

5885
04:57:00,920 --> 04:57:05,320
Certainly we know from studies
like the mind --

5886
04:57:05,320 --> 04:57:06,800
SPRINT MIND
trial,

5887
04:57:06,800 --> 04:57:09,440
that, you know,
just decreasing blood pressure

5888
04:57:09,440 --> 04:57:12,240
has a big effect
on decreasing mild

5889
04:57:12,240 --> 04:57:14,560
cognitive impairment incidents,

5890
04:57:14,560 --> 04:57:18,120
so that means that other things
probably could have a big effect

5891
04:57:18,120 --> 04:57:20,280
if you study them before,

5892
04:57:20,280 --> 04:57:22,080
you know, manifestations
were too severe,

5893
04:57:22,080 --> 04:57:24,000
and that means biomarkers,

5894
04:57:24,000 --> 04:57:25,840
whether it's current ones
or other ones,

5895
04:57:25,840 --> 04:57:27,480
to identify
preclinical disease

5896
04:57:27,480 --> 04:57:30,760
are probably going to be
really super important.

5897
04:57:30,760 --> 04:57:32,120
-Very good.

5898
04:57:32,120 --> 04:57:33,720
Okay.

5899
04:57:33,720 --> 04:57:36,400
Natasha, you're --
Natalia, you're back?

5900
04:57:36,400 --> 04:57:37,800
-I'm back.
I'm really sorry.

5901
04:57:37,800 --> 04:57:40,000
That's what happens
when you're, you know,

5902
04:57:40,000 --> 04:57:42,320
you're absorbing
that Wi-Fi so intensely.

5903
04:57:42,320 --> 04:57:45,200
It just crashes when you finally
get an opportunity to speak.

5904
04:57:45,200 --> 04:57:47,280
I just wanted to say, and I
missed most of the discussion

5905
04:57:47,280 --> 04:57:48,880
on that
while I was reconnecting,

5906
04:57:48,880 --> 04:57:50,680
but I wanted to say
there is also --

5907
04:57:50,680 --> 04:57:52,800
While we are in this process,

5908
04:57:52,800 --> 04:57:57,120
we are also learning something
by some of the trials

5909
04:57:57,120 --> 04:58:00,360
that I feel will be coming in
with repurposing of the drugs.

5910
04:58:00,360 --> 04:58:04,200
You know, there is a lot
of interest in drug makers

5911
04:58:04,200 --> 04:58:08,080
right now to try out some of
the anti-inflammatory therapy,

5912
04:58:08,080 --> 04:58:09,480
some of the more targeted.

5913
04:58:09,480 --> 04:58:12,280
Some, you know,
some are less targeted,

5914
04:58:12,280 --> 04:58:15,640
but they're trying to also
widen stroke space

5915
04:58:15,640 --> 04:58:19,440
and, you know, and --
by extension and VCID.

5916
04:58:19,440 --> 04:58:22,160
So we will learn
something from it.

5917
04:58:22,160 --> 04:58:24,640
Maybe some of the, you know,
so to speak,

5918
04:58:24,640 --> 04:58:28,600
translation into clinical models
is not as perfect as we would,

5919
04:58:28,600 --> 04:58:30,640
you know, would've, you know,
wanted it to be,

5920
04:58:30,640 --> 04:58:33,320
but we will gain
some knowledge from that,

5921
04:58:33,320 --> 04:58:36,200
and I think that's going to be,
you know, just contributing

5922
04:58:36,200 --> 04:58:40,160
to accumulating a base
of knowledge in that space.

5923
04:58:40,160 --> 04:58:41,000
-Okay.
Thank you.

5924
04:58:41,000 --> 04:58:42,600
Let me do one more,

5925
04:58:42,600 --> 04:58:44,960
and Niccolo has been
standing by for some time,

5926
04:58:44,960 --> 04:58:47,200
and I want to get to him.

5927
04:58:47,200 --> 04:58:49,480
And the other couple
of questions we'll get to,

5928
04:58:49,480 --> 04:58:51,400
I think, later off-line.

5929
04:58:51,400 --> 04:58:52,840
I appreciate your patience.

5930
04:58:52,840 --> 04:58:55,560
But Niccolo Terrando.

5931
04:58:55,560 --> 04:58:57,280
-Thank you very much first
of all to the whole panel.

5932
04:58:57,280 --> 04:59:00,200
This was very informative,
great talks.

5933
04:59:00,200 --> 04:59:02,440
Fairly hard question
for a last minute, I guess,

5934
04:59:02,440 --> 04:59:07,000
but it was very intriguing,
the role of vascular dysfunction

5935
04:59:07,000 --> 04:59:09,120
in the neuroinflammatory
processes,

5936
04:59:09,120 --> 04:59:12,440
so I'm wondering if there are
some kind of recommendation

5937
04:59:12,440 --> 04:59:15,800
or just general thoughts in
terms of causality in the system

5938
04:59:15,800 --> 04:59:19,720
and whether this [Indistinct]
as the systemic dysfunction

5939
04:59:19,720 --> 04:59:22,800
might actually be
a CNS-originated problem

5940
04:59:22,800 --> 04:59:24,640
that then impacts the vascular
[Indistinct]

5941
04:59:24,640 --> 04:59:26,720
from inside out to some extent,

5942
04:59:26,720 --> 04:59:29,760
so I'm just wondering if there
are some thoughts on this,

5943
04:59:29,760 --> 04:59:33,120
and thank you very much.

5944
04:59:33,120 --> 04:59:36,200
-Comments, responses
from the group?

5945
04:59:39,080 --> 04:59:40,560
-I can speak
of that a little bit.

5946
04:59:40,560 --> 04:59:44,960
I think that's a fantastic
question, and it's true.

5947
04:59:44,960 --> 04:59:47,000
You know, even
the vascular-based

5948
04:59:47,000 --> 04:59:48,520
defects like
the blood-brain barrier

5949
04:59:48,520 --> 04:59:51,520
will lead to neuroinflammation,

5950
04:59:51,520 --> 04:59:53,600
but then the neuroinflammatory
reactions

5951
04:59:53,600 --> 04:59:55,120
irrespective of the vasculature

5952
04:59:55,120 --> 04:59:58,720
can then work backward
and act on the vessels so,

5953
04:59:58,720 --> 05:00:00,280
you know,
chicken-and-egg problem,

5954
05:00:00,280 --> 05:00:01,640
and I think that the --

5955
05:00:01,640 --> 05:00:04,160
some of the studies
that we have we want to,

5956
05:00:04,160 --> 05:00:05,480
we want to do
to better understand

5957
05:00:05,480 --> 05:00:07,280
the etiology of the disease
to go back

5958
05:00:07,280 --> 05:00:09,880
and see which came first
to go much earlier,

5959
05:00:09,880 --> 05:00:12,200
can help to address some of
those types of questions,

5960
05:00:12,200 --> 05:00:13,880
to see which --

5961
05:00:13,880 --> 05:00:15,360
You know, if we could measure
both the neuroinflammation

5962
05:00:15,360 --> 05:00:17,000
and the vascular defects
at the same time,

5963
05:00:17,000 --> 05:00:20,320
one probably emerges
before the other.

5964
05:00:20,320 --> 05:00:23,280
Maybe it's too intermixed for us
to ever dissociate properly,

5965
05:00:23,280 --> 05:00:26,200
but then maybe that's
where genetic approaches

5966
05:00:26,200 --> 05:00:29,400
that allow us to target
the vessels independently

5967
05:00:29,400 --> 05:00:32,360
or the parenchymal
cell types independently

5968
05:00:32,360 --> 05:00:35,480
and then tease apart
that complexity.

5969
05:00:35,480 --> 05:00:37,040
-Very good, thank you.

5970
05:00:37,040 --> 05:00:39,240
I think, Keith, we probably
have to wrap up

5971
05:00:39,240 --> 05:00:41,600
so we don't steal too much
of the break time here

5972
05:00:41,600 --> 05:00:43,440
and intrude
on the next session, so --

5973
05:00:43,440 --> 05:00:45,560
but let me draw a line here

5974
05:00:45,560 --> 05:00:48,000
and say thank you
to all the panelists,

5975
05:00:48,000 --> 05:00:52,000
especially the speakers today,
Andy, Prashanthi,

5976
05:00:52,000 --> 05:00:54,280
Sudha, my cochair,
Donna,

5977
05:00:54,280 --> 05:00:57,320
and I want to thank
Dr. Koroshetz, Dr. Corriveau

5978
05:00:57,320 --> 05:01:01,600
for putting all this together,
Keith for organizing it,

5979
05:01:01,600 --> 05:01:05,200
and I think we'll take
a break now, Keith.

5980
05:01:05,200 --> 05:01:07,040
Is that right?
-Yeah, for a few minutes.

5981
05:01:07,040 --> 05:01:10,200
We'll be back at 3:40 p.m.
Eastern.

5982
05:01:10,200 --> 05:01:13,640
-Welcome back for our
last session of the day

5983
05:01:13,640 --> 05:01:16,480
dedicated
to Lewy body dementias,

5984
05:01:16,480 --> 05:01:19,680
and it's my pleasure
to introduce to you session

5985
05:01:19,680 --> 05:01:23,560
cochairs Dr. Kejal Kantarci
and James Leverenz.

5986
05:01:23,560 --> 05:01:25,800
Welcome.

5987
05:01:25,800 --> 05:01:28,080
-Thank you, Natalia.

5988
05:01:28,080 --> 05:01:30,440
It's my pleasure
with my cochair,

5989
05:01:30,440 --> 05:01:32,200
Dr. Jim Leverenz,

5990
05:01:32,200 --> 05:01:33,680
that we would like
to welcome you

5991
05:01:33,680 --> 05:01:36,320
to the Lewy Body
Dementia session.

5992
05:01:36,320 --> 05:01:39,760
Lewy Body Dementia includes
both dementia with Lewy Bodies

5993
05:01:39,760 --> 05:01:42,560
and Parkinson's Disease
dementia.

5994
05:01:42,560 --> 05:01:45,680
And if you go to the next
slide, right, that's good.

5995
05:01:45,680 --> 05:01:47,800
I would like to acknowledge
my colleagues

5996
05:01:47,800 --> 05:01:50,920
who have contributed
to the draft recommendations

5997
05:01:50,920 --> 05:01:53,800
on the Lewy Body Dementia
topic.

5998
05:01:53,800 --> 05:01:56,560
They are from
academic institutions

5999
05:01:56,560 --> 05:01:58,160
as well as industry.

6000
05:01:58,160 --> 05:02:01,600
I would also like to acknowledge
our advisors,

6001
05:02:01,600 --> 05:02:05,720
Dr. Babcock from NINDS,
Dr. Masliah from NIA

6002
05:02:05,720 --> 05:02:10,080
and Angela Taylor from Lewy Body
Dementia Association.

6003
05:02:10,080 --> 05:02:14,160
We have four talks
in this session.

6004
05:02:14,160 --> 05:02:17,360
Two are focused on
clinical characterization

6005
05:02:17,360 --> 05:02:19,480
and information,

6006
05:02:19,480 --> 05:02:22,480
and the other two
are on pathogenesis

6007
05:02:22,480 --> 05:02:25,800
and mechanisms of toxicity.

6008
05:02:25,800 --> 05:02:28,320
Now, if we go to the next slide,

6009
05:02:28,320 --> 05:02:31,600
I will now hand it over
to my cochair,

6010
05:02:31,600 --> 05:02:34,760
Dr. Jim Leverenz,
from Cleveland Clinic,

6011
05:02:34,760 --> 05:02:37,080
who will talk about
the recommendations

6012
05:02:37,080 --> 05:02:40,920
on clinical trials
and study cohorts.

6013
05:02:40,920 --> 05:02:42,480
-Thank you, Kejal.

6014
05:02:44,560 --> 05:02:47,040
Now, I want to thank
the theme members for your --

6015
05:02:47,040 --> 05:02:49,600
Brad Boeve, Jesse Cedarbaum,

6016
05:02:49,600 --> 05:02:53,280
Doug Galasko and Angela Taylor
from the LBDA.

6017
05:02:53,280 --> 05:02:56,680
Next.

6018
05:02:56,680 --> 05:02:59,600
My disclaimer, my disclosure,

6019
05:02:59,600 --> 05:03:02,520
I also receive grant support
from the NINDS,

6020
05:03:02,520 --> 05:03:06,200
NIA, Lewy
Body Dementia Association

6021
05:03:06,200 --> 05:03:07,800
[Indistinct] health care.

6022
05:03:07,800 --> 05:03:11,200
Next slide.

6023
05:03:11,200 --> 05:03:13,280
So we're going to go back
to 2019

6024
05:03:13,280 --> 05:03:17,920
and look at two of the
priorities, number one and two,

6025
05:03:17,920 --> 05:03:20,400
and review what
we've seen so far

6026
05:03:20,400 --> 05:03:22,560
and where we want
to go from here.

6027
05:03:22,560 --> 05:03:24,760
So this includes
the clinical trials,

6028
05:03:24,760 --> 05:03:28,480
priority one, recommendation
one and recommendation two,

6029
05:03:28,480 --> 05:03:31,400
priority two,
the longitudinal antimortem

6030
05:03:31,400 --> 05:03:33,600
LBDA characterization.

6031
05:03:33,600 --> 05:03:37,120
Next.

6032
05:03:37,120 --> 05:03:40,040
So first recommendation,
number one and priority one,

6033
05:03:40,040 --> 05:03:43,040
was, prepare for
and initiate clinical trials

6034
05:03:43,040 --> 05:03:45,080
that aim to alleviate
or slow the course

6035
05:03:45,080 --> 05:03:47,320
of Lewy Body
Dementia symptoms,

6036
05:03:47,320 --> 05:03:50,680
delay or prevent
the onset of disease.

6037
05:03:50,680 --> 05:03:54,000
Next slide.

6038
05:03:54,000 --> 05:03:57,000
Actually, it was
a very active area,

6039
05:03:57,000 --> 05:04:00,600
and over the last,
what, 3 years now,

6040
05:04:00,600 --> 05:04:02,960
there have been five
pharmaceutical trials

6041
05:04:02,960 --> 05:04:05,760
complete at
the different phases,

6042
05:04:05,760 --> 05:04:08,360
phase one, two and three,
and there are actually

6043
05:04:08,360 --> 05:04:11,680
quite a number
of currently active trials,

6044
05:04:11,680 --> 05:04:15,560
both pharma-based,
NIA-funded-based

6045
05:04:15,560 --> 05:04:21,000
and some nonpharmaceutical
interventions, as well.

6046
05:04:21,000 --> 05:04:22,600
Next slide.

6047
05:04:25,000 --> 05:04:29,560
Really a wide range
of mechanisms of action, again,

6048
05:04:29,560 --> 05:04:32,280
with the idea
of treating either symptoms

6049
05:04:32,280 --> 05:04:36,760
or actually addressing
disease modification.

6050
05:04:36,760 --> 05:04:39,440
I'm not going to go through
each one on this list here.

6051
05:04:39,440 --> 05:04:42,000
But again, many of these
are still active,

6052
05:04:42,000 --> 05:04:48,880
so this has been a very active
area of research and success.

6053
05:04:48,880 --> 05:04:52,200
Next slide.

6054
05:04:52,200 --> 05:04:55,400
So one thing that
we've been looking for

6055
05:04:55,400 --> 05:05:00,360
is to develop better clinical
trials for the LBD area.

6056
05:05:00,360 --> 05:05:02,760
One is to include biomarkers.

6057
05:05:02,760 --> 05:05:04,440
We've been hearing a lot
about biomarkers today,

6058
05:05:04,440 --> 05:05:08,720
and we'll hear many more
in the subsequent session,

6059
05:05:08,720 --> 05:05:12,000
though particularly around
the idea of addressing issues

6060
05:05:12,000 --> 05:05:17,400
both of Lewy Body Dementia
accurate diagnosis

6061
05:05:17,400 --> 05:05:20,880
as well as the fact
that we do have lots of patients

6062
05:05:20,880 --> 05:05:22,320
with mixed disease,

6063
05:05:22,320 --> 05:05:25,600
particularly coexistent
Alzheimer's disease.

6064
05:05:25,600 --> 05:05:28,360
Lots of discussion,
as well, around, do we --

6065
05:05:28,360 --> 05:05:30,640
When should we be using,
for example,

6066
05:05:30,640 --> 05:05:35,840
amyloid therapies
in the LBDA arena?

6067
05:05:35,840 --> 05:05:37,440
Also, progress in the area

6068
05:05:37,440 --> 05:05:41,760
of making several working groups
with different programs

6069
05:05:41,760 --> 05:05:46,000
focused on developing better
study protocols and design

6070
05:05:46,000 --> 05:05:51,720
that are more specifically
linked to Lewy Body Dementia.

6071
05:05:51,720 --> 05:05:55,000
Next slide.

6072
05:05:55,000 --> 05:06:00,800
So recommend one still remains,
and priority number one,

6073
05:06:00,800 --> 05:06:03,600
prepare for and initiate
clinical trials

6074
05:06:03,600 --> 05:06:07,520
that aim to alleviate or slow
the course of LBD symptoms,

6075
05:06:07,520 --> 05:06:12,400
slow disease progression
or prevent onset of disease.

6076
05:06:12,400 --> 05:06:15,240
Next slide.

6077
05:06:15,240 --> 05:06:16,800
Where are the gaps?

6078
05:06:16,800 --> 05:06:18,880
Well, this is
a common theme today,

6079
05:06:18,880 --> 05:06:22,160
so clearly diversity
is a big issue here,

6080
05:06:22,160 --> 05:06:25,200
and involving more
diverse populations

6081
05:06:25,200 --> 05:06:30,400
in the clinical trial arena
is critical.

6082
05:06:30,400 --> 05:06:33,480
We also need to
integrate biomarkers

6083
05:06:33,480 --> 05:06:37,080
for optimal participant
selection both from a,

6084
05:06:37,080 --> 05:06:38,920
"Do they have
Lewy Body disease?"

6085
05:06:38,920 --> 05:06:40,080
but also,
"Do they have" --

6086
05:06:40,080 --> 05:06:41,240
what other copathologies
they have,

6087
05:06:41,240 --> 05:06:43,760
particular
Alzheimer's disease,

6088
05:06:43,760 --> 05:06:48,200
and you'll hear more about that
in the biomarkers section.

6089
05:06:48,200 --> 05:06:50,840
We do need more
Lewy-Body-Dementia-sensitive

6090
05:06:50,840 --> 05:06:52,360
outcome measures.

6091
05:06:52,360 --> 05:06:55,080
A lot of studies are based
on Alzheimer's disease

6092
05:06:55,080 --> 05:06:57,600
clinical trials.

6093
05:06:57,600 --> 05:07:01,840
We do need to promote data
sharing for larger Ns,

6094
05:07:01,840 --> 05:07:05,000
novel mechanisms
and actually a pipeline

6095
05:07:05,000 --> 05:07:07,200
as we get to recommendations
seven

6096
05:07:07,200 --> 05:07:10,720
and eight, pipeline
from discovery to intervention

6097
05:07:10,720 --> 05:07:15,240
to also address new,
novel mechanisms.

6098
05:07:15,240 --> 05:07:16,840
Next slide.

6099
05:07:19,200 --> 05:07:21,760
2019, recommendation number two

6100
05:07:21,760 --> 05:07:24,000
was to develop
longitudinal antimortem

6101
05:07:24,000 --> 05:07:27,240
Lewy Body Dementia
characterization.

6102
05:07:27,240 --> 05:07:28,840
Next slide.

6103
05:07:30,880 --> 05:07:32,240
Actually, in that context,

6104
05:07:32,240 --> 05:07:35,760
a number of studies
were funded from the NIH

6105
05:07:35,760 --> 05:07:40,400
including the NINDS Parkinson's
Disease Biomarker Program.

6106
05:07:40,400 --> 05:07:44,880
That funded a number of
Lewy Body Dementia studies.

6107
05:07:44,880 --> 05:07:48,440
There also was the REM
sleep behavior disorders cohort,

6108
05:07:48,440 --> 05:07:52,600
NAPS and now NAPS2
and actually Lewy Body Dementia

6109
05:07:52,600 --> 05:07:59,000
cohorts within the NIAP30
Alzheimer's Center program.

6110
05:07:59,000 --> 05:08:02,440
Increasingly involved
are groups like PPMI,

6111
05:08:02,440 --> 05:08:06,600
looking at de novo Parkinson's,
prodromal and genetic cohorts,

6112
05:08:06,600 --> 05:08:08,240
AMP-PD,

6113
05:08:08,240 --> 05:08:11,600
and I think there continues
to be a nice collaboration

6114
05:08:11,600 --> 05:08:15,720
and a communication
across US

6115
05:08:15,720 --> 05:08:19,000
and European cohorts
on common data elements

6116
05:08:19,000 --> 05:08:23,120
and needs usually highlighted
during international meeting.

6117
05:08:25,920 --> 05:08:29,040
Next slide.

6118
05:08:29,040 --> 05:08:32,720
So what are some of
the key developments?

6119
05:08:32,720 --> 05:08:34,240
Parkinson's Disease
Biomarker Program

6120
05:08:34,240 --> 05:08:38,800
has led to a nice, broad
Lewy Body Disease focus.

6121
05:08:38,800 --> 05:08:43,200
There is a biorepository linked,
the BioSend, Data Management

6122
05:08:43,200 --> 05:08:46,640
Resource or DMR
and some Systematic

6123
05:08:46,640 --> 05:08:48,720
Assessment of Cohorts
across the Lewy Body

6124
05:08:48,720 --> 05:08:52,920
Disease Spectrum, so we can
have comparisons across groups.

6125
05:08:52,920 --> 05:08:54,520
Slide.

6126
05:08:56,600 --> 05:09:00,600
With the PDBP NINDS UO1 program,

6127
05:09:00,600 --> 05:09:03,000
there have been
a number of funded studies,

6128
05:09:03,000 --> 05:09:05,800
the Dementia with Lewy
Bodies Consortium

6129
05:09:05,800 --> 05:09:08,480
across nine sites, GBA

6130
05:09:08,480 --> 05:09:11,920
Pathway from Scherzer,
Lewy Body

6131
05:09:11,920 --> 05:09:15,760
Dementia Biomarker program
at Michigan, Longitudinal

6132
05:09:15,760 --> 05:09:21,560
Imaging Biomarker program
led or coled by my cochair here,

6133
05:09:23,640 --> 05:09:25,600
and the Lewy-Body-Specific
Pathology

6134
05:09:25,600 --> 05:09:29,200
Using Biomarkers
at Columbia University.

6135
05:09:29,200 --> 05:09:30,800
Next slide.

6136
05:09:33,000 --> 05:09:37,360
Just some of the progress
to date,

6137
05:09:37,360 --> 05:09:40,400
there are approximately
359 individuals

6138
05:09:40,400 --> 05:09:42,400
who participated
across the NINDS

6139
05:09:42,400 --> 05:09:47,920
U01 program that are in the DMR,
average age around 70,

6140
05:09:47,920 --> 05:09:51,400
a low percentage of women,

6141
05:09:51,400 --> 05:09:53,680
which may be partly
the biology of Lewy Body

6142
05:09:53,680 --> 05:09:59,400
Disease, a modest amount
of motor Parkinsonism

6143
05:09:59,400 --> 05:10:03,160
and, again, a common theme where
we're seeing predominantly

6144
05:10:03,160 --> 05:10:06,720
a Caucasian, European,
white population

6145
05:10:06,720 --> 05:10:09,960
within this cohort
or these cohorts.

6146
05:10:09,960 --> 05:10:13,200
Next slide.

6147
05:10:13,200 --> 05:10:17,400
An, again, great resource
from an imaging point of view

6148
05:10:17,400 --> 05:10:22,080
combining the Mayo
Imaging-Focused Project

6149
05:10:22,080 --> 05:10:23,600
and, again,
I mentioned, Lewy Body

6150
05:10:23,600 --> 05:10:29,200
Consortium, we have close to 200
MRIs, 192 CAT scans.

6151
05:10:29,200 --> 05:10:31,680
You see amyloid PET and tau PET

6152
05:10:31,680 --> 05:10:36,040
to really look at how we discern
these copathologies.

6153
05:10:36,040 --> 05:10:37,680
Probably the one weakness so far

6154
05:10:37,680 --> 05:10:41,120
is that these programs
are still looking to increase

6155
05:10:41,120 --> 05:10:45,000
the longitudinal follow-up
in terms of imaging.

6156
05:10:45,000 --> 05:10:46,320
Next slide.

6157
05:10:46,320 --> 05:10:49,520
And this also links
into the biofluid,

6158
05:10:49,520 --> 05:10:53,560
so really strong
blood-based biofluids

6159
05:10:53,560 --> 05:10:57,160
that are available
as well as spinal fluid

6160
05:10:57,160 --> 05:10:59,400
and link to the blood,

6161
05:10:59,400 --> 05:11:04,240
but we see this diminishing
longitudinal data.

6162
05:11:04,240 --> 05:11:07,400
Next slide.

6163
05:11:07,400 --> 05:11:09,800
We do have quite a lot
of aliquots

6164
05:11:09,800 --> 05:11:13,520
that have been sent
to the program

6165
05:11:13,520 --> 05:11:17,800
and I think now at 117,000

6166
05:11:17,800 --> 05:11:21,960
including a link to CSF
and blood aliquots,

6167
05:11:21,960 --> 05:11:24,000
so this is something
that investigators

6168
05:11:24,000 --> 05:11:26,200
will want
to take advantage of.

6169
05:11:26,200 --> 05:11:29,160
Next slide.

6170
05:11:29,160 --> 05:11:32,600
And finally, there have been
some limited efforts

6171
05:11:32,600 --> 05:11:34,840
for autopsies so far,

6172
05:11:34,840 --> 05:11:37,880
and that's going to be,
again, a common theme today

6173
05:11:37,880 --> 05:11:43,800
to really link this back to the
clinical biomarker development.

6174
05:11:43,800 --> 05:11:45,400
Next slide.

6175
05:11:47,600 --> 05:11:49,920
All right.
So where are our issues?

6176
05:11:49,920 --> 05:11:52,920
Again, coming back to diversity

6177
05:11:52,920 --> 05:11:55,840
and particularly
in the African-American

6178
05:11:55,840 --> 05:11:58,760
and more other
diverse populations,

6179
05:11:58,760 --> 05:12:02,600
the sex difference, we can do,
perhaps, some selection

6180
05:12:02,600 --> 05:12:06,480
for more women to participate,
although again,

6181
05:12:06,480 --> 05:12:10,160
particularly within the pure
dementia Lewy Bodies

6182
05:12:10,160 --> 05:12:12,800
without, actually, coexistent
Alzheimer's, we don't see --

6183
05:12:12,800 --> 05:12:16,080
We see a tendency for
a strong male predominance,

6184
05:12:16,080 --> 05:12:18,600
which is telling us
something.

6185
05:12:18,600 --> 05:12:21,160
We are looking for preclinical
and prodromal cohorts

6186
05:12:21,160 --> 05:12:23,200
and, of course, we have
the NAPS program in part

6187
05:12:23,200 --> 05:12:25,800
to deal
with this prodromal cohort.

6188
05:12:25,800 --> 05:12:28,600
I'd like to see expanded
and optimized

6189
05:12:28,600 --> 05:12:30,120
longitudinal characterization

6190
05:12:30,120 --> 05:12:32,360
with continued linkage
of biofluid collection

6191
05:12:32,360 --> 05:12:34,720
imaging in autopsy.

6192
05:12:34,720 --> 05:12:37,040
There are a number of,
I think, exciting new areas,

6193
05:12:37,040 --> 05:12:39,840
particularly around
the RT-QuIC/PMCA

6194
05:12:39,840 --> 05:12:42,440
and biofluids and tissues.

6195
05:12:42,440 --> 05:12:45,360
This is something that really
can solidify the diagnosis

6196
05:12:45,360 --> 05:12:50,360
of Lewy Body Disease,
linking that to imaging, digital

6197
05:12:50,360 --> 05:12:53,320
and electrophysiologic
techniques.

6198
05:12:53,320 --> 05:12:58,200
And again, we'd like to promote
harmonization across cohorts

6199
05:12:58,200 --> 05:13:01,120
both in terms of programs
that are already funded

6200
05:13:01,120 --> 05:13:03,760
but non-US sites, PPMI,

6201
05:13:03,760 --> 05:13:05,880
to allow us
for larger [Indistinct]

6202
05:13:05,880 --> 05:13:09,240
studies that we
would like to do.

6203
05:13:09,240 --> 05:13:12,400
Next slide.

6204
05:13:12,400 --> 05:13:17,680
So we have made and continue
to make clinical trials,

6205
05:13:17,680 --> 05:13:22,640
and LBD recommendation number
one and priority number one,

6206
05:13:22,640 --> 05:13:25,040
in terms of
the longitudinal follow-up,

6207
05:13:25,040 --> 05:13:27,640
we've moved that down
to priority four.

6208
05:13:27,640 --> 05:13:29,320
This is an ongoing program,
again.

6209
05:13:29,320 --> 05:13:32,200
We want to support
the longitudinal

6210
05:13:32,200 --> 05:13:33,720
expansion of these studies,

6211
05:13:33,720 --> 05:13:39,960
but this is already
well-developed.

6212
05:13:39,960 --> 05:13:43,120
Next slide.

6213
05:13:43,120 --> 05:13:46,400
So I'm going to move on
to Dr. Kantarci,

6214
05:13:46,400 --> 05:13:47,880
who's going to
discuss biomarkers

6215
05:13:47,880 --> 05:13:50,000
in terms of imaging
and biofluids.

6216
05:13:50,000 --> 05:13:52,320
Kejal, all yours.

6217
05:13:52,320 --> 05:13:55,200
-Thank you, Jim,
for the great introduction.

6218
05:13:55,200 --> 05:13:57,800
So I will be talking
about biomarkers,

6219
05:13:57,800 --> 05:14:01,200
which will include imaging
biomarkers and biomarkers

6220
05:14:01,200 --> 05:14:02,840
utilizing biofluids,

6221
05:14:02,840 --> 05:14:06,800
tissues, digital
and electrophysiologic methods.

6222
05:14:06,800 --> 05:14:09,240
And I would like to acknowledge
my colleagues,

6223
05:14:09,240 --> 05:14:13,200
who have contributed to the
recommendations on biomarkers,

6224
05:14:13,200 --> 05:14:16,600
Drs. Vallencourt,
Marder and Galasko.

6225
05:14:16,600 --> 05:14:23,080
And if you go to the next slide,
disclosure is listed here.

6226
05:14:23,080 --> 05:14:25,960
Next slide.

6227
05:14:25,960 --> 05:14:29,000
Biomarker
validation is a stepwise process

6228
05:14:29,000 --> 05:14:31,920
that start with the discovery
of the biomarker

6229
05:14:31,920 --> 05:14:34,920
with cross-sectional studies
looking into sensitivity,

6230
05:14:34,920 --> 05:14:38,200
specificity and accuracy
of the biomarker.

6231
05:14:38,200 --> 05:14:39,960
And then in the next step,

6232
05:14:39,960 --> 05:14:42,720
it can involve
longitudinal studies

6233
05:14:42,720 --> 05:14:45,080
looking at
reliability, repeatability

6234
05:14:45,080 --> 05:14:47,040
and reproducibility.

6235
05:14:47,040 --> 05:14:49,600
And now that we have
tested the biomarker

6236
05:14:49,600 --> 05:14:51,400
in clinically
diagnosed cohorts,

6237
05:14:51,400 --> 05:14:54,000
a critical next step
is the validation

6238
05:14:54,000 --> 05:14:56,800
in pathologically
diagnosed cohorts.

6239
05:14:56,800 --> 05:15:00,400
And finally, the biomarkers
tested in cohorts

6240
05:15:00,400 --> 05:15:04,400
enrolled in clinical trials
for patient selection,

6241
05:15:04,400 --> 05:15:08,800
target engagement and assessment
of disease modification.

6242
05:15:08,800 --> 05:15:11,600
So one of the biomarkers
that have passed

6243
05:15:11,600 --> 05:15:16,200
these validation steps
is analog imaging with PET.

6244
05:15:16,200 --> 05:15:20,200
And if we go to the next slide.

6245
05:15:20,200 --> 05:15:23,320
And it's important to note
that not all biomarkers

6246
05:15:23,320 --> 05:15:27,200
may demonstrate excellence
in all of these steps.

6247
05:15:27,200 --> 05:15:31,800
And FDA has this comprehensive
classification of biomarkers

6248
05:15:31,800 --> 05:15:34,640
based on their performance
for different goals,

6249
05:15:34,640 --> 05:15:36,880
as you can see here.

6250
05:15:36,880 --> 05:15:40,000
We go to the next slide.

6251
05:15:40,000 --> 05:15:44,480
So in 2019, when the
recommendations were written

6252
05:15:44,480 --> 05:15:46,640
for Lewy Body Dementia,

6253
05:15:46,640 --> 05:15:48,880
the neuroimaging biomarkers
were considered

6254
05:15:48,880 --> 05:15:53,720
as the third priority in
the clinical science focus area,

6255
05:15:53,720 --> 05:15:57,200
and biomarkers for biofluids,
tissues, digital

6256
05:15:57,200 --> 05:16:00,120
and electrophysiologic methods
were considered

6257
05:16:00,120 --> 05:16:03,120
as the first priority
in the basic science focus

6258
05:16:03,120 --> 05:16:05,920
are because there was
a lot of interest

6259
05:16:05,920 --> 05:16:10,320
in development of these
biomarkers as a top priority.

6260
05:16:10,320 --> 05:16:12,040
So if we go to the next slide,

6261
05:16:12,040 --> 05:16:16,840
in the current draft
recommendations we have,

6262
05:16:16,840 --> 05:16:20,560
Lewy Body work group
placed biomarker recommendations

6263
05:16:20,560 --> 05:16:22,920
to priority number two
for neuroimaging

6264
05:16:22,920 --> 05:16:25,280
and priority number
three for biomarkers

6265
05:16:25,280 --> 05:16:32,400
utilizing other tissues,
biofluids and digital methods.

6266
05:16:32,400 --> 05:16:38,160
And they were listed under
the clinical characterization

6267
05:16:38,160 --> 05:16:40,120
and intervention focus area

6268
05:16:40,120 --> 05:16:43,800
because these recommendations
emphasize

6269
05:16:43,800 --> 05:16:47,800
applications of biomarkers
that were developed,

6270
05:16:47,800 --> 05:16:52,320
so applications
in the clinical research

6271
05:16:52,320 --> 05:16:54,760
as the top priority.

6272
05:16:54,760 --> 05:16:58,360
Now, if we go the next one,

6273
05:16:58,360 --> 05:17:01,440
so the pathogenesis
and disease mechanisms

6274
05:17:01,440 --> 05:17:03,760
in Lewy Body Dementia
is complex.

6275
05:17:03,760 --> 05:17:06,000
That involves not
only alpha-synuclein

6276
05:17:06,000 --> 05:17:09,920
but frequently accompanied
by other proteinopathies

6277
05:17:09,920 --> 05:17:16,720
including a beta, tau and TDP-43
as well as vascular disease.

6278
05:17:16,720 --> 05:17:20,840
On the right-hand side,
in a study of a large European

6279
05:17:20,840 --> 05:17:23,240
and North American
cohort of dementia

6280
05:17:23,240 --> 05:17:25,480
with Lewy Bodies cases,

6281
05:17:25,480 --> 05:17:29,000
it was demonstrated that
a majority of the cohort

6282
05:17:29,000 --> 05:17:33,720
fulfilled
the diagnostic criteria

6283
05:17:33,720 --> 05:17:35,440
for dementia
with Lewy Bodies,

6284
05:17:35,440 --> 05:17:39,080
had high levels
of amyloid or tau

6285
05:17:39,080 --> 05:17:43,160
or had both protein deposits,

6286
05:17:43,160 --> 05:17:47,600
and a smaller proportion
did not have high levels.

6287
05:17:47,600 --> 05:17:51,040
Therefore, we recommended
utilizing established

6288
05:17:51,040 --> 05:17:54,680
and new imaging tools
to determine the evolution

6289
05:17:54,680 --> 05:18:00,560
of this multiproteinopathy
in Lewy Body Dementia

6290
05:18:00,560 --> 05:18:05,040
including synergistic
interactions of proteins

6291
05:18:05,040 --> 05:18:08,680
across brain regions
and across time

6292
05:18:08,680 --> 05:18:11,080
in Lewy Body Dementia.

6293
05:18:11,080 --> 05:18:14,280
We go to the next slide.

6294
05:18:14,280 --> 05:18:18,160
Biomarkers can inform
the temporal progression

6295
05:18:18,160 --> 05:18:20,880
and evolution of different
clinical phenotypes

6296
05:18:20,880 --> 05:18:22,320
of cognition,

6297
05:18:22,320 --> 05:18:26,600
motor, sleep and behavior
in Lewy Body Dementia,

6298
05:18:26,600 --> 05:18:28,560
and they can also
inform the clinical

6299
05:18:28,560 --> 05:18:30,920
and genetic subgroups
of patients

6300
05:18:30,920 --> 05:18:35,320
with rapid versus
slow progression of Parkinson's

6301
05:18:35,320 --> 05:18:38,600
Disease dementia versus dementia
with Lewy Bodies,

6302
05:18:38,600 --> 05:18:42,520
GBA or alpha-synuclein
mutation carriers

6303
05:18:42,520 --> 05:18:47,520
and also inform relative
contribution of alpha-synuclein

6304
05:18:47,520 --> 05:18:49,400
and Alzheimer's Disease pathways

6305
05:18:49,400 --> 05:18:52,880
and burden
to the clinical phenotype.

6306
05:18:52,880 --> 05:18:56,320
Finally, biomarkers are critical
in clinical trials

6307
05:18:56,320 --> 05:19:00,800
and can be used for target
engagement and efficacy

6308
05:19:00,800 --> 05:19:02,960
and clinical outcomes.

6309
05:19:02,960 --> 05:19:05,120
And to answer all of
these questions,

6310
05:19:05,120 --> 05:19:08,000
we feel that we need
big data approaches,

6311
05:19:08,000 --> 05:19:11,400
and data sharing will be
necessary to integrate

6312
05:19:11,400 --> 05:19:14,280
biomarkers and clinical data.

6313
05:19:14,280 --> 05:19:17,600
And if we go to the next slide,

6314
05:19:17,600 --> 05:19:21,640
there have been several requests
for applications

6315
05:19:21,640 --> 05:19:24,560
by the NIH
within the last several years

6316
05:19:24,560 --> 05:19:28,720
focused on biomarkers
including the center data,

6317
05:19:28,720 --> 05:19:33,840
Centers without Walls for PET
Ligand Development for ADRD,

6318
05:19:33,840 --> 05:19:37,400
in particular
for alpha-synuclein,

6319
05:19:37,400 --> 05:19:39,400
looking at
the peripheral pathology

6320
05:19:39,400 --> 05:19:42,000
in Lewy Body Dementias,

6321
05:19:42,000 --> 05:19:46,320
the UO1 biomarkers
for Lewy Body Dementias program

6322
05:19:46,320 --> 05:19:50,360
that Jim Leverenz
has mentioned

6323
05:19:50,360 --> 05:19:55,160
and also progression markers
of cognitive impairment

6324
05:19:55,160 --> 05:19:58,120
in Parkinson's
Disease dementia.

6325
05:19:58,120 --> 05:20:00,840
And there are others
that are not specific

6326
05:20:00,840 --> 05:20:02,280
to Lewy Body Dementia

6327
05:20:02,280 --> 05:20:06,120
but were funded by
several biomarker projects

6328
05:20:06,120 --> 05:20:09,720
in Lewy Body Dementia.

6329
05:20:09,720 --> 05:20:11,960
So if we go to the next slide.

6330
05:20:14,280 --> 05:20:17,760
And currently there are ongoing
and new cohorts

6331
05:20:17,760 --> 05:20:21,800
that have contributed
to biomarker programs,

6332
05:20:21,800 --> 05:20:26,520
and this was mentioned
also in the cohorts talk,

6333
05:20:26,520 --> 05:20:30,600
but these are specifically
focusing on biomarkers,

6334
05:20:30,600 --> 05:20:33,680
the Parkinson's Disease
Biomarkers Program

6335
05:20:33,680 --> 05:20:35,760
that includes dementia
with Lewy Bodies

6336
05:20:35,760 --> 05:20:37,720
and Parkinson's
disease patients.

6337
05:20:37,720 --> 05:20:41,920
The North American Prodromal
Synucleinopathy Consortium,

6338
05:20:41,920 --> 05:20:46,600
that has a large
biomarker-characterized cohort

6339
05:20:46,600 --> 05:20:49,920
and ADRC cohorts
with the SCAN

6340
05:20:49,920 --> 05:20:53,600
initiative to standardize
imaging across the ADRCs,

6341
05:20:53,600 --> 05:20:59,520
which will likely include
a lot of dementia-with-Lewy-

6342
05:20:59,520 --> 05:21:02,240
Bodies cases.

6343
05:21:02,240 --> 05:21:04,400
The Parkinson's Progression
Markers

6344
05:21:04,400 --> 05:21:09,520
initiative of PD, prodromal PD
and genetic cohorts

6345
05:21:09,520 --> 05:21:15,360
and also the AMP-PD is
collecting data on biomarkers,

6346
05:21:15,360 --> 05:21:17,600
and then as was mentioned,

6347
05:21:17,600 --> 05:21:21,800
there is a lot of efforts for
harmonization of biomarker data

6348
05:21:21,800 --> 05:21:26,760
across European and Canadian
cohorts with the US cohorts

6349
05:21:26,760 --> 05:21:30,600
to establish common
data elements.

6350
05:21:30,600 --> 05:21:35,320
So the goals are
for these efforts

6351
05:21:35,320 --> 05:21:37,840
to standardize
biomarker collection

6352
05:21:37,840 --> 05:21:42,760
including imaging, DNA, plasma,
whole blood and CSF.

6353
05:21:42,760 --> 05:21:45,680
And longitudinal biomarker
collection

6354
05:21:45,680 --> 05:21:47,560
and clinical follow-up,

6355
05:21:47,560 --> 05:21:51,600
harmonization
for clinical phenotyping

6356
05:21:51,600 --> 05:21:54,600
and also encourage
brain donation,

6357
05:21:54,600 --> 05:21:59,600
that is critical for validation
of imaging biomarkers.

6358
05:21:59,600 --> 05:22:02,160
We go to the next slide.

6359
05:22:02,160 --> 05:22:06,800
Since 2019 with
accumulating data

6360
05:22:06,800 --> 05:22:10,200
from these funded research
and ongoing cohorts,

6361
05:22:10,200 --> 05:22:13,400
we have seen several
important developments.

6362
05:22:13,400 --> 05:22:18,040
We certainly do not have an
alpha-synuclein radioligand yet,

6363
05:22:18,040 --> 05:22:19,680
but we are getting closer,

6364
05:22:19,680 --> 05:22:23,680
so there has been a lot
of developments in this area,

6365
05:22:23,680 --> 05:22:27,600
and we hope that
this will become a reality

6366
05:22:27,600 --> 05:22:30,000
in the near future.

6367
05:22:30,000 --> 05:22:34,520
Now, we continue to establish
biomarkers for earlier stages

6368
05:22:34,520 --> 05:22:39,160
such as the prodromal
Lewy Body Dementia stages,

6369
05:22:39,160 --> 05:22:41,640
and we now understand
the contribution

6370
05:22:41,640 --> 05:22:43,320
of Alzheimer's pathology

6371
05:22:43,320 --> 05:22:47,640
to the clinical syndrome
better in Lewy Body Dementia,

6372
05:22:47,640 --> 05:22:54,720
which may inform us on treating
this pathology down the road.

6373
05:22:54,720 --> 05:22:58,400
And alpha-synuclein biomarkers
such as seeding assays

6374
05:22:58,400 --> 05:23:02,120
with RT-QuIC and PMCA in CSF

6375
05:23:02,120 --> 05:23:08,400
and skin have also seen
major diagnostic advances.

6376
05:23:08,400 --> 05:23:11,600
And, furthermore,
there have been developments

6377
05:23:11,600 --> 05:23:12,920
in digital biomarkers,

6378
05:23:12,920 --> 05:23:15,760
and these require
new analytic approaches

6379
05:23:15,760 --> 05:23:19,640
in Lewy Body Dementia.

6380
05:23:19,640 --> 05:23:27,000
Now, next slide, so biomarkers
were already integrated

6381
05:23:27,000 --> 05:23:31,960
in the dementia-with-Lewy-Bodies
criteria back in 2017,

6382
05:23:31,960 --> 05:23:35,520
and they are now also included
in the research criteria

6383
05:23:35,520 --> 05:23:39,160
for prodromal stage of dementia
with Lewy Bodies.

6384
05:23:39,160 --> 05:23:42,480
And this framework not
only includes biomarkers

6385
05:23:42,480 --> 05:23:47,000
of Lewy-Body-related pathology
but also Alzheimer's pathology,

6386
05:23:47,000 --> 05:23:50,960
emphasizing that the clinical
phenotype may be determined

6387
05:23:50,960 --> 05:23:54,200
by the contribution
from multiple proteinopathies

6388
05:23:54,200 --> 05:23:58,720
and not just
alpha-synuclein pathology.

6389
05:23:58,720 --> 05:24:01,440
Next slide.

6390
05:24:01,440 --> 05:24:06,960
Biomarkers from biofluids
and tissues can inform us

6391
05:24:06,960 --> 05:24:11,760
about various aspects of Lewy
Body Dementia pathophysiology,

6392
05:24:11,760 --> 05:24:16,760
and different pathological
processes may require sampling

6393
05:24:16,760 --> 05:24:21,080
from a variety
of biofluids and tissues.

6394
05:24:21,080 --> 05:24:23,320
So we recommend that,
where appropriate,

6395
05:24:23,320 --> 05:24:26,400
biomarker discovery
and evaluation

6396
05:24:26,400 --> 05:24:29,320
should be carried out
in multiple tissues

6397
05:24:29,320 --> 05:24:34,120
such as skin, colon,
salivary gland and others,

6398
05:24:34,120 --> 05:24:37,720
also biofluids such
as whole blood, plasma,

6399
05:24:37,720 --> 05:24:46,480
CSF, urine, saliva, tears, even,
and microbial samples.

6400
05:24:46,480 --> 05:24:48,080
Next slide.

6401
05:24:50,320 --> 05:24:53,880
There are digital and
electrophysiological biomarkers

6402
05:24:53,880 --> 05:24:56,040
that are being developed
in the field,

6403
05:24:56,040 --> 05:24:59,000
and we need to try
and validate these biomarkers

6404
05:24:59,000 --> 05:25:01,360
in Lewy Body Dementia
cohorts.

6405
05:25:01,360 --> 05:25:05,560
So we recommend workshops
to define modalities

6406
05:25:05,560 --> 05:25:08,880
and best practices
with data sharing

6407
05:25:08,880 --> 05:25:12,000
and paying attention
to privacy

6408
05:25:12,000 --> 05:25:15,000
that would help bring
these promising technologies

6409
05:25:15,000 --> 05:25:20,760
into Lewy Body Dementia
biomarker field.

6410
05:25:20,760 --> 05:25:22,760
Next slide.

6411
05:25:22,760 --> 05:25:25,280
And coming to the gaps
that we still need

6412
05:25:25,280 --> 05:25:30,160
to fill regarding biomarkers
in Lewy Body Dementia,

6413
05:25:30,160 --> 05:25:31,600
first we need to develop,

6414
05:25:31,600 --> 05:25:35,080
refine and validate biomarkers
for prodromal

6415
05:25:35,080 --> 05:25:36,840
and, perhaps, eventually,

6416
05:25:36,840 --> 05:25:41,720
the preclinical stages
of the disease processes.

6417
05:25:41,720 --> 05:25:45,360
Now, development of the
alpha-synuclein tracers

6418
05:25:45,360 --> 05:25:47,080
will be highly impactful

6419
05:25:47,080 --> 05:25:50,760
for alpha-synuclein-modifying
treatments,

6420
05:25:50,760 --> 05:25:53,280
potentially for
patient selection,

6421
05:25:53,280 --> 05:25:56,880
treatment engagement
and efficacy.

6422
05:25:56,880 --> 05:26:01,400
Now, cohorts with
biomarker collection

6423
05:26:01,400 --> 05:26:05,800
should be harmonized
across NINDS

6424
05:26:05,800 --> 05:26:11,200
and NIA ADRC programs,
foundation-supported programs,

6425
05:26:11,200 --> 05:26:14,280
and should be diverse
and representative,

6426
05:26:14,280 --> 05:26:17,200
as we have discussed
this morning.

6427
05:26:17,200 --> 05:26:22,040
And the targeted as well
as Omics-type

6428
05:26:22,040 --> 05:26:25,640
approaches to biomarker
discovery and development

6429
05:26:25,640 --> 05:26:31,320
should also be pursued and more
integration of biofluid markers

6430
05:26:31,320 --> 05:26:36,000
across existing cohorts
that include imaging, genetic,

6431
05:26:36,000 --> 05:26:39,520
clinical and autopsy data,
is needed.

6432
05:26:39,520 --> 05:26:41,560
And a good example of this

6433
05:26:41,560 --> 05:26:45,800
is the Parkinson's Disease
Biomarkers Program.

6434
05:26:45,800 --> 05:26:49,960
We certainly have more work
to do on the applications

6435
05:26:49,960 --> 05:26:53,720
of digital and
electrophysiological biomarkers

6436
05:26:53,720 --> 05:27:00,400
that are being developed
in Lewy Body Disease Dementia.

6437
05:27:00,400 --> 05:27:04,760
So if we go to the next slide.

6438
05:27:04,760 --> 05:27:07,360
So these are the recommendations

6439
05:27:07,360 --> 05:27:11,640
for neuroimaging biomarkers
to develop, refine

6440
05:27:11,640 --> 05:27:13,600
and refine
neuroimaging biomarkers

6441
05:27:13,600 --> 05:27:15,320
that track disease
progression,

6442
05:27:15,320 --> 05:27:17,600
assist in differential
diagnosis,

6443
05:27:17,600 --> 05:27:20,400
provide therapeutic
target engagement

6444
05:27:20,400 --> 05:27:22,960
and relate to pathology.

6445
05:27:22,960 --> 05:27:25,920
To do that, we recommend
developing

6446
05:27:25,920 --> 05:27:31,000
and refining biomarkers
for Lewy Body Dementia

6447
05:27:31,000 --> 05:27:35,800
as well as the preclinical and
prodromal stages of the disease

6448
05:27:35,800 --> 05:27:39,600
and also supporting alpha-
synuclein tracer development.

6449
05:27:39,600 --> 05:27:41,640
There is potential
to repurpose

6450
05:27:41,640 --> 05:27:45,440
currently available
cost-effective imaging tools

6451
05:27:45,440 --> 05:27:48,520
that can be accessible
and applicable

6452
05:27:48,520 --> 05:27:52,200
in diverse settings
and diverse cohorts

6453
05:27:52,200 --> 05:27:57,200
and including sex differences,
as Dr. Leverenz has pointed out.

6454
05:27:57,200 --> 05:28:01,760
There is a really important
sex difference with women

6455
05:28:01,760 --> 05:28:06,040
being underrepresented
for a biological reason,

6456
05:28:06,040 --> 05:28:08,560
potentially, in these cohorts,

6457
05:28:08,560 --> 05:28:12,360
so that's an important
area of study, as well,

6458
05:28:12,360 --> 05:28:15,800
and also utilizing
a multisensor approach

6459
05:28:15,800 --> 05:28:19,840
to determine the scalability
of these techniques

6460
05:28:19,840 --> 05:28:24,040
and prepare for phase-three
multisensor trials

6461
05:28:24,040 --> 05:28:29,000
with harmonization and data
sharing in large cohorts.

6462
05:28:29,000 --> 05:28:30,600
Next slide.

6463
05:28:30,600 --> 05:28:32,200
-Two minutes remaining.

6464
05:28:34,960 --> 05:28:39,000
-Okay, so this is
recommendation number three

6465
05:28:39,000 --> 05:28:44,200
for the development
and refinement of biomarkers

6466
05:28:44,200 --> 05:28:47,320
for diagnosis, prediction
and prognosis

6467
05:28:47,320 --> 05:28:49,840
using the biofluids,

6468
05:28:49,840 --> 05:28:56,160
tissues and the digital
and electrophysiologic methods.

6469
05:28:56,160 --> 05:29:00,960
These biomarkers need to reflect
pathophysiological changes

6470
05:29:00,960 --> 05:29:02,880
related to Lewy Body Dementia

6471
05:29:02,880 --> 05:29:07,560
including multiple proteins
and vascular changes.

6472
05:29:07,560 --> 05:29:12,080
Also, biomarker measurements
need to have a defined context

6473
05:29:12,080 --> 05:29:15,400
in different biofluids
and tissue specimens.

6474
05:29:18,120 --> 05:29:22,080
We need to address study
disclosure of results

6475
05:29:22,080 --> 05:29:25,720
in asymptomatic
and mildly affected individuals,

6476
05:29:25,720 --> 05:29:28,600
and we need to develop
comparable biomarkers

6477
05:29:28,600 --> 05:29:33,800
in model systems including
animals and cell lines.

6478
05:29:33,800 --> 05:29:36,800
The digital and
electrophysiologic biomarkers

6479
05:29:36,800 --> 05:29:40,320
need to be applied
to Lewy Body Dementia,

6480
05:29:40,320 --> 05:29:48,280
and these may include wearables,
EEG and polysomnography,

6481
05:29:48,280 --> 05:29:52,680
computerized testing
and home-based monitoring.

6482
05:29:52,680 --> 05:29:55,000
That can include lifestyle,
behavior,

6483
05:29:55,000 --> 05:29:58,520
cognition
and neuropsychiatric symptoms

6484
05:29:58,520 --> 05:30:04,480
as well as autonomic function,
activity and sleep.

6485
05:30:04,480 --> 05:30:07,880
And finally, we need
to harmonize protocols

6486
05:30:07,880 --> 05:30:12,000
and common data elements
to allow integrated research.

6487
05:30:14,080 --> 05:30:18,360
And finally I would like
to get to the next slide.

6488
05:30:21,520 --> 05:30:24,400
I would like to thank you
for your attention

6489
05:30:24,400 --> 05:30:26,600
on the biomarkers topic.

6490
05:30:26,600 --> 05:30:28,480
Now it's my pleasure
to introduce

6491
05:30:28,480 --> 05:30:33,800
Dr. Sonja Scholz
from NINDs and NIH.

6492
05:30:33,800 --> 05:30:36,880
Dr. Scholz will be presenting
the recommendations

6493
05:30:36,880 --> 05:30:40,560
on neuropathology and genetics.
-Right.

6494
05:30:40,560 --> 05:30:42,120
Thank you for your introduction,

6495
05:30:42,120 --> 05:30:43,560
and thank you
for the opportunity

6496
05:30:43,560 --> 05:30:45,800
to talk to you today.

6497
05:30:45,800 --> 05:30:49,200
So we are now going to pivot
from the clinical focus area

6498
05:30:49,200 --> 05:30:51,960
to the more basic science side,

6499
05:30:51,960 --> 05:30:55,600
and so I will specifically talk
about the neuropathology

6500
05:30:55,600 --> 05:30:57,600
and genetic recommendations,

6501
05:30:57,600 --> 05:31:00,600
and then I have my colleague,
Dr. David Irwin,

6502
05:31:00,600 --> 05:31:05,120
following up on the disease
mechanisms recommendations.

6503
05:31:05,120 --> 05:31:08,480
I would like to recognize
my team members,

6504
05:31:08,480 --> 05:31:11,280
Dr. Clemens Scherzer,
Dr. Brittany Dugger,

6505
05:31:11,280 --> 05:31:12,680
Dr. David Irwin

6506
05:31:12,680 --> 05:31:16,920
and Dr. Dennis Dickson
for their contributions.

6507
05:31:16,920 --> 05:31:19,160
So next slide, please.

6508
05:31:19,160 --> 05:31:21,480
These are my disclosures.

6509
05:31:21,480 --> 05:31:23,080
Next one, please.

6510
05:31:25,120 --> 05:31:26,840
All right.

6511
05:31:26,840 --> 05:31:29,480
So these are specifically the
recommendations number five

6512
05:31:29,480 --> 05:31:31,440
and six in the handout.

6513
05:31:31,440 --> 05:31:37,200
If we go to the next one,
next one.

6514
05:31:37,200 --> 05:31:38,760
All right.

6515
05:31:38,760 --> 05:31:40,560
So it's exciting to see
that there has been really

6516
05:31:40,560 --> 05:31:45,320
a lot of progress happening
on the basic science side,

6517
05:31:45,320 --> 05:31:46,440
and I think it is --

6518
05:31:46,440 --> 05:31:49,280
We all recognized
and understanding

6519
05:31:49,280 --> 05:31:51,560
the very basic genetic,

6520
05:31:51,560 --> 05:31:54,400
epigenetic lifestyle
environmental factors

6521
05:31:54,400 --> 05:31:56,720
that are playing a role
in Lewy body dementias

6522
05:31:56,720 --> 05:31:59,280
is fundamental
for disease modeling

6523
05:31:59,280 --> 05:32:02,400
but also ultimately
for paving the way

6524
05:32:02,400 --> 05:32:05,400
for disease modification.

6525
05:32:05,400 --> 05:32:07,800
So specifically
on the genetic side,

6526
05:32:07,800 --> 05:32:10,240
there has been
a lot of progress,

6527
05:32:10,240 --> 05:32:13,200
and a lot of this progress
is really based on,

6528
05:32:13,200 --> 05:32:15,200
you know,
implementing recommendations

6529
05:32:15,200 --> 05:32:18,160
from previous ADRD summits.

6530
05:32:18,160 --> 05:32:20,400
We go to the next slide.

6531
05:32:20,400 --> 05:32:23,400
So, you know, really
making good use

6532
05:32:23,400 --> 05:32:25,760
of the various brain
donation programs

6533
05:32:25,760 --> 05:32:27,080
that have been established

6534
05:32:27,080 --> 05:32:30,520
but also, you know,
biorepositories.

6535
05:32:30,520 --> 05:32:34,040
We've been able to already
gain a lot of valuable insights

6536
05:32:34,040 --> 05:32:38,280
into the genetic architecture
of Lewy body dementia,

6537
05:32:38,280 --> 05:32:40,840
and so showing here,
for example,

6538
05:32:40,840 --> 05:32:43,320
is the LBD genome
sequencing initiative

6539
05:32:43,320 --> 05:32:45,600
which was really a team
science effort,

6540
05:32:45,600 --> 05:32:50,160
intramural, extramural effort
trying to combine whole genome

6541
05:32:50,160 --> 05:32:52,880
sequence data
from multiple sources

6542
05:32:52,880 --> 05:32:54,680
and perform state
of the art genome

6543
05:32:54,680 --> 05:32:58,160
sequencing for various
genomic analysis,

6544
05:32:58,160 --> 05:33:01,480
but also to generate
a foundational genomic resource

6545
05:33:01,480 --> 05:33:05,680
that can be used broadly to
accelerate the pace of discovery

6546
05:33:05,680 --> 05:33:07,360
in this understudied
disease field

6547
05:33:07,360 --> 05:33:10,200
and to democratize
data access.

6548
05:33:10,200 --> 05:33:11,920
Go to the next one.

6549
05:33:11,920 --> 05:33:16,200
So we've already learned
a lot of interesting lessons

6550
05:33:16,200 --> 05:33:20,720
just based on this
publicly available data,

6551
05:33:20,720 --> 05:33:24,040
so we know that Lewy body
dementia is a complex disease.

6552
05:33:24,040 --> 05:33:27,320
There are both common disease
risk variants playing a role,

6553
05:33:27,320 --> 05:33:30,240
but also rare variants
playing a role.

6554
05:33:30,240 --> 05:33:34,520
We recognize that in reality,
most patients, it is polygenic,

6555
05:33:34,520 --> 05:33:36,800
so it's a combination
of multiple variants

6556
05:33:36,800 --> 05:33:38,520
that are playing a role,

6557
05:33:38,520 --> 05:33:41,440
and they really have an impact
on the disease heterogeneity

6558
05:33:41,440 --> 05:33:43,600
that we clearly appreciate.

6559
05:33:43,600 --> 05:33:45,880
We also recognize,
just based on the genetics,

6560
05:33:45,880 --> 05:33:50,720
it tells us that there are very
clear molecular relationships

6561
05:33:50,720 --> 05:33:52,120
between Lewy body dementia

6562
05:33:52,120 --> 05:33:54,320
and other neurodegenerative
diseases,

6563
05:33:54,320 --> 05:33:56,600
so we can see
overlapping risk closer

6564
05:33:56,600 --> 05:33:59,480
with Alzheimer's
and Parkinson's disease,

6565
05:33:59,480 --> 05:34:03,480
but we also appreciate
overlapping disease pathways,

6566
05:34:03,480 --> 05:34:05,200
and that's particularly
exciting

6567
05:34:05,200 --> 05:34:08,960
because these pathways
are particularly relevant

6568
05:34:08,960 --> 05:34:11,600
for possible disease
modification interventions

6569
05:34:11,600 --> 05:34:15,320
that could be relevant to much
broader patient population

6570
05:34:15,320 --> 05:34:18,800
than just the Lewy
body dementia cases.

6571
05:34:18,800 --> 05:34:21,040
However, most of the progress
that has been made

6572
05:34:21,040 --> 05:34:24,560
on the genetics side
is really predominantly done

6573
05:34:24,560 --> 05:34:27,280
in individuals
of European ancestry,

6574
05:34:27,280 --> 05:34:31,000
and we already appreciate,
based on Canada gene approaches,

6575
05:34:31,000 --> 05:34:34,360
that there is considerable
population heterogeneity.

6576
05:34:34,360 --> 05:34:39,320
So improving the diversity
of patients that we study

6577
05:34:39,320 --> 05:34:41,600
is an important need
for the field,

6578
05:34:41,600 --> 05:34:43,600
as we are also building up

6579
05:34:43,600 --> 05:34:48,000
and continue to improve
powerful genetic discovery.

6580
05:34:48,000 --> 05:34:49,920
Next slide, please.

6581
05:34:49,920 --> 05:34:51,600
But it's not just
a numbers game.

6582
05:34:51,600 --> 05:34:53,920
It's not just the number of
biospecimens that are available.

6583
05:34:53,920 --> 05:34:56,040
I think we also need to be smart

6584
05:34:56,040 --> 05:34:58,680
about generating
foundational datasets

6585
05:34:58,680 --> 05:35:00,760
that can accelerate
the pace of discovery

6586
05:35:00,760 --> 05:35:02,960
and kind of inform discovery,

6587
05:35:02,960 --> 05:35:05,960
and, you know,
it's been great to see

6588
05:35:05,960 --> 05:35:09,120
how a lot of the recommendations
have been put in place

6589
05:35:09,120 --> 05:35:12,360
to make these knowledge
platforms available.

6590
05:35:12,360 --> 05:35:17,160
So for example, the genome
resource that we generated

6591
05:35:17,160 --> 05:35:18,640
has been,

6592
05:35:18,640 --> 05:35:20,320
you know, made available
to the research community,

6593
05:35:20,320 --> 05:35:24,040
even prior to any publication,
and it's been really great

6594
05:35:24,040 --> 05:35:27,280
to see how it's being
used quite broadly,

6595
05:35:27,280 --> 05:35:30,720
accelerating the pace of
discovery in this disease field,

6596
05:35:30,720 --> 05:35:33,440
and we know that these
kind of knowledge platforms,

6597
05:35:33,440 --> 05:35:34,880
they will have to expand.

6598
05:35:34,880 --> 05:35:37,040
So it's not just genetic
information,

6599
05:35:37,040 --> 05:35:40,600
but we also in different
layers of homage data

6600
05:35:40,600 --> 05:35:42,520
to interpret
the functional variants

6601
05:35:42,520 --> 05:35:45,280
and put them in
a functional genomic context

6602
05:35:45,280 --> 05:35:47,280
and come up
with disease models

6603
05:35:47,280 --> 05:35:50,560
that we can then study
for therapeutic interventions.

6604
05:35:50,560 --> 05:35:53,040
Next, please.

6605
05:35:53,040 --> 05:35:54,760
Next, please.

6606
05:35:54,760 --> 05:35:59,200
Okay, but it's --
Sorry, just one back, please.

6607
05:36:02,040 --> 05:36:03,320
It's okay.

6608
05:36:03,320 --> 05:36:06,840
So we definitely need
more samples,

6609
05:36:06,840 --> 05:36:09,200
so biospecimens
and brain donation programs

6610
05:36:09,200 --> 05:36:12,520
will have to expand,
but we also need

6611
05:36:12,520 --> 05:36:15,600
a lot of accompanying
phenotypic information,

6612
05:36:15,600 --> 05:36:18,520
and ideally,
in-depth phenotype information

6613
05:36:18,520 --> 05:36:20,920
all the way from
the programmable stage

6614
05:36:20,920 --> 05:36:22,800
to the final stages
of the disease,

6615
05:36:22,800 --> 05:36:25,360
and this type of information
can be really valuable,

6616
05:36:25,360 --> 05:36:29,000
and I'm showing you
just an example of how,

6617
05:36:29,000 --> 05:36:32,360
you know, these
kind of data can be used.

6618
05:36:32,360 --> 05:36:36,240
In a recent study
by Dr. Scherzer's group,

6619
05:36:36,240 --> 05:36:38,600
you know, we've been
able to show

6620
05:36:38,600 --> 05:36:42,200
that there are risk loci
that modify the survival,

6621
05:36:42,200 --> 05:36:46,000
and so these kind of disease
modification genetic loci,

6622
05:36:46,000 --> 05:36:48,680
you know, identifying those,
it's only possible

6623
05:36:48,680 --> 05:36:52,640
because the available of
in-depth phenotypic information,

6624
05:36:52,640 --> 05:36:55,640
and so there is a lot
of interesting angle to that,

6625
05:36:55,640 --> 05:36:58,080
but again,
we need to improve

6626
05:36:58,080 --> 05:37:00,600
the number of ancestrally
diverse individuals

6627
05:37:00,600 --> 05:37:03,520
to see how broadly
that it really affects

6628
05:37:03,520 --> 05:37:05,440
the patient population.

6629
05:37:05,440 --> 05:37:09,600
Going to the next one,
there are many --

6630
05:37:09,600 --> 05:37:11,800
You know, there are many gaps
in our knowledge,

6631
05:37:11,800 --> 05:37:13,600
so obviously we have
to still address

6632
05:37:13,600 --> 05:37:15,000
the missing heritability,

6633
05:37:15,000 --> 05:37:18,240
and this is where
increasing biorepositories,

6634
05:37:18,240 --> 05:37:22,240
brain donation programs
are really going to be key,

6635
05:37:22,240 --> 05:37:25,240
but also using modern
technologies as they unfold

6636
05:37:25,240 --> 05:37:30,400
to study rarer-used
genetic variation type.

6637
05:37:30,400 --> 05:37:34,920
Integrating the multi-omic data
into a knowledge platform

6638
05:37:34,920 --> 05:37:37,400
that can be easily shared
and accessed

6639
05:37:37,400 --> 05:37:41,400
is also key
to advancing the field

6640
05:37:41,400 --> 05:37:42,840
and particularly taking,

6641
05:37:42,840 --> 05:37:44,440
you know,
the genetic information

6642
05:37:44,440 --> 05:37:47,320
that we see into a cellular
context and understand

6643
05:37:47,320 --> 05:37:51,120
how it actually is causing
disease on a molecular level.

6644
05:37:51,120 --> 05:37:53,480
I think we have already heard
from other groups

6645
05:37:53,480 --> 05:37:56,720
that we all need
to double down on our efforts

6646
05:37:56,720 --> 05:38:00,040
to increase the diversity
of patient study

6647
05:38:00,040 --> 05:38:03,000
in the genetic context
in particular.

6648
05:38:03,000 --> 05:38:06,000
You can go to the next one.

6649
05:38:06,000 --> 05:38:08,400
So coming to our specific
recommendations

6650
05:38:08,400 --> 05:38:10,720
for the genetics of LBD,

6651
05:38:10,720 --> 05:38:13,480
so we recommend to delineate
the genetic loci

6652
05:38:13,480 --> 05:38:14,960
on the functions,

6653
05:38:14,960 --> 05:38:17,280
contributing to the onset
and progression of LBDs

6654
05:38:17,280 --> 05:38:21,400
using genetic,
transcriptomic, epigenetic

6655
05:38:21,400 --> 05:38:23,680
and environmental analysis,

6656
05:38:23,680 --> 05:38:25,400
and so this is going
to be used to --

6657
05:38:25,400 --> 05:38:29,760
obviously to discover and
replicate genetic risk variants

6658
05:38:29,760 --> 05:38:33,320
which is at the core,
at the foundation for getting

6659
05:38:33,320 --> 05:38:35,680
insights
into the genetic architecture

6660
05:38:35,680 --> 05:38:38,320
and the molecular
function of LBD.

6661
05:38:38,320 --> 05:38:40,600
Next one.

6662
05:38:40,600 --> 05:38:43,600
We have to expand the
recruitment of cross-sectional

6663
05:38:43,600 --> 05:38:45,720
and longitudinal
deeply phenotype

6664
05:38:45,720 --> 05:38:50,400
cohorts and families,
ideally of diverse ancestry.

6665
05:38:50,400 --> 05:38:51,960
Next.

6666
05:38:51,960 --> 05:38:54,880
We have to translate
these risk variants

6667
05:38:54,880 --> 05:38:56,240
that we're identifying

6668
05:38:56,240 --> 05:38:58,160
using predominantly
through association

6669
05:38:58,160 --> 05:39:00,720
studies into disease
mechanisms.

6670
05:39:00,720 --> 05:39:03,200
Next.

6671
05:39:03,200 --> 05:39:05,800
And we want to examine
our relationships

6672
05:39:05,800 --> 05:39:09,200
between Lewy body dementia
and also related diseases,

6673
05:39:09,200 --> 05:39:12,280
as there are real cross-disease
treatment opportunities

6674
05:39:12,280 --> 05:39:15,600
that are emerging based on these
so-called pleiotropic

6675
05:39:15,600 --> 05:39:17,000
risk alleles.

6676
05:39:17,000 --> 05:39:19,880
Next one.

6677
05:39:19,880 --> 05:39:21,600
And as I already alluded to,

6678
05:39:21,600 --> 05:39:25,400
we want to have an expansion
of the data platforms

6679
05:39:25,400 --> 05:39:28,120
for user-friendly analytics.

6680
05:39:28,120 --> 05:39:29,800
Now we go to the next slide.

6681
05:39:32,000 --> 05:39:33,640
So there's also been
notable progress

6682
05:39:33,640 --> 05:39:35,480
on the neuropathological side.

6683
05:39:35,480 --> 05:39:37,480
So I think we appreciate,
you know,

6684
05:39:37,480 --> 05:39:39,360
the type and location of the,

6685
05:39:39,360 --> 05:39:41,720
I'll say, nuclear pathology,

6686
05:39:41,720 --> 05:39:44,200
and the classifications
have already been developed

6687
05:39:44,200 --> 05:39:46,520
and are broadly used.
Next slide.

6688
05:39:46,520 --> 05:39:50,120
But we recognize that we have
to standardize

6689
05:39:50,120 --> 05:39:55,120
the way the neuropathological
characterization is happening,

6690
05:39:55,120 --> 05:39:58,880
and the standardization
is not just relating

6691
05:39:58,880 --> 05:40:01,480
to the quantification
of the pathology that is there

6692
05:40:01,480 --> 05:40:05,120
but also relates to the
different type of techniques,

6693
05:40:05,120 --> 05:40:07,600
from the staining
to the type of sampling

6694
05:40:07,600 --> 05:40:09,240
that has to occur.

6695
05:40:09,240 --> 05:40:11,320
Next.

6696
05:40:11,320 --> 05:40:14,400
In addition, we recognize
that LBD,

6697
05:40:14,400 --> 05:40:17,920
pathologically speaking,
is a very heterogeneous disease.

6698
05:40:17,920 --> 05:40:21,040
There is -- You know,
the copathologies that exist,

6699
05:40:21,040 --> 05:40:22,920
they are not
there by chance.

6700
05:40:22,920 --> 05:40:24,280
They really matter.

6701
05:40:24,280 --> 05:40:26,640
They affect the phenotypic
presentations,

6702
05:40:26,640 --> 05:40:29,160
so we know that 60
to 80 percent of all cases

6703
05:40:29,160 --> 05:40:31,440
have Alzheimer's
copathology,

6704
05:40:31,440 --> 05:40:34,560
and, you know,
and even genetically speaking,

6705
05:40:34,560 --> 05:40:37,040
we already start to see
different architectures

6706
05:40:37,040 --> 05:40:38,480
in these high --

6707
05:40:38,480 --> 05:40:42,400
you know, pure versus
mixed pathology cases.

6708
05:40:42,400 --> 05:40:43,480
Next, please.

6709
05:40:43,480 --> 05:40:44,840
But we also appreciate

6710
05:40:44,840 --> 05:40:48,200
that there are other
pathological changes

6711
05:40:48,200 --> 05:40:50,480
that haven't been
sufficiently explored,

6712
05:40:50,480 --> 05:40:54,960
such as the TDP-43 copathology
that we increasingly appreciate

6713
05:40:54,960 --> 05:40:57,680
in about 20 percent of cases

6714
05:40:57,680 --> 05:41:01,080
as well as the vascular
disease copathologies with,

6715
05:41:01,080 --> 05:41:04,760
you know, microvasc
and macrovascular changes.

6716
05:41:04,760 --> 05:41:06,760
Next, please.

6717
05:41:06,760 --> 05:41:08,640
So there are notable gaps,

6718
05:41:08,640 --> 05:41:11,160
especially on
the neuropathology side as well,

6719
05:41:11,160 --> 05:41:14,560
so it is important
that we link information

6720
05:41:14,560 --> 05:41:17,000
all the way from the scientist
to the samples

6721
05:41:17,000 --> 05:41:21,280
to clinical information
using user-friendly portals

6722
05:41:21,280 --> 05:41:24,200
and unique identifiers.

6723
05:41:24,200 --> 05:41:28,240
We want to make it as easy as
possible to use these portals,

6724
05:41:28,240 --> 05:41:31,240
and in order to work
across different centers

6725
05:41:31,240 --> 05:41:34,320
that are generating samples,
that are collecting them,

6726
05:41:34,320 --> 05:41:37,680
it is important that we have
standardized techniques

6727
05:41:37,680 --> 05:41:40,600
for the quantification
of the pathology

6728
05:41:40,600 --> 05:41:44,000
but also for the sampling
process and the staining itself.

6729
05:41:44,000 --> 05:41:46,800
I think there are a lot
of unrealized opportunities

6730
05:41:46,800 --> 05:41:52,200
emerging on the digital image
analysis and deep learning side,

6731
05:41:52,200 --> 05:41:54,440
and I think we can
all agree that,

6732
05:41:54,440 --> 05:41:56,520
you know, we will
all benefit as a field

6733
05:41:56,520 --> 05:41:58,720
if we increase
the number of cases

6734
05:41:58,720 --> 05:42:01,040
that are ancestrally diverse.

6735
05:42:01,040 --> 05:42:03,560
So with that, I want to go
to the next side.

6736
05:42:03,560 --> 05:42:06,800
So here are recommendations
for the neuropathology.

6737
05:42:06,800 --> 05:42:09,320
So we want to enhance
and standardize the techniques

6738
05:42:09,320 --> 05:42:12,800
for neuropathological
characterization of LBD

6739
05:42:12,800 --> 05:42:15,920
and the use of
LBD pathology cohorts.

6740
05:42:15,920 --> 05:42:17,160
Next, please.

6741
05:42:17,160 --> 05:42:20,720
We want to establish
best practices

6742
05:42:20,720 --> 05:42:23,800
for the neuropathological
evaluation.

6743
05:42:23,800 --> 05:42:25,600
Next, please.

6744
05:42:25,600 --> 05:42:28,560
We have to develop
scalable methods

6745
05:42:28,560 --> 05:42:31,160
to assess the quality
of tissue samples.

6746
05:42:31,160 --> 05:42:33,200
Next.

6747
05:42:33,200 --> 05:42:35,600
We have to enhance
the infrastructure,

6748
05:42:35,600 --> 05:42:39,400
also to collect
tissue specimens

6749
05:42:39,400 --> 05:42:41,600
that are not
routinely collected.

6750
05:42:41,600 --> 05:42:44,600
We've already heard about
the importance of skin,

6751
05:42:44,600 --> 05:42:47,600
salivary gland, GI tissue

6752
05:42:47,600 --> 05:42:51,240
and perhaps even
solid organ samplings,

6753
05:42:51,240 --> 05:42:53,320
and we should facilitate that.

6754
05:42:53,320 --> 05:42:55,800
Next, please.

6755
05:42:55,800 --> 05:42:57,400
Next.

6756
05:42:59,400 --> 05:43:01,000
As I already mentioned,

6757
05:43:01,000 --> 05:43:06,640
we need very well-characterized
autopsy collections,

6758
05:43:06,640 --> 05:43:09,760
especially from ancestrally
diverse cases.

6759
05:43:09,760 --> 05:43:11,040
Next.

6760
05:43:11,040 --> 05:43:13,200
This will inform a lot
of the molecular,

6761
05:43:13,200 --> 05:43:16,640
you know, characterizations
and have already been ongoing,

6762
05:43:16,640 --> 05:43:18,320
and in order
to achieve that,

6763
05:43:18,320 --> 05:43:21,520
I think it's really
of fundamental importance

6764
05:43:21,520 --> 05:43:25,360
that we improve our outreach
and our education

6765
05:43:25,360 --> 05:43:27,040
to underrepresented groups

6766
05:43:27,040 --> 05:43:29,800
to engage them
in our research enterprise.

6767
05:43:29,800 --> 05:43:32,480
Next, please.

6768
05:43:32,480 --> 05:43:36,240
And we want to link
the tissue resources

6769
05:43:36,240 --> 05:43:37,440
that are being generated.

6770
05:43:37,440 --> 05:43:38,960
There's a concerted amount
of effort

6771
05:43:38,960 --> 05:43:41,400
that goes into there
with all the clinical,

6772
05:43:41,400 --> 05:43:45,960
that molecular biomarker data
using a single portal.

6773
05:43:45,960 --> 05:43:46,800
Next, please.

6774
05:43:46,800 --> 05:43:49,240
All right.

6775
05:43:49,240 --> 05:43:51,320
And so I'm going to hand
over the microphone

6776
05:43:51,320 --> 05:43:53,920
to the next speaker,
Dr. David Irwin.

6777
05:43:53,920 --> 05:43:56,560
Dr. Irwin is a cognitive
neurologist

6778
05:43:56,560 --> 05:43:58,960
at the University of Penn,

6779
05:43:58,960 --> 05:44:02,280
where he's particularly
interested in the brain behavior

6780
05:44:02,280 --> 05:44:04,800
and relationships of the ADRDs.

6781
05:44:04,800 --> 05:44:06,280
So the floor is yours.

6782
05:44:06,280 --> 05:44:07,400
Thank you.

6783
05:44:07,400 --> 05:44:08,600
-Thank you very much, Sonja.

6784
05:44:08,600 --> 05:44:11,120
Thank you to the organizers.

6785
05:44:11,120 --> 05:44:12,400
I'll be talking about
recommendations

6786
05:44:12,400 --> 05:44:14,040
seven and eight today,

6787
05:44:14,040 --> 05:44:16,120
that are focused on mechanisms
of Lewy body dementias,

6788
05:44:16,120 --> 05:44:19,320
and I want to recognize
the team members,

6789
05:44:19,320 --> 05:44:22,200
Drs. Cedarbaum, Dugger,
Lee and Scherzer,

6790
05:44:22,200 --> 05:44:27,120
who worked together with me
on these recommendations

6791
05:44:27,120 --> 05:44:29,520
as well as our
Lewy body group.

6792
05:44:29,520 --> 05:44:32,240
Next slide, please.

6793
05:44:32,240 --> 05:44:33,760
I have no disclosures.

6794
05:44:33,760 --> 05:44:35,880
Next slide, please.

6795
05:44:35,880 --> 05:44:39,000
So in review of our
2019 recommendations,

6796
05:44:39,000 --> 05:44:42,800
recommendation seven was
the understanding the molecular,

6797
05:44:42,800 --> 05:44:45,600
cellular pathophysiology
of alpha-synuclein

6798
05:44:45,600 --> 05:44:48,240
in the context
of non-motor brain regions,

6799
05:44:48,240 --> 05:44:51,760
and this focus was on
alpha-synuclein function

6800
05:44:51,760 --> 05:44:56,240
both in health and also
in the setting of human disease,

6801
05:44:56,240 --> 05:44:59,440
Lewy body dementia and a focus
outside of the motor areas

6802
05:44:59,440 --> 05:45:01,480
in the striatonigral system,

6803
05:45:01,480 --> 05:45:05,040
where there's been a large focus
in the context of PD,

6804
05:45:05,040 --> 05:45:08,680
and this is more to examine
the correlates

6805
05:45:08,680 --> 05:45:13,200
of the clinical features of LBD,
of Lewy body dementias.

6806
05:45:13,200 --> 05:45:16,240
Recommendation eight was
to identify mechanisms

6807
05:45:16,240 --> 05:45:18,840
by which Lewy body diseases
may spread between

6808
05:45:18,840 --> 05:45:20,960
and affect different
brain regions

6809
05:45:20,960 --> 05:45:23,400
and how Lewy bodies interact
with other pathologies.

6810
05:45:23,400 --> 05:45:25,600
So the focus of this
recommendation

6811
05:45:25,600 --> 05:45:28,960
was on the prion-like
spread mechanism from cell

6812
05:45:28,960 --> 05:45:32,920
to cell of pathogenic species
of alpha-synuclein

6813
05:45:32,920 --> 05:45:38,480
and how this may interact
with mixed pathologies of aging,

6814
05:45:38,480 --> 05:45:42,200
and the timeline
for these recommendations

6815
05:45:42,200 --> 05:45:44,000
was 2 to 4 years
for seven,

6816
05:45:44,000 --> 05:45:48,960
5 to 7 for recommendation eight
based on the amount of time

6817
05:45:48,960 --> 05:45:52,600
needed to make fundamental
basic advances

6818
05:45:52,600 --> 05:45:55,800
in scientific knowledge
for these recommendations.

6819
05:45:55,800 --> 05:45:59,360
Next slide, please.

6820
05:45:59,360 --> 05:46:01,720
So there's been
significant progress

6821
05:46:01,720 --> 05:46:03,200
in the field since 2019,

6822
05:46:03,200 --> 05:46:06,360
and to highlight
some general areas

6823
05:46:06,360 --> 05:46:10,160
and specific
exemplary studies

6824
05:46:10,160 --> 05:46:14,080
and reviews that capture some of
the main areas of advances,

6825
05:46:14,080 --> 05:46:16,600
one is the ability
to visualize alpha-synuclein

6826
05:46:16,600 --> 05:46:18,160
from the human brain.

6827
05:46:18,160 --> 05:46:19,640
We've heard earlier today

6828
05:46:19,640 --> 05:46:23,400
about different cryo-EM methods
to visualize tau,

6829
05:46:23,400 --> 05:46:26,800
and they've been similarly
applied to alpha-synuclein.

6830
05:46:26,800 --> 05:46:29,000
Here is, from a recent review,
a schematic

6831
05:46:29,000 --> 05:46:33,040
of 3D reconstructions
of alpha-synuclein,

6832
05:46:33,040 --> 05:46:36,720
both from preform fibrils
as well as from human brain,

6833
05:46:36,720 --> 05:46:42,400
in this case, from MSA brains,
and what these studies suggest

6834
05:46:42,400 --> 05:46:46,800
is that genetic alterations
of alpha-synuclein introduced

6835
05:46:46,800 --> 05:46:49,600
into preform fibrils
or modifications

6836
05:46:49,600 --> 05:46:51,200
can alter the structure,

6837
05:46:51,200 --> 05:46:53,400
and there may be
strain-like properties

6838
05:46:53,400 --> 05:46:55,520
of these structures
of alpha-synuclein

6839
05:46:55,520 --> 05:46:58,240
that are only more
recently visualized

6840
05:46:58,240 --> 05:47:00,800
in this level of detail.

6841
05:47:00,800 --> 05:47:04,120
Next slide, please.

6842
05:47:04,120 --> 05:47:08,120
Similarly, visualization
of alpha-synuclein specie

6843
05:47:08,120 --> 05:47:11,480
both in cell culture
and in human brain

6844
05:47:11,480 --> 05:47:15,080
using advanced
methods of microscopy

6845
05:47:15,080 --> 05:47:18,080
can help us understand
more of the complex nature

6846
05:47:18,080 --> 05:47:20,880
of alpha-synuclein
mediated neurodegeneration,

6847
05:47:20,880 --> 05:47:25,400
and what's depicted here
from a study from [Indistinct]

6848
05:47:25,400 --> 05:47:28,000
using a cell model
of alpha-synuclein seeding

6849
05:47:28,000 --> 05:47:30,880
with high-resolution
microscopy methods

6850
05:47:30,880 --> 05:47:33,520
paired with multi-omics,
proteomics

6851
05:47:33,520 --> 05:47:36,200
and gene
expression studies,

6852
05:47:36,200 --> 05:47:39,680
able to visualize
different cellular changes

6853
05:47:39,680 --> 05:47:44,440
related to synaptic
dysfunction, autophagy

6854
05:47:44,440 --> 05:47:46,800
and regulation
of protein turnover,

6855
05:47:46,800 --> 05:47:48,880
as well as mitochondrial
dysfunction

6856
05:47:48,880 --> 05:47:53,080
on the different steps from
alpha-synuclein misfolded seeds

6857
05:47:53,080 --> 05:47:56,400
to protofibrils
to more preform fibrils

6858
05:47:56,400 --> 05:47:59,720
and then more
advanced aggregations

6859
05:47:59,720 --> 05:48:04,480
reminiscent of Lewy bodies
in the human brain.

6860
05:48:04,480 --> 05:48:08,000
So this exemplify how these
newer methods are able

6861
05:48:08,000 --> 05:48:11,000
to enhance cellular models
for our understandings

6862
05:48:11,000 --> 05:48:14,000
of these complex
cellular processes.

6863
05:48:14,000 --> 05:48:15,600
Next slide, please.

6864
05:48:17,800 --> 05:48:25,080
This is the prion-like spread
data in animal and cell models,

6865
05:48:25,080 --> 05:48:27,920
continues to grow
for a mechanism

6866
05:48:27,920 --> 05:48:31,800
for alpha-synuclein mediated
neurodegeneration, as does --

6867
05:48:31,800 --> 05:48:34,360
As we heard earlier
in the biomarker

6868
05:48:34,360 --> 05:48:38,000
talk about the presence
of pathogenic alpha-synuclein

6869
05:48:38,000 --> 05:48:39,400
in peripheral tissues,

6870
05:48:39,400 --> 05:48:41,560
and in these series
of elegant experiments

6871
05:48:41,560 --> 05:48:43,800
from the group
at Johns Hopkins

6872
05:48:43,800 --> 05:48:46,600
showing that
peripherally administered

6873
05:48:46,600 --> 05:48:48,400
preform fibrils
of alpha-synuclein

6874
05:48:48,400 --> 05:48:51,440
into the myenteric plexus
of wild type mice

6875
05:48:51,440 --> 05:48:54,480
can induce a time-space
dependent

6876
05:48:54,480 --> 05:48:57,280
spread of pathogenic
alpha-synuclein in the brain,

6877
05:48:57,280 --> 05:49:00,040
recapitulating human disease
with motor

6878
05:49:00,040 --> 05:49:03,120
and cognitive impairments,
and importantly,

6879
05:49:03,120 --> 05:49:06,480
that process was ameliorated
by either vagotomy

6880
05:49:06,480 --> 05:49:10,200
to block that transmission
from cell to cell

6881
05:49:10,200 --> 05:49:13,440
or in a transgenic animal

6882
05:49:13,440 --> 05:49:15,960
that does not express
endogenous alpha-synuclein,

6883
05:49:15,960 --> 05:49:19,800
so importantly highlighting that
downregulating alpha-synuclein

6884
05:49:19,800 --> 05:49:22,240
may be one mechanism
to help us slow

6885
05:49:22,240 --> 05:49:26,800
or halt the propagation
of pathogenic alpha-synuclein.

6886
05:49:26,800 --> 05:49:28,400
Next slide, please.

6887
05:49:31,560 --> 05:49:35,840
As we heard earlier from Kejal,
in the Lewy body dementia,

6888
05:49:35,840 --> 05:49:38,560
mixed pathology is the rule,
not the exception,

6889
05:49:38,560 --> 05:49:41,520
and model systems need
to appropriately help us

6890
05:49:41,520 --> 05:49:43,800
understand the interactions
of these proteins.

6891
05:49:43,800 --> 05:49:47,000
This is from Virginia Lee
at Penn,

6892
05:49:47,000 --> 05:49:49,680
showing that
an amyloidosis model,

6893
05:49:49,680 --> 05:49:56,120
the 5xFAD mouse model that has
human pathogenic mutations

6894
05:49:56,120 --> 05:49:58,200
closing amyloidosis
in the mouse model

6895
05:49:58,200 --> 05:50:02,680
can accelerate the propagation
of both

6896
05:50:02,680 --> 05:50:04,720
preform fibrils
of alpha-synuclein

6897
05:50:04,720 --> 05:50:06,160
as well as human

6898
05:50:06,160 --> 05:50:09,160
Lewy body dementia-derived
pathogenic species

6899
05:50:09,160 --> 05:50:12,920
of alpha-synuclein
throughout the brain,

6900
05:50:12,920 --> 05:50:16,040
helping model
the interaction

6901
05:50:16,040 --> 05:50:18,320
between A-beta
and alpha-synuclein,

6902
05:50:18,320 --> 05:50:20,200
as depicted here,

6903
05:50:20,200 --> 05:50:24,320
aggregations of human
brain-derived alpha-synuclein

6904
05:50:24,320 --> 05:50:28,920
in these transgenic animals,
but not in wild type.

6905
05:50:28,920 --> 05:50:30,520
Next slide, please.

6906
05:50:32,520 --> 05:50:34,200
Model systems are advancing,

6907
05:50:34,200 --> 05:50:35,680
and we've heard
throughout the day

6908
05:50:35,680 --> 05:50:38,040
in different content areas,

6909
05:50:38,040 --> 05:50:42,480
the ability to have patient-
derived sources for models,

6910
05:50:42,480 --> 05:50:44,760
and this schematic
from a recent review

6911
05:50:44,760 --> 05:50:49,880
shows how induced pluripotent
stem cells technology,

6912
05:50:49,880 --> 05:50:53,920
the ability to program
fibroblast cells

6913
05:50:53,920 --> 05:50:56,640
or peripheral blood
mononuclear cells

6914
05:50:56,640 --> 05:51:00,360
into either 2D
patient-derived cultures

6915
05:51:00,360 --> 05:51:02,200
of specific types
of neurons.

6916
05:51:02,200 --> 05:51:04,920
In this case, visualized here
is dopaminergic neurons,

6917
05:51:04,920 --> 05:51:08,800
but can be programmed into
various other neuronal subtypes,

6918
05:51:08,800 --> 05:51:12,640
as well as 3D organoids provide
a very unique opportunity

6919
05:51:12,640 --> 05:51:16,000
not only to model disease
on an individual patient level

6920
05:51:16,000 --> 05:51:20,200
but also a possibility
to do drug screening

6921
05:51:20,200 --> 05:51:23,600
for various compounds.

6922
05:51:23,600 --> 05:51:26,800
This is an important step
towards a more personalized

6923
05:51:26,800 --> 05:51:29,800
medicine approach for treatment
of the Lewy body dementias

6924
05:51:29,800 --> 05:51:35,680
and also an ability to introduce
discoveries from genetic work,

6925
05:51:35,680 --> 05:51:40,400
as highlighted by Sonja,
into these models to then

6926
05:51:40,400 --> 05:51:43,360
help us understand
disease mechanisms.

6927
05:51:43,360 --> 05:51:44,960
Next slide, please.

6928
05:51:47,960 --> 05:51:52,600
In this schematic,
highlights the increasing role

6929
05:51:52,600 --> 05:51:56,280
that's thought to be related
to the immune system

6930
05:51:56,280 --> 05:52:00,560
in the pathogenesis of Lewy
body disease and dementias,

6931
05:52:00,560 --> 05:52:03,720
and what's highlighted here
in both the adaptive

6932
05:52:03,720 --> 05:52:06,560
and elements
of the innate immune system

6933
05:52:06,560 --> 05:52:09,200
and particularly in glia
in the brain,

6934
05:52:09,200 --> 05:52:12,400
both the normal function
of alpha-synuclein

6935
05:52:12,400 --> 05:52:15,360
that may involve certain aspects
of immune function

6936
05:52:15,360 --> 05:52:20,200
that's highlighted in red boxes
for the different cell types

6937
05:52:20,200 --> 05:52:22,080
as well as the ability
for normal

6938
05:52:22,080 --> 05:52:23,480
functioning alpha-synuclein

6939
05:52:23,480 --> 05:52:27,480
to bind to specific
immune receptors in blue,

6940
05:52:27,480 --> 05:52:33,120
and then finally, changes
biologically in immune cells

6941
05:52:33,120 --> 05:52:34,800
in response

6942
05:52:34,800 --> 05:52:38,440
to pathogenic aggregations
of alpha-synuclein in yellow,

6943
05:52:38,440 --> 05:52:42,160
and there are several aspects
here that they're missing data,

6944
05:52:42,160 --> 05:52:45,680
and a lot more to learn,
but there's increasing role

6945
05:52:45,680 --> 05:52:48,560
of non-cell autonomous
inflammatory mechanisms

6946
05:52:48,560 --> 05:52:53,000
that could contribute to
the neurodegenerative process.

6947
05:52:53,000 --> 05:52:56,240
Next slide, please.

6948
05:52:56,240 --> 05:52:59,800
And finally, recent work
highlighted here

6949
05:52:59,800 --> 05:53:02,600
showing two different
potential mechanisms

6950
05:53:02,600 --> 05:53:05,800
of enhancing immunotherapies

6951
05:53:05,800 --> 05:53:07,760
as potential
disease-modifying therapies

6952
05:53:07,760 --> 05:53:11,920
targeting alpha-synuclein
either with DNA vaccines

6953
05:53:11,920 --> 05:53:14,720
or through generation
of specific

6954
05:53:14,720 --> 05:53:16,480
conformers
of alpha-synuclein

6955
05:53:16,480 --> 05:53:20,320
to have a more specific target
for pathogenic alpha-synuclein

6956
05:53:20,320 --> 05:53:25,720
and potentially reduce
side effects of immunotherapy.

6957
05:53:25,720 --> 05:53:28,600
Next slide, please.

6958
05:53:28,600 --> 05:53:32,920
So despite these advances
since the previous summit,

6959
05:53:32,920 --> 05:53:36,400
there still remains fundamental
gaps to address in 2022,

6960
05:53:36,400 --> 05:53:39,480
which was the focus
of our work in our meetings

6961
05:53:39,480 --> 05:53:43,680
to prepare the revised
recommendations.

6962
05:53:43,680 --> 05:53:46,600
These include, you know,
advancing models even further

6963
05:53:46,600 --> 05:53:50,200
to fully recapitulate bona fide
human Lewy body disease

6964
05:53:50,200 --> 05:53:54,520
and dementias with aspects
that are directly related

6965
05:53:54,520 --> 05:53:59,400
to what we see in human disease
and particularly for mechanisms

6966
05:53:59,400 --> 05:54:02,560
that can help us understand
selective vulnerability

6967
05:54:02,560 --> 05:54:04,880
and the specific
neuronal subpopulations

6968
05:54:04,880 --> 05:54:07,680
that are particularly
vulnerable to develop

6969
05:54:07,680 --> 05:54:11,280
alpha-synuclein pathology
and neurodegeneration

6970
05:54:11,280 --> 05:54:15,200
and how these relate to the
heterogeneous clinical features

6971
05:54:15,200 --> 05:54:18,720
of Lewy body dementia
such as cognitive fluctuations,

6972
05:54:18,720 --> 05:54:22,280
visual hallucinations
and neuropsychiatric symptoms

6973
05:54:22,280 --> 05:54:23,560
as well as sleep disruption,

6974
05:54:23,560 --> 05:54:25,760
like REM sleep
behavior disorder.

6975
05:54:28,880 --> 05:54:33,760
And as well, there's a need to
develop further infrastructure

6976
05:54:33,760 --> 05:54:38,120
that can support the process
of screening potential compounds

6977
05:54:38,120 --> 05:54:43,080
and developing advances
in therapeutic developments

6978
05:54:43,080 --> 05:54:46,600
from the discoveries
for mechanistic models,

6979
05:54:46,600 --> 05:54:50,120
and then finally, how to more
fully integrate discoveries

6980
05:54:50,120 --> 05:54:54,200
from human genetic work
into model systems to help us

6981
05:54:54,200 --> 05:54:58,240
develop new targets
for drug discovery.

6982
05:54:58,240 --> 05:55:01,720
Slide, please.

6983
05:55:01,720 --> 05:55:06,280
So here are revised
recommendations seven and eight,

6984
05:55:06,280 --> 05:55:08,600
which we'll go through
and highlight

6985
05:55:08,600 --> 05:55:12,560
the main changes
and evolution from 2019.

6986
05:55:12,560 --> 05:55:16,160
So next slide, please.

6987
05:55:16,160 --> 05:55:20,400
So our 2022 recommendation seven

6988
05:55:20,400 --> 05:55:22,120
is to develop models
to understand

6989
05:55:22,120 --> 05:55:25,960
the pathophysiology and normal
molecular cellular functions

6990
05:55:25,960 --> 05:55:29,160
of alpha-synuclein
to support drug discovery,

6991
05:55:29,160 --> 05:55:33,400
and the goals for this
are 5 to 7 years.

6992
05:55:33,400 --> 05:55:34,800
Thank you.

6993
05:55:34,800 --> 05:55:38,200
So the focus and the major
changes to this

6994
05:55:38,200 --> 05:55:42,960
from the previous include
added focus to help accelerate

6995
05:55:42,960 --> 05:55:45,120
the translation
of mechanistic discoveries

6996
05:55:45,120 --> 05:55:48,800
to support drug discoveries
in therapeutics

6997
05:55:48,800 --> 05:55:52,120
and in collaboration
with priority one,

6998
05:55:52,120 --> 05:55:55,560
mentioned by Jim before,
and some of the highlights

6999
05:55:55,560 --> 05:56:00,480
of how to do this include
identifying regulators of SNCA,

7000
05:56:00,480 --> 05:56:04,200
alpha-synuclein gene expression,
and understanding the mechanisms

7001
05:56:04,200 --> 05:56:06,280
and potential effects
of downregulation

7002
05:56:06,280 --> 05:56:11,200
as a potential targetable
therapeutic strategy.

7003
05:56:11,200 --> 05:56:13,320
Next, please.

7004
05:56:13,320 --> 05:56:16,480
Characterization of pathological
alpha-synuclein strains

7005
05:56:16,480 --> 05:56:18,600
from the human brain,

7006
05:56:18,600 --> 05:56:20,520
further understanding
the variation

7007
05:56:20,520 --> 05:56:25,160
and structure and function
and features of alpha-synuclein

7008
05:56:25,160 --> 05:56:27,240
that are derived
from human brain

7009
05:56:27,240 --> 05:56:30,600
and the importance
of brain donation and autopsy

7010
05:56:30,600 --> 05:56:33,640
is critical for those efforts,
as is, we heard from Sonja,

7011
05:56:33,640 --> 05:56:36,920
efforts to help
accelerate access

7012
05:56:36,920 --> 05:56:40,040
to these tissues
in the research community.

7013
05:56:40,040 --> 05:56:42,680
Next, please.

7014
05:56:42,680 --> 05:56:45,800
Identifying mechanisms of aging
and sex differences

7015
05:56:45,800 --> 05:56:49,560
that are observed in human
autopsy and clinical work

7016
05:56:49,560 --> 05:56:52,360
that may play an important role,
these mechanisms,

7017
05:56:52,360 --> 05:56:54,240
in helping us
understand resilience

7018
05:56:54,240 --> 05:56:57,920
and how some individuals
may be resilient

7019
05:56:57,920 --> 05:57:01,880
to the accumulation
of alpha-synuclein pathology.

7020
05:57:01,880 --> 05:57:03,840
Next, please.

7021
05:57:03,840 --> 05:57:07,240
And finally, these efforts
work towards the goal

7022
05:57:07,240 --> 05:57:10,560
of promoting the discovery
of at least one new, novel drug

7023
05:57:10,560 --> 05:57:14,840
targeting emerging genetic
or neuropathological mechanisms

7024
05:57:14,840 --> 05:57:16,280
implicated in LBD,

7025
05:57:16,280 --> 05:57:19,760
so our focus is on
that translational pathway

7026
05:57:19,760 --> 05:57:22,200
to drug discovery.

7027
05:57:22,200 --> 05:57:23,800
Next slide, please.

7028
05:57:26,800 --> 05:57:30,200
So recommendation eight is
to identify mechanisms

7029
05:57:30,200 --> 05:57:33,600
of selective vulnerability,
disease heterogeneity,

7030
05:57:33,600 --> 05:57:36,240
disease spread and propagation
and interaction

7031
05:57:36,240 --> 05:57:38,240
with other
age-related pathologies

7032
05:57:38,240 --> 05:57:40,160
as therapeutic targets.

7033
05:57:40,160 --> 05:57:43,760
So this recommendation
has a similar time

7034
05:57:43,760 --> 05:57:45,640
frame of 5 to 7 years,

7035
05:57:45,640 --> 05:57:50,080
based on the nature
of these important fundamental,

7036
05:57:50,080 --> 05:57:53,680
basic mechanistic work
that's required

7037
05:57:53,680 --> 05:57:57,000
to address
these important issues.

7038
05:57:57,000 --> 05:57:59,920
Next, please.

7039
05:57:59,920 --> 05:58:03,920
So in particular,
identifying mechanisms

7040
05:58:03,920 --> 05:58:06,120
in which
alpha-synuclein interacts

7041
05:58:06,120 --> 05:58:08,240
with other age-related
copathologies,

7042
05:58:08,240 --> 05:58:11,360
that's been a theme that
we've heard throughout today,

7043
05:58:11,360 --> 05:58:13,440
of the common
co-occurrence of A-beta

7044
05:58:13,440 --> 05:58:19,480
and TDP-43 vascular pathology,
and how these may potentiate

7045
05:58:19,480 --> 05:58:23,840
or accelerate
different neurodegenerative.

7046
05:58:23,840 --> 05:58:26,800
Next slide, please.

7047
05:58:26,800 --> 05:58:28,600
Understanding the role
of the immune system

7048
05:58:28,600 --> 05:58:32,200
and inflammation
in LBD pathogenesis further,

7049
05:58:32,200 --> 05:58:36,000
models that help incorporate
aspects of the immune system

7050
05:58:36,000 --> 05:58:40,240
and the role of glia in
the neurodegenerative process.

7051
05:58:40,240 --> 05:58:43,400
Next slide, please.

7052
05:58:43,400 --> 05:58:46,200
Identifying biochemical/
molecular underpinnings

7053
05:58:46,200 --> 05:58:48,200
of regional
brain pathology in LBD,

7054
05:58:48,200 --> 05:58:51,960
this is important for us to help
link mechanistic findings

7055
05:58:51,960 --> 05:58:58,000
with clinical heterogeneity
and the varied symptoms of LBD,

7056
05:58:58,000 --> 05:59:00,920
and this would identify,
you know, potential targets

7057
05:59:00,920 --> 05:59:05,160
that could be mechanistic
as well as asymptomatic,

7058
05:59:05,160 --> 05:59:07,400
finding these
mechanistic substrates

7059
05:59:07,400 --> 05:59:10,680
of the core
features of LBD.

7060
05:59:10,680 --> 05:59:13,040
Next slide, please.

7061
05:59:13,040 --> 05:59:15,640
And finally, support for
preclinical drug development

7062
05:59:15,640 --> 05:59:17,840
based on new findings
from mechanistic studies,

7063
05:59:17,840 --> 05:59:23,480
so the ability to take these
model systems and harness them

7064
05:59:23,480 --> 05:59:26,080
and take these discoveries
to identify targets,

7065
05:59:26,080 --> 05:59:31,760
screen for new targets and go
from the bench to the bedside.

7066
05:59:31,760 --> 05:59:34,800
Next slide, please.

7067
05:59:34,800 --> 05:59:36,680
This concludes my presentation.

7068
05:59:36,680 --> 05:59:39,800
I look forward to
the Q&A session, so thank you.

7069
05:59:43,240 --> 05:59:45,880
-Thank you, Dr. Irwin.

7070
05:59:45,880 --> 05:59:49,600
I think we're heading on
to Q&A now,

7071
05:59:49,600 --> 05:59:55,800
and we have our first question.
-We do.

7072
05:59:55,800 --> 05:59:58,520
So the first one is going to be
Mr. Ellenbogen.

7073
06:00:01,640 --> 06:00:02,800
Michael, are you ready?

7074
06:00:02,800 --> 06:00:05,120
-Yes, thank you so much.

7075
06:00:05,120 --> 06:00:06,960
First, I'd like to say

7076
06:00:06,960 --> 06:00:10,760
I will miss my friend,
John Junkowitzski --

7077
06:00:10,760 --> 06:00:13,400
I'm sorry, Trojanowski.

7078
06:00:13,400 --> 06:00:16,000
He and I served on the
Pennsylvania planning committee,

7079
06:00:16,000 --> 06:00:18,600
and he was great.

7080
06:00:18,600 --> 06:00:20,080
Thank you for giving me
the opportunity

7081
06:00:20,080 --> 06:00:23,240
to speak here today
to all you directly

7082
06:00:23,240 --> 06:00:25,880
because, as a person
living with dementia,

7083
06:00:25,880 --> 06:00:30,760
I would not have been able
to place the writing in a chat.

7084
06:00:30,760 --> 06:00:34,800
We have made progress
in the last few years

7085
06:00:34,800 --> 06:00:38,400
sharing data among those
in the dementia arena,

7086
06:00:38,400 --> 06:00:41,000
but we still need to do better.

7087
06:00:41,000 --> 06:00:43,880
While I'm not a scientist
or an expert,

7088
06:00:43,880 --> 06:00:46,840
I do believe there is
some overlap

7089
06:00:46,840 --> 06:00:50,200
in some of these
other neurological disorders

7090
06:00:50,200 --> 06:00:54,320
that fall outside
of the dementia box.

7091
06:00:54,320 --> 06:00:59,000
I would recommend we find a way
to share information

7092
06:00:59,000 --> 06:01:03,520
among all of the neurological
diseases,

7093
06:01:03,520 --> 06:01:06,760
as together,
we will be stronger.

7094
06:01:06,760 --> 06:01:11,560
Thank you very much
for a great session today.

7095
06:01:11,560 --> 06:01:14,040
-Thanks, that was a great --
Some great comments,

7096
06:01:14,040 --> 06:01:18,960
and of course we'll all miss
John, John Trojanowski,

7097
06:01:18,960 --> 06:01:21,760
and I couldn't agree more.

7098
06:01:21,760 --> 06:01:25,880
I think most of the dementias
are multi-etiologic,

7099
06:01:25,880 --> 06:01:31,120
and again, appreciate
you sharing.

7100
06:01:31,120 --> 06:01:32,920
Are there other comments?

7101
06:01:35,200 --> 06:01:38,000
You want to go
to the next question?

7102
06:01:38,000 --> 06:01:39,280
-Sure.

7103
06:01:39,280 --> 06:01:42,600
The next question
is from Dale Lestina.

7104
06:01:42,600 --> 06:01:45,880
Dale, are you ready?

7105
06:01:45,880 --> 06:01:48,560
-I am now.
Take the mute off.

7106
06:01:51,080 --> 06:01:54,120
I find these sessions excellent.

7107
06:01:54,120 --> 06:02:00,400
I think my first one was 2018,
then 2019, and I learned a lot.

7108
06:02:00,400 --> 06:02:04,440
I'm learning more even now,
and I have some questions

7109
06:02:04,440 --> 06:02:11,120
that are related
to the previous sessions.

7110
06:02:11,120 --> 06:02:15,200
I learned that beta-amyloid
is associated

7111
06:02:15,200 --> 06:02:17,600
with the plaques quite literally

7112
06:02:17,600 --> 06:02:20,440
in between
the neurons in the brain.

7113
06:02:20,440 --> 06:02:26,680
I learned that tau is inside the
neuron, tangles and so forth.

7114
06:02:26,680 --> 06:02:31,000
What I didn't know,
as we're talking about here now,

7115
06:02:31,000 --> 06:02:35,040
is alpha-synuclein.

7116
06:02:35,040 --> 06:02:36,880
To me, that's a new one.

7117
06:02:36,880 --> 06:02:38,200
What does that --

7118
06:02:38,200 --> 06:02:41,280
How does that relate,
and what's --

7119
06:02:41,280 --> 06:02:46,600
to the other two and TDP-43.

7120
06:02:46,600 --> 06:02:50,120
What does the T and the P
and the D stand for?

7121
06:02:50,120 --> 06:02:52,520
Folks have got a lot of alphabet
soup for somebody

7122
06:02:52,520 --> 06:02:54,120
that just comes
in off the street

7123
06:02:54,120 --> 06:02:56,000
to try to catch up on,

7124
06:02:56,000 --> 06:03:02,400
and so I need a little schooling
on the vernacular that you use,

7125
06:03:02,400 --> 06:03:05,600
that you guys know,
you know, like everything,

7126
06:03:05,600 --> 06:03:07,080
but somebody like me,

7127
06:03:07,080 --> 06:03:10,360
I got a different alphabet soup
that I deal with.

7128
06:03:10,360 --> 06:03:15,760
So if you would, whoever would
help me out, James,

7129
06:03:15,760 --> 06:03:17,360
if you can pick who it is.

7130
06:03:17,360 --> 06:03:21,200
If it's you, fine, but I'd like
to learn on those two --

7131
06:03:21,200 --> 06:03:24,240
on those areas.
-Sure.

7132
06:03:24,240 --> 06:03:26,480
Those are great questions.

7133
06:03:26,480 --> 06:03:29,080
Who wants to handle
the explanation

7134
06:03:29,080 --> 06:03:32,280
of the different alphabet soup?

7135
06:03:34,440 --> 06:03:37,360
Somebody has to volunteer,
or I'll pick them.

7136
06:03:37,360 --> 06:03:39,320
-I'm going to put
something there for TDP-43

7137
06:03:39,320 --> 06:03:40,800
in the chat
because I don't know if --

7138
06:03:40,800 --> 06:03:42,400
I'm sure you've all tried
to explain it verbally,

7139
06:03:42,400 --> 06:03:46,920
but deacronym-izing TDP-43
is nearly impossible.

7140
06:03:46,920 --> 06:03:48,600
I think it's easier in writing,
so forgive me.

7141
06:03:48,600 --> 06:03:50,960
I'm going to put it in the chat.
-All right.

7142
06:03:50,960 --> 06:03:54,160
And I'll get it from that.

7143
06:03:54,160 --> 06:03:56,520
-Alpha-synuclein, I'll mention.

7144
06:03:56,520 --> 06:03:58,560
-Is it a tangle as well
when you look

7145
06:03:58,560 --> 06:04:00,560
at the molecule and so forth?

7146
06:04:00,560 --> 06:04:04,600
Is it a tangle like tau?
-It's --

7147
06:04:04,600 --> 06:04:08,760
TDP-43 is a different
kind of inclusion that we tend

7148
06:04:08,760 --> 06:04:11,880
to see in the brain cells

7149
06:04:11,880 --> 06:04:15,200
and particularly, we see it
in the frontotemporal dementias

7150
06:04:15,200 --> 06:04:18,800
as we talk about
frontotemporal dementia later.

7151
06:04:18,800 --> 06:04:20,320
I'm going to give Brittany
a chance,

7152
06:04:20,320 --> 06:04:21,880
and she raised her hand here

7153
06:04:21,880 --> 06:04:25,240
to talk as well about
some of the other acronyms.

7154
06:04:25,240 --> 06:04:28,600
-Thanks, Brittany, a lot.
-Oh, these are great questions,

7155
06:04:28,600 --> 06:04:31,760
and this is the whole point
of this too is dialog, right,

7156
06:04:31,760 --> 06:04:34,800
to form these dialogs,
and so the best way to describe

7157
06:04:34,800 --> 06:04:36,760
a lot of those things
that you mentioned,

7158
06:04:36,760 --> 06:04:39,000
these are normally
in our bodies, okay?

7159
06:04:39,000 --> 06:04:42,400
So just, like, think about how
cars are normally on a freeway

7160
06:04:42,400 --> 06:04:44,480
but then sometimes,
cars can run into each other,

7161
06:04:44,480 --> 06:04:46,160
and they get tangled up.

7162
06:04:46,160 --> 06:04:48,640
-Yep.
-So tau can get tangled up.

7163
06:04:48,640 --> 06:04:52,400
The amyloid can get tangled up,
the amyloid beta, so can TDP-43

7164
06:04:52,400 --> 06:04:55,160
and so can alpha-synuclein,
and these are all specific.

7165
06:04:55,160 --> 06:04:56,520
You could think of just maybe

7166
06:04:56,520 --> 06:04:58,960
even different types
of cars, right?

7167
06:04:58,960 --> 06:05:00,440
One could be a Honda, a Toyota.

7168
06:05:00,440 --> 06:05:01,960
I'm from Detroit, right?
So I'm going to be, like,

7169
06:05:01,960 --> 06:05:04,800
"That's
a Ford, a GM or a Chrysler,"

7170
06:05:04,800 --> 06:05:07,560
but does that help a little bit
from that analogy?

7171
06:05:07,560 --> 06:05:09,640
That helps me when I try
to understand things.

7172
06:05:09,640 --> 06:05:12,560
-Are they all proteins?
-Yeah, they're all proteins,

7173
06:05:12,560 --> 06:05:14,440
and they all get
into these car accidents.

7174
06:05:14,440 --> 06:05:16,200
So we all normally have them
in our body

7175
06:05:16,200 --> 06:05:20,240
but what we try to study is,
when do they go awry?

7176
06:05:20,240 --> 06:05:25,120
-Do the TD-43
and alpha-synuclein,

7177
06:05:25,120 --> 06:05:28,440
are they predominantly
in the neuron itself?

7178
06:05:28,440 --> 06:05:30,000
-Yes.
-Okay.

7179
06:05:30,000 --> 06:05:31,360
That helps me.

7180
06:05:31,360 --> 06:05:33,400
-And TDP normally stays
in the nucleus,

7181
06:05:33,400 --> 06:05:35,400
but what happens a lot
in these diseases is,

7182
06:05:35,400 --> 06:05:37,600
it goes away from that nucleus
of the neuron,

7183
06:05:37,600 --> 06:05:39,560
and we try to understand why.

7184
06:05:39,560 --> 06:05:41,600
-Oh, and how does it get out?

7185
06:05:41,600 --> 06:05:45,560
-Those are great questions
that we try to answer.

7186
06:05:45,560 --> 06:05:47,120
-Okay.

7187
06:05:47,120 --> 06:05:49,240
Well, I'm looking forward
to the next one as we go forward

7188
06:05:49,240 --> 06:05:55,880
is because I thought that
once inside the neuron

7189
06:05:55,880 --> 06:06:00,400
that you don't have to bust up
or die in order to get out,

7190
06:06:00,400 --> 06:06:01,920
but maybe not.

7191
06:06:01,920 --> 06:06:04,160
And now, is that
for alpha-synuclein,

7192
06:06:04,160 --> 06:06:06,840
and that's also in the nucleus?

7193
06:06:06,840 --> 06:06:09,400
And as I understood
the pictures here,

7194
06:06:09,400 --> 06:06:12,440
it looked like in the molecule
for that is a long,

7195
06:06:12,440 --> 06:06:15,800
stringy thing
just like for tau,

7196
06:06:15,800 --> 06:06:18,400
and then you can get them
all wrapped up,

7197
06:06:18,400 --> 06:06:21,600
and if that happens,
I've heard

7198
06:06:21,600 --> 06:06:27,400
that they can trigger the neuron
to commit suicide, kill itself.

7199
06:06:27,400 --> 06:06:29,080
Does that make sense?

7200
06:06:29,080 --> 06:06:31,600
-I'm going to pass this
to my colleague, Dr. Mosley.

7201
06:06:31,600 --> 06:06:33,600
I think he can help too.
He has his hand up.

7202
06:06:33,600 --> 06:06:35,240
-Well, you have
to write a grant.

7203
06:06:35,240 --> 06:06:37,440
You have a lot of stuff in here.

7204
06:06:37,440 --> 06:06:40,600
-Those are all great questions.
-Thank you, Brittany.

7205
06:06:40,600 --> 06:06:42,560
-Eliezer.
-Oh, yeah.

7206
06:06:42,560 --> 06:06:44,000
Thank you, James.

7207
06:06:44,000 --> 06:06:46,480
Yeah, alpha-synuclein
is a little bit different

7208
06:06:46,480 --> 06:06:50,280
because under normal conditions,
it's at the site

7209
06:06:50,280 --> 06:06:53,600
where the neurons connect
with each other sort of like,

7210
06:06:53,600 --> 06:06:55,160
you know, the same type
of connections

7211
06:06:55,160 --> 06:06:58,480
that you see in a computer
between transistors.

7212
06:06:58,480 --> 06:07:03,880
It's the same thing, but under
pathological conditions

7213
06:07:03,880 --> 06:07:05,880
like in Lewy body disease,

7214
06:07:05,880 --> 06:07:08,360
it means localized,
and it aggregates.

7215
06:07:08,360 --> 06:07:10,880
It accumulates in the cell body,

7216
06:07:10,880 --> 06:07:14,960
so it goes from the synaptic
connection to the cell body

7217
06:07:14,960 --> 06:07:17,960
where it causes
a traffic jam in the cell,

7218
06:07:17,960 --> 06:07:20,000
as Brittany was discussing,

7219
06:07:20,000 --> 06:07:25,600
but also it gets spit out
of the cell and propagates

7220
06:07:25,600 --> 06:07:29,680
from one cell to another
including inflammatory cells

7221
06:07:29,680 --> 06:07:34,160
causing a firestorm
in the brain, so to speak.

7222
06:07:34,160 --> 06:07:40,400
So -- But, you know, we'll be
happy to post on the chat

7223
06:07:40,400 --> 06:07:45,080
the link to our website,
the NIA and NINDS website,

7224
06:07:45,080 --> 06:07:50,080
where all this information,
it's available and a lot more.

7225
06:07:50,080 --> 06:07:52,800
I think you'll find it
very helpful.

7226
06:07:52,800 --> 06:07:55,200
-Well, I appreciate you
all that have chimed

7227
06:07:55,200 --> 06:07:57,840
in on my question.

7228
06:07:57,840 --> 06:07:58,840
Thank you very much.

7229
06:07:58,840 --> 06:08:01,800
That's always nice to learn.

7230
06:08:01,800 --> 06:08:03,080
-Thank you, Dale.

7231
06:08:03,080 --> 06:08:05,280
-These are great questions,
actually.

7232
06:08:07,680 --> 06:08:10,400
Kejal, do you want to handle
the next one, next question?

7233
06:08:10,400 --> 06:08:11,680
-Sure.

7234
06:08:11,680 --> 06:08:14,440
The next question
comes from Helen Medsger,

7235
06:08:14,440 --> 06:08:17,000
if you could
take the microphone.

7236
06:08:17,000 --> 06:08:18,640
-Hello, there.

7237
06:08:18,640 --> 06:08:20,640
I want to thank
everybody for today.

7238
06:08:20,640 --> 06:08:23,200
I've been in this battle
with Lewy body dementia

7239
06:08:23,200 --> 06:08:25,000
for over 30 years.

7240
06:08:25,000 --> 06:08:27,240
I've had three
first-degree relatives

7241
06:08:27,240 --> 06:08:28,480
that have succumbed to it:

7242
06:08:28,480 --> 06:08:31,200
my dad, my sister
and my youngest brother,

7243
06:08:31,200 --> 06:08:33,960
and I've had the pleasure,
actually, to either work with

7244
06:08:33,960 --> 06:08:36,920
or meet some of you
at various conferences.

7245
06:08:36,920 --> 06:08:40,040
But I'm wondering because
I already have,

7246
06:08:40,040 --> 06:08:43,440
you know, two generations
in my family in genetic study,

7247
06:08:43,440 --> 06:08:47,720
but those were formulated
back in, you know, the 2000s,

7248
06:08:47,720 --> 06:08:51,120
and so it's part of
Parkinson's disease study,

7249
06:08:51,120 --> 06:08:56,520
and even though I'm currently
involved in a variety of PPMI,

7250
06:08:56,520 --> 06:08:59,200
healthy brain aging
and all the rest,

7251
06:08:59,200 --> 06:09:02,840
is there a pipeline for those
of us that have been this

7252
06:09:02,840 --> 06:09:07,600
impacted to kind of fast-track
into certain studies

7253
06:09:07,600 --> 06:09:11,560
or at least put ourselves
on a specialized registry

7254
06:09:11,560 --> 06:09:14,920
so that you have access to us?

7255
06:09:14,920 --> 06:09:18,080
Because I think that, you know,
I'm pushing my family

7256
06:09:18,080 --> 06:09:22,240
to be more and more involved
because I want to see,

7257
06:09:22,240 --> 06:09:24,880
you know, research
as accelerated as possible

7258
06:09:24,880 --> 06:09:26,360
to get answers,

7259
06:09:26,360 --> 06:09:28,360
and that's kind
of my first question.

7260
06:09:28,360 --> 06:09:29,960
My second one has to do is,

7261
06:09:29,960 --> 06:09:33,720
we didn't directly address
GBA today,

7262
06:09:33,720 --> 06:09:35,320
and I know that, Dr. Scholz,

7263
06:09:35,320 --> 06:09:38,360
you had done that at the last
international conference,

7264
06:09:38,360 --> 06:09:40,560
so I was wondering
why that wasn't --

7265
06:09:40,560 --> 06:09:47,560
SNCA was mostly targeted today,
why GBA was not highlighted.

7266
06:09:47,560 --> 06:09:49,160
-Thank you for this question,

7267
06:09:49,160 --> 06:09:52,120
and thank you for participating
in research studies

7268
06:09:52,120 --> 06:09:55,360
and cohort studies
with your family as well.

7269
06:09:55,360 --> 06:09:57,240
That's wonderful.

7270
06:09:57,240 --> 06:09:59,600
I will direct this question
to Sonja

7271
06:09:59,600 --> 06:10:01,800
because it's about genetics.

7272
06:10:01,800 --> 06:10:05,360
-Yes, so thank you so much
for this interesting discussion

7273
06:10:05,360 --> 06:10:07,080
and really good question.

7274
06:10:07,080 --> 06:10:10,280
So we definitely
appreciate participant

7275
06:10:10,280 --> 06:10:12,840
in the various
clinical trials.

7276
06:10:12,840 --> 06:10:16,480
At the present time, I mean,
we don't have a one-stop-shop

7277
06:10:16,480 --> 06:10:20,040
where anybody
with a family history can go,

7278
06:10:20,040 --> 06:10:21,600
so people, you know,

7279
06:10:21,600 --> 06:10:25,480
usually find an array
of different study centers,

7280
06:10:25,480 --> 06:10:29,240
but many of them are now feeding
into these biorepositories

7281
06:10:29,240 --> 06:10:30,880
that researchers can access.

7282
06:10:30,880 --> 06:10:34,800
So, for example, the Parkinson's
disease biomarker program,

7283
06:10:34,800 --> 06:10:38,000
they receive samples
from different studies

7284
06:10:38,000 --> 06:10:41,000
but for the researchers,
we can access them,

7285
06:10:41,000 --> 06:10:44,280
and so it doesn't always
have to be a one-stop-shop.

7286
06:10:44,280 --> 06:10:46,800
So some of these
resources exist,

7287
06:10:46,800 --> 06:10:48,800
and they're definitely
very used,

7288
06:10:48,800 --> 06:10:51,160
and they're extremely helpful.

7289
06:10:51,160 --> 06:10:55,120
There's a lot of, you know,
exciting development on many,

7290
06:10:55,120 --> 06:10:56,800
you know, already no-risk
[Indistinct]

7291
06:10:56,800 --> 06:10:59,760
and you mentioned GBA
as one of them,

7292
06:10:59,760 --> 06:11:02,600
so aside from ACOE
that we've talked a little bit.

7293
06:11:02,600 --> 06:11:05,200
You know, about 13 percent
of LBD cases

7294
06:11:05,200 --> 06:11:09,000
actually have a risk variant
in this particular gene,

7295
06:11:09,000 --> 06:11:11,720
and it's told us
a lot already about,

7296
06:11:11,720 --> 06:11:16,840
you know, where in the cell
the misfunction is happening.

7297
06:11:16,840 --> 06:11:19,000
It tells us that the handling
of the proteins

7298
06:11:19,000 --> 06:11:21,280
is not functioning
well enough.

7299
06:11:21,280 --> 06:11:24,200
There's already, you know,
exciting clinical trials

7300
06:11:24,200 --> 06:11:30,160
ongoing mainly on
the Parkinson's disease side

7301
06:11:30,160 --> 06:11:31,600
because the Parkinson's
disease side

7302
06:11:31,600 --> 06:11:33,560
is a little bit
further along.

7303
06:11:33,560 --> 06:11:36,240
They have already developed
a lot of the outcome measures

7304
06:11:36,240 --> 06:11:38,600
that we use
for clinical trials,

7305
06:11:38,600 --> 06:11:42,200
but it's obvious that
the next patient population

7306
06:11:42,200 --> 06:11:43,760
in which,
you know,

7307
06:11:43,760 --> 06:11:45,800
GBA-targeted interventions
are going to be started

7308
06:11:45,800 --> 06:11:48,720
is going to be
the Lewy body dementia cases.

7309
06:11:48,720 --> 06:11:50,240
So it's just --

7310
06:11:50,240 --> 06:11:52,840
But it tells us very nicely
that we actually,

7311
06:11:52,840 --> 06:11:55,560
by paying attention
to the related fields,

7312
06:11:55,560 --> 06:11:57,320
we can learn a lot
from each other,

7313
06:11:57,320 --> 06:11:59,560
and so the Parkinson's field
has accelerated

7314
06:11:59,560 --> 06:12:01,480
Lewy body
dementia research,

7315
06:12:01,480 --> 06:12:04,360
and I think it's happening
now also in return.

7316
06:12:04,360 --> 06:12:06,600
A lot of insights that we're
gaining in Lewy body dementia

7317
06:12:06,600 --> 06:12:09,000
is also informing
Parkinson's disease.

7318
06:12:09,000 --> 06:12:11,280
So the similarities and
the differences

7319
06:12:11,280 --> 06:12:12,640
are really quite instructive

7320
06:12:12,640 --> 06:12:15,320
about very fundamental
mechanisms

7321
06:12:15,320 --> 06:12:16,560
that are happening
in the brain.

7322
06:12:16,560 --> 06:12:18,400
There's more work to be done,

7323
06:12:18,400 --> 06:12:21,200
but I appreciate, you know,
your participant,

7324
06:12:21,200 --> 06:12:23,880
and, you know, I'm sure
we have more to talk about

7325
06:12:23,880 --> 06:12:27,080
at the next summit as well.

7326
06:12:27,080 --> 06:12:29,000
-And I just want to,
as an after --

7327
06:12:29,000 --> 06:12:32,480
you know, an after-statement,
I just want to promote the fact

7328
06:12:32,480 --> 06:12:35,040
that the International
Lewy Body Dementia Conference

7329
06:12:35,040 --> 06:12:37,720
is coming up in June
in Newcastle,

7330
06:12:37,720 --> 06:12:40,640
so I'm hoping to see
many of you there, please.

7331
06:12:40,640 --> 06:12:43,040
-Thank you.
-See you there.

7332
06:12:43,040 --> 06:12:45,960
-Yeah.

7333
06:12:45,960 --> 06:12:50,280
-The next question, Jim,
would you like to take that?

7334
06:12:50,280 --> 06:12:53,240
-Sure.
I think this is Barbara Boehm.

7335
06:12:57,600 --> 06:12:58,600
-Hi.
Hello.

7336
06:12:58,600 --> 06:13:00,720
This is my first time,

7337
06:13:00,720 --> 06:13:05,840
and it's a pleasure listening
to all of you and meeting you.

7338
06:13:05,840 --> 06:13:11,200
My father was diagnosed last
year with Lewy body dementia.

7339
06:13:11,200 --> 06:13:13,200
He was originally diagnosed
with Alzheimer's

7340
06:13:13,200 --> 06:13:14,760
and Parkinson's disease,

7341
06:13:14,760 --> 06:13:18,440
so this is fairly new,
so my question is basically,

7342
06:13:18,440 --> 06:13:21,000
his family has a history
of Parkinson's disease,

7343
06:13:21,000 --> 06:13:23,040
and I'm wondering if there's
a genetic connection

7344
06:13:23,040 --> 06:13:24,640
associated with that.

7345
06:13:27,000 --> 06:13:28,680
You know, based on the research

7346
06:13:28,680 --> 06:13:30,240
that I've been
listening from Sonja,

7347
06:13:30,240 --> 06:13:32,920
have you noticed any kind of
trends of behaviors that,

7348
06:13:32,920 --> 06:13:38,800
you know, indicate that it's
more genetic than an anomaly?

7349
06:13:38,800 --> 06:13:42,720
-So it looks like Dr. Scherzer
has hand up, so he can start.

7350
06:13:42,720 --> 06:13:45,240
-Okay.
-Then we can go to Sonja.

7351
06:13:45,240 --> 06:13:47,240
-Yeah, so, yes.

7352
06:13:47,240 --> 06:13:49,880
So actually, this is a very
important area

7353
06:13:49,880 --> 06:13:53,920
where we're starting to unravel
the genetic contribution

7354
06:13:53,920 --> 06:13:56,000
to Lewy body dementias,

7355
06:13:56,000 --> 06:14:01,000
and there's clearly
an important genetic factor,

7356
06:14:01,000 --> 06:14:02,560
but what you're also
pointing out

7357
06:14:02,560 --> 06:14:07,160
is that there's
an important linkage.

7358
06:14:07,160 --> 06:14:10,120
We used to think about these
diseases as different silos,

7359
06:14:10,120 --> 06:14:12,280
Parkinson's disease,
Alzheimer's disease,

7360
06:14:12,280 --> 06:14:13,600
Lewy body dementia,

7361
06:14:13,600 --> 06:14:17,000
but in reality,
these clinical silos,

7362
06:14:17,000 --> 06:14:21,000
this is a very simplistic view
and at the level of genetics

7363
06:14:21,000 --> 06:14:24,040
and at the level of looking
at the brain, these,

7364
06:14:24,040 --> 06:14:29,440
the pathways for these three
diseases are actually linked,

7365
06:14:29,440 --> 06:14:33,600
and so we see that some --

7366
06:14:33,600 --> 06:14:37,600
There are some genetic closeness
like APOE

7367
06:14:37,600 --> 06:14:42,800
and perhaps WWOX-1
that are linked to Alzheimer's

7368
06:14:42,800 --> 06:14:44,960
but also to Lewy body dementia

7369
06:14:44,960 --> 06:14:47,840
and also linked to
Parkinson's patients at risk

7370
06:14:47,840 --> 06:14:49,680
for developing dementia.

7371
06:14:54,280 --> 06:14:55,920
-I just want to say that,
you know,

7372
06:14:55,920 --> 06:14:58,560
the genetics is just
one piece of the puzzle.

7373
06:14:58,560 --> 06:15:01,200
I think there are so many
different factors

7374
06:15:01,200 --> 06:15:05,000
that are playing a role,
so I mentioned genetics,

7375
06:15:05,000 --> 06:15:08,240
but there's also lifestyle,
environmental factors

7376
06:15:08,240 --> 06:15:09,920
and what we call epigenetics

7377
06:15:09,920 --> 06:15:12,440
which is kind of
the intersection

7378
06:15:12,440 --> 06:15:16,680
between the environment
and the genetic fingerprint.

7379
06:15:16,680 --> 06:15:21,200
And so while we recognize
the genetic plays a role,

7380
06:15:21,200 --> 06:15:22,960
it's not everything.

7381
06:15:22,960 --> 06:15:27,240
So it gives us at least some,
you know, areas in the cell

7382
06:15:27,240 --> 06:15:30,080
that we can put our fingers on,
and we can model it,

7383
06:15:30,080 --> 06:15:32,560
but not everybody
who carries risk variant

7384
06:15:32,560 --> 06:15:35,800
necessarily will have
to develop the disease.

7385
06:15:35,800 --> 06:15:39,400
We recognize it is one piece
of the puzzle,

7386
06:15:39,400 --> 06:15:42,840
but there's many other factors,
in particular the aging,

7387
06:15:42,840 --> 06:15:44,440
that are playing a role.

7388
06:15:44,440 --> 06:15:47,840
And so, you know, in aggregate,
we'll have to understand

7389
06:15:47,840 --> 06:15:50,160
the more complex changes
of aging

7390
06:15:50,160 --> 06:15:53,960
and how some of these, you know,
risk factors are then in contact

7391
06:15:53,960 --> 06:15:55,760
with aging
and environmental factors

7392
06:15:55,760 --> 06:16:01,600
are causing the cell death
and the disease to happen.

7393
06:16:01,600 --> 06:16:03,560
-So, Sonja, just to --

7394
06:16:03,560 --> 06:16:05,600
a question in regards
to what you're saying.

7395
06:16:05,600 --> 06:16:07,320
As far as the
environmental factors,

7396
06:16:07,320 --> 06:16:11,600
can you provide me an example
as far as environmental?

7397
06:16:11,600 --> 06:16:14,240
Is it toxins
or a particular job?

7398
06:16:14,240 --> 06:16:16,200
Let's say if he was working
in manufacturing,

7399
06:16:16,200 --> 06:16:18,720
and there was a lot of toxins
in the environment.

7400
06:16:18,720 --> 06:16:21,640
Would that be
a contribution factor?

7401
06:16:21,640 --> 06:16:23,120
-Yeah.
That's a great question.

7402
06:16:23,120 --> 06:16:25,600
I think, you know,
there's definitely --

7403
06:16:25,600 --> 06:16:27,040
We've gained some insights,

7404
06:16:27,040 --> 06:16:29,560
but I also want to say
that the epidemiology,

7405
06:16:29,560 --> 06:16:32,200
there's still a lot of room
to grow.

7406
06:16:32,200 --> 06:16:36,600
So we're seeing, for example,
the pesticides are associated.

7407
06:16:36,600 --> 06:16:39,720
Rural living is associated
with higher risk

7408
06:16:39,720 --> 06:16:44,160
for Lewy body dementia
but also related diseases,

7409
06:16:44,160 --> 06:16:46,600
Parkinson's disease,
and I think, you know,

7410
06:16:46,600 --> 06:16:49,320
what these kind of toxins
are doing

7411
06:16:49,320 --> 06:16:54,000
is that they are targeting
specific functions in the cell,

7412
06:16:54,000 --> 06:16:56,960
in the machinery,
and so maybe in concert

7413
06:16:56,960 --> 06:17:00,680
with being a little bit
genetically predisposed,

7414
06:17:00,680 --> 06:17:04,320
if you have a lot of exposure
to these toxins,

7415
06:17:04,320 --> 06:17:06,400
it may be enough
to drive the disease

7416
06:17:06,400 --> 06:17:09,200
mechanism as you're aging.

7417
06:17:09,200 --> 06:17:11,280
And so that, for example,

7418
06:17:11,280 --> 06:17:14,600
there's also been discussion
about heavy metals,

7419
06:17:14,600 --> 06:17:18,040
solvents, but I think
we still don't understand

7420
06:17:18,040 --> 06:17:20,200
all of the environmental factors

7421
06:17:20,200 --> 06:17:24,360
that are playing a role
especially over a lifetime.

7422
06:17:24,360 --> 06:17:25,760
-Okay.
All right.

7423
06:17:25,760 --> 06:17:27,440
Thank you so much
for answering my questions.

7424
06:17:27,440 --> 06:17:29,000
I really appreciate it.

7425
06:17:29,000 --> 06:17:31,320
Thank you, again, for all
the hard work you're doing.

7426
06:17:31,320 --> 06:17:32,440
-Thank you.

7427
06:17:32,440 --> 06:17:34,360
-Thanks for the
great questions.

7428
06:17:34,360 --> 06:17:37,000
Worth noting as well,
I hate to be my recruiter,

7429
06:17:37,000 --> 06:17:41,040
but there are lots of centers
around the country now focused

7430
06:17:41,040 --> 06:17:44,000
on Lewy body disease,
and if there's any interest,

7431
06:17:44,000 --> 06:17:49,680
people can certainly look
at the PWP website, for example.

7432
06:17:49,680 --> 06:17:54,280
I think you're up next.
-John Paul Taylor, I believe,

7433
06:17:54,280 --> 06:17:59,920
has joined us and willing
to ask his question.

7434
06:17:59,920 --> 06:18:01,760
Hi, John Paul.
-Hi, y'all.

7435
06:18:01,760 --> 06:18:04,400
-He's joining us from UK.

7436
06:18:04,400 --> 06:18:05,880
-It's been a really
great session,

7437
06:18:05,880 --> 06:18:08,400
and I'm so pleased
to have joined you guys.

7438
06:18:08,400 --> 06:18:12,040
I just have a question with
regard to disease heterogeneity,

7439
06:18:12,040 --> 06:18:14,360
and I suppose this is coming
from my basis

7440
06:18:14,360 --> 06:18:17,720
of being a clinician
who sees people with LBD,

7441
06:18:17,720 --> 06:18:21,760
and I'm always struck by the
range and tapestry of symptoms

7442
06:18:21,760 --> 06:18:23,800
that people experience,
you know,

7443
06:18:23,800 --> 06:18:26,000
and it really is diverse
and, you know,

7444
06:18:26,000 --> 06:18:29,720
the range of progression
that people experience,

7445
06:18:29,720 --> 06:18:33,200
and I suppose I did wonder
through the recommendations

7446
06:18:33,200 --> 06:18:35,400
if there needs to be
a little bit more of, I suppose,

7447
06:18:35,400 --> 06:18:39,240
a nod towards this heterogeneity
so we can move beyond,

7448
06:18:39,240 --> 06:18:43,720
I suppose, our categorical
diagnostic nomenclatures

7449
06:18:43,720 --> 06:18:46,880
or, I think,
silos was a good term

7450
06:18:46,880 --> 06:18:49,800
towards perhaps more phenotypic
dimensional axes?

7451
06:18:49,800 --> 06:18:52,520
So we think about the severity
of motor symptoms,

7452
06:18:52,520 --> 06:18:55,800
sleep symptoms,
autonomic, neuropsychiatric

7453
06:18:55,800 --> 06:18:57,360
and, indeed,
also progression

7454
06:18:57,360 --> 06:19:01,200
and, I suppose importantly,
resilience to damage.

7455
06:19:01,200 --> 06:19:03,400
So I just wanted to get
the panel's view

7456
06:19:03,400 --> 06:19:06,200
on that perspective.

7457
06:19:06,200 --> 06:19:08,520
-Very good question, John Paul.

7458
06:19:08,520 --> 06:19:13,200
I can talk to the biomarker
perspective that heterogeneity

7459
06:19:13,200 --> 06:19:19,040
is definitely there in terms
of the variety of biomarker,

7460
06:19:19,040 --> 06:19:20,440
you know, measurements
we're seeing

7461
06:19:20,440 --> 06:19:23,840
in Lewy body
dementia patients,

7462
06:19:23,840 --> 06:19:27,600
and how that translates
into the clinical phenotyping

7463
06:19:27,600 --> 06:19:29,160
is also important,

7464
06:19:29,160 --> 06:19:34,200
and certain biomarkers hatch
on to certain phenotypes,

7465
06:19:34,200 --> 06:19:38,440
and that really explains
some of the heterogeneity,

7466
06:19:38,440 --> 06:19:41,200
but there's, of course,
all the other ones

7467
06:19:41,200 --> 06:19:46,200
with genetics and pathologic
heterogeneity and so on.

7468
06:19:46,200 --> 06:19:51,280
So I will give some time
to Dr. Cedarbaum here

7469
06:19:51,280 --> 06:19:56,640
and Angela Taylor to make
comments on this as well.

7470
06:19:56,640 --> 06:19:59,280
-Yeah, so, thanks, Kejal.

7471
06:19:59,280 --> 06:20:01,520
John Paul,
that's a great question,

7472
06:20:01,520 --> 06:20:02,720
and I wanted to come at it

7473
06:20:02,720 --> 06:20:05,760
from the clinical
trials perspective

7474
06:20:05,760 --> 06:20:08,760
because I, like you,
find this a challenge

7475
06:20:08,760 --> 06:20:10,960
but also an opportunity,

7476
06:20:10,960 --> 06:20:15,240
and it's sort of
an RDoC-like thing,

7477
06:20:15,240 --> 06:20:18,200
and the fact
that Lewy body dementia

7478
06:20:18,200 --> 06:20:23,200
is really the classic
multiproteinopathy,

7479
06:20:23,200 --> 06:20:26,680
if you will, disease
where we think,

7480
06:20:26,680 --> 06:20:32,240
at least, we have some idea of
how to trace certain symptoms

7481
06:20:32,240 --> 06:20:36,680
to certain underlying
protein abnormalities

7482
06:20:36,680 --> 06:20:39,840
in the brain or circuits
in the brain,

7483
06:20:39,840 --> 06:20:42,520
we shouldn't let it
overwhelm us.

7484
06:20:42,520 --> 06:20:45,480
And I think you're absolutely
right that this disease

7485
06:20:45,480 --> 06:20:50,840
provides us an opportunity
to test out drugs

7486
06:20:50,840 --> 06:20:52,360
directed at various targets

7487
06:20:52,360 --> 06:20:54,960
not only for disease
modification

7488
06:20:54,960 --> 06:20:59,640
but for symptom control which
patients desperately need now

7489
06:20:59,640 --> 06:21:01,040
as we're working out

7490
06:21:01,040 --> 06:21:04,440
the mechanisms
of disease modification,

7491
06:21:04,440 --> 06:21:06,080
and I think it is something.
I agree with you.

7492
06:21:06,080 --> 06:21:09,240
This is something
we should keep in mind

7493
06:21:09,240 --> 06:21:12,600
as we think about therapeutics
and therapeutics development

7494
06:21:12,600 --> 06:21:14,400
for Lewy body dementia.

7495
06:21:16,840 --> 06:21:18,240
-Thank you, Jesse.

7496
06:21:18,240 --> 06:21:21,480
Angela?
-Hi, John Paul.

7497
06:21:21,480 --> 06:21:23,920
I just want to respond to your
question

7498
06:21:23,920 --> 06:21:25,680
through the lens
of the Dementia Nomenclature

7499
06:21:25,680 --> 06:21:30,320
Initiative which actually has
its roots here in this summit.

7500
06:21:30,320 --> 06:21:32,240
One of the things,
one of the recommendations

7501
06:21:32,240 --> 06:21:34,400
that's coming up
out of this initiative

7502
06:21:34,400 --> 06:21:38,240
is the importance
of clear communication

7503
06:21:38,240 --> 06:21:41,160
and perhaps
different definitions

7504
06:21:41,160 --> 06:21:45,200
between the syndromes
from the pathophysiologies

7505
06:21:45,200 --> 06:21:48,480
and the importance of maybe
using those syndromic

7506
06:21:48,480 --> 06:21:53,360
descriptive
terms to allow for more focus

7507
06:21:53,360 --> 06:21:58,120
on the underlying disease
process itself.

7508
06:21:58,120 --> 06:22:02,480
We also are going to be looking
at highlighting the importance

7509
06:22:02,480 --> 06:22:07,400
of communicating severity
by domain, symptomatic domains,

7510
06:22:07,400 --> 06:22:08,960
and not just looking at it

7511
06:22:08,960 --> 06:22:11,760
all through the lens
of how severe is the dementia

7512
06:22:11,760 --> 06:22:14,560
but making sure
that through research

7513
06:22:14,560 --> 06:22:16,680
all the way
through delivery, diagnosis

7514
06:22:16,680 --> 06:22:22,880
and clinical management
that we open up the information

7515
06:22:22,880 --> 06:22:26,480
flow about
those different domains

7516
06:22:26,480 --> 06:22:31,760
as a matter of clinical
management and ongoing care

7517
06:22:31,760 --> 06:22:35,800
and helping the families look
at this from a perspective of,

7518
06:22:35,800 --> 06:22:42,080
where are we in comparison
to where we might be going?

7519
06:22:42,080 --> 06:22:47,400
So I hope that's also helpful.
-Thanks, all.

7520
06:22:47,400 --> 06:22:49,080
That's really, really useful.

7521
06:22:49,080 --> 06:22:52,000
Great chat.

7522
06:22:52,000 --> 06:22:57,960
-Thank you, and I think we have
come to the end of our session.

7523
06:22:57,960 --> 06:23:02,080
I will hand it over to Jim
to close our session.

7524
06:23:02,080 --> 06:23:06,680
-Just great questions
and nice discussion.

7525
06:23:06,680 --> 06:23:09,000
I really appreciate
the contributions, Kejal.

7526
06:23:09,000 --> 06:23:13,600
Thank you and all the members
of the LBD group,

7527
06:23:13,600 --> 06:23:18,800
and end of the first day,
I guess, and onto day two.

7528
06:23:18,800 --> 06:23:22,400
-Yes, and thank you to you,
Dr. Leverenz and Dr. Kantarci.

7529
06:23:22,400 --> 06:23:24,240
Fantastic day one, everybody.

7530
06:23:24,240 --> 06:23:26,160
We've been waiting for this
for 3 years

7531
06:23:26,160 --> 06:23:30,280
and, you know, preparing for
6 months, and here we are.

7532
06:23:30,280 --> 06:23:33,720
So see you tomorrow at 10
o'clock Eastern Standard Time,

7533
06:23:33,720 --> 06:23:37,560
same place, same time and for
another day of fantastic summit.

7534
06:23:37,560 --> 06:23:39,240
Have a good night, everybody.

7535
06:23:39,240 --> 06:23:40,360
-Thank you.
-Good chat, folks.

7536
06:23:40,360 --> 06:23:41,200
Thank you.

7537
06:23:41,200 --> 06:23:43,360
-All right.