-Good morning, everyone.
I'm Natalia Rost, and I'm Scientific Chair
of the 2022 ADRD Summit,
and this is the moment we've been waiting for
for 3 years to get together again,
and on behalf of our entire program-planning team,
it is my great honor to officially open the summit
and to introduce our first speaker, Dr. Walter Koroshetz,
Director of the National Institute
of Neurological Disorders and Stroke.
Welcome.
-Oh, thank you, Natalia.
Can you hear me all right?
Very good.
Yep, well, I want to welcome everyone who's attending
and also thank all the people who put a lot of work
into what we're going to hear in the next 2 days.
This was really the result of a lot of hard thinking
and very smart people,
all dedicated to this common goal of trying to figure out
how we can better reduce the burden of illness
due to Alzheimer-related dementias.
The next slide, please.
And again, special thanks to Natalia for leading the group.
I think it was a good group,
so it wasn't as hard as some of the other groups
I made her lead in the past.
Next slide.
So what we're talking about is a national priority
that Congress has spoken about and actually funded generously
to try to make a difference in this problem
of Alzheimer-disease-related dementias.
We're talking about irreversible,
right now, irreversible, progressive brain diseases
that rob people of the ability to interact and communicate,
and eventually many of these are fatal diseases.
They slowly destroy brain function,
leading to cognitive decline,
behavioral and psychiatric disorders and inability
to even function and activities of daily
living and requiring care.
It's a major public health issue
affecting the health and finances,
but it's really a tragedy for the individual
and the family particularly.
So the NAPA law in 2011 offered historic opportunity
to address the Alzheimer's disease issue
and Alzheimer's disease-related dementias,
and we will be talking mostly
about the Alzheimer's disease-related dementias
as opposed to Alzheimer's as a pure entity.
That is -- comes under the purview
of the National Institute of Aging Summit
that we intersperse with our summit.
But as you'll see, there is tremendous overlap
in the Alzheimer's and the Alzheimer-related dementias,
and so learning from one really helps learning in the others.
Next slide.
So what we're talking about in terms of the congressionally
defined Alzheimer's disease-related dementias
are basically the vascular contributions of dementia,
so as our brains age,
our blood vessels to the brain age.
This is easily seen under the microscope,
but also the contributions of vascular aging
and several vascular diseases are very apparent on MRI scans,
a very sensitive technique to pick up these changes,
and so these are things that are standing right in front of us,
easy to identify but tricky so far to figure out
how to decrease the contribution of vascular disease
and vascular risk factors for dementia
although if one looks at the literature
in terms of a short-term win,
all the data points to the fact that controlling vascular health
will actually reduce cognitive impairment as we age
and also potentially reduce the risk of developing dementia.
Lewy body dementia is a term that's used for conditions
where there's dementia related
to what are called these aggregates of a protein
called synuclein inside of neurons,
also in the neurites themselves, the processes of the neurons.
You get these aggregates of synuclein,
and that is also the signature of Parkinson's disease,
and many patients with Parkinson's develop
cognitive impairment over time
because these Lewy bodies start to move throughout the brain,
and there's also a condition in which the Lewy bodies
start in the thinking area of the brain
and cause dementia first and then Parkinson's later.
Frontal temporal dementia
is also a very common cause of dementia,
one of the more common causes of dementia
in people who are younger, in their 50s or 60s,
and these, again, are associated with atrophy
and loss of brain tissue
in particular areas of the brain.
Depending on the area, there are these certain symptoms,
frequently troubles with behavior or language.
And also, of interest, we found more recently
is there's a strong association
with some of these frontal dementias
with amyotrophic lateral sclerosis,
which causes progressive and fatal paralysis
of all the muscles in the body
due to loss of the motor neurons that control those muscles.
And finally probably also incredibly important
is the discussion of the fact that when people's brains
are examined who have dementia in this elderly space,
more frequently than not, there's a combination
of different pathologies in the brain,
so the cause of the dementia, we think,
is related to a combination of the Alzheimer problem,
the synuclein problem, the cerebrovascular problem,
and so we see those combinations,
and certainly we're going to treat Alzheimer's.
We're going to have to try to understand
how each of these contributing pathologies are best treated.
Next slide.
And so the research is focused right now
on trying to understand the biological mechanisms.
Without understanding those,
we really can't develop treatments,
but there has been a lot of progress in this space,
in discovery of targets
that could be pursued to develop therapies,
and also importantly is the progress
in developing biomarkers, so these are measurements
that one can make in living individuals
that will predict what kind of pathology
there is going on in the brain.
And lastly we want to mention
that the research that's being done,
Alzheimer's disease and related dementias,
includes a lot of gaps in knowledge,
but there is a lot of research going on, very basic research
in how the brain works and how it organizes
and how inflammatory cells interact with the brain,
both normally and abnormally, that all kind of come together
in trying to improve our understanding
of Alzheimer's and Alzheimer's-related dementias.
Next slide.
And this is just to tell you
that we, you know, it is complicated
because there are so many factors
that go into the development of dementia.
It's something that occurs usually in the,
you know, the age of individual,
and so, so many things have happened to the brain over time,
whether it's traumatic brain injury
or stroke or vascular disease,
the development of these abnormal proteins,
but we have to piece this apart...
piece this together and identify the pieces
that are going to be most potentially important
as targets for therapies,
but that's kind of the just simplistic version
of what our goal is,
is to understand the features, understand how they fit together
and then develop treatments that are going to be effective.
Next slide.
And there has certainly been advances over time,
particularly in the biomarker space,
for Alzheimer's, and also, the Alzheimer-related dementias
is, we think, very good now,
accurate ways of testing spinal fluid
or even skin biopsies to detect the synuclein
aggregates that are associated with Parkinson's disease
and Lewy body disease.
There are certain radioactive scans
that one can do to detect dopamine loss in people
who have Lewy body disease,
separates them from Alzheimer's disease,
and there's now really interesting,
very predictive studies
looking at evidence of Alzheimer pathology in people
with Lewy body disease and Parkinson's disease
that contributes to their troubles with cognition,
so we're getting now the ability to look at living individuals
and actually get evidence for what is going on in the brain,
and as I mentioned before,
that's the critical thing to know in determining
what treatment is going to be best for what patient,
and so there was tremendous progress in this space now.
Next slide.
And right, and so, even on the vascular side,
I said, yeah, the MRI is incredibly sensitive
to picking up changes in the white matter of the brain,
which is very common, associated with hypertension
and several vascular disease,
present in probably 80 percent of people
at some degree after the age of 80.
These are kind of things that we can,
you know, follow over time
and see if therapy affects their progression over time
because you're not born with this,
but it develops over time,
and it's easy to see on the MRI scan.
Next slide.
And just important to mention that we are really doubling down
in looking to the future where there are treatments
to make sure that those treatments
are going to be available for everyone in our society,
and that is unfortunately not a trivial task.
People may present differently depending on their culture,
the racial, ethnic background.
You don't want to miss...
If you need to treat early in the dementia,
you don't want to miss that
because there's some inequities in the system
in terms of picking it up in addition
to being able to make sure
that all the treatments are accessible to folks.
You do a lot of genetic studies to determine,
you know, genetic risk factors.
I'm sorry to say most of that genetic work has been done
on Caucasians of European descent,
and we know now that some things like APOE are --
may act very different in African Americans,
so we really need to think as we move forward
so that what we discover is relevant
to all segments of our population.
They may not all be the same,
but we need to know what those differences are.
So thank you.
Next slide.
And I want to just end up by thanking our partner
in this effort,
working hand in hand with the National Institute of Aging
for many years.
We initially started, you know, putting out the plan
not realizing that there was going to be funding coming,
and with the funding coming, both NIA, NINDS
and the other partners have really put together
what I think is a really earth-shattering series
of research projects
over the years that really opening the door
to therapies for these diseases now.
So I want to thank everybody and looking forward
to hearing the recommendations
coming out of the different work groups.
Thank you very much.
-Thank you. Good morning.
Thank you, Dr. Koroshetz.
My name is Cindy Carlsson.
I'm a physician in geriatrics
of University of Wisconsin in Madison,
Professor of Medicine there,
and also with the VA hospital in Madison, Wisconsin,
and as Chair of the Advisory Council on Alzheimer's Research,
Care and Services, I'll be speaking next
just for the next few minutes to share with you
all a little bit of perspective based on the NAPA Council.
So the National Plan to Address Alzheimer's Disease
has already been addressed by Dr. Koroshetz,
and we'll hear more from Dr. Rose, Dr. Corriveau,
but again, the national plan really,
really bases a lot of its input
from these important research summits,
so again, as you'll see today and as we'll touch on briefly,
these summits really feed into helping develop these ideas
and moving this work forward, so the NAPA plan,
which I'll talk about, covers clinical care,
long-term services and support and research
and has a new goal of risk reduction,
so we have four subcommittees that really help alter
the national plan and move it forward,
but these summits are critically important
as we move forward in these areas.
Next slide, please.
So by way of disclosure, again, these are my views,
not NIH's views or NAPA or ASPE,
and I do receive funding from NIH,
the VA, NIH/Lilly and NIH/Eisai.
Next slide.
So then the National Alzheimer's Project Act was first enacted
just over 10 years ago in 2011 as Dr. Koroshetz mentioned,
and one thing that's extremely important to note
for this meeting is that this...
although it's called the Alzheimer's Act,
it's really meant to include Alzheimer's-related dementias
as well, so again, for brevity's sake,
it just says, "Alzheimer's," throughout the plan,
but it says in introduction that this is really meant
to include all the different forms of dementias,
and so as we speak about NAPA,
it should be whatever the abbreviation would be pronounced
with all the other dementias included.
So again, this is led by the Assistant Secretary's Offices
for Planning and Evaluation,
and they became the lead right after that,
and then the first Advisory Council
was in September of 2011.
The first national plan was developed
and released just almost 10 years ago,
so one thing, I think, that's important for us to step back
and think about is, as far as perspective,
is not only to look to the future
about what areas need to be evaluated still,
what gaps there are in research
but also for us to take a step back
and to think about the progress that's been made
in the last 10 years,
so thinking about new, novel PET-scan tools, biomarker tools
that really help us pinpoint the disease
and help us to understand that many of these dementias
are multiple-etiology dementias.
So again, having these factors can really help us
find the commonalities and the differences
between these types of dementias among many other advances.
So in our upcoming NAPA meeting, we'll be highlighting,
having the federal agencies highlight
the accomplishments over the past 10 years,
so again, taking a step back to think,
"What have we accomplished so far,
and how can we use that momentum to move forward?"
Next slide.
So the National Alzheimer's Project Act
required that the Department of Health and Human Services
establish the following items,
so again, there's two main products out of this
that have generated a lot of synergy with these summits,
so for example, to create and maintain a national plan
to overcome Alzheimer's disease and related dementias,
to coordinate research and services across federal agencies
and, again, not just federal agencies.
This is a national plan, so again,
to serve as a blueprint for states,
counties, communities to really align their work
together to move things forward,
to accelerate the development of treatments
that would hopefully prevent, halt or reverse the disease,
the numerous disease we'll be talking about today,
improve early diagnosis in coordination of care
and treatment of the disease,
improve outcomes for people from racial
and ethnic-diverse communities
throughout our country who are at higher risk
in some cases for developing dementia
and then coordinating with international bodies as well,
so we really want to make sure that we're leading the way
globally in these efforts,
and then creating an advisory council,
which again, I currently serve as chair,
to review and comment on the national plan
and its implementation.
Next slide.
So the advisory council, again,
works together to review the national plan,
to integrate ideas from summits just like this one
to make sure that the plan reflects
the current scientific thinking, clinical care,
policies that are there,
and so the public arm of the council includes 12 members,
and so these 12 members
come from diverse backgrounds from...
Some are patient advocates, again,
including people who are living with dementia
and mild cognitive impairment.
There's caregivers, providers, state
and local representatives, researchers
and then two voluntary health association representatives.
So again, this input is really important as we shape the future
of research, clinical care and long-term support services,
and again, we want people to continue to provide input,
and as I'll mention at the end,
there's always room for public comment,
and so we want the public, whether it be a researcher,
advocate, a caregiver, to really speak into these goals
and help shape this national plan.
We also have colleagues from our federal --
from the federal government, so again,
we have colleagues from the Department of Health
and Human Services, Veterans Affairs,
Department of Defense, National Science Foundation,
and you'll see within Health and Human Services we have:
the Office of the Assistant Secretary
for Planning and Evaluation,
or ASPE, Indian Health Service, NIH, of course,
National Centers for Medicare and Medicaid Services, CMS,
Agency for Healthcare Research Equality,
Administration for Community Living,
Centers for Disease Control, Health Services Administration
and Food and Drug Administration.
So you, again, see that there's this partnership
for the public team bringing in a perspective
of patients, caregivers, researchers
and then the federal partners helping guide
that towards actionable items.
Next slide.
So here are current members for both the public
and federal components of the advisory council,
so again, you'll see we have four subcommittees.
So Research Subcommittee, the LTSS stands for Long-Term
Support Services Subcommittee,
Clinical Subcommittee and Risk Reduction Subcommittee,
and as we'll discuss, the risk reduction
is a new goal this year,
and really while there's always been a goal
to prevent and treat Alzheimer's disease
and related dementias,
this really helps us move into the public-health space,
try to reduce risk in a large-scale effort
as Dr. Koroshetz mentioned with several of the other --
with numerous agencies making efforts in,
for example, reduction of hypertension,
increased exercise and other areas.
Next slide.
So the national plan focuses on initially five and now,
again, with a new sixth goal, so goal one is ambitious,
to prevent and effectively treat Alzheimer's disease
and related dementias by 2025,
so again, we're coming up against that benchmark,
but again, I think it's important for us to step back
and think where we've come, so again, there's the first...
While controversial, the first agent has been approved
by the FDA to treat Alzheimer's disease,
so the first step in helping us to think
through what kind of research needs to be done
to help us focus disease-modifying therapies
and effective treatment strategies.
And also, how does our health care system
respond to these agents being approved?
Do we have the infrastructure available
to help monitor safety for patients?
Do we have clinicians who are trained in diagnosing
and managing patients to be able to use
these new, novel therapies?
So again, prevention and treatment
is one of the first goals.
Second goal, again, to enhance care, quality and efficiency,
so again, it takes research to do this as well,
and you'll see today the multi-etiology dementia group,
that there's discussion about, how do you initially diagnose,
and how do you make sure that we have the workforce
to provide good care, quality and efficiency?
The goal three is to support people
with Alzheimer's-related dementias and their families,
so again, there's a caregiving summit
that occurs every third year in this summit series,
and that came out of NAPA goals with the need...
understanding that we need more research
and how to best support people with dementia
and their families.
Increasing public awareness and engagement, so again,
we want people to be a part of these meetings.
We want people to be a part of NAPA meetings.
If people aren't aware of dementia,
then they're not going to get in to get the care that they need.
They're not going to become a part of clinical trials.
They're not going to spread the word among their colleagues
and engage in risk-reduction activity,
so again, these are very important areas to promote.
And then improving data to track progress
so that we can see, how are we doing now,
and how are we doing in the future with these initiatives?
So accelerating action to promote healthy aging
and risk reduction is our new goal,
so again, moving into public health space
and reducing risk for these factors
but also needing research to make sure that we understand,
what are the most promising risk-reduction factors?
Next slide.
-Two minutes remaining. -Thank you.
So the...
Again, the summits really influence the NIH plan by --
the NAPA plan by really determining
the highest research questions
that can really drive the field forward and coordinate efforts
and serve as a blueprint for not only federal programs
but also national programs outside of the government,
state programs and international programs.
Next slide.
So what you'll see today Dr. Corriveau will go over
in more detail next
is that we have with the ADRD Summit,
as you'll see listed off to the right,
there are overarching topics that really impact
all of the different phases of dementia
and all the different goals that are addressed,
so under multiple-etiology dementia,
as mentioned, we'll be talking about,
how do you diagnose Alzheimer's?
How do you diagnose other dementias?
Do we have the workforce available
to make these diagnoses?
Are we including people who are at high risk
for the disease in our clinical trials?
Are we making sure that a therapy for developing
are effective in all people in all communities?
Lewy body disease, are we helping people
to understand frontal temporal dementia,
Lewy body disease, vascular contributions?
Do clinicians understand how to diagnose these?
Do we have the therapies needed
to specifically treat these conditions?
And then you'll see that we'll be talking about today
about new and arising issues, such as COVID-19,
newer pathologies that have been discovered,
TDP-43 and also the impact,
which is important to veterans who I work with,
on post-traumatic brain injury in people who are risk
for Alzheimer's and related dementias.
So you'll see that the summit today really informs
a lot of the goals that NAPA covers, so next slide.
So again, I encourage people to stay involved,
provide public comment, provide feedback,
and then, again, our next NAPA meeting will be
May 2nd and 3rd, and we'll address some of the research
and risk-reduction goals
and also hit the highlights of the last 10 years
and the progress that's been made,
so thank you for this chance to share with you
the integration of NAPA with the summit.
-Wonderful.
Thank you, Dr. Carlsson, and I also want to mention
that Dr. Carlsson joins us today in her capacity
as the Chair of the NAPA Council.
She's also an endowed professor in Alzheimer's disease
and the Director of the Wisconsin Alzheimer's Institute,
and so really appreciate you helping us frame this meeting.
Next slide, please.
I'm just going to focus on the last point on this slide,
and that is, under the National Plan
to Address Alzheimer's Disease,
there's an action item to regularly convene
on Alzheimer's Disease-Related Dementia Summit
to consider progress and research recommendations
to help drive the field forward.
That's what we're doing today.
This is the fourth of these summits,
and we take it very seriously,
and we really want your input today.
Next slide, please.
So to also put it in context of how seriously
and the scope of what we're doing is,
this is a process that has involved at least 6 months,
probably more of planning with more than 120 scientists,
physicians and administrators.
I'm the NINDS lead, and Natalia Rost is our Scientific Chair.
We have a distinguished steering committee,
including past chairs of these summits,
and the session committees are --
just to review them quickly once more,
multiple-etiology dementias,
health equity in AD/ADRD, Lewy body dementias,
frontal temporal dementia,
vascular contributions to cognitive-impairment dementia.
We also have special topics.
This has been a tradition in the Alzheimer's
Disease-Related Dementia Summits.
Impact of COVID-19 on AD/ADRD risk
and outcomes is a new topic.
We're also following up on LATE, TDP-43 pathology
in common, late-onset dementias and post TBI AD/ADRD.
The goals of the meeting are really to present
the rationale for the draft research recommendations
that you will be seeing,
to encourage discussion amongst stakeholders.
These are, again, draft recommendations.
We want your input.
We want these recommendations to be as strong
and as impactful as they can possibly be.
So we're soliciting feedback,
and this feedback will be considered
and considered seriously
when drafting the final draft recommendations.
Next slide, please.
Over the years, funds available for Alzheimer's
and Alzheimer's disease-related
dementia research have increased.
I won't go over the details of this slide,
but you can see that there are now considerable
more funds available
now than there were even 5 or 6 years ago.
Next slide, please.
Through our partnership with the National Institute on Aging,
which leads the NIH's response to the National Plan
to Address Alzheimer's Disease, funds are available,
made available to the NINDS for research,
and the NINDS uses these funds for investigator-initiated
research as well as Alzheimer's disease
and Alzheimer's disease-related dementias
funding opportunity announcements
that are directed at specific areas
that are responsible to the milestones in the national plan
that come from these summits.
Next slide, please.
To illustrate the level of activity and responsive,
NINDS led 14 new funding announcements
in fiscal year 2022,
and there are number of them that are still open,
and there are 14 new NINDS funding-announcement concepts
that are planned for fiscal year 2023.
We have an ongoing process.
We work closely within NINDS
and collaboration with other institutes,
in particular with the NIA,
and we create funding- opportunity announcements
that are responsive to workforce
needs as well as research needs that are detailed here.
Next slide, please.
So these summits set national research priorities
for the Alzheimer's disease-related dementias.
Over the years, we've had 62 NINDS
Alzheimer's disease-related funding initiatives
that have resulted in major ADRD programs and consortia,
and you see some of the logos
for those programs here on this slide.
And NIH ADRD research funding has increased from 2015 to 2020
to around 600 million per year at this point.
I'm going to - In interest of time,
I'm going to not talk about these programs specifically.
There's a lot of science to come today,
and I want to be able to move on to that, so next slide.
Just to give you a quick guide to the ADRD
draft recommendations, next slide, please.
As you're look at - looking at these recommendations
and as the scientific chair are presenting them
and you're thinking about them
and thinking about what your input might be -
And please, use the open mic time,
the question-and-answer time in this meeting.
Please use it. Please provide input.
You know, put your name in the question-and-answer box
that's down at the middle of your screen,
and let's have a lively discussion
during the open mic time.
But you'll see that there's a recommendation number.
There's a prioritization.
Priority one is the highest level prioritization.
It goes down, two, three four.
Keep in mind, anything that is mentioned in this summit
as a recommendation is a very high priority.
There are many, many things that could have been written up
as recommendations,
but didn't kind of make the final list for top priorities.
There are timelines that indicate the number of years
to complete or make fully operational a goal,
and so this just, I hope, helps you orient a little bit
to the recommendations as they're presented.
Next slide, please.
And I would like to introduce our scientific chair,
Dr. Natalia Rost.
Thank you.
-Thank you, Rod.
It is my great pleasure and privilege
to be part of this initiative, which is, as you know,
critical to scientific progress in dementia
but more importantly in translating this science
into clinical practice of diagnosis, treatment
and most importantly prevention of dementia
in the U.S. and worldwide, so next slide.
So these are my disclaimer and disclosures.
Next slide?
I would like to begin with a global view
of why our work here is so important
and remind everyone that despite the recent advances,
there is certainly much more to be done,
and I find this recent map generated
by the Global Burden of Disease Collaborative
of estimated percent change of dementia
prevalence to be a very effective tool
to demonstrate the ongoing challenge.
Even with some reports of, so to speak,
flattening the curve and, in dementia incidents
in some regions of the world, according to this report,
there is still uniformly projected growth
in prevalence of dementia cases expected between 2019 and 2050
with the estimated percent-change variant
anywhere between 20 to 40-percent increase
as the smallest and up to 2000-percent increase
in some regions, with the U.S. projected
to be in 80 to 100-percent increase by 2050.
Next slide.
But despite the need for global vigilance with this issue,
as clinician-scientists,
our focus is always on individual patients,
a focus that has always guided
the principles of dementia science,
our North Star, so to speak,
from bedside to bench and back to bedside,
and our patients' questions like, "What is happening to me?"
lead to development of cutting-edge diagnostics.
Questions like, "Why is it happening?" and "Why now?"
lead us to pursue some deep understanding
of basic mechanisms of disease.
When patients and their families ask,
"Where do we go from here?"
we seek novel interventions, we test support systems,
and we forge ahead with clinical trials,
and when our patients ask, "Am I going to be all right?"
we develop prognostication tools,
a screening test and employ robust support systems.
Next slide.
But the task at hand remains quite complex,
as you know.
There's been a fascinating evolution of dementia
as a clinical syndrome concept, especially over the few past
decades with the accumulation of knowledge
about underlying disease pathology,
you know, variability of clinical features,
molecular genetics
and environmental interactions as well,
and while science continues to evolve,
prior dogmas, like "One pathology equals one disease,"
are rapidly changing and understanding evolves
that multiple pathways may lead to a clinical dementia syndrome.
Next slide.
Furthermore, we'll learn that,
on the wide spectrum between brain health
on one end and brain disease
such as AD and ADRD on the other,
there is literally a lifetime where,
at every stage of our individual chronological lifespan,
including influences that occurred
during brain development,
there are innate as well as environmental factors
that impact the risk of developing dementia
at a later stage.
Most of these life stages are, of course, arbitrary,
and manufactures,
in part, their influence across their entire life,
of course, including those that have cumulative effects,
such as health disparities
related to historic societal structures.
Next slide.
So unsurprisingly, to overcome the complexities
of AD and ADRD as a disease process,
our approach to science has to remain nimble,
robust and informed by patient experiences,
and to stay on mission,
we must bring together diverse expertise,
close-cutting science and the perpetual cycle
of innovation, collaboration and communication in research,
and this is what 2022 ADRD Summit is all about.
After almost six - more than 6 months
of intense preparations, we're excited to present to you
a product of our scientific workgroups.
Next slide.
So by the way, a brief introduction, as an example,
the top priorities to be discussed by
the Health Equity in AD/ADRD group,
led by Dr. González and Zissimopoulos,
are to advance equity in AD
and ADRD research via inclusion science
and to expand the AD and the ADRD scientific workforce
of persons historically underrepresented in science.
Next slide.
The Frontotemporal Degeneration group,
led by Doctors Boxer and Karch will provide the rationale
for their top-priority recommendations
of understanding FTD epidemiology and genetics
in diverse populations
and in advancing understanding of FTD
with a goal of identifying therapeutic targets.
Next slide.
VCID group, cochaired by Doctors Wilcock and Petersen
will present their top priority recommendations
to establish and refine experimental models
and technologies to identify disease-relevant mechanisms
and to develop and validate markers of VCID
in diverse populations.
Next slide.
Lewy Body Dementias group,
led by Dr. Leverenz and Kantarci,
will share their top-priority recommendations
including the need for clinical trials to alleviate
or slow the course of LBD
while continuing to work on delineate genetic loci
and their functions that contribute
to the onset and progression of LBD.
Next slide.
On day two, the Multiple Etiology Dementias group,
led by Dr. Possin, continues its work on high priority
to evaluate pragmatic approaches to detect cognitive impairment
and moving conducting clinical studies
on a proofed or promising interventions
to mitigate cognitive decline.
Next slide.
In this Special Topics from the 2019 summit, post-TBI,
AD and ADRD and TDP-43 in Common Late-Onset Dementias or LATE,
as you will learn later in day two,
will present their top priorities
of promoting collaboration
among TBI and dementia researchers
and defining late classification
and diagnostic boundaries respectively.
Next slide.
And finally, I wanted to highlight the topic
that we have been very anxious to bring forward
for your consideration at this summit,
and it's the topic that clearly dominated our discussions
over the past two years:
the impact of COVID-19 pandemic on risk
and outcomes of AD and ADRD.
Clearly, a topic that is truly worthy
of an emerging science topic status in 2022.
Next slide.
As we all know, there are nearly 80 million COVID-19 survivors
in the U.S. alone,
and what we as clinicians learn from beginning of this pandemic
is that neurological, neuropsychiatric and cognitive
complaints are common in those suffering from COVID
and in survivors.
We have learned that SARS-CoV-2 infection has acute
and long-term effects on the brain
and that there are multiple mechanisms
by which the virus can cause the damage,
including the potential downstream effects
on neurodegenerative and vascular injury pathways,
and while the overall impact on AD and ADRD risk
and outcomes and is not yet known.
Potential detrimental effects may include increase
in incidents of cognitive impairment in dementia cases,
accelerated course of cognitive decline
among already diagnosed with AD and ADRD diagnosis,
accelerated neurodegeneration and vascular pathologies
in the brain among currently symptomatic,
shift in the population timeline
of cognitive decline toward younger ages
and increased incidents of early-onset dementias
and unfortunately, increased mortality
among those with advanced dementia.
-One minute remaining. -At this time, however,
the data is still scarce and knowledge is rapidly evolving,
but even in this very early stage,
the impact of SARS-CoV-2 infection
on the brain can be detected, as in, for example,
this recent study published by the UK Biobank on the left,
examining brain MRI in 400 patients
who tested positive for COVID-19 between their two scans
or the effects of the pandemic
on the newer psychiatric symptoms of dementia patients,
and notably their caretakers, as shown by a recent
international collaboration on the right.
So we have a lot of questions to answer in the future
as related to this special topic,
and I'm delighted that our newly formed working group,
cochaired with me by Dr. Sudha Seshadri,
will present to you our initial set of recommendations tomorrow.
Next slide.
But for now, I would like to welcome you again
to the 2022 ADRD Summit,
and I hope you all take advantage
of the open microphone sessions after each topic
like all of my colleagues urge you to.
This is, after all, an open forum,
and we would like to have a robust dialogue
or as robust as possible,
and thank you in advance for your contribution.
So we're on time, and without further ado,
I would like to welcome Doctors Hector González
and Dr. Julie Zissimopoulos,
cochairs of the Health Equity in AD and ADRD group,
who will kick off our scientific session program.
Welcome.
-Thank you.
On behalf of our health equity panel,
I thank Dr. Koroshetz, Corriveau
and the organizers for bringing our topic area
to the forefront of the 2022 Alzheimer's Disease
and Related Dementias Summit.
As a panel, we appreciate this opportunity
to further scientific attention and commitment
toward achieving Alzheimer's disease
and related dementia health equity through research.
In this health equity model - Next, please.
Oops, those are my disclosures.
Nothing to report.
In this health equity model,
dementia disparities are apparent in later life,
but we know this, and we've known this for years,
as Dr. Rost had mentioned before.
The big and unanswered questions are, "Why?
Why do these AD/ADRD disparities exist,
and when in the life course did they begin?"
and most importantly,
"How do we resolve the major public health problems
facing so many underrepresented minority communities?"
Some key implementation questions include,
"Does the scientific community have the tools necessary?
If not, then what research infrastructure
is needed to achieve research equity?"
To address these questions,
we recommend moving beyond disparities
and to seek new and innovative ways
to achieve health equity through our research.
Ethnic racial differences can only tell us
that the disparities exist
but not the means for achieving health equity.
As this life-course model suggests, within-group research
can tell us the origins and sources of the problems
and promising means for resolving AD/ADRD disparities.
Next slide, please.
As we - We as an ADRD health equity panel
were tasked with providing recommendations
for achieving health equity through research.
Our panelists - Our health equity panelists
responded to the challenge by recommending four focus areas
shown in these rectangles on the slide here.
First and foremost,
our panelists agreed that growing a diverse
and committed scientific workforce
is needed for achieving AD/ADRD health equity.
As shown here, the workforce encompasses and forms
a basic substrate for achieving health
equity goals of the other focus areas within.
Appropriate assessment tools and data
from underrepresented minority communities
is still woefully lacking.
Important data, for example, genomics,
are largely unavailable, as it was mentioned before,
which means that underrepresented
minority communities
have been left out of recent advances in biomarkers,
genomics, neuroimaging and other cutting-edge areas of research.
Additionally, replication studies so important
for scientific rigor are nearly impossible,
thereby compounding research inequalities.
Epidemiologic research progress is hampered
by a lack of basic tools that are largely nonexistent
for underrepresented minority communities.
Randomized clinical trials have been large -
have largely omitted
underrepresented minority communities
and so are so statistically underpowered
that inferences to non-white communities are,
at best, inconclusive.
Ultimately, the inequalities in available research tools
and data for underrepresented communities
affects patient care and quality,
which is compounded by the inaccessibility of health
care to so many underrepresented minority communities.
So moving forward, next, Dr. Luis Medina.
Next slide, please.
Dr. Luis Medina will provide the workforce panels recommendations
for achieving Alzheimer's disease
and related dementia health equity through research.
Thank you very much.
-Hi, everyone.
I'm delighted to be here.
For the next few minutes, Dr. Medina and myself
will talk about the importance of a diverse
and inclusive workforce trained in health equity.
Next slide, please.
As you can see in this slide, the views that we're expressing
are not those of the NIH or NINDS,
and we have received funding, both Dr. Medina and myself,
from the NIH and the Alzheimer's Association.
Next slide, please.
So workforce diversity is critical.
It drives innovation.
It helps facilitate the translation
of scientific findings
and results into advances in health,
and it prepares the healthcare professional workforce
to better care for our increasingly diverse population,
and this includes the population over age 65,
so the age [Indistinct]
really relevant when we're discussing AD and ADRD.
Next slide, please?
With that in mind, I want to describe,
a bit, the current state of workforce diversity in the U.S.,
and as you can see in this figure,
the percent of individuals who identify as Black,
African-American, Hispanic, Latino,
American Indian or Alaska Native in science and engineering field
has grown across all degrees,
so those three lines with the different degrees,
since 1993.
However, they are underrepresented
when you look at the occupations
because they account for only 29 percent of the science
and engineering workforce,
while they represent 52 percent of U.S. residents above age 21,
and this underrepresentation also exists when we look at -
through our PIs of R01s and R01-equivalent awards.
In 2020, only 6.7 percent of PIs of those types of grants
identified as Hispanic, Latino, Black or African-American.
This means that the workforce not only
doesn't reflect the diversity of the U.S.,
but it also means that the workforce doesn't reflect
those most affected by AD and ADRD,
which disproportionately affects minoritized populations.
Next slide, please.
Though the prior slide focused on racial and ethnic diversity,
there are many additional domains to consider
when we're talking about a diverse workforce,
and that includes but is not limited to dimensions
such as sex, gender, age, socioeconomic status
and many other aspects
that affect people's lived experiences.
An inclusive and diverse workforce
brings additional perspectives.
It promotes creativity,
and it broadens the research question -
the research scope by including more questions
or encouraging more questions
because it's critical and essential
when thinking about health equity research.
Studies have found that diverse groups
produce more paper
and that those papers are cited more often,
and this is valuable as a proxy to show that they are -
There's increasing knowledge and quality knowledge,
and this, in turn, hopefully, is knowledge
that can be used to promote health equity.
In his research, Dr. Scott Page
stated that diverse groups of problem
solvers consistently outperformed groups of the best
and the brightest.
Next slide, please?
Additionally, a representative workforce
that aligns with the diverse communities is important
because it facilitates better commute -
communication between researchers and the community.
It can help mitigate implicit bias.
It increases enrollment and can increase retention.
Both of those are really critical.
It can also lead to greater validity of data.
Again, this is really valuable
because it helps expand our knowledge,
enabling us to promote health equity.
I now let Dr. Medina take over. -Next slide, please.
And so as - Some of the work that's come out of
NIH, some wonderful tool kits,
as I'll show in one of the upcoming slides,
but Dr. Marie Bernard even cited,
"As a woman of color in science,
I have seen the missed opportunities to take advantage
of this full spectrum of scientific talent.
It is profoundly important for all members
of the biomedical workforce to feel included,
welcomed, supported and that they have a fair
and equal opportunity to pursue their passion
for research and scientific discovery.
Our institutions and society
must take steps to eliminate threats
that create barriers such as structural racism,
incivility, harassment and bias."
Next slide, please.
And so how do we address these issues
and these potential barriers?
There are several resources from the NIH,
as well as outside the NIH,
including the Scientific Workforce Diversity
Toolkit to help address some of these workforce disparities.
There are various administrative supplements
and other notices of special interest
that have been announced to help address some of these issues,
including this one relating to recognizing excellence
in diversity, equity, inclusion and accessibility.
Various funding opportunities for individuals
have various training levels,
including K99/R00 opportunities but also F31s,
F32s for individuals in their graduate training
or in their post-doctoral training,
as well as the National Research Mentoring Network
to help, again, address some of these workforce disparities.
Next slide, please.
And so before I provide the recommendations
from our particular workforce, workgroup,
we highlight this here, which is that workforce diversity
is critical to aspects of science of AD
and ADRD, from neurons to nations,
as it affects the quality of the data collected,
the knowledge accumulated
and representativeness of future research
and the workforce pipeline.
Next slide, please.
So with that, our recommendation to increase
training support and capacity
of an AD/ADRD scientific workforce
or persons historically underrepresented
in biomedical, behavioral and social sciences;
suggest that we leverage existing diverse AD/ADRD
health equity research groups and organizations,
that we partner with relevant stakeholders
to invest in promising trainees early in the pipeline;
that we enhance existing systems for tracking
and monitoring progress in diversification
of the AD/ADRD scientific workforce;
that we incentivize mentors and institutions
to sponsor training awards for underrepresented scholars,
target training mechanisms, writing workshops
and other career-development resources
to support underrepresented scientists is also recommended.
Next slide, please.
In order to promote career development
of biomedical, behavioral and social scientists
conducting AD/ADRD health equity research,
we suggest and recommend an iterative training framework
for ADRD health equity research be used;
that we retool and expand the knowledge base
on conducting inclusive science
of mid-career and senior scientists,
again, highlighting the need to address
these issues across the training spectrum;
that we require training and education
in health equity principles for all scholars;
that provide training and education
in health equity research to all grant reviewers;
that we increase participation on study sections of scientists
with expertise in health equity research,
including individuals
who are members of underrepresented populations
and that we increase opportunities for participation
in high-level decision-making committees and opportunities
for underrepresented scholars.
Next slide, please.
The NIH is already addressing some of these issues.
In addition to some of the resources that I showed earlier,
we see special calls for understanding
and addressing the impact of structural racism
and discrimination on minority health and health disparities,
this particular R01 opportunity,
the Health Disparities Research Institute
and these administrative supplements for research
on sexual and gender minority populations,
as well as other opportunities not listed here.
Next slide, please?
Now, I will hand it over to our moderators.
Thank you.
-Yes, next is the assessment
and data focus area recommendations
that I believe Dr. Gottesman will be presenting.
-I'll be taking - I'll be taking over.
Good morning, all.
On behalf of my colleagues, I want to thank the NINDS
for putting this summit together
and providing us the opportunity to share our thoughts
on how to advance health equity through AD/ADRD research.
My name is Wassim Tarraf,
and I'll be presenting on behalf of my colleagues in the data
and assessment focus area, including Dr. Gottesman,
Dr. O'Bryant, Dr. Fornage and Dr. González.
Next slide, please?
I have no conflicts to report.
Next slide, please.
So over the next few slides,
I'm going to try to make a few observations
to place in context -
discussions as a group, leading to our recommendations.
As you probably know,
the U.S. population is becoming increasingly more diverse,
but ethnic and racial groups remain underrepresented
in clinical trials, which are, as an example,
the primary pathway for the development of therapeutics,
so scientists need more resources to understand
and bring down the barriers to participation
in clinical trials for these underrepresented groups.
We've made progress over time,
and the rates of participation for traditionally
underrepresented groups have increased,
but these rates still do not fully represent
the overall population of the United States.
As you see here, as of 2013,
72 percent of clinical trial participants
were non-Hispanic whites,
and among ethnic and racial minorities
that do participate in clinical trials,
the rates vary drastically by the groups included.
This lack of representation
has critical implications to the health
and well-being of racial and ethnic minorities
but also the general population.
A better understanding of the factors
that affect these groups can shed light on novel pathways
that will have implications for the overall public health.
So existing policies do recognize this as an issue,
and there are many efforts to increase
the representation of minorities in clinical trials,
but policy alone is insufficient to overcome
some of these existing barriers to inclusion.
We believe that the science of inclusion
plays a critical role in how to improve representation,
and over the next few years,
we believe that we should continue to invest in programs
that increase the awareness and visibility
of the science of recruitment,
establish AD/ADRD diversity recruitment
and retention centers
and build accountability mechanisms for recruitment goals
within existing NIH-funded networks.
Establishing these processes can potentially bring
about this meaningful participation
of all population groups and yield potential gains
to improve the public health.
Next slide, please?
So the statistics that you seen on the previous slide
also extend to observational data.
What you see here is a breakdown of some data
provided by the NIH
RCDC Inclusion Statistics Report.
These figures, to a large extent,
mirror the story that we've -
was told in the clinical trials case.
It is critical to point here
that there's significant variability across institutes,
and all institutes are making progress,
but more is needed to advance the process
and provide the data that is required to allow
appropriate generalizability to a diversely aging population.
Next slide, please?
So moving beyond disparities and towards equity,
as the chair of many - and many other speakers have emphasized -
And proving participation for better representation
has the potential to yield better data,
and that can help improve assessment tools,
better measures, better quantification
and better studies for pathways to ADRD
and will enhance the generalizability
and equity of scientific research.
On the cognitive assessment front,
we have ample evidence from years of studies
that existing cutoffs on cognitive tests
have major shortcomings for epidemiological estimates
of disease across racial and ethnic groups,
across socioeconomic status groups,
particularly across educational level groups,
and we have clear calls
and supportive efforts to create better tools
and invest scientific efforts to identify metrics
that allow appropriate generalization.
So this includes generating the deep data
that we need that could enable stratification by race,
ethnicity, by education, by SES and ensure better detection,
particularly at early stages of disease,
example, mild cognitive impairment,
but also critically to permit clear demarcation
across disease stages across and within groups.
Unfortunately, we're not at that level of data yet.
The point and our view is made clear
by looking at recent reviews of the evidence,
which you see on the slide here,
that shows that data for some groups, as an example,
American Indians or Alaska Natives
to note one, is near nonexistent.
Data on other groups, while we have some,
is potentially insufficient
to provide precise estimates of the problem,
particularly at the earlier stages of the disease process,
and this evidence also points that there's a clear need
to generate data that allows disaggregation
of large race-ethnic classifications,
among Asian Americans, among Black Americans,
among Hispanic Americans,
to kind of disentangle this heterogeneity
within these large non-monolithic groups.
So given the state of the evidence,
we recommend a national effort for developing novel
and unbiased normative methods
that will lay the ground for recommendations,
for guidelines and for guidance on how
and when to use or not to use race
or ethnic-based norms in cognitive data.
Next slide, please.
On the biomarkers and the evidence base
regarding availability,
let alone equivalency of AD/ADRD biomarkers,
is even much thinner than what's available
for cognitive assessment.
For example, recent study looking at screening
and enrollments in the Alzheimer's Disease
Neuroimaging Initiative, ADNI,
shows that of the enrolled participants
between 2004 and 2020, only 11 percent of the data
came from individuals that identified
as being from ethnoculturally underrepresented populations
and only 15 percent from individuals
with less than 12 years of education.
Both of these rates are drastically lower
than what comparative census data
would allow for these categories.
Now serious observers of the field of AD
and ADRD biomarkers recognize that this is an exciting time
to be doing research in AD and ADRD with,
you know, potential tools at our disposal
that have the promise, as was mentioned,
of better understanding complex pathologies,
transforming care and diagnostics
and even disease monitoring.
But despite this excitement, there's also clear recognition
that there are critical shortcomings in existing data
and clear limitations
in the lack of diversity of existing data
which limits the potential for extending any findings
to real-world clinical problems.
So the figure that you see on this slide
provides some hints from existing data.
These data are largely limited
in terms of representation based on small n,
but they show that biomarkers of AD
present in complex ways across population groups
and are likely to differ by race and ethnicity.
So planning for achieving equity in AD and ADRD research
is the only way, in our view, to avoid neglecting,
leaving behind, omitting major sections of the US populations
and potentially jeopardizing the public health
for future generations.
We recommend developing resources to address
the fundamental questions of biomarker equivalency
in distinct race and ethnic groups,
to explore alternative frameworks,
recognizing that the ATN framework
may not apply as well in diverse populations
given the lack, as an example,
for considerations of cardiovascular disease,
misdistribution of the population.
And biomarkers may have different meaning and value
in different groups.
Next slide, please.
We think also that a similar story comes up
when we look at the evidence for genetic data.
So research finding suggest
that even for relatively simple links,
as in the APOE epsilon 4 story,
when more data becomes available,
it shows more complexity.
And it shows that conclusive evidence still alludes us
until more sampling and higher levels of inclusion
to clarify the potential of within group heterogeneities
and links
and the synergistic effects that could happen within groups.
But also it shows a particular need for availability of data
that enables replication.
We think that better and more inclusive data
will open doors for discovery.
It'll enable newer and more nuanced ways
of thinking about the pathways.
And to get there, we recommend enhancing
the availability of studies
that better characterize genetic risk factors,
particularly in the context of other nongenetic factors.
So our view is that any genetic discovery,
in order to translate the real-world benefits,
need to be examined in the context of environmental,
behavioral and socioeconomic cultural factors
in order to have the data necessary
to allow these kinds of associations.
Next slide, please.
-Two minutes remaining. -In the interest of time,
the excitement about the potential of new technologies
and their capacities for collecting rich,
almost instantaneous data through digital biomarkers
to improve the health of Americans is tremendous.
The question, however, in our view is, which Americans?
And the hope is that we're not setting ourselves up
for a new wave of scientific excitement
that passes underrepresented populations.
I want to thank you for the opportunity
to share some of our stats, and it is now my pleasure
to pass the baton to Dr. Khachaturian.
Thank you.
-Thank you, Dr. Tarraf.
Hello, my name is Ara Khachaturian,
and I'm representing the focus area on diagnosis,
treatment and care.
These are recommendations for four and eight.
Next slide, please.
These are my disclaimers, and this is my disclosure.
Next slide.
I want to acknowledge that our focus area
included Dr. Julie Zissimopoulos,
Dr. Erica Littlejohn, Dr. Alberto Ramos
and also, Dr. Michael Wolf.
We really took upon this question
of looking at the issues of diagnosis, treatment
and care in terms of really thinking about
from broadly the patient journey
when one has Alzheimer's or a related dementia
as well as also thinking about,
what it's going to take to have new quote, unquote,
learning health systems of the future
and how are we actually going to arrive
at providing equitable care for individuals,
particularly from underrepresented
and underserved populations.
Our first recommendation, recommendation four,
is to assess the social, economic, structural impediments
to equity in Alzheimer's and Alzheimer's-related
disorders assessment, diagnosis and referrals
and impacts on health and economic outcomes.
Within this recommendation, there's really an opportunity
to think about several important research questions,
public health questions and public policy questions.
We're going to take a look at some of those questions.
These are not exhaustive, but really illustrative.
Next slide, please.
We think that these questions are really going to be
sort of examined more critically and perhaps even really become
sort of dominating the literature
over the next 3 to 5 years.
One if these first questions is,
how does CMS and private insurance benefit designs,
payment and reimbursement policies impact the assessment,
diagnosis of dementia in diverse populations?
We know that there is an ongoing tension
in the US health care system
about how best to enhance quality care.
In one way, this question seeks to pinpoint those opportunities
to gain efficiencies in the US health care system.
Next slide, please.
Another important question for supporting
this recommendation is, how generalizable are provider
and specific health system factors?
This will include access to dementia specialists,
the role of race concordance and also other providers
and practice-level organization factors
among diverse populations.
Next slide, please.
This question, what socio-, behavioral and environmental
and economic health care system factors
impede equitable assessment and detection and diagnosis
and referrals of individuals
with Alzheimer's and related disorders?
Next slide, please.
And the related question of, how best to quantify
the assessment, detection, diagnosis and referrals
on health, social and economic outcomes?
As Dr. Tarraf had mentioned in the previous outcome --
in the previous presentation,
there is very much an important need for new data
and new assessments.
As our group thought about these questions,
we really were thinking in terms of both
from how public health and information sciences
can come together to really think
about looking at these questions from a complexity point of view,
thinking about that there are complex interactions,
and certainly many of these related factors
are not going to be linear.
In fact, how are we going to be able to think
about modeling nonlinear relationships
across these various measures.
And certainly, this is going to be proved to be
very important over the next couple of years.
Next slide, please.
So our group sort of went from asking these questions,
important questions of how to really look
at the issues of diagnosis, treatment and care
to really provide better assurance for health equity,
to thinking about this from a structural point of view
and really looking at what are going to be
some of the tools and methods
that are going to help drive exploration of these questions.
So recommendation eight looks at and makes the recommendation
that we need to support infrastructure and policy
research to understand individuals,
community and societal drivers of inequities
in cost of and access to treatments, care
and the impact on Alzheimer's
and Alzheimer's-related disorders outcomes.
Next slide, please.
This recommendation really sort of points
to what are going to be some of the specific needs
that we're going to have to think about.
So our group actually started to think in terms of,
how can we start to go from this recommendation stage
to an implementation?
One of the ideas was really in terms of trying
to define one's concepts.
Certainly having national standards for dementia costs
and health outcomes is going to be absolutely imperative.
Dr. González, in his opening remarks to this session,
really sort of laid out the NINDS framework.
And so, one of the ideas that we hope that perhaps future
working groups will look at is,
how to parameterize some of these key
constructs in terms of looking at how to model better
and also to think about inclusion
into a national data repository.
And that really leads to our third point here,
which is a national database for dementia equity research
on social, economic and health-related factors.
Next slide, please.
We also seek to think that it's going to be very important
to have measures to look at inequities in pharmacological,
non-pharmacological, medical and social care services,
with a focus looking at impact on cost and health outcomes.
Also, health outcomes and care quality of managed care
and associated access among diverse populations
is going to be another important area to examine.
Next slide, please.
Looking at this thoroughly from the health economic perspective,
supply-side factors are also going to be
an important area to measure.
This is going to require looking at health system ownership,
for example, of physician practices
and also looking at the equity of Medicare benefit plans.
Another idea that we discussed as well
is this adoption of something called the model-base.
Here, the idea would be
to actually not just have data available,
but really to have a collection of models,
health economic models of pharmacological,
non-pharmacological and health care interventions
that will help measure and predict access,
costs and health care outcomes.
And next slide, please.
And finally, we are really interested in seeing
what is going to happen in terms of the examine
of sociocultural, behavioral, environmental, health
and other care system factors
that will influence equitable access.
This is a topic that certainly is beginning to gain
a lot of interest within journals,
and we really anticipate
seeing a lot of this research coming forward
over perhaps even shorter than the 5 to 7 years
that we anticipate.
And as noted by Dr. Rost
also at the beginning of the presentation,
the impact of COVID in terms of what that has meant
to our health care systems in terms
of delivering better diagnosis, treatment and care,
certainly telemedicine and mobile health care options
on reducing some of the financial burdens
and some of the communications problems
are going to be absolutely essential.
Next slide.
Thank you, and I'd like to now introduce my colleague,
Professor Jennifer Weuve
at Boston University School of Public Health,
who's going to be talking about the focus area on epidemiology.
-Thank you, Ara.
I will be summarizing recommendations
that address how to use epidemiology to understand
and intervene on health inequities in AD/ADRD.
Next.
I have no disclosures to report.
Next.
Our first recommendation concerns the documentation
of health inequities in AD/ADRD.
Specifically, we recommend applying existing and novel
surveillance methods
to assess inequities in AD/ADRD prevalence,
incidence, diagnosis, treatment and care.
We also advocate attention to trends in inequities.
That is, how inequities might be changing over time,
whether shrinking or expanding.
Next.
Now, acts of documentation are integral
to achieving health equity in AD/ADRD
by informing public health priorities,
as well as prevention and treatment strategies.
Now, some inequities have already been quantified,
but many remain unknown.
For example, numerous studies have reported declines
in dementia incidence rates,
but most of these studies focused
on non-Latinx white persons in the US and Europe.
Little has been reported about whether dementia incidence
has been falling in underrepresented populations
or in other geographic regions.
Next.
Now, in addition to more attention on trends,
we recommend that inequities be estimated
across a range of social determinants of health,
such as across racialized group
or indices of neighborhood environment,
and as for explaining those inequities,
we directly address this in our second recommendation.
Still, the very monitoring of inequities in AD/ADRD
can reveal impacts of historic and contemporary policies
and events, such as civil rights policy and pandemics.
Next.
Now, I've outlined the nature of inequities in AD/ADRD
that we recommend monitoring, and now to the how.
Now, valid estimates of inequities
should come from samples
that are representative of the US population,
but we can expand what useful representativeness
means beyond proportions
that are consistent with the US census.
Many smaller or minoritized or marginalized groups
will need to be oversampled to provide adequate numbers
for accurate and precise estimates.
Historically, cohort studies of AD/ADRD
have underincluded specific communities and populations,
as you've heard.
And as a result, adequately estimating
the experience of AD/ADRD in these communities
may require establishing new cohorts.
New cohorts combined with other methods
may also be helpful in shedding light
on prevalence and incidence of rare dementias
in previously underrepresented groups.
Next.
And whether the cohort is established or new,
to make it useful for accurately gauging inequities,
investigators must identify and act on determinants
of underinclusion in these cohorts...
[Audio drop]
-Dr. Weuve, your microphone is muted.
-Yeah, I'm not sure how that happened.
My apologies.
I'm going to start here.
And whether the cohort is established or new,
to make it useful for accurately gauging inequities,
investigators must identify and act
on determinants of underinclusion in these cohorts,
as you've heard.
Now, the levers of inclusion could involve aspects
of recruitment and retention practices,
economic barriers and stigma, for example.
Now, some key levers may lie outside
investigator's own experience and imagination,
and developing the capacity to appreciate them and act
on them may require intentional acts of partnership
and engagement with communities.
Next.
Our second recommendation that uses the tools of epidemiology
concerns determining how health inequities in AD/ADRD occur.
Specifically, we recommend identifying life course
and multilevel mechanisms of pathways to AD/ADRD inequities
and use the discoveries to reduce these inequities.
Next.
As a foundational act of that recommendation,
we encourage researchers to make a standard practice
in their research on inequities in AD/ADRD
to disclose the conceptual model that is guiding their work.
Some broad examples include race as a social construct
or even defining age-group cohorts to specific places,
times and even policy.
Now, the absence of such a disclosure
can leave open the door for interpretations
that veer toward bioessentialism.
Next.
Among populations facing inequities in AD/ADRD,
we suggest that putative risk factors AD/ADRD inequities
be measured over several dimensions of time, for example,
over the life course across generations
and specific risk periods,
and that these risk factors be assessed in relation to AD/ADRD
or well-known determinants of AD/ADRD.
Next.
The interplay between social,
environmental and biological mechanisms
in producing AD/ADRD inequities is multidimensional
and, as a result, likely to be complicated.
This complicated interplay can be evaluated
with new intentionally designed AD/ADRD
cohorts for harmonization efforts.
Next.
Now, this figure,
based on the work of Bailey and colleagues,
illustrates the potential complexity of mechanisms
leading to inequities in AD/ADRD.
You can see multiple and nested mechanistic domains
represented here, from policy structures to phenotype.
And these are all implicitly embedded
in various dimensions of time.
Next.
The studies of the mechanisms of and pathways
to AD/ADRD inequities might also examine the extent
to which excess risk in AD/ADRD is intersectional,
for example, involving combinations of race
and gender or race and education.
This is another line of evidence that can be generated
with sufficiency large or oversampled populations.
And to the point of this research,
we encourage researchers to work toward translating discoveries
in this domain to the underrepresented groups
and/or regions from which they are drawn.
And finally, age-related disorders, such a AD/ADRD,
disproportionately affect those among us
who may be marginalized,
stigmatized and underrepresented.
So clearly, these disorders are not agnostic
to the structures and cascades of inequity.
And as long as inequities exist in our societies,
it is imperative for researchers to document them,
identify the determinants and strive to resolve them.
And thank you so much.
I turn over the platform to Dr. Zissimopoulos.
-Oh, thank you so much.
Thank you to our speakers
for your excellent presentations.
My name is Julie Zissimopoulos.
I serve as cochair with Dr. Hector González
over the Health Equity in Alzheimer's Disease
and Alzheimer's Diseased-Related Dementias Working Group.
It is my privilege to briefly summarize
the recommendations of the working group
and present our priority order.
Next slide, please.
The views do not reflect the official policy of NINDS
or NIH.
I receive funding from the NIA
and no other relevant financial relationship disclosed.
Next slide, please.
In driving final recommendations,
we built from prior year recommendations,
insights from research and patient care
and a framework for achieving health equity
that considers life course health,
socioeconomic historical policy and place-based factors,
that may act as barriers to or opportunities
for achieving health equity.
We identified four focus areas with distinctive significance
for health equity in Alzheimer's Disease
and Related Dementias through research, workforce,
data and assessment, epidemiology and diagnosis,
treatment and care.
You just heard two recommendations
aligned with each focus area from our experts
from the Health Equity Working Group.
I will now present our prioritization
of these recommendations in a summarized form.
Our priority one recommendation
is establish the high importance of actions
that increase participation of underrepresented groups
in clinical trials.
We also addressed the significance of a diverse
workforce for building knowledge and capability
to achieve our goal of health equity.
Our priority two recommendations emphasize educating
and retooling scientists across the biomedical,
behavioral and social science fields,
for achieving excellence in health equity research.
We also recommend new research into impediments
to equitable assessments, diagnosis and referrals,
as well as the health and economic consequences
of inequities in accurate and timely diagnoses.
Our priority three recommendations address
the need for biomarkers, assessment tools and methods
that are applicable to different racial and ethnic groups
and how improvements to them provide opportunities
for advancing equitable scientific research.
Similarly, a second priority three recommends
complementing the existing
but limited surveillance methods for assessing inequities
with novel ones to inform risk reduction,
prevention and treatment strategies.
And finally, our priority four recommendations focus
on how inequities occur.
They propose establishing conceptual models
for identifying the health, socioeconomic historical policy
in place-based mechanisms
that are producing inequities and also in risk
and also the inequities in the cost of disease
and access to care and social services and treatment.
They recommend new data
and improved methods for quantifying inequities
and the consequences of those inequities.
Before turning to the open microphone discussion,
and on behalf of Dr. Hector González and myself,
I want to thank the summit organizers,
our speakers and all the working group members
and the participants here today.
Now, I invite all Health Equity Working Group
panelists to turn on their cameras
for the open microphone discussion.
Dr. Hector González will invite participants by name,
and in the order that we receive the question,
to turn on their cameras and verbally ask their questions.
Following this, panelists may indicate their interest
in responding via the chat or verbally,
and Dr. González will invite you to respond.
Dr. González, I turn the session back over to you.
-Dr. Zissimopoulos, thank you very much.
And now we go to the open mic session,
and I invite all the panelists to be on screen
as we field these questions.
We have several in the Q and A,
and I believe one person has been invited to speak
or present his question verbally.
And so that might be the best opportunity
to go to start there.
If not, I'll go ahead and read some questions
here in the question and answer chat box.
-Hi, Doctor.
Dr. Ellenbogen is ready, so let's go ahead and move to him.
-Very good. Thank you.
-Go ahead, Michael.
-[Audio drop]
-Yeah, regrettably, there's some audio problems.
-[Audio drop]
-Yeah.
-Yeah, Michael, we're going mute you,
and you need to toggle your microphone.
And we're going to go ahead do Charlie
while you get it sorted out, and we'll come back to you.
Dr. DeCarli, are you available?
-Yes. Can you hear me well enough?
-Yeah, of course, Charlie. Thank you.
-I want to start by saying, I'm a little bit more optimistic
about how much work has been done.
At the level of the epidemiology,
I think that there are members of this panel
and others who have been leading incredibly important studies
on diverse populations
and that have resulted in some really unique findings.
My question for the group is,
how do we take those epidemiological studies
and dive deeper,
as we have done with our European white individuals,
to really look at these important mechanisms
that may differ by life experience and cultural effects
and possibly some minor genetic effects?
I think about our own ADRC,
in which we have three different groups that we look at,
but that's not enough.
You know, we're missing other groups,
and we need to take the tools that have been developed
in the European studies through core resources
and extend them to our diverse communities
to really start to understand mechanistic --
mechanisms of dementia, and I just would like the panel
to speak to how they feel about that digging deeper
and getting into, you know, the mechanistic approaches.
-Thank you, Dr. DeCarli.
We great appreciate your question.
I think I will go ahead and pass this over
to Dr. Khachaturian, who has his hand raised,
and I believe wants to field the...
No, Jennifer.
-I'll start out here.
I think, Charlie, you touch on this aspect
of the richness and informativeness of experiences
that we're missing out when we aim for cohorts to be
proportionately representative of the US population.
So we miss out on the experience
of traditionally underrepresented groups,
and so I think that is one of many justifications
for developing cohorts
that are composed completely of groups from specific communities
that have traditionally not been represented,
and that gives us an opportunity
to look at the range of those experiences
that you were mentioning,
and I know there's some people on the panel here
who, in fact, are the PIs of such cohorts.
So that would be one start into that,
but I certainly open up the panel or open up the floor
to others who have suggestions and thoughts on this.
-Yeah. Dr. Weuve I think
that's something we have been stressing in this shift
from health disparities
to a focus more on health equities
and to achieve such lofty goals,
I think as you mentioned, looking within the life
course of individual ethnic racial groups
may be preferred, if not desirable
and underscoring this notion of life course
and the midlife perspective in particular
that seems to be so rich
in terms of finding new opportunities
or risks and resilience factors for healthy
or unhealthy cognitive aging.
And so perspective cohort studies,
beginning earlier in life,
certainly are of high interest and seem to be addressing
what you are suggesting here in your question.
-No, I'm going to interrupt.
I apologize, I'm going to push back a little.
-Sure.
-When I'm talking about are studies
where we can follow these individuals
and get in depth, biologically meaningful information,
that extend beyond...
the epidemiological studies are very important,
critically important to get perspective.
But then we need to dig down, and that includes,
I mean, missing from this are --
has been alluded to serum plasma,
CSF biomarkers, neuropathological materials.
When you look at what's out there
in terms of neuropathological materials,
it's very limited,
and I believe we need to be moving in that direction,
just as we've done in other populations,
with European population.
That's where discovery occurs, in mechanisms.
-I think we have several panelists
that are also wishing to respond.
So...
-Yeah, can I jump in, Hector, just to quickly...
-Yeah, sure, Lisa, please, Dr. Barnes.
-Charlie, I think you answered your own question.
I do believe we need to move beyond descriptive epidemiology
with these minoritized populations and understand
some of the barriers to getting more of the more invasive data,
you know, like the pathology data, biomarker data.
As you know, we at Rush work very hard
to get brains from minoritized populations
and it takes decades of effort and relationship building,
but that is how we are going to discover
these underlying mechanisms that are leading to the disparities,
but also something that you said,
I don't think we should just take what we've learned
from the white homogeneous samples.
I think we have to work to understand
the unique race or ethnic relevant factors
in the populations that we're studying.
And you cannot get that
unless you have people enrolled in the study,
you build relationships, and you work to educate them
on why these types of data are needed.
So thank you for that question.
-Okay, so now we invite any other speaker to --
or person with a question to step up.
-Well, Sid and Toni, do you guys want to answer
that one or can we move on? -Yes.
I'd just like to say a couple of things
to reiterate what Dr. Barnes has said,
and a little bit about what our group reported on.
When we said we need to address issues from neurons
to neighborhoods, and that's what we need.
I mean, it's not a one-size-fits-all.
It's not a one approach fits all.
It's we need a combination of multiple perspectives,
and we need to go wide and deep.
So we need a within and a between approach.
We need life course cumulative studies.
We need an accumulation across studies
that have perhaps been more width than breadth.
So I just want to say that we need multiple methods.
We need multiple approaches.
We need multiple samples, and we need to understand
that good science will help us across a variety of approaches.
And I think these are words people will understand.
I just want to bring it forward
in addressing the question that was raised.
-Thank you, Dr. Antonucci.
Next up, I'd like to invite Mr. Dr. Michael Ellenbogen
to ask -- try his question again, please.
-Can you hear me?
-Quite well, thank you.
-Great, thank you so much.
First, let me correct you.
I appreciate being upgraded, but I'm not a doctor.
I'm just a patient living with dementia.
I would like to thank you all for what you have done.
I've been a part of these summits for many years,
and every time I am at one of these,
you folks always take my recommendations
and follow through with them.
So I thank you so much for making all this happen.
I'd like to speak though, in reference to the health
equity for people with dementia.
And I think that is a very important subject
because there are so many places out there,
like the University of Pennsylvania,
who you folks tend to fund for various clinical trials.
But some of the problems we have is, places like that,
believe it or not, charge money to get into the clinical trial.
Most clinical trials you do not have to pay money for.
So I think NIH and NIA needs to find a way
that when you ask
for these folks to do clinical trials for you,
that you put some kind of stipulations to make it
so that it's going to be free.
Because if it's not, it's going to hold up for getting people
who are Hispanics, African Americans
to get into these clinical trials.
University of Pennsylvania happens to be
in a very big minority area,
yet if you look at the amount of minorities
they have included in their clinical trials,
you'll see they're not able to get into them.
I try to get into it and I wasn't able to get into it
because they wanted to charge money.
So therefore, I went to some other place,
and there's many places to go to.
But most people don't have the luxury
I have that they can drive to further places.
So I would hope you folks consider
how you address this kind of situations
so more people of minorities can get into clinical trials,
because to me, I think they're the most important people to be
in the clinical trials.
-Mr. Ellenbogen, thank you so much for your comments.
Greatly appreciate hearing not PhD or MD's perspective,
but the patient perspective of the patient's journey
through the clinical trials experiences.
And you're absolutely right, as you said at the beginning,
your recommendations now that you just voiced will be
addressed in the final recommendations that we make.
I don't have a particular response for you,
but I want you to rest assured
that we will address your comment and your recommendation.
Thank you so much.
Moving right along, and again, thank you for your question.
I believe Ms. or Dr. Florence Johnson --
how's that? -- will take the floor or the mic next please.
-Good morning, thank you all for a great presentation.
I would like to say to Mr. Ellenburg
that you're not just a patient living with dementia.
You have a strong voice.
People living with dementia are definitely teachers for us
and we need to listen to your life experiences
as we continue with our research.
I'm a second year student
in the University of Michigan School of Nursing,
and I -- my focus of research is on family caregivers.
I would just like some historical background
on how we got to the term Alzheimer's disease
and related dementias.
Thank you.
-I will turn this...
I don't see anybody volunteering to respond to this question,
which I think would be -- so let me give it a shot
and I'll invite others to step up and respond as well.
How did we come to this term,
Alzheimer's disease and related dementias?
And that's an excellent question
as a second year nursing student,
and I certainly wish you the best
at one of the great institutions in our country,
the University of Michigan.
Go blue.
Yes, we got thumbs up from Dr. Antonucci too,
who's a Michigan person here.
So all that said, is that this started with some seminal work
over 100 years ago about -- from pathology,
from a pathological study by a man named Alzheimer's.
Now, I'm not going to go into the full history
of Alzheimer's and related dementias,
but since then we've come to recognize
that dementia has different etiologies.
Alzheimer's disease is just one etiology,
and I think we need to keep that in mind
as we look across the field.
There are other etiologies, and in particular etiologies
that we think may impact people of color
are vascular dementias in particular.
You know, you're probably learning right now
about the high rates of hypertension, diabetes
and these other terrible, chronic conditions
that so disproportionately affect Latino,
Black, African American and other populations.
We think these are major contributors
to dementias among dementias,
now I'm saying because we're going to be agnostic
in terms of the etiology, dementias that may be drivers.
But we don't know.
We need the data, as has been mentioned before,
as Dr. Barnes and others have said we need the data,
we need to move forward in gathering this data.
But we're kind of feeling around in the dark,
and until we have the light of new data, new research,
I think we will -- there's much work to be done.
I see there's other people wishing to respond
and I'll start with Dr. Peterson.
-Thanks very much, Hector.
I will take some responsibility for this term,
going back to the beginning of the advisory council
for the national plan.
And as was outlined initially, earlier this morning,
the terminology focused on Alzheimer's disease,
but clearly the law, the NAPA activity,
wanted to include the other
major dementic disorders as well.
And while it's imperfect, this was the term
that was decided upon to capture these related disorders.
Now there's a whole nomenclature initiative
that has been part of these summits in the past
that is addressing this topic.
But it is a bit confusing, I will admit that,
because these disorders may or may not be related
to Alzheimer's disease itself,
but it is sort of a historical explanation.
-Thank you.
-Thank you, Dr. Peterson.
If you could lower your hand now, please.
Next up, I'd like to invite Dale Lestina,
and I'm not going to scribe any titles or honorifics
to anybody here now,
just please, Dale Lestina, if you would.
-With some apologies, we're actually having trouble
getting Dale promoted up.
So the next one is Rene Anand, I think you're with us here.
-Yeah, hi. Good afternoon.
Thank you, by the way for this wonderful webinar.
My question related -- it's a three-part question.
It relates to how genetics,
environment and nutrition interact
to actually get susceptibility to clinical disease.
Just to disclose, we make brain organoid models
of Alzheimer's disease,
so we are very advanced in our studies
and they're very replicable.
What we find, and this is why I was asking the question is,
orotic Alzheimer's also genetic origin.
What I'm asking actually, is all Alzheimer's genetic?
And we find, by making models of sporadic
Alzheimer's versus familiar Alzheimer's
that in fact there's a convergent for data sets,
which leads us to believe -- our samples are small --
leads us to believe that in fact the genetic risk
that exists at birth for all Alzheimer's,
however the risk is not necessarily clinical disease.
There's a gene and environmental interactions
that occur throughout life, somewhere along the way,
either at birth or during childhood
to take that risk into disease.
And the risk that we are finding are environmental,
as well as nutritional.
And so I think it's a game changer
in how we think about Alzheimer's
because a lot of discussion about health equity.
And I think we have the ability
to begin to answer this question,
but however our sample size, I must admit,
are rather small at this time.
So is there any other evidence from the other types of studies
that leads us to believe
that what we are seeing might be correct?
-For this one, I think I will turn it over to Dr. Fornage.
I was thinking of you, Miriam,
when Dr. Anand presented his question.
So I'll hand it over to you, please, Dr. Fornage.
-Yes, so thank you for the question.
So Alzheimer's disease, the sporadic form
is indeed genetic, but it's not fully genetic.
So it's a poster child for multifactorial disease,
as you mentioned.
It is a combination of genes and the environment.
And so as geneticists spend a lot of time looking for genes,
and in fact, we have identified quite a number of genetic loci
across the genome in human studies,
including APOE being the major risk factors --
genetic risk factor.
But others, we have probably around 40 loci at the moment
for Alzheimer's disease,
and individually this loci don't contribute much to the risk,
but collectively they do quite a bit.
And as you mentioned, certainly the environment is important.
And it's not -- we haven't done very in depth studies
to look at this gene environment interaction problem
because this is a difficult problem
that requires very, very large sample size
and good measures of environment.
And so for that,
we still in the infancy of these types of studies.
But as you mentioned, this is a very critical area of focus
for us to understand how genetic behaves
or the genetic risk to Alzheimer's disease
and dementia is modified
by environment and environment factors.
So thank you for the question, I hope that answered it.
-Thank you, Dr. Fornage.
-Yeah, thank you, Myriam. I just wanted to add --
I think poverty that leads to the nutritional deficiencies
is in fact one of the drivers.
That's where I'm going with the question.
And if it's not addressed, it just shows up
much later in life
in ways that are much harder to deal with.
But thank you all.
-Thank you very much, Dr. Anand.
And I think Martine --
Martin had a response or a question.
Or if it's a question, I'd just like to follow up
with Dr. Fornage, what she had to say.
And I am very curious and interested
in some of the work that's being done with organoids
and I think it holds great promise for our science.
My understanding of the organoid work that's been done
is we have a limited spectrum of patients
from which organoids have been derived.
And I think this is something that Dr. Turoff
and his group had alluded to is that truly we need to expand
that diversity of people with dementias
to include people of different ethnic racial heritages
so that we can understand if there's any variability
between how those organoids respond to,
whether it be shotgun approaches for therapies or what have you.
So I just wanted to follow up with that comment of my own.
Martin, you had your hand up?
-Hi, yes. Good morning.
I'm a program director at NIA,
but I just wanted to follow up on a comment
on the importance of really trying to understand
how the environment also contributes
and interacts with the genetics.
This is particularly important for health equity research,
since most of our minoritized operations
are often the ones that are living in an environment
with the worse environmental exposures.
And so I believe that there is a lot of room
to do additional work in this regard
and really understand it
and how we measure environmental exposures,
how we assess the multiple sources of exposures
over a life course
and how this relates to the etiology of the disease overall.
-Thank you very much for your insights.
Before we get to the next question, Milan Fiala...
...you had your hand raised.
Well while we're waiting,
I'd like to invite Patricia Heyn to the mic please.
-Thank you so much for the opportunity.
This is such a great meeting
and I'm so excited to see all the developments.
And I just made a suggestion to, as we plan for the workforce
and for the diversity and inclusion,
to also think in the support of research, mentoring,
leadership training through a life span perspective.
There's so much of work now in the early career,
in the stages of the very early development of your profession,
but we as professionals, we also have a life span
in terms of the different phases and the different needs.
And I think we also need to start to think about
how we're going to be developing our research and portfolio,
that we'll take that into consideration for us
to avoid to be age discriminating
or maybe career stage is in discrimination
because we are not thinking about this perspective
of career span development or the different needs,
especially for researchers
that come from underserved background or minority,
where they're already going to be
in a position of less privilege
when they're going to be starting the development.
And that contribution does not only come
by evaluating the number of grants of other ones,
but is also diverse in terms of the contribution
that professionals can bring to their field in different sectors
that sometimes is not by grant awards.
-Thank you for your comments.
I am going to turn this over to either Dr. Gilsanz or Medina,
who may wish to respond.
But I think yours is a recommendation
to enhance workforce development,
not only for the new people coming into the field,
maybe leaning towards younger perhaps,
but also across the life span
and also to ensure that workforce development continues
and is available throughout the life course.
There are some efforts, but we certainly will add the --
your recommendation or consider your recommendation
as we develop --
as we finalize our recommendations
shown here on the screen right now.
So thank you very much for your comments.
I see Milan Fiala has her hand raised again,
would you please try your mic this time, take two?
Yeah, you're still muted.
So, okay, go for it.
You just need to unmute yourself.
-Okay, can you hear me now?
-Yes, I can. Yes we can, I hope.
-This summit has been about health equity
and ways to overcome this.
But on the other hand, in cardiology the progress
has been made by identifying the common factors
and then showing how each group deviates from this norm.
And I think our basic research in neuroimmunology shows
that there are common factors,
a common norm that should be applied
and then identify the diversity.
And the diversity lies in the lifestyle
and especially in the diet, because the most important thing
is to identify how the brain is cleared of amyloid beta
and flushed with tau.
Those are the drivers of the disease.
And we showed that the immune system in the brain
is what the lymphatics are doing elsewhere in the body
and there are lymphatic connections in the brain,
to the meninges that help the immune system
to clean the brain.
And the problem is that the immune system does not have
the energy to do its job, that's one problem.
And the other problem is that the immune system is inhibited
by accumulation of amyloid beta in the vessels.
And so, if we can push forward
this way of treating the disease,
that we needs to have the right carbohydrate --
complex carbohydrate,
and then we have the right sources of fats,
energy, which are plant-based energies,
then we can then identify
how each group deviates from this norm
and advance changes in the diet and the lifestyle
and this will help us to be more effective.
As it is now, the diet is driven by economic interests,
not by science.
Thank you.
-Thank you for your comments.
I think now we will turn to the Q and A box.
How's our time?
-Hector, we actually managed to get Dale Lestina,
so can we go to Dale?
-Oh, please, I'm sorry. Thank you.
-Oh, no problem.
-Thank you very much.
I have a recommendation based on being a caregiver.
One can --
there are some cancers that are curable,
but Alzheimer's, that is not curable, it just ends in death.
And as a former caregiver, my wife has now passed on,
the role of a caregiver really, during this process
is to keep the person that they're care giving to
as calm and stress free and comfortable as possible
during the time that they're going through the journey.
What happens is that when -- at least in my case,
and I know it in the support groups,
almost without exception
is that the neurologist that treats this,
and that you go to first in the process,
won't tell you it's terminal, will give you a medicine,
and you do get a little better for it for a while
and then it doesn't work anymore.
Then you get another medicine, same kind of result.
I think that to be four-square
and to tell the caregiver offline if necessary...
-Mr. Lestina, we're firstly,
my condolences to you for the loss of your wife.
But your audio visual seems to have frozen,
so regrettably you're unable
to complete your important thoughts.
Okay, I think we're going to have to move on,
but certainly, I, again, want to offer my condolences
on behalf of the panel.
And I think that your comments as a caregiver are very valuable
and important to the panelists, and I will certainly --
we will take note of your comments about disclosure
and being open and candid and transparent
with the caregivers
about a loved one's condition and ultimate fate.
So thank you very much for your comments.
-Well yes.
-Oh, there you are.
-I just -- I don't know what happened.
I didn't touch a thing.
-It was the gremlins again, but please proceed.
-Okay, well this would be good to know, right up front if --
that your wife or the person that you're care giving
is not going to get better and that what your role is
just to help him or her along through the process
as stress free as possible, didn't have that.
And for my view, that's a pretty common thing,
if it's not pervasive of the medical profession
not letting a person know where in the world this is headed.
That is my recommendation.
-Yes, thanks again.
And this is what the open mic is about,
to solicit your recommendations as a caregiver,
and I'm very grateful to you for sharing your experience
but also your recommendation here in this open forum.
Thank you very much.
-You're welcome.
-You have been heard, and you will be heard.
[ Chatter ]
-So we're going to extend
for about 4 more minutes into the break,
but for everyone that's in line to ask questions, apologies,
just like in the live version of this,
we're not going to be able to get to everyone.
We will open up the chat for everyone during all the breaks.
If you want to ask your questions
in a less formal way there,
the panelists may or may not choose to interact there,
but again just like in the live sessions,
we're not going to be able to get to everyone.
So we're going to do our best.
The next questioner is Diane Bovenkamp.
-Thank you, Keith. Diane Bovenkamp.
-Yeah, so I'm with BrightFocus Foundation.
We fund research for Alzheimer's and related to dementia,
glaucoma and macular degeneration.
So this has been a wonderful session.
Thank you so much to everyone,
and I'm really excited about all the recommendations.
So my question for the panel
is when considering health equity and differences
of underrepresented and minority communities,
how can we consider the whole person,
not just the brain but perhaps crossover mechanisms
with the retina and eye, right, as well?
So have the committees here considered
bringing in vision researchers, maybe the National Eye Institute
when making future plans for research or trial design,
perhaps collecting eyes as well as brains at banks?
And so the context of that
is that there are a lot of biomarkers,
a lot of genes they're finding like ApoE, APBB2,
right that there are risk genes in African Americans
different from Caucasians,
and in many cases there could be inverse effects
that increase the risk of vision versus ADRD,
and, you know, also in light of many groups
using the eye to diagnose dementia, as well, right?
So I guess my question is --
And the other thing is so perhaps
there could be unintended consequences
for future treatments in differing groups,
and so you definitely need to go
the route of personalized medicine, right?
So my question is just to, you know,
ask the panel to comment that
and maybe have you considered, you know, including vision
and maybe the NEI and eye researchers in the plans?
-Thank you Ms. Bovenkamp, or Dr. Bovenkamp.
Anyway, I'm going to turn this over to Dr. O'Bryant,
who quickly responded with a raised hand,
but before he does, I do want to say
that our own ADRC is collecting other nervous tissue,
in particular eye,
and so I think this is a brilliant recommendation.
I think it's more of a recommendation instead
of a question
but certainly to gather additional tissue
that may be useful, but first we got to get there.
I think that's something that Dr. Barnes has alluded to
is we do not have the level of autopsy enrollment
that is parallel or equal to that among whites,
so I think this is something that as a panel we need
to bring to the forefront not only just additional tissue,
but just getting the tissue in the first place
and engaging communities
to be willing to enroll in autopsy studies.
That's a major challenge facing us.
Dr. O'Bryant, sorry to steal your time there, but you're up.
-That's a great point, Diane, great question,
and it actually circles back to one of our initial comments
by Charlie of this isn't...
The eye for example,
is a great way to get into additional research
because there's research showing different medical comorbidities
and so the diabetic neuropathy
may be more common among certain groups
which may predispose to cognitive dysfunction.
One way I like to conceptualize this
and think about is as scientists,
we really bear the responsible of increasing access
to research methods too.
These advanced methods of getting at pathology
all within a sociocultural context
is something that has not been done enough,
and so we must increase access
to these cutting-edge technologies
that have been used in research
among non-Hispanic white populations
since they've been invented,
and so the breadth of the examinations and methods
that we do in diverse communities
really has to mirror that among...
That we've done among non-Hispanic whites,
and so I view that as increasing access
even to the research methods themselves
because we're going to learn more.
And the research already coming out among diverse populations
says that many of these markers change,
so this is of incredible importance,
and so it's a great comment.
-Dr. Khachaturian, and thank you Dr. O'Bryant.
-I'll be brief, and thank you, Diane, for the question.
I mean, and I really think
that this topic around patient journey
and learning health systems is going to be something
that we're really now going to have to focus on,
I mean, certainly the decision by FDA around aducanumab
certainly opened up and laid bare
some of the regulatory issues that we have to deal with
in terms of not just efficacy decisions of drugs
but also the reimbursement side of the equation, and I think,
you know, your concepts and those of many others
looking at sort of this more holistic question
is really going to have to figure out
how we're actually going to pay for these things
and how are we going to help the general practitioners,
the primary care physicians be able to manage patients
particularly from these underserved
and underrepresented communities more holistically.
And I think it's a great point,
and I think it's really going to be sort of an exciting 2022
as we talk about that further.
-Thank you, Dr. Khachaturian, and again thank you, Diane,
for your insightful recommendation.
I think we had Dr. Whitfield --
as Whitaker has suggested, we're going to go over 5 minutes
but now I see we've gone over 7 minutes.
I don't know, I'm going to yield the floor to Dr. Whitaker
for his guidance on how to proceed,
but on behalf of the Health Equities Committee,
thank you to all for your stepping up to the mic
and also for your comments in the chat box.
We will be responding to those online
and as I said before, we will --
are definitely taking your comments into consideration.
So thank you for providing your insights.
-Our next scientific session
is dedicated to frontotemporal degeneration.
And it's my pleasure to introduce the session
cochairs Drs. Adam Boxer and Celeste Karch.
Welcome.
-Hi. -Thank you.
Hi, I'm Celeste Karch, and along with Adam Boxer
we served as cochairs of this session
to focus on the priorities for FTD research.
And this has been such an outstanding group to work
with that has been led by Thomas Cheever at NINDS
and really represents
outstanding investigators in academia,
in industry and from patient advocacy groups.
Next slide.
So in this session, we're hoping to address
some of the major accomplishments
that have come as a result of the 2019 recommendations,
and these were really focused in two main areas,
clinical science and basic science
with a focus on pathogenesis and toxicity,
and with the results that have come in the intervening years,
we've set a series of eight major recommendations for 2022,
and you'll hear about the first three.
Adam, do you want to say those, or should I jump to the fourth?
-Maybe you can just keep going, and I'll jump back.
-Great.
So you'll hear in just a bit from Adam
about recommendations one through three,
and throughout this session you'll hear
about how these different recommendations have emerged
based on the prior research.
And so in recommendation four, we are hoping to identify
overlapping pathogenic mechanisms
between FTD and other neurodegenerative diseases.
In recommendation five,
we hope to advance the understanding of FTD
and to identify therapeutic targets through preclinical
and translational tools and resources.
And in recommendation six to accelerate preclinical disease
modifying and somatic therapeutic development.
And in recommendation seven to elucidate
the mechanisms of cell type vulnerability
both cell intrinsic and cell extrinsic.
And finally in recommendation eight to define the genetic
and molecular modifiers of FTD with a special emphasis
on including diverse populations in these efforts.
-Great.
Well, thank you, Celeste,
and also wanted to thank the committee
and I'm going to be the first speaker,
and I am going to focus on recommendations
one through three.
And just wanted to highlight that these recommendations
really are an evolution of some of the recommendations in 2019,
and we've made really good progress,
we think, and so recommendation
one is to understand FTD epidemiology
genetics in diverse populations.
Our recommendation two is to develop
an array of FTD biomarkers
for diagnosis, prediction and disease monitoring.
Recommendation three is to accelerate
the evaluation of novel FTD treatments
by developing new clinical trial resources
and FTD-specific designs and by conducting new trials,
and then I'll highlight some things
that also influence recommendation
eight which is defining genetic and molecular modifiers of FTD.
Next slide, please.
Here are my disclosures.
There are quite a number to go through.
So we'll just skip this.
Next.
So first I wanted to highlight some of the progress that we,
as the FTD research community,
have made since the 2019 recommendations,
and one is the initiation of a large clinical research
network called ALLFTD
which was the continuation of two previously funded projects
called ARTFL and LEFFTDS. This began in 2019,
and unfortunately we were heavily
impacted by the COVID pandemic,
but we were able to initiate 23 centers, and next, please.
This project enrolls both individuals
with genetic forms of FTD
and about 40 percent of individuals
have a strong family history as well as sporadic individuals
who do not have a clear genetic or family history of FTD,
and you can see the different genetic cohorts
that we have as well as the main sporadic cohorts,
and there are about 1,000 in each, next.
And this is...
This ALLFTD network has really allowed for multiple
other research projects to be funded and built
and this is a nice infrastructure
on which we can also work
with our patient advocacy group partners
including the FTD Disorders Registry
and the Bluefield Project which sponsors a project
to further develop a plasma neurofilament light
as a biomarker through the neurofilament
light surveillance project as well as increasingly this
is serving to promote clinical trials.
Next slide.
So these are some of the studies that have either been published
or will be published soon from the ALLFTD network.
One is to show...
Many of them are focusing on blood biomarkers
which has really been a focus,
and you can see that neurofilament light chain
is a good predictor of disease progression
in genetic forms of FTD on the left
and on the right is also very elevated
in sporadic forms of FTD,
and so maybe a good biomarker for both groups.
Next.
We've also put quite a bit of effort into biomarkers
that can differentiate sporadic forms of FTD
from Alzheimer's disease because clinically these are
difficult diseases to differentiate,
and here you can see that plasma phosphorylated forms of tau
are really very useful
at differentiating Alzheimer's disease
from different FTD neuropathologies
and really quite accurate.
We think this is going to help clinicians
to more accurately diagnose FTD
but also to enable new clinical trials of sporadic FTD.
We've also learned quite a bit about risk factors
and potential interventions that might help individuals
both with genetic and sporadic forms of FTD.
And so on the left you can see that in mutation carriers,
that there is now increasing evidence
that both physical activity and cognitive activity
are associated with slower rates of disease progression
and less brain atrophy over time,
and we think that this may also apply to sporadic forms of FTD.
Next.
And we've been trying to harmonize
the genetic and sporadic FTD studies,
and here is an example showing that brain atrophy
in genetic forms of FTD is very similar
to what you see in sporadic FTD, and this gives us confidence
that what we learn from the genetic forms of FTD
can be applied to sporadic FTD and hopefully vice verse.
Next slide.
So one of the exciting developments,
and this is a study that's funded by the NIH
and the Alzheimer's Association,
is through the ALLFTD network we can now start to think about
putting together novel clinical trials for our patients with,
in this case sporadic FTD,
and this is for semantic variant primary progressive aphasia,
and you can see in the images
and on the left side of the slide
that in this form of primary progressive aphasia
there is very strong evidence
that inflammation in the brain plays a big role.
So there's a PET scan and color picture on the left
showing inflammation in the left temporal lobe,
and this correlates with where we see damage by brain atrophy,
and this is from one of our sites
in the ALLFTD network in Houston.
And so we think
that the inflammation promotes TDP 43 pathology,
and we will be soon testing a new drug,
a myeloperoxidase inhibitor
that we hope can block this inflammation in microglia,
and we hope will slow the progression
of primary progressive aphasia or semantic variant PPA.
So very excited about this. Next slide.
But we've also learned,
and I think there were comments earlier,
that FTD is a very rare disease,
and it's going to take a global effort to really prevent FTD
and to possibly understand it,
and so in collaboration with our colleagues around the world
we formed a new organization
called the FTD Prevention Initiative, and next, please.
This started as a collaboration between ALLFTD
and the genetic FTD initiative in Europe and Canada
and the UK led by our colleague John Rohrer,
and next, we're now...
And this was supported initially by our patient advocacy
group partners, the AFTD and the Bluefield project
and the FTD Disorders Registry.
Next.
We're now working to incorporate other FTD research
networks around the world,
so the ReDLat study funded by the NIH
led by Augustine Ibanez in South America
and the DINAD and FTDGen studies in Australia and New Zealand,
next, as well as networks throughout Asia
that we're starting to form links with,
and the goal is to share data
to really understand FTD in diverse populations
but to plan global FTD prevention trials as well.
Next.
So here I want to show you an example
of one of the collaborative studies
that has come out of this global network,
and this is data in FTD mutation carriers
with the three most common FTD causing mutations
C9 open reading frame for granulin
and tau on the three panels at the top,
and this is data from combined across the USA, Canada,
Europe and the UK, and what you can see is that
we can start to harmonize the different clinical measures,
MRI biomarkers and blood neurofilament levels
to understand what the earliest signs of disease
are prior to the onset of symptoms
which is on the X axis indicated by a zero.
And hopefully what you can appreciate
is that due to the different mutations
there are slightly different patterns
of presymptomatic changes.
On the left in C9 open reading frame mutation carriers,
you see very early MRI changes,
whereas in tau mutation carriers on the right,
we see a later rise in purple of neurofilament.
Next.
-A few minutes remaining. -Yep, next.
And so these are the raw data on which they're based,
and you can see these are harmonized
across the different networks.
Next.
And what we're learning from looking at all these data
is that there are bits of noise you can see prior
to the onset of symptoms
that means that really what we need are new biomarkers
to detect and measure disease in the early presymptomatic stage,
and so this needs to be a focus of our future research.
Next.
And so the new recommendations really are focused --
come out of these challenges in various FTD research.
Next.
So first is just -- one back, but this is fine --
lack of diversity, and really everything that we know is
from data in non-Latin white individuals,
and despite a lot of efforts we haven't been very successful
in including people from diverse populations
in FTD studies around the world, and this needs to be a focus
because we're learning that the genetics of FTD
are different in different populations.
So this is not just a diversity, equity and inclusion issue
but also a scientific flaw in our previous work.
We've heard that FTD diseases are rare diseases,
and so to do large clinical trials
we're going to need a global effort.
Next.
And as I mentioned, we have some biomarkers,
but we need much more particularly for sporadic
diseases where late diagnosis is a real problem
for testing therapies.
Next.
And then we've learned from COVID that in all these rare
and geographically dispersed populations,
it's very hard for people
particularly from underrepresented populations
to travel to research centers,
and so we need to think about remote assessment tools,
particularly biomarkers that we can deploy
even in third-world countries where PET scans or MRI
may not be available.
Next.
And so I'm just going to end that these are the priorities
that I hopefully talked to you a bit about
and that really you'll hear much more about it
throughout the future talks,
and I want to thank you for your attention
and now introduce the next speakers
who are Anthony Fitzpatrick and Leonard Petrucelli.
-Thanks very much, Adam.
My name is Anthony Fitzpatrick
from Columbia University in New York,
and today Leonard Petrucelli and I from Mayo Clinic Florida
will be talking about recently published work
that we've been doing on FTD.
Next slide, please.
So we have nothing to disclose.
Next slide, please.
So my lab primarily is using
a very powerful microscopy technique
known as cyro-electron microscopy
to actually study at the atomic level
those protein tangles associated
with many different neurodegenerative diseases.
This started in 2017 whenever we solved
the first structure of tau filaments
from Alzheimer's disease shown here on the right,
and over the last few years
we've been systematically going through other diseases
such as progressive supranuclear palsy
and also CBD and solving their structures
at the neuro-atomic level,
so that we can understand better what the differences
are between the molecular signatures
of each of these terrible diseases.
And what we're finding is that each different tauopathy
has a unique molecular signature.
So you can see that these cross sections
which we're showing here in the figure look quite different,
and if we go to the next slide, please.
And as a result of that,
we can actually begin to understand better
not only what the differences are at a molecular level
between tau filaments in each of these different diseases
but also how we can better design biomarkers
that bind to each of these tau filaments in different diseases.
So what we've shown here is a kind of cartoon representation
of the molecules,
and you can see that there's a big difference
between the accessible regions of the tau molecule.
So we consider them broken down into what we call microtubule
binding repeats so R1, 2, 3 and 4,
and looking at those different colors you can see
that the actual cross sections across these different diseases
are incredibly different.
So even between CBD and PSP which are two very closely,
very difficult to distinguish tauopathies,
you can actually see that there's a great deal
of difference in terms of where you could bind,
say small molecules or antibodies.
Next slide, please.
I think one of the very exciting findings that we just made
and just published in "Cell" a month ago
is the finding that basically we were looking along
with Ian MacKenzie at University of British Columbia
and tissue also from Dennis Dixon at Mayo Clinic,
Florida the sort of range of filaments
that you find in FTLD TDP,
and so we looked at a range of different FTLD TDP subtypes,
A, B and C, and we found surprisingly
that there was a common filament
that we were finding in each of these different cases
that were phenotypically different
and also pathologically distinct,
and what was surprising was we also found
the same filament in PSP along with tau filaments
and also in dementia with Lewy bodies.
And with the unique resolving power of cryo-EM,
we were actually able to identify
what these filaments were composed of
because we can actually image right down to the individual
building blocks of the filaments themselves.
Next slide, please.
So it turned out that actually these filaments
are all composed of a protein
that we previously did not know much about,
TMEM106B which has been known
since 2012 to be a risk factor for aging and FTLD TDP,
but the protein itself was thought to have an end terminus
which is associated with trafficking of lysosomes
and endosomes but not much was known about the C terminus,
and it turns out that this luminal C terminal fragment
is extremely aggregation prone
and when it gets cleaved can actually go on
to form these filaments that we find.
Next slide, please.
So I think the really exciting thing about cryo-EM
in this regard is that it can actually identify
uniquely the actual molecular constituent and shape
and form of the molecules forming these filaments,
and we really did not expect to find something
other than TDP-43 or tau in these diseases,
and we've now found a new fibrillization factor
and pathway entirely
from just imaging postmortem human brain tissue.
And as you can see here, this is the highest resolution map
that we have at 2.7 angstrom,
and not only can you see the individual amino acids
that build up this filament
and the shape and form of the filament,
but you can also see the post-translation modifications.
We have a lot of glycosylations.
We can also see the disease-associated T185 site
which we think is also phosphorylated,
and so this begins to tell you more
about the biology of why these filaments are forming
and what their possible impact could be.
Next slide, please.
So it's early days, this was an unexpected finding
but given that the TMEM106B is a lysosomal,
endosomal protein we feel like
whenever it gets cleaved and forms these fibrils,
this may be associated with additional lysosomal stress
and given that the lysosome is a mechanism
by which other filaments form by say tau
or TDP-43 get degraded,
it could be that this fibrillization of TMEM106B
is actually causing additional problems
in terms of getting rid of those filaments,
and this could in fact be leading to wider accumulation
of more disease- associated filaments
such as TDP tau or synuclein.
And I think with that, I'll hand over to Len
who will then talk about his recent work.
Thank you. -Thank you, Anthony.
Next slide, please.
So as Dr. Walter Koroshetz mentioned in the beginning,
really a lot of the field has focused their understanding
on delving into the biologic mechanism with the intent
that this will lead to improved and identification of novel
therapeutic targets as well as novel biomarkers,
and so this is work that, in collaboration
with Dr. Aaron Gitler from Stanford University
as well as my team at Mayo Clinic.
In addition there was a paper also with our colleagues
from Dr. Michael Ward from NIH and Dr. Pietro Fratta from UCL.
Next slide.
And what this paper fundamentally describes
is a novel TDP-43 RNA target.
TDP-43 normally is within the nucleus
where it regulates many DNA and RNA events,
and as a result of its mislocalization to the cytoplasm
there is an apparent loss of function.
So work from Dr. Eddy Lee from UPenn
took the first approach which really enabled these studies,
and that was to fact sort, to fundamentally separate nuclei
based on the nuclear levels of TDP-43,
and when we mined that data
looking for potential alterations in particular
with cryptic exon events we noticed
that there were numerous targets,
but one target as denoted in red really stood out.
Next slide, please.
And the reason why that it stood out
was because of the fact that prior work
had really focused on this gene called UNC13A,
a very important protein that's involved
in synaptic neurotransmission release,
pinpointed that it was a risk factor for ALS and FTD/ALS,
and so it really highlighted the importance
that perhaps RNA -- excuse me,
that TDP-43 was involved in the regulation of UNC13A.
Next slide. And so through a series of...
-Two minutes remaining.
-...through a series of cell culture experiments,
which are not shown here but really highlighting
the human postmortem studies in collaboration
with Dr. Dennis Dickson at Mayo Clinic,
we show that this abnormal cryptic exon splicing event
is significantly elevated in FTD TDP-43,
as you can see in the tissues,
which correlate with the amount of Phospho-TDP-43 burden.
Next slide.
And so as we heard from Dr. Boxer as well as,
you know, from our previous speakers,
really the need for TDP-43 biomarkers...
This is just a typical case report
that my colleagues in neurology will see,
and fundamentally it's hard to diagnose
whether or not they have FTD TDP-43 or an FTD tau.
Next slide.
So our approach is to work towards this capitalizing
on the TDP-43 function in collaboration
with Dr. Michael Ward,
the intraneural program, and Dr. Andy Qi.
We've fostered a collaboration to really pursue this
from a proteomic and amino-based assay.
Next slide.
And so we wanted to harness the cryptic splicing events
whereby we would be able to either generate RNA
or peptide biomarker candidates.
Next slide.
And as you can see here, in the left,
an ideal biomarker is one in which the cryptic exon event
is actually occurring within the protein itself,
generating a novel fusion protein.
Other nonideal biomarkers such as actually UNC13A
from a protein perspective or Stathmin-2
would be less ideal because of the fact
that they have premature termination codon
or premature poly(A).
So I'm just going to give you one such example
of an RNA target, next slide,
that really captures our efforts from a proteomic-based approach,
and this just validates a novel RNA target called MYO18A,
and you can see that it's significantly elevated,
this abnormal splicing event,
in iPS neurons as well as in human brain,
but using an antibody against that novel epitope,
we were able to identify this protein
in the iPSCs in which TDP-43 has been knocked down.
So this is just, you know, one --
somewhat of a textbook example, if you will, in which, you know,
we are confident that if we can take a look at TDP-43 targets,
and there's many of them, as I had showed you,
that we might be able to identify a marker
or a surrogate marker of TDP-43 biological activity
with the intent that we can discriminate
FTD tau versus FTD TDP-43,
and certainly the implications are clear for ALS.
And with that, I'll stop and turn it over
to Drs. Boxer and Karch.
-Okay, thank you.
So my name is Celeste Karch, again,
and I'm at Washington University in St. Louis,
and here I'll be sharing some of our advances
and next steps for using genetics
to understand the biology of disease,
and this really builds off of some of the successes
from the 2019 milestones
and has led to the identification
of some new recommendations for 2022.
Next slide.
I've no disclosures.
Next slide.
So ultimately we know that in FTD
as well as with other neurodegenerative diseases,
the genetic architecture is quite complex,
and there's an additional level of complexity for FTD genetics
given that FTD has many subtypes,
but what we know is that the exceedingly rare variants
shown in the upper --
top upper panel on the left, such as variants in MAPT,
in granulin, in VCP expansions in C9orf72
and a number of other genes, that carrying these variants
is really sufficient to cause disease,
and these are typically termed pathogenic mutations,
and understanding the mechanism
by which these genes and variants lead to disease,
cause disease is really central to understanding
those events that are central to disease mechanisms,
and ultimately these genes, their resulting protein products
can be used as biomarkers and even targeted
therapeutically with antisense oligos and other mechanisms.
But even beyond the pathogenic mutations,
there's still a lot we can learn from sporadic populations
because really these rare variants
that confer risk and resilience for disease and common variants
can tell us a lot about how we can manipulate the system
to support or protect against disease,
and so some of these variants have been identified
in genome-wide association studies
and in other rare variant sequencing studies and --
but ultimately,
while we know some about the genetic architecture of FTD,
there remains a lot that has been --
remains unexplained,
and this is particularly the case among diverse populations,
and so that's a major goal of our recommendations in 2022,
is to expand these efforts.
But beyond understanding the contribution
of rare variants to disease, we can also leverage existing
and emerging antemortem biomarkers
in order to understand how variants across the genome
may impact these analytes.
This can be a really powerful approach
for understanding additional cells
and gene mechanisms that may be contributing to disease
and that could be monitored in therapeutic trials
and address in biologic assays,
and additionally, one goal for 2022,
which has also been highlighted by Dr. Boxer, is that while --
one really interesting example in FTD
are these rare variants in the MAPT gene that confer --
that lead to one form of disease, FTD,
but beyond these very rare mutations that cause disease,
we also know that there's a number of common variants,
and you can see this in the lower right panel,
common variants in the MAPT gene that confer risk
for a number of different diseases,
including FTD, PSP, CBD, and even Parkinson's disease,
but this region remains very poorly understood,
and so additional efforts to resolve this genetic region
and to understand the biologic impact is critical.
Next set, next slide.
So here I'm going to highlight some of the outstanding progress
that's been made to resolve the function
and to develop biomarkers for using pathogenic mutations,
risk factors and protective variants.
This is just a snapshot,
and we're leaving out a number of incredible studies,
but one really exciting finding was that VCP,
which is known to be mutated and cause FTD, is --
has been reported to actually act as a tau disaggregase,
so it can interfere with and block
the aggregation of soluble tau into fibril --
tau fibrils and aggregates,
and so this finding is really central
to understanding the function of VCP,
to understand the impact of a mutation
that may block this disaggregase function
and promote aggregation,
as well as to set up potential new avenues
for efforts in other diseases
where the tau protein aggregates.
Additionally, in the last few years,
there's been huge progress made
in our understanding of the expansion of C9orf72
and how these expansions can lead to loss of function
of the C9orf72 protein and gain of toxic function,
and these efforts have resolved
a lot of the biology underlining --
underlying the function and dysfunction of these expansions
but, really importantly,
has also led to new opportunities
in the development of biomarkers to monitor some of these DPRs
and also to consider therapeutic approaches
that target these mechanisms.
Next slide, please.
We just heard about UNC13A, and this is a risk variant
that's been identified in ALS and FTD, and importantly,
the new findings in these parallel studies,
that were just published in "Nature,"
really highlight and place UNC13A in the --
right in the center of TDP-43 biology,
and so not only does this tell us about individuals
that carry these variants
but also provides additional mechanisms
that we can apply to TDP-43 proteinopathies.
Next slide.
-Two minutes remaining.
-So we can learn a lot from these rare pathogenic mutations
and common risk factors,
but we can also learn a lot from these protective variants,
where we can sort of leverage the biology of the system
that's actually promoting protection,
and TMEM106B, which you just heard about, was --
rare variants were actually originally --
or variants were originally identified
in genome-wide association studies of FTD,
and in fact it was found that,
if you carried the minor allele of a variant in TMEM106B,
that carrying that allele
while also carrying a causative mutation in progranulin
extended survival.
And so in fact, TMEM106B
represents this very interesting molecule
that both may confer protection as well
as what you heard previously may play a role in pathogenesis,
and huge efforts have gone on to demonstrate a role of TMEM106B
in lysosomal function
and in trafficking of lysosomes through axons
and both to highlight the impact of TMEM106B
in neurons as well as glia.
Next slide, please.
But ultimately I think we've had a lot of success
in not only understanding individual variants in genes
and their functions in the cell
but to use high throughput genomics
to identify additional pathways in genes
and networks that we can target therapeutically,
and one example from 2019 looked at mouse
and human tissue from FTD caused by tau mutations
and FTD caused by progranulin mutations
and identified a number of common genes
that were dysregulated,
and among these genes were a number of microRNAs,
and using computational techniques,
it was identified that there was a small molecule
that in fact targeted and modified a number of the genes
and microRNAs that were identified to be dysregulated.
These could be then taken into cell in mouse models
to understand the effectiveness of these molecules and pathways,
and more recently there's been outstanding work
showing essentially a map of tau interactomes in human neurons,
and using a PAX2 in human-induced pluripotent
stem cells, it's been shown that tau in fact
interacts with a number of mitochondrial proteins,
and in the context of mutations in tau that cause FTD,
these interactions are disrupted.
So these findings using unbiased approaches
have really highlighted
a potential role of bioenergetics in tauopathies
and FTD tauopathies that can be further investigated.
Next slide, please.
-Your time has expired.
-And so just with this remaining,
we've seen great progress in organoids
that are derived from induced pluripotent stem cells
that model disease-relevant phenotypes
including phospho-tau, autophagy and glutamatergic loss
that could be further rescued upon treatment
with drugs such as apilimod.
And final.
And all of this has really highlighted the need
for stem cell models and somatic cell models
that are genetically defined
as well as from sporadic individuals,
and moving forward, additional efforts
are needed to build more diverse biorepositories
and to leverage these lines to understand therapeutics,
to understand disease mechanism and build therapeutics.
So final slide.
So just briefly to end here, this all highlights work
that has led to our 2022 recommendations
to understand FTD genetics in diverse populations,
to understand overlapping pathogenic mechanisms
and to better elucidate the mechanisms
of cell type vulnerability and to further dissect
and extend these genetic and molecular modifiers of FTD.
So I apologize for going over,
and I'll next turn it over to Dr. Frost.
-Thank you, Dr. Karch.
So I'm Bess Frost.
I'm at the University of Texas Health in San Antonio
and the Biggs Institute ADRC,
and I'll be going over some real successes
since 2019 that are relevant to milestones one and two
and that provide rationale for recommendations
number four through seven about the basic science
of frontotemporal dementia.
Next slide.
I do serve as a consultant
for the Neurodegeneration Consortium at MD Anderson,
and I have a sponsored research agreement with them
as well as with Transposon Therapeutics.
Next slide.
So I'll first focus on milestone one,
which was really focused on trying to understand
the shared mechanisms of disease among different proteins
that are known to accumulate in frontotemporal dementias.
So tau, TDP-43 and dipeptide repeats
originating from C9orf72 expansions
are some of the proteins
that accumulate in frontotemporal dementia.
This is not comprehensive,
but I felt that the most progress
in terms of shared mechanisms have come out of work
focusing on these three different aspects of FTD.
Next slide.
We have really gained a greater understanding
of how these proteins affect overall nuclear architecture
and what's going on in the nucleus,
and importantly, these studies have ranged from,
you know, flies to iPSC cultures to analyzing human brain tissue.
Next slide.
For example, we see in the context of tauopathies
that there are invaginations of the nucleus
deep into the nucleoplasm.
This also occurs in the context of TDP-43 toxicity
and in some models but not all of C9orf72 expansions.
In the context of these proteins, nuclear pore proteins
have been shown to be depleted in some contexts
and even pulled out of the nucleus
and accumulate in the cytoplasm.
Nucleocytoplasmic transport deficits have been reported
in the contexts of all of these proteins.
These affect how RNA is trafficked out of the nucleus.
For example, in the context of tauopathy,
we see that RNA accumulates within these
nuclear envelope invaginations as well as how proteins
are trafficked in and out of the nucleus.
Next slide.
We've also seen quite a bit of work
suggesting that all of these factors disrupt
heterochromatin-mediated gene silencing,
so the overall structure of how DNA is localized in the nucleus,
and the specific type of epigenetic changes
that are being seen are a loss of heterochromatin-mediated
gene silencing.
Next slide.
So we see that tau, TDP-43 and in the context of C9orf72
expansions that heterochromatin protein 1,
which is really important for maintaining a tight packaging
of DNA near the centromere, is becoming disrupted,
and when this protein becomes disrupted,
you see increased expression, transcription
of repetitive elements that are located near the centromere.
Next slide.
One of the types of elements that is silenced by this really,
really condensed type of DNA are the transposable elements.
So these transposable elements
make up 45 percent of the human genome.
They're very similar to --
They're very similar in sequence to exogenous viruses,
and it's thought that these elements
got stuck in the human genome
due to infection of the germ line,
you know, over the course of evolution,
and our cells have developed strategies,
one of which is silencing by heterochromatin,
to keep these elements silenced.
However, in the context of all of these types
of frontotemporal dementia...
Next slide --
we see that these transposable elements
are becoming activated, and in fact,
the basic mechanistic studies in the context of tau
and C9orf have led to two clinical trials
that are currently ongoing for the treatment
of Alzheimer's disease
that are leveraging antiretroviral therapies
to stop transposable element activation
and suppress neurodegeneration.
There are also currently trials enrolling for PSP and ALS/FTD
associated with C9orf72 expansion.
Next slide.
We also --
There's a lot of accumulating work from many different groups
about the effects of these proteins
on splicing and RNA metabolism.
You heard from Dr. Petrucelli and Dr. Karch
about links between TDP -- effects of TDP-43 on splicing.
I have to include FUS in here as well
because FUS is a well-known regulator of RNA splicing.
Next slide.
So these proteins have either been shown
to interact directly with the spliceosome
or to affect spliceosome function.
We see splicing aberrations in all of these contexts.
For example, in the context of tau pathology,
there's an increase in intron retention.
We heard about cryptic exon inclusion in TDP-43,
et cetera,
and there's accumulating evidence
that the overall quality of RNA is compromised in the context
of these -- this type of front--
these types of frontotemporal dementia.
Next slide.
-Two minutes remaining. -New work reports that tau
and C9orf72 are associated with senescence.
So this is a cellular phenotype, where if the cell is
replicative, it stops replicating,
and it starts to secrete inflammatory factors
that are detrimental for the cells next to it.
In the context of tauopathy, we now know that --
or there is evidence supporting senescence in neurons,
which oppose mitotic -- most of which oppose mitotic,
the vasculature and in astrocytes,
and this work has led to two clinical trials
now using senolytics for the purpose of Alzheimer's disease,
where these drugs are killing the senescent cells.
And I realize that Alzheimer's disease
is not frontotemporal dementia,
but because these mechanisms are tau-based,
it's possible that if we see success
in the Alzheimer's disease area,
these trials could also be relevant for FTD tauopathies
and C9orf72 expansions, which is already enrolling.
Next slide.
So for milestone two, this is focused on aggregation
from 2019, aggregation and intercellular
spread of FTD-associated proteins.
There's new work in the tau area,
really nice work from Judith Steen
using her FLEXITau technology,
really creating a barcode of tau phosphorylation,
acetylation, ubiquitination and methylation events
that are associated with tau aggregation.
Next slide.
In terms of tau spread, we know now that LRP1
is a major regulator of cell-to-cell tau spread.
We know that microglia are important cell types
that facilitate the spread of tau between cells,
and we now know that viral capsid proteins
may be also facilitating the spread of tau between cells.
Next slide.
TDP-43, great work from the past few years shows
that S-nitrosylation is important for TDP-43 aggregation
and spread.
Next slide.
So based on all of these successes since 2019,
we thought it was important to leverage what's really working
and continue doing that for the future,
so recommendations four, five, six
and seven are all relevant to what I spoke about today,
and you can read more about them in the meeting materials.
Thank you.
-All right.
Thank you, Dr. Frost.
So I'm Richard Tsai.
I'm a Senior Medical Director at Denali Therapeutics,
and I've been asked to sort of give a overview
of clinical trials in FTD and all the advances recently
but also give a perspective from the industry side
on developing therapeutics for FTD
and, most of all, talk about what reflect
2022 recommendations one through three.
Next slide.
These are the disclaimers and disclosures,
and go ahead, next slide.
Okay, so the speakers before me
have really illustrated a lot of the advancements in FTD,
whether it's genetics, tau structure,
protein homeostasis, cell senescence,
and really the advancements in these areas
have really resulted in an explosion
of clinical trials in FTD,
and really it's such an exciting time to be in this field.
If you see on the right there, this is derived from a recent
"Lancet Neurology" review article.
There's a lot of clinical trials,
most of them thought to be disease-modifying therapy,
especially in FTD caused by the granulin gene mutation
or the C9 mutation as well,
but what I want to point out here
is that despite the improved availability of clinical trials,
more has to be done, especially if you look here.
Not a lot is being done in MAPT mutation or sporadic FTD,
and really, if you pay a little more close attention,
you know, the trials currently available
for MAPT mutation and sporadic FTD
are actually all investigator-initiated trials,
which really emphasizes sort of the importance
of NIH-funded, academia-started,
investigator-initiated clinical trials
and maybe a reflection on some of the novel
and risk-taking measures available
through that mechanism.
And finally, also, these are all pharmacological clinical trials,
and as I said, most of them are thought to be disease-modifying,
but we really shouldn't forget the importance of drugs
that could offer symptomatic benefits to clinical trials,
as well as nonpharmacological interventions
that are not listed here.
Next slide, please.
So first, I just want to go over how really academic consortiums,
such as ALLFTD that Adam Boxer mentioned earlier or GENFI
over in Canada and parts of Europe,
have really enabled drug development.
These international cohorts with longitudinal clinical data,
biomarker collection and infrastructure
have really enabled drug development and trial design.
So what's maybe not super obvious here
is you see both consortiums have identified
and are following a lot of patients,
collecting a lot of data,
but what's not so obvious here is that also they have --
they're working with sites
across the U.S. and Europe and Canada,
and that's also really important for drug development
and clinical trial design
because this enables industry folks, like us,
to really have sort of a first...
Not firsthand but a ready knowledge of which sites
have the physicians and staff and infrastructure
that is already sort of known
to be able to handle a clinical trial for FTD.
Next slide, please.
So I want to give a case example
of how all of this effort in the past 3 years
have really helped developing drugs for FTD,
and this is the case example for FTD
caused by the granulin gene mutation,
which we all know results in haploinsufficiency,
30 to 50 percent of progranulin in the CSF peripheral blood,
which we think, you know, is...
Progranulin is critical for lysosomal function,
so it may lead to lysosomal dysfunction
and may ultimately lead to inflammation, microgliosis,
TDP-43 pathology and neurodegeneration,
as illustrated by the highly elevated
NF-L there in the CS set.
So in this case study, you know,
we thought that we would give --
solve this problem by giving back progranulin
using a brain penetrant progranulin technology.
Next slide, please.
But does this really work?
So next slide.
What we were able to do in collaboration with ALLFTD
is to really use the large amounts of clinical data
as well as biofluid samples in a collaborative study,
and we used it to identify a series of abnormal biomarkers
in patients with FTD caused by the granulin gene mutation
that really sort of reflects the pathophysiology hypothesis
of lysosomal dysfunction,
inflammation, gliosis and neurodegeneration.
So here you can see on the top row data from ALLFTD,
patients with the granulin gene mutation
on the right, orange and dark red,
and you can see that asymptomatic carriers
have elevated glucosylsphingosine
or lysosomal biomarker,
and patients in dark red are symptomatic FTD
with a granulin gene mutation
but even higher elevated glucosylsphingosine,
and they also have elevated YKL-40
or biomarker of astrogliosis
and, of course, highly elevated NF-L
when they become symptomatic.
So that sort of reflects the pathophysiology hypothesis,
but what's nice is that we were able to find
the same abnormal biomarkers in granulin knockout mouse
and treat them with this drug,
this brain penetrant progranulin,
and we see a near dose-responsive
improvement or correction of these same biomarkers
that are abnormal in patients that are also abnormal in mouse,
so, you know, improvements in glucosylsphingosine,
improvements in YKL-40 and also improvements in NF-L.
So this really helped accelerate
a preclinical proof of concept for drug developers like us
in order to bring the drug into the clinic,
and I'll further add that all this clinical data
obtained from ALLFTD and GENFI has really helped drug companies
sort of determine the right size and duration of clinical trials
to accurately...
So that we can have more confidence that we'll see
the effect size in these biomarkers that we want.
Next slide, please.
-Two minutes remaining. -Oh, that was quick.
Okay, so I just want to quickly go over
some of the challenges we're facing.
I think sample size estimated at FTD
you'll need about 200 patients in the pivotal trial
to gain a clinical meaningful effect.
And on the right there, we see that, you know,
as a case study for FTD progranulin,
just back-of-the-envelope calculation
after taking the prevalence and estimates
for the number of Americans we...
That's just maybe 400 trial-ready patients,
meaning patients with a mutation,
right stage of disease severity,
not just severe and also not asymptomatic.
And so, you know, there may not be enough patients
to support multiple investigational efforts for FTD,
especially for male FTD.
So to solve this, we either enhance
the availability of patients
or improve clinical trial efficiency.
So next slide, please.
One way, of course, as many people understand,
is to gain better understanding
of underrepresented diverse populations in FTD.
And on the left here, you can see that we know
quite a bit about FTD in North America and Europe,
but very little in South America, Asia
and virtually nothing Africa.
And, you know, I think by understanding FTD better
in these populations,
we sort of enhance the availability
to the pool of patients that we needed,
we were able to study and develop drugs
with because we need better tools to understand FTD
in these populations
and better measurements for end points as well.
Next slide, please.
And just want to illustrate that other ways to make trials
more efficient is through biomarkers,
and this is data that shows that NfL really rises
dramatically during the conversion stage
from asymptomatic to symptomatic on the left here,
and so that may help us identify patients that progress rapidly
and maybe decrease the sample size.
And here in the middle is a paper that shows that baseline
NfL levels may also predict disease progression,
which may also help us identify patients
that change more rapidly during clinical trial.
And on the right here is a paper from the ALLFTD group.
This shows the MRI atrophy rates differ
and change in MAPT and granulin gene mutation carriers,
but not so much in C9 carriers, which also helps drug companies
design sample sizes and treatment durations
as we are developing therapies and clinical trials.
Next slide, please.
-We are at time. -Oh, okay.
And finally, I just want to end with, you know,
novel clinical trial designs will also really help us.
On the left, I took a sample from the HEALEY ALS Platform
Trial just to emphasize that, you know, novel trial designs
can allow us to evaluate multiple therapies,
decrease the placebo group as they share placebo groups,
but a three to one randomization.
And on the right here is another example of a basket
trial conducted by UCS, where we took a single drug
and evaluated it against multiple diseases
in a single trial that all have tau pathology.
And this also may increase the efficiency of clinical trials,
so thank you for your time.
-Good afternoon, everyone, and thank you for being here.
I'm Chiadi Onyike from Johns Hopkins University
and along with Dr. Penny Dacks
from The Association for Frontotemporal Dementia.
It falls on us both essentially to land this ship.
We will be summarizing the objectives
of our committees' recommendations.
May I have the next slide, please?
So for transparency, I will mention
that I have sponsored research with Alector
and conversations with Transposon and Denali
about sponsored research,
and I'm also a consultant with Alector.
Dr. Dacks has no disclosures.
Let's have the next one.
Thank you.
Now, the last 15 odd years
have been an especially dynamic period for FTD research,
and the extraordinary leaps in our knowledge
have been so well illustrated in the early presentations,
as you've seen.
In saluting this progress then, I would like to take a moment
to remember two important figures
that we lost in the last year, Professor John Trojanowski
and Professor Stuart Pickering-Brown.
So their hugely influential contributions are deeply,
deeply appreciated.
The new recommendations are designed to build
on the progress since 2019, and that's been a period
in which the leveraging of large international FTD cohorts
primarily in North America and Europe and new technologies,
leveraging the many penetrating lines of research
have led to important clinical and biological discoveries.
And these have yielded, as Dr. Tsai
has just illustrated, an impressive first wave
of disease-modifying opportunities and drugs.
Now the activities that are encapsulated
in any recommendations
are intended to build on this momentum by firstly,
incorporating ethnocultural and socioeconomic questions
at the clinical and preclinical levels.
And this is explicit in recommendation one,
but the recommendation two speaks to it
in terms of access of diagnosis and care,
and in recommendation eight in terms
of linking this preclinical level.
Now, we also expect to deepen and cross-link
the preclinical lines of research,
and this is illustrated or mentioned
in recommendations four, seven and eight.
There's an explicit emphasis on preclinical drug development
activities in recommendations five and six,
emphasis on translation of discoveries
into buy markets and novel drugs in recommendations two,
three, five and six.
And altogether, the overarching agenda
is an expansion of clinical -- or the culminating agenda --
We expect this to culminate in an expansion
of clinical trials and treatments
that will arrest progression,
hopefully also rehabilitate impairments.
So our committee has also recognized
and sought to make explicit in its recommendations
the importance of cross- disciplinary collaboration
within and between preclinical and clinical sciences
and across neurodegenerative disease research communities.
In other words, it is our view that cross-linking research
in FTD and ALS, in AD and other ADRD fields
to identify biological commonalities, intersections
and points of divergence will accelerate discovery.
And this is explicitly codified in recommendation four.
-Thank you, Dr. Onyike.
Our colleagues today have outlined the incredible progress
in FTD research over recent years.
As we all speak together about the future,
we have to remember that the progress to date
has not yet had a tangible impact
on the lives of those who suffer from FTD --
struggle with inequity and access to accurate,
timely diagnoses -- fatal dementia with no --
with zero approved treatments despite profounding
for both symptomatic and disease-modifying therapies.
And despite that sobering reflection,
when we look at those recommendations we know
that the coming 3 years will not take us fully
where we need to go.
But -- pragmatic, realistic and incredibly exciting road map
to getting us closer to improve peoples' lives.
Now, I want to make sure that we have the time
for really a rich discussion,
so I'm going to just say a couple things.
One is that the need for more comprehensive understanding
of FTD in diverse populations has been really richly,
eloquently articulated into the prior session
and this one --
still in early stages of understanding
how socioeconomic and ethnocultural status
can affect disease risk manifestations
as well as access to diagnosis, care and research opportunities.
An array of biomarkers to support diagnosis,
clinical monitoring and clinical trial design
going to be foundationally important to transform
how we define and treat these disorders to categorize people
not only by the clinical phenotype
that can be treated symptomatically
but by the underlying pathobiologies
that can be targeted with disease-modifying therapies.
Since we are at time, I'm going to skip
some of my remaining comments
and just say that on behalf of all the families
that are out there needing help,
thanks to all the researchers, funders and companies
that are working on FTD and the people
who are volunteering to participate in research
and to spread awareness of FTD and reduce stigma.
All of us working together are the key
to improving peoples' lives.
-Yeah, Dr. Dacks, apologies for having to cut you off.
So we are going to go to the Q and A.
The first four people that are in cue,
the cue is the Q and A box at the bottom of your screen.
We've promoted them over to panelists.
They can turn on their cameras if you wouldn't mind.
The first question is going to be from David Pfeifer,
and I'm going to yield back to the chairs.
Thank you.
-Thank you all so very much.
I cannot see myself.
I'm not sure if you can see me, but my name is David Pfeifer,
and I am the Board Chair, the current Board Chair of AFTD.
I had prepared a few comments regarding reaching
all with FTD diagnostic tools and the need for biomarkers.
However, these very thoughtful presentations
have touched on everything that I had intended to say,
so I'm simply going to include those in the Q and A
for the record.
I want to thank you all for all of your hard work
on FTD research.
I lost my wife, Cathy, in 2016 to FTD and ALS.
Most of all, I want to express sincere thanks to the NIH
for the summit and for funding this research,
which is advancing the science
and providing hope to our entire community
that a true understanding of these diseases
and effective therapeutics are on the horizon.
I'd also like to note that as was evidence
in our patient-focused drug development meeting
with the FDA last year,
our community is extremely energized and eager
to step up and participate
in the clinical trials that are emerging.
We're ready to do our part once the drugs reach clinical trials.
Again, thank you all so very much
for all of the work that you do.
-Thank you, appreciate it.
Does anyone on the panel want to address anything from that,
or should I go onto the next question?
-No, those are great comments.
Thank you, David, and maybe the next.
-Matthew Sharp?
-Hi. Thanks for the opportunity to comment today.
I'm Matt Sharp, the Advocacy Manager with AFTD.
And I just want to say thank you to the FTD working group
for making a better understanding
of the epidemiology, genetics,
and risk and resilience factors in FTD a top priority.
Inequity to access in diagnostics
is a fundamental problem in FTD, and it affects pretty much
everything from the lived experience,
as well as research participation.
So trying to understand it better
is really the necessary first step
in order to make advances across the board.
That's all. Thank you.
-All right. Thank you.
-Thank you for those great comments.
And, yes, you know, I just thought I would comment
that one of our priorities is to develop new biomarkers
and particularly biomarkers that are more accessible
to people throughout the world,
but in different communities so that we can make it easier
for an early and accurate diagnosis of different FTDs.
So thank you for your comment.
Should we go onto the next question?
-That sounds great.
The next one is from Jean Swidler.
-Yes, hi.
Thank you all so much for all the work you do.
My name is Jean Swidler.
I'm a leader in the pre-manifest ALS and FTD genetic community.
I don't know if this is fully understood
by everyone in this summit.
There are hundreds and thousands of people
who are at risk for genetic FTD in this country and, you know,
you have that about half of them will have the gene.
And then you look at the slides that Dr. Boxer showed.
About 30, 40 percent of those people
are actively undergoing neurodegeneration
as we speak ahead of major symptoms.
So I did not see in the very long page of recommendations
that was developed, and I'm sure a lot of work went into that,
and I thank everyone for it,
I did not see the word prevention once.
We need to be thinking of this as a crisis
because it is a crisis.
If my brain is melting, that's a problem.
And we know that there are hundreds...
There's probably close to 100,000 people
undergoing presymptomatic neurodegeneration,
excessive neurodegeneration in these genetic ALS families
and genetic FTD families as we speak.
NfL is ready to go.
NfL is a surrogate end point.
We do not need to wait for anything else.
If we should find out these other ones, that's great.
That's excellent.
But we have this powerful tool to measure neurodegeneration,
and guess what?
We can see if neurodegeneration is modulated
with interventional therapies.
It's time, and, you know, that really will unlock
the ability to have shorter clinical trials,
to have clinical trials for all these hundreds,
all these people undergoing
presymptomatic neurodegeneration.
Also, you know, I know we're not...
You know, this is NIH-focused, but somehow we got to figure out
how to get neurofilament-light as a commercial test.
It should not be locked in research anymore.
You know, think about what this could be doing
for people who are undergoing
FTD and interacting with the court system
or the criminal justice system,
if people could have their neurodegeneration measured
and, you know, show that what's going on is relevant
to what's happening in their life.
So those are my big things.
We need to focus on prevention in addition
to treating people with the disease.
We've got to focus on getting NfL over the finish line here.
We've got to focus on, you know, using the tools that we have.
Thank you so much. -Right.
Those are really terrific comments,
and I see that Penny Dacks on the panel wanted to respond.
Penny?
-Yeah, thank you, Dr. Boxer.
And, Mrs. Swidler, I just wanted to emphasize
how important what you said is,
that it may not be clear enough in the recommendations
that prevention is absolutely one of the main
focuses of those who are doing clinical trials,
to find people who are at the very stages of conversion
into symptomatic manifestation of disease
so that that's manifestation can be delayed.
I think it's a major focus of all of the researchers,
and if that's not clear enough in the recommendations,
then that's something we can go back and revise.
And I hear you, as well, in terms of neurofilament,
and I think there's a lot of energy
there in trying to get it validated to the point
that it can be used in the clinic.
We very much are aligned with your priorities,
and thank you for the point about
how we can all make it more clear.
-Any other comments from our panelists -- responses?
I would just like to, you know,
add in thanks, Dr. Dacks, for your comments.
Yeah, so, you know, I'm aware
that there are a number of efforts
to qualify a neurofilament and to bring it into the clinic.
And, you know, I think it's...
We hope that within the next couple of years,
this will be a much more clinically available test,
and completely agree with Dr. Dacks' comment
that although we did mention prevention trials
in one of our recommendations,
perhaps we could make that a bit clearer.
But the global effort that I mentioned,
the FTD Prevention Initiative, is really targeting
what the question was about that really,
we want to get to the point where we can prevent
the onset of disease and not just treat it.
So I think we'll move onto the next question.
-That would be Esther Kane.
-Thank you.
So my name is Esther Kane,
and I am AFTD's Director of Support and Education.
I am a registered nurse who has spent most of my career
caring for those living with dementia
and supporting their care partners.
While progress is being made in genetics and biomarker research,
a quick overview of funded FTD-specific projects in eye
drop shows
that the number of projects in care and services research
is dwarfed by the number of projects
in basic translational and clinical research.
In addition, there is already a large population of people
with FTD that are past the point of help
from disease-modifying therapies.
The need for new and better symptomatic therapies
is immediate,
and there are still precious few medical options
to help people now.
We need to increasing funding in research to assist
those living with the disease now,
in addition to other research initiatives.
Thank you.
-Thank you for that comment.
Do any of the panelists want to respond?
I'll just say that I completely agree,
and I think as we build a larger clinical research population,
we really need to focus on these other issues much more.
So thank you for the comment.
Maybe we'll move onto the next question.
-That would be great. So Arvind?
-Yeah. So thank you, [Indistinct].
So my question is linked to diagnostic
and presymptomatic conditions.
What the biomarker we have --
capable enough to diagnose people
who have presymptomatic or asymptomatic situation,
and if not, then what effort going on to finding that?
Thank you.
-So that's a terrific question, and I think, you know,
I'll start, but I'm going to ask some of the panelists whether,
you know, you guys would also want to comment as well.
So we're very limited.
We heard about neurofilament-light chain,
and I showed a little bit of data very quickly
as something that seems to change
before the onset of symptoms in genetic forms of FTD.
And we also have seen that brain volume changes occur,
and yet those are really the two biomarkers
that are changing the most.
And we have very few other biomarkers that we can use,
and so in our international efforts
to model the onset of disease,
it seems that we can start to describe
what happens before the onset of symptoms
but not accurately enough, we think,
that we can really effectively
and in all cases predict exactly when someone will get sick.
So there's still a lot of uncertainty,
and that's why we think that even more, you know, biomarkers,
whether they be biologic, fluid biomarkers,
different types of brain scans, PET scans,
looking at particular molecular species,
but also clinical changes
and maybe remote monitoring with movement changes,
or subtle behavioral or clinical changes,
social changes.
All of these are likely to be important,
and we think should be a focus of future research.
Other comments?
Any of the panelists want to respond?
-Or if not, I completely agree,
and did that answer your question?
-Yes, thank you.
-So maybe we'll move onto the next question.
-Kathleen Welsh-Balmer? -Yeah, hi.
Kathy Welsh-Balmer here from Duke University.
I'm with the Duke Clinical Research Institute
in the Duke/UNC ADRC.
It's tremendous the amount of progress that's been made
just since 2019 recommendations.
So I can't keep up with it,
and I just applaud all the panelists in summarizing
what is an incredible amount of discovery
that's occurred in just several years.
My comment really echoes what you were just saying, Adam,
which is, you know,
it's incredible the work that's been done
and the progress made in the biomarker area.
As we move particularly
into the presymptomatic area and start to look
for end points for clinical trials,
or even end points for monitoring patients in practice,
I think there really does need to be
some emphasis on the development
of novel end points, the pick-up
on the clinical expression of these diverse types of FTDs,
whether that is the social end points,
cognitive functional, behavioral motor.
I think there's tremendous opportunity,
and I'd love to see the investment of effort
in developing those clinical end points
similar to what we've done
with the development of biological biomarkers.
Thank you.
-Yeah, those are great comments. Thank you.
And maybe I wanted to ask --
Oh, it looks like Dr. Onyike raised his hand.
So I was just about to call on you, so, great.
-Okay, yes. -Thank you.
Thank you, Adam.
Thank you, Kathleen.
Yes, we completely agree.
Adam touched on this earlier,
and there is actually also work and already work in the field,
you know, seeking to address this question.
You know, I think one of the challenges is trying
to figure out where the goalpost should lie,
especially in relation to clinical trials.
The earlier you go, of course,
the more difficult it is to use clinical indices.
And so part of the effort involves, for example,
linking clinical outcomes or clinical indices
to physiological measurements,
whether they be electrophysiological,
which is an interesting new area...
Or not so new, but a re-emphasized area,
and then also linking it to other things,
blood-based biomarkers, CSF-based biomarkers
because we have to, you know,
adjust the goalpost according to the therapeutic goals.
And so we're going to need a multitude
and the diversity of what are biomarkers
to address these objectives,
and that's implicit in the recommendations.
It's unfortunately difficult
to specify everything in the documents.
-Thanks. Thanks, Dr. Onyike.
And Dr. Irwin also wanted to respond, I believe.
-Yeah, I just wanted to briefly comment to agree
on the need for different objective clinical measures
and that link to biology
in a biologically heterogeneous disorder,
the importance of brain donation to try to help link
some of the clinical physiology that we see microscopically,
the antemortem biomarkers, I think is also important.
-Great.
If there are no more comments from the panelists,
then maybe we'll move onto the next question.
-Mr. Ellenbogen.
-Can you hear me? -Sound clear.
-Over the years, I participated in about 12 clinical trials.
At that time, they thought I had Alzheimer's.
Since the science has gotten better,
they now believe I have semantic dementia, which falls under FTD.
Since my second diagnosis, I have not been able
to get into any clinical trials.
Why must we be placed into a box
with this specific type of dementia
when I actually learned right here at NIH
that 50 to 60 percent of those who had a biopsy after death
died of three or four types of dementia?
On another note,
I don't want to sound like a conspiracy theorist,
but I've been living with dementia for a long time.
I would have never said this in the past,
but I do believe I found
a way to address a way to delay dementia
by using a cocktail of drugs
and other habit-changing ways.
While I cannot say this with certainty,
I do have some proof it's working.
I'd be happy to speak to anyone
who may be interested in chatting with me about this.
I would sure hate to just be ignored
when there may actually be something here
that could actually help others.
Thank you.
-Well, I wanted to thank you, Mr. Ellenbogen,
for your comments.
And thank you also for participating in research
in so many clinical trials,
and, you know, I want to say I'm sorry
that it's taken such a long time to get an accurate diagnosis.
I think your points are very well taken,
and one of our recommendations is around
developing new clinical trial designs.
And one idea is that maybe, you know,
we could think about different ways of testing therapies
or finding what helps people
so that we're not so exclusive,
or that anyone who feels --
who is part of the community could participate.
So one idea is called a pragmatic clinical trial,
where we would allow many different people to participate
and share their experiences, perhaps, you know, the cocktail
that you've developed or learned about that's helping you.
And we would love to learn and get more about that as well,
and so we hope that through other recommendations
where we're developing less expensive
and easier-deployed biomarkers and clinical measures,
that might enable clinical trials sort of
like you're suggesting
that more people could participate in.
So I also want to call again on Dr. Onyike,
who wanted to comment as well, I think,
unless your hand was...
-Yeah, no. Thank you, Michael.
I think in addition
to what Dr. Boxer has just gone over,
you also highlighted the issue
of delayed, you know, late diagnosis
and what that can mean for access to clinical trials.
And this is a reason why there's an explicit emphasis on the...
And I recall, you mentioned in the earlier panel the issue,
how it relates to diverse communities.
And so this is a reason why we have an explicit focus
on these ethnocultural and socioeconomic,
if you will, factors that influence,
essentially permeate everything that we're trying to do here
including, in particular, access to care
and access to timely diagnosis.
So I just wanted to thank you again
for highlighting those issues
and giving us the opportunity to speak to them.
Thank you.
-Thanks.
We're close to time.
Do we have time for one more question, Keith?
-We're going to extend into the break a little bit
and hope to have a couple more, actually.
So, Dr. Niehoff?
-Thank you. I'm Debra Niehoff,
and I'm the Director of Research and Grants for AFTD.
And many of the advances
that we've heard so well described this afternoon
are the result of the increasing wealth
of genomic, transcriptomic, epigenomic, proteomic,
and biomarker data.
But one type of data that's still in very short supply
is quantitative data,
and that would be information on parameters
such as association, dissociation rates
for critical protein-protein interactome,
binding constants, catalytic rates.
And these are data that could not only reveal
unknown vulnerabilities in the Tau or TDP-43 interaction.
They could also be the starting point for computational
and mechanistic modeling that could generate novel
hypotheses about disease, pathogenesis and progression.
And I'm wondering if the panel
could please comment on the lack of quantitative data
and whether under recommendation five,
one of the goals could be to encourage the acquisition
of such data.
-Yes, and I'm going to ask some of the panelists.
Anyone want to comment, since I've been speaking a lot?
-Yeah. So I think that I totally agree with you
that there's going to be huge value
to expanding our ability
to leverage the genomic findings
and to use these quantitative traits
to extend our understanding of disease,
both to distinguish between different FTD subtypes
and to understand converging indistinct mechanisms.
-Thanks.
So I think we have time just for a few more comments...
Oh, I think Anthony wanted to make a comment.
-Yeah. I would just add to what Celeste said.
With regard to the quantitative aspect, Deb,
I think that, you know, cryo-EM as a tool
has been very powerful,
and, you know, our lab and others
have really shown the power of understanding
the filament structures, individual filaments
when we extract them from postmortem human tissue.
But I think in the context of those interactions
and the interactome, as you mentioned,
in think that cryotomography is going to play a great role
in the coming years to understand
when we directly visualize the filaments in situ
and watch the various interactions happening,
and what those filaments are actually doing
in the context of disease,
I think that's going to be very powerful
for the field moving forward.
-Great. So maybe just a few more comments and questions,
and I think we're going to the break a little bit,
but thank you for your patience.
I believe that Dr. Barnes had a comment.
I don't know if she's still online.
But, Dr. Barnes, did you want to discuss
your comment a little bit more?
-Oh, hi. Well, I just --
My comment was just about your opening statement,
and not to call you out,
because I think we're all guilty of it,
but that we often make this artificial separation
between recruitment and rigor of science,
and I just think that we need to think
about diversity, inclusion and equity
as integral to everything we do in research
because it's going to impact how we are able to recruit,
how we're able to keep people in our studies,
and the community can tell that we're looking at these things
in two different ways.
So I guess the general point is that they're not separate
and that we need to think about it
as a key to our scientific progress in this area.
-Yeah, and I --
You know, I apologize if I misspoke.
That's sort of the point that I wanted to make as well,
but I didn't do it in a very eloquent way,
so thank you for clarifying and emphasizing that point.
Thank you.
I think there were two more comment --
or maybe we have time for one more comment.
-David, you're next in line. -My apologies.
I don't have a question.
I just put my... -Okay.
-...those comments, as I had mentioned in my remarks,
I think all these thoughtful presentations had addressed,
so I don't have any further follow-up.
-Thanks, appreciate that. -Thank you.
-Zeynep Demir.
This will be your last question before we go to lunch.
-Hey.
I'm a clinical fellow at the NIH.
I have a quick question.
We are working on developing early MRI markers,
and I am curious, is there any platform specific
to those imaging markers and how we can collaborate?
-I'll take that, and yes.
So the ALLFTD study is collecting MRI.
I'm not sure if your question
is about the availability of data or --
Yeah, so you can apply --
-Reaching out the patient as well.
-I'm sorry.
I didn't understand that last. -Oh, sorry.
We are collecting the data
as well as reaching out the patients,
so testing our markers as well, so just collaborate as a site.
-Yeah, so let's discuss that offline
if you want to send me an e-mail, or we could --
can also contact us through our website.
Great. But definitely happy to discuss.
Well, I think we're probably out of time
and want to thank all of the panel members
as well as everyone who made comments and asked questions,
and apologies to those individuals
who we didn't get to,
but we will definitely address your comments
in the recommendations and try to do our best offline.
Thanks again.
-And it's my pleasure to introduce to you
our session cochairs, Drs. Donna Wilcock and Ron Petersen.
Welcome.
-Thank you, Natalia.
Thank you to the NINDS for their organization.
It's my pleasure to open the VCID session this afternoon,
and I think we've got a great session for you.
We've got a wonderful committee,
and everybody has worked really hard on these recommendations,
so we look forward to your input at the end.
Please can we go to the next slide?
So my disclosures, I think you've seen this from everybody.
So these are my views,
not necessarily official views of the NIH,
and I do not have any financial disclosures to make.
Next slide, please.
So VCID, vascular contributions to cognitive impairment
and dementia,
the science of VCID really does overlay
these two clinical syndromes, clinical stroke where we think
about cardio and cerebrovascular disease
and then the clinical Alzheimer's and dementia
where we think more about cognitive decline and dementia,
and I love this image,
and this image was from Dr. Corriveau.
Next slide, please.
Because of this complexity, the science of VCID
I think is truly interdisciplinary.
When we think about the science of VCID,
even just thinking about the neurovascular unit
where a lot of the insults are occurring in the brain,
you have such a density of different cell types
in that area, astrocytes, neurons, pericytes, microglia,
capillaries, smooth muscle cells.
They all meet in that neurovascular unit,
and so there are many different specialists,
special areas of focus to think about,
cerebrovascular and cardiovascular, biology.
We have metabolism.
We have the different proteinopathies with dementia,
which VCID often is comorbid with some of,
if not all of, these proteinopathies,
and then we also have unique immune responses.
Next slide, please.
And you'll hear about some of those
in the presentations this afternoon.
VCID also reflects really an umbrella
of different vascular pathologies,
and so some of these might be more associated
with a modest cognitive impairment
whereas some may actually be associated more
with a full dementia, and these run on a spectrum
as you can see there on the left.
So we have pathologies like microinfarcts,
microbleeds, very common, very, very focal
and a lone, a single one, may not have an impact.
Multiple, obviously, the more you accumulate,
the more likely you are to have a functional outcome from those,
and then we move through silent strokes, TIAs.
Obviously, CADASIL is a genetic condition
that we think about with respect to small vessel disease,
and then we start to get into the larger vessel involvement
where you have a much larger area of the brain involved,
CAA, ischemic stroke, hemorrhagic stroke,
and so as a committee,
we feel that it's really important to develop
clinical outcomes, biomarkers,
interventions that are going to match
these particular vascular injuries and diseases.
VCID most certainly will not be a one-size-fits-all,
and I think that's why those of us
who study it embrace that heterogeneity that exists there,
and so for successful VCID intervention,
we need mechanisms.
We need interventions.
We need biomarkers, and we need clinical trials,
and hopefully you'll hear about plans for all of those
and where we think the field should move.
Next slide, please.
So I just want to take a second to thank our committee.
Everybody, I'm not going to name everybody,
but we had a wonderful committee.
A lot of work went into this,
and what you see is a product of everybody's input.
Next slide, please.
So we're going to have three presentations this afternoon.
The first is the Focus Area 1.
So our recommendations are broken down
into three focus areas,
Focus Area 1, basic mechanisms and experimental models,
and Dr. Andy Shih from Seattle Children's Hospital
is going to speak to you about those recommendations.
Focus Area 2 is three recommendations
focused around human studies, and Dr. Prashanthi Vemuri
will be presenting those recommendations,
and she is from the Mayo Clinic, and then our last focus area,
we have two recommendations on translational studies,
and Dr. Sudha Seshardi will be presenting those,
and she is from the University of Texas
Health Science Center in San Antonio.
So without further ado,
I will hand over to Dr. Andy Shih,
who will present those first focus area recommendations.
Thank you, Andy. >> Thanks, Donna.
And real honored to speak on behalf of the committee
and all that we've discussed.
Next slide, please.
So these are my disclaimers and disclosures.
These are my own views, not of the NIH,
but they were shaped and guided by the committee members,
and I receive funding from the NIH and NINDS for ADRD research.
Next slide.
So what I'm focusing on today is on the basic mechanism
and experimental models that we use to study VCID
at a preclinical level.
Now, I want to emphasize how important animal models are here
because it is the sandbox, essentially,
that we use to study the different mechanisms
that might be contributing to disease
but also where we start to, you know,
test whether the drugs that we have come up with
are actually useful in treating the disease.
We talked about a lot of things in these meetings,
but we have the painful, you know,
role of trying to distill down all these important topics,
the three recommendations
that I'm going dig a lot deeper into in this talk:
so, first, to establish and refine experimental models
and technologies to identify disease-relevant mechanisms
that underlie VCID; second,
to study the neurovascular unit structure and function
and to establish how it is impacted by VCID;
and then, three, to use experimental models
to investigate how aging cerebrovascular
and cardiovascular disease impacts myelin,
white matter degeneration and neurodegeneration.
Next slide.
So when we start to think about modeling VCID,
we have to appreciate that VCID is really an umbrella term
for many different vascular disease
processes that are happening in a human,
and all these processes converge down
to create neurodegeneration and cognitive decline.
The vascular problems can exist
both extracranially in the large vessels
but also in the small vessels within the brain,
the arteries, the small arterioles,
capillaries and venules, and various types of pathologies
occurring at all these different levels of the vasculature
can lead to a progressive loss
of vascular perfusion and structure,
and this might involve occlusion of the vessels,
partial occlusion of the vessels,
impairment of the responsivity of the vessels,
damage to the vessel wall that cause them to leak
or various types of inflammatory reactions
in the vessels that impair the perfusion.
Next slide, please.
So we're tasked with trying to model
a constellation of different disease processes,
and by looking at this, you can already imagine
that there is no magic bullet.
There's no one model that captures the complexity
of what's going on in the human brain,
and so therefore, we have to think about,
as we develop models,
a number of fundamental core concepts
that we have to keep with each of the new models
that we develop, and they're listed here.
So, first, they have to reproduce small vessel disease
and other key pathogenic mechanisms
thought to result in cognitive impairment
and that reflect the human condition.
Second, they have to address contributions to damage
in both the white matter and the gray matter.
Three, they have to include genetic
and acquired conditions that are associated with human VCID,
and three, because aging is the key risk factor
that we all can't avoid,
incorporating aging as a key factor
in the disease progression is going to be very important.
Next slide.
So because the pathogenic diversity of VCID
is so great, it's logical for us
to be creating many different types of models,
and each of these models should recapitulate features
of the human disease process.
So we have many models now that reproduce different
clinically relevant manifestations
that we see in the pathology postmortem
but also using in vivo MRI,
and they include topics such as white matter degeneration,
lacunar strokes, cerebral microinfarcts,
microbleeds, superficial siderosis,
dilated perivascular spaces,
and certainly as we study these injuries to the vessels,
we want to understand how they are contributing
to neurodegeneration and the disease progression,
but we also need to think earlier in the etiology
of when these arise.
We know that these are actually end points
of a vascular disease.
Next slide.
Or next, yeah.
And so therefore, we need to think about --
In order to really define therapeutic targets,
we need to think about the early microvascular changes
that are occurring that have created these manifestations,
and there's numerous different types,
and I've just listed a few here,
but I'm certain that you can all think
of many different types of vascular pathologies
that could lead to these fundamental outcomes.
Next slide.
So when we think about the models that exist
in our field right now, we're actually quite rich.
We have got many different types of models to think about,
ranging from ones that are induced,
for example using a surgical manipulation
to go and modify the way that blood flows into the brain
or to include small vessels.
We've got dietary strategies that will mimic comorbid factors
such as diabetes and high-fat diet.
We've got genetic factors, for example manipulating
or knocking out genes that are involved,
known to be involved in human VCID,
and there's a wide variety of different types
with different phenotypes.
Embedded within these genetic models
are CAA mice or models of Alzheimer's disease,
where they try to overexpress amyloid beta
or express amyloid beta from the human,
and they sometimes lead to the aggregation of amyloid
beta around the outside of the vessel,
creating cerebral amyloid angiopathy,
or also called CAA.
So when you think about the different types of models
that could be used,
you have to first dial down to your research question,
you know, what is the question that you're going after,
and find the right model that fits that question in order
to really utilize the tools that we have at our disposal.
So for example, if you wanted to study white matter degeneration,
you've got to be sure that these models
have white matter degeneration in them.
Next.
So this is where we come -- we fall a little bit short.
We would think that most of these models
are actually relatively undercharacterized
with respect to the types of vascular pathologies that exist,
when they arise and also that behavioral phenotype
that might arise in these animals,
so we need this information in order to make critical decisions
about which models are appropriate.
Next.
And also, we sometimes take these models
and mix them with other models
in order to study certain cell types,
and when we do so, we mix genetic backgrounds,
and we now know that depending
on the genetic background of the mouse,
the phenotype of the model might change significantly,
so we have to be careful of that as well.
Next.
It also then makes sense to think
about adding these different models together,
mixing them and multiplexing them,
and here are some examples of what have been.
You know, models that are relevant to CAA
can be mixed with models of dietary
or lifestyle-acquired pathologies,
and you can imagine this leads to an explosion
in the richness of the different possibilities to explore,
and it creates additional features of VCID pathology
that you can't necessarily see
with one individual model on its own.
Next.
So here's one example from Cos and Nicole's lab,
a really nice one that shows the ApoE4 mice,
you know, that express the main risk factor ApoE4 for AD,
these animals don't have white matter hypoperfusion or hypoxia
until you give them BCAS,
which is the bilateral carotid artery stenosis model,
and you don't see that with the wild-type or the ApoE3.
Next.
But there are some gaps.
Although we're rich in the different models,
most of them are mirroring,
and we have to think about higher-order mammals as well.
The higher-order mammals will allow us to study more
because their brains are larger.
They can show additional phenotypes
or features of VCID pathology
that we don't see in a simple mouse brain.
Their larger brains have more white matter,
and because they have larger brains,
the limited spatial resolution of MRI
can be used to study the defects a little bit more closely.
Further, you can use these larger animal models
to do sophisticated neurocognitive testing.
Next.
And so here's one example from Bill Van Nostrand
and Helena Benveniste
recently where they developed a CAA model of rat
where the rat brain is about four
to five times larger than the mouse brain,
and you can see here that there is white matter degeneration
occurring within this model,
and they've been using this model with MRI
to very carefully track white matter degeneration
using routine MRI clinical scanning approaches.
Next.
We also want to think about larger mammals
beyond the rat as well.
There are important studies that are being done in canine,
porcine and nonhuman primate animals
that are going to be important to further study as well.
Next.
Now, moving to the other end of the scale,
there are also important developments in the
in vitro space as well.
The reductionist methods of in vitro models are very important,
not only because this is where we can do a lot of drug testing
but also because a lot of times, the animal model,
the vasculature in the animal models
might not represent what's going on in the human brain.
So, therefore, we need to take human tissues
and try to culture them.
So in this space, the inducible pluripotent stem cells
from human tissue
highlighted here from Li-Huei Tsai's lab
has been used to differentiate
into different types of vessel cell types,
including endothelial cells and mural cells and astrocytes,
that then can be collated back together again into hydrogels
and then be developed into cell culture systems
that have a human
blood-brain-barrier-like phenotype.
Next slide.
And so these models are going to be very important
for understanding mechanism but also drug testing as well,
but care is needed to ensure that they are reasonably
modeling in vivo features of the vascular cell types
in vivo or in humans.
Next.
We've also been very excited by the development
and application of next-generation technologies.
In particular in the last 3 years,
some really exciting techniques have come about that,
if applied to VCID research, can be very, very insightful.
They include deep multiphoton microscopy
to image subcortical white matter in vivo,
more sophisticated cognitive and behavioral
testing approaches such as touch screen
testing for mice and rodents,
which mimic more what we're doing in the clinic as well;
home cage assessments that look across the clock
to understand what the animals are doing in their cages;
higher resolution MRI and CT and PET modalities;
spatial proteomics and transcriptomic analyses;
and finally, CRISPR editing, gene editing approaches
to create more physiologically relevant rodent models.
Next.
And so just one highlight from Chris Xu's lab
where they've used multicolor three-photon microscopy
to study the neural and vascular architecture
and function of blood vessels within the white matter,
so that blue streak in the middle of that image
on the left shows the white matter,
and now we're able to image all the way down to that
in the living brain of an animal in order to study
what's going on to the blood vessels over time
and also to study the different cell types
and the responses to the blood vessel
changes that are occurring,
and we can even image much deeper beyond the white matter,
into the hippocampus,
opening up completely different types of questions
to the research field.
Next.
We want to continue investigation
of how neurovascular unit contributions
are regulating neurovascular coupling and basal blood flow.
The area of understanding
how blood flow is regulated in the brain
is still an actively researched area,
but in order to get at what is going on
in the diseased condition,
we need to understand the fundamentals
of blood flow regulation in the normal brain.
Next.
And so one thing that we'd like to do is encourage researchers
to think about the neurovascular unit
across the different microvascular zones
and think about how VCID pathology
affects each of these zones.
The extracranial vessels in comparison
to the smaller intercranial vessels
are completely different in their composition,
in their thickness, in their dynamics,
and therefore, disease mechanisms that act
on the different zones of the blood vessels
might have completely different underlying bases.
Not included in this diagram are also veins.
All that blood has to come through the arteries
and come out through the veins,
and we don't really think about veins very much
in the context of VCID.
So it's important to think about the drainage networks as well.
Next.
So some very exciting work in this area of single-cell
and spatial technologies for transcriptomic analysis
of the cerebrovasculature has come about
in the last 5 years or so.
Pioneering work from Christopher Bechtel
has shown that it's possible to isolate blood vessels
from the adult mouse brain, and this has been used
to study the transcriptional phenotypes of cells
across different zones of the blood vessels
within the cerebrovasculature.
Next.
And -- Next, please.
Oops, sorry, go back.
Something didn't pop up here.
Okay.
Interestingly, the --
Even more recently, just in the last month or so,
new work has come out from a number of different groups
showing that it's also possible to isolate blood vessels
from fresh human brain tissue, and this has led to,
essentially, a nice correlate across comparison
between the animal studies and the human studies
that allow us to think about the cell types of the blood vessels,
driving the possibility of exciting new hypotheses
in the animal research arena but also to help us think
about what we might be missing with animal models
or what types of differences are not captured adequately
between the mouse and the human brain vasculature,
and what do we need to do to make them align better.
Next.
-Two minutes remaining. -Okay.
We also have to think about the clearance mechanisms
of waste from the brain,
and the vasculature has become a central focus in this.
Removal of waste metabolites
through the blood-brain barrier along perivascular spaces
that are filled with CSF or through phagocytic degradation
need to be thought about more carefully.
Next.
And in particular, dilated perivascular spaces,
which are often seen as an increased risk factor
and increased with age and also with vascular risk factors
are interesting biomarkers, perhaps, for VCID,
but we'd also want to understand
what this actually means for brain clearance
in the context of human neuroimaging.
Next.
So this is where animal models come back into the spotlight.
A lot of these questions are very difficult
to address in the human brain,
but if we could study them in the rodent brain
or in the animal brain,
we can get much more information,
and so recent studies from Macon Utgaard's lab,
for example, are shown, the ability to use optical
imaging to track the movement of dyes or different small beads
that have been injected into the CSF.
MRI has also been used to watch the diffusion
of intercortically injected dyes within the interstitial space
to see how they clear over time.
Next.
But also different -- It's becoming more clear
that different types of physiological rhythms
might be involved in augmenting this clearance
and driving the clearance of CSF and metabolic waste as well,
and this is heartbeat, breathing,
vasomotor oscillations of the blood vessels,
neural activity, sleep.
A lot of different factors might be involved,
and so animal models can be used to help disentangle
some of these complexities.
Thanks.
We also want to think about the cells
that actually make the white matter white,
the oligodendrocytes.
We know that white matter is particularly vulnerable in VCID,
but yet we know very little
about the pathophysiology of oligodendrocytes
and the repair mechanisms that are involved --
that they mount in the face of vascular and neurodegeneration.
Next.
And so through in vivo imaging approaches --
Next, yeah.
-Time has expired. -Oh, okay, very quick.
Yeah, and so through using in vivo
imaging approaches here from Ethan Hughes Lab,
you can see that you can track the remodeling
and the remyelination of these cells over time
in living animals, and then next.
My final slide here is just to say
that the development of new tools
are what lead to major gap leaps within our insight
into a disease progression,
and so we want to encourage the development of new tools,
and this is just one slide showing from [Indistinct] lab
at University of Southern California
that's designed a new Cre driver
that allows us to target a very specific cell type
within the brain, a pericyte, that wouldn't have been possible
without single-cell transcriptomic analyses
identifying specific genes
that allow us to do this genetic targeting.
So with that, I'd like to thank you.
Sorry for going over a little bit,
and I'll pass the baton onto Prashanthi Vemuri.
-Thank you, Andy.
It's an honor to be here on behalf of the committee
and represent the great discussions
we had coming up with these recommendations.
Next, please.
I have nothing to disclose.
Next.
So the recommendations came through based on three
guiding principles specific to human studies.
VCID is really common.
It coexists with other deteriorative pathologies,
so detection and screening for these is very important.
Number two, on the next slide,
is that VCID is preventable.
So there's decreasing prevalence of raised blood pressure
because of better blood control across the globe,
and this has resulted in declining incidence rate
of dementia in Europe and U.S.A. across seven studies.
So the fact that VCID is preventable
is an important fact to consider
when designing these recommendations.
The next slide shows that we understand VCID
as a heterogeneous and a broad phenomenon.
So it captures all forms of cerebrovascular brain injury,
not solely stroke.
Therefore, studying this in the context
of mild cognitive impairment
or fully developed dementia is really important,
and these are the three guiding principles
that set us up for the recommendations,
and we also wanted to take into consideration
the progress that has been made so far.
Next slide, please.
Next.
There's been tremendous progress that has been made in VCID,
like Donna alluded to right in the beginning,
but one of the major improvements in the field
has been that in the last couple of decades,
we really understand the mechanisms and biology of VCID,
like Dr. Shih showed.
Here's an example of studies across NIH-funded VCID cohorts.
These are examples of studies, and we have tried to understand
how risk factors, lifestyle as well as genetic variants
can express and increase the risk
for large and small vessel diseases
as well as contribute to the burden of dementia.
Next.
We've also gotten really good with imaging markers of VCID.
I'd really like to look at the image
on the top left in blue,
which shows some of the earliest images
of white matter hyperintensities,
which are manifestations of vascular disease,
and from then to now, these are images taken last year.
You can really see that on the top panel,
we have gotten very good at detecting lesions,
quantifying them.
At the bottom panel, you can see that we have quantitative
imaging available right now in human studies
where we can capture various aspects of the brain
as well as measure vessel structure and function.
So we made tremendous progress there.
Next slide, please.
We've also been able to try and understand
what the clinical implications of VCID are.
So if someone has a positive amyloid scan,
how do the vascular disease contributions
add onto Alzheimer's disease and cause cognitive impairment,
which is very similar over an age range
of 70 plus or 5 years.
And on the next slide, I'll talk about the successes
that have come through AD/ADRD summits,
where there's several NIH initiatives for VCID.
MarkVCID, which has been focused on analyzing,
optimizing and validating VCID biomarkers
and has really brought into the field of AD/ADRD
to have tools to be able to detect vascular disease.
DISCOVERY Study, which has been fantastic at bringing together
and trying to understand mechanisms of poststroke VCID.
And the newly funded DiverseVCID,
which has been focused on white matter lesions
in diverse individuals across US.
So we did -- have made a lot of progress in VCID,
but when the committee met, on the next slide,
we thought that our recommendations
should reflect the common theme
across all the things that I've talked about so far
as well as consider the progress that we've made so far.
Next slide.
Before I get into the recommendation,
I wanted to bring this health equity concept back again
because in each of the recommendations
that we talked about,
the crosscutting theme was that specific populations
with high vascular risk factors, as well as inequalities,
are not considered in the studies
that we're conducting right now.
And this should be a key aspect
of what we're going to do in the future.
After setting up this, we came up with recommendations,
and the first recommendation was developing
and validating markers of VCID.
So one might say that they made a lot of progress.
We have imaging markers.
We have emerging plasma markers.
Why would we need this recommendation?
The committee felt that, on the next slide,
their could be cost-effective ways
to measure the presence and progression of VCID.
If you remember the first slide that I showed,
VCID is extremely common,
so we really need cost-effective ways
to be able to detect the presence of VCID
and track the progression of VCID.
There's several ways you could go about it,
and I wanted to give you two examples
to kind of get us thinking about,
what kind of tools would be optimal to consider this?
Next slide, please.
This is a simple example of how you could look
at the electronic health care records and look at the ICD-9,
10 codes for the patients in the health care records
and consider the seven conditions
proposed by US Department of Health and Human Services
for measuring cardiovascular metabolic conditions.
In this particular example,
what we did was we looked at individuals
who had two or more of these conditions,
a very simple cutoff,
and we found that people who had two or more of these conditions,
which can be easily obtained,
are predictable of greater white matter hyperintensities,
which is manifestation of vascular disease,
as well as greater progression over time.
So tools like this could be very helpful.
Next slide, please.
There's another example that Dr. Eric Smith
brought up, which was --
which elegantly looked at natural language
processing in EHR
and how you could actually look at MRI
and CT scans for a non-stroke indication in EHR
and come up with ways in which you can detect people
who are at greater risk of dementia
because of vascular cognitive contributions
to impairment and dementia.
In this particular study,
they said that when they looked at CT and MRI,
they were able to recognize and identify a group of individuals
who are at greater risk of declining over the next 5 years,
which is a tremendous progress.
Next slide.
We talked about new markers.
The other thing that was recurring
when we talked about markers was that,
we need to refine and validate the markers we have.
We're doing a really good job with coming up with markers.
For example, plasma NfL is a fantastic marker
for several vascular disease,
but we also talk about being a great marker
for other neurodegenerative diseases.
There is emerging evidence that plasma NfL values
are impacted by renal function.
So considering them while you're measuring it,
refining your measurements will go a long way.
The other aspect of that, goal standard is always pathology.
We can come up with biomarkers.
We can measure them, but what do they mean pathologically?
That meets a better focus than we have done in the past.
Next slide, please.
And the elephant in the room, or the elephant
and the six blind men, is that we have been --
We understand the concept three,
which is VCID is extremely broad.
When we are measuring biomarkers,
we need more specificity,
and we need to consider the heterogeneity.
When we are saying VCID, what are we exactly measuring,
and what is the contribution of our biomarker
to the measurement we are making?
In some certain senses,
it could be a blood-brain barrier dysfunction.
In other cases, it could be white matter damage
that Dr. Shir talked about in his presentation.
But increasing the specificity
and understanding the heterogeneity in the population
as well as in the ways it manifests,
vascular disease manifests, is very important.
Next slide.
So as I said, recommendation four was focused on biomarkers.
How do we develop new,
better biomarkers as well as refine what we have?
Recommendation five was given a priority two,
and we thought interventions,
especially given the fact that VCID is preventable,
there should be a focus on interventions.
Developing and identifying
as well as validating interventions,
testing the efficacy as well as treatment of VCID
across spectrum of severity
as well as in diverse populations
is extremely important.
On the next slide, you'll see that the committee brought up
the SPRINT Mind Study,
where it's been shown that intensive blood pressure
controls can reduce the risk of MCI and dementia.
So trying to focus back on what randomized clinical trials
can we begin and test the efficacy of?
There are a wide range of vascular risk factors
we could target and how we could target them.
But designing them and optimizing them
should be a priority,
so we can translate it into prevention.
And we also talked about incorporating biomarkers
in our clinical trials.
When we talked about the biomarkers for VCID,
more often than not, they're not included
in other AD/ADRD studies for when you're studying,
let's say, FTD or Alzheimer's disease.
But the point I'd like to bring across
is that we thought given that VCID is manifested along
with several neurodegenerative diseases,
incorporating VCID markers,
some of them MarkVCID initiative,
would be helpful across all studies.
Next slide, please.
At this point, it was brought forward
by Dr. Eric Smith through our discussions,
and he thought that early phase clinical trials
would be very important.
An example of this is by a study led by Dr. Joanna Wardlaw.
Their goal was to see if they could increase
cerebrovascular function using a method called CVR,
where there's inhalation of CO2,
in individuals who had lacunar ischemic strokes
and if they could increase cerebrovascular function
over an 8-week period.
And they found that medication Vascepa, specific medication
did improve cerebrovascular function,
but what really helped them is the ability to measure
these early changes to cerebrovascular function.
So incorporating surrogate biomarkers
to try and improve function would be really important.
Next slide.
Finally, coming to our last recommendation
for human studies, this was a difficult one
because there are many concepts
that emerge through this recommendation,
which is that we have a lot of observational data,
observation study-led data,
but we need to bring back the idea
that we need to study life course in diverse population,
and we really need to consider the fact
that VCID is complex and broad.
There's several dementia-related risk factors
as well as several biomarkers of neurodegeneration
that can be leveraged to try and understand,
how does VCID emerge and change over the life span.
And this recommendation on the next slide
could be used in the context of hypertension.
This is an example how you would go about a life span approach.
Let's say you're studying hypertension.
You could collaborate across individuals and scientists
who are studying systemic health and brain health,
study extracranial vessel as well as intercranial health,
and try to map out how the disease is progressing,
how the changes fold in the body
as well as the brain are progressing,
and that could really help us design and feedback
into better interventions in the future.
On the next slide, there's a slide
from Dr. Tim Hughes from the MESA study,
and this slide beautifully makes the point
that there are complex pathways involved.
There are upstream vascular measures
that influence the imaging measurements that we make,
and they also impact neuropsychology
outcomes that we measure.
So how do we go about modeling these complex pathways?
How do we leverage the methods that we have so far,
and how do we design studies
that can better study the evolution of VCID changes?
That would be really important as we go forward.
On the last slide, I'd like to close on some of the thoughts
that we had about study design.
The group thought that we should really focus on rigor
and reproducibility of our results,
consider heterogeneity of VCID in all our studies,
as well as improve the generalizability of the samples
that we are studying to include diverse population
as well as move more towards open science
so that the whole field benefits as such while studying VCID.
With that, I'll stop here
and pass it on to Dr. Sudha Seshardi.
-Hi, I am Sudha from UT Health San Antonio,
and again, it's my honor to present.
Next slide.
On behalf of our working group,
these are my disclaimer and disclosures.
Next slide.
Focus area three, which is on translational studies.
As you know, translation is where we take insights
from basic science, like Dr. Shih outlined,
and assess their applicability in the design of human trials,
targeting prevention or treatment of dementia and MCI,
so that was our recommendation seven.
And recommendation eight was conversely to look
at associations, hypotheses that we can generate
based on the large community-based diverse
human studies, that Dr. Vemuri outlined,
and see are these associations valid?
What is the biology underlying these associations?
So there is a large amount of biospecimens,
genetic, biometric imaging,
longitudinal data in human studies,
but only if we understand the biology of these markers,
whether it's NfL or something else,
can we apply them appropriately.
So this reciprocal flow of information
between basic science studies and human studies
is key to rapidly advancing our understanding
and to more successful trials and interventions.
I'd like to highlight this, you know,
explain what the rationale for our working group
was to make these recommendations
using about five examples.
Next slide.
One of these is something you've heard about.
In 2012 in science, there was this exciting
finding that the glymphatic system of the brain
and the perivascular, the paravertebral
and the paravenus pathways were --
had a role in clearing in substances,
including amyloid,
and at least in mice as you can see from that graph,
where the green line is the amount of CSF tracer
on the y-axis removed during sleep
and the orange line during the wake state.
Sleep seemed to be more important
in removing these agents, these molecules.
Simultaneously, in human studies
that put together observations on MRI,
observations whose significance
we were earlier less clear of with neuropathology,
it was seen that these in perivascular spaces
corresponded with what was seen on pathology as enlarged spaces,
and they were greater in number in conditions
where we would experience the protein clearance
to be poor, like in Alzheimer's.
So here, you had a pathology in animals
correlating with a highly valued outcome in humans,
which is clearance of the amyloid, and next slide.
How could this be incorporated in clinical trials?
Clearly, we want clinical trials
looking at these modifiable vascular and metabolic factors,
so can we use what we have learned in animals?
In animal studies, as you see in the panels below on the left,
B is obese mice, and A is control mice.
And you can see these enlarged perivascular spaces
on the animal MRI are more abundant in the obese mice.
The next panel shows, in yellow,
the CSF spaces in control rats on your left
and aging spontaneously hypertensive rats on the right,
again showing larger spaces.
So if perhaps in humans as well, the impact --
the adverse impact of vascular risk factors
on brain cognition and dementia
is partly mediated through glymphatic function,
and MRI enlarged perivascular spaces
are a marker of this glymphatic function,
we can then assess the success of the vascular intervention
using the specific biomarker.
And going back to animal studies,
you can understand better why this may be so.
Next slide.
Some of the unanswered questions are,
how important is this pathway for amyloid clearance
in the common Alzheimer's disease?
How is it modified by coexisting VCID?
In humans, how important is sleep and stage of sleep?
And of course, how well do these enlarged perivascular spaces,
which after all are a static, structural finding on the MRI,
how does the volume or location
of this ePVS reflect glymphatic clearance?
Would it be better if we had a more functional,
real-time MRI biomarker for glymphatic clearance,
and how might we develop that?
Next.
As Dr. Shih alluded,
one way of developing a human-based technique
for assessing clearance may be looking at animal studies.
Next.
Professor Van Nostrand, who is in this panel,
and others showed in a rat model of cerebral amyloid angiopathy
that the movement of biomolecules across the brain
and into the neck vessels could be seen
using dynamic MRI imaging,
and our group felt that developing powerful
techniques in humans could be very valuable.
Next slide.
We know that cerebral amyloid angiopathy,
one of the VCID types that is seen in people
with Alzheimer's
appears to be a risk factor for what is called ARIA,
or amyloid-related imaging abnormalities.
This is an area of great interest now
when the FDA and Medicare are assessing
the risk-benefit ratio of amyloid lowering therapies.
One of these risks, of course,
is this edema that you see in the left two MRI panels
as those white changes or the hemorrhages that you see
in the right two MRI panels as small black dots.
The fact that coexisting VCID increases the risk
is also an opportunity for mitigating therapies that could,
perhaps, be coadministered with amyloid-lowering agents.
There also seems to be an individual propensity
to develop these side effects.
The study showed that if you were an E4 carrier,
you had three times the risk as if you were not an E4 carrier
of developing this type of ARIA edema.
Next.
How does APOE actually increase the risk of ARIA, E4?
Is it only because E4 is associated
with the greater prevalence of cerebral amyloid angiopathy?
What is the mechanism of the ARIA
developing in cerebral amyloid angiopathy?
You know, in humans, we have imaging or blood or CSF
and then pathology,
but in animals, you can look at the different stages.
So clearly, next slide,
we need better models of cerebral amyloid
angiopathy and ARIA, and we need them now.
One of the reasons we did no suspect ARIA in human studies
is because it is not very common in mice,
so we need other models.
Another question is that in human studies,
the ARIA develops.
You stop the agent, the MRI apparently returns to normal,
but people want to know, is there any lasting,
long-term injury or side effects?
And one larger animal model, as Dr. Shih referred to,
is the squirrel monkey.
These are genetically predisposed to accumulate
amyloid along their blood vessels,
so a CAA model.
And as these monkeys age, they develop ARIA-E-like
changes on MRI,
like you can see in the left panel with those white areas,
as well as ARIA-H-like changes,
as you can see with the white arrows in the middle panel.
And when these monkeys die, if you look at the brain,
the regions that had ARIA-E have this changes in the myelin
and structure injury,
raising concern that ARIA-E, even if it reverses,
might leave residual cognitive or functional deficits.
Next.
To go to another example,
you heard about the SPRINT MIND study
that showed that intensive control of blood pressure
to 120 millimeters mercury
reduced white matter hyperintensity accumulation
compared to more standard blood pressure control to 140,
but white matter hyperintensity
is something that accrues over time.
Can we use a more sensitive measure
that reflects functional changes?
And one that was discussed was cerebrovascular reactivity.
What is this? Next slide.
This is something that was also initially developed in mice,
like transgenic mice having Swedish,
Dutch and Iowa mutations.
When the concentration of carbon dioxide is slightly increased,
there is a real-time response of vasodilation
and increased blood flow.
In the MarkVCID study, Dr. Hanzhang Lu at Hopkins
has led the standardization and application of these to humans,
and so this could be applied in a study
not just like SPRINT or ADNI,
but even something like an FTD study.
And this change in flow is seen with just an MRI BOLD.
Next slide.
Conversely, speaking about looking at data
accrued in population studies,
what can that tell us that could then be taken to animal studies?
In the CHARGE Consortium in about 50,000 people,
white matter hyperintensity, a large GWAS,
we found about 27 loci.
During a transcriptome-wide association study,
there were about 39 genes at these 27 loci,
four of them encoding for drugable targets.
Interestingly, these genes were also associated
with white matter integrity measured in a sensitive measure,
diffusion tensor imaging measure,
in nearly 2,000 young adults,
who were college students, completely healthy.
And Mendelian randomization using this composite score
suggested that white matter hyperintensity volume
was associated with subsequent
risk of cognitive decline, dementia and ADRD.
So if these risk variances are acting across the life span,
there is an opportunity here for prevention,
but we need to understand their function through animal studies.
Next slide.
Another example of using animal studies to understand biology
and develop human biomarkers
to understand the specific role of individual cell types,
like the cell types in the blood-brain barrier,
is work from [Indistinct] lab.
The parasite is part of the blood-brain barrier,
and in mice that have the APP mutation
that gives them a propensity to accumulate beta amyloid.
If you also partially knock out parasites
so that they have dysfunctional parasites,
you can see, in the second panel on the right,
amyloid accrues even faster.
So this was then extended to humans by measuring this marker,
platelet-derived growth factor receptor-beta,
which is expressed on the surface of the parasites.
Next.
And you can see that levels of PDFGR beta
and the CSF are higher with worse cognition,
a Clinical Dementia Rating scale score of 0.501
is associated with higher levels,
suggesting that here we have a biomarker for parasite
to add to biomarkers like YKL-40 and NfL,
which are for glia and neurons.
Next.
The gut-brain axis is emerging as another important factor
in many neurological disorders,
and there's a fascinating animal example that showed us this.
In mice, next, that have a KRIT1 mutation,
there is these development
of the cerebral cavernous malformations,
just like the ones humans have.
This KRIT1 gene is associated with CCM in humans,
but if you deliver the mice aseptically through
Cesarean section
and have them foster by germ-free mothers,
you can see the eight panels below.
Most of those nice developed the cavernous malformations.
Could this have relevance for humans?
Next slide.
In fact, humans who are genetically predisposed
to higher levels of inflammatory factors,
like TLR4 or CB14, were more likely to have
larger number of cavernous malformations in the brain
when they carried a KRIT1 mutation.
Next.
And can this be related to their microbiome?
In fact, a recent study showed
that the fetal microbiota are different.
There are those three phyla in green
that differed between people with cerebral cavernous angiomas
and people without cavernous angiomas.
So here, you have a gene environment interaction,
an environmental modification that could really improve
the clinical picture in these patients.
Next.
A final example comes from an overlap, next slide,
of a gene TREM2 discovered about a decade ago
to be associated with risk of AD.
This gene, next, is known to be expressed not in neurons,
but microglia and to play a role in clearance of substances.
And if you have a TREM2 knockout,
then a stroke in the mouse model results in
a larger infarc, and TREM2 is expressed around vessels.
Next.
So we are learning something about this gene,
about this marker.
Soluble TREM2 was found to be a potential marker
of cerebrovascular disease in neurodegenerative disorders
in some persons with hemorrhagic stroke,
who had either small vessel disease
because of CAA or small vessel disease because of hypertension.
Higher levels of TREM2 were associated
with greater white matter hyperintensity,
and this was also true as shown in a paper in "Brain."
When you looked at people
who had tau pathology in the brain,
the red circles are people with AD,
and they had higher levels of soluble TREM2.
But soluble TREM2 may not be all bad.
The levels vary over time.
And if you looked at people with AD, amyloid positive,
tau positive, higher levels of soluble TREM2
in the plasma were actually associated
with better MMSE scores,
so you see the importance of understanding
something that we have identified as a biomarker
based on just genetic association.
So these were some of the reasons for the strong
push on recommendation seven and eight,
and I look forward to further feedback and discussions.
Thank you.
Handing back to Donna.
-Maybe I'll jump in here, Ron Petersen.
Thanks very much, Sudha, for that wonderful,
kind of tying everything together.
And I'd like to thank Andy and Prashanthi
also for summarizing the work of the three work groups
and very, very nicely.
I think it's been an exciting time
to discuss the possibilities, and as Prashanthi outlined,
there has been significant movement in this area
funded by NIH since the 2019 summit.
MarkVCID, DISCOVERY, DiverseVCID on the human side
have all been launched,
and we've had numerous animal model studies.
So again, Andy nicely outlined
where we are with regard to the modeling of VCID,
and he pointed out, Prashanthi pointed out,
Sudha pointed out the complexity of VCID disorders,
that is the heterogeneity of them.
So not only does VCID exist in a heterogeneous environment
in the aging human with amyloid,
tau, alpha-synuclein, TDP-43, but within VCID itself,
it is heterogeneous, multifactorial.
That's the tough news.
The good news is that
May addressed some therapeutic options.
Each of those different mechanisms that Andy outlined
could potentially be amenable to intervention,
so I think the pathologic diversity is encouraging,
and I think what he outlined was an approach using genetics,
lifestyle modifications, looking at age, looking at sex,
taking into account the VCID-AD interactions
that are likely in many, many situations,
but I think this does give us the opportunity to move forward.
The basic group also focused on the neurovascular unit,
so both single-cell,
cell-specific technologies are being developed,
looking at neurovascular coupling,
blood-brain barrier integrity,
clearance of toxic proteins as Sudha outlined
and the aging process itself.
Aging on top of this.
Why is it that aging is --
How is aging contributing to the increase
in vascular disease as we go forward?
The experimental models then,
learning from cardiovascular disease,
cerebrovascular disease,
their impact on myelin white matter and neurodegeneration
are all becoming more apparent as these studies continue.
The human studies group also looked
at the diversity of the disease and, as Prashanthi indicated,
really focused on biomarkers because biomarker says --
We're hearing throughout this meeting.
We'll hear it tomorrow.
Biomarkers are really key at trying
to separate out the individual components
of these various pathologies,
so I think that the group focused on the fact
that these tools need to be evaluated
in diverse communities.
Among all the ADRDs that we'll be discussed today and tomorrow,
perhaps VCID is among the most important with regard
to understanding in diverse communities
because of increased prevalence of some of the cardiovascular
and cerebrovascular comorbidities,
so VCID is really in the crosshairs of this exercise,
and I think the group certainly was aware of that
and focused many of the recommendations
in that direction.
So certainly standardizing evaluations,
assessments, behavioral, functional, noninvasive,
using some of the digital tools that are emerging now
will allow us to evaluate a variety of populations,
again, looking at heterogeneity
and focusing also on fluid biomarkers,
exosomes and what they will tell us
about the underlying pathology.
Getting into interventions, we can talk then
about either pharmacologic or lifestyle modifications.
Lifestyle for vascular disease right now are very important,
and we really need to be concerned.
This morning, we had heard about the strategy
of possibly oversampling underrepresented groups.
Maybe that is the strategy that we use --
need to use here in VCID studies as well.
Of course, harmonization of data is critical.
The combination of risk factors throughout the life course,
as both Prashanthi and Sudha mentioned,
is increasingly important because we know
that these diseases don't develop overnight.
The pathology evolves over many, many years.
So we need to look at a life-course projection
not only with age but with sex, complex pathways.
But interestingly, the other side of the coin is --
Involves resilience.
That is, there are people who have these various
risk factors who do just fine,
and so while we do this in the Alzheimer's disease space,
we need to do it in the vascular space as well.
And then Sudha very nicely put this together.
What are learning from the animal models,
and how in fact are we going to apply it
from the animal models to the human model?
So again, I want to thank the entire committee.
If the committee could turn on their cameras,
I please would offer them the opportunity to comment
on any of the questions that are out there,
and I think we have -- see some that are posting already,
so let me start with Steve Greenberg.
Steve? -Hey.
Really great to see everybody,
and I know I'm speaking for a big audience here to say
those were just spectacular overviews of the field,
and the talks were great, and the field is great.
I mean, it's really an exciting time.
I'm just going to pick up on one thread that came up.
The cross-link between vascular and neurodegenerative disease
came up in --
as a recommendation priority item in multiple sections,
and really just to continue the line of sights
that Sudha showed,
you know, of all the different postulated mechanisms
for the interaction
between the vascular system and neurodegenerative,
probably the one that's most well substantiated
is the role of vascular disease
in affecting cardiovascular clearance
in the lymphatic system.
That seems to be a really striking area,
kind of nexus between the two processes,
and it fits into really well --
It fits very well with what we understand
about amyloid clearance, and amyloid is an extracellular,
sort of interstitial fluid peptide
that needs to be cleared,
and if the clearance system is mucked up,
that's going to increase deposition.
You know, more broadly speaking, it's hard to believe
that clearance of the fluid in the interstitial space
isn't a much broader mechanism in disease,
so even outside of the amyloid context,
which maybe, you know, maybe is the most important one
from a disease standpoint,
you know, it's hard to believe that there aren't other disease
processes that are affected by having stuff that does
or doesn't get cleared out of the interstitial fluid
and especially with the number of ADRDs
and ther disease that are driven by protein deposits.
Not all of them have this prominent
extracellular phase that amyloid does,
but all of them have some sort of extracellular phase,
and, you know, one of the advantages
of having an ADRD summit
is the chance to do what we don't do very often,
which is getting together as an ADRD community
and thinking in a very cross-disciplinary way.
So the question if we could all sit in the same room together
or at least virtually would be, you know, broadly speaking,
what else do we think that loss of perivascular clearance
might be doing to promote neurodegenerative disease,
and how would that translate into either biomarkers?
And Sudha brought up the, you know,
the high position of lymphatic markers
on our wish list for biomarkers
but how it might move into trials,
so anyway, it's a broad question,
and it's hard, again, hard to believe
it isn't playing a role in a lot of disease states.
-Absolutely, Steve. Thanks very much.
Comments?
Sudha, other folks on the panel, comments for Steve?
-Completely agree that it probably plays a role.
Other molecules that might be involved in the pathway
like [Indistinct]
also potentially valuable biomarkers completely.
Thank you for bringing this up and for the pioneering work
that MarkVCID and is doing, for instance,
to establish these as usable, pragmatic, biologically
and technologically validated biomarkers
that can then be extended
the studies of other neurodegeneration
as well as of vascular interventions.
-All right. Thank you.
Couple up.
Prashanthi, you have your hand up and then Dave.
-Quick point, I think there's emerging evidence
that it's the same with tau,
so I think studying the changes locally
and globally would be very important
to move this concept forward.
-Very good. Dave?
-In regard to Steve Greenberg's point,
I think there's a lot of emerging evidence
from labs like the Cos Iadecola,
Jony Kipnis' and others that strongly suggest
that specific cells that surround blood vessels,
such as perivascular macrophages,
are really important in regulating the connection
between interstitial fluid flow and lymph --
ultimately flow out through the lymphatic system,
so I think that those could easily affect not just amyloid
but lots of other functions, such as blood-vessel function,
so I think that's an area that really needs a lot more study.
-Yeah, rich area of study.
Speaking of Cos Iadecola, Cos, I have you up next.
-Yeah, I like to make two points,
so one is that the focus of the field,
you know, very masterfully, you know,
described by the speakers has been of vascular failure
being linked to starvation of the brain of oxygen and glucose.
I think now, as Dave pointed out,
the clearance of the blood vessels is now becoming
another potential pathogenic mechanism.
The blood-brain barrier has emerged
as a pathogenic mechanism,
all right, which are independent of the delivery of oxygen
and glucose to the brain,
which has been traditionally considered
the basis of vascular injury.
All right?
But the brain, I mean,
the vessels of the brain do more than that.
They deliver growth factors to the neurons,
and that's been very well described in development.
And for example, even in neurogenesis in adult animals
where the vessels deliver vital factors,
including nitric oxide,
that keeps the neurogenic niche alive.
The recent paper in neuron shows that [Indistinct]
of the blood vessels in hippocampus
is vital for maintaining the neurogenic niche.
For example, the other [Indistinct]
suggests that, you know, [Indistinct]
from the endothelial is required to maintain
tau homeostasis in neurons.
All right?
So there is a new area out there,
and I think that that is very ripe for [Indistinct]
that will explore nonischemia-related aspect
of vascular function
which are ever very important role
in the maintenance of brain health.
All right? That's really --
The other point I want to make is that,
you know, the diversity of the brain in VCID
combines with the diversity of the mechanism of VCID.
Now this proposes a number of issues or problems
that we need to address.
One is that there is a diversity of cell types in the brain,
so anything that you do in vitro we used to do with cultured
and endothelial cells.
Now we know there are eight kinds
of endothelial cells in a brain.
They all look the same.
They have completely different transcriptomic profiles.
So what kind of cells are we going to use organoids, right?
What kind of, you know,
what kind of parasite are we going to use?
There are now three classes of parasites in humans.
What kinds of smooth muscle cells are you going to use?
So that's a level of complexity.
The other level of complexity is regional complexity.
White-matter regulation of blood flow
is different than cortical regulation of blood flow,
which has been one traditionally studied
because it's there easily for us to drill a hole in the head
and look at the cortex.
All right? But what about, you know,
the cerebellum has a completely different vascular regulation
than the cortex does?
Nitrous oxide being responsible for 100 percent
on [Indistinct]
whereas, in the cortex, it's only 50, 60 percent,
so there is regional complexity.
And finally there is a mechanistic complexity.
I've heard, you know, both, you know,
Prashanth and Sudha mention, you know, CO2 reactivity.
That's only one aspect of vascular regulation.
The mechanism of which
are completely different from neurovascular coupling,
for example, or endothelial function,
so if you study CO2 reactivity and it's normal,
doesn't mean that the vessels of the brain are working normally
because, you know, the endothelial may be failing.
You know, CO2 is multifactorial in the brain,
depends on number of factors
coming from every single cells in the brain.
So we need to kind of also be aware of that,
and I grant you that is very difficult to study,
you know, neurovascular coupling versus
to get the guy to breathe CO2.
All right?
It's very easy to do that.
That's why people do it.
All right? We got to start somewhere,
and I'm all, you know, in support of that,
but I believe that, you know, we need to kind of be,
you know, much more nuanced approach
when we start to translate these findings to the humans,
and thank you for allowing me to express my thoughts on this.
-Well, thanks very much, Cos,
for simplifying the whole situation,
making it pretty straightforward.
But, Sudha, please comment.
-Just wanted to --
Cos, you're obviously a leader in the field,
always on the cutting edge, and couldn't agree more.
Some of the emerging imaging technologies like the 7-Tesla
imaging that may show the hippocamp or microvasculature
to a greater extent, things like C11-FDP PET,
which we are employing in a study of rapamycin funded,
you know, where we can see different aspects of blood flow
and things like correlating the postmortem MRI
with the kind of [Indistinct]
study that Andy Shih showed
where you can actually look at single-cell omics
and different perhaps regions of the brain.
Yes, it seems like increasing complexity
seems inevitable before we arrive at simplicity,
but at least the attention to VCID
is very exciting as a key factor in all of ADRD.
-Okay. Thanks.
Let's -- In the interest of getting to
as many individuals as we can, let's turn to Charlie.
Charlie, your thoughts?
-Thank you, and first, I want to say
this is so exciting having been in this field
for such a long time to see how new innovation is going,
and I just want to say shout-out to Dr. Corriveau
for leading this charge and supporting this through NINDS.
I'm very, very grateful.
My point and question is, how do we tie this together?
And my feeling is that vascular cognitive impairment
is a systemic disease.
It involves the endothelial.
It involves vascular remodeling,
and it involves disruption of the blood-brain barrier,
or subtle dysfunction might be a better word.
And I think it's rife, or the opportunity exists
to look at that interaction through cell-cell communication.
Right now, we're looking at some exosome signaling,
but it could be circulating factors
and new data that's coming out suggesting
that, you know, placental growth factor
may be important, but inflammation --
And my point here is that a broader view
as it's been alluded to that combines animal models
with human health injury and teases apart
how the system itself is affecting the brain,
and I think that that emphasis is important,
and I'd love to hear thoughts on that.
-Thanks, Charlie. Comments for him?
Eric, what do you think?
Charlie on target here?
-Yeah, I didn't raise my hand
because I agree with Charlie's point.
I think of putting it all together.
I raised my hand and lowered it before too
because Sudha made a point, which is that the extent
that we can also drive human biomarkers
of these processes to help us link,
you know, how the complexity is being unraveled
in the basic science lab
and translate it to human studies
and then use those as targets for early phase
therapeutic trials,
I think, is something the field has to be considering.
Thank you.
-Very good. Thanks, Eric.
Okay.
Alexandria Early or Alexandria Linton, comments?
-Recent name change.
I just wanted to start by saying thank you so much
to all of the speakers for a very clear and engaging talk.
Dr. Vemuri, you made a great point in your conclusion slide
about prioritizing rigor and reproducibility,
but I wanted to actually bring
that point back to Dr. Shih's section.
So, Dr. Shih, you showcased
many innovative methods in your section,
but as a trainee studying in this area,
I was wondering how the committee plans to address
or prioritize the repeatability and reproducibility problem
that we've encountered as these techniques
and these methods tend to evolve and advance so quickly,
especially in light of the heterogeneity
that we recently discussed.
Thank you. -Thank you.
Let me throw that to Rema Raman.
Rema, you've been the one who've been pushing us
on the rigor and reproducibility.
Comments?
-Yeah, that's a great point, Alexandria.
I think it's something that we should all be cognizant of
as we develop experimental to make sure that the designs --
It's a discussion that's had at the design stage,
the training of scientists who are [Indistinct]
clinical research, you know,
so sort of addressing it across the board
starting with training, focus on experimental design,
focus on data collection,
focus on data quality that would then --
and then open science, sharing these results,
making sure that everything is shared at the global level
so that studies can be reproduced,
and so taking that comprehensive view
around the need for rigor and reproducibility
right from the start all the way through the end
and open sharing sort of will help us get there,
and that's some of the discussions
we've been having as part of this discussion.
-Very good. -Thank you.
-Thanks, Rema. Okay.
Let me turn to Atticus Hainsworth.
Question, comments? -I thank you very much.
Great to be part of this.
Atticus Hainsworth dialing in from London, UK.
Great to hear about all these fantastic new biomarkers,
new models, new targets.
My question is, what do you rate as the chances
of attracting the drug companies
back into the space of brain vascular disease,
and is it something you even would want to do?
-Excellent question, excellent question.
There's been a migration away over the years.
Let me -- Maybe let me throw --
You're not paying attention, Natalia,
but I'm going to throw this one to you.
What do you think about bringing the pharmaceutical industry
back into the business here?
-Well, I think it's already happening, right?
So there's already some interest and...
-Are you freezing?
-I think she's frozen.
-You may have frozen there, Natalia.
We'll let you unfreeze.
Donna, you have a comment.
Natalia is back? -No, I apologize.
I'm sure -- I'm sorry.
This says, "Zoom quit" -- Oh, no.
-It did that to me over our lunch break, Natalia.
You're just going to have to sign off, come back in.
-Okay. -So, I mean...
-Donna.
-...I'll just give my two cents.
You know, I think we have to at some point
get the drug companies back in.
I don't think this is something we can solve...
-I'm --
-...just ourselves. -Yeah.
Oh. -That's okay.
But it takes us to find the targets, and it takes us to,
you know, get to mechanism,
and I think that's where, Atticus,
we really need those mechanistic studies,
and, you know,
I think Sudha's presentation brought it all back together
where we need that backwards and forwards translation from,
you know, from our animal models to our,
you know, our clinical human studies
and then back to the mice to see,
you know, what we find in the humans.
What does that mean mechanistically
when we manipulate that system?
Then you start looking at targets, you know,
but there's got to be a back and forth,
and for me, I think we need a metal, you know, mammal.
You know, mouse-to-human translation
has not served as well today
in the dementia field as a whole.
So... -Thank you.
Eric, you have your hand up?
-Yeah, sure, no, I think Natalia is right.
There does seem to be some beginning glimmers
of interest in this space.
There has not been a lot of commercial interest
in clinical trials in therapies for VCID.
I think what's needed are targets that Donna mentioned,
you know, like innovative aspects of the biology
of the neurovascular unit that can be exploited
for a therapeutic benefit ideally
where genetic modifiers, the process can be discovered
because I think they put a lot of stock in
Mendelian randomization studies to suggest
that the quantifying target might improve outcomes,
and we need standardization of our methods
for clinical trials in this population too,
and I think MarkVCID, you know,
has given a package of biomarkers that can be used,
but it's also standardization,
the clinical assessment on definition
of who has the disease and how to measure it on outcomes,
not only cognitive but also behavioral and functional.
I'm part of a group called Finesse.
Some others on this call are part of this too led
by Hugh Markus and Martin Dichgans
to try to provide some consensus around,
you know, how a trial for VCID should be run.
That hopefully will give companies more confidence
that we have achieved the ability to run a trial
with high-quality, standardized methods.
Thanks.
-Very good. Thank you.
Steve, you had some comments?
-Just going to add that although we always want
a better mechanistic understanding,
we certainly want it for small vessel disease.
I don't think we have a shortage of rational targets.
The issue that, you know, everyone on this call is aware
is that VCID is in a different position from --
certainly from the FTD or LBD
in that it's a highly prevalent pathology.
Almost everybody has it,
and it almost never is the sole cause of cognitive impairment.
It almost always coexists with other pathologies.
So for a highly prevalent, you know,
modestly contributing pathology,
but the overall attributable risk is extremely high
because it's so prevalent,
so we need biomarkers that can live in a world
where small vessel disease or other vascular pathologies
are coexisting with neurodegenerative pathologies
and that we're able to not use that
as a reason not to do trials but as a reason to say,
"Okay. We need biomarkers that can at least help select
out the vascular contribution
and then make that the focus of a trial,"
so I think that that's a concept that's a little harder
for drug companies to get their teeth around
where they're used to saying, "Okay. You've got this disease,
and we're going to give you this therapy for this disease.
The mixed world is messier, but it's also the real world,
and it's certainly a big unmet need,
so, you know, it's a little self-serving of me to say,
"Biomarkers are important,"
but I think that's going to be the key
to getting the companies back.
-I think so too [Indistinct].
Gareth.
-Yeah, and I think this is what Andy mentioned in his talk,
which is we have a panel of models,
but they're not particularly well defined
in terms of what they show and when and in what order,
and so when companies would look to the preclinical studies,
it's hard for them to, you know, design the next step,
either preclinical or even clinical studies,
and so first step, I think, would be to better define
what it is that the models actually recapitulate
and also then make the call as to whether those models
and the panel of models is sufficient,
which then means we would then need to go back
and generate better models that better recreate
particularly the heterogeneity of this pretty complex disease.
-Very good. Thank you.
Rod?
-Thanks, yeah, I just want to build a bit agreeing
with Steve and just -- and say it in a slightly --
or add to it, and that is that if we're thinking about,
you know, if we think about VCID and you think about, you know,
who will be involved in the clinical trials,
biomarkers are absolutely critical.
It's also critical for companies
and actually individuals to recognize
and be able to embrace that concept,
and right now those companies and individuals
for the most part are looking at clinical Alzheimer's disease.
That's the biggest space for VCID clinical trials,
clinical Alzheimer's disease,
and connecting those things, you know,
in terms of molecular mechanisms and with biomarkers
also just with the light bulb going off and everyone say,
"Oh, my goodness, yes, I have clinical Alzheimer's.
I'm going to enroll in a clinical trial for VCID,"
from my perspective is part of the challenge
that this field faces.
-Very good.
Keith is giving us 5 additional clinics.
There are a couple of questions left.
Dave, you got a quick comment?
-Just a quick comment about the --
developing drugs for VCID, I think,
as in Alzheimer's disease, I think the biggest success
is going to be prevention or secondary prevention.
Certainly we know from studies like the mind --
SPRINT MIND trial,
that, you know, just decreasing blood pressure
has a big effect on decreasing mild
cognitive impairment incidents,
so that means that other things probably could have a big effect
if you study them before,
you know, manifestations were too severe,
and that means biomarkers,
whether it's current ones or other ones,
to identify preclinical disease
are probably going to be really super important.
-Very good.
Okay.
Natasha, you're -- Natalia, you're back?
-I'm back. I'm really sorry.
That's what happens when you're, you know,
you're absorbing that Wi-Fi so intensely.
It just crashes when you finally get an opportunity to speak.
I just wanted to say, and I missed most of the discussion
on that while I was reconnecting,
but I wanted to say there is also --
While we are in this process,
we are also learning something by some of the trials
that I feel will be coming in with repurposing of the drugs.
You know, there is a lot of interest in drug makers
right now to try out some of the anti-inflammatory therapy,
some of the more targeted.
Some, you know, some are less targeted,
but they're trying to also widen stroke space
and, you know, and -- by extension and VCID.
So we will learn something from it.
Maybe some of the, you know, so to speak,
translation into clinical models is not as perfect as we would,
you know, would've, you know, wanted it to be,
but we will gain some knowledge from that,
and I think that's going to be, you know, just contributing
to accumulating a base of knowledge in that space.
-Okay. Thank you.
Let me do one more,
and Niccolo has been standing by for some time,
and I want to get to him.
And the other couple of questions we'll get to,
I think, later off-line.
I appreciate your patience.
But Niccolo Terrando.
-Thank you very much first of all to the whole panel.
This was very informative, great talks.
Fairly hard question for a last minute, I guess,
but it was very intriguing, the role of vascular dysfunction
in the neuroinflammatory processes,
so I'm wondering if there are some kind of recommendation
or just general thoughts in terms of causality in the system
and whether this [Indistinct] as the systemic dysfunction
might actually be a CNS-originated problem
that then impacts the vascular [Indistinct]
from inside out to some extent,
so I'm just wondering if there are some thoughts on this,
and thank you very much.
-Comments, responses from the group?
-I can speak of that a little bit.
I think that's a fantastic question, and it's true.
You know, even the vascular-based
defects like the blood-brain barrier
will lead to neuroinflammation,
but then the neuroinflammatory reactions
irrespective of the vasculature
can then work backward and act on the vessels so,
you know, chicken-and-egg problem,
and I think that the --
some of the studies that we have we want to,
we want to do to better understand
the etiology of the disease to go back
and see which came first to go much earlier,
can help to address some of those types of questions,
to see which --
You know, if we could measure both the neuroinflammation
and the vascular defects at the same time,
one probably emerges before the other.
Maybe it's too intermixed for us to ever dissociate properly,
but then maybe that's where genetic approaches
that allow us to target the vessels independently
or the parenchymal cell types independently
and then tease apart that complexity.
-Very good, thank you.
I think, Keith, we probably have to wrap up
so we don't steal too much of the break time here
and intrude on the next session, so --
but let me draw a line here
and say thank you to all the panelists,
especially the speakers today, Andy, Prashanthi,
Sudha, my cochair, Donna,
and I want to thank Dr. Koroshetz, Dr. Corriveau
for putting all this together, Keith for organizing it,
and I think we'll take a break now, Keith.
Is that right? -Yeah, for a few minutes.
We'll be back at 3:40 p.m. Eastern.
-Welcome back for our last session of the day
dedicated to Lewy body dementias,
and it's my pleasure to introduce to you session
cochairs Dr. Kejal Kantarci and James Leverenz.
Welcome.
-Thank you, Natalia.
It's my pleasure with my cochair,
Dr. Jim Leverenz,
that we would like to welcome you
to the Lewy Body Dementia session.
Lewy Body Dementia includes both dementia with Lewy Bodies
and Parkinson's Disease dementia.
And if you go to the next slide, right, that's good.
I would like to acknowledge my colleagues
who have contributed to the draft recommendations
on the Lewy Body Dementia topic.
They are from academic institutions
as well as industry.
I would also like to acknowledge our advisors,
Dr. Babcock from NINDS, Dr. Masliah from NIA
and Angela Taylor from Lewy Body Dementia Association.
We have four talks in this session.
Two are focused on clinical characterization
and information,
and the other two are on pathogenesis
and mechanisms of toxicity.
Now, if we go to the next slide,
I will now hand it over to my cochair,
Dr. Jim Leverenz, from Cleveland Clinic,
who will talk about the recommendations
on clinical trials and study cohorts.
-Thank you, Kejal.
Now, I want to thank the theme members for your --
Brad Boeve, Jesse Cedarbaum,
Doug Galasko and Angela Taylor from the LBDA.
Next.
My disclaimer, my disclosure,
I also receive grant support from the NINDS,
NIA, Lewy Body Dementia Association
[Indistinct] health care.
Next slide.
So we're going to go back to 2019
and look at two of the priorities, number one and two,
and review what we've seen so far
and where we want to go from here.
So this includes the clinical trials,
priority one, recommendation one and recommendation two,
priority two, the longitudinal antimortem
LBDA characterization.
Next.
So first recommendation, number one and priority one,
was, prepare for and initiate clinical trials
that aim to alleviate or slow the course
of Lewy Body Dementia symptoms,
delay or prevent the onset of disease.
Next slide.
Actually, it was a very active area,
and over the last, what, 3 years now,
there have been five pharmaceutical trials
complete at the different phases,
phase one, two and three, and there are actually
quite a number of currently active trials,
both pharma-based, NIA-funded-based
and some nonpharmaceutical interventions, as well.
Next slide.
Really a wide range of mechanisms of action, again,
with the idea of treating either symptoms
or actually addressing disease modification.
I'm not going to go through each one on this list here.
But again, many of these are still active,
so this has been a very active area of research and success.
Next slide.
So one thing that we've been looking for
is to develop better clinical trials for the LBD area.
One is to include biomarkers.
We've been hearing a lot about biomarkers today,
and we'll hear many more in the subsequent session,
though particularly around the idea of addressing issues
both of Lewy Body Dementia accurate diagnosis
as well as the fact that we do have lots of patients
with mixed disease,
particularly coexistent Alzheimer's disease.
Lots of discussion, as well, around, do we --
When should we be using, for example,
amyloid therapies in the LBDA arena?
Also, progress in the area
of making several working groups with different programs
focused on developing better study protocols and design
that are more specifically linked to Lewy Body Dementia.
Next slide.
So recommend one still remains, and priority number one,
prepare for and initiate clinical trials
that aim to alleviate or slow the course of LBD symptoms,
slow disease progression or prevent onset of disease.
Next slide.
Where are the gaps?
Well, this is a common theme today,
so clearly diversity is a big issue here,
and involving more diverse populations
in the clinical trial arena is critical.
We also need to integrate biomarkers
for optimal participant selection both from a,
"Do they have Lewy Body disease?"
but also, "Do they have" --
what other copathologies they have,
particular Alzheimer's disease,
and you'll hear more about that in the biomarkers section.
We do need more Lewy-Body-Dementia-sensitive
outcome measures.
A lot of studies are based on Alzheimer's disease
clinical trials.
We do need to promote data sharing for larger Ns,
novel mechanisms and actually a pipeline
as we get to recommendations seven
and eight, pipeline from discovery to intervention
to also address new, novel mechanisms.
Next slide.
2019, recommendation number two
was to develop longitudinal antimortem
Lewy Body Dementia characterization.
Next slide.
Actually, in that context,
a number of studies were funded from the NIH
including the NINDS Parkinson's Disease Biomarker Program.
That funded a number of Lewy Body Dementia studies.
There also was the REM sleep behavior disorders cohort,
NAPS and now NAPS2 and actually Lewy Body Dementia
cohorts within the NIAP30 Alzheimer's Center program.
Increasingly involved are groups like PPMI,
looking at de novo Parkinson's, prodromal and genetic cohorts,
AMP-PD,
and I think there continues to be a nice collaboration
and a communication across US
and European cohorts on common data elements
and needs usually highlighted during international meeting.
Next slide.
So what are some of the key developments?
Parkinson's Disease Biomarker Program
has led to a nice, broad Lewy Body Disease focus.
There is a biorepository linked, the BioSend, Data Management
Resource or DMR and some Systematic
Assessment of Cohorts across the Lewy Body
Disease Spectrum, so we can have comparisons across groups.
Slide.
With the PDBP NINDS UO1 program,
there have been a number of funded studies,
the Dementia with Lewy Bodies Consortium
across nine sites, GBA
Pathway from Scherzer, Lewy Body
Dementia Biomarker program at Michigan, Longitudinal
Imaging Biomarker program led or coled by my cochair here,
and the Lewy-Body-Specific Pathology
Using Biomarkers at Columbia University.
Next slide.
Just some of the progress to date,
there are approximately 359 individuals
who participated across the NINDS
U01 program that are in the DMR, average age around 70,
a low percentage of women,
which may be partly the biology of Lewy Body
Disease, a modest amount of motor Parkinsonism
and, again, a common theme where we're seeing predominantly
a Caucasian, European, white population
within this cohort or these cohorts.
Next slide.
An, again, great resource from an imaging point of view
combining the Mayo Imaging-Focused Project
and, again, I mentioned, Lewy Body
Consortium, we have close to 200 MRIs, 192 CAT scans.
You see amyloid PET and tau PET
to really look at how we discern these copathologies.
Probably the one weakness so far
is that these programs are still looking to increase
the longitudinal follow-up in terms of imaging.
Next slide.
And this also links into the biofluid,
so really strong blood-based biofluids
that are available as well as spinal fluid
and link to the blood,
but we see this diminishing longitudinal data.
Next slide.
We do have quite a lot of aliquots
that have been sent to the program
and I think now at 117,000
including a link to CSF and blood aliquots,
so this is something that investigators
will want to take advantage of.
Next slide.
And finally, there have been some limited efforts
for autopsies so far,
and that's going to be, again, a common theme today
to really link this back to the clinical biomarker development.
Next slide.
All right. So where are our issues?
Again, coming back to diversity
and particularly in the African-American
and more other diverse populations,
the sex difference, we can do, perhaps, some selection
for more women to participate, although again,
particularly within the pure dementia Lewy Bodies
without, actually, coexistent Alzheimer's, we don't see --
We see a tendency for a strong male predominance,
which is telling us something.
We are looking for preclinical and prodromal cohorts
and, of course, we have the NAPS program in part
to deal with this prodromal cohort.
I'd like to see expanded and optimized
longitudinal characterization
with continued linkage of biofluid collection
imaging in autopsy.
There are a number of, I think, exciting new areas,
particularly around the RT-QuIC/PMCA
and biofluids and tissues.
This is something that really can solidify the diagnosis
of Lewy Body Disease, linking that to imaging, digital
and electrophysiologic techniques.
And again, we'd like to promote harmonization across cohorts
both in terms of programs that are already funded
but non-US sites, PPMI,
to allow us for larger [Indistinct]
studies that we would like to do.
Next slide.
So we have made and continue to make clinical trials,
and LBD recommendation number one and priority number one,
in terms of the longitudinal follow-up,
we've moved that down to priority four.
This is an ongoing program, again.
We want to support the longitudinal
expansion of these studies,
but this is already well-developed.
Next slide.
So I'm going to move on to Dr. Kantarci,
who's going to discuss biomarkers
in terms of imaging and biofluids.
Kejal, all yours.
-Thank you, Jim, for the great introduction.
So I will be talking about biomarkers,
which will include imaging biomarkers and biomarkers
utilizing biofluids,
tissues, digital and electrophysiologic methods.
And I would like to acknowledge my colleagues,
who have contributed to the recommendations on biomarkers,
Drs. Vallencourt, Marder and Galasko.
And if you go to the next slide, disclosure is listed here.
Next slide.
Biomarker validation is a stepwise process
that start with the discovery of the biomarker
with cross-sectional studies looking into sensitivity,
specificity and accuracy of the biomarker.
And then in the next step,
it can involve longitudinal studies
looking at reliability, repeatability
and reproducibility.
And now that we have tested the biomarker
in clinically diagnosed cohorts,
a critical next step is the validation
in pathologically diagnosed cohorts.
And finally, the biomarkers tested in cohorts
enrolled in clinical trials for patient selection,
target engagement and assessment of disease modification.
So one of the biomarkers that have passed
these validation steps is analog imaging with PET.
And if we go to the next slide.
And it's important to note that not all biomarkers
may demonstrate excellence in all of these steps.
And FDA has this comprehensive classification of biomarkers
based on their performance for different goals,
as you can see here.
We go to the next slide.
So in 2019, when the recommendations were written
for Lewy Body Dementia,
the neuroimaging biomarkers were considered
as the third priority in the clinical science focus area,
and biomarkers for biofluids, tissues, digital
and electrophysiologic methods were considered
as the first priority in the basic science focus
are because there was a lot of interest
in development of these biomarkers as a top priority.
So if we go to the next slide,
in the current draft recommendations we have,
Lewy Body work group placed biomarker recommendations
to priority number two for neuroimaging
and priority number three for biomarkers
utilizing other tissues, biofluids and digital methods.
And they were listed under the clinical characterization
and intervention focus area
because these recommendations emphasize
applications of biomarkers that were developed,
so applications in the clinical research
as the top priority.
Now, if we go the next one,
so the pathogenesis and disease mechanisms
in Lewy Body Dementia is complex.
That involves not only alpha-synuclein
but frequently accompanied by other proteinopathies
including a beta, tau and TDP-43 as well as vascular disease.
On the right-hand side, in a study of a large European
and North American cohort of dementia
with Lewy Bodies cases,
it was demonstrated that a majority of the cohort
fulfilled the diagnostic criteria
for dementia with Lewy Bodies,
had high levels of amyloid or tau
or had both protein deposits,
and a smaller proportion did not have high levels.
Therefore, we recommended utilizing established
and new imaging tools to determine the evolution
of this multiproteinopathy in Lewy Body Dementia
including synergistic interactions of proteins
across brain regions and across time
in Lewy Body Dementia.
We go to the next slide.
Biomarkers can inform the temporal progression
and evolution of different clinical phenotypes
of cognition,
motor, sleep and behavior in Lewy Body Dementia,
and they can also inform the clinical
and genetic subgroups of patients
with rapid versus slow progression of Parkinson's
Disease dementia versus dementia with Lewy Bodies,
GBA or alpha-synuclein mutation carriers
and also inform relative contribution of alpha-synuclein
and Alzheimer's Disease pathways
and burden to the clinical phenotype.
Finally, biomarkers are critical in clinical trials
and can be used for target engagement and efficacy
and clinical outcomes.
And to answer all of these questions,
we feel that we need big data approaches,
and data sharing will be necessary to integrate
biomarkers and clinical data.
And if we go to the next slide,
there have been several requests for applications
by the NIH within the last several years
focused on biomarkers including the center data,
Centers without Walls for PET Ligand Development for ADRD,
in particular for alpha-synuclein,
looking at the peripheral pathology
in Lewy Body Dementias,
the UO1 biomarkers for Lewy Body Dementias program
that Jim Leverenz has mentioned
and also progression markers of cognitive impairment
in Parkinson's Disease dementia.
And there are others that are not specific
to Lewy Body Dementia
but were funded by several biomarker projects
in Lewy Body Dementia.
So if we go to the next slide.
And currently there are ongoing and new cohorts
that have contributed to biomarker programs,
and this was mentioned also in the cohorts talk,
but these are specifically focusing on biomarkers,
the Parkinson's Disease Biomarkers Program
that includes dementia with Lewy Bodies
and Parkinson's disease patients.
The North American Prodromal Synucleinopathy Consortium,
that has a large biomarker-characterized cohort
and ADRC cohorts with the SCAN
initiative to standardize imaging across the ADRCs,
which will likely include a lot of dementia-with-Lewy-
Bodies cases.
The Parkinson's Progression Markers
initiative of PD, prodromal PD and genetic cohorts
and also the AMP-PD is collecting data on biomarkers,
and then as was mentioned,
there is a lot of efforts for harmonization of biomarker data
across European and Canadian cohorts with the US cohorts
to establish common data elements.
So the goals are for these efforts
to standardize biomarker collection
including imaging, DNA, plasma, whole blood and CSF.
And longitudinal biomarker collection
and clinical follow-up,
harmonization for clinical phenotyping
and also encourage brain donation,
that is critical for validation of imaging biomarkers.
We go to the next slide.
Since 2019 with accumulating data
from these funded research and ongoing cohorts,
we have seen several important developments.
We certainly do not have an alpha-synuclein radioligand yet,
but we are getting closer,
so there has been a lot of developments in this area,
and we hope that this will become a reality
in the near future.
Now, we continue to establish biomarkers for earlier stages
such as the prodromal Lewy Body Dementia stages,
and we now understand the contribution
of Alzheimer's pathology
to the clinical syndrome better in Lewy Body Dementia,
which may inform us on treating this pathology down the road.
And alpha-synuclein biomarkers such as seeding assays
with RT-QuIC and PMCA in CSF
and skin have also seen major diagnostic advances.
And, furthermore, there have been developments
in digital biomarkers,
and these require new analytic approaches
in Lewy Body Dementia.
Now, next slide, so biomarkers were already integrated
in the dementia-with-Lewy-Bodies criteria back in 2017,
and they are now also included in the research criteria
for prodromal stage of dementia with Lewy Bodies.
And this framework not only includes biomarkers
of Lewy-Body-related pathology but also Alzheimer's pathology,
emphasizing that the clinical phenotype may be determined
by the contribution from multiple proteinopathies
and not just alpha-synuclein pathology.
Next slide.
Biomarkers from biofluids and tissues can inform us
about various aspects of Lewy Body Dementia pathophysiology,
and different pathological processes may require sampling
from a variety of biofluids and tissues.
So we recommend that, where appropriate,
biomarker discovery and evaluation
should be carried out in multiple tissues
such as skin, colon, salivary gland and others,
also biofluids such as whole blood, plasma,
CSF, urine, saliva, tears, even, and microbial samples.
Next slide.
There are digital and electrophysiological biomarkers
that are being developed in the field,
and we need to try and validate these biomarkers
in Lewy Body Dementia cohorts.
So we recommend workshops to define modalities
and best practices with data sharing
and paying attention to privacy
that would help bring these promising technologies
into Lewy Body Dementia biomarker field.
Next slide.
And coming to the gaps that we still need
to fill regarding biomarkers in Lewy Body Dementia,
first we need to develop,
refine and validate biomarkers for prodromal
and, perhaps, eventually,
the preclinical stages of the disease processes.
Now, development of the alpha-synuclein tracers
will be highly impactful
for alpha-synuclein-modifying treatments,
potentially for patient selection,
treatment engagement and efficacy.
Now, cohorts with biomarker collection
should be harmonized across NINDS
and NIA ADRC programs, foundation-supported programs,
and should be diverse and representative,
as we have discussed this morning.
And the targeted as well as Omics-type
approaches to biomarker discovery and development
should also be pursued and more integration of biofluid markers
across existing cohorts that include imaging, genetic,
clinical and autopsy data, is needed.
And a good example of this
is the Parkinson's Disease Biomarkers Program.
We certainly have more work to do on the applications
of digital and electrophysiological biomarkers
that are being developed in Lewy Body Disease Dementia.
So if we go to the next slide.
So these are the recommendations
for neuroimaging biomarkers to develop, refine
and refine neuroimaging biomarkers
that track disease progression,
assist in differential diagnosis,
provide therapeutic target engagement
and relate to pathology.
To do that, we recommend developing
and refining biomarkers for Lewy Body Dementia
as well as the preclinical and prodromal stages of the disease
and also supporting alpha- synuclein tracer development.
There is potential to repurpose
currently available cost-effective imaging tools
that can be accessible and applicable
in diverse settings and diverse cohorts
and including sex differences, as Dr. Leverenz has pointed out.
There is a really important sex difference with women
being underrepresented for a biological reason,
potentially, in these cohorts,
so that's an important area of study, as well,
and also utilizing a multisensor approach
to determine the scalability of these techniques
and prepare for phase-three multisensor trials
with harmonization and data sharing in large cohorts.
Next slide.
-Two minutes remaining.
-Okay, so this is recommendation number three
for the development and refinement of biomarkers
for diagnosis, prediction and prognosis
using the biofluids,
tissues and the digital and electrophysiologic methods.
These biomarkers need to reflect pathophysiological changes
related to Lewy Body Dementia
including multiple proteins and vascular changes.
Also, biomarker measurements need to have a defined context
in different biofluids and tissue specimens.
We need to address study disclosure of results
in asymptomatic and mildly affected individuals,
and we need to develop comparable biomarkers
in model systems including animals and cell lines.
The digital and electrophysiologic biomarkers
need to be applied to Lewy Body Dementia,
and these may include wearables, EEG and polysomnography,
computerized testing and home-based monitoring.
That can include lifestyle, behavior,
cognition and neuropsychiatric symptoms
as well as autonomic function, activity and sleep.
And finally, we need to harmonize protocols
and common data elements to allow integrated research.
And finally I would like to get to the next slide.
I would like to thank you for your attention
on the biomarkers topic.
Now it's my pleasure to introduce
Dr. Sonja Scholz from NINDs and NIH.
Dr. Scholz will be presenting the recommendations
on neuropathology and genetics. -Right.
Thank you for your introduction,
and thank you for the opportunity
to talk to you today.
So we are now going to pivot from the clinical focus area
to the more basic science side,
and so I will specifically talk about the neuropathology
and genetic recommendations,
and then I have my colleague, Dr. David Irwin,
following up on the disease mechanisms recommendations.
I would like to recognize my team members,
Dr. Clemens Scherzer, Dr. Brittany Dugger,
Dr. David Irwin
and Dr. Dennis Dickson for their contributions.
So next slide, please.
These are my disclosures.
Next one, please.
All right.
So these are specifically the recommendations number five
and six in the handout.
If we go to the next one, next one.
All right.
So it's exciting to see that there has been really
a lot of progress happening on the basic science side,
and I think it is --
We all recognized and understanding
the very basic genetic,
epigenetic lifestyle environmental factors
that are playing a role in Lewy body dementias
is fundamental for disease modeling
but also ultimately for paving the way
for disease modification.
So specifically on the genetic side,
there has been a lot of progress,
and a lot of this progress is really based on,
you know, implementing recommendations
from previous ADRD summits.
We go to the next slide.
So, you know, really making good use
of the various brain donation programs
that have been established
but also, you know, biorepositories.
We've been able to already gain a lot of valuable insights
into the genetic architecture of Lewy body dementia,
and so showing here, for example,
is the LBD genome sequencing initiative
which was really a team science effort,
intramural, extramural effort trying to combine whole genome
sequence data from multiple sources
and perform state of the art genome
sequencing for various genomic analysis,
but also to generate a foundational genomic resource
that can be used broadly to accelerate the pace of discovery
in this understudied disease field
and to democratize data access.
Go to the next one.
So we've already learned a lot of interesting lessons
just based on this publicly available data,
so we know that Lewy body dementia is a complex disease.
There are both common disease risk variants playing a role,
but also rare variants playing a role.
We recognize that in reality, most patients, it is polygenic,
so it's a combination of multiple variants
that are playing a role,
and they really have an impact on the disease heterogeneity
that we clearly appreciate.
We also recognize, just based on the genetics,
it tells us that there are very clear molecular relationships
between Lewy body dementia
and other neurodegenerative diseases,
so we can see overlapping risk closer
with Alzheimer's and Parkinson's disease,
but we also appreciate overlapping disease pathways,
and that's particularly exciting
because these pathways are particularly relevant
for possible disease modification interventions
that could be relevant to much broader patient population
than just the Lewy body dementia cases.
However, most of the progress that has been made
on the genetics side is really predominantly done
in individuals of European ancestry,
and we already appreciate, based on Canada gene approaches,
that there is considerable population heterogeneity.
So improving the diversity of patients that we study
is an important need for the field,
as we are also building up
and continue to improve powerful genetic discovery.
Next slide, please.
But it's not just a numbers game.
It's not just the number of biospecimens that are available.
I think we also need to be smart
about generating foundational datasets
that can accelerate the pace of discovery
and kind of inform discovery,
and, you know, it's been great to see
how a lot of the recommendations have been put in place
to make these knowledge platforms available.
So for example, the genome resource that we generated
has been,
you know, made available to the research community,
even prior to any publication, and it's been really great
to see how it's being used quite broadly,
accelerating the pace of discovery in this disease field,
and we know that these kind of knowledge platforms,
they will have to expand.
So it's not just genetic information,
but we also in different layers of homage data
to interpret the functional variants
and put them in a functional genomic context
and come up with disease models
that we can then study for therapeutic interventions.
Next, please.
Okay, but it's -- Sorry, just one back, please.
It's okay.
So we definitely need more samples,
so biospecimens and brain donation programs
will have to expand, but we also need
a lot of accompanying phenotypic information,
and ideally, in-depth phenotype information
all the way from the programmable stage
to the final stages of the disease,
and this type of information can be really valuable,
and I'm showing you just an example of how,
you know, these kind of data can be used.
In a recent study by Dr. Scherzer's group,
you know, we've been able to show
that there are risk loci that modify the survival,
and so these kind of disease modification genetic loci,
you know, identifying those, it's only possible
because the available of in-depth phenotypic information,
and so there is a lot of interesting angle to that,
but again, we need to improve
the number of ancestrally diverse individuals
to see how broadly that it really affects
the patient population.
Going to the next one, there are many --
You know, there are many gaps in our knowledge,
so obviously we have to still address
the missing heritability,
and this is where increasing biorepositories,
brain donation programs are really going to be key,
but also using modern technologies as they unfold
to study rarer-used genetic variation type.
Integrating the multi-omic data into a knowledge platform
that can be easily shared and accessed
is also key to advancing the field
and particularly taking,
you know, the genetic information
that we see into a cellular context and understand
how it actually is causing disease on a molecular level.
I think we have already heard from other groups
that we all need to double down on our efforts
to increase the diversity of patient study
in the genetic context in particular.
You can go to the next one.
So coming to our specific recommendations
for the genetics of LBD,
so we recommend to delineate the genetic loci
on the functions,
contributing to the onset and progression of LBDs
using genetic, transcriptomic, epigenetic
and environmental analysis,
and so this is going to be used to --
obviously to discover and replicate genetic risk variants
which is at the core, at the foundation for getting
insights into the genetic architecture
and the molecular function of LBD.
Next one.
We have to expand the recruitment of cross-sectional
and longitudinal deeply phenotype
cohorts and families, ideally of diverse ancestry.
Next.
We have to translate these risk variants
that we're identifying
using predominantly through association
studies into disease mechanisms.
Next.
And we want to examine our relationships
between Lewy body dementia and also related diseases,
as there are real cross-disease treatment opportunities
that are emerging based on these so-called pleiotropic
risk alleles.
Next one.
And as I already alluded to,
we want to have an expansion of the data platforms
for user-friendly analytics.
Now we go to the next slide.
So there's also been notable progress
on the neuropathological side.
So I think we appreciate, you know,
the type and location of the,
I'll say, nuclear pathology,
and the classifications have already been developed
and are broadly used. Next slide.
But we recognize that we have to standardize
the way the neuropathological characterization is happening,
and the standardization is not just relating
to the quantification of the pathology that is there
but also relates to the different type of techniques,
from the staining to the type of sampling
that has to occur.
Next.
In addition, we recognize that LBD,
pathologically speaking, is a very heterogeneous disease.
There is -- You know, the copathologies that exist,
they are not there by chance.
They really matter.
They affect the phenotypic presentations,
so we know that 60 to 80 percent of all cases
have Alzheimer's copathology,
and, you know, and even genetically speaking,
we already start to see different architectures
in these high --
you know, pure versus mixed pathology cases.
Next, please.
But we also appreciate
that there are other pathological changes
that haven't been sufficiently explored,
such as the TDP-43 copathology that we increasingly appreciate
in about 20 percent of cases
as well as the vascular disease copathologies with,
you know, microvasc and macrovascular changes.
Next, please.
So there are notable gaps,
especially on the neuropathology side as well,
so it is important that we link information
all the way from the scientist to the samples
to clinical information using user-friendly portals
and unique identifiers.
We want to make it as easy as possible to use these portals,
and in order to work across different centers
that are generating samples, that are collecting them,
it is important that we have standardized techniques
for the quantification of the pathology
but also for the sampling process and the staining itself.
I think there are a lot of unrealized opportunities
emerging on the digital image analysis and deep learning side,
and I think we can all agree that,
you know, we will all benefit as a field
if we increase the number of cases
that are ancestrally diverse.
So with that, I want to go to the next side.
So here are recommendations for the neuropathology.
So we want to enhance and standardize the techniques
for neuropathological characterization of LBD
and the use of LBD pathology cohorts.
Next, please.
We want to establish best practices
for the neuropathological evaluation.
Next, please.
We have to develop scalable methods
to assess the quality of tissue samples.
Next.
We have to enhance the infrastructure,
also to collect tissue specimens
that are not routinely collected.
We've already heard about the importance of skin,
salivary gland, GI tissue
and perhaps even solid organ samplings,
and we should facilitate that.
Next, please.
Next.
As I already mentioned,
we need very well-characterized autopsy collections,
especially from ancestrally diverse cases.
Next.
This will inform a lot of the molecular,
you know, characterizations and have already been ongoing,
and in order to achieve that,
I think it's really of fundamental importance
that we improve our outreach and our education
to underrepresented groups
to engage them in our research enterprise.
Next, please.
And we want to link the tissue resources
that are being generated.
There's a concerted amount of effort
that goes into there with all the clinical,
that molecular biomarker data using a single portal.
Next, please.
All right.
And so I'm going to hand over the microphone
to the next speaker, Dr. David Irwin.
Dr. Irwin is a cognitive neurologist
at the University of Penn,
where he's particularly interested in the brain behavior
and relationships of the ADRDs.
So the floor is yours.
Thank you.
-Thank you very much, Sonja.
Thank you to the organizers.
I'll be talking about recommendations
seven and eight today,
that are focused on mechanisms of Lewy body dementias,
and I want to recognize the team members,
Drs. Cedarbaum, Dugger, Lee and Scherzer,
who worked together with me on these recommendations
as well as our Lewy body group.
Next slide, please.
I have no disclosures.
Next slide, please.
So in review of our 2019 recommendations,
recommendation seven was the understanding the molecular,
cellular pathophysiology of alpha-synuclein
in the context of non-motor brain regions,
and this focus was on alpha-synuclein function
both in health and also in the setting of human disease,
Lewy body dementia and a focus outside of the motor areas
in the striatonigral system,
where there's been a large focus in the context of PD,
and this is more to examine the correlates
of the clinical features of LBD, of Lewy body dementias.
Recommendation eight was to identify mechanisms
by which Lewy body diseases may spread between
and affect different brain regions
and how Lewy bodies interact with other pathologies.
So the focus of this recommendation
was on the prion-like spread mechanism from cell
to cell of pathogenic species of alpha-synuclein
and how this may interact with mixed pathologies of aging,
and the timeline for these recommendations
was 2 to 4 years for seven,
5 to 7 for recommendation eight based on the amount of time
needed to make fundamental basic advances
in scientific knowledge for these recommendations.
Next slide, please.
So there's been significant progress
in the field since 2019,
and to highlight some general areas
and specific exemplary studies
and reviews that capture some of the main areas of advances,
one is the ability to visualize alpha-synuclein
from the human brain.
We've heard earlier today
about different cryo-EM methods to visualize tau,
and they've been similarly applied to alpha-synuclein.
Here is, from a recent review, a schematic
of 3D reconstructions of alpha-synuclein,
both from preform fibrils as well as from human brain,
in this case, from MSA brains, and what these studies suggest
is that genetic alterations of alpha-synuclein introduced
into preform fibrils or modifications
can alter the structure,
and there may be strain-like properties
of these structures of alpha-synuclein
that are only more recently visualized
in this level of detail.
Next slide, please.
Similarly, visualization of alpha-synuclein specie
both in cell culture and in human brain
using advanced methods of microscopy
can help us understand more of the complex nature
of alpha-synuclein mediated neurodegeneration,
and what's depicted here from a study from [Indistinct]
using a cell model of alpha-synuclein seeding
with high-resolution microscopy methods
paired with multi-omics, proteomics
and gene expression studies,
able to visualize different cellular changes
related to synaptic dysfunction, autophagy
and regulation of protein turnover,
as well as mitochondrial dysfunction
on the different steps from alpha-synuclein misfolded seeds
to protofibrils to more preform fibrils
and then more advanced aggregations
reminiscent of Lewy bodies in the human brain.
So this exemplify how these newer methods are able
to enhance cellular models for our understandings
of these complex cellular processes.
Next slide, please.
This is the prion-like spread data in animal and cell models,
continues to grow for a mechanism
for alpha-synuclein mediated neurodegeneration, as does --
As we heard earlier in the biomarker
talk about the presence of pathogenic alpha-synuclein
in peripheral tissues,
and in these series of elegant experiments
from the group at Johns Hopkins
showing that peripherally administered
preform fibrils of alpha-synuclein
into the myenteric plexus of wild type mice
can induce a time-space dependent
spread of pathogenic alpha-synuclein in the brain,
recapitulating human disease with motor
and cognitive impairments, and importantly,
that process was ameliorated by either vagotomy
to block that transmission from cell to cell
or in a transgenic animal
that does not express endogenous alpha-synuclein,
so importantly highlighting that downregulating alpha-synuclein
may be one mechanism to help us slow
or halt the propagation of pathogenic alpha-synuclein.
Next slide, please.
As we heard earlier from Kejal, in the Lewy body dementia,
mixed pathology is the rule, not the exception,
and model systems need to appropriately help us
understand the interactions of these proteins.
This is from Virginia Lee at Penn,
showing that an amyloidosis model,
the 5xFAD mouse model that has human pathogenic mutations
closing amyloidosis in the mouse model
can accelerate the propagation of both
preform fibrils of alpha-synuclein
as well as human
Lewy body dementia-derived pathogenic species
of alpha-synuclein throughout the brain,
helping model the interaction
between A-beta and alpha-synuclein,
as depicted here,
aggregations of human brain-derived alpha-synuclein
in these transgenic animals, but not in wild type.
Next slide, please.
Model systems are advancing,
and we've heard throughout the day
in different content areas,
the ability to have patient- derived sources for models,
and this schematic from a recent review
shows how induced pluripotent stem cells technology,
the ability to program fibroblast cells
or peripheral blood mononuclear cells
into either 2D patient-derived cultures
of specific types of neurons.
In this case, visualized here is dopaminergic neurons,
but can be programmed into various other neuronal subtypes,
as well as 3D organoids provide a very unique opportunity
not only to model disease on an individual patient level
but also a possibility to do drug screening
for various compounds.
This is an important step towards a more personalized
medicine approach for treatment of the Lewy body dementias
and also an ability to introduce discoveries from genetic work,
as highlighted by Sonja, into these models to then
help us understand disease mechanisms.
Next slide, please.
In this schematic, highlights the increasing role
that's thought to be related to the immune system
in the pathogenesis of Lewy body disease and dementias,
and what's highlighted here in both the adaptive
and elements of the innate immune system
and particularly in glia in the brain,
both the normal function of alpha-synuclein
that may involve certain aspects of immune function
that's highlighted in red boxes for the different cell types
as well as the ability for normal
functioning alpha-synuclein
to bind to specific immune receptors in blue,
and then finally, changes biologically in immune cells
in response
to pathogenic aggregations of alpha-synuclein in yellow,
and there are several aspects here that they're missing data,
and a lot more to learn, but there's increasing role
of non-cell autonomous inflammatory mechanisms
that could contribute to the neurodegenerative process.
Next slide, please.
And finally, recent work highlighted here
showing two different potential mechanisms
of enhancing immunotherapies
as potential disease-modifying therapies
targeting alpha-synuclein either with DNA vaccines
or through generation of specific
conformers of alpha-synuclein
to have a more specific target for pathogenic alpha-synuclein
and potentially reduce side effects of immunotherapy.
Next slide, please.
So despite these advances since the previous summit,
there still remains fundamental gaps to address in 2022,
which was the focus of our work in our meetings
to prepare the revised recommendations.
These include, you know, advancing models even further
to fully recapitulate bona fide human Lewy body disease
and dementias with aspects that are directly related
to what we see in human disease and particularly for mechanisms
that can help us understand selective vulnerability
and the specific neuronal subpopulations
that are particularly vulnerable to develop
alpha-synuclein pathology and neurodegeneration
and how these relate to the heterogeneous clinical features
of Lewy body dementia such as cognitive fluctuations,
visual hallucinations and neuropsychiatric symptoms
as well as sleep disruption,
like REM sleep behavior disorder.
And as well, there's a need to develop further infrastructure
that can support the process of screening potential compounds
and developing advances in therapeutic developments
from the discoveries for mechanistic models,
and then finally, how to more fully integrate discoveries
from human genetic work into model systems to help us
develop new targets for drug discovery.
Slide, please.
So here are revised recommendations seven and eight,
which we'll go through and highlight
the main changes and evolution from 2019.
So next slide, please.
So our 2022 recommendation seven
is to develop models to understand
the pathophysiology and normal molecular cellular functions
of alpha-synuclein to support drug discovery,
and the goals for this are 5 to 7 years.
Thank you.
So the focus and the major changes to this
from the previous include added focus to help accelerate
the translation of mechanistic discoveries
to support drug discoveries in therapeutics
and in collaboration with priority one,
mentioned by Jim before, and some of the highlights
of how to do this include identifying regulators of SNCA,
alpha-synuclein gene expression, and understanding the mechanisms
and potential effects of downregulation
as a potential targetable therapeutic strategy.
Next, please.
Characterization of pathological alpha-synuclein strains
from the human brain,
further understanding the variation
and structure and function and features of alpha-synuclein
that are derived from human brain
and the importance of brain donation and autopsy
is critical for those efforts, as is, we heard from Sonja,
efforts to help accelerate access
to these tissues in the research community.
Next, please.
Identifying mechanisms of aging and sex differences
that are observed in human autopsy and clinical work
that may play an important role, these mechanisms,
in helping us understand resilience
and how some individuals may be resilient
to the accumulation of alpha-synuclein pathology.
Next, please.
And finally, these efforts work towards the goal
of promoting the discovery of at least one new, novel drug
targeting emerging genetic or neuropathological mechanisms
implicated in LBD,
so our focus is on that translational pathway
to drug discovery.
Next slide, please.
So recommendation eight is to identify mechanisms
of selective vulnerability, disease heterogeneity,
disease spread and propagation and interaction
with other age-related pathologies
as therapeutic targets.
So this recommendation has a similar time
frame of 5 to 7 years,
based on the nature of these important fundamental,
basic mechanistic work that's required
to address these important issues.
Next, please.
So in particular, identifying mechanisms
in which alpha-synuclein interacts
with other age-related copathologies,
that's been a theme that we've heard throughout today,
of the common co-occurrence of A-beta
and TDP-43 vascular pathology, and how these may potentiate
or accelerate different neurodegenerative.
Next slide, please.
Understanding the role of the immune system
and inflammation in LBD pathogenesis further,
models that help incorporate aspects of the immune system
and the role of glia in the neurodegenerative process.
Next slide, please.
Identifying biochemical/ molecular underpinnings
of regional brain pathology in LBD,
this is important for us to help link mechanistic findings
with clinical heterogeneity and the varied symptoms of LBD,
and this would identify, you know, potential targets
that could be mechanistic as well as asymptomatic,
finding these mechanistic substrates
of the core features of LBD.
Next slide, please.
And finally, support for preclinical drug development
based on new findings from mechanistic studies,
so the ability to take these model systems and harness them
and take these discoveries to identify targets,
screen for new targets and go from the bench to the bedside.
Next slide, please.
This concludes my presentation.
I look forward to the Q&A session, so thank you.
-Thank you, Dr. Irwin.
I think we're heading on to Q&A now,
and we have our first question. -We do.
So the first one is going to be Mr. Ellenbogen.
Michael, are you ready?
-Yes, thank you so much.
First, I'd like to say
I will miss my friend, John Junkowitzski --
I'm sorry, Trojanowski.
He and I served on the Pennsylvania planning committee,
and he was great.
Thank you for giving me the opportunity
to speak here today to all you directly
because, as a person living with dementia,
I would not have been able to place the writing in a chat.
We have made progress in the last few years
sharing data among those in the dementia arena,
but we still need to do better.
While I'm not a scientist or an expert,
I do believe there is some overlap
in some of these other neurological disorders
that fall outside of the dementia box.
I would recommend we find a way to share information
among all of the neurological diseases,
as together, we will be stronger.
Thank you very much for a great session today.
-Thanks, that was a great -- Some great comments,
and of course we'll all miss John, John Trojanowski,
and I couldn't agree more.
I think most of the dementias are multi-etiologic,
and again, appreciate you sharing.
Are there other comments?
You want to go to the next question?
-Sure.
The next question is from Dale Lestina.
Dale, are you ready?
-I am now. Take the mute off.
I find these sessions excellent.
I think my first one was 2018, then 2019, and I learned a lot.
I'm learning more even now, and I have some questions
that are related to the previous sessions.
I learned that beta-amyloid is associated
with the plaques quite literally
in between the neurons in the brain.
I learned that tau is inside the neuron, tangles and so forth.
What I didn't know, as we're talking about here now,
is alpha-synuclein.
To me, that's a new one.
What does that --
How does that relate, and what's --
to the other two and TDP-43.
What does the T and the P and the D stand for?
Folks have got a lot of alphabet soup for somebody
that just comes in off the street
to try to catch up on,
and so I need a little schooling on the vernacular that you use,
that you guys know, you know, like everything,
but somebody like me,
I got a different alphabet soup that I deal with.
So if you would, whoever would help me out, James,
if you can pick who it is.
If it's you, fine, but I'd like to learn on those two --
on those areas. -Sure.
Those are great questions.
Who wants to handle the explanation
of the different alphabet soup?
Somebody has to volunteer, or I'll pick them.
-I'm going to put something there for TDP-43
in the chat because I don't know if --
I'm sure you've all tried to explain it verbally,
but deacronym-izing TDP-43 is nearly impossible.
I think it's easier in writing, so forgive me.
I'm going to put it in the chat. -All right.
And I'll get it from that.
-Alpha-synuclein, I'll mention.
-Is it a tangle as well when you look
at the molecule and so forth?
Is it a tangle like tau? -It's --
TDP-43 is a different kind of inclusion that we tend
to see in the brain cells
and particularly, we see it in the frontotemporal dementias
as we talk about frontotemporal dementia later.
I'm going to give Brittany a chance,
and she raised her hand here
to talk as well about some of the other acronyms.
-Thanks, Brittany, a lot. -Oh, these are great questions,
and this is the whole point of this too is dialog, right,
to form these dialogs, and so the best way to describe
a lot of those things that you mentioned,
these are normally in our bodies, okay?
So just, like, think about how cars are normally on a freeway
but then sometimes, cars can run into each other,
and they get tangled up.
-Yep. -So tau can get tangled up.
The amyloid can get tangled up, the amyloid beta, so can TDP-43
and so can alpha-synuclein, and these are all specific.
You could think of just maybe
even different types of cars, right?
One could be a Honda, a Toyota.
I'm from Detroit, right? So I'm going to be, like,
"That's a Ford, a GM or a Chrysler,"
but does that help a little bit from that analogy?
That helps me when I try to understand things.
-Are they all proteins? -Yeah, they're all proteins,
and they all get into these car accidents.
So we all normally have them in our body
but what we try to study is, when do they go awry?
-Do the TD-43 and alpha-synuclein,
are they predominantly in the neuron itself?
-Yes. -Okay.
That helps me.
-And TDP normally stays in the nucleus,
but what happens a lot in these diseases is,
it goes away from that nucleus of the neuron,
and we try to understand why.
-Oh, and how does it get out?
-Those are great questions that we try to answer.
-Okay.
Well, I'm looking forward to the next one as we go forward
is because I thought that once inside the neuron
that you don't have to bust up or die in order to get out,
but maybe not.
And now, is that for alpha-synuclein,
and that's also in the nucleus?
And as I understood the pictures here,
it looked like in the molecule for that is a long,
stringy thing just like for tau,
and then you can get them all wrapped up,
and if that happens, I've heard
that they can trigger the neuron to commit suicide, kill itself.
Does that make sense?
-I'm going to pass this to my colleague, Dr. Mosley.
I think he can help too. He has his hand up.
-Well, you have to write a grant.
You have a lot of stuff in here.
-Those are all great questions. -Thank you, Brittany.
-Eliezer. -Oh, yeah.
Thank you, James.
Yeah, alpha-synuclein is a little bit different
because under normal conditions, it's at the site
where the neurons connect with each other sort of like,
you know, the same type of connections
that you see in a computer between transistors.
It's the same thing, but under pathological conditions
like in Lewy body disease,
it means localized, and it aggregates.
It accumulates in the cell body,
so it goes from the synaptic connection to the cell body
where it causes a traffic jam in the cell,
as Brittany was discussing,
but also it gets spit out of the cell and propagates
from one cell to another including inflammatory cells
causing a firestorm in the brain, so to speak.
So -- But, you know, we'll be happy to post on the chat
the link to our website, the NIA and NINDS website,
where all this information, it's available and a lot more.
I think you'll find it very helpful.
-Well, I appreciate you all that have chimed
in on my question.
Thank you very much.
That's always nice to learn.
-Thank you, Dale.
-These are great questions, actually.
Kejal, do you want to handle the next one, next question?
-Sure.
The next question comes from Helen Medsger,
if you could take the microphone.
-Hello, there.
I want to thank everybody for today.
I've been in this battle with Lewy body dementia
for over 30 years.
I've had three first-degree relatives
that have succumbed to it:
my dad, my sister and my youngest brother,
and I've had the pleasure, actually, to either work with
or meet some of you at various conferences.
But I'm wondering because I already have,
you know, two generations in my family in genetic study,
but those were formulated back in, you know, the 2000s,
and so it's part of Parkinson's disease study,
and even though I'm currently involved in a variety of PPMI,
healthy brain aging and all the rest,
is there a pipeline for those of us that have been this
impacted to kind of fast-track into certain studies
or at least put ourselves on a specialized registry
so that you have access to us?
Because I think that, you know, I'm pushing my family
to be more and more involved because I want to see,
you know, research as accelerated as possible
to get answers,
and that's kind of my first question.
My second one has to do is,
we didn't directly address GBA today,
and I know that, Dr. Scholz,
you had done that at the last international conference,
so I was wondering why that wasn't --
SNCA was mostly targeted today, why GBA was not highlighted.
-Thank you for this question,
and thank you for participating in research studies
and cohort studies with your family as well.
That's wonderful.
I will direct this question to Sonja
because it's about genetics.
-Yes, so thank you so much for this interesting discussion
and really good question.
So we definitely appreciate participant
in the various clinical trials.
At the present time, I mean, we don't have a one-stop-shop
where anybody with a family history can go,
so people, you know,
usually find an array of different study centers,
but many of them are now feeding into these biorepositories
that researchers can access.
So, for example, the Parkinson's disease biomarker program,
they receive samples from different studies
but for the researchers, we can access them,
and so it doesn't always have to be a one-stop-shop.
So some of these resources exist,
and they're definitely very used,
and they're extremely helpful.
There's a lot of, you know, exciting development on many,
you know, already no-risk [Indistinct]
and you mentioned GBA as one of them,
so aside from ACOE that we've talked a little bit.
You know, about 13 percent of LBD cases
actually have a risk variant in this particular gene,
and it's told us a lot already about,
you know, where in the cell the misfunction is happening.
It tells us that the handling of the proteins
is not functioning well enough.
There's already, you know, exciting clinical trials
ongoing mainly on the Parkinson's disease side
because the Parkinson's disease side
is a little bit further along.
They have already developed a lot of the outcome measures
that we use for clinical trials,
but it's obvious that the next patient population
in which, you know,
GBA-targeted interventions are going to be started
is going to be the Lewy body dementia cases.
So it's just --
But it tells us very nicely that we actually,
by paying attention to the related fields,
we can learn a lot from each other,
and so the Parkinson's field has accelerated
Lewy body dementia research,
and I think it's happening now also in return.
A lot of insights that we're gaining in Lewy body dementia
is also informing Parkinson's disease.
So the similarities and the differences
are really quite instructive
about very fundamental mechanisms
that are happening in the brain.
There's more work to be done,
but I appreciate, you know, your participant,
and, you know, I'm sure we have more to talk about
at the next summit as well.
-And I just want to, as an after --
you know, an after-statement, I just want to promote the fact
that the International Lewy Body Dementia Conference
is coming up in June in Newcastle,
so I'm hoping to see many of you there, please.
-Thank you. -See you there.
-Yeah.
-The next question, Jim, would you like to take that?
-Sure. I think this is Barbara Boehm.
-Hi. Hello.
This is my first time,
and it's a pleasure listening to all of you and meeting you.
My father was diagnosed last year with Lewy body dementia.
He was originally diagnosed with Alzheimer's
and Parkinson's disease,
so this is fairly new, so my question is basically,
his family has a history of Parkinson's disease,
and I'm wondering if there's a genetic connection
associated with that.
You know, based on the research
that I've been listening from Sonja,
have you noticed any kind of trends of behaviors that,
you know, indicate that it's more genetic than an anomaly?
-So it looks like Dr. Scherzer has hand up, so he can start.
-Okay. -Then we can go to Sonja.
-Yeah, so, yes.
So actually, this is a very important area
where we're starting to unravel the genetic contribution
to Lewy body dementias,
and there's clearly an important genetic factor,
but what you're also pointing out
is that there's an important linkage.
We used to think about these diseases as different silos,
Parkinson's disease, Alzheimer's disease,
Lewy body dementia,
but in reality, these clinical silos,
this is a very simplistic view and at the level of genetics
and at the level of looking at the brain, these,
the pathways for these three diseases are actually linked,
and so we see that some --
There are some genetic closeness like APOE
and perhaps WWOX-1 that are linked to Alzheimer's
but also to Lewy body dementia
and also linked to Parkinson's patients at risk
for developing dementia.
-I just want to say that, you know,
the genetics is just one piece of the puzzle.
I think there are so many different factors
that are playing a role, so I mentioned genetics,
but there's also lifestyle, environmental factors
and what we call epigenetics
which is kind of the intersection
between the environment and the genetic fingerprint.
And so while we recognize the genetic plays a role,
it's not everything.
So it gives us at least some, you know, areas in the cell
that we can put our fingers on, and we can model it,
but not everybody who carries risk variant
necessarily will have to develop the disease.
We recognize it is one piece of the puzzle,
but there's many other factors, in particular the aging,
that are playing a role.
And so, you know, in aggregate, we'll have to understand
the more complex changes of aging
and how some of these, you know, risk factors are then in contact
with aging and environmental factors
are causing the cell death and the disease to happen.
-So, Sonja, just to --
a question in regards to what you're saying.
As far as the environmental factors,
can you provide me an example as far as environmental?
Is it toxins or a particular job?
Let's say if he was working in manufacturing,
and there was a lot of toxins in the environment.
Would that be a contribution factor?
-Yeah. That's a great question.
I think, you know, there's definitely --
We've gained some insights,
but I also want to say that the epidemiology,
there's still a lot of room to grow.
So we're seeing, for example, the pesticides are associated.
Rural living is associated with higher risk
for Lewy body dementia but also related diseases,
Parkinson's disease, and I think, you know,
what these kind of toxins are doing
is that they are targeting specific functions in the cell,
in the machinery, and so maybe in concert
with being a little bit genetically predisposed,
if you have a lot of exposure to these toxins,
it may be enough to drive the disease
mechanism as you're aging.
And so that, for example,
there's also been discussion about heavy metals,
solvents, but I think we still don't understand
all of the environmental factors
that are playing a role especially over a lifetime.
-Okay. All right.
Thank you so much for answering my questions.
I really appreciate it.
Thank you, again, for all the hard work you're doing.
-Thank you.
-Thanks for the great questions.
Worth noting as well, I hate to be my recruiter,
but there are lots of centers around the country now focused
on Lewy body disease, and if there's any interest,
people can certainly look at the PWP website, for example.
I think you're up next. -John Paul Taylor, I believe,
has joined us and willing to ask his question.
Hi, John Paul. -Hi, y'all.
-He's joining us from UK.
-It's been a really great session,
and I'm so pleased to have joined you guys.
I just have a question with regard to disease heterogeneity,
and I suppose this is coming from my basis
of being a clinician who sees people with LBD,
and I'm always struck by the range and tapestry of symptoms
that people experience, you know,
and it really is diverse and, you know,
the range of progression that people experience,
and I suppose I did wonder through the recommendations
if there needs to be a little bit more of, I suppose,
a nod towards this heterogeneity so we can move beyond,
I suppose, our categorical diagnostic nomenclatures
or, I think, silos was a good term
towards perhaps more phenotypic dimensional axes?
So we think about the severity of motor symptoms,
sleep symptoms, autonomic, neuropsychiatric
and, indeed, also progression
and, I suppose importantly, resilience to damage.
So I just wanted to get the panel's view
on that perspective.
-Very good question, John Paul.
I can talk to the biomarker perspective that heterogeneity
is definitely there in terms of the variety of biomarker,
you know, measurements we're seeing
in Lewy body dementia patients,
and how that translates into the clinical phenotyping
is also important,
and certain biomarkers hatch on to certain phenotypes,
and that really explains some of the heterogeneity,
but there's, of course, all the other ones
with genetics and pathologic heterogeneity and so on.
So I will give some time to Dr. Cedarbaum here
and Angela Taylor to make comments on this as well.
-Yeah, so, thanks, Kejal.
John Paul, that's a great question,
and I wanted to come at it
from the clinical trials perspective
because I, like you, find this a challenge
but also an opportunity,
and it's sort of an RDoC-like thing,
and the fact that Lewy body dementia
is really the classic multiproteinopathy,
if you will, disease where we think,
at least, we have some idea of how to trace certain symptoms
to certain underlying protein abnormalities
in the brain or circuits in the brain,
we shouldn't let it overwhelm us.
And I think you're absolutely right that this disease
provides us an opportunity to test out drugs
directed at various targets
not only for disease modification
but for symptom control which patients desperately need now
as we're working out
the mechanisms of disease modification,
and I think it is something. I agree with you.
This is something we should keep in mind
as we think about therapeutics and therapeutics development
for Lewy body dementia.
-Thank you, Jesse.
Angela? -Hi, John Paul.
I just want to respond to your question
through the lens of the Dementia Nomenclature
Initiative which actually has its roots here in this summit.
One of the things, one of the recommendations
that's coming up out of this initiative
is the importance of clear communication
and perhaps different definitions
between the syndromes from the pathophysiologies
and the importance of maybe using those syndromic
descriptive terms to allow for more focus
on the underlying disease process itself.
We also are going to be looking at highlighting the importance
of communicating severity by domain, symptomatic domains,
and not just looking at it
all through the lens of how severe is the dementia
but making sure that through research
all the way through delivery, diagnosis
and clinical management that we open up the information
flow about those different domains
as a matter of clinical management and ongoing care
and helping the families look at this from a perspective of,
where are we in comparison to where we might be going?
So I hope that's also helpful. -Thanks, all.
That's really, really useful.
Great chat.
-Thank you, and I think we have come to the end of our session.
I will hand it over to Jim to close our session.
-Just great questions and nice discussion.
I really appreciate the contributions, Kejal.
Thank you and all the members of the LBD group,
and end of the first day, I guess, and onto day two.
-Yes, and thank you to you, Dr. Leverenz and Dr. Kantarci.
Fantastic day one, everybody.
We've been waiting for this for 3 years
and, you know, preparing for 6 months, and here we are.
So see you tomorrow at 10 o'clock Eastern Standard Time,
same place, same time and for another day of fantastic summit.
Have a good night, everybody.
-Thank you. -Good chat, folks.
Thank you.
-All right.