-Good morning, and welcome
to Day 2 of the ADRD Summit 2022.
We're really excited for the continued presentations
and feedback on draft research recommendations.
And to start the day off, it's my honor and privilege
to introduce a video highlighting experience
of people living with dementia and those caring for them.
This video was developed by the NINDS
Office of Neuroscience, Communications, and Engagement.
♪♪
-I'm Jim Taylor, and this is my wife Jerry.
And Jerry was diagnosed first with MCI nine
and a half years ago.
And, subsequently, when she was --
became a participant in the aducanumab trial,
she had a brain scan, a PET scan,
amyloid plaque on the brain;
and the diagnosis was changed to Alzheimer's.
As she progressed, our first --
Jerry and I have always spoken 50/50 until recently,
and her communication is more challenged at this point.
So she corrects me whenever I make mistakes
but is often quiet other than that.
So her diagnosis was not an easy situation for me.
Jerry is a professional health --
she has an RN and an MPH from Columbia
and spent her health, her career in healthcare.
So -- and she's a double four.
She got a bad gene from each parent.
So there's a number of Alzheimer's patients,
people living with the disease in her family,
so she was not as surprised by the diagnosis as I was.
-My father was a practicing surgeon
until about 20 years ago
when a neck injury which was exacerbated --
which was exacerbated in surgery required him to step back
from practicing medicine in that way.
And he founded a center for the commitment to --
commitment to compassion and medical care at his hospital,
which involved all sorts of wonderful programming.
And it was actually out of that experience
that we started talking with my college roommate
about putting some of his writings into a book.
But just as we were getting into a groove with that,
my father suffered two strokes three months apart
at the end of 2017.
And that led to a lot of limitations for my dad
beginning with left neglect.
So while he could see out of his left side,
he didn't perceive it.
And that meant that he was at a fall risk.
And that began having 24-hour caregivers with him.
And as if that weren't enough, a little over a year ago,
on New Year's Eve 2020,
my folks got the double whammy diagnosis
of Parkinson's and early stage Alzheimer's.
-Apparently she was in fairly good spirits.
And we already knew that there was a dementia
of one kind or another involved
because she had had this for about seven years
by the time we got around to diagnosing.
And mostly that was because we were considering a facility.
So I think it's harder when it's your own parent
and you see them like that,
and you're kind of like more frustrated
because you know they didn't used to be like that.
And it's more annoying to you because they --
they're not being who they used to be.
-So my mother was diagnosed with Parkinson's
in about 2015, 2016.
And they said to us at that time that we could expect
that there's about an 80 to 90% correlation
that she would develop dementia.
What complicated matters in her situation
was that she was already cognitively impaired.
So it was hard to judge what a baseline was and measure
when things were starting -- when the habit onset versus
what was her normal cognitive impairment.
In addition to her cognitive impairment,
my mother is Korean, was Korean;
and English was not her first language.
And she was not literate in her native language of Korean.
So she had all these issues that came out
that impacted her cognitive state.
So, again, it was really hard to tell
how much of it was dementia, how much was progressing,
and how much was just from normal,
you know, every day cognitive impairment.
♪♪
Now, I'm here a week, you know, at best every other month.
It's very different than what it's like for my mom
who's here all the time.
And she would say her life is also different
because of these incredible caregivers
that are also here with her and with my dad.
But for all the bright spots, it's -- there's --
you know, there's a lot of challenges.
And for a man who was very independent
and was a surgeon and a clinician and a researcher
and a teacher and a writer to continue to feel boxed in
by some of these diagnoses is difficult.
And he'll say that he really just wants to be of service.
And my father can put on a very positive front
and try to be in the moment and count his blessings
and begins every day with Hebrew blessings for waking up
and for the food on his plate.
And I think from my mother, who deals with the actuality
of managing caregivers and doctors
and trying to be his advocate and trying to figure out
when more is more and more is not more
and when to stop pushing so hard, it's a much --
it's a much harder challenge.
It's easy for me to swoop in and out
and spend quality time and then whoosh away.
And I think it's much harder to be the, you know,
online caregiver 24/7.
-I think just allowing myself
to be human
and recognize my limitations...
...is so real and so human
that I think it's incredibly important
that any caregiver accept that responsibility willing,
willingly, willing -- -Ly.
-Willingly.
And it's just the human condition
in its most human form.
-On the occasions now where I just go to the store
for an hour or something like that,
I can come back to mayhem.
So that means that somebody really has to be here.
So that's the biggest impact right now.
We're getting ready in my office
to go back to work in the office,
at least part of the week, starting in April.
So I'm not sure what I'm going to do
because, on occasion, I'll be here working.
And, you know, I'll hear the door click;
and she's gone out to check on her car to see if she locked it,
or she wants to go get the trash bins, trash cans in.
And so she will sometimes not realize
she hasn't kept the door unlocked.
So if I wasn't here, she would have just locked herself out.
-There's not enough resources, I think,
put towards that, the well-being
and the care of the healthcare provider or the caretaker.
I don't think enough emphasis is put on that,
that if you're not taking care of yourself and your well-being,
you're not able to take care of anybody.
-You were saying recently that you have just a hard time
even with the word dementia and Alzheimer's.
Can you talk a little about why those words feel so hard?
-Because you've spoken to people
about I've had strokes, even I have Parkinson's.
But dementia and Alzheimer's really just --
-It's been hard accepting my limitations
and wanting just to think of myself as being limited.
It's been very complicated for me.
-And especially something related to the brain.
-Yes.
-Even more so than the body because with the stroke
and with Parkinson's there have been movement limitations,
but it seems like the brain, the cognitive being impacted
has been particularly chilling.
-Quite so.
-Both thing that he does is he lets me be me.
And he is not ahead of me or back with me.
He is able to figure out if he's going too far
or he's being too coddling.
And that allows me to be me.
And we as a couple can continue to be as much as we possibly
can with the fact being that, in fact, my brain is different.
There is different thoughts.
And that's -- it takes a bit of work,
and it takes a lot of changing from both of us.
And -- but that happens, of course, the course of life.
You know, things happen.
And it doesn't stay just the same.
♪♪
-The things I like to tell everybody with the disease
is there's a choice in how you live with this disease.
You can choose to realize that you have been given
a number of years ahead of you that can be joyful, purposeful.
The person with the disease is somewhat more forgetful.
But, remember, this is a long-term disease.
Many people live over 10 years, 10 to 15 years or longer.
And the early stage and mid-stage
can be a wonderful time of life.
And we've been given a diagnosis,
so that makes every day more valuable.
So grab it. Choose it. Live it fully.
Mark things off your bucket list.
Contribute to others. I mean, for us,
the most rewarding and joyful part of this
has been our advocacy
and our ability to help other individuals with dementia.
-And I so -- the silver lining,
while it sounds really maybe cold and unfeeling,
to get your affairs in order soon enough.
You know, do your will. Do your living will.
Do your MLTS.
Do your power of attorney. Get your affairs in order.
Make sure that you're living in a situation
that's the safest and healthiest for you
and for your family members and for your loved ones.
I think that's really, really important.
And you think there's always time.
Oh, I'll have time to do a will. I'll have time to do that.
I'll have time to -- you know, to -- this is too early.
You just can't do it early enough.
And that's what I've learned from it
because all the physical stuff, you can't control.
You know, you can take medication
up to a certain point, right, that helped --
that might or might not help, slow down,
or stabilize your condition.
But you can't control the acceleration
or the decline of your health to some extent,
but you can control some other factors
that might make living with that situation a little bit easier.
There is some good in the experience.
Okay. Sounds like it's all awful and emotionally draining.
But there is some good learnings from something like this.
It does make you a more compassionate person.
It does make you question your mortality
and how do you want to live the rest of your life
and what's important to you. And I think that's a good thing.
-I guess the other thing is to forgive them.
These behaviors are classic dementia behaviors.
That's what a person with dementia does.
So forgive them for having dementia.
It's, you know, quite likely not their fault.
So that makes things a little lighter is --
-So one label, there's not one size fit all.
-I don't think so.
-And I know you want to be seen in your totality.
-Yes.
-You don't want to be labeled keys X.
-There are better words to use.
-Are there better words that you can think of?
How would you want someone to talk
about those cognitive challenges?
-I think that's a great question,
and I don't know how to answer that.
-But you're more than just a label.
-Thank you.
♪♪
-Keep working.
-What else?
-Well, the first thing I'd say is,
from the bottom of our hearts, thank you.
I don't think they hear that nearly often enough.
They're giving parts of their life,
their careers trying to find a cure for our granddaughter.
And nothing means more to us than that.
And so we are tremendously grateful for researchers
and clinicians and people who are involved in the field.
And I think as people who are impacted by the disease,
we need to express that gratitude
more profoundly and more often.
And, secondly, remember that, you know, we are a continuum.
But it's a continuum of a disease, start to late stage.
We have lots of ideas and advantages,
and we can promote clinical trials.
And we can help you. But we're so rarely asked.
We're rarely asked, well, what are your ideas
about recruiting additional trial participants?
Or what do you think of this procedure versus that procedure
if we're designing the next clinical trial?
Jerry's a brilliant person.
And she didn't lose her brilliance
when somebody told her she had MCI.
So I would encourage scientists to realize
what a wealth of resource they have in their patients
and in their care partners.
Take advantage of us by asking us.
Don't hesitate because, if you don't ask us,
you deny us the opportunity to feel valuable,
to feel like we can help
to get the positive psychological benefit
of helping fight to find a cure.
♪♪
-Thank you to the families and to the Communications Office
for this wonderful presentation.
It's very impactful, very appreciated.
And it just gets to the heart of the matters that were --
that are important and critical to this Summit.
I want to now introduce the scientific chair
of the multiple etiologies dementias session,
Dr. Kate Possin.
-Thank you. And, yes.
Thank you for that inspirational video
and remembering to always include the patient
and caregiver voice.
So it is with great pleasure that I introduce the 2022
Draft Recommendations for Multiple Etiology Dementias.
Next. Here are my disclosures. Next.
Our committee is focused on multiple etiology dementias
and also two special topics.
So Post-TBI AD/ADRD is chaired by Dr. Dams-O'Connor,
and Late is chaired by Dr. Snyder.
And these will be presented separately. Next.
So before we review the draft recommendations,
I will overview what our session covers
and why MED research is crucial.
In dementia, multiple or mixed underlying ideologies
is the norm.
More than 50% of people diagnosed with Alzheimer's
have pathologic evidence of more than one cause of dementia.
If we are going to accurately diagnose and treat Alzheimer's,
we need to understand these contributing pathologies,
including how they can be identified,
treated, and even prevented.
We must continue to advance research
on differential diagnosis,
treatments for people with multiple etiology dementias,
basic science on common and interacting disease mechanisms,
and training in different dementia syndromes.
In the AD ADRD field,
some critical research gaps apply across all etiologies
and are subsumed also in the MED session.
This includes advancing work on early detection,
caregiver support, and data harmonization. Next.
In 2019, TDP-43 and common dementia is now termed LATE,
and TBI and AD ADRD risk were emerging topics.
And these -- this year, these are included in the MED session
but with separate subcommittees. Next.
So here's the list of the committee members
who have worked hard over the last six months
to prepare draft recommendations
that we seek your input on today.
Our charge is to recommend research on mixed etiologies
and key themes that apply across all etiologies.
Next.
so now I will introduce you to the focus areas of MED,
starting with detect and diagnose.
More than 50% of people living with dementia are not diagnosed
until moderate to advanced stages of dementia.
And these delays are longest for race and ethnic minorities.
People with symptomatic cognitive decline
need an evaluation with quality follow-up care.
Furthermore, too often the dementia diagnosis is generic,
such as unspecified dementia, which is a huge problem
as we move towards an era of disease modifying therapies.
We need scalable solutions to achieve accurate
and timely ideological diagnosis in diverse populations.
Interventions and treatment, we recommend research
that moves forward promising interventions and treatments
that address modifiable risks to prevent cognitive decline
and that support persons living with dementia
and care partners to maximize quality of life.
Basic science,
MED is the norm among older adults with dementia.
Although basic science research
often focuses on a single etiology,
there have been substantial advancements in understanding,
interacting, and common mechanisms of mixed pathologies.
Continued work in this area is crucial
if we're going to develop accurate methods to diagnose
and to treat these diseases. Next.
Workforce, MED recommends work to address gaps
in the dementia clinical and research workforce.
We need to develop, implement, and evaluate training programs
in different dementia syndromes for health professionals.
We need to incentivize mentorship
and provide opportunities for new researchers,
particularly from groups underrepresented in science.
Furthermore, it is crucial that we promote
and support researchers to recruit and retain diverse
cohorts in all types of studies.
Harmonization is a new proposed focus in 2022.
The goal of this focus area is to maximize the impact of data
collected to address important questions in MED.
Our session is recommending for the first time
that we incentivize and conduct research
to improve data harmonization
and sharing practices across MED studies. Next.
Infused through all of these five focus areas of MED
is the requirement that research be inclusive.
For us to make meaningful progress towards NAPA goals,
we must conduct inclusive science.
There's been increasing attention
and work in recent years
to address the problem that our research participant samples
are frequently not representative.
For example, Black, African-American, Latino,
other minority groups are insufficiently included.
And this means that our interpretations
are also not inclusive. This is particularly concerning
given that some minority populations,
including Blacks, African-Americans,
and Latinos are at a greater risk for dementia.
Our committee recommends that all MED research be conducted
in a way that is culturally sensitive and relevant
to the populations that suffer from MED
so that everyone will have the potential
to benefit from the advances.
The requirement that MED research
be inclusive of diverse populations
is central to all of the recommendations
that we present today. Next.
So here's a summary of the MED draft recommendations.
Focus area 1, detection and diagnosis
of cognitive impairment in MED.
You will hear from Mike Wolf and Jeffrey Burns
about our recommendations to improve
the detection of cognitive impairment,
to evaluate cognitive screening, and to support
the identification of multiple etiologies.
You will hear from Malú Tansey on our recommendations
to advance basic science research on the common
and interacting risk factors and mechanisms.
For Focus Area 3, you will hear from Ozioma Okonkwo
and myself on our recommendations
to advance interventions and treatments.
And, last, you'll hear from Heather Snyder
on Focus Area 4, dementia capable workforce;
and Focus Area 5, data harmonization.
So now I have the pleasure of introducing Michael Wolf
from the Northwestern Feinberg School of Medicine,
who will present on Focus Area 1. Next.
-Good morning.
As the slide states, I have no relevant disclosures.
And I will be talking about recommendations 1 and 2.
Next. And next.
So Recommendation 1, which has been flagged
as of the highest priority at this summit since 2016,
addresses the need for interventions
that promote objective detection of cognitive impairment
linked to quality care whenever a patient,
care partner, or clinician reports cognitive,
behavioral, or functional changes.
An emphasis is specifically placed on strategies
at the frontlines of healthcare including primary care
and other everyday clinical settings.
It should be stressed that interventions must focus
not only on improving detection but also follow-up activities
including referral, diagnosis, care planning,
and ongoing management of any impairment
or identified cognitive functional change.
The need is also heightened among populations
experiencing health disparities in ADRD.
Therefore, research should prioritize these communities.
Next.
Recognition 1 and being flagged
at the highest priority is well-justified.
Despite long-standing opportunities,
including the Medicare annual wellness visit,
rates of detection, particularly in primary care settings,
remain very low.
This is especially true for early detection of ADRD
with mild cognitive impairment.
And there are many root causes steeped
in the reality of typical clinical workflows.
Primary care practices often have limited resources
in terms of staffing and time with patients.
But, also, there's a lack of training
and awareness on the availability
and use of various cognitive assessments.
Further, the presence of comorbidities
may mask the detection of cognitive, behavioral,
or functional changes warranting further assessment.
As with the past two ADRD summits,
there continues to be an urgent need
for objective cognitive assessments
that are amenable for use in primary care settings,
brief in nature, tethered to electronic health records,
with easily interpretable and actionable findings,
again, linking to quality care with TRNKE recommendations.
These are desperately needed. Next.
I'd also like to highlight a recent study
that underscores the presence of disparities
particularly among Asian, Black,
and Hispanic Latinx older adults.
So when colleagues leveraged California Medicare data
and found that disparities among these groups,
Asian, Black, and Hispanic adults,
were less likely to receive a timely diagnosis;
and Asian adults specifically received
fewer diagnostic elements.
This underscores the recommendations
priority studying among health --
studies among health desperate populations. Next.
In response to this recommendation set forth
at the 2016 ADRD Summit,
NINDS immediately took action with a request for applications,
forming the Detect Cognitive Impairment
Including Dementia Consortium or DetectCID.
This is led by Dr. Corriveau and Dr Hummer.
And I'd also like to acknowledge Dr. Claudia Moyes' role
in consortium's creation as well.
DetectCID was founded in 2017
as a network of research programs
validating strategies in everyday clinical settings,
including primary care that include cognitive assessments
linked to quality care.
The goal is to improve both the frequency
and quality of cognitive evaluations
and to better understand the various barriers
to routine detection,
especially among populations experiencing health disparities.
Dr. Possin and her team serve as a coordinating site
for this consortium. Next. There are three paradigms
currently include in the DetectCID --
I'm sorry. Next.
You know, the three current programs in DetectCID,
you can see the actual -- the partners here.
They each have their own paradigm being tested
in diverse settings.
All seek to have as brief as possible assessments,
whenever possible, less than 10 minutes
and even, ideally, shorter than seven minutes,
tethered to electronic health record
and, again, with turnkey recommendations. Next.
In the fall of 2021, NINDS
made another commitment to extend and expand
the DetectCID consortium with an RFA
linked to this recommendation,
providing a five-year renewal within a UL 1 mechanism.
This time the consortium will focus
on pragmatic clinical trials;
testing paradigms based in everyday clinical settings,
including primary care to improve detection
of cognitive impairment with a mandate
to target populations experiencing disparities.
These pragmatic trials will also seek to evaluate
not just the effectiveness of early detection
and management strategies but their fidelity as well.
Next. Of note, a soon-to-be-released article
shared many of the early learnings
across the consortium partners with regards to the lessons
learned on hardwiring early detection
strategies in primary care. One particular challenge,
especially in community health center settings,
that may disproportionately provide care
to help disparate populations
is the need to identify pathways for primary care clinicians
in terms of doing the diagnostic workup,
referral and later ongoing care management of adults
with suspected impairment. Next.
Moving on to Recommendation 2, this is set at priority 4
with a focus over the next five to seven years,
addressing the needs for improving our understanding
of the benefits, burdens,
and harms of screening for cognitive impairment.
Specifically, in the absence of a patient
care partner or clinician report
of cognitive, behavioral, or functional changes.
A strong emphasis is yet again placed on the importance
of having any early detection strategy
linked to diagnostic services and quality care.
In addition, research studies should be able to determine
whether certain populations are more likely to benefit
from screening as well as whether other populations
may be more likely to be harmed. Next.
The justification for Recommendation 2 flows directly
From the US Preventive Services Task Force
continued I or insufficient evidence recommendation
made as recently as February 2020,
with regard to cognitive screening. Next.
The primary reason was that, in fact,
there continues to be very limited data
investigating benefits and harms of cognitive screening.
One trial by Fowler and colleagues
was recently conducted,
finding no differences in quality of life
among those who did or did not receive screening.
Prior to the Fowler study,
scant evidence has been available
to further inform the Task Force.
Other justifications for the lack of endorsement of cognitive
screening includes the lack of accurate well-tested instruments
for assessing cognitive impairment
that would work in primary care settings
and that there also is little evidence
supporting any benefit from screening
or any earlier diagnosis on decision-making.
Yet there's also mixed evidence on potential harms
due to false positives derived from diagnostic inaccuracies.
Next.
Interestingly, we do have a natural experiment
brewing with the Medicare annual wellness visit.
These covered primary care encounters have been around
since 2011 and require a cognitive assessment.
So, in essence, despite the US
Preventive Services Task Force recommendations,
there is a cognitive screening mandate.
However, Medicare wellness visits
are often not performed for a myriad of reasons.
And, when they are performed, as many as half may not include
the required cognitive assessment.
A prior Alzheimer's Association survey
found one in five primary care doctors
were unaware that such a Medicare visit
required a cognitive screening,
this after several years of Medicare annual wellness
visit being in place next.
Finally, as we move forward,
an important take-home to reiterate
is the need to develop strategies
for early detection of cognitive impairment
that will not widen existing disparities
by not having adequate linkages to quality care
and clear recommendations
for ongoing follow-up and care management.
Partnerships, partnerships with CMS
and other large health systems
might also expedite answers for Recommendation 2
by examining the Medicare annual wellness visit data.
Thank you.
-Alright. Great.
So how I'm Jeff Burns, thanks Mike.
I am going to discuss recommendation
three in this focus area about detecting
and diagnosing cognitive impairment
in multi-etiology dementia. I do have a couple disclosures,
I've done some consultation for a couple of companies
and I lead some clinical trials
as site PI for a number of different companies.
Next.
So this recommendation, recommendation three,
is about moving forward,
clinical and translational research
as opposed to basic science which we'll hear about next.
But clinical and translational research
focused on identifying the multi-etiologies of dementia
in diverse populations. Next slide.
So, we know and we're, I believe the field is really beginning
to embrace this idea of heterogeneity
of Alzheimer's and dementia, as a multi-etiology dementia
which heard about it today and yesterday.
But we know there's multiple interacting
and co-occurring pathologies.
These are the classic ones we look at. Next.
This study here from the Rush Group from 2013
reminds us that we can't really see
and count everything that's related
to the common neurodegenerative pathology,
or actually late life cognitive decline.
So this study identified about 41% of the variants
that explains the late life
cognitive decline through pathology.
But, what remains is about 60% of the variants of late life
cognitive decline that's unexplained by these,
you know, more common neurodegenerative pathologies.
It reminds us we really can't see
and count everything that's related
to these late life dementia's.
Next slide. And go ahead again.
And another study from the same group in 2019 on individuals
who are diagnosed with Alzheimer's Disease
clinically found that really the,
from a neuropathological perspective,
these dementia's can be attributed
to a variety of common neuropathologies.
So, reminding us that when we think it's Alzheimer's,
that the things that we can count are multiple
and overlapping.
And hence the need for thinking about dementia
in these broader terms in multi-etiologies. Next.
So, back to the recommendation of, you know,
how do we identify these multi-etiologies of dementia
in diverse populations?
My recommendation is to really promote
and grow the observational studies
that include multi-modal, deep phenotyping.
So that we can begin to understand,
better understand clinical phenotypes and biomarkers
and how those predict and relate to the neuropathologies
and combinations of neuropathologies.
We need to identify risk factors for these pathologies,
prevalence estimates and how sex and genetic factors relate.
And importantly we need to understand the life course.
Including social determinants of health,
and I'll talk about that more in a second,
but, we need to focus also on populations
most at risk for Alzheimer's Disease and related dementia's,
including as we've heard already this morning racial
and ethnic minorities that appear to be more at risk.
And groups such as Downs Syndrome.
Next slide.
So, we need to, we need to build this idea out more as well,
this life course model of dementia.
So this came from the Lancet Commissions
Report in 2020 on dementia prevention,
intervention and care.
And focused on the 12 risk factors,
12 strongest risk factors.
And how they influence dementia risks across the life course.
So that backwards s is a figure that shows the risk factors
and their apparent roles in dementia
risks across the life course.
And we need to build this idea out more,
really begin to understand better how the environment,
how social determinants of health,
and other factors across the lifespan
interact with genetics and influence
an individuals risk of developing dementia
late in life. Next slide.
And a reminder that it's not to early
to begin to move these ideas into primary care,
we just heard about that from Mike as well.
But, and this is beginning to happen already,
this scientific statement from the American Heart Association
from last year was recommendations
for how to move many of these ideas
into primary care practice.
And so, primary care physicians are interested
and beginning to use these ideas in practice,
we need to accelerate that.
Next slide. So how do we do that?
Well we need to continue to validate
these multi biomarker approaches,
really understand and validate how they predict
and relate to these neuropathologies.
And importantly we need to do research to understand
how they influence clinical practice.
What signs and symptoms best identify these etiologies.
And are they clinically actionable?
Can we identify and stratify,
can we identify these factors or stratify individuals
into risk groups to target them with disease specific therapies?
And lastly, we need to think hard about access
to these new diagnostics and new therapies.
And then how do we scale them to the population
so they reach everybody who needs them?
We need to do this through more pragmatic trials
and community-based trials. And we need to focus again
as we've heard yesterday and today,
on reducing inequities and reducing poor access
to these new therapies and new diagnostics.
And next slide.
And this headline is a reminder of why we need to do that.
We can't develop new diagnostics and new treatments
that deepen these inequities of care.
And last slide, just to bring it back to the big picture.
The recommendation three, set at a priority three
is to conduct multi-modal clinical
and translational research that supports the identification
of these multiple ideologies in diverse populations.
And so now I'll turn it over to Malu Gamez Tansey
who's going to talk about basic research in MED.
-Thank you Jeff.
Thank you for your time everybody.
The focus area two for basic research in MED,
recommendation four,
priority two to advance basic research on a common
and interacting risk factors and mechanisms of multiple etiology
cognitive impairment in dementia in diverse populations.
Was put together by contributions
from Dr. Brad Hyman and Lea Grinberg.
Next slide.
You see our disclosures and there are several.
So I won't read through them.
We will go to the next slide and start the recommendation.
Again, under that main recommendation
we have four sub-recommendations.
And they are to define the interactions
at the molecular and cellular level of the common
and newly identify pathobiologies of MED.
To define the molecular signatures
of vulnerable versus resilient neuronal populations.
To incentivize innovation, to address technological gaps
and to incentivize creation of multidisciplinary,
multi-sector, multi-career stage teams
to address both the heterogeneity
and the common mechanism questions of MED.
And in the next few slides I'm going to show you
the progress towards these four sub-recommendations
and where we still need to do more.
So, the first thing you see is that research efforts
to advance basic science since the 2019 summit
have involved of course the four main proteins.
Tau, alpha-synuclein, TDP43 and amyloid beta.
And we know that the mechanisms of toxicity of these proteins
involve the organization, their propagation
and there's an, if there's an imbalance
in the synthesis aggregation or clearance of these proteins
in can result in chronic accumulation
that leads to further aggregation, and propagation
and potentially interactions with inflammation,
eventually neurodegeneration.
That's the model that everybody's testing.
However, in the next slide you will see
that it gets very complex because we see
that they are different strains of these seeds.
And so, in the seminal work
by John Trojanwoski and Virginia Lee,
where they showed that there were unique pathological
tau conformers from brain
that could transmit in non-transgenic mice.
We now know from work of Michelle Goddard
and other investigators including a review
from Kejal Ashul
that the complexity of these amyloid strains
is very very high.
And interestingly enough from the work
of Brad Hyman and Safar's group,
we see that this molecular diversity
may contribute to clinical heterogeneity in AD
and may be associated with rapidly progressing Alzheimer's.
And so, and on the next slide what you will see is this idea
that we may not be able to get away with
just targeting one of these,
we may have to think about combination immunotherapy
and as well as targeting the inflammation
that comes from these interactions.
And finally there's a new kid in town and that's TM106B,
which was recently reported by Michelle Goddard's group.
That forms AIDS dependent amyloid filaments
in human brain.
And then the next slide what you will see
and I'd like to highlight is that,
targeting tau is not just about immunotherapy,
there are other non-immunotherapy approaches
such as anti-sense oligose from Tim Muller's group back in 2017
and also from Brad Hyman's group the, a way to repress tau
is by using zinc-finger protein nucleases
that will, you know,
repress the transcription and formation of tau.
And in the next slide I'd like to highlight
basically that one of the seminal discoveries
since the last summit and expanded upon is,
linking tau to immunity and lipid biology.
Much of this work has come from the lab of David Holtzman.
Where they tied ApoE4 to exacerbation
of tomigated neurodegeneration in mouse models.
Followed by linking it to interactions
between APOE and TRIM2. And finally a very recent report
that implicates the glymphatic system
and that clearance of extracellular tau
and protection again Tau aggregation.
And then in the next slide
I would like to highlight the fact that we know
as well that in addition to these protein apathies
there are incidental copathologies
that co-occur with neurodegeneration.
But the consequences are unknown.
Some of these may impact cognition
and some may protect against spread.
So there's much work to be done in this area.
And in the next slide we'd like to highlight
that there's been good progress in implicating immunity
in lipid processing with genetic loci.
And this is important
because all the geneticists need to have it grounded in genes
in order to really understand that it's important.
And so this is a good advance in my book and many other books.
There's also the importance of the gut,
brain microbiome access,
where we know that there are bacteria
that produce short-chain fatty acids
and those may be associated with protection
against early onset of certain forms of dementia.
In the next slide we'd like to highlight the fact
that there's been lots of advances in the next slide,
in iPSCs or select vulnerability for understanding
that in any kind of injury the cell type matters.
Because it will, the degree of dysfunction
depends on which cell is injured.
And for instance excitatory neurons
can be more prone to accumulate tau and die
compared to, you know, other subtypes if they're,
you know, if they're not a certain phenotype.
And so in the next slide we also know
that there are advances in iPSCs in the next slide.
That have been important, but, they're limited by the fact
that not everybody's growing them in two and 3D culture.
And so, the phenotype is forward with iPSC work
that they're grown in the proper environment
so that we know that they are more closely
recapitulating their normal allele.
And more importantly we also need to stress that with,
the development of iPSC lines from individuals
with diverse genetic backgrounds
and diverse ethnic backgrounds is needed.
And in the next slide we need to integrate
everything into a o-mix approach.
So that we know the genome, the transcriptome,
the proteome and the metabolome all come together
into a systems biology scenario
where team science is really the way to go.
And so, as we integrate these various aspects of basic science
into a holistic systems biology approach,
we'll be able to really understand the pathogenesis
and the pathobiology of AD and MED.
And in the next slide,
is an example of what some of this,
that has occurred, like Move AD,
is a huge partnership between NIH,
industry, non-profit organizations involving,
you know, lots of labs with complimentary projects.
And importantly it builds on the open science approach
and big data infrastructure established by the AMP AD.
And it's a real example of science being a team sport.
And in the next slide are just a few examples of FOAs
that have come out since 2019.
Especially in the bottom highlighting,
you know, one of the centers that was funded with this FOA,
which is the Office of Nuclear Strains in the business lab.
As well as the more recent Center Without Walls
to address mechanisms of degeneration in FTD.
And in the next slide I just want to summarize
basically what we are saying in the four sub-recommendations.
The areas of focus are the proteinopathy,
inflammaging and immuno essence interactions
that lead to cognitive decline in diverse populations.
And understanding those mechanisms.
Second, understanding the mechanisms of cell
vulnerability and resilience in diverse populations
and how they interact with neurodegeneration.
Third, we need to incentivize the development of iPSC lines
in two and 3D environments and from individuals
with diverse ethnic backgrounds.
And finally we need to incentivize basic research
by diverse multidisciplinary, multi-sector,
multi-career stage individuals and teams.
Such as the CWOS.
And I will pass it on to Doctors Okonkwo and Doctors Possin.
Thank you.
-Thank you so much. That has been wonderful so far.
So now we're going trying to focus area trade
is focused on interventions and treatments.
And I'm going to be delivering recommendation five.
And Dr. Possin is going to take six.
Next slide please.
I have no disclosures for this talk. Next slide.
So for this recommendation the focus as mentioned earlier
is conducting clinical studies on approved
or promising interventions and treatments
to mitigate risk for cognitive decline.
And under here we have three elements
that you're going to be hearing more about
in the subsequent slides.
But, in summary the key elements are focused on conducted,
inclusive and pragmatic clinical trials.
Supporting the development
of practice-based research networks.
And develop within health risks and effectiveness of hierarchies
in diverse populations. Next slide.
This recommendation was first introduced
in the last ADRD summit in 2019.
And in the years since then the progress report
that was shared with the scientific community in 2021
indicated that there has been several research milestones
that have been accomplished.
And some of the highlights of that,
or a focus on post-stroke vascular contributions
to cognitive impairment and dementia
was released as a u19.
And consequent on that area of then,
the diverse VCID project was initiated
that was under still led by Angela and the colleague.
And also as part of the accomplishment
also the discoveries and study
that is focused on post-stroke cognitive
outcomes led by Natalia Rost and Steve Greenberg
is now underway.
So there's been remarkable progress made under this effort
to conduct intervention studies up until now.
Next slide please.
And in thinking about then the, where we wanted to take this
for the 2022 updates for this summit.
This happened against the backdrop
of two recent developments.
You already saw this slide in Jeff Burns talk.
And this is the dementia prevention reports
from the Lancet Commission.
And which identified some very key risk factors for dementia.
And these risk factors then can now be understood
as potential targets that we can hit in order
to forestall the projected increases in dementia prevalence
and incidents in the coming years.
Next slide. And the second development
is at the end of last year we received,
well we all received an update from the National Plans
for Addressing Alzheimer's and Disease.
And in that update a new goal was added to the plan.
And this goal was specific developing
and promoting health agent
and with this risk factors for AD.
Which was a very interesting and exciting development
given that the targets and for not all along
has been to prevent AD by 2025.
Which also is why in this 2022 version of the ADRD Summit,
recommendation five has now been moved
from priority two to priority one.
Given the imminence of the deadline
we all have of preventing AD.
So this focus on reducing risk factors
we believe is very timely and informed the operation
that we took the recommendation five on interventions.
Next slide please.
So the first element under this recommendation five
is the conduct of inclusive and pragmatic clinical trials.
In settings where risk factors for cognitive decline
can be appropriately targeted for intervention.
A search of clinical trials that's dove, earlier days,
reveal that in the ten years between 2001 and 2011.
Approximately 450 studies in dementia studies
that were focus on dementia.
None of them had the keyword pragmatic associated with them.
First four, ten years and there the last decade,
the number of intervention studies focused on dementia
have exploded thanks to the massive inclusion of firms
to ADRD studies.
However, of this I am more than 1,000 studies known
that are focused on dementia,
only 25 of them have the word pragmatic
and attached to them as a keyword.
So obviously in this were some progress has been made
in a greater recognition
for the need for cognitive clinical trials.
And there is still a lag and opportunities for the field
to begin to think more in terms
of conducting studies in the settings
where the people who actually are going to be
impacted the most by these trials.
Actually are look at where they live, work and play.
However though,
despite that it's also important to underscore
the progress has continued to be made.
And on this slide we highlight some of the big studies
that have been,
that are currently occurring or have been underway
in the last decade in the area of both pharmacological
and non-pharmacological treatments
and interventions for ADRDs.
We highlight the A4 and the head studies.
Which are anti-angular therapies focused on individuals
who currently are cognitively unimpaired.
We also highlight the Hope for MCI study.
Which as the name indicates is focused on individuals with MCI.
And this study is focused
on addressing people hypocampal, hyperactivation.
And then the Libit Study that is focused on individuals
in the dementia stage of the disease.
And this target is to understand the role that CBD and THC
might play in the present agitation in dementia.
For the non-pharmacological treatments
we highlight the exert study, the mind study,
the achieve study and the US Plan Study.
And we think that the non-pharmacological treatments
help make more progress in beginning to think
about how soon interventions within communities
that actually are going to be impacted
by the outcomes of this study.
For example the exert study and the US Plan Study
partnered with community-based organizations like the YMCAs
to actually conduct the intervention pieces
of the studies within the community
where individuals are located.
So the exert study is an exercise study,
the mind study is focused on diet,
the achieve study is focused on treating hearing loss
and the US Plan Study is a multi-domain study
that includes exercise, diets, cognitive stimulation
and also health coaching. Next slide.
The second element of recommendation five
is focused on supporting the development
of practice-based research networks.
To facilitate a translation of effective assessment
and intervention strategies into practice at a large scale.
And we think that this is truly a place where the NIA
and the NDS has made tremendous, tremendous progress.
As you can see that there are now
a number of versioning practice-based research networks
that have been developed to support the conduct
of pragmatic clinical trials
and other community-based type studies.
On this slide you will see that we have also highlighted
the NIA Intramural Center for Alzheimer's
and Related Dementia's, CARD.
CARD as you may know is the NINDS,
NIA crown jewel if I may use that word.
But currently it is focused
on the conduct of basic science and data science.
We would like to suggest that CARD is uniquely positioned
for serving as a hub for intervention studies.
Perhaps in partnerships
with practice-based research networks.
Next slide please.
And then the last element of this recommendation five
is to evaluate health risks and effectiveness of AD therapies.
Such as anti-amyloid therapies
and more patients from diverse culture
and socioeconomic backgrounds.
The topic of inclusion and equity
was the focus of an entire session yesterday.
And we already have heard a lot
about it this morning from my colleagues.
But just in highlight form, we all understand and appreciate
that ADRD more prevalent in minoritized groups.
However, a recent survey in 2020 of nine
of the large scale observational
and clinical studies in the ADRD field
indicated that the vast majority of participants
who enrolled in these studies are not Hispanic whites.
More recently a few months ago, another survey that this focused
on drug trials in the ADRD space,
indicated that about 95% of all the participants
in these studies again were not Hispanic whites.
So I think, you know, it is certainly obvious to say
that this statistical is no longer tenable.
And the field has a moral and ethical impurity
to begin to move the middle. Next slide please.
And again, you know, this is now reflected in some book
lay and scientific articles like the one by Jan Manley
and her colleague.
Addressing the, and developments in lab
and how the lack of diversity in the patient group
is something that needs to become to new to be explored
as this trial, as this drug move
towards further community and developments.
Next slide please. So what then are our next steps?
And I want to focus on the three key elements
on this recommendation.
The first one being intervention.
We want to call attention that there is need to look
at the settings in which these studies are being conducted.
And also the modalities and the majority of studies in,
are still single modality studies.
But as you heard, you know, in Jeff Burns talk,
you know, it is the rare occasion
that an individual with AD at autopsy
only has AD as a neuropathology. So want to begin to think more
in terms of more multi-modal studies.
Also in terms of targets,
the most prevalence and hierarchies studies for ADRD
are at this point focused on anti-amyloid.
And we want to highlight that it is time for the field
to begin to pay more specific attention
to the other part of it physiologist
that underlie ADRDs.
And that's the different populations of interest
is an area to consider.
We want to highlight the need to expand the spectrum
from individuals who are cognitively unimpaired,
all the way to individuals who have dementia.
In terms of infrastructure we believe that there is a need
not only for an increased development of PBRNs,
the practice-based research networks,
but also for an increased use of those networks.
Because it is critical that as disparities
and interventions are being developed,
that they are housed within the areas
where the people who are going to be
using the outcomes of these studies where they live,
work and play.
And finally, you know, we think that there is a need
to continue to pay attention to issues of representation.
And this is going to require us to be very critical
of the inclusion and exclusion criteria.
That we implement in these studies.
Because that is actually the first place
that we begin to exclude individuals
who actually are most affected by these diseases.
I want to leave you then with some resources in terms of
funding opportunities that people can apply
for in order to begin to propose interventions.
Both from a pharmacological and non-pharmacological ones.
And we want to call specific attention
to the very last bullet there.
The request for information on capacity and support.
That the NIH, sorry that the NIA has released to receive
information from the community in terms of how the NIA
can build some community-based research networks.
To increase the participation of diverse groups
in ADRD clinical trials.
And I believe that is my last slide
and I'd like to hand it off now to my colleague Dr. Kate Possin.
Thank you.
-Okay thank you so much.
Great, so I'm going to be presenting recommendation six.
Which is to implement and evaluate outcomes
for effective dementia care programs
that support persons living with dementia and their caregivers.
Including those of socially,
ethnically and racially diverse populations.
This recommendation includes advancing research
to identify barriers and facilitators
to widespread diffusion of promising interventions,
conducting implementation studies,
developing and evaluating payment models and developing
and evaluating core components of culturally sensitive
collaborative dementia care models,
that deliver high quality care. Next.
So I'll start by setting the context
for this recommendation with a quote from Julia,
a person living with early stage Alzheimer's Disease.
It took us nearly four years to get a diagnosis.
The doctor told us it was Alzheimer's,
that there was nothing he could do
and to come back in a year.
We were first devastated then angry.
I also have diabetes, I got medication, education
and care management for that.
Now I have a fatal brain disease and I got diagnosed and adios.
We have to do better.
So we, those of you who were at the health equity session
yesterday also heard from Mr. Lacina
during the question and answer period,
a caregiver who highlighted the importance
of transparent disclosure of diagnosis.
And prognosis and of guiding caregivers into their role.
And we started today with those poignant inspirational videos
of people living with dementia and their caregivers.
That also highlighted the importance
of supporting the caregiver.
Planning ahead, getting affairs in order
and focusing on well-being. Next.
Yet dementia care is too often crisis oriented and fragmented.
Frequent emergency department visits and hospitalizations,
multiple care transitions, inappropriate
and potentially harmful medication use.
Patients experience aggressive end of life care
that's often inconsistent with their values and expensive.
Informal caregivers shoulder substantial burdens
with minimal support
from our patient-centric healthcare models.
And when caregivers are depressed,
people living with dementia use the emergency department more.
The COVID-19 pandemic has disproportionately disrupted
the lives of people living with dementia and their caregivers.
Next.
In 2019 this ADRD specific milestone
was given two success criteria.
They were, to write a white paper
on proven dementia care programs.
That effectively support persons with dementia
and their caregivers.
And to establish a national consortium
tasked with applied research
to determine how to implement widely across the country
in everyday care settings, proving care programs.
The first of these milestones has been completed
and I will now share the results. Next.
A systematic review of dementia care models was produced by AHRQ
at the request of NIA.
And this review evaluated the evidence that care models were,
that which care models were ready
for broad dissemination and implementation.
This report was followed by a consensus study report
by the National Academy's of Science,
Engineering and Medicine.
Together these reports provide a helpful overview
of the evidence landscape.
And they concluded that evidence is sufficient
to justify implementation of two types of interventions
in a broad spectrum of community settings with evaluation
conducted to continue expanding the evidence-base.
These are collaborative care models
and multi-component caregiver support. Next.
So collaborative care models use multidisciplinary teams
to coordinate psychosocial and medical care.
Typically with a care navigator,
or care manager as the primary point of contact for the family.
They emphasize the immediate needs of the person
living with dementia and the caregiver.
Often called a diad.
And they also prioritized proactive care planning,
personalized to the diad.
So these programs have been shown to improve quality of life
for the person living with dementia,
caregiver well-being, health system level markers,
including improvements in quality indicators
and reducing emergency room visits. Next.
Multi-component caregiver support provides
caregivers with the knowledge, skills and access
to resources they need to promote their own well-being
as well as that of the person living with dementia
for whom they care.
And outcomes improved include caregiver depression. Next.
So we know that collaborative care
and multi-component caregiver support models
improve outcomes for people living with dementia
and their families.
Yet these programs remain unavailable
to the vast majority. Scientists have a critical role
in bridging the science practice gap.
Too often scientists expect that the implementation
and dissemination of their interventions
will be taken up by other parties.
Which is often not the case.
And as scientists need to understand the barriers
to dissemination effective dementia care
and trial implementation methods to bridge the gap.
Next.
So in closing, please imagine with me
a near future of dementia care.
Imagine if every patient was a concern for cognitive decline
is evaluated, giving appropriate treatment, connected to care.
Imagine that once diagnosed with dementia
and their caregivers have someone in the medical system
who helps navigate them through the challenges
of living with dementia.
The medical system partners with caregivers,
prepares them for their role.
Tailors support to their needs and preferences.
Quality of life, well-being,
for both the person with dementia
and the caregiver, are made a priority.
We can do this. Next.
I would now like to introduce Heather Snyder
from the Alzheimer's Association.
Who will close our presentation with the last two focus areas.
-Thank you so much and hi everybody
and I think building on all of the presentations
that you've heard today, the last two focus areas
really are all encompassing of those recommendations.
Thinking about a dementia capable workforce
and data harmonization. Next slide.
In terms of my disclosures I'm a full-time employee
of the Alzheimer's Association. Next slide.
So looking at the first recommendation
or the first focus area, the dementia capable workforce
and specifically recommendation seven,
priority two. I'm promoting education,
training on multiple etiology cognitive impairment
and dementia to increase the dementia capable workforce.
Advanced researchers including from groups underrepresented
in science and foster includes their research practices.
There's a number of components within this recommendation,
but really to set the stage of the need
and we heard a little bit in the session yesterday,
the healthy equity session by Dr. Medina,
Doctors Medina and Dr. Gilsanz. The next slide.
In the world today the global population is aging.
By 2030 one in six individuals in the world
will be age 60 and over
and you can see some of the other statistics
that are listed here.
Alzheimer's Disease International estimates
that today there are more than 55 million individuals
living with dementia in the global world.
And the reason Facts and Figures
reports that there are more than six million Americans
that are living with Alzheimer today,
not to mention the full spectrum of dementia.
Next slide.
What we do look at when, in a number of different studies,
in a number of different reviews,
have looked at the dementia care specialists.
So those that were within the workforce
that are poised to provide the care and support
and really make that linkage of care
into research and back again.
And so whether you're looking at primary care physicians,
whether you're looking at geriatricians
or practicing geriatricians that,
and neurologists with dementia expertise,
or whether you're looking at licensed nurse practitioners
in the United States with either an expertise
in geriatric care or dementia.
There is a serious shortfall and this is something
that when we think about the workforce,
whether we're talking about care,
whether we're talking about research
and really the intersection of the two,
is certainly a gap in where we are as a community
and as a field. Next slide.
And in fact when you look at the number of states that,
across the country that are lacking dementia care experts,
or specialists, you can see that listed here
that the number of practicing geriatricians needs to increase
at least five times by 2050
in order to take care of the individuals
with Alzheimer's and other dementia.
And in fact 55, the recent Facts and Figures Report suggest
that 55% of primary care physicians
that are caring for individuals with Alzheimer's
and other dementia,
report that there are not enough dementia care specialists
in their community. Next slide.
So as the global prevalence of Alzheimer's
and other dementia increases, there is absolutely a need
for members of the paid dementia care workforce to increase.
And again, whether we're talking about those providing care,
or those engaging in the research,
and the intersection of the two, this is across the board.
Next slide.
So within the priority, or within the recommendation,
promoting education and training,
there's a number of different components.
And this includes developing, implementing
and evaluating training programs,
incentivizing mentorship and providing research opportunities
and promoting education of researchers
in recruiting and retaining research participants
from population that experience health disparities
in research studies.
So in looking at the first aspect of this in developing,
implementing and evaluating training programs.
This just gives you a snapshot of some of the training programs
and that are really poised
and are addressing some of these gaps.
But this is only a step in the right direction
and certainly as we think about the need to scale up,
there will be a significant need to increase and expand the scale
and the scope of these types of initiatives.
Next slide.
And it's really important to think about
as we look at the types of training's,
that's it not a one size fits all.
In fact one of the examples
that I shared the Global Brain Health Institute,
shared a quote from one of their mentors.
That I think the biggest strength
is that mentorship can be personalized.
Our fellows are all so different,
they're coming from unique backgrounds
and experience expertise and lived experiences.
So as we think about developing the types
of training and mentorship programs,
really taking this into account
that it's not a one size fits all.
And when we need to be thinking
about the different types of landscape
and the different types of programs and opportunities
that need to come together and support the growing workforce.
Next slide.
And a big component of this is the mentorship
and thinking about incentivizing mentors
and providing research opportunities
within mixed etiology,
dementia for the current and emerging generation.
We heard yesterday, I think one of the discussion items
was the need not only to support
and grow early career researchers,
but really think about supporting the network
of researchers throughout their entire career.
And what you see here is a listing
of some of the different ongoing initiatives,
thinking about mentorship,
thinking about supporting mentors
as well as building out mentorship programs.
So whether you're looking at the college age level,
such as the NIH funded StarU program.
GBHI which I mentioned, you're looking at the Interdisciplinary
Summer Research Institute.
So this is just a snapshot of organizations and groups
that are doing some of these programs and have initiated.
But again, as we think about the scope and scale
of what is needed to go forward,
we need to continue to see these programs grow.
As well as new programs that get to that
it's not a one size fits all. Next slide.
And so thinking about also the idea
of promoting education of researchers
and recruiting and retaining diverse research participants.
So throughout this entire recommendation
we really include activities that are promoting a conceptual
and theoretical perspective shaping recruitment.
And retention practices.
And building the necessary tools and again
you see some of those tools listed here.
But there are certainly others
that are continuing to be developed and expanded upon.
And continuing to build and expand these opportunities.
Next slide. Such as webinars, workshops,
and other types of training programs.
And again you see a snapshot of some of these here.
This is also an opportunity for funding organizations,
I know Michael J. Fox Foundation for Parkinson's Research
recently launched and initiated a large scale program
as one of those examples. Next slide.
So across this entire recommendation
you can see the full thing,
the full recommendation listed here.
There's been a number of work
since the original summit in 2014
and the continuing summits,
to grow and build out these educational
and training programs.
But there certainly is an opportunity to continue to scale
and think about, it's not a one size fits all
and how do we grow and expand the opportunities
within mixed etiology dementia? Next slide.
-Two minutes remaining.
-So thinking about the last recommendation and again
this all encompassing.
The idea to incentivize and conduct research
to improve pre and post-data collection harmonization
and sharing across multiple etiology cognitive impairment
and dementia studies. Next slides.
This includes developing and evaluating common data elements
and standardized consent language.
And again, you see a snapshot
of some of these ongoing initiatives.
Particularly focused on Mac and the uniform data set,
as well as the CDISK
and the tools that are growing and expanding.
But, next slide.
It's really important to think about
how we identify the barriers and facilitators
to incorporation of these common data elements and their usage.
So this could include opportunities to link
and share data overcoming some of these barriers.
Linking between some of the different data platforms,
including the common data elements
and some of the initiation studies
and I'll show a snapshot of some of the papers
that have started to do this in unique ways. Next slide.
And within this recommendation we also added in promotion
and, promoting the incorporation of common data elements
into data collection for observation
and intervention studies.
This is a tremendous opportunity for funding organizations,
whether it be NIH, or others.
As we look at promoting and really incentivizing
the incorporation of these common data elements.
The last component within this recommendation
is to develop and evaluate training opportunities
to promote methodological rigorous
in efficient data sharing. Next slide.
So across the board again this is a snapshot
of some of the different recent papers
that have been published, that really look at harmonizing
across different longitudinal studies of cognitive measures.
Looking at some of the considerations when we,
when we bring together different types of data.
What are some of the best practices in data sharing?
If you look at for instance the Cap Guidelines,
what are some of the initiatives and platforms such as Gain,
the Critical Path Institute,
and others that have data available
and that are working to cross-link
across these different types of platforms more broadly
and specifically providing an opportunity to use and to,
and to build upon prior work.
But there's also a really important component of providing
and developing and evaluating training opportunities
that promote the use of this data,
both the sharing of it, but also the use of it.
And again, that's a tremendous opportunity
for funding organizations.
So I think in summary, that brings us
to the multiple etiology dementia draft recommendations
and I think I'm passing back to Dr. Possin
to take us into the discussion. Kate.
-Thank you.
Thank you so much to all of our speakers today
and now we get to begin
what I hope will be a really engaging discussion.
We have our first question in chat from Dale Lestina,
so, Mr. Lestina, please ask your question.
-Thanks for your patience while I'm getting myself back
in the tune with the rest of you folks.
Just a minute. I got to get my picture.
Well, I'm tapping on it, but it doesn't come up.
Oh, there I am. I have a couple recommendations.
I applaud the presentations of this whole group.
And in your mind's eye when you look at the video
that we saw in the beginning,
and you saw the gentleman with his wife,
she's diagnosed,
there's two parties involved with this thing.
Now I would recommend
that if in the continuation of this presentation
is to show for the folks what is now about
to happen as time goes on with the woman or the doctor.
When the brain starts shutting down,
the ability to control bowels,
to control urination, to control the legs.
That end right there and what that does to the caregiver
trying to cope with this situation with a minimum,
if any, understanding what's going on.
And how to give the patient,
keeping that person comfortable
and as relaxed as possible
because there are periods of really hallucination
that they know what's going on. And how that must feel.
Because as you and I all know, there's no cure for this thing.
That's what's going to happen. And so I would say Dr. Ochen,
if you were involved with the continuation of that video
is to track it a little further
so that the folks who are doing the research
also can see what's transpiring,
where the rubber meets the road of the individuals
who are going through this.
It's extremely important to know all of the various things
that happen in the brain that causes the problem.
But then when you're dealing with the problem,
that's where I think we need to have more concentration.
And I would say that Kate, your presentation,
and your colleagues, you're the same thing,
I very much appreciate the recognition
of what is involved with this particular end of the process.
So that's my first recommendation
is to follow that now, those videos,
and make that as part of the presentation as well.
Now my second recommendation is are any of you familiar
with an organization called Insight?
I don't see any hands. Okay.
Insight is located, well, not too far from NIH.
It's in Northern Virginia.
It's on the west side of Fairfax City.
And they have -- their executive director is Anita Irvine.
I-R-W -- I-R-V-I-N.
And what they do is they treat the person
who has been identified with dementia,
and the caregiver together.
And they move them through a process where --
sessions, where the initial diagnosis of the individual
who has dementia is dealt with.
They're dealt together, and then separately.
One of the things that I was fortunate enough to learn about
Insight is that for being a caregiver,
they had groups where they --
support groups, where they would put me together
with maybe 15 other people
who were going through the same thing.
And we learned from one another.
"Oh, you dealt with it this way."
And, "Oh, that's -- I got to give that a try."
That kind of thing. And you have a support group
that after your spouse dies, continues on.
And I think that if you would look into that, if you want,
I can give you her contact information,
and explore what they're doing.
It's at least something to look at together.
And when you're looking at expanding things,
they don't want to expand too fast
because they want to keep doing a good job.
And they're just now beginning their second office
that they're about to expand to. So thank you for your attention
and listening to what I would recommend,
and having been a fellow who's gone through it
from a caregiver's point of view.
I appreciate your kind attention. Thank you.
-Thank you, Mr. Lastina.
Your comments are really important to our committee,
and we will definitely make note
of both of these recommendations.
And I personally will into the Insight program as well.
So thank you for those recommendations.
-Thank you.
-So let's see, next I believe is Penny Dacks.
-Thank you, Dr. Christine.
I actually want to defer to Ian first
because I think he had his name in first.
So -- -Okay. Let's do that.
Ian Kremer?
-Hi there, everyone.
Penny, thank you. Very kind of you.
Hi, everyone. I'm Ian Kremer.
I'm executive director of the LEAD Coalition.
We're a coalition of 100-member organization,
so about another 100 allied organizations
doing Alzheimer's and related dementias advocacy at the level.
I have a couple of recommendations.
I just want to preface it by saying
that I've had the pleasure of serving
on the steering committee for NIH's two Dementia Care
and Services Research Summits.
In those summits, we did not, for a variety of reasons
that I probably shouldn't get into today,
we didn't have bandwidth to get into detection and diagnosis
in the level of depth that we all would have liked to.
And that so that's still on our agenda
for subsequent care and services research summits,
but I'm delighted that you have taken time today
on your agenda to dive into this.
And I want to commend you all
for remarkably strong presentations
that get at the heart of much
of what makes detection and diagnosis so challenging.
Nobody can be comprehensive about that in any one session,
but you've all done a remarkable job.
So that's the context for what will follow,
which is maybe a recommendation or two.
I think there are opportunities for collaborative
funding agreements between NINDS, and NIA,
particularly BSR at NIA, around the psychological aspects
necessary to support effective detection and diagnosis.
And to walk you through that as briefly as I can,
I'll just make a few points.
I've advocated for about a decade work
for an informal framework,
a framework that I informally called TACA, T-A-C-A.
And that is that the detection and diagnosis
should be timely, accurate, compassionate, and actionable.
T-A-C-A.
I think you all today have addressed
remarkably well the need for detection and diagnosis
to be timely, accurate, and actionable.
And there have been some allusions to,
but maybe less direct reference to the compassionate
or empathetic part of this process.
But I think it's really key and pivotal
to the efficacy of detection and diagnosis,
and so it's an opportunity for research investments
by an NIA, NINDS,
and maybe sister institutes across the NIH,
and certainly private funders as well.
And I'll flesh it out in the way.
So you made reference, for instance,
to diagnose and adiós problem that is endemic in the field,
and we all know that that plays a role
in when it happens at the detection stage
where there is identification of possible cognitive impairment
and referral to a specialist for a formal diagnosis
that often families, individual patients,
do not proceed to that specialist.
And part of the reason for that is health system infrastructure,
but part is also the psychological impact
of a poorly-conveyed detection outcome.
So if the news is given in a way that is unhelpful,
unempathetic, lacking compassion,
it makes it that much harder psychologically for people,
for patients and their families to take the next step
and go to the specialist for confirmation or refutation
of what detection set might turn into a diagnosis
of cognitive impairment.
This is fundamentally devastating news for most people
that know anything about Alzheimer's disease
or any other form of dementia,
or they just know the umbrella term "dementia".
So if this is bad news is not given well,
it interferes with the likelihood
that someone will then pursue the specialist confirmation
or refutation of what detection indicated
might be at a forthcoming diagnosis.
So I think it has to be done better.
It can be done better.
We know clinicians to do it beautifully.
We have to figure out how they do it beautifully,
why they do it beautifully,
and how to replicate in scale that compassionate element
of an otherwise professional detection and diagnosis process.
And I would say the same at the diagnosis
process by the specialist.
All the good recommendations about making it actionable,
referral to community services, getting one's legal, medical,
and other affairs in order, etc.,
that all goes out the window if patients
and families emotionally shut down
because the news was not given in a way that was supportive.
So we can do it a little research figure out
how to do it well. And then two last points.
I apologize for taking so much time.
We have to be thoughtful
about the psychological burden on providers,
on healthcare providers themselves.
It is traumatizing to give bad news for a living.
It can be a little less traumatizing
if you have tools and resources
to give to patients and their families,
but there is still the potential,
and I think the likelihood for some accumulation
of psychological,
negative psychological impact on providers.
And to the point that Heather drew out,
I thought really beautifully in her presentation,
all the workforce challenges that we've got
are that much more vulnerable to becoming worse
if we don't look after the well-being,
the psychological well-being of the providers themselves.
So if we're going to get five-fold increase in the field,
but have people fall out of the field
because of the psychological burdens that we don't attend to,
we'll never get there. And then the last thing,
and again I won't belabor the point
because you all have correctly
and beautifully identified health equity
as a crosscutting core element of the work,
but all of the research about how to passionately,
psychologically,
appropriately convey and conduct detection and diagnosis,
that all has to be tailored in a culturally-appropriate way.
One-size-fits-all is going to be a recipe for failure
both for physicians and their ancillary staff,
as well as for patients, human beings,
and their ancillary care and support teams.
So I'll end there.
Thank you again for your indulgence of time.
-Thank you.
I took careful note of these really insightful
and important recommendations about compassionate disclosure,
culturally-appropriate disclosure,
and considering the burdens on providers.
I agree these need to be
highlighted more in our recommendations,
so we'll bring us back to our committee
and review those together. Thank you.
So moving onto Penny Dax.
-Thank you. Penny Dacks with the Association
for Frontotemporal Degeneration.
I just wanted to offer a couple quick comments.
I really applaud the incredible work your group has done.
And in the interest of time,
I am not suggesting necessarily response to my comments
but just something to reflect on
that we've heard so much throughout the whole meeting
as we should about the need for inclusivity
in how we design our research.
And at the same time, we heard about the need
for more widespread detection of cognitive impairment
to detect it earlier.
And there was a rich discussion of some of the benefits
and risks as it relates,
say, to the quality of life and psychological well-being.
I think there's a lot across those two topics
that I know I have a lot to learn about,
and I think the field needs to make sure we're very careful
about with how do people from different socioeconomic,
geographic, and racial, and ethnic backgrounds differ
in their perception of screening for dementia.
Not just in how they'll receive it,
but what do they actually want.
How are they going to respond to it?
And very importantly, how did their risks and benefits differ?
So for example, if cognitive impairment
gets detected in the clinic before families even suspected
that this is on the horizon,
it maybe blocks some long-term care insurance.
You know, has the insurance that we've already gotten to show
that certain groups are at higher risk of dementia,
has that already translated into higher insurance
premiums for individuals?
I think there's just so much we have to understand
as we focus on developing preventative therapies
to understand
how these things are translating into financial ramifications
because the insurance groups and all of their technologies
and all of their policies might be taking our research
and using it in ways that we may not be anticipating.
I think we need policy research to understand
how our advances are affecting the most vulnerable
in our communities at that financial and policy level,
and how it's affecting employment risk,
insurance risks.
And I just wanted to also emphasize
that some of the pragmatic intervention research
that Dr. Okonkwo really eloquently framed
I think it's also really foundational
and important to communicate
when we're asking these groups to participate in research
to help them understand that value is to them
and their communities is first and foremost in everybody's mind
as we ask them to participate in research.
And I thank you again for all of your time.
-Thank you. Well put, Penny.
I think these are important points that we can incorporate
perhaps into our recommendation too.
If there's no comment from the panel,
we'll just take note of this
and bring it back for discussion to our group.
I agree with these points. Sorry, Penny, one more thing?
-I'm so sorry. I just also forgot to say that
for those that are early detection of dementia
and early onset dementia,
that's when people are the most reliant
on their income and their employment.
And I think that's where we need to pay really careful attention.
-Thank you. So in the interest of time,
I think will move on to the next question,
which I believe was Dezheap?
Let's see. I don't have the full name here, but.
-Yeah. Yeah.
-Okay. Great.
Please introduce yourself and ask your --
or offer your point.
-Okay. So I'm Dezarell.
I'm a professor in the University of Minnesota.
So I have a question.
So I studied cell biology and the also animal model.
So all, like, [Indistinct] nuclei, beta, mechanic injury,
infection, all affect how.
So POW is a common downstream mechanism.
And my question is what proportion of dementia patients,
have a POW pathology? Can anyone answer that?
Maybe we should -- and I don't want to --
maybe we should increase the research effort on POW
because it started coming downstream pocket
for so many multiple newly-degenerative disease.
I will stop here. Thank you.
-Dazerell, thank you very much.
This is Dr. Lea Grinberg. I'm a neuropathologist at UCSF,
and it's a pleasure trying to answer this question
with the best of my knowledge.
Thank you very much for your question.
I think for a neuropathologist and many others in the field,
this is a quite important question that we face every day.
Actually one of the recommendations for this group
is to try to promote even better mapping studies
especially using human neuropathology
to understand these questions.
And this is based on the amazing results
that we got from a recent clinical pathological cohort
and how much we learned from this.
So a simple answer to your question
is that most of the patients that have dementia
and come to autopsy, they have multiple pathologies,
and pathologies that involve POW is one of them.
In neuropathological studies, we have the ability
to try to classify these neuropathies.
And in most cases, we see POW that is related
to Alzheimer's disease neuropathological changes.
When it comes from amyloid,
we call this Alzheimer's disease.
When it doesn't come with amyloid,
we might call this Scart.
Some call early Alzheimer disease stages.
We have POW that deposits in glial cells and astroglia,
what we call rTag that it's very common during aging.
And in populations over 80, we might find it in
at least 50% of the cases. And it's the same for a change
that call agraphiac brain disease
that the field doesn't know exactly what it does,
if it's a foe or if it's a friend.
Now to answer the question in another way,
when we look at patients
that the primary neuropathological diagnosis
is not related to POW, for instance, Lewy body disease,
or to TDP 43 protein properties, it's still just a minority.
We won't have any kind of POW deposits,
especially of the AD-type. So thank you for a question.
It's something that certainly this group thinks
we have to pursue, especially in diverse population
because most of our understanding
comes from Caucasians. Thank you very much.
-Thank you, Dr. Grinberg.
We have just a couple more minutes.
We're cutting into the break for those of you
who are still with us.
Let's try to get some brief comments
if possible from Constantino, and then Helen Metzger,
and then we'll take a break. So Constantino?
-Hi. Thank you. It was wonderful overview.
So you know, by listening to vascular dementia,
you know, lectures, the series of contributions yesterday,
it seems to me there is a lot overlap
between what was discussed today
and what was discussed yesterday.
Particularly at the level of the basic science
because vascular components
is going to be one of the most common. All right?
So I would urge you to kind of harmonize better the multiple,
the, you know, cause of dementia with the vascular component
because that's going to have an impact on the diagnoses
and impact on the prevention.
Because as far as I can tell, that may be the strongest,
you know, tool we have in terms of overall dementia.
But there finger studies, and you know,
the mind screen and so on.
And so that would be very important.
Also at the level of care delivery,
for example, cardiologists, you know,
may not know as much about, you know, about how to deal
with the vascular conditions in the brain
so there is a better need for harmonization
also at that level.
So that's just a plea for a perhaps more harmonization
with the vascular dementia aspects.
-Thank you for that important point.
If there's no comments from the panel,
we will absolutely review carefully
the VCID recommendations in ours
and look for areas of harmonization.
I really appreciate that comment.
So in closing, our last comment will be from Helen Metzger.
-Hi, Kate. I'd like to thank the committee
for what I've heard this morning.
I want to reinforce, Dale had a lot to contribute,
but Ian, what you and Penny brought to the floor
has said a lot to me.
I've been in this for 30 years with Lewy body dementia.
Kate knows me well.
I've been part of the care ecosystem
and part of the committee
that helped develop the Care Ecosystem.
I'm also involved in the PPV/PPI committee
at the Global Brain Health Institute,
and been working with them for over a year
on making certain that the voices of those people
affected with these diseases are at the table.
So I just want to remind the committee
because I didn't see it directly,
you know, touched upon this morning,
is that the voices, the care partners
and those living with disease have to be brought forth
and need to be integrated from the area
all the way from conceptive research to execution,
to outcomes and implementation.
So that is, that's all I want to say this morning,
but thank you for all of your amazing work.
I sincerely appreciate it.
And we'll bring it to those people
that I work with in the trenches.
-Thank you, Helen for your participation and your advocacy.
You are continuing to make a huge difference,
and we will take that point back
and find a way to weave it into our recommendations
so it is explicit.
Thank you, and thank you everyone on the panel,
and everyone for your participation
as we shift now to the break.
-We're ready to start the next session.
I'm pleased to introduce Dr. Kristen Dams-O'Connor
as the scientific chair of the Traumatic Brain Injury
in Alzheimer's Disease and Alzheimer's Disease-related
Dementias session. Kristen?
-Thank you. Next slide.
Okay. Let's get started. Next slide.
Our speakers have no disclosures.
Next slide. I am very grateful
and would like to thank the subcommittee members
who shared their expertise,
and the NIH program staff who supported our work.
It has been a privilege to work with this awesome group.
Next slide.
This session on post-TDI, AD/ADRD base was first included
in the ADR Base Summit in 2019 as an emerging topic.
And we're now very well-placed
in the multiple ideology of dementias session.
We've heard throughout the last day
and a half about the importance
of considering life course exposures.
TBI is one of many life course exposures
associated with dementia risk.
And one thing that is unique about TBI
is that it's an exposure with a time zero,
a clear point from which we can investigate the pathways
through which it may influence the proliferation
of distinct pathological processes.
This knowledge may open doors for understanding
the pathogenesis of dementias of multiple ideologies.
Next slide. I'll start was just quick definitions.
A traumatic brain injury is a blow or jolt to the head
or neck that result in a loss or alteration of consciousness.
The pyramid on the right illustrates the CDC's estimate
that almost three million Americans need care
in the emergency department for TBI each year.
Next slide.
TBI can result in a range of symptoms.
In general, we expect that most people
with an uncomplicated mild TBI,
which is sometimes called a concussion,
to recover completely within days or weeks.
Next slide.
However, those with more severe injuries
may experience more severe consequences,
including lifelong disability or death.
The estimates you see here are based on data
collected through the NIDILRR-funded
TBI Model Systems National Data.
And as you can see about one in five have died
within five years of injury.
Thirty % experienced deterioration and function
between one and five years, and the remaining survivors
either remain functionally-stable or improved.
Next slide.
But how does this observed decline relate to dementia?
For years, we have been taught that
TBI is one of the strongest environmental risk factors
for Alzheimer's disease.
But as this area of study has matured,
we have learned that the reality is far more complex.
Results vary across studies
that differ tremendously in their methodology,
their sampling strategies
and their definitions of TBI and dementia.
In general though, we do see that more severe injury
tends to be associated with greater dementia risk,
and TBI is a well-recognized
and potentially modifiable risk factor for dementia.
Next slide.
Although a global pandemic began just months
after releasing our 2019 research recommendations,
substantial progress has been made.
Next slide.
First, we have -- oh, next slide.
First we have an updated consensus definition
for the post-mortem diagnosis CTE neuropathology.
CTE is believed to be related to repetitive head trauma exposure
and revised criteria provide a more precise definition
of the pathognomonic lesion.
We also now have a preliminary consensus definition
for research
diagnosis of traumatic encephalopathy syndrome,
which is the proposed clinical correlate of CTE neuropathology.
This represents an important first step
towards in vivo diagnosis.
Our colleagues at BU have begun the hard work of validating
in vivo criteria for TES,
and these are the types of studies
that will pave the way for further refinements.
Major questions remain though about the minimum thresholds
for CTE diagnosis, the role of the isolated
traumatic brain injury in CTE and NTES,
and the relationships between these pathologies
and clinical symptoms with other ADRDs.
Next slide.
-Two minutes remaining.
-One major initiative that has resulted since 2019
is that Connect TBI Study led by Doug Smith and Willie Stewart,
and 13 institutions also represented.
This project will evaluate brain tissue
from cases with traumatic brain injury
and creative brain repository for tissue sharing.
Next. We also have a large initiative
led Ann McKee at Boston University
that will leverage existing brain banks to --
that have very well-characterized
and fully-harmonized clinical and head trauma
exposure histories to characterized pathologies
related to repetitive traumatic brain injury
and head trauma, and their clinical phenotypes.
Next slide.
We've also been able to expand the late effects of TBI Project,
which is a perspective brain donor program
with autopsy endpoints,
and this will allow us to expand to our community recruitment
and longitudinal follow-up.
Next slide. Okay.
So our subcommittee's first recommendation reflects the fact
that this is a relatively new area of investigation.
And we really feel that we can learn from our colleagues
who have been studying dementia for decades.
We identify really important opportunities
for interdisciplinary crosstalk and expanding collaboration
across traditionally siloed areas of study.
Next slide.
For starters, we hope to convene a working group of stakeholders
in the TBI and multiple ideology dementia communities
to evaluate the extent to which current knowledge in ADRD
can the applied to the study of dementia after TBI,
and also how our understanding of the acute
and chronic pathophysiology of TBI
can contribute to our understanding of ADRDs.
Again, since TBI is a risk factor with a time zero,
we believe that further study
will benefit the entire ADRD community.
I also say, and this is a figure you've seen before,
is when we recalculate the population
attributable factor of dementia risk using population
representative data on TBI prevalence,
we see that the number of dementia cases
that may be at least partially attributable to TBI
is actually perhaps much greater.
Next slide.
Another component of our first recommendation
is to harmonize existing data
across longitudinal TBI and ADRD studies.
Here we illustrate one example of an effort along these lines
to pull data from five studies of cognitive aging.
So we have newly collected very detailed characterization
of lifetime TBI exposure,
which will allow us to examine late life implications of TBI.
And we're using IRT-based methods to co-calibrate data
that were gathered from different measures
of the same constructs, such as cognition and mood.
Efforts like this can allow us
to conduct more granular investigation
into the intersecting factors that influence risk for ADRD
well beyond what would be possible in a single study.
Next slide. Ideally, future efforts
will maximize measurement harmonization from the start
by prospectively collecting multimodal common data elements
to facilitate comparisons and data sharing.
The ENIGMA Brain Injury Initiative
is one example of a global working group with these goals.
Next slide.
Post-mortem TBI common data elements,
which is actually another area of progress since 2019,
provide a road map for prospective collection
of harmonized data.
Our hope is that existing brain banks
will use these common neuropathological methods
and post-mortem family interview methods
to characterize post-TBI ADRD and facilitate data
sharing and cross study comparisons.
Next slide.
The Olympic Sensi studies provide another great roadmap
for neural imaging, harmonization in particular.
So they aligned with ADME from the start
by maximizing overlap of both clinical and imaging metrics.
For example, they used a unique phantom
that has an isotropic diffusion capabilities
with hollow fibers the size of axons
to mimic the diffusion properties
of diffused axonal injury
and other tissue properties of relevance
to both traumatic brain injury and neurodegenerative disease.
Next slide.
Our committee believes that neuroinformatics
will play an important role as well.
So our first recommendation will require modern cloud-based
informatics and analytics harmonization platforms
for QA, post-processing,
and harmonizing data across sites,
and scanners, and software.
Historically, we have had to sometimes sacrifice precision
for generalizability successfully harmonizing
only relatively crude metrics
across major scanner vendors and software platforms.
But modern informatics platforms
can automate many aspects of this,
which again is necessary for multi-site studies. Next.
Recent examples of an international collaboration
that required harmonization across continents
is seen on the track TBI and center TBI studies.
And again, this may be a great future opportunity.
Next slide.
The final component of recommendation one
is the need to encourage collaboration
between clinical researchers, biostatisticians,
epidemiologists,
and data scientists to incorporate
multi-dimensional, multimodal data,
and employ more sophisticated causal inference methodologies,
and work with implementation scientists
to maximize the clinical translatability of this work.
This is inherently interdisciplinary,
and collaboration is required to move the science forward.
Next slide.
Our second recommendation pertains to clinical phenotyping
across exposure histories
to pave the way for in vivo diagnostics.
Next slide.
First, we need to establish and validate
a quantitative index of lifetime head trauma exposure.
One thing we have learned is that administrative data
only identifies those who have sought and received care.
So self-report is considered
the gold standard for lifetime TBI exposure.
We consistently find that structured questionnaires
that use contextual cueing for lifetime injury reporting,
such as the Ohio State University
TBI identification method,
or the brain injury screening questionnaire,
are really required
for comprehensive exposure ascertainment.
So this notion that all important TBIs
are in the medical record is simply untrue.
Our colleagues have actually found
that those who never sought care
have worse long-term outcomes after injury.
So this not seeking care may actually be an important proxy
for other factors that matter a lot in long-term outcomes.
The last thing I'll say about this
is in the upper righthand corner there,
you see that single TBI rarely exists in isolation
so you see their data from a moderate severe TBI study
that shows that about half of the sample
with a single TBI also have repetitive head injury
in the context of sports, or military service,
or intimate partner violence.
Many also had multiple isolated TBIs.
So the question of how to quantify lifetime exposure
in a way that reflects clinical reality
will be foundational to this area of study.
Next slide.
Similarly crucial is the need to establish
and validate a provisional definition,
a clinical definition of post-TBI dementias
that distinguishes chronic effects of TBI
from a progressive neurodegenerative disease.
So because the term "dementia" is broad
and has multiple clinical definitions,
it has sometimes been used to characterize
the acute effects of TBI
or the stable chronic effects of TBI.
And so a definition such as what you see here,
wherein post-TBI ADRD is defined as post-recovery decline
really requires further study and validation. Next.
Out committee felt that longitudinal studies
are especially essential to recommendation two,
which is to characterize the clinical phenotype
and the phenotypic heterogeneity and clinical course,
the protective factors
and the effect modifiers of post-TBI ADRDs.
It may be especially informative
to study people prospectively from the time of injury
to understand the primary pathology,
the secondary injury processes,
and the long-term outcomes as they evolve over time.
The TBI model systems,
for example the track TBI Study and Evolve Study
are three examples of these prospective studies
with complementary strengths.
So the Evolve Study, for example,
led by Christine McDonald follows active duty
military service members from the battlefield
and is now approaching a 10-year follow-up.
And this has uncovered a pattern suggesting evolution
as opposed to a resolution of symptoms over time.
The TBI model system is the largest prospective
TBI outcome study in the world.
But with telephone data collection,
it doesn't currently include biological markers.
So we have a tremendous opportunity
to learn from these types of studies.
Next slide. We currently do not know
how post-TBI ADRD relates to other ADRDs.
The studies illustrated here suggests that older adults
with TBI have more motor impairment
and more pronounced neurobehavioral symptoms
relative to those
with Alzheimer's disease in particular.
And on the right, you see that compared to older adults
without TBI, their cognitive profiles
suggest more difficulty with executive
functioning and processing speed,
which are hallmark characteristics of TBI,
but not characteristic of AD-type dementia.
Next slide.
Phenotyping a heterogenous multi-ideology disease
process is no small task,
and efforts to-date were recently summarized
in this brain trauma blueprint paper
that was just published last year.
These studies do suggest
that clinically-distinguishable subtypes exist.
And on the right, we see evidence of a TBI phenotype
that overlaps with clinical correlates of AD and FTD
in a sample of post-9/11 veterans
with early onset dementia. Next slide.
Central to recommendation two is the need to develop
and validate post-TBI ADRD biomarkers
to non-invasively identify progressive pathologies
and to monitor clinical disease progression over time.
The radiology biomarkers at the top
are used for more acute TBI studies
that can inform studies of the evolution of TBI
in the transition to recovery or to decline.
Like other dementias, TBI is not a single disease process
with the unified path of physiological mechanisms.
So characterizing the acute and chronic changes
ideally in longitudinal studies will be highly informative.
Although substantial progress has been made in acute
diagnostic and prognostic markers for TBI,
there has been relatively little investigation
into biomarkers of posttraumatic neurodegeneration.
The top candidates though are those
that can detect traumatic and neuroinflammatory injury,
and that can also detect the onset
and progression of neurodegenerative diseases.
As you can see in the figure on the right,
our colleague studying Alzheimer's disease
has found excellent correspondence
between blood CSF and PET markers.
And this appears to provide information
on disease progression of pathologies
that are also known to be implicated in post-TBI ADRD.
So these candidate markers really require further study
in the chronic stages following TBI.
Finally, the need to recruit diverse samples
warrants particular mention here.
This includes men and women with repetitive,
or isolated, or very diverse injury exposure histories.
It includes underrepresented minorities.
It includes, again, a range of head trauma exposures,
mechanisms, and chronicity.
And it includes -- it requires clinic
and community-based recruitment.
Our colleagues who have been studying dementia for decades
have demonstrated that those who are recruited
in the community differ in important ways from those
who are recruited from clinic-based settings.
And we expect those differences to, if anything,
to be more pronounced in the study of post-TBI
ADRD given the high rates of TBI in homeless shelters,
substance use disorder treatment settings, prisons,
and among multiply marginalized populations.
So we need to ensure that studies of post-TBI
AD and ADRD include representative samples
of individuals living with TBI. With that, next slide,
I will pass the microphone to Dr. Dirk Keene
from the University of Washington
who will discuss recommendation three.
-Thanks, Kristin. Next slide. Great. Next slide.
So these are the --
so recommendation three is really a bridge
from the first two recommendations
to the fourth recommendation.
This is the recommendation listed out
into the sub recommendations. But if you go to the next slide,
I've tried to summarize to capture the, you know,
the recommendations by its essence.
And really what recommendation three is about
is supporting and building research infrastructure
to make sure that we take advantage of the,
of what's come before us especially with AD
and other ADRD research to understand
and bridge what we know about AD and ADRD for TBI-related ADRD.
And so we need to study representative cohort.
That can't be emphasized enough.
At every step, we need to be studying
the breadth of TBI exposure from ethnic and socioeconomic,
and other backgrounds.
We need to studying the representative samples.
We need to build and enhance our biorepositories,
that's from a brain biorepositories,
biofluid biorepositories,
and then develop standardized approaches.
So in the next few slides, I'll go over each of these
in a little bit more depth. Next.
So the Alzheimer's Disease Research Centers have --
it's a really robust multi-center network
that's been -- that was established by NIA
over 30 years ago.
On the right, you can see that states
that have one or more centers.
The light blue ones are the exploratory centers.
This program continues to build.
And each center has really robust infrastructure
developed along the lines of cores
that have led the way in helping us understand
how to develop prospective studies
and these multimodal approaches to study disease
from even pre-symptomatic levels
all the way through to brain donation
and neuropathological studies.
And so I think TBI ADRD can really learn
from what's been done in Alzheimer's disease
and Parkinson's disease, these established networks.
And I think the Alzheimer Center Network
is a prime example of how AD can leverage
that infrastructure and that expertise.
And then also there's other resources
that have been built up around other focuses,
other areas of study.
The National Alzheimer's Coordinating Center
is a centralized data repository for the Alzheimer's Centers
and Alzheimer's Disease Research Participant Data.
The National Centralized Repository for AD,
and Related Dementias NCRAD
is really leading the way along with other centers
on biospecimen storage sharing and characterization.
And then there's a multitude of other
really well-established studies in ADRD
that I think TBI research can leverage and build upon
so that we're not reinventing the wheel,
so that we're taking advantage of the incredible investment
that's been made and it's being made for TBI-related ADRD.
Next slide. It's really critical to study representative cohorts,
and to study those cohorts prospectively.
And so I've listed some community-based cohorts there.
There's many others.
But the idea is that you need to start,
you need to start at the very beginning with cohorts
that you can characterize clinically, with biomarkers,
all the way through as the --
as TBI-related ADRD and other diseases advance.
And so these community-based cohorts are really critical
in representing the diversity of traumatic brain injury exposure,
the diversity of the population that we're studying
so that we have inclusion and can understand differences
and similarities across the population.
And then what I think is really important
is to take TBI-related expertise
and build that into existing and prospective ADRD studies.
And the same goes for TBI studies
to really leverage what we know
and what we've learned through ADRD,
through our Alzheimer's center and other centers
to build that into our TBI-related studies
so that we're talking the same language
across these different cohorts. Next.
Kristen mentioned Delayed Effects
of Traumatic Brain Injury study.
It's a prime example, I think, of a multimodal approach
from the time a person enrolls all the way through
to the time a person dies, if that's the case.
And collecting as much data along the way
so that we can relate the different biofluid,
and cognitive, and other biomarkers to exposure history.
And also moving forward to neuroimaging
and also neuropathology markers so that we can link the data
from one aspect of a study participant all the way back.
So that we can understand during life what underlies
the kinds of cognitive deficits or behavioral abnormalities
that are happening in people that have suffered a TBI.
And how does that relate to neurodegenerative disease. Next.
We need to build and enhance brain bio repositories.
Again, this is the Connect TBI group,
which is, I think, one very good example,
along with the BU group,
of how to leverage existing brain bio repositories
with a focus on TBI-related neurodegeneration.
Bringing resources together
that previously hadn't been brought together
to try to understand what the relationship
between TBI exposure and neurodegeneration is.
There's a number of different other --
there's a lot of infrastructure out there
that we can use to build this together.
And ultimately use that experience to --
into prospective cohort studies where we can tailor
our characterization of folks all the way through.
Using the TBI and ADRD-related assessments
from the time a person enters a study,
all the way through their different neuroimaging
and other biomarker studies, through the end of the study.
Next.
And so we need to enhance brain bio repositories.
I use the Brain Initiative here as an example.
The Brain Initiative is really leading the way.
It's a major effort from NIH to understand the structure,
and connectivity, and function of the normal brain.
They have pioneered new methodologies
to study human brain tissue
and those efforts I think we need to work from
and learn from those efforts when we study ADRD,
and specifically TBI-related ADRD.
So that we're maximizing the investment of the NIH
and other stakeholders in this research.
And doing everything we can for every person that donates
their brain to learn as much as we can from their brain.
And I think this is one example.
Many of the different brain banks
are pioneering new methodologies.
And to the extent that we can learn as much as possible
from each one of these samples by studying cohort people
who have been studied all the way during life
with well-known exposures.
And then maximizing the technological approaches
that we have to understanding the different pathways
to injury and dementia is really important.
Next slide. And then to establish
and implement standards for neuropathology.
Kristen mentioned the CDBs.
It's really exciting the way this has developed.
So on the left, in 2012, the National Institute on Aging
and its Alzheimer's Association guidelines
for the pathological assessment of AD were published.
And those really sent the standard
for how neuropathologists talk to each other about what the --
what each brain that they're studying shows.
The NINDS and NIBIB consensus meetings,
both the first and second for CTE,
really built on this in the fact
that we took those recommendations
for AD and ADRD neuropath.
And built on those for the CTE consensus recommendation
so that we can refer back to brain biorepositories
even 20, 30 years ago
with similar sampling processes and assessments.
To sort of leverage that so that we're understanding TBI
in the context of neurodegenerative disease.
And then, finally, thanks to a great group of people,
the accommodated elements for neuropathology
that Kristen mentions are essentially done
and ready for people to start using.
So we really need, as a community,
to be hopefully implementing and using these recommendations
so that, again, we can talk to each other.
So that the Alzheimer's Disease researcher
can talk to the TBI researcher
and we're all using the same language.
Importantly, in the CDEs, I just want to highlight,
we intentionally built in the possibility, too,
for flexibility, so that there's a common baseline.
But it opens up the --
it encourages different biorepositories to study areas
that they have expertise in,
areas that may contribute down the road
to new approaches to this.
Which I think is really exciting for these CDEs.
Next slide.
-Two minutes remaining.
-Got you. Whoops.
So the last thing is to leverage and build infrastructure
to promote tissue and data sharing.
So this slide is just highlighting what we can do
once a person has donated their brain.
We can perform ex vivo neuroimaging,
extensive sampling.
We have the ability in many groups
are imaging and scanning microscope slides
and there are multiple different repositories
available to share this information.
We need to really promote the ability for each of us
to see what each other is doing
so that we can learn from each other
and maximize the investment of the donors
and the stakeholders. Next slide.
So this is just highlighting the really critical relevance
of human brain donation and human research
in helping us to eventually establish mechanism,
and that's a mouse brain on the bottom.
And so what we can learn from human brain
is what's relevant to the disease or the impairment
and we can generate hypotheses.
But the only way we can go test those hypotheses,
and establish mechanism, and ultimately develop treatments
to test in back in people is with these experimental systems.
Next slide.
And so human neuropathology and these --
and from really well-studied and representative diverse
cohorts is just essential.
And neuropathology can provide a bridge
from those outstanding representative cohort --
prospective cohort studies.
Ultimately to where we can understand mechanisms
and develop treatments.
And so with that, I'm going to hand it off
to Dr. Vicky Johnson from the University of Pennsylvania.
-Thanks, Dirk. Hi, everyone,
and thank you, also, to the organizers.
It's a pleasure to be here and participate in this summit.
Next slide, please.
So first, I don't have any disclosures,
and I'm going to talk about recommendation for Priority 4.
Which is to promote the basic translational research
to elucidate the mechanistic pathways, development,
and progression of post-TBI AD/ADRD neuropathologies.
And their associations with clinical symptoms.
Next slide, please. So I'm just going to start
with a little bit of background about TBI.
And some of the important considerations
that are going to be necessary in understanding
how TBI might ultimately lead to neurodegeneration.
So TBI is caused by some mechanical event
resulting in trauma to the brain.
We often talk about it like it's one disease, one disorder,
but in reality, the acute pathologies of TBI
are really very diverse and complex.
And you can see here some examples of different CT scans,
all with displaying very different types of injuries.
But importantly, all falling into that category
of severe TBI.
There's also a spectrum of severity.
We've heard about repetitive mild TBI
as a risk factor for later neurodegeneration.
And the pathophysiology of or what's happening in the brain
in mild TBI even acutely
and even following very low-level repetitive exposures
is something that's far less-well understood.
So in summation, TBI is really heterogeneous
with a wide spectrum in both the nature and severity of injury.
Next slide, please. So what we do know,
at least in the more severe forms of injury,
is that there are evolving pathologies
over a temporal course.
There are the acute primary pathologies
directly related to the mechanical injury.
For example, this might be direct perturbation
of the vasculature
resulting in hemorrhage or direct injury to neurons
and axons causing things like traumatic axonal injury.
And what we know is that this can lead
to really very complex and diverse secondary pathologies.
And these some of which are listed here of being studied
over many years both clinically and experimentally.
And what we've come to appreciate
is that some of these secondary processes
can occur over many weeks
and really quite protracted periods of time post-injury.
And then, of course, what we're interested in here today
is that some of these individuals, certainly not all,
who have chronic pathologies, including those which are --
encompass AD and ADRD-associated pathologies.
And I think important to remember
over that same time frame,
there may very well be processes of recovery or reorganization
that are also occurring in the brain in response to injury.
And critically, and as Kristen mentioned,
is perhaps what's a little bit different
from other neurodegenerative disease,
at least in the case of more severe injuries.
Is that we have a clear start point or time zero essentially
when we know that this specific event has occurred
and I put an individual
on a pathway towards delayed neurodegeneration.
What we don't really have a great understanding of
is if and how this relates to the nature, extent,
and evolution of these earlier pathologies.
Next slide. So with respect to the neuropathology,
there's been a lot of focus on type pathologies,
but I think it's important to note
that through various different cohorts, K series, descriptions.
And some individuals fall into the eye
of various other pathologies have been described.
Including amyloid-beta, TDP 43 proteinopathies,
vascular pathologies, chronic inflammatory processes,
axonal degeneration, axonal and atrophic processes in the brain.
And a big question around this is what we refer
to as the clinical pathological correlation.
So what aspects of these pathologies
are important contributors
to the clinical symptoms and clinical progression
that Kristen has so nicely described?
And what do these pathologies potentially interact
in some way?
And another important question is whether
and in what way these various pathologies
relate to the number, severity, and types of TBI.
And perhaps other factors such as age at injury.
So there has been some progress in this regard
and examining these various questions.
And as part of our recommendation as shown here,
the committee felt it's important to sort of
further characterize and advance our understanding
of how the various aspects of these pathologies.
And their potential interactions contribute
to the clinical manifestations after a TBI.
And importantly, also how the TBI exposure history,
which has its own complexities,
influences the nature and extent of those pathologies.
Next slide.
So as I mentioned, there's been a lot of focus on tau.
This was something that was first really described
in postmortem examinations of former boxers many years ago.
As you can see an example of that
from one of these early papers on the left.
And then was later described in various cohorts since,
including other participants of contact sports,
more severe forms of injury earlier referred to
as dementia pugilistica specific to boxers.
And later, the term chronic traumatic encephalopathy,
or CTE [Indistinct].
So various aspects of these pathologies,
and you can see here the paper of the recent consensus meeting.
Various aspects of these pathologies have been described
as being potentially distinct
in their morphologies and distributions.
And, therefore, considered just possibly useful
diagnostically in distinguishing TBI-related neurodegeneration
from that of other neurodegenerative disease.
And this was the papers that outlining
this pathognomonic CTE lesion that came out of that
NINDS-funded consensus efforts to define CTE
and these type pathologies following TBI.
And describes the depths of critical sulci region.
So and next slide, please.
So there really has been limited characterizer
over the broader spectrum of post-TBI pathologies
that have been described
including some of those described
as being potentially specific to trauma.
And in particular how they may be similar
or different to other pathologies observed
and other neurodegenerative disease
and perhaps better established neurodegenerative disease.
And there's been some emerging reports
that have started using advanced technologies,
proteomic RNA-sequencing technologies,
to begin to further characterize this.
There's also been studies that, including by our group,
to try and look at the differences using
immunohistochemistry directly by comparing to other disease.
And then some also some interesting work
you can see on this paper on the right here
from the group in Cambridge
looking at small series of cases.
And showing potentially unique aspects
in the structure of tau in CTE as identified using cryo-EM.
But certainly direct further comparisons
with other types of neurodegenerative disease.
And these will offer potentially important information
relevant to both diagnoses,
as well as offering potential mechanistic insights.
So as such, the committee has included recommendations
to apply both traditional and advanced approaches
to really deeply characterize these post-TBI neuropathologies.
And comparative analysis with other NEDs
and neurodegenerative disorders. Next slide.
So with this diversity of and complexity
of the clinical and neuropathological, it comes --
it starts to present obvious challenges
when we start to think about how to model
these processes experimentally. Now there is an experiment
established in literature on this.
Where various groups have worked to see if they can introduce --
induce these neurodegenerative pathologies
and experimental TBI models,
mostly with a focus on tau and amyloid-beta.
And while we don't have time to go into
that whole literature in detail, to sort of summarize it
and saying that it really encompasses various models,
established models, the vast majority in rodents,
both with and without inoculated genetic backgrounds
and considerable diversity in the sort of mechanics,
and severity, and approach to injury applied.
There's also been various outcome measures
that have been examined, some using immunohistochemistry
to look at pathology, for example.
Others looking at biochemical outcome,
biochemistry as an outcome, looking at changes
and quantification of cross-correlated tau.
So perhaps not surprisingly, there's been a large range
in the results from those where you can see
and some examples of this work here.
Those where there was observed changes in tau amyloid
to those where trauma did not result
in the presence of pathology.
And even some studies where a regression of pathology
was seen in models where there was predisposition.
So next slide, please.
So the committee agreed that really further development
of consistent and reproducible models
that are clinically relevant. Is going to be really important
advancing our understanding of how and why TBI might be able
to contribute to neurodegenerative processes.
With the recognition that various aspects of this
are challenging.
Models that accurately reproduce real-world biomechanics
of injury is going to be important
and these are obviously extremely diverse and complex.
Various aspects of preclinical models
add to the challenges
of recapitulating those biomechanics,
things like anatomic differences,
brain size, weight matter volumes.
And of course, we know
that aspects of gyrencephalic structure,
these depth of cell site pathologies
seem to be important.
So gyrencephalic structure is something of consideration
when thinking about our models.
Of course, we're talking about pathologies
that regress over the order of years,
lifespan may be important.
And finally, I'll just sort of mention very briefly
in vitro models which have their own complexity
when it comes to biomechanics. But may play an important role
in addressing specific mechanistic questions.
Next slide.
So we're dealing with these complex
and heterogeneous pathologies over a long temporal course.
And our group felt with the data, the human data,
which is still very much being characterized.
And we've heard of the efforts to do that,
including data such as biomechanics data,
neuropathology data, clinical phenotyping data.
Are going to be really critical for further
developing our quantic phase models of TBI
and to inform us really what is important
to be modeling and to be relevant.
And then, it's likely that a range of models
will be helpful in addressing specific questions.
And of course, the infrastructure building
that's being described and Recommendations 1, 2, and 3
are going to be critical for facilitating those mechanistic
and translational priorities.
So here, the recommendation was to really promote collaboration,
as Dirk sort of mentioned,
as well, between clinical and translational researchers
to accelerate the development
of these clinically-relevant TBI models.
And my last slide here, if we move forward one,
is just to mention this idea of resilience.
We know that many people with a history of trauma TBI,
including even very severe injuries
or highly-repetitive exposures, for example, in boxers.
Don't develop CTE or trauma- related neurodegeneration
or progressive decline.
And understanding why this might be might
be helpful and informative.
And we can think about that in several ways.
There may be people who just by exposure
are resistant to developing the pathology,
and thus, the clinical decline that comes with it.
And there are possible genetic environmental factors
that then contribute to them.
And secondly, there may be individuals
that demonstrate resilience to the clinical symptoms
despite having TDI-related neurodegenerative pathologies.
And this brings the idea of reserve
or pre-morbid factors that might influence
the clinical trajectory in some people.
So we really know very little about this and TBI,
and it's certainly challenging to examine,
and particularly, as Kristen noted,
the -- in the latter scenario, when looking at clinical data.
We don't have enough complex data clinical impairments
and possibly in recovery related to injury
to disentangle from any progressive changes.
So longitudinal studies will obviously be important.
So nonetheless, understanding these processes
may be important in contributing
to our understanding of mechanisms of disease.
So as shown here, the committee included
the identification of intrinsic and environmental factors
and that confer resilience as our final recommendation.
So thank you, and I will pass back over to Kristen
for our question and answer session.
-Great, thank you to Vicky and to Dirk for those great talks.
If you could go to the next slide.
Thank you. So our primary goal today
really is to seek feedback on these recommendations
to really ensure that they're consistent
with and reflective of the stakeholder priorities.
That many of our attendees today represent.
So let's start.
I see a question from Mr. Ellenbogen.
-Thank you so much.
I was unable to speak at the earlier session
and just wanted to add one comment
before I go into my TBI comment.
I will have to say that detection
is a very complicated matter.
And as a person living with this disease,
I may not want someone to know I have some kind of dementia.
The second thing, add some type of dementia
on your medical record,
I instantly have my rights taken away from me.
We need to change the laws around that
before we expect our doctors and the people to come forward.
For example, I would lose driving capabilities,
depending on what state I'm in,
lose my job or get fired instantly from it,
or even lose insurances that I would be entitled to.
So there are things that need to be addressed
and it's very complicated.
It's just not as easy as just being able
to diagnose the disease. But as far as my TBI comment,
we have learned so much about ways to possibly delay dementia
and we now encourage that in many public ways.
As an expert who's living with this horrible disease,
I would not wish this on my worst enemy.
What I cannot understand, though,
is that we have learned so much about TBI,
yet we don't do much to educate our children
to no longer play games such as football.
We clearly know that this will increase their risk
to brain damage.
Why don't we make this very public
so at least these folks have a chance?
Thank you.
-Thank you, Mr. Ellenbogen.
You, again, raise such an important point.
So what I'm hearing is that we need to consider
in our recommendations, and our colleagues,
and across the multiple etiology dementia subgroups.
The potential consequences of detection and diagnosis
to those living with dementia, with traumatic brain injury.
And I'm also hearing a need to for us
to consider the post-TBI ADRD group
expanding our efforts to educate the public
about the potential sequelae of traumatic brain injury.
So that people can make evidence-based decisions
about their individual risk tolerance.
Very well-taken point. Thank you for that.
Let's see, Dr. Schneider, I see a question.
-Hi, Kristen.
Thank you for the -- those great presentations.
I had a question about Recommendation Number 2,
which is the clinical heterogeneity
and the need for more clinical characterization.
And I'm just wondering whether or not the biomarker component
should be brought to the top of that list.
Because as we know in dementia,
you know, in all these dementias,
there's so much heterogeneity in what we see.
And, you know, do we really expect
that there's going to be a single clinical feature
that's going to tell us something different?
I mean, I think we should certainly be looking,
but wouldn't it, like the other diseases,
be more important to have a biomarker,
something that tells us
that there's actually been injury to the brain.
And so just your thoughts on that second recommendation
and the elevation perhaps of biomarkers.
-That's a great thought.
Dr. Henrik Zetterberg, do you have thoughts on that,
the potential elevation of biological markers
within Recommendation 2?
-Yes, I think definitely it can be included
and we should also separate them,
the acute phase of TBI with the more chronic phase.
And perhaps also address what happens in repetitive TBIs
and how one with biomarks could follow
sort of the amount of injury to the brain tissue
using the existing biomarkers.
But we would also need to develop new biomarkers
because the tau that is seen in chronic TBI,
for example, is not possible to detect the monitor
using the existing fluid biomarkers for tau pathogen.
And the imaging biomarker data
will also need to become different.
So it's almost like we perhaps should try to also emphasize
that we need to also develop and validate biomarkers
for TBI-related brain tissue changes.
So basically what I'm trying to say
is that we can't just lean back and use existing biomarkers,
also, because they might not represent
the TBI-related pathogens completely.
But acute accelerator injury
and [Indistinct] calculation works.
There the biomarkers works --
work across the different types of TBI
and also we can make use of them developed
for Neurodegenerative dementias.
-Thank you, Henrik.
Pratik, I wander if you have any comments about this, too,
with respect to imaging biomarkers.
So part of Julie's point is that we do not expect
to see one isolated biomarker but perhaps panels of biomarkers
that we required for earliest detection.
-Yeah, no. I absolutely agree, you know,
and I think we need to emphasize capturing
as much data as possible from early after the injury.
Where we can characterize, you know,
the particular pathophysiological mechanism
operating in that particular patient.
So...
...all of the acute TBI studies are generally set up
as precision medicine studies for that reason.
And once we've captured that data through imaging biomarkers,
blood specimen biomarkers,
then phenotyping of the clinical characteristics,
and cognitive function,
and behavioral function at that acute phase.
Then we can follow it longitudinally
and see how it evolves like the slide
you showed from the different studies
showing how different patients may have different evolution.
And there's certain latent classes
that can be discovered from that data.
So that's a main priority
of a lot of the acute TBI studies right now
with the qualifications for multiple years.
And I think that imaging is interesting, too,
because not only can you get a biomarker
of the injury pathophysiology
and its progression or degeneration
during the recovery process.
But there -- you can also get biomarkers
that may be related to innate resilience properties
that may account for some of the inter-individual variability
of the recovery process.
You know, despite, you know, the injury.
So some patients do well because they have innate resilience
despite a greater severity of injury
and others do poorly even though the injury may be considered
mild by standard clinical criteria.
We see this all the time and we don't understand
right now the factors that cause that variability
and our inability to predict,
you know, the longer-term outcomes.
So it's going to be important to characterize in the acute phase
both the injury pathophysiology and the resilience factors.
And I think that's a common theme of many of the ADRDs,
as well, where resilience is taking a larger role
in evaluating the disease progression process.
-That's a great point. Thank you.
I agree, we should further consider this as we revise.
Let's see, I see in the chat
we have a question from Dr. Bob Stern.
-Thanks, Kristen. Thanks to the panel
and all the incredible work you've been doing.
This is just such an amazing transformation
since the previous time this was brought up.
I just want to try to bring up a complex point
between chronic traumatic encephalopathy
and post-TBI dementia.
And that has to do with the acute phase of the injuries.
And really what it is that we're trying to measure
clinically biomarker and then neuropathologically.
That with the repetitive head impact
exposure over several years in individuals
like contact collision sport athletes.
There may not be a single injury that would be considered
a symptomatic traumatic brain injury.
And yet, because of that repetitive exposure,
there seems to be set in motion this cascade of changes
leading to a progressive telopathy.
And in that case, it is so different to try to detect,
and diagnose, and come up with clinical features.
Because there's this period of...
...delay between that time of exposure to injuries
and then the beginning of a progressive neurodegeneration.
So I just want to have people try to keep that in mind
that we're not talking about an injury that then recovers
and then there can be a chronic
and potentially degenerative phase later.
When it comes to many of the cases of CTE.
-Excellent point.
So I'm hearing you say that it's not quite sufficient for us
to state in our recommendations that we are interested
in considering a broad range of exposure histories.
But actually investigating more carefully the distinctions
between the acute and chronic pathologies
of distinct exposure histories.
-That's right. -Okay. Thank you, Doctor.
-I think that's going to help really elucidate
the differential pathologies going on
by differentiating it at the acute phase.
-Great point. Thank you, Bob.
I see a question now from Dr. Bellgowan.
-Oh, yes.
I'll turn my camera on. Thank you.
So there seem to be I know the Recommendation 4
was about these translational models
and Dr. Keene showed a bridge to those models.
But we know that, you know, so I was --
the recommendation to me is fairly unspecific
because, you know, TBI, there's a lot of TBI models.
And are you talking about developing --
is there a way to develop a consensus about
which is going to be the most informative model to use
and to bring in people from the AD/ADRD community.
To help us choose which models might be most effective?
I mean, you could even look at whether we injure a mouse early
and then follow them over, you know, their life,
or we injure an aged mouse and see what happens.
I mean, I just see the --
a proliferation of preclinical studies.
And I was just wondering if part of the recommendation
was to figure out which might be the most,
you know, defining which models
and which parameters of models would be most effective.
And I wrote in the chat the VA has already put together
a similar effort for model development
in traumatic brain injury in itself.
But I'm not sure it includes
the dementia component of it, really.
-All right, great point.
Dr. Johnson, would you like to speak to that?
-Sure, yeah. No, I think that's an important point.
I think one of the important points
that we were trying to get at
is obviously there's been an evolution
in our understanding of the human pathology.
Which is still very much evolving
and being characterized.
And part of that recommendation was to really --
so and I think that was what Dirk was getting to.
Was the picture of the bridge, as well,
is really that essentially collaboration
between preclinical and clinical work.
And there are pathology-based studies to really inform
what aspects of these models are relevant
and even potentially to different populations.
I think there's a lot of work to be done
even to be further characterized into the chronic phase
in many of the existing models.
But, you know, many of these models
are going to be useful in different respects
for looking at specific phenotypes of injury
and how they evolve into the chronic phase.
So I think we were really getting at the sort of the gap
in information between the clinical and preclinical.
That's going to be really important for driving our --
the sort of further characterization development
and utility of those models.
-Thank you. Okay, so we will make sure --
we'll take that back to the committee
and make sure that we discuss and clarify that.
Thanks, Vicky. Let's see, Dr. Hoffman, I see hand raised.
-Yeah.
Thank you, Dr. Bellgowan for that shout out, there.
Yeah, we're -- the VA's working with the other agencies, DOD,
NIH, different institutes of NIH, like NIA and NINDS.
To develop these -- a categorization
and standardization of animal models.
And since the VA doesn't look at acute injury.
We have veterans who've had brain injuries.
Sometimes we don't know what time zero is.
So having models that can show the pathological progression
of one or more brain injuries
is something that is a goal of that initiative
which is called precise TBI. Thank you.
-Thank you, Stu.
Okay, Dr. Corriveau, I think to turn it back to you.
-Okay. Thank you so much for a wonderful session
and lively discussion
including specifics about the recommendations.
We really appreciate that.
So with no further ado, I would like to --
I'll -- to introduce Dr. Julie Schneider,
the scientific chair of the Late Committee for TDP 34 --
TDP 43 Pathology and Common Late-Onset Dementias. Thank you.
-Thank you, Rod, and thank you to the organizers
for inviting me. And I apologize
that you have to listen to me instead of have lunch,
because I thought there was a break, too.
Next slide.
Again, the views expressed in these presentations are not --
are those of the authors and not of the NIH.
I'm listing all the disclosures here, both mine, Dr. Wolk,
and Dr. Gitcho, who will also be speaking,
so we don't have to each do it on our own.
Next slide.
I want to thank the committee members Konstantinos Arfanakis,
Maria Corrada, Michael Gitcho,
Brian Kraemer, Pete Nelson, David Wolk, Hyun-Sik Yang;
and our cross committee members, Donna Wilcock and Dirk Keene.
We had lively discussions
and I think just a really good working group of people.
Everyone pitched in.
And thank you to the NIH staff too.
Next slide.
So I'm going to give you an introduction
and then briefly talk about a couple new recommendations.
I'm going to tell you --
tell you what is LATE, why do we -- what is --
what are we calling LATE? Why is it important?
And that's going to be followed up with Dr. Wolk,
who's going to give you a lot more information
on why LATE is important.
We, like the TBI session, we were new to the ADRD summit
as a emerging topic in the 2019 Summit.
And we've really come a long way.
Our initial recommendations involved biomarkers,
clinical manifestations, basic science, and pathology.
And we're going to continue with our push for biomarkers
and basic science, which are really,
really needed in LATE research.
But we're going to pivot a little bit
with the clinical and pathology recommendations
and really expand that to two completely new recommendations
with specific topics
that include clinical and pathology
but go beyond that to --
and discuss or investigates the boundaries
with other diseases in the intersections
with hippocampal sclerosis, vascular disease, and age.
And I'll talk about those in just a little bit.
Next slide. So when we talk about LATE,
we're basically talking about TDP-43 pathology
in common dementias in aging.
But the TDP-43 story really started 2006
with the seminal papers describing TDP-43
as the ubiquitin positive tau negative inclusion
of frontotemporal lobar degeneration, ALS.
So this was a pivotal discovery. It really changed the field
for frontotemporal lobar degeneration
and initially very short period of time
was thought to be specific. Next slide.
But as we looked at TDP-43
as this novel neurodegenerative proteinopathy,
it became clear very quickly that TDP-43 was not
only positive in frontotemporal lobar degeneration
but it's positive in other diseases
just like alpha synuclein
and tau, these misfolded proteins aren't --
don't define one disease necessarily.
And, lo and behold, TDP-43 positivity
was quickly found to be evident
in Alzheimer's disease, pathology,
as well as hippocampal sclerosis pathology.
Next slide.
But even more astounding was that this TDP-43 pathology
was sometimes found in older people
completely lacking Alzheimer's disease,
or hippocampal sclerosis.
And as you'll see in a following slide,
that is why we came up with a new name for this
because, as of 2018, there was no name for this.
And if you look at the pie chart at the bottom of the slide,
this is a study that we did looking at people
who are called Alzheimer's disease in the community.
No biomarkers; they have an amnestic dementia.
And the red is showing people
with Alzheimer's disease pathology.
The purple is showing those people
with Alzheimer's disease pathology and TDP.
So the vast majority of these Alzheimer's,
these cases that we see in the community have TDP.
The blue slice is showing people
who did not have amyloid and tau but have LATE.
So they have a different diagnosis.
The white would be vascular dementia, Lewy body dementia.
So clearly a big part of this pie
is being completely disregarded by the community.
And this was very concerning.
There was very little research being done.
But at the same time, it was noted that
in biomarker studies that --
that in biomarker studies that, you know, a good third of people
who are thought to have Alzheimer's disease don't.
But most of the research on TDP,
even though we saw this pathologically,
was really being done in the FTLD community.
Next slide. So to increase awareness
and really increase research in this TDP-43 pathology
and aging and Alzheimer's disease,
we convened a panel of 22 experts across 22 centers
and really discuss how are we going
to make this a research of focus.
And it's -- and a much needed focus.
And as Dr. Wolk will be showing you,
that, as an isolated pathology, it mimics Alzheimer's disease.
But even more commonly, when it's in conjunction
with Alzheimer's disease neuropathologic changes
of mixed pathology,
it accelerates decline and worsens memory.
It makes the person much worse.
So we clearly know that this needed to be studied,
and we needed to kind of upset the field to get it --
to get it going.
And that is where we came up with the term limbic predominant
age-related TDP-43 encephalopathy,
which is also LATE, the pathology is called LATE NC
so LATE neuropathologic changes. A couple things to mention.
There is no frontotemporal lobar degeneration in these cases,
and there's not a frontal temporal dementia syndrome.
Instead, there's a prominent amnesia of people
with this pathology. Next slide.
So our 2022 LATE recommendations
continues this dire need for biomarkers.
We really need to be able to delineate
when somebody who does not have Alzheimer's disease has LATE,
and we need to know when someone with Alzheimer's disease
has LATE in addition to Alzheimer's disease
because maybe they won't respond to the amyloid therapy as well.
We need experimental models to start looking at this age
related TDP-43 update.
So biomarkers, experimental models,
still really important. But, in addition --
and I'll show you in the next few slides --
these boundaries that you've been hearing
about all of yesterday and today,
we really think need to be explored with LATE
and frontotemporal lobar degeneration,
as well as LATE with Alzheimer's disease and Lewy Body disease.
And I'll show you a little bit more about that
in just a minute.
But in addition to those boundaries,
we also see the need to look at the intersection of LATE
with hippocampal sclerosis,
which is a very important pathology in aging.
And especially as our population ages,
you're going to see that those numbers continue
to go up of hippocampal sclerosis,
the vast majority of which have TDP-43 pathology,
as well as an intersection with vascular disease
and aging senescence.
And I'll show you a little bit more about that too.
Next slide. So here is Recommendation 1,
define LATE pathologic clinical genetic molecular classification
and diagnostic boundaries across FTLD TDP, AD,
and other dementia-related pathologies
and their syndromes to enhance diagnosis, research,
and awareness. Next slide.
So here I'm just going to show you why this is so complex.
So here's -- in the white circle
is Alzheimer's disease neuropathologic changes occurs,
you know, in a large segment of the population, as we know.
And then, in red, you have people
with Alzheimer's disease neuropathologic changes
who also have TDP, so they have LATE neuropathologic changes.
So there's a lot of overlap there.
And you can see that there's a group
that does not have Alzheimer's disease
that may have a dementia just related to LATE.
But, in addition, I put in a purple circle
because that's hippocampal sclerosis.
And hippocampal sclerosis intersects with all of these.
The majority of them have TDP-43 pathology.
Some of them have Alzheimer's disease in addition.
In fact, the majority of them also have Alzheimer's disease.
Next; next, please.
And this is frontotemporal lobar degeneration.
And I made the circle small
because Alzheimer's disease is so much more common,
the frontotemporal lobar degeneration with TDP.
Next slide or next, yes.
But frontotemporal lobar degeneration
also has hippocampal sclerosis.
So there's something really going on with this --
these proteinopathies,
especially TDP-43 and hippocampal sclerosis. Next.
And then there's Lewy body disease.
So we know already from the research that's been done
just over the past few years that Lewy bodies
are independently related to TDP-43 pathology,
even separate from Alzheimer's disease.
So, again, we're seeing this mixture of these different
proteinopathies being tremendously important.
And these intersections
aren't well-recognized clinically, pathologically.
They're not studied as well as they should be studied,
and this has been brought up multiple times
by multiple people. And this intersection
with frontotemporal lobar degeneration
is also very important,
and I'll show you a couple of reasons.
Next slide. So it quickly became clear --
and this is just a snapshot of some papers --
of the clinical and pathologic overlaps
or, you know, difficulty in classifying someone's cases
with TDP-43 and Alzheimer's disease
or with frontotemporal lobar degeneration
and limbic predominant TDP-43 deposition.
So, clearly, even though we'd like to make these all separate,
the frontal temporal lobar degeneration
and LATE, there's cases that intersect.
And we don't really understand the intersection
of these different proteinopathies again,
and a lot more work needs to be done.
Next slide.
But I don't think the clinical and pathology
is going to get us everywhere.
And we need the genetic, molecular,
and structural boundaries to really understand.
And you've heard a lot about that, too,
about the different strains
and different configurations and morphologies.
But look here on this first study
where APOE is not only a risk factor for Alzheimer's disease
but it also increases risk for Lewy body disease,
as well as TDP-43.
TMEM106B,
a risk factor for frontotemporal lobar degeneration,
increases TDP-43 pathology in aging.
So, clearly, these mechanisms overlap across disease states.
And then, as you've heard through this conference,
you know, we're learning more still about what these different
aggregates look like in different disease states.
Next slide.
-Two minutes remaining.
-So the last thing I want to talk about is that the --
our fourth and final recommendation,
which is really to pay attention
or to study this intersection of hippocampal sclerosis
in the role of age and vascular disease.
So we've known about hippocampal sclerosis
in the pathology world for a long time.
We know that it can mimic an Alzheimer's type dementia.
We know it's very common in the oldest old.
And there's a lot of interest in hippocampal sclerosis
in the pathology world,
but it's not really noted clinically very well or studied
from a nonclinical or pathologic standpoint.
Almost all cases of hippocampal sclerosis
with aging have TDP-43 pathology,
but it's not a specific pathology.
All hippocampal sclerosis is,
is severe degeneration of the hippocampus in aging.
And you can also see it interestingly
with apoptsic ischemic injury. Next slide.
I should also mention that there are no pathologic standards
for hippocampal sclerosis.
So we have no consensus criteria.
We take one section of hippocampus, a huge structure,
and do a six micron section to look for it.
But we know from that finished study on the other slot --
slide that it's patchy,
and we might not always be seeing the pathology.
But we also, in addition to that,
know that both TDP-43 and hippocampal sclerosis
are age-related pathologies.
And this is a study by Leah Greenberg and Salvatore Spina,
showing that cerebral amyloid angiopathy in Lewy body disease
are actually very common in early onset Alzheimer's disease,
whereas TDP-43 and hippocampus sclerosis are rarely present.
They're really an age-related phenomenon.
And we have an aging society, so we really need to understand
in studies that use aging within their models what is happening.
And then, finally, there's inflammation
or there's data suggesting for multiple groups
now that vascular disease also intersects.
So here we have a couple different groups
showing that arterial sclerosis
is related to hippocampal sclerosis.
We in our group found that arteriosclerosis
was related to TDP-43 pathology.
So what that exactly means or why that would be interacting
is completely at this point unknown.
Next slide.
-Time.
-Next slide. So this is my last slide.
So, this is recommendation number 4.
To study this intersection with hippocampal sclerosis
and LATE NC within and across all disciplines again,
not just clinical and pathologic
but diagnostic, genetic, molecular,
and to consider the roles of vasculopathy and senescence
and other potential contributing factors.
So thank you for your attention.
And I'm going to hand the reins over to Dr. Wolk.
-Thanks so much, Julie. Next slide.
So, I'm going to focus, as Julie said, on recommendation 2.
We'll talk about our current understanding and knowledge gaps
in the clinical manifestations of LATE.
And then I think we'll discuss where we are now
with clinical detection of LATE
and kind of where we need to go moving forward.
Next slide. So this is recommendation 2.
It is -- sort of builds off of the prior summit.
It developed -- it's to develop biomarkers, classifiers,
and risk profiles to establish
an in vivo diagnostic criteria for LATE
in people in the preclinical phase of the disease,
as well as those with an amnestic
LATE life dementia syndrome.
I won't go through each of these bullet points
because I think they get set up in the later slides.
But I will point out the last bullet point,
which is that, ultimately, we really do need to develop
bio fluid and neuro imaging and/or neuroimaging biomarkers
of the molecular pathology of LATE
and, in particular, TDP-43.
However, until we get to that goal,
we felt that we really need to develop
probabilistic classifiers that are validated for us
to be able to do in vivo studies in this population.
Next slide.
So just wanted to provide a little bit of context
and in part because this demonstrates
that we see these cases in our clinics already.
This is a 78-year-old woman who had arthritis,
prior hysterectomy for uterine cancer; and depression.
She had several years of memory loss.
She would forget where she parked her car,
and she was misplacing things.
She previously was great with the computer
and had increasing difficulty,
and her family felt she seemed a little more stressed out
and struggled more with decisions.
Next slide.
These are her initial standard psychometric testing.
And the important thing to point out here
is in purple where she's impaired are all tests
that have to do with verbal or visual memory.
Other cognitive demands were essentially intact.
Next slide. So this was her initial MRI,
and I hope you can appreciate that,
in the right anterior hippocampus,
there was some degree of atrophy.
But there wasn't a lot of cortical atrophy otherwise
and maybe a little bit of vascular disease,
small vessel disease. Next slide.
So she had a very slow course.
We followed her for over nine years.
On the left, you can see her psychometric testing,
which kind of barely changed over time
but did get a little bit worse.
She had poor memory, but that remained relatively stable.
They noticed some decreases in her attention and motivation.
She also had a little bit of disinhibition.
She would say negative things about people
while they were in the room, which embarrassed her daughter.
The important point is, throughout her entire course,
she had a diagnosis of Alzheimer's disease.
Next slide. This is her CAT scan
that was done just a few months before she passed away.
And now I think you can really appreciate
both anterior hippocampal
and anterior temporal atrophy bilaterally,
a little bit more on the right than the left,
and some cortical atrophy perhaps a little bit frontal
but, otherwise, not too much. Next slide.
So she went on to autopsy
and was found as a primary pathologic diagnosis
to have a LATE neuropathic change
without any evidence of Alzheimer's disease.
So, again, this would be an example of a case
that we misdiagnosed as Alzheimer's disease.
Next slide.
So I think since the last summit
we actually have made a fair bit of progress
in defining the clinical features of LATE.
For example, on the left, you can see and consistent
with this case that LATE neuropathic changes
associated with a relatively slow course of decline
compared to Alzheimer's disease.
Episodic memory tends to be
the most prominently affected domain,
and that can be very significantly affected.
There's still some question about whether
other domains are affected
and to what extent, such as semantic memory.
While these cases certainly do not have
the behavioral manifestations
of full blown FTD spectrum disorders,
there's also some question whether they have
some behavioral associations such as this case.
The important point is, when you look at population
and community based autopsy studies,
these individuals represent about 1 in 10 individuals.
This is a common condition. Next slide.
In terms of thinking about what other kinds
of cognitive and behavioral symptoms
may be present in these individuals,
I think it's useful to think about where TDP-43
spreads in the brain in the context of LATE.
And I should note there are three different
staging systems out there,
all with different levels of granularity.
But the bottom line is they show regions
that are affected such as anterior temporal cortex,
orbital frontal cortex, insula, middle frontal gyrus,
which suggests that there may be additional impairments
and semantic memory behavior and perhaps,
to some extent, executive functioning.
Next slide. It turns out,
when LATE is associated with hippocampal sclerosis,
we actually do see more significant decline
not only in memory but we do see involvement in semantic memory
and perhaps to some extent perceptual speed.
Next slide.
So -- and this touches a little bit on recommendation 4,
but we really need to understand the clinical phenotype
that differentiates LATE with hippocampal sclerosis
versus LATE without hippocampal sclerosis.
But as Julie mentioned,
we also really need to study the drivers of LATE.
We do know some things about how hippocampal sclerosis
presents in the setting of LATE.
These individuals, as I mentioned already do seem
to show more severe cognitive impairment,
particularly memory,
but they also tend to have a higher or later stage of LATE
in terms of the spread of TDP-43.
So it's not surprising that these individuals
have other domains of cognitive impairment
like semantic memory affected.
As was also mentioned before, these individuals seem to have
some relationship with vascular disease.
They have a higher rate of atherosclerosis
that's been described.
Interestingly, the genetics of LATE
alone versus LATE with hippocampal sclerosis
may differ as shown on the right.
And, importantly, as we are starting to develop
these sort of genetic risks of LATE,
these are features that can be included
in classification models
as we move forward to define the disease in vivo.
Next slide.
So we've been talking about LATE neuropathic change alone,
but I think one of the really important areas
is how it interacts with other neurodegenerative conditions,
particularly Alzheimer's disease.
So on the left is relatively new data from 13 community
and population based autopsy cohorts,
which suggests that up to half of individuals
who have late stage Alzheimer's disease,
neuropathic change also have LATE neuropathic change.
And, importantly,
in the combination of Alzheimer's disease and LATE
seems to be associated with a much accelerated decline
over time that we see relative to Alzheimer's disease.
So it's really the fastest progressing form
of Alzheimer's disease in some ways.
And, actually, if you look at different stages of Alzheimer's
based on Braak stage, at any of those stages,
the presence of LATE is associated with poor cognition.
Next slide.
So detection of LATE in clinical populations,
I think, is critically important.
It's a common source of cognitive impairment
in older adults.
And in clinical diagnosis of Alzheimer's disease
probably makes up 20% of the attributable risk.
It has important prognostic
and potentially treatment implications
and amnestic cognitive impairment presentations.
A slower course is expected in someone
who has it in the absence of Alzheimer's,
but a much more rapid course is expected in patients
who do have Alzheimer's disease.
And, really, our ability to be able to detect it in vivo
is what's going to allow us to do broader studies of risk,
genetics, clinical and cognitive phenotype
and eventually intervention studies.
I think, though, critically important
to the Alzheimer's disease field
is that it's a major source of variability in progression
that can impact clinical trials and may also limit the efficacy
when specifically targeting AD pathophysiology.
And, currently, there are no molecularly specific markers
of TDP-43. Next slide.
So then how can we detect it now?
And, again, there have been some progress since the last summit.
For one thing, there are spatial patterns of neurodegeneration
based on atrophy or hypometabolism on PET,
which can be suggestive of LATE neuropathic change.
And they've been linked to post mortem data to various extents.
One also can inferentially determine the likelihood of LATE
based on Alzheimer's disease markers.
So Alzheimer's disease is defined
by the presence of amyloid and tau biomarkers.
And neurodegeneration is used to sort of stage individuals,
the so-called ATN framework.
Well, if an individual is amyloid negative
with an amnestic syndrome,
particularly if they have atrophy in a LATE like pattern,
they're much more likely to have LATE.
But we really want to be able to detect it
when individuals also have Alzheimer's disease.
And what we know is,
within that Alzheimer's disease continuum,
tau is tightly linked to neurodegeneration.
So if an individual has significant medial
temporal lobe atrophy
and a LATE like pattern in the absence of tau pathology,
that may suggest LATE. Or if they have tau pathology
but neurodegeneration exceeds what we expect,
that, too, might be a marker to use for LATE.
Next slide.
So, again, there have been -- there has been work showing
that there are spatial patterns to change that occur with LATE
that may differentiate it from Alzheimer's disease.
So, for example, on the left is post mortem work
showing amygdala patterns of atrophy or shape change.
And on the right is a study we did
where we looked at antemortem MRI
and found that Alzheimer's disease with TDP-43
tended to have more anterior medial temporal atrophy
than Alzheimer's disease without it.
And, actually, if you took a ratio of anterior
to posterior MTL,
there was fairly good discrimination
between these groups. Next slide.
-Two minutes remaining.
-We also have seen that there are cortical patterns
of atrophy in LATE. So, for example, on the left
is a post mortem study showing atrophy
in temporal polar regions and frontal regions.
And this has also been seen in vivo as well,
where in particular, again,
you see this gradient of greater anterior
than posterior temporal involvement. Next slide.
There also have been FDG PET signatures of LATE,
some really nice work done by the Mayo group,
which has found
particularly severe medial temporal hypometabolism
relative to inferior temporal hypometabolism.
And this discriminates between Alzheimer's disease and LATE.
And if, in more recent work,
if you add orbital frontal cortex,
that further increases discrimination.
Next slide.
But, again, we can establish the diagnosis
inferentially through AD biomarkers.
So this is a case of someone
who's 83 with an amnestic presentation
who has had positive amyloid marker but negative tau.
Next slide. However, they also had
very significant hippocampal atrophy --
next slide -- as well as a little bit of athero.
So this is a case that had neurodegeneration
in the medial temporal lobe without tau.
And so we might expect a non AD driver of Alzheimer's disease.
Next slide.
And, indeed, this was a stage two LATE case.
Next slide. We've also been trying to look
at the relative amount of tau to atrophy.
And I've had -- found people who have more atrophy
than expected for a given level of tau.
And, in fact, some of those individuals have that increase
or mismatch of neurodegeneration in LATE-like regions.
And, actually, we can cluster these groups together
using machine learning based approaches.
Next slide.
-Time.
-And what we've found is that
there's a limbic vulnerable group
and a limbic resilient group.
But, importantly, the vulnerable group
tends to have high levels of TDP-43 in post mortem analyses
whereas the limbic has, if anything, low levels.
Next slide. And just very quickly, to end,
I think we need to bring all of this knowledge into the clinic
by incorporating multiple biomarkers
for probabilistic models,
including cognitive data risk factors and genomics.
And all of this, though, needs to be validated
and replicated in large post mortem studies.
But, again, ultimately, we need to find TDP-43 biomarkers.
And so I will now turn the mic over to my colleague,
Michael Gitcho.
-Thank you very much.
I'm going to talk about experimental models
of LATE that incorporate aging and relevant phenotypes.
There's nothing --
recommendation is to build new experimental models
that incorporate aging with behavior,
pathological, molecular phenotypes
of TDP-43, proteinopathy or hippocampal sclerosis,
advanced knowledge enable testing and therapeutics.
Overall, to develop and characterize models
that incorporate aging, designed to simulate latency,
TDP-43 dependent clinical
and pathological phenotypes potential. Next.
There are mobile models to study aging
and maybe looking for innerve generation
with nontraditional models may be --
may be helpful in understanding the disease better.
Next, please --
was talking about this really exciting paper
that came out by our senior colleagues
that using nicarwine maps of TDP-43,
they're able to map TDP-43 pathological filaments
aggregation from ALS with an FTLD case,
two cases they looked at.
This is real exciting because previously,
this C terminal region, this glycine rich region
has been fairly undefined until now.
And we can start to --
and understanding the structure will give us a better idea
as far as understanding disease mechanisms,
maybe possibly development of drug targets,
in addition to maybe develop even some PET ligands
that may be useful detection of TDP-43.
And I guess the big question to ask on this, too, is,
is the structure of these pathological filaments
of TDP-43 in AOS FTLD different in LATE,
and maybe that will be determined at some point.
Next, please.
So to look at this, we're going to --
one of the recommendations is to look
at virally transduced animal models using age animals.
Caudry and Associates looked at 10-
to 12-month-old mice using the cAMP
kinase tetracycline response element,
the doxycycline response element.
So they introduced AB virus
with specific expression into the hippocampus
using this model, model regulatory expression.
And they show that just over 15 days post transduction
TDP-43 causes neuronal loss in the hippocampus in stage 2 here.
There's no change with alpha synuclein.
I think it's important to emphasize
the use of multiple pathologies
when it comes to look at these changes with TDP-43 in LATE
to maybe possibly use this together in sync
with the same animal to look at some nucleon or tau
or other pathological proteins together.
Next, please.
Knock-in, gene edited, or stress induced models.
Deboin colleagues looked at this,
developed these humanized knock-in lines
that are driving TDP-43 along SO D1, also FAS,
but driving TDP-43 using the endogenous promoter,
humanized lines as they possibly can be used
for introducing mutations for FTLD.
But this could maybe be applied to LATE as well.
Introducing modifications or seeing what changes occur here,
looking at this endogenous promoter.
Next slide, please. Stress induced cellular models.
Roddy and Associates looked at this,
and they use an oxidative stress model,
but arsenide treated, fibroblast or IPS motor cells.
It's important to note on two
on this phosphorylate TDP-43 aggregation
to look at all the bio for cellular models
in particular to look at --
be able to replicate aggregation as far as changes in solubility
and to have the biochemical signatures
with the cleavage products and other things as well.
But this could be definitely used as a model
to maybe use for drug studies or other ones as well.
Next slide, please. Next slide, please.
No. Back one. I'm sorry.
Can you go back. There we go. Now we're good.
So interaction between TDP-43 and other pathological proteins,
tau, alpha synuclein, amyloid proteinopathies
and other pathological proteins, Tomie and Colleagues
found an interaction between TDP-43
and tau using immunoprecipitation
but also show some colocalization
between phosphorylated TDP-43 and phospho tau
in pre AD and symptomatic AD cases.
Next slide, please.
She and colleagues looked at an interaction
between TDP-43 and amyloid beta.
They show a complex interaction here through immunoprecipitation
This is kind of an interesting study, too,
because they used bilateral interhippocampal injections
of recombinant full-length TDP-43.
This has been a challenge in the field
for isolating recombinant TDP-43 this stage,
so this is real exciting.
And this goes back to the structural component, too,
that we're starting to understand
as far as a structural understanding
these pathological filaments that maybe
that could be utilized too as far as injecting --
well, later on. Next slide, please.
One thing that would like to focus, too,
is to develop models for vascular contributions
of TDP-43 proteinopathy or hippocampal sclerosis.
We really need models to develop this
and to be able to see these changes
and how they can be replicated
or at least be consistent with those with LATE.
Glial and neuron interaction plus inflammatory contributions,
that's a TDP-43 proteinopathy, specifically as aging.
We'll see to replicate within the models,
what we're seeing in the human disease.
Next slide, please.
-Study the transmission of pathological TDP 43,
the prion-like transmission of pathological TDP 43 species
that simulate anatomical progression latency,
TDP pathology in common dementia.
This is a great classical experiment from Luton College
that did a --
used a small peptide of mutant alpha-synuclein
into stereotactic injections.
And they show, over the course of time,
it causes this prion effect
to affect endogenous synuclein-inducing pathology
across the spread of the mice in just a few months.
They further looked at this same model,
the same group, azoladel.
And then they looked at synuclein and how it modulates
tau pathology as well.
I think because of the recent discovery
of the structure of these filaments,
that we're going to see more prion-like -- to invest --
to be able to investigate this prion-like transmission,
or pathological TDP 43 species, using this type of system.
Next, please. Next slide, please.
Transgenic animals that express wild-type or immune TDP 43
or developed hippocampal sclerosis.
Back one, please.
Back one slide, please. Thank you.
So, Wuhan colleagues did a conditional knockout
in the hippocampus. And, over the course of time,
at 12 months of age they show distinct degenerate --
distinct severe hippocampal degeneration
over the course of time at 12 months of age.
Next slide, please.
This is unpublished work from our lab.
We looked at hippocampal degeneration
as seen in 24-month-old mice expressing nuclear localization
signal defective TDP at 43 months.
These are in -- these are six genotypes
that we looked at with wild-type APP-PS1,
a low expressing TDP mouse.
And it's TDP in the mouse expressing lower TDP
43 expression in an APP background.
They show no neuronal loss at 24 months of age.
And they show no change in hippocampal area.
However, when we derive expression
of TDP 43 in the cytoplasm --
and this is end stage for these mice.
These mice only live 24 to 25 months of age,
the NLS mice in particular.
When we derive TDP 43 in the cytoplasm,
we get this severe degeneration of the hippocampus.
And we get a decrease in hippocampal volume.
And in the end in the APP background,
there's no additive effect with these.
And this will go into the next slide,
where I can talk about model limitations.
Next slide, please.
So, model limitations
I want to talk about the cAMP kinase model,
that I described for the one that we use.
Gowan and Associates from Jackson lab
is an excellent paper.
They mapped quite a few different transgenic lines
for their integration sites.
And it just so happens the cAMP kinase TTA model
that we use was mapped in five coding regions, the gene.
And there's, also, some abnormalities
with some motor deficits in these mice
as well that show some clasping later on.
So, this brings us to rigor and reproducibility.
And I think we can --
if we think about this for animal models,
this has been a challenge for reproducibility
on animal models from consistently.
If we look at, for instance, the APP-PS1 model,
we can see that there are multiple groups.
There's maybe over 1,000 papers
or so that describe this model and characterize it.
But multiple groups show early age-dependent changes
at three or four months of age, or even five months of age,
they show memory deficits where other groups don't show it
'till they're 12 months of age, or even 18 months of age.
Same mouse, same background, same experiment.
The environment may play a big role in this,
and this may be the handling of the mice.
And how this can be addressed, I'm not really sure.
But, take suggestions.
But I think that age is really going to be a key factor
with this understanding this, too.
And that's going to be hypothesis-driven for LATE.
And that's going to be up to the researcher.
We're suggesting single copy, maybe endogenous promoter,
inducible expression, or other approaches to replicate LATE.
Next slide, please. Next slide, please. Thank you.
So, this is an overview of the recommendation
is to build new experimental models,
and incorporate aging behavioral pathological phenotype.
And I talked about developing and characterizing models
that incorporate aging, designated to --
designed to simulate latency.
Barley transduce models knock in,
gene-editing stress models, transgenic models
that express to the wild-type or mutant TDP 43.
Consider using inducible promoters
to derive expression, disease relevant cells.
But attention has to be played
to the appropriate time of life in the animal.
The vascular contribution
to TDP 43 proteinopathy hippocampal sclerosis
is going to be important to develop, too,
as far as models. And the interaction of TDP 43
with other pathological proteins,
and understanding those pathologies is important.
In addition to glial neuronal interaction,
plus inflammatory and neuroinflammation contributions
to TDP proteinopathy to be able to model this in --
they're replicates of what's seen in LATE,
specifically in aging.
And then study the prion-like transmission
of pathological TDP 43 species
that simulate anatomical progression of latency.
With this structure now,
we may be able to develop good candidates
for different areas of the protein,
in order to induce these changes.
Maybe starting it in the amygdala,
and seeing how the transmission progresses.
Next slide, please.
-Two minutes remaining.
-Next slide, please.
So, in general, we want to develop
translationally actual cellular and animal models,
to enable preclinical therapeutic development,
and testing pipelines and latency.
Most of the models to date focus on ALS or FTLD.
And we've just seen we really need models
that replicate LATE, and other models of LATE.
Not just animal models, but other models
[Indistinct] as well.
We need to study this in the context of multiple pathologies.
It's important to look at these interactions
in more of a complex nature with TDP 43,
as we're seeing it in the human disease.
And we may be able to model it better
by looking in more pathological proteins in that.
And then what's real important is the intersection
with the hippocampal atrophy and vascular disease,
and developmental models or other systems as well.
But in all of the models,
aging should be incorporated in everything,
as far as I understand.
I want to thank you for your time.
And the next part will be the Open Mic and Questions.
Thank you very much.
-Thank you so much.
So, we have a question from Penny Dacks.
-Thank you all.
I've got to say, I learned so much listening to all of you.
And I deeply appreciate your work here,
and your leadership in this space.
I was -- you know, Dr. Gitcho just spoke on the models.
And I think his -- and supplied your ability
to convey so much complexities about how do we --
when we take the complexities
and we try to distill it into models,
sometimes we go too far.
And I think you did such a phenomenal job
discussing how there's so many different ways
that we can be using the models in a deeper way,
to be looking at the interaction of factors,
rather than solely distilling them down into singular ways.
I want to encourage the group to consider
looking at long-term sleep impairments as well,
because I do think there's a lot
that's there that we don't fully understand
when you're going at aging biology.
And, in general, systems biology and computational models
I think are important to consider.
But my core suggestion is, really,
just to emphasize the broader mixed etiologies
dementia recommendation at round,
building proactively towards harmonized data
and biosample collection,
so that the work that's happening on TDP
43 within all of the ADRDs, as well as related fields like
ALS, can really be able to benefit from each other.
We don't yet know,
and I don't think we'll know for a long time,
how much, you know, the biomarker work in one space,
or the basic science work in one space
is actually going to be relevant to a related space.
And I hope that one day we can get to the place
where our clinical phenotypes are being very carefully
and [Indistinct] characterized for prognosis,
but that the underlying molecular pathology
is what is being defined in individuals,
so that that is what can be tackled
clinically with new therapies. Thank you all.
-Thank you so much. Those are great points.
And I've written them all down.
I think the harmonization is super important.
And I think we do have that in some of our bullets,
as far as recognizing that need for harmonization,
as well as this intersection
with frontotemporal lower degeneration,
harmonization with other diseases
that might be in their own isolated coves.
Eric, Eric Smith?
-Yes, Thanks, Julie. My question is,
"Are we ready for provisional diagnostic criteria
in vivo like probable or possible LATE?"
I'm a neurologist and a clinician scientist.
I think I recognize this syndrome sometimes,
or a pattern like what was described, right,
with the slowly progressive amnestic syndrome.
And I was encouraged to see all the work
on like hippocampal volumes and patterns of atrophy.
Are we ready to try to identify prospectively,
and then follow people and validate
pathologically? Thanks.
-David?
-Thanks so much for the question.
And I'll be interested to hear what other panelists say.
I do think there are cases that we see clinically
that I feel fairly comfortable nowadays,
particularly if we have rich biomarker data
for classifying them, as having LATE.
I think, LATE alone has relatively distinctive features
associated with it,
that we probably could create criteria,
that, again, probabilistically would give us
a reasonable degree of certainty about the underlying pathology.
I think, in the context of Alzheimer's disease,
it obviously gets trickier.
But, again, I think there are features in the imaging,
as well as cognitively, that may allow us, again,
to kind of probabilistically say
there's a high likelihood of LATE copathology.
But I'll let the others weigh in as well.
-David?
-This is a great session. Thanks for doing this so far.
I was going to comment on the issue
that I think it's going to be very difficult
actually to study this in live people
without a marker of the pathology.
And I think, until we get there,
it's going to be where we can rule out
AD pathology with biomarkers or in.
But I just would feel very uncomfortable
diagnosing somebody with this,
with the current information that we have.
Now that we have cryo-EM of TDP 43 structure, I mean,
you theoretically should be able
to develop an imaging agent for it.
At least in the patients I see that.
I mean, most patients who come to clinic,
not research, don't even get AD biomarkers,
let alone anything else, so...
-Right. So, yeah.
Yeah, I think that's a great point.
I mean, you know, in the population-based
studies and community-based studies,
it would be exceedingly hard to do.
It would definitely have to be a research study with biomarkers.
Pete?
-Thank you very much to everybody.
Thank you, Dr. Schneider.
And I agree with both David's points
that we need better biomarkers.
However, there are a lot of people
now that are getting screened for AD.
And when they have some degree of neurodegeneration,
or some cognitive wobbling, but they screen failed,
there's no option for them. That's it. They're done.
And we've seen that from the patient advocacy
here that there's a lot of frustration with that.
Well, here at University of Kentucky,
we have what I think is the first LATE clinical trial.
And, so, we can employ the information of screen
failing for an AD clinical trial,
and give somebody an option.
And I really think that what I believe
I'm hearing from the patients, patient advocacy,
is a little bit of a disconnect to what I'm hearing
in the AD dementia neurology field
of trying to be a little bit more proactive
about giving patients options.
It's not telling them what to do, but giving them options.
And to try to get shots on goal, to see if we can't start to bend
some of the cognitive trajectories
in the survival curves.
So, for us, we have people that are clearly cognitively
not totally intact, and having some MRI changes,
but are negative on the amyloid biomarkers.
And we have an option for them to get into clinical research.
And at least it's a start.
And, so, I think that that's a really important --
at least trying to get on the hill of effectiveness.
Other areas of research, like cancer,
have been much more proactive,
and have reflectively gotten much better results
than we have in the dementia research field.
-Thank you, Pete. David, did you want to respond?
-Yeah, I agree with, actually, both David and Pete.
And I think they are great points.
I think, to David's point about clinical practice,
in general clinical practice I do think it --
you know, we just don't get the biomarkers
to make the diagnosis there.
But I do think that we can establish some criteria
in research cohorts.
And, again, that is kind of a goal of this,
you know, committee is to push for more harmonized data
collection across different studies and populations.
And I think that will ultimately allow us, again,
probabilistically, just like how we used to diagnose
Alzheimer's disease in the past,
to, you know, allow us to at least classify individuals,
perhaps incorporate genomics
and other factors that also help stratify individuals,
and their likelihood of -- the point's obviously well taken
that we really do need a molecularly specific biomarker
to truly move the needle forward.
-Dave? David?
-Yeah, I think we should
definitely be enrolling all people
who might have LATE into our research studies for sure.
I mean, one possibility would be
if you think somebody has LATE based on other criteria,
on all the criteria you discussed,
I mean, maybe there can be clinical trials
done in those for people,
if the target is not necessarily, you know, TDP 43,
but something that is present in everybody,
that you might try to hit,
but they wouldn't be in an AD trial,
because they don't have AD.
-Right. -Right.
So, not specifically amyloid or tau,
but if it's an inflammatory -- -Right.
-Mechanism or something else.
-Right. Exactly.
-Right. No, those are all great points.
And, interestingly, you know,
this intersection between TDP and vascular,
I think is going to become more and more important.
And I think -- you know,
we have Maria on our team with the 90+ Study.
And I know from our cohorts, you know,
in those over 90, what are we seeing?
We're seeing TDP and vascular disease.
So, it's very common. It's going to be increasing.
The neurologists are going to see more
and more of these cases as time goes on.
This is not going away. So, yeah.
Anyway, the last comment I think was from Susanne Van Veluw. 16
-Thanks, Julie. Yeah, to your point, actually,
Julie, you mentioned a role in the intersection
between TDP 43 and vascular disease.
And I wonder might there be a role for impaired
perivascular clearance as a disease mechanism.
We heard a great deal about it yesterday in the VCID section.
And I was wondering if that could be
another potential causal mechanism
that's worth considering as a focus of interest.
And, if so, if you agree
if that be a good addition to the recommendations.
-So, does anybody on the team want to take that one?
No, perivascular clearance mechanism people on our team?
I, personally, think it's a great idea.
You know, there's huge interest in the vascular field.
And I don't know if Donna's still on,
but she was part of our team.
The perivascular clearance is, you know, highly topical
in the vascular disease, VCID, session.
And, certainly, when we talk about this intersection
between neurodegenerative disease and vascular disease,
especially small vessel disease,
I think it is something that we should highlight.
So, I appreciate the comment.
And I think we should highlight that.
And we can discuss it among our committee.
-Just to add, Julie. Hi, everyone.
So, just to follow up on that, Susanne,
you know, when we talk about the perivascular
kind of drainage pathways in the VCID recommendations,
we talk about solutes,
and, you know, neurodegenerative proteins.
We're not specifically talking about amyloid.
So, I think that does open up kind of that recommendation
to being draining --
you know, clearance of TDP 43 clearance of other,
you know, proteins as well. So, yeah, it's a good point.
-Yeah, and maybe something we can at least touch upon
in our recommendations, too.
-Julie, very quickly, I just wanted to mention that
before it was mentioned that many of these
are age-related pathologies.
And one of the things that will be important
to kind of try to disentangle is that,
especially like with vascular and TDP 43,
are they there co-occurrent
because it's just a factor of age?
Or is it because they actually have
a mechanistic interaction in some way?
So, I think that's an important point to try to disentangle.
-Right. And I agree, Maria, it's really important.
And, you know, residual confounding
is certainly a possibility.
We controlled for age in our studies.
I'm sure Pete did, too.
And we looked at that pretty carefully.
But, yeah, these are people who are surviving.
These are people in their 90s. Right? So, you know,
association doesn't mean that there's causation.
So, that certainly is something
that we need to figure out still.
Pete?
-I would say -- thank you.
I would say a couple other things are also maybe relevant.
We found that arteriosclerosis connection
with TDP 43 and hippocampal sclerosis.
But Dr. Selenich's animal model,
where they do the viral transduction with TDP.
it's very interesting, because it produces
both an HS phenotype into mice,
but also perivascular sort of changes as well,
and gliosis that seems to be deleterious.
So, it seems to recapitulate
a number of the features of the pathology.
And I think Dr. Selenich's model is a very interesting one,
that allows both aging TDP HS-like and vascular changes.
So, I think it's really provocative.
-Thank you, Pete.
So, we have a question -- or a comment from Ian Premmer.
-Hi.
I think Keith wanted me on to reiterate something I --
just a small comment I put in Q&A.
And please understand none of this in any way reduces
the importance of the point that Dr. Nelson made.
But in response to two points ago
that he made about the patient and family advocacy
community wanting more options.
I think that's completely true and critically important.
My minor quibble is I think the data is pretty clear
that those advocacy communities
are not primarily interested in extended lifespan.
They're primarily interested in expanded
health span quality of life.
So, those things are not at odds.
But the primacy is on what can be done to improve the here
and now in the short term,
even if sometimes that may be at the expense of the longer term.
Because it's end stage dementia
that scares the bejesus out of people, rightfully.
And where there is maximum opportunity
for improved quality of life, may be at earlier stages.
Hence, the urgency to have better
means of detection and diagnosis with precision.
Which I think goes back to Dr. Nelson's point.
We want options as we are working
toward greater precision,
greater accuracy, greater, therefore,
actionability based on a differential diagnosis.
So, I think I'm in complete agreement with Dr. Nelson.
But he is, certainly, welcome to tell me
if I've missed the thrust, or misrepresented his view.
-You a thumbs up from Pete.
-Thank golly. Okay.
-But I, also, want to point out that,
you know, LATE is interesting
in that it is very slowly progressive.
So, when we see people with LATE, you know,
they have some mild memory problems
that very slowly progress.
So, their quality of life may not decline,
or isn't declining as fast as people with Alzheimer's
or Alzheimer's plus TDP 43. So, I agree with you.
But I do think that there -- that that group is important.
David? Or Dave?
-Just to piggyback on top of that.
That's why, you know, correct diagnosis
is also particularly important in that group,
because being told that you have Alzheimer's
has a different connotation, at least to some patients.
And, so, some of these cases are more likely to be slow.
And I think it's important for us
to get the diagnosis right, so that we have a better sense
of what the prognosis is in those individuals.
-If I could just add one more quick point,
you know, following on piggybacking on that point.
There is -- often, I think we all are sensitive to this,
a lot of prescription nihilism.
And it's misplaced, because so many people, not all,
but so many people in the patient and family communities
want to know what we are facing, and what we aren't,
even in the absence of, never mind a cure,
even an effective disease-modifying treatment,
or even a symptomatic treatment.
It just helps to be able to put a name to it.
Or in the case of multiple etiology,
mixed dementias, put names on them.
So, we know what we're facing, we know what we're not.
And, so, we can enroll in the right clinical trials,
if we are privileged enough to have access to trials at all.
-I agree. Pete?
-And this is just something to make a point
about that, actually,
in Dr. Schneider's excellent introductory talk was made.
But it needs to be underscored that you think about LATE or AD
and C, but they're frequently combined.
Not only is it such that LATE is a little bit more mellow
than AD per se.
And the combination is worse than either alone.
Which is intuitive. But the very important point
that Dr. Schneider's data
showed better than anybody's in the world
is that pure LATE is the least common,
but it's still quite common.
Pure AD is a little bit more common,
I mean, significantly more common.
But even more common than that is the combination.
So, this combination is where LATE actually exerts itself,
and where it's a bedevilment for the clinical trials as well.
So, I think that more people need to be much more aware
of this combination,
because it's the most common and the most impactful of them.
And, so, we need to have better therapeutics and diagnostics
for both of those scenarios.
-And awareness across research,
as well as non-research communities.
-Thank you for a wonderful session.
I think we probably need to stop there,
unless anybody has a burning comment
they'd like to finish off with.
We're going to go ahead and restart at 2:25
with the Special Session on COVID-19 and AD/ADRD.
So, thank you so much, everyone. And we'll see you back soon.
We're going to start the next session
of this ADRD Summit 2022.
It gives me great pleasure to introduce the Scientific Chair
of the meeting, Dr. Natalia Rost,
who will bring us into the session
on impact of COVID-19 on AD/ADRD risk and outcomes.
-Thank you, Rod.
Homestretch, everybody. That's the last session,
last scientific session of the meeting,
before the general and the closing.
And we're excited as part of this new working group
brings to you a topic that is of most urgency
and necessity to investigate in deeper detail.
Namely, the impact of COVID-19 on ADRD risk and outcomes.
And I'm delighted to pass the baton to my Co-Chair,
Dr. Sudha Seshardi,
who is Director of the Glenn Biggs
Institute for Alzheimer's and Neurodegenerative Diseases
at the University of Texas San Antonio.
Sudha?
-Thank you, Natalia.
And it's my distinct honor and privilege to work with you,
and with an outstanding team of diverse experts,
to address this important emerging topic on COVID
impact on AD/ADRD risks and outcomes.
So, I'll touch upon the introduction,
scope of the problem,
and the recommendations that this working group arrived at.
And then colleagues in the group
will expand on our thinking behind these recommendations,
and what we know at present
about different aspects of this infection. Next.
These are the opinions of myself and our committee,
and not official NIH policy. And this is my disclosure.
Next. And we have --
I have to extend thanks to all the outstanding members
who served on this committee, three of whom will be speaking,
as I do, on behalf of the whole group.
They pulled together in a very short time. Next.
And we were charged with making four recommendations.
And we ordered them in the order in which we thought, logically,
these need to be done. But all are equally important.
And we are recommending that all of them be addressed right away.
Although they may continue to be addressed
for varying periods of time.
The first priority the group emphasized
was the need for research infrastructure
to be established,
infrastructure in clinical, epidemiological
and basic research studies of the COVID-19 impact on ADRD.
Prioritizing disproportionately affected
and vulnerable populations with a view
to having clinical trial readiness
as quickly as possible.
So, for this, we believe the second recommendation
was to focus on characterizing the clinical phenotype
of neurocognitive consequences of COVID-19,
and developing diagnostic criteria,
both in persons with and those without
pre-existing neurocognitive impairment and dementia
at the time that they became infected.
The third priority was to recognize
that this is a complex issue,
and explore the interaction with social, structural
and systemic inequalities, comorbidities,
and social and medical interventions,
both the access and specifics of the interventions,
on the risk and cognitive -- sequelae
of neurocognitive deficits after COVID-19.
And equally important was to understand
the basic mechanisms underlying this neurocognitive impairment,
so that we can develop appropriate biomarkers,
establish risk profiles,
and lay the foundation for early interventional trials.
Next. Next.
So, I'll be touching on the epidemiology and biology
as we know of SARS CoV-2, why we think there may be
an excess of this pandemic with AD/ADRD,
and what are the types of infrastructure
we are talking about.
And my colleagues, Professor Avindra Nath
from the NIH will address neuropathology,
Professor Gabriel de Erausquin
will address the clinical spectrum
and the modifying systemic factors,
and Professor Serena Spudich from Yale
will speak about biomarkers and possible promising interventions
that we might study. Next.
So, this -- next. This virus is an RNA virus.
It has and it's called the spike protein.
Which is how the virus enters the cells.
But it's, also, how vaccines confer immunity.
And then there are the nucleocapsid proteins presence
of immunity to which can address --
can suggest that there was native infection,
and not just vaccine-induced immunity. Next.
As of a month ago, over half a billion people
were known to have been infected with this virus.
And, likely, there are many more unsuspected cases,
so that as much as one in 10 persons worldwide
have had this infection. Next slide.
And we know that over time the virus has evolved.
So, you have had the Delta surges,
recently the Omicron surge.
And, next, unfortunately, large parts of the world,
the areas in brown, remain very poorly vaccinated.
And, so, the virus is likely to spread
and evolve in these regions.
Which may lead to persistence of the pandemic. Next.
So, why worry about ADRD in the midst of this pandemic?
Next. Some of the early reasons for alarm, next,
were that we know SARS and MERS, which are similar coronaviruses,
could affect the brain in some patients.
We know that anosmia, which is characteristic of COVID-19,
is an early sign in some neurodegenerative diseases,
like Alzheimer's and Parkinson's.
And the last time we had a pandemic of this proportion,
there was delayed post-encephalitic parkinsonism.
Next. There was, also, alarm
because there was a suspicion of trans-synaptic transmission
from the olfactory mucosa into the brain, next,
as well as perhaps trans-endothelial are carried
by macrophages movement from the blood system into the brain.
Next. However, at autopsy, the virus,
or even evidence of past viral replication,
is rarely seen. Next.
And, so, there are a number of theories,
some of which you will hear about,
about how the virus may be having the unquestionable impact
on thinking, memory.
Some of it may be that the virus enters certain glial cells,
and other parts, through receptors,
such as the H2 receptor in urapalin.
There is endothelial damage, micro trauma
by the impact of both systemic as well as local inflammation,
as well as changes in neurotransmitters.
What is unquestionable is that there are symptoms.
Next. What we do not yet know,
because the virus has only been with us for two years,
is that are these mostly temporary.
Clearly, in some people, they appear to be persistent.
And might they be progressive?
And what is the biology around this?
Here, I do want to emphasize that the working group
recognized that ADRD is a broad umbrella.
We are not necessarily only wanting to focus on amyloid
and tau pathology,
nor suggesting we know enough to suggest that the virus,
in fact, increases the risk of traditional AD.
But ADRD does also include VCID. It includes all the conditions
that have been discussed over the last two days,
as well as immune-mediated cognitive decline,
sequelae of sexes and inflammation.
Here is an opportunity to study this area,
as well as other mechanisms like mitochondrial dysfunction.
Next. And, so, we need models.
And, unfortunately, we are just at the beginning
of developing cell and animal models.
And, also, we need to understand
their translational relevance to human disease.
Some of the models that have been developed include,
next, IPSC organoids and assembloids
that have neurons and glial cells,
vascular and perivascular cells susceptible to the virus,
next, zebrafish with H2 receptors,
next, where you can see the impact of the spike protein
in inducing immunological and inflammatory changes.
Next. Some mouse models that appear
to be susceptible to COVID-induced,
next, anosmia resulting in being unable to detect food
or partners of the opposite sex. How relevant are these models?
These are things we need to study in the translational way.
Next.
We need to query the data hidden in electronic health records.
We already have data suggesting that the risk of COVID
is doubled in persons with pre-existing dementia.
It's, also, clear that certain populations,
like African-Americans, are more vulnerable to COVID,
having three times the risk of Whites. Next.
Is it, also, true that these populations
are more vulnerable to ADRD type pathology
developing or accelerating after COVID?
And, if so, why? Next.
One suggestion was that, in the pandemic,
caregivers were already under stress,
persons living with dementia
were less able to follow precautions,
and may suffer from withdrawal of things like social support.
Next. So, was the higher risk entirely
due to behavioral and environmental factors?
Next. There is a suggestion
that there was some biological and genetic factors
as well that may underlie the higher susceptibility to COVID
in persons with dementia. In this study from Finland,
3,000 hospitalized now patient cases
were matched to controls in this Finland cohort.
And persons who had APLE 4 were more likely to have severe
COVID, to have micro hemorrhages,
and also to have post-COVID mental fatigue.
So, genetic studies may help with risk prediction,
as well as understanding the biology,
and perhaps finding intervention targets. Next.
In the GEN-COVID,
which is looking at the genetics of COVID,
some genes not previously strongly associated with AD,
like oligoadenylate synthetase 1, were identified.
And then, subsequently, it was found
that these may have a role in AD as well.
Next. For instance, the OAS1 gene
seems to determine whether microglia are more
in the interferon responsive subtype,
or the amyloid response of an amyloid removing subtype.
And if you have a genetic variation
that predisposes you to have more microglia
of the interferon responsive subtype,
the hypothesis goes that you may be more susceptible
to both AD and severe COVID.
Again, this needs to be validated in further studies.
But this is the preliminary data. Next slide.
So, what are the kinds of infrastructure
we wish to emphasize? Next.
We, next, want to recognize
that there is opportunity in the pandemic,
in that factors beyond biology,
factors such as national health policies,
and the effectiveness in controlling the pandemic,
may also have a role in whatever we see in terms of sequelae.
For instance, when the global burden of disease
looked at depression and anxiety,
not surprisingly, during the pandemic, it went up.
But it, also, went up more in countries
where the health policies and effectiveness
in controlling COVID was less.
And this is, again, understandable. Next. So --
-Two minutes remaining.
-Next. We recognize that there are many factors,
such as the virus and variations in the virus,
next, as well as indirect factors like access
to physical activity and diet, next,
as well as, next, modifiers in the environment.
And, therefore, our recommendation, next,
emphasizes the need to carefully ascertain details
about the infection and treatment,
as well as the impact of policy interventions,
like paid family leave,
as well as the role of access to care,
and the possible benefit from innovative technologies
like telemedicine. Next.
We emphasize the need to use established clinical cohorts,
like the NIH, NINDSC
4R, the UK Biobank, which you'll hear about later,
as well as new longitudinal cohorts,
like the recovery effort, existing dementia cohorts,
like the ADRCs and NAC,
as well as the cohorts that were exposed to acute trials,
like monoclonals that might reduce the severity of COVID.
Next. And to record --
to collect fluids and use novel imaging techniques,
next, harmonize the various measures of cognition
and other modalities, next, so that we can rapidly implement
in parallel candidate drug screening.
And with this natural history and biomarkers known,
go forward for treatment tracks. Next.
-Time.
-We will be looking at both population-based,
hospital-based, and other types of clinics,
next, novel methods that look at areas
that may be susceptible to MRI --
to COVID, such as the locus coeruleus
and the olfactory lobes, next,
and emphasize longitudinal data collection.
Because there may be a delayed impact of the virus
that is only detectable with repeated assessment. Next.
So, I'll now hand over to my colleague,
Professor Avindra Nath,
to discuss the neuropathology of the virus.
-Thank you, Sudha, for the wonderful introduction.
And so I'm going to talk about the neuropathology.
And if you look at the various syndromes associated with COVID,
can be divided into three major categories.
One is during the acute phase
when the patient is admitted to the hospital.
At that time, there is a lot of end-organ damage,
and so there's no surprise
that the brain is going to get involved.
However, the brain can be directly involved
by vascular disease and very, very rarely,
are there any cases of true viral encephalitis.
Then you have the subacute phase
where these are largely post-viral syndromes,
but they're all inflammatory syndromes.
And you can see them with almost any kind of viral infection.
So they are acute disseminated encephalomyelitis,
necrotizing encephalopathy, limbic encephalitis.
So they are mediated by very specific types of immune cells.
And then there's a unique syndrome
associated with the virus in children
that is called multi-system inflammatory syndrome.
Well, we're going to spend a lot of time
talking about chronic manifestation,
which is long COVID. Next slide.
So just as Sudha said,
you know, the concern was, early in the pandemic,
that can the virus really enter the brain.
As you can see here, in the cribriform plate
is this very thin piece of bone
that's separating the brain from the nasal cavity,
and there are all these olfactory nerves
traversing this cribriform plate.
So the question is, can the virus really get in?
It turns out that the olfactory nerves
themselves never get infected,
and what gets infected are really the sustentacular cells,
which are the support cells. So next slide.
And so if you actually look for virus in these regions,
what you find is that the olfactory --
because it has a lot of virus, okay?
And the olfactory bulb and the tubercule,
very rarely do you find any virus at all.
So it really stays in the mucosa.
And as you can see on the right-hand side,
these small viral particles,
these round structures are viral particles here
that causes a huge amount of virus,
and because of that, that's where it stays.
Next slide, please. So there are other groups
that have detected small amounts of virus in the brain,
but you find it very infrequently,
and when you do find it, you don't find any inflammation
around the areas when they detect them,
so we don't think that is of much pathogenic significance.
We, and several other groups,
have failed to detect any virus in the brain
using a wide variety of very sensitive techniques.
Next slide, please. And what I want to emphasize
is that the major pathology really is vascular injury,
and I think that has a lot of implications
for microvascular disease and Alzheimer's-like pathology.
So next slide, please. And so the vascular pathology
can present in many different ways.
You can get frank infarcts. You can get bilateral infarcts.
You can get brain and other organ systems
where blood vessels can get occluded.
And then there are individuals who can get microhemorrhages
and other individuals who can occlude the venous system,
and you can get cerebral venous thromboses as well.
Interestingly, the study here looked at microhemorrhages,
and what they found was that those individuals
who are APOE positive are at greater risk
of developing hemorrhages,
looking at different parts of the brain,
as you can see here.
And there's more severe hemorrhages,
and more areas are involved. Next slide, please.
So besides frank hemorrhages, you can also see --
without the presence of hemorrhage,
you can still see microvascular pathology.
And here, what we did is, we did postmortem MRI scans,
and these are very high-resolution scans
using 11 Tesla scanner.
And you can see, these blood vessels here,
they look abnormal.
And when we stain them for fibrinogen,
which is a protein that should be present
only in the blood and not outside,
you actually see the leakage of fibrinogen.
So these blood vessels are really very leaky.
So they aren't leaking RBCs, but they're leaking proteins.
Here in the olfactory bulb,
you find the exact same thing, too.
There was a lot of fibrinogen there.
But within the blood vessel itself,
you can see aggregation of platelets.
So this is another form of microvascular disease here now.
Instead of them leaking,
the endothelial cells are activated
to whereby the platelets stick to them, and they get activated.
And you can see occlusion of the small blood vessels
here as well from these platelets.
And what we find is that you see it more often in the hindbrain,
which is the brain stem and the cerebellum,
and we looked at all kinds of controls.
You don't really see them. You only find them --
it's quite specific for these COVID patients.
Next, please.
There are some individuals who developed tinnitus,
acute onset of ringing of ears.
It's associated with loss of hearing.
And next slide, please.
And others that would develop acute onset of vertigo.
We think these are actually vascular phenomenon,
and that is possible that the small blood vessels
supplying the inner ear get occluded
because it's fairly sudden onset in these individuals.
Next slide, please. Okay.
Then there's the subacute phase. Next slide.
And as I said, you know,
you can get acute disseminated encephalomyelitis
as shown over here.
This is largely a T-cell-mediated phenomenon.
Some get necrotizing encephalopathy,
which is largely a cytokine-mediated phenomenon,
so those things are very important to recognize
because they're treatable very differently,
and the long-term implications are also different.
Next slide, please. And then, in children,
you can get this multi-inflammatory syndrome.
As you can see on the screen, in the corpus callosum,
there's a high-signal intensity lesion here
and loss of inflammatory markers.
So the long-term consequences of this
are not fully understood. Next slide, please.
Then, as I showed you earlier,
you know, there's leakage of proteins,
but if you look for the cellular infiltrates,
you find they're largely macrophages.
I think they're coming in there to clean out
all the proteins that are leaking,
but once the macrophages enter there, they don't leave.
So they will cause a lot of damage to surrounding tissues.
You hardly ever find any T cells,
and that tells you that, if it was a viral encephalitis,
you should see a lot of T cells.
You actually don't see any. No.
And you got astrocyte activation here, too.
Yeah, next slide. You can get peripheral nerve involvement.
So you can see the cranial nerves
as well as the roots coming out
can get inflamed and involved as well.
So you can get widespread peripheral nerve involvement.
Next.
And in some patients, you can also get myositis.
As I said, inflammatory myositis,
that responds to treatment with high-dose corticosteroids.
Next slide, please.
-Two minutes remaining.
-Next slide.
Well, what is important is that most patients,
they will recover early on for about three months or so.
If they don't recover by three months,
most of the symptoms start to persist,
and you see it more often in women as compared to men.
That again suggests to you
that it's an immune-mediated phenomenon,
most likely. Next slide.
So there are these individuals who, as I showed you,
they have severe symptoms initially.
They gradually got better, but not completely.
Then there are other individuals with mild symptoms,
they get better, but after a certain latent period,
they then get new symptoms again.
Okay. Next slide.
And we looked at a cohort of these individuals.
Almost all of them have cognitive abnormalities
as well as fatigue
and then a whole host of neurological symptoms
that are to a lesser degree. Next slide.
And so you can divide these patients into four groups,
some that have largely cognitive and mood and sleep disorders,
and I think that's the category that you're more interested in,
but there are other types of long COVID syndromes
that can present in these individuals.
Next slide.
And PET scan shows that these individuals
have decreased uptake of glucose in a more symmetric manner
involving the cortex.
So the cortex is diffusely involved
in these patients in the subacute group.
Next slide.
And this very recent study from the UK
shows that there is also -- they looked at this cohort
before and after development of COVID,
and it was a unique cohort,
that the total intracranial volume is decreased.
There is hippocampal --
the gyrus is actually decreased and preferentially
and is associated with impairment of cognition as well.
So I think this is actually quite concerning,
and long-term follow-up will reveal what's happening.
Next slide, please.
-Time.
-Okay. Next slide. I'll just skip this one.
-And eventually, you can actually see neuronal loss here,
and we've shown that in the brainstem.
Note when you get activated microglia,
you can see loss over here. Next slide.
So, in conclusion,
direct invasion of the brain by SARS is rare,
and neuroimmune dysfunction, I think,
is by activation of innate immune responses,
and endothelial damage is the primary
pathophysiological process in Nero-COVID.
Next slide.
And these are our acknowledgements.
I'd like to thank each other people
who helped us with obtaining the tissues.
Serena and I ordered a review on this quite recently.
And these are the people in my lab who did all the work.
So I'll stop here. Thanks.
-Yes, Professor Erausquin.
-Thank you very much.
I'll get straight into it in the interest of time.
My run is to cover the clinical side
of the neurocognitive dysfunction after COVID-19.
Next slide, please. I don't have any disclosures.
Next slide, please.
And this has been a topic of concern
right from the beginning of the pandemic.
The publications about cognitive impairment in initial case
reports began in the immediate months
after the onset of the spread of the virus
and have continued to increase over the past 18 or 20 months.
What's more remarkable is that, from very early on,
the public eye also caught interest
in this particular phenomenon,
those initially described by patients,
by sufferers, as brain fog. Next slide, please.
The source of data have become increasingly sophisticated.
Initially, where I also mentioned case reports,
then more protracted,
more extended case series began to appear
involving primarily hospitalized patients
during or immediately after the acute phase of the illness,
and those follow-up appointments in clinics
describing persistent symptoms, as Dr. Nath already mentioned.
But better quality data perhaps and more relevant
from the point of view of the neurological importance
of this particular phenomenon
began to appear in surveys of patients
who were well characterized and being followed as part of
longitudinal cohorts,
such as the ones that Dr. Seshadri mentioned,
including Nath the framing of her study
or the San Antonio Mexican-American
pharmacy studies, which had --
all the individuals who had been well characterized
and followed for a protracted period of time.
The biggest disadvantage of those cohorts
is that the relative number of affected individuals
was small and persists rather small.
So the better quality data are beginning to emerge
from new cohorts developed from population-based databases
or registries and include all individuals
who have been tested for COVID
during the course of the pandemic,
whether they came back positive or negative,
and that will be where I would focus more of my comments.
Next slide, please.
For instance, again, as Dr. Nath already mentioned,
there are good quality data from separate port of patients.
This is coming primarily from the UK biobank
that Dr. Seshadri mentioned,
pointing to the fact on the left top panel
that persisting symptoms are quite sustained.
Once they're present, after the few initial weeks
of the recording of the illness, they don't seem to go away.
More notably, the bulk of those symptoms
and the ones with highest probability,
they are on the bottom left panel --
brain fog, memory issues, and difficulties with language.
But if you disclose a bit more on the top right panel,
you find that include primarily short-term memory loss
and word-finding difficulties. What's most remarkable is that,
if you consider the presence of the symptoms
on average across age groups, they seem to be, you know,
more or less the same across different strata of aging,
but when you disclose that in greater detail,
it turns out that younger individuals
have more much prominent problems
with attention, concentration, and executive dysfunction,
as opposed to true fewer memory problems
that appear to be much more prevalent
and severe in other individuals.
Next slide, please.
In the largest US-based study that was published
by Biden's administration recently,
they found that the neurocognitive decline
was actually two times more common in individuals
who had suffered COVID
and recovered within a relatively short time,
30 days after recovery than in historical controls,
when they looked at a very large sample
of close to 6 million people or contemporaneous,
so having controls that did not have
the disease in equal large number.
So this is quite clearly a unique phenomenon
to recovery from COVID. Next slide, please.
What's most important is that it's not
just when you compare the individuals that recover
from COVID to the general population,
but also if you compare them with individuals
who recovered from other,
similar respiratory flu-like syndromes.
And in this particular case,
the comparison was made to influenza.
And you can see that, as far as six months after recovery
from an acute respiratory severe illness,
flu-like illness, if the illness was COVID,
the likelihood of cognitive impairment
is almost two-fold
that of the patients that recovered from the regular flu.
The pattern of symptoms is actually similar, too.
Again, to what Dr. Nath mentioned, quite broad.
It includes things such as fatigue, muscle pain,
other forms of bodily pains,
occasionally anxiety and depression,
but more prominently, cognitive impairment.
Next slide, please.
The predictors of this COVID impairment
that appears to be quite peculiar
to recovery from SARS-CoV-2 or to the infection of COVID
are still open to question.
I'm going to show you two studies
from different sources of data
that lead to somewhat different conclusions,
and I will go back to this point a little bit later.
On the bottom two panels,
what you see is data from the UK biobank.
So these are retrospective data on patients across the board
who had suffered COVID and most of whom were hospitalized,
but as you will see in a moment, not all of them.
It's a very large sample.
And on the left panel, what you see is the prevalence
of what they called dementia-like symptoms,
meaning prominent impairment in several cognitive domains,
including memory, language, and executive function.
And this was compared to other respiratory tract infections,
patients who had recovered
from other respiratory tract infections.
You see again that the likelihood of developing
these chronic symptoms following COVID is almost two-fold.
And this was much more prominent
in the post-hospitalized patients who had encephalitis,
and that's the red line here,
compared to the dotted line there,
which are hospitalized patients without encephalitis,
or inpatients who were not hospitalized
the length here that did not have --
compared to those that did not have the respiratory infection
in the bottom dotted line.
So the bottom line is, in the UK biobank data samples,
severity of the disease, particularly having encephalitis
or being hospitalized, resulted in much more likelihood
of having dementia-like symptoms.
The top part, on the other hand,
is the community-based sample for Amerindians
from Northern Argentina in the Andes Mountains
that shows that mechanical ventilation, ICU admission,
or oxygen dependency during the acute phase of the illness
did not predict a positive outcome,
and on the other hand, the presence of persistent
anosmia several months after the recovery, did.
Next slide, please.
-Two minutes remaining.
-What this translates to is to a very large increase
potentially in cases of cognitive impairment
for the US population as a whole.
If you consider that as many as 3 and 1/2 million cases
of new cognitive impairment
will be present in the next two or three years, you know,
assuming that this data remain as they are now,
that would represent a more than two-fold
increase in the number of cases and a large increasing burden.
Next slide, please. What's most concerning
is that this may not be evenly distributed
among different subpopulations within the United States.
Indeed, we don't know if rate of infection
or rate of hospitalization will result, as I mentioned,
in higher increases in cognitive decline.
But we do know that under-represented populations
are at much higher risk of having severe disease
and having hospitalization.
So there is a chance that they may also sustain
a much larger burden of disease.
Next slide.
This is particularly important because,
as I mentioned, in the Amerindian population
that we started with the registry,
the severity and frequency of cognitive impairment
reaches about 40% of the sample. Next slide.
So, as next steps, I think we need to concentrate
on understanding what are the variations
in the clinical phenotype of neurocognitive amoralities
following COVID that are just now beginning to be described,
and particularly the relationships of clinical
manifestations with underlying biology
as Dr. Seshadri described in great detail.
I think it's of the highest importance
to establish and detail a course of this cognitive impairment
as well as histology resiliency cultures
and possible targets for myofibril risk,
and we need to understand the role of variations
in the viral genome as well as the interactions
between the various variants and host risk/resilience
factors affecting this cognitive decline.
Environmental factors,
including social structure and systemic inequalities,
appear to have profound effects
in the morbidity and mortality of COVID,
and it is really urgent to understand
if they will also affect the long-term cognitive outcomes.
Thank you very much.
-So thank you very much for inviting me to give this talk,
and as I'm following a couple of really fantastic presentations
that really, I think, set this talk up very nicely.
So the focus of this talk is really looking at biomarkers
of COVID-19 and thinking about what they may be able
to teach us about potential clinical trial targets for AD
and ADRD-related to COVID. Next slide, please.
So I have no disclosures. Next slide.
So, again, I'm reflecting and following up
on three wonderful presentations that have really highlighted
the questions that are laid out for us in identifying biomarkers
and disease treatment targets.
And just to take a step back to the clinical presentations,
of what the clinical presentations have taught us
about pathophysiologies, underlying neurological
and psychiatric conditions in acute COVID-19,
a really fantastic UK-wide surveillance study
has looked at cases of people reporting to the hospital
with clinical presentations
that relate to COVID and neuro and psych symptoms.
And I think what their investigation
has really highlighted is that there's different
pathophysiologies underlying the conditions,
as we've heard from the previous presenters.
So in this graph, in the first column,
we have cerebrovascular disorders,
and these are organized by relative frequency of onset
related to the onset of respiratory symptoms.
And the cerebrovascular disorders in the first column
are starting very early and even pre-dating
the COVID-19 respiratory symptoms,
but the other disorders highlighted in the red boxes
here are disorders that we typically think of
as being immune mediated or inflammatory diseases,
as Dr. Nath pointed out beautifully.
Many of these started a week or two
after the onset of respiratory symptoms.
And I think that what this highlights
is that there are diverse pathophysiologies,
and we really need to try to understand all of them.
Next slide, please.
So thinking about acute COVID-19 and what kinds of biomarkers
have been revealing and seemingly showing us
what some of the biological mechanisms
are in these conditions. And you heard about inflammation
and looking actually at autopsy samples,
but in fact, cerebrospinal fluid has been collected
in limited numbers of people who have had acute COVID-19,
and they have also revealed neural inflammation.
This is a very small study of only six people studied early
in the pandemic who had neurological complications
during acute COVID-19, and these samples revealed
elevations in biomarkers of immune activation,
such as neopterin and beta-2 microglobulin
in the spinal fluid.
Here on the left, you can see that the dotted line
is the normal value in healthy control subjects,
indicating that inflammation was very prominent in these people.
At the same time, this group did not definitively
detect SARS-CoV-2,
and again confirming what's been pointed out
in previous talks that viral invasion does not seem
to be a prominent part of the disorder.
Next slide, please. So other CSF biomarkers --
and you saw this slide briefly earlier --
have also been looked at,
and I think this is particularly of interest in a group
that's concerned about the onset of neurodegenerative diseases.
So again, in acute COVID-19,
CSF samples that have been collected in people with COVID
and neurologic symptoms
have revealed changes in amyloid processing,
so reductions in soluble amyloid precursor protein
and amyloid beta during acute COVID-19
with neurologic symptoms.
I think, again, this is something that raises concerns,
but we really don't know the long-term implications
of these findings.
Next slide, please. How about blood samples?
And I think it's been very fortunate
that, of course, blood has been much more readily detected,
readily measured and collected for research
purposes in patients with COVID-19.
So this is a much larger study coming out of NYU
that collected blood in 246 individuals
who had acute COVID-19 while they were hospitalized.
And this study very nicely
compared levels of neurofilament light chain,
which is a marker of active neuronal injury,
as well as glial fibrillary acid protein,
which is a marker of astrocyte injury.
And this study revealed quite robust elevations
in both of these markers in people who had acute COVID-19,
and they very nicely compared those to people
who they considered normal, healthy controls as well
as those with mild cognitive impairment
and active Alzheimer's disease,
showing that the extent of these elevations
was really quite marked,
even compared to the individuals with neurodegenerative disease.
I'll say that both these changes,
as well as the changes in amyloid precursor proteins
and amyloid measures,
are also seen in other acute infectious conditions,
including an acute HIV infection.
So I think that we have to look at this
as a marker of an acute injury
that may not have long-term clinical effects.
Next slide, please.
A much more sort of in-depth research study
has been recently conducted here at Yale
by one of my collaborators, Dr. Shelli Farhadian,
where she looked not only at markers in immune activation --
and this is looking at CSF cytokines on the left
where those in purple are those with COVID-19
and those in green were healthy controls --
and showed that the CSF cytokine patterns
were not only abnormally elevated in the COVID patients,
but they actually were different than the cytokines
observed in the blood, suggesting that there's
a compartmentalized immune reaction.
She also found that there was an elevation
in the frequency of B cells in the cerebrospinal fluid.
And when the B cells --
since B cells produce antibodies,
she investigated whether or not the antibodies
seem to be directed against SARS-CoV-2 or some other target.
And in all of the examples, there were antibodies
detected against SARS-CoV-2 in the spinal fluid,
and some of these differ than the patterns
of those in the blood.
But interestingly, some of these antibodies
also were autoreactive to brain tissue,
suggesting an element of autoimmunity
underlying some of these conditions.
I'll say that I also indicate on the slide that, again,
looking for presence of virus, very few published cases
have detected SARS-CoV-2 in spinal fluid --
less than 3% of published cases --
suggesting again
a neuropathogenesis that's really immune mediated
and potentially vascularly mediated,
as you've heard from Dr. Nath,
rather than a direct viral infection.
Next slide, please.
So moving to this issue of long COVID --
and I think, here, we have many more questions
than we have answers and data,
but one can imagine that some of these underlying conditions
that we're seeing in people who are having persistent issues
after recovery from acute COVID-19
could be related to some of the pathophysiologies
that are seen in acute COVID. Next slide, please.
-Two minutes remaining.
-Great. So one possibility is that persistent inflammation
or ongoing immune activation or abnormalities is underlying
some of the longer-term complications of COVID
after recovery from acute illness.
I have to say, I think we have very little clear evidence
that that's actually true at this point,
but many studies are ongoing.
This is a tiny study of individuals
who had cancer and neurologic symptoms,
and those in red here are shown
who have cancer and neurologic symptoms after COVID,
versus cancer and neurologic symptoms without COVID.
And in this study, there was a higher CSF inflammatory score
in those people who had COVID. Next, please.
Another nice study has looked at individuals
who were prospectively studied from the time
of their acute hospitalization and then three months later.
And in this study, individuals
who had very high baseline blood inflammatory markers
were more likely to have long-term depression
and neurocognition abnormalities at three months. Next.
I think both of these studies are just little hints
that these may be issues, but we really need to understand
how these relate to more long-term symptoms
in people who have had milder disease.
Next slide.
What about neuroimaging biomarkers?
You heard again from Dr. Nath
already about another study, different from this one,
that found regional hypometabolism,
changes in glucose uptake in the brain of individuals
after COVID who were having long-term neurologic symptoms.
And in this study, the PET metabolic values
were actually related to the degree of symptoms,
such as changes in memory, pain symptoms, or anosmia.
Next slide.
-Time.
-So you also heard already about this UK biobank study,
and I think this is also very convincing
and concerning that, in people in whom data
was available before and after COVID,
there were regional changes in brain structure size.
Next slide.
-So, with apologies, Serena,
we have to go the question and answer.
-Yeah. That's no problem.
My last slide is just really a summary
of the questions to be looked at,
so the next slide, you can just show this one,
and looking at targets for treatment.
Thank you so much.
-Thank you all very much. Really appreciate that.
So we're going to go to the Q and A for this session.
I think everyone's gotten the hang
of putting their name into the Q and A box.
We have a few people there queued up.
Dr. Rost, I don't know if you're going to want to enter,
talking to the question askers, or do you want me to do it?
You're muted.
-Natalia, your sound is not working.
-Yeah, your sound is a little funny.
So why don't I do it first?
Dr. Dacks, Penny Dacks, you're the first questioner for us.
-Thank you. Hi, Penny Dacks again with AFTD.
Though I should say that I'm not commenting
right now on behalf of AFTD
but as a family member of two very sick people,
including a 10 year old child.
There's a lot that I think we still need to disentangle,
right, in terms of,
and I think you guys did a really great job
of outlining the different areas
there where we've got aspects of long-term chronic stress,
social isolation, anxiety and depression.
And we know from epidemiology for years
that those all have links to dementia onset
that may not necessarily
be long-term pathological factors there.
And we can assume that severe acute COVID infection
that has hospitalization,
that has ventilation is going to pose hypoxia
for one thing that could have immediate acute effects
on vascular function,
on the underlying neuropathologies of the ADRDs.
And we have this third situation where you've got young people,
right, who had mild acute infections
that are having this long COVID, of chronic fatigue, anxiety,
depression, headaches, neurological symptoms,
all different kinds of stuff.
And every single one of those different clinical situations
are profoundly important to understand.
When we think about how this is going to impact
their long-term risks of dementias.
And I just wanted to put a plea out there
that we are very, very careful
about how we define the work that we do.
Because the work that's being done in the hospital
as patients who have severe acute symptoms,
I think biologically could be very, very different
from what's happening in the more mild acute
but chronic situations.
So it's really just a plea
that as we come up with a nomenclature
and as we come up with how we define these things,
we are very cautious with the data
that we put in there to make sure
that these are the separations across these categories
of clinical situations can be more readily understood.
So that if you've got blood data
that's being drawn from the clinic,
for example, in the hospital, you can better,
you actually know how severe was that initial acute infection
and separate that out from the people
who are two years out
still having severe cognitive problems.
So thank you for all the work you're doing.
-Thank you so much for that personal perspective
and those important points Serena, did you want to respond?
-Yeah, sure. That's an absolutely critical point,
and I think one of the major gaps
that we have in knowledge
about what's happening in the nervous system in COVID-19
is actually in people who have mild disease.
Most of those individuals
are never enrolled in research studies,
and even now, we have very little sort of, you know,
ability to capture those kinds of data
in people who have acute COVID-19, right.
And then there are concerns for research participation
and infection risk. But it may be that it's a very,
very different type of trigger of symptoms and of syndromes,
and the biology may be different.
So we're taking clues from what we've learned from people
in whom data and sample, et cetera,
have been able to be collected. But I think thinking about
how there may really be different categories,
and the nomenclature is absolutely critical.
And one of the things we've learned from COVID
is there's incredible heterogeneity in this condition,
in all organ systems in all ways.
And we have to be very accurate and careful
making sure we don't group things inaccurately
because then we will not necessarily
make the right decisions and recommendations going forward.
-Thank you.
-Professor Bovenkamp.
-Well, Gabriel has his hand up first.
Sorry, my voice, my mike is back on.
-Thank you, Natalia. Yes, I agree.
I think those are hugely important questions.
And not just questions at this point
but rather what appears to emerge
as the one supported line of thought
which is that the disease in milder cases,
that are detected in the community
that have not been hospitalized that have,
you know, cold symptoms or a mild flu-like syndrome
and normal chills has chronic manifestations
that are phenotypically different from those
who had severe incapacities or other acute severe illness.
And they, the point that Dr. Nath made
which is that this is going to be, manifestations of this
is appearing more common in women,
is true only for the younger population.
Not necessarily for the older population.
But that's one of the phenotypic differences.
Another one is that in the younger individuals,
the cognitive symptoms appear to be most prominently
in attention and difficulties with sphere of processing
as well as some executive dysfunction.
Whereas with all the individuals,
the most prominent feature in at least half the individuals
appears to be intense episodic memory impairment,
more resembling what you would expect to see
in a patient with early Alzheimer's disease.
So I agree. These are massively important questions.
And there are enough data readily available to suggest
that there may well be more than one clinical picture
emerging in the chronic space.
-Thank you, Gabriel. Diane, Diane Bovenkamp.
-Yeah.
So yeah, so I just had a number of questions kind of,
this has been a really great session, thank you.
I think, and I think in terms of detection,
we need to be able to detect it even
if they don't have COVID listed in their record, right.
There needs to be a way to detect it
because of the stigma associated with it
and people not wanting to miss work, right.
So and then talking about, you know,
women might get it more,
and then are there comorbidities?
We need to mark that.
Are people who already have inflammatory diseases,
are they more prone to it?
So this is where we need to collect the big data,
and we're all about the data sharing.
That's pretty important too.
So but one of the things that Avi was saying
was the vascularity.
So is this where, again, jumping on the eye bandwagon,
you know, we're looking for something that's noninvasive,
that you can try and detect.
Can you try and look at these differences
that might appear in the eye?
And I'm just going from the associate, the AAO.
It's an association, there's like four differences
that you can see in the eye from COVID.
So there's like cotton wool spots.
There's retinal vein occlusions,
things like that, that can be looked for.
So maybe just include some of those.
I don't know if I saw those in the description here,
but if those can just be addressed by the committee,
that would be great.
-Avi, do you want to speak to that?
-Yeah, sure. So I agree.
I think the eye is the window to the brain,
and the vascularature is a good place
to look at certainly in the retina.
But in addition to that, the other noninvasive ways
of looking at the vasculature, you know,
one can look at a number of blood-borne markers,
for example, B-select and E-select
and VJEF you know, and some of the MMPs.
So they indicate not only vascular damage but angiogenesis
that is probably taking place at the same time.
So they are currently available in research labs,
but there's no reason why they couldn't be standardized
and be used more commonly in patient compilations.
-Thank you.
-Ron, do you want to comment on that as well?
-No, I have a different question.
-A different question.
Before we move to a different question,
I actually wanted to ask Andrea Troxel to comment
on what's already been collected
and whether there are any additional systemic tissues
or tissues that could be helpful to diagnose
this experience of the biobank and databank.
-Thank you.
So far we are collecting samples that are preexisting for,
that have been used for diagnostic or other reasons
and are left over.
So we're sort of up and running to accept anything.
And I'd actually love to turn that question back around
to this group and hear from all of you
if there are particular kinds of samples
that would inform this question more directly.
We can certainly reach out to our sites and let them know
that those are specifically what we're looking for.
And in terms of data elements, similarly,
we have a set of common data elements that we're asking for.
We have a relatively restrictive set of sort of required elements
so as not to overburden sites with data entry.
But we have a much wider set of optional data elements.
And so again, if there are particular suggestions
that folks have for what would be most useful.
You know, whether it's related to this recent, very recent,
very interesting discussion about the eye issues
or other more general things
that have come up during the session today.
We'd be very eager to hear from any of you about that
and try to think about adding those to our, to our set.
-Sudha, are you trying to comment on that?
Do you want to comment? -Yes.
In the neurocognitive working group of recover,
sensory motor biomarkers are being refined.
Not on everybody but particularly on persons
who endure some symptoms.
And this is just a participant burden issue.
So any comments are very welcome.
So there are individual studies that are looking at things like
OCTA as potential markers of future development
of ADRD-like symptoms.
-Thank you. Ron.
-Yeah, I have a question for Serena actually.
You mentioned in passing implications
for clinical trials in AD and ADRD.
Do you think that trialists should be taking a history
now of their participants?
Have you been exposed to COVID? What's the documentation?
And secondarily, since fluid biomarkers
are being used commonly
and are projected to be used even more avidly,
going forward for enrollment in clinical trials,
might the markers that you have identified
vis-a-vis COVID exposure alter those,
those biomarkers, those fluid biomarkers,
and how might we take that into account?
Simple answer, I'm sure.
-Those are two fantastic questions.
So for the first one, you know,
when I was talking about clinical trials,
I was really going to kind of outline
some potentially protistic clinical trials for COVID.
So people who are maybe having long COVID symptoms,
maybe immune interventions or sort of vascular interventions,
et cetera.
I do think that this, you know, has changed the landscape
for all clinical trials for everything.
And certainly now when we see patients,
I'm a clinician, when I see patients
I ask every single patient, have you had COVID?
Do you know what's your test results?
When was it?
How severe was your disease? Were you hospitalized?
That actually goes into I think a relevant medical history
for pretty much everybody these days.
And I think related to clinical trials
and outcomes and interventions and clinical trials,
that that should be important and integrated.
I think in terms of the biomarker changes,
the, for example, fluid biomarker changes,
the neuronal injury markers, I think before we know
what long term effects may be reflected by COVID,
we need more studies.
So for example, the data that I showed,
very relevant to the very first comment.
They were all in acute, hospitalized,
very sick patients.
We have no idea whether those things
will be persistently abnormal in people with long COVID,
but that's what we need to learn.
Because it may be that that has implications
for subsequent neurogenerative diagnosis or conditions.
So fantastic questions.
-Good, thank you.
-Thank you, Serena. Gabriel.
-I think he's muted.
-I thought you were muted.
-If I may go back to the stigma question for a second.
In our long COVID clinic, we routinely ran, get this off,
a relatively well-documented profile,
chronic inflammatory markers
in people who continued to express cognitive
or other physical symptoms,
you know, chronic fatigue and whatnot.
And we have found that actually either,
usually two or three C-reactive protein [Indistinct]
consistently abnormal in these people.
So that is helpful in terms of their own,
if you will, recognition of the state of being ill
and as the documentation in the chart
that they are not making up their symptoms.
So I, you know, they may not be very useful
as long term markers of specific aspects of the disease,
but they are enough to show that these people
do have a chronic inflammatory process
that seems to be affecting them, their performance.
-Thank you. We're going to take a couple more questions,
and then we're going to take a short break.
And just remember that we have a general session.
So everybody is going to be able to have an open mike
once we go into that. So next is Nick Torado.
-Thank you.
It was a really fantastic panel, so thank you very much.
My question was related to a fairly common complication
that has been reported in COVID-19
and also outside of the sphere about delirium.
And I wanted to hear from the panel
if there is a way to disentangle complications
that are raised from delirium which already connects to AD
and ADRDs versus something
that might just be very specific to COVID-19.
Thank you.
-Thank you. Nicole wants to take a crack at that.
-That's a very important point.
Both to disentangle and, I think,
some of the studies are trying to get illness controls,
non-COVID illness controls from the same period of time
or refer to historical controls
like the European study in Denmark did.
But we may also,
by studying delirium in the setting of COVID,
learn something about a condition
we have still inadequate understanding of,
which is the acceleration of dementia
after episodes of sepsis.
So you bring up a very good point.
This is something we need to carefully address.
The fact that symptoms are occurring
even in persons who never go to an ICU
or never have delirium means
that there's probably different pathologies
perhaps of these subgroups.
Speaking again to the earlier point
that we shouldn't lump cognitive impairment after COVID
into only one biological box.
-Thank you so much.
And that delirium was on my mind
as I was listening both to Avi's and Serena's presentations
thinking about how do we,
how do we, how do we measure that pathology, you know?
How do we measure the cell injury
or perhaps network injury in vivo as we are monitoring
these patients both in, you know, with severe illness,
you know, not necessarily, you know, systemic illness.
And also, those who are just so easily tipped,
you know, over the, you know, over the edge with,
you know, even with mild infection.
So that's something to think about.
And I'll take the last question from Helen,
and then we will move into a break.
And then we will go into a general session. Helen please.
-Yeah, Dr. Rost, I just wanted to comment
that I have a daughter who's an RN
and works in a large medical center.
And throughout these last several surges,
they've had infected nurses on the units
infecting their fellow coworkers.
And as, as you're looking at sampling
and access to individuals
who may be available to be participants in your studies,
I would look to the workforces that were responding to this.
They include a broad age range.
We have several that, you know, yes recovered.
Some that have mild long COVID.
Others that are profoundly infected.
So that was, that was the only thing
that I wanted to contribute.
This has been an extraordinarily in depth
and very, very important presentation. Thank you.
-Thank you very much.
Anybody from the panel wants to comment on that
or we just leave it as an acknowledgement.
Thank you, Helen, for this comment.
All right, well this was a fantastic presentation
by this very newly formed working group,
and I hope this heralds the many more years of,
you know, exploring this problem and answering
some very important questions in the future.
And we wish we didn't have this problem
starting two years ago, but we do.
And that only adds to the complexity of the AD and ADRD.
And I think we are ready to take it on.
So thank you again everybody.
We're going to have 10 minutes of a break and --
-Can I just, can I, sorry,
can I just say I just want to really enthuse
for a second about this session and what we just saw.
And I also want to, I want to really encourage
everybody to come to the, to the open session
that Dr. Rost will lead in a few minutes.
It's an opportunity to kind of synthesize
with our scientific chair leading the kind of
input that we've heard over the course of the meeting,
and this is a consensus process.
It's the final opportunity at this meeting to provide input.
So please join us for that
which should be a very lively discussion.
Thank you.
So the first session yesterday was health equity in AD/ADRD.
And, and some of the, of the comments
that I wrote down during the session include
that the, there's been a conscious shift,
certainly there's been a conscious shift over time
to prioritizing health equity.
As well as life course in the ADRD summit
and in the field in general.
We'll want to follow people in depth
and get perspective including about individuals
from diverse backgrounds and develop tools and materials
that will inform on trajectories for AD/ADRD in health equity.
And I think, you know,
you see the recommendations in front of you.
I think a nice way for this to work
is just to kind of take a look at them,
and we will open up the floor to people's final thoughts,
comments and questions on health equity.
And first up in the queue
we have Michael Ellenbogen. So Michael.
-Thank you so much. -Yeah, please, go ahead.
-As you know, ADRD is not high on the radar
because it's not contagious.
I am also not one to be an alarmist,
but given what we have learned in the last year,
should we place ADRD at a much higher priority
as we don't know what the outcome will be
because of COVID-19.
We already know that existing ADRD projectory
can bankrupt this country.
I sure hate to see if COVID accelerates the process,
what would that likely mean if we're not prepared?
Thank you.
-Thank you for that comment.
I think that it's very important for all of us
to continue to put Alzheimer's disease
and Alzheimer's disease-related dementia
and related dementias higher in our priorities.
And we hope this summit is helping to do that.
Next up in the queue we have Kathy Service.
-Thank you. Thanks so much.
And I've really been enjoying this conference
or symposium, so thank you.
But I'm talking related to diversity and accessibility,
and I wanted to remind the group
to remember people with neuro atypical conditions,
such as intellectual disabilities,
which includes Down syndrome.
And I was pleased to see that mentioned on an earlier slide.
And also people with autism. Lifelong sensory impairment,
severe mental illnesses and TBI which you addressed.
I'm a nurse practitioner. I've worked for over 40 years
with people with intellectual disabilities.
I'm also on the board of the National Task Group
for Intellectual Disability and Dementia Practices.
I'm also a family supportive volunteer
with the Alzheimer's Association
and Dementia Friends champion trainer and volunteer.
At our local hospitals, they have a care ecosystem program,
and I volunteer with a 90 year old woman
living with dementia doing some socialization.
But in all these endeavors,
and I'm find that increasingly more that people
with these atypical conditions
are coming more and more into our realm.
You know, people living outside institutions, et cetera.
And all this people also from this population
have a variety of caretakers,
many of whom provide lifelong caregiving for people.
And I just wanted to give you an example
that a local geriatrician asked me to kind of help out with.
She was asked to assess a 70 year old man with autism
because his PCP suspected he may have dementia.
Because this man had demonstrated
some behavioral stress in an office visit.
And most the screening tools we know are inadequate
for these groups of people.
It took me a while to make an assessment,
and I suspect he might have had maybe possible MCI,
which has been reported. As you probably can imagine,
there's really scant literature on this.
Although there were a lot of confusing
and confounding environmental factors.
And I'm not gong to go on and on,
but I find this, you know,
in one of our dementia friends trainings
there was a woman with autism who was wondering about
how to help and support her husband, et cetera.
So people are out there.
I just also want to bring to your attention
is that there is a report that the national task group
that spearheaded called examining adults
with neurotypical conditions for MCI
and dementia during cognitive impairment assessments.
And a report of an expert consultative panel,
and it's available on the NTG website.
But you know, when we talk about diversity,
you know, I rarely see this population of people,
unless we talk about Down syndrome
acknowledged and supported.
So I just wanted to make sure that you don't forget
about this specific group of people in your endeavors.
So and thanks so much for listening to me.
-Thank you so much, Kathy. This is Dr. Rost.
I'm back online. I really apologize.
We planned for months for this particular moment,
and I really, I apologize for the technical problem.
And I would like if you don't mind
I would like to take the screensharing capacity.
And I will share with you my slides.
-Perfect, and welcome back.
-I apologize for that.
So thank God I have an extra laptop in my office.
And I just wanted to start
with a few very general comments and observations.
Again, this is the, this is an endeavor
that's been planned for months and months and months.
And really, short of a few technical issues,
you know, this has been a seamless, you know,
execution by the entire planning team.
And my special thanks to the panelists and participants
and the entire NINDS planning team.
And also to the Infinity Group for their preparation.
We started with, you know, trepidations
and how the virtual format for this summit is going to work.
I can, you know, assuredly say that now
that it's working quite well.
We really appreciate participation
from all the registrants.
We started with 1,400 plus registrants
who represented the very wide spectrum of the,
of the public nonprofit industry government
and academic and clinical sectors.
And I have to say throughout the entire duration
of the summit thus far, we had an average, you know,
500 attendees at different times.
And, you know, anywhere between 300
as we have now at the end of the second day to 700
at the beginning of the meeting.
So that's been fantastic.
We had two intense days, eight scientific sessions,
128 panelists and 44 individual talks.
So you know, that's really a great,
you know, a great opportunity for us to engage.
And thank you to particularly patients and caregivers.
As I've said before, it's the voices that keep us honest
and also wanted to give a shoutout
to the NINDS Communications Office
for preparing that very special video presentation
this morning that we've enjoyed. And thank you to all of you.
I just wanted to share a few comment things
that I have heard throughout the sessions.
I've taken notes, and what I'm looking forward to
is that at the end of my brief presentation
that all of you will have an opportunity to jump in
and either, you know, add, correct or, you know,
or have, provide different point of view.
I think that we hear that the great progress has been made,
but more needs to be done.
I hear a very strong voice of patients and caregivers
and across the very broad spectrum
of input which I think is much needed within different topics.
I hear that there is an urgent need for methods of prevention,
for pre-symptomatic vigilance so to speak
and also for support of those who are living with disease.
This is the three areas that patients and caregivers
specifically
and also the organizations that advocate
on their behalf have been, have been communicating with us.
I also hear biomarkers, biomarkers, biomarkers.
It's, you know, across all of the topics,
this conversation is, you know, enriched by the fact that,
you know, biomarkers at every stage of,
you know, detection, diagnosis, management, treatment,
response to treatments, prognosis, all of this I think
in such a complex disease constellation as AD/ADRD is,
biomarkers are going to make a difference.
I also hear the theme of a need for novel models,
new disease biology paradigms.
And going off the beaten path, so to speak,
seeking synergies within different diseases
or also maximizing a divergence in pathological pathways.
And I think this is something that, you know, all of us,
you know, in the working group need to go back
and kind of think about how can we incorporate
that into our recommendations and make,
and turn them into milestones.
Then clinical trials have been, you know, on everybody's mind.
And you know, there's some diseases
that have terrific progress already in that directions,
others that need to move there.
And I think that that's the voices that we heard.
And then also one big theme of the need
for resurgent implementation
of pragmatic approaches and solutions in ADRD.
This is something that a lot of you
have been commenting on throughout the summit.
I'm going to go into, if my slides allow me,
I'm going to go into topics specific,
comments or themes that I have captured
as I was listening to the discussion
following the conversations
within the health equity discussion.
There was a clear kind of underscoring of the need
for biomarkers to understand ADRD
in diverse populations with dedicated studies
of minoritized populations covering entire lifespan.
And with special focus on brain donation that has to,
has to help us advance understanding of disease
that's specific to the diverse populations.
There's been a call for research studies
that go wide and deep highlighting multiple approaches
that, you know, that are necessary to solve,
to solve the problems or give, find the answers.
Breaking the barriers to recruitment
of diverse populations.
There was a theme of improving access to clinical trials,
especially to ensure equity.
Making sure that the trials that are partnered through NIH
are free of cost.
That's a patient's perspective that we heard.
Gene environment interaction has been a really big theme
in a discussion following the health equity session.
Understanding that including health disparities
related to life course
or life course of environmental exposures
such as nutrition, lifestyle, toxicities,
and the need for normal models like organelles, for example,
to thoroughly account for the variability
and specifics of diverse environments.
There was a theme for, of the need to encourage and expand
by specimen and tissue collection beyond brain tissue,
including retinal in this case for discovery
in order to consider a whole person.
And perspectives from a caregiver
that we heard in that particular session
included the transparency and communication
with caregivers regarding diagnosis and prognosis.
That them continued to emerge in different topics.
And I think that that's something
that each working group has to,
has to, you know, accommodate for as we think about,
as we think about recommendations going forward.
And finally, a strong foundation
for developing diverse workforce,
retention and support of mentors
at all stages of their career span.
In the FTD group discussion,
biomarkers were front and center.
Almost every, every comment had some reference to biomarkers
including particularly pre- symptomatic neural degeneration,
you know, with a clinical translation
for current biomarkers such as NfL being an urgent need
and developing novel ones for disease progression monitoring,
et cetera. Innovative clinical markers
including those that capture social, behavioral and movement,
you know, metrics that may help make,
you know, participation and research
as well as perhaps further translation
of the recent research findings into care
and make those accessible. And also developing novel
endpoints that capture the broad spectrum of clinical disease.
So that's something that was very,
very robust in terms of discussion.
Also within the FTD session discussion,
there was a lot of focus on prevention
and the need to assist those who are living with FTD.
And I think that that's a very strong patient
as well as a caretaker perspective.
A risk and resilience factor characterization
came into discussion and also continued to be a theme
throughout the rest of the summit.
Quantitative data was highlighted,
the need for quantitative data was highlighted.
Not only the all mix level but the level of protein biology
and other precision methods
of molecular characterization of disease.
And then from the patient perspective,
the question of, you know, delayed diagnosis,
is the detection delayed diagnosis.
And reconsideration of this kind of single diagnosis
box that patients are frequently dealing with in real world.
For VCID session,
there was a very robust scientific discussion
that followed presentation.
And there were certainly VCID has been identified
as one of the areas of clear intersection of science
and, you know, emerging need to explore novel pathways
and also finetuning the existing models.
VCID is dementia and sleep intersection
was used as an example of kind of evolving
understanding of the disease with,
you know, moving from the concepts
of ischemic models of disease
into understanding the mechanisms of clearance that,
you know, may have that novel pivot
in our understanding of disease.
And as a result, developing novel
approaches to nonischemic mechanisms,
for example, in this particular area
including the impaired clearance.
There was a very robust
and also I think fascinating discussion with regard
to the nuances of how we approach modeling of ischemia
and in general VCID considering the diversity
in cell types that we are,
you know, increasingly understand original blood
flows in the brain, vascular reactivity,
et cetera, et cetera.
All of the foundations of the VCID disease
processes as we know them right now.
But with a broadening so to speak spectrum
and portfolio of understanding of these nuances
I think is something that we need to think
on how that may enhance our recommendations going forward.
And also, big focus on reproducibility,
repeatability of models at every stage
including design, data collection, data sharing.
Understanding VCID is a systemic disease
and the role in that of circulating biomarkers.
Obviously, this I something that,
you know, being done currently,
but there are perhaps opportunities for novel
approaches and emerging,
using emerging systemic circulating biomarkers
as well as imaging technologies.
And I just wanted to quote Dr. Seshadri's,
I think kind of a statement
which kind of culminated this discussion of VCID
is that perhaps the science or our approach to science in VCID
is going to, you know, through increasing complexity
until we arrive at some simplicity.
And I think that that may be, may be the thing here as well.
In LBD, group discussion,
I think that the big things were sharing of information
across the disease entities considering how heterogeneous
and also perhaps in some areas overlapping,
you know, disease pathology clinical,
clinical syndromes that we are dealing with.
Making sure that the dialogue is accessible for the public
in conveying the complexity of disease.
The patient kind of a guidance to us with regard
to access to clinical trials across the spectrum of LBD,
especially as diagnostic precision evolves and patients
seek new opportunities as their diagnosis
of which is actually a theme that came up
in at least a couple of sessions throughout the summit.
Which I thought was very, very curious.
Biomarkers were front and center with LBD as well.
Pre-symptomatic, pre-clinical diagnostic prognostic,
all of these have been on the mind of our scientists
as well as patients and families and care partners.
Focus on disease heterogeneities also led to a discussion
of both clinical and precision characterization.
Moving away from silos and again clearer communications.
And then developing opportunities for disease
modification and symptom control of patients
who are already living with LBDs is something that, again,
was reverberated in the discussion session
following this.
Now this morning we had a very robust discussion
following the mixed etiology dementia session.
It was an outstanding session.
And I think there was quite a bit of caregiver
and patient perspective
that was introduced in the, in the discussion there.
The need for engagement across the entire spectrum of disease
and transparency in communication
was underlined multiple times.
Opportunities to impact care and engagement
via a compassionate and culturally appropriate detection
and diagnosis process.
So this is something that I wanted to personally thank
for this feedback from our participants.
And I think that this is duly noted
by the members of the MED working group
but as well as our entire, entire community.
There was a note of consideration of provider
burden and wellbeing, which obviously contributes
in some sort of either positive perpetuating cycle
or perhaps an ambitious cycle on the other,
on the other side of the equation
where we need to ensure that the providers remain engaged
and well in being able to provide the needed compassion
for the patients and families.
I also enjoyed the discussion on research
that's needed on cultural aspects
of risk and benefit perception
and potentially policy research into economic impact
of screening and early detection of cognitive impairment
and dementia on diverse populations.
I think it's a very important
and potentially very impactful area
that we may need to address. We also had opportunities to,
or discussed opportunities to amplify effectiveness
of multiple approaches via harmonization
between MED and VCID topics.
And then also, the important care partners input from,
that we again restated from both, from the beginning,
from the research concept from one side of the spectrum
to execution of research, and this input is needed.
There were a few important points in post-TBI,
AD and ADRD session that I have captured,
and one of them is central role of biomarkers in diagnosis
that has been discussed with a great degree of robustness.
In the face of clinical heterogeneity
of post-TBI ADRD syndromes,
I think the panel has ultimately arrived
at a conclusion that biomarkers in this,
in this role, would provide probably a greater degree
of fidelity of diagnosis.
There was also a very robust discussion
of post-TBI ADRD versus CTE,
chronic traumatic encephalopathy,
where the acknowledgement was made that the study design,
include specifics of exposure history and biomarker arrays
are needed to differentiate between the impact
of acute versus chronic injury.
There was also point discuss regarding standardization
and prioritization of translational models.
A note has been made of a great existing history
of TBI models prior and also ongoing work done
by Veterans Administration Department of Defense
in collaboration with NIH, both NIA and NIDS,
and these collaborations perhaps are best to be maximized
on as the models of post-TBI, AD and ADRD are being developed.
And then of course a very important patient perspective
that was proposed into this discussion
with regard to availability and accessibility of public
facing education in this area.
I made also a few notes with regard to our late session.
The discussion was also robust,
and I think the emerging themes were that there's a need
for harmonization of data and sample collection.
And you know, using this in order to benefit other fields
related within the ADRD
but also perhaps neurological disorders
or brain disorders outside of ADRD as well.
There was a discussion on VCID and late interface,
particularly with a good proportion of,
you know, nonagenarians or late octogenarians who survive
and are diagnosed with late disorder or syndrome.
I should say they also have a high predominance
of cerebral vascular findings and exploring
or exploiting this opportunity
to study coexistence of this type of pathology,
neuropathology offers great opportunities to address
some of the, you know, evolving pathophysiology.
And in this context, the role of perivascular spaces
and, you know, clearance in the brain,
proteinopathies, you know, in the brain was addressed
as well as opportunities to study
let's say impact of chronic sleep disorders
in this patient population.
There was also a discussion on clinical diagnosis readiness,
including biomarkers, clinical criteria
that are needed to validate prospectively the diagnosis
and to give options for patients and families.
And I think while the jury is still out on
where is the risk and benefit ratio stands with regard
to whether we want to quote/unquote rush in
in providing a diagnosis to a patient
or whether we should step back
until we are actually able to provide something that,
you know, the diagnosis that not only,
you know, not only a preliminary but also actionable.
I think that's the sort of a discussion
that we will continue to have over
the, you know, over the next few years.
And I'll be very interested to see how much progress
we will make in this space in the next three years.
Because it clearly in the prior three years, you know,
since the LATE has been introduced TDP
for the three topic has been introduced in this context,
so much progress has been already established.
And we finished off with a COVID session
which, you know is just very fresh in our memory.
And due to my technical errors,
I have not been able to update my slides very thoroughly.
But what I heard in our discussion,
which was a fantastic discussion,
and I thank all the panelists, is that, you know,
data sharing is something that is urgently needed.
You know, data harmonization, syndrome characterizations
and, you know, focusing on detection,
you know, of the COVID-19 exposures in patients
not only with severe diseases
but obviously those who experienced even mild infections
or perhaps asymptomatic is needed
and how to translate these concepts
into future clinical trials
is something that we're going to have focus on,
you know, for the duration of the, you know,
of the next study period so to speak for this group.
So I'm going to end here,
and I will offer everybody a forum for the,
for the comments both on the general comments that I made
but also anything else in the context of the summit
that you can offer. And Hector, I see you --
-Well I think there was a question
that was being asked of Dr. Carlson
when the transition between you and me occurred.
Is that right?
-I just wanted, this is Cindy Carlsson,
so I just want to address Kathy Service thank you
for your comments about thinking about people
with neurotypical symptoms
and people who have intellectual disability and Down syndrome.
Because again, I think your comment
that we need to better understand
what their baseline is.
Make sure we're doing a good job of including them in studies
but also making sure that we are training clinicians
to really get a good sense of people's baseline.
So that's an extremely important point.
I want to apply the work of national task group
that's been working so hard in developing toolkits
for people to help with this training.
And we had addressed this at the last NAPA meeting
because it's such an important issue.
So thank you for brining that up.
I think that'll have a lot of implications
for the early detection group
so that we can make we get a good baseline on people
whether it be different educational backgrounds,
neurotypical symptoms, et cetera.
So thank you for bringing that comment up
and for your work with the group.
-Sorry, Natalia, please carry on.
-No worries. Thank you, Dr. Carlsson.
Apologies, I jumped right in the middle
of your initial discussion. Hector, you had your hand up.
-Yeah, thank you, Natalia.
And I want to share your thanks to the organizers
for doing a splendid job on bringing us all together here.
Thank you very much on behalf of the health equities panel.
Just a quick comment.
Something that I observed from the 2016 to the 2019
to the now 2022 ADRD summits
is just this elevation if you will,
the recognition of the importance of inclusive research
in Alzheimer's disease and related dementias
that what I heard over the last couple of days
was that health equity was mentioned and acknowledged.
And the LTN to each of the different panels
and to my fellow panelists I want to say
thank you for this recognition and also to NINDS
for elevating the importance of an inclusive research field
of Alzheimer's disease and related dementias.
Thanks again.
-You're exactly right, Hector.
And thank you and Dr. Zissimopoulos
for leading the effort with your working group.
I believe next comment is by Elaine Swift.
-Yes, thank you.
And I wanted to echo Dr. Gonzalez's comments
on just the importance of equity and how gratifying it
is to see it front and center at this terrific conference.
I was also happy to see the recognition,
especially in recommendation eight on the importance of data
infrastructure to research these very complicated conditions
over long periods of time
and to do it in a way that advances equity.
And I certainly, you know, in that regard,
of casting a broad net over the data infrastructure,
I'd like to underscore the importance
of the HR data infrastructure.
And this will require attention to building a far more robust
and interoperable data infrastructure as, for example,
is being done in NDS's long-running work
on comma data elements.
But I'd also like to call attention
to the M-code initiative for EHR data
that is working to standardize data on oncology,
to diversify clinical trials,
to support precision medicine, all of those good things.
And as it's being done for cancer,
it could also be done for AD/ADRD.
Constance Lyketsos, Howard Fillit, Diane Bovenkamp,
Ian Kramer and MITRE researchers.
I'm Elaine Swift. I'm from MITRE.
We have an article coming out on NJ pad,
on how we could leverage and an M-code approach for ADRD.
And by casting a broad net for EHR data.
It's, of course, an extremely important way to diversify
the patients who are involved in research
or prevention or treatment,
who are surveilled when new treatments come out.
Just a key approach that I'd like to call attention to.
Thank you.
-Thank you very much. Thank you, Elaine.
Next --
-I'll just comment, thank you, Elaine.
I'll bring this back to the MED committee
so we can think about how to incorporate
that into our harmonization recommendation.
Thank you for that point.
-Thank you.
-And Elaine, I think your paper
just came out the other day actually.
I was just reading it.
-I, I actually, it's not quite out yet.
It's, but it should be shortly. -Okay.
-You might have seen a copy from a colleague, though.
Thank you.
-Thank you for your comment.
I think next question in Q and A is Nancy Smith.
-Thank you very much.
This has really been an exceptional two days.
I can only call it scientific speed dating.
It's just been great.
My comment is relative to the health equity
recommendation number one,
and it comes from a study-specific perspective.
As many of you may be aware, NIA has funded
two rounds of our 24 projects
focused on examining different approaches
to diversity recruitment and retention and aging,
some 20 in total over the past three, four years.
I've been involved in one, involved in Mount Sinai
and SUNY Upstate Medical University
focused on cognitive research in African Americans.
And despite, we have annual meetings,
of course, of all those that are funded.
And despite the wide variety
and the focus and approaches in populations,
there's three very key themes from the institutional level
that have come up.
And one is it takes time to build
and gain the community trust to even begin to think
about diversifying participation and research.
But equally important, it requires changes
to the research designs and recruitment methods
that traditionally are either excluded or discouraged
or just don't address the interest
in the situations of diverse populations.
And that both of these require changes
in the research infrastructure at the study level
and the institutional level.
And that takes time, requires more resources,
and it has financial implications.
So my comment is that I definitely support the concept
of establishing recruitment and retention centers.
But I hope also that we can talk about
how NIH funding has got to be acknowledged.
That to do this work really right,
it's going to take more time,
more resources and more finances at the study level.
And that's my comment.
-Thank you, Nancy.
Does anybody want to provide feedback?
-Nancy, I'll take a shot.
Thank you very much for your comments,
and I appreciate what you're saying,
and the nuances of what your --
implications of what you're saying
is that it's going to take time.
It's going to take some infrastructure-building,
and I think what I see is, over the last two decades
I've been doing this work, is just how, I guess,
far behind we are in working with diverse communities,
and the need to really build it out from the ground up.
There is some existing material infrastructure,
but you're absolutely right. Your point's well-taken,
and thank you very much for your comment.
-Susan Dickinson?
-Thanks, Dr. Rost.
I appreciate it. You can hear me okay?
-Yes.
-Great. I want to thank you and all the subcommittee chairs.
It has been so energizing to see how much progress we've made
since we last convened three years ago,
and I applaud everybody in setting such an ambitious path
for the next three years.
I did also want to thank Dr. Carlson
and other members of the NAPA Council,
who meet year-round, and do so much to provide leadership
to the whole initiative nationally,
and to make sure that we're ensuring we meet the milestones
that we set each year at these different summits.
I want to make just one comment, and ask a question, if I may.
During this morning's multiple etiology dementia session,
we heard Ian Kremmer weigh in with the importance
of making sure that diagnosis becomes more accurate,
more timely, more compassionate, and more actionable.
And I just wanted to make a comment on that --
the point of compassion.
And the other thing I'd say is this relates
to a lot of the points that you included,
Dr. Rost, in your summary, which is how many times
the importance of having clarity in communication
has come through in each of these sessions.
One of the results of the last summit in 2019
was the dementia nomenclature initiative,
which both Ron Peterson and Angela Taylor
mentioned yesterday.
Over the past three years, they've led groups,
including scientists, and clinicians,
and public stakeholders,
to really look at how we are -- the nomenclature we use,
the whole communication framework we use
in talking about these diseases
can be more accurate, can be more clear.
Which I would argue equals more compassionate,
when the end result, you know, happens in the exam room,
where some -- a family's getting a diagnosis,
or the family has to then go home,
and then figure out what it means,
and how they're going to cope with it.
And I just wanted to put a plug for how important
this new communication framework they are suggesting is,
and to encourage everybody to become familiar with it,
and do whatever you can to help the initiative advance.
I think we're all in this business
to help people on this journey,
until we have a cure or some kind of prevention.
I think the best we can hope to do
while we advance the science is
to help people maintain their quality of life,
and have as easy a journey on the path as they can.
And my question relates to the fact
that I've been part of all of these summits since 2013,
and we get more ambitious every year, which is wonderful.
But we've expanded from five sessions to eight by now,
and I was wondering if somebody can just speak
to how we're going to ensure
that there are robust resources dedicated to --
that are going to enable us to meet the milestones
for all eight of these sets of wonderful recommendations?
I think they're all important. I think they're all ambitious,
and I think they all deserve to be invested in,
but we all know, you know, there are limited resources.
So I don't know who might be able to speak to that.
-Well, I'll reach out to the panelists.
Rod, do you want to speak to that?
-I think Walter unmuted.
-Yeah, Susan, I think you point to the bigger picture,
which is, as you really look at these issues in total,
it's -- you're looking at an entire ocean of problems.
So I think the strategy is to not leave a stone unturned,
but focus on what looks like it's going to move most quickly
to a solution that's going to help people.
I think it's that balance.
I think, you know, if it hadn't been for the increased funding
that's come from Congress, it would just be --
it would be very depressing
to have these kind of conversations.
But I'm very optimistic that the funding
is really quite good now,
and that there's actually another increase in this budget.
So I think our real bottleneck
is actually building the workforce,
and -- but the good news there is,
the funding is permanent going forward, on the base of --
and we manage about 10% of that funding for the ADRDs.
But as -- because it is permanent,
I think that gives us the opportunity to look --
not just be disappointed at how big the problems are,
but to realize that we can actually -- over time, work --
can take on a large number of these problems.
So I'm pretty optimistic.
Compared to the other diseases in my portfolio,
I'm much more optimistic here,
in terms of the resources. I think we should all be.
I mean, we're in a really good spot,
something really, really impactful.
I think we're getting really close.
So if we can cure one by the next time we meet,
I'll be very happy, but we got to get a cure.
-Thank you, Walter. Tony, you had your hand up.
I'll let you speak right now. Tony Antonucci?
-Thank you.
I'm a little -- this comment was --
back goes to something we were discussing earlier.
I think -- but Walter mentioned we really need the workforce,
so I think I'd like to reiterate that.
In our comments, the first group,
we talked about training for a diverse workforce.
That's critical, but it's not unrelated to the issue
of engaging a population willing to participate in research.
And that's not secondary.
That's very primary, and it takes a lot of investment.
In a couple of other areas that I work in,
we have years of investment in the community,
working with community members,
working with community advisory boards to build up trust.
I mean, there's really no other way to put it,
and in this case,
we have the issue of ethnic minority distrust,
which, unfortunately, is well-earned.
And secondly, we have the whole stigma attached
to this kind of an illness, ADRD.
People don't want to admit it under any circumstances,
but especially under circumstances
where they don't trust
the people talking to them about it,
or inviting them to participate.
So I think a real concerted effort needs to be invested,
both in the workforce and in developing a relationship
with the community that we want to work with,
and in finding a way to give back.
Because we can't just helicopter in,
do our study, and helicopter out.
That's all I wanted to say.
-Good point.
Anybody wants to further comment,
or provide anything back? I think everybody agrees, Tony.
I think that's the consensus here.
I'd like to try to -- -It takes time and money.
I mean, you can't just do it with one shot.
I mean, there's one group I work with that's had 20 years
of developing relationship with the community,
another group that's going on four or five.
And it's still slow going.
So I think we, as researchers and NIH
as funders need to recognize
just how long-term a commitment this must be.
Sorry.
-Cindy, do you want to comment on that?
-Yes, just that, again, I support what Tony's saying.
I think that, from what we're hearing from our black leaders
for brain health, and here in Madison,
Wisconsin is that they are saying
we need to have investigators of color
who are out there doing the work,
and that's going to bring people into the studies,
and have diverse representation.
So, again, that -- just that emphasis that has to be,
first and foremost, a training that has mentioned,
so that we can get that diverse workforce,
and then the representation in studies will follow.
Thank you.
-And, Ron, were you following on that same?
-Just a comment, thank Susan for mentioning
the nomenclature initiative.
And that's one of the goals of the nomenclature initiative,
to bring some consistency of language
across different stakeholders, from the public,
to the clinicians, to the scientists,
and in particular with regard to diversity.
I think we're getting feedback
from a lot of the underrepresented groups
that the language, the words are getting in the way
with regard to understanding their particular condition
and participation in research.
So I think that the framework that has been developed
in phase one of the nomenclature initiative
will help in that direction,
and now we have to move it out into a general acceptance,
in terms of utilization.
So we'll be presenting to Cindy and the advisory council
on the first of May with our findings.
-Perfect, thank you.
I'm going to try to bring back Ms. Carolyn Rogers,
who's been trying to talk to us for a while.
Michelle, do we have Carolyn with us?
-We did. I think she actually has departed.
-Well, I'm really sorry to hear that.
She's been trying to make a point with regard to,
you know, root causes of mixed dementia pathology,
and I think that she made a comment
in one of the either MED sessions,
or late sessions,
and I think that that's something
that we could not get to that time.
And I'm really sorry she hasn't had a chance to stay with us,
to answer. But I think we all agree,
this is what this work is all about.
Okay, I have Sonya Valab next on the -- online.
-Hi.
Thank you so much for making the time for me to speak.
So I'll quickly introduce myself first.
So I'm Sonya Valab.
I run a prion lab at the Brode Institute in Cambridge,
Massachusetts, where we work on drug develop,
biomarker development, natural history,
et cetera, for prion disease,
which as you all know is a rapidly-progressive,
currently untreatable dementia.
I'm also at risk myself for genetic prion disease,
so I inherited a fatal mutation
in the prion protein gene from my mom,
who died of genetic prion disease in 2010.
So I've been on the patient side
and on the caregiver side of this disease,
as well as having, inspired by that experience
to get into the research side.
So all of that is a preface to say
that I really just have a targeted plea for the committee.
Thank you for all of the great work
that you're doing on Alzheimer's and related dementias,
and I just want to raise for consideration
the possibility that prion disease could be named
among the Alzheimer's disease-related dementias.
I think, mechanistically, we've seen over the past
few years a real sort of dovetailing
of some of the insights in the prion field
that have sort of come out of propagated prion misfolding,
including diagnostic assays
that leverage the sort of prion concept,
but now have been applied more broadly
to other neurodegenerative diseases,
in which we see templated protein misfolding.
And on the flip side, for example,
much of the biomarker work and need for better biomarkers
that was discussed earlier this afternoon
and in these past two days certainly has enriched our work,
as we look for many of the same biomarkers
in our natural history work.
On the theme of prevention and pre-symptomatic vigilance,
this is an area where we have really tried to advocate --
you know, myself as a healthy carrier myself --
for novel biomarker-based and genetically-informed
clinical trial models, and I think there could be
shared learnings across these diseases.
So with that, I'll just say I think very much hearing
the themes that have been touched on,
I think we feel a kinship with this community,
and see a lot of research questions, tools,
and needs that are shared across these domains.
So I would love for prion disease
to be considered among the list of diseases.
Thanks so much.
-Thank you, Sonya.
-I wonder if Ryan wants to go near this one.
We've discussed this multiple times, Sonya,
and from what we can figure out,
it would take somebody to go to Congress to change it.
Now, it's not impossible, so you should think about it,
but Congress, we understand, made this determination,
and these are the ones -- these three are the only ones.
Everything else has got to be somehow related.
Ron, is that --
-Yeah, thanks for throwing the ball to me, Walter.
-Oh, I'm sorry. You don't have to --
-No --
-I have other dementing diseases in our portfolio,
like Huntington's for instance, and it's not allowed.
-No, we've had extensive discussions about this,
going back to day one of the NAPA Advisory Council,
as to what's in and out.
And to be honest, in fairness to Congress,
if I may, I think they were just talking
about Alzheimer's disease,
and then in the -- in writing the legislation,
said, well, don't we mean other dementing disorders as well?
Yeah, of course we do.
And then they listed the common ones.
You know, I think that's really what happened.
You know, the legislation,
if it's going to be reauthorized,
will happen not tomorrow, but in 2025,
and certainly all of these considerations
need to be included.
But we need to get on prion disorders before 2025,
so I understand your urgency, Sonya.
-Thank you, and Ron, if you want to address this.
-Yeah, that's -- thank you for your input, Sonya,
and I wanted to add --
to mention that while prion diseases
aren't right now official AD,
ADRD disorders under the national plan,
the National Institute of Health does recognize the relevance,
inasmuch as when there are prion research is proposed,
and it's also very relevant for Alzheimer's disease
and Alzheimer's disease-related dementias research,
that also gets special consideration.
So acknowledging that it's not explicitly named,
I also want to assure you that the relevance is not lost to us,
and that we definitely --
that type of research is included
under the special pay lines when it's relevant to AD, ADRD.
Thank you.
-Thank you. -And Cindy?
-And again, Sonya, thank you for your comments.
I think another venue would be for you to present
and make some public comments also at the NAPA meeting.
So again, trying to bring that to people's attention,
and I'll carry that to the groups as well,
to think about these other, less common,
but just as important, diseases that maybe should work
their way into the national plan.
Thank you.
-Thank you.
-Thank you, and thank you, Sonya.
Thank you for your comments. Our next question --
we are rapidly coming to an end of an hour.
Penny, are you on? Yes, fair.
-Thank you, Dr. Rost, yeah.
So my comment's going to intersect a little bit
with the one from Nancy Smith earlier,
so my apologies for that.
But it's for the health equity committee to consider
that when we think about the emerging trends
in research and policy,
I think we're all going to be learning
how those trends are going to be
affecting the comfort level of participation
from people of distinct socioeconomic, regional,
and ethnocultural backgrounds.
And I think a centralized group
that tries to help us understand and anticipate
that could be really valuable for all of us,
and I'm thinking about things like open data
and open sharing, open science,
knowing that different groups of folks
have very different trust levels
with what's going to happen to their data,
and who's sharing it, who's buying it,
who's selling it, as well as on the digital biomarkers.
A lot of the individual sessions
talked about the importance of digital biomarkers
and digital assessment tools to transform clinical research.
Many of us are very hopeful
that it's going to improve inclusivity
and improve power for clinical research
by having more frequent measurements
within people's homes of individual measure of function.
But the comfort levels of people from distinct cultures
with having those measurements taken, where you have devices
monitoring their activity at the home,
I think is something we haven't fully understood yet.
And I think it's something we're all going to be dealing
with separately when the clinical trials
are active for FTD,
for Alzheimer's, for vascular dementia.
I think we're all going to be realizing
that the decisions we make around research design,
and the policy, and what happens to the data
is going to affect the comfort level of participants.
So the more that we have some centralized learnings
of community and cultural differences, and comfort level,
and how our choices will affect that,
the more I think all of our fields can move forward
to really implement the technology that we need.
-Great comment, Penny.
Anybody wants to provide feedback,
particular from the health equity group?
-Think it was more of a statement,
rather than a question, Penny.
I think everybody's uniformly supporting your standpoint here,
and I think it's duly noted. Thank you.
Thank you for your input throughout the entire summit,
actually. It was very helpful.
Right, our last -- yeah, go ahead.
-Oh, sorry.
Ms. Dax, thanks for your comments,
and I think I share some of your concerns
about how some communities may be a bit more concerned
about some of these monitoring devices if you will.
And I think your comment about a centralized
or some kind of open-source availability
of best practices recommendations,
if I'm hearing what you've said correctly,
is a brilliant idea.
And I think that science of inclusion
should take note of what you just pointed out.
So, thank you.
-Thank you, hector.
And very appropriately, we have our last panelist,
Mr. Dale Listina, to provide -- to ask his question,
or provide his final comments. Dale, are you with us?
-Yes, I am. Thank you, Natalia.
-Sure.
-Let me congratulate you on the excellent summary of --
that you gave. You have a gift,
to be able to listen to all these presentations
and to summarize them like you did.
Please accept my congratulations.
I would like to speak to the first session
of this morning, MED,
which Kate Poston was the leader.
And commented about the video that you opened up with,
and I will not go over my comments.
I still stand by them, but I have a post-script, Kate.
And that is that --
well, I talked about insight here in northern Virginia,
and the things that they do.
I want to add another thing, and that --
we're talking about community involvement,
and community understanding.
They are experimenting with enlightening
the community itself about dementia,
and I have an example. I took --
my wife used to go along with me to the grocery store,
and in the process of doing it,
all of a sudden, she didn't recognize me anymore,
and she thought I was somebody trying to kidnap her.
And she let the folks in the store
rather loudly know about that.
The manager of the store knew that --
about this kind of thing, although I didn't know him,
and separated us. He had staff stay with my wife,
and it took about an hour, hour and a half.
And things settled down,
and the understanding of that manager and his staff --
it was no small store. It was Wegman's.
You know, that's a pretty good-sized store,
and they handled the situation very, very well.
And so, I would like to add to the recommendations,
if, indeed, Kate,
and your group is going to look into that group,
which I absolutely recommend to you to do,
is to look at their experimentation
of dealing with local doctors,
and with local restaurants, and so forth,
for people to understand what dementia is,
and what it is like,
and to be a bit more sympathetic as to what's happening,
and cooperative in dealing with the situation.
That's my comment. I thank you all very much.
This has, as usual, been an excellent,
excellent couple sessions, and I thank you very much.
-Thank you, Mr. Listina.
Your comments have been really important
throughout this session,
and they are going to shape, I think, our recommendations.
Thank you for bringing your voice,
and closing with this really important point,
that I think is not well-represented
in the recommendations right now.
So I will also bring this point back to the MED committee,
so we can think about how we can advance awareness
around dementia in a compassionate with,
with providers, people in business,
and the broader society.
So, thank you for that really important comment.
-Thank you very much, Kate. I have one last thing.
We have as a goal to cure some dementia by 2025.
Walter had mentioned this in the opening of the session.
By 2025, to cure a dementia, to cure one.
I would invite, if you would, prognosticate with me.
Which one is the best candidate for that to happen?
-Who is brave on this panel?
-Maybe it's a rhetorical question,
but nevertheless, it's coming up --
whoa, I see Walter is going to give it a shot. Go ahead.
-I was going to ask David Holzcomb.
I mean, you don't put your money down
until you know who's going to win,
but there's a couple horses in the field here.
We'll see.
Certainly, the anti-amyloid therapy of Alzheimer's,
going to get answers pretty quickly
whether that's effective, and that, you know --
that's a kind of foot in the door.
But I would just say it's somewhat more exciting
now than 50 years ago,
when we really didn't know anything
about what we were doing.
So, David, would you want to take a shot at --
I mean, there's so many different opportunities,
it's hard to pick one.
-I don't know which -- I certainly --
none of us know which one might be first,
but I think actually Sonya,
who was speaking about genetic prion disease --
I mean, I think
some of the genetic neurodegenerative diseases,
where lowering the level of the gene and protein
in animals really can prevent or very much delay the disease,
I think, are the most amenable to the earliest big effect,
like with the SMA as a various specific example
that is pretty much curable now. But that --
I wouldn't necessarily call it a neurodegenerative disease,
but it's close.
But I think something where you could knock the protein down
to have a big impact is probably the best first candidate.
-I -- again, Walter,
you said a while ago, just in this particular session,
that the demand on these sessions,
and the size of the scope is getting bigger,
and bigger, and bigger.
And I would say yes, this is a very big problem.
And it will get bigger, but I implore all of us --
don't give up because it's getting bigger.
It's getting bigger because the need is getting bigger,
and just hang in there.
I'll do my best on my end, and I know you will, too.
And that's -- we've just got to do it.
We cannot give up. Thank you.
-I cannot think of better closing remarks
for this session, putting into perspective
not only the humanity of the work that so many do,
some in a laboratory, some in clinic,
and some in providing care to patients with,
you know, this terrible disease. So humanity, purpose, passion --
I think all of that has been inspiring,
you know, throughout these two days,
and I think we have our work cut out for us going forward.
And there's some immediate steps to do.
You know, we'll work on the recommendations,
and put the reports forward,
but I think there's also some long-term work to do.
And I promise you, Mr. Listina, we're not going to give up.
That's just the only thing I can say,
and I think we're in our closing comments session.
At this point, Walter,
if there's anything you want to say to wrap the session up --
you're on mute.
-I think you did a fantastic job
going through the details, presentations,
and please send me those slides.
Because we're going to go in through all the recommendations
in detail, too, so it's very helpful.
You know, I just -- just in closing,
say that, as I referred to earlier,
you know, some of the people have been in this field
for 30 or 40 years, look back,
and, you know, how do we think about this 30 or 40 years ago?
And just, like, what were you thinking?
Really it's such a much more sophisticated place now.
The problems are bigger also,
because we know more about the complexity,
not as simple as we initially thought.
But there's so many potential targets that have appeared,
and takes persistence and a little bit of luck.
But we're dealing with things
that are really inherent to the diseases now.
So I think we can feel comfortable
that these efforts --
you know, you can't say which one is going to bear fruit,
but I would put a lot of money that one of them is,
just because there's so much going on in the field.
There's industry involvement now we didn't have before.
So I think we're entering a pretty exciting period.
There are a lot that we know,
and we talked about some of those today,
the heterogeneity, the different topologies,
the different molecules that are involved,
the interactions between the different pathologies.
Talking about brain health,
which, you know, is something that we know.
If we had a way of, you know, enticing people to think
about brain health in the early midlife,
that this could have a major impact
on decreasing the chance of dementia in,
you know, 30 or 40 years later in their life.
We do know that, you know,
Alzheimer's disease modification is potentially there.
We don't know for sure yet,
but there is some enticing data that the anti-amyloid therapies
may actually have mental benefit.
We'll have to wait and see, but they're very powerful
at taking amyloid out of the brain,
no question about that. That's pretty amazing.
Then there's a lot of known unknowns.
So we know a lot about the genetic drivers,
but we don't know exactly how to move those -- that knowledge.
We know that the mutations
manipulate the system to cause disease.
Now, what we have to figure out is,
how do we compensate or prevent that from happening,
so that we end up with a treatment
based on what we know out of the genetics?
I think that's low-hanging fruit.
The second one, which is harder, but is actually surprisingly --
some of the FTDs, been very interesting,
where something we find out form the genetics turns out to be,
you know -- and all the sporadics as well.
So TDD43 story's a good one, and all the ALS cases,
a lot of the other dementias as well.
So there are these things that -- where you don't --
we know what they are. We know what we don't know,
and we have a path forward that we think,
you know, will get us the answers in the end.
So we call it the known unknowns.
Then, there is the issue of the unknown unknowns,
and that's usually the scariest part of the business,
where you think you know what the problem is.
Spend 10 years, and it doesn't work,
and you realize, well,
I made some assumptions that were wrong.
I didn't know X, Y, or Z, and that's led to the final failure.
So you always have to think that, you know, as a community,
we tend to want to look under the lamp post,
and that's what we know.
That's the known unknowns, but we've got to be really careful.
There's something out there beyond the lamp post
that's really relevant to what we need to do.
And so, that's, I think, keeping your eye out for things
that are going on in other areas of biology --
cancer, you know, basic molecular biology.
Sometimes that's where the real breakthroughs come from,
and so, I think that's how I look at the picture we have,
where we are now.
The recommendations that were put together here,
I think, are, you know, very well thought-out,
and we can work with those, and make progress.
It's not going to be easy,
but I think, you know, with the workforce dedication
and the funding that's now available through NAPA,
we can really make progress.
So I'm very optimistic, and a lot of the optimism
is because the last two days, the people that have, you know,
shown their passion and dedication for this field.
I think we have a good team.
We need more players, but we have a good team.
So I want to thank everybody for the teamwork
to put this together, and for all the work
you're going to do in the next three years.
So, thanks very much.
-Thank you, Walter. It's a perfect wrap.
So I think Keith wants to take a last picture, screenshot.
So, everybody smile before we say see you in 2025.
Whenever you're ready, Keith, you let us know.
-I took, like, seven. We're good.
-Excellent, well, thank you again,
tremendous whirlwind of science, you know, compassion,
and pointers for the future.
And we'll see you in 2025. Thank you.
-Thank you, guys. -Bye, everybody.
-Probably see you earlier than that.
-I hope so. Bye-bye. -Bye.