1
00:00:00,320 --> 00:00:02,200
-Good morning, and welcome

2
00:00:02,200 --> 00:00:07,200
to Day 2
of the ADRD Summit 2022.

3
00:00:07,200 --> 00:00:10,000
We're really excited for
the continued presentations

4
00:00:10,000 --> 00:00:12,440
and feedback on draft
research recommendations.

5
00:00:12,440 --> 00:00:16,000
And to start the day off,
it's my honor and privilege

6
00:00:16,000 --> 00:00:18,600
to introduce a video
highlighting experience

7
00:00:18,600 --> 00:00:22,120
of people living with dementia
and those caring for them.

8
00:00:22,120 --> 00:00:24,200
This video was developed
by the NINDS

9
00:00:24,200 --> 00:00:27,200
Office of Neuroscience,
Communications, and Engagement.

10
00:00:28,080 --> 00:00:35,680
♪♪

11
00:00:35,680 --> 00:00:43,000
♪♪

12
00:00:43,000 --> 00:00:45,960
-I'm Jim Taylor,
and this is my wife Jerry.

13
00:00:45,960 --> 00:00:50,040
And Jerry was diagnosed
first with MCI nine

14
00:00:50,040 --> 00:00:51,600
and a half years ago.

15
00:00:51,600 --> 00:00:55,480
And, subsequently,
when she was --

16
00:00:55,480 --> 00:00:58,600
became a participant
in the aducanumab trial,

17
00:00:58,600 --> 00:01:02,200
she had a brain scan,
a PET scan,

18
00:01:02,200 --> 00:01:04,240
amyloid plaque on the brain;

19
00:01:04,240 --> 00:01:08,680
and the diagnosis
was changed to Alzheimer's.

20
00:01:08,680 --> 00:01:13,400
As she progressed, our first --

21
00:01:13,400 --> 00:01:18,320
Jerry and I have always
spoken 50/50 until recently,

22
00:01:18,320 --> 00:01:21,080
and her communication is
more challenged at this point.

23
00:01:21,080 --> 00:01:23,840
So she corrects me
whenever I make mistakes

24
00:01:23,840 --> 00:01:26,040
but is often quiet
other than that.

25
00:01:26,040 --> 00:01:33,280
So her diagnosis was not
an easy situation for me.

26
00:01:33,280 --> 00:01:36,080
Jerry is
a professional health --

27
00:01:36,080 --> 00:01:39,560
she has an RN
and an MPH from Columbia

28
00:01:39,560 --> 00:01:42,760
and spent her health,
her career in healthcare.

29
00:01:42,760 --> 00:01:44,920
So -- and she's a double four.

30
00:01:44,920 --> 00:01:46,840
She got a bad gene
from each parent.

31
00:01:46,840 --> 00:01:51,800
So there's a number
of Alzheimer's patients,

32
00:01:51,800 --> 00:01:53,800
people living with the disease
in her family,

33
00:01:53,800 --> 00:01:58,000
so she was not as surprised
by the diagnosis as I was.

34
00:01:58,000 --> 00:02:02,200
-My father was
a practicing surgeon

35
00:02:02,200 --> 00:02:04,360
until about 20 years ago

36
00:02:04,360 --> 00:02:07,400
when a neck injury
which was exacerbated --

37
00:02:07,400 --> 00:02:11,200
which was exacerbated in surgery
required him to step back

38
00:02:11,200 --> 00:02:13,120
from practicing medicine
in that way.

39
00:02:13,120 --> 00:02:17,440
And he founded a center
for the commitment to --

40
00:02:17,440 --> 00:02:20,720
commitment to compassion and
medical care at his hospital,

41
00:02:20,720 --> 00:02:23,000
which involved all sorts
of wonderful programming.

42
00:02:23,000 --> 00:02:25,680
And it was actually out
of that experience

43
00:02:25,680 --> 00:02:28,400
that we started talking
with my college roommate

44
00:02:28,400 --> 00:02:31,400
about putting some of
his writings into a book.

45
00:02:31,400 --> 00:02:35,320
But just as we were getting
into a groove with that,

46
00:02:35,320 --> 00:02:38,240
my father suffered two
strokes three months apart

47
00:02:38,240 --> 00:02:40,240
at the end of 2017.

48
00:02:40,240 --> 00:02:43,600
And that led to a lot
of limitations for my dad

49
00:02:43,600 --> 00:02:46,040
beginning with left neglect.

50
00:02:46,040 --> 00:02:48,560
So while he could see
out of his left side,

51
00:02:48,560 --> 00:02:50,040
he didn't perceive it.

52
00:02:50,040 --> 00:02:52,000
And that meant that
he was at a fall risk.

53
00:02:52,000 --> 00:02:57,280
And that began having
24-hour caregivers with him.

54
00:02:57,280 --> 00:03:00,880
And as if that weren't enough,
a little over a year ago,

55
00:03:00,880 --> 00:03:04,120
on New Year's Eve 2020,

56
00:03:04,120 --> 00:03:06,800
my folks got the double
whammy diagnosis

57
00:03:06,800 --> 00:03:10,280
of Parkinson's
and early stage Alzheimer's.

58
00:03:10,280 --> 00:03:12,600
-Apparently she was
in fairly good spirits.

59
00:03:12,600 --> 00:03:15,360
And we already knew
that there was a dementia

60
00:03:15,360 --> 00:03:17,000
of one kind
or another involved

61
00:03:17,000 --> 00:03:21,120
because she had had this
for about seven years

62
00:03:21,120 --> 00:03:25,040
by the time we got around
to diagnosing.

63
00:03:25,040 --> 00:03:29,160
And mostly that was because
we were considering a facility.

64
00:03:29,160 --> 00:03:31,480
So I think it's harder
when it's your own parent

65
00:03:31,480 --> 00:03:32,800
and you see them like that,

66
00:03:32,800 --> 00:03:34,520
and you're kind of
like more frustrated

67
00:03:34,520 --> 00:03:36,080
because you know they
didn't used to be like that.

68
00:03:36,080 --> 00:03:38,920
And it's more annoying to you
because they --

69
00:03:38,920 --> 00:03:40,600
they're not being
who they used to be.

70
00:03:40,600 --> 00:03:45,200
-So my mother was diagnosed
with Parkinson's

71
00:03:45,200 --> 00:03:49,120
in about 2015, 2016.

72
00:03:49,120 --> 00:03:52,240
And they said to us at that time
that we could expect

73
00:03:52,240 --> 00:03:54,480
that there's about an 80
to 90% correlation

74
00:03:54,480 --> 00:03:56,560
that she would
develop dementia.

75
00:03:56,560 --> 00:03:59,600
What complicated matters
in her situation

76
00:03:59,600 --> 00:04:03,000
was that she was already
cognitively impaired.

77
00:04:03,000 --> 00:04:06,840
So it was hard to judge
what a baseline was and measure

78
00:04:06,840 --> 00:04:11,440
when things were starting --
when the habit onset versus

79
00:04:11,440 --> 00:04:14,960
what was her normal
cognitive impairment.

80
00:04:14,960 --> 00:04:16,640
In addition to her
cognitive impairment,

81
00:04:16,640 --> 00:04:18,600
my mother is Korean,
was Korean;

82
00:04:18,600 --> 00:04:21,600
and English was not her
first language.

83
00:04:21,600 --> 00:04:24,560
And she was not literate in her
native language of Korean.

84
00:04:24,560 --> 00:04:31,120
So she had all these issues
that came out

85
00:04:31,120 --> 00:04:32,760
that impacted
her cognitive state.

86
00:04:32,760 --> 00:04:34,400
So, again, it was really hard
to tell

87
00:04:34,400 --> 00:04:37,200
how much of it was dementia,
how much was progressing,

88
00:04:37,200 --> 00:04:39,320
and how much was just
from normal,

89
00:04:39,320 --> 00:04:42,480
you know, every day
cognitive impairment.

90
00:04:42,480 --> 00:04:49,720
♪♪

91
00:04:49,720 --> 00:04:53,480
Now, I'm here a week, you know,
at best every other month.

92
00:04:53,480 --> 00:04:56,840
It's very different than what
it's like for my mom

93
00:04:56,840 --> 00:04:58,360
who's here all the time.

94
00:04:58,360 --> 00:05:01,960
And she would say her life
is also different

95
00:05:01,960 --> 00:05:04,160
because of these
incredible caregivers

96
00:05:04,160 --> 00:05:08,600
that are also here
with her and with my dad.

97
00:05:08,600 --> 00:05:11,720
But for all the bright spots,
it's -- there's --

98
00:05:11,720 --> 00:05:13,400
you know,
there's a lot of challenges.

99
00:05:13,400 --> 00:05:16,240
And for a man
who was very independent

100
00:05:16,240 --> 00:05:19,600
and was a surgeon
and a clinician and a researcher

101
00:05:19,600 --> 00:05:24,280
and a teacher and a writer
to continue to feel boxed in

102
00:05:24,280 --> 00:05:27,000
by some of these diagnoses
is difficult.

103
00:05:27,000 --> 00:05:30,640
And he'll say that he really
just wants to be of service.

104
00:05:30,640 --> 00:05:35,360
And my father can put on
a very positive front

105
00:05:35,360 --> 00:05:38,440
and try to be in the moment
and count his blessings

106
00:05:38,440 --> 00:05:42,800
and begins every day with
Hebrew blessings for waking up

107
00:05:42,800 --> 00:05:44,680
and for the food on his plate.

108
00:05:44,680 --> 00:05:47,920
And I think from my mother,
who deals with the actuality

109
00:05:47,920 --> 00:05:51,000
of managing caregivers
and doctors

110
00:05:51,000 --> 00:05:53,760
and trying to be his advocate
and trying to figure out

111
00:05:53,760 --> 00:05:56,640
when more
is more and more is not more

112
00:05:56,640 --> 00:05:59,720
and when to stop
pushing so hard, it's a much --

113
00:05:59,720 --> 00:06:01,840
it's a much harder challenge.

114
00:06:01,840 --> 00:06:04,400
It's easy for me
to swoop in and out

115
00:06:04,400 --> 00:06:06,720
and spend quality time
and then whoosh away.

116
00:06:06,720 --> 00:06:11,040
And I think it's much harder
to be the, you know,

117
00:06:11,040 --> 00:06:14,080
online caregiver 24/7.

118
00:06:14,080 --> 00:06:18,480
-I think just allowing myself

119
00:06:18,480 --> 00:06:21,640
to be human

120
00:06:21,640 --> 00:06:27,160
and recognize my limitations...

121
00:06:32,080 --> 00:06:46,040
...is so real and so human

122
00:06:46,040 --> 00:06:52,200
that I think
it's incredibly important

123
00:06:52,200 --> 00:07:01,120
that any caregiver accept
that responsibility willing,

124
00:07:01,120 --> 00:07:04,440
willingly, willing --
-Ly.

125
00:07:04,440 --> 00:07:06,000
-Willingly.

126
00:07:08,280 --> 00:07:15,600
And it's just
the human condition

127
00:07:15,600 --> 00:07:19,200
in its most human form.

128
00:07:19,200 --> 00:07:21,320
-On the occasions now
where I just go to the store

129
00:07:21,320 --> 00:07:23,400
for an hour
or something like that,

130
00:07:23,400 --> 00:07:25,080
I can come back to mayhem.

131
00:07:25,080 --> 00:07:27,920
So that means that somebody
really has to be here.

132
00:07:27,920 --> 00:07:30,000
So that's the biggest
impact right now.

133
00:07:30,000 --> 00:07:33,000
We're getting ready in my office

134
00:07:33,000 --> 00:07:35,000
to go back to work
in the office,

135
00:07:35,000 --> 00:07:40,280
at least part of the week,
starting in April.

136
00:07:40,280 --> 00:07:43,440
So I'm not sure
what I'm going to do

137
00:07:43,440 --> 00:07:46,640
because, on occasion,
I'll be here working.

138
00:07:46,640 --> 00:07:50,000
And, you know,
I'll hear the door click;

139
00:07:50,000 --> 00:07:54,400
and she's gone out to check on
her car to see if she locked it,

140
00:07:54,400 --> 00:07:58,480
or she wants to go get
the trash bins, trash cans in.

141
00:07:58,480 --> 00:08:00,400
And so she will sometimes
not realize

142
00:08:00,400 --> 00:08:02,800
she hasn't kept
the door unlocked.

143
00:08:02,800 --> 00:08:05,200
So if I wasn't here, she would
have just locked herself out.

144
00:08:05,200 --> 00:08:06,840
-There's not enough resources,
I think,

145
00:08:06,840 --> 00:08:09,560
put towards that, the well-being

146
00:08:09,560 --> 00:08:14,560
and the care of the healthcare
provider or the caretaker.

147
00:08:14,560 --> 00:08:17,280
I don't think enough emphasis
is put on that,

148
00:08:17,280 --> 00:08:20,520
that if you're not taking care
of yourself and your well-being,

149
00:08:20,520 --> 00:08:23,200
you're not able to
take care of anybody.

150
00:08:25,240 --> 00:08:28,480
-You were saying recently
that you have just a hard time

151
00:08:28,480 --> 00:08:32,040
even with the word dementia
and Alzheimer's.

152
00:08:32,040 --> 00:08:36,880
Can you talk a little about
why those words feel so hard?

153
00:08:36,880 --> 00:08:38,320
-Because you've spoken
to people

154
00:08:38,320 --> 00:08:40,880
about I've had strokes,
even I have Parkinson's.

155
00:08:40,880 --> 00:08:44,880
But dementia and Alzheimer's
really just --

156
00:08:44,880 --> 00:08:51,280
-It's been hard accepting
my limitations

157
00:08:51,280 --> 00:09:05,200
and wanting just to think
of myself as being limited.

158
00:09:05,200 --> 00:09:08,120
It's been very complicated
for me.

159
00:09:10,320 --> 00:09:13,400
-And especially
something related to the brain.

160
00:09:13,400 --> 00:09:15,000
-Yes.

161
00:09:15,000 --> 00:09:17,720
-Even more so than the body
because with the stroke

162
00:09:17,720 --> 00:09:23,080
and with Parkinson's there
have been movement limitations,

163
00:09:23,080 --> 00:09:28,400
but it seems like the brain,
the cognitive being impacted

164
00:09:28,400 --> 00:09:31,120
has been particularly chilling.

165
00:09:33,640 --> 00:09:35,280
-Quite so.

166
00:09:35,280 --> 00:09:40,400
-Both thing that he does
is he lets me be me.

167
00:09:40,400 --> 00:09:47,200
And he is not ahead of me
or back with me.

168
00:09:47,200 --> 00:09:58,960
He is able to figure out
if he's going too far

169
00:09:58,960 --> 00:10:03,400
or he's being too coddling.

170
00:10:03,400 --> 00:10:07,800
And that allows me to be me.

171
00:10:07,800 --> 00:10:15,040
And we as a couple can continue
to be as much as we possibly

172
00:10:15,040 --> 00:10:21,000
can with the fact being that,
in fact, my brain is different.

173
00:10:21,000 --> 00:10:23,800
There is different thoughts.

174
00:10:23,800 --> 00:10:27,720
And that's --
it takes a bit of work,

175
00:10:27,720 --> 00:10:34,440
and it takes a lot of changing
from both of us.

176
00:10:34,440 --> 00:10:39,480
And -- but that happens,
of course, the course of life.

177
00:10:39,480 --> 00:10:41,680
You know, things happen.

178
00:10:41,680 --> 00:10:46,040
And it doesn't stay
just the same.

179
00:10:46,040 --> 00:10:53,000
♪♪

180
00:10:53,000 --> 00:10:55,880
-The things I like to tell
everybody with the disease

181
00:10:55,880 --> 00:10:59,480
is there's a choice in how
you live with this disease.

182
00:10:59,480 --> 00:11:03,840
You can choose to realize
that you have been given

183
00:11:03,840 --> 00:11:09,200
a number of years ahead of you
that can be joyful, purposeful.

184
00:11:11,200 --> 00:11:14,640
The person with the disease
is somewhat more forgetful.

185
00:11:14,640 --> 00:11:19,440
But, remember,
this is a long-term disease.

186
00:11:19,440 --> 00:11:23,440
Many people live over 10 years,
10 to 15 years or longer.

187
00:11:23,440 --> 00:11:25,760
And the early stage
and mid-stage

188
00:11:25,760 --> 00:11:28,120
can be a wonderful time of life.

189
00:11:28,120 --> 00:11:29,800
And we've been
given a diagnosis,

190
00:11:29,800 --> 00:11:32,560
so that makes every day
more valuable.

191
00:11:32,560 --> 00:11:35,840
So grab it. Choose it.
Live it fully.

192
00:11:37,920 --> 00:11:41,320
Mark things off
your bucket list.

193
00:11:41,320 --> 00:11:43,200
Contribute to others.
I mean, for us,

194
00:11:43,200 --> 00:11:46,040
the most rewarding
and joyful part of this

195
00:11:46,040 --> 00:11:47,800
has been our advocacy

196
00:11:47,800 --> 00:11:53,480
and our ability to help
other individuals with dementia.

197
00:11:53,480 --> 00:11:55,720
-And I so --
the silver lining,

198
00:11:55,720 --> 00:12:00,880
while it sounds really
maybe cold and unfeeling,

199
00:12:00,880 --> 00:12:04,400
to get your affairs
in order soon enough.

200
00:12:04,400 --> 00:12:06,800
You know, do your will.
Do your living will.

201
00:12:06,800 --> 00:12:10,080
Do your MLTS.

202
00:12:10,080 --> 00:12:15,200
Do your power of attorney.
Get your affairs in order.

203
00:12:15,200 --> 00:12:16,880
Make sure that you're living
in a situation

204
00:12:16,880 --> 00:12:20,000
that's the safest
and healthiest for you

205
00:12:20,000 --> 00:12:22,160
and for your family members
and for your loved ones.

206
00:12:22,160 --> 00:12:23,600
I think that's really,
really important.

207
00:12:23,600 --> 00:12:25,240
And you think
there's always time.

208
00:12:25,240 --> 00:12:27,800
Oh, I'll have time to do a will.
I'll have time to do that.

209
00:12:27,800 --> 00:12:30,640
I'll have time to -- you know,
to -- this is too early.

210
00:12:30,640 --> 00:12:32,240
You just can't do it
early enough.

211
00:12:32,240 --> 00:12:33,800
And that's what
I've learned from it

212
00:12:33,800 --> 00:12:40,000
because all the physical stuff,
you can't control.

213
00:12:40,000 --> 00:12:41,440
You know,
you can take medication

214
00:12:41,440 --> 00:12:43,160
up to a certain point,
right, that helped --

215
00:12:43,160 --> 00:12:44,840
that might or might not help,
slow down,

216
00:12:44,840 --> 00:12:46,800
or stabilize your condition.

217
00:12:46,800 --> 00:12:51,320
But you can't control
the acceleration

218
00:12:51,320 --> 00:12:53,920
or the decline of your health
to some extent,

219
00:12:53,920 --> 00:12:55,640
but you can control
some other factors

220
00:12:55,640 --> 00:12:59,640
that might make living with that
situation a little bit easier.

221
00:12:59,640 --> 00:13:01,400
There is some good
in the experience.

222
00:13:01,400 --> 00:13:04,360
Okay. Sounds like it's all awful
and emotionally draining.

223
00:13:04,360 --> 00:13:08,800
But there is some good learnings
from something like this.

224
00:13:08,800 --> 00:13:10,520
It does make you
a more compassionate person.

225
00:13:10,520 --> 00:13:12,880
It does make you question
your mortality

226
00:13:12,880 --> 00:13:14,800
and how do you want to live
the rest of your life

227
00:13:14,800 --> 00:13:18,680
and what's important to you.
And I think that's a good thing.

228
00:13:18,680 --> 00:13:20,640
-I guess the other thing
is to forgive them.

229
00:13:20,640 --> 00:13:23,880
These behaviors
are classic dementia behaviors.

230
00:13:23,880 --> 00:13:27,000
That's what a person
with dementia does.

231
00:13:27,000 --> 00:13:30,040
So forgive them
for having dementia.

232
00:13:30,040 --> 00:13:32,840
It's, you know,
quite likely not their fault.

233
00:13:32,840 --> 00:13:36,600
So that makes things
a little lighter is --

234
00:13:36,600 --> 00:13:39,160
-So one label,
there's not one size fit all.

235
00:13:39,160 --> 00:13:40,920
-I don't think so.

236
00:13:40,920 --> 00:13:44,240
-And I know you want to be
seen in your totality.

237
00:13:44,240 --> 00:13:45,560
-Yes.

238
00:13:45,560 --> 00:13:47,520
-You don't want to be
labeled keys X.

239
00:13:47,520 --> 00:13:50,120
-There are better words
to use.

240
00:13:50,120 --> 00:13:52,720
-Are there better words
that you can think of?

241
00:13:52,720 --> 00:13:54,000
How would you want
someone to talk

242
00:13:54,000 --> 00:13:58,680
about those
cognitive challenges?

243
00:13:58,680 --> 00:14:02,600
-I think that's a great
question,

244
00:14:02,600 --> 00:14:05,360
and I don't know
how to answer that.

245
00:14:05,360 --> 00:14:07,280
-But you're more
than just a label.

246
00:14:07,280 --> 00:14:08,760
-Thank you.

247
00:14:08,760 --> 00:14:16,240
♪♪

248
00:14:16,240 --> 00:14:17,840
-Keep working.

249
00:14:19,960 --> 00:14:22,360
-What else?

250
00:14:22,360 --> 00:14:25,000
-Well, the first thing
I'd say is,

251
00:14:25,000 --> 00:14:27,720
from the bottom
of our hearts, thank you.

252
00:14:27,720 --> 00:14:30,400
I don't think they hear
that nearly often enough.

253
00:14:30,400 --> 00:14:32,440
They're giving parts
of their life,

254
00:14:32,440 --> 00:14:38,240
their careers trying to find
a cure for our granddaughter.

255
00:14:38,240 --> 00:14:41,080
And nothing means
more to us than that.

256
00:14:41,080 --> 00:14:44,400
And so we are tremendously
grateful for researchers

257
00:14:44,400 --> 00:14:47,720
and clinicians and people
who are involved in the field.

258
00:14:47,720 --> 00:14:52,040
And I think as people
who are impacted by the disease,

259
00:14:52,040 --> 00:14:54,320
we need to express
that gratitude

260
00:14:54,320 --> 00:14:56,800
more profoundly and more often.

261
00:14:56,800 --> 00:15:03,040
And, secondly, remember that,
you know, we are a continuum.

262
00:15:03,040 --> 00:15:07,760
But it's a continuum of a
disease, start to late stage.

263
00:15:07,760 --> 00:15:10,520
We have lots of ideas
and advantages,

264
00:15:10,520 --> 00:15:13,000
and we can promote
clinical trials.

265
00:15:13,000 --> 00:15:17,600
And we can help you.
But we're so rarely asked.

266
00:15:17,600 --> 00:15:19,360
We're rarely asked, well,
what are your ideas

267
00:15:19,360 --> 00:15:23,000
about recruiting additional
trial participants?

268
00:15:23,000 --> 00:15:26,840
Or what do you think of this
procedure versus that procedure

269
00:15:26,840 --> 00:15:31,200
if we're designing
the next clinical trial?

270
00:15:31,200 --> 00:15:33,760
Jerry's a brilliant person.

271
00:15:33,760 --> 00:15:35,360
And she didn't
lose her brilliance

272
00:15:35,360 --> 00:15:37,840
when somebody told her
she had MCI.

273
00:15:37,840 --> 00:15:41,600
So I would encourage scientists
to realize

274
00:15:41,600 --> 00:15:45,800
what a wealth of resource
they have in their patients

275
00:15:45,800 --> 00:15:47,240
and in their care partners.

276
00:15:47,240 --> 00:15:51,000
Take advantage of us
by asking us.

277
00:15:51,000 --> 00:15:53,080
Don't hesitate because,
if you don't ask us,

278
00:15:53,080 --> 00:15:57,440
you deny us the opportunity
to feel valuable,

279
00:15:57,440 --> 00:15:58,920
to feel like we can help

280
00:15:58,920 --> 00:16:02,200
to get the positive
psychological benefit

281
00:16:02,200 --> 00:16:06,160
of helping fight
to find a cure.

282
00:16:06,160 --> 00:16:15,760
♪♪

283
00:16:15,760 --> 00:16:19,200
-Thank you to the families
and to the Communications Office

284
00:16:19,200 --> 00:16:22,080
for this wonderful
presentation.

285
00:16:22,080 --> 00:16:27,400
It's very impactful,
very appreciated.

286
00:16:27,400 --> 00:16:33,160
And it just gets to the heart
of the matters that were --

287
00:16:33,160 --> 00:16:35,680
that are important and critical
to this Summit.

288
00:16:37,840 --> 00:16:41,160
I want to now introduce
the scientific chair

289
00:16:41,160 --> 00:16:44,240
of the multiple etiologies
dementias session,

290
00:16:44,240 --> 00:16:45,840
Dr. Kate Possin.

291
00:16:47,920 --> 00:16:49,520
-Thank you.
And, yes.

292
00:16:49,520 --> 00:16:52,000
Thank you
for that inspirational video

293
00:16:52,000 --> 00:16:54,400
and remembering to always
include the patient

294
00:16:54,400 --> 00:16:56,960
and caregiver voice.

295
00:16:56,960 --> 00:17:00,400
So it is with great pleasure
that I introduce the 2022

296
00:17:00,400 --> 00:17:04,760
Draft Recommendations
for Multiple Etiology Dementias.

297
00:17:04,760 --> 00:17:11,280
Next.
Here are my disclosures. Next.

298
00:17:11,280 --> 00:17:14,960
Our committee is focused
on multiple etiology dementias

299
00:17:14,960 --> 00:17:18,400
and also two special topics.

300
00:17:18,400 --> 00:17:23,720
So Post-TBI AD/ADRD is chaired
by Dr. Dams-O'Connor,

301
00:17:23,720 --> 00:17:26,600
and Late is chaired
by Dr. Snyder.

302
00:17:26,600 --> 00:17:30,440
And these will be presented
separately. Next.

303
00:17:30,440 --> 00:17:33,160
So before we review
the draft recommendations,

304
00:17:33,160 --> 00:17:36,120
I will overview
what our session covers

305
00:17:36,120 --> 00:17:40,640
and why MED research
is crucial.

306
00:17:40,640 --> 00:17:44,520
In dementia, multiple
or mixed underlying ideologies

307
00:17:44,520 --> 00:17:46,280
is the norm.

308
00:17:46,280 --> 00:17:49,800
More than 50% of people
diagnosed with Alzheimer's

309
00:17:49,800 --> 00:17:54,760
have pathologic evidence of more
than one cause of dementia.

310
00:17:54,760 --> 00:17:58,520
If we are going to accurately
diagnose and treat Alzheimer's,

311
00:17:58,520 --> 00:18:02,040
we need to understand
these contributing pathologies,

312
00:18:02,040 --> 00:18:03,800
including how they
can be identified,

313
00:18:03,800 --> 00:18:07,080
treated,
and even prevented.

314
00:18:07,080 --> 00:18:09,360
We must continue
to advance research

315
00:18:09,360 --> 00:18:11,600
on differential diagnosis,

316
00:18:11,600 --> 00:18:15,160
treatments for people with
multiple etiology dementias,

317
00:18:15,160 --> 00:18:19,320
basic science on common and
interacting disease mechanisms,

318
00:18:19,320 --> 00:18:23,440
and training in different
dementia syndromes.

319
00:18:23,440 --> 00:18:26,080
In the AD ADRD field,

320
00:18:26,080 --> 00:18:30,440
some critical research gaps
apply across all etiologies

321
00:18:30,440 --> 00:18:33,520
and are subsumed
also in the MED session.

322
00:18:33,520 --> 00:18:36,680
This includes advancing work
on early detection,

323
00:18:36,680 --> 00:18:40,520
caregiver support,
and data harmonization. Next.

324
00:18:45,000 --> 00:18:49,880
In 2019, TDP-43 and common
dementia is now termed LATE,

325
00:18:49,880 --> 00:18:55,560
and TBI and AD ADRD
risk were emerging topics.

326
00:18:55,560 --> 00:18:58,720
And these -- this year, these
are included in the MED session

327
00:18:58,720 --> 00:19:03,400
but with separate
subcommittees. Next.

328
00:19:03,400 --> 00:19:05,480
So here's the list
of the committee members

329
00:19:05,480 --> 00:19:07,840
who have worked hard
over the last six months

330
00:19:07,840 --> 00:19:09,840
to prepare draft recommendations

331
00:19:09,840 --> 00:19:12,760
that we seek
your input on today.

332
00:19:12,760 --> 00:19:16,920
Our charge is to recommend
research on mixed etiologies

333
00:19:16,920 --> 00:19:21,400
and key themes that apply
across all etiologies.

334
00:19:21,400 --> 00:19:23,120
Next.

335
00:19:23,120 --> 00:19:27,440
so now I will introduce you
to the focus areas of MED,

336
00:19:27,440 --> 00:19:30,640
starting with detect
and diagnose.

337
00:19:30,640 --> 00:19:35,200
More than 50% of people living
with dementia are not diagnosed

338
00:19:35,200 --> 00:19:38,840
until moderate to advanced
stages of dementia.

339
00:19:38,840 --> 00:19:44,160
And these delays are longest
for race and ethnic minorities.

340
00:19:44,160 --> 00:19:46,520
People with symptomatic
cognitive decline

341
00:19:46,520 --> 00:19:50,400
need an evaluation
with quality follow-up care.

342
00:19:50,400 --> 00:19:54,760
Furthermore, too often the
dementia diagnosis is generic,

343
00:19:54,760 --> 00:19:58,600
such as unspecified dementia,
which is a huge problem

344
00:19:58,600 --> 00:20:02,400
as we move towards an era
of disease modifying therapies.

345
00:20:02,400 --> 00:20:05,280
We need scalable solutions
to achieve accurate

346
00:20:05,280 --> 00:20:11,200
and timely ideological diagnosis
in diverse populations.

347
00:20:11,200 --> 00:20:14,240
Interventions and treatment,
we recommend research

348
00:20:14,240 --> 00:20:17,280
that moves forward promising
interventions and treatments

349
00:20:17,280 --> 00:20:21,400
that address modifiable risks
to prevent cognitive decline

350
00:20:21,400 --> 00:20:23,600
and that support persons
living with dementia

351
00:20:23,600 --> 00:20:28,560
and care partners
to maximize quality of life.

352
00:20:28,560 --> 00:20:30,480
Basic science,

353
00:20:30,480 --> 00:20:34,480
MED is the norm among
older adults with dementia.

354
00:20:34,480 --> 00:20:36,200
Although basic science research

355
00:20:36,200 --> 00:20:39,200
often focuses
on a single etiology,

356
00:20:39,200 --> 00:20:41,960
there have been substantial
advancements in understanding,

357
00:20:41,960 --> 00:20:46,160
interacting, and common
mechanisms of mixed pathologies.

358
00:20:46,160 --> 00:20:48,520
Continued work in this area
is crucial

359
00:20:48,520 --> 00:20:51,640
if we're going to develop
accurate methods to diagnose

360
00:20:51,640 --> 00:20:57,320
and to treat these diseases.
Next.

361
00:20:57,320 --> 00:21:01,200
Workforce, MED recommends
work to address gaps

362
00:21:01,200 --> 00:21:04,360
in the dementia clinical
and research workforce.

363
00:21:04,360 --> 00:21:07,760
We need to develop, implement,
and evaluate training programs

364
00:21:07,760 --> 00:21:11,960
in different dementia syndromes
for health professionals.

365
00:21:11,960 --> 00:21:13,960
We need to incentivize
mentorship

366
00:21:13,960 --> 00:21:17,200
and provide opportunities
for new researchers,

367
00:21:17,200 --> 00:21:21,720
particularly from groups
underrepresented in science.

368
00:21:21,720 --> 00:21:23,800
Furthermore, it is crucial
that we promote

369
00:21:23,800 --> 00:21:26,640
and support researchers
to recruit and retain diverse

370
00:21:26,640 --> 00:21:29,280
cohorts in all types of studies.

371
00:21:31,480 --> 00:21:35,240
Harmonization is a new
proposed focus in 2022.

372
00:21:35,240 --> 00:21:39,000
The goal of this focus area is
to maximize the impact of data

373
00:21:39,000 --> 00:21:42,440
collected to address
important questions in MED.

374
00:21:42,440 --> 00:21:45,200
Our session is recommending
for the first time

375
00:21:45,200 --> 00:21:47,160
that we incentivize
and conduct research

376
00:21:47,160 --> 00:21:49,040
to improve data harmonization

377
00:21:49,040 --> 00:21:54,560
and sharing practices
across MED studies. Next.

378
00:21:54,560 --> 00:21:59,000
Infused through all of these
five focus areas of MED

379
00:21:59,000 --> 00:22:02,400
is the requirement
that research be inclusive.

380
00:22:02,400 --> 00:22:05,320
For us to make meaningful
progress towards NAPA goals,

381
00:22:05,320 --> 00:22:08,040
we must conduct
inclusive science.

382
00:22:08,040 --> 00:22:09,880
There's been
increasing attention

383
00:22:09,880 --> 00:22:11,560
and work in recent years

384
00:22:11,560 --> 00:22:14,200
to address the problem that
our research participant samples

385
00:22:14,200 --> 00:22:17,080
are frequently
not representative.

386
00:22:17,080 --> 00:22:20,040
For example, Black,
African-American, Latino,

387
00:22:20,040 --> 00:22:23,160
other minority groups
are insufficiently included.

388
00:22:23,160 --> 00:22:25,200
And this means
that our interpretations

389
00:22:25,200 --> 00:22:29,600
are also not inclusive.
This is particularly concerning

390
00:22:29,600 --> 00:22:32,000
given that some minority
populations,

391
00:22:32,000 --> 00:22:33,760
including Blacks,
African-Americans,

392
00:22:33,760 --> 00:22:37,600
and Latinos are at a greater
risk for dementia.

393
00:22:37,600 --> 00:22:40,960
Our committee recommends that
all MED research be conducted

394
00:22:40,960 --> 00:22:43,920
in a way that is culturally
sensitive and relevant

395
00:22:43,920 --> 00:22:46,760
to the populations
that suffer from MED

396
00:22:46,760 --> 00:22:48,520
so that everyone will have
the potential

397
00:22:48,520 --> 00:22:51,920
to benefit from the advances.

398
00:22:51,920 --> 00:22:53,640
The requirement
that MED research

399
00:22:53,640 --> 00:22:55,720
be inclusive
of diverse populations

400
00:22:55,720 --> 00:22:57,800
is central to all of
the recommendations

401
00:22:57,800 --> 00:23:00,920
that we present today.
Next.

402
00:23:00,920 --> 00:23:05,400
So here's a summary of the MED
draft recommendations.

403
00:23:05,400 --> 00:23:08,000
Focus area 1,
detection and diagnosis

404
00:23:08,000 --> 00:23:10,600
of cognitive impairment in MED.

405
00:23:10,600 --> 00:23:13,960
You will hear from Mike Wolf
and Jeffrey Burns

406
00:23:13,960 --> 00:23:16,000
about our recommendations
to improve

407
00:23:16,000 --> 00:23:18,640
the detection
of cognitive impairment,

408
00:23:18,640 --> 00:23:22,280
to evaluate cognitive screening,
and to support

409
00:23:22,280 --> 00:23:25,840
the identification
of multiple etiologies.

410
00:23:25,840 --> 00:23:30,040
You will hear from Malú Tansey
on our recommendations

411
00:23:30,040 --> 00:23:33,600
to advance basic science
research on the common

412
00:23:33,600 --> 00:23:38,800
and interacting risk factors
and mechanisms.

413
00:23:38,800 --> 00:23:42,560
For Focus Area 3, you will hear
from Ozioma Okonkwo

414
00:23:42,560 --> 00:23:45,560
and myself
on our recommendations

415
00:23:45,560 --> 00:23:48,760
to advance interventions
and treatments.

416
00:23:48,760 --> 00:23:51,400
And, last, you'll hear
from Heather Snyder

417
00:23:51,400 --> 00:23:54,920
on Focus Area 4,
dementia capable workforce;

418
00:23:54,920 --> 00:23:58,400
and Focus Area 5,
data harmonization.

419
00:23:58,400 --> 00:24:01,760
So now I have the pleasure
of introducing Michael Wolf

420
00:24:01,760 --> 00:24:04,760
from the Northwestern Feinberg
School of Medicine,

421
00:24:04,760 --> 00:24:08,440
who will present
on Focus Area 1. Next.

422
00:24:11,800 --> 00:24:14,960
-Good morning.

423
00:24:14,960 --> 00:24:17,480
As the slide states,
I have no relevant disclosures.

424
00:24:17,480 --> 00:24:23,000
And I will be talking
about recommendations 1 and 2.

425
00:24:23,000 --> 00:24:27,560
Next.
And next.

426
00:24:27,560 --> 00:24:29,440
So Recommendation 1,
which has been flagged

427
00:24:29,440 --> 00:24:32,800
as of the highest priority
at this summit since 2016,

428
00:24:32,800 --> 00:24:34,400
addresses the need
for interventions

429
00:24:34,400 --> 00:24:37,320
that promote objective detection
of cognitive impairment

430
00:24:37,320 --> 00:24:39,680
linked to quality care
whenever a patient,

431
00:24:39,680 --> 00:24:42,360
care partner, or clinician
reports cognitive,

432
00:24:42,360 --> 00:24:44,920
behavioral,
or functional changes.

433
00:24:44,920 --> 00:24:47,240
An emphasis is specifically
placed on strategies

434
00:24:47,240 --> 00:24:49,760
at the frontlines of healthcare
including primary care

435
00:24:49,760 --> 00:24:52,160
and other everyday
clinical settings.

436
00:24:52,160 --> 00:24:54,240
It should be stressed
that interventions must focus

437
00:24:54,240 --> 00:24:57,560
not only on improving detection
but also follow-up activities

438
00:24:57,560 --> 00:25:00,120
including referral,
diagnosis, care planning,

439
00:25:00,120 --> 00:25:01,920
and ongoing management
of any impairment

440
00:25:01,920 --> 00:25:05,120
or identified cognitive
functional change.

441
00:25:05,120 --> 00:25:07,000
The need is also heightened
among populations

442
00:25:07,000 --> 00:25:09,440
experiencing health
disparities in ADRD.

443
00:25:09,440 --> 00:25:12,240
Therefore, research should
prioritize these communities.

444
00:25:12,240 --> 00:25:13,840
Next.

445
00:25:16,400 --> 00:25:18,160
Recognition 1
and being flagged

446
00:25:18,160 --> 00:25:20,400
at the highest priority
is well-justified.

447
00:25:20,400 --> 00:25:22,240
Despite long-standing
opportunities,

448
00:25:22,240 --> 00:25:24,600
including the Medicare
annual wellness visit,

449
00:25:24,600 --> 00:25:26,880
rates of detection, particularly
in primary care settings,

450
00:25:26,880 --> 00:25:28,480
remain very low.

451
00:25:28,480 --> 00:25:30,760
This is especially true
for early detection of ADRD

452
00:25:30,760 --> 00:25:33,280
with mild cognitive impairment.

453
00:25:33,280 --> 00:25:35,040
And there are many root
causes steeped

454
00:25:35,040 --> 00:25:37,760
in the reality
of typical clinical workflows.

455
00:25:37,760 --> 00:25:40,280
Primary care practices
often have limited resources

456
00:25:40,280 --> 00:25:42,840
in terms of staffing
and time with patients.

457
00:25:42,840 --> 00:25:44,200
But, also, there's a lack
of training

458
00:25:44,200 --> 00:25:45,800
and awareness
on the availability

459
00:25:45,800 --> 00:25:47,880
and use of various
cognitive assessments.

460
00:25:47,880 --> 00:25:50,080
Further, the presence
of comorbidities

461
00:25:50,080 --> 00:25:52,200
may mask the detection
of cognitive, behavioral,

462
00:25:52,200 --> 00:25:55,640
or functional changes
warranting further assessment.

463
00:25:55,640 --> 00:25:57,840
As with the past
two ADRD summits,

464
00:25:57,840 --> 00:25:59,160
there continues to be
an urgent need

465
00:25:59,160 --> 00:26:00,680
for objective
cognitive assessments

466
00:26:00,680 --> 00:26:03,600
that are amenable for use
in primary care settings,

467
00:26:03,600 --> 00:26:06,760
brief in nature, tethered
to electronic health records,

468
00:26:06,760 --> 00:26:09,320
with easily interpretable
and actionable findings,

469
00:26:09,320 --> 00:26:12,480
again, linking to quality care
with TRNKE recommendations.

470
00:26:12,480 --> 00:26:17,080
These are
desperately needed. Next.

471
00:26:17,080 --> 00:26:18,920
I'd also like to highlight
a recent study

472
00:26:18,920 --> 00:26:20,840
that underscores
the presence of disparities

473
00:26:20,840 --> 00:26:22,400
particularly among Asian, Black,

474
00:26:22,400 --> 00:26:24,960
and Hispanic Latinx
older adults.

475
00:26:24,960 --> 00:26:27,280
So when colleagues leveraged
California Medicare data

476
00:26:27,280 --> 00:26:29,600
and found that disparities
among these groups,

477
00:26:29,600 --> 00:26:31,600
Asian, Black,
and Hispanic adults,

478
00:26:31,600 --> 00:26:34,160
were less likely to receive
a timely diagnosis;

479
00:26:34,160 --> 00:26:35,920
and Asian adults
specifically received

480
00:26:35,920 --> 00:26:37,960
fewer diagnostic elements.

481
00:26:37,960 --> 00:26:39,440
This underscores
the recommendations

482
00:26:39,440 --> 00:26:41,400
priority studying
among health --

483
00:26:41,400 --> 00:26:46,320
studies among health
desperate populations. Next.

484
00:26:46,320 --> 00:26:48,240
In response to this
recommendation set forth

485
00:26:48,240 --> 00:26:50,680
at the 2016 ADRD Summit,

486
00:26:50,680 --> 00:26:54,440
NINDS immediately took action
with a request for applications,

487
00:26:54,440 --> 00:26:56,240
forming the
Detect Cognitive Impairment

488
00:26:56,240 --> 00:27:00,240
Including Dementia Consortium
or DetectCID.

489
00:27:00,240 --> 00:27:02,600
This is led by Dr.
Corriveau and Dr Hummer.

490
00:27:02,600 --> 00:27:04,800
And I'd also like to acknowledge
Dr. Claudia Moyes' role

491
00:27:04,800 --> 00:27:08,120
in consortium's creation
as well.

492
00:27:08,120 --> 00:27:10,000
DetectCID was founded in 2017

493
00:27:10,000 --> 00:27:11,720
as a network
of research programs

494
00:27:11,720 --> 00:27:14,600
validating strategies
in everyday clinical settings,

495
00:27:14,600 --> 00:27:17,720
including primary care that
include cognitive assessments

496
00:27:17,720 --> 00:27:19,400
linked to quality care.

497
00:27:19,400 --> 00:27:21,440
The goal is to improve
both the frequency

498
00:27:21,440 --> 00:27:23,400
and quality
of cognitive evaluations

499
00:27:23,400 --> 00:27:25,240
and to better understand
the various barriers

500
00:27:25,240 --> 00:27:26,920
to routine detection,

501
00:27:26,920 --> 00:27:29,960
especially among populations
experiencing health disparities.

502
00:27:29,960 --> 00:27:31,960
Dr. Possin and her team
serve as a coordinating site

503
00:27:31,960 --> 00:27:37,520
for this consortium. Next.
There are three paradigms

504
00:27:37,520 --> 00:27:41,360
currently include
in the DetectCID --

505
00:27:41,360 --> 00:27:42,960
I'm sorry. Next.

506
00:27:45,760 --> 00:27:48,880
You know, the three
current programs in DetectCID,

507
00:27:48,880 --> 00:27:52,440
you can see the actual --
the partners here.

508
00:27:52,440 --> 00:27:54,320
They each have their own
paradigm being tested

509
00:27:54,320 --> 00:27:55,800
in diverse settings.

510
00:27:55,800 --> 00:27:58,240
All seek to have as brief
as possible assessments,

511
00:27:58,240 --> 00:27:59,800
whenever possible,
less than 10 minutes

512
00:27:59,800 --> 00:28:02,440
and even, ideally,
shorter than seven minutes,

513
00:28:02,440 --> 00:28:03,920
tethered to electronic
health record

514
00:28:03,920 --> 00:28:07,960
and, again, with turnkey
recommendations. Next.

515
00:28:10,160 --> 00:28:12,400
In the fall of 2021, NINDS

516
00:28:12,400 --> 00:28:14,560
made another commitment
to extend and expand

517
00:28:14,560 --> 00:28:16,760
the DetectCID consortium
with an RFA

518
00:28:16,760 --> 00:28:18,440
linked to this recommendation,

519
00:28:18,440 --> 00:28:22,080
providing a five-year renewal
within a UL 1 mechanism.

520
00:28:22,080 --> 00:28:23,600
This time the consortium
will focus

521
00:28:23,600 --> 00:28:25,240
on pragmatic clinical trials;

522
00:28:25,240 --> 00:28:27,880
testing paradigms based
in everyday clinical settings,

523
00:28:27,880 --> 00:28:30,360
including primary care
to improve detection

524
00:28:30,360 --> 00:28:32,240
of cognitive impairment
with a mandate

525
00:28:32,240 --> 00:28:35,400
to target populations
experiencing disparities.

526
00:28:35,400 --> 00:28:37,600
These pragmatic trials
will also seek to evaluate

527
00:28:37,600 --> 00:28:39,520
not just the effectiveness
of early detection

528
00:28:39,520 --> 00:28:43,000
and management strategies
but their fidelity as well.

529
00:28:43,000 --> 00:28:47,040
Next. Of note,
a soon-to-be-released article

530
00:28:47,040 --> 00:28:48,760
shared many of
the early learnings

531
00:28:48,760 --> 00:28:52,000
across the consortium partners
with regards to the lessons

532
00:28:52,000 --> 00:28:53,800
learned on hardwiring
early detection

533
00:28:53,800 --> 00:28:57,000
strategies in primary care.
One particular challenge,

534
00:28:57,000 --> 00:28:59,240
especially in community
health center settings,

535
00:28:59,240 --> 00:29:00,800
that may disproportionately
provide care

536
00:29:00,800 --> 00:29:02,600
to help disparate populations

537
00:29:02,600 --> 00:29:05,720
is the need to identify pathways
for primary care clinicians

538
00:29:05,720 --> 00:29:07,720
in terms of doing
the diagnostic workup,

539
00:29:07,720 --> 00:29:10,400
referral and later ongoing
care management of adults

540
00:29:10,400 --> 00:29:13,280
with suspected impairment.
Next.

541
00:29:16,440 --> 00:29:20,520
Moving on to Recommendation 2,
this is set at priority 4

542
00:29:20,520 --> 00:29:22,920
with a focus over the next five
to seven years,

543
00:29:22,920 --> 00:29:25,240
addressing the needs
for improving our understanding

544
00:29:25,240 --> 00:29:26,680
of the benefits, burdens,

545
00:29:26,680 --> 00:29:29,040
and harms of screening
for cognitive impairment.

546
00:29:29,040 --> 00:29:31,200
Specifically, in the absence
of a patient

547
00:29:31,200 --> 00:29:32,760
care partner
or clinician report

548
00:29:32,760 --> 00:29:35,800
of cognitive, behavioral,
or functional changes.

549
00:29:35,800 --> 00:29:38,200
A strong emphasis is yet again
placed on the importance

550
00:29:38,200 --> 00:29:40,600
of having any
early detection strategy

551
00:29:40,600 --> 00:29:43,800
linked to diagnostic services
and quality care.

552
00:29:43,800 --> 00:29:46,320
In addition, research studies
should be able to determine

553
00:29:46,320 --> 00:29:48,800
whether certain populations
are more likely to benefit

554
00:29:48,800 --> 00:29:51,840
from screening as well
as whether other populations

555
00:29:51,840 --> 00:29:54,800
may be more likely to be harmed.
Next.

556
00:29:57,440 --> 00:30:00,000
The justification for
Recommendation 2 flows directly

557
00:30:00,000 --> 00:30:02,760
From the US
Preventive Services Task Force

558
00:30:02,760 --> 00:30:06,080
continued I or insufficient
evidence recommendation

559
00:30:06,080 --> 00:30:07,800
made as recently
as February 2020,

560
00:30:07,800 --> 00:30:10,800
with regard to cognitive
screening. Next.

561
00:30:13,400 --> 00:30:15,000
The primary reason
was that, in fact,

562
00:30:15,000 --> 00:30:16,920
there continues to be
very limited data

563
00:30:16,920 --> 00:30:20,040
investigating benefits and harms
of cognitive screening.

564
00:30:20,040 --> 00:30:21,480
One trial by Fowler
and colleagues

565
00:30:21,480 --> 00:30:22,840
was recently conducted,

566
00:30:22,840 --> 00:30:24,920
finding no differences
in quality of life

567
00:30:24,920 --> 00:30:27,640
among those who did or did
not receive screening.

568
00:30:27,640 --> 00:30:29,120
Prior to the Fowler study,

569
00:30:29,120 --> 00:30:30,680
scant evidence
has been available

570
00:30:30,680 --> 00:30:33,560
to further inform
the Task Force.

571
00:30:33,560 --> 00:30:37,160
Other justifications for the
lack of endorsement of cognitive

572
00:30:37,160 --> 00:30:40,200
screening includes the lack of
accurate well-tested instruments

573
00:30:40,200 --> 00:30:41,880
for assessing
cognitive impairment

574
00:30:41,880 --> 00:30:44,040
that would work
in primary care settings

575
00:30:44,040 --> 00:30:45,560
and that there also
is little evidence

576
00:30:45,560 --> 00:30:47,200
supporting any benefit
from screening

577
00:30:47,200 --> 00:30:49,800
or any earlier diagnosis
on decision-making.

578
00:30:49,800 --> 00:30:51,920
Yet there's also mixed evidence
on potential harms

579
00:30:51,920 --> 00:30:55,880
due to false positives derived
from diagnostic inaccuracies.

580
00:30:55,880 --> 00:30:58,960
Next.

581
00:30:58,960 --> 00:31:01,160
Interestingly, we do have
a natural experiment

582
00:31:01,160 --> 00:31:03,400
brewing with the Medicare
annual wellness visit.

583
00:31:03,400 --> 00:31:05,360
These covered primary care
encounters have been around

584
00:31:05,360 --> 00:31:08,400
since 2011 and require
a cognitive assessment.

585
00:31:08,400 --> 00:31:09,920
So, in essence,
despite the US

586
00:31:09,920 --> 00:31:12,200
Preventive Services
Task Force recommendations,

587
00:31:12,200 --> 00:31:14,240
there is a cognitive
screening mandate.

588
00:31:14,240 --> 00:31:15,680
However,
Medicare wellness visits

589
00:31:15,680 --> 00:31:18,240
are often not performed
for a myriad of reasons.

590
00:31:18,240 --> 00:31:20,840
And, when they are performed,
as many as half may not include

591
00:31:20,840 --> 00:31:22,800
the required
cognitive assessment.

592
00:31:22,800 --> 00:31:24,520
A prior Alzheimer's
Association survey

593
00:31:24,520 --> 00:31:26,280
found one in five
primary care doctors

594
00:31:26,280 --> 00:31:28,440
were unaware
that such a Medicare visit

595
00:31:28,440 --> 00:31:30,120
required
a cognitive screening,

596
00:31:30,120 --> 00:31:32,400
this after several years
of Medicare annual wellness

597
00:31:32,400 --> 00:31:35,400
visit being in place next.

598
00:31:37,680 --> 00:31:39,400
Finally, as we move forward,

599
00:31:39,400 --> 00:31:41,400
an important take-home
to reiterate

600
00:31:41,400 --> 00:31:42,960
is the need
to develop strategies

601
00:31:42,960 --> 00:31:44,600
for early detection
of cognitive impairment

602
00:31:44,600 --> 00:31:46,600
that will not widen
existing disparities

603
00:31:46,600 --> 00:31:49,160
by not having adequate linkages
to quality care

604
00:31:49,160 --> 00:31:50,560
and clear recommendations

605
00:31:50,560 --> 00:31:53,240
for ongoing follow-up
and care management.

606
00:31:53,240 --> 00:31:54,960
Partnerships,
partnerships with CMS

607
00:31:54,960 --> 00:31:56,560
and other large health systems

608
00:31:56,560 --> 00:31:59,200
might also expedite answers
for Recommendation 2

609
00:31:59,200 --> 00:32:02,440
by examining the Medicare
annual wellness visit data.

610
00:32:02,440 --> 00:32:04,000
Thank you.

611
00:32:07,800 --> 00:32:09,400
-Alright. Great.

612
00:32:09,400 --> 00:32:13,000
So how I'm Jeff Burns,
thanks Mike.

613
00:32:13,000 --> 00:32:16,000
I am going to
discuss recommendation

614
00:32:16,000 --> 00:32:18,960
three in this focus area
about detecting

615
00:32:18,960 --> 00:32:21,280
and diagnosing
cognitive impairment

616
00:32:21,280 --> 00:32:24,520
in multi-etiology dementia.
I do have a couple disclosures,

617
00:32:24,520 --> 00:32:27,200
I've done some consultation
for a couple of companies

618
00:32:27,200 --> 00:32:29,960
and I lead
some clinical trials

619
00:32:29,960 --> 00:32:34,720
as site PI for a number
of different companies.

620
00:32:34,720 --> 00:32:37,520
Next.

621
00:32:37,520 --> 00:32:40,200
So this recommendation,
recommendation three,

622
00:32:40,200 --> 00:32:42,600
is about moving forward,

623
00:32:42,600 --> 00:32:44,400
clinical
and translational research

624
00:32:44,400 --> 00:32:47,800
as opposed to basic science
which we'll hear about next.

625
00:32:47,800 --> 00:32:49,520
But clinical
and translational research

626
00:32:49,520 --> 00:32:54,640
focused on identifying
the multi-etiologies of dementia

627
00:32:54,640 --> 00:32:59,120
in diverse populations.
Next slide.

628
00:32:59,120 --> 00:33:03,720
So, we know and we're, I believe
the field is really beginning

629
00:33:03,720 --> 00:33:06,320
to embrace
this idea of heterogeneity

630
00:33:06,320 --> 00:33:09,640
of Alzheimer's and dementia,
as a multi-etiology dementia

631
00:33:09,640 --> 00:33:11,800
which heard about it
today and yesterday.

632
00:33:11,800 --> 00:33:13,360
But we know
there's multiple interacting

633
00:33:13,360 --> 00:33:15,360
and co-occurring
pathologies.

634
00:33:15,360 --> 00:33:19,960
These are the classic ones
we look at. Next.

635
00:33:19,960 --> 00:33:24,400
This study here
from the Rush Group from 2013

636
00:33:24,400 --> 00:33:27,080
reminds us that
we can't really see

637
00:33:27,080 --> 00:33:28,880
and count everything
that's related

638
00:33:28,880 --> 00:33:32,240
to the common
neurodegenerative pathology,

639
00:33:32,240 --> 00:33:35,360
or actually late life
cognitive decline.

640
00:33:35,360 --> 00:33:38,960
So this study identified
about 41% of the variants

641
00:33:38,960 --> 00:33:40,600
that explains the late life

642
00:33:40,600 --> 00:33:44,000
cognitive decline
through pathology.

643
00:33:44,000 --> 00:33:49,280
But, what remains is about
60% of the variants of late life

644
00:33:49,280 --> 00:33:52,160
cognitive decline
that's unexplained by these,

645
00:33:52,160 --> 00:33:54,440
you know, more common
neurodegenerative pathologies.

646
00:33:54,440 --> 00:33:56,200
It reminds us
we really can't see

647
00:33:56,200 --> 00:33:58,200
and count everything
that's related

648
00:33:58,200 --> 00:34:01,240
to these late
life dementia's.

649
00:34:01,240 --> 00:34:05,760
Next slide.
And go ahead again.

650
00:34:05,760 --> 00:34:11,000
And another study from the same
group in 2019 on individuals

651
00:34:11,000 --> 00:34:13,840
who are diagnosed
with Alzheimer's Disease

652
00:34:13,840 --> 00:34:16,200
clinically found
that really the,

653
00:34:16,200 --> 00:34:18,600
from a neuropathological
perspective,

654
00:34:18,600 --> 00:34:20,280
these dementia's
can be attributed

655
00:34:20,280 --> 00:34:25,000
to a variety
of common neuropathologies.

656
00:34:25,000 --> 00:34:28,400
So, reminding us that when
we think it's Alzheimer's,

657
00:34:28,400 --> 00:34:30,760
that the things that we can
count are multiple

658
00:34:30,760 --> 00:34:32,240
and overlapping.

659
00:34:32,240 --> 00:34:35,480
And hence the need for thinking
about dementia

660
00:34:35,480 --> 00:34:40,680
in these broader terms
in multi-etiologies. Next.

661
00:34:40,680 --> 00:34:44,120
So, back to the recommendation
of, you know,

662
00:34:44,120 --> 00:34:46,920
how do we identify these
multi-etiologies of dementia

663
00:34:46,920 --> 00:34:48,400
in diverse populations?

664
00:34:48,400 --> 00:34:50,320
My recommendation
is to really promote

665
00:34:50,320 --> 00:34:52,560
and grow
the observational studies

666
00:34:52,560 --> 00:34:56,920
that include
multi-modal, deep phenotyping.

667
00:34:56,920 --> 00:34:58,600
So that we can begin
to understand,

668
00:34:58,600 --> 00:35:02,960
better understand clinical
phenotypes and biomarkers

669
00:35:02,960 --> 00:35:07,560
and how those predict and relate
to the neuropathologies

670
00:35:07,560 --> 00:35:10,240
and combinations
of neuropathologies.

671
00:35:10,240 --> 00:35:14,480
We need to identify risk factors
for these pathologies,

672
00:35:14,480 --> 00:35:19,040
prevalence estimates and how sex
and genetic factors relate.

673
00:35:19,040 --> 00:35:22,320
And importantly we need
to understand the life course.

674
00:35:22,320 --> 00:35:25,800
Including social
determinants of health,

675
00:35:25,800 --> 00:35:27,200
and I'll talk about
that more in a second,

676
00:35:27,200 --> 00:35:30,600
but, we need to focus
also on populations

677
00:35:30,600 --> 00:35:33,440
most at risk for Alzheimer's
Disease and related dementia's,

678
00:35:33,440 --> 00:35:36,000
including as we've heard
already this morning racial

679
00:35:36,000 --> 00:35:39,680
and ethnic minorities
that appear to be more at risk.

680
00:35:39,680 --> 00:35:42,560
And groups such
as Downs Syndrome.

681
00:35:42,560 --> 00:35:45,000
Next slide.

682
00:35:45,000 --> 00:35:49,000
So, we need to, we need to build
this idea out more as well,

683
00:35:49,000 --> 00:35:51,200
this life course
model of dementia.

684
00:35:51,200 --> 00:35:53,440
So this came from
the Lancet Commissions

685
00:35:53,440 --> 00:35:56,200
Report in 2020 on dementia
prevention,

686
00:35:56,200 --> 00:35:57,600
intervention and care.

687
00:35:57,600 --> 00:35:59,560
And focused on
the 12 risk factors,

688
00:35:59,560 --> 00:36:02,920
12 strongest risk factors.

689
00:36:02,920 --> 00:36:07,560
And how they influence dementia
risks across the life course.

690
00:36:07,560 --> 00:36:13,200
So that backwards s is a figure
that shows the risk factors

691
00:36:13,200 --> 00:36:16,000
and their apparent roles
in dementia

692
00:36:16,000 --> 00:36:17,520
risks across the life course.

693
00:36:17,520 --> 00:36:19,920
And we need to build
this idea out more,

694
00:36:19,920 --> 00:36:23,080
really begin to understand
better how the environment,

695
00:36:23,080 --> 00:36:24,920
how social determinants
of health,

696
00:36:24,920 --> 00:36:27,600
and other factors
across the lifespan

697
00:36:27,600 --> 00:36:30,120
interact with genetics
and influence

698
00:36:30,120 --> 00:36:33,080
an individuals risk
of developing dementia

699
00:36:33,080 --> 00:36:37,160
late in life.
Next slide.

700
00:36:37,160 --> 00:36:39,800
And a reminder
that it's not to early

701
00:36:39,800 --> 00:36:42,920
to begin to move these ideas
into primary care,

702
00:36:42,920 --> 00:36:45,520
we just heard about that
from Mike as well.

703
00:36:45,520 --> 00:36:48,760
But, and this is beginning
to happen already,

704
00:36:48,760 --> 00:36:51,760
this scientific statement from
the American Heart Association

705
00:36:51,760 --> 00:36:54,600
from last year
was recommendations

706
00:36:54,600 --> 00:36:57,400
for how to move
many of these ideas

707
00:36:57,400 --> 00:36:59,400
into primary care practice.

708
00:36:59,400 --> 00:37:02,000
And so, primary care physicians
are interested

709
00:37:02,000 --> 00:37:04,320
and beginning to use
these ideas in practice,

710
00:37:04,320 --> 00:37:06,000
we need to accelerate that.

711
00:37:06,000 --> 00:37:09,120
Next slide.
So how do we do that?

712
00:37:09,120 --> 00:37:11,120
Well we need to continue
to validate

713
00:37:11,120 --> 00:37:13,600
these multi
biomarker approaches,

714
00:37:13,600 --> 00:37:16,600
really understand and validate
how they predict

715
00:37:16,600 --> 00:37:19,440
and relate
to these neuropathologies.

716
00:37:19,440 --> 00:37:23,400
And importantly we need
to do research to understand

717
00:37:23,400 --> 00:37:25,960
how they influence
clinical practice.

718
00:37:25,960 --> 00:37:29,720
What signs and symptoms
best identify these etiologies.

719
00:37:29,720 --> 00:37:32,680
And are they
clinically actionable?

720
00:37:32,680 --> 00:37:34,920
Can we identify and stratify,

721
00:37:34,920 --> 00:37:38,200
can we identify these factors
or stratify individuals

722
00:37:38,200 --> 00:37:44,200
into risk groups to target them
with disease specific therapies?

723
00:37:44,200 --> 00:37:47,880
And lastly, we need
to think hard about access

724
00:37:47,880 --> 00:37:51,360
to these new diagnostics
and new therapies.

725
00:37:51,360 --> 00:37:53,600
And then how do we scale them
to the population

726
00:37:53,600 --> 00:37:56,200
so they reach everybody
who needs them?

727
00:37:56,200 --> 00:37:59,320
We need to do this
through more pragmatic trials

728
00:37:59,320 --> 00:38:03,240
and community-based trials.
And we need to focus again

729
00:38:03,240 --> 00:38:05,200
as we've heard yesterday
and today,

730
00:38:05,200 --> 00:38:10,000
on reducing inequities
and reducing poor access

731
00:38:10,000 --> 00:38:12,960
to these new therapies
and new diagnostics.

732
00:38:12,960 --> 00:38:15,520
And next slide.

733
00:38:15,520 --> 00:38:19,800
And this headline is a reminder
of why we need to do that.

734
00:38:19,800 --> 00:38:22,600
We can't develop new diagnostics
and new treatments

735
00:38:22,600 --> 00:38:26,480
that deepen
these inequities of care.

736
00:38:26,480 --> 00:38:32,440
And last slide, just to bring
it back to the big picture.

737
00:38:32,440 --> 00:38:35,440
The recommendation three,
set at a priority three

738
00:38:35,440 --> 00:38:38,680
is to conduct
multi-modal clinical

739
00:38:38,680 --> 00:38:41,200
and translational research
that supports the identification

740
00:38:41,200 --> 00:38:45,000
of these multiple ideologies
in diverse populations.

741
00:38:45,000 --> 00:38:50,120
And so now I'll turn it over
to Malu Gamez Tansey

742
00:38:50,120 --> 00:38:52,800
who's going to talk
about basic research in MED.

743
00:38:55,120 --> 00:38:57,120
-Thank you Jeff.

744
00:38:57,120 --> 00:39:00,320
Thank you
for your time everybody.

745
00:39:00,320 --> 00:39:03,840
The focus area two
for basic research in MED,

746
00:39:03,840 --> 00:39:05,400
recommendation four,

747
00:39:05,400 --> 00:39:07,720
priority two to advance
basic research on a common

748
00:39:07,720 --> 00:39:11,400
and interacting risk factors and
mechanisms of multiple etiology

749
00:39:11,400 --> 00:39:15,160
cognitive impairment in dementia
in diverse populations.

750
00:39:15,160 --> 00:39:17,840
Was put together
by contributions

751
00:39:17,840 --> 00:39:21,320
from Dr. Brad Hyman
and Lea Grinberg.

752
00:39:21,320 --> 00:39:22,880
Next slide.

753
00:39:22,880 --> 00:39:25,160
You see our disclosures
and there are several.

754
00:39:25,160 --> 00:39:27,720
So I won't read through them.

755
00:39:27,720 --> 00:39:30,600
We will go to the next slide
and start the recommendation.

756
00:39:30,600 --> 00:39:32,840
Again, under that
main recommendation

757
00:39:32,840 --> 00:39:34,840
we have four
sub-recommendations.

758
00:39:34,840 --> 00:39:36,600
And they are to define
the interactions

759
00:39:36,600 --> 00:39:39,240
at the molecular
and cellular level of the common

760
00:39:39,240 --> 00:39:42,200
and newly identify
pathobiologies of MED.

761
00:39:42,200 --> 00:39:44,000
To define
the molecular signatures

762
00:39:44,000 --> 00:39:47,640
of vulnerable versus resilient
neuronal populations.

763
00:39:47,640 --> 00:39:51,400
To incentivize innovation,
to address technological gaps

764
00:39:51,400 --> 00:39:54,280
and to incentivize creation
of multidisciplinary,

765
00:39:54,280 --> 00:39:58,000
multi-sector,
multi-career stage teams

766
00:39:58,000 --> 00:39:59,920
to address
both the heterogeneity

767
00:39:59,920 --> 00:40:02,360
and the common mechanism
questions of MED.

768
00:40:02,360 --> 00:40:04,960
And in the next few slides
I'm going to show you

769
00:40:04,960 --> 00:40:08,640
the progress towards these four
sub-recommendations

770
00:40:08,640 --> 00:40:10,880
and where we still need
to do more.

771
00:40:10,880 --> 00:40:14,160
So, the first thing you see
is that research efforts

772
00:40:14,160 --> 00:40:17,400
to advance basic science
since the 2019 summit

773
00:40:17,400 --> 00:40:21,000
have involved of course
the four main proteins.

774
00:40:21,000 --> 00:40:25,080
Tau, alpha-synuclein,
TDP43 and amyloid beta.

775
00:40:25,080 --> 00:40:29,120
And we know that the mechanisms
of toxicity of these proteins

776
00:40:29,120 --> 00:40:32,040
involve the organization,
their propagation

777
00:40:32,040 --> 00:40:34,440
and there's an,
if there's an imbalance

778
00:40:34,440 --> 00:40:37,240
in the synthesis aggregation
or clearance of these proteins

779
00:40:37,240 --> 00:40:39,800
in can result
in chronic accumulation

780
00:40:39,800 --> 00:40:42,840
that leads to further
aggregation, and propagation

781
00:40:42,840 --> 00:40:45,800
and potentially interactions
with inflammation,

782
00:40:45,800 --> 00:40:47,280
eventually neurodegeneration.

783
00:40:47,280 --> 00:40:49,880
That's the model
that everybody's testing.

784
00:40:49,880 --> 00:40:52,040
However, in the next slide
you will see

785
00:40:52,040 --> 00:40:55,280
that it gets very complex
because we see

786
00:40:55,280 --> 00:40:58,600
that they are different
strains of these seeds.

787
00:40:58,600 --> 00:41:00,360
And so, in the seminal work

788
00:41:00,360 --> 00:41:03,760
by John Trojanwoski
and Virginia Lee,

789
00:41:03,760 --> 00:41:05,840
where they showed that there
were unique pathological

790
00:41:05,840 --> 00:41:07,800
tau conformers from brain

791
00:41:07,800 --> 00:41:10,480
that could transmit
in non-transgenic mice.

792
00:41:10,480 --> 00:41:13,200
We now know from work
of Michelle Goddard

793
00:41:13,200 --> 00:41:16,760
and other investigators
including a review

794
00:41:16,760 --> 00:41:18,400
from Kejal Ashul

795
00:41:18,400 --> 00:41:21,360
that the complexity
of these amyloid strains

796
00:41:21,360 --> 00:41:23,640
is very very high.

797
00:41:23,640 --> 00:41:26,040
And interestingly enough
from the work

798
00:41:26,040 --> 00:41:30,120
of Brad Hyman
and Safar's group,

799
00:41:30,120 --> 00:41:32,280
we see that
this molecular diversity

800
00:41:32,280 --> 00:41:35,880
may contribute to clinical
heterogeneity in AD

801
00:41:35,880 --> 00:41:39,560
and may be associated with
rapidly progressing Alzheimer's.

802
00:41:39,560 --> 00:41:43,200
And so, and on the next slide
what you will see is this idea

803
00:41:43,200 --> 00:41:46,040
that we may not be able
to get away with

804
00:41:46,040 --> 00:41:47,640
just targeting
one of these,

805
00:41:47,640 --> 00:41:50,920
we may have to think
about combination immunotherapy

806
00:41:50,920 --> 00:41:53,560
and as well as targeting
the inflammation

807
00:41:53,560 --> 00:41:56,480
that comes from
these interactions.

808
00:41:56,480 --> 00:42:01,240
And finally there's a new kid
in town and that's TM106B,

809
00:42:01,240 --> 00:42:04,760
which was recently reported
by Michelle Goddard's group.

810
00:42:04,760 --> 00:42:07,920
That forms AIDS
dependent amyloid filaments

811
00:42:07,920 --> 00:42:09,440
in human brain.

812
00:42:09,440 --> 00:42:12,720
And then the next slide
what you will see

813
00:42:12,720 --> 00:42:14,680
and I'd like to highlight
is that,

814
00:42:14,680 --> 00:42:17,960
targeting tau is not just
about immunotherapy,

815
00:42:17,960 --> 00:42:20,000
there are other
non-immunotherapy approaches

816
00:42:20,000 --> 00:42:24,600
such as anti-sense oligose from
Tim Muller's group back in 2017

817
00:42:24,600 --> 00:42:29,120
and also from Brad Hyman's
group the, a way to repress tau

818
00:42:29,120 --> 00:42:32,000
is by using zinc-finger
protein nucleases

819
00:42:32,000 --> 00:42:33,480
that will, you know,

820
00:42:33,480 --> 00:42:37,640
repress the transcription
and formation of tau.

821
00:42:37,640 --> 00:42:40,440
And in the next slide
I'd like to highlight

822
00:42:40,440 --> 00:42:42,960
basically that one of
the seminal discoveries

823
00:42:42,960 --> 00:42:46,680
since the last summit
and expanded upon is,

824
00:42:46,680 --> 00:42:49,960
linking tau to immunity
and lipid biology.

825
00:42:49,960 --> 00:42:53,720
Much of this work has come
from the lab of David Holtzman.

826
00:42:53,720 --> 00:42:57,680
Where they tied ApoE4
to exacerbation

827
00:42:57,680 --> 00:43:01,360
of tomigated neurodegeneration
in mouse models.

828
00:43:01,360 --> 00:43:04,120
Followed by linking it
to interactions

829
00:43:04,120 --> 00:43:08,800
between APOE and TRIM2.
And finally a very recent report

830
00:43:08,800 --> 00:43:11,160
that implicates
the glymphatic system

831
00:43:11,160 --> 00:43:13,360
and that clearance
of extracellular tau

832
00:43:13,360 --> 00:43:16,120
and protection again
Tau aggregation.

833
00:43:16,120 --> 00:43:18,160
And then in the next slide

834
00:43:18,160 --> 00:43:21,320
I would like to highlight
the fact that we know

835
00:43:21,320 --> 00:43:24,800
as well that in addition
to these protein apathies

836
00:43:24,800 --> 00:43:27,680
there are
incidental copathologies

837
00:43:27,680 --> 00:43:30,200
that co-occur
with neurodegeneration.

838
00:43:30,200 --> 00:43:32,320
But the consequences
are unknown.

839
00:43:32,320 --> 00:43:35,160
Some of these
may impact cognition

840
00:43:35,160 --> 00:43:37,480
and some may protect
against spread.

841
00:43:37,480 --> 00:43:40,480
So there's much work
to be done in this area.

842
00:43:40,480 --> 00:43:43,880
And in the next slide
we'd like to highlight

843
00:43:43,880 --> 00:43:48,400
that there's been good progress
in implicating immunity

844
00:43:48,400 --> 00:43:52,480
in lipid processing
with genetic loci.

845
00:43:52,480 --> 00:43:54,160
And this is important

846
00:43:54,160 --> 00:43:58,320
because all the geneticists need
to have it grounded in genes

847
00:43:58,320 --> 00:44:01,480
in order to really understand
that it's important.

848
00:44:01,480 --> 00:44:05,760
And so this is a good advance
in my book and many other books.

849
00:44:05,760 --> 00:44:07,640
There's also the importance
of the gut,

850
00:44:07,640 --> 00:44:09,600
brain microbiome access,

851
00:44:09,600 --> 00:44:12,720
where we know that
there are bacteria

852
00:44:12,720 --> 00:44:15,360
that produce short-chain
fatty acids

853
00:44:15,360 --> 00:44:19,880
and those may be associated
with protection

854
00:44:19,880 --> 00:44:23,240
against early onset
of certain forms of dementia.

855
00:44:23,240 --> 00:44:26,680
In the next slide we'd like
to highlight the fact

856
00:44:26,680 --> 00:44:30,400
that there's been lots of
advances in the next slide,

857
00:44:30,400 --> 00:44:36,400
in iPSCs or select vulnerability
for understanding

858
00:44:36,400 --> 00:44:40,200
that in any kind of injury
the cell type matters.

859
00:44:40,200 --> 00:44:42,480
Because it will,
the degree of dysfunction

860
00:44:42,480 --> 00:44:45,000
depends on which cell
is injured.

861
00:44:45,000 --> 00:44:48,240
And for instance
excitatory neurons

862
00:44:48,240 --> 00:44:51,600
can be more prone
to accumulate tau and die

863
00:44:51,600 --> 00:44:55,840
compared to, you know,
other subtypes if they're,

864
00:44:55,840 --> 00:44:58,720
you know, if they're not
a certain phenotype.

865
00:44:58,720 --> 00:45:01,600
And so in the next slide
we also know

866
00:45:01,600 --> 00:45:06,040
that there are advances
in iPSCs in the next slide.

867
00:45:06,040 --> 00:45:12,880
That have been important,
but, they're limited by the fact

868
00:45:12,880 --> 00:45:16,920
that not everybody's growing
them in two and 3D culture.

869
00:45:16,920 --> 00:45:23,440
And so, the phenotype
is forward with iPSC work

870
00:45:23,440 --> 00:45:25,480
that they're grown
in the proper environment

871
00:45:25,480 --> 00:45:28,320
so that we know
that they are more closely

872
00:45:28,320 --> 00:45:30,920
recapitulating
their normal allele.

873
00:45:30,920 --> 00:45:34,920
And more importantly we also
need to stress that with,

874
00:45:34,920 --> 00:45:37,880
the development of iPSC lines
from individuals

875
00:45:37,880 --> 00:45:39,800
with diverse genetic backgrounds

876
00:45:39,800 --> 00:45:42,360
and diverse ethnic
backgrounds is needed.

877
00:45:42,360 --> 00:45:44,600
And in the next slide
we need to integrate

878
00:45:44,600 --> 00:45:49,280
everything into
a o-mix approach.

879
00:45:49,280 --> 00:45:51,440
So that we know the genome,
the transcriptome,

880
00:45:51,440 --> 00:45:54,480
the proteome and the metabolome
all come together

881
00:45:54,480 --> 00:45:57,240
into a systems
biology scenario

882
00:45:57,240 --> 00:46:01,240
where team science
is really the way to go.

883
00:46:01,240 --> 00:46:05,640
And so, as we integrate these
various aspects of basic science

884
00:46:05,640 --> 00:46:07,880
into a holistic systems
biology approach,

885
00:46:07,880 --> 00:46:12,520
we'll be able to really
understand the pathogenesis

886
00:46:12,520 --> 00:46:15,760
and the pathobiology
of AD and MED.

887
00:46:15,760 --> 00:46:17,120
And in the next slide,

888
00:46:17,120 --> 00:46:21,120
is an example
of what some of this,

889
00:46:21,120 --> 00:46:23,400
that has occurred,
like Move AD,

890
00:46:23,400 --> 00:46:26,200
is a huge partnership
between NIH,

891
00:46:26,200 --> 00:46:28,200
industry, non-profit
organizations involving,

892
00:46:28,200 --> 00:46:31,480
you know, lots of labs
with complimentary projects.

893
00:46:31,480 --> 00:46:34,720
And importantly it builds
on the open science approach

894
00:46:34,720 --> 00:46:38,240
and big data infrastructure
established by the AMP AD.

895
00:46:38,240 --> 00:46:42,400
And it's a real example
of science being a team sport.

896
00:46:42,400 --> 00:46:45,760
And in the next slide
are just a few examples of FOAs

897
00:46:45,760 --> 00:46:48,360
that have come out
since 2019.

898
00:46:48,360 --> 00:46:52,000
Especially in the bottom
highlighting,

899
00:46:52,000 --> 00:46:56,280
you know, one of the centers
that was funded with this FOA,

900
00:46:56,280 --> 00:47:02,440
which is the Office of Nuclear
Strains in the business lab.

901
00:47:02,440 --> 00:47:05,320
As well as the more recent
Center Without Walls

902
00:47:05,320 --> 00:47:08,520
to address mechanisms
of degeneration in FTD.

903
00:47:08,520 --> 00:47:11,400
And in the next slide
I just want to summarize

904
00:47:11,400 --> 00:47:16,600
basically what we are saying
in the four sub-recommendations.

905
00:47:16,600 --> 00:47:20,400
The areas of focus
are the proteinopathy,

906
00:47:20,400 --> 00:47:23,280
inflammaging and immuno
essence interactions

907
00:47:23,280 --> 00:47:25,960
that lead to cognitive decline
in diverse populations.

908
00:47:25,960 --> 00:47:27,800
And understanding
those mechanisms.

909
00:47:27,800 --> 00:47:30,280
Second, understanding
the mechanisms of cell

910
00:47:30,280 --> 00:47:33,400
vulnerability and resilience
in diverse populations

911
00:47:33,400 --> 00:47:36,600
and how they interact
with neurodegeneration.

912
00:47:36,600 --> 00:47:39,920
Third, we need to incentivize
the development of iPSC lines

913
00:47:39,920 --> 00:47:42,400
in two and 3D environments
and from individuals

914
00:47:42,400 --> 00:47:44,160
with diverse
ethnic backgrounds.

915
00:47:44,160 --> 00:47:47,200
And finally we need
to incentivize basic research

916
00:47:47,200 --> 00:47:50,360
by diverse multidisciplinary,
multi-sector,

917
00:47:50,360 --> 00:47:53,840
multi-career stage individuals
and teams.

918
00:47:53,840 --> 00:47:55,800
Such as the CWOS.

919
00:47:55,800 --> 00:48:02,000
And I will pass it on to Doctors
Okonkwo and Doctors Possin.

920
00:48:02,000 --> 00:48:04,280
Thank you.

921
00:48:04,280 --> 00:48:08,760
-Thank you so much.
That has been wonderful so far.

922
00:48:08,760 --> 00:48:11,240
So now we're going trying
to focus area trade

923
00:48:11,240 --> 00:48:14,200
is focused on interventions
and treatments.

924
00:48:14,200 --> 00:48:17,280
And I'm going to be
delivering recommendation five.

925
00:48:17,280 --> 00:48:20,200
And Dr. Possin
is going to take six.

926
00:48:20,200 --> 00:48:23,720
Next slide please.

927
00:48:23,720 --> 00:48:29,000
I have no disclosures
for this talk. Next slide.

928
00:48:29,000 --> 00:48:32,600
So for this recommendation
the focus as mentioned earlier

929
00:48:32,600 --> 00:48:36,000
is conducting
clinical studies on approved

930
00:48:36,000 --> 00:48:38,280
or promising
interventions and treatments

931
00:48:38,280 --> 00:48:41,440
to mitigate risk
for cognitive decline.

932
00:48:41,440 --> 00:48:43,560
And under here
we have three elements

933
00:48:43,560 --> 00:48:45,320
that you're going to be
hearing more about

934
00:48:45,320 --> 00:48:47,400
in the subsequent slides.

935
00:48:47,400 --> 00:48:50,960
But, in summary the key elements
are focused on conducted,

936
00:48:50,960 --> 00:48:54,120
inclusive and pragmatic
clinical trials.

937
00:48:54,120 --> 00:48:55,720
Supporting the development

938
00:48:55,720 --> 00:48:58,600
of practice-based
research networks.

939
00:48:58,600 --> 00:49:02,800
And develop within health risks
and effectiveness of hierarchies

940
00:49:02,800 --> 00:49:06,120
in diverse populations.
Next slide.

941
00:49:08,600 --> 00:49:11,800
This recommendation
was first introduced

942
00:49:11,800 --> 00:49:15,680
in the last ADRD summit in 2019.

943
00:49:15,680 --> 00:49:19,240
And in the years since then
the progress report

944
00:49:19,240 --> 00:49:23,960
that was shared with
the scientific community in 2021

945
00:49:23,960 --> 00:49:28,200
indicated that there has been
several research milestones

946
00:49:28,200 --> 00:49:30,000
that have been accomplished.

947
00:49:30,000 --> 00:49:33,240
And some of
the highlights of that,

948
00:49:33,240 --> 00:49:36,840
or a focus on post-stroke
vascular contributions

949
00:49:36,840 --> 00:49:38,640
to cognitive impairment
and dementia

950
00:49:38,640 --> 00:49:41,800
was released as a u19.

951
00:49:41,800 --> 00:49:44,440
And consequent
on that area of then,

952
00:49:44,440 --> 00:49:48,600
the diverse VCID project
was initiated

953
00:49:48,600 --> 00:49:52,800
that was under still led
by Angela and the colleague.

954
00:49:52,800 --> 00:49:54,680
And also as part
of the accomplishment

955
00:49:54,680 --> 00:49:57,600
also the discoveries
and study

956
00:49:57,600 --> 00:49:59,960
that is focused
on post-stroke cognitive

957
00:49:59,960 --> 00:50:04,680
outcomes led by Natalia Rost
and Steve Greenberg

958
00:50:04,680 --> 00:50:06,400
is now underway.

959
00:50:06,400 --> 00:50:10,400
So there's been remarkable
progress made under this effort

960
00:50:10,400 --> 00:50:13,160
to conduct intervention
studies up until now.

961
00:50:13,160 --> 00:50:14,760
Next slide please.

962
00:50:17,000 --> 00:50:20,920
And in thinking about then the,
where we wanted to take this

963
00:50:20,920 --> 00:50:25,240
for the 2022
updates for this summit.

964
00:50:25,240 --> 00:50:27,400
This happened
against the backdrop

965
00:50:27,400 --> 00:50:29,480
of two recent developments.

966
00:50:29,480 --> 00:50:33,520
You already saw this slide
in Jeff Burns talk.

967
00:50:33,520 --> 00:50:37,000
And this is the dementia
prevention reports

968
00:50:37,000 --> 00:50:38,960
from the Lancet Commission.

969
00:50:38,960 --> 00:50:44,280
And which identified some very
key risk factors for dementia.

970
00:50:44,280 --> 00:50:47,360
And these risk factors
then can now be understood

971
00:50:47,360 --> 00:50:50,320
as potential targets
that we can hit in order

972
00:50:50,320 --> 00:50:57,000
to forestall the projected
increases in dementia prevalence

973
00:50:57,000 --> 00:50:59,280
and incidents
in the coming years.

974
00:50:59,280 --> 00:51:04,960
Next slide.
And the second development

975
00:51:04,960 --> 00:51:09,480
is at the end of last year
we received,

976
00:51:09,480 --> 00:51:13,600
well we all received an update
from the National Plans

977
00:51:13,600 --> 00:51:15,480
for Addressing Alzheimer's
and Disease.

978
00:51:15,480 --> 00:51:19,800
And in that update a new goal
was added to the plan.

979
00:51:19,800 --> 00:51:23,400
And this goal
was specific developing

980
00:51:23,400 --> 00:51:25,680
and promoting health agent

981
00:51:25,680 --> 00:51:28,520
and with this risk factors
for AD.

982
00:51:28,520 --> 00:51:31,680
Which was a very interesting
and exciting development

983
00:51:31,680 --> 00:51:34,760
given that the targets
and for not all along

984
00:51:34,760 --> 00:51:38,120
has been to prevent AD by 2025.

985
00:51:38,120 --> 00:51:44,200
Which also is why in this
2022 version of the ADRD Summit,

986
00:51:44,200 --> 00:51:46,040
recommendation five
has now been moved

987
00:51:46,040 --> 00:51:48,720
from priority two
to priority one.

988
00:51:48,720 --> 00:51:50,840
Given the imminence
of the deadline

989
00:51:50,840 --> 00:51:53,160
we all have of preventing AD.

990
00:51:53,160 --> 00:51:56,440
So this focus on reducing
risk factors

991
00:51:56,440 --> 00:52:00,640
we believe is very timely
and informed the operation

992
00:52:00,640 --> 00:52:04,320
that we took the recommendation
five on interventions.

993
00:52:04,320 --> 00:52:05,920
Next slide please.

994
00:52:08,760 --> 00:52:11,720
So the first element
under this recommendation five

995
00:52:11,720 --> 00:52:16,120
is the conduct of inclusive
and pragmatic clinical trials.

996
00:52:16,120 --> 00:52:19,080
In settings where risk factors
for cognitive decline

997
00:52:19,080 --> 00:52:24,000
can be appropriately targeted
for intervention.

998
00:52:24,000 --> 00:52:28,800
A search of clinical trials
that's dove, earlier days,

999
00:52:28,800 --> 00:52:35,200
reveal that in the ten years
between 2001 and 2011.

1000
00:52:35,200 --> 00:52:40,000
Approximately 450 studies
in dementia studies

1001
00:52:40,000 --> 00:52:43,000
that were focus on dementia.

1002
00:52:43,000 --> 00:52:48,600
None of them had the keyword
pragmatic associated with them.

1003
00:52:48,600 --> 00:52:52,240
First four, ten years
and there the last decade,

1004
00:52:52,240 --> 00:52:55,720
the number of intervention
studies focused on dementia

1005
00:52:55,720 --> 00:53:00,320
have exploded thanks to
the massive inclusion of firms

1006
00:53:00,320 --> 00:53:03,400
to ADRD studies.

1007
00:53:03,400 --> 00:53:07,160
However, of this I am more
than 1,000 studies known

1008
00:53:07,160 --> 00:53:09,800
that are focused on dementia,

1009
00:53:09,800 --> 00:53:13,600
only 25 of them
have the word pragmatic

1010
00:53:13,600 --> 00:53:16,480
and attached to them
as a keyword.

1011
00:53:16,480 --> 00:53:20,960
So obviously in this were
some progress has been made

1012
00:53:20,960 --> 00:53:23,320
in a greater recognition

1013
00:53:23,320 --> 00:53:25,920
for the need
for cognitive clinical trials.

1014
00:53:25,920 --> 00:53:31,320
And there is still a lag
and opportunities for the field

1015
00:53:31,320 --> 00:53:33,080
to begin to think more in terms

1016
00:53:33,080 --> 00:53:35,400
of conducting studies
in the settings

1017
00:53:35,400 --> 00:53:37,920
where the people who actually
are going to be

1018
00:53:37,920 --> 00:53:41,000
impacted the most
by these trials.

1019
00:53:41,000 --> 00:53:45,280
Actually are look at
where they live, work and play.

1020
00:53:45,280 --> 00:53:47,200
However though,

1021
00:53:47,200 --> 00:53:50,320
despite that it's also
important to underscore

1022
00:53:50,320 --> 00:53:53,840
the progress
has continued to be made.

1023
00:53:53,840 --> 00:53:57,400
And on this slide we highlight
some of the big studies

1024
00:53:57,400 --> 00:53:59,400
that have been,

1025
00:53:59,400 --> 00:54:02,960
that are currently occurring
or have been underway

1026
00:54:02,960 --> 00:54:07,400
in the last decade in the area
of both pharmacological

1027
00:54:07,400 --> 00:54:09,080
and non-pharmacological
treatments

1028
00:54:09,080 --> 00:54:12,600
and interventions for ADRDs.

1029
00:54:12,600 --> 00:54:15,680
We highlight the A4
and the head studies.

1030
00:54:15,680 --> 00:54:19,640
Which are anti-angular therapies
focused on individuals

1031
00:54:19,640 --> 00:54:23,000
who currently are
cognitively unimpaired.

1032
00:54:23,000 --> 00:54:26,200
We also highlight the Hope
for MCI study.

1033
00:54:26,200 --> 00:54:31,080
Which as the name indicates is
focused on individuals with MCI.

1034
00:54:31,080 --> 00:54:33,320
And this study is focused

1035
00:54:33,320 --> 00:54:37,880
on addressing people
hypocampal, hyperactivation.

1036
00:54:37,880 --> 00:54:41,360
And then the Libit Study
that is focused on individuals

1037
00:54:41,360 --> 00:54:44,240
in the dementia stage
of the disease.

1038
00:54:44,240 --> 00:54:48,800
And this target is to understand
the role that CBD and THC

1039
00:54:48,800 --> 00:54:53,480
might play in the present
agitation in dementia.

1040
00:54:53,480 --> 00:54:55,680
For the
non-pharmacological treatments

1041
00:54:55,680 --> 00:54:58,960
we highlight the exert study,
the mind study,

1042
00:54:58,960 --> 00:55:02,920
the achieve study
and the US Plan Study.

1043
00:55:02,920 --> 00:55:07,480
And we think that the
non-pharmacological treatments

1044
00:55:07,480 --> 00:55:10,880
help make more progress
in beginning to think

1045
00:55:10,880 --> 00:55:15,880
about how soon interventions
within communities

1046
00:55:15,880 --> 00:55:17,680
that actually are going
to be impacted

1047
00:55:17,680 --> 00:55:19,680
by the outcomes
of this study.

1048
00:55:19,680 --> 00:55:24,240
For example the exert study
and the US Plan Study

1049
00:55:24,240 --> 00:55:29,080
partnered with community-based
organizations like the YMCAs

1050
00:55:29,080 --> 00:55:32,000
to actually conduct
the intervention pieces

1051
00:55:32,000 --> 00:55:33,880
of the studies
within the community

1052
00:55:33,880 --> 00:55:36,000
where individuals are located.

1053
00:55:36,000 --> 00:55:38,800
So the exert study
is an exercise study,

1054
00:55:38,800 --> 00:55:41,440
the mind study
is focused on diet,

1055
00:55:41,440 --> 00:55:45,800
the achieve study is focused
on treating hearing loss

1056
00:55:45,800 --> 00:55:50,240
and the US Plan Study
is a multi-domain study

1057
00:55:50,240 --> 00:55:54,800
that includes exercise, diets,
cognitive stimulation

1058
00:55:54,800 --> 00:55:58,480
and also health coaching.
Next slide.

1059
00:56:01,000 --> 00:56:04,000
The second element
of recommendation five

1060
00:56:04,000 --> 00:56:06,240
is focused on supporting
the development

1061
00:56:06,240 --> 00:56:08,960
of practice-based
research networks.

1062
00:56:08,960 --> 00:56:12,120
To facilitate a translation
of effective assessment

1063
00:56:12,120 --> 00:56:16,520
and intervention strategies
into practice at a large scale.

1064
00:56:16,520 --> 00:56:19,200
And we think that this is truly
a place where the NIA

1065
00:56:19,200 --> 00:56:24,520
and the NDS has made tremendous,
tremendous progress.

1066
00:56:24,520 --> 00:56:26,400
As you can see
that there are now

1067
00:56:26,400 --> 00:56:31,920
a number of versioning
practice-based research networks

1068
00:56:31,920 --> 00:56:36,440
that have been developed
to support the conduct

1069
00:56:36,440 --> 00:56:39,200
of pragmatic clinical trials

1070
00:56:39,200 --> 00:56:42,920
and other community-based
type studies.

1071
00:56:42,920 --> 00:56:45,600
On this slide you will see
that we have also highlighted

1072
00:56:45,600 --> 00:56:49,120
the NIA Intramural Center
for Alzheimer's

1073
00:56:49,120 --> 00:56:52,880
and Related Dementia's,
CARD.

1074
00:56:52,880 --> 00:56:55,840
CARD as you may know
is the NINDS,

1075
00:56:55,840 --> 00:56:59,760
NIA crown jewel
if I may use that word.

1076
00:56:59,760 --> 00:57:03,200
But currently it is focused

1077
00:57:03,200 --> 00:57:07,320
on the conduct of basic science
and data science.

1078
00:57:07,320 --> 00:57:11,440
We would like to suggest
that CARD is uniquely positioned

1079
00:57:11,440 --> 00:57:15,480
for serving as a hub
for intervention studies.

1080
00:57:15,480 --> 00:57:17,160
Perhaps in partnerships

1081
00:57:17,160 --> 00:57:20,400
with practice-based
research networks.

1082
00:57:20,400 --> 00:57:23,640
Next slide please.

1083
00:57:23,640 --> 00:57:26,760
And then the last element
of this recommendation five

1084
00:57:26,760 --> 00:57:32,840
is to evaluate health risks and
effectiveness of AD therapies.

1085
00:57:32,840 --> 00:57:35,240
Such as anti-amyloid therapies

1086
00:57:35,240 --> 00:57:37,720
and more patients
from diverse culture

1087
00:57:37,720 --> 00:57:41,120
and socioeconomic backgrounds.

1088
00:57:41,120 --> 00:57:44,640
The topic of inclusion
and equity

1089
00:57:44,640 --> 00:57:49,000
was the focus
of an entire session yesterday.

1090
00:57:49,000 --> 00:57:50,720
And we already have heard a lot

1091
00:57:50,720 --> 00:57:53,000
about it this morning
from my colleagues.

1092
00:57:53,000 --> 00:57:59,120
But just in highlight form,
we all understand and appreciate

1093
00:57:59,120 --> 00:58:04,120
that ADRD more prevalent
in minoritized groups.

1094
00:58:04,120 --> 00:58:09,800
However, a recent survey
in 2020 of nine

1095
00:58:09,800 --> 00:58:13,800
of the large scale observational

1096
00:58:13,800 --> 00:58:17,400
and clinical studies
in the ADRD field

1097
00:58:17,400 --> 00:58:21,480
indicated that the vast
majority of participants

1098
00:58:21,480 --> 00:58:25,920
who enrolled in these studies
are not Hispanic whites.

1099
00:58:25,920 --> 00:58:30,520
More recently a few months ago,
another survey that this focused

1100
00:58:30,520 --> 00:58:33,760
on drug trials
in the ADRD space,

1101
00:58:33,760 --> 00:58:39,880
indicated that about 95%
of all the participants

1102
00:58:39,880 --> 00:58:44,480
in these studies again
were not Hispanic whites.

1103
00:58:44,480 --> 00:58:46,960
So I think, you know,
it is certainly obvious to say

1104
00:58:46,960 --> 00:58:51,200
that this statistical
is no longer tenable.

1105
00:58:51,200 --> 00:58:55,920
And the field has a moral
and ethical impurity

1106
00:58:55,920 --> 00:59:00,440
to begin to move the middle.
Next slide please.

1107
00:59:00,440 --> 00:59:03,600
And again, you know, this is now
reflected in some book

1108
00:59:03,600 --> 00:59:07,800
lay and scientific articles
like the one by Jan Manley

1109
00:59:07,800 --> 00:59:09,520
and her colleague.

1110
00:59:09,520 --> 00:59:12,800
Addressing the,
and developments in lab

1111
00:59:12,800 --> 00:59:18,800
and how the lack of diversity
in the patient group

1112
00:59:18,800 --> 00:59:21,440
is something that needs
to become to new to be explored

1113
00:59:21,440 --> 00:59:23,560
as this trial,
as this drug move

1114
00:59:23,560 --> 00:59:29,000
towards further community
and developments.

1115
00:59:29,000 --> 00:59:34,720
Next slide please.
So what then are our next steps?

1116
00:59:34,720 --> 00:59:38,040
And I want to focus
on the three key elements

1117
00:59:38,040 --> 00:59:40,400
on this recommendation.

1118
00:59:40,400 --> 00:59:42,400
The first one
being intervention.

1119
00:59:42,400 --> 00:59:46,400
We want to call attention
that there is need to look

1120
00:59:46,400 --> 00:59:50,480
at the settings in which these
studies are being conducted.

1121
00:59:50,480 --> 00:59:54,600
And also the modalities
and the majority of studies in,

1122
00:59:54,600 --> 00:59:57,080
are still single
modality studies.

1123
00:59:57,080 --> 01:00:01,200
But as you heard, you know,
in Jeff Burns talk,

1124
01:00:01,200 --> 01:00:04,800
you know,
it is the rare occasion

1125
01:00:04,800 --> 01:00:07,640
that an individual with AD
at autopsy

1126
01:00:07,640 --> 01:00:12,800
only has AD as a neuropathology.
So want to begin to think more

1127
01:00:12,800 --> 01:00:16,320
in terms of more
multi-modal studies.

1128
01:00:16,320 --> 01:00:18,800
Also in terms of targets,

1129
01:00:18,800 --> 01:00:24,520
the most prevalence
and hierarchies studies for ADRD

1130
01:00:24,520 --> 01:00:28,800
are at this point
focused on anti-amyloid.

1131
01:00:28,800 --> 01:00:32,720
And we want to highlight
that it is time for the field

1132
01:00:32,720 --> 01:00:35,080
to begin to pay
more specific attention

1133
01:00:35,080 --> 01:00:37,560
to the other part
of it physiologist

1134
01:00:37,560 --> 01:00:39,800
that underlie ADRDs.

1135
01:00:39,800 --> 01:00:41,720
And that's the different
populations of interest

1136
01:00:41,720 --> 01:00:45,400
is an area to consider.

1137
01:00:45,400 --> 01:00:49,640
We want to highlight the need
to expand the spectrum

1138
01:00:49,640 --> 01:00:53,200
from individuals
who are cognitively unimpaired,

1139
01:00:53,200 --> 01:00:57,040
all the way to individuals
who have dementia.

1140
01:00:57,040 --> 01:01:01,880
In terms of infrastructure
we believe that there is a need

1141
01:01:01,880 --> 01:01:05,760
not only for an increased
development of PBRNs,

1142
01:01:05,760 --> 01:01:08,080
the practice-based
research networks,

1143
01:01:08,080 --> 01:01:12,080
but also for an increased
use of those networks.

1144
01:01:12,080 --> 01:01:15,160
Because it is critical
that as disparities

1145
01:01:15,160 --> 01:01:17,200
and interventions
are being developed,

1146
01:01:17,200 --> 01:01:19,400
that they are housed
within the areas

1147
01:01:19,400 --> 01:01:22,080
where the people
who are going to be

1148
01:01:22,080 --> 01:01:25,160
using the outcomes of these
studies where they live,

1149
01:01:25,160 --> 01:01:27,240
work and play.

1150
01:01:27,240 --> 01:01:29,480
And finally, you know,
we think that there is a need

1151
01:01:29,480 --> 01:01:34,200
to continue to pay attention
to issues of representation.

1152
01:01:34,200 --> 01:01:37,640
And this is going to require us
to be very critical

1153
01:01:37,640 --> 01:01:41,200
of the inclusion
and exclusion criteria.

1154
01:01:41,200 --> 01:01:43,400
That we implement
in these studies.

1155
01:01:43,400 --> 01:01:45,280
Because that is actually
the first place

1156
01:01:45,280 --> 01:01:47,800
that we begin
to exclude individuals

1157
01:01:47,800 --> 01:01:52,680
who actually are most affected
by these diseases.

1158
01:01:52,680 --> 01:01:58,080
I want to leave you then
with some resources in terms of

1159
01:01:58,080 --> 01:02:01,440
funding opportunities
that people can apply

1160
01:02:01,440 --> 01:02:04,960
for in order to begin
to propose interventions.

1161
01:02:04,960 --> 01:02:08,680
Both from a pharmacological
and non-pharmacological ones.

1162
01:02:08,680 --> 01:02:11,120
And we want to call
specific attention

1163
01:02:11,120 --> 01:02:14,080
to the very last bullet there.

1164
01:02:14,080 --> 01:02:18,840
The request for information
on capacity and support.

1165
01:02:18,840 --> 01:02:23,360
That the NIH, sorry that the NIA
has released to receive

1166
01:02:23,360 --> 01:02:27,960
information from the community
in terms of how the NIA

1167
01:02:27,960 --> 01:02:31,680
can build some community-based
research networks.

1168
01:02:31,680 --> 01:02:34,800
To increase the participation
of diverse groups

1169
01:02:34,800 --> 01:02:37,640
in ADRD clinical trials.

1170
01:02:37,640 --> 01:02:39,600
And I believe
that is my last slide

1171
01:02:39,600 --> 01:02:43,200
and I'd like to hand it off now
to my colleague Dr. Kate Possin.

1172
01:02:43,200 --> 01:02:46,440
Thank you.

1173
01:02:46,440 --> 01:02:48,880
-Okay thank you so much.

1174
01:02:48,880 --> 01:02:52,560
Great, so I'm going to be
presenting recommendation six.

1175
01:02:52,560 --> 01:02:55,640
Which is to implement
and evaluate outcomes

1176
01:02:55,640 --> 01:02:57,880
for effective
dementia care programs

1177
01:02:57,880 --> 01:03:01,560
that support persons living with
dementia and their caregivers.

1178
01:03:01,560 --> 01:03:03,000
Including those of socially,

1179
01:03:03,000 --> 01:03:06,120
ethnically and racially
diverse populations.

1180
01:03:06,120 --> 01:03:10,440
This recommendation
includes advancing research

1181
01:03:10,440 --> 01:03:12,840
to identify
barriers and facilitators

1182
01:03:12,840 --> 01:03:17,120
to widespread diffusion
of promising interventions,

1183
01:03:17,120 --> 01:03:19,200
conducting implementation
studies,

1184
01:03:19,200 --> 01:03:22,520
developing and evaluating
payment models and developing

1185
01:03:22,520 --> 01:03:25,800
and evaluating core components
of culturally sensitive

1186
01:03:25,800 --> 01:03:27,880
collaborative dementia
care models,

1187
01:03:27,880 --> 01:03:31,360
that deliver
high quality care. Next.

1188
01:03:31,360 --> 01:03:35,000
So I'll start
by setting the context

1189
01:03:35,000 --> 01:03:38,080
for this recommendation
with a quote from Julia,

1190
01:03:38,080 --> 01:03:41,800
a person living with early
stage Alzheimer's Disease.

1191
01:03:41,800 --> 01:03:47,280
It took us nearly four years
to get a diagnosis.

1192
01:03:47,280 --> 01:03:49,960
The doctor told us
it was Alzheimer's,

1193
01:03:49,960 --> 01:03:51,440
that there was nothing
he could do

1194
01:03:51,440 --> 01:03:53,240
and to come back in a year.

1195
01:03:53,240 --> 01:03:55,960
We were first devastated
then angry.

1196
01:03:55,960 --> 01:03:59,160
I also have diabetes,
I got medication, education

1197
01:03:59,160 --> 01:04:01,400
and care management
for that.

1198
01:04:01,400 --> 01:04:07,920
Now I have a fatal brain disease
and I got diagnosed and adios.

1199
01:04:07,920 --> 01:04:09,560
We have to do better.

1200
01:04:11,600 --> 01:04:14,200
So we, those of you who were
at the health equity session

1201
01:04:14,200 --> 01:04:16,280
yesterday
also heard from Mr. Lacina

1202
01:04:16,280 --> 01:04:17,960
during the question
and answer period,

1203
01:04:17,960 --> 01:04:20,480
a caregiver who highlighted
the importance

1204
01:04:20,480 --> 01:04:23,720
of transparent
disclosure of diagnosis.

1205
01:04:23,720 --> 01:04:27,400
And prognosis and of guiding
caregivers into their role.

1206
01:04:27,400 --> 01:04:30,680
And we started today with those
poignant inspirational videos

1207
01:04:30,680 --> 01:04:33,120
of people living with dementia
and their caregivers.

1208
01:04:33,120 --> 01:04:34,600
That also highlighted
the importance

1209
01:04:34,600 --> 01:04:36,600
of supporting the caregiver.

1210
01:04:36,600 --> 01:04:39,000
Planning ahead,
getting affairs in order

1211
01:04:39,000 --> 01:04:42,400
and focusing on well-being.
Next.

1212
01:04:42,400 --> 01:04:48,000
Yet dementia care is too often
crisis oriented and fragmented.

1213
01:04:48,000 --> 01:04:51,760
Frequent emergency department
visits and hospitalizations,

1214
01:04:51,760 --> 01:04:55,000
multiple care transitions,
inappropriate

1215
01:04:55,000 --> 01:04:58,280
and potentially
harmful medication use.

1216
01:04:58,280 --> 01:05:01,120
Patients experience
aggressive end of life care

1217
01:05:01,120 --> 01:05:05,680
that's often inconsistent
with their values and expensive.

1218
01:05:05,680 --> 01:05:08,360
Informal caregivers
shoulder substantial burdens

1219
01:05:08,360 --> 01:05:09,680
with minimal support

1220
01:05:09,680 --> 01:05:13,560
from our patient-centric
healthcare models.

1221
01:05:13,560 --> 01:05:15,360
And when caregivers
are depressed,

1222
01:05:15,360 --> 01:05:19,480
people living with dementia use
the emergency department more.

1223
01:05:19,480 --> 01:05:22,880
The COVID-19 pandemic
has disproportionately disrupted

1224
01:05:22,880 --> 01:05:27,120
the lives of people living with
dementia and their caregivers.

1225
01:05:27,120 --> 01:05:30,640
Next.

1226
01:05:30,640 --> 01:05:34,880
In 2019
this ADRD specific milestone

1227
01:05:34,880 --> 01:05:38,200
was given two success criteria.

1228
01:05:38,200 --> 01:05:40,360
They were,
to write a white paper

1229
01:05:40,360 --> 01:05:43,040
on proven dementia
care programs.

1230
01:05:43,040 --> 01:05:45,680
That effectively support persons
with dementia

1231
01:05:45,680 --> 01:05:47,520
and their caregivers.

1232
01:05:47,520 --> 01:05:50,680
And to establish
a national consortium

1233
01:05:50,680 --> 01:05:52,280
tasked with applied research

1234
01:05:52,280 --> 01:05:55,640
to determine how to implement
widely across the country

1235
01:05:55,640 --> 01:05:59,720
in everyday care settings,
proving care programs.

1236
01:05:59,720 --> 01:06:02,600
The first of these milestones
has been completed

1237
01:06:02,600 --> 01:06:06,040
and I will now
share the results. Next.

1238
01:06:06,040 --> 01:06:10,720
A systematic review of dementia
care models was produced by AHRQ

1239
01:06:10,720 --> 01:06:13,160
at the request of NIA.

1240
01:06:13,160 --> 01:06:17,840
And this review evaluated the
evidence that care models were,

1241
01:06:17,840 --> 01:06:19,440
that which care models
were ready

1242
01:06:19,440 --> 01:06:22,520
for broad dissemination
and implementation.

1243
01:06:22,520 --> 01:06:25,600
This report was followed
by a consensus study report

1244
01:06:25,600 --> 01:06:27,560
by the National Academy's
of Science,

1245
01:06:27,560 --> 01:06:29,760
Engineering and Medicine.

1246
01:06:29,760 --> 01:06:32,760
Together these reports
provide a helpful overview

1247
01:06:32,760 --> 01:06:34,760
of the evidence landscape.

1248
01:06:34,760 --> 01:06:37,680
And they concluded
that evidence is sufficient

1249
01:06:37,680 --> 01:06:41,880
to justify implementation
of two types of interventions

1250
01:06:41,880 --> 01:06:45,360
in a broad spectrum of community
settings with evaluation

1251
01:06:45,360 --> 01:06:49,520
conducted to continue
expanding the evidence-base.

1252
01:06:49,520 --> 01:06:52,320
These are collaborative
care models

1253
01:06:52,320 --> 01:06:56,800
and multi-component
caregiver support. Next.

1254
01:06:56,800 --> 01:07:00,680
So collaborative care models
use multidisciplinary teams

1255
01:07:00,680 --> 01:07:04,280
to coordinate psychosocial
and medical care.

1256
01:07:04,280 --> 01:07:06,080
Typically with a care navigator,

1257
01:07:06,080 --> 01:07:10,400
or care manager as the primary
point of contact for the family.

1258
01:07:10,400 --> 01:07:13,000
They emphasize the immediate
needs of the person

1259
01:07:13,000 --> 01:07:15,000
living with dementia
and the caregiver.

1260
01:07:15,000 --> 01:07:17,080
Often called a diad.

1261
01:07:17,080 --> 01:07:20,600
And they also prioritized
proactive care planning,

1262
01:07:20,600 --> 01:07:23,360
personalized to the diad.

1263
01:07:23,360 --> 01:07:26,800
So these programs have been
shown to improve quality of life

1264
01:07:26,800 --> 01:07:28,840
for the person living
with dementia,

1265
01:07:28,840 --> 01:07:32,200
caregiver well-being,
health system level markers,

1266
01:07:32,200 --> 01:07:35,000
including improvements
in quality indicators

1267
01:07:35,000 --> 01:07:39,200
and reducing emergency
room visits. Next.

1268
01:07:39,200 --> 01:07:44,760
Multi-component
caregiver support provides

1269
01:07:44,760 --> 01:07:47,200
caregivers with the knowledge,
skills and access

1270
01:07:47,200 --> 01:07:51,160
to resources they need
to promote their own well-being

1271
01:07:51,160 --> 01:07:54,880
as well as that of the person
living with dementia

1272
01:07:54,880 --> 01:07:56,680
for whom they care.

1273
01:07:56,680 --> 01:08:01,480
And outcomes improved include
caregiver depression. Next.

1274
01:08:04,600 --> 01:08:06,720
So we know
that collaborative care

1275
01:08:06,720 --> 01:08:10,160
and multi-component
caregiver support models

1276
01:08:10,160 --> 01:08:12,840
improve outcomes for people
living with dementia

1277
01:08:12,840 --> 01:08:14,120
and their families.

1278
01:08:14,120 --> 01:08:16,480
Yet these programs
remain unavailable

1279
01:08:16,480 --> 01:08:20,880
to the vast majority.
Scientists have a critical role

1280
01:08:20,880 --> 01:08:24,360
in bridging the science
practice gap.

1281
01:08:24,360 --> 01:08:27,160
Too often scientists expect
that the implementation

1282
01:08:27,160 --> 01:08:28,800
and dissemination
of their interventions

1283
01:08:28,800 --> 01:08:30,800
will be taken up
by other parties.

1284
01:08:30,800 --> 01:08:32,640
Which is often not the case.

1285
01:08:32,640 --> 01:08:35,200
And as scientists need
to understand the barriers

1286
01:08:35,200 --> 01:08:37,880
to dissemination
effective dementia care

1287
01:08:37,880 --> 01:08:41,880
and trial implementation methods
to bridge the gap.

1288
01:08:41,880 --> 01:08:43,320
Next.

1289
01:08:43,320 --> 01:08:46,360
So in closing,
please imagine with me

1290
01:08:46,360 --> 01:08:49,160
a near future
of dementia care.

1291
01:08:49,160 --> 01:08:52,800
Imagine if every patient was a
concern for cognitive decline

1292
01:08:52,800 --> 01:08:57,400
is evaluated, giving appropriate
treatment, connected to care.

1293
01:08:57,400 --> 01:08:59,840
Imagine that once diagnosed
with dementia

1294
01:08:59,840 --> 01:09:03,280
and their caregivers have
someone in the medical system

1295
01:09:03,280 --> 01:09:06,200
who helps navigate them
through the challenges

1296
01:09:06,200 --> 01:09:08,000
of living with dementia.

1297
01:09:08,000 --> 01:09:11,000
The medical system
partners with caregivers,

1298
01:09:11,000 --> 01:09:13,440
prepares them for their role.

1299
01:09:13,440 --> 01:09:16,960
Tailors support to their needs
and preferences.

1300
01:09:16,960 --> 01:09:19,120
Quality of life, well-being,

1301
01:09:19,120 --> 01:09:20,720
for both the person
with dementia

1302
01:09:20,720 --> 01:09:24,040
and the caregiver,
are made a priority.

1303
01:09:24,040 --> 01:09:27,600
We can do this. Next.

1304
01:09:27,600 --> 01:09:29,880
I would now like
to introduce Heather Snyder

1305
01:09:29,880 --> 01:09:32,040
from the Alzheimer's
Association.

1306
01:09:32,040 --> 01:09:37,240
Who will close our presentation
with the last two focus areas.

1307
01:09:37,240 --> 01:09:39,400
-Thank you so much
and hi everybody

1308
01:09:39,400 --> 01:09:41,640
and I think building
on all of the presentations

1309
01:09:41,640 --> 01:09:44,600
that you've heard today,
the last two focus areas

1310
01:09:44,600 --> 01:09:47,880
really are all encompassing
of those recommendations.

1311
01:09:47,880 --> 01:09:50,000
Thinking about a dementia
capable workforce

1312
01:09:50,000 --> 01:09:52,440
and data harmonization.
Next slide.

1313
01:09:54,800 --> 01:09:57,200
In terms of my disclosures
I'm a full-time employee

1314
01:09:57,200 --> 01:10:01,520
of the Alzheimer's Association.
Next slide.

1315
01:10:01,520 --> 01:10:03,400
So looking at
the first recommendation

1316
01:10:03,400 --> 01:10:06,600
or the first focus area,
the dementia capable workforce

1317
01:10:06,600 --> 01:10:08,480
and specifically
recommendation seven,

1318
01:10:08,480 --> 01:10:10,920
priority two.
I'm promoting education,

1319
01:10:10,920 --> 01:10:14,600
training on multiple etiology
cognitive impairment

1320
01:10:14,600 --> 01:10:17,600
and dementia to increase
the dementia capable workforce.

1321
01:10:17,600 --> 01:10:20,320
Advanced researchers including
from groups underrepresented

1322
01:10:20,320 --> 01:10:23,800
in science and foster includes
their research practices.

1323
01:10:23,800 --> 01:10:26,880
There's a number of components
within this recommendation,

1324
01:10:26,880 --> 01:10:28,960
but really to set
the stage of the need

1325
01:10:28,960 --> 01:10:31,400
and we heard a little bit
in the session yesterday,

1326
01:10:31,400 --> 01:10:34,240
the healthy equity session
by Dr. Medina,

1327
01:10:34,240 --> 01:10:39,200
Doctors Medina and Dr. Gilsanz.
The next slide.

1328
01:10:39,200 --> 01:10:42,400
In the world today
the global population is aging.

1329
01:10:42,400 --> 01:10:45,040
By 2030 one in six individuals
in the world

1330
01:10:45,040 --> 01:10:46,480
will be age 60 and over

1331
01:10:46,480 --> 01:10:48,800
and you can see some of
the other statistics

1332
01:10:48,800 --> 01:10:50,240
that are listed here.

1333
01:10:50,240 --> 01:10:52,680
Alzheimer's Disease
International estimates

1334
01:10:52,680 --> 01:10:55,800
that today there are more than
55 million individuals

1335
01:10:55,800 --> 01:10:59,040
living with dementia
in the global world.

1336
01:10:59,040 --> 01:11:00,680
And the reason
Facts and Figures

1337
01:11:00,680 --> 01:11:02,520
reports that there are more
than six million Americans

1338
01:11:02,520 --> 01:11:04,360
that are living
with Alzheimer today,

1339
01:11:04,360 --> 01:11:07,480
not to mention the full
spectrum of dementia.

1340
01:11:07,480 --> 01:11:09,800
Next slide.

1341
01:11:09,800 --> 01:11:12,840
What we do look at when, in a
number of different studies,

1342
01:11:12,840 --> 01:11:14,680
in a number
of different reviews,

1343
01:11:14,680 --> 01:11:16,960
have looked at the dementia
care specialists.

1344
01:11:16,960 --> 01:11:18,800
So those that were
within the workforce

1345
01:11:18,800 --> 01:11:21,200
that are poised to provide
the care and support

1346
01:11:21,200 --> 01:11:23,160
and really make
that linkage of care

1347
01:11:23,160 --> 01:11:25,040
into research and back again.

1348
01:11:25,040 --> 01:11:27,360
And so whether you're looking
at primary care physicians,

1349
01:11:27,360 --> 01:11:29,200
whether you're looking
at geriatricians

1350
01:11:29,200 --> 01:11:31,640
or practicing
geriatricians that,

1351
01:11:31,640 --> 01:11:34,240
and neurologists
with dementia expertise,

1352
01:11:34,240 --> 01:11:36,760
or whether you're looking
at licensed nurse practitioners

1353
01:11:36,760 --> 01:11:38,720
in the United States
with either an expertise

1354
01:11:38,720 --> 01:11:40,920
in geriatric care
or dementia.

1355
01:11:40,920 --> 01:11:43,400
There is a serious shortfall
and this is something

1356
01:11:43,400 --> 01:11:45,000
that when we think
about the workforce,

1357
01:11:45,000 --> 01:11:46,280
whether we're talking
about care,

1358
01:11:46,280 --> 01:11:48,000
whether we're talking
about research

1359
01:11:48,000 --> 01:11:50,120
and really the intersection
of the two,

1360
01:11:50,120 --> 01:11:53,600
is certainly a gap in where
we are as a community

1361
01:11:53,600 --> 01:11:56,320
and as a field.
Next slide.

1362
01:11:56,320 --> 01:11:59,600
And in fact when you look
at the number of states that,

1363
01:11:59,600 --> 01:12:02,840
across the country that are
lacking dementia care experts,

1364
01:12:02,840 --> 01:12:05,200
or specialists, you can see
that listed here

1365
01:12:05,200 --> 01:12:08,880
that the number of practicing
geriatricians needs to increase

1366
01:12:08,880 --> 01:12:10,760
at least five times by 2050

1367
01:12:10,760 --> 01:12:12,640
in order to take care
of the individuals

1368
01:12:12,640 --> 01:12:14,680
with Alzheimer's
and other dementia.

1369
01:12:14,680 --> 01:12:18,480
And in fact 55, the recent
Facts and Figures Report suggest

1370
01:12:18,480 --> 01:12:21,680
that 55%
of primary care physicians

1371
01:12:21,680 --> 01:12:23,520
that are caring for individuals
with Alzheimer's

1372
01:12:23,520 --> 01:12:25,080
and other dementia,

1373
01:12:25,080 --> 01:12:27,040
report that there are not
enough dementia care specialists

1374
01:12:27,040 --> 01:12:29,640
in their community.
Next slide.

1375
01:12:29,640 --> 01:12:32,000
So as the global
prevalence of Alzheimer's

1376
01:12:32,000 --> 01:12:34,800
and other dementia increases,
there is absolutely a need

1377
01:12:34,800 --> 01:12:37,920
for members of the paid dementia
care workforce to increase.

1378
01:12:37,920 --> 01:12:40,400
And again, whether we're talking
about those providing care,

1379
01:12:40,400 --> 01:12:42,040
or those engaging
in the research,

1380
01:12:42,040 --> 01:12:45,760
and the intersection of the two,
this is across the board.

1381
01:12:45,760 --> 01:12:47,600
Next slide.

1382
01:12:47,600 --> 01:12:50,400
So within the priority,
or within the recommendation,

1383
01:12:50,400 --> 01:12:51,800
promoting education
and training,

1384
01:12:51,800 --> 01:12:53,400
there's a number
of different components.

1385
01:12:53,400 --> 01:12:55,920
And this includes developing,
implementing

1386
01:12:55,920 --> 01:12:58,000
and evaluating
training programs,

1387
01:12:58,000 --> 01:13:01,400
incentivizing mentorship and
providing research opportunities

1388
01:13:01,400 --> 01:13:03,600
and promoting education
of researchers

1389
01:13:03,600 --> 01:13:06,400
in recruiting and retaining
research participants

1390
01:13:06,400 --> 01:13:10,080
from population that experience
health disparities

1391
01:13:10,080 --> 01:13:11,760
in research studies.

1392
01:13:11,760 --> 01:13:15,960
So in looking at the first
aspect of this in developing,

1393
01:13:15,960 --> 01:13:18,200
implementing and evaluating
training programs.

1394
01:13:18,200 --> 01:13:21,200
This just gives you a snapshot
of some of the training programs

1395
01:13:21,200 --> 01:13:24,240
and that are really poised

1396
01:13:24,240 --> 01:13:26,400
and are addressing
some of these gaps.

1397
01:13:26,400 --> 01:13:28,400
But this is only a step
in the right direction

1398
01:13:28,400 --> 01:13:31,200
and certainly as we think
about the need to scale up,

1399
01:13:31,200 --> 01:13:35,600
there will be a significant need
to increase and expand the scale

1400
01:13:35,600 --> 01:13:38,000
and the scope
of these types of initiatives.

1401
01:13:38,000 --> 01:13:40,080
Next slide.

1402
01:13:40,080 --> 01:13:41,480
And it's really important
to think about

1403
01:13:41,480 --> 01:13:43,000
as we look
at the types of training's,

1404
01:13:43,000 --> 01:13:44,800
that's it not
a one size fits all.

1405
01:13:44,800 --> 01:13:46,240
In fact one of the examples

1406
01:13:46,240 --> 01:13:48,640
that I shared the
Global Brain Health Institute,

1407
01:13:48,640 --> 01:13:50,760
shared a quote
from one of their mentors.

1408
01:13:50,760 --> 01:13:52,080
That I think
the biggest strength

1409
01:13:52,080 --> 01:13:54,000
is that mentorship
can be personalized.

1410
01:13:54,000 --> 01:13:55,440
Our fellows
are all so different,

1411
01:13:55,440 --> 01:13:57,160
they're coming
from unique backgrounds

1412
01:13:57,160 --> 01:14:00,240
and experience expertise
and lived experiences.

1413
01:14:00,240 --> 01:14:02,080
So as we think about
developing the types

1414
01:14:02,080 --> 01:14:03,560
of training
and mentorship programs,

1415
01:14:03,560 --> 01:14:06,880
really taking this
into account

1416
01:14:06,880 --> 01:14:08,800
that it's not
a one size fits all.

1417
01:14:08,800 --> 01:14:10,040
And when we need
to be thinking

1418
01:14:10,040 --> 01:14:11,680
about the different types
of landscape

1419
01:14:11,680 --> 01:14:14,640
and the different types
of programs and opportunities

1420
01:14:14,640 --> 01:14:18,480
that need to come together and
support the growing workforce.

1421
01:14:18,480 --> 01:14:20,760
Next slide.

1422
01:14:20,760 --> 01:14:22,800
And a big component of this
is the mentorship

1423
01:14:22,800 --> 01:14:25,320
and thinking about
incentivizing mentors

1424
01:14:25,320 --> 01:14:27,200
and providing
research opportunities

1425
01:14:27,200 --> 01:14:28,560
within mixed etiology,

1426
01:14:28,560 --> 01:14:31,240
dementia for the current
and emerging generation.

1427
01:14:31,240 --> 01:14:33,600
We heard yesterday, I think
one of the discussion items

1428
01:14:33,600 --> 01:14:35,520
was the need not only to support

1429
01:14:35,520 --> 01:14:37,440
and grow early career
researchers,

1430
01:14:37,440 --> 01:14:39,800
but really think about
supporting the network

1431
01:14:39,800 --> 01:14:42,400
of researchers
throughout their entire career.

1432
01:14:42,400 --> 01:14:43,760
And what you see here
is a listing

1433
01:14:43,760 --> 01:14:46,760
of some of the different
ongoing initiatives,

1434
01:14:46,760 --> 01:14:48,000
thinking about mentorship,

1435
01:14:48,000 --> 01:14:49,440
thinking about
supporting mentors

1436
01:14:49,440 --> 01:14:51,920
as well as building
out mentorship programs.

1437
01:14:51,920 --> 01:14:53,960
So whether you're looking
at the college age level,

1438
01:14:53,960 --> 01:14:57,160
such as the NIH
funded StarU program.

1439
01:14:57,160 --> 01:15:00,880
GBHI which I mentioned, you're
looking at the Interdisciplinary

1440
01:15:00,880 --> 01:15:02,920
Summer Research Institute.

1441
01:15:02,920 --> 01:15:05,360
So this is just a snapshot
of organizations and groups

1442
01:15:05,360 --> 01:15:08,000
that are doing some of these
programs and have initiated.

1443
01:15:08,000 --> 01:15:10,440
But again, as we think
about the scope and scale

1444
01:15:10,440 --> 01:15:12,280
of what is needed
to go forward,

1445
01:15:12,280 --> 01:15:15,240
we need to continue
to see these programs grow.

1446
01:15:15,240 --> 01:15:17,440
As well as new programs
that get to that

1447
01:15:17,440 --> 01:15:22,080
it's not a one size fits all.
Next slide.

1448
01:15:22,080 --> 01:15:23,640
And so thinking about
also the idea

1449
01:15:23,640 --> 01:15:25,400
of promoting
education of researchers

1450
01:15:25,400 --> 01:15:29,000
and recruiting and retaining
diverse research participants.

1451
01:15:29,000 --> 01:15:30,800
So throughout this
entire recommendation

1452
01:15:30,800 --> 01:15:34,520
we really include activities
that are promoting a conceptual

1453
01:15:34,520 --> 01:15:38,080
and theoretical perspective
shaping recruitment.

1454
01:15:38,080 --> 01:15:39,400
And retention practices.

1455
01:15:39,400 --> 01:15:41,240
And building the necessary tools
and again

1456
01:15:41,240 --> 01:15:43,720
you see some
of those tools listed here.

1457
01:15:43,720 --> 01:15:45,280
But there are certainly others

1458
01:15:45,280 --> 01:15:48,400
that are continuing to be
developed and expanded upon.

1459
01:15:48,400 --> 01:15:52,680
And continuing to build
and expand these opportunities.

1460
01:15:52,680 --> 01:15:55,480
Next slide.
Such as webinars, workshops,

1461
01:15:55,480 --> 01:15:57,200
and other types
of training programs.

1462
01:15:57,200 --> 01:15:59,640
And again you see a snapshot
of some of these here.

1463
01:15:59,640 --> 01:16:01,960
This is also an opportunity
for funding organizations,

1464
01:16:01,960 --> 01:16:04,880
I know Michael J. Fox Foundation
for Parkinson's Research

1465
01:16:04,880 --> 01:16:07,680
recently launched and initiated
a large scale program

1466
01:16:07,680 --> 01:16:12,400
as one of those examples.
Next slide.

1467
01:16:12,400 --> 01:16:15,480
So across this
entire recommendation

1468
01:16:15,480 --> 01:16:16,880
you can see the full thing,

1469
01:16:16,880 --> 01:16:18,920
the full recommendation
listed here.

1470
01:16:18,920 --> 01:16:20,200
There's been a number of work

1471
01:16:20,200 --> 01:16:22,000
since the original summit
in 2014

1472
01:16:22,000 --> 01:16:23,520
and the continuing summits,

1473
01:16:23,520 --> 01:16:25,760
to grow and build out
these educational

1474
01:16:25,760 --> 01:16:27,400
and training programs.

1475
01:16:27,400 --> 01:16:30,240
But there certainly is an
opportunity to continue to scale

1476
01:16:30,240 --> 01:16:32,400
and think about,
it's not a one size fits all

1477
01:16:32,400 --> 01:16:36,240
and how do we grow
and expand the opportunities

1478
01:16:36,240 --> 01:16:40,040
within mixed etiology dementia?
Next slide.

1479
01:16:40,040 --> 01:16:41,560
-Two minutes remaining.

1480
01:16:41,560 --> 01:16:43,880
-So thinking about the last
recommendation and again

1481
01:16:43,880 --> 01:16:45,320
this all encompassing.

1482
01:16:45,320 --> 01:16:47,360
The idea to incentivize
and conduct research

1483
01:16:47,360 --> 01:16:49,960
to improve pre and post-data
collection harmonization

1484
01:16:49,960 --> 01:16:54,000
and sharing across multiple
etiology cognitive impairment

1485
01:16:54,000 --> 01:16:56,360
and dementia studies.
Next slides.

1486
01:16:56,360 --> 01:16:59,280
This includes developing and
evaluating common data elements

1487
01:16:59,280 --> 01:17:01,240
and standardized
consent language.

1488
01:17:01,240 --> 01:17:02,920
And again,
you see a snapshot

1489
01:17:02,920 --> 01:17:04,480
of some of these
ongoing initiatives.

1490
01:17:04,480 --> 01:17:07,240
Particularly focused on Mac
and the uniform data set,

1491
01:17:07,240 --> 01:17:08,680
as well as the CDISK

1492
01:17:08,680 --> 01:17:11,360
and the tools that are
growing and expanding.

1493
01:17:11,360 --> 01:17:12,640
But, next slide.

1494
01:17:12,640 --> 01:17:14,000
It's really important
to think about

1495
01:17:14,000 --> 01:17:17,120
how we identify the barriers
and facilitators

1496
01:17:17,120 --> 01:17:21,000
to incorporation of these common
data elements and their usage.

1497
01:17:21,000 --> 01:17:22,800
So this could include
opportunities to link

1498
01:17:22,800 --> 01:17:25,400
and share data overcoming
some of these barriers.

1499
01:17:25,400 --> 01:17:28,560
Linking between some of
the different data platforms,

1500
01:17:28,560 --> 01:17:30,280
including the common
data elements

1501
01:17:30,280 --> 01:17:31,680
and some of
the initiation studies

1502
01:17:31,680 --> 01:17:33,440
and I'll show a snapshot
of some of the papers

1503
01:17:33,440 --> 01:17:38,560
that have started to do this
in unique ways. Next slide.

1504
01:17:38,560 --> 01:17:42,000
And within this recommendation
we also added in promotion

1505
01:17:42,000 --> 01:17:44,840
and, promoting the incorporation
of common data elements

1506
01:17:44,840 --> 01:17:46,680
into data collection
for observation

1507
01:17:46,680 --> 01:17:48,320
and intervention studies.

1508
01:17:48,320 --> 01:17:50,520
This is a tremendous opportunity
for funding organizations,

1509
01:17:50,520 --> 01:17:52,760
whether it be NIH, or others.

1510
01:17:52,760 --> 01:17:55,760
As we look at promoting
and really incentivizing

1511
01:17:55,760 --> 01:17:58,400
the incorporation
of these common data elements.

1512
01:17:58,400 --> 01:18:01,560
The last component
within this recommendation

1513
01:18:01,560 --> 01:18:04,160
is to develop and evaluate
training opportunities

1514
01:18:04,160 --> 01:18:05,880
to promote
methodological rigorous

1515
01:18:05,880 --> 01:18:08,880
in efficient data sharing.
Next slide.

1516
01:18:08,880 --> 01:18:10,640
So across the board again
this is a snapshot

1517
01:18:10,640 --> 01:18:12,280
of some of the different
recent papers

1518
01:18:12,280 --> 01:18:15,360
that have been published,
that really look at harmonizing

1519
01:18:15,360 --> 01:18:20,400
across different longitudinal
studies of cognitive measures.

1520
01:18:20,400 --> 01:18:22,960
Looking at some of
the considerations when we,

1521
01:18:22,960 --> 01:18:25,400
when we bring together
different types of data.

1522
01:18:25,400 --> 01:18:27,320
What are some of the best
practices in data sharing?

1523
01:18:27,320 --> 01:18:29,480
If you look at for instance
the Cap Guidelines,

1524
01:18:29,480 --> 01:18:32,520
what are some of the initiatives
and platforms such as Gain,

1525
01:18:32,520 --> 01:18:34,040
the Critical Path Institute,

1526
01:18:34,040 --> 01:18:36,000
and others that
have data available

1527
01:18:36,000 --> 01:18:37,560
and that are working
to cross-link

1528
01:18:37,560 --> 01:18:40,880
across these different types
of platforms more broadly

1529
01:18:40,880 --> 01:18:45,920
and specifically providing
an opportunity to use and to,

1530
01:18:45,920 --> 01:18:48,280
and to build upon prior work.

1531
01:18:48,280 --> 01:18:50,920
But there's also a really
important component of providing

1532
01:18:50,920 --> 01:18:53,040
and developing and evaluating
training opportunities

1533
01:18:53,040 --> 01:18:54,920
that promote
the use of this data,

1534
01:18:54,920 --> 01:18:57,160
both the sharing of it,
but also the use of it.

1535
01:18:57,160 --> 01:18:59,280
And again, that's
a tremendous opportunity

1536
01:18:59,280 --> 01:19:01,360
for funding organizations.

1537
01:19:01,360 --> 01:19:03,680
So I think in summary,
that brings us

1538
01:19:03,680 --> 01:19:06,680
to the multiple etiology
dementia draft recommendations

1539
01:19:06,680 --> 01:19:09,120
and I think I'm passing
back to Dr. Possin

1540
01:19:09,120 --> 01:19:14,320
to take us
into the discussion. Kate.

1541
01:19:14,320 --> 01:19:15,720
-Thank you.

1542
01:19:15,720 --> 01:19:17,920
Thank you so much
to all of our speakers today

1543
01:19:17,920 --> 01:19:19,480
and now we get to begin

1544
01:19:19,480 --> 01:19:21,960
what I hope will be
a really engaging discussion.

1545
01:19:21,960 --> 01:19:25,800
We have our first question
in chat from Dale Lestina,

1546
01:19:25,800 --> 01:19:29,640
so, Mr. Lestina,
please ask your question.

1547
01:19:38,240 --> 01:19:41,880
-Thanks for your patience
while I'm getting myself back

1548
01:19:41,880 --> 01:19:45,040
in the tune
with the rest of you folks.

1549
01:19:45,040 --> 01:19:47,440
Just a minute.
I got to get my picture.

1550
01:19:51,960 --> 01:19:54,640
Well, I'm tapping on it,
but it doesn't come up.

1551
01:19:54,640 --> 01:20:00,400
Oh, there I am.
I have a couple recommendations.

1552
01:20:00,400 --> 01:20:06,000
I applaud the presentations
of this whole group.

1553
01:20:06,000 --> 01:20:14,280
And in your mind's eye
when you look at the video

1554
01:20:14,280 --> 01:20:17,240
that we saw
in the beginning,

1555
01:20:17,240 --> 01:20:21,800
and you saw the gentleman
with his wife,

1556
01:20:21,800 --> 01:20:24,200
she's diagnosed,

1557
01:20:24,200 --> 01:20:26,240
there's two parties
involved with this thing.

1558
01:20:26,240 --> 01:20:29,480
Now I would recommend

1559
01:20:29,480 --> 01:20:35,080
that if in the continuation
of this presentation

1560
01:20:35,080 --> 01:20:39,800
is to show for the folks
what is now about

1561
01:20:39,800 --> 01:20:46,600
to happen as time goes on
with the woman or the doctor.

1562
01:20:46,600 --> 01:20:48,400
When the brain
starts shutting down,

1563
01:20:48,400 --> 01:20:51,120
the ability to control bowels,

1564
01:20:51,120 --> 01:20:56,480
to control urination,
to control the legs.

1565
01:20:56,480 --> 01:21:01,320
That end right there and what
that does to the caregiver

1566
01:21:01,320 --> 01:21:07,200
trying to cope with
this situation with a minimum,

1567
01:21:07,200 --> 01:21:11,680
if any, understanding
what's going on.

1568
01:21:11,680 --> 01:21:19,280
And how to give the patient,

1569
01:21:19,280 --> 01:21:26,800
keeping that person comfortable

1570
01:21:26,800 --> 01:21:31,840
and as relaxed as possible

1571
01:21:31,840 --> 01:21:35,960
because there are periods
of really hallucination

1572
01:21:35,960 --> 01:21:43,400
that they know what's going on.
And how that must feel.

1573
01:21:43,400 --> 01:21:46,840
Because as you and I all know,
there's no cure for this thing.

1574
01:21:46,840 --> 01:21:54,040
That's what's going to happen.
And so I would say Dr. Ochen,

1575
01:21:54,040 --> 01:22:02,360
if you were involved with
the continuation of that video

1576
01:22:02,360 --> 01:22:04,560
is to track it
a little further

1577
01:22:04,560 --> 01:22:08,320
so that the folks
who are doing the research

1578
01:22:08,320 --> 01:22:11,800
also can see
what's transpiring,

1579
01:22:11,800 --> 01:22:16,600
where the rubber meets
the road of the individuals

1580
01:22:16,600 --> 01:22:19,480
who are going through this.

1581
01:22:19,480 --> 01:22:26,920
It's extremely important to know
all of the various things

1582
01:22:26,920 --> 01:22:30,240
that happen in the brain
that causes the problem.

1583
01:22:30,240 --> 01:22:34,960
But then when you're dealing
with the problem,

1584
01:22:34,960 --> 01:22:40,000
that's where I think we need
to have more concentration.

1585
01:22:40,000 --> 01:22:47,400
And I would say that Kate,
your presentation,

1586
01:22:47,400 --> 01:22:51,200
and your colleagues,
you're the same thing,

1587
01:22:51,200 --> 01:22:54,960
I very much appreciate
the recognition

1588
01:22:54,960 --> 01:23:02,680
of what is involved with this
particular end of the process.

1589
01:23:02,680 --> 01:23:05,000
So that's my
first recommendation

1590
01:23:05,000 --> 01:23:09,640
is to follow that now,
those videos,

1591
01:23:09,640 --> 01:23:14,560
and make that as part
of the presentation as well.

1592
01:23:14,560 --> 01:23:21,200
Now my second recommendation
is are any of you familiar

1593
01:23:21,200 --> 01:23:26,520
with an organization
called Insight?

1594
01:23:26,520 --> 01:23:29,160
I don't see any hands.
Okay.

1595
01:23:29,160 --> 01:23:33,880
Insight is located,
well, not too far from NIH.

1596
01:23:33,880 --> 01:23:35,400
It's in Northern Virginia.

1597
01:23:35,400 --> 01:23:39,400
It's on the west side
of Fairfax City.

1598
01:23:39,400 --> 01:23:47,320
And they have -- their executive
director is Anita Irvine.

1599
01:23:47,320 --> 01:23:51,680
I-R-W -- I-R-V-I-N.

1600
01:23:51,680 --> 01:23:55,760
And what they do
is they treat the person

1601
01:23:55,760 --> 01:23:59,280
who has been identified
with dementia,

1602
01:23:59,280 --> 01:24:02,120
and the caregiver together.

1603
01:24:02,120 --> 01:24:06,000
And they move them
through a process where --

1604
01:24:06,000 --> 01:24:12,880
sessions, where the initial
diagnosis of the individual

1605
01:24:12,880 --> 01:24:17,560
who has dementia
is dealt with.

1606
01:24:17,560 --> 01:24:20,640
They're dealt together,
and then separately.

1607
01:24:20,640 --> 01:24:26,040
One of the things that I was
fortunate enough to learn about

1608
01:24:26,040 --> 01:24:31,960
Insight is that
for being a caregiver,

1609
01:24:31,960 --> 01:24:35,200
they had groups
where they --

1610
01:24:35,200 --> 01:24:39,200
support groups,
where they would put me together

1611
01:24:39,200 --> 01:24:41,760
with maybe 15 other people

1612
01:24:41,760 --> 01:24:44,160
who were going through
the same thing.

1613
01:24:44,160 --> 01:24:46,560
And we learned
from one another.

1614
01:24:46,560 --> 01:24:48,440
"Oh, you dealt
with it this way."

1615
01:24:48,440 --> 01:24:52,480
And, "Oh, that's --
I got to give that a try."

1616
01:24:52,480 --> 01:24:59,040
That kind of thing.
And you have a support group

1617
01:24:59,040 --> 01:25:07,920
that after your spouse dies,
continues on.

1618
01:25:07,920 --> 01:25:15,760
And I think that if you would
look into that, if you want,

1619
01:25:15,760 --> 01:25:19,720
I can give you
her contact information,

1620
01:25:19,720 --> 01:25:21,720
and explore what they're doing.

1621
01:25:21,720 --> 01:25:26,640
It's at least something
to look at together.

1622
01:25:26,640 --> 01:25:30,400
And when you're looking
at expanding things,

1623
01:25:30,400 --> 01:25:32,400
they don't want
to expand too fast

1624
01:25:32,400 --> 01:25:36,160
because they want
to keep doing a good job.

1625
01:25:36,160 --> 01:25:39,560
And they're just now
beginning their second office

1626
01:25:39,560 --> 01:25:46,680
that they're about to expand to.
So thank you for your attention

1627
01:25:46,680 --> 01:25:52,400
and listening to
what I would recommend,

1628
01:25:52,400 --> 01:25:56,200
and having been a fellow
who's gone through it

1629
01:25:56,200 --> 01:25:58,800
from a caregiver's
point of view.

1630
01:25:58,800 --> 01:26:02,760
I appreciate
your kind attention. Thank you.

1631
01:26:02,760 --> 01:26:04,280
-Thank you, Mr. Lastina.

1632
01:26:04,280 --> 01:26:09,520
Your comments are really
important to our committee,

1633
01:26:09,520 --> 01:26:12,280
and we will definitely make note

1634
01:26:12,280 --> 01:26:14,200
of both of
these recommendations.

1635
01:26:14,200 --> 01:26:17,080
And I personally will into
the Insight program as well.

1636
01:26:17,080 --> 01:26:22,160
So thank you for
those recommendations.

1637
01:26:22,160 --> 01:26:23,600
-Thank you.

1638
01:26:23,600 --> 01:26:29,560
-So let's see,
next I believe is Penny Dacks.

1639
01:26:29,560 --> 01:26:30,760
-Thank you, Dr. Christine.

1640
01:26:30,760 --> 01:26:32,640
I actually want to defer
to Ian first

1641
01:26:32,640 --> 01:26:34,120
because I think
he had his name in first.

1642
01:26:34,120 --> 01:26:37,840
So --
-Okay. Let's do that.

1643
01:26:37,840 --> 01:26:39,400
Ian Kremer?

1644
01:26:39,400 --> 01:26:40,760
-Hi there, everyone.

1645
01:26:40,760 --> 01:26:42,920
Penny, thank you.
Very kind of you.

1646
01:26:42,920 --> 01:26:44,360
Hi, everyone. I'm Ian Kremer.

1647
01:26:44,360 --> 01:26:46,200
I'm executive director
of the LEAD Coalition.

1648
01:26:46,200 --> 01:26:49,000
We're a coalition
of 100-member organization,

1649
01:26:49,000 --> 01:26:51,520
so about another
100 allied organizations

1650
01:26:51,520 --> 01:26:56,800
doing Alzheimer's and related
dementias advocacy at the level.

1651
01:26:56,800 --> 01:26:58,680
I have a couple
of recommendations.

1652
01:26:58,680 --> 01:27:00,160
I just want to preface it
by saying

1653
01:27:00,160 --> 01:27:02,640
that I've had
the pleasure of serving

1654
01:27:02,640 --> 01:27:06,480
on the steering committee
for NIH's two Dementia Care

1655
01:27:06,480 --> 01:27:08,560
and Services Research Summits.

1656
01:27:08,560 --> 01:27:12,120
In those summits, we did not,
for a variety of reasons

1657
01:27:12,120 --> 01:27:14,080
that I probably shouldn't
get into today,

1658
01:27:14,080 --> 01:27:18,040
we didn't have bandwidth to get
into detection and diagnosis

1659
01:27:18,040 --> 01:27:21,880
in the level of depth
that we all would have liked to.

1660
01:27:21,880 --> 01:27:24,120
And that so that's still
on our agenda

1661
01:27:24,120 --> 01:27:26,800
for subsequent care
and services research summits,

1662
01:27:26,800 --> 01:27:30,360
but I'm delighted
that you have taken time today

1663
01:27:30,360 --> 01:27:33,000
on your agenda
to dive into this.

1664
01:27:33,000 --> 01:27:34,400
And I want to commend you all

1665
01:27:34,400 --> 01:27:36,960
for remarkably
strong presentations

1666
01:27:36,960 --> 01:27:38,840
that get at the heart of much

1667
01:27:38,840 --> 01:27:42,280
of what makes detection
and diagnosis so challenging.

1668
01:27:42,280 --> 01:27:46,120
Nobody can be comprehensive
about that in any one session,

1669
01:27:46,120 --> 01:27:48,160
but you've all done
a remarkable job.

1670
01:27:48,160 --> 01:27:51,040
So that's the context
for what will follow,

1671
01:27:51,040 --> 01:27:54,360
which is maybe
a recommendation or two.

1672
01:27:54,360 --> 01:27:58,200
I think there are opportunities
for collaborative

1673
01:27:58,200 --> 01:28:03,800
funding agreements
between NINDS, and NIA,

1674
01:28:03,800 --> 01:28:08,360
particularly BSR at NIA,
around the psychological aspects

1675
01:28:08,360 --> 01:28:12,160
necessary to support effective
detection and diagnosis.

1676
01:28:12,160 --> 01:28:15,200
And to walk you through that
as briefly as I can,

1677
01:28:15,200 --> 01:28:18,560
I'll just make a few points.

1678
01:28:18,560 --> 01:28:20,960
I've advocated
for about a decade work

1679
01:28:20,960 --> 01:28:22,560
for an informal framework,

1680
01:28:22,560 --> 01:28:25,800
a framework that I informally
called TACA, T-A-C-A.

1681
01:28:25,800 --> 01:28:27,680
And that is that
the detection and diagnosis

1682
01:28:27,680 --> 01:28:31,880
should be timely, accurate,
compassionate, and actionable.

1683
01:28:31,880 --> 01:28:34,000
T-A-C-A.

1684
01:28:34,000 --> 01:28:36,280
I think you all today
have addressed

1685
01:28:36,280 --> 01:28:40,280
remarkably well the need
for detection and diagnosis

1686
01:28:40,280 --> 01:28:42,720
to be timely, accurate,
and actionable.

1687
01:28:42,720 --> 01:28:45,040
And there have been
some allusions to,

1688
01:28:45,040 --> 01:28:48,120
but maybe less direct reference
to the compassionate

1689
01:28:48,120 --> 01:28:50,400
or empathetic part
of this process.

1690
01:28:50,400 --> 01:28:53,360
But I think it's really
key and pivotal

1691
01:28:53,360 --> 01:28:55,800
to the efficacy
of detection and diagnosis,

1692
01:28:55,800 --> 01:28:59,120
and so it's an opportunity
for research investments

1693
01:28:59,120 --> 01:29:02,000
by an NIA,
NINDS,

1694
01:29:02,000 --> 01:29:05,160
and maybe sister
institutes across the NIH,

1695
01:29:05,160 --> 01:29:08,160
and certainly
private funders as well.

1696
01:29:08,160 --> 01:29:12,040
And I'll flesh it out
in the way.

1697
01:29:12,040 --> 01:29:15,000
So you made reference,
for instance,

1698
01:29:15,000 --> 01:29:19,200
to diagnose and adiós problem
that is endemic in the field,

1699
01:29:19,200 --> 01:29:21,200
and we all know
that that plays a role

1700
01:29:21,200 --> 01:29:24,480
in when it happens
at the detection stage

1701
01:29:24,480 --> 01:29:27,840
where there is identification
of possible cognitive impairment

1702
01:29:27,840 --> 01:29:31,640
and referral to a specialist
for a formal diagnosis

1703
01:29:31,640 --> 01:29:34,960
that often families,
individual patients,

1704
01:29:34,960 --> 01:29:37,920
do not proceed
to that specialist.

1705
01:29:37,920 --> 01:29:42,840
And part of the reason for that
is health system infrastructure,

1706
01:29:42,840 --> 01:29:45,520
but part is also
the psychological impact

1707
01:29:45,520 --> 01:29:49,680
of a poorly-conveyed
detection outcome.

1708
01:29:49,680 --> 01:29:53,400
So if the news is given
in a way that is unhelpful,

1709
01:29:53,400 --> 01:29:57,720
unempathetic,
lacking compassion,

1710
01:29:57,720 --> 01:30:00,800
it makes it that much harder
psychologically for people,

1711
01:30:00,800 --> 01:30:03,120
for patients and their families
to take the next step

1712
01:30:03,120 --> 01:30:06,840
and go to the specialist
for confirmation or refutation

1713
01:30:06,840 --> 01:30:10,760
of what detection set might
turn into a diagnosis

1714
01:30:10,760 --> 01:30:12,320
of cognitive impairment.

1715
01:30:12,320 --> 01:30:16,840
This is fundamentally
devastating news for most people

1716
01:30:16,840 --> 01:30:19,240
that know anything
about Alzheimer's disease

1717
01:30:19,240 --> 01:30:20,680
or any other form
of dementia,

1718
01:30:20,680 --> 01:30:23,200
or they just know
the umbrella term "dementia".

1719
01:30:23,200 --> 01:30:28,080
So if this is bad news
is not given well,

1720
01:30:28,080 --> 01:30:29,840
it interferes
with the likelihood

1721
01:30:29,840 --> 01:30:33,000
that someone will then pursue
the specialist confirmation

1722
01:30:33,000 --> 01:30:36,200
or refutation
of what detection indicated

1723
01:30:36,200 --> 01:30:38,280
might be
at a forthcoming diagnosis.

1724
01:30:38,280 --> 01:30:40,000
So I think it has
to be done better.

1725
01:30:40,000 --> 01:30:41,360
It can be done better.

1726
01:30:41,360 --> 01:30:44,040
We know clinicians
to do it beautifully.

1727
01:30:44,040 --> 01:30:46,520
We have to figure out
how they do it beautifully,

1728
01:30:46,520 --> 01:30:48,200
why they do it beautifully,

1729
01:30:48,200 --> 01:30:53,520
and how to replicate in scale
that compassionate element

1730
01:30:53,520 --> 01:30:59,000
of an otherwise professional
detection and diagnosis process.

1731
01:30:59,000 --> 01:31:01,080
And I would say the same
at the diagnosis

1732
01:31:01,080 --> 01:31:04,120
process by the specialist.

1733
01:31:04,120 --> 01:31:07,400
All the good recommendations
about making it actionable,

1734
01:31:07,400 --> 01:31:11,680
referral to community services,
getting one's legal, medical,

1735
01:31:11,680 --> 01:31:13,280
and other affairs
in order, etc.,

1736
01:31:13,280 --> 01:31:17,000
that all goes out the window
if patients

1737
01:31:17,000 --> 01:31:20,920
and families
emotionally shut down

1738
01:31:20,920 --> 01:31:25,720
because the news was not given
in a way that was supportive.

1739
01:31:25,720 --> 01:31:28,920
So we can do it
a little research figure out

1740
01:31:28,920 --> 01:31:32,440
how to do it well.
And then two last points.

1741
01:31:32,440 --> 01:31:35,280
I apologize for taking
so much time.

1742
01:31:35,280 --> 01:31:36,720
We have to be thoughtful

1743
01:31:36,720 --> 01:31:39,720
about the psychological
burden on providers,

1744
01:31:39,720 --> 01:31:42,760
on healthcare providers
themselves.

1745
01:31:42,760 --> 01:31:46,600
It is traumatizing
to give bad news for a living.

1746
01:31:46,600 --> 01:31:48,560
It can be a little
less traumatizing

1747
01:31:48,560 --> 01:31:50,640
if you have tools
and resources

1748
01:31:50,640 --> 01:31:53,800
to give to patients
and their families,

1749
01:31:53,800 --> 01:31:55,400
but there is still
the potential,

1750
01:31:55,400 --> 01:32:00,560
and I think the likelihood
for some accumulation

1751
01:32:00,560 --> 01:32:01,960
of psychological,

1752
01:32:01,960 --> 01:32:04,360
negative psychological
impact on providers.

1753
01:32:04,360 --> 01:32:07,120
And to the point
that Heather drew out,

1754
01:32:07,120 --> 01:32:09,800
I thought really beautifully
in her presentation,

1755
01:32:09,800 --> 01:32:12,120
all the workforce challenges
that we've got

1756
01:32:12,120 --> 01:32:17,760
are that much more vulnerable
to becoming worse

1757
01:32:17,760 --> 01:32:20,040
if we don't look
after the well-being,

1758
01:32:20,040 --> 01:32:24,000
the psychological well-being
of the providers themselves.

1759
01:32:24,000 --> 01:32:27,120
So if we're going to get
five-fold increase in the field,

1760
01:32:27,120 --> 01:32:29,360
but have people
fall out of the field

1761
01:32:29,360 --> 01:32:34,040
because of the psychological
burdens that we don't attend to,

1762
01:32:34,040 --> 01:32:37,120
we'll never get there.
And then the last thing,

1763
01:32:37,120 --> 01:32:38,680
and again I won't belabor
the point

1764
01:32:38,680 --> 01:32:41,160
because you all have correctly

1765
01:32:41,160 --> 01:32:43,720
and beautifully
identified health equity

1766
01:32:43,720 --> 01:32:47,120
as a crosscutting core
element of the work,

1767
01:32:47,120 --> 01:32:51,320
but all of the research
about how to passionately,

1768
01:32:51,320 --> 01:32:52,840
psychologically,

1769
01:32:52,840 --> 01:32:57,080
appropriately convey and
conduct detection and diagnosis,

1770
01:32:57,080 --> 01:33:01,040
that all has to be tailored
in a culturally-appropriate way.

1771
01:33:01,040 --> 01:33:04,720
One-size-fits-all is going to be
a recipe for failure

1772
01:33:04,720 --> 01:33:08,240
both for physicians
and their ancillary staff,

1773
01:33:08,240 --> 01:33:12,800
as well as for patients,
human beings,

1774
01:33:12,800 --> 01:33:16,760
and their ancillary care
and support teams.

1775
01:33:16,760 --> 01:33:18,200
So I'll end there.

1776
01:33:18,200 --> 01:33:21,800
Thank you again
for your indulgence of time.

1777
01:33:21,800 --> 01:33:23,280
-Thank you.

1778
01:33:23,280 --> 01:33:25,080
I took careful note
of these really insightful

1779
01:33:25,080 --> 01:33:28,520
and important recommendations
about compassionate disclosure,

1780
01:33:28,520 --> 01:33:30,920
culturally-appropriate
disclosure,

1781
01:33:30,920 --> 01:33:33,080
and considering the burdens
on providers.

1782
01:33:33,080 --> 01:33:34,760
I agree these need to be

1783
01:33:34,760 --> 01:33:36,400
highlighted more
in our recommendations,

1784
01:33:36,400 --> 01:33:38,120
so we'll bring us
back to our committee

1785
01:33:38,120 --> 01:33:40,960
and review those together.
Thank you.

1786
01:33:40,960 --> 01:33:46,000
So moving onto Penny Dax.

1787
01:33:46,000 --> 01:33:47,920
-Thank you.
Penny Dacks with the Association

1788
01:33:47,920 --> 01:33:49,920
for Frontotemporal Degeneration.

1789
01:33:49,920 --> 01:33:53,240
I just wanted to offer
a couple quick comments.

1790
01:33:53,240 --> 01:33:56,160
I really applaud the incredible
work your group has done.

1791
01:33:56,160 --> 01:33:57,840
And in the interest of time,

1792
01:33:57,840 --> 01:34:00,280
I am not suggesting necessarily
response to my comments

1793
01:34:00,280 --> 01:34:01,800
but just something
to reflect on

1794
01:34:01,800 --> 01:34:05,800
that we've heard so much
throughout the whole meeting

1795
01:34:05,800 --> 01:34:08,320
as we should about
the need for inclusivity

1796
01:34:08,320 --> 01:34:10,800
in how we design
our research.

1797
01:34:10,800 --> 01:34:13,800
And at the same time,
we heard about the need

1798
01:34:13,800 --> 01:34:16,400
for more widespread detection
of cognitive impairment

1799
01:34:16,400 --> 01:34:18,080
to detect it earlier.

1800
01:34:18,080 --> 01:34:20,400
And there was a rich discussion
of some of the benefits

1801
01:34:20,400 --> 01:34:22,120
and risks as it relates,

1802
01:34:22,120 --> 01:34:25,680
say, to the quality of life
and psychological well-being.

1803
01:34:25,680 --> 01:34:28,680
I think there's a lot
across those two topics

1804
01:34:28,680 --> 01:34:31,880
that I know I have
a lot to learn about,

1805
01:34:31,880 --> 01:34:34,280
and I think the field needs
to make sure we're very careful

1806
01:34:34,280 --> 01:34:38,200
about with how do people
from different socioeconomic,

1807
01:34:38,200 --> 01:34:41,200
geographic, and racial,
and ethnic backgrounds differ

1808
01:34:41,200 --> 01:34:43,920
in their perception
of screening for dementia.

1809
01:34:43,920 --> 01:34:45,320
Not just in
how they'll receive it,

1810
01:34:45,320 --> 01:34:47,520
but what do they
actually want.

1811
01:34:47,520 --> 01:34:49,680
How are they going
to respond to it?

1812
01:34:49,680 --> 01:34:52,800
And very importantly, how did
their risks and benefits differ?

1813
01:34:52,800 --> 01:34:54,920
So for example,
if cognitive impairment

1814
01:34:54,920 --> 01:34:57,960
gets detected in the clinic
before families even suspected

1815
01:34:57,960 --> 01:34:59,840
that this is on the horizon,

1816
01:34:59,840 --> 01:35:03,800
it maybe blocks some
long-term care insurance.

1817
01:35:03,800 --> 01:35:06,040
You know, has the insurance that
we've already gotten to show

1818
01:35:06,040 --> 01:35:08,000
that certain groups are
at higher risk of dementia,

1819
01:35:08,000 --> 01:35:09,880
has that already translated
into higher insurance

1820
01:35:09,880 --> 01:35:12,320
premiums for individuals?

1821
01:35:12,320 --> 01:35:14,880
I think there's just so much
we have to understand

1822
01:35:14,880 --> 01:35:18,800
as we focus on developing
preventative therapies

1823
01:35:18,800 --> 01:35:20,480
to understand

1824
01:35:20,480 --> 01:35:23,600
how these things are translating
into financial ramifications

1825
01:35:23,600 --> 01:35:27,200
because the insurance groups
and all of their technologies

1826
01:35:27,200 --> 01:35:30,000
and all of their policies
might be taking our research

1827
01:35:30,000 --> 01:35:33,200
and using it in ways
that we may not be anticipating.

1828
01:35:33,200 --> 01:35:35,360
I think we need policy research
to understand

1829
01:35:35,360 --> 01:35:38,440
how our advances are affecting
the most vulnerable

1830
01:35:38,440 --> 01:35:42,520
in our communities at that
financial and policy level,

1831
01:35:42,520 --> 01:35:45,000
and how it's affecting
employment risk,

1832
01:35:45,000 --> 01:35:48,200
insurance risks.

1833
01:35:48,200 --> 01:35:50,760
And I just wanted
to also emphasize

1834
01:35:50,760 --> 01:35:52,960
that some of the pragmatic
intervention research

1835
01:35:52,960 --> 01:35:56,600
that Dr. Okonkwo
really eloquently framed

1836
01:35:56,600 --> 01:35:58,120
I think it's also
really foundational

1837
01:35:58,120 --> 01:35:59,800
and important to communicate

1838
01:35:59,800 --> 01:36:03,160
when we're asking these groups
to participate in research

1839
01:36:03,160 --> 01:36:07,040
to help them understand
that value is to them

1840
01:36:07,040 --> 01:36:09,880
and their communities is first
and foremost in everybody's mind

1841
01:36:09,880 --> 01:36:12,640
as we ask them
to participate in research.

1842
01:36:12,640 --> 01:36:15,120
And I thank you again
for all of your time.

1843
01:36:17,720 --> 01:36:19,600
-Thank you. Well put, Penny.

1844
01:36:19,600 --> 01:36:24,200
I think these are important
points that we can incorporate

1845
01:36:24,200 --> 01:36:27,000
perhaps into our
recommendation too.

1846
01:36:27,000 --> 01:36:29,920
If there's no comment
from the panel,

1847
01:36:29,920 --> 01:36:31,320
we'll just take note of this

1848
01:36:31,320 --> 01:36:33,400
and bring it back
for discussion to our group.

1849
01:36:33,400 --> 01:36:36,000
I agree with these points.
Sorry, Penny, one more thing?

1850
01:36:36,000 --> 01:36:38,520
-I'm so sorry.
I just also forgot to say that

1851
01:36:38,520 --> 01:36:41,160
for those that are early
detection of dementia

1852
01:36:41,160 --> 01:36:43,400
and early onset dementia,

1853
01:36:43,400 --> 01:36:45,280
that's when people
are the most reliant

1854
01:36:45,280 --> 01:36:48,000
on their income
and their employment.

1855
01:36:48,000 --> 01:36:52,120
And I think that's where we need
to pay really careful attention.

1856
01:36:52,120 --> 01:36:55,640
-Thank you.
So in the interest of time,

1857
01:36:55,640 --> 01:36:57,440
I think will move on
to the next question,

1858
01:36:57,440 --> 01:37:01,600
which I believe was Dezheap?

1859
01:37:01,600 --> 01:37:04,080
Let's see. I don't have
the full name here, but.

1860
01:37:04,080 --> 01:37:05,640
-Yeah. Yeah.

1861
01:37:05,640 --> 01:37:06,960
-Okay. Great.

1862
01:37:06,960 --> 01:37:08,800
Please introduce yourself
and ask your --

1863
01:37:08,800 --> 01:37:10,680
or offer your point.

1864
01:37:10,680 --> 01:37:13,120
-Okay. So I'm Dezarell.

1865
01:37:13,120 --> 01:37:17,040
I'm a professor in
the University of Minnesota.

1866
01:37:17,040 --> 01:37:18,560
So I have a question.

1867
01:37:18,560 --> 01:37:22,800
So I studied cell biology
and the also animal model.

1868
01:37:22,800 --> 01:37:30,240
So all, like, [Indistinct]
nuclei, beta, mechanic injury,

1869
01:37:30,240 --> 01:37:33,400
infection, all affect how.

1870
01:37:33,400 --> 01:37:37,960
So POW is a common
downstream mechanism.

1871
01:37:37,960 --> 01:37:44,520
And my question is what
proportion of dementia patients,

1872
01:37:44,520 --> 01:37:49,440
have a POW pathology?
Can anyone answer that?

1873
01:37:49,440 --> 01:37:53,760
Maybe we should --
and I don't want to --

1874
01:37:53,760 --> 01:37:57,680
maybe we should increase
the research effort on POW

1875
01:37:57,680 --> 01:38:02,400
because it started
coming downstream pocket

1876
01:38:02,400 --> 01:38:05,840
for so many multiple
newly-degenerative disease.

1877
01:38:05,840 --> 01:38:08,040
I will stop here. Thank you.

1878
01:38:08,040 --> 01:38:09,680
-Dazerell, thank you very much.

1879
01:38:09,680 --> 01:38:12,320
This is Dr. Lea Grinberg.
I'm a neuropathologist at UCSF,

1880
01:38:12,320 --> 01:38:15,160
and it's a pleasure
trying to answer this question

1881
01:38:15,160 --> 01:38:17,200
with the best
of my knowledge.

1882
01:38:17,200 --> 01:38:18,960
Thank you very much
for your question.

1883
01:38:18,960 --> 01:38:21,920
I think for a neuropathologist
and many others in the field,

1884
01:38:21,920 --> 01:38:27,000
this is a quite important
question that we face every day.

1885
01:38:27,000 --> 01:38:29,600
Actually one of the
recommendations for this group

1886
01:38:29,600 --> 01:38:34,360
is to try to promote
even better mapping studies

1887
01:38:34,360 --> 01:38:36,440
especially using
human neuropathology

1888
01:38:36,440 --> 01:38:38,280
to understand
these questions.

1889
01:38:38,280 --> 01:38:40,480
And this is based
on the amazing results

1890
01:38:40,480 --> 01:38:44,160
that we got from a recent
clinical pathological cohort

1891
01:38:44,160 --> 01:38:46,440
and how much we learned
from this.

1892
01:38:46,440 --> 01:38:48,160
So a simple answer
to your question

1893
01:38:48,160 --> 01:38:51,080
is that most of the patients
that have dementia

1894
01:38:51,080 --> 01:38:55,720
and come to autopsy,
they have multiple pathologies,

1895
01:38:55,720 --> 01:38:59,920
and pathologies that
involve POW is one of them.

1896
01:38:59,920 --> 01:39:03,200
In neuropathological studies,
we have the ability

1897
01:39:03,200 --> 01:39:06,520
to try to classify
these neuropathies.

1898
01:39:06,520 --> 01:39:10,480
And in most cases, we see POW
that is related

1899
01:39:10,480 --> 01:39:14,760
to Alzheimer's disease
neuropathological changes.

1900
01:39:14,760 --> 01:39:16,400
When it comes from amyloid,

1901
01:39:16,400 --> 01:39:17,920
we call this
Alzheimer's disease.

1902
01:39:17,920 --> 01:39:19,800
When it doesn't
come with amyloid,

1903
01:39:19,800 --> 01:39:21,200
we might call this Scart.

1904
01:39:21,200 --> 01:39:24,600
Some call early
Alzheimer disease stages.

1905
01:39:24,600 --> 01:39:28,400
We have POW that deposits
in glial cells and astroglia,

1906
01:39:28,400 --> 01:39:31,600
what we call rTag that
it's very common during aging.

1907
01:39:31,600 --> 01:39:35,000
And in populations over 80,
we might find it in

1908
01:39:35,000 --> 01:39:39,200
at least 50% of the cases.
And it's the same for a change

1909
01:39:39,200 --> 01:39:41,160
that call agraphiac
brain disease

1910
01:39:41,160 --> 01:39:43,640
that the field doesn't know
exactly what it does,

1911
01:39:43,640 --> 01:39:47,240
if it's a foe
or if it's a friend.

1912
01:39:47,240 --> 01:39:50,400
Now to answer the question
in another way,

1913
01:39:50,400 --> 01:39:51,760
when we look at patients

1914
01:39:51,760 --> 01:39:54,000
that the primary
neuropathological diagnosis

1915
01:39:54,000 --> 01:39:57,120
is not related to POW,
for instance, Lewy body disease,

1916
01:39:57,120 --> 01:40:03,440
or to TDP 43 protein properties,
it's still just a minority.

1917
01:40:03,440 --> 01:40:06,120
We won't have any kind of
POW deposits,

1918
01:40:06,120 --> 01:40:09,760
especially of the AD-type.
So thank you for a question.

1919
01:40:09,760 --> 01:40:11,600
It's something that certainly
this group thinks

1920
01:40:11,600 --> 01:40:14,880
we have to pursue,
especially in diverse population

1921
01:40:14,880 --> 01:40:16,640
because most of
our understanding

1922
01:40:16,640 --> 01:40:20,000
comes from Caucasians.
Thank you very much.

1923
01:40:22,280 --> 01:40:23,840
-Thank you, Dr. Grinberg.

1924
01:40:23,840 --> 01:40:25,520
We have just
a couple more minutes.

1925
01:40:25,520 --> 01:40:27,400
We're cutting into the break
for those of you

1926
01:40:27,400 --> 01:40:29,240
who are still with us.

1927
01:40:29,240 --> 01:40:30,960
Let's try to get
some brief comments

1928
01:40:30,960 --> 01:40:34,840
if possible from Constantino,
and then Helen Metzger,

1929
01:40:34,840 --> 01:40:38,200
and then we'll take a break.
So Constantino?

1930
01:40:38,200 --> 01:40:40,920
-Hi. Thank you.
It was wonderful overview.

1931
01:40:40,920 --> 01:40:47,080
So you know, by listening
to vascular dementia,

1932
01:40:47,080 --> 01:40:51,760
you know, lectures, the series
of contributions yesterday,

1933
01:40:51,760 --> 01:40:54,160
it seems to me
there is a lot overlap

1934
01:40:54,160 --> 01:40:57,000
between
what was discussed today

1935
01:40:57,000 --> 01:40:59,040
and what was
discussed yesterday.

1936
01:40:59,040 --> 01:41:04,160
Particularly at the level
of the basic science

1937
01:41:04,160 --> 01:41:05,720
because vascular components

1938
01:41:05,720 --> 01:41:09,120
is going to be one of
the most common. All right?

1939
01:41:09,120 --> 01:41:14,960
So I would urge you to kind of
harmonize better the multiple,

1940
01:41:14,960 --> 01:41:19,040
the, you know, cause of dementia
with the vascular component

1941
01:41:19,040 --> 01:41:21,240
because that's going to have
an impact on the diagnoses

1942
01:41:21,240 --> 01:41:23,200
and impact on the prevention.

1943
01:41:23,200 --> 01:41:26,080
Because as far as I can tell,
that may be the strongest,

1944
01:41:26,080 --> 01:41:30,480
you know, tool we have in terms
of overall dementia.

1945
01:41:30,480 --> 01:41:33,280
But there finger studies,
and you know,

1946
01:41:33,280 --> 01:41:35,080
the mind screen and so on.

1947
01:41:35,080 --> 01:41:38,240
And so that would be
very important.

1948
01:41:38,240 --> 01:41:40,800
Also at the level
of care delivery,

1949
01:41:40,800 --> 01:41:43,000
for example,
cardiologists, you know,

1950
01:41:43,000 --> 01:41:46,480
may not know as much about,
you know, about how to deal

1951
01:41:46,480 --> 01:41:49,600
with the vascular conditions
in the brain

1952
01:41:49,600 --> 01:41:52,160
so there is a better
need for harmonization

1953
01:41:52,160 --> 01:41:53,720
also at that level.

1954
01:41:53,720 --> 01:41:57,200
So that's just a plea
for a perhaps more harmonization

1955
01:41:57,200 --> 01:42:01,000
with the vascular
dementia aspects.

1956
01:42:03,520 --> 01:42:05,280
-Thank you for
that important point.

1957
01:42:05,280 --> 01:42:07,840
If there's no comments
from the panel,

1958
01:42:07,840 --> 01:42:10,960
we will absolutely
review carefully

1959
01:42:10,960 --> 01:42:13,200
the VCID recommendations
in ours

1960
01:42:13,200 --> 01:42:15,320
and look for areas
of harmonization.

1961
01:42:15,320 --> 01:42:17,920
I really appreciate
that comment.

1962
01:42:17,920 --> 01:42:22,800
So in closing, our last comment
will be from Helen Metzger.

1963
01:42:22,800 --> 01:42:25,240
-Hi, Kate.
I'd like to thank the committee

1964
01:42:25,240 --> 01:42:27,640
for what I've heard
this morning.

1965
01:42:27,640 --> 01:42:31,800
I want to reinforce,
Dale had a lot to contribute,

1966
01:42:31,800 --> 01:42:34,960
but Ian, what you and Penny
brought to the floor

1967
01:42:34,960 --> 01:42:36,520
has said a lot to me.

1968
01:42:36,520 --> 01:42:40,200
I've been in this for 30 years
with Lewy body dementia.

1969
01:42:40,200 --> 01:42:41,400
Kate knows me well.

1970
01:42:41,400 --> 01:42:43,240
I've been part of
the care ecosystem

1971
01:42:43,240 --> 01:42:44,600
and part of the committee

1972
01:42:44,600 --> 01:42:46,800
that helped develop
the Care Ecosystem.

1973
01:42:46,800 --> 01:42:50,400
I'm also involved
in the PPV/PPI committee

1974
01:42:50,400 --> 01:42:52,800
at the Global Brain
Health Institute,

1975
01:42:52,800 --> 01:42:55,120
and been working with them
for over a year

1976
01:42:55,120 --> 01:42:58,200
on making certain that
the voices of those people

1977
01:42:58,200 --> 01:43:01,800
affected with these diseases
are at the table.

1978
01:43:01,800 --> 01:43:03,600
So I just want
to remind the committee

1979
01:43:03,600 --> 01:43:06,560
because I didn't
see it directly,

1980
01:43:06,560 --> 01:43:08,800
you know,
touched upon this morning,

1981
01:43:08,800 --> 01:43:11,360
is that the voices,
the care partners

1982
01:43:11,360 --> 01:43:16,040
and those living with disease
have to be brought forth

1983
01:43:16,040 --> 01:43:19,200
and need to be integrated
from the area

1984
01:43:19,200 --> 01:43:23,640
all the way from conceptive
research to execution,

1985
01:43:23,640 --> 01:43:26,280
to outcomes
and implementation.

1986
01:43:26,280 --> 01:43:28,880
So that is, that's all I want
to say this morning,

1987
01:43:28,880 --> 01:43:31,440
but thank you for all
of your amazing work.

1988
01:43:31,440 --> 01:43:33,440
I sincerely appreciate it.

1989
01:43:33,440 --> 01:43:34,920
And we'll bring it
to those people

1990
01:43:34,920 --> 01:43:38,520
that I work with
in the trenches.

1991
01:43:38,520 --> 01:43:42,880
-Thank you, Helen for your
participation and your advocacy.

1992
01:43:42,880 --> 01:43:45,520
You are continuing
to make a huge difference,

1993
01:43:45,520 --> 01:43:47,600
and we will take
that point back

1994
01:43:47,600 --> 01:43:50,560
and find a way to weave it
into our recommendations

1995
01:43:50,560 --> 01:43:51,960
so it is explicit.

1996
01:43:51,960 --> 01:43:54,520
Thank you, and thank you
everyone on the panel,

1997
01:43:54,520 --> 01:43:56,800
and everyone
for your participation

1998
01:43:56,800 --> 01:43:58,440
as we shift now to the break.

1999
01:43:58,440 --> 01:44:01,400
-We're ready to start
the next session.

2000
01:44:01,400 --> 01:44:04,960
I'm pleased to introduce
Dr. Kristen Dams-O'Connor

2001
01:44:04,960 --> 01:44:08,760
as the scientific chair
of the Traumatic Brain Injury

2002
01:44:08,760 --> 01:44:11,440
in Alzheimer's Disease
and Alzheimer's Disease-related

2003
01:44:11,440 --> 01:44:14,760
Dementias session.
Kristen?

2004
01:44:14,760 --> 01:44:17,040
-Thank you. Next slide.

2005
01:44:19,240 --> 01:44:22,440
Okay. Let's get started.
Next slide.

2006
01:44:22,440 --> 01:44:24,960
Our speakers
have no disclosures.

2007
01:44:24,960 --> 01:44:30,760
Next slide.
I am very grateful

2008
01:44:30,760 --> 01:44:34,480
and would like to thank
the subcommittee members

2009
01:44:34,480 --> 01:44:36,960
who shared their expertise,

2010
01:44:36,960 --> 01:44:40,040
and the NIH program staff
who supported our work.

2011
01:44:40,040 --> 01:44:43,240
It has been a privilege to work
with this awesome group.

2012
01:44:43,240 --> 01:44:46,240
Next slide.

2013
01:44:46,240 --> 01:44:50,720
This session on post-TDI,
AD/ADRD base was first included

2014
01:44:50,720 --> 01:44:56,880
in the ADR Base Summit
in 2019 as an emerging topic.

2015
01:44:56,880 --> 01:44:59,000
And we're now very well-placed

2016
01:44:59,000 --> 01:45:02,880
in the multiple ideology
of dementias session.

2017
01:45:02,880 --> 01:45:04,240
We've heard throughout
the last day

2018
01:45:04,240 --> 01:45:05,800
and a half about the importance

2019
01:45:05,800 --> 01:45:09,160
of considering life
course exposures.

2020
01:45:09,160 --> 01:45:11,960
TBI is one of many life
course exposures

2021
01:45:11,960 --> 01:45:13,760
associated with dementia risk.

2022
01:45:13,760 --> 01:45:16,880
And one thing
that is unique about TBI

2023
01:45:16,880 --> 01:45:19,760
is that it's an exposure
with a time zero,

2024
01:45:19,760 --> 01:45:22,600
a clear point from which
we can investigate the pathways

2025
01:45:22,600 --> 01:45:25,480
through which it may influence
the proliferation

2026
01:45:25,480 --> 01:45:28,400
of distinct
pathological processes.

2027
01:45:28,400 --> 01:45:31,360
This knowledge may open doors
for understanding

2028
01:45:31,360 --> 01:45:36,120
the pathogenesis of dementias
of multiple ideologies.

2029
01:45:36,120 --> 01:45:40,000
Next slide. I'll start
was just quick definitions.

2030
01:45:40,000 --> 01:45:43,480
A traumatic brain injury
is a blow or jolt to the head

2031
01:45:43,480 --> 01:45:48,520
or neck that result in a loss
or alteration of consciousness.

2032
01:45:48,520 --> 01:45:51,640
The pyramid on the right
illustrates the CDC's estimate

2033
01:45:51,640 --> 01:45:54,400
that almost three million
Americans need care

2034
01:45:54,400 --> 01:45:57,840
in the emergency department
for TBI each year.

2035
01:45:57,840 --> 01:46:00,200
Next slide.

2036
01:46:00,200 --> 01:46:03,040
TBI can result
in a range of symptoms.

2037
01:46:03,040 --> 01:46:05,800
In general, we expect
that most people

2038
01:46:05,800 --> 01:46:08,600
with an uncomplicated mild TBI,

2039
01:46:08,600 --> 01:46:10,800
which is sometimes
called a concussion,

2040
01:46:10,800 --> 01:46:14,440
to recover completely
within days or weeks.

2041
01:46:14,440 --> 01:46:17,080
Next slide.

2042
01:46:17,080 --> 01:46:19,400
However, those with more
severe injuries

2043
01:46:19,400 --> 01:46:22,040
may experience more
severe consequences,

2044
01:46:22,040 --> 01:46:24,800
including lifelong
disability or death.

2045
01:46:24,800 --> 01:46:27,800
The estimates you see here
are based on data

2046
01:46:27,800 --> 01:46:29,600
collected through
the NIDILRR-funded

2047
01:46:29,600 --> 01:46:32,440
TBI Model Systems
National Data.

2048
01:46:32,440 --> 01:46:34,960
And as you can see
about one in five have died

2049
01:46:34,960 --> 01:46:37,120
within five years of injury.

2050
01:46:37,120 --> 01:46:40,200
Thirty % experienced
deterioration and function

2051
01:46:40,200 --> 01:46:43,920
between one and five years,
and the remaining survivors

2052
01:46:43,920 --> 01:46:46,800
either remain
functionally-stable or improved.

2053
01:46:46,800 --> 01:46:48,880
Next slide.

2054
01:46:48,880 --> 01:46:52,040
But how does this observed
decline relate to dementia?

2055
01:46:52,040 --> 01:46:54,000
For years,
we have been taught that

2056
01:46:54,000 --> 01:46:57,800
TBI is one of the strongest
environmental risk factors

2057
01:46:57,800 --> 01:47:00,160
for Alzheimer's disease.

2058
01:47:00,160 --> 01:47:02,160
But as this area
of study has matured,

2059
01:47:02,160 --> 01:47:05,440
we have learned that the reality
is far more complex.

2060
01:47:05,440 --> 01:47:07,360
Results vary across studies

2061
01:47:07,360 --> 01:47:10,440
that differ tremendously
in their methodology,

2062
01:47:10,440 --> 01:47:11,880
their sampling strategies

2063
01:47:11,880 --> 01:47:15,840
and their definitions
of TBI and dementia.

2064
01:47:15,840 --> 01:47:18,800
In general though, we do see
that more severe injury

2065
01:47:18,800 --> 01:47:21,800
tends to be associated
with greater dementia risk,

2066
01:47:21,800 --> 01:47:24,080
and TBI is a well-recognized

2067
01:47:24,080 --> 01:47:27,560
and potentially modifiable
risk factor for dementia.

2068
01:47:27,560 --> 01:47:29,800
Next slide.

2069
01:47:29,800 --> 01:47:32,440
Although a global pandemic
began just months

2070
01:47:32,440 --> 01:47:36,800
after releasing our 2019
research recommendations,

2071
01:47:36,800 --> 01:47:39,160
substantial progress
has been made.

2072
01:47:39,160 --> 01:47:41,600
Next slide.

2073
01:47:41,600 --> 01:47:45,240
First, we have --
oh, next slide.

2074
01:47:45,240 --> 01:47:48,000
First we have an updated
consensus definition

2075
01:47:48,000 --> 01:47:52,000
for the post-mortem
diagnosis CTE neuropathology.

2076
01:47:52,000 --> 01:47:56,200
CTE is believed to be related to
repetitive head trauma exposure

2077
01:47:56,200 --> 01:47:59,440
and revised criteria provide
a more precise definition

2078
01:47:59,440 --> 01:48:02,040
of the pathognomonic lesion.

2079
01:48:02,040 --> 01:48:05,440
We also now have a preliminary
consensus definition

2080
01:48:05,440 --> 01:48:07,160
for research

2081
01:48:07,160 --> 01:48:10,440
diagnosis of traumatic
encephalopathy syndrome,

2082
01:48:10,440 --> 01:48:14,800
which is the proposed clinical
correlate of CTE neuropathology.

2083
01:48:14,800 --> 01:48:17,080
This represents
an important first step

2084
01:48:17,080 --> 01:48:20,360
towards in vivo diagnosis.

2085
01:48:20,360 --> 01:48:23,640
Our colleagues at BU have begun
the hard work of validating

2086
01:48:23,640 --> 01:48:26,200
in vivo criteria for TES,

2087
01:48:26,200 --> 01:48:27,640
and these are the types
of studies

2088
01:48:27,640 --> 01:48:31,560
that will pave the way
for further refinements.

2089
01:48:31,560 --> 01:48:35,200
Major questions remain though
about the minimum thresholds

2090
01:48:35,200 --> 01:48:39,280
for CTE diagnosis,
the role of the isolated

2091
01:48:39,280 --> 01:48:43,120
traumatic brain injury
in CTE and NTES,

2092
01:48:43,120 --> 01:48:45,800
and the relationships
between these pathologies

2093
01:48:45,800 --> 01:48:49,000
and clinical symptoms
with other ADRDs.

2094
01:48:49,000 --> 01:48:51,040
Next slide.

2095
01:48:51,040 --> 01:48:52,600
-Two minutes remaining.

2096
01:48:52,600 --> 01:48:56,840
-One major initiative
that has resulted since 2019

2097
01:48:56,840 --> 01:49:00,720
is that Connect TBI Study led by
Doug Smith and Willie Stewart,

2098
01:49:00,720 --> 01:49:04,320
and 13 institutions
also represented.

2099
01:49:04,320 --> 01:49:06,200
This project will evaluate
brain tissue

2100
01:49:06,200 --> 01:49:08,200
from cases
with traumatic brain injury

2101
01:49:08,200 --> 01:49:11,560
and creative brain repository
for tissue sharing.

2102
01:49:11,560 --> 01:49:14,240
Next.
We also have a large initiative

2103
01:49:14,240 --> 01:49:17,400
led Ann McKee
at Boston University

2104
01:49:17,400 --> 01:49:21,320
that will leverage
existing brain banks to --

2105
01:49:21,320 --> 01:49:23,040
that have very
well-characterized

2106
01:49:23,040 --> 01:49:25,040
and fully-harmonized clinical
and head trauma

2107
01:49:25,040 --> 01:49:28,920
exposure histories
to characterized pathologies

2108
01:49:28,920 --> 01:49:31,160
related to repetitive
traumatic brain injury

2109
01:49:31,160 --> 01:49:34,440
and head trauma,
and their clinical phenotypes.

2110
01:49:34,440 --> 01:49:36,280
Next slide.

2111
01:49:36,280 --> 01:49:39,840
We've also been able to expand
the late effects of TBI Project,

2112
01:49:39,840 --> 01:49:42,080
which is a perspective
brain donor program

2113
01:49:42,080 --> 01:49:43,960
with autopsy endpoints,

2114
01:49:43,960 --> 01:49:47,160
and this will allow us to expand
to our community recruitment

2115
01:49:47,160 --> 01:49:49,520
and longitudinal follow-up.

2116
01:49:49,520 --> 01:49:52,680
Next slide.
Okay.

2117
01:49:52,680 --> 01:49:57,720
So our subcommittee's first
recommendation reflects the fact

2118
01:49:57,720 --> 01:50:00,960
that this is a relatively
new area of investigation.

2119
01:50:00,960 --> 01:50:03,680
And we really feel that we can
learn from our colleagues

2120
01:50:03,680 --> 01:50:06,640
who have been studying
dementia for decades.

2121
01:50:06,640 --> 01:50:09,040
We identify
really important opportunities

2122
01:50:09,040 --> 01:50:13,160
for interdisciplinary crosstalk
and expanding collaboration

2123
01:50:13,160 --> 01:50:17,560
across traditionally
siloed areas of study.

2124
01:50:17,560 --> 01:50:19,680
Next slide.

2125
01:50:19,680 --> 01:50:23,000
For starters, we hope to convene
a working group of stakeholders

2126
01:50:23,000 --> 01:50:26,600
in the TBI and multiple
ideology dementia communities

2127
01:50:26,600 --> 01:50:31,000
to evaluate the extent to which
current knowledge in ADRD

2128
01:50:31,000 --> 01:50:35,000
can the applied to the study
of dementia after TBI,

2129
01:50:35,000 --> 01:50:38,280
and also how our understanding
of the acute

2130
01:50:38,280 --> 01:50:40,640
and chronic
pathophysiology of TBI

2131
01:50:40,640 --> 01:50:44,640
can contribute to
our understanding of ADRDs.

2132
01:50:44,640 --> 01:50:48,000
Again, since TBI is a risk
factor with a time zero,

2133
01:50:48,000 --> 01:50:49,320
we believe that further study

2134
01:50:49,320 --> 01:50:52,800
will benefit
the entire ADRD community.

2135
01:50:52,800 --> 01:50:55,360
I also say, and this is a figure
you've seen before,

2136
01:50:55,360 --> 01:50:57,640
is when we recalculate
the population

2137
01:50:57,640 --> 01:51:02,800
attributable factor of dementia
risk using population

2138
01:51:02,800 --> 01:51:06,000
representative data
on TBI prevalence,

2139
01:51:06,000 --> 01:51:09,480
we see that the number
of dementia cases

2140
01:51:09,480 --> 01:51:12,160
that may be at least
partially attributable to TBI

2141
01:51:12,160 --> 01:51:14,040
is actually perhaps
much greater.

2142
01:51:14,040 --> 01:51:16,200
Next slide.

2143
01:51:16,200 --> 01:51:18,080
Another component
of our first recommendation

2144
01:51:18,080 --> 01:51:20,520
is to harmonize
existing data

2145
01:51:20,520 --> 01:51:24,800
across longitudinal TBI
and ADRD studies.

2146
01:51:24,800 --> 01:51:29,000
Here we illustrate one example
of an effort along these lines

2147
01:51:29,000 --> 01:51:32,640
to pull data from five studies
of cognitive aging.

2148
01:51:32,640 --> 01:51:38,040
So we have newly collected
very detailed characterization

2149
01:51:38,040 --> 01:51:40,200
of lifetime TBI exposure,

2150
01:51:40,200 --> 01:51:44,160
which will allow us to examine
late life implications of TBI.

2151
01:51:44,160 --> 01:51:50,200
And we're using IRT-based
methods to co-calibrate data

2152
01:51:50,200 --> 01:51:52,680
that were gathered
from different measures

2153
01:51:52,680 --> 01:51:56,240
of the same constructs,
such as cognition and mood.

2154
01:51:56,240 --> 01:51:58,480
Efforts like this can allow us

2155
01:51:58,480 --> 01:52:01,200
to conduct
more granular investigation

2156
01:52:01,200 --> 01:52:07,520
into the intersecting factors
that influence risk for ADRD

2157
01:52:07,520 --> 01:52:11,280
well beyond what would be
possible in a single study.

2158
01:52:11,280 --> 01:52:15,600
Next slide.
Ideally, future efforts

2159
01:52:15,600 --> 01:52:19,920
will maximize measurement
harmonization from the start

2160
01:52:19,920 --> 01:52:24,600
by prospectively collecting
multimodal common data elements

2161
01:52:24,600 --> 01:52:27,760
to facilitate comparisons
and data sharing.

2162
01:52:27,760 --> 01:52:29,680
The ENIGMA
Brain Injury Initiative

2163
01:52:29,680 --> 01:52:33,840
is one example of a global
working group with these goals.

2164
01:52:33,840 --> 01:52:36,200
Next slide.

2165
01:52:36,200 --> 01:52:39,000
Post-mortem
TBI common data elements,

2166
01:52:39,000 --> 01:52:43,200
which is actually another area
of progress since 2019,

2167
01:52:43,200 --> 01:52:46,720
provide a road map
for prospective collection

2168
01:52:46,720 --> 01:52:48,880
of harmonized data.

2169
01:52:48,880 --> 01:52:52,080
Our hope is that existing
brain banks

2170
01:52:52,080 --> 01:52:55,960
will use these common
neuropathological methods

2171
01:52:55,960 --> 01:52:58,920
and post-mortem
family interview methods

2172
01:52:58,920 --> 01:53:03,800
to characterize post-TBI ADRD
and facilitate data

2173
01:53:03,800 --> 01:53:07,000
sharing and cross study
comparisons.

2174
01:53:07,000 --> 01:53:09,240
Next slide.

2175
01:53:09,240 --> 01:53:13,120
The Olympic Sensi studies
provide another great roadmap

2176
01:53:13,120 --> 01:53:16,040
for neural imaging,
harmonization in particular.

2177
01:53:16,040 --> 01:53:19,440
So they aligned with ADME
from the start

2178
01:53:19,440 --> 01:53:24,000
by maximizing overlap of both
clinical and imaging metrics.

2179
01:53:24,000 --> 01:53:26,960
For example,
they used a unique phantom

2180
01:53:26,960 --> 01:53:29,600
that has an isotropic
diffusion capabilities

2181
01:53:29,600 --> 01:53:32,720
with hollow fibers
the size of axons

2182
01:53:32,720 --> 01:53:35,480
to mimic
the diffusion properties

2183
01:53:35,480 --> 01:53:38,200
of diffused axonal injury

2184
01:53:38,200 --> 01:53:40,520
and other tissue
properties of relevance

2185
01:53:40,520 --> 01:53:45,000
to both traumatic brain injury
and neurodegenerative disease.

2186
01:53:45,000 --> 01:53:46,600
Next slide.

2187
01:53:48,640 --> 01:53:50,640
Our committee believes
that neuroinformatics

2188
01:53:50,640 --> 01:53:53,560
will play
an important role as well.

2189
01:53:53,560 --> 01:53:58,720
So our first recommendation
will require modern cloud-based

2190
01:53:58,720 --> 01:54:01,520
informatics and analytics
harmonization platforms

2191
01:54:01,520 --> 01:54:04,400
for QA,
post-processing,

2192
01:54:04,400 --> 01:54:07,160
and harmonizing data
across sites,

2193
01:54:07,160 --> 01:54:09,200
and scanners,
and software.

2194
01:54:09,200 --> 01:54:13,320
Historically, we have had
to sometimes sacrifice precision

2195
01:54:13,320 --> 01:54:16,480
for generalizability
successfully harmonizing

2196
01:54:16,480 --> 01:54:18,400
only relatively crude metrics

2197
01:54:18,400 --> 01:54:22,320
across major scanner vendors
and software platforms.

2198
01:54:22,320 --> 01:54:24,520
But modern informatics platforms

2199
01:54:24,520 --> 01:54:27,080
can automate
many aspects of this,

2200
01:54:27,080 --> 01:54:32,200
which again is necessary
for multi-site studies. Next.

2201
01:54:32,200 --> 01:54:35,600
Recent examples of
an international collaboration

2202
01:54:35,600 --> 01:54:38,800
that required harmonization
across continents

2203
01:54:38,800 --> 01:54:42,480
is seen on the track TBI
and center TBI studies.

2204
01:54:42,480 --> 01:54:44,960
And again, this may be
a great future opportunity.

2205
01:54:44,960 --> 01:54:48,240
Next slide.

2206
01:54:48,240 --> 01:54:50,280
The final component
of recommendation one

2207
01:54:50,280 --> 01:54:52,880
is the need
to encourage collaboration

2208
01:54:52,880 --> 01:54:56,480
between clinical researchers,
biostatisticians,

2209
01:54:56,480 --> 01:54:58,200
epidemiologists,

2210
01:54:58,200 --> 01:55:01,360
and data scientists
to incorporate

2211
01:55:01,360 --> 01:55:04,360
multi-dimensional,
multimodal data,

2212
01:55:04,360 --> 01:55:08,360
and employ more sophisticated
causal inference methodologies,

2213
01:55:08,360 --> 01:55:10,800
and work with
implementation scientists

2214
01:55:10,800 --> 01:55:15,560
to maximize the clinical
translatability of this work.

2215
01:55:15,560 --> 01:55:18,320
This is inherently
interdisciplinary,

2216
01:55:18,320 --> 01:55:22,600
and collaboration is required
to move the science forward.

2217
01:55:22,600 --> 01:55:24,880
Next slide.

2218
01:55:24,880 --> 01:55:27,840
Our second recommendation
pertains to clinical phenotyping

2219
01:55:27,840 --> 01:55:30,200
across exposure histories

2220
01:55:30,200 --> 01:55:33,880
to pave the way for
in vivo diagnostics.

2221
01:55:33,880 --> 01:55:36,320
Next slide.

2222
01:55:36,320 --> 01:55:39,960
First, we need to establish
and validate

2223
01:55:39,960 --> 01:55:44,040
a quantitative index of lifetime
head trauma exposure.

2224
01:55:44,040 --> 01:55:46,440
One thing we have learned
is that administrative data

2225
01:55:46,440 --> 01:55:50,400
only identifies those who have
sought and received care.

2226
01:55:50,400 --> 01:55:52,520
So self-report is considered

2227
01:55:52,520 --> 01:55:56,840
the gold standard
for lifetime TBI exposure.

2228
01:55:56,840 --> 01:55:59,480
We consistently find
that structured questionnaires

2229
01:55:59,480 --> 01:56:03,720
that use contextual cueing
for lifetime injury reporting,

2230
01:56:03,720 --> 01:56:06,240
such as the Ohio
State University

2231
01:56:06,240 --> 01:56:08,200
TBI identification method,

2232
01:56:08,200 --> 01:56:09,920
or the brain injury
screening questionnaire,

2233
01:56:09,920 --> 01:56:11,240
are really required

2234
01:56:11,240 --> 01:56:14,320
for comprehensive
exposure ascertainment.

2235
01:56:14,320 --> 01:56:16,880
So this notion
that all important TBIs

2236
01:56:16,880 --> 01:56:19,640
are in the medical record
is simply untrue.

2237
01:56:19,640 --> 01:56:21,160
Our colleagues
have actually found

2238
01:56:21,160 --> 01:56:23,000
that those who never
sought care

2239
01:56:23,000 --> 01:56:25,800
have worse long-term
outcomes after injury.

2240
01:56:25,800 --> 01:56:29,680
So this not seeking care may
actually be an important proxy

2241
01:56:29,680 --> 01:56:33,720
for other factors that matter
a lot in long-term outcomes.

2242
01:56:33,720 --> 01:56:35,080
The last thing
I'll say about this

2243
01:56:35,080 --> 01:56:36,920
is in the upper
righthand corner there,

2244
01:56:36,920 --> 01:56:41,280
you see that single TBI
rarely exists in isolation

2245
01:56:41,280 --> 01:56:45,680
so you see their data
from a moderate severe TBI study

2246
01:56:45,680 --> 01:56:47,960
that shows that about
half of the sample

2247
01:56:47,960 --> 01:56:51,800
with a single TBI
also have repetitive head injury

2248
01:56:51,800 --> 01:56:54,680
in the context of sports,
or military service,

2249
01:56:54,680 --> 01:56:56,600
or intimate partner violence.

2250
01:56:56,600 --> 01:57:00,720
Many also had multiple
isolated TBIs.

2251
01:57:00,720 --> 01:57:04,400
So the question of how
to quantify lifetime exposure

2252
01:57:04,400 --> 01:57:07,280
in a way that reflects
clinical reality

2253
01:57:07,280 --> 01:57:09,840
will be foundational
to this area of study.

2254
01:57:09,840 --> 01:57:11,800
Next slide.

2255
01:57:11,800 --> 01:57:14,600
Similarly crucial
is the need to establish

2256
01:57:14,600 --> 01:57:17,400
and validate
a provisional definition,

2257
01:57:17,400 --> 01:57:21,080
a clinical definition
of post-TBI dementias

2258
01:57:21,080 --> 01:57:25,400
that distinguishes
chronic effects of TBI

2259
01:57:25,400 --> 01:57:29,400
from a progressive
neurodegenerative disease.

2260
01:57:29,400 --> 01:57:33,240
So because the term "dementia"
is broad

2261
01:57:33,240 --> 01:57:35,680
and has multiple
clinical definitions,

2262
01:57:35,680 --> 01:57:38,160
it has sometimes been used
to characterize

2263
01:57:38,160 --> 01:57:40,400
the acute effects of TBI

2264
01:57:40,400 --> 01:57:44,280
or the stable
chronic effects of TBI.

2265
01:57:44,280 --> 01:57:47,320
And so a definition
such as what you see here,

2266
01:57:47,320 --> 01:57:53,200
wherein post-TBI ADRD is defined
as post-recovery decline

2267
01:57:53,200 --> 01:57:58,200
really requires further study
and validation. Next.

2268
01:57:58,200 --> 01:58:00,720
Out committee felt
that longitudinal studies

2269
01:58:00,720 --> 01:58:03,880
are especially essential
to recommendation two,

2270
01:58:03,880 --> 01:58:06,480
which is to characterize
the clinical phenotype

2271
01:58:06,480 --> 01:58:10,240
and the phenotypic heterogeneity
and clinical course,

2272
01:58:10,240 --> 01:58:12,680
the protective factors

2273
01:58:12,680 --> 01:58:17,560
and the effect modifiers
of post-TBI ADRDs.

2274
01:58:17,560 --> 01:58:19,200
It may be especially informative

2275
01:58:19,200 --> 01:58:22,400
to study people prospectively
from the time of injury

2276
01:58:22,400 --> 01:58:24,800
to understand
the primary pathology,

2277
01:58:24,800 --> 01:58:27,040
the secondary injury
processes,

2278
01:58:27,040 --> 01:58:30,880
and the long-term outcomes
as they evolve over time.

2279
01:58:30,880 --> 01:58:32,320
The TBI model systems,

2280
01:58:32,320 --> 01:58:35,160
for example the track TBI Study
and Evolve Study

2281
01:58:35,160 --> 01:58:37,640
are three examples
of these prospective studies

2282
01:58:37,640 --> 01:58:39,880
with complementary strengths.

2283
01:58:39,880 --> 01:58:42,240
So the Evolve Study,
for example,

2284
01:58:42,240 --> 01:58:45,080
led by Christine McDonald
follows active duty

2285
01:58:45,080 --> 01:58:47,680
military service members
from the battlefield

2286
01:58:47,680 --> 01:58:50,440
and is now approaching
a 10-year follow-up.

2287
01:58:50,440 --> 01:58:53,640
And this has uncovered
a pattern suggesting evolution

2288
01:58:53,640 --> 01:58:58,080
as opposed to a resolution
of symptoms over time.

2289
01:58:58,080 --> 01:59:01,400
The TBI model system
is the largest prospective

2290
01:59:01,400 --> 01:59:04,640
TBI outcome study
in the world.

2291
01:59:04,640 --> 01:59:06,200
But with telephone
data collection,

2292
01:59:06,200 --> 01:59:09,400
it doesn't currently
include biological markers.

2293
01:59:09,400 --> 01:59:11,400
So we have
a tremendous opportunity

2294
01:59:11,400 --> 01:59:14,360
to learn from these
types of studies.

2295
01:59:14,360 --> 01:59:19,160
Next slide.
We currently do not know

2296
01:59:19,160 --> 01:59:24,560
how post-TBI ADRD
relates to other ADRDs.

2297
01:59:24,560 --> 01:59:27,160
The studies illustrated here
suggests that older adults

2298
01:59:27,160 --> 01:59:30,040
with TBI
have more motor impairment

2299
01:59:30,040 --> 01:59:33,120
and more pronounced
neurobehavioral symptoms

2300
01:59:33,120 --> 01:59:34,360
relative to those

2301
01:59:34,360 --> 01:59:36,800
with Alzheimer's disease
in particular.

2302
01:59:36,800 --> 01:59:40,400
And on the right, you see
that compared to older adults

2303
01:59:40,400 --> 01:59:43,920
without TBI,
their cognitive profiles

2304
01:59:43,920 --> 01:59:46,000
suggest more difficulty
with executive

2305
01:59:46,000 --> 01:59:48,120
functioning
and processing speed,

2306
01:59:48,120 --> 01:59:51,080
which are hallmark
characteristics of TBI,

2307
01:59:51,080 --> 01:59:54,800
but not characteristic
of AD-type dementia.

2308
01:59:54,800 --> 01:59:57,800
Next slide.

2309
01:59:57,800 --> 02:00:01,640
Phenotyping a heterogenous
multi-ideology disease

2310
02:00:01,640 --> 02:00:04,000
process is no small task,

2311
02:00:04,000 --> 02:00:07,600
and efforts to-date
were recently summarized

2312
02:00:07,600 --> 02:00:10,680
in this brain trauma
blueprint paper

2313
02:00:10,680 --> 02:00:13,640
that was just
published last year.

2314
02:00:13,640 --> 02:00:15,160
These studies do suggest

2315
02:00:15,160 --> 02:00:19,240
that clinically-distinguishable
subtypes exist.

2316
02:00:19,240 --> 02:00:22,680
And on the right, we see
evidence of a TBI phenotype

2317
02:00:22,680 --> 02:00:28,160
that overlaps with clinical
correlates of AD and FTD

2318
02:00:28,160 --> 02:00:30,400
in a sample
of post-9/11 veterans

2319
02:00:30,400 --> 02:00:34,960
with early onset dementia.
Next slide.

2320
02:00:34,960 --> 02:00:38,280
Central to recommendation two
is the need to develop

2321
02:00:38,280 --> 02:00:42,520
and validate
post-TBI ADRD biomarkers

2322
02:00:42,520 --> 02:00:47,560
to non-invasively
identify progressive pathologies

2323
02:00:47,560 --> 02:00:51,480
and to monitor clinical
disease progression over time.

2324
02:00:51,480 --> 02:00:53,840
The radiology biomarkers
at the top

2325
02:00:53,840 --> 02:00:56,640
are used for more acute
TBI studies

2326
02:00:56,640 --> 02:01:00,400
that can inform studies
of the evolution of TBI

2327
02:01:00,400 --> 02:01:04,800
in the transition
to recovery or to decline.

2328
02:01:04,800 --> 02:01:08,960
Like other dementias, TBI is not
a single disease process

2329
02:01:08,960 --> 02:01:11,440
with the unified path
of physiological mechanisms.

2330
02:01:11,440 --> 02:01:15,480
So characterizing the acute
and chronic changes

2331
02:01:15,480 --> 02:01:19,160
ideally in longitudinal studies
will be highly informative.

2332
02:01:21,400 --> 02:01:25,160
Although substantial progress
has been made in acute

2333
02:01:25,160 --> 02:01:29,480
diagnostic
and prognostic markers for TBI,

2334
02:01:29,480 --> 02:01:32,200
there has been relatively
little investigation

2335
02:01:32,200 --> 02:01:37,000
into biomarkers of
posttraumatic neurodegeneration.

2336
02:01:37,000 --> 02:01:39,880
The top candidates
though are those

2337
02:01:39,880 --> 02:01:44,400
that can detect traumatic
and neuroinflammatory injury,

2338
02:01:44,400 --> 02:01:46,600
and that can also
detect the onset

2339
02:01:46,600 --> 02:01:50,640
and progression of
neurodegenerative diseases.

2340
02:01:50,640 --> 02:01:54,000
As you can see in the figure
on the right,

2341
02:01:54,000 --> 02:01:56,160
our colleague studying
Alzheimer's disease

2342
02:01:56,160 --> 02:01:58,360
has found
excellent correspondence

2343
02:01:58,360 --> 02:02:02,200
between blood
CSF and PET markers.

2344
02:02:02,200 --> 02:02:05,360
And this appears
to provide information

2345
02:02:05,360 --> 02:02:07,920
on disease progression
of pathologies

2346
02:02:07,920 --> 02:02:13,440
that are also known to be
implicated in post-TBI ADRD.

2347
02:02:13,440 --> 02:02:17,360
So these candidate markers
really require further study

2348
02:02:17,360 --> 02:02:21,800
in the chronic stages
following TBI.

2349
02:02:21,800 --> 02:02:25,240
Finally, the need to recruit
diverse samples

2350
02:02:25,240 --> 02:02:27,400
warrants
particular mention here.

2351
02:02:27,400 --> 02:02:31,880
This includes men
and women with repetitive,

2352
02:02:31,880 --> 02:02:37,800
or isolated, or very diverse
injury exposure histories.

2353
02:02:37,800 --> 02:02:40,680
It includes
underrepresented minorities.

2354
02:02:40,680 --> 02:02:45,400
It includes, again, a range
of head trauma exposures,

2355
02:02:45,400 --> 02:02:47,600
mechanisms, and chronicity.

2356
02:02:47,600 --> 02:02:51,040
And it includes --
it requires clinic

2357
02:02:51,040 --> 02:02:54,120
and community-based
recruitment.

2358
02:02:54,120 --> 02:02:57,600
Our colleagues who have been
studying dementia for decades

2359
02:02:57,600 --> 02:03:00,640
have demonstrated
that those who are recruited

2360
02:03:00,640 --> 02:03:03,800
in the community differ
in important ways from those

2361
02:03:03,800 --> 02:03:07,080
who are recruited
from clinic-based settings.

2362
02:03:07,080 --> 02:03:10,800
And we expect those differences
to, if anything,

2363
02:03:10,800 --> 02:03:14,280
to be more pronounced
in the study of post-TBI

2364
02:03:14,280 --> 02:03:20,280
ADRD given the high rates of TBI
in homeless shelters,

2365
02:03:20,280 --> 02:03:23,880
substance use disorder
treatment settings, prisons,

2366
02:03:23,880 --> 02:03:27,000
and among multiply
marginalized populations.

2367
02:03:27,000 --> 02:03:31,080
So we need to ensure
that studies of post-TBI

2368
02:03:31,080 --> 02:03:35,400
AD and ADRD include
representative samples

2369
02:03:35,400 --> 02:03:39,840
of individuals living with TBI.
With that, next slide,

2370
02:03:39,840 --> 02:03:43,280
I will pass the microphone
to Dr. Dirk Keene

2371
02:03:43,280 --> 02:03:45,200
from the University
of Washington

2372
02:03:45,200 --> 02:03:48,000
who will discuss
recommendation three.

2373
02:03:50,160 --> 02:03:55,720
-Thanks, Kristin. Next slide.
Great. Next slide.

2374
02:03:55,720 --> 02:03:57,120
So these are the --

2375
02:03:57,120 --> 02:04:00,160
so recommendation three
is really a bridge

2376
02:04:00,160 --> 02:04:02,000
from the first
two recommendations

2377
02:04:02,000 --> 02:04:03,720
to the fourth
recommendation.

2378
02:04:03,720 --> 02:04:06,880
This is the recommendation
listed out

2379
02:04:06,880 --> 02:04:09,800
into the sub recommendations.
But if you go to the next slide,

2380
02:04:09,800 --> 02:04:16,320
I've tried to summarize
to capture the, you know,

2381
02:04:16,320 --> 02:04:18,400
the recommendations
by its essence.

2382
02:04:18,400 --> 02:04:21,440
And really what recommendation
three is about

2383
02:04:21,440 --> 02:04:24,400
is supporting and building
research infrastructure

2384
02:04:24,400 --> 02:04:29,200
to make sure that we
take advantage of the,

2385
02:04:29,200 --> 02:04:32,680
of what's come before us
especially with AD

2386
02:04:32,680 --> 02:04:38,320
and other ADRD research
to understand

2387
02:04:38,320 --> 02:04:45,880
and bridge what we know about AD
and ADRD for TBI-related ADRD.

2388
02:04:45,880 --> 02:04:48,400
And so we need to study
representative cohort.

2389
02:04:48,400 --> 02:04:50,840
That can't be
emphasized enough.

2390
02:04:50,840 --> 02:04:55,880
At every step,
we need to be studying

2391
02:04:55,880 --> 02:05:02,320
the breadth of TBI exposure
from ethnic and socioeconomic,

2392
02:05:02,320 --> 02:05:03,840
and other backgrounds.

2393
02:05:03,840 --> 02:05:07,440
We need to studying
the representative samples.

2394
02:05:07,440 --> 02:05:10,960
We need to build and enhance
our biorepositories,

2395
02:05:10,960 --> 02:05:13,000
that's from a brain
biorepositories,

2396
02:05:13,000 --> 02:05:15,200
biofluid biorepositories,

2397
02:05:15,200 --> 02:05:16,960
and then develop
standardized approaches.

2398
02:05:16,960 --> 02:05:19,720
So in the next few slides,
I'll go over each of these

2399
02:05:19,720 --> 02:05:23,240
in a little bit more depth.
Next.

2400
02:05:23,240 --> 02:05:29,240
So the Alzheimer's Disease
Research Centers have --

2401
02:05:29,240 --> 02:05:34,160
it's a really robust
multi-center network

2402
02:05:34,160 --> 02:05:36,800
that's been --
that was established by NIA

2403
02:05:36,800 --> 02:05:38,280
over 30 years ago.

2404
02:05:38,280 --> 02:05:40,280
On the right,
you can see that states

2405
02:05:40,280 --> 02:05:41,840
that have one or more centers.

2406
02:05:41,840 --> 02:05:44,480
The light blue ones
are the exploratory centers.

2407
02:05:44,480 --> 02:05:46,000
This program
continues to build.

2408
02:05:46,000 --> 02:05:50,120
And each center has really
robust infrastructure

2409
02:05:50,120 --> 02:05:52,760
developed
along the lines of cores

2410
02:05:52,760 --> 02:05:56,640
that have led the way
in helping us understand

2411
02:05:56,640 --> 02:05:59,240
how to develop
prospective studies

2412
02:05:59,240 --> 02:06:04,160
and these multimodal approaches
to study disease

2413
02:06:04,160 --> 02:06:06,400
from even
pre-symptomatic levels

2414
02:06:06,400 --> 02:06:09,200
all the way through
to brain donation

2415
02:06:09,200 --> 02:06:10,680
and neuropathological studies.

2416
02:06:10,680 --> 02:06:16,080
And so I think TBI ADRD
can really learn

2417
02:06:16,080 --> 02:06:18,600
from what's been done
in Alzheimer's disease

2418
02:06:18,600 --> 02:06:21,800
and Parkinson's disease,
these established networks.

2419
02:06:21,800 --> 02:06:23,880
And I think
the Alzheimer Center Network

2420
02:06:23,880 --> 02:06:26,680
is a prime example
of how AD can leverage

2421
02:06:26,680 --> 02:06:29,080
that infrastructure
and that expertise.

2422
02:06:29,080 --> 02:06:31,160
And then also
there's other resources

2423
02:06:31,160 --> 02:06:34,160
that have been built up
around other focuses,

2424
02:06:34,160 --> 02:06:35,520
other areas of study.

2425
02:06:35,520 --> 02:06:37,840
The National Alzheimer's
Coordinating Center

2426
02:06:37,840 --> 02:06:40,640
is a centralized data repository
for the Alzheimer's Centers

2427
02:06:40,640 --> 02:06:45,200
and Alzheimer's Disease Research
Participant Data.

2428
02:06:45,200 --> 02:06:48,640
The National Centralized
Repository for AD,

2429
02:06:48,640 --> 02:06:50,600
and Related Dementias NCRAD

2430
02:06:50,600 --> 02:06:54,800
is really leading the way
along with other centers

2431
02:06:54,800 --> 02:07:01,400
on biospecimen storage
sharing and characterization.

2432
02:07:01,400 --> 02:07:03,600
And then there's
a multitude of other

2433
02:07:03,600 --> 02:07:05,600
really well-established
studies in ADRD

2434
02:07:05,600 --> 02:07:10,480
that I think TBI research
can leverage and build upon

2435
02:07:10,480 --> 02:07:12,200
so that we're not
reinventing the wheel,

2436
02:07:12,200 --> 02:07:15,800
so that we're taking advantage
of the incredible investment

2437
02:07:15,800 --> 02:07:21,200
that's been made and it's
being made for TBI-related ADRD.

2438
02:07:21,200 --> 02:07:27,440
Next slide. It's really critical
to study representative cohorts,

2439
02:07:27,440 --> 02:07:29,640
and to study those
cohorts prospectively.

2440
02:07:29,640 --> 02:07:32,400
And so I've listed some
community-based cohorts there.

2441
02:07:32,400 --> 02:07:33,720
There's many others.

2442
02:07:33,720 --> 02:07:36,960
But the idea is that
you need to start,

2443
02:07:36,960 --> 02:07:39,880
you need to start at
the very beginning with cohorts

2444
02:07:39,880 --> 02:07:44,000
that you can characterize
clinically, with biomarkers,

2445
02:07:44,000 --> 02:07:46,400
all the way through as the --

2446
02:07:46,400 --> 02:07:49,720
as TBI-related ADRD
and other diseases advance.

2447
02:07:49,720 --> 02:07:53,040
And so these community-based
cohorts are really critical

2448
02:07:53,040 --> 02:07:56,520
in representing the diversity of
traumatic brain injury exposure,

2449
02:07:56,520 --> 02:07:59,840
the diversity of the population
that we're studying

2450
02:07:59,840 --> 02:08:03,600
so that we have inclusion
and can understand differences

2451
02:08:03,600 --> 02:08:06,600
and similarities
across the population.

2452
02:08:06,600 --> 02:08:08,400
And then what I think
is really important

2453
02:08:08,400 --> 02:08:12,200
is to take
TBI-related expertise

2454
02:08:12,200 --> 02:08:16,960
and build that into existing
and prospective ADRD studies.

2455
02:08:16,960 --> 02:08:19,440
And the same
goes for TBI studies

2456
02:08:19,440 --> 02:08:21,280
to really leverage what we know

2457
02:08:21,280 --> 02:08:23,600
and what we've learned
through ADRD,

2458
02:08:23,600 --> 02:08:26,000
through our Alzheimer's center
and other centers

2459
02:08:26,000 --> 02:08:28,160
to build that
into our TBI-related studies

2460
02:08:28,160 --> 02:08:30,320
so that we're talking
the same language

2461
02:08:30,320 --> 02:08:32,880
across these different cohorts.
Next.

2462
02:08:35,680 --> 02:08:37,320
Kristen mentioned
Delayed Effects

2463
02:08:37,320 --> 02:08:40,600
of Traumatic Brain
Injury study.

2464
02:08:40,600 --> 02:08:43,920
It's a prime example, I think,
of a multimodal approach

2465
02:08:43,920 --> 02:08:46,800
from the time a person enrolls
all the way through

2466
02:08:46,800 --> 02:08:51,720
to the time a person dies,
if that's the case.

2467
02:08:51,720 --> 02:08:53,760
And collecting as much data
along the way

2468
02:08:53,760 --> 02:08:56,560
so that we can relate
the different biofluid,

2469
02:08:56,560 --> 02:09:00,200
and cognitive, and other
biomarkers to exposure history.

2470
02:09:00,200 --> 02:09:03,800
And also moving forward
to neuroimaging

2471
02:09:03,800 --> 02:09:08,120
and also neuropathology markers
so that we can link the data

2472
02:09:08,120 --> 02:09:12,800
from one aspect of a study
participant all the way back.

2473
02:09:12,800 --> 02:09:16,440
So that we can understand
during life what underlies

2474
02:09:16,440 --> 02:09:21,760
the kinds of cognitive deficits
or behavioral abnormalities

2475
02:09:21,760 --> 02:09:24,080
that are happening in people
that have suffered a TBI.

2476
02:09:24,080 --> 02:09:29,080
And how does that relate to
neurodegenerative disease. Next.

2477
02:09:29,080 --> 02:09:32,360
We need to build and enhance
brain bio repositories.

2478
02:09:32,360 --> 02:09:34,760
Again, this is
the Connect TBI group,

2479
02:09:34,760 --> 02:09:38,080
which is, I think,
one very good example,

2480
02:09:38,080 --> 02:09:39,640
along with the BU group,

2481
02:09:39,640 --> 02:09:43,040
of how to leverage existing
brain bio repositories

2482
02:09:43,040 --> 02:09:45,680
with a focus on
TBI-related neurodegeneration.

2483
02:09:45,680 --> 02:09:47,600
Bringing resources together

2484
02:09:47,600 --> 02:09:50,800
that previously
hadn't been brought together

2485
02:09:50,800 --> 02:09:53,800
to try to understand
what the relationship

2486
02:09:53,800 --> 02:09:56,720
between TBI exposure
and neurodegeneration is.

2487
02:09:56,720 --> 02:09:59,160
There's a number of different
other --

2488
02:09:59,160 --> 02:10:00,600
there's a lot of
infrastructure out there

2489
02:10:00,600 --> 02:10:03,160
that we can use
to build this together.

2490
02:10:03,160 --> 02:10:06,240
And ultimately use
that experience to --

2491
02:10:06,240 --> 02:10:10,000
into prospective cohort
studies where we can tailor

2492
02:10:10,000 --> 02:10:13,040
our characterization of folks
all the way through.

2493
02:10:13,040 --> 02:10:20,200
Using the TBI
and ADRD-related assessments

2494
02:10:20,200 --> 02:10:22,000
from the time
a person enters a study,

2495
02:10:22,000 --> 02:10:24,040
all the way through
their different neuroimaging

2496
02:10:24,040 --> 02:10:27,760
and other biomarker studies,
through the end of the study.

2497
02:10:27,760 --> 02:10:30,400
Next.

2498
02:10:30,400 --> 02:10:33,080
And so we need to enhance
brain bio repositories.

2499
02:10:33,080 --> 02:10:35,720
I use the Brain Initiative
here as an example.

2500
02:10:35,720 --> 02:10:38,040
The Brain Initiative
is really leading the way.

2501
02:10:38,040 --> 02:10:41,960
It's a major effort from NIH
to understand the structure,

2502
02:10:41,960 --> 02:10:45,840
and connectivity, and function
of the normal brain.

2503
02:10:45,840 --> 02:10:51,600
They have pioneered
new methodologies

2504
02:10:51,600 --> 02:10:54,280
to study human brain tissue

2505
02:10:54,280 --> 02:10:57,920
and those efforts I think
we need to work from

2506
02:10:57,920 --> 02:11:00,720
and learn from those efforts
when we study ADRD,

2507
02:11:00,720 --> 02:11:03,520
and specifically
TBI-related ADRD.

2508
02:11:03,520 --> 02:11:08,000
So that we're maximizing
the investment of the NIH

2509
02:11:08,000 --> 02:11:10,560
and other stakeholders
in this research.

2510
02:11:10,560 --> 02:11:13,600
And doing everything we can
for every person that donates

2511
02:11:13,600 --> 02:11:16,560
their brain to learn as much
as we can from their brain.

2512
02:11:16,560 --> 02:11:18,600
And I think this is one example.

2513
02:11:18,600 --> 02:11:19,920
Many of
the different brain banks

2514
02:11:19,920 --> 02:11:22,200
are pioneering
new methodologies.

2515
02:11:22,200 --> 02:11:25,000
And to the extent that we can
learn as much as possible

2516
02:11:25,000 --> 02:11:28,400
from each one of these samples
by studying cohort people

2517
02:11:28,400 --> 02:11:31,160
who have been studied
all the way during life

2518
02:11:31,160 --> 02:11:32,680
with well-known exposures.

2519
02:11:32,680 --> 02:11:35,400
And then maximizing
the technological approaches

2520
02:11:35,400 --> 02:11:38,800
that we have to understanding
the different pathways

2521
02:11:38,800 --> 02:11:41,960
to injury and dementia
is really important.

2522
02:11:41,960 --> 02:11:46,320
Next slide.
And then to establish

2523
02:11:46,320 --> 02:11:48,240
and implement
standards for neuropathology.

2524
02:11:48,240 --> 02:11:50,600
Kristen mentioned the CDBs.

2525
02:11:50,600 --> 02:11:53,280
It's really exciting the way
this has developed.

2526
02:11:53,280 --> 02:11:58,680
So on the left, in 2012,
the National Institute on Aging

2527
02:11:58,680 --> 02:12:01,400
and its Alzheimer's Association
guidelines

2528
02:12:01,400 --> 02:12:07,000
for the pathological
assessment of AD were published.

2529
02:12:07,000 --> 02:12:08,760
And those really sent
the standard

2530
02:12:08,760 --> 02:12:14,240
for how neuropathologists talk
to each other about what the --

2531
02:12:14,240 --> 02:12:18,320
what each brain
that they're studying shows.

2532
02:12:18,320 --> 02:12:21,880
The NINDS and NIBIB
consensus meetings,

2533
02:12:21,880 --> 02:12:24,720
both the first
and second for CTE,

2534
02:12:24,720 --> 02:12:27,040
really built on this in the fact

2535
02:12:27,040 --> 02:12:29,880
that we took
those recommendations

2536
02:12:29,880 --> 02:12:32,800
for AD and ADRD neuropath.

2537
02:12:32,800 --> 02:12:37,360
And built on those for the CTE
consensus recommendation

2538
02:12:37,360 --> 02:12:42,480
so that we can refer back
to brain biorepositories

2539
02:12:42,480 --> 02:12:44,080
even 20,
30 years ago

2540
02:12:44,080 --> 02:12:48,040
with similar sampling
processes and assessments.

2541
02:12:48,040 --> 02:12:51,880
To sort of leverage that so that
we're understanding TBI

2542
02:12:51,880 --> 02:12:54,520
in the context of
neurodegenerative disease.

2543
02:12:54,520 --> 02:12:58,680
And then, finally, thanks
to a great group of people,

2544
02:12:58,680 --> 02:13:01,400
the accommodated elements
for neuropathology

2545
02:13:01,400 --> 02:13:05,040
that Kristen mentions
are essentially done

2546
02:13:05,040 --> 02:13:07,920
and ready
for people to start using.

2547
02:13:07,920 --> 02:13:10,360
So we really need,
as a community,

2548
02:13:10,360 --> 02:13:14,800
to be hopefully implementing
and using these recommendations

2549
02:13:14,800 --> 02:13:16,680
so that, again,
we can talk to each other.

2550
02:13:16,680 --> 02:13:18,560
So that the Alzheimer's
Disease researcher

2551
02:13:18,560 --> 02:13:20,200
can talk to the TBI researcher

2552
02:13:20,200 --> 02:13:22,320
and we're all using
the same language.

2553
02:13:22,320 --> 02:13:26,600
Importantly, in the CDEs,
I just want to highlight,

2554
02:13:26,600 --> 02:13:30,000
we intentionally built
in the possibility, too,

2555
02:13:30,000 --> 02:13:33,440
for flexibility, so that
there's a common baseline.

2556
02:13:33,440 --> 02:13:35,760
But it opens up the --

2557
02:13:35,760 --> 02:13:40,680
it encourages different
biorepositories to study areas

2558
02:13:40,680 --> 02:13:42,120
that they have expertise in,

2559
02:13:42,120 --> 02:13:43,960
areas that may contribute
down the road

2560
02:13:43,960 --> 02:13:45,680
to new approaches to this.

2561
02:13:45,680 --> 02:13:49,360
Which I think is really
exciting for these CDEs.

2562
02:13:49,360 --> 02:13:51,360
Next slide.

2563
02:13:51,360 --> 02:13:52,560
-Two minutes remaining.

2564
02:13:52,560 --> 02:13:58,120
-Got you. Whoops.

2565
02:14:00,400 --> 02:14:04,560
So the last thing is to leverage
and build infrastructure

2566
02:14:04,560 --> 02:14:06,200
to promote tissue
and data sharing.

2567
02:14:06,200 --> 02:14:08,600
So this slide is just
highlighting what we can do

2568
02:14:08,600 --> 02:14:11,400
once a person
has donated their brain.

2569
02:14:11,400 --> 02:14:14,200
We can perform ex vivo
neuroimaging,

2570
02:14:14,200 --> 02:14:16,080
extensive sampling.

2571
02:14:16,080 --> 02:14:17,800
We have the ability
in many groups

2572
02:14:17,800 --> 02:14:21,200
are imaging
and scanning microscope slides

2573
02:14:21,200 --> 02:14:23,600
and there are multiple
different repositories

2574
02:14:23,600 --> 02:14:25,680
available to share
this information.

2575
02:14:25,680 --> 02:14:28,160
We need to really promote
the ability for each of us

2576
02:14:28,160 --> 02:14:29,760
to see what each other is doing

2577
02:14:29,760 --> 02:14:31,600
so that we can learn
from each other

2578
02:14:31,600 --> 02:14:33,600
and maximize the investment
of the donors

2579
02:14:33,600 --> 02:14:37,600
and the stakeholders.
Next slide.

2580
02:14:37,600 --> 02:14:41,920
So this is just highlighting
the really critical relevance

2581
02:14:41,920 --> 02:14:45,960
of human brain donation
and human research

2582
02:14:45,960 --> 02:14:49,560
in helping us to eventually
establish mechanism,

2583
02:14:49,560 --> 02:14:51,160
and that's a mouse brain
on the bottom.

2584
02:14:51,160 --> 02:14:54,000
And so what we can learn
from human brain

2585
02:14:54,000 --> 02:14:58,760
is what's relevant
to the disease or the impairment

2586
02:14:58,760 --> 02:15:00,440
and we can generate hypotheses.

2587
02:15:00,440 --> 02:15:02,640
But the only way we can
go test those hypotheses,

2588
02:15:02,640 --> 02:15:05,880
and establish mechanism, and
ultimately develop treatments

2589
02:15:05,880 --> 02:15:10,320
to test in back in people is
with these experimental systems.

2590
02:15:10,320 --> 02:15:11,840
Next slide.

2591
02:15:11,840 --> 02:15:14,680
And so human neuropathology
and these --

2592
02:15:14,680 --> 02:15:18,960
and from really well-studied
and representative diverse

2593
02:15:18,960 --> 02:15:21,080
cohorts is just essential.

2594
02:15:21,080 --> 02:15:24,000
And neuropathology
can provide a bridge

2595
02:15:24,000 --> 02:15:26,680
from those outstanding
representative cohort --

2596
02:15:26,680 --> 02:15:28,600
prospective cohort studies.

2597
02:15:28,600 --> 02:15:31,000
Ultimately to where we can
understand mechanisms

2598
02:15:31,000 --> 02:15:32,800
and develop treatments.

2599
02:15:32,800 --> 02:15:35,080
And so with that,
I'm going to hand it off

2600
02:15:35,080 --> 02:15:39,800
to Dr. Vicky Johnson from
the University of Pennsylvania.

2601
02:15:39,800 --> 02:15:41,640
-Thanks, Dirk.
Hi, everyone,

2602
02:15:41,640 --> 02:15:43,760
and thank you,
also, to the organizers.

2603
02:15:43,760 --> 02:15:47,680
It's a pleasure to be here
and participate in this summit.

2604
02:15:47,680 --> 02:15:49,200
Next slide, please.

2605
02:15:49,200 --> 02:15:53,760
So first, I don't have
any disclosures,

2606
02:15:53,760 --> 02:15:56,920
and I'm going to talk about
recommendation for Priority 4.

2607
02:15:56,920 --> 02:16:00,360
Which is to promote
the basic translational research

2608
02:16:00,360 --> 02:16:03,480
to elucidate the mechanistic
pathways, development,

2609
02:16:03,480 --> 02:16:07,320
and progression of post-TBI
AD/ADRD neuropathologies.

2610
02:16:07,320 --> 02:16:10,160
And their associations
with clinical symptoms.

2611
02:16:10,160 --> 02:16:13,080
Next slide, please.
So I'm just going to start

2612
02:16:13,080 --> 02:16:14,840
with a little bit
of background about TBI.

2613
02:16:14,840 --> 02:16:16,520
And some of
the important considerations

2614
02:16:16,520 --> 02:16:18,800
that are going to be
necessary in understanding

2615
02:16:18,800 --> 02:16:22,280
how TBI might ultimately
lead to neurodegeneration.

2616
02:16:22,280 --> 02:16:25,040
So TBI is caused by
some mechanical event

2617
02:16:25,040 --> 02:16:26,800
resulting in trauma
to the brain.

2618
02:16:26,800 --> 02:16:29,720
We often talk about it like
it's one disease, one disorder,

2619
02:16:29,720 --> 02:16:32,440
but in reality,
the acute pathologies of TBI

2620
02:16:32,440 --> 02:16:34,800
are really very diverse
and complex.

2621
02:16:34,800 --> 02:16:39,200
And you can see here some
examples of different CT scans,

2622
02:16:39,200 --> 02:16:42,840
all with displaying very
different types of injuries.

2623
02:16:42,840 --> 02:16:44,960
But importantly, all falling
into that category

2624
02:16:44,960 --> 02:16:47,080
of severe TBI.

2625
02:16:47,080 --> 02:16:48,920
There's also a spectrum
of severity.

2626
02:16:48,920 --> 02:16:50,720
We've heard about
repetitive mild TBI

2627
02:16:50,720 --> 02:16:54,000
as a risk factor
for later neurodegeneration.

2628
02:16:54,000 --> 02:16:57,200
And the pathophysiology of
or what's happening in the brain

2629
02:16:57,200 --> 02:16:59,200
in mild TBI even acutely

2630
02:16:59,200 --> 02:17:02,000
and even following very
low-level repetitive exposures

2631
02:17:02,000 --> 02:17:05,120
is something that's far
less-well understood.

2632
02:17:05,120 --> 02:17:07,400
So in summation,
TBI is really heterogeneous

2633
02:17:07,400 --> 02:17:13,080
with a wide spectrum in both the
nature and severity of injury.

2634
02:17:13,080 --> 02:17:15,720
Next slide, please.
So what we do know,

2635
02:17:15,720 --> 02:17:18,040
at least in the more
severe forms of injury,

2636
02:17:18,040 --> 02:17:19,800
is that there are
evolving pathologies

2637
02:17:19,800 --> 02:17:21,680
over a temporal course.

2638
02:17:21,680 --> 02:17:23,480
There are the acute
primary pathologies

2639
02:17:23,480 --> 02:17:25,600
directly related
to the mechanical injury.

2640
02:17:25,600 --> 02:17:28,680
For example, this might be
direct perturbation

2641
02:17:28,680 --> 02:17:30,280
of the vasculature

2642
02:17:30,280 --> 02:17:33,400
resulting in hemorrhage
or direct injury to neurons

2643
02:17:33,400 --> 02:17:35,920
and axons causing things
like traumatic axonal injury.

2644
02:17:35,920 --> 02:17:37,800
And what we know
is that this can lead

2645
02:17:37,800 --> 02:17:41,360
to really very complex and
diverse secondary pathologies.

2646
02:17:41,360 --> 02:17:44,280
And these some of which
are listed here of being studied

2647
02:17:44,280 --> 02:17:47,800
over many years both clinically
and experimentally.

2648
02:17:47,800 --> 02:17:49,200
And what we've come
to appreciate

2649
02:17:49,200 --> 02:17:51,280
is that some of these
secondary processes

2650
02:17:51,280 --> 02:17:53,760
can occur over many weeks

2651
02:17:53,760 --> 02:17:57,360
and really quite protracted
periods of time post-injury.

2652
02:17:57,360 --> 02:18:00,120
And then, of course, what we're
interested in here today

2653
02:18:00,120 --> 02:18:03,080
is that some of these
individuals, certainly not all,

2654
02:18:03,080 --> 02:18:08,880
who have chronic pathologies,
including those which are --

2655
02:18:08,880 --> 02:18:12,600
encompass AD and ADRD-associated
pathologies.

2656
02:18:12,600 --> 02:18:13,880
And I think important
to remember

2657
02:18:13,880 --> 02:18:15,600
over that same time frame,

2658
02:18:15,600 --> 02:18:18,440
there may very well be processes
of recovery or reorganization

2659
02:18:18,440 --> 02:18:22,320
that are also occurring in
the brain in response to injury.

2660
02:18:22,320 --> 02:18:25,080
And critically,
and as Kristen mentioned,

2661
02:18:25,080 --> 02:18:27,040
is perhaps what's
a little bit different

2662
02:18:27,040 --> 02:18:28,520
from other neurodegenerative
disease,

2663
02:18:28,520 --> 02:18:31,120
at least in the case
of more severe injuries.

2664
02:18:31,120 --> 02:18:35,400
Is that we have a clear start
point or time zero essentially

2665
02:18:35,400 --> 02:18:37,960
when we know that
this specific event has occurred

2666
02:18:37,960 --> 02:18:39,440
and I put an individual

2667
02:18:39,440 --> 02:18:42,800
on a pathway towards
delayed neurodegeneration.

2668
02:18:42,800 --> 02:18:44,320
What we don't really have
a great understanding of

2669
02:18:44,320 --> 02:18:47,040
is if and how this relates
to the nature, extent,

2670
02:18:47,040 --> 02:18:49,560
and evolution of these
earlier pathologies.

2671
02:18:49,560 --> 02:18:54,600
Next slide. So with respect
to the neuropathology,

2672
02:18:54,600 --> 02:18:57,880
there's been a lot of focus
on type pathologies,

2673
02:18:57,880 --> 02:18:59,600
but I think
it's important to note

2674
02:18:59,600 --> 02:19:03,160
that through various different
cohorts, K series, descriptions.

2675
02:19:03,160 --> 02:19:05,880
And some individuals
fall into the eye

2676
02:19:05,880 --> 02:19:09,400
of various other pathologies
have been described.

2677
02:19:09,400 --> 02:19:13,080
Including amyloid-beta,
TDP 43 proteinopathies,

2678
02:19:13,080 --> 02:19:16,760
vascular pathologies,
chronic inflammatory processes,

2679
02:19:16,760 --> 02:19:21,600
axonal degeneration, axonal and
atrophic processes in the brain.

2680
02:19:21,600 --> 02:19:23,560
And a big question around this
is what we refer

2681
02:19:23,560 --> 02:19:25,640
to as the clinical
pathological correlation.

2682
02:19:25,640 --> 02:19:27,600
So what aspects
of these pathologies

2683
02:19:27,600 --> 02:19:28,960
are important contributors

2684
02:19:28,960 --> 02:19:31,560
to the clinical symptoms
and clinical progression

2685
02:19:31,560 --> 02:19:34,200
that Kristen has
so nicely described?

2686
02:19:34,200 --> 02:19:38,440
And what do these pathologies
potentially interact

2687
02:19:38,440 --> 02:19:39,880
in some way?

2688
02:19:39,880 --> 02:19:41,960
And another important question
is whether

2689
02:19:41,960 --> 02:19:43,800
and in what way
these various pathologies

2690
02:19:43,800 --> 02:19:47,400
relate to the number,
severity, and types of TBI.

2691
02:19:47,400 --> 02:19:50,160
And perhaps other factors
such as age at injury.

2692
02:19:50,160 --> 02:19:55,440
So there has been some progress
in this regard

2693
02:19:55,440 --> 02:19:57,800
and examining
these various questions.

2694
02:19:57,800 --> 02:20:00,080
And as part of our
recommendation as shown here,

2695
02:20:00,080 --> 02:20:02,200
the committee felt
it's important to sort of

2696
02:20:02,200 --> 02:20:04,400
further characterize
and advance our understanding

2697
02:20:04,400 --> 02:20:06,840
of how the various aspects
of these pathologies.

2698
02:20:06,840 --> 02:20:08,720
And their potential
interactions contribute

2699
02:20:08,720 --> 02:20:11,640
to the clinical
manifestations after a TBI.

2700
02:20:11,640 --> 02:20:14,080
And importantly, also how
the TBI exposure history,

2701
02:20:14,080 --> 02:20:17,080
which has its own complexities,

2702
02:20:17,080 --> 02:20:20,320
influences the nature
and extent of those pathologies.

2703
02:20:20,320 --> 02:20:23,240
Next slide.

2704
02:20:23,240 --> 02:20:26,200
So as I mentioned, there's been
a lot of focus on tau.

2705
02:20:26,200 --> 02:20:27,920
This was something that was
first really described

2706
02:20:27,920 --> 02:20:31,440
in postmortem examinations
of former boxers many years ago.

2707
02:20:31,440 --> 02:20:32,920
As you can see
an example of that

2708
02:20:32,920 --> 02:20:35,120
from one of these
early papers on the left.

2709
02:20:35,120 --> 02:20:37,600
And then was later described
in various cohorts since,

2710
02:20:37,600 --> 02:20:40,800
including other participants
of contact sports,

2711
02:20:40,800 --> 02:20:43,800
more severe forms of injury
earlier referred to

2712
02:20:43,800 --> 02:20:46,560
as dementia
pugilistica specific to boxers.

2713
02:20:46,560 --> 02:20:49,960
And later, the term chronic
traumatic encephalopathy,

2714
02:20:49,960 --> 02:20:51,400
or CTE [Indistinct].

2715
02:20:51,400 --> 02:20:54,240
So various aspects
of these pathologies,

2716
02:20:54,240 --> 02:21:01,560
and you can see here the paper
of the recent consensus meeting.

2717
02:21:01,560 --> 02:21:05,080
Various aspects of these
pathologies have been described

2718
02:21:05,080 --> 02:21:06,920
as being potentially distinct

2719
02:21:06,920 --> 02:21:09,680
in their morphologies
and distributions.

2720
02:21:09,680 --> 02:21:11,400
And, therefore, considered
just possibly useful

2721
02:21:11,400 --> 02:21:15,200
diagnostically in distinguishing
TBI-related neurodegeneration

2722
02:21:15,200 --> 02:21:18,360
from that of other
neurodegenerative disease.

2723
02:21:18,360 --> 02:21:22,560
And this was the papers
that outlining

2724
02:21:22,560 --> 02:21:24,960
this pathognomonic CTE lesion
that came out of that

2725
02:21:24,960 --> 02:21:29,080
NINDS-funded consensus
efforts to define CTE

2726
02:21:29,080 --> 02:21:31,840
and these type pathologies
following TBI.

2727
02:21:31,840 --> 02:21:35,520
And describes the depths
of critical sulci region.

2728
02:21:35,520 --> 02:21:38,600
So and next slide, please.

2729
02:21:38,600 --> 02:21:42,080
So there really has been
limited characterizer

2730
02:21:42,080 --> 02:21:45,480
over the broader spectrum
of post-TBI pathologies

2731
02:21:45,480 --> 02:21:46,800
that have been described

2732
02:21:46,800 --> 02:21:48,480
including
some of those described

2733
02:21:48,480 --> 02:21:50,200
as being potentially specific
to trauma.

2734
02:21:50,200 --> 02:21:52,600
And in particular
how they may be similar

2735
02:21:52,600 --> 02:21:55,400
or different
to other pathologies observed

2736
02:21:55,400 --> 02:21:57,080
and other neurodegenerative
disease

2737
02:21:57,080 --> 02:22:00,640
and perhaps better established
neurodegenerative disease.

2738
02:22:00,640 --> 02:22:02,480
And there's been
some emerging reports

2739
02:22:02,480 --> 02:22:04,040
that have started using
advanced technologies,

2740
02:22:04,040 --> 02:22:06,240
proteomic RNA-sequencing
technologies,

2741
02:22:06,240 --> 02:22:09,040
to begin to further
characterize this.

2742
02:22:09,040 --> 02:22:11,160
There's also been studies that,
including by our group,

2743
02:22:11,160 --> 02:22:13,560
to try and look
at the differences using

2744
02:22:13,560 --> 02:22:18,080
immunohistochemistry directly by
comparing to other disease.

2745
02:22:18,080 --> 02:22:19,720
And then some also
some interesting work

2746
02:22:19,720 --> 02:22:21,600
you can see on this paper
on the right here

2747
02:22:21,600 --> 02:22:23,960
from the group in Cambridge

2748
02:22:23,960 --> 02:22:25,400
looking at small
series of cases.

2749
02:22:25,400 --> 02:22:27,120
And showing potentially
unique aspects

2750
02:22:27,120 --> 02:22:32,200
in the structure of tau in CTE
as identified using cryo-EM.

2751
02:22:32,200 --> 02:22:34,600
But certainly direct
further comparisons

2752
02:22:34,600 --> 02:22:36,760
with other types
of neurodegenerative disease.

2753
02:22:36,760 --> 02:22:40,640
And these will offer potentially
important information

2754
02:22:40,640 --> 02:22:43,000
relevant to both diagnoses,

2755
02:22:43,000 --> 02:22:46,320
as well as offering
potential mechanistic insights.

2756
02:22:46,320 --> 02:22:49,720
So as such, the committee
has included recommendations

2757
02:22:49,720 --> 02:22:52,000
to apply both traditional
and advanced approaches

2758
02:22:52,000 --> 02:22:55,680
to really deeply characterize
these post-TBI neuropathologies.

2759
02:22:55,680 --> 02:22:58,240
And comparative analysis
with other NEDs

2760
02:22:58,240 --> 02:23:01,640
and neurodegenerative disorders.
Next slide.

2761
02:23:04,000 --> 02:23:07,320
So with this diversity
of and complexity

2762
02:23:07,320 --> 02:23:09,600
of the clinical and
neuropathological, it comes --

2763
02:23:09,600 --> 02:23:12,160
it starts to present
obvious challenges

2764
02:23:12,160 --> 02:23:13,920
when we start to think
about how to model

2765
02:23:13,920 --> 02:23:17,680
these processes experimentally.
Now there is an experiment

2766
02:23:17,680 --> 02:23:19,400
established in literature
on this.

2767
02:23:19,400 --> 02:23:22,400
Where various groups have worked
to see if they can introduce --

2768
02:23:22,400 --> 02:23:24,320
induce these neurodegenerative
pathologies

2769
02:23:24,320 --> 02:23:26,320
and experimental TBI models,

2770
02:23:26,320 --> 02:23:30,080
mostly with a focus
on tau and amyloid-beta.

2771
02:23:30,080 --> 02:23:31,720
And while we don't have time
to go into

2772
02:23:31,720 --> 02:23:34,840
that whole literature in detail,
to sort of summarize it

2773
02:23:34,840 --> 02:23:37,280
and saying that it really
encompasses various models,

2774
02:23:37,280 --> 02:23:40,000
established models,
the vast majority in rodents,

2775
02:23:40,000 --> 02:23:42,400
both with and without
inoculated genetic backgrounds

2776
02:23:42,400 --> 02:23:46,040
and considerable diversity
in the sort of mechanics,

2777
02:23:46,040 --> 02:23:49,280
and severity,
and approach to injury applied.

2778
02:23:49,280 --> 02:23:51,280
There's also been various
outcome measures

2779
02:23:51,280 --> 02:23:53,840
that have been examined,
some using immunohistochemistry

2780
02:23:53,840 --> 02:23:55,520
to look at pathology,
for example.

2781
02:23:55,520 --> 02:23:57,480
Others looking
at biochemical outcome,

2782
02:23:57,480 --> 02:24:00,840
biochemistry as an outcome,
looking at changes

2783
02:24:00,840 --> 02:24:03,000
and quantification
of cross-correlated tau.

2784
02:24:03,000 --> 02:24:06,080
So perhaps not surprisingly,
there's been a large range

2785
02:24:06,080 --> 02:24:08,800
in the results from those
where you can see

2786
02:24:08,800 --> 02:24:12,560
and some examples
of this work here.

2787
02:24:12,560 --> 02:24:15,880
Those where there was observed
changes in tau amyloid

2788
02:24:15,880 --> 02:24:17,600
to those where trauma
did not result

2789
02:24:17,600 --> 02:24:19,800
in the presence of pathology.

2790
02:24:19,800 --> 02:24:22,360
And even some studies
where a regression of pathology

2791
02:24:22,360 --> 02:24:26,320
was seen in models
where there was predisposition.

2792
02:24:26,320 --> 02:24:28,680
So next slide, please.

2793
02:24:28,680 --> 02:24:32,880
So the committee agreed
that really further development

2794
02:24:32,880 --> 02:24:35,200
of consistent
and reproducible models

2795
02:24:35,200 --> 02:24:37,400
that are clinically relevant.
Is going to be really important

2796
02:24:37,400 --> 02:24:40,760
advancing our understanding
of how and why TBI might be able

2797
02:24:40,760 --> 02:24:43,440
to contribute
to neurodegenerative processes.

2798
02:24:43,440 --> 02:24:45,600
With the recognition
that various aspects of this

2799
02:24:45,600 --> 02:24:47,200
are challenging.

2800
02:24:47,200 --> 02:24:50,200
Models that accurately reproduce
real-world biomechanics

2801
02:24:50,200 --> 02:24:52,280
of injury
is going to be important

2802
02:24:52,280 --> 02:24:56,160
and these are obviously
extremely diverse and complex.

2803
02:24:56,160 --> 02:24:59,120
Various aspects
of preclinical models

2804
02:24:59,120 --> 02:25:00,920
add to the challenges

2805
02:25:00,920 --> 02:25:02,920
of recapitulating
those biomechanics,

2806
02:25:02,920 --> 02:25:04,480
things like
anatomic differences,

2807
02:25:04,480 --> 02:25:06,840
brain size,
weight matter volumes.

2808
02:25:06,840 --> 02:25:08,200
And of course, we know

2809
02:25:08,200 --> 02:25:09,920
that aspects
of gyrencephalic structure,

2810
02:25:09,920 --> 02:25:11,320
these depth of cell
site pathologies

2811
02:25:11,320 --> 02:25:13,200
seem to be important.

2812
02:25:13,200 --> 02:25:16,400
So gyrencephalic structure
is something of consideration

2813
02:25:16,400 --> 02:25:18,960
when thinking
about our models.

2814
02:25:18,960 --> 02:25:20,440
Of course, we're talking
about pathologies

2815
02:25:20,440 --> 02:25:23,000
that regress over
the order of years,

2816
02:25:23,000 --> 02:25:24,560
lifespan may be important.

2817
02:25:24,560 --> 02:25:26,760
And finally, I'll just
sort of mention very briefly

2818
02:25:26,760 --> 02:25:28,800
in vitro models which have
their own complexity

2819
02:25:28,800 --> 02:25:32,120
when it comes to biomechanics.
But may play an important role

2820
02:25:32,120 --> 02:25:35,320
in addressing specific
mechanistic questions.

2821
02:25:35,320 --> 02:25:37,880
Next slide.

2822
02:25:37,880 --> 02:25:39,640
So we're dealing
with these complex

2823
02:25:39,640 --> 02:25:42,560
and heterogeneous pathologies
over a long temporal course.

2824
02:25:42,560 --> 02:25:45,000
And our group felt
with the data, the human data,

2825
02:25:45,000 --> 02:25:47,000
which is still very much
being characterized.

2826
02:25:47,000 --> 02:25:50,000
And we've heard of the efforts
to do that,

2827
02:25:50,000 --> 02:25:54,120
including data such
as biomechanics data,

2828
02:25:54,120 --> 02:25:56,520
neuropathology data,
clinical phenotyping data.

2829
02:25:56,520 --> 02:25:58,240
Are going to be really
critical for further

2830
02:25:58,240 --> 02:26:01,000
developing
our quantic phase models of TBI

2831
02:26:01,000 --> 02:26:02,920
and to inform us really
what is important

2832
02:26:02,920 --> 02:26:05,440
to be modeling
and to be relevant.

2833
02:26:05,440 --> 02:26:08,320
And then, it's likely
that a range of models

2834
02:26:08,320 --> 02:26:11,360
will be helpful in
addressing specific questions.

2835
02:26:11,360 --> 02:26:13,120
And of course,
the infrastructure building

2836
02:26:13,120 --> 02:26:16,880
that's being described
and Recommendations 1, 2, and 3

2837
02:26:16,880 --> 02:26:19,440
are going to be critical for
facilitating those mechanistic

2838
02:26:19,440 --> 02:26:22,040
and translational priorities.

2839
02:26:22,040 --> 02:26:26,080
So here, the recommendation was
to really promote collaboration,

2840
02:26:26,080 --> 02:26:27,680
as Dirk sort of mentioned,

2841
02:26:27,680 --> 02:26:30,040
as well, between clinical
and translational researchers

2842
02:26:30,040 --> 02:26:31,520
to accelerate
the development

2843
02:26:31,520 --> 02:26:34,560
of these
clinically-relevant TBI models.

2844
02:26:34,560 --> 02:26:38,680
And my last slide here,
if we move forward one,

2845
02:26:38,680 --> 02:26:41,800
is just to mention
this idea of resilience.

2846
02:26:41,800 --> 02:26:44,920
We know that many people
with a history of trauma TBI,

2847
02:26:44,920 --> 02:26:47,200
including even
very severe injuries

2848
02:26:47,200 --> 02:26:50,400
or highly-repetitive exposures,
for example, in boxers.

2849
02:26:50,400 --> 02:26:53,440
Don't develop CTE or trauma-
related neurodegeneration

2850
02:26:53,440 --> 02:26:55,560
or progressive decline.

2851
02:26:55,560 --> 02:26:57,440
And understanding
why this might be might

2852
02:26:57,440 --> 02:26:58,800
be helpful and informative.

2853
02:26:58,800 --> 02:27:01,160
And we can think about that
in several ways.

2854
02:27:01,160 --> 02:27:02,800
There may be people
who just by exposure

2855
02:27:02,800 --> 02:27:05,640
are resistant to developing
the pathology,

2856
02:27:05,640 --> 02:27:09,800
and thus, the clinical decline
that comes with it.

2857
02:27:09,800 --> 02:27:12,000
And there are possible
genetic environmental factors

2858
02:27:12,000 --> 02:27:13,800
that then
contribute to them.

2859
02:27:13,800 --> 02:27:15,320
And secondly,
there may be individuals

2860
02:27:15,320 --> 02:27:17,720
that demonstrate resilience
to the clinical symptoms

2861
02:27:17,720 --> 02:27:21,320
despite having TDI-related
neurodegenerative pathologies.

2862
02:27:21,320 --> 02:27:23,120
And this brings the idea
of reserve

2863
02:27:23,120 --> 02:27:25,200
or pre-morbid factors
that might influence

2864
02:27:25,200 --> 02:27:28,000
the clinical trajectory
in some people.

2865
02:27:28,000 --> 02:27:31,440
So we really know very little
about this and TBI,

2866
02:27:31,440 --> 02:27:33,560
and it's certainly
challenging to examine,

2867
02:27:33,560 --> 02:27:35,600
and particularly,
as Kristen noted,

2868
02:27:35,600 --> 02:27:39,280
the -- in the latter scenario,
when looking at clinical data.

2869
02:27:39,280 --> 02:27:42,240
We don't have enough complex
data clinical impairments

2870
02:27:42,240 --> 02:27:44,520
and possibly in recovery
related to injury

2871
02:27:44,520 --> 02:27:47,720
to disentangle
from any progressive changes.

2872
02:27:47,720 --> 02:27:50,920
So longitudinal studies
will obviously be important.

2873
02:27:50,920 --> 02:27:53,600
So nonetheless,
understanding these processes

2874
02:27:53,600 --> 02:27:55,080
may be important
in contributing

2875
02:27:55,080 --> 02:27:57,960
to our understanding
of mechanisms of disease.

2876
02:27:57,960 --> 02:27:59,640
So as shown here,
the committee included

2877
02:27:59,640 --> 02:28:02,600
the identification of intrinsic
and environmental factors

2878
02:28:02,600 --> 02:28:07,000
and that confer resilience
as our final recommendation.

2879
02:28:07,000 --> 02:28:10,400
So thank you, and I will
pass back over to Kristen

2880
02:28:10,400 --> 02:28:13,800
for our question
and answer session.

2881
02:28:13,800 --> 02:28:17,840
-Great, thank you to Vicky and
to Dirk for those great talks.

2882
02:28:17,840 --> 02:28:19,880
If you could go
to the next slide.

2883
02:28:21,920 --> 02:28:24,480
Thank you.
So our primary goal today

2884
02:28:24,480 --> 02:28:27,800
really is to seek feedback
on these recommendations

2885
02:28:27,800 --> 02:28:30,200
to really ensure
that they're consistent

2886
02:28:30,200 --> 02:28:34,440
with and reflective
of the stakeholder priorities.

2887
02:28:34,440 --> 02:28:36,840
That many of our attendees
today represent.

2888
02:28:36,840 --> 02:28:39,120
So let's start.

2889
02:28:39,120 --> 02:28:42,000
I see a question
from Mr. Ellenbogen.

2890
02:28:44,600 --> 02:28:47,160
-Thank you so much.

2891
02:28:47,160 --> 02:28:49,800
I was unable to speak
at the earlier session

2892
02:28:49,800 --> 02:28:51,360
and just wanted
to add one comment

2893
02:28:51,360 --> 02:28:56,840
before I go
into my TBI comment.

2894
02:28:56,840 --> 02:28:59,320
I will have to say
that detection

2895
02:28:59,320 --> 02:29:02,000
is a very complicated matter.

2896
02:29:02,000 --> 02:29:04,840
And as a person living
with this disease,

2897
02:29:04,840 --> 02:29:09,200
I may not want someone to know
I have some kind of dementia.

2898
02:29:09,200 --> 02:29:11,600
The second thing,
add some type of dementia

2899
02:29:11,600 --> 02:29:13,520
on your medical record,

2900
02:29:13,520 --> 02:29:17,160
I instantly have my rights
taken away from me.

2901
02:29:17,160 --> 02:29:20,000
We need to change
the laws around that

2902
02:29:20,000 --> 02:29:24,400
before we expect our doctors
and the people to come forward.

2903
02:29:24,400 --> 02:29:27,800
For example, I would lose
driving capabilities,

2904
02:29:27,800 --> 02:29:30,280
depending on what state I'm in,

2905
02:29:30,280 --> 02:29:33,600
lose my job or get fired
instantly from it,

2906
02:29:33,600 --> 02:29:37,240
or even lose insurances
that I would be entitled to.

2907
02:29:37,240 --> 02:29:40,520
So there are things
that need to be addressed

2908
02:29:40,520 --> 02:29:41,880
and it's very complicated.

2909
02:29:41,880 --> 02:29:43,440
It's just not as easy
as just being able

2910
02:29:43,440 --> 02:29:49,360
to diagnose the disease.
But as far as my TBI comment,

2911
02:29:49,360 --> 02:29:54,640
we have learned so much about
ways to possibly delay dementia

2912
02:29:54,640 --> 02:29:58,320
and we now encourage
that in many public ways.

2913
02:29:58,320 --> 02:30:01,920
As an expert who's living
with this horrible disease,

2914
02:30:01,920 --> 02:30:05,240
I would not wish this
on my worst enemy.

2915
02:30:05,240 --> 02:30:07,600
What I cannot understand,
though,

2916
02:30:07,600 --> 02:30:11,880
is that we have learned
so much about TBI,

2917
02:30:11,880 --> 02:30:15,880
yet we don't do much
to educate our children

2918
02:30:15,880 --> 02:30:18,720
to no longer play games
such as football.

2919
02:30:18,720 --> 02:30:21,160
We clearly know that
this will increase their risk

2920
02:30:21,160 --> 02:30:22,760
to brain damage.

2921
02:30:22,760 --> 02:30:25,720
Why don't we make
this very public

2922
02:30:25,720 --> 02:30:28,520
so at least these folks
have a chance?

2923
02:30:28,520 --> 02:30:31,800
Thank you.

2924
02:30:31,800 --> 02:30:33,440
-Thank you, Mr. Ellenbogen.

2925
02:30:33,440 --> 02:30:37,160
You, again,
raise such an important point.

2926
02:30:37,160 --> 02:30:40,120
So what I'm hearing
is that we need to consider

2927
02:30:40,120 --> 02:30:42,800
in our recommendations,
and our colleagues,

2928
02:30:42,800 --> 02:30:47,040
and across the multiple
etiology dementia subgroups.

2929
02:30:47,040 --> 02:30:51,040
The potential consequences
of detection and diagnosis

2930
02:30:51,040 --> 02:30:54,640
to those living with dementia,
with traumatic brain injury.

2931
02:30:54,640 --> 02:30:57,200
And I'm also hearing
a need to for us

2932
02:30:57,200 --> 02:31:02,040
to consider
the post-TBI ADRD group

2933
02:31:02,040 --> 02:31:06,000
expanding our efforts
to educate the public

2934
02:31:06,000 --> 02:31:08,680
about the potential sequelae
of traumatic brain injury.

2935
02:31:08,680 --> 02:31:13,080
So that people can make
evidence-based decisions

2936
02:31:13,080 --> 02:31:16,800
about their individual
risk tolerance.

2937
02:31:16,800 --> 02:31:21,160
Very well-taken point.
Thank you for that.

2938
02:31:21,160 --> 02:31:23,520
Let's see, Dr. Schneider,
I see a question.

2939
02:31:27,240 --> 02:31:28,840
-Hi, Kristen.

2940
02:31:28,840 --> 02:31:31,920
Thank you for the --
those great presentations.

2941
02:31:31,920 --> 02:31:36,120
I had a question about
Recommendation Number 2,

2942
02:31:36,120 --> 02:31:39,640
which is the clinical
heterogeneity

2943
02:31:39,640 --> 02:31:43,800
and the need for more
clinical characterization.

2944
02:31:43,800 --> 02:31:48,440
And I'm just wondering whether
or not the biomarker component

2945
02:31:48,440 --> 02:31:51,880
should be brought
to the top of that list.

2946
02:31:51,880 --> 02:31:54,520
Because as we know
in dementia,

2947
02:31:54,520 --> 02:31:56,000
you know,
in all these dementias,

2948
02:31:56,000 --> 02:31:59,240
there's so much heterogeneity
in what we see.

2949
02:31:59,240 --> 02:32:01,440
And, you know,
do we really expect

2950
02:32:01,440 --> 02:32:05,800
that there's going to be
a single clinical feature

2951
02:32:05,800 --> 02:32:08,040
that's going to tell us
something different?

2952
02:32:08,040 --> 02:32:11,800
I mean, I think we should
certainly be looking,

2953
02:32:11,800 --> 02:32:15,600
but wouldn't it,
like the other diseases,

2954
02:32:15,600 --> 02:32:18,240
be more important
to have a biomarker,

2955
02:32:18,240 --> 02:32:19,680
something that tells us

2956
02:32:19,680 --> 02:32:22,680
that there's actually
been injury to the brain.

2957
02:32:22,680 --> 02:32:27,960
And so just your thoughts
on that second recommendation

2958
02:32:27,960 --> 02:32:31,600
and the elevation
perhaps of biomarkers.

2959
02:32:31,600 --> 02:32:33,720
-That's a great thought.

2960
02:32:33,720 --> 02:32:36,880
Dr. Henrik Zetterberg,
do you have thoughts on that,

2961
02:32:36,880 --> 02:32:39,760
the potential elevation
of biological markers

2962
02:32:39,760 --> 02:32:42,280
within Recommendation 2?

2963
02:32:42,280 --> 02:32:44,760
-Yes, I think definitely
it can be included

2964
02:32:44,760 --> 02:32:46,320
and we should also
separate them,

2965
02:32:46,320 --> 02:32:48,640
the acute phase of TBI
with the more chronic phase.

2966
02:32:48,640 --> 02:32:52,800
And perhaps also address
what happens in repetitive TBIs

2967
02:32:52,800 --> 02:32:55,280
and how one with biomarks
could follow

2968
02:32:55,280 --> 02:33:00,680
sort of the amount of injury
to the brain tissue

2969
02:33:00,680 --> 02:33:03,560
using the existing biomarkers.

2970
02:33:03,560 --> 02:33:07,320
But we would also need
to develop new biomarkers

2971
02:33:07,320 --> 02:33:10,360
because the tau that is seen
in chronic TBI,

2972
02:33:10,360 --> 02:33:14,440
for example, is not possible
to detect the monitor

2973
02:33:14,440 --> 02:33:18,600
using the existing fluid
biomarkers for tau pathogen.

2974
02:33:18,600 --> 02:33:20,000
And the imaging biomarker data

2975
02:33:20,000 --> 02:33:22,080
will also need
to become different.

2976
02:33:22,080 --> 02:33:26,800
So it's almost like we perhaps
should try to also emphasize

2977
02:33:26,800 --> 02:33:30,480
that we need to also develop
and validate biomarkers

2978
02:33:30,480 --> 02:33:35,040
for TBI-related brain
tissue changes.

2979
02:33:35,040 --> 02:33:37,240
So basically
what I'm trying to say

2980
02:33:37,240 --> 02:33:40,800
is that we can't just lean back
and use existing biomarkers,

2981
02:33:40,800 --> 02:33:46,160
also, because they might
not represent

2982
02:33:46,160 --> 02:33:49,000
the TBI-related
pathogens completely.

2983
02:33:49,000 --> 02:33:50,320
But acute accelerator injury

2984
02:33:50,320 --> 02:33:53,200
and [Indistinct]
calculation works.

2985
02:33:53,200 --> 02:33:55,040
There the biomarkers works --

2986
02:33:55,040 --> 02:33:59,960
work across
the different types of TBI

2987
02:33:59,960 --> 02:34:03,240
and also we can make use of them
developed

2988
02:34:03,240 --> 02:34:06,360
for Neurodegenerative dementias.

2989
02:34:06,360 --> 02:34:08,080
-Thank you, Henrik.

2990
02:34:08,080 --> 02:34:09,800
Pratik, I wander if you have
any comments about this, too,

2991
02:34:09,800 --> 02:34:11,480
with respect
to imaging biomarkers.

2992
02:34:11,480 --> 02:34:15,160
So part of Julie's point
is that we do not expect

2993
02:34:15,160 --> 02:34:19,680
to see one isolated biomarker
but perhaps panels of biomarkers

2994
02:34:19,680 --> 02:34:23,080
that we required
for earliest detection.

2995
02:34:23,080 --> 02:34:25,280
-Yeah, no.
I absolutely agree, you know,

2996
02:34:25,280 --> 02:34:28,720
and I think we need
to emphasize capturing

2997
02:34:28,720 --> 02:34:33,320
as much data as possible
from early after the injury.

2998
02:34:33,320 --> 02:34:35,400
Where we can characterize,
you know,

2999
02:34:35,400 --> 02:34:38,560
the particular
pathophysiological mechanism

3000
02:34:38,560 --> 02:34:42,000
operating in that
particular patient.

3001
02:34:42,000 --> 02:34:43,600
So...

3002
02:34:46,200 --> 02:34:49,120
...all of the acute TBI studies
are generally set up

3003
02:34:49,120 --> 02:34:51,360
as precision medicine studies
for that reason.

3004
02:34:51,360 --> 02:34:55,000
And once we've captured that
data through imaging biomarkers,

3005
02:34:55,000 --> 02:34:56,840
blood specimen biomarkers,

3006
02:34:56,840 --> 02:35:00,240
then phenotyping of
the clinical characteristics,

3007
02:35:00,240 --> 02:35:01,680
and cognitive function,

3008
02:35:01,680 --> 02:35:03,880
and behavioral function
at that acute phase.

3009
02:35:03,880 --> 02:35:05,360
Then we can follow
it longitudinally

3010
02:35:05,360 --> 02:35:07,400
and see how it evolves
like the slide

3011
02:35:07,400 --> 02:35:09,240
you showed from
the different studies

3012
02:35:09,240 --> 02:35:13,760
showing how different patients
may have different evolution.

3013
02:35:13,760 --> 02:35:15,280
And there's certain
latent classes

3014
02:35:15,280 --> 02:35:19,000
that can be discovered
from that data.

3015
02:35:19,000 --> 02:35:20,440
So that's a main priority

3016
02:35:20,440 --> 02:35:22,720
of a lot of the acute
TBI studies right now

3017
02:35:22,720 --> 02:35:26,800
with the qualifications
for multiple years.

3018
02:35:26,800 --> 02:35:30,000
And I think that imaging
is interesting, too,

3019
02:35:30,000 --> 02:35:33,720
because not only can you
get a biomarker

3020
02:35:33,720 --> 02:35:36,320
of the injury pathophysiology

3021
02:35:36,320 --> 02:35:39,960
and its progression
or degeneration

3022
02:35:39,960 --> 02:35:41,920
during the recovery process.

3023
02:35:41,920 --> 02:35:44,400
But there --
you can also get biomarkers

3024
02:35:44,400 --> 02:35:48,800
that may be related to
innate resilience properties

3025
02:35:48,800 --> 02:35:52,920
that may account for some of
the inter-individual variability

3026
02:35:52,920 --> 02:35:54,320
of the recovery process.

3027
02:35:54,320 --> 02:35:59,720
You know, despite,
you know, the injury.

3028
02:35:59,720 --> 02:36:04,400
So some patients do well because
they have innate resilience

3029
02:36:04,400 --> 02:36:07,200
despite a greater severity
of injury

3030
02:36:07,200 --> 02:36:10,480
and others do poorly even though
the injury may be considered

3031
02:36:10,480 --> 02:36:12,600
mild by standard
clinical criteria.

3032
02:36:12,600 --> 02:36:15,520
We see this all the time
and we don't understand

3033
02:36:15,520 --> 02:36:19,720
right now the factors
that cause that variability

3034
02:36:19,720 --> 02:36:21,640
and our inability
to predict,

3035
02:36:21,640 --> 02:36:23,920
you know,
the longer-term outcomes.

3036
02:36:23,920 --> 02:36:26,880
So it's going to be important to
characterize in the acute phase

3037
02:36:26,880 --> 02:36:30,480
both the injury pathophysiology
and the resilience factors.

3038
02:36:30,480 --> 02:36:34,200
And I think that's a common
theme of many of the ADRDs,

3039
02:36:34,200 --> 02:36:39,120
as well, where resilience
is taking a larger role

3040
02:36:39,120 --> 02:36:43,800
in evaluating the disease
progression process.

3041
02:36:43,800 --> 02:36:45,440
-That's a great point.
Thank you.

3042
02:36:45,440 --> 02:36:49,800
I agree, we should further
consider this as we revise.

3043
02:36:49,800 --> 02:36:51,200
Let's see, I see in the chat

3044
02:36:51,200 --> 02:36:55,000
we have a question
from Dr. Bob Stern.

3045
02:36:55,000 --> 02:36:57,800
-Thanks, Kristen.
Thanks to the panel

3046
02:36:57,800 --> 02:36:59,520
and all the incredible work
you've been doing.

3047
02:36:59,520 --> 02:37:02,680
This is just such
an amazing transformation

3048
02:37:02,680 --> 02:37:07,400
since the previous time
this was brought up.

3049
02:37:07,400 --> 02:37:11,320
I just want to try to bring up
a complex point

3050
02:37:11,320 --> 02:37:15,320
between chronic
traumatic encephalopathy

3051
02:37:15,320 --> 02:37:20,160
and post-TBI dementia.

3052
02:37:20,160 --> 02:37:26,600
And that has to do with
the acute phase of the injuries.

3053
02:37:26,600 --> 02:37:30,080
And really what it is
that we're trying to measure

3054
02:37:30,080 --> 02:37:34,080
clinically biomarker
and then neuropathologically.

3055
02:37:34,080 --> 02:37:38,920
That with the repetitive
head impact

3056
02:37:38,920 --> 02:37:44,320
exposure over several years
in individuals

3057
02:37:44,320 --> 02:37:48,040
like contact collision
sport athletes.

3058
02:37:48,040 --> 02:37:53,240
There may not be a single injury
that would be considered

3059
02:37:53,240 --> 02:37:55,600
a symptomatic traumatic
brain injury.

3060
02:37:55,600 --> 02:37:58,040
And yet, because
of that repetitive exposure,

3061
02:37:58,040 --> 02:38:03,240
there seems to be set in motion
this cascade of changes

3062
02:38:03,240 --> 02:38:07,800
leading to a progressive
telopathy.

3063
02:38:07,800 --> 02:38:13,000
And in that case, it is
so different to try to detect,

3064
02:38:13,000 --> 02:38:17,640
and diagnose, and come up
with clinical features.

3065
02:38:17,640 --> 02:38:20,200
Because there's
this period of...

3066
02:38:24,000 --> 02:38:27,320
...delay between that time
of exposure to injuries

3067
02:38:27,320 --> 02:38:31,240
and then the beginning of
a progressive neurodegeneration.

3068
02:38:31,240 --> 02:38:33,800
So I just want to have people
try to keep that in mind

3069
02:38:33,800 --> 02:38:39,120
that we're not talking about
an injury that then recovers

3070
02:38:39,120 --> 02:38:41,600
and then there can be a chronic

3071
02:38:41,600 --> 02:38:44,400
and potentially degenerative
phase later.

3072
02:38:44,400 --> 02:38:48,200
When it comes to many
of the cases of CTE.

3073
02:38:51,120 --> 02:38:52,800
-Excellent point.

3074
02:38:52,800 --> 02:38:54,680
So I'm hearing you say that
it's not quite sufficient for us

3075
02:38:54,680 --> 02:38:57,360
to state in our recommendations
that we are interested

3076
02:38:57,360 --> 02:38:59,760
in considering a broad range
of exposure histories.

3077
02:38:59,760 --> 02:39:03,120
But actually investigating
more carefully the distinctions

3078
02:39:03,120 --> 02:39:05,800
between the acute
and chronic pathologies

3079
02:39:05,800 --> 02:39:08,200
of distinct
exposure histories.

3080
02:39:08,200 --> 02:39:09,600
-That's right.
-Okay. Thank you, Doctor.

3081
02:39:09,600 --> 02:39:12,520
-I think that's going to help
really elucidate

3082
02:39:12,520 --> 02:39:16,000
the differential pathologies
going on

3083
02:39:16,000 --> 02:39:19,440
by differentiating it
at the acute phase.

3084
02:39:19,440 --> 02:39:22,360
-Great point. Thank you, Bob.

3085
02:39:22,360 --> 02:39:25,400
I see a question now
from Dr. Bellgowan.

3086
02:39:28,600 --> 02:39:29,840
-Oh, yes.

3087
02:39:29,840 --> 02:39:32,080
I'll turn my camera on.
Thank you.

3088
02:39:32,080 --> 02:39:37,760
So there seem to be I know
the Recommendation 4

3089
02:39:37,760 --> 02:39:39,680
was about
these translational models

3090
02:39:39,680 --> 02:39:45,000
and Dr. Keene showed
a bridge to those models.

3091
02:39:45,000 --> 02:39:48,000
But we know that,
you know, so I was --

3092
02:39:48,000 --> 02:39:50,440
the recommendation to me
is fairly unspecific

3093
02:39:50,440 --> 02:39:54,600
because, you know, TBI,
there's a lot of TBI models.

3094
02:39:54,600 --> 02:39:58,200
And are you talking
about developing --

3095
02:39:58,200 --> 02:40:00,240
is there a way to develop
a consensus about

3096
02:40:00,240 --> 02:40:03,000
which is going to be the most
informative model to use

3097
02:40:03,000 --> 02:40:06,800
and to bring in people
from the AD/ADRD community.

3098
02:40:06,800 --> 02:40:11,720
To help us choose which models
might be most effective?

3099
02:40:11,720 --> 02:40:15,840
I mean, you could even look at
whether we injure a mouse early

3100
02:40:15,840 --> 02:40:19,080
and then follow them over,
you know, their life,

3101
02:40:19,080 --> 02:40:21,680
or we injure an aged mouse
and see what happens.

3102
02:40:21,680 --> 02:40:24,120
I mean, I just see the --

3103
02:40:24,120 --> 02:40:26,800
a proliferation
of preclinical studies.

3104
02:40:26,800 --> 02:40:29,200
And I was just wondering
if part of the recommendation

3105
02:40:29,200 --> 02:40:31,200
was to figure out
which might be the most,

3106
02:40:31,200 --> 02:40:32,760
you know, defining which models

3107
02:40:32,760 --> 02:40:37,480
and which parameters of models
would be most effective.

3108
02:40:37,480 --> 02:40:41,040
And I wrote in the chat the VA
has already put together

3109
02:40:41,040 --> 02:40:44,240
a similar effort
for model development

3110
02:40:44,240 --> 02:40:46,160
in traumatic brain injury
in itself.

3111
02:40:46,160 --> 02:40:47,600
But I'm not sure it includes

3112
02:40:47,600 --> 02:40:49,440
the dementia component
of it, really.

3113
02:40:49,440 --> 02:40:52,680
-All right, great point.

3114
02:40:52,680 --> 02:40:55,440
Dr. Johnson, would you like
to speak to that?

3115
02:40:55,440 --> 02:40:58,120
-Sure, yeah. No, I think
that's an important point.

3116
02:40:58,120 --> 02:41:00,880
I think one of
the important points

3117
02:41:00,880 --> 02:41:02,120
that we were trying to get at

3118
02:41:02,120 --> 02:41:03,600
is obviously there's been
an evolution

3119
02:41:03,600 --> 02:41:07,000
in our understanding
of the human pathology.

3120
02:41:07,000 --> 02:41:09,200
Which is still
very much evolving

3121
02:41:09,200 --> 02:41:11,560
and being characterized.

3122
02:41:11,560 --> 02:41:16,520
And part of that recommendation
was to really --

3123
02:41:16,520 --> 02:41:18,920
so and I think that was what
Dirk was getting to.

3124
02:41:18,920 --> 02:41:20,600
Was the picture of the bridge,
as well,

3125
02:41:20,600 --> 02:41:24,400
is really that
essentially collaboration

3126
02:41:24,400 --> 02:41:28,080
between preclinical
and clinical work.

3127
02:41:28,080 --> 02:41:31,880
And there are pathology-based
studies to really inform

3128
02:41:31,880 --> 02:41:35,400
what aspects
of these models are relevant

3129
02:41:35,400 --> 02:41:38,960
and even potentially
to different populations.

3130
02:41:38,960 --> 02:41:40,520
I think there's a lot of work
to be done

3131
02:41:40,520 --> 02:41:43,160
even to be further characterized
into the chronic phase

3132
02:41:43,160 --> 02:41:46,840
in many of the existing models.

3133
02:41:46,840 --> 02:41:49,160
But, you know,
many of these models

3134
02:41:49,160 --> 02:41:51,640
are going to be useful
in different respects

3135
02:41:51,640 --> 02:41:55,640
for looking at specific
phenotypes of injury

3136
02:41:55,640 --> 02:41:57,640
and how they evolve
into the chronic phase.

3137
02:41:57,640 --> 02:42:02,120
So I think we were really
getting at the sort of the gap

3138
02:42:02,120 --> 02:42:04,800
in information between
the clinical and preclinical.

3139
02:42:04,800 --> 02:42:09,200
That's going to be really
important for driving our --

3140
02:42:09,200 --> 02:42:12,000
the sort of further
characterization development

3141
02:42:12,000 --> 02:42:15,720
and utility of those models.

3142
02:42:15,720 --> 02:42:18,400
-Thank you.
Okay, so we will make sure --

3143
02:42:18,400 --> 02:42:19,840
we'll take that back
to the committee

3144
02:42:19,840 --> 02:42:21,600
and make sure that we discuss
and clarify that.

3145
02:42:21,600 --> 02:42:26,960
Thanks, Vicky. Let's see,
Dr. Hoffman, I see hand raised.

3146
02:42:26,960 --> 02:42:28,440
-Yeah.

3147
02:42:28,440 --> 02:42:33,400
Thank you, Dr. Bellgowan
for that shout out, there.

3148
02:42:33,400 --> 02:42:38,200
Yeah, we're -- the VA's working
with the other agencies, DOD,

3149
02:42:38,200 --> 02:42:48,440
NIH, different institutes
of NIH, like NIA and NINDS.

3150
02:42:48,440 --> 02:42:52,280
To develop these --
a categorization

3151
02:42:52,280 --> 02:42:55,920
and standardization
of animal models.

3152
02:42:55,920 --> 02:43:00,080
And since the VA
doesn't look at acute injury.

3153
02:43:00,080 --> 02:43:03,280
We have veterans
who've had brain injuries.

3154
02:43:03,280 --> 02:43:05,640
Sometimes we don't know
what time zero is.

3155
02:43:05,640 --> 02:43:13,400
So having models that can show
the pathological progression

3156
02:43:13,400 --> 02:43:16,080
of one or more brain injuries

3157
02:43:16,080 --> 02:43:19,960
is something that
is a goal of that initiative

3158
02:43:19,960 --> 02:43:24,600
which is called precise TBI.
Thank you.

3159
02:43:24,600 --> 02:43:26,560
-Thank you, Stu.

3160
02:43:26,560 --> 02:43:29,880
Okay, Dr. Corriveau,
I think to turn it back to you.

3161
02:43:32,440 --> 02:43:37,160
-Okay. Thank you so much
for a wonderful session

3162
02:43:37,160 --> 02:43:38,640
and lively discussion

3163
02:43:38,640 --> 02:43:41,320
including specifics
about the recommendations.

3164
02:43:41,320 --> 02:43:43,440
We really appreciate that.

3165
02:43:43,440 --> 02:43:46,760
So with no further ado,
I would like to --

3166
02:43:46,760 --> 02:43:50,520
I'll -- to introduce
Dr. Julie Schneider,

3167
02:43:50,520 --> 02:43:56,000
the scientific chair of the
Late Committee for TDP 34 --

3168
02:43:56,000 --> 02:44:01,800
TDP 43 Pathology and Common
Late-Onset Dementias. Thank you.

3169
02:44:01,800 --> 02:44:04,640
-Thank you, Rod,
and thank you to the organizers

3170
02:44:04,640 --> 02:44:09,600
for inviting me.
And I apologize

3171
02:44:09,600 --> 02:44:12,040
that you have to listen to me
instead of have lunch,

3172
02:44:12,040 --> 02:44:15,480
because I thought
there was a break, too.

3173
02:44:15,480 --> 02:44:17,080
Next slide.

3174
02:44:21,080 --> 02:44:24,920
Again, the views expressed in
these presentations are not --

3175
02:44:24,920 --> 02:44:27,800
are those of the authors
and not of the NIH.

3176
02:44:27,800 --> 02:44:31,560
I'm listing all the disclosures
here, both mine, Dr. Wolk,

3177
02:44:31,560 --> 02:44:35,760
and Dr. Gitcho,
who will also be speaking,

3178
02:44:35,760 --> 02:44:39,520
so we don't have
to each do it on our own.

3179
02:44:39,520 --> 02:44:41,320
Next slide.

3180
02:44:41,320 --> 02:44:44,800
I want to thank the committee
members Konstantinos Arfanakis,

3181
02:44:44,800 --> 02:44:46,920
Maria Corrada,
Michael Gitcho,

3182
02:44:46,920 --> 02:44:51,080
Brian Kraemer, Pete Nelson,
David Wolk, Hyun-Sik Yang;

3183
02:44:51,080 --> 02:44:54,400
and our cross committee members,
Donna Wilcock and Dirk Keene.

3184
02:44:54,400 --> 02:44:56,160
We had lively discussions

3185
02:44:56,160 --> 02:45:00,600
and I think just a really good
working group of people.

3186
02:45:00,600 --> 02:45:01,960
Everyone pitched in.

3187
02:45:01,960 --> 02:45:04,080
And thank you
to the NIH staff too.

3188
02:45:04,080 --> 02:45:07,240
Next slide.

3189
02:45:07,240 --> 02:45:10,000
So I'm going to give you
an introduction

3190
02:45:10,000 --> 02:45:13,400
and then briefly talk about
a couple new recommendations.

3191
02:45:13,400 --> 02:45:14,880
I'm going to tell you --

3192
02:45:14,880 --> 02:45:17,880
tell you what is LATE,
why do we -- what is --

3193
02:45:17,880 --> 02:45:20,400
what are we calling LATE?
Why is it important?

3194
02:45:20,400 --> 02:45:22,720
And that's going to be
followed up with Dr. Wolk,

3195
02:45:22,720 --> 02:45:24,800
who's going to give you
a lot more information

3196
02:45:24,800 --> 02:45:28,000
on why LATE is important.

3197
02:45:28,000 --> 02:45:33,720
We, like the TBI session,
we were new to the ADRD summit

3198
02:45:33,720 --> 02:45:38,360
as a emerging topic
in the 2019 Summit.

3199
02:45:38,360 --> 02:45:42,200
And we've really
come a long way.

3200
02:45:42,200 --> 02:45:45,280
Our initial recommendations
involved biomarkers,

3201
02:45:45,280 --> 02:45:49,400
clinical manifestations,
basic science, and pathology.

3202
02:45:49,400 --> 02:45:52,680
And we're going to continue
with our push for biomarkers

3203
02:45:52,680 --> 02:45:55,640
and basic science,
which are really,

3204
02:45:55,640 --> 02:45:59,360
really needed in LATE research.

3205
02:45:59,360 --> 02:46:01,720
But we're going to pivot
a little bit

3206
02:46:01,720 --> 02:46:06,040
with the clinical
and pathology recommendations

3207
02:46:06,040 --> 02:46:10,160
and really expand that to two
completely new recommendations

3208
02:46:10,160 --> 02:46:12,120
with specific topics

3209
02:46:12,120 --> 02:46:14,840
that include clinical
and pathology

3210
02:46:14,840 --> 02:46:17,400
but go beyond that to --

3211
02:46:17,400 --> 02:46:21,840
and discuss or investigates
the boundaries

3212
02:46:21,840 --> 02:46:24,360
with other diseases
in the intersections

3213
02:46:24,360 --> 02:46:27,360
with hippocampal sclerosis,
vascular disease, and age.

3214
02:46:27,360 --> 02:46:30,680
And I'll talk about those
in just a little bit.

3215
02:46:30,680 --> 02:46:36,240
Next slide.
So when we talk about LATE,

3216
02:46:36,240 --> 02:46:40,400
we're basically talking
about TDP-43 pathology

3217
02:46:40,400 --> 02:46:43,800
in common dementias
in aging.

3218
02:46:43,800 --> 02:46:47,640
But the TDP-43 story
really started 2006

3219
02:46:47,640 --> 02:46:52,000
with the seminal papers
describing TDP-43

3220
02:46:52,000 --> 02:46:55,400
as the ubiquitin positive
tau negative inclusion

3221
02:46:55,400 --> 02:46:58,600
of frontotemporal lobar
degeneration, ALS.

3222
02:46:58,600 --> 02:47:04,080
So this was a pivotal discovery.
It really changed the field

3223
02:47:04,080 --> 02:47:06,720
for frontotemporal
lobar degeneration

3224
02:47:06,720 --> 02:47:08,800
and initially very short
period of time

3225
02:47:08,800 --> 02:47:11,400
was thought to be specific.
Next slide.

3226
02:47:15,120 --> 02:47:18,120
But as we looked
at TDP-43

3227
02:47:18,120 --> 02:47:21,480
as this novel neurodegenerative
proteinopathy,

3228
02:47:21,480 --> 02:47:26,160
it became clear very quickly
that TDP-43 was not

3229
02:47:26,160 --> 02:47:29,480
only positive in frontotemporal
lobar degeneration

3230
02:47:29,480 --> 02:47:31,680
but it's positive
in other diseases

3231
02:47:31,680 --> 02:47:33,120
just like alpha synuclein

3232
02:47:33,120 --> 02:47:36,440
and tau, these misfolded
proteins aren't --

3233
02:47:36,440 --> 02:47:41,000
don't define one disease
necessarily.

3234
02:47:41,000 --> 02:47:44,600
And, lo and behold,
TDP-43 positivity

3235
02:47:44,600 --> 02:47:46,640
was quickly found
to be evident

3236
02:47:46,640 --> 02:47:49,880
in Alzheimer's disease,
pathology,

3237
02:47:49,880 --> 02:47:52,360
as well as hippocampal
sclerosis pathology.

3238
02:47:52,360 --> 02:47:53,960
Next slide.

3239
02:47:56,000 --> 02:48:00,560
But even more astounding
was that this TDP-43 pathology

3240
02:48:00,560 --> 02:48:03,360
was sometimes found
in older people

3241
02:48:03,360 --> 02:48:05,720
completely lacking
Alzheimer's disease,

3242
02:48:05,720 --> 02:48:08,280
or hippocampal sclerosis.

3243
02:48:08,280 --> 02:48:10,800
And as you'll see
in a following slide,

3244
02:48:10,800 --> 02:48:14,000
that is why we came up
with a new name for this

3245
02:48:14,000 --> 02:48:19,760
because, as of 2018,
there was no name for this.

3246
02:48:19,760 --> 02:48:23,200
And if you look at the pie chart
at the bottom of the slide,

3247
02:48:23,200 --> 02:48:26,080
this is a study that we did
looking at people

3248
02:48:26,080 --> 02:48:29,720
who are called Alzheimer's
disease in the community.

3249
02:48:29,720 --> 02:48:33,120
No biomarkers;
they have an amnestic dementia.

3250
02:48:33,120 --> 02:48:35,400
And the red is showing people

3251
02:48:35,400 --> 02:48:37,680
with Alzheimer's
disease pathology.

3252
02:48:37,680 --> 02:48:39,720
The purple is showing
those people

3253
02:48:39,720 --> 02:48:42,920
with Alzheimer's disease
pathology and TDP.

3254
02:48:42,920 --> 02:48:45,080
So the vast majority
of these Alzheimer's,

3255
02:48:45,080 --> 02:48:48,320
these cases that we see
in the community have TDP.

3256
02:48:48,320 --> 02:48:51,400
The blue slice
is showing people

3257
02:48:51,400 --> 02:48:55,760
who did not have amyloid
and tau but have LATE.

3258
02:48:55,760 --> 02:48:57,920
So they have
a different diagnosis.

3259
02:48:57,920 --> 02:49:01,760
The white would be vascular
dementia, Lewy body dementia.

3260
02:49:01,760 --> 02:49:05,000
So clearly a big part
of this pie

3261
02:49:05,000 --> 02:49:09,320
is being completely disregarded
by the community.

3262
02:49:09,320 --> 02:49:10,720
And this was very concerning.

3263
02:49:10,720 --> 02:49:12,880
There was very little research
being done.

3264
02:49:12,880 --> 02:49:14,800
But at the same time,
it was noted that

3265
02:49:14,800 --> 02:49:18,840
in biomarker studies that --

3266
02:49:18,840 --> 02:49:23,760
that in biomarker studies that,
you know, a good third of people

3267
02:49:23,760 --> 02:49:27,040
who are thought to have
Alzheimer's disease don't.

3268
02:49:27,040 --> 02:49:29,000
But most of the research on TDP,

3269
02:49:29,000 --> 02:49:30,440
even though we saw
this pathologically,

3270
02:49:30,440 --> 02:49:33,600
was really being done
in the FTLD community.

3271
02:49:33,600 --> 02:49:39,480
Next slide.
So to increase awareness

3272
02:49:39,480 --> 02:49:43,440
and really increase research
in this TDP-43 pathology

3273
02:49:43,440 --> 02:49:45,040
and aging
and Alzheimer's disease,

3274
02:49:45,040 --> 02:49:50,600
we convened a panel
of 22 experts across 22 centers

3275
02:49:50,600 --> 02:49:52,280
and really discuss
how are we going

3276
02:49:52,280 --> 02:49:56,280
to make this
a research of focus.

3277
02:49:56,280 --> 02:49:59,320
And it's --
and a much needed focus.

3278
02:49:59,320 --> 02:50:02,680
And as Dr. Wolk
will be showing you,

3279
02:50:02,680 --> 02:50:07,800
that, as an isolated pathology,
it mimics Alzheimer's disease.

3280
02:50:07,800 --> 02:50:11,880
But even more commonly,
when it's in conjunction

3281
02:50:11,880 --> 02:50:14,000
with Alzheimer's disease
neuropathologic changes

3282
02:50:14,000 --> 02:50:15,480
of mixed pathology,

3283
02:50:15,480 --> 02:50:18,040
it accelerates decline
and worsens memory.

3284
02:50:18,040 --> 02:50:21,280
It makes the person
much worse.

3285
02:50:21,280 --> 02:50:25,800
So we clearly know
that this needed to be studied,

3286
02:50:25,800 --> 02:50:28,400
and we needed to kind of upset
the field to get it --

3287
02:50:28,400 --> 02:50:30,600
to get it going.

3288
02:50:30,600 --> 02:50:33,680
And that is where we came up
with the term limbic predominant

3289
02:50:33,680 --> 02:50:36,800
age-related
TDP-43 encephalopathy,

3290
02:50:36,800 --> 02:50:40,080
which is also LATE,
the pathology is called LATE NC

3291
02:50:40,080 --> 02:50:44,160
so LATE neuropathologic changes.
A couple things to mention.

3292
02:50:44,160 --> 02:50:47,880
There is no frontotemporal lobar
degeneration in these cases,

3293
02:50:47,880 --> 02:50:51,520
and there's not a frontal
temporal dementia syndrome.

3294
02:50:51,520 --> 02:50:54,360
Instead, there's a prominent
amnesia of people

3295
02:50:54,360 --> 02:50:56,560
with this pathology.
Next slide.

3296
02:51:00,320 --> 02:51:03,800
So our 2022
LATE recommendations

3297
02:51:03,800 --> 02:51:07,160
continues this dire need
for biomarkers.

3298
02:51:07,160 --> 02:51:11,520
We really need
to be able to delineate

3299
02:51:11,520 --> 02:51:15,800
when somebody who does not have
Alzheimer's disease has LATE,

3300
02:51:15,800 --> 02:51:17,800
and we need to know when someone
with Alzheimer's disease

3301
02:51:17,800 --> 02:51:19,680
has LATE in addition
to Alzheimer's disease

3302
02:51:19,680 --> 02:51:22,600
because maybe they won't respond
to the amyloid therapy as well.

3303
02:51:22,600 --> 02:51:26,040
We need experimental models
to start looking at this age

3304
02:51:26,040 --> 02:51:29,640
related TDP-43 update.

3305
02:51:29,640 --> 02:51:32,400
So biomarkers,
experimental models,

3306
02:51:32,400 --> 02:51:36,040
still really important.
But, in addition --

3307
02:51:36,040 --> 02:51:38,960
and I'll show you
in the next few slides --

3308
02:51:38,960 --> 02:51:40,880
these boundaries that
you've been hearing

3309
02:51:40,880 --> 02:51:42,800
about all of yesterday
and today,

3310
02:51:42,800 --> 02:51:46,880
we really think need
to be explored with LATE

3311
02:51:46,880 --> 02:51:49,200
and frontotemporal
lobar degeneration,

3312
02:51:49,200 --> 02:51:54,120
as well as LATE with Alzheimer's
disease and Lewy Body disease.

3313
02:51:54,120 --> 02:51:56,000
And I'll show you a little bit
more about that

3314
02:51:56,000 --> 02:51:57,680
in just a minute.

3315
02:51:57,680 --> 02:52:00,360
But in addition
to those boundaries,

3316
02:52:00,360 --> 02:52:04,680
we also see the need to look
at the intersection of LATE

3317
02:52:04,680 --> 02:52:06,160
with hippocampal sclerosis,

3318
02:52:06,160 --> 02:52:09,520
which is a very important
pathology in aging.

3319
02:52:09,520 --> 02:52:13,320
And especially
as our population ages,

3320
02:52:13,320 --> 02:52:15,520
you're going to see
that those numbers continue

3321
02:52:15,520 --> 02:52:17,520
to go up
of hippocampal sclerosis,

3322
02:52:17,520 --> 02:52:21,760
the vast majority of which
have TDP-43 pathology,

3323
02:52:21,760 --> 02:52:24,400
as well as an intersection
with vascular disease

3324
02:52:24,400 --> 02:52:26,200
and aging senescence.

3325
02:52:26,200 --> 02:52:28,560
And I'll show you a little bit
more about that too.

3326
02:52:28,560 --> 02:52:34,320
Next slide.
So here is Recommendation 1,

3327
02:52:34,320 --> 02:52:40,120
define LATE pathologic clinical
genetic molecular classification

3328
02:52:40,120 --> 02:52:45,440
and diagnostic boundaries
across FTLD TDP, AD,

3329
02:52:45,440 --> 02:52:48,000
and other
dementia-related pathologies

3330
02:52:48,000 --> 02:52:52,480
and their syndromes to enhance
diagnosis, research,

3331
02:52:52,480 --> 02:52:57,600
and awareness.
Next slide.

3332
02:52:57,600 --> 02:53:00,720
So here I'm just going to
show you why this is so complex.

3333
02:53:00,720 --> 02:53:02,760
So here's --
in the white circle

3334
02:53:02,760 --> 02:53:06,200
is Alzheimer's disease
neuropathologic changes occurs,

3335
02:53:06,200 --> 02:53:10,360
you know, in a large segment
of the population, as we know.

3336
02:53:10,360 --> 02:53:12,200
And then, in red,
you have people

3337
02:53:12,200 --> 02:53:14,240
with Alzheimer's disease
neuropathologic changes

3338
02:53:14,240 --> 02:53:19,400
who also have TDP, so they have
LATE neuropathologic changes.

3339
02:53:19,400 --> 02:53:22,000
So there's a lot
of overlap there.

3340
02:53:22,000 --> 02:53:24,000
And you can see
that there's a group

3341
02:53:24,000 --> 02:53:25,720
that does not have
Alzheimer's disease

3342
02:53:25,720 --> 02:53:29,280
that may have a dementia
just related to LATE.

3343
02:53:29,280 --> 02:53:31,800
But, in addition,
I put in a purple circle

3344
02:53:31,800 --> 02:53:34,320
because that's
hippocampal sclerosis.

3345
02:53:34,320 --> 02:53:38,000
And hippocampal sclerosis
intersects with all of these.

3346
02:53:38,000 --> 02:53:42,520
The majority of them
have TDP-43 pathology.

3347
02:53:42,520 --> 02:53:45,560
Some of them have
Alzheimer's disease in addition.

3348
02:53:45,560 --> 02:53:49,000
In fact, the majority of them
also have Alzheimer's disease.

3349
02:53:49,000 --> 02:53:50,680
Next; next, please.

3350
02:53:53,160 --> 02:53:55,440
And this is frontotemporal
lobar degeneration.

3351
02:53:55,440 --> 02:53:57,040
And I made the circle small

3352
02:53:57,040 --> 02:53:59,320
because Alzheimer's disease
is so much more common,

3353
02:53:59,320 --> 02:54:03,080
the frontotemporal lobar
degeneration with TDP.

3354
02:54:03,080 --> 02:54:06,720
Next slide or next, yes.

3355
02:54:06,720 --> 02:54:08,600
But frontotemporal
lobar degeneration

3356
02:54:08,600 --> 02:54:10,680
also has hippocampal
sclerosis.

3357
02:54:10,680 --> 02:54:13,200
So there's something
really going on with this --

3358
02:54:13,200 --> 02:54:14,640
these proteinopathies,

3359
02:54:14,640 --> 02:54:20,000
especially TDP-43
and hippocampal sclerosis. Next.

3360
02:54:20,000 --> 02:54:21,640
And then there's
Lewy body disease.

3361
02:54:21,640 --> 02:54:23,680
So we know already from
the research that's been done

3362
02:54:23,680 --> 02:54:26,600
just over the past few years
that Lewy bodies

3363
02:54:26,600 --> 02:54:30,400
are independently
related to TDP-43 pathology,

3364
02:54:30,400 --> 02:54:32,480
even separate
from Alzheimer's disease.

3365
02:54:32,480 --> 02:54:35,600
So, again, we're seeing
this mixture of these different

3366
02:54:35,600 --> 02:54:39,200
proteinopathies
being tremendously important.

3367
02:54:39,200 --> 02:54:40,760
And these intersections

3368
02:54:40,760 --> 02:54:42,800
aren't well-recognized
clinically, pathologically.

3369
02:54:42,800 --> 02:54:44,840
They're not studied as well
as they should be studied,

3370
02:54:44,840 --> 02:54:46,800
and this has been
brought up multiple times

3371
02:54:46,800 --> 02:54:49,840
by multiple people.
And this intersection

3372
02:54:49,840 --> 02:54:51,560
with frontotemporal
lobar degeneration

3373
02:54:51,560 --> 02:54:53,280
is also very important,

3374
02:54:53,280 --> 02:54:55,880
and I'll show you
a couple of reasons.

3375
02:54:55,880 --> 02:55:02,080
Next slide.
So it quickly became clear --

3376
02:55:02,080 --> 02:55:04,560
and this is just a snapshot
of some papers --

3377
02:55:04,560 --> 02:55:07,360
of the clinical
and pathologic overlaps

3378
02:55:07,360 --> 02:55:13,600
or, you know, difficulty
in classifying someone's cases

3379
02:55:13,600 --> 02:55:16,680
with TDP-43
and Alzheimer's disease

3380
02:55:16,680 --> 02:55:19,240
or with frontotemporal
lobar degeneration

3381
02:55:19,240 --> 02:55:22,360
and limbic predominant
TDP-43 deposition.

3382
02:55:22,360 --> 02:55:26,280
So, clearly, even though we'd
like to make these all separate,

3383
02:55:26,280 --> 02:55:28,200
the frontal temporal
lobar degeneration

3384
02:55:28,200 --> 02:55:31,840
and LATE, there's cases
that intersect.

3385
02:55:31,840 --> 02:55:35,520
And we don't really
understand the intersection

3386
02:55:35,520 --> 02:55:37,600
of these different
proteinopathies again,

3387
02:55:37,600 --> 02:55:39,920
and a lot more work
needs to be done.

3388
02:55:39,920 --> 02:55:43,400
Next slide.

3389
02:55:43,400 --> 02:55:45,800
But I don't think
the clinical and pathology

3390
02:55:45,800 --> 02:55:47,600
is going to get us
everywhere.

3391
02:55:47,600 --> 02:55:50,000
And we need the genetic,
molecular,

3392
02:55:50,000 --> 02:55:52,800
and structural boundaries
to really understand.

3393
02:55:52,800 --> 02:55:54,280
And you've heard a lot
about that, too,

3394
02:55:54,280 --> 02:55:55,680
about the different strains

3395
02:55:55,680 --> 02:55:57,960
and different configurations
and morphologies.

3396
02:55:57,960 --> 02:56:00,680
But look here
on this first study

3397
02:56:00,680 --> 02:56:05,560
where APOE is not only a risk
factor for Alzheimer's disease

3398
02:56:05,560 --> 02:56:08,200
but it also increases risk
for Lewy body disease,

3399
02:56:08,200 --> 02:56:10,640
as well as TDP-43.

3400
02:56:10,640 --> 02:56:12,160
TMEM106B,

3401
02:56:12,160 --> 02:56:15,320
a risk factor for frontotemporal
lobar degeneration,

3402
02:56:15,320 --> 02:56:19,000
increases TDP-43 pathology
in aging.

3403
02:56:19,000 --> 02:56:24,760
So, clearly, these mechanisms
overlap across disease states.

3404
02:56:24,760 --> 02:56:27,680
And then, as you've heard
through this conference,

3405
02:56:27,680 --> 02:56:31,480
you know, we're learning more
still about what these different

3406
02:56:31,480 --> 02:56:34,440
aggregates look like
in different disease states.

3407
02:56:34,440 --> 02:56:36,200
Next slide.

3408
02:56:36,200 --> 02:56:37,800
-Two minutes remaining.

3409
02:56:40,200 --> 02:56:43,000
-So the last thing I want
to talk about is that the --

3410
02:56:43,000 --> 02:56:45,760
our fourth and final
recommendation,

3411
02:56:45,760 --> 02:56:47,320
which is really
to pay attention

3412
02:56:47,320 --> 02:56:50,000
or to study this intersection
of hippocampal sclerosis

3413
02:56:50,000 --> 02:56:52,840
in the role of age
and vascular disease.

3414
02:56:52,840 --> 02:56:55,240
So we've known about
hippocampal sclerosis

3415
02:56:55,240 --> 02:56:58,000
in the pathology world
for a long time.

3416
02:56:58,000 --> 02:57:01,280
We know that it can mimic
an Alzheimer's type dementia.

3417
02:57:01,280 --> 02:57:05,000
We know it's very common
in the oldest old.

3418
02:57:05,000 --> 02:57:08,000
And there's a lot of interest
in hippocampal sclerosis

3419
02:57:08,000 --> 02:57:09,640
in the pathology world,

3420
02:57:09,640 --> 02:57:11,600
but it's not really noted
clinically very well or studied

3421
02:57:11,600 --> 02:57:15,800
from a nonclinical
or pathologic standpoint.

3422
02:57:15,800 --> 02:57:18,000
Almost all cases
of hippocampal sclerosis

3423
02:57:18,000 --> 02:57:21,000
with aging
have TDP-43 pathology,

3424
02:57:21,000 --> 02:57:23,000
but it's not
a specific pathology.

3425
02:57:23,000 --> 02:57:25,000
All hippocampal sclerosis is,

3426
02:57:25,000 --> 02:57:28,760
is severe degeneration
of the hippocampus in aging.

3427
02:57:28,760 --> 02:57:30,400
And you can also
see it interestingly

3428
02:57:30,400 --> 02:57:35,120
with apoptsic ischemic injury.
Next slide.

3429
02:57:35,120 --> 02:57:39,000
I should also mention that there
are no pathologic standards

3430
02:57:39,000 --> 02:57:40,560
for hippocampal sclerosis.

3431
02:57:40,560 --> 02:57:42,360
So we have no
consensus criteria.

3432
02:57:42,360 --> 02:57:45,360
We take one section of
hippocampus, a huge structure,

3433
02:57:45,360 --> 02:57:47,640
and do a six micron section
to look for it.

3434
02:57:47,640 --> 02:57:50,160
But we know from that finished
study on the other slot --

3435
02:57:50,160 --> 02:57:52,200
slide that it's patchy,

3436
02:57:52,200 --> 02:57:56,080
and we might not always
be seeing the pathology.

3437
02:57:56,080 --> 02:57:58,200
But we also,
in addition to that,

3438
02:57:58,200 --> 02:58:01,480
know that both TDP-43
and hippocampal sclerosis

3439
02:58:01,480 --> 02:58:03,200
are age-related pathologies.

3440
02:58:03,200 --> 02:58:09,240
And this is a study by Leah
Greenberg and Salvatore Spina,

3441
02:58:09,240 --> 02:58:12,120
showing that cerebral amyloid
angiopathy in Lewy body disease

3442
02:58:12,120 --> 02:58:15,720
are actually very common in
early onset Alzheimer's disease,

3443
02:58:15,720 --> 02:58:18,880
whereas TDP-43 and hippocampus
sclerosis are rarely present.

3444
02:58:18,880 --> 02:58:21,200
They're really
an age-related phenomenon.

3445
02:58:21,200 --> 02:58:25,040
And we have an aging society,
so we really need to understand

3446
02:58:25,040 --> 02:58:29,600
in studies that use aging within
their models what is happening.

3447
02:58:29,600 --> 02:58:34,240
And then, finally,
there's inflammation

3448
02:58:34,240 --> 02:58:37,000
or there's data suggesting
for multiple groups

3449
02:58:37,000 --> 02:58:40,640
now that vascular disease
also intersects.

3450
02:58:40,640 --> 02:58:42,400
So here we have
a couple different groups

3451
02:58:42,400 --> 02:58:44,040
showing that arterial sclerosis

3452
02:58:44,040 --> 02:58:45,800
is related
to hippocampal sclerosis.

3453
02:58:45,800 --> 02:58:49,520
We in our group found
that arteriosclerosis

3454
02:58:49,520 --> 02:58:53,400
was related
to TDP-43 pathology.

3455
02:58:53,400 --> 02:58:59,120
So what that exactly means
or why that would be interacting

3456
02:58:59,120 --> 02:59:01,800
is completely
at this point unknown.

3457
02:59:01,800 --> 02:59:03,800
Next slide.

3458
02:59:03,800 --> 02:59:05,040
-Time.

3459
02:59:05,040 --> 02:59:08,000
-Next slide.
So this is my last slide.

3460
02:59:08,000 --> 02:59:09,640
So, this is recommendation
number 4.

3461
02:59:09,640 --> 02:59:12,880
To study this intersection
with hippocampal sclerosis

3462
02:59:12,880 --> 02:59:16,160
and LATE NC within and across
all disciplines again,

3463
02:59:16,160 --> 02:59:17,560
not just clinical
and pathologic

3464
02:59:17,560 --> 02:59:20,280
but diagnostic,
genetic, molecular,

3465
02:59:20,280 --> 02:59:23,800
and to consider the roles
of vasculopathy and senescence

3466
02:59:23,800 --> 02:59:26,720
and other potential
contributing factors.

3467
02:59:26,720 --> 02:59:28,280
So thank you
for your attention.

3468
02:59:28,280 --> 02:59:32,480
And I'm going to hand
the reins over to Dr. Wolk.

3469
02:59:32,480 --> 02:59:37,040
-Thanks so much, Julie.
Next slide.

3470
02:59:37,040 --> 02:59:41,880
So, I'm going to focus, as Julie
said, on recommendation 2.

3471
02:59:41,880 --> 02:59:45,760
We'll talk about our current
understanding and knowledge gaps

3472
02:59:45,760 --> 02:59:48,640
in the clinical
manifestations of LATE.

3473
02:59:48,640 --> 02:59:52,000
And then I think we'll discuss
where we are now

3474
02:59:52,000 --> 02:59:53,800
with clinical detection
of LATE

3475
02:59:53,800 --> 02:59:57,000
and kind of where we need
to go moving forward.

3476
02:59:57,000 --> 03:00:02,160
Next slide.
So this is recommendation 2.

3477
03:00:02,160 --> 03:00:07,160
It is -- sort of builds
off of the prior summit.

3478
03:00:07,160 --> 03:00:10,280
It developed -- it's to
develop biomarkers, classifiers,

3479
03:00:10,280 --> 03:00:12,800
and risk profiles to establish

3480
03:00:12,800 --> 03:00:16,840
an in vivo
diagnostic criteria for LATE

3481
03:00:16,840 --> 03:00:20,360
in people in the preclinical
phase of the disease,

3482
03:00:20,360 --> 03:00:23,200
as well as those
with an amnestic

3483
03:00:23,200 --> 03:00:25,560
LATE life dementia syndrome.

3484
03:00:25,560 --> 03:00:27,560
I won't go through
each of these bullet points

3485
03:00:27,560 --> 03:00:30,360
because I think they get set up
in the later slides.

3486
03:00:30,360 --> 03:00:32,680
But I will point out
the last bullet point,

3487
03:00:32,680 --> 03:00:36,000
which is that, ultimately,
we really do need to develop

3488
03:00:36,000 --> 03:00:40,600
bio fluid and neuro imaging
and/or neuroimaging biomarkers

3489
03:00:40,600 --> 03:00:42,800
of the molecular pathology
of LATE

3490
03:00:42,800 --> 03:00:45,480
and, in particular, TDP-43.

3491
03:00:45,480 --> 03:00:48,440
However, until we get
to that goal,

3492
03:00:48,440 --> 03:00:52,480
we felt that we really need
to develop

3493
03:00:52,480 --> 03:00:55,800
probabilistic classifiers
that are validated for us

3494
03:00:55,800 --> 03:00:59,480
to be able to do in vivo studies
in this population.

3495
03:00:59,480 --> 03:01:02,000
Next slide.

3496
03:01:02,000 --> 03:01:04,320
So just wanted to provide
a little bit of context

3497
03:01:04,320 --> 03:01:07,480
and in part
because this demonstrates

3498
03:01:07,480 --> 03:01:11,600
that we see these cases
in our clinics already.

3499
03:01:11,600 --> 03:01:14,640
This is a 78-year-old woman
who had arthritis,

3500
03:01:14,640 --> 03:01:18,560
prior hysterectomy for
uterine cancer; and depression.

3501
03:01:18,560 --> 03:01:20,680
She had several years
of memory loss.

3502
03:01:20,680 --> 03:01:23,120
She would forget
where she parked her car,

3503
03:01:23,120 --> 03:01:25,480
and she was misplacing things.

3504
03:01:25,480 --> 03:01:27,440
She previously was great
with the computer

3505
03:01:27,440 --> 03:01:29,440
and had
increasing difficulty,

3506
03:01:29,440 --> 03:01:32,200
and her family felt she seemed
a little more stressed out

3507
03:01:32,200 --> 03:01:34,000
and struggled more
with decisions.

3508
03:01:34,000 --> 03:01:36,880
Next slide.

3509
03:01:36,880 --> 03:01:39,680
These are her initial standard
psychometric testing.

3510
03:01:39,680 --> 03:01:42,200
And the important thing
to point out here

3511
03:01:42,200 --> 03:01:45,760
is in purple where
she's impaired are all tests

3512
03:01:45,760 --> 03:01:48,120
that have to do
with verbal or visual memory.

3513
03:01:48,120 --> 03:01:51,520
Other cognitive demands
were essentially intact.

3514
03:01:51,520 --> 03:01:55,880
Next slide.
So this was her initial MRI,

3515
03:01:55,880 --> 03:01:59,560
and I hope
you can appreciate that,

3516
03:01:59,560 --> 03:02:02,400
in the right anterior
hippocampus,

3517
03:02:02,400 --> 03:02:04,000
there was some degree
of atrophy.

3518
03:02:04,000 --> 03:02:06,600
But there wasn't a lot
of cortical atrophy otherwise

3519
03:02:06,600 --> 03:02:09,000
and maybe a little bit
of vascular disease,

3520
03:02:09,000 --> 03:02:13,080
small vessel disease.
Next slide.

3521
03:02:13,080 --> 03:02:15,200
So she had a very slow course.

3522
03:02:15,200 --> 03:02:18,000
We followed her
for over nine years.

3523
03:02:18,000 --> 03:02:20,120
On the left, you can see her
psychometric testing,

3524
03:02:20,120 --> 03:02:21,800
which kind of barely
changed over time

3525
03:02:21,800 --> 03:02:23,400
but did get a little bit worse.

3526
03:02:23,400 --> 03:02:28,800
She had poor memory, but
that remained relatively stable.

3527
03:02:28,800 --> 03:02:33,200
They noticed some decreases
in her attention and motivation.

3528
03:02:33,200 --> 03:02:35,080
She also had a little bit
of disinhibition.

3529
03:02:35,080 --> 03:02:37,000
She would say negative things
about people

3530
03:02:37,000 --> 03:02:41,280
while they were in the room,
which embarrassed her daughter.

3531
03:02:41,280 --> 03:02:43,520
The important point is,
throughout her entire course,

3532
03:02:43,520 --> 03:02:47,000
she had a diagnosis
of Alzheimer's disease.

3533
03:02:47,000 --> 03:02:51,160
Next slide.
This is her CAT scan

3534
03:02:51,160 --> 03:02:54,120
that was done just a few months
before she passed away.

3535
03:02:54,120 --> 03:02:56,240
And now I think
you can really appreciate

3536
03:02:56,240 --> 03:02:57,640
both anterior hippocampal

3537
03:02:57,640 --> 03:03:01,120
and anterior temporal
atrophy bilaterally,

3538
03:03:01,120 --> 03:03:03,920
a little bit more
on the right than the left,

3539
03:03:03,920 --> 03:03:06,920
and some cortical atrophy
perhaps a little bit frontal

3540
03:03:06,920 --> 03:03:10,600
but, otherwise, not too much.
Next slide.

3541
03:03:10,600 --> 03:03:12,800
So she went on to autopsy

3542
03:03:12,800 --> 03:03:16,600
and was found as
a primary pathologic diagnosis

3543
03:03:16,600 --> 03:03:19,000
to have a LATE
neuropathic change

3544
03:03:19,000 --> 03:03:21,720
without any evidence
of Alzheimer's disease.

3545
03:03:21,720 --> 03:03:24,440
So, again, this would be
an example of a case

3546
03:03:24,440 --> 03:03:28,000
that we misdiagnosed
as Alzheimer's disease.

3547
03:03:28,000 --> 03:03:30,320
Next slide.

3548
03:03:30,320 --> 03:03:32,040
So I think since
the last summit

3549
03:03:32,040 --> 03:03:34,200
we actually have made
a fair bit of progress

3550
03:03:34,200 --> 03:03:38,600
in defining the clinical
features of LATE.

3551
03:03:38,600 --> 03:03:41,160
For example, on the left,
you can see and consistent

3552
03:03:41,160 --> 03:03:43,560
with this case
that LATE neuropathic changes

3553
03:03:43,560 --> 03:03:46,560
associated with a relatively
slow course of decline

3554
03:03:46,560 --> 03:03:50,000
compared to
Alzheimer's disease.

3555
03:03:50,000 --> 03:03:52,600
Episodic memory tends to be

3556
03:03:52,600 --> 03:03:54,720
the most prominently
affected domain,

3557
03:03:54,720 --> 03:03:57,520
and that can be
very significantly affected.

3558
03:03:57,520 --> 03:03:58,920
There's still some question
about whether

3559
03:03:58,920 --> 03:04:01,400
other domains
are affected

3560
03:04:01,400 --> 03:04:04,760
and to what extent,
such as semantic memory.

3561
03:04:04,760 --> 03:04:07,920
While these cases
certainly do not have

3562
03:04:07,920 --> 03:04:10,360
the behavioral manifestations

3563
03:04:10,360 --> 03:04:13,000
of full blown
FTD spectrum disorders,

3564
03:04:13,000 --> 03:04:14,480
there's also some question
whether they have

3565
03:04:14,480 --> 03:04:17,960
some behavioral associations
such as this case.

3566
03:04:17,960 --> 03:04:20,160
The important point is,
when you look at population

3567
03:04:20,160 --> 03:04:22,400
and community
based autopsy studies,

3568
03:04:22,400 --> 03:04:25,120
these individuals represent
about 1 in 10 individuals.

3569
03:04:25,120 --> 03:04:28,000
This is a common condition.
Next slide.

3570
03:04:30,080 --> 03:04:32,920
In terms of thinking about
what other kinds

3571
03:04:32,920 --> 03:04:35,000
of cognitive
and behavioral symptoms

3572
03:04:35,000 --> 03:04:37,600
may be present
in these individuals,

3573
03:04:37,600 --> 03:04:41,520
I think it's useful to think
about where TDP-43

3574
03:04:41,520 --> 03:04:44,240
spreads in the brain
in the context of LATE.

3575
03:04:44,240 --> 03:04:45,640
And I should note
there are three different

3576
03:04:45,640 --> 03:04:47,800
staging systems out there,

3577
03:04:47,800 --> 03:04:50,280
all with different levels
of granularity.

3578
03:04:50,280 --> 03:04:53,640
But the bottom line
is they show regions

3579
03:04:53,640 --> 03:04:56,200
that are affected such
as anterior temporal cortex,

3580
03:04:56,200 --> 03:05:00,240
orbital frontal cortex,
insula, middle frontal gyrus,

3581
03:05:00,240 --> 03:05:03,000
which suggests that there may be
additional impairments

3582
03:05:03,000 --> 03:05:06,640
and semantic memory behavior
and perhaps,

3583
03:05:06,640 --> 03:05:09,400
to some extent,
executive functioning.

3584
03:05:09,400 --> 03:05:14,200
Next slide.
It turns out,

3585
03:05:14,200 --> 03:05:18,520
when LATE is associated
with hippocampal sclerosis,

3586
03:05:18,520 --> 03:05:21,520
we actually do see
more significant decline

3587
03:05:21,520 --> 03:05:25,880
not only in memory but we do see
involvement in semantic memory

3588
03:05:25,880 --> 03:05:30,360
and perhaps to some
extent perceptual speed.

3589
03:05:30,360 --> 03:05:33,920
Next slide.

3590
03:05:33,920 --> 03:05:37,920
So -- and this touches a little
bit on recommendation 4,

3591
03:05:37,920 --> 03:05:43,240
but we really need to understand
the clinical phenotype

3592
03:05:43,240 --> 03:05:47,040
that differentiates LATE
with hippocampal sclerosis

3593
03:05:47,040 --> 03:05:49,960
versus LATE without
hippocampal sclerosis.

3594
03:05:49,960 --> 03:05:51,520
But as Julie mentioned,

3595
03:05:51,520 --> 03:05:57,440
we also really need
to study the drivers of LATE.

3596
03:05:57,440 --> 03:06:02,160
We do know some things about
how hippocampal sclerosis

3597
03:06:02,160 --> 03:06:04,120
presents in the setting of LATE.

3598
03:06:04,120 --> 03:06:07,400
These individuals,
as I mentioned already do seem

3599
03:06:07,400 --> 03:06:10,040
to show more severe
cognitive impairment,

3600
03:06:10,040 --> 03:06:11,760
particularly memory,

3601
03:06:11,760 --> 03:06:16,560
but they also tend to have
a higher or later stage of LATE

3602
03:06:16,560 --> 03:06:19,520
in terms of the spread
of TDP-43.

3603
03:06:19,520 --> 03:06:22,040
So it's not surprising
that these individuals

3604
03:06:22,040 --> 03:06:24,120
have other domains
of cognitive impairment

3605
03:06:24,120 --> 03:06:26,800
like semantic memory affected.

3606
03:06:26,800 --> 03:06:31,800
As was also mentioned before,
these individuals seem to have

3607
03:06:31,800 --> 03:06:34,080
some relationship
with vascular disease.

3608
03:06:34,080 --> 03:06:36,760
They have a higher rate
of atherosclerosis

3609
03:06:36,760 --> 03:06:38,600
that's been described.

3610
03:06:38,600 --> 03:06:41,000
Interestingly,
the genetics of LATE

3611
03:06:41,000 --> 03:06:44,280
alone versus LATE
with hippocampal sclerosis

3612
03:06:44,280 --> 03:06:46,800
may differ as shown
on the right.

3613
03:06:46,800 --> 03:06:49,760
And, importantly, as we are
starting to develop

3614
03:06:49,760 --> 03:06:52,200
these sort of genetic risks
of LATE,

3615
03:06:52,200 --> 03:06:54,600
these are features
that can be included

3616
03:06:54,600 --> 03:06:56,120
in classification models

3617
03:06:56,120 --> 03:07:00,960
as we move forward
to define the disease in vivo.

3618
03:07:00,960 --> 03:07:04,320
Next slide.

3619
03:07:04,320 --> 03:07:08,160
So we've been talking about
LATE neuropathic change alone,

3620
03:07:08,160 --> 03:07:11,120
but I think one of the really
important areas

3621
03:07:11,120 --> 03:07:15,240
is how it interacts with other
neurodegenerative conditions,

3622
03:07:15,240 --> 03:07:18,480
particularly
Alzheimer's disease.

3623
03:07:18,480 --> 03:07:23,720
So on the left is relatively
new data from 13 community

3624
03:07:23,720 --> 03:07:26,400
and population
based autopsy cohorts,

3625
03:07:26,400 --> 03:07:29,360
which suggests that up
to half of individuals

3626
03:07:29,360 --> 03:07:31,800
who have late stage
Alzheimer's disease,

3627
03:07:31,800 --> 03:07:36,280
neuropathic change also have
LATE neuropathic change.

3628
03:07:36,280 --> 03:07:38,520
And, importantly,

3629
03:07:38,520 --> 03:07:41,400
in the combination
of Alzheimer's disease and LATE

3630
03:07:41,400 --> 03:07:45,520
seems to be associated
with a much accelerated decline

3631
03:07:45,520 --> 03:07:49,600
over time that we see relative
to Alzheimer's disease.

3632
03:07:49,600 --> 03:07:52,040
So it's really the fastest
progressing form

3633
03:07:52,040 --> 03:07:54,160
of Alzheimer's disease
in some ways.

3634
03:07:54,160 --> 03:07:57,600
And, actually, if you look at
different stages of Alzheimer's

3635
03:07:57,600 --> 03:07:59,960
based on Braak stage,
at any of those stages,

3636
03:07:59,960 --> 03:08:05,120
the presence of LATE is
associated with poor cognition.

3637
03:08:05,120 --> 03:08:08,040
Next slide.

3638
03:08:08,040 --> 03:08:11,200
So detection of LATE
in clinical populations,

3639
03:08:11,200 --> 03:08:13,520
I think,
is critically important.

3640
03:08:13,520 --> 03:08:15,520
It's a common source
of cognitive impairment

3641
03:08:15,520 --> 03:08:16,960
in older adults.

3642
03:08:16,960 --> 03:08:20,280
And in clinical diagnosis
of Alzheimer's disease

3643
03:08:20,280 --> 03:08:24,000
probably makes up 20%
of the attributable risk.

3644
03:08:24,000 --> 03:08:25,520
It has important prognostic

3645
03:08:25,520 --> 03:08:27,120
and potentially
treatment implications

3646
03:08:27,120 --> 03:08:30,080
and amnestic cognitive
impairment presentations.

3647
03:08:30,080 --> 03:08:33,240
A slower course is expected
in someone

3648
03:08:33,240 --> 03:08:35,240
who has it in
the absence of Alzheimer's,

3649
03:08:35,240 --> 03:08:38,520
but a much more rapid course
is expected in patients

3650
03:08:38,520 --> 03:08:40,600
who do have
Alzheimer's disease.

3651
03:08:40,600 --> 03:08:43,560
And, really, our ability
to be able to detect it in vivo

3652
03:08:43,560 --> 03:08:46,400
is what's going to allow us
to do broader studies of risk,

3653
03:08:46,400 --> 03:08:49,000
genetics, clinical
and cognitive phenotype

3654
03:08:49,000 --> 03:08:52,200
and eventually
intervention studies.

3655
03:08:52,200 --> 03:08:54,200
I think, though,
critically important

3656
03:08:54,200 --> 03:08:56,480
to the Alzheimer's
disease field

3657
03:08:56,480 --> 03:09:00,440
is that it's a major source
of variability in progression

3658
03:09:00,440 --> 03:09:04,200
that can impact clinical trials
and may also limit the efficacy

3659
03:09:04,200 --> 03:09:07,400
when specifically targeting
AD pathophysiology.

3660
03:09:07,400 --> 03:09:11,080
And, currently, there are
no molecularly specific markers

3661
03:09:11,080 --> 03:09:14,640
of TDP-43.
Next slide.

3662
03:09:14,640 --> 03:09:17,200
So then how can
we detect it now?

3663
03:09:17,200 --> 03:09:21,000
And, again, there have been some
progress since the last summit.

3664
03:09:21,000 --> 03:09:24,440
For one thing, there are spatial
patterns of neurodegeneration

3665
03:09:24,440 --> 03:09:28,600
based on atrophy
or hypometabolism on PET,

3666
03:09:28,600 --> 03:09:31,040
which can be suggestive
of LATE neuropathic change.

3667
03:09:31,040 --> 03:09:34,960
And they've been linked to post
mortem data to various extents.

3668
03:09:34,960 --> 03:09:39,080
One also can inferentially
determine the likelihood of LATE

3669
03:09:39,080 --> 03:09:41,240
based on Alzheimer's
disease markers.

3670
03:09:41,240 --> 03:09:42,800
So Alzheimer's disease
is defined

3671
03:09:42,800 --> 03:09:46,560
by the presence of amyloid
and tau biomarkers.

3672
03:09:46,560 --> 03:09:51,800
And neurodegeneration is used
to sort of stage individuals,

3673
03:09:51,800 --> 03:09:54,400
the so-called ATN framework.

3674
03:09:54,400 --> 03:09:56,520
Well, if an individual
is amyloid negative

3675
03:09:56,520 --> 03:09:58,520
with an amnestic syndrome,

3676
03:09:58,520 --> 03:10:01,600
particularly if they have
atrophy in a LATE like pattern,

3677
03:10:01,600 --> 03:10:04,160
they're much more likely
to have LATE.

3678
03:10:04,160 --> 03:10:05,640
But we really want
to be able to detect it

3679
03:10:05,640 --> 03:10:09,560
when individuals also have
Alzheimer's disease.

3680
03:10:09,560 --> 03:10:10,960
And what we know is,

3681
03:10:10,960 --> 03:10:13,080
within that Alzheimer's
disease continuum,

3682
03:10:13,080 --> 03:10:15,840
tau is tightly linked
to neurodegeneration.

3683
03:10:15,840 --> 03:10:18,640
So if an individual
has significant medial

3684
03:10:18,640 --> 03:10:20,240
temporal lobe atrophy

3685
03:10:20,240 --> 03:10:22,800
and a LATE like pattern
in the absence of tau pathology,

3686
03:10:22,800 --> 03:10:27,880
that may suggest LATE.
Or if they have tau pathology

3687
03:10:27,880 --> 03:10:30,360
but neurodegeneration exceeds
what we expect,

3688
03:10:30,360 --> 03:10:33,360
that, too, might be a marker
to use for LATE.

3689
03:10:33,360 --> 03:10:36,280
Next slide.

3690
03:10:36,280 --> 03:10:39,840
So, again, there have been --
there has been work showing

3691
03:10:39,840 --> 03:10:43,640
that there are spatial patterns
to change that occur with LATE

3692
03:10:43,640 --> 03:10:46,320
that may differentiate it
from Alzheimer's disease.

3693
03:10:46,320 --> 03:10:48,960
So, for example, on the left
is post mortem work

3694
03:10:48,960 --> 03:10:53,400
showing amygdala patterns
of atrophy or shape change.

3695
03:10:53,400 --> 03:10:55,200
And on the right
is a study we did

3696
03:10:55,200 --> 03:10:57,400
where we looked
at antemortem MRI

3697
03:10:57,400 --> 03:11:00,760
and found that Alzheimer's
disease with TDP-43

3698
03:11:00,760 --> 03:11:03,600
tended to have more anterior
medial temporal atrophy

3699
03:11:03,600 --> 03:11:05,400
than Alzheimer's disease
without it.

3700
03:11:05,400 --> 03:11:07,520
And, actually, if you took
a ratio of anterior

3701
03:11:07,520 --> 03:11:09,640
to posterior MTL,

3702
03:11:09,640 --> 03:11:12,360
there was fairly
good discrimination

3703
03:11:12,360 --> 03:11:15,040
between these groups.
Next slide.

3704
03:11:15,040 --> 03:11:16,640
-Two minutes remaining.

3705
03:11:19,040 --> 03:11:21,920
-We also have seen that there
are cortical patterns

3706
03:11:21,920 --> 03:11:25,640
of atrophy in LATE.
So, for example, on the left

3707
03:11:25,640 --> 03:11:28,800
is a post mortem study
showing atrophy

3708
03:11:28,800 --> 03:11:32,000
in temporal polar regions
and frontal regions.

3709
03:11:32,000 --> 03:11:34,920
And this has also been seen
in vivo as well,

3710
03:11:34,920 --> 03:11:36,320
where in particular, again,

3711
03:11:36,320 --> 03:11:38,000
you see this gradient
of greater anterior

3712
03:11:38,000 --> 03:11:41,520
than posterior temporal
involvement. Next slide.

3713
03:11:44,920 --> 03:11:48,320
There also have been
FDG PET signatures of LATE,

3714
03:11:48,320 --> 03:11:50,760
some really nice work done
by the Mayo group,

3715
03:11:50,760 --> 03:11:52,320
which has found

3716
03:11:52,320 --> 03:11:54,760
particularly severe medial
temporal hypometabolism

3717
03:11:54,760 --> 03:11:58,320
relative to inferior
temporal hypometabolism.

3718
03:11:58,320 --> 03:12:01,360
And this discriminates between
Alzheimer's disease and LATE.

3719
03:12:01,360 --> 03:12:02,800
And if, in more recent work,

3720
03:12:02,800 --> 03:12:04,840
if you add orbital
frontal cortex,

3721
03:12:04,840 --> 03:12:06,880
that further increases
discrimination.

3722
03:12:06,880 --> 03:12:09,200
Next slide.

3723
03:12:09,200 --> 03:12:13,160
But, again, we can establish
the diagnosis

3724
03:12:13,160 --> 03:12:18,000
inferentially through
AD biomarkers.

3725
03:12:18,000 --> 03:12:20,040
So this is a case
of someone

3726
03:12:20,040 --> 03:12:22,440
who's 83 with
an amnestic presentation

3727
03:12:22,440 --> 03:12:26,400
who has had positive
amyloid marker but negative tau.

3728
03:12:26,400 --> 03:12:29,880
Next slide.
However, they also had

3729
03:12:29,880 --> 03:12:31,840
very significant
hippocampal atrophy --

3730
03:12:31,840 --> 03:12:35,640
next slide -- as well
as a little bit of athero.

3731
03:12:35,640 --> 03:12:38,400
So this is a case
that had neurodegeneration

3732
03:12:38,400 --> 03:12:40,400
in the medial temporal lobe
without tau.

3733
03:12:40,400 --> 03:12:43,400
And so we might expect a non AD
driver of Alzheimer's disease.

3734
03:12:43,400 --> 03:12:45,520
Next slide.

3735
03:12:45,520 --> 03:12:48,000
And, indeed,
this was a stage two LATE case.

3736
03:12:48,000 --> 03:12:51,840
Next slide.
We've also been trying to look

3737
03:12:51,840 --> 03:12:54,640
at the relative amount
of tau to atrophy.

3738
03:12:54,640 --> 03:12:56,880
And I've had -- found people
who have more atrophy

3739
03:12:56,880 --> 03:12:59,360
than expected
for a given level of tau.

3740
03:12:59,360 --> 03:13:04,400
And, in fact, some of those
individuals have that increase

3741
03:13:04,400 --> 03:13:08,440
or mismatch of neurodegeneration
in LATE-like regions.

3742
03:13:08,440 --> 03:13:10,640
And, actually, we can cluster
these groups together

3743
03:13:10,640 --> 03:13:12,520
using machine
learning based approaches.

3744
03:13:12,520 --> 03:13:14,200
Next slide.

3745
03:13:14,200 --> 03:13:15,800
-Time.

3746
03:13:15,800 --> 03:13:17,640
-And what we've found is that

3747
03:13:17,640 --> 03:13:19,880
there's a limbic
vulnerable group

3748
03:13:19,880 --> 03:13:21,120
and a limbic resilient group.

3749
03:13:21,120 --> 03:13:22,960
But, importantly,
the vulnerable group

3750
03:13:22,960 --> 03:13:27,560
tends to have high levels of
TDP-43 in post mortem analyses

3751
03:13:27,560 --> 03:13:31,680
whereas the limbic has,
if anything, low levels.

3752
03:13:31,680 --> 03:13:35,440
Next slide.
And just very quickly, to end,

3753
03:13:35,440 --> 03:13:39,400
I think we need to bring all of
this knowledge into the clinic

3754
03:13:39,400 --> 03:13:42,440
by incorporating
multiple biomarkers

3755
03:13:42,440 --> 03:13:44,360
for probabilistic models,

3756
03:13:44,360 --> 03:13:47,320
including cognitive data
risk factors and genomics.

3757
03:13:47,320 --> 03:13:49,560
And all of this, though,
needs to be validated

3758
03:13:49,560 --> 03:13:53,040
and replicated
in large post mortem studies.

3759
03:13:53,040 --> 03:13:57,160
But, again, ultimately, we
need to find TDP-43 biomarkers.

3760
03:13:57,160 --> 03:14:02,160
And so I will now turn the mic
over to my colleague,

3761
03:14:02,160 --> 03:14:05,240
Michael Gitcho.

3762
03:14:05,240 --> 03:14:06,880
-Thank you very much.

3763
03:14:06,880 --> 03:14:09,000
I'm going to talk about
experimental models

3764
03:14:09,000 --> 03:14:13,000
of LATE that incorporate aging
and relevant phenotypes.

3765
03:14:16,440 --> 03:14:19,200
There's nothing --

3766
03:14:19,200 --> 03:14:21,080
recommendation is to build
new experimental models

3767
03:14:21,080 --> 03:14:22,800
that incorporate
aging with behavior,

3768
03:14:22,800 --> 03:14:24,760
pathological,
molecular phenotypes

3769
03:14:24,760 --> 03:14:28,160
of TDP-43, proteinopathy
or hippocampal sclerosis,

3770
03:14:28,160 --> 03:14:31,320
advanced knowledge enable
testing and therapeutics.

3771
03:14:31,320 --> 03:14:34,000
Overall, to develop
and characterize models

3772
03:14:34,000 --> 03:14:37,040
that incorporate aging,
designed to simulate latency,

3773
03:14:37,040 --> 03:14:39,480
TDP-43 dependent clinical

3774
03:14:39,480 --> 03:14:43,000
and pathological phenotypes
potential. Next.

3775
03:14:46,560 --> 03:14:48,720
There are mobile models
to study aging

3776
03:14:48,720 --> 03:14:50,520
and maybe looking
for innerve generation

3777
03:14:50,520 --> 03:14:52,280
with nontraditional models
may be --

3778
03:14:52,280 --> 03:14:56,680
may be helpful in understanding
the disease better.

3779
03:14:56,680 --> 03:15:00,240
Next, please --

3780
03:15:00,240 --> 03:15:05,200
was talking about this
really exciting paper

3781
03:15:05,200 --> 03:15:08,440
that came out
by our senior colleagues

3782
03:15:08,440 --> 03:15:11,800
that using nicarwine maps
of TDP-43,

3783
03:15:11,800 --> 03:15:15,360
they're able to map
TDP-43 pathological filaments

3784
03:15:15,360 --> 03:15:21,600
aggregation from ALS
with an FTLD case,

3785
03:15:21,600 --> 03:15:23,000
two cases they looked at.

3786
03:15:23,000 --> 03:15:26,680
This is real exciting
because previously,

3787
03:15:26,680 --> 03:15:30,000
this C terminal region,
this glycine rich region

3788
03:15:30,000 --> 03:15:32,920
has been fairly undefined
until now.

3789
03:15:32,920 --> 03:15:34,640
And we can start to --

3790
03:15:34,640 --> 03:15:36,080
and understanding the structure
will give us a better idea

3791
03:15:36,080 --> 03:15:38,400
as far as understanding
disease mechanisms,

3792
03:15:38,400 --> 03:15:42,240
maybe possibly development
of drug targets,

3793
03:15:42,240 --> 03:15:47,000
in addition to maybe develop
even some PET ligands

3794
03:15:47,000 --> 03:15:50,280
that may be useful
detection of TDP-43.

3795
03:15:50,280 --> 03:15:53,560
And I guess the big question
to ask on this, too, is,

3796
03:15:53,560 --> 03:15:57,000
is the structure
of these pathological filaments

3797
03:15:57,000 --> 03:16:03,040
of TDP-43 in AOS
FTLD different in LATE,

3798
03:16:03,040 --> 03:16:05,600
and maybe that will be
determined at some point.

3799
03:16:05,600 --> 03:16:07,200
Next, please.

3800
03:16:09,720 --> 03:16:12,200
So to look at this,
we're going to --

3801
03:16:12,200 --> 03:16:14,360
one of the recommendations
is to look

3802
03:16:14,360 --> 03:16:18,040
at virally transduced
animal models using age animals.

3803
03:16:18,040 --> 03:16:19,720
Caudry and Associates
looked at 10-

3804
03:16:19,720 --> 03:16:22,200
to 12-month-old mice
using the cAMP

3805
03:16:22,200 --> 03:16:26,000
kinase tetracycline
response element,

3806
03:16:26,000 --> 03:16:27,600
the doxycycline
response element.

3807
03:16:27,600 --> 03:16:31,760
So they introduced AB virus

3808
03:16:31,760 --> 03:16:36,160
with specific expression
into the hippocampus

3809
03:16:36,160 --> 03:16:38,440
using this model,
model regulatory expression.

3810
03:16:38,440 --> 03:16:42,160
And they show that just over
15 days post transduction

3811
03:16:42,160 --> 03:16:49,040
TDP-43 causes neuronal loss in
the hippocampus in stage 2 here.

3812
03:16:49,040 --> 03:16:51,040
There's no change
with alpha synuclein.

3813
03:16:51,040 --> 03:16:53,840
I think it's important
to emphasize

3814
03:16:53,840 --> 03:16:55,560
the use of multiple pathologies

3815
03:16:55,560 --> 03:17:00,600
when it comes to look at these
changes with TDP-43 in LATE

3816
03:17:00,600 --> 03:17:03,840
to maybe possibly use
this together in sync

3817
03:17:03,840 --> 03:17:06,800
with the same animal
to look at some nucleon or tau

3818
03:17:06,800 --> 03:17:08,960
or other pathological
proteins together.

3819
03:17:08,960 --> 03:17:10,560
Next, please.

3820
03:17:12,640 --> 03:17:16,240
Knock-in, gene edited,
or stress induced models.

3821
03:17:16,240 --> 03:17:18,760
Deboin colleagues
looked at this,

3822
03:17:18,760 --> 03:17:21,040
developed these humanized
knock-in lines

3823
03:17:21,040 --> 03:17:26,000
that are driving TDP-43
along SO D1, also FAS,

3824
03:17:26,000 --> 03:17:30,800
but driving TDP-43 using
the endogenous promoter,

3825
03:17:30,800 --> 03:17:33,800
humanized lines as they possibly
can be used

3826
03:17:33,800 --> 03:17:35,440
for introducing
mutations for FTLD.

3827
03:17:35,440 --> 03:17:38,400
But this could maybe
be applied to LATE as well.

3828
03:17:38,400 --> 03:17:42,800
Introducing modifications or
seeing what changes occur here,

3829
03:17:42,800 --> 03:17:45,920
looking at this
endogenous promoter.

3830
03:17:45,920 --> 03:17:51,320
Next slide, please.
Stress induced cellular models.

3831
03:17:51,320 --> 03:17:52,640
Roddy and Associates
looked at this,

3832
03:17:52,640 --> 03:17:55,400
and they use
an oxidative stress model,

3833
03:17:55,400 --> 03:17:59,320
but arsenide treated,
fibroblast or IPS motor cells.

3834
03:17:59,320 --> 03:18:00,680
It's important to note on two

3835
03:18:00,680 --> 03:18:02,800
on this phosphorylate
TDP-43 aggregation

3836
03:18:02,800 --> 03:18:04,960
to look at all the bio
for cellular models

3837
03:18:04,960 --> 03:18:07,680
in particular to look at --

3838
03:18:07,680 --> 03:18:12,920
be able to replicate aggregation
as far as changes in solubility

3839
03:18:12,920 --> 03:18:15,200
and to have
the biochemical signatures

3840
03:18:15,200 --> 03:18:17,400
with the cleavage products
and other things as well.

3841
03:18:17,400 --> 03:18:19,440
But this could be
definitely used as a model

3842
03:18:19,440 --> 03:18:22,480
to maybe use for drug studies
or other ones as well.

3843
03:18:22,480 --> 03:18:27,600
Next slide, please.
Next slide, please.

3844
03:18:30,640 --> 03:18:32,240
No. Back one.
I'm sorry.

3845
03:18:37,040 --> 03:18:38,880
Can you go back. There we go.
Now we're good.

3846
03:18:38,880 --> 03:18:41,880
So interaction between TDP-43
and other pathological proteins,

3847
03:18:41,880 --> 03:18:44,160
tau, alpha synuclein,
amyloid proteinopathies

3848
03:18:44,160 --> 03:18:48,280
and other pathological
proteins, Tomie and Colleagues

3849
03:18:48,280 --> 03:18:51,000
found an interaction
between TDP-43

3850
03:18:51,000 --> 03:18:53,600
and tau
using immunoprecipitation

3851
03:18:53,600 --> 03:18:55,800
but also show
some colocalization

3852
03:18:55,800 --> 03:18:59,440
between phosphorylated
TDP-43 and phospho tau

3853
03:18:59,440 --> 03:19:04,000
in pre AD
and symptomatic AD cases.

3854
03:19:04,000 --> 03:19:05,600
Next slide, please.

3855
03:19:08,480 --> 03:19:10,560
She and colleagues
looked at an interaction

3856
03:19:10,560 --> 03:19:14,040
between TDP-43
and amyloid beta.

3857
03:19:14,040 --> 03:19:18,600
They show a complex interaction
here through immunoprecipitation

3858
03:19:18,600 --> 03:19:20,280
This is kind of
an interesting study, too,

3859
03:19:20,280 --> 03:19:22,600
because they used bilateral
interhippocampal injections

3860
03:19:22,600 --> 03:19:25,920
of recombinant
full-length TDP-43.

3861
03:19:25,920 --> 03:19:27,880
This has been a challenge
in the field

3862
03:19:27,880 --> 03:19:32,760
for isolating
recombinant TDP-43 this stage,

3863
03:19:32,760 --> 03:19:34,360
so this is real exciting.

3864
03:19:34,360 --> 03:19:36,560
And this goes back to
the structural component, too,

3865
03:19:36,560 --> 03:19:38,600
that we're starting
to understand

3866
03:19:38,600 --> 03:19:42,320
as far as
a structural understanding

3867
03:19:42,320 --> 03:19:45,400
these pathological filaments
that maybe

3868
03:19:45,400 --> 03:19:48,160
that could be utilized
too as far as injecting --

3869
03:19:48,160 --> 03:19:50,920
well, later on.
Next slide, please.

3870
03:19:53,960 --> 03:19:56,240
One thing that would like
to focus, too,

3871
03:19:56,240 --> 03:19:58,920
is to develop models
for vascular contributions

3872
03:19:58,920 --> 03:20:02,360
of TDP-43 proteinopathy
or hippocampal sclerosis.

3873
03:20:02,360 --> 03:20:04,480
We really need models
to develop this

3874
03:20:04,480 --> 03:20:06,560
and to be able to see
these changes

3875
03:20:06,560 --> 03:20:09,160
and how they
can be replicated

3876
03:20:09,160 --> 03:20:13,640
or at least be consistent
with those with LATE.

3877
03:20:13,640 --> 03:20:18,760
Glial and neuron interaction
plus inflammatory contributions,

3878
03:20:18,760 --> 03:20:23,000
that's a TDP-43 proteinopathy,
specifically as aging.

3879
03:20:23,000 --> 03:20:26,040
We'll see to replicate
within the models,

3880
03:20:26,040 --> 03:20:29,480
what we're seeing
in the human disease.

3881
03:20:29,480 --> 03:20:31,080
Next slide, please.

3882
03:20:36,600 --> 03:20:41,200
-Study the transmission
of pathological TDP 43,

3883
03:20:41,200 --> 03:20:44,640
the prion-like transmission
of pathological TDP 43 species

3884
03:20:44,640 --> 03:20:47,600
that simulate anatomical
progression latency,

3885
03:20:47,600 --> 03:20:50,840
TDP pathology
in common dementia.

3886
03:20:50,840 --> 03:20:54,520
This is a great classical
experiment from Luton College

3887
03:20:54,520 --> 03:20:57,600
that did a --

3888
03:20:57,600 --> 03:21:01,680
used a small peptide
of mutant alpha-synuclein

3889
03:21:01,680 --> 03:21:04,480
into stereotactic injections.

3890
03:21:04,480 --> 03:21:06,560
And they show,
over the course of time,

3891
03:21:06,560 --> 03:21:08,080
it causes this prion effect

3892
03:21:08,080 --> 03:21:12,080
to affect endogenous
synuclein-inducing pathology

3893
03:21:12,080 --> 03:21:16,400
across the spread of the mice
in just a few months.

3894
03:21:16,400 --> 03:21:19,880
They further looked
at this same model,

3895
03:21:19,880 --> 03:21:23,000
the same group, azoladel.

3896
03:21:23,000 --> 03:21:25,520
And then they looked at
synuclein and how it modulates

3897
03:21:25,520 --> 03:21:27,960
tau pathology as well.

3898
03:21:27,960 --> 03:21:30,880
I think because of
the recent discovery

3899
03:21:30,880 --> 03:21:33,120
of the structure
of these filaments,

3900
03:21:33,120 --> 03:21:36,000
that we're going to see
more prion-like -- to invest --

3901
03:21:36,000 --> 03:21:39,000
to be able to investigate
this prion-like transmission,

3902
03:21:39,000 --> 03:21:44,280
or pathological TDP 43 species,
using this type of system.

3903
03:21:44,280 --> 03:21:51,480
Next, please.
Next slide, please.

3904
03:21:51,480 --> 03:21:54,600
Transgenic animals that express
wild-type or immune TDP 43

3905
03:21:54,600 --> 03:21:56,560
or developed
hippocampal sclerosis.

3906
03:21:56,560 --> 03:21:58,160
Back one, please.

3907
03:22:01,240 --> 03:22:04,640
Back one slide, please.
Thank you.

3908
03:22:04,640 --> 03:22:06,880
So, Wuhan colleagues
did a conditional knockout

3909
03:22:06,880 --> 03:22:10,760
in the hippocampus.
And, over the course of time,

3910
03:22:10,760 --> 03:22:15,160
at 12 months of age
they show distinct degenerate --

3911
03:22:15,160 --> 03:22:17,600
distinct severe
hippocampal degeneration

3912
03:22:17,600 --> 03:22:21,320
over the course of time
at 12 months of age.

3913
03:22:21,320 --> 03:22:22,920
Next slide, please.

3914
03:22:27,080 --> 03:22:29,480
This is unpublished work
from our lab.

3915
03:22:29,480 --> 03:22:31,880
We looked at
hippocampal degeneration

3916
03:22:31,880 --> 03:22:37,120
as seen in 24-month-old mice
expressing nuclear localization

3917
03:22:37,120 --> 03:22:40,000
signal defective TDP
at 43 months.

3918
03:22:40,000 --> 03:22:41,960
These are in --
these are six genotypes

3919
03:22:41,960 --> 03:22:45,000
that we looked at
with wild-type APP-PS1,

3920
03:22:45,000 --> 03:22:47,760
a low expressing TDP mouse.

3921
03:22:47,760 --> 03:22:52,160
And it's TDP in the mouse
expressing lower TDP

3922
03:22:52,160 --> 03:22:54,920
43 expression
in an APP background.

3923
03:22:54,920 --> 03:22:57,360
They show no neuronal loss
at 24 months of age.

3924
03:22:57,360 --> 03:22:59,800
And they show no change
in hippocampal area.

3925
03:22:59,800 --> 03:23:01,400
However,
when we derive expression

3926
03:23:01,400 --> 03:23:03,200
of TDP 43
in the cytoplasm --

3927
03:23:03,200 --> 03:23:04,840
and this is end stage
for these mice.

3928
03:23:04,840 --> 03:23:08,720
These mice only live 24
to 25 months of age,

3929
03:23:08,720 --> 03:23:10,440
the NLS mice in particular.

3930
03:23:10,440 --> 03:23:12,960
When we derive TDP 43
in the cytoplasm,

3931
03:23:12,960 --> 03:23:18,160
we get this severe degeneration
of the hippocampus.

3932
03:23:18,160 --> 03:23:20,800
And we get a decrease
in hippocampal volume.

3933
03:23:20,800 --> 03:23:22,400
And in the end
in the APP background,

3934
03:23:22,400 --> 03:23:24,800
there's no additive effect
with these.

3935
03:23:24,800 --> 03:23:26,160
And this will go
into the next slide,

3936
03:23:26,160 --> 03:23:29,200
where I can talk about
model limitations.

3937
03:23:29,200 --> 03:23:32,240
Next slide, please.

3938
03:23:32,240 --> 03:23:34,320
So, model limitations

3939
03:23:34,320 --> 03:23:35,760
I want to talk about the cAMP
kinase model,

3940
03:23:35,760 --> 03:23:38,040
that I described
for the one that we use.

3941
03:23:38,040 --> 03:23:39,960
Gowan and Associates
from Jackson lab

3942
03:23:39,960 --> 03:23:41,600
is an excellent paper.

3943
03:23:41,600 --> 03:23:46,840
They mapped quite a few
different transgenic lines

3944
03:23:46,840 --> 03:23:49,120
for their integration sites.

3945
03:23:49,120 --> 03:23:52,000
And it just so happens
the cAMP kinase TTA model

3946
03:23:52,000 --> 03:23:56,120
that we use was mapped in five
coding regions, the gene.

3947
03:23:56,120 --> 03:23:58,680
And there's, also,
some abnormalities

3948
03:23:58,680 --> 03:24:01,920
with some motor deficits
in these mice

3949
03:24:01,920 --> 03:24:06,560
as well that show
some clasping later on.

3950
03:24:06,560 --> 03:24:09,480
So, this brings us to rigor
and reproducibility.

3951
03:24:09,480 --> 03:24:11,440
And I think we can --

3952
03:24:11,440 --> 03:24:14,600
if we think about this
for animal models,

3953
03:24:14,600 --> 03:24:18,720
this has been a challenge
for reproducibility

3954
03:24:18,720 --> 03:24:20,360
on animal models
from consistently.

3955
03:24:20,360 --> 03:24:24,640
If we look at, for instance,
the APP-PS1 model,

3956
03:24:24,640 --> 03:24:27,200
we can see that there
are multiple groups.

3957
03:24:27,200 --> 03:24:29,680
There's maybe
over 1,000 papers

3958
03:24:29,680 --> 03:24:33,720
or so that describe this model
and characterize it.

3959
03:24:33,720 --> 03:24:37,200
But multiple groups show
early age-dependent changes

3960
03:24:37,200 --> 03:24:39,200
at three or four months of age,
or even five months of age,

3961
03:24:39,200 --> 03:24:41,000
they show memory deficits
where other groups don't show it

3962
03:24:41,000 --> 03:24:44,720
'till they're 12 months of age,
or even 18 months of age.

3963
03:24:44,720 --> 03:24:48,800
Same mouse, same background,
same experiment.

3964
03:24:48,800 --> 03:24:51,000
The environment may play
a big role in this,

3965
03:24:51,000 --> 03:24:54,320
and this may be
the handling of the mice.

3966
03:24:54,320 --> 03:24:58,760
And how this can be addressed,
I'm not really sure.

3967
03:24:58,760 --> 03:25:00,320
But, take suggestions.

3968
03:25:00,320 --> 03:25:02,360
But I think that age is really
going to be a key factor

3969
03:25:02,360 --> 03:25:03,920
with this
understanding this, too.

3970
03:25:03,920 --> 03:25:06,000
And that's going to be
hypothesis-driven for LATE.

3971
03:25:06,000 --> 03:25:08,000
And that's going to be up
to the researcher.

3972
03:25:08,000 --> 03:25:12,080
We're suggesting single copy,
maybe endogenous promoter,

3973
03:25:12,080 --> 03:25:17,840
inducible expression, or other
approaches to replicate LATE.

3974
03:25:17,840 --> 03:25:25,000
Next slide, please.
Next slide, please. Thank you.

3975
03:25:25,000 --> 03:25:28,200
So, this is an overview
of the recommendation

3976
03:25:28,200 --> 03:25:29,800
is to build
new experimental models,

3977
03:25:29,800 --> 03:25:32,760
and incorporate aging behavioral
pathological phenotype.

3978
03:25:32,760 --> 03:25:35,000
And I talked about developing
and characterizing models

3979
03:25:35,000 --> 03:25:38,920
that incorporate aging,
designated to --

3980
03:25:38,920 --> 03:25:42,680
designed to simulate latency.

3981
03:25:42,680 --> 03:25:44,080
Barley transduce models
knock in,

3982
03:25:44,080 --> 03:25:46,000
gene-editing stress models,
transgenic models

3983
03:25:46,000 --> 03:25:49,200
that express to the wild-type
or mutant TDP 43.

3984
03:25:49,200 --> 03:25:51,440
Consider using inducible
promoters

3985
03:25:51,440 --> 03:25:55,920
to derive expression,
disease relevant cells.

3986
03:25:55,920 --> 03:25:57,480
But attention has to be played

3987
03:25:57,480 --> 03:25:59,920
to the appropriate time
of life in the animal.

3988
03:25:59,920 --> 03:26:01,400
The vascular contribution

3989
03:26:01,400 --> 03:26:03,800
to TDP 43 proteinopathy
hippocampal sclerosis

3990
03:26:03,800 --> 03:26:05,320
is going to be important
to develop, too,

3991
03:26:05,320 --> 03:26:08,320
as far as models.
And the interaction of TDP 43

3992
03:26:08,320 --> 03:26:12,200
with other
pathological proteins,

3993
03:26:12,200 --> 03:26:16,200
and understanding
those pathologies is important.

3994
03:26:16,200 --> 03:26:18,920
In addition to glial
neuronal interaction,

3995
03:26:18,920 --> 03:26:22,320
plus inflammatory and
neuroinflammation contributions

3996
03:26:22,320 --> 03:26:26,280
to TDP proteinopathy
to be able to model this in --

3997
03:26:26,280 --> 03:26:29,240
they're replicates
of what's seen in LATE,

3998
03:26:29,240 --> 03:26:30,680
specifically in aging.

3999
03:26:30,680 --> 03:26:32,840
And then study
the prion-like transmission

4000
03:26:32,840 --> 03:26:35,040
of pathological
TDP 43 species

4001
03:26:35,040 --> 03:26:40,800
that simulate anatomical
progression of latency.

4002
03:26:40,800 --> 03:26:42,120
With this structure now,

4003
03:26:42,120 --> 03:26:45,480
we may be able to develop
good candidates

4004
03:26:45,480 --> 03:26:47,040
for different areas
of the protein,

4005
03:26:47,040 --> 03:26:49,000
in order to induce
these changes.

4006
03:26:49,000 --> 03:26:50,440
Maybe starting it
in the amygdala,

4007
03:26:50,440 --> 03:26:53,000
and seeing how
the transmission progresses.

4008
03:26:53,000 --> 03:26:55,200
Next slide, please.

4009
03:26:55,200 --> 03:26:57,600
-Two minutes remaining.

4010
03:26:57,600 --> 03:26:59,200
-Next slide, please.

4011
03:27:01,640 --> 03:27:03,200
So, in general,
we want to develop

4012
03:27:03,200 --> 03:27:05,840
translationally actual cellular
and animal models,

4013
03:27:05,840 --> 03:27:08,200
to enable preclinical
therapeutic development,

4014
03:27:08,200 --> 03:27:10,480
and testing pipelines
and latency.

4015
03:27:10,480 --> 03:27:14,120
Most of the models
to date focus on ALS or FTLD.

4016
03:27:14,120 --> 03:27:16,000
And we've just seen
we really need models

4017
03:27:16,000 --> 03:27:19,360
that replicate LATE,
and other models of LATE.

4018
03:27:19,360 --> 03:27:21,520
Not just animal models,
but other models

4019
03:27:21,520 --> 03:27:26,680
[Indistinct] as well.

4020
03:27:26,680 --> 03:27:29,920
We need to study this in the
context of multiple pathologies.

4021
03:27:29,920 --> 03:27:32,080
It's important to look
at these interactions

4022
03:27:32,080 --> 03:27:34,600
in more of a complex nature
with TDP 43,

4023
03:27:34,600 --> 03:27:36,360
as we're seeing it
in the human disease.

4024
03:27:36,360 --> 03:27:39,400
And we may be able
to model it better

4025
03:27:39,400 --> 03:27:42,800
by looking in more pathological
proteins in that.

4026
03:27:42,800 --> 03:27:45,160
And then what's real important
is the intersection

4027
03:27:45,160 --> 03:27:47,960
with the hippocampal
atrophy and vascular disease,

4028
03:27:47,960 --> 03:27:51,960
and developmental models
or other systems as well.

4029
03:27:51,960 --> 03:27:53,400
But in all of the models,

4030
03:27:53,400 --> 03:27:56,080
aging should be
incorporated in everything,

4031
03:27:56,080 --> 03:27:58,400
as far as I understand.

4032
03:27:58,400 --> 03:28:01,240
I want to thank you
for your time.

4033
03:28:01,240 --> 03:28:05,240
And the next part will be
the Open Mic and Questions.

4034
03:28:05,240 --> 03:28:06,840
Thank you very much.

4035
03:28:11,920 --> 03:28:14,360
-Thank you so much.

4036
03:28:14,360 --> 03:28:18,800
So, we have a question
from Penny Dacks.

4037
03:28:24,200 --> 03:28:25,840
-Thank you all.

4038
03:28:25,840 --> 03:28:29,000
I've got to say, I learned
so much listening to all of you.

4039
03:28:29,000 --> 03:28:31,400
And I deeply appreciate
your work here,

4040
03:28:31,400 --> 03:28:34,800
and your leadership
in this space.

4041
03:28:34,800 --> 03:28:37,480
I was -- you know, Dr. Gitcho
just spoke on the models.

4042
03:28:37,480 --> 03:28:40,640
And I think his --
and supplied your ability

4043
03:28:40,640 --> 03:28:43,640
to convey so much complexities
about how do we --

4044
03:28:43,640 --> 03:28:45,480
when we take the complexities

4045
03:28:45,480 --> 03:28:46,800
and we try to distill it
into models,

4046
03:28:46,800 --> 03:28:48,200
sometimes we go too far.

4047
03:28:48,200 --> 03:28:49,680
And I think you did
such a phenomenal job

4048
03:28:49,680 --> 03:28:51,920
discussing how there's
so many different ways

4049
03:28:51,920 --> 03:28:54,200
that we can be using
the models in a deeper way,

4050
03:28:54,200 --> 03:28:57,600
to be looking at
the interaction of factors,

4051
03:28:57,600 --> 03:29:03,160
rather than solely distilling
them down into singular ways.

4052
03:29:03,160 --> 03:29:05,120
I want to encourage
the group to consider

4053
03:29:05,120 --> 03:29:07,600
looking at long-term
sleep impairments as well,

4054
03:29:07,600 --> 03:29:09,040
because I do think
there's a lot

4055
03:29:09,040 --> 03:29:10,760
that's there that we don't
fully understand

4056
03:29:10,760 --> 03:29:13,360
when you're going
at aging biology.

4057
03:29:13,360 --> 03:29:16,400
And, in general, systems biology
and computational models

4058
03:29:16,400 --> 03:29:19,360
I think are important
to consider.

4059
03:29:19,360 --> 03:29:21,680
But my core suggestion
is, really,

4060
03:29:21,680 --> 03:29:24,920
just to emphasize
the broader mixed etiologies

4061
03:29:24,920 --> 03:29:26,600
dementia
recommendation at round,

4062
03:29:26,600 --> 03:29:30,760
building proactively
towards harmonized data

4063
03:29:30,760 --> 03:29:32,800
and biosample collection,

4064
03:29:32,800 --> 03:29:35,800
so that the work
that's happening on TDP

4065
03:29:35,800 --> 03:29:39,600
43 within all of the ADRDs,
as well as related fields like

4066
03:29:39,600 --> 03:29:43,760
ALS, can really be able
to benefit from each other.

4067
03:29:43,760 --> 03:29:45,120
We don't yet know,

4068
03:29:45,120 --> 03:29:46,640
and I don't think we'll know
for a long time,

4069
03:29:46,640 --> 03:29:49,600
how much, you know,
the biomarker work in one space,

4070
03:29:49,600 --> 03:29:51,880
or the basic science
work in one space

4071
03:29:51,880 --> 03:29:55,000
is actually going to be relevant
to a related space.

4072
03:29:55,000 --> 03:29:57,560
And I hope that one day
we can get to the place

4073
03:29:57,560 --> 03:30:01,200
where our clinical phenotypes
are being very carefully

4074
03:30:01,200 --> 03:30:03,800
and [Indistinct]
characterized for prognosis,

4075
03:30:03,800 --> 03:30:07,080
but that the underlying
molecular pathology

4076
03:30:07,080 --> 03:30:09,560
is what is being defined
in individuals,

4077
03:30:09,560 --> 03:30:11,400
so that that is what
can be tackled

4078
03:30:11,400 --> 03:30:17,040
clinically with new therapies.
Thank you all.

4079
03:30:17,040 --> 03:30:20,720
-Thank you so much.
Those are great points.

4080
03:30:20,720 --> 03:30:22,520
And I've written them all down.

4081
03:30:22,520 --> 03:30:26,400
I think the harmonization
is super important.

4082
03:30:26,400 --> 03:30:30,160
And I think we do have that
in some of our bullets,

4083
03:30:30,160 --> 03:30:34,920
as far as recognizing
that need for harmonization,

4084
03:30:34,920 --> 03:30:36,400
as well as this intersection

4085
03:30:36,400 --> 03:30:38,600
with frontotemporal
lower degeneration,

4086
03:30:38,600 --> 03:30:40,800
harmonization
with other diseases

4087
03:30:40,800 --> 03:30:46,080
that might be
in their own isolated coves.

4088
03:30:46,080 --> 03:30:48,240
Eric, Eric Smith?

4089
03:30:50,440 --> 03:30:53,200
-Yes, Thanks, Julie.
My question is,

4090
03:30:53,200 --> 03:30:59,320
"Are we ready for provisional
diagnostic criteria

4091
03:30:59,320 --> 03:31:02,840
in vivo like probable
or possible LATE?"

4092
03:31:02,840 --> 03:31:05,040
I'm a neurologist
and a clinician scientist.

4093
03:31:05,040 --> 03:31:07,440
I think I recognize
this syndrome sometimes,

4094
03:31:07,440 --> 03:31:10,320
or a pattern like
what was described, right,

4095
03:31:10,320 --> 03:31:12,600
with the slowly progressive
amnestic syndrome.

4096
03:31:12,600 --> 03:31:14,160
And I was encouraged
to see all the work

4097
03:31:14,160 --> 03:31:19,800
on like hippocampal volumes
and patterns of atrophy.

4098
03:31:19,800 --> 03:31:22,160
Are we ready to try
to identify prospectively,

4099
03:31:22,160 --> 03:31:25,400
and then follow people
and validate

4100
03:31:25,400 --> 03:31:27,200
pathologically?
Thanks.

4101
03:31:27,200 --> 03:31:28,800
-David?

4102
03:31:31,120 --> 03:31:33,240
-Thanks so much
for the question.

4103
03:31:33,240 --> 03:31:36,360
And I'll be interested to hear
what other panelists say.

4104
03:31:36,360 --> 03:31:39,240
I do think there are cases
that we see clinically

4105
03:31:39,240 --> 03:31:42,680
that I feel fairly
comfortable nowadays,

4106
03:31:42,680 --> 03:31:45,640
particularly if we have
rich biomarker data

4107
03:31:45,640 --> 03:31:49,200
for classifying them,
as having LATE.

4108
03:31:49,200 --> 03:31:54,120
I think, LATE alone has
relatively distinctive features

4109
03:31:54,120 --> 03:31:55,360
associated with it,

4110
03:31:55,360 --> 03:31:58,800
that we probably could
create criteria,

4111
03:31:58,800 --> 03:32:01,440
that, again,
probabilistically would give us

4112
03:32:01,440 --> 03:32:06,680
a reasonable degree of certainty
about the underlying pathology.

4113
03:32:06,680 --> 03:32:08,480
I think, in the context
of Alzheimer's disease,

4114
03:32:08,480 --> 03:32:10,320
it obviously gets trickier.

4115
03:32:10,320 --> 03:32:14,080
But, again, I think there are
features in the imaging,

4116
03:32:14,080 --> 03:32:19,120
as well as cognitively,
that may allow us, again,

4117
03:32:19,120 --> 03:32:20,640
to kind of probabilistically say

4118
03:32:20,640 --> 03:32:25,840
there's a high likelihood
of LATE copathology.

4119
03:32:25,840 --> 03:32:28,320
But I'll let the others
weigh in as well.

4120
03:32:30,440 --> 03:32:32,200
-David?

4121
03:32:32,200 --> 03:32:34,680
-This is a great session.
Thanks for doing this so far.

4122
03:32:34,680 --> 03:32:36,640
I was going to comment
on the issue

4123
03:32:36,640 --> 03:32:39,000
that I think it's going
to be very difficult

4124
03:32:39,000 --> 03:32:42,800
actually to study this
in live people

4125
03:32:42,800 --> 03:32:45,000
without a marker
of the pathology.

4126
03:32:45,000 --> 03:32:46,400
And I think,
until we get there,

4127
03:32:46,400 --> 03:32:48,760
it's going to be
where we can rule out

4128
03:32:48,760 --> 03:32:51,200
AD pathology
with biomarkers or in.

4129
03:32:51,200 --> 03:32:55,320
But I just would feel
very uncomfortable

4130
03:32:55,320 --> 03:32:56,800
diagnosing somebody
with this,

4131
03:32:56,800 --> 03:33:00,400
with the current information
that we have.

4132
03:33:00,400 --> 03:33:03,400
Now that we have cryo-EM
of TDP 43 structure, I mean,

4133
03:33:03,400 --> 03:33:05,280
you theoretically
should be able

4134
03:33:05,280 --> 03:33:07,640
to develop
an imaging agent for it.

4135
03:33:09,800 --> 03:33:11,360
At least in the patients
I see that.

4136
03:33:11,360 --> 03:33:13,200
I mean, most patients
who come to clinic,

4137
03:33:13,200 --> 03:33:15,800
not research,
don't even get AD biomarkers,

4138
03:33:15,800 --> 03:33:18,840
let alone anything else, so...

4139
03:33:18,840 --> 03:33:20,400
-Right. So, yeah.

4140
03:33:20,400 --> 03:33:21,840
Yeah, I think
that's a great point.

4141
03:33:21,840 --> 03:33:23,520
I mean, you know,
in the population-based

4142
03:33:23,520 --> 03:33:25,520
studies
and community-based studies,

4143
03:33:25,520 --> 03:33:27,280
it would be
exceedingly hard to do.

4144
03:33:27,280 --> 03:33:31,400
It would definitely have to be a
research study with biomarkers.

4145
03:33:31,400 --> 03:33:33,320
Pete?

4146
03:33:33,320 --> 03:33:34,440
-Thank you very
much to everybody.

4147
03:33:34,440 --> 03:33:36,160
Thank you, Dr. Schneider.

4148
03:33:36,160 --> 03:33:39,560
And I agree
with both David's points

4149
03:33:39,560 --> 03:33:41,400
that we need better biomarkers.

4150
03:33:41,400 --> 03:33:43,080
However, there are
a lot of people

4151
03:33:43,080 --> 03:33:46,040
now that are getting
screened for AD.

4152
03:33:46,040 --> 03:33:49,200
And when they have some
degree of neurodegeneration,

4153
03:33:49,200 --> 03:33:52,600
or some cognitive wobbling,
but they screen failed,

4154
03:33:52,600 --> 03:33:55,800
there's no option for them.
That's it. They're done.

4155
03:33:55,800 --> 03:33:58,400
And we've seen that
from the patient advocacy

4156
03:33:58,400 --> 03:34:01,400
here that there's a lot
of frustration with that.

4157
03:34:01,400 --> 03:34:03,040
Well, here at University
of Kentucky,

4158
03:34:03,040 --> 03:34:07,000
we have what I think is
the first LATE clinical trial.

4159
03:34:07,000 --> 03:34:11,600
And, so, we can employ
the information of screen

4160
03:34:11,600 --> 03:34:13,880
failing for an AD
clinical trial,

4161
03:34:13,880 --> 03:34:15,600
and give somebody an option.

4162
03:34:15,600 --> 03:34:18,200
And I really think
that what I believe

4163
03:34:18,200 --> 03:34:20,680
I'm hearing from the patients,
patient advocacy,

4164
03:34:20,680 --> 03:34:23,080
is a little bit of a disconnect
to what I'm hearing

4165
03:34:23,080 --> 03:34:26,120
in the AD dementia
neurology field

4166
03:34:26,120 --> 03:34:28,440
of trying to be
a little bit more proactive

4167
03:34:28,440 --> 03:34:30,280
about giving patients options.

4168
03:34:30,280 --> 03:34:33,120
It's not telling them what to
do, but giving them options.

4169
03:34:33,120 --> 03:34:37,520
And to try to get shots on goal,
to see if we can't start to bend

4170
03:34:37,520 --> 03:34:39,200
some of
the cognitive trajectories

4171
03:34:39,200 --> 03:34:40,840
in the survival curves.

4172
03:34:40,840 --> 03:34:47,400
So, for us, we have people
that are clearly cognitively

4173
03:34:47,400 --> 03:34:51,000
not totally intact,
and having some MRI changes,

4174
03:34:51,000 --> 03:34:54,400
but are negative
on the amyloid biomarkers.

4175
03:34:54,400 --> 03:34:58,800
And we have an option for them
to get into clinical research.

4176
03:34:58,800 --> 03:35:00,400
And at least it's a start.

4177
03:35:00,400 --> 03:35:02,760
And, so, I think that
that's a really important --

4178
03:35:02,760 --> 03:35:07,920
at least trying to get
on the hill of effectiveness.

4179
03:35:07,920 --> 03:35:09,400
Other areas of research,
like cancer,

4180
03:35:09,400 --> 03:35:11,320
have been much more proactive,

4181
03:35:11,320 --> 03:35:15,040
and have reflectively
gotten much better results

4182
03:35:15,040 --> 03:35:18,040
than we have in
the dementia research field.

4183
03:35:18,040 --> 03:35:20,400
-Thank you, Pete.
David, did you want to respond?

4184
03:35:20,400 --> 03:35:25,600
-Yeah, I agree with, actually,
both David and Pete.

4185
03:35:25,600 --> 03:35:27,800
And I think
they are great points.

4186
03:35:27,800 --> 03:35:32,800
I think, to David's point
about clinical practice,

4187
03:35:32,800 --> 03:35:34,840
in general clinical practice
I do think it --

4188
03:35:34,840 --> 03:35:37,000
you know, we just don't get
the biomarkers

4189
03:35:37,000 --> 03:35:39,480
to make the diagnosis there.

4190
03:35:39,480 --> 03:35:43,840
But I do think that we can
establish some criteria

4191
03:35:43,840 --> 03:35:45,320
in research cohorts.

4192
03:35:45,320 --> 03:35:49,960
And, again, that is kind of
a goal of this,

4193
03:35:49,960 --> 03:35:54,120
you know, committee is to push
for more harmonized data

4194
03:35:54,120 --> 03:35:58,240
collection across different
studies and populations.

4195
03:35:58,240 --> 03:36:01,160
And I think that will ultimately
allow us, again,

4196
03:36:01,160 --> 03:36:04,000
probabilistically, just like
how we used to diagnose

4197
03:36:04,000 --> 03:36:06,720
Alzheimer's disease
in the past,

4198
03:36:06,720 --> 03:36:10,400
to, you know, allow us to
at least classify individuals,

4199
03:36:10,400 --> 03:36:12,800
perhaps incorporate genomics

4200
03:36:12,800 --> 03:36:17,000
and other factors that also
help stratify individuals,

4201
03:36:17,000 --> 03:36:19,880
and their likelihood of --
the point's obviously well taken

4202
03:36:19,880 --> 03:36:24,040
that we really do need
a molecularly specific biomarker

4203
03:36:24,040 --> 03:36:28,480
to truly move
the needle forward.

4204
03:36:28,480 --> 03:36:29,760
-Dave? David?

4205
03:36:29,760 --> 03:36:31,320
-Yeah, I think we should

4206
03:36:31,320 --> 03:36:33,000
definitely be
enrolling all people

4207
03:36:33,000 --> 03:36:36,480
who might have LATE into
our research studies for sure.

4208
03:36:36,480 --> 03:36:38,040
I mean, one possibility
would be

4209
03:36:38,040 --> 03:36:41,600
if you think somebody has LATE
based on other criteria,

4210
03:36:41,600 --> 03:36:43,120
on all the criteria
you discussed,

4211
03:36:43,120 --> 03:36:45,600
I mean, maybe there
can be clinical trials

4212
03:36:45,600 --> 03:36:47,160
done in those for people,

4213
03:36:47,160 --> 03:36:52,200
if the target is not
necessarily, you know, TDP 43,

4214
03:36:52,200 --> 03:36:54,800
but something that is
present in everybody,

4215
03:36:54,800 --> 03:36:57,600
that you might try to hit,

4216
03:36:57,600 --> 03:36:58,920
but they wouldn't be
in an AD trial,

4217
03:36:58,920 --> 03:37:00,720
because they don't have AD.

4218
03:37:00,720 --> 03:37:02,000
-Right.
-Right.

4219
03:37:02,000 --> 03:37:03,320
So, not
specifically amyloid or tau,

4220
03:37:03,320 --> 03:37:04,400
but if it's an inflammatory --
-Right.

4221
03:37:04,400 --> 03:37:05,600
-Mechanism or something else.

4222
03:37:05,600 --> 03:37:07,800
-Right. Exactly.

4223
03:37:07,800 --> 03:37:11,600
-Right.
No, those are all great points.

4224
03:37:11,600 --> 03:37:13,080
And, interestingly, you know,

4225
03:37:13,080 --> 03:37:17,160
this intersection
between TDP and vascular,

4226
03:37:17,160 --> 03:37:19,840
I think is going to become
more and more important.

4227
03:37:19,840 --> 03:37:21,240
And I think -- you know,

4228
03:37:21,240 --> 03:37:24,240
we have Maria on our team
with the 90+ Study.

4229
03:37:24,240 --> 03:37:26,200
And I know from our cohorts,
you know,

4230
03:37:26,200 --> 03:37:28,160
in those over 90,
what are we seeing?

4231
03:37:28,160 --> 03:37:30,800
We're seeing TDP
and vascular disease.

4232
03:37:30,800 --> 03:37:34,920
So, it's very common.
It's going to be increasing.

4233
03:37:34,920 --> 03:37:36,400
The neurologists
are going to see more

4234
03:37:36,400 --> 03:37:39,000
and more of these cases
as time goes on.

4235
03:37:39,000 --> 03:37:43,400
This is not going away.
So, yeah.

4236
03:37:43,400 --> 03:37:51,920
Anyway, the last comment I think
was from Susanne Van Veluw. 16

4237
03:37:51,920 --> 03:37:53,560
-Thanks, Julie.
Yeah, to your point, actually,

4238
03:37:53,560 --> 03:37:55,960
Julie, you mentioned a role
in the intersection

4239
03:37:55,960 --> 03:37:57,880
between TDP 43
and vascular disease.

4240
03:37:57,880 --> 03:38:00,600
And I wonder might there be
a role for impaired

4241
03:38:00,600 --> 03:38:02,600
perivascular clearance
as a disease mechanism.

4242
03:38:02,600 --> 03:38:05,800
We heard a great deal about it
yesterday in the VCID section.

4243
03:38:05,800 --> 03:38:07,480
And I was wondering
if that could be

4244
03:38:07,480 --> 03:38:09,400
another
potential causal mechanism

4245
03:38:09,400 --> 03:38:11,560
that's worth considering
as a focus of interest.

4246
03:38:11,560 --> 03:38:13,240
And, if so, if you agree

4247
03:38:13,240 --> 03:38:17,600
if that be a good addition
to the recommendations.

4248
03:38:17,600 --> 03:38:21,400
-So, does anybody on the team
want to take that one?

4249
03:38:24,360 --> 03:38:27,800
No, perivascular clearance
mechanism people on our team?

4250
03:38:27,800 --> 03:38:32,440
I, personally, think
it's a great idea.

4251
03:38:32,440 --> 03:38:35,280
You know, there's huge interest
in the vascular field.

4252
03:38:35,280 --> 03:38:36,920
And I don't know
if Donna's still on,

4253
03:38:36,920 --> 03:38:39,600
but she was part of our team.

4254
03:38:39,600 --> 03:38:44,800
The perivascular clearance is,
you know, highly topical

4255
03:38:44,800 --> 03:38:49,000
in the vascular disease,
VCID, session.

4256
03:38:49,000 --> 03:38:51,240
And, certainly, when we talk
about this intersection

4257
03:38:51,240 --> 03:38:54,040
between neurodegenerative
disease and vascular disease,

4258
03:38:54,040 --> 03:38:56,120
especially small
vessel disease,

4259
03:38:56,120 --> 03:38:58,520
I think it is something
that we should highlight.

4260
03:38:58,520 --> 03:39:00,320
So, I appreciate the comment.

4261
03:39:00,320 --> 03:39:02,080
And I think
we should highlight that.

4262
03:39:02,080 --> 03:39:05,920
And we can discuss it
among our committee.

4263
03:39:05,920 --> 03:39:08,960
-Just to add, Julie.
Hi, everyone.

4264
03:39:08,960 --> 03:39:11,680
So, just to follow up
on that, Susanne,

4265
03:39:11,680 --> 03:39:15,400
you know, when we talk
about the perivascular

4266
03:39:15,400 --> 03:39:19,600
kind of drainage pathways
in the VCID recommendations,

4267
03:39:19,600 --> 03:39:21,160
we talk about solutes,

4268
03:39:21,160 --> 03:39:24,920
and, you know,
neurodegenerative proteins.

4269
03:39:24,920 --> 03:39:26,720
We're not specifically
talking about amyloid.

4270
03:39:26,720 --> 03:39:31,000
So, I think that does open up
kind of that recommendation

4271
03:39:31,000 --> 03:39:32,960
to being draining --

4272
03:39:32,960 --> 03:39:36,880
you know, clearance of TDP
43 clearance of other,

4273
03:39:36,880 --> 03:39:41,920
you know, proteins as well.
So, yeah, it's a good point.

4274
03:39:41,920 --> 03:39:44,960
-Yeah, and maybe something
we can at least touch upon

4275
03:39:44,960 --> 03:39:47,680
in our recommendations, too.

4276
03:39:47,680 --> 03:39:51,160
-Julie, very quickly,
I just wanted to mention that

4277
03:39:51,160 --> 03:39:53,560
before it was mentioned
that many of these

4278
03:39:53,560 --> 03:39:55,000
are age-related pathologies.

4279
03:39:55,000 --> 03:39:56,800
And one of the things
that will be important

4280
03:39:56,800 --> 03:39:59,400
to kind of try
to disentangle is that,

4281
03:39:59,400 --> 03:40:01,880
especially like with vascular
and TDP 43,

4282
03:40:01,880 --> 03:40:03,480
are they there co-occurrent

4283
03:40:03,480 --> 03:40:06,600
because it's just
a factor of age?

4284
03:40:06,600 --> 03:40:08,200
Or is it because
they actually have

4285
03:40:08,200 --> 03:40:10,480
a mechanistic interaction
in some way?

4286
03:40:10,480 --> 03:40:14,440
So, I think that's an important
point to try to disentangle.

4287
03:40:14,440 --> 03:40:17,760
-Right. And I agree, Maria,
it's really important.

4288
03:40:17,760 --> 03:40:20,200
And, you know,
residual confounding

4289
03:40:20,200 --> 03:40:21,520
is certainly a possibility.

4290
03:40:21,520 --> 03:40:23,760
We controlled for age
in our studies.

4291
03:40:23,760 --> 03:40:26,280
I'm sure Pete did, too.

4292
03:40:26,280 --> 03:40:28,960
And we looked at that
pretty carefully.

4293
03:40:28,960 --> 03:40:31,000
But, yeah, these are people
who are surviving.

4294
03:40:31,000 --> 03:40:35,080
These are people in their 90s.
Right? So, you know,

4295
03:40:35,080 --> 03:40:38,080
association doesn't mean
that there's causation.

4296
03:40:38,080 --> 03:40:39,600
So, that certainly is something

4297
03:40:39,600 --> 03:40:42,480
that we need
to figure out still.

4298
03:40:42,480 --> 03:40:43,680
Pete?

4299
03:40:43,680 --> 03:40:45,400
-I would say -- thank you.

4300
03:40:45,400 --> 03:40:48,400
I would say a couple other
things are also maybe relevant.

4301
03:40:48,400 --> 03:40:50,600
We found that
arteriosclerosis connection

4302
03:40:50,600 --> 03:40:53,200
with TDP 43
and hippocampal sclerosis.

4303
03:40:53,200 --> 03:40:56,400
But Dr. Selenich's
animal model,

4304
03:40:56,400 --> 03:40:59,560
where they do
the viral transduction with TDP.

4305
03:40:59,560 --> 03:41:01,200
it's very interesting,
because it produces

4306
03:41:01,200 --> 03:41:03,800
both an HS phenotype into mice,

4307
03:41:03,800 --> 03:41:09,400
but also perivascular
sort of changes as well,

4308
03:41:09,400 --> 03:41:13,080
and gliosis that seems
to be deleterious.

4309
03:41:13,080 --> 03:41:16,080
So, it seems to recapitulate

4310
03:41:16,080 --> 03:41:19,200
a number of the features
of the pathology.

4311
03:41:19,200 --> 03:41:21,680
And I think Dr. Selenich's model
is a very interesting one,

4312
03:41:21,680 --> 03:41:26,280
that allows both aging TDP
HS-like and vascular changes.

4313
03:41:26,280 --> 03:41:30,120
So, I think it's really
provocative.

4314
03:41:30,120 --> 03:41:31,720
-Thank you, Pete.

4315
03:41:31,720 --> 03:41:35,240
So, we have a question --
or a comment from Ian Premmer.

4316
03:41:37,520 --> 03:41:39,160
-Hi.

4317
03:41:39,160 --> 03:41:41,400
I think Keith wanted me on
to reiterate something I --

4318
03:41:41,400 --> 03:41:44,680
just a small comment
I put in Q&A.

4319
03:41:44,680 --> 03:41:50,680
And please understand
none of this in any way reduces

4320
03:41:50,680 --> 03:41:53,680
the importance of the point
that Dr. Nelson made.

4321
03:41:53,680 --> 03:41:56,880
But in response
to two points ago

4322
03:41:56,880 --> 03:42:01,000
that he made about the patient
and family advocacy

4323
03:42:01,000 --> 03:42:02,600
community wanting more options.

4324
03:42:02,600 --> 03:42:06,240
I think that's completely true
and critically important.

4325
03:42:06,240 --> 03:42:10,800
My minor quibble is I think
the data is pretty clear

4326
03:42:10,800 --> 03:42:13,120
that those advocacy communities

4327
03:42:13,120 --> 03:42:17,000
are not primarily interested
in extended lifespan.

4328
03:42:17,000 --> 03:42:19,680
They're primarily interested
in expanded

4329
03:42:19,680 --> 03:42:21,960
health span quality of life.

4330
03:42:21,960 --> 03:42:24,520
So, those things
are not at odds.

4331
03:42:24,520 --> 03:42:29,200
But the primacy is on what can
be done to improve the here

4332
03:42:29,200 --> 03:42:31,200
and now in the short term,

4333
03:42:31,200 --> 03:42:35,200
even if sometimes that may be at
the expense of the longer term.

4334
03:42:35,200 --> 03:42:37,600
Because it's end stage dementia

4335
03:42:37,600 --> 03:42:40,880
that scares the bejesus
out of people, rightfully.

4336
03:42:40,880 --> 03:42:43,440
And where there is
maximum opportunity

4337
03:42:43,440 --> 03:42:46,320
for improved quality of life,
may be at earlier stages.

4338
03:42:46,320 --> 03:42:48,400
Hence, the urgency
to have better

4339
03:42:48,400 --> 03:42:53,560
means of detection
and diagnosis with precision.

4340
03:42:53,560 --> 03:42:55,760
Which I think goes back
to Dr. Nelson's point.

4341
03:42:55,760 --> 03:42:59,000
We want options
as we are working

4342
03:42:59,000 --> 03:43:00,920
toward greater precision,

4343
03:43:00,920 --> 03:43:03,600
greater accuracy,
greater, therefore,

4344
03:43:03,600 --> 03:43:06,160
actionability based on
a differential diagnosis.

4345
03:43:06,160 --> 03:43:09,360
So, I think I'm in complete
agreement with Dr. Nelson.

4346
03:43:09,360 --> 03:43:11,680
But he is, certainly,
welcome to tell me

4347
03:43:11,680 --> 03:43:15,240
if I've missed the thrust,
or misrepresented his view.

4348
03:43:15,240 --> 03:43:17,600
-You a thumbs up from Pete.

4349
03:43:17,600 --> 03:43:19,600
-Thank golly. Okay.

4350
03:43:19,600 --> 03:43:21,160
-But I, also,
want to point out that,

4351
03:43:21,160 --> 03:43:23,040
you know, LATE is interesting

4352
03:43:23,040 --> 03:43:25,600
in that it is
very slowly progressive.

4353
03:43:25,600 --> 03:43:27,920
So, when we see people
with LATE, you know,

4354
03:43:27,920 --> 03:43:29,880
they have
some mild memory problems

4355
03:43:29,880 --> 03:43:31,280
that very slowly progress.

4356
03:43:31,280 --> 03:43:34,600
So, their quality of life
may not decline,

4357
03:43:34,600 --> 03:43:37,640
or isn't declining as fast
as people with Alzheimer's

4358
03:43:37,640 --> 03:43:42,600
or Alzheimer's plus TDP 43.
So, I agree with you.

4359
03:43:42,600 --> 03:43:46,520
But I do think that there --
that that group is important.

4360
03:43:46,520 --> 03:43:47,880
David? Or Dave?

4361
03:43:47,880 --> 03:43:50,600
-Just to piggyback
on top of that.

4362
03:43:50,600 --> 03:43:53,000
That's why, you know,
correct diagnosis

4363
03:43:53,000 --> 03:43:55,240
is also particularly important
in that group,

4364
03:43:55,240 --> 03:43:58,000
because being told
that you have Alzheimer's

4365
03:43:58,000 --> 03:44:01,200
has a different connotation,
at least to some patients.

4366
03:44:01,200 --> 03:44:04,480
And, so, some of these cases
are more likely to be slow.

4367
03:44:04,480 --> 03:44:06,600
And I think it's important
for us

4368
03:44:06,600 --> 03:44:08,960
to get the diagnosis right,
so that we have a better sense

4369
03:44:08,960 --> 03:44:11,640
of what the prognosis
is in those individuals.

4370
03:44:11,640 --> 03:44:13,200
-If I could just add
one more quick point,

4371
03:44:13,200 --> 03:44:17,280
you know, following
on piggybacking on that point.

4372
03:44:17,280 --> 03:44:20,400
There is -- often, I think
we all are sensitive to this,

4373
03:44:20,400 --> 03:44:23,000
a lot of prescription nihilism.

4374
03:44:23,000 --> 03:44:27,720
And it's misplaced,
because so many people, not all,

4375
03:44:27,720 --> 03:44:32,000
but so many people in the
patient and family communities

4376
03:44:32,000 --> 03:44:35,400
want to know what we are facing,
and what we aren't,

4377
03:44:35,400 --> 03:44:39,160
even in the absence of,
never mind a cure,

4378
03:44:39,160 --> 03:44:42,120
even an effective
disease-modifying treatment,

4379
03:44:42,120 --> 03:44:43,640
or even a symptomatic treatment.

4380
03:44:43,640 --> 03:44:46,600
It just helps to be able
to put a name to it.

4381
03:44:46,600 --> 03:44:49,000
Or in the case
of multiple etiology,

4382
03:44:49,000 --> 03:44:52,400
mixed dementias,
put names on them.

4383
03:44:52,400 --> 03:44:54,640
So, we know what we're facing,
we know what we're not.

4384
03:44:54,640 --> 03:44:57,640
And, so, we can enroll
in the right clinical trials,

4385
03:44:57,640 --> 03:45:02,840
if we are privileged enough
to have access to trials at all.

4386
03:45:02,840 --> 03:45:05,200
-I agree. Pete?

4387
03:45:05,200 --> 03:45:07,080
-And this is just something
to make a point

4388
03:45:07,080 --> 03:45:08,920
about that,
actually,

4389
03:45:08,920 --> 03:45:11,720
in Dr. Schneider's excellent
introductory talk was made.

4390
03:45:11,720 --> 03:45:16,880
But it needs to be underscored
that you think about LATE or AD

4391
03:45:16,880 --> 03:45:19,440
and C,
but they're frequently combined.

4392
03:45:19,440 --> 03:45:23,200
Not only is it such that
LATE is a little bit more mellow

4393
03:45:23,200 --> 03:45:24,800
than AD per se.

4394
03:45:24,800 --> 03:45:27,680
And the combination is worse
than either alone.

4395
03:45:27,680 --> 03:45:30,280
Which is intuitive.
But the very important point

4396
03:45:30,280 --> 03:45:32,600
that Dr. Schneider's data

4397
03:45:32,600 --> 03:45:34,800
showed better than anybody's
in the world

4398
03:45:34,800 --> 03:45:37,400
is that pure LATE
is the least common,

4399
03:45:37,400 --> 03:45:39,240
but it's still quite common.

4400
03:45:39,240 --> 03:45:42,080
Pure AD is a little bit
more common,

4401
03:45:42,080 --> 03:45:43,760
I mean,
significantly more common.

4402
03:45:43,760 --> 03:45:46,360
But even more common
than that is the combination.

4403
03:45:46,360 --> 03:45:50,600
So, this combination is where
LATE actually exerts itself,

4404
03:45:50,600 --> 03:45:54,200
and where it's a bedevilment for
the clinical trials as well.

4405
03:45:54,200 --> 03:45:56,880
So, I think that more people
need to be much more aware

4406
03:45:56,880 --> 03:45:58,640
of this combination,

4407
03:45:58,640 --> 03:46:02,880
because it's the most common
and the most impactful of them.

4408
03:46:02,880 --> 03:46:07,400
And, so, we need to have better
therapeutics and diagnostics

4409
03:46:07,400 --> 03:46:10,760
for both of those scenarios.

4410
03:46:10,760 --> 03:46:13,200
-And awareness
across research,

4411
03:46:13,200 --> 03:46:16,800
as well as
non-research communities.

4412
03:46:16,800 --> 03:46:18,680
-Thank you for
a wonderful session.

4413
03:46:18,680 --> 03:46:21,400
I think we probably need
to stop there,

4414
03:46:21,400 --> 03:46:23,480
unless anybody has
a burning comment

4415
03:46:23,480 --> 03:46:27,320
they'd like to finish off with.

4416
03:46:27,320 --> 03:46:31,040
We're going to go ahead
and restart at 2:25

4417
03:46:31,040 --> 03:46:36,480
with the Special Session
on COVID-19 and AD/ADRD.

4418
03:46:36,480 --> 03:46:39,560
So, thank you so much, everyone.
And we'll see you back soon.

4419
03:46:42,080 --> 03:46:43,560
We're going to start
the next session

4420
03:46:43,560 --> 03:46:46,840
of this ADRD Summit 2022.

4421
03:46:46,840 --> 03:46:50,320
It gives me great pleasure to
introduce the Scientific Chair

4422
03:46:50,320 --> 03:46:52,440
of the meeting,
Dr. Natalia Rost,

4423
03:46:52,440 --> 03:46:54,280
who will bring us
into the session

4424
03:46:54,280 --> 03:46:59,920
on impact of COVID-19
on AD/ADRD risk and outcomes.

4425
03:46:59,920 --> 03:47:01,360
-Thank you, Rod.

4426
03:47:01,360 --> 03:47:04,640
Homestretch, everybody.
That's the last session,

4427
03:47:04,640 --> 03:47:06,880
last scientific session
of the meeting,

4428
03:47:06,880 --> 03:47:09,320
before the general
and the closing.

4429
03:47:09,320 --> 03:47:12,560
And we're excited as part
of this new working group

4430
03:47:12,560 --> 03:47:16,640
brings to you a topic
that is of most urgency

4431
03:47:16,640 --> 03:47:21,920
and necessity
to investigate in deeper detail.

4432
03:47:21,920 --> 03:47:27,000
Namely, the impact of COVID-19
on ADRD risk and outcomes.

4433
03:47:27,000 --> 03:47:31,720
And I'm delighted to pass
the baton to my Co-Chair,

4434
03:47:31,720 --> 03:47:33,640
Dr. Sudha Seshardi,

4435
03:47:33,640 --> 03:47:35,920
who is Director
of the Glenn Biggs

4436
03:47:35,920 --> 03:47:38,880
Institute for Alzheimer's
and Neurodegenerative Diseases

4437
03:47:38,880 --> 03:47:41,040
at the University
of Texas San Antonio.

4438
03:47:41,040 --> 03:47:42,640
Sudha?

4439
03:47:42,640 --> 03:47:44,360
-Thank you, Natalia.

4440
03:47:44,360 --> 03:47:48,960
And it's my distinct honor
and privilege to work with you,

4441
03:47:48,960 --> 03:47:53,240
and with an outstanding
team of diverse experts,

4442
03:47:53,240 --> 03:47:57,200
to address this important
emerging topic on COVID

4443
03:47:57,200 --> 03:48:01,520
impact on AD/ADRD risks
and outcomes.

4444
03:48:01,520 --> 03:48:04,440
So, I'll touch
upon the introduction,

4445
03:48:04,440 --> 03:48:06,200
scope of the problem,

4446
03:48:06,200 --> 03:48:10,200
and the recommendations that
this working group arrived at.

4447
03:48:10,200 --> 03:48:12,360
And then colleagues
in the group

4448
03:48:12,360 --> 03:48:16,800
will expand on our thinking
behind these recommendations,

4449
03:48:16,800 --> 03:48:18,600
and what we know at present

4450
03:48:18,600 --> 03:48:22,960
about different aspects
of this infection. Next.

4451
03:48:25,000 --> 03:48:28,240
These are the opinions
of myself and our committee,

4452
03:48:28,240 --> 03:48:32,480
and not official NIH policy.
And this is my disclosure.

4453
03:48:32,480 --> 03:48:36,640
Next.
And we have --

4454
03:48:36,640 --> 03:48:40,800
I have to extend thanks
to all the outstanding members

4455
03:48:40,800 --> 03:48:45,200
who served on this committee,
three of whom will be speaking,

4456
03:48:45,200 --> 03:48:48,600
as I do, on behalf
of the whole group.

4457
03:48:48,600 --> 03:48:53,040
They pulled together
in a very short time. Next.

4458
03:48:55,400 --> 03:49:00,560
And we were charged with
making four recommendations.

4459
03:49:00,560 --> 03:49:06,360
And we ordered them in the order
in which we thought, logically,

4460
03:49:06,360 --> 03:49:10,840
these need to be done.
But all are equally important.

4461
03:49:10,840 --> 03:49:17,200
And we are recommending that all
of them be addressed right away.

4462
03:49:17,200 --> 03:49:19,600
Although they may continue
to be addressed

4463
03:49:19,600 --> 03:49:21,560
for varying periods of time.

4464
03:49:21,560 --> 03:49:23,960
The first priority
the group emphasized

4465
03:49:23,960 --> 03:49:26,760
was the need
for research infrastructure

4466
03:49:26,760 --> 03:49:28,200
to be established,

4467
03:49:28,200 --> 03:49:31,360
infrastructure in clinical,
epidemiological

4468
03:49:31,360 --> 03:49:36,080
and basic research studies
of the COVID-19 impact on ADRD.

4469
03:49:36,080 --> 03:49:39,200
Prioritizing
disproportionately affected

4470
03:49:39,200 --> 03:49:41,960
and vulnerable populations
with a view

4471
03:49:41,960 --> 03:49:44,080
to having
clinical trial readiness

4472
03:49:44,080 --> 03:49:46,480
as quickly as possible.

4473
03:49:46,480 --> 03:49:49,960
So, for this, we believe
the second recommendation

4474
03:49:49,960 --> 03:49:54,120
was to focus on characterizing
the clinical phenotype

4475
03:49:54,120 --> 03:49:59,640
of neurocognitive
consequences of COVID-19,

4476
03:49:59,640 --> 03:50:04,160
and developing
diagnostic criteria,

4477
03:50:04,160 --> 03:50:07,920
both in persons with
and those without

4478
03:50:07,920 --> 03:50:11,360
pre-existing neurocognitive
impairment and dementia

4479
03:50:11,360 --> 03:50:13,920
at the time
that they became infected.

4480
03:50:13,920 --> 03:50:16,680
The third priority
was to recognize

4481
03:50:16,680 --> 03:50:18,960
that this is
a complex issue,

4482
03:50:18,960 --> 03:50:23,080
and explore the interaction
with social, structural

4483
03:50:23,080 --> 03:50:27,080
and systemic inequalities,
comorbidities,

4484
03:50:27,080 --> 03:50:29,760
and social
and medical interventions,

4485
03:50:29,760 --> 03:50:33,160
both the access and specifics
of the interventions,

4486
03:50:33,160 --> 03:50:35,920
on the risk and cognitive --
sequelae

4487
03:50:35,920 --> 03:50:40,160
of neurocognitive
deficits after COVID-19.

4488
03:50:40,160 --> 03:50:42,840
And equally important
was to understand

4489
03:50:42,840 --> 03:50:47,200
the basic mechanisms underlying
this neurocognitive impairment,

4490
03:50:47,200 --> 03:50:51,160
so that we can develop
appropriate biomarkers,

4491
03:50:51,160 --> 03:50:53,240
establish risk profiles,

4492
03:50:53,240 --> 03:50:56,680
and lay the foundation
for early interventional trials.

4493
03:50:56,680 --> 03:51:01,000
Next.
Next.

4494
03:51:01,000 --> 03:51:04,240
So, I'll be touching
on the epidemiology and biology

4495
03:51:04,240 --> 03:51:07,800
as we know of SARS CoV-2,
why we think there may be

4496
03:51:07,800 --> 03:51:11,720
an excess of this pandemic
with AD/ADRD,

4497
03:51:11,720 --> 03:51:13,800
and what are the types
of infrastructure

4498
03:51:13,800 --> 03:51:15,480
we are talking about.

4499
03:51:15,480 --> 03:51:18,600
And my colleagues,
Professor Avindra Nath

4500
03:51:18,600 --> 03:51:21,880
from the NIH
will address neuropathology,

4501
03:51:21,880 --> 03:51:24,280
Professor Gabriel
de Erausquin

4502
03:51:24,280 --> 03:51:26,320
will address
the clinical spectrum

4503
03:51:26,320 --> 03:51:29,120
and the modifying
systemic factors,

4504
03:51:29,120 --> 03:51:31,800
and Professor Serena
Spudich from Yale

4505
03:51:31,800 --> 03:51:36,760
will speak about biomarkers and
possible promising interventions

4506
03:51:36,760 --> 03:51:39,800
that we might study.
Next.

4507
03:51:41,800 --> 03:51:48,000
So, this -- next.
This virus is an RNA virus.

4508
03:51:48,000 --> 03:51:50,720
It has and it's called
the spike protein.

4509
03:51:50,720 --> 03:51:52,800
Which is how the virus
enters the cells.

4510
03:51:52,800 --> 03:51:57,560
But it's, also,
how vaccines confer immunity.

4511
03:51:57,560 --> 03:52:01,600
And then there are the
nucleocapsid proteins presence

4512
03:52:01,600 --> 03:52:03,880
of immunity
to which can address --

4513
03:52:03,880 --> 03:52:06,280
can suggest that there
was native infection,

4514
03:52:06,280 --> 03:52:09,760
and not just vaccine-induced
immunity. Next.

4515
03:52:12,360 --> 03:52:16,920
As of a month ago,
over half a billion people

4516
03:52:16,920 --> 03:52:19,880
were known to have been
infected with this virus.

4517
03:52:19,880 --> 03:52:25,680
And, likely, there are
many more unsuspected cases,

4518
03:52:25,680 --> 03:52:29,680
so that as much as one
in 10 persons worldwide

4519
03:52:29,680 --> 03:52:33,200
have had this infection.
Next slide.

4520
03:52:33,200 --> 03:52:36,800
And we know that over time
the virus has evolved.

4521
03:52:36,800 --> 03:52:39,000
So, you have had
the Delta surges,

4522
03:52:39,000 --> 03:52:41,400
recently the Omicron surge.

4523
03:52:41,400 --> 03:52:46,040
And, next, unfortunately,
large parts of the world,

4524
03:52:46,040 --> 03:52:51,640
the areas in brown,
remain very poorly vaccinated.

4525
03:52:51,640 --> 03:52:53,880
And, so, the virus
is likely to spread

4526
03:52:53,880 --> 03:52:55,800
and evolve in these regions.

4527
03:52:55,800 --> 03:53:01,600
Which may lead to persistence
of the pandemic. Next.

4528
03:53:01,600 --> 03:53:07,680
So, why worry about ADRD
in the midst of this pandemic?

4529
03:53:07,680 --> 03:53:13,800
Next. Some of the early reasons
for alarm, next,

4530
03:53:13,800 --> 03:53:19,040
were that we know SARS and MERS,
which are similar coronaviruses,

4531
03:53:19,040 --> 03:53:22,000
could affect the brain
in some patients.

4532
03:53:22,000 --> 03:53:25,360
We know that anosmia, which is
characteristic of COVID-19,

4533
03:53:25,360 --> 03:53:28,360
is an early sign in some
neurodegenerative diseases,

4534
03:53:28,360 --> 03:53:30,640
like Alzheimer's
and Parkinson's.

4535
03:53:30,640 --> 03:53:33,520
And the last time we had
a pandemic of this proportion,

4536
03:53:33,520 --> 03:53:37,200
there was delayed
post-encephalitic parkinsonism.

4537
03:53:37,200 --> 03:53:39,640
Next.
There was, also, alarm

4538
03:53:39,640 --> 03:53:43,920
because there was a suspicion
of trans-synaptic transmission

4539
03:53:43,920 --> 03:53:48,320
from the olfactory mucosa
into the brain, next,

4540
03:53:48,320 --> 03:53:51,800
as well as perhaps
trans-endothelial are carried

4541
03:53:51,800 --> 03:53:57,400
by macrophages movement from
the blood system into the brain.

4542
03:53:57,400 --> 03:54:01,600
Next.
However, at autopsy, the virus,

4543
03:54:01,600 --> 03:54:04,480
or even evidence
of past viral replication,

4544
03:54:04,480 --> 03:54:07,400
is rarely seen.
Next.

4545
03:54:07,400 --> 03:54:10,320
And, so, there are
a number of theories,

4546
03:54:10,320 --> 03:54:12,440
some of which
you will hear about,

4547
03:54:12,440 --> 03:54:17,280
about how the virus may be
having the unquestionable impact

4548
03:54:17,280 --> 03:54:20,840
on thinking, memory.

4549
03:54:20,840 --> 03:54:25,080
Some of it may be that the virus
enters certain glial cells,

4550
03:54:25,080 --> 03:54:27,160
and other parts,
through receptors,

4551
03:54:27,160 --> 03:54:30,000
such as the H2
receptor in urapalin.

4552
03:54:30,000 --> 03:54:32,280
There is endothelial damage,
micro trauma

4553
03:54:32,280 --> 03:54:37,240
by the impact of both systemic
as well as local inflammation,

4554
03:54:37,240 --> 03:54:40,880
as well as changes
in neurotransmitters.

4555
03:54:40,880 --> 03:54:44,240
What is unquestionable
is that there are symptoms.

4556
03:54:44,240 --> 03:54:48,880
Next.
What we do not yet know,

4557
03:54:48,880 --> 03:54:51,800
because the virus has only been
with us for two years,

4558
03:54:51,800 --> 03:54:56,560
is that are these
mostly temporary.

4559
03:54:56,560 --> 03:55:00,240
Clearly, in some people,
they appear to be persistent.

4560
03:55:00,240 --> 03:55:02,520
And might they be progressive?

4561
03:55:02,520 --> 03:55:06,080
And what is the biology
around this?

4562
03:55:06,080 --> 03:55:08,600
Here, I do want to emphasize
that the working group

4563
03:55:08,600 --> 03:55:12,240
recognized that ADRD
is a broad umbrella.

4564
03:55:12,240 --> 03:55:16,800
We are not necessarily
only wanting to focus on amyloid

4565
03:55:16,800 --> 03:55:18,480
and tau pathology,

4566
03:55:18,480 --> 03:55:21,480
nor suggesting we know enough
to suggest that the virus,

4567
03:55:21,480 --> 03:55:25,520
in fact, increases
the risk of traditional AD.

4568
03:55:25,520 --> 03:55:30,800
But ADRD does also include VCID.
It includes all the conditions

4569
03:55:30,800 --> 03:55:33,200
that have been discussed
over the last two days,

4570
03:55:33,200 --> 03:55:35,760
as well as immune-mediated
cognitive decline,

4571
03:55:35,760 --> 03:55:38,080
sequelae of sexes
and inflammation.

4572
03:55:38,080 --> 03:55:41,200
Here is an opportunity
to study this area,

4573
03:55:41,200 --> 03:55:44,360
as well as other mechanisms
like mitochondrial dysfunction.

4574
03:55:44,360 --> 03:55:49,600
Next.
And, so, we need models.

4575
03:55:49,600 --> 03:55:51,600
And, unfortunately,
we are just at the beginning

4576
03:55:51,600 --> 03:55:54,160
of developing cell
and animal models.

4577
03:55:54,160 --> 03:55:55,760
And, also, we need
to understand

4578
03:55:55,760 --> 03:55:58,520
their translational relevance
to human disease.

4579
03:55:58,520 --> 03:56:01,080
Some of the models that have
been developed include,

4580
03:56:01,080 --> 03:56:05,120
next, IPSC organoids
and assembloids

4581
03:56:05,120 --> 03:56:07,440
that have neurons
and glial cells,

4582
03:56:07,440 --> 03:56:11,680
vascular and perivascular cells
susceptible to the virus,

4583
03:56:11,680 --> 03:56:16,600
next,
zebrafish with H2 receptors,

4584
03:56:16,600 --> 03:56:19,920
next, where you can see
the impact of the spike protein

4585
03:56:19,920 --> 03:56:24,320
in inducing immunological
and inflammatory changes.

4586
03:56:24,320 --> 03:56:27,240
Next.
Some mouse models that appear

4587
03:56:27,240 --> 03:56:30,440
to be susceptible
to COVID-induced,

4588
03:56:30,440 --> 03:56:36,400
next, anosmia resulting
in being unable to detect food

4589
03:56:36,400 --> 03:56:40,760
or partners of the opposite sex.
How relevant are these models?

4590
03:56:40,760 --> 03:56:43,800
These are things we need to
study in the translational way.

4591
03:56:43,800 --> 03:56:46,520
Next.

4592
03:56:46,520 --> 03:56:52,400
We need to query the data hidden
in electronic health records.

4593
03:56:52,400 --> 03:56:56,320
We already have data suggesting
that the risk of COVID

4594
03:56:56,320 --> 03:57:00,160
is doubled in persons
with pre-existing dementia.

4595
03:57:00,160 --> 03:57:03,440
It's, also, clear that
certain populations,

4596
03:57:03,440 --> 03:57:06,640
like African-Americans,
are more vulnerable to COVID,

4597
03:57:06,640 --> 03:57:10,400
having three times
the risk of Whites. Next.

4598
03:57:10,400 --> 03:57:12,680
Is it, also,
true that these populations

4599
03:57:12,680 --> 03:57:16,120
are more vulnerable
to ADRD type pathology

4600
03:57:16,120 --> 03:57:18,600
developing or accelerating
after COVID?

4601
03:57:18,600 --> 03:57:21,800
And, if so, why?
Next.

4602
03:57:21,800 --> 03:57:25,000
One suggestion was that,
in the pandemic,

4603
03:57:25,000 --> 03:57:28,360
caregivers were already
under stress,

4604
03:57:28,360 --> 03:57:29,840
persons living with dementia

4605
03:57:29,840 --> 03:57:32,480
were less able
to follow precautions,

4606
03:57:32,480 --> 03:57:36,600
and may suffer from withdrawal
of things like social support.

4607
03:57:36,600 --> 03:57:40,400
Next.
So, was the higher risk entirely

4608
03:57:40,400 --> 03:57:43,000
due to behavioral
and environmental factors?

4609
03:57:43,000 --> 03:57:45,360
Next.
There is a suggestion

4610
03:57:45,360 --> 03:57:48,240
that there was some biological
and genetic factors

4611
03:57:48,240 --> 03:57:52,200
as well that may underlie the
higher susceptibility to COVID

4612
03:57:52,200 --> 03:57:56,880
in persons with dementia.
In this study from Finland,

4613
03:57:56,880 --> 03:57:59,920
3,000 hospitalized
now patient cases

4614
03:57:59,920 --> 03:58:03,360
were matched to controls
in this Finland cohort.

4615
03:58:03,360 --> 03:58:07,360
And persons who had APLE 4
were more likely to have severe

4616
03:58:07,360 --> 03:58:09,880
COVID,
to have micro hemorrhages,

4617
03:58:09,880 --> 03:58:13,080
and also to have
post-COVID mental fatigue.

4618
03:58:13,080 --> 03:58:17,080
So, genetic studies may help
with risk prediction,

4619
03:58:17,080 --> 03:58:19,080
as well as understanding
the biology,

4620
03:58:19,080 --> 03:58:23,520
and perhaps finding
intervention targets. Next.

4621
03:58:26,000 --> 03:58:27,760
In the GEN-COVID,

4622
03:58:27,760 --> 03:58:30,200
which is looking
at the genetics of COVID,

4623
03:58:30,200 --> 03:58:34,760
some genes not previously
strongly associated with AD,

4624
03:58:34,760 --> 03:58:39,400
like oligoadenylate synthetase
1, were identified.

4625
03:58:39,400 --> 03:58:41,120
And then, subsequently,
it was found

4626
03:58:41,120 --> 03:58:43,520
that these may have
a role in AD as well.

4627
03:58:43,520 --> 03:58:47,680
Next.
For instance, the OAS1 gene

4628
03:58:47,680 --> 03:58:51,000
seems to determine
whether microglia are more

4629
03:58:51,000 --> 03:58:53,720
in the interferon
responsive subtype,

4630
03:58:53,720 --> 03:58:57,400
or the amyloid response
of an amyloid removing subtype.

4631
03:58:57,400 --> 03:58:59,240
And if you have
a genetic variation

4632
03:58:59,240 --> 03:59:02,000
that predisposes you
to have more microglia

4633
03:59:02,000 --> 03:59:04,280
of the interferon
responsive subtype,

4634
03:59:04,280 --> 03:59:07,160
the hypothesis goes
that you may be more susceptible

4635
03:59:07,160 --> 03:59:09,200
to both AD
and severe COVID.

4636
03:59:09,200 --> 03:59:12,400
Again, this needs to be
validated in further studies.

4637
03:59:12,400 --> 03:59:16,080
But this is the preliminary
data. Next slide.

4638
03:59:16,080 --> 03:59:18,240
So, what are the kinds
of infrastructure

4639
03:59:18,240 --> 03:59:22,240
we wish to emphasize?
Next.

4640
03:59:22,240 --> 03:59:27,800
We, next,
want to recognize

4641
03:59:27,800 --> 03:59:32,720
that there is opportunity
in the pandemic,

4642
03:59:32,720 --> 03:59:36,000
in that factors
beyond biology,

4643
03:59:36,000 --> 03:59:39,240
factors such as national
health policies,

4644
03:59:39,240 --> 03:59:42,000
and the effectiveness
in controlling the pandemic,

4645
03:59:42,000 --> 03:59:45,800
may also have a role in whatever
we see in terms of sequelae.

4646
03:59:45,800 --> 03:59:47,880
For instance, when
the global burden of disease

4647
03:59:47,880 --> 03:59:50,240
looked at depression
and anxiety,

4648
03:59:50,240 --> 03:59:53,560
not surprisingly,
during the pandemic, it went up.

4649
03:59:53,560 --> 03:59:56,760
But it, also, went up
more in countries

4650
03:59:56,760 --> 03:59:59,520
where the health policies
and effectiveness

4651
03:59:59,520 --> 04:00:03,600
in controlling COVID
was less.

4652
04:00:03,600 --> 04:00:07,840
And this is, again,
understandable. Next. So --

4653
04:00:07,840 --> 04:00:09,360
-Two minutes remaining.

4654
04:00:09,360 --> 04:00:12,000
-Next. We recognize
that there are many factors,

4655
04:00:12,000 --> 04:00:14,720
such as the virus
and variations in the virus,

4656
04:00:14,720 --> 04:00:19,560
next, as well
as indirect factors like access

4657
04:00:19,560 --> 04:00:23,440
to physical activity
and diet, next,

4658
04:00:23,440 --> 04:00:29,240
as well as, next,
modifiers in the environment.

4659
04:00:29,240 --> 04:00:32,800
And, therefore,
our recommendation, next,

4660
04:00:32,800 --> 04:00:36,360
emphasizes the need
to carefully ascertain details

4661
04:00:36,360 --> 04:00:38,920
about the infection
and treatment,

4662
04:00:38,920 --> 04:00:41,600
as well as the impact
of policy interventions,

4663
04:00:41,600 --> 04:00:43,520
like paid family leave,

4664
04:00:43,520 --> 04:00:46,200
as well as the role
of access to care,

4665
04:00:46,200 --> 04:00:49,240
and the possible benefit
from innovative technologies

4666
04:00:49,240 --> 04:00:53,000
like telemedicine. Next.

4667
04:00:53,000 --> 04:00:58,240
We emphasize the need to use
established clinical cohorts,

4668
04:00:58,240 --> 04:01:00,160
like the NIH, NINDSC

4669
04:01:00,160 --> 04:01:04,000
4R, the UK Biobank,
which you'll hear about later,

4670
04:01:04,000 --> 04:01:06,320
as well as new
longitudinal cohorts,

4671
04:01:06,320 --> 04:01:10,320
like the recovery effort,
existing dementia cohorts,

4672
04:01:10,320 --> 04:01:12,560
like the ADRCs and NAC,

4673
04:01:12,560 --> 04:01:16,920
as well as the cohorts that were
exposed to acute trials,

4674
04:01:16,920 --> 04:01:20,360
like monoclonals that might
reduce the severity of COVID.

4675
04:01:20,360 --> 04:01:24,120
Next.
And to record --

4676
04:01:24,120 --> 04:01:28,480
to collect fluids and use novel
imaging techniques,

4677
04:01:28,480 --> 04:01:33,440
next, harmonize the various
measures of cognition

4678
04:01:33,440 --> 04:01:39,200
and other modalities, next,
so that we can rapidly implement

4679
04:01:39,200 --> 04:01:41,760
in parallel candidate
drug screening.

4680
04:01:41,760 --> 04:01:44,680
And with this natural history
and biomarkers known,

4681
04:01:44,680 --> 04:01:47,600
go forward for treatment tracks.
Next.

4682
04:01:47,600 --> 04:01:49,360
-Time.

4683
04:01:49,360 --> 04:01:53,720
-We will be looking at both
population-based,

4684
04:01:53,720 --> 04:01:56,240
hospital-based,
and other types of clinics,

4685
04:01:56,240 --> 04:02:02,320
next, novel methods
that look at areas

4686
04:02:02,320 --> 04:02:04,680
that may be susceptible
to MRI --

4687
04:02:04,680 --> 04:02:07,880
to COVID, such as
the locus coeruleus

4688
04:02:07,880 --> 04:02:10,600
and the olfactory lobes, next,

4689
04:02:10,600 --> 04:02:14,120
and emphasize
longitudinal data collection.

4690
04:02:14,120 --> 04:02:17,280
Because there may be
a delayed impact of the virus

4691
04:02:17,280 --> 04:02:23,400
that is only detectable
with repeated assessment. Next.

4692
04:02:23,400 --> 04:02:27,320
So, I'll now hand
over to my colleague,

4693
04:02:27,320 --> 04:02:28,760
Professor Avindra Nath,

4694
04:02:28,760 --> 04:02:31,560
to discuss the neuropathology
of the virus.

4695
04:02:36,400 --> 04:02:40,160
-Thank you, Sudha,
for the wonderful introduction.

4696
04:02:40,160 --> 04:02:44,880
And so I'm going to talk
about the neuropathology.

4697
04:02:44,880 --> 04:02:49,800
And if you look at the various
syndromes associated with COVID,

4698
04:02:49,800 --> 04:02:53,000
can be divided into
three major categories.

4699
04:02:53,000 --> 04:02:54,480
One is during the acute phase

4700
04:02:54,480 --> 04:02:56,840
when the patient is admitted
to the hospital.

4701
04:02:56,840 --> 04:02:59,680
At that time, there is
a lot of end-organ damage,

4702
04:02:59,680 --> 04:03:01,160
and so there's no surprise

4703
04:03:01,160 --> 04:03:02,720
that the brain is going
to get involved.

4704
04:03:02,720 --> 04:03:04,600
However, the brain can be
directly involved

4705
04:03:04,600 --> 04:03:09,160
by vascular disease
and very, very rarely,

4706
04:03:09,160 --> 04:03:13,120
are there any cases
of true viral encephalitis.

4707
04:03:13,120 --> 04:03:14,600
Then you have
the subacute phase

4708
04:03:14,600 --> 04:03:17,120
where these are largely
post-viral syndromes,

4709
04:03:17,120 --> 04:03:18,800
but they're all
inflammatory syndromes.

4710
04:03:18,800 --> 04:03:21,480
And you can see them with almost
any kind of viral infection.

4711
04:03:21,480 --> 04:03:24,960
So they are acute
disseminated encephalomyelitis,

4712
04:03:24,960 --> 04:03:28,120
necrotizing encephalopathy,
limbic encephalitis.

4713
04:03:28,120 --> 04:03:35,480
So they are mediated by very
specific types of immune cells.

4714
04:03:35,480 --> 04:03:37,640
And then there's
a unique syndrome

4715
04:03:37,640 --> 04:03:39,800
associated with the virus
in children

4716
04:03:39,800 --> 04:03:44,000
that is called multi-system
inflammatory syndrome.

4717
04:03:44,000 --> 04:03:45,320
Well, we're going to spend
a lot of time

4718
04:03:45,320 --> 04:03:48,800
talking about
chronic manifestation,

4719
04:03:48,800 --> 04:03:50,800
which is long COVID.
Next slide.

4720
04:03:53,000 --> 04:03:54,600
So just as Sudha said,

4721
04:03:54,600 --> 04:03:59,000
you know, the concern was,
early in the pandemic,

4722
04:03:59,000 --> 04:04:01,520
that can the virus
really enter the brain.

4723
04:04:01,520 --> 04:04:06,080
As you can see here,
in the cribriform plate

4724
04:04:06,080 --> 04:04:07,920
is this very thin piece of bone

4725
04:04:07,920 --> 04:04:10,960
that's separating the brain
from the nasal cavity,

4726
04:04:10,960 --> 04:04:13,480
and there are all these
olfactory nerves

4727
04:04:13,480 --> 04:04:15,280
traversing this
cribriform plate.

4728
04:04:15,280 --> 04:04:18,480
So the question is,
can the virus really get in?

4729
04:04:18,480 --> 04:04:20,120
It turns out that
the olfactory nerves

4730
04:04:20,120 --> 04:04:21,840
themselves never get infected,

4731
04:04:21,840 --> 04:04:23,880
and what gets infected are
really the sustentacular cells,

4732
04:04:23,880 --> 04:04:29,200
which are the support cells.
So next slide.

4733
04:04:29,200 --> 04:04:33,200
And so if you actually look
for virus in these regions,

4734
04:04:33,200 --> 04:04:34,800
what you find
is that the olfactory --

4735
04:04:34,800 --> 04:04:37,440
because it has
a lot of virus, okay?

4736
04:04:37,440 --> 04:04:39,640
And the olfactory bulb
and the tubercule,

4737
04:04:39,640 --> 04:04:42,600
very rarely do you
find any virus at all.

4738
04:04:42,600 --> 04:04:44,800
So it really stays
in the mucosa.

4739
04:04:44,800 --> 04:04:47,080
And as you can see
on the right-hand side,

4740
04:04:47,080 --> 04:04:49,720
these small viral particles,

4741
04:04:49,720 --> 04:04:51,800
these round structures
are viral particles here

4742
04:04:51,800 --> 04:04:54,240
that causes
a huge amount of virus,

4743
04:04:54,240 --> 04:04:56,560
and because of that,
that's where it stays.

4744
04:04:56,560 --> 04:05:01,000
Next slide, please.
So there are other groups

4745
04:05:01,000 --> 04:05:04,400
that have detected small amounts
of virus in the brain,

4746
04:05:04,400 --> 04:05:06,640
but you find it
very infrequently,

4747
04:05:06,640 --> 04:05:10,880
and when you do find it,
you don't find any inflammation

4748
04:05:10,880 --> 04:05:13,080
around the areas
when they detect them,

4749
04:05:13,080 --> 04:05:16,200
so we don't think that is
of much pathogenic significance.

4750
04:05:16,200 --> 04:05:17,840
We, and several other groups,

4751
04:05:17,840 --> 04:05:21,680
have failed to detect
any virus in the brain

4752
04:05:21,680 --> 04:05:25,040
using a wide variety
of very sensitive techniques.

4753
04:05:25,040 --> 04:05:29,600
Next slide, please.
And what I want to emphasize

4754
04:05:29,600 --> 04:05:33,320
is that the major pathology
really is vascular injury,

4755
04:05:33,320 --> 04:05:35,800
and I think that has a lot
of implications

4756
04:05:35,800 --> 04:05:39,400
for microvascular disease
and Alzheimer's-like pathology.

4757
04:05:39,400 --> 04:05:43,520
So next slide, please.
And so the vascular pathology

4758
04:05:43,520 --> 04:05:45,280
can present
in many different ways.

4759
04:05:45,280 --> 04:05:47,720
You can get frank infarcts.
You can get bilateral infarcts.

4760
04:05:47,720 --> 04:05:50,360
You can get brain
and other organ systems

4761
04:05:50,360 --> 04:05:52,400
where blood vessels
can get occluded.

4762
04:05:52,400 --> 04:05:56,800
And then there are individuals
who can get microhemorrhages

4763
04:05:56,800 --> 04:06:00,960
and other individuals who can
occlude the venous system,

4764
04:06:00,960 --> 04:06:04,200
and you can get cerebral
venous thromboses as well.

4765
04:06:04,200 --> 04:06:07,400
Interestingly, the study here
looked at microhemorrhages,

4766
04:06:07,400 --> 04:06:09,520
and what they found was
that those individuals

4767
04:06:09,520 --> 04:06:12,840
who are APOE positive
are at greater risk

4768
04:06:12,840 --> 04:06:14,200
of developing hemorrhages,

4769
04:06:14,200 --> 04:06:15,960
looking at different
parts of the brain,

4770
04:06:15,960 --> 04:06:17,440
as you can see here.

4771
04:06:17,440 --> 04:06:20,000
And there's more
severe hemorrhages,

4772
04:06:20,000 --> 04:06:24,640
and more areas are involved.
Next slide, please.

4773
04:06:26,680 --> 04:06:30,800
So besides frank hemorrhages,
you can also see --

4774
04:06:30,800 --> 04:06:32,040
without the presence
of hemorrhage,

4775
04:06:32,040 --> 04:06:36,880
you can still see
microvascular pathology.

4776
04:06:36,880 --> 04:06:40,600
And here, what we did is,
we did postmortem MRI scans,

4777
04:06:40,600 --> 04:06:42,880
and these are very
high-resolution scans

4778
04:06:42,880 --> 04:06:44,360
using 11 Tesla scanner.

4779
04:06:44,360 --> 04:06:47,280
And you can see,
these blood vessels here,

4780
04:06:47,280 --> 04:06:48,680
they look abnormal.

4781
04:06:48,680 --> 04:06:51,600
And when we stain them
for fibrinogen,

4782
04:06:51,600 --> 04:06:53,000
which is a protein
that should be present

4783
04:06:53,000 --> 04:06:55,200
only in the blood
and not outside,

4784
04:06:55,200 --> 04:06:57,400
you actually see
the leakage of fibrinogen.

4785
04:06:57,400 --> 04:07:00,400
So these blood vessels
are really very leaky.

4786
04:07:00,400 --> 04:07:03,960
So they aren't leaking RBCs,
but they're leaking proteins.

4787
04:07:03,960 --> 04:07:05,200
Here in the olfactory bulb,

4788
04:07:05,200 --> 04:07:07,280
you find the exact
same thing, too.

4789
04:07:07,280 --> 04:07:09,800
There was a lot
of fibrinogen there.

4790
04:07:09,800 --> 04:07:12,280
But within
the blood vessel itself,

4791
04:07:12,280 --> 04:07:14,680
you can see aggregation
of platelets.

4792
04:07:14,680 --> 04:07:17,520
So this is another form of
microvascular disease here now.

4793
04:07:17,520 --> 04:07:18,800
Instead of them leaking,

4794
04:07:18,800 --> 04:07:20,520
the endothelial cells
are activated

4795
04:07:20,520 --> 04:07:24,200
to whereby the platelets stick
to them, and they get activated.

4796
04:07:24,200 --> 04:07:26,920
And you can see occlusion
of the small blood vessels

4797
04:07:26,920 --> 04:07:29,200
here as well
from these platelets.

4798
04:07:29,200 --> 04:07:33,800
And what we find is that you see
it more often in the hindbrain,

4799
04:07:33,800 --> 04:07:37,800
which is the brain stem
and the cerebellum,

4800
04:07:37,800 --> 04:07:40,120
and we looked
at all kinds of controls.

4801
04:07:40,120 --> 04:07:42,000
You don't really see them.
You only find them --

4802
04:07:42,000 --> 04:07:44,800
it's quite specific
for these COVID patients.

4803
04:07:44,800 --> 04:07:46,400
Next, please.

4804
04:07:48,560 --> 04:07:51,200
There are some individuals
who developed tinnitus,

4805
04:07:51,200 --> 04:07:54,080
acute onset of ringing of
ears.

4806
04:07:54,080 --> 04:07:56,720
It's associated
with loss of hearing.

4807
04:07:56,720 --> 04:07:59,200
And next slide, please.

4808
04:07:59,200 --> 04:08:03,760
And others that would develop
acute onset of vertigo.

4809
04:08:03,760 --> 04:08:06,320
We think these are actually
vascular phenomenon,

4810
04:08:06,320 --> 04:08:08,680
and that is possible
that the small blood vessels

4811
04:08:08,680 --> 04:08:10,880
supplying the inner ear
get occluded

4812
04:08:10,880 --> 04:08:14,400
because it's fairly sudden onset
in these individuals.

4813
04:08:14,400 --> 04:08:17,280
Next slide, please.
Okay.

4814
04:08:17,280 --> 04:08:22,520
Then there's the subacute phase.
Next slide.

4815
04:08:22,520 --> 04:08:23,960
And as I said, you know,

4816
04:08:23,960 --> 04:08:26,680
you can get acute
disseminated encephalomyelitis

4817
04:08:26,680 --> 04:08:28,200
as shown over here.

4818
04:08:28,200 --> 04:08:30,800
This is largely
a T-cell-mediated phenomenon.

4819
04:08:30,800 --> 04:08:32,920
Some get necrotizing
encephalopathy,

4820
04:08:32,920 --> 04:08:34,960
which is largely
a cytokine-mediated phenomenon,

4821
04:08:34,960 --> 04:08:36,880
so those things are
very important to recognize

4822
04:08:36,880 --> 04:08:38,760
because they're treatable
very differently,

4823
04:08:38,760 --> 04:08:42,000
and the long-term implications
are also different.

4824
04:08:42,000 --> 04:08:45,320
Next slide, please.
And then, in children,

4825
04:08:45,320 --> 04:08:47,400
you can get this
multi-inflammatory syndrome.

4826
04:08:47,400 --> 04:08:49,200
As you can see on the screen,
in the corpus callosum,

4827
04:08:49,200 --> 04:08:51,480
there's a high-signal
intensity lesion here

4828
04:08:51,480 --> 04:08:53,400
and loss
of inflammatory markers.

4829
04:08:53,400 --> 04:08:55,280
So the long-term
consequences of this

4830
04:08:55,280 --> 04:08:58,800
are not fully understood.
Next slide, please.

4831
04:09:01,080 --> 04:09:04,680
Then, as I showed you earlier,

4832
04:09:04,680 --> 04:09:06,160
you know,
there's leakage of proteins,

4833
04:09:06,160 --> 04:09:07,800
but if you look
for the cellular infiltrates,

4834
04:09:07,800 --> 04:09:09,240
you find they're
largely macrophages.

4835
04:09:09,240 --> 04:09:11,560
I think they're coming in there
to clean out

4836
04:09:11,560 --> 04:09:14,200
all the proteins
that are leaking,

4837
04:09:14,200 --> 04:09:18,000
but once the macrophages
enter there, they don't leave.

4838
04:09:18,000 --> 04:09:21,960
So they will cause a lot of
damage to surrounding tissues.

4839
04:09:21,960 --> 04:09:23,680
You hardly ever find
any T cells,

4840
04:09:23,680 --> 04:09:26,000
and that tells you that,
if it was a viral encephalitis,

4841
04:09:26,000 --> 04:09:27,240
you should see
a lot of T cells.

4842
04:09:27,240 --> 04:09:29,480
You actually don't see any.
No.

4843
04:09:29,480 --> 04:09:31,680
And you got
astrocyte activation here, too.

4844
04:09:31,680 --> 04:09:37,000
Yeah, next slide. You can get
peripheral nerve involvement.

4845
04:09:37,000 --> 04:09:39,640
So you can see
the cranial nerves

4846
04:09:39,640 --> 04:09:42,960
as well as the roots
coming out

4847
04:09:42,960 --> 04:09:45,680
can get inflamed
and involved as well.

4848
04:09:45,680 --> 04:09:49,800
So you can get widespread
peripheral nerve involvement.

4849
04:09:49,800 --> 04:09:52,840
Next.

4850
04:09:52,840 --> 04:09:56,360
And in some patients,
you can also get myositis.

4851
04:09:56,360 --> 04:09:58,200
As I said,
inflammatory myositis,

4852
04:09:58,200 --> 04:10:02,920
that responds to treatment
with high-dose corticosteroids.

4853
04:10:02,920 --> 04:10:05,000
Next slide, please.

4854
04:10:05,000 --> 04:10:07,560
-Two minutes remaining.

4855
04:10:07,560 --> 04:10:10,800
-Next slide.

4856
04:10:10,800 --> 04:10:15,600
Well, what is important
is that most patients,

4857
04:10:15,600 --> 04:10:19,400
they will recover early on
for about three months or so.

4858
04:10:19,400 --> 04:10:21,320
If they don't recover
by three months,

4859
04:10:21,320 --> 04:10:23,480
most of the symptoms
start to persist,

4860
04:10:23,480 --> 04:10:27,360
and you see it more often
in women as compared to men.

4861
04:10:27,360 --> 04:10:28,720
That again suggests to you

4862
04:10:28,720 --> 04:10:30,240
that it's an immune-mediated
phenomenon,

4863
04:10:30,240 --> 04:10:33,400
most likely.
Next slide.

4864
04:10:33,400 --> 04:10:36,600
So there are these individuals
who, as I showed you,

4865
04:10:36,600 --> 04:10:38,480
they have severe symptoms
initially.

4866
04:10:38,480 --> 04:10:41,200
They gradually got better,
but not completely.

4867
04:10:41,200 --> 04:10:43,320
Then there are other individuals
with mild symptoms,

4868
04:10:43,320 --> 04:10:46,120
they get better, but after
a certain latent period,

4869
04:10:46,120 --> 04:10:47,800
they then get
new symptoms again.

4870
04:10:47,800 --> 04:10:50,360
Okay. Next slide.

4871
04:10:50,360 --> 04:10:52,600
And we looked at a cohort
of these individuals.

4872
04:10:52,600 --> 04:10:54,920
Almost all of them
have cognitive abnormalities

4873
04:10:54,920 --> 04:10:56,320
as well as fatigue

4874
04:10:56,320 --> 04:10:59,120
and then a whole host
of neurological symptoms

4875
04:10:59,120 --> 04:11:03,600
that are to a lesser degree.
Next slide.

4876
04:11:03,600 --> 04:11:07,960
And so you can divide
these patients into four groups,

4877
04:11:07,960 --> 04:11:11,640
some that have largely cognitive
and mood and sleep disorders,

4878
04:11:11,640 --> 04:11:15,600
and I think that's the category
that you're more interested in,

4879
04:11:15,600 --> 04:11:18,240
but there are other types
of long COVID syndromes

4880
04:11:18,240 --> 04:11:20,360
that can present
in these individuals.

4881
04:11:20,360 --> 04:11:22,720
Next slide.

4882
04:11:22,720 --> 04:11:25,680
And PET scan shows
that these individuals

4883
04:11:25,680 --> 04:11:29,320
have decreased uptake of glucose
in a more symmetric manner

4884
04:11:29,320 --> 04:11:30,600
involving the cortex.

4885
04:11:30,600 --> 04:11:32,760
So the cortex
is diffusely involved

4886
04:11:32,760 --> 04:11:35,040
in these patients
in the subacute group.

4887
04:11:35,040 --> 04:11:38,080
Next slide.

4888
04:11:38,080 --> 04:11:40,960
And this very recent study
from the UK

4889
04:11:40,960 --> 04:11:45,480
shows that there is also --
they looked at this cohort

4890
04:11:45,480 --> 04:11:48,360
before
and after development of COVID,

4891
04:11:48,360 --> 04:11:49,880
and it was a unique cohort,

4892
04:11:49,880 --> 04:11:52,080
that the total intracranial
volume is decreased.

4893
04:11:52,080 --> 04:11:54,120
There is hippocampal --

4894
04:11:54,120 --> 04:12:00,360
the gyrus is actually decreased
and preferentially

4895
04:12:00,360 --> 04:12:05,680
and is associated with
impairment of cognition as well.

4896
04:12:05,680 --> 04:12:07,960
So I think this is actually
quite concerning,

4897
04:12:07,960 --> 04:12:10,040
and long-term follow-up
will reveal what's happening.

4898
04:12:10,040 --> 04:12:12,200
Next slide, please.

4899
04:12:12,200 --> 04:12:13,520
-Time.

4900
04:12:13,520 --> 04:12:17,920
-Okay. Next slide.
I'll just skip this one.

4901
04:12:17,920 --> 04:12:21,160
-And eventually, you can
actually see neuronal loss here,

4902
04:12:21,160 --> 04:12:22,520
and we've shown that
in the brainstem.

4903
04:12:22,520 --> 04:12:25,200
Note when you get
activated microglia,

4904
04:12:25,200 --> 04:12:29,120
you can see loss over here.
Next slide.

4905
04:12:29,120 --> 04:12:30,600
So, in conclusion,

4906
04:12:30,600 --> 04:12:33,200
direct invasion
of the brain by SARS is rare,

4907
04:12:33,200 --> 04:12:34,800
and neuroimmune dysfunction,
I think,

4908
04:12:34,800 --> 04:12:37,640
is by activation
of innate immune responses,

4909
04:12:37,640 --> 04:12:40,480
and endothelial damage
is the primary

4910
04:12:40,480 --> 04:12:42,400
pathophysiological process
in Nero-COVID.

4911
04:12:42,400 --> 04:12:44,680
Next slide.

4912
04:12:44,680 --> 04:12:48,080
And these are
our acknowledgements.

4913
04:12:48,080 --> 04:12:49,640
I'd like to thank
each other people

4914
04:12:49,640 --> 04:12:52,480
who helped us
with obtaining the tissues.

4915
04:12:52,480 --> 04:12:55,600
Serena and I ordered a review
on this quite recently.

4916
04:12:55,600 --> 04:12:57,600
And these are the people
in my lab who did all the work.

4917
04:12:57,600 --> 04:12:59,800
So I'll stop here. Thanks.

4918
04:13:08,320 --> 04:13:11,960
-Yes, Professor Erausquin.

4919
04:13:11,960 --> 04:13:14,400
-Thank you very much.

4920
04:13:14,400 --> 04:13:18,280
I'll get straight into it
in the interest of time.

4921
04:13:18,280 --> 04:13:21,280
My run is to cover
the clinical side

4922
04:13:21,280 --> 04:13:26,000
of the neurocognitive
dysfunction after COVID-19.

4923
04:13:26,000 --> 04:13:28,360
Next slide, please.
I don't have any disclosures.

4924
04:13:28,360 --> 04:13:31,080
Next slide, please.

4925
04:13:31,080 --> 04:13:34,240
And this has been
a topic of concern

4926
04:13:34,240 --> 04:13:35,880
right from the beginning
of the pandemic.

4927
04:13:35,880 --> 04:13:40,200
The publications about cognitive
impairment in initial case

4928
04:13:40,200 --> 04:13:43,920
reports began
in the immediate months

4929
04:13:43,920 --> 04:13:47,800
after the onset
of the spread of the virus

4930
04:13:47,800 --> 04:13:52,040
and have continued to increase
over the past 18 or 20 months.

4931
04:13:52,040 --> 04:13:54,760
What's more remarkable is that,
from very early on,

4932
04:13:54,760 --> 04:13:57,600
the public eye
also caught interest

4933
04:13:57,600 --> 04:13:59,800
in this particular phenomenon,

4934
04:13:59,800 --> 04:14:02,600
those initially described
by patients,

4935
04:14:02,600 --> 04:14:07,480
by sufferers, as brain fog.
Next slide, please.

4936
04:14:07,480 --> 04:14:10,800
The source of data have become
increasingly sophisticated.

4937
04:14:10,800 --> 04:14:12,920
Initially, where I also
mentioned case reports,

4938
04:14:12,920 --> 04:14:17,360
then more protracted,

4939
04:14:17,360 --> 04:14:20,240
more extended case series
began to appear

4940
04:14:20,240 --> 04:14:23,080
involving
primarily hospitalized patients

4941
04:14:23,080 --> 04:14:26,520
during or immediately after
the acute phase of the illness,

4942
04:14:26,520 --> 04:14:30,240
and those follow-up
appointments in clinics

4943
04:14:30,240 --> 04:14:35,240
describing persistent symptoms,
as Dr. Nath already mentioned.

4944
04:14:35,240 --> 04:14:39,680
But better quality data
perhaps and more relevant

4945
04:14:39,680 --> 04:14:43,440
from the point of view
of the neurological importance

4946
04:14:43,440 --> 04:14:45,280
of this particular phenomenon

4947
04:14:45,280 --> 04:14:50,400
began to appear
in surveys of patients

4948
04:14:50,400 --> 04:14:54,360
who were well characterized
and being followed as part of

4949
04:14:54,360 --> 04:14:55,720
longitudinal cohorts,

4950
04:14:55,720 --> 04:14:58,080
such as the ones
that Dr. Seshadri mentioned,

4951
04:14:58,080 --> 04:15:02,040
including Nath
the framing of her study

4952
04:15:02,040 --> 04:15:04,280
or the San Antonio
Mexican-American

4953
04:15:04,280 --> 04:15:07,240
pharmacy studies,
which had --

4954
04:15:07,240 --> 04:15:09,480
all the individuals
who had been well characterized

4955
04:15:09,480 --> 04:15:11,840
and followed for
a protracted period of time.

4956
04:15:11,840 --> 04:15:13,440
The biggest disadvantage
of those cohorts

4957
04:15:13,440 --> 04:15:15,720
is that the relative number
of affected individuals

4958
04:15:15,720 --> 04:15:18,800
was small and persists
rather small.

4959
04:15:18,800 --> 04:15:22,000
So the better quality data
are beginning to emerge

4960
04:15:22,000 --> 04:15:29,280
from new cohorts developed
from population-based databases

4961
04:15:29,280 --> 04:15:32,160
or registries
and include all individuals

4962
04:15:32,160 --> 04:15:35,360
who have been
tested for COVID

4963
04:15:35,360 --> 04:15:36,800
during the course
of the pandemic,

4964
04:15:36,800 --> 04:15:39,200
whether they came back
positive or negative,

4965
04:15:39,200 --> 04:15:42,600
and that will be where I would
focus more of my comments.

4966
04:15:42,600 --> 04:15:45,040
Next slide, please.

4967
04:15:45,040 --> 04:15:48,000
For instance, again,
as Dr. Nath already mentioned,

4968
04:15:48,000 --> 04:15:51,160
there are good quality data
from separate port of patients.

4969
04:15:51,160 --> 04:15:53,880
This is coming primarily
from the UK biobank

4970
04:15:53,880 --> 04:15:56,920
that Dr. Seshadri mentioned,

4971
04:15:56,920 --> 04:15:59,120
pointing to the fact
on the left top panel

4972
04:15:59,120 --> 04:16:03,520
that persisting symptoms
are quite sustained.

4973
04:16:03,520 --> 04:16:07,200
Once they're present,
after the few initial weeks

4974
04:16:07,200 --> 04:16:12,320
of the recording of the illness,
they don't seem to go away.

4975
04:16:12,320 --> 04:16:14,720
More notably, the bulk
of those symptoms

4976
04:16:14,720 --> 04:16:19,240
and the ones
with highest probability,

4977
04:16:19,240 --> 04:16:22,360
they are on the bottom
left panel --

4978
04:16:22,360 --> 04:16:27,520
brain fog, memory issues,
and difficulties with language.

4979
04:16:27,520 --> 04:16:32,920
But if you disclose a bit more
on the top right panel,

4980
04:16:32,920 --> 04:16:36,760
you find that include
primarily short-term memory loss

4981
04:16:36,760 --> 04:16:40,480
and word-finding difficulties.
What's most remarkable is that,

4982
04:16:40,480 --> 04:16:44,800
if you consider the presence
of the symptoms

4983
04:16:44,800 --> 04:16:50,520
on average across age groups,
they seem to be, you know,

4984
04:16:50,520 --> 04:16:56,400
more or less the same across
different strata of aging,

4985
04:16:56,400 --> 04:16:59,120
but when you disclose
that in greater detail,

4986
04:16:59,120 --> 04:17:01,720
it turns out
that younger individuals

4987
04:17:01,720 --> 04:17:03,400
have more much
prominent problems

4988
04:17:03,400 --> 04:17:07,600
with attention, concentration,
and executive dysfunction,

4989
04:17:07,600 --> 04:17:11,520
as opposed to true
fewer memory problems

4990
04:17:11,520 --> 04:17:14,080
that appear to be
much more prevalent

4991
04:17:14,080 --> 04:17:16,320
and severe
in other individuals.

4992
04:17:16,320 --> 04:17:17,920
Next slide, please.

4993
04:17:20,200 --> 04:17:25,400
In the largest US-based study
that was published

4994
04:17:25,400 --> 04:17:30,400
by Biden's
administration recently,

4995
04:17:30,400 --> 04:17:33,400
they found that
the neurocognitive decline

4996
04:17:33,400 --> 04:17:36,800
was actually two times
more common in individuals

4997
04:17:36,800 --> 04:17:38,160
who had suffered COVID

4998
04:17:38,160 --> 04:17:41,640
and recovered within
a relatively short time,

4999
04:17:41,640 --> 04:17:45,000
30 days after recovery
than in historical controls,

5000
04:17:45,000 --> 04:17:46,480
when they looked at
a very large sample

5001
04:17:46,480 --> 04:17:50,320
of close to 6 million people
or contemporaneous,

5002
04:17:50,320 --> 04:17:52,360
so having controls
that did not have

5003
04:17:52,360 --> 04:17:55,480
the disease
in equal large number.

5004
04:17:55,480 --> 04:17:59,800
So this is quite clearly
a unique phenomenon

5005
04:17:59,800 --> 04:18:04,080
to recovery from COVID.
Next slide, please.

5006
04:18:04,080 --> 04:18:05,800
What's most important
is that it's not

5007
04:18:05,800 --> 04:18:10,440
just when you compare
the individuals that recover

5008
04:18:10,440 --> 04:18:12,600
from COVID
to the general population,

5009
04:18:12,600 --> 04:18:15,680
but also if you compare them
with individuals

5010
04:18:15,680 --> 04:18:17,720
who recovered from other,

5011
04:18:17,720 --> 04:18:20,520
similar respiratory
flu-like syndromes.

5012
04:18:20,520 --> 04:18:22,160
And in this particular case,

5013
04:18:22,160 --> 04:18:24,560
the comparison was made
to influenza.

5014
04:18:24,560 --> 04:18:29,400
And you can see that, as far
as six months after recovery

5015
04:18:29,400 --> 04:18:32,760
from an acute respiratory
severe illness,

5016
04:18:32,760 --> 04:18:36,320
flu-like illness,
if the illness was COVID,

5017
04:18:36,320 --> 04:18:38,320
the likelihood
of cognitive impairment

5018
04:18:38,320 --> 04:18:40,600
is almost two-fold

5019
04:18:40,600 --> 04:18:45,640
that of the patients that
recovered from the regular flu.

5020
04:18:45,640 --> 04:18:49,000
The pattern of symptoms
is actually similar, too.

5021
04:18:49,000 --> 04:18:52,080
Again, to what Dr. Nath
mentioned, quite broad.

5022
04:18:52,080 --> 04:18:56,840
It includes things
such as fatigue, muscle pain,

5023
04:18:56,840 --> 04:18:59,280
other forms of bodily pains,

5024
04:18:59,280 --> 04:19:00,720
occasionally anxiety
and depression,

5025
04:19:00,720 --> 04:19:03,080
but more prominently,
cognitive impairment.

5026
04:19:03,080 --> 04:19:04,680
Next slide, please.

5027
04:19:06,920 --> 04:19:09,040
The predictors
of this COVID impairment

5028
04:19:09,040 --> 04:19:11,440
that appears to be
quite peculiar

5029
04:19:11,440 --> 04:19:17,600
to recovery from SARS-CoV-2
or to the infection of COVID

5030
04:19:17,600 --> 04:19:20,680
are still open to question.

5031
04:19:20,680 --> 04:19:22,120
I'm going to show you
two studies

5032
04:19:22,120 --> 04:19:23,560
from different sources of data

5033
04:19:23,560 --> 04:19:26,200
that lead to somewhat
different conclusions,

5034
04:19:26,200 --> 04:19:29,600
and I will go back to this point
a little bit later.

5035
04:19:29,600 --> 04:19:30,880
On the bottom two panels,

5036
04:19:30,880 --> 04:19:33,600
what you see is data from the UK
biobank.

5037
04:19:33,600 --> 04:19:40,200
So these are retrospective data
on patients across the board

5038
04:19:40,200 --> 04:19:43,360
who had suffered COVID and most
of whom were hospitalized,

5039
04:19:43,360 --> 04:19:46,120
but as you will see
in a moment, not all of them.

5040
04:19:46,120 --> 04:19:47,800
It's a very large sample.

5041
04:19:47,800 --> 04:19:51,440
And on the left panel,
what you see is the prevalence

5042
04:19:51,440 --> 04:19:54,520
of what they called
dementia-like symptoms,

5043
04:19:54,520 --> 04:19:59,000
meaning prominent impairment
in several cognitive domains,

5044
04:19:59,000 --> 04:20:03,040
including memory, language,
and executive function.

5045
04:20:03,040 --> 04:20:08,200
And this was compared to other
respiratory tract infections,

5046
04:20:08,200 --> 04:20:09,480
patients who had recovered

5047
04:20:09,480 --> 04:20:10,960
from other respiratory
tract infections.

5048
04:20:10,960 --> 04:20:13,200
You see again that
the likelihood of developing

5049
04:20:13,200 --> 04:20:16,400
these chronic symptoms following
COVID is almost two-fold.

5050
04:20:16,400 --> 04:20:18,840
And this was
much more prominent

5051
04:20:18,840 --> 04:20:22,280
in the post-hospitalized
patients who had encephalitis,

5052
04:20:22,280 --> 04:20:23,960
and that's the red line here,

5053
04:20:23,960 --> 04:20:25,600
compared to the dotted
line there,

5054
04:20:25,600 --> 04:20:29,200
which are hospitalized patients
without encephalitis,

5055
04:20:29,200 --> 04:20:31,600
or inpatients who were
not hospitalized

5056
04:20:31,600 --> 04:20:36,640
the length here
that did not have --

5057
04:20:36,640 --> 04:20:39,800
compared to those that did not
have the respiratory infection

5058
04:20:39,800 --> 04:20:41,920
in the bottom dotted line.

5059
04:20:41,920 --> 04:20:46,960
So the bottom line is,
in the UK biobank data samples,

5060
04:20:46,960 --> 04:20:50,000
severity of the disease,
particularly having encephalitis

5061
04:20:50,000 --> 04:20:54,920
or being hospitalized,
resulted in much more likelihood

5062
04:20:54,920 --> 04:20:56,840
of having
dementia-like symptoms.

5063
04:20:56,840 --> 04:20:58,280
The top part,
on the other hand,

5064
04:20:58,280 --> 04:21:00,600
is the community-based
sample for Amerindians

5065
04:21:00,600 --> 04:21:03,720
from Northern Argentina
in the Andes Mountains

5066
04:21:03,720 --> 04:21:07,840
that shows that mechanical
ventilation, ICU admission,

5067
04:21:07,840 --> 04:21:11,200
or oxygen dependency during
the acute phase of the illness

5068
04:21:11,200 --> 04:21:15,960
did not predict
a positive outcome,

5069
04:21:15,960 --> 04:21:18,800
and on the other hand,
the presence of persistent

5070
04:21:18,800 --> 04:21:22,440
anosmia several months
after the recovery, did.

5071
04:21:22,440 --> 04:21:25,120
Next slide, please.

5072
04:21:25,120 --> 04:21:27,600
-Two minutes remaining.

5073
04:21:27,600 --> 04:21:31,160
-What this translates to is
to a very large increase

5074
04:21:31,160 --> 04:21:34,000
potentially in cases
of cognitive impairment

5075
04:21:34,000 --> 04:21:36,080
for the US population
as a whole.

5076
04:21:36,080 --> 04:21:43,680
If you consider that as many
as 3 and 1/2 million cases

5077
04:21:43,680 --> 04:21:45,320
of new cognitive impairment

5078
04:21:45,320 --> 04:21:49,200
will be present in the next two
or three years, you know,

5079
04:21:49,200 --> 04:21:53,840
assuming that this data remain
as they are now,

5080
04:21:53,840 --> 04:21:55,640
that would represent a more
than two-fold

5081
04:21:55,640 --> 04:21:59,720
increase in the number of cases
and a large increasing burden.

5082
04:21:59,720 --> 04:22:02,880
Next slide, please.
What's most concerning

5083
04:22:02,880 --> 04:22:06,440
is that this may not be
evenly distributed

5084
04:22:06,440 --> 04:22:08,960
among different subpopulations
within the United States.

5085
04:22:08,960 --> 04:22:12,880
Indeed, we don't know
if rate of infection

5086
04:22:12,880 --> 04:22:15,600
or rate of hospitalization
will result, as I mentioned,

5087
04:22:15,600 --> 04:22:18,000
in higher increases
in cognitive decline.

5088
04:22:18,000 --> 04:22:21,880
But we do know that
under-represented populations

5089
04:22:21,880 --> 04:22:25,320
are at much higher risk
of having severe disease

5090
04:22:25,320 --> 04:22:27,720
and having hospitalization.

5091
04:22:27,720 --> 04:22:30,680
So there is a chance
that they may also sustain

5092
04:22:30,680 --> 04:22:32,240
a much larger burden
of disease.

5093
04:22:32,240 --> 04:22:34,320
Next slide.

5094
04:22:34,320 --> 04:22:36,040
This is particularly important
because,

5095
04:22:36,040 --> 04:22:40,680
as I mentioned,
in the Amerindian population

5096
04:22:40,680 --> 04:22:44,560
that we started
with the registry,

5097
04:22:44,560 --> 04:22:51,040
the severity and frequency
of cognitive impairment

5098
04:22:51,040 --> 04:22:55,000
reaches about 40% of the sample.
Next slide.

5099
04:22:55,000 --> 04:22:58,920
So, as next steps,
I think we need to concentrate

5100
04:22:58,920 --> 04:23:01,080
on understanding
what are the variations

5101
04:23:01,080 --> 04:23:03,160
in the clinical phenotype of
neurocognitive amoralities

5102
04:23:03,160 --> 04:23:07,400
following COVID that are just
now beginning to be described,

5103
04:23:07,400 --> 04:23:09,480
and particularly
the relationships of clinical

5104
04:23:09,480 --> 04:23:11,360
manifestations
with underlying biology

5105
04:23:11,360 --> 04:23:14,680
as Dr. Seshadri described
in great detail.

5106
04:23:14,680 --> 04:23:16,560
I think it's of
the highest importance

5107
04:23:16,560 --> 04:23:20,240
to establish and detail a course
of this cognitive impairment

5108
04:23:20,240 --> 04:23:22,800
as well as histology
resiliency cultures

5109
04:23:22,800 --> 04:23:26,480
and possible targets
for myofibril risk,

5110
04:23:26,480 --> 04:23:28,240
and we need to understand
the role of variations

5111
04:23:28,240 --> 04:23:30,040
in the viral genome
as well as the interactions

5112
04:23:30,040 --> 04:23:33,800
between the various variants
and host risk/resilience

5113
04:23:33,800 --> 04:23:37,480
factors affecting
this cognitive decline.

5114
04:23:37,480 --> 04:23:39,080
Environmental factors,

5115
04:23:39,080 --> 04:23:41,440
including social structure
and systemic inequalities,

5116
04:23:41,440 --> 04:23:42,840
appear to have profound effects

5117
04:23:42,840 --> 04:23:45,320
in the morbidity
and mortality of COVID,

5118
04:23:45,320 --> 04:23:47,040
and it is really urgent
to understand

5119
04:23:47,040 --> 04:23:51,200
if they will also affect the
long-term cognitive outcomes.

5120
04:23:51,200 --> 04:23:52,800
Thank you very much.

5121
04:23:58,080 --> 04:24:01,800
-So thank you very much for
inviting me to give this talk,

5122
04:24:01,800 --> 04:24:06,440
and as I'm following a couple of
really fantastic presentations

5123
04:24:06,440 --> 04:24:09,160
that really, I think,
set this talk up very nicely.

5124
04:24:09,160 --> 04:24:12,080
So the focus of this talk
is really looking at biomarkers

5125
04:24:12,080 --> 04:24:15,520
of COVID-19 and thinking about
what they may be able

5126
04:24:15,520 --> 04:24:18,880
to teach us about potential
clinical trial targets for AD

5127
04:24:18,880 --> 04:24:23,400
and ADRD-related to COVID.
Next slide, please.

5128
04:24:23,400 --> 04:24:27,040
So I have no disclosures.
Next slide.

5129
04:24:27,040 --> 04:24:29,400
So, again, I'm reflecting
and following up

5130
04:24:29,400 --> 04:24:34,040
on three wonderful presentations
that have really highlighted

5131
04:24:34,040 --> 04:24:38,560
the questions that are laid out
for us in identifying biomarkers

5132
04:24:38,560 --> 04:24:40,880
and disease treatment
targets.

5133
04:24:40,880 --> 04:24:44,800
And just to take a step back
to the clinical presentations,

5134
04:24:44,800 --> 04:24:47,000
of what the clinical
presentations have taught us

5135
04:24:47,000 --> 04:24:51,000
about pathophysiologies,
underlying neurological

5136
04:24:51,000 --> 04:24:55,000
and psychiatric conditions
in acute COVID-19,

5137
04:24:55,000 --> 04:24:57,960
a really fantastic
UK-wide surveillance study

5138
04:24:57,960 --> 04:25:01,600
has looked at cases of people
reporting to the hospital

5139
04:25:01,600 --> 04:25:03,160
with clinical presentations

5140
04:25:03,160 --> 04:25:07,000
that relate to COVID and neuro
and psych symptoms.

5141
04:25:07,000 --> 04:25:09,080
And I think what
their investigation

5142
04:25:09,080 --> 04:25:11,040
has really highlighted
is that there's different

5143
04:25:11,040 --> 04:25:13,280
pathophysiologies
underlying the conditions,

5144
04:25:13,280 --> 04:25:16,280
as we've heard from
the previous presenters.

5145
04:25:16,280 --> 04:25:18,120
So in this graph,
in the first column,

5146
04:25:18,120 --> 04:25:20,440
we have
cerebrovascular disorders,

5147
04:25:20,440 --> 04:25:24,200
and these are organized
by relative frequency of onset

5148
04:25:24,200 --> 04:25:26,840
related to the onset
of respiratory symptoms.

5149
04:25:26,840 --> 04:25:29,400
And the cerebrovascular
disorders in the first column

5150
04:25:29,400 --> 04:25:32,120
are starting very early
and even pre-dating

5151
04:25:32,120 --> 04:25:34,400
the COVID-19
respiratory symptoms,

5152
04:25:34,400 --> 04:25:37,040
but the other disorders
highlighted in the red boxes

5153
04:25:37,040 --> 04:25:39,480
here are disorders
that we typically think of

5154
04:25:39,480 --> 04:25:42,320
as being immune mediated
or inflammatory diseases,

5155
04:25:42,320 --> 04:25:44,480
as Dr. Nath pointed
out beautifully.

5156
04:25:44,480 --> 04:25:46,200
Many of these started
a week or two

5157
04:25:46,200 --> 04:25:49,000
after the onset
of respiratory symptoms.

5158
04:25:49,000 --> 04:25:50,360
And I think that
what this highlights

5159
04:25:50,360 --> 04:25:52,680
is that there are
diverse pathophysiologies,

5160
04:25:52,680 --> 04:25:55,200
and we really need to try
to understand all of them.

5161
04:25:55,200 --> 04:25:57,320
Next slide, please.

5162
04:25:57,320 --> 04:26:00,680
So thinking about acute COVID-19
and what kinds of biomarkers

5163
04:26:00,680 --> 04:26:04,800
have been revealing
and seemingly showing us

5164
04:26:04,800 --> 04:26:06,560
what some of
the biological mechanisms

5165
04:26:06,560 --> 04:26:09,880
are in these conditions.
And you heard about inflammation

5166
04:26:09,880 --> 04:26:13,560
and looking actually
at autopsy samples,

5167
04:26:13,560 --> 04:26:16,120
but in fact, cerebrospinal fluid
has been collected

5168
04:26:16,120 --> 04:26:19,320
in limited numbers of people
who have had acute COVID-19,

5169
04:26:19,320 --> 04:26:21,560
and they have also revealed
neural inflammation.

5170
04:26:21,560 --> 04:26:24,960
This is a very small study
of only six people studied early

5171
04:26:24,960 --> 04:26:27,680
in the pandemic who had
neurological complications

5172
04:26:27,680 --> 04:26:30,720
during acute COVID-19,
and these samples revealed

5173
04:26:30,720 --> 04:26:34,400
elevations in biomarkers
of immune activation,

5174
04:26:34,400 --> 04:26:37,040
such as neopterin
and beta-2 microglobulin

5175
04:26:37,040 --> 04:26:38,440
in the spinal fluid.

5176
04:26:38,440 --> 04:26:40,760
Here on the left,
you can see that the dotted line

5177
04:26:40,760 --> 04:26:44,080
is the normal value
in healthy control subjects,

5178
04:26:44,080 --> 04:26:47,640
indicating that inflammation was
very prominent in these people.

5179
04:26:47,640 --> 04:26:51,120
At the same time,
this group did not definitively

5180
04:26:51,120 --> 04:26:52,640
detect SARS-CoV-2,

5181
04:26:52,640 --> 04:26:54,920
and again confirming
what's been pointed out

5182
04:26:54,920 --> 04:26:58,800
in previous talks that
viral invasion does not seem

5183
04:26:58,800 --> 04:27:01,120
to be a prominent
part of the disorder.

5184
04:27:01,120 --> 04:27:05,720
Next slide, please.
So other CSF biomarkers --

5185
04:27:05,720 --> 04:27:07,760
and you saw this
slide briefly earlier --

5186
04:27:07,760 --> 04:27:09,320
have also been looked at,

5187
04:27:09,320 --> 04:27:11,560
and I think this is particularly
of interest in a group

5188
04:27:11,560 --> 04:27:15,600
that's concerned about the onset
of neurodegenerative diseases.

5189
04:27:15,600 --> 04:27:17,440
So again, in acute COVID-19,

5190
04:27:17,440 --> 04:27:20,680
CSF samples that have been
collected in people with COVID

5191
04:27:20,680 --> 04:27:22,200
and neurologic symptoms

5192
04:27:22,200 --> 04:27:25,320
have revealed changes
in amyloid processing,

5193
04:27:25,320 --> 04:27:28,720
so reductions in soluble amyloid
precursor protein

5194
04:27:28,720 --> 04:27:32,280
and amyloid beta
during acute COVID-19

5195
04:27:32,280 --> 04:27:33,960
with neurologic symptoms.

5196
04:27:33,960 --> 04:27:36,560
I think, again, this is
something that raises concerns,

5197
04:27:36,560 --> 04:27:38,920
but we really don't know
the long-term implications

5198
04:27:38,920 --> 04:27:40,280
of these findings.

5199
04:27:40,280 --> 04:27:43,760
Next slide, please.
How about blood samples?

5200
04:27:43,760 --> 04:27:45,520
And I think it's been
very fortunate

5201
04:27:45,520 --> 04:27:47,800
that, of course, blood has been
much more readily detected,

5202
04:27:47,800 --> 04:27:49,680
readily measured
and collected for research

5203
04:27:49,680 --> 04:27:52,720
purposes in patients
with COVID-19.

5204
04:27:52,720 --> 04:27:56,120
So this is a much larger study
coming out of NYU

5205
04:27:56,120 --> 04:27:59,800
that collected blood
in 246 individuals

5206
04:27:59,800 --> 04:28:03,600
who had acute COVID-19
while they were hospitalized.

5207
04:28:03,600 --> 04:28:05,080
And this study very nicely

5208
04:28:05,080 --> 04:28:08,000
compared levels
of neurofilament light chain,

5209
04:28:08,000 --> 04:28:11,800
which is a marker
of active neuronal injury,

5210
04:28:11,800 --> 04:28:14,000
as well as glial
fibrillary acid protein,

5211
04:28:14,000 --> 04:28:16,440
which is a marker
of astrocyte injury.

5212
04:28:16,440 --> 04:28:19,520
And this study revealed
quite robust elevations

5213
04:28:19,520 --> 04:28:23,120
in both of these markers in
people who had acute COVID-19,

5214
04:28:23,120 --> 04:28:25,400
and they very nicely
compared those to people

5215
04:28:25,400 --> 04:28:27,640
who they considered normal,
healthy controls as well

5216
04:28:27,640 --> 04:28:30,000
as those
with mild cognitive impairment

5217
04:28:30,000 --> 04:28:31,920
and active Alzheimer's disease,

5218
04:28:31,920 --> 04:28:34,120
showing that the extent
of these elevations

5219
04:28:34,120 --> 04:28:36,240
was really quite marked,

5220
04:28:36,240 --> 04:28:39,560
even compared to the individuals
with neurodegenerative disease.

5221
04:28:39,560 --> 04:28:41,200
I'll say that both
these changes,

5222
04:28:41,200 --> 04:28:43,680
as well as the changes
in amyloid precursor proteins

5223
04:28:43,680 --> 04:28:45,240
and amyloid measures,

5224
04:28:45,240 --> 04:28:48,400
are also seen in other acute
infectious conditions,

5225
04:28:48,400 --> 04:28:50,680
including an acute
HIV infection.

5226
04:28:50,680 --> 04:28:52,840
So I think that
we have to look at this

5227
04:28:52,840 --> 04:28:54,520
as a marker
of an acute injury

5228
04:28:54,520 --> 04:28:57,480
that may not have
long-term clinical effects.

5229
04:28:57,480 --> 04:29:01,040
Next slide, please.

5230
04:29:01,040 --> 04:29:03,440
A much more sort of
in-depth research study

5231
04:29:03,440 --> 04:29:05,680
has been recently
conducted here at Yale

5232
04:29:05,680 --> 04:29:08,440
by one of my collaborators,
Dr. Shelli Farhadian,

5233
04:29:08,440 --> 04:29:11,400
where she looked not only at
markers in immune activation --

5234
04:29:11,400 --> 04:29:14,600
and this is looking at
CSF cytokines on the left

5235
04:29:14,600 --> 04:29:16,880
where those in purple
are those with COVID-19

5236
04:29:16,880 --> 04:29:19,040
and those in green
were healthy controls --

5237
04:29:19,040 --> 04:29:20,800
and showed that
the CSF cytokine patterns

5238
04:29:20,800 --> 04:29:23,440
were not only abnormally
elevated in the COVID patients,

5239
04:29:23,440 --> 04:29:25,800
but they actually were different
than the cytokines

5240
04:29:25,800 --> 04:29:27,800
observed in the blood,
suggesting that there's

5241
04:29:27,800 --> 04:29:30,160
a compartmentalized
immune reaction.

5242
04:29:30,160 --> 04:29:31,840
She also found that
there was an elevation

5243
04:29:31,840 --> 04:29:35,440
in the frequency of B cells
in the cerebrospinal fluid.

5244
04:29:35,440 --> 04:29:36,960
And when the B cells --

5245
04:29:36,960 --> 04:29:39,000
since B cells
produce antibodies,

5246
04:29:39,000 --> 04:29:41,200
she investigated
whether or not the antibodies

5247
04:29:41,200 --> 04:29:45,800
seem to be directed against
SARS-CoV-2 or some other target.

5248
04:29:45,800 --> 04:29:48,400
And in all of the examples,
there were antibodies

5249
04:29:48,400 --> 04:29:51,040
detected against SARS-CoV-2
in the spinal fluid,

5250
04:29:51,040 --> 04:29:52,600
and some of these differ
than the patterns

5251
04:29:52,600 --> 04:29:53,920
of those in the blood.

5252
04:29:53,920 --> 04:29:55,800
But interestingly,
some of these antibodies

5253
04:29:55,800 --> 04:29:58,960
also were autoreactive
to brain tissue,

5254
04:29:58,960 --> 04:30:01,440
suggesting an element
of autoimmunity

5255
04:30:01,440 --> 04:30:03,640
underlying some
of these conditions.

5256
04:30:03,640 --> 04:30:06,320
I'll say that I also indicate
on the slide that, again,

5257
04:30:06,320 --> 04:30:09,680
looking for presence of virus,
very few published cases

5258
04:30:09,680 --> 04:30:12,000
have detected SARS-CoV-2
in spinal fluid --

5259
04:30:12,000 --> 04:30:14,800
less than 3% of
published cases --

5260
04:30:14,800 --> 04:30:16,360
suggesting again

5261
04:30:16,360 --> 04:30:20,000
a neuropathogenesis
that's really immune mediated

5262
04:30:20,000 --> 04:30:21,720
and potentially
vascularly mediated,

5263
04:30:21,720 --> 04:30:23,320
as you've heard
from Dr. Nath,

5264
04:30:23,320 --> 04:30:25,560
rather than a direct
viral infection.

5265
04:30:25,560 --> 04:30:28,400
Next slide, please.

5266
04:30:28,400 --> 04:30:30,960
So moving to this issue
of long COVID --

5267
04:30:30,960 --> 04:30:32,800
and I think, here,
we have many more questions

5268
04:30:32,800 --> 04:30:34,960
than we have answers and data,

5269
04:30:34,960 --> 04:30:38,400
but one can imagine that some of
these underlying conditions

5270
04:30:38,400 --> 04:30:41,200
that we're seeing in people
who are having persistent issues

5271
04:30:41,200 --> 04:30:43,400
after recovery
from acute COVID-19

5272
04:30:43,400 --> 04:30:46,120
could be related to some of
the pathophysiologies

5273
04:30:46,120 --> 04:30:49,880
that are seen in acute COVID.
Next slide, please.

5274
04:30:49,880 --> 04:30:51,600
-Two minutes remaining.

5275
04:30:51,600 --> 04:30:55,960
-Great. So one possibility
is that persistent inflammation

5276
04:30:55,960 --> 04:30:59,440
or ongoing immune activation
or abnormalities is underlying

5277
04:30:59,440 --> 04:31:02,400
some of the longer-term
complications of COVID

5278
04:31:02,400 --> 04:31:05,200
after recovery
from acute illness.

5279
04:31:05,200 --> 04:31:08,000
I have to say, I think we have
very little clear evidence

5280
04:31:08,000 --> 04:31:09,960
that that's actually true
at this point,

5281
04:31:09,960 --> 04:31:11,880
but many studies are ongoing.

5282
04:31:11,880 --> 04:31:13,680
This is a tiny study
of individuals

5283
04:31:13,680 --> 04:31:16,560
who had cancer
and neurologic symptoms,

5284
04:31:16,560 --> 04:31:18,160
and those in red here
are shown

5285
04:31:18,160 --> 04:31:20,720
who have cancer and neurologic
symptoms after COVID,

5286
04:31:20,720 --> 04:31:23,800
versus cancer and neurologic
symptoms without COVID.

5287
04:31:23,800 --> 04:31:27,720
And in this study, there was
a higher CSF inflammatory score

5288
04:31:27,720 --> 04:31:32,000
in those people who had COVID.
Next, please.

5289
04:31:32,000 --> 04:31:33,960
Another nice study
has looked at individuals

5290
04:31:33,960 --> 04:31:36,600
who were prospectively studied
from the time

5291
04:31:36,600 --> 04:31:40,000
of their acute hospitalization
and then three months later.

5292
04:31:40,000 --> 04:31:41,600
And in this study, individuals

5293
04:31:41,600 --> 04:31:44,920
who had very high baseline
blood inflammatory markers

5294
04:31:44,920 --> 04:31:47,120
were more likely to have
long-term depression

5295
04:31:47,120 --> 04:31:51,920
and neurocognition abnormalities
at three months. Next.

5296
04:31:51,920 --> 04:31:53,920
I think both of these studies
are just little hints

5297
04:31:53,920 --> 04:31:56,640
that these may be issues,
but we really need to understand

5298
04:31:56,640 --> 04:31:59,320
how these relate
to more long-term symptoms

5299
04:31:59,320 --> 04:32:01,400
in people who have
had milder disease.

5300
04:32:01,400 --> 04:32:03,360
Next slide.

5301
04:32:03,360 --> 04:32:05,360
What about
neuroimaging biomarkers?

5302
04:32:05,360 --> 04:32:07,040
You heard again from Dr. Nath

5303
04:32:07,040 --> 04:32:09,720
already about another study,
different from this one,

5304
04:32:09,720 --> 04:32:12,400
that found regional
hypometabolism,

5305
04:32:12,400 --> 04:32:15,680
changes in glucose uptake
in the brain of individuals

5306
04:32:15,680 --> 04:32:19,080
after COVID who were having
long-term neurologic symptoms.

5307
04:32:19,080 --> 04:32:21,560
And in this study,
the PET metabolic values

5308
04:32:21,560 --> 04:32:25,160
were actually related
to the degree of symptoms,

5309
04:32:25,160 --> 04:32:28,880
such as changes in memory,
pain symptoms, or anosmia.

5310
04:32:28,880 --> 04:32:31,080
Next slide.

5311
04:32:31,080 --> 04:32:32,800
-Time.

5312
04:32:32,800 --> 04:32:35,240
-So you also heard already
about this UK biobank study,

5313
04:32:35,240 --> 04:32:37,320
and I think this is also
very convincing

5314
04:32:37,320 --> 04:32:40,200
and concerning that,
in people in whom data

5315
04:32:40,200 --> 04:32:42,040
was available before
and after COVID,

5316
04:32:42,040 --> 04:32:45,000
there were regional changes
in brain structure size.

5317
04:32:45,000 --> 04:32:46,720
Next slide.

5318
04:32:46,720 --> 04:32:48,000
-So, with apologies, Serena,

5319
04:32:48,000 --> 04:32:50,880
we have to go
the question and answer.

5320
04:32:50,880 --> 04:32:52,120
-Yeah. That's no problem.

5321
04:32:52,120 --> 04:32:54,080
My last slide
is just really a summary

5322
04:32:54,080 --> 04:32:55,840
of the questions
to be looked at,

5323
04:32:55,840 --> 04:32:57,920
so the next slide,
you can just show this one,

5324
04:32:57,920 --> 04:33:00,800
and looking at targets
for treatment.

5325
04:33:00,800 --> 04:33:02,400
Thank you so much.

5326
04:33:07,040 --> 04:33:09,920
-Thank you all very much.
Really appreciate that.

5327
04:33:09,920 --> 04:33:13,560
So we're going to go to the Q
and A for this session.

5328
04:33:13,560 --> 04:33:15,000
I think everyone's gotten
the hang

5329
04:33:15,000 --> 04:33:16,400
of putting their name
into the Q and A box.

5330
04:33:16,400 --> 04:33:19,680
We have a few people
there queued up.

5331
04:33:19,680 --> 04:33:22,960
Dr. Rost, I don't know if you're
going to want to enter,

5332
04:33:22,960 --> 04:33:26,200
talking to the question askers,
or do you want me to do it?

5333
04:33:31,760 --> 04:33:34,120
You're muted.

5334
04:33:34,120 --> 04:33:36,040
-Natalia, your sound
is not working.

5335
04:33:36,040 --> 04:33:37,440
-Yeah, your sound
is a little funny.

5336
04:33:37,440 --> 04:33:40,440
So why don't I do it first?

5337
04:33:40,440 --> 04:33:45,200
Dr. Dacks, Penny Dacks, you're
the first questioner for us.

5338
04:33:45,200 --> 04:33:48,400
-Thank you.
Hi, Penny Dacks again with AFTD.

5339
04:33:48,400 --> 04:33:50,040
Though I should say
that I'm not commenting

5340
04:33:50,040 --> 04:33:51,520
right now on behalf of AFTD

5341
04:33:51,520 --> 04:33:54,320
but as a family member
of two very sick people,

5342
04:33:54,320 --> 04:33:56,240
including a 10 year old child.

5343
04:33:59,280 --> 04:34:03,640
There's a lot that I think
we still need to disentangle,

5344
04:34:03,640 --> 04:34:05,200
right, in terms of,

5345
04:34:05,200 --> 04:34:06,960
and I think you guys
did a really great job

5346
04:34:06,960 --> 04:34:08,680
of outlining
the different areas

5347
04:34:08,680 --> 04:34:11,760
there where we've got aspects
of long-term chronic stress,

5348
04:34:11,760 --> 04:34:13,960
social isolation,
anxiety and depression.

5349
04:34:13,960 --> 04:34:15,840
And we know from epidemiology
for years

5350
04:34:15,840 --> 04:34:18,280
that those all have links
to dementia onset

5351
04:34:18,280 --> 04:34:19,800
that may not necessarily

5352
04:34:19,800 --> 04:34:24,880
be long-term pathological
factors there.

5353
04:34:24,880 --> 04:34:28,320
And we can assume that severe
acute COVID infection

5354
04:34:28,320 --> 04:34:29,800
that has hospitalization,

5355
04:34:29,800 --> 04:34:33,800
that has ventilation
is going to pose hypoxia

5356
04:34:33,800 --> 04:34:37,480
for one thing that could have
immediate acute effects

5357
04:34:37,480 --> 04:34:40,000
on vascular function,

5358
04:34:40,000 --> 04:34:44,960
on the underlying
neuropathologies of the ADRDs.

5359
04:34:44,960 --> 04:34:48,600
And we have this third situation
where you've got young people,

5360
04:34:48,600 --> 04:34:54,480
right,
who had mild acute infections

5361
04:34:54,480 --> 04:34:59,160
that are having this long COVID,
of chronic fatigue, anxiety,

5362
04:34:59,160 --> 04:35:02,400
depression, headaches,
neurological symptoms,

5363
04:35:02,400 --> 04:35:04,400
all different kinds of stuff.

5364
04:35:04,400 --> 04:35:08,800
And every single one of those
different clinical situations

5365
04:35:08,800 --> 04:35:11,640
are profoundly important
to understand.

5366
04:35:11,640 --> 04:35:14,720
When we think about
how this is going to impact

5367
04:35:14,720 --> 04:35:18,320
their long-term risks
of dementias.

5368
04:35:18,320 --> 04:35:20,200
And I just wanted
to put a plea out there

5369
04:35:20,200 --> 04:35:22,960
that we are very, very careful

5370
04:35:22,960 --> 04:35:26,120
about how we define
the work that we do.

5371
04:35:26,120 --> 04:35:29,200
Because the work that's
being done in the hospital

5372
04:35:29,200 --> 04:35:32,880
as patients who have
severe acute symptoms,

5373
04:35:32,880 --> 04:35:36,600
I think biologically
could be very, very different

5374
04:35:36,600 --> 04:35:41,080
from what's happening
in the more mild acute

5375
04:35:41,080 --> 04:35:43,640
but chronic situations.

5376
04:35:43,640 --> 04:35:45,120
So it's really just a plea

5377
04:35:45,120 --> 04:35:47,160
that as we come up
with a nomenclature

5378
04:35:47,160 --> 04:35:49,640
and as we come up with
how we define these things,

5379
04:35:49,640 --> 04:35:51,560
we are very cautious
with the data

5380
04:35:51,560 --> 04:35:53,200
that we put in there
to make sure

5381
04:35:53,200 --> 04:35:57,800
that these are the separations
across these categories

5382
04:35:57,800 --> 04:36:01,200
of clinical situations
can be more readily understood.

5383
04:36:01,200 --> 04:36:02,520
So that if you've got blood data

5384
04:36:02,520 --> 04:36:03,880
that's being drawn
from the clinic,

5385
04:36:03,880 --> 04:36:07,000
for example,
in the hospital, you can better,

5386
04:36:07,000 --> 04:36:12,760
you actually know how severe
was that initial acute infection

5387
04:36:12,760 --> 04:36:14,520
and separate that out
from the people

5388
04:36:14,520 --> 04:36:16,000
who are two years out

5389
04:36:16,000 --> 04:36:19,000
still having severe
cognitive problems.

5390
04:36:19,000 --> 04:36:22,720
So thank you for
all the work you're doing.

5391
04:36:22,720 --> 04:36:26,680
-Thank you so much
for that personal perspective

5392
04:36:26,680 --> 04:36:31,560
and those important points
Serena, did you want to respond?

5393
04:36:31,560 --> 04:36:34,400
-Yeah, sure. That's
an absolutely critical point,

5394
04:36:34,400 --> 04:36:36,400
and I think one
of the major gaps

5395
04:36:36,400 --> 04:36:38,000
that we have in knowledge

5396
04:36:38,000 --> 04:36:40,840
about what's happening in
the nervous system in COVID-19

5397
04:36:40,840 --> 04:36:43,520
is actually in people
who have mild disease.

5398
04:36:43,520 --> 04:36:44,840
Most of those individuals

5399
04:36:44,840 --> 04:36:46,360
are never enrolled
in research studies,

5400
04:36:46,360 --> 04:36:50,400
and even now, we have very
little sort of, you know,

5401
04:36:50,400 --> 04:36:53,120
ability to capture
those kinds of data

5402
04:36:53,120 --> 04:36:55,720
in people who have
acute COVID-19, right.

5403
04:36:55,720 --> 04:36:58,000
And then there are concerns
for research participation

5404
04:36:58,000 --> 04:37:00,800
and infection risk.
But it may be that it's a very,

5405
04:37:00,800 --> 04:37:04,000
very different type of trigger
of symptoms and of syndromes,

5406
04:37:04,000 --> 04:37:05,680
and the biology
may be different.

5407
04:37:05,680 --> 04:37:08,160
So we're taking clues from
what we've learned from people

5408
04:37:08,160 --> 04:37:10,600
in whom data and sample,
et cetera,

5409
04:37:10,600 --> 04:37:13,960
have been able to be collected.
But I think thinking about

5410
04:37:13,960 --> 04:37:16,000
how there may really
be different categories,

5411
04:37:16,000 --> 04:37:19,160
and the nomenclature
is absolutely critical.

5412
04:37:19,160 --> 04:37:21,080
And one of the things
we've learned from COVID

5413
04:37:21,080 --> 04:37:24,560
is there's incredible
heterogeneity in this condition,

5414
04:37:24,560 --> 04:37:27,320
in all organ systems
in all ways.

5415
04:37:27,320 --> 04:37:29,400
And we have to be very accurate
and careful

5416
04:37:29,400 --> 04:37:31,640
making sure we don't
group things inaccurately

5417
04:37:31,640 --> 04:37:33,600
because then we will not
necessarily

5418
04:37:33,600 --> 04:37:37,160
make the right decisions and
recommendations going forward.

5419
04:37:37,160 --> 04:37:38,240
-Thank you.

5420
04:37:38,240 --> 04:37:40,400
-Professor Bovenkamp.

5421
04:37:40,400 --> 04:37:42,160
-Well, Gabriel
has his hand up first.

5422
04:37:42,160 --> 04:37:47,320
Sorry, my voice,
my mike is back on.

5423
04:37:47,320 --> 04:37:49,080
-Thank you, Natalia.
Yes, I agree.

5424
04:37:49,080 --> 04:37:51,600
I think those are
hugely important questions.

5425
04:37:51,600 --> 04:37:55,560
And not just questions
at this point

5426
04:37:55,560 --> 04:37:58,040
but rather what appears
to emerge

5427
04:37:58,040 --> 04:38:01,160
as the one supported line
of thought

5428
04:38:01,160 --> 04:38:04,960
which is that the disease
in milder cases,

5429
04:38:04,960 --> 04:38:07,520
that are detected
in the community

5430
04:38:07,520 --> 04:38:09,880
that have not been hospitalized
that have,

5431
04:38:09,880 --> 04:38:14,080
you know, cold symptoms
or a mild flu-like syndrome

5432
04:38:14,080 --> 04:38:18,000
and normal chills
has chronic manifestations

5433
04:38:18,000 --> 04:38:21,200
that are phenotypically
different from those

5434
04:38:21,200 --> 04:38:26,400
who had severe incapacities
or other acute severe illness.

5435
04:38:26,400 --> 04:38:31,400
And they, the point
that Dr. Nath made

5436
04:38:31,400 --> 04:38:35,800
which is that this is going
to be, manifestations of this

5437
04:38:35,800 --> 04:38:39,480
is appearing more common
in women,

5438
04:38:39,480 --> 04:38:42,240
is true only for
the younger population.

5439
04:38:42,240 --> 04:38:44,120
Not necessarily for
the older population.

5440
04:38:44,120 --> 04:38:46,040
But that's one of
the phenotypic differences.

5441
04:38:46,040 --> 04:38:49,200
Another one is that
in the younger individuals,

5442
04:38:49,200 --> 04:38:53,520
the cognitive symptoms appear
to be most prominently

5443
04:38:53,520 --> 04:38:58,720
in attention and difficulties
with sphere of processing

5444
04:38:58,720 --> 04:39:01,000
as well as some
executive dysfunction.

5445
04:39:01,000 --> 04:39:04,200
Whereas with all
the individuals,

5446
04:39:04,200 --> 04:39:07,200
the most prominent feature
in at least half the individuals

5447
04:39:07,200 --> 04:39:12,960
appears to be intense
episodic memory impairment,

5448
04:39:12,960 --> 04:39:16,800
more resembling
what you would expect to see

5449
04:39:16,800 --> 04:39:18,720
in a patient with early
Alzheimer's disease.

5450
04:39:18,720 --> 04:39:22,560
So I agree. These are massively
important questions.

5451
04:39:22,560 --> 04:39:26,200
And there are enough data
readily available to suggest

5452
04:39:26,200 --> 04:39:30,120
that there may well be more
than one clinical picture

5453
04:39:30,120 --> 04:39:32,400
emerging in
the chronic space.

5454
04:39:36,680 --> 04:39:40,200
-Thank you, Gabriel.
Diane, Diane Bovenkamp.

5455
04:39:40,200 --> 04:39:41,800
-Yeah.

5456
04:39:41,800 --> 04:39:45,320
So yeah, so I just had
a number of questions kind of,

5457
04:39:45,320 --> 04:39:49,200
this has been a really
great session, thank you.

5458
04:39:49,200 --> 04:39:53,600
I think, and I think
in terms of detection,

5459
04:39:53,600 --> 04:39:55,600
we need to be able
to detect it even

5460
04:39:55,600 --> 04:39:59,480
if they don't have COVID
listed in their record, right.

5461
04:39:59,480 --> 04:40:01,160
There needs to be a way
to detect it

5462
04:40:01,160 --> 04:40:03,400
because of the stigma
associated with it

5463
04:40:03,400 --> 04:40:06,680
and people not wanting
to miss work, right.

5464
04:40:06,680 --> 04:40:11,600
So and then talking about,
you know,

5465
04:40:11,600 --> 04:40:13,400
women might get it more,

5466
04:40:13,400 --> 04:40:15,520
and then are there
comorbidities?

5467
04:40:15,520 --> 04:40:17,080
We need to mark that.

5468
04:40:17,080 --> 04:40:20,160
Are people who already
have inflammatory diseases,

5469
04:40:20,160 --> 04:40:22,440
are they more prone to it?

5470
04:40:22,440 --> 04:40:24,600
So this is where we need
to collect the big data,

5471
04:40:24,600 --> 04:40:26,360
and we're all about
the data sharing.

5472
04:40:26,360 --> 04:40:27,720
That's pretty important too.

5473
04:40:27,720 --> 04:40:32,560
So but one of the things
that Avi was saying

5474
04:40:32,560 --> 04:40:34,120
was the vascularity.

5475
04:40:34,120 --> 04:40:39,000
So is this where, again,
jumping on the eye bandwagon,

5476
04:40:39,000 --> 04:40:41,480
you know, we're looking for
something that's noninvasive,

5477
04:40:41,480 --> 04:40:43,240
that you can try and detect.

5478
04:40:43,240 --> 04:40:47,160
Can you try and look
at these differences

5479
04:40:47,160 --> 04:40:48,640
that might appear in the eye?

5480
04:40:48,640 --> 04:40:52,640
And I'm just going
from the associate, the AAO.

5481
04:40:52,640 --> 04:40:54,840
It's an association,
there's like four differences

5482
04:40:54,840 --> 04:40:56,800
that you can see
in the eye from COVID.

5483
04:40:56,800 --> 04:40:58,600
So there's like
cotton wool spots.

5484
04:40:58,600 --> 04:41:00,400
There's retinal vein occlusions,

5485
04:41:00,400 --> 04:41:02,920
things like that,
that can be looked for.

5486
04:41:02,920 --> 04:41:07,680
So maybe just include
some of those.

5487
04:41:07,680 --> 04:41:10,520
I don't know if I saw those
in the description here,

5488
04:41:10,520 --> 04:41:12,960
but if those can just be
addressed by the committee,

5489
04:41:12,960 --> 04:41:16,200
that would be great.

5490
04:41:16,200 --> 04:41:17,560
-Avi, do you want
to speak to that?

5491
04:41:17,560 --> 04:41:19,800
-Yeah, sure. So I agree.

5492
04:41:19,800 --> 04:41:22,280
I think the eye
is the window to the brain,

5493
04:41:22,280 --> 04:41:24,400
and the vascularature
is a good place

5494
04:41:24,400 --> 04:41:26,800
to look at certainly
in the retina.

5495
04:41:26,800 --> 04:41:29,040
But in addition to that,
the other noninvasive ways

5496
04:41:29,040 --> 04:41:31,720
of looking at the vasculature,
you know,

5497
04:41:31,720 --> 04:41:34,840
one can look at a number
of blood-borne markers,

5498
04:41:34,840 --> 04:41:39,120
for example,
B-select and E-select

5499
04:41:39,120 --> 04:41:44,200
and VJEF you know,
and some of the MMPs.

5500
04:41:44,200 --> 04:41:47,520
So they indicate not only
vascular damage but angiogenesis

5501
04:41:47,520 --> 04:41:50,920
that is probably taking place
at the same time.

5502
04:41:50,920 --> 04:41:53,600
So they are currently
available in research labs,

5503
04:41:53,600 --> 04:41:56,080
but there's no reason why
they couldn't be standardized

5504
04:41:56,080 --> 04:42:03,320
and be used more commonly
in patient compilations.

5505
04:42:03,320 --> 04:42:04,680
-Thank you.

5506
04:42:04,680 --> 04:42:07,400
-Ron, do you want to comment
on that as well?

5507
04:42:07,400 --> 04:42:08,400
-No,
I have a different question.

5508
04:42:08,400 --> 04:42:09,640
-A different question.

5509
04:42:09,640 --> 04:42:11,400
Before we move
to a different question,

5510
04:42:11,400 --> 04:42:14,400
I actually wanted
to ask Andrea Troxel to comment

5511
04:42:14,400 --> 04:42:18,320
on what's already been collected

5512
04:42:18,320 --> 04:42:21,440
and whether there are
any additional systemic tissues

5513
04:42:21,440 --> 04:42:23,480
or tissues that could be helpful
to diagnose

5514
04:42:23,480 --> 04:42:28,280
this experience
of the biobank and databank.

5515
04:42:28,280 --> 04:42:29,880
-Thank you.

5516
04:42:29,880 --> 04:42:36,000
So far we are collecting samples
that are preexisting for,

5517
04:42:36,000 --> 04:42:38,480
that have been used for
diagnostic or other reasons

5518
04:42:38,480 --> 04:42:40,080
and are left over.

5519
04:42:40,080 --> 04:42:44,080
So we're sort of up
and running to accept anything.

5520
04:42:44,080 --> 04:42:46,560
And I'd actually love to turn
that question back around

5521
04:42:46,560 --> 04:42:47,960
to this group
and hear from all of you

5522
04:42:47,960 --> 04:42:50,560
if there are
particular kinds of samples

5523
04:42:50,560 --> 04:42:53,880
that would inform
this question more directly.

5524
04:42:53,880 --> 04:42:56,800
We can certainly reach out
to our sites and let them know

5525
04:42:56,800 --> 04:43:00,400
that those are specifically
what we're looking for.

5526
04:43:00,400 --> 04:43:02,720
And in terms of data elements,
similarly,

5527
04:43:02,720 --> 04:43:06,080
we have a set of common data
elements that we're asking for.

5528
04:43:06,080 --> 04:43:10,040
We have a relatively restrictive
set of sort of required elements

5529
04:43:10,040 --> 04:43:12,360
so as not to overburden sites
with data entry.

5530
04:43:12,360 --> 04:43:16,920
But we have a much wider
set of optional data elements.

5531
04:43:16,920 --> 04:43:19,520
And so again, if there are
particular suggestions

5532
04:43:19,520 --> 04:43:23,080
that folks have
for what would be most useful.

5533
04:43:23,080 --> 04:43:26,040
You know, whether it's related
to this recent, very recent,

5534
04:43:26,040 --> 04:43:28,840
very interesting discussion
about the eye issues

5535
04:43:28,840 --> 04:43:30,960
or other more general things

5536
04:43:30,960 --> 04:43:33,600
that have come up
during the session today.

5537
04:43:33,600 --> 04:43:37,160
We'd be very eager to hear
from any of you about that

5538
04:43:37,160 --> 04:43:40,920
and try to think about
adding those to our, to our set.

5539
04:43:43,000 --> 04:43:45,000
-Sudha, are you trying
to comment on that?

5540
04:43:45,000 --> 04:43:46,680
Do you want to comment?
-Yes.

5541
04:43:46,680 --> 04:43:51,280
In the neurocognitive
working group of recover,

5542
04:43:51,280 --> 04:43:56,320
sensory motor biomarkers
are being refined.

5543
04:43:56,320 --> 04:43:59,720
Not on everybody
but particularly on persons

5544
04:43:59,720 --> 04:44:01,800
who endure some symptoms.

5545
04:44:01,800 --> 04:44:04,000
And this is just
a participant burden issue.

5546
04:44:04,000 --> 04:44:06,000
So any comments
are very welcome.

5547
04:44:06,000 --> 04:44:09,360
So there are individual studies
that are looking at things like

5548
04:44:09,360 --> 04:44:15,480
OCTA as potential markers
of future development

5549
04:44:15,480 --> 04:44:18,440
of ADRD-like symptoms.

5550
04:44:20,640 --> 04:44:24,200
-Thank you. Ron.

5551
04:44:24,200 --> 04:44:27,320
-Yeah, I have a question
for Serena actually.

5552
04:44:27,320 --> 04:44:30,320
You mentioned
in passing implications

5553
04:44:30,320 --> 04:44:33,960
for clinical trials
in AD and ADRD.

5554
04:44:33,960 --> 04:44:37,400
Do you think that trialists
should be taking a history

5555
04:44:37,400 --> 04:44:39,160
now of their participants?

5556
04:44:39,160 --> 04:44:43,120
Have you been exposed to COVID?
What's the documentation?

5557
04:44:43,120 --> 04:44:47,080
And secondarily,
since fluid biomarkers

5558
04:44:47,080 --> 04:44:48,480
are being used commonly

5559
04:44:48,480 --> 04:44:51,200
and are projected to be used
even more avidly,

5560
04:44:51,200 --> 04:44:54,280
going forward for enrollment
in clinical trials,

5561
04:44:54,280 --> 04:44:57,400
might the markers
that you have identified

5562
04:44:57,400 --> 04:45:01,480
vis-a-vis
COVID exposure alter those,

5563
04:45:01,480 --> 04:45:03,920
those biomarkers,
those fluid biomarkers,

5564
04:45:03,920 --> 04:45:07,840
and how might we take
that into account?

5565
04:45:07,840 --> 04:45:09,080
Simple answer, I'm sure.

5566
04:45:09,080 --> 04:45:10,800
-Those are two
fantastic questions.

5567
04:45:10,800 --> 04:45:12,400
So for the first one,
you know,

5568
04:45:12,400 --> 04:45:14,600
when I was talking
about clinical trials,

5569
04:45:14,600 --> 04:45:16,640
I was really going
to kind of outline

5570
04:45:16,640 --> 04:45:20,320
some potentially protistic
clinical trials for COVID.

5571
04:45:20,320 --> 04:45:22,800
So people who are maybe
having long COVID symptoms,

5572
04:45:22,800 --> 04:45:25,920
maybe immune interventions or
sort of vascular interventions,

5573
04:45:25,920 --> 04:45:27,560
et cetera.

5574
04:45:27,560 --> 04:45:30,720
I do think that this, you know,
has changed the landscape

5575
04:45:30,720 --> 04:45:32,600
for all clinical trials
for everything.

5576
04:45:32,600 --> 04:45:34,840
And certainly now
when we see patients,

5577
04:45:34,840 --> 04:45:36,800
I'm a clinician,
when I see patients

5578
04:45:36,800 --> 04:45:39,320
I ask every single patient,
have you had COVID?

5579
04:45:39,320 --> 04:45:40,800
Do you know what's
your test results?

5580
04:45:40,800 --> 04:45:42,360
When was it?

5581
04:45:42,360 --> 04:45:44,080
How severe was your disease?
Were you hospitalized?

5582
04:45:44,080 --> 04:45:46,360
That actually goes into I think
a relevant medical history

5583
04:45:46,360 --> 04:45:48,680
for pretty much
everybody these days.

5584
04:45:48,680 --> 04:45:51,160
And I think related
to clinical trials

5585
04:45:51,160 --> 04:45:53,480
and outcomes and interventions
and clinical trials,

5586
04:45:53,480 --> 04:45:56,320
that that should be
important and integrated.

5587
04:45:56,320 --> 04:45:58,760
I think in terms
of the biomarker changes,

5588
04:45:58,760 --> 04:46:00,920
the, for example,
fluid biomarker changes,

5589
04:46:00,920 --> 04:46:05,200
the neuronal injury markers,
I think before we know

5590
04:46:05,200 --> 04:46:08,880
what long term effects
may be reflected by COVID,

5591
04:46:08,880 --> 04:46:10,480
we need more studies.

5592
04:46:10,480 --> 04:46:12,360
So for example,
the data that I showed,

5593
04:46:12,360 --> 04:46:14,200
very relevant
to the very first comment.

5594
04:46:14,200 --> 04:46:16,560
They were all in acute,
hospitalized,

5595
04:46:16,560 --> 04:46:17,920
very sick patients.

5596
04:46:17,920 --> 04:46:19,600
We have no idea
whether those things

5597
04:46:19,600 --> 04:46:21,600
will be persistently abnormal
in people with long COVID,

5598
04:46:21,600 --> 04:46:23,040
but that's what
we need to learn.

5599
04:46:23,040 --> 04:46:25,280
Because it may be that
that has implications

5600
04:46:25,280 --> 04:46:29,640
for subsequent neurogenerative
diagnosis or conditions.

5601
04:46:29,640 --> 04:46:31,440
So fantastic questions.

5602
04:46:31,440 --> 04:46:33,000
-Good, thank you.

5603
04:46:33,000 --> 04:46:35,000
-Thank you, Serena. Gabriel.

5604
04:46:40,000 --> 04:46:41,320
-I think he's muted.

5605
04:46:41,320 --> 04:46:44,640
-I thought you were muted.

5606
04:46:44,640 --> 04:46:48,280
-If I may go back to the
stigma question for a second.

5607
04:46:48,280 --> 04:46:56,160
In our long COVID clinic,
we routinely ran, get this off,

5608
04:46:56,160 --> 04:47:00,400
a relatively
well-documented profile,

5609
04:47:00,400 --> 04:47:02,400
chronic inflammatory markers

5610
04:47:02,400 --> 04:47:05,240
in people who continued
to express cognitive

5611
04:47:05,240 --> 04:47:06,520
or other physical symptoms,

5612
04:47:06,520 --> 04:47:08,440
you know,
chronic fatigue and whatnot.

5613
04:47:08,440 --> 04:47:12,880
And we have found
that actually either,

5614
04:47:12,880 --> 04:47:17,800
usually two or three
C-reactive protein [Indistinct]

5615
04:47:17,800 --> 04:47:20,120
consistently abnormal
in these people.

5616
04:47:20,120 --> 04:47:23,280
So that is helpful
in terms of their own,

5617
04:47:23,280 --> 04:47:26,560
if you will, recognition
of the state of being ill

5618
04:47:26,560 --> 04:47:27,920
and as the documentation
in the chart

5619
04:47:27,920 --> 04:47:30,600
that they are not
making up their symptoms.

5620
04:47:30,600 --> 04:47:33,880
So I, you know,
they may not be very useful

5621
04:47:33,880 --> 04:47:37,480
as long term markers of specific
aspects of the disease,

5622
04:47:37,480 --> 04:47:40,000
but they are enough to show
that these people

5623
04:47:40,000 --> 04:47:42,720
do have a chronic
inflammatory process

5624
04:47:42,720 --> 04:47:48,000
that seems to be affecting them,
their performance.

5625
04:47:48,000 --> 04:47:51,200
-Thank you. We're going to
take a couple more questions,

5626
04:47:51,200 --> 04:47:52,760
and then we're going
to take a short break.

5627
04:47:52,760 --> 04:47:55,120
And just remember that
we have a general session.

5628
04:47:55,120 --> 04:47:58,200
So everybody is going to be
able to have an open mike

5629
04:47:58,200 --> 04:48:03,560
once we go into that.
So next is Nick Torado.

5630
04:48:03,560 --> 04:48:05,160
-Thank you.

5631
04:48:05,160 --> 04:48:07,400
It was a really fantastic panel,
so thank you very much.

5632
04:48:07,400 --> 04:48:10,400
My question was related
to a fairly common complication

5633
04:48:10,400 --> 04:48:12,800
that has been reported
in COVID-19

5634
04:48:12,800 --> 04:48:15,920
and also outside of the sphere
about delirium.

5635
04:48:15,920 --> 04:48:18,680
And I wanted to hear
from the panel

5636
04:48:18,680 --> 04:48:21,880
if there is a way
to disentangle complications

5637
04:48:21,880 --> 04:48:25,520
that are raised from delirium
which already connects to AD

5638
04:48:25,520 --> 04:48:27,680
and ADRDs versus something

5639
04:48:27,680 --> 04:48:31,200
that might just be
very specific to COVID-19.

5640
04:48:31,200 --> 04:48:34,400
Thank you.

5641
04:48:34,400 --> 04:48:36,800
-Thank you. Nicole wants
to take a crack at that.

5642
04:48:41,200 --> 04:48:43,960
-That's a very important point.

5643
04:48:43,960 --> 04:48:47,040
Both to disentangle
and, I think,

5644
04:48:47,040 --> 04:48:53,200
some of the studies are trying
to get illness controls,

5645
04:48:53,200 --> 04:48:56,920
non-COVID illness controls
from the same period of time

5646
04:48:56,920 --> 04:48:59,160
or refer to historical controls

5647
04:48:59,160 --> 04:49:02,720
like the European study
in Denmark did.

5648
04:49:02,720 --> 04:49:04,080
But we may also,

5649
04:49:04,080 --> 04:49:07,920
by studying delirium
in the setting of COVID,

5650
04:49:07,920 --> 04:49:10,760
learn something
about a condition

5651
04:49:10,760 --> 04:49:14,920
we have still inadequate
understanding of,

5652
04:49:14,920 --> 04:49:17,400
which is the acceleration
of dementia

5653
04:49:17,400 --> 04:49:19,400
after episodes of sepsis.

5654
04:49:19,400 --> 04:49:21,480
So you bring up
a very good point.

5655
04:49:21,480 --> 04:49:24,080
This is something we need
to carefully address.

5656
04:49:24,080 --> 04:49:26,200
The fact that symptoms
are occurring

5657
04:49:26,200 --> 04:49:28,920
even in persons
who never go to an ICU

5658
04:49:28,920 --> 04:49:30,840
or never have delirium means

5659
04:49:30,840 --> 04:49:35,600
that there's probably
different pathologies

5660
04:49:35,600 --> 04:49:37,240
perhaps of these subgroups.

5661
04:49:37,240 --> 04:49:39,440
Speaking again
to the earlier point

5662
04:49:39,440 --> 04:49:43,040
that we shouldn't lump
cognitive impairment after COVID

5663
04:49:43,040 --> 04:49:47,520
into only one biological box.

5664
04:49:47,520 --> 04:49:48,640
-Thank you so much.

5665
04:49:48,640 --> 04:49:51,400
And that delirium
was on my mind

5666
04:49:51,400 --> 04:49:55,400
as I was listening both to Avi's
and Serena's presentations

5667
04:49:55,400 --> 04:49:57,800
thinking about how do we,

5668
04:49:57,800 --> 04:50:01,680
how do we, how do we measure
that pathology, you know?

5669
04:50:01,680 --> 04:50:03,560
How do we measure
the cell injury

5670
04:50:03,560 --> 04:50:09,200
or perhaps network injury
in vivo as we are monitoring

5671
04:50:09,200 --> 04:50:12,760
these patients both in,
you know, with severe illness,

5672
04:50:12,760 --> 04:50:16,120
you know, not necessarily,
you know, systemic illness.

5673
04:50:16,120 --> 04:50:19,800
And also, those who are
just so easily tipped,

5674
04:50:19,800 --> 04:50:22,600
you know, over the, you know,
over the edge with,

5675
04:50:22,600 --> 04:50:24,080
you know,
even with mild infection.

5676
04:50:24,080 --> 04:50:25,920
So that's something
to think about.

5677
04:50:25,920 --> 04:50:28,440
And I'll take the last
question from Helen,

5678
04:50:28,440 --> 04:50:30,600
and then we will move
into a break.

5679
04:50:30,600 --> 04:50:33,080
And then we will go into
a general session. Helen please.

5680
04:50:33,080 --> 04:50:36,280
-Yeah, Dr. Rost,
I just wanted to comment

5681
04:50:36,280 --> 04:50:39,320
that I have a daughter
who's an RN

5682
04:50:39,320 --> 04:50:42,520
and works
in a large medical center.

5683
04:50:42,520 --> 04:50:45,800
And throughout
these last several surges,

5684
04:50:45,800 --> 04:50:49,400
they've had infected nurses
on the units

5685
04:50:49,400 --> 04:50:51,920
infecting
their fellow coworkers.

5686
04:50:51,920 --> 04:50:55,720
And as, as you're
looking at sampling

5687
04:50:55,720 --> 04:50:57,600
and access to individuals

5688
04:50:57,600 --> 04:51:01,080
who may be available to be
participants in your studies,

5689
04:51:01,080 --> 04:51:05,240
I would look to the workforces
that were responding to this.

5690
04:51:05,240 --> 04:51:07,400
They include
a broad age range.

5691
04:51:07,400 --> 04:51:10,680
We have several that,
you know, yes recovered.

5692
04:51:10,680 --> 04:51:13,000
Some that have mild long COVID.

5693
04:51:13,000 --> 04:51:15,400
Others that are
profoundly infected.

5694
04:51:15,400 --> 04:51:17,200
So that was,
that was the only thing

5695
04:51:17,200 --> 04:51:18,600
that I wanted to contribute.

5696
04:51:18,600 --> 04:51:20,840
This has been
an extraordinarily in depth

5697
04:51:20,840 --> 04:51:24,240
and very, very important
presentation. Thank you.

5698
04:51:24,240 --> 04:51:27,320
-Thank you very much.

5699
04:51:27,320 --> 04:51:29,560
Anybody from the panel
wants to comment on that

5700
04:51:29,560 --> 04:51:32,800
or we just leave it
as an acknowledgement.

5701
04:51:32,800 --> 04:51:35,960
Thank you, Helen,
for this comment.

5702
04:51:35,960 --> 04:51:39,680
All right, well this was
a fantastic presentation

5703
04:51:39,680 --> 04:51:42,240
by this very newly formed
working group,

5704
04:51:42,240 --> 04:51:46,840
and I hope this heralds
the many more years of,

5705
04:51:46,840 --> 04:51:49,240
you know, exploring this problem
and answering

5706
04:51:49,240 --> 04:51:51,560
some very important
questions in the future.

5707
04:51:51,560 --> 04:51:54,240
And we wish we didn't
have this problem

5708
04:51:54,240 --> 04:51:56,440
starting two years ago,
but we do.

5709
04:51:56,440 --> 04:51:59,520
And that only adds to the
complexity of the AD and ADRD.

5710
04:51:59,520 --> 04:52:02,800
And I think we are ready
to take it on.

5711
04:52:02,800 --> 04:52:04,400
So thank you again everybody.

5712
04:52:04,400 --> 04:52:08,200
We're going to have
10 minutes of a break and --

5713
04:52:08,200 --> 04:52:10,320
-Can I just, can I, sorry,

5714
04:52:10,320 --> 04:52:12,560
can I just say I just want
to really enthuse

5715
04:52:12,560 --> 04:52:15,840
for a second about this session
and what we just saw.

5716
04:52:15,840 --> 04:52:18,440
And I also want to,
I want to really encourage

5717
04:52:18,440 --> 04:52:22,040
everybody to come to the,
to the open session

5718
04:52:22,040 --> 04:52:25,920
that Dr. Rost will lead
in a few minutes.

5719
04:52:25,920 --> 04:52:28,480
It's an opportunity
to kind of synthesize

5720
04:52:28,480 --> 04:52:32,120
with our scientific chair
leading the kind of

5721
04:52:32,120 --> 04:52:35,080
input that we've heard
over the course of the meeting,

5722
04:52:35,080 --> 04:52:37,680
and this is
a consensus process.

5723
04:52:37,680 --> 04:52:41,800
It's the final opportunity at
this meeting to provide input.

5724
04:52:41,800 --> 04:52:43,640
So please join us for that

5725
04:52:43,640 --> 04:52:45,600
which should be
a very lively discussion.

5726
04:52:45,600 --> 04:52:48,680
Thank you.

5727
04:52:48,680 --> 04:52:53,200
So the first session yesterday
was health equity in AD/ADRD.

5728
04:52:53,200 --> 04:53:01,400
And, and some of the,
of the comments

5729
04:53:01,400 --> 04:53:05,560
that I wrote down
during the session include

5730
04:53:05,560 --> 04:53:07,800
that the, there's been
a conscious shift,

5731
04:53:07,800 --> 04:53:10,480
certainly there's been
a conscious shift over time

5732
04:53:10,480 --> 04:53:12,960
to prioritizing health equity.

5733
04:53:12,960 --> 04:53:17,040
As well as life course
in the ADRD summit

5734
04:53:17,040 --> 04:53:20,040
and in the field in general.

5735
04:53:20,040 --> 04:53:22,240
We'll want to follow
people in depth

5736
04:53:22,240 --> 04:53:25,760
and get perspective
including about individuals

5737
04:53:25,760 --> 04:53:31,240
from diverse backgrounds
and develop tools and materials

5738
04:53:31,240 --> 04:53:38,560
that will inform on trajectories
for AD/ADRD in health equity.

5739
04:53:40,840 --> 04:53:42,280
And I think, you know,

5740
04:53:42,280 --> 04:53:44,280
you see the recommendations
in front of you.

5741
04:53:44,280 --> 04:53:46,200
I think a nice way
for this to work

5742
04:53:46,200 --> 04:53:49,320
is just to kind of
take a look at them,

5743
04:53:49,320 --> 04:53:53,200
and we will open up the floor
to people's final thoughts,

5744
04:53:53,200 --> 04:53:58,080
comments and questions
on health equity.

5745
04:53:58,080 --> 04:54:05,880
And first up in the queue

5746
04:54:05,880 --> 04:54:11,600
we have Michael Ellenbogen.
So Michael.

5747
04:54:11,600 --> 04:54:14,400
-Thank you so much.
-Yeah, please, go ahead.

5748
04:54:14,400 --> 04:54:20,360
-As you know, ADRD is not high
on the radar

5749
04:54:20,360 --> 04:54:23,200
because it's not contagious.

5750
04:54:23,200 --> 04:54:26,640
I am also not one
to be an alarmist,

5751
04:54:26,640 --> 04:54:30,960
but given what we have learned
in the last year,

5752
04:54:30,960 --> 04:54:36,000
should we place ADRD
at a much higher priority

5753
04:54:36,000 --> 04:54:38,440
as we don't know
what the outcome will be

5754
04:54:38,440 --> 04:54:40,840
because of COVID-19.

5755
04:54:40,840 --> 04:54:45,400
We already know that existing
ADRD projectory

5756
04:54:45,400 --> 04:54:47,520
can bankrupt this country.

5757
04:54:47,520 --> 04:54:52,160
I sure hate to see if COVID
accelerates the process,

5758
04:54:52,160 --> 04:54:56,400
what would that likely mean
if we're not prepared?

5759
04:54:56,400 --> 04:54:58,920
Thank you.

5760
04:54:58,920 --> 04:55:01,000
-Thank you for that comment.

5761
04:55:01,000 --> 04:55:05,800
I think that it's very important
for all of us

5762
04:55:05,800 --> 04:55:08,520
to continue
to put Alzheimer's disease

5763
04:55:08,520 --> 04:55:10,080
and Alzheimer's
disease-related dementia

5764
04:55:10,080 --> 04:55:13,160
and related dementias
higher in our priorities.

5765
04:55:13,160 --> 04:55:16,960
And we hope this summit
is helping to do that.

5766
04:55:16,960 --> 04:55:21,120
Next up in the queue
we have Kathy Service.

5767
04:55:21,120 --> 04:55:23,600
-Thank you. Thanks so much.

5768
04:55:23,600 --> 04:55:26,920
And I've really been enjoying
this conference

5769
04:55:26,920 --> 04:55:29,160
or symposium,
so thank you.

5770
04:55:29,160 --> 04:55:32,720
But I'm talking related
to diversity and accessibility,

5771
04:55:32,720 --> 04:55:34,280
and I wanted
to remind the group

5772
04:55:34,280 --> 04:55:37,200
to remember people
with neuro atypical conditions,

5773
04:55:37,200 --> 04:55:39,320
such as
intellectual disabilities,

5774
04:55:39,320 --> 04:55:41,200
which includes
Down syndrome.

5775
04:55:41,200 --> 04:55:45,160
And I was pleased to see that
mentioned on an earlier slide.

5776
04:55:45,160 --> 04:55:48,560
And also people with autism.
Lifelong sensory impairment,

5777
04:55:48,560 --> 04:55:52,080
severe mental illnesses
and TBI which you addressed.

5778
04:55:52,080 --> 04:55:55,000
I'm a nurse practitioner.
I've worked for over 40 years

5779
04:55:55,000 --> 04:55:56,840
with people with
intellectual disabilities.

5780
04:55:56,840 --> 04:55:59,720
I'm also on the board
of the National Task Group

5781
04:55:59,720 --> 04:56:02,800
for Intellectual Disability
and Dementia Practices.

5782
04:56:02,800 --> 04:56:05,000
I'm also a family
supportive volunteer

5783
04:56:05,000 --> 04:56:08,000
with the Alzheimer's Association

5784
04:56:08,000 --> 04:56:11,000
and Dementia Friends champion
trainer and volunteer.

5785
04:56:11,000 --> 04:56:15,000
At our local hospitals, they
have a care ecosystem program,

5786
04:56:15,000 --> 04:56:16,720
and I volunteer with
a 90 year old woman

5787
04:56:16,720 --> 04:56:20,400
living with dementia
doing some socialization.

5788
04:56:20,400 --> 04:56:22,160
But in all these endeavors,

5789
04:56:22,160 --> 04:56:27,400
and I'm find that
increasingly more that people

5790
04:56:27,400 --> 04:56:29,800
with these atypical conditions

5791
04:56:29,800 --> 04:56:33,000
are coming more
and more into our realm.

5792
04:56:33,000 --> 04:56:36,640
You know, people living
outside institutions, et cetera.

5793
04:56:36,640 --> 04:56:40,280
And all this people
also from this population

5794
04:56:40,280 --> 04:56:41,880
have a variety of caretakers,

5795
04:56:41,880 --> 04:56:45,520
many of whom provide lifelong
caregiving for people.

5796
04:56:45,520 --> 04:56:47,320
And I just wanted
to give you an example

5797
04:56:47,320 --> 04:56:50,880
that a local geriatrician asked
me to kind of help out with.

5798
04:56:50,880 --> 04:56:55,000
She was asked to assess
a 70 year old man with autism

5799
04:56:55,000 --> 04:56:59,040
because his PCP suspected
he may have dementia.

5800
04:56:59,040 --> 04:57:00,720
Because this man
had demonstrated

5801
04:57:00,720 --> 04:57:03,480
some behavioral stress
in an office visit.

5802
04:57:03,480 --> 04:57:06,080
And most the screening tools
we know are inadequate

5803
04:57:06,080 --> 04:57:07,440
for these groups of people.

5804
04:57:07,440 --> 04:57:09,280
It took me a while
to make an assessment,

5805
04:57:09,280 --> 04:57:12,600
and I suspect he might have
had maybe possible MCI,

5806
04:57:12,600 --> 04:57:15,520
which has been reported.
As you probably can imagine,

5807
04:57:15,520 --> 04:57:18,040
there's really scant
literature on this.

5808
04:57:18,040 --> 04:57:19,720
Although there were
a lot of confusing

5809
04:57:19,720 --> 04:57:22,080
and confounding
environmental factors.

5810
04:57:22,080 --> 04:57:23,400
And I'm not gong
to go on and on,

5811
04:57:23,400 --> 04:57:24,680
but I find this, you know,

5812
04:57:24,680 --> 04:57:27,000
in one of our dementia
friends trainings

5813
04:57:27,000 --> 04:57:29,400
there was a woman with autism
who was wondering about

5814
04:57:29,400 --> 04:57:31,960
how to help and support
her husband, et cetera.

5815
04:57:31,960 --> 04:57:34,240
So people are out there.

5816
04:57:34,240 --> 04:57:37,560
I just also want to bring
to your attention

5817
04:57:37,560 --> 04:57:40,600
is that there is a report
that the national task group

5818
04:57:40,600 --> 04:57:43,120
that spearheaded
called examining adults

5819
04:57:43,120 --> 04:57:45,480
with neurotypical conditions
for MCI

5820
04:57:45,480 --> 04:57:49,160
and dementia during cognitive
impairment assessments.

5821
04:57:49,160 --> 04:57:51,840
And a report of an expert
consultative panel,

5822
04:57:51,840 --> 04:57:54,240
and it's available
on the NTG website.

5823
04:57:54,240 --> 04:57:56,800
But you know, when we talk
about diversity,

5824
04:57:56,800 --> 04:57:59,160
you know, I rarely see
this population of people,

5825
04:57:59,160 --> 04:58:01,800
unless we talk about
Down syndrome

5826
04:58:01,800 --> 04:58:04,400
acknowledged and supported.

5827
04:58:04,400 --> 04:58:06,480
So I just wanted to make sure
that you don't forget

5828
04:58:06,480 --> 04:58:10,560
about this specific group
of people in your endeavors.

5829
04:58:10,560 --> 04:58:14,880
So and thanks so much
for listening to me.

5830
04:58:14,880 --> 04:58:16,640
-Thank you so much, Kathy.
This is Dr. Rost.

5831
04:58:16,640 --> 04:58:18,760
I'm back online.
I really apologize.

5832
04:58:18,760 --> 04:58:22,240
We planned for months
for this particular moment,

5833
04:58:22,240 --> 04:58:26,640
and I really, I apologize
for the technical problem.

5834
04:58:26,640 --> 04:58:29,640
And I would like
if you don't mind

5835
04:58:29,640 --> 04:58:36,440
I would like to take
the screensharing capacity.

5836
04:58:36,440 --> 04:58:42,320
And I will share
with you my slides.

5837
04:58:42,320 --> 04:58:44,560
-Perfect, and welcome back.

5838
04:58:44,560 --> 04:58:46,120
-I apologize for that.

5839
04:58:46,120 --> 04:58:49,440
So thank God I have
an extra laptop in my office.

5840
04:58:49,440 --> 04:58:51,440
And I just wanted to start

5841
04:58:51,440 --> 04:58:56,000
with a few very general
comments and observations.

5842
04:58:56,000 --> 04:58:59,960
Again, this is the,
this is an endeavor

5843
04:58:59,960 --> 04:59:02,360
that's been planned for months
and months and months.

5844
04:59:02,360 --> 04:59:05,560
And really, short of
a few technical issues,

5845
04:59:05,560 --> 04:59:08,800
you know, this has been
a seamless, you know,

5846
04:59:08,800 --> 04:59:11,800
execution by
the entire planning team.

5847
04:59:11,800 --> 04:59:16,120
And my special thanks to
the panelists and participants

5848
04:59:16,120 --> 04:59:18,200
and the entire NINDS
planning team.

5849
04:59:18,200 --> 04:59:23,200
And also to the Infinity Group
for their preparation.

5850
04:59:23,200 --> 04:59:26,400
We started with,
you know, trepidations

5851
04:59:26,400 --> 04:59:29,600
and how the virtual format for
this summit is going to work.

5852
04:59:29,600 --> 04:59:32,560
I can, you know,
assuredly say that now

5853
04:59:32,560 --> 04:59:34,560
that it's working quite well.

5854
04:59:34,560 --> 04:59:36,400
We really
appreciate participation

5855
04:59:36,400 --> 04:59:38,360
from all the registrants.

5856
04:59:38,360 --> 04:59:41,680
We started with 1,400
plus registrants

5857
04:59:41,680 --> 04:59:45,440
who represented the very wide
spectrum of the,

5858
04:59:45,440 --> 04:59:47,800
of the public
nonprofit industry government

5859
04:59:47,800 --> 04:59:50,120
and academic
and clinical sectors.

5860
04:59:50,120 --> 04:59:53,240
And I have to say
throughout the entire duration

5861
04:59:53,240 --> 04:59:56,320
of the summit thus far,
we had an average, you know,

5862
04:59:56,320 --> 04:59:59,000
500 attendees
at different times.

5863
04:59:59,000 --> 05:00:01,680
And, you know,
anywhere between 300

5864
05:00:01,680 --> 05:00:04,840
as we have now at the end
of the second day to 700

5865
05:00:04,840 --> 05:00:06,280
at the beginning
of the meeting.

5866
05:00:06,280 --> 05:00:07,760
So that's been fantastic.

5867
05:00:07,760 --> 05:00:11,000
We had two intense days,
eight scientific sessions,

5868
05:00:11,000 --> 05:00:13,920
128 panelists
and 44 individual talks.

5869
05:00:13,920 --> 05:00:18,200
So you know,
that's really a great,

5870
05:00:18,200 --> 05:00:21,160
you know, a great opportunity
for us to engage.

5871
05:00:21,160 --> 05:00:24,720
And thank you to particularly
patients and caregivers.

5872
05:00:24,720 --> 05:00:29,400
As I've said before, it's the
voices that keep us honest

5873
05:00:29,400 --> 05:00:31,840
and also wanted
to give a shoutout

5874
05:00:31,840 --> 05:00:33,920
to the NINDS
Communications Office

5875
05:00:33,920 --> 05:00:36,880
for preparing that
very special video presentation

5876
05:00:36,880 --> 05:00:42,200
this morning that we've enjoyed.
And thank you to all of you.

5877
05:00:42,200 --> 05:00:44,520
I just wanted to share
a few comment things

5878
05:00:44,520 --> 05:00:47,720
that I have heard
throughout the sessions.

5879
05:00:47,720 --> 05:00:50,640
I've taken notes,
and what I'm looking forward to

5880
05:00:50,640 --> 05:00:53,240
is that at the end
of my brief presentation

5881
05:00:53,240 --> 05:00:55,960
that all of you will have
an opportunity to jump in

5882
05:00:55,960 --> 05:00:58,480
and either, you know,
add, correct or, you know,

5883
05:00:58,480 --> 05:01:01,200
or have,
provide different point of view.

5884
05:01:01,200 --> 05:01:04,200
I think that we hear that the
great progress has been made,

5885
05:01:04,200 --> 05:01:06,240
but more needs to be done.

5886
05:01:06,240 --> 05:01:09,800
I hear a very strong voice
of patients and caregivers

5887
05:01:09,800 --> 05:01:13,600
and across
the very broad spectrum

5888
05:01:13,600 --> 05:01:19,880
of input which I think is much
needed within different topics.

5889
05:01:19,880 --> 05:01:24,880
I hear that there is an urgent
need for methods of prevention,

5890
05:01:24,880 --> 05:01:27,960
for pre-symptomatic vigilance
so to speak

5891
05:01:27,960 --> 05:01:30,560
and also for support of those
who are living with disease.

5892
05:01:30,560 --> 05:01:33,400
This is the three areas
that patients and caregivers

5893
05:01:33,400 --> 05:01:34,760
specifically

5894
05:01:34,760 --> 05:01:36,680
and also the organizations
that advocate

5895
05:01:36,680 --> 05:01:40,400
on their behalf have been,
have been communicating with us.

5896
05:01:40,400 --> 05:01:43,520
I also hear biomarkers,
biomarkers, biomarkers.

5897
05:01:43,520 --> 05:01:46,400
It's, you know, across
all of the topics,

5898
05:01:46,400 --> 05:01:50,840
this conversation is, you know,
enriched by the fact that,

5899
05:01:50,840 --> 05:01:53,920
you know, biomarkers
at every stage of,

5900
05:01:53,920 --> 05:01:57,920
you know, detection, diagnosis,
management, treatment,

5901
05:01:57,920 --> 05:02:02,400
response to treatments,
prognosis, all of this I think

5902
05:02:02,400 --> 05:02:08,280
in such a complex disease
constellation as AD/ADRD is,

5903
05:02:08,280 --> 05:02:10,480
biomarkers are going
to make a difference.

5904
05:02:10,480 --> 05:02:14,800
I also hear the theme
of a need for novel models,

5905
05:02:14,800 --> 05:02:17,360
new disease biology paradigms.

5906
05:02:17,360 --> 05:02:19,680
And going off the beaten path,
so to speak,

5907
05:02:19,680 --> 05:02:22,320
seeking synergies
within different diseases

5908
05:02:22,320 --> 05:02:26,880
or also maximizing a divergence
in pathological pathways.

5909
05:02:26,880 --> 05:02:30,800
And I think this is something
that, you know, all of us,

5910
05:02:30,800 --> 05:02:34,360
you know, in the working group
need to go back

5911
05:02:34,360 --> 05:02:37,680
and kind of think about
how can we incorporate

5912
05:02:37,680 --> 05:02:40,880
that into our recommendations
and make,

5913
05:02:40,880 --> 05:02:42,680
and turn them
into milestones.

5914
05:02:42,680 --> 05:02:46,800
Then clinical trials have been,
you know, on everybody's mind.

5915
05:02:46,800 --> 05:02:48,640
And you know,
there's some diseases

5916
05:02:48,640 --> 05:02:51,400
that have terrific progress
already in that directions,

5917
05:02:51,400 --> 05:02:53,320
others that need
to move there.

5918
05:02:53,320 --> 05:02:55,960
And I think that that's
the voices that we heard.

5919
05:02:55,960 --> 05:02:59,320
And then also one
big theme of the need

5920
05:02:59,320 --> 05:03:01,000
for resurgent implementation

5921
05:03:01,000 --> 05:03:04,040
of pragmatic approaches
and solutions in ADRD.

5922
05:03:04,040 --> 05:03:06,760
This is something
that a lot of you

5923
05:03:06,760 --> 05:03:11,640
have been commenting on
throughout the summit.

5924
05:03:11,640 --> 05:03:17,280
I'm going to go into,
if my slides allow me,

5925
05:03:17,280 --> 05:03:22,400
I'm going to go into
topics specific,

5926
05:03:22,400 --> 05:03:24,680
comments or themes
that I have captured

5927
05:03:24,680 --> 05:03:26,520
as I was listening
to the discussion

5928
05:03:26,520 --> 05:03:28,640
following the conversations

5929
05:03:28,640 --> 05:03:32,080
within the health
equity discussion.

5930
05:03:32,080 --> 05:03:36,760
There was a clear kind
of underscoring of the need

5931
05:03:36,760 --> 05:03:39,080
for biomarkers
to understand ADRD

5932
05:03:39,080 --> 05:03:42,640
in diverse populations
with dedicated studies

5933
05:03:42,640 --> 05:03:46,320
of minoritized populations
covering entire lifespan.

5934
05:03:46,320 --> 05:03:49,600
And with special focus
on brain donation that has to,

5935
05:03:49,600 --> 05:03:52,960
has to help us advance
understanding of disease

5936
05:03:52,960 --> 05:03:57,320
that's specific
to the diverse populations.

5937
05:03:57,320 --> 05:03:59,000
There's been a call
for research studies

5938
05:03:59,000 --> 05:04:02,600
that go wide and deep
highlighting multiple approaches

5939
05:04:02,600 --> 05:04:06,080
that, you know,
that are necessary to solve,

5940
05:04:06,080 --> 05:04:09,720
to solve the problems
or give, find the answers.

5941
05:04:09,720 --> 05:04:11,360
Breaking the barriers
to recruitment

5942
05:04:11,360 --> 05:04:13,600
of diverse populations.

5943
05:04:13,600 --> 05:04:16,520
There was a theme of improving
access to clinical trials,

5944
05:04:16,520 --> 05:04:19,000
especially to ensure equity.

5945
05:04:19,000 --> 05:04:22,520
Making sure that the trials
that are partnered through NIH

5946
05:04:22,520 --> 05:04:23,960
are free of cost.

5947
05:04:23,960 --> 05:04:26,080
That's a patient's perspective
that we heard.

5948
05:04:26,080 --> 05:04:29,520
Gene environment interaction
has been a really big theme

5949
05:04:29,520 --> 05:04:32,800
in a discussion following
the health equity session.

5950
05:04:32,800 --> 05:04:35,920
Understanding that including
health disparities

5951
05:04:35,920 --> 05:04:38,000
related to life course

5952
05:04:38,000 --> 05:04:41,000
or life course
of environmental exposures

5953
05:04:41,000 --> 05:04:44,520
such as nutrition,
lifestyle, toxicities,

5954
05:04:44,520 --> 05:04:48,080
and the need for normal models
like organelles, for example,

5955
05:04:48,080 --> 05:04:50,640
to thoroughly account
for the variability

5956
05:04:50,640 --> 05:04:53,560
and specifics
of diverse environments.

5957
05:04:53,560 --> 05:04:58,240
There was a theme for, of the
need to encourage and expand

5958
05:04:58,240 --> 05:05:02,160
by specimen and tissue
collection beyond brain tissue,

5959
05:05:02,160 --> 05:05:04,480
including retinal in this case
for discovery

5960
05:05:04,480 --> 05:05:08,480
in order to consider
a whole person.

5961
05:05:08,480 --> 05:05:14,520
And perspectives
from a caregiver

5962
05:05:14,520 --> 05:05:17,120
that we heard
in that particular session

5963
05:05:17,120 --> 05:05:20,000
included the transparency
and communication

5964
05:05:20,000 --> 05:05:22,960
with caregivers regarding
diagnosis and prognosis.

5965
05:05:22,960 --> 05:05:26,640
That them continued
to emerge in different topics.

5966
05:05:26,640 --> 05:05:27,840
And I think that
that's something

5967
05:05:27,840 --> 05:05:30,480
that each working group
has to,

5968
05:05:30,480 --> 05:05:35,000
has to, you know, accommodate
for as we think about,

5969
05:05:35,000 --> 05:05:37,560
as we think about
recommendations going forward.

5970
05:05:37,560 --> 05:05:39,600
And finally,
a strong foundation

5971
05:05:39,600 --> 05:05:41,600
for developing
diverse workforce,

5972
05:05:41,600 --> 05:05:43,320
retention and support
of mentors

5973
05:05:43,320 --> 05:05:46,880
at all stages
of their career span.

5974
05:05:46,880 --> 05:05:50,920
In the FTD group discussion,

5975
05:05:50,920 --> 05:05:52,920
biomarkers were front
and center.

5976
05:05:52,920 --> 05:05:57,520
Almost every, every comment
had some reference to biomarkers

5977
05:05:57,520 --> 05:06:01,560
including particularly pre-
symptomatic neural degeneration,

5978
05:06:01,560 --> 05:06:03,280
you know,
with a clinical translation

5979
05:06:03,280 --> 05:06:06,760
for current biomarkers
such as NfL being an urgent need

5980
05:06:06,760 --> 05:06:09,800
and developing novel ones for
disease progression monitoring,

5981
05:06:09,800 --> 05:06:13,280
et cetera.
Innovative clinical markers

5982
05:06:13,280 --> 05:06:18,600
including those that capture
social, behavioral and movement,

5983
05:06:18,600 --> 05:06:24,520
you know, metrics
that may help make,

5984
05:06:24,520 --> 05:06:26,000
you know, participation
and research

5985
05:06:26,000 --> 05:06:31,720
as well as perhaps
further translation

5986
05:06:31,720 --> 05:06:35,320
of the recent research
findings into care

5987
05:06:35,320 --> 05:06:39,360
and make those accessible.
And also developing novel

5988
05:06:39,360 --> 05:06:42,760
endpoints that capture the broad
spectrum of clinical disease.

5989
05:06:42,760 --> 05:06:45,440
So that's something
that was very,

5990
05:06:45,440 --> 05:06:48,440
very robust
in terms of discussion.

5991
05:06:48,440 --> 05:06:51,320
Also within the FTD session
discussion,

5992
05:06:51,320 --> 05:06:53,880
there was a lot of focus
on prevention

5993
05:06:53,880 --> 05:06:56,520
and the need to assist those
who are living with FTD.

5994
05:06:56,520 --> 05:07:00,120
And I think that that's
a very strong patient

5995
05:07:00,120 --> 05:07:02,520
as well as
a caretaker perspective.

5996
05:07:02,520 --> 05:07:05,040
A risk and resilience
factor characterization

5997
05:07:05,040 --> 05:07:08,200
came into discussion
and also continued to be a theme

5998
05:07:08,200 --> 05:07:10,400
throughout the rest
of the summit.

5999
05:07:10,400 --> 05:07:15,240
Quantitative data
was highlighted,

6000
05:07:15,240 --> 05:07:17,720
the need for quantitative data
was highlighted.

6001
05:07:17,720 --> 05:07:21,760
Not only the all mix level
but the level of protein biology

6002
05:07:21,760 --> 05:07:23,160
and other precision methods

6003
05:07:23,160 --> 05:07:25,560
of molecular characterization
of disease.

6004
05:07:25,560 --> 05:07:28,560
And then from
the patient perspective,

6005
05:07:28,560 --> 05:07:32,560
the question of, you know,
delayed diagnosis,

6006
05:07:32,560 --> 05:07:34,880
is the detection
delayed diagnosis.

6007
05:07:34,880 --> 05:07:38,200
And reconsideration of this
kind of single diagnosis

6008
05:07:38,200 --> 05:07:43,120
box that patients are frequently
dealing with in real world.

6009
05:07:43,120 --> 05:07:45,320
For VCID session,

6010
05:07:45,320 --> 05:07:48,200
there was a very robust
scientific discussion

6011
05:07:48,200 --> 05:07:50,320
that followed presentation.

6012
05:07:50,320 --> 05:07:53,920
And there were certainly
VCID has been identified

6013
05:07:53,920 --> 05:07:57,080
as one of the areas
of clear intersection of science

6014
05:07:57,080 --> 05:08:01,960
and, you know, emerging need
to explore novel pathways

6015
05:08:01,960 --> 05:08:05,360
and also finetuning
the existing models.

6016
05:08:05,360 --> 05:08:07,920
VCID is dementia
and sleep intersection

6017
05:08:07,920 --> 05:08:11,200
was used as an example of kind
of evolving

6018
05:08:11,200 --> 05:08:14,080
understanding
of the disease with,

6019
05:08:14,080 --> 05:08:17,200
you know, moving
from the concepts

6020
05:08:17,200 --> 05:08:19,800
of ischemic models of disease

6021
05:08:19,800 --> 05:08:23,880
into understanding the
mechanisms of clearance that,

6022
05:08:23,880 --> 05:08:27,840
you know, may have
that novel pivot

6023
05:08:27,840 --> 05:08:31,800
in our understanding
of disease.

6024
05:08:31,800 --> 05:08:34,000
And as a result,
developing novel

6025
05:08:34,000 --> 05:08:36,960
approaches to
nonischemic mechanisms,

6026
05:08:36,960 --> 05:08:40,320
for example,
in this particular area

6027
05:08:40,320 --> 05:08:43,200
including
the impaired clearance.

6028
05:08:43,200 --> 05:08:45,440
There was a very robust

6029
05:08:45,440 --> 05:08:50,080
and also I think fascinating
discussion with regard

6030
05:08:50,080 --> 05:08:56,040
to the nuances of how
we approach modeling of ischemia

6031
05:08:56,040 --> 05:09:00,400
and in general VCID
considering the diversity

6032
05:09:00,400 --> 05:09:02,760
in cell types
that we are,

6033
05:09:02,760 --> 05:09:06,000
you know, increasingly
understand original blood

6034
05:09:06,000 --> 05:09:08,440
flows in the brain,
vascular reactivity,

6035
05:09:08,440 --> 05:09:09,840
et cetera, et cetera.

6036
05:09:09,840 --> 05:09:12,600
All of the foundations
of the VCID disease

6037
05:09:12,600 --> 05:09:14,400
processes as we know
them right now.

6038
05:09:14,400 --> 05:09:17,800
But with a broadening
so to speak spectrum

6039
05:09:17,800 --> 05:09:20,960
and portfolio of understanding
of these nuances

6040
05:09:20,960 --> 05:09:23,280
I think is something
that we need to think

6041
05:09:23,280 --> 05:09:30,000
on how that may enhance our
recommendations going forward.

6042
05:09:30,000 --> 05:09:32,600
And also, big focus
on reproducibility,

6043
05:09:32,600 --> 05:09:35,000
repeatability of models
at every stage

6044
05:09:35,000 --> 05:09:38,640
including design,
data collection, data sharing.

6045
05:09:38,640 --> 05:09:41,680
Understanding VCID
is a systemic disease

6046
05:09:41,680 --> 05:09:44,720
and the role in that
of circulating biomarkers.

6047
05:09:44,720 --> 05:09:46,520
Obviously,
this I something that,

6048
05:09:46,520 --> 05:09:48,000
you know, being done currently,

6049
05:09:48,000 --> 05:09:50,160
but there are perhaps
opportunities for novel

6050
05:09:50,160 --> 05:09:52,200
approaches
and emerging,

6051
05:09:52,200 --> 05:09:55,880
using emerging systemic
circulating biomarkers

6052
05:09:55,880 --> 05:09:58,280
as well as
imaging technologies.

6053
05:09:58,280 --> 05:10:01,520
And I just wanted
to quote Dr. Seshadri's,

6054
05:10:01,520 --> 05:10:04,920
I think kind of a statement

6055
05:10:04,920 --> 05:10:07,320
which kind of culminated
this discussion of VCID

6056
05:10:07,320 --> 05:10:12,560
is that perhaps the science or
our approach to science in VCID

6057
05:10:12,560 --> 05:10:15,200
is going to, you know,
through increasing complexity

6058
05:10:15,200 --> 05:10:17,000
until we arrive
at some simplicity.

6059
05:10:17,000 --> 05:10:20,320
And I think that that may be,
may be the thing here as well.

6060
05:10:20,320 --> 05:10:23,880
In LBD, group discussion,

6061
05:10:23,880 --> 05:10:27,520
I think that the big things
were sharing of information

6062
05:10:27,520 --> 05:10:30,560
across the disease entities
considering how heterogeneous

6063
05:10:30,560 --> 05:10:34,040
and also perhaps
in some areas overlapping,

6064
05:10:34,040 --> 05:10:37,480
you know, disease pathology
clinical,

6065
05:10:37,480 --> 05:10:41,560
clinical syndromes
that we are dealing with.

6066
05:10:41,560 --> 05:10:46,480
Making sure that the dialogue
is accessible for the public

6067
05:10:46,480 --> 05:10:50,240
in conveying
the complexity of disease.

6068
05:10:50,240 --> 05:10:56,040
The patient kind of a guidance
to us with regard

6069
05:10:56,040 --> 05:10:59,840
to access to clinical trials
across the spectrum of LBD,

6070
05:10:59,840 --> 05:11:03,360
especially as diagnostic
precision evolves and patients

6071
05:11:03,360 --> 05:11:06,000
seek new opportunities
as their diagnosis

6072
05:11:06,000 --> 05:11:08,520
of which is actually a theme
that came up

6073
05:11:08,520 --> 05:11:10,920
in at least a couple of sessions
throughout the summit.

6074
05:11:10,920 --> 05:11:15,280
Which I thought was very,
very curious.

6075
05:11:15,280 --> 05:11:18,120
Biomarkers were front
and center with LBD as well.

6076
05:11:18,120 --> 05:11:21,160
Pre-symptomatic, pre-clinical
diagnostic prognostic,

6077
05:11:21,160 --> 05:11:27,560
all of these have been
on the mind of our scientists

6078
05:11:27,560 --> 05:11:32,520
as well as patients
and families and care partners.

6079
05:11:32,520 --> 05:11:36,000
Focus on disease heterogeneities
also led to a discussion

6080
05:11:36,000 --> 05:11:40,160
of both clinical
and precision characterization.

6081
05:11:40,160 --> 05:11:43,720
Moving away from silos and again
clearer communications.

6082
05:11:43,720 --> 05:11:46,160
And then developing
opportunities for disease

6083
05:11:46,160 --> 05:11:48,800
modification
and symptom control of patients

6084
05:11:48,800 --> 05:11:54,280
who are already living with LBDs
is something that, again,

6085
05:11:54,280 --> 05:11:57,800
was reverberated
in the discussion session

6086
05:11:57,800 --> 05:12:00,160
following this.

6087
05:12:00,160 --> 05:12:03,160
Now this morning we had
a very robust discussion

6088
05:12:03,160 --> 05:12:06,360
following the mixed etiology
dementia session.

6089
05:12:06,360 --> 05:12:08,440
It was an outstanding session.

6090
05:12:08,440 --> 05:12:11,720
And I think there was
quite a bit of caregiver

6091
05:12:11,720 --> 05:12:14,040
and patient perspective

6092
05:12:14,040 --> 05:12:19,840
that was introduced in the,
in the discussion there.

6093
05:12:19,840 --> 05:12:23,640
The need for engagement across
the entire spectrum of disease

6094
05:12:23,640 --> 05:12:26,000
and transparency
in communication

6095
05:12:26,000 --> 05:12:29,400
was underlined
multiple times.

6096
05:12:29,400 --> 05:12:32,160
Opportunities to impact
care and engagement

6097
05:12:32,160 --> 05:12:35,200
via a compassionate and
culturally appropriate detection

6098
05:12:35,200 --> 05:12:36,840
and diagnosis process.

6099
05:12:36,840 --> 05:12:39,120
So this is something that I
wanted to personally thank

6100
05:12:39,120 --> 05:12:43,680
for this feedback
from our participants.

6101
05:12:43,680 --> 05:12:46,600
And I think that
this is duly noted

6102
05:12:46,600 --> 05:12:49,680
by the members
of the MED working group

6103
05:12:49,680 --> 05:12:54,800
but as well as our entire,
entire community.

6104
05:12:54,800 --> 05:12:57,520
There was a note
of consideration of provider

6105
05:12:57,520 --> 05:13:00,400
burden and wellbeing,
which obviously contributes

6106
05:13:00,400 --> 05:13:03,960
in some sort of either
positive perpetuating cycle

6107
05:13:03,960 --> 05:13:06,880
or perhaps an ambitious
cycle on the other,

6108
05:13:06,880 --> 05:13:08,800
on the other side
of the equation

6109
05:13:08,800 --> 05:13:13,200
where we need to ensure that
the providers remain engaged

6110
05:13:13,200 --> 05:13:19,200
and well in being able
to provide the needed compassion

6111
05:13:19,200 --> 05:13:21,600
for the patients
and families.

6112
05:13:21,600 --> 05:13:24,640
I also enjoyed
the discussion on research

6113
05:13:24,640 --> 05:13:26,720
that's needed
on cultural aspects

6114
05:13:26,720 --> 05:13:28,880
of risk and benefit perception

6115
05:13:28,880 --> 05:13:32,000
and potentially policy research
into economic impact

6116
05:13:32,000 --> 05:13:35,800
of screening and early detection
of cognitive impairment

6117
05:13:35,800 --> 05:13:37,760
and dementia
on diverse populations.

6118
05:13:37,760 --> 05:13:39,520
I think it's
a very important

6119
05:13:39,520 --> 05:13:41,680
and potentially
very impactful area

6120
05:13:41,680 --> 05:13:46,480
that we may need to address.
We also had opportunities to,

6121
05:13:46,480 --> 05:13:49,280
or discussed opportunities
to amplify effectiveness

6122
05:13:49,280 --> 05:13:51,960
of multiple
approaches via harmonization

6123
05:13:51,960 --> 05:13:55,000
between MED and VCID topics.

6124
05:13:55,000 --> 05:14:00,600
And then also, the important
care partners input from,

6125
05:14:00,600 --> 05:14:07,240
that we again restated
from both, from the beginning,

6126
05:14:07,240 --> 05:14:10,000
from the research concept
from one side of the spectrum

6127
05:14:10,000 --> 05:14:15,600
to execution of research,
and this input is needed.

6128
05:14:15,600 --> 05:14:18,640
There were a few important
points in post-TBI,

6129
05:14:18,640 --> 05:14:21,800
AD and ADRD session
that I have captured,

6130
05:14:21,800 --> 05:14:27,800
and one of them is central
role of biomarkers in diagnosis

6131
05:14:27,800 --> 05:14:34,000
that has been discussed with
a great degree of robustness.

6132
05:14:34,000 --> 05:14:36,360
In the face of
clinical heterogeneity

6133
05:14:36,360 --> 05:14:39,520
of post-TBI ADRD syndromes,

6134
05:14:39,520 --> 05:14:42,880
I think the panel
has ultimately arrived

6135
05:14:42,880 --> 05:14:47,120
at a conclusion
that biomarkers in this,

6136
05:14:47,120 --> 05:14:51,800
in this role, would provide
probably a greater degree

6137
05:14:51,800 --> 05:14:54,200
of fidelity of diagnosis.

6138
05:14:54,200 --> 05:14:56,120
There was also
a very robust discussion

6139
05:14:56,120 --> 05:14:59,800
of post-TBI ADRD versus CTE,

6140
05:14:59,800 --> 05:15:02,000
chronic traumatic
encephalopathy,

6141
05:15:02,000 --> 05:15:05,960
where the acknowledgement
was made that the study design,

6142
05:15:05,960 --> 05:15:10,400
include specifics of exposure
history and biomarker arrays

6143
05:15:10,400 --> 05:15:13,600
are needed to differentiate
between the impact

6144
05:15:13,600 --> 05:15:16,960
of acute
versus chronic injury.

6145
05:15:16,960 --> 05:15:20,080
There was also point discuss
regarding standardization

6146
05:15:20,080 --> 05:15:22,880
and prioritization
of translational models.

6147
05:15:22,880 --> 05:15:26,440
A note has been made
of a great existing history

6148
05:15:26,440 --> 05:15:32,760
of TBI models prior
and also ongoing work done

6149
05:15:32,760 --> 05:15:37,080
by Veterans Administration
Department of Defense

6150
05:15:37,080 --> 05:15:41,200
in collaboration
with NIH, both NIA and NIDS,

6151
05:15:41,200 --> 05:15:45,720
and these collaborations
perhaps are best to be maximized

6152
05:15:45,720 --> 05:15:50,680
on as the models of post-TBI,
AD and ADRD are being developed.

6153
05:15:50,680 --> 05:15:53,200
And then of course a very
important patient perspective

6154
05:15:53,200 --> 05:15:54,880
that was proposed
into this discussion

6155
05:15:54,880 --> 05:15:58,600
with regard to availability
and accessibility of public

6156
05:15:58,600 --> 05:16:01,200
facing education in this area.

6157
05:16:01,200 --> 05:16:06,960
I made also a few notes
with regard to our late session.

6158
05:16:06,960 --> 05:16:08,720
The discussion was also robust,

6159
05:16:08,720 --> 05:16:12,600
and I think the emerging themes
were that there's a need

6160
05:16:12,600 --> 05:16:16,200
for harmonization of data
and sample collection.

6161
05:16:16,200 --> 05:16:23,120
And you know, using this
in order to benefit other fields

6162
05:16:23,120 --> 05:16:24,920
related within the ADRD

6163
05:16:24,920 --> 05:16:27,480
but also perhaps
neurological disorders

6164
05:16:27,480 --> 05:16:30,400
or brain disorders
outside of ADRD as well.

6165
05:16:30,400 --> 05:16:34,080
There was a discussion on VCID
and late interface,

6166
05:16:34,080 --> 05:16:40,000
particularly with
a good proportion of,

6167
05:16:40,000 --> 05:16:45,720
you know, nonagenarians or
late octogenarians who survive

6168
05:16:45,720 --> 05:16:51,440
and are diagnosed
with late disorder or syndrome.

6169
05:16:51,440 --> 05:16:57,040
I should say they also have
a high predominance

6170
05:16:57,040 --> 05:17:00,240
of cerebral vascular findings
and exploring

6171
05:17:00,240 --> 05:17:03,000
or exploiting
this opportunity

6172
05:17:03,000 --> 05:17:06,560
to study coexistence
of this type of pathology,

6173
05:17:06,560 --> 05:17:12,600
neuropathology offers
great opportunities to address

6174
05:17:12,600 --> 05:17:15,600
some of the, you know,
evolving pathophysiology.

6175
05:17:15,600 --> 05:17:19,880
And in this context,
the role of perivascular spaces

6176
05:17:19,880 --> 05:17:23,920
and, you know,
clearance in the brain,

6177
05:17:23,920 --> 05:17:26,920
proteinopathies, you know,
in the brain was addressed

6178
05:17:26,920 --> 05:17:29,280
as well as opportunities
to study

6179
05:17:29,280 --> 05:17:33,560
let's say impact
of chronic sleep disorders

6180
05:17:33,560 --> 05:17:35,600
in this patient population.

6181
05:17:35,600 --> 05:17:38,600
There was also a discussion
on clinical diagnosis readiness,

6182
05:17:38,600 --> 05:17:41,400
including biomarkers,
clinical criteria

6183
05:17:41,400 --> 05:17:45,800
that are needed to validate
prospectively the diagnosis

6184
05:17:45,800 --> 05:17:48,480
and to give options
for patients and families.

6185
05:17:48,480 --> 05:17:51,040
And I think while the jury
is still out on

6186
05:17:51,040 --> 05:17:55,680
where is the risk and benefit
ratio stands with regard

6187
05:17:55,680 --> 05:17:58,720
to whether we want
to quote/unquote rush in

6188
05:17:58,720 --> 05:18:00,600
in providing a diagnosis
to a patient

6189
05:18:00,600 --> 05:18:02,240
or whether
we should step back

6190
05:18:02,240 --> 05:18:05,640
until we are actually able
to provide something that,

6191
05:18:05,640 --> 05:18:09,200
you know, the diagnosis
that not only,

6192
05:18:09,200 --> 05:18:12,840
you know, not only a preliminary
but also actionable.

6193
05:18:12,840 --> 05:18:15,920
I think that's the sort
of a discussion

6194
05:18:15,920 --> 05:18:17,560
that we will continue
to have over

6195
05:18:17,560 --> 05:18:21,120
the, you know,
over the next few years.

6196
05:18:21,120 --> 05:18:25,000
And I'll be very interested
to see how much progress

6197
05:18:25,000 --> 05:18:27,800
we will make in this space
in the next three years.

6198
05:18:27,800 --> 05:18:30,960
Because it clearly in the prior
three years, you know,

6199
05:18:30,960 --> 05:18:34,720
since the LATE has been
introduced TDP

6200
05:18:34,720 --> 05:18:38,200
for the three topic has been
introduced in this context,

6201
05:18:38,200 --> 05:18:41,320
so much progress
has been already established.

6202
05:18:41,320 --> 05:18:44,560
And we finished off
with a COVID session

6203
05:18:44,560 --> 05:18:47,760
which, you know is just
very fresh in our memory.

6204
05:18:47,760 --> 05:18:50,320
And due to my technical errors,

6205
05:18:50,320 --> 05:18:53,600
I have not been able to update
my slides very thoroughly.

6206
05:18:53,600 --> 05:18:56,600
But what I heard
in our discussion,

6207
05:18:56,600 --> 05:18:58,120
which was a fantastic
discussion,

6208
05:18:58,120 --> 05:19:00,400
and I thank all the panelists,
is that, you know,

6209
05:19:00,400 --> 05:19:04,200
data sharing is something
that is urgently needed.

6210
05:19:04,200 --> 05:19:08,200
You know, data harmonization,
syndrome characterizations

6211
05:19:08,200 --> 05:19:11,080
and, you know,
focusing on detection,

6212
05:19:11,080 --> 05:19:14,640
you know, of the COVID-19
exposures in patients

6213
05:19:14,640 --> 05:19:16,240
not only with severe diseases

6214
05:19:16,240 --> 05:19:19,040
but obviously those who
experienced even mild infections

6215
05:19:19,040 --> 05:19:22,200
or perhaps asymptomatic
is needed

6216
05:19:22,200 --> 05:19:24,760
and how to translate
these concepts

6217
05:19:24,760 --> 05:19:27,360
into future clinical trials

6218
05:19:27,360 --> 05:19:30,480
is something that we're going
to have focus on,

6219
05:19:30,480 --> 05:19:33,080
you know, for the duration
of the, you know,

6220
05:19:33,080 --> 05:19:35,640
of the next study period
so to speak for this group.

6221
05:19:35,640 --> 05:19:37,760
So I'm going to end here,

6222
05:19:37,760 --> 05:19:43,200
and I will offer everybody
a forum for the,

6223
05:19:43,200 --> 05:19:47,160
for the comments both on
the general comments that I made

6224
05:19:47,160 --> 05:19:51,400
but also anything else
in the context of the summit

6225
05:19:51,400 --> 05:19:54,640
that you can offer.
And Hector, I see you --

6226
05:19:54,640 --> 05:19:56,240
-Well I think
there was a question

6227
05:19:56,240 --> 05:19:59,840
that was being asked
of Dr. Carlson

6228
05:19:59,840 --> 05:20:01,880
when the transition
between you and me occurred.

6229
05:20:01,880 --> 05:20:03,600
Is that right?

6230
05:20:03,600 --> 05:20:05,240
-I just wanted,
this is Cindy Carlsson,

6231
05:20:05,240 --> 05:20:08,400
so I just want to address
Kathy Service thank you

6232
05:20:08,400 --> 05:20:11,400
for your comments
about thinking about people

6233
05:20:11,400 --> 05:20:13,120
with neurotypical symptoms

6234
05:20:13,120 --> 05:20:18,000
and people who have intellectual
disability and Down syndrome.

6235
05:20:18,000 --> 05:20:20,200
Because again,
I think your comment

6236
05:20:20,200 --> 05:20:21,720
that we need
to better understand

6237
05:20:21,720 --> 05:20:23,400
what their baseline is.

6238
05:20:23,400 --> 05:20:25,960
Make sure we're doing a good job
of including them in studies

6239
05:20:25,960 --> 05:20:29,800
but also making sure
that we are training clinicians

6240
05:20:29,800 --> 05:20:31,600
to really get a good sense
of people's baseline.

6241
05:20:31,600 --> 05:20:34,000
So that's an extremely
important point.

6242
05:20:34,000 --> 05:20:36,800
I want to apply the work
of national task group

6243
05:20:36,800 --> 05:20:39,480
that's been working so hard
in developing toolkits

6244
05:20:39,480 --> 05:20:41,640
for people to help
with this training.

6245
05:20:41,640 --> 05:20:45,240
And we had addressed
this at the last NAPA meeting

6246
05:20:45,240 --> 05:20:46,760
because it's such
an important issue.

6247
05:20:46,760 --> 05:20:48,400
So thank you
for brining that up.

6248
05:20:48,400 --> 05:20:51,080
I think that'll have
a lot of implications

6249
05:20:51,080 --> 05:20:54,400
for the early detection group

6250
05:20:54,400 --> 05:20:57,000
so that we can make we get
a good baseline on people

6251
05:20:57,000 --> 05:20:58,880
whether it be different
educational backgrounds,

6252
05:20:58,880 --> 05:21:00,600
neurotypical symptoms,
et cetera.

6253
05:21:00,600 --> 05:21:02,200
So thank you for bringing
that comment up

6254
05:21:02,200 --> 05:21:04,520
and for your work
with the group.

6255
05:21:04,520 --> 05:21:06,520
-Sorry, Natalia,
please carry on.

6256
05:21:06,520 --> 05:21:08,400
-No worries.
Thank you, Dr. Carlsson.

6257
05:21:08,400 --> 05:21:10,120
Apologies, I jumped
right in the middle

6258
05:21:10,120 --> 05:21:14,200
of your initial discussion.
Hector, you had your hand up.

6259
05:21:14,200 --> 05:21:15,760
-Yeah, thank you, Natalia.

6260
05:21:15,760 --> 05:21:18,480
And I want to share
your thanks to the organizers

6261
05:21:18,480 --> 05:21:22,040
for doing a splendid job on
bringing us all together here.

6262
05:21:22,040 --> 05:21:26,400
Thank you very much on behalf
of the health equities panel.

6263
05:21:26,400 --> 05:21:28,320
Just a quick comment.

6264
05:21:28,320 --> 05:21:31,960
Something that I observed
from the 2016 to the 2019

6265
05:21:31,960 --> 05:21:36,000
to the now 2022 ADRD summits

6266
05:21:36,000 --> 05:21:40,400
is just this elevation
if you will,

6267
05:21:40,400 --> 05:21:45,280
the recognition of the
importance of inclusive research

6268
05:21:45,280 --> 05:21:48,320
in Alzheimer's disease
and related dementias

6269
05:21:48,320 --> 05:21:51,240
that what I heard over
the last couple of days

6270
05:21:51,240 --> 05:21:56,880
was that health equity
was mentioned and acknowledged.

6271
05:21:56,880 --> 05:22:01,520
And the LTN to each of
the different panels

6272
05:22:01,520 --> 05:22:03,760
and to my fellow panelists
I want to say

6273
05:22:03,760 --> 05:22:07,720
thank you for this recognition
and also to NINDS

6274
05:22:07,720 --> 05:22:13,320
for elevating the importance
of an inclusive research field

6275
05:22:13,320 --> 05:22:15,800
of Alzheimer's disease
and related dementias.

6276
05:22:15,800 --> 05:22:17,960
Thanks again.

6277
05:22:17,960 --> 05:22:19,920
-You're exactly right, Hector.

6278
05:22:19,920 --> 05:22:22,760
And thank you
and Dr. Zissimopoulos

6279
05:22:22,760 --> 05:22:26,320
for leading the effort
with your working group.

6280
05:22:26,320 --> 05:22:29,880
I believe next comment
is by Elaine Swift.

6281
05:22:29,880 --> 05:22:31,320
-Yes, thank you.

6282
05:22:31,320 --> 05:22:34,280
And I wanted to echo
Dr. Gonzalez's comments

6283
05:22:34,280 --> 05:22:37,760
on just the importance of equity
and how gratifying it

6284
05:22:37,760 --> 05:22:43,160
is to see it front and center
at this terrific conference.

6285
05:22:43,160 --> 05:22:45,760
I was also happy
to see the recognition,

6286
05:22:45,760 --> 05:22:50,040
especially in recommendation
eight on the importance of data

6287
05:22:50,040 --> 05:22:54,920
infrastructure to research these
very complicated conditions

6288
05:22:54,920 --> 05:22:57,200
over long periods of time

6289
05:22:57,200 --> 05:23:00,240
and to do it in a way
that advances equity.

6290
05:23:00,240 --> 05:23:03,280
And I certainly, you know,
in that regard,

6291
05:23:03,280 --> 05:23:07,520
of casting a broad net
over the data infrastructure,

6292
05:23:07,520 --> 05:23:09,520
I'd like to underscore
the importance

6293
05:23:09,520 --> 05:23:12,600
of the HR data
infrastructure.

6294
05:23:12,600 --> 05:23:16,360
And this will require attention
to building a far more robust

6295
05:23:16,360 --> 05:23:19,880
and interoperable data
infrastructure as, for example,

6296
05:23:19,880 --> 05:23:22,960
is being done
in NDS's long-running work

6297
05:23:22,960 --> 05:23:25,080
on comma data elements.

6298
05:23:25,080 --> 05:23:26,960
But I'd also like
to call attention

6299
05:23:26,960 --> 05:23:30,520
to the M-code initiative
for EHR data

6300
05:23:30,520 --> 05:23:35,400
that is working to
standardize data on oncology,

6301
05:23:35,400 --> 05:23:37,280
to diversify clinical trials,

6302
05:23:37,280 --> 05:23:43,000
to support precision medicine,
all of those good things.

6303
05:23:43,000 --> 05:23:46,080
And as it's being done
for cancer,

6304
05:23:46,080 --> 05:23:51,080
it could also be done
for AD/ADRD.

6305
05:23:51,080 --> 05:23:55,480
Constance Lyketsos,
Howard Fillit, Diane Bovenkamp,

6306
05:23:55,480 --> 05:23:59,800
Ian Kramer
and MITRE researchers.

6307
05:23:59,800 --> 05:24:02,080
I'm Elaine Swift.
I'm from MITRE.

6308
05:24:02,080 --> 05:24:05,000
We have an article
coming out on NJ pad,

6309
05:24:05,000 --> 05:24:10,160
on how we could leverage
and an M-code approach for ADRD.

6310
05:24:10,160 --> 05:24:15,120
And by casting a broad net
for EHR data.

6311
05:24:15,120 --> 05:24:20,880
It's, of course, an extremely
important way to diversify

6312
05:24:20,880 --> 05:24:24,800
the patients who are
involved in research

6313
05:24:24,800 --> 05:24:27,400
or prevention or treatment,

6314
05:24:27,400 --> 05:24:30,800
who are surveilled
when new treatments come out.

6315
05:24:30,800 --> 05:24:33,480
Just a key approach that
I'd like to call attention to.

6316
05:24:33,480 --> 05:24:35,080
Thank you.

6317
05:24:38,080 --> 05:24:40,920
-Thank you very much.
Thank you, Elaine.

6318
05:24:40,920 --> 05:24:42,680
Next --

6319
05:24:42,680 --> 05:24:45,080
-I'll just comment,
thank you, Elaine.

6320
05:24:45,080 --> 05:24:46,840
I'll bring this back
to the MED committee

6321
05:24:46,840 --> 05:24:48,480
so we can think about
how to incorporate

6322
05:24:48,480 --> 05:24:50,760
that into our
harmonization recommendation.

6323
05:24:50,760 --> 05:24:52,080
Thank you for that point.

6324
05:24:52,080 --> 05:24:53,320
-Thank you.

6325
05:24:53,320 --> 05:24:54,640
-And Elaine, I think
your paper

6326
05:24:54,640 --> 05:24:56,000
just came out
the other day actually.

6327
05:24:56,000 --> 05:24:59,000
I was just reading it.

6328
05:24:59,000 --> 05:25:02,360
-I, I actually,
it's not quite out yet.

6329
05:25:02,360 --> 05:25:05,000
It's, but it should be shortly.
-Okay.

6330
05:25:05,000 --> 05:25:07,840
-You might have seen a copy
from a colleague, though.

6331
05:25:07,840 --> 05:25:10,640
Thank you.

6332
05:25:10,640 --> 05:25:12,200
-Thank you for your comment.

6333
05:25:12,200 --> 05:25:18,680
I think next question in Q
and A is Nancy Smith.

6334
05:25:18,680 --> 05:25:20,040
-Thank you very much.

6335
05:25:20,040 --> 05:25:21,760
This has really been
an exceptional two days.

6336
05:25:21,760 --> 05:25:24,400
I can only call it
scientific speed dating.

6337
05:25:24,400 --> 05:25:25,800
It's just been great.

6338
05:25:25,800 --> 05:25:29,320
My comment is relative
to the health equity

6339
05:25:29,320 --> 05:25:30,760
recommendation number one,

6340
05:25:30,760 --> 05:25:34,400
and it comes from
a study-specific perspective.

6341
05:25:34,400 --> 05:25:36,520
As many of you may be aware,
NIA has funded

6342
05:25:36,520 --> 05:25:39,000
two rounds
of our 24 projects

6343
05:25:39,000 --> 05:25:41,000
focused on examining
different approaches

6344
05:25:41,000 --> 05:25:44,800
to diversity recruitment
and retention and aging,

6345
05:25:44,800 --> 05:25:48,400
some 20 in total
over the past three, four years.

6346
05:25:48,400 --> 05:25:51,600
I've been involved in one,
involved in Mount Sinai

6347
05:25:51,600 --> 05:25:53,800
and SUNY
Upstate Medical University

6348
05:25:53,800 --> 05:25:57,560
focused on cognitive research
in African Americans.

6349
05:25:57,560 --> 05:25:59,640
And despite,
we have annual meetings,

6350
05:25:59,640 --> 05:26:01,200
of course, of all those
that are funded.

6351
05:26:01,200 --> 05:26:03,120
And despite the wide variety

6352
05:26:03,120 --> 05:26:06,280
and the focus
and approaches in populations,

6353
05:26:06,280 --> 05:26:10,520
there's three very key themes
from the institutional level

6354
05:26:10,520 --> 05:26:12,000
that have come up.

6355
05:26:12,000 --> 05:26:15,200
And one is it takes time
to build

6356
05:26:15,200 --> 05:26:18,200
and gain the community trust
to even begin to think

6357
05:26:18,200 --> 05:26:21,720
about diversifying participation
and research.

6358
05:26:21,720 --> 05:26:24,360
But equally important,
it requires changes

6359
05:26:24,360 --> 05:26:26,800
to the research designs
and recruitment methods

6360
05:26:26,800 --> 05:26:30,360
that traditionally are either
excluded or discouraged

6361
05:26:30,360 --> 05:26:32,400
or just don't address
the interest

6362
05:26:32,400 --> 05:26:35,040
in the situations
of diverse populations.

6363
05:26:35,040 --> 05:26:37,480
And that both of these
require changes

6364
05:26:37,480 --> 05:26:40,360
in the research infrastructure
at the study level

6365
05:26:40,360 --> 05:26:41,960
and the institutional level.

6366
05:26:41,960 --> 05:26:44,680
And that takes time,
requires more resources,

6367
05:26:44,680 --> 05:26:46,240
and it has financial
implications.

6368
05:26:46,240 --> 05:26:50,000
So my comment is that
I definitely support the concept

6369
05:26:50,000 --> 05:26:53,960
of establishing recruitment
and retention centers.

6370
05:26:53,960 --> 05:26:56,800
But I hope also
that we can talk about

6371
05:26:56,800 --> 05:26:59,960
how NIH funding
has got to be acknowledged.

6372
05:26:59,960 --> 05:27:02,480
That to do this work
really right,

6373
05:27:02,480 --> 05:27:04,000
it's going to take more time,

6374
05:27:04,000 --> 05:27:07,920
more resources and more finances
at the study level.

6375
05:27:07,920 --> 05:27:10,200
And that's my comment.

6376
05:27:10,200 --> 05:27:11,440
-Thank you, Nancy.

6377
05:27:11,440 --> 05:27:15,720
Does anybody want
to provide feedback?

6378
05:27:18,360 --> 05:27:20,280
-Nancy, I'll take a shot.

6379
05:27:20,280 --> 05:27:22,000
Thank you very much
for your comments,

6380
05:27:22,000 --> 05:27:25,360
and I appreciate
what you're saying,

6381
05:27:25,360 --> 05:27:27,800
and the nuances
of what your --

6382
05:27:27,800 --> 05:27:29,440
implications
of what you're saying

6383
05:27:29,440 --> 05:27:31,360
is that it's going to take time.

6384
05:27:31,360 --> 05:27:34,000
It's going to take
some infrastructure-building,

6385
05:27:34,000 --> 05:27:39,120
and I think what I see is,
over the last two decades

6386
05:27:39,120 --> 05:27:44,680
I've been doing this work,
is just how, I guess,

6387
05:27:44,680 --> 05:27:49,920
far behind we are in working
with diverse communities,

6388
05:27:49,920 --> 05:27:53,080
and the need to really build
it out from the ground up.

6389
05:27:53,080 --> 05:27:57,160
There is some existing
material infrastructure,

6390
05:27:57,160 --> 05:28:00,080
but you're absolutely right.
Your point's well-taken,

6391
05:28:00,080 --> 05:28:02,720
and thank you very much
for your comment.

6392
05:28:02,720 --> 05:28:04,080
-Susan Dickinson?

6393
05:28:04,080 --> 05:28:05,320
-Thanks, Dr. Rost.

6394
05:28:05,320 --> 05:28:07,520
I appreciate it.
You can hear me okay?

6395
05:28:07,520 --> 05:28:09,200
-Yes.

6396
05:28:09,200 --> 05:28:12,400
-Great. I want to thank you
and all the subcommittee chairs.

6397
05:28:12,400 --> 05:28:15,400
It has been so energizing to see
how much progress we've made

6398
05:28:15,400 --> 05:28:18,120
since we last convened
three years ago,

6399
05:28:18,120 --> 05:28:21,800
and I applaud everybody in
setting such an ambitious path

6400
05:28:21,800 --> 05:28:23,920
for the next three years.

6401
05:28:23,920 --> 05:28:26,240
I did also want
to thank Dr. Carlson

6402
05:28:26,240 --> 05:28:28,120
and other members
of the NAPA Council,

6403
05:28:28,120 --> 05:28:32,600
who meet year-round, and do
so much to provide leadership

6404
05:28:32,600 --> 05:28:34,800
to the whole initiative
nationally,

6405
05:28:34,800 --> 05:28:38,440
and to make sure that we're
ensuring we meet the milestones

6406
05:28:38,440 --> 05:28:42,120
that we set each year
at these different summits.

6407
05:28:42,120 --> 05:28:47,080
I want to make just one comment,
and ask a question, if I may.

6408
05:28:47,080 --> 05:28:50,480
During this morning's multiple
etiology dementia session,

6409
05:28:50,480 --> 05:28:54,200
we heard Ian Kremmer weigh in
with the importance

6410
05:28:54,200 --> 05:28:57,440
of making sure that diagnosis
becomes more accurate,

6411
05:28:57,440 --> 05:29:01,120
more timely, more compassionate,
and more actionable.

6412
05:29:01,120 --> 05:29:03,200
And I just wanted
to make a comment on that --

6413
05:29:03,200 --> 05:29:06,160
the point of compassion.

6414
05:29:06,160 --> 05:29:07,960
And the other thing I'd say
is this relates

6415
05:29:07,960 --> 05:29:10,680
to a lot of the points
that you included,

6416
05:29:10,680 --> 05:29:13,480
Dr. Rost, in your summary,
which is how many times

6417
05:29:13,480 --> 05:29:16,200
the importance of having clarity
in communication

6418
05:29:16,200 --> 05:29:18,720
has come through
in each of these sessions.

6419
05:29:18,720 --> 05:29:21,480
One of the results
of the last summit in 2019

6420
05:29:21,480 --> 05:29:24,600
was the dementia
nomenclature initiative,

6421
05:29:24,600 --> 05:29:27,360
which both Ron Peterson
and Angela Taylor

6422
05:29:27,360 --> 05:29:29,960
mentioned yesterday.

6423
05:29:29,960 --> 05:29:32,600
Over the past three years,
they've led groups,

6424
05:29:32,600 --> 05:29:34,720
including scientists,
and clinicians,

6425
05:29:34,720 --> 05:29:36,480
and public stakeholders,

6426
05:29:36,480 --> 05:29:40,000
to really look at how we are --
the nomenclature we use,

6427
05:29:40,000 --> 05:29:41,920
the whole communication
framework we use

6428
05:29:41,920 --> 05:29:44,120
in talking
about these diseases

6429
05:29:44,120 --> 05:29:47,040
can be more accurate,
can be more clear.

6430
05:29:47,040 --> 05:29:49,480
Which I would argue
equals more compassionate,

6431
05:29:49,480 --> 05:29:54,960
when the end result, you know,
happens in the exam room,

6432
05:29:54,960 --> 05:29:57,080
where some --
a family's getting a diagnosis,

6433
05:29:57,080 --> 05:29:58,960
or the family has
to then go home,

6434
05:29:58,960 --> 05:30:00,800
and then figure out
what it means,

6435
05:30:00,800 --> 05:30:03,600
and how they're going
to cope with it.

6436
05:30:03,600 --> 05:30:07,720
And I just wanted to put a plug
for how important

6437
05:30:07,720 --> 05:30:10,920
this new communication framework
they are suggesting is,

6438
05:30:10,920 --> 05:30:13,560
and to encourage everybody
to become familiar with it,

6439
05:30:13,560 --> 05:30:16,400
and do whatever you can
to help the initiative advance.

6440
05:30:16,400 --> 05:30:18,400
I think we're all
in this business

6441
05:30:18,400 --> 05:30:20,600
to help people
on this journey,

6442
05:30:20,600 --> 05:30:24,120
until we have a cure
or some kind of prevention.

6443
05:30:24,120 --> 05:30:26,080
I think the best
we can hope to do

6444
05:30:26,080 --> 05:30:28,840
while we advance
the science is

6445
05:30:28,840 --> 05:30:31,320
to help people maintain
their quality of life,

6446
05:30:31,320 --> 05:30:36,000
and have as easy a journey
on the path as they can.

6447
05:30:36,000 --> 05:30:40,000
And my question
relates to the fact

6448
05:30:40,000 --> 05:30:46,200
that I've been part of all of
these summits since 2013,

6449
05:30:46,200 --> 05:30:50,400
and we get more ambitious
every year, which is wonderful.

6450
05:30:50,400 --> 05:30:54,440
But we've expanded from
five sessions to eight by now,

6451
05:30:54,440 --> 05:30:58,120
and I was wondering
if somebody can just speak

6452
05:30:58,120 --> 05:31:02,560
to how we're going to ensure

6453
05:31:02,560 --> 05:31:06,360
that there are robust resources
dedicated to --

6454
05:31:06,360 --> 05:31:08,600
that are going to enable us
to meet the milestones

6455
05:31:08,600 --> 05:31:12,800
for all eight of these sets
of wonderful recommendations?

6456
05:31:12,800 --> 05:31:15,600
I think they're all important.
I think they're all ambitious,

6457
05:31:15,600 --> 05:31:20,280
and I think they all deserve
to be invested in,

6458
05:31:20,280 --> 05:31:24,120
but we all know, you know,
there are limited resources.

6459
05:31:24,120 --> 05:31:26,840
So I don't know who might
be able to speak to that.

6460
05:31:30,840 --> 05:31:33,000
-Well, I'll reach out
to the panelists.

6461
05:31:33,000 --> 05:31:35,280
Rod, do you want
to speak to that?

6462
05:31:35,280 --> 05:31:39,240
-I think Walter unmuted.

6463
05:31:39,240 --> 05:31:45,040
-Yeah, Susan, I think you
point to the bigger picture,

6464
05:31:45,040 --> 05:31:51,880
which is, as you really look
at these issues in total,

6465
05:31:51,880 --> 05:31:57,120
it's -- you're looking at
an entire ocean of problems.

6466
05:31:57,120 --> 05:32:08,200
So I think the strategy is
to not leave a stone unturned,

6467
05:32:08,200 --> 05:32:16,000
but focus on what looks like
it's going to move most quickly

6468
05:32:16,000 --> 05:32:18,440
to a solution
that's going to help people.

6469
05:32:18,440 --> 05:32:20,600
I think it's that balance.

6470
05:32:20,600 --> 05:32:27,400
I think, you know, if it hadn't
been for the increased funding

6471
05:32:27,400 --> 05:32:30,920
that's come from Congress,
it would just be --

6472
05:32:30,920 --> 05:32:32,600
it would be very depressing

6473
05:32:32,600 --> 05:32:34,640
to have these kind of
conversations.

6474
05:32:34,640 --> 05:32:38,400
But I'm very optimistic
that the funding

6475
05:32:38,400 --> 05:32:40,160
is really quite good now,

6476
05:32:40,160 --> 05:32:45,800
and that there's actually
another increase in this budget.

6477
05:32:45,800 --> 05:32:48,320
So I think our real bottleneck

6478
05:32:48,320 --> 05:32:52,040
is actually building
the workforce,

6479
05:32:52,040 --> 05:32:55,080
and --
but the good news there is,

6480
05:32:55,080 --> 05:33:00,800
the funding is permanent
going forward, on the base of --

6481
05:33:00,800 --> 05:33:08,320
and we manage about 10%
of that funding for the ADRDs.

6482
05:33:08,320 --> 05:33:11,600
But as --
because it is permanent,

6483
05:33:11,600 --> 05:33:16,080
I think that gives us
the opportunity to look --

6484
05:33:16,080 --> 05:33:19,560
not just be disappointed
at how big the problems are,

6485
05:33:19,560 --> 05:33:23,680
but to realize that we can
actually -- over time, work --

6486
05:33:23,680 --> 05:33:28,480
can take on a large number
of these problems.

6487
05:33:28,480 --> 05:33:31,600
So I'm pretty optimistic.

6488
05:33:31,600 --> 05:33:34,800
Compared to the other diseases
in my portfolio,

6489
05:33:34,800 --> 05:33:38,000
I'm much more optimistic here,

6490
05:33:38,000 --> 05:33:41,520
in terms of the resources.
I think we should all be.

6491
05:33:41,520 --> 05:33:46,200
I mean, we're in
a really good spot,

6492
05:33:46,200 --> 05:33:50,520
something really,
really impactful.

6493
05:33:50,520 --> 05:33:52,400
I think we're getting
really close.

6494
05:33:52,400 --> 05:33:56,840
So if we can cure one
by the next time we meet,

6495
05:33:56,840 --> 05:33:59,480
I'll be very happy,
but we got to get a cure.

6496
05:34:02,040 --> 05:34:05,400
-Thank you, Walter.
Tony, you had your hand up.

6497
05:34:05,400 --> 05:34:08,360
I'll let you speak right now.
Tony Antonucci?

6498
05:34:08,360 --> 05:34:10,200
-Thank you.

6499
05:34:10,200 --> 05:34:13,200
I'm a little --
this comment was --

6500
05:34:13,200 --> 05:34:16,320
back goes to something
we were discussing earlier.

6501
05:34:16,320 --> 05:34:20,200
I think -- but Walter mentioned
we really need the workforce,

6502
05:34:20,200 --> 05:34:22,880
so I think I'd like
to reiterate that.

6503
05:34:22,880 --> 05:34:24,600
In our comments,
the first group,

6504
05:34:24,600 --> 05:34:28,680
we talked about training
for a diverse workforce.

6505
05:34:28,680 --> 05:34:33,520
That's critical, but it's not
unrelated to the issue

6506
05:34:33,520 --> 05:34:39,040
of engaging a population willing
to participate in research.

6507
05:34:39,040 --> 05:34:41,520
And that's not secondary.

6508
05:34:41,520 --> 05:34:46,320
That's very primary, and it
takes a lot of investment.

6509
05:34:46,320 --> 05:34:50,200
In a couple of other areas
that I work in,

6510
05:34:50,200 --> 05:34:53,800
we have years of investment
in the community,

6511
05:34:53,800 --> 05:34:55,600
working with community members,

6512
05:34:55,600 --> 05:35:01,000
working with community advisory
boards to build up trust.

6513
05:35:01,000 --> 05:35:03,040
I mean, there's really
no other way to put it,

6514
05:35:03,040 --> 05:35:04,800
and in this case,

6515
05:35:04,800 --> 05:35:10,120
we have the issue
of ethnic minority distrust,

6516
05:35:10,120 --> 05:35:13,520
which, unfortunately,
is well-earned.

6517
05:35:13,520 --> 05:35:16,200
And secondly, we have
the whole stigma attached

6518
05:35:16,200 --> 05:35:19,200
to this kind
of an illness, ADRD.

6519
05:35:19,200 --> 05:35:22,000
People don't want to admit it
under any circumstances,

6520
05:35:22,000 --> 05:35:24,040
but especially
under circumstances

6521
05:35:24,040 --> 05:35:25,480
where they don't trust

6522
05:35:25,480 --> 05:35:26,920
the people talking
to them about it,

6523
05:35:26,920 --> 05:35:28,600
or inviting them
to participate.

6524
05:35:28,600 --> 05:35:33,400
So I think a real concerted
effort needs to be invested,

6525
05:35:33,400 --> 05:35:37,120
both in the workforce and in
developing a relationship

6526
05:35:37,120 --> 05:35:40,280
with the community
that we want to work with,

6527
05:35:40,280 --> 05:35:42,200
and in finding a way
to give back.

6528
05:35:42,200 --> 05:35:44,600
Because we can't
just helicopter in,

6529
05:35:44,600 --> 05:35:48,200
do our study,
and helicopter out.

6530
05:35:48,200 --> 05:35:50,800
That's all I wanted to say.

6531
05:35:50,800 --> 05:35:52,080
-Good point.

6532
05:35:52,080 --> 05:35:54,200
Anybody wants
to further comment,

6533
05:35:54,200 --> 05:36:01,880
or provide anything back?
I think everybody agrees, Tony.

6534
05:36:01,880 --> 05:36:04,280
I think that's
the consensus here.

6535
05:36:04,280 --> 05:36:06,760
I'd like to try to --
-It takes time and money.

6536
05:36:06,760 --> 05:36:09,480
I mean, you can't just
do it with one shot.

6537
05:36:09,480 --> 05:36:12,200
I mean, there's one group I work
with that's had 20 years

6538
05:36:12,200 --> 05:36:14,200
of developing relationship
with the community,

6539
05:36:14,200 --> 05:36:16,560
another group that's
going on four or five.

6540
05:36:16,560 --> 05:36:17,880
And it's still slow going.

6541
05:36:17,880 --> 05:36:22,720
So I think we,
as researchers and NIH

6542
05:36:22,720 --> 05:36:24,600
as funders need to recognize

6543
05:36:24,600 --> 05:36:27,920
just how long-term
a commitment this must be.

6544
05:36:27,920 --> 05:36:29,280
Sorry.

6545
05:36:29,280 --> 05:36:30,920
-Cindy, do you want
to comment on that?

6546
05:36:30,920 --> 05:36:33,800
-Yes, just that, again,
I support what Tony's saying.

6547
05:36:33,800 --> 05:36:37,320
I think that, from what we're
hearing from our black leaders

6548
05:36:37,320 --> 05:36:39,040
for brain health,
and here in Madison,

6549
05:36:39,040 --> 05:36:41,080
Wisconsin is that
they are saying

6550
05:36:41,080 --> 05:36:42,960
we need to have
investigators of color

6551
05:36:42,960 --> 05:36:44,720
who are out there
doing the work,

6552
05:36:44,720 --> 05:36:47,520
and that's going to bring
people into the studies,

6553
05:36:47,520 --> 05:36:49,080
and have diverse
representation.

6554
05:36:49,080 --> 05:36:51,600
So, again, that -- just that
emphasis that has to be,

6555
05:36:51,600 --> 05:36:54,000
first and foremost,
a training that has mentioned,

6556
05:36:54,000 --> 05:36:56,040
so that we can get
that diverse workforce,

6557
05:36:56,040 --> 05:36:59,360
and then the representation
in studies will follow.

6558
05:36:59,360 --> 05:37:01,440
Thank you.

6559
05:37:01,440 --> 05:37:04,040
-And, Ron, were you
following on that same?

6560
05:37:04,040 --> 05:37:07,880
-Just a comment, thank Susan
for mentioning

6561
05:37:07,880 --> 05:37:10,040
the nomenclature initiative.

6562
05:37:10,040 --> 05:37:12,680
And that's one of the goals
of the nomenclature initiative,

6563
05:37:12,680 --> 05:37:15,160
to bring some consistency
of language

6564
05:37:15,160 --> 05:37:18,000
across different stakeholders,
from the public,

6565
05:37:18,000 --> 05:37:20,040
to the clinicians,
to the scientists,

6566
05:37:20,040 --> 05:37:22,560
and in particular
with regard to diversity.

6567
05:37:22,560 --> 05:37:24,080
I think we're
getting feedback

6568
05:37:24,080 --> 05:37:26,000
from a lot of the
underrepresented groups

6569
05:37:26,000 --> 05:37:30,320
that the language, the words
are getting in the way

6570
05:37:30,320 --> 05:37:33,560
with regard to understanding
their particular condition

6571
05:37:33,560 --> 05:37:35,320
and participation
in research.

6572
05:37:35,320 --> 05:37:38,880
So I think that the framework
that has been developed

6573
05:37:38,880 --> 05:37:42,320
in phase one of
the nomenclature initiative

6574
05:37:42,320 --> 05:37:44,000
will help in that direction,

6575
05:37:44,000 --> 05:37:48,480
and now we have to move it out
into a general acceptance,

6576
05:37:48,480 --> 05:37:50,200
in terms of utilization.

6577
05:37:50,200 --> 05:37:54,240
So we'll be presenting to Cindy
and the advisory council

6578
05:37:54,240 --> 05:37:58,040
on the first of May
with our findings.

6579
05:38:00,200 --> 05:38:01,600
-Perfect, thank you.

6580
05:38:01,600 --> 05:38:04,680
I'm going to try to bring
back Ms. Carolyn Rogers,

6581
05:38:04,680 --> 05:38:06,800
who's been trying to talk
to us for a while.

6582
05:38:06,800 --> 05:38:11,400
Michelle, do we have
Carolyn with us?

6583
05:38:11,400 --> 05:38:16,600
-We did. I think
she actually has departed.

6584
05:38:16,600 --> 05:38:19,400
-Well, I'm really sorry
to hear that.

6585
05:38:19,400 --> 05:38:23,760
She's been trying to make
a point with regard to,

6586
05:38:23,760 --> 05:38:26,800
you know, root causes
of mixed dementia pathology,

6587
05:38:26,800 --> 05:38:28,240
and I think that
she made a comment

6588
05:38:28,240 --> 05:38:31,000
in one of the either
MED sessions,

6589
05:38:31,000 --> 05:38:32,920
or late sessions,

6590
05:38:32,920 --> 05:38:36,360
and I think that
that's something

6591
05:38:36,360 --> 05:38:39,200
that we could not
get to that time.

6592
05:38:39,200 --> 05:38:43,560
And I'm really sorry she hasn't
had a chance to stay with us,

6593
05:38:43,560 --> 05:38:47,680
to answer.
But I think we all agree,

6594
05:38:47,680 --> 05:38:50,000
this is what this work
is all about.

6595
05:38:50,000 --> 05:38:54,400
Okay, I have Sonya Valab
next on the -- online.

6596
05:38:54,400 --> 05:38:55,960
-Hi.

6597
05:38:55,960 --> 05:38:59,840
Thank you so much for making
the time for me to speak.

6598
05:38:59,840 --> 05:39:02,280
So I'll quickly
introduce myself first.

6599
05:39:02,280 --> 05:39:03,920
So I'm Sonya Valab.

6600
05:39:03,920 --> 05:39:07,000
I run a prion lab at the Brode
Institute in Cambridge,

6601
05:39:07,000 --> 05:39:11,400
Massachusetts, where we work
on drug develop,

6602
05:39:11,400 --> 05:39:14,080
biomarker development,
natural history,

6603
05:39:14,080 --> 05:39:15,520
et cetera,
for prion disease,

6604
05:39:15,520 --> 05:39:18,600
which as you all know
is a rapidly-progressive,

6605
05:39:18,600 --> 05:39:21,880
currently untreatable
dementia.

6606
05:39:21,880 --> 05:39:24,800
I'm also at risk myself
for genetic prion disease,

6607
05:39:24,800 --> 05:39:27,800
so I inherited
a fatal mutation

6608
05:39:27,800 --> 05:39:29,520
in the prion protein gene
from my mom,

6609
05:39:29,520 --> 05:39:33,000
who died of genetic
prion disease in 2010.

6610
05:39:33,000 --> 05:39:35,720
So I've been on the patient side

6611
05:39:35,720 --> 05:39:38,600
and on the caregiver side
of this disease,

6612
05:39:38,600 --> 05:39:41,800
as well as having,
inspired by that experience

6613
05:39:41,800 --> 05:39:45,240
to get into the research side.

6614
05:39:45,240 --> 05:39:47,240
So all of that
is a preface to say

6615
05:39:47,240 --> 05:39:51,120
that I really just have a
targeted plea for the committee.

6616
05:39:51,120 --> 05:39:52,680
Thank you for
all of the great work

6617
05:39:52,680 --> 05:39:56,040
that you're doing on Alzheimer's
and related dementias,

6618
05:39:56,040 --> 05:39:58,240
and I just want to raise
for consideration

6619
05:39:58,240 --> 05:40:01,600
the possibility that
prion disease could be named

6620
05:40:01,600 --> 05:40:04,960
among the Alzheimer's
disease-related dementias.

6621
05:40:04,960 --> 05:40:07,400
I think, mechanistically,
we've seen over the past

6622
05:40:07,400 --> 05:40:09,480
few years
a real sort of dovetailing

6623
05:40:09,480 --> 05:40:12,600
of some of the insights
in the prion field

6624
05:40:12,600 --> 05:40:17,200
that have sort of come out
of propagated prion misfolding,

6625
05:40:17,200 --> 05:40:19,440
including diagnostic assays

6626
05:40:19,440 --> 05:40:22,960
that leverage the sort
of prion concept,

6627
05:40:22,960 --> 05:40:25,320
but now have been
applied more broadly

6628
05:40:25,320 --> 05:40:26,920
to other neurodegenerative
diseases,

6629
05:40:26,920 --> 05:40:30,920
in which we see templated
protein misfolding.

6630
05:40:30,920 --> 05:40:33,480
And on the flip side,
for example,

6631
05:40:33,480 --> 05:40:36,480
much of the biomarker work
and need for better biomarkers

6632
05:40:36,480 --> 05:40:39,280
that was discussed earlier
this afternoon

6633
05:40:39,280 --> 05:40:43,600
and in these past two days
certainly has enriched our work,

6634
05:40:43,600 --> 05:40:45,360
as we look for many of
the same biomarkers

6635
05:40:45,360 --> 05:40:47,400
in our natural history work.

6636
05:40:47,400 --> 05:40:51,760
On the theme of prevention
and pre-symptomatic vigilance,

6637
05:40:51,760 --> 05:40:55,080
this is an area where we
have really tried to advocate --

6638
05:40:55,080 --> 05:40:57,760
you know, myself
as a healthy carrier myself --

6639
05:40:57,760 --> 05:41:02,040
for novel biomarker-based
and genetically-informed

6640
05:41:02,040 --> 05:41:05,320
clinical trial models,
and I think there could be

6641
05:41:05,320 --> 05:41:07,800
shared learnings
across these diseases.

6642
05:41:07,800 --> 05:41:12,440
So with that, I'll just say
I think very much hearing

6643
05:41:12,440 --> 05:41:15,400
the themes
that have been touched on,

6644
05:41:15,400 --> 05:41:17,440
I think we feel a kinship
with this community,

6645
05:41:17,440 --> 05:41:19,600
and see a lot of
research questions, tools,

6646
05:41:19,600 --> 05:41:23,040
and needs that are shared
across these domains.

6647
05:41:23,040 --> 05:41:25,040
So I would love
for prion disease

6648
05:41:25,040 --> 05:41:28,520
to be considered
among the list of diseases.

6649
05:41:28,520 --> 05:41:30,640
Thanks so much.

6650
05:41:30,640 --> 05:41:32,320
-Thank you, Sonya.

6651
05:41:32,320 --> 05:41:35,920
-I wonder if Ryan wants
to go near this one.

6652
05:41:35,920 --> 05:41:40,600
We've discussed
this multiple times, Sonya,

6653
05:41:40,600 --> 05:41:43,800
and from what
we can figure out,

6654
05:41:43,800 --> 05:41:48,440
it would take somebody to go
to Congress to change it.

6655
05:41:48,440 --> 05:41:51,720
Now, it's not impossible,
so you should think about it,

6656
05:41:51,720 --> 05:41:55,040
but Congress, we understand,
made this determination,

6657
05:41:55,040 --> 05:41:59,560
and these are the ones --
these three are the only ones.

6658
05:41:59,560 --> 05:42:04,080
Everything else has got
to be somehow related.

6659
05:42:04,080 --> 05:42:07,040
Ron, is that --

6660
05:42:07,040 --> 05:42:10,240
-Yeah, thanks for throwing
the ball to me, Walter.

6661
05:42:10,240 --> 05:42:12,200
-Oh, I'm sorry.
You don't have to --

6662
05:42:12,200 --> 05:42:13,720
-No --

6663
05:42:13,720 --> 05:42:17,360
-I have other dementing diseases
in our portfolio,

6664
05:42:17,360 --> 05:42:21,760
like Huntington's for instance,
and it's not allowed.

6665
05:42:21,760 --> 05:42:24,880
-No, we've had extensive
discussions about this,

6666
05:42:24,880 --> 05:42:27,840
going back to day one of
the NAPA Advisory Council,

6667
05:42:27,840 --> 05:42:29,360
as to what's in and out.

6668
05:42:29,360 --> 05:42:32,560
And to be honest,
in fairness to Congress,

6669
05:42:32,560 --> 05:42:35,720
if I may, I think
they were just talking

6670
05:42:35,720 --> 05:42:37,360
about Alzheimer's disease,

6671
05:42:37,360 --> 05:42:41,960
and then in the --
in writing the legislation,

6672
05:42:41,960 --> 05:42:45,440
said, well, don't we mean other
dementing disorders as well?

6673
05:42:45,440 --> 05:42:46,960
Yeah, of course we do.

6674
05:42:46,960 --> 05:42:49,600
And then they listed
the common ones.

6675
05:42:49,600 --> 05:42:52,320
You know, I think
that's really what happened.

6676
05:42:52,320 --> 05:42:53,880
You know, the legislation,

6677
05:42:53,880 --> 05:42:56,600
if it's going
to be reauthorized,

6678
05:42:56,600 --> 05:43:00,200
will happen not tomorrow,
but in 2025,

6679
05:43:00,200 --> 05:43:02,200
and certainly all of
these considerations

6680
05:43:02,200 --> 05:43:03,760
need to be included.

6681
05:43:03,760 --> 05:43:07,600
But we need to get
on prion disorders before 2025,

6682
05:43:07,600 --> 05:43:12,280
so I understand
your urgency, Sonya.

6683
05:43:12,280 --> 05:43:15,040
-Thank you, and Ron,
if you want to address this.

6684
05:43:15,040 --> 05:43:17,800
-Yeah, that's --
thank you for your input, Sonya,

6685
05:43:17,800 --> 05:43:20,360
and I wanted to add --

6686
05:43:20,360 --> 05:43:24,760
to mention that
while prion diseases

6687
05:43:24,760 --> 05:43:27,000
aren't right now official AD,

6688
05:43:27,000 --> 05:43:30,160
ADRD disorders
under the national plan,

6689
05:43:30,160 --> 05:43:33,600
the National Institute of Health
does recognize the relevance,

6690
05:43:33,600 --> 05:43:38,800
inasmuch as when there are
prion research is proposed,

6691
05:43:38,800 --> 05:43:42,000
and it's also very relevant
for Alzheimer's disease

6692
05:43:42,000 --> 05:43:45,200
and Alzheimer's disease-related
dementias research,

6693
05:43:45,200 --> 05:43:47,640
that also gets
special consideration.

6694
05:43:47,640 --> 05:43:50,000
So acknowledging that
it's not explicitly named,

6695
05:43:50,000 --> 05:43:54,400
I also want to assure you that
the relevance is not lost to us,

6696
05:43:54,400 --> 05:43:56,680
and that we definitely --

6697
05:43:58,680 --> 05:44:00,440
that type of research
is included

6698
05:44:00,440 --> 05:44:03,840
under the special pay lines
when it's relevant to AD, ADRD.

6699
05:44:03,840 --> 05:44:05,320
Thank you.

6700
05:44:05,320 --> 05:44:08,000
-Thank you.
-And Cindy?

6701
05:44:08,000 --> 05:44:10,080
-And again, Sonya,
thank you for your comments.

6702
05:44:10,080 --> 05:44:13,720
I think another venue
would be for you to present

6703
05:44:13,720 --> 05:44:16,080
and make some public comments
also at the NAPA meeting.

6704
05:44:16,080 --> 05:44:18,600
So again, trying to bring that
to people's attention,

6705
05:44:18,600 --> 05:44:21,120
and I'll carry that
to the groups as well,

6706
05:44:21,120 --> 05:44:25,000
to think about these other,
less common,

6707
05:44:25,000 --> 05:44:28,480
but just as important,
diseases that maybe should work

6708
05:44:28,480 --> 05:44:29,920
their way
into the national plan.

6709
05:44:29,920 --> 05:44:31,400
Thank you.

6710
05:44:31,400 --> 05:44:32,640
-Thank you.

6711
05:44:32,640 --> 05:44:34,560
-Thank you,
and thank you, Sonya.

6712
05:44:34,560 --> 05:44:37,400
Thank you for your comments.
Our next question --

6713
05:44:37,400 --> 05:44:40,440
we are rapidly coming
to an end of an hour.

6714
05:44:40,440 --> 05:44:43,080
Penny, are you on?
Yes, fair.

6715
05:44:43,080 --> 05:44:45,320
-Thank you, Dr. Rost, yeah.

6716
05:44:45,320 --> 05:44:48,160
So my comment's
going to intersect a little bit

6717
05:44:48,160 --> 05:44:49,760
with the one
from Nancy Smith earlier,

6718
05:44:49,760 --> 05:44:51,360
so my apologies for that.

6719
05:44:51,360 --> 05:44:55,040
But it's for the health
equity committee to consider

6720
05:44:55,040 --> 05:44:59,160
that when we think
about the emerging trends

6721
05:44:59,160 --> 05:45:01,840
in research and policy,

6722
05:45:01,840 --> 05:45:04,480
I think we're all going
to be learning

6723
05:45:04,480 --> 05:45:05,840
how those trends
are going to be

6724
05:45:05,840 --> 05:45:07,680
affecting the comfort level
of participation

6725
05:45:07,680 --> 05:45:10,600
from people of distinct
socioeconomic, regional,

6726
05:45:10,600 --> 05:45:12,640
and ethnocultural backgrounds.

6727
05:45:12,640 --> 05:45:14,440
And I think a centralized group

6728
05:45:14,440 --> 05:45:16,640
that tries to help us
understand and anticipate

6729
05:45:16,640 --> 05:45:19,400
that could be really valuable
for all of us,

6730
05:45:19,400 --> 05:45:21,600
and I'm thinking about things
like open data

6731
05:45:21,600 --> 05:45:24,680
and open sharing,
open science,

6732
05:45:24,680 --> 05:45:26,800
knowing that
different groups of folks

6733
05:45:26,800 --> 05:45:28,200
have very different
trust levels

6734
05:45:28,200 --> 05:45:30,320
with what's going
to happen to their data,

6735
05:45:30,320 --> 05:45:32,400
and who's sharing it,
who's buying it,

6736
05:45:32,400 --> 05:45:36,640
who's selling it, as well as
on the digital biomarkers.

6737
05:45:36,640 --> 05:45:38,240
A lot of the individual sessions

6738
05:45:38,240 --> 05:45:42,000
talked about the importance
of digital biomarkers

6739
05:45:42,000 --> 05:45:45,000
and digital assessment tools
to transform clinical research.

6740
05:45:45,000 --> 05:45:46,320
Many of us are very hopeful

6741
05:45:46,320 --> 05:45:48,800
that it's going
to improve inclusivity

6742
05:45:48,800 --> 05:45:51,160
and improve power
for clinical research

6743
05:45:51,160 --> 05:45:52,760
by having more
frequent measurements

6744
05:45:52,760 --> 05:45:56,080
within people's homes of
individual measure of function.

6745
05:45:56,080 --> 05:45:59,640
But the comfort levels
of people from distinct cultures

6746
05:45:59,640 --> 05:46:03,080
with having those measurements
taken, where you have devices

6747
05:46:03,080 --> 05:46:05,920
monitoring their activity
at the home,

6748
05:46:05,920 --> 05:46:09,760
I think is something we haven't
fully understood yet.

6749
05:46:09,760 --> 05:46:11,760
And I think it's something
we're all going to be dealing

6750
05:46:11,760 --> 05:46:13,600
with separately
when the clinical trials

6751
05:46:13,600 --> 05:46:14,880
are active for FTD,

6752
05:46:14,880 --> 05:46:17,320
for Alzheimer's,
for vascular dementia.

6753
05:46:17,320 --> 05:46:18,920
I think we're all going
to be realizing

6754
05:46:18,920 --> 05:46:21,960
that the decisions we make
around research design,

6755
05:46:21,960 --> 05:46:24,280
and the policy,
and what happens to the data

6756
05:46:24,280 --> 05:46:27,240
is going to affect the
comfort level of participants.

6757
05:46:27,240 --> 05:46:30,720
So the more that we have
some centralized learnings

6758
05:46:30,720 --> 05:46:33,920
of community and cultural
differences, and comfort level,

6759
05:46:33,920 --> 05:46:36,240
and how our choices
will affect that,

6760
05:46:36,240 --> 05:46:39,000
the more I think all
of our fields can move forward

6761
05:46:39,000 --> 05:46:41,600
to really implement
the technology that we need.

6762
05:46:44,040 --> 05:46:45,160
-Great comment, Penny.

6763
05:46:45,160 --> 05:46:48,000
Anybody wants to provide
feedback,

6764
05:46:48,000 --> 05:46:50,360
particular from the health
equity group?

6765
05:46:56,080 --> 05:46:57,600
-Think it was
more of a statement,

6766
05:46:57,600 --> 05:46:59,320
rather than a question, Penny.

6767
05:46:59,320 --> 05:47:03,400
I think everybody's uniformly
supporting your standpoint here,

6768
05:47:03,400 --> 05:47:05,800
and I think it's duly noted.
Thank you.

6769
05:47:05,800 --> 05:47:08,200
Thank you for your input
throughout the entire summit,

6770
05:47:08,200 --> 05:47:11,440
actually.
It was very helpful.

6771
05:47:11,440 --> 05:47:15,360
Right, our last --
yeah, go ahead.

6772
05:47:15,360 --> 05:47:17,480
-Oh, sorry.

6773
05:47:17,480 --> 05:47:19,360
Ms. Dax,
thanks for your comments,

6774
05:47:19,360 --> 05:47:21,720
and I think I share
some of your concerns

6775
05:47:21,720 --> 05:47:27,800
about how some communities
may be a bit more concerned

6776
05:47:27,800 --> 05:47:32,160
about some of these
monitoring devices if you will.

6777
05:47:32,160 --> 05:47:35,960
And I think your comment
about a centralized

6778
05:47:35,960 --> 05:47:40,880
or some kind
of open-source availability

6779
05:47:40,880 --> 05:47:43,320
of best practices
recommendations,

6780
05:47:43,320 --> 05:47:48,200
if I'm hearing
what you've said correctly,

6781
05:47:48,200 --> 05:47:50,080
is a brilliant idea.

6782
05:47:50,080 --> 05:47:53,160
And I think that science
of inclusion

6783
05:47:53,160 --> 05:47:57,760
should take note
of what you just pointed out.

6784
05:47:57,760 --> 05:48:00,760
So, thank you.

6785
05:48:00,760 --> 05:48:02,440
-Thank you, hector.

6786
05:48:02,440 --> 05:48:07,000
And very appropriately,
we have our last panelist,

6787
05:48:07,000 --> 05:48:10,120
Mr. Dale Listina, to provide --
to ask his question,

6788
05:48:10,120 --> 05:48:14,280
or provide his final comments.
Dale, are you with us?

6789
05:48:14,280 --> 05:48:17,200
-Yes, I am.
Thank you, Natalia.

6790
05:48:17,200 --> 05:48:18,760
-Sure.

6791
05:48:18,760 --> 05:48:22,400
-Let me congratulate you
on the excellent summary of --

6792
05:48:22,400 --> 05:48:25,040
that you gave.
You have a gift,

6793
05:48:25,040 --> 05:48:30,000
to be able to listen
to all these presentations

6794
05:48:30,000 --> 05:48:32,960
and to summarize them
like you did.

6795
05:48:32,960 --> 05:48:37,360
Please accept
my congratulations.

6796
05:48:37,360 --> 05:48:41,320
I would like to speak
to the first session

6797
05:48:41,320 --> 05:48:43,240
of this morning, MED,

6798
05:48:43,240 --> 05:48:48,400
which Kate Poston
was the leader.

6799
05:48:48,400 --> 05:48:53,400
And commented about the video
that you opened up with,

6800
05:48:53,400 --> 05:48:55,760
and I will not go
over my comments.

6801
05:48:55,760 --> 05:48:59,760
I still stand by them,
but I have a post-script, Kate.

6802
05:48:59,760 --> 05:49:01,720
And that is that --

6803
05:49:04,440 --> 05:49:09,000
well, I talked about insight
here in northern Virginia,

6804
05:49:09,000 --> 05:49:11,800
and the things that they do.

6805
05:49:11,800 --> 05:49:13,800
I want to add another thing,
and that --

6806
05:49:13,800 --> 05:49:15,960
we're talking about
community involvement,

6807
05:49:15,960 --> 05:49:17,520
and community understanding.

6808
05:49:17,520 --> 05:49:22,680
They are experimenting
with enlightening

6809
05:49:22,680 --> 05:49:26,640
the community itself
about dementia,

6810
05:49:26,640 --> 05:49:29,520
and I have an example.
I took --

6811
05:49:29,520 --> 05:49:33,720
my wife used to go along
with me to the grocery store,

6812
05:49:33,720 --> 05:49:35,160
and in the process of doing it,

6813
05:49:35,160 --> 05:49:37,760
all of a sudden,
she didn't recognize me anymore,

6814
05:49:37,760 --> 05:49:42,200
and she thought I was somebody
trying to kidnap her.

6815
05:49:42,200 --> 05:49:44,400
And she let the folks
in the store

6816
05:49:44,400 --> 05:49:47,080
rather loudly know about that.

6817
05:49:47,080 --> 05:49:51,520
The manager of the store
knew that --

6818
05:49:51,520 --> 05:49:56,200
about this kind of thing,
although I didn't know him,

6819
05:49:56,200 --> 05:50:01,840
and separated us.
He had staff stay with my wife,

6820
05:50:01,840 --> 05:50:05,800
and it took about an hour,
hour and a half.

6821
05:50:05,800 --> 05:50:08,680
And things settled down,

6822
05:50:08,680 --> 05:50:14,520
and the understanding
of that manager and his staff --

6823
05:50:14,520 --> 05:50:18,240
it was no small store.
It was Wegman's.

6824
05:50:18,240 --> 05:50:20,800
You know, that's a pretty
good-sized store,

6825
05:50:20,800 --> 05:50:25,760
and they handled the situation
very, very well.

6826
05:50:25,760 --> 05:50:29,320
And so, I would like to add
to the recommendations,

6827
05:50:29,320 --> 05:50:30,840
if, indeed, Kate,

6828
05:50:30,840 --> 05:50:33,560
and your group is
going to look into that group,

6829
05:50:33,560 --> 05:50:38,040
which I absolutely recommend
to you to do,

6830
05:50:38,040 --> 05:50:41,080
is to look
at their experimentation

6831
05:50:41,080 --> 05:50:43,760
of dealing with local doctors,

6832
05:50:43,760 --> 05:50:46,640
and with local restaurants,
and so forth,

6833
05:50:46,640 --> 05:50:51,480
for people to understand
what dementia is,

6834
05:50:51,480 --> 05:50:53,200
and what it is like,

6835
05:50:53,200 --> 05:50:58,680
and to be a bit more sympathetic
as to what's happening,

6836
05:50:58,680 --> 05:51:03,040
and cooperative in dealing
with the situation.

6837
05:51:03,040 --> 05:51:05,720
That's my comment.
I thank you all very much.

6838
05:51:05,720 --> 05:51:08,800
This has, as usual,
been an excellent,

6839
05:51:08,800 --> 05:51:13,520
excellent couple sessions,
and I thank you very much.

6840
05:51:13,520 --> 05:51:15,720
-Thank you, Mr. Listina.

6841
05:51:15,720 --> 05:51:19,200
Your comments have been
really important

6842
05:51:19,200 --> 05:51:20,920
throughout this session,

6843
05:51:20,920 --> 05:51:24,360
and they are going to shape,
I think, our recommendations.

6844
05:51:24,360 --> 05:51:25,840
Thank you for
bringing your voice,

6845
05:51:25,840 --> 05:51:29,520
and closing with this
really important point,

6846
05:51:29,520 --> 05:51:32,520
that I think is not
well-represented

6847
05:51:32,520 --> 05:51:34,240
in the recommendations
right now.

6848
05:51:34,240 --> 05:51:37,560
So I will also bring this point
back to the MED committee,

6849
05:51:37,560 --> 05:51:43,240
so we can think about
how we can advance awareness

6850
05:51:43,240 --> 05:51:46,720
around dementia
in a compassionate with,

6851
05:51:46,720 --> 05:51:49,480
with providers,
people in business,

6852
05:51:49,480 --> 05:51:51,200
and the broader society.

6853
05:51:51,200 --> 05:51:55,200
So, thank you for that
really important comment.

6854
05:51:55,200 --> 05:52:01,040
-Thank you very much, Kate.
I have one last thing.

6855
05:52:01,040 --> 05:52:05,720
We have as a goal to cure
some dementia by 2025.

6856
05:52:05,720 --> 05:52:09,760
Walter had mentioned this
in the opening of the session.

6857
05:52:09,760 --> 05:52:20,120
By 2025, to cure a dementia,
to cure one.

6858
05:52:20,120 --> 05:52:24,400
I would invite, if you would,
prognosticate with me.

6859
05:52:24,400 --> 05:52:28,000
Which one is the best candidate
for that to happen?

6860
05:52:34,320 --> 05:52:38,880
-Who is brave on this panel?

6861
05:52:38,880 --> 05:52:41,200
-Maybe it's a rhetorical
question,

6862
05:52:41,200 --> 05:52:42,880
but nevertheless,
it's coming up --

6863
05:52:42,880 --> 05:52:46,680
whoa, I see Walter is going
to give it a shot. Go ahead.

6864
05:52:46,680 --> 05:52:49,840
-I was going to ask
David Holzcomb.

6865
05:52:49,840 --> 05:52:55,000
I mean, you don't put
your money down

6866
05:52:55,000 --> 05:52:56,480
until you know
who's going to win,

6867
05:52:56,480 --> 05:52:59,760
but there's a couple horses
in the field here.

6868
05:52:59,760 --> 05:53:02,200
We'll see.

6869
05:53:02,200 --> 05:53:05,560
Certainly, the anti-amyloid
therapy of Alzheimer's,

6870
05:53:05,560 --> 05:53:07,040
going to get answers
pretty quickly

6871
05:53:07,040 --> 05:53:10,880
whether that's effective,
and that, you know --

6872
05:53:10,880 --> 05:53:12,680
that's a kind of foot
in the door.

6873
05:53:17,560 --> 05:53:20,520
But I would just say
it's somewhat more exciting

6874
05:53:20,520 --> 05:53:23,000
now than 50 years ago,

6875
05:53:23,000 --> 05:53:25,560
when we really
didn't know anything

6876
05:53:25,560 --> 05:53:28,000
about what we were doing.

6877
05:53:28,000 --> 05:53:31,160
So, David, would you want
to take a shot at --

6878
05:53:31,160 --> 05:53:35,760
I mean, there's so many
different opportunities,

6879
05:53:35,760 --> 05:53:38,080
it's hard to pick one.

6880
05:53:38,080 --> 05:53:40,000
-I don't know which --
I certainly --

6881
05:53:40,000 --> 05:53:41,960
none of us know
which one might be first,

6882
05:53:41,960 --> 05:53:44,200
but I think actually Sonya,

6883
05:53:44,200 --> 05:53:47,240
who was speaking about
genetic prion disease --

6884
05:53:47,240 --> 05:53:48,760
I mean, I think

6885
05:53:48,760 --> 05:53:51,080
some of the genetic
neurodegenerative diseases,

6886
05:53:51,080 --> 05:53:54,320
where lowering the level
of the gene and protein

6887
05:53:54,320 --> 05:54:00,240
in animals really can prevent
or very much delay the disease,

6888
05:54:00,240 --> 05:54:05,320
I think, are the most amenable
to the earliest big effect,

6889
05:54:05,320 --> 05:54:09,120
like with the SMA
as a various specific example

6890
05:54:09,120 --> 05:54:12,000
that is pretty much curable now.
But that --

6891
05:54:12,000 --> 05:54:14,240
I wouldn't necessarily call it
a neurodegenerative disease,

6892
05:54:14,240 --> 05:54:16,400
but it's close.

6893
05:54:16,400 --> 05:54:19,440
But I think something where
you could knock the protein down

6894
05:54:19,440 --> 05:54:23,360
to have a big impact is probably
the best first candidate.

6895
05:54:25,720 --> 05:54:27,520
-I -- again, Walter,

6896
05:54:27,520 --> 05:54:33,200
you said a while ago,
just in this particular session,

6897
05:54:33,200 --> 05:54:37,520
that the demand
on these sessions,

6898
05:54:37,520 --> 05:54:40,800
and the size of the scope
is getting bigger,

6899
05:54:40,800 --> 05:54:43,200
and bigger, and bigger.

6900
05:54:43,200 --> 05:54:49,000
And I would say yes,
this is a very big problem.

6901
05:54:49,000 --> 05:54:55,640
And it will get bigger,
but I implore all of us --

6902
05:54:55,640 --> 05:54:58,200
don't give up because
it's getting bigger.

6903
05:54:58,200 --> 05:55:02,040
It's getting bigger because
the need is getting bigger,

6904
05:55:02,040 --> 05:55:05,080
and just hang in there.

6905
05:55:05,080 --> 05:55:11,680
I'll do my best on my end,
and I know you will, too.

6906
05:55:11,680 --> 05:55:14,800
And that's --
we've just got to do it.

6907
05:55:14,800 --> 05:55:19,600
We cannot give up.
Thank you.

6908
05:55:19,600 --> 05:55:21,880
-I cannot think of better
closing remarks

6909
05:55:21,880 --> 05:55:25,120
for this session,
putting into perspective

6910
05:55:25,120 --> 05:55:30,360
not only the humanity
of the work that so many do,

6911
05:55:30,360 --> 05:55:33,000
some in a laboratory,
some in clinic,

6912
05:55:33,000 --> 05:55:36,240
and some in providing care
to patients with,

6913
05:55:36,240 --> 05:55:42,600
you know, this terrible disease.
So humanity, purpose, passion --

6914
05:55:42,600 --> 05:55:47,920
I think all of that
has been inspiring,

6915
05:55:47,920 --> 05:55:49,640
you know, throughout
these two days,

6916
05:55:49,640 --> 05:55:53,840
and I think we have our work
cut out for us going forward.

6917
05:55:53,840 --> 05:55:58,400
And there's some
immediate steps to do.

6918
05:55:58,400 --> 05:56:01,480
You know, we'll work
on the recommendations,

6919
05:56:01,480 --> 05:56:03,000
and put the reports forward,

6920
05:56:03,000 --> 05:56:06,280
but I think there's also
some long-term work to do.

6921
05:56:06,280 --> 05:56:09,520
And I promise you, Mr. Listina,
we're not going to give up.

6922
05:56:09,520 --> 05:56:11,320
That's just the only thing
I can say,

6923
05:56:11,320 --> 05:56:14,880
and I think we're in
our closing comments session.

6924
05:56:14,880 --> 05:56:16,640
At this point, Walter,

6925
05:56:16,640 --> 05:56:20,000
if there's anything you want
to say to wrap the session up --

6926
05:56:25,400 --> 05:56:27,800
you're on mute.

6927
05:56:27,800 --> 05:56:31,080
-I think you did a fantastic job

6928
05:56:31,080 --> 05:56:33,720
going through the details,
presentations,

6929
05:56:33,720 --> 05:56:37,120
and please send me
those slides.

6930
05:56:37,120 --> 05:56:39,200
Because we're going to go in
through all the recommendations

6931
05:56:39,200 --> 05:56:43,000
in detail, too,
so it's very helpful.

6932
05:56:43,000 --> 05:56:45,720
You know, I just --
just in closing,

6933
05:56:45,720 --> 05:56:48,800
say that,
as I referred to earlier,

6934
05:56:48,800 --> 05:56:51,960
you know, some of the people
have been in this field

6935
05:56:51,960 --> 05:56:54,600
for 30 or 40 years,
look back,

6936
05:56:54,600 --> 05:56:59,160
and, you know, how do we think
about this 30 or 40 years ago?

6937
05:56:59,160 --> 05:57:03,680
And just, like,
what were you thinking?

6938
05:57:03,680 --> 05:57:07,360
Really it's such a much more
sophisticated place now.

6939
05:57:07,360 --> 05:57:08,760
The problems are bigger also,

6940
05:57:08,760 --> 05:57:12,200
because we know more
about the complexity,

6941
05:57:12,200 --> 05:57:14,600
not as simple
as we initially thought.

6942
05:57:14,600 --> 05:57:19,400
But there's so many potential
targets that have appeared,

6943
05:57:19,400 --> 05:57:24,080
and takes persistence
and a little bit of luck.

6944
05:57:24,080 --> 05:57:27,520
But we're dealing with things

6945
05:57:27,520 --> 05:57:31,160
that are really inherent
to the diseases now.

6946
05:57:31,160 --> 05:57:32,880
So I think
we can feel comfortable

6947
05:57:32,880 --> 05:57:38,800
that these efforts --

6948
05:57:38,800 --> 05:57:42,000
you know, you can't say which
one is going to bear fruit,

6949
05:57:42,000 --> 05:57:47,240
but I would put a lot of money
that one of them is,

6950
05:57:47,240 --> 05:57:50,280
just because there's so much
going on in the field.

6951
05:57:50,280 --> 05:57:54,360
There's industry involvement
now we didn't have before.

6952
05:57:54,360 --> 05:57:58,160
So I think we're entering
a pretty exciting period.

6953
05:57:58,160 --> 05:58:00,520
There are a lot that we know,

6954
05:58:00,520 --> 05:58:04,600
and we talked about
some of those today,

6955
05:58:04,600 --> 05:58:07,200
the heterogeneity,
the different topologies,

6956
05:58:07,200 --> 05:58:10,560
the different molecules
that are involved,

6957
05:58:10,560 --> 05:58:14,200
the interactions between
the different pathologies.

6958
05:58:14,200 --> 05:58:15,520
Talking about brain health,

6959
05:58:15,520 --> 05:58:18,800
which, you know,
is something that we know.

6960
05:58:18,800 --> 05:58:23,240
If we had a way of, you know,
enticing people to think

6961
05:58:23,240 --> 05:58:26,520
about brain health
in the early midlife,

6962
05:58:26,520 --> 05:58:29,320
that this could have
a major impact

6963
05:58:29,320 --> 05:58:32,560
on decreasing the chance
of dementia in,

6964
05:58:32,560 --> 05:58:36,120
you know, 30
or 40 years later in their life.

6965
05:58:36,120 --> 05:58:38,200
We do know that, you know,

6966
05:58:38,200 --> 05:58:43,400
Alzheimer's disease modification
is potentially there.

6967
05:58:43,400 --> 05:58:45,240
We don't know for sure yet,

6968
05:58:45,240 --> 05:58:50,680
but there is some enticing data
that the anti-amyloid therapies

6969
05:58:50,680 --> 05:58:52,600
may actually have
mental benefit.

6970
05:58:52,600 --> 05:58:55,480
We'll have to wait and see,
but they're very powerful

6971
05:58:55,480 --> 05:58:56,960
at taking amyloid
out of the brain,

6972
05:58:56,960 --> 05:59:01,040
no question about that.
That's pretty amazing.

6973
05:59:01,040 --> 05:59:03,480
Then there's a lot
of known unknowns.

6974
05:59:03,480 --> 05:59:07,000
So we know a lot
about the genetic drivers,

6975
05:59:07,000 --> 05:59:13,600
but we don't know exactly how
to move those -- that knowledge.

6976
05:59:13,600 --> 05:59:15,200
We know that the mutations

6977
05:59:15,200 --> 05:59:18,160
manipulate the system
to cause disease.

6978
05:59:18,160 --> 05:59:19,760
Now, what we have
to figure out is,

6979
05:59:19,760 --> 05:59:27,360
how do we compensate
or prevent that from happening,

6980
05:59:27,360 --> 05:59:29,480
so that we end up
with a treatment

6981
05:59:29,480 --> 05:59:32,040
based on what we know
out of the genetics?

6982
05:59:32,040 --> 05:59:35,400
I think that's
low-hanging fruit.

6983
05:59:35,400 --> 05:59:39,840
The second one, which is harder,
but is actually surprisingly --

6984
05:59:39,840 --> 05:59:43,600
some of the FTDs,
been very interesting,

6985
05:59:43,600 --> 05:59:48,120
where something we find out form
the genetics turns out to be,

6986
05:59:48,120 --> 05:59:50,200
you know --
and all the sporadics as well.

6987
05:59:50,200 --> 05:59:55,880
So TDD43 story's a good one,
and all the ALS cases,

6988
05:59:55,880 --> 06:00:00,440
a lot of the other dementias
as well.

6989
06:00:00,440 --> 06:00:04,240
So there are these things
that -- where you don't --

6990
06:00:04,240 --> 06:00:06,360
we know what they are.
We know what we don't know,

6991
06:00:06,360 --> 06:00:09,720
and we have a path forward
that we think,

6992
06:00:09,720 --> 06:00:11,680
you know, will get us
the answers in the end.

6993
06:00:11,680 --> 06:00:15,440
So we call it
the known unknowns.

6994
06:00:15,440 --> 06:00:18,920
Then, there is the issue
of the unknown unknowns,

6995
06:00:18,920 --> 06:00:22,360
and that's usually the scariest
part of the business,

6996
06:00:22,360 --> 06:00:25,000
where you think you know
what the problem is.

6997
06:00:25,000 --> 06:00:26,640
Spend 10 years,
and it doesn't work,

6998
06:00:26,640 --> 06:00:28,320
and you realize,
well,

6999
06:00:28,320 --> 06:00:30,800
I made some assumptions
that were wrong.

7000
06:00:30,800 --> 06:00:36,200
I didn't know X, Y, or Z, and
that's led to the final failure.

7001
06:00:36,200 --> 06:00:41,800
So you always have to think
that, you know, as a community,

7002
06:00:41,800 --> 06:00:45,040
we tend to want to look
under the lamp post,

7003
06:00:45,040 --> 06:00:47,360
and that's what we know.

7004
06:00:47,360 --> 06:00:50,880
That's the known unknowns, but
we've got to be really careful.

7005
06:00:50,880 --> 06:00:53,080
There's something out there
beyond the lamp post

7006
06:00:53,080 --> 06:00:56,520
that's really relevant
to what we need to do.

7007
06:00:56,520 --> 06:01:01,800
And so, that's, I think,
keeping your eye out for things

7008
06:01:01,800 --> 06:01:04,960
that are going on
in other areas of biology --

7009
06:01:04,960 --> 06:01:09,640
cancer, you know,
basic molecular biology.

7010
06:01:09,640 --> 06:01:14,800
Sometimes that's where the real
breakthroughs come from,

7011
06:01:14,800 --> 06:01:21,280
and so, I think that's how
I look at the picture we have,

7012
06:01:21,280 --> 06:01:22,800
where we are now.

7013
06:01:22,800 --> 06:01:26,920
The recommendations
that were put together here,

7014
06:01:26,920 --> 06:01:31,120
I think, are, you know,
very well thought-out,

7015
06:01:31,120 --> 06:01:38,120
and we can work with those,
and make progress.

7016
06:01:38,120 --> 06:01:39,720
It's not going to be easy,

7017
06:01:39,720 --> 06:01:43,120
but I think, you know,
with the workforce dedication

7018
06:01:43,120 --> 06:01:47,200
and the funding that's now
available through NAPA,

7019
06:01:47,200 --> 06:01:49,400
we can really make progress.

7020
06:01:49,400 --> 06:01:53,880
So I'm very optimistic,
and a lot of the optimism

7021
06:01:53,880 --> 06:01:57,800
is because the last two days,
the people that have, you know,

7022
06:01:57,800 --> 06:02:03,160
shown their passion
and dedication for this field.

7023
06:02:03,160 --> 06:02:06,440
I think we have a good team.

7024
06:02:06,440 --> 06:02:09,000
We need more players,
but we have a good team.

7025
06:02:09,000 --> 06:02:12,160
So I want to thank everybody
for the teamwork

7026
06:02:12,160 --> 06:02:14,360
to put this together,
and for all the work

7027
06:02:14,360 --> 06:02:17,160
you're going to do
in the next three years.

7028
06:02:17,160 --> 06:02:20,520
So, thanks very much.

7029
06:02:20,520 --> 06:02:24,240
-Thank you, Walter.
It's a perfect wrap.

7030
06:02:24,240 --> 06:02:29,000
So I think Keith wants to take
a last picture, screenshot.

7031
06:02:29,000 --> 06:02:35,240
So, everybody smile
before we say see you in 2025.

7032
06:02:35,240 --> 06:02:37,720
Whenever you're ready,
Keith, you let us know.

7033
06:02:40,040 --> 06:02:43,120
-I took, like, seven.
We're good.

7034
06:02:43,120 --> 06:02:45,160
-Excellent, well,
thank you again,

7035
06:02:45,160 --> 06:02:48,440
tremendous whirlwind of science,
you know, compassion,

7036
06:02:48,440 --> 06:02:50,800
and pointers for the future.

7037
06:02:50,800 --> 06:02:53,800
And we'll see you in 2025.
Thank you.

7038
06:02:53,800 --> 06:02:56,160
-Thank you, guys.
-Bye, everybody.

7039
06:02:56,160 --> 06:02:59,040
-Probably see you
earlier than that.

7040
06:02:59,040 --> 06:03:01,880
-I hope so. Bye-bye.
-Bye.

7041
06:03:01,880 --> 06:03:03,360
-Bye.