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TODAY WE WILL BE HEARING

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00:00:13,226 --> 00:00:14,060
SOMETHING DIFFERENT, WHICH I

3
00:00:14,060 --> 00:00:19,099
THINK IS VERY BENEFICIAL FOR US

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00:00:19,099 --> 00:00:28,608
[INDISCERNIBLE]  PROT  PROTEOMI,

5
00:00:28,608 --> 00:00:31,411
AND ALSO TECHNOLOGY DEVELOPMENT

6
00:00:31,411 --> 00:00:34,748
SO TODAY IT'S A GREAT FACTOR TO

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HAVE 1 OF OUR OWN NIH

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INVESTIGATORS HERE TO GIVE US A

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TALK DR. KEENAN WALKER IS A

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TENURED TRACK INVESTIGATOR AT

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THE NATIONAL INSTITUTE ON AGING

12
00:00:45,492 --> 00:00:48,328
IN THE INTRAMURAL PROGRAM.

13
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HE RECEIVED HIS Ph.D. HAD

14
00:00:51,398 --> 00:00:53,566
CLINICAL PSYCHOLOGY FROM

15
00:00:53,566 --> 00:00:58,238
ST. JOHNS UNIVERSITY AND THEN

16
00:00:58,238 --> 00:00:59,406
DID HIS PREDOCTORAL INTERNSHIP

17
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AT THE UNIVERSITY OF CALIFORNIA

18
00:01:02,008 --> 00:01:03,143
SAN DIEGO IN THE HEALTHCARE

19
00:01:03,143 --> 00:01:03,376
SYSTEM.

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AFTER THAT HE DID A NIH FUNDED

21
00:01:06,913 --> 00:01:09,015
POST DOC AT JOHNS HOPKINS

22
00:01:09,015 --> 00:01:11,151
UNIVERSITY SCHOOL OF MEDICINE IN

23
00:01:11,151 --> 00:01:13,219
AGE RELATED COGNITIVE DISORDERS.

24
00:01:13,219 --> 00:01:18,191
I GUESS THAT'S WHAT BROUGHT YOU

25
00:01:18,191 --> 00:01:20,327
TO OUR AREA.

26
00:01:20,327 --> 00:01:22,529
HE LATER TRANSITIONED TO

27
00:01:22,529 --> 00:01:24,164
ASSISTANT PROFESSOR OF NEUROLOGY

28
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AFTER RECEIVING A K3 CAREER

29
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DEVELOPMENT AWARD.

30
00:01:26,967 --> 00:01:29,936
AND THEN SHORTLY AFTER THAT HE

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BEGAN AS A TENURED TRACKER AT

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NIA.

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00:01:33,440 --> 00:01:36,977
CURRENTLY DR. WALKER IS A

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00:01:36,977 --> 00:01:39,079
[INDISCERNIBLE] OF THE

35
00:01:39,079 --> 00:01:40,580
MULTIMODAL IMAGES OF

36
00:01:40,580 --> 00:01:41,614
NEURODEGENERATIVE DISEASE, AND

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THE LABORATORY OF BEHAVIORIAL

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00:01:44,918 --> 00:01:48,755
NEUROSCIENCE, HIS RESEARCH

39
00:01:48,755 --> 00:01:51,157
FOCUSES ON THE ROLE OF

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00:01:51,157 --> 00:01:52,325
UNDERSTANDING NORMAL IMMUNE

41
00:01:52,325 --> 00:01:55,395
FUNCTION AND INFLAMMATION IN

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00:01:55,395 --> 00:01:58,398
[INDISCERNIBLE] DISEASE AND LATE

43
00:01:58,398 --> 00:01:59,132
[INDISCERNIBLE] COGNITIVE

44
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DECLINE.

45
00:01:59,366 --> 00:02:05,939
SO WITHOUT FURTHER ADO HERE IS

46
00:02:05,939 --> 00:02:06,573
DR. WALKER.

47
00:02:06,573 --> 00:02:08,341
>> WELL, THANK YOU, THANK
YOU

48
00:02:08,341 --> 00:02:10,143
FOR THE INVITATION, APPRECIATE

49
00:02:10,143 --> 00:02:11,644
THE INTRODUCTION, SO, YEAH, IT'S

50
00:02:11,644 --> 00:02:14,381
A SMALL GROUP SO WE'LL KEEP IT

51
00:02:14,381 --> 00:02:16,816
INFORMAL IF IMK HAS ANY

52
00:02:16,816 --> 00:02:18,685
QUESTIONS, FEEL FREE TO TOP AND

53
00:02:18,685 --> 00:02:19,853
ASK, HOPEFULLY THAT'S OKAY WITH

54
00:02:19,853 --> 00:02:21,187
THE VIDEOCAST SO WE WILL GO

55
00:02:21,187 --> 00:02:26,226
AHEAD AND GET STARTED.

56
00:02:26,226 --> 00:02:29,896
LIKE WAS SAID, I WAS TRAINED AS

57
00:02:29,896 --> 00:02:30,830
A CLINICAL NEUROPSYCHOLOGIST,

58
00:02:30,830 --> 00:02:34,367
ALTHOUGH, WHY AM I DOING

59
00:02:34,367 --> 00:02:37,837
PROTEOMIC, MAKE IT GOES TO SHOW

60
00:02:37,837 --> 00:02:39,039
HOW DEMOCRATIZES PROTEOMICS HAS

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00:02:39,039 --> 00:02:40,306
GOTTEN WITH THE ADVENT OF SOME

62
00:02:40,306 --> 00:02:42,308
OF THESE LARGE SCALE PLATFORMS

63
00:02:42,308 --> 00:02:44,277
LIKE THE 1S I WILL TALK ABOUT

64
00:02:44,277 --> 00:02:47,380
TODAY, I CLEARLY HAVE MADE A

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PRETTY STARK TRANSITION FROM MY

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00:02:48,281 --> 00:02:51,051
AREA OF THE PAINTING BUT I THINK

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00:02:51,051 --> 00:02:52,786
HOPEFULLY IT BECOMES CLEAR WHY

68
00:02:52,786 --> 00:02:54,220
WE PLANNED ON USING PROTEOMICS

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00:02:54,220 --> 00:02:57,090
AS A TOOL, UNDERSTANDING MORE

70
00:02:57,090 --> 00:02:58,925
ABOUT DEMENTIA SO SOME

71
00:02:58,925 --> 00:03:01,861
DISCLOSURES, YOU DON'T NEED

72
00:03:01,861 --> 00:03:03,396
THOSE, SO, I KNOW EVERYONE

73
00:03:03,396 --> 00:03:04,764
STUDIES SOMETHING DIFFERENT IN

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00:03:04,764 --> 00:03:06,132
TERMS OF DISEASES HERE, SO I

75
00:03:06,132 --> 00:03:07,434
THOUGHT WE WOULD JUST START BY

76
00:03:07,434 --> 00:03:09,536
TALKING ABOUT WHAT I STUDY JUST

77
00:03:09,536 --> 00:03:11,971
SO WE'RE ALLOT SAME PLAYING

78
00:03:11,971 --> 00:03:13,239
FIELD, SO ALZHEIMER'S DISEASE IS

79
00:03:13,239 --> 00:03:15,108
JUST 1 FORM OF DEMENTIA, THERE

80
00:03:15,108 --> 00:03:19,746
ARE MANY FORMS OF DEMENTIA, IT

81
00:03:19,746 --> 00:03:21,347
REPRESENTS TWIN STUDIES THIRDS

82
00:03:21,347 --> 00:03:22,415
OF ALL DEMENTIA CASES.

83
00:03:22,415 --> 00:03:24,751
SO YOU KNOW YOU CAN--ABOUT,

84
00:03:24,751 --> 00:03:30,723
WELL, OVER 10% OF PEOPLE OVER 65

85
00:03:30,723 --> 00:03:32,258
RIGHT NOW ALZHEIMER'S DISEASE,

86
00:03:32,258 --> 00:03:33,560
DEMENTIA AND THIS IS ONLY GOING

87
00:03:33,560 --> 00:03:35,662
TO INCREASE WITH TIME ESPECIALLY

88
00:03:35,662 --> 00:03:38,064
AS THE POPULATION AGES, SO WHAT

89
00:03:38,064 --> 00:03:41,634
DO WE MEAN WHEN I SAY

90
00:03:41,634 --> 00:03:44,304
ALZHEIMER'S DISEASE OR DEMENTIA?

91
00:03:44,304 --> 00:03:46,239
WELL, REALLY BIOLOGICALLY IT'S

92
00:03:46,239 --> 00:03:48,308
THE BY AND BY AMYLOID AGGREGATES

93
00:03:48,308 --> 00:03:52,178
THAT OCCUR OUTSIDE THE CELL AND

94
00:03:52,178 --> 00:03:54,781
THESE TAU TANGLES THAT HAPPEN

95
00:03:54,781 --> 00:03:56,282
INSIDE THE CELL AND BEYOND THAT,

96
00:03:56,282 --> 00:03:58,051
THERE ARE A NUMBER OF OTHER

97
00:03:58,051 --> 00:04:02,455
PROCESSES THAT OCCUR INCLUDING

98
00:04:02,455 --> 00:04:04,190
MICROGLIAL ACTIVATION WHICH

99
00:04:04,190 --> 00:04:05,492
SPARKS NEURAL INFLAMMATION

100
00:04:05,492 --> 00:04:07,293
SPECIFICALLY.

101
00:04:07,293 --> 00:04:10,797
SO MY HYPOTHESIS AND THIS IS

102
00:04:10,797 --> 00:04:13,032
WITH THE A LOT OF WORK WE DO IS

103
00:04:13,032 --> 00:04:14,501
THAT CONDITIONS OUTSIDE THE

104
00:04:14,501 --> 00:04:17,070
CENTRAL NERVOUS SYSTEM CAN

105
00:04:17,070 --> 00:04:18,138
INFLUENCE DEMENTIA RISK, THIS

106
00:04:18,138 --> 00:04:22,609
HAS BEEN UPDATED BUT THE YOU

107
00:04:22,609 --> 00:04:24,410
KNOW THE POINT I WANT TO DRIVE

108
00:04:24,410 --> 00:04:27,147
HOME IS ANYWHERE FROM 30-40% OF

109
00:04:27,147 --> 00:04:28,648
THE ATTRIBUTABLE RISK FOR

110
00:04:28,648 --> 00:04:30,283
DEMENTIA IS DUE TO CONDITIONS

111
00:04:30,283 --> 00:04:31,818
THAT LARGELY LIE OUTSIDE THE

112
00:04:31,818 --> 00:04:33,219
CENTRAL NERVOUS SYSTEM, SO THESE

113
00:04:33,219 --> 00:04:35,622
ARE CONDITIONS THAT ARE LARGELY

114
00:04:35,622 --> 00:04:37,157
MODIFIABLE TO EXTENT IN AITION

115
00:04:37,157 --> 00:04:38,992
TO WHATEVER BENEFITS CAN OCCUR

116
00:04:38,992 --> 00:04:41,528
THROUGH, YOU KNOW CNS DIRECTED

117
00:04:41,528 --> 00:04:41,895
THERAPY.

118
00:04:41,895 --> 00:04:45,532
AND YOU KNOW IT'S OUR BELIEF

119
00:04:45,532 --> 00:04:46,833
THAT PROTEINS IN CIRCULATION,

120
00:04:46,833 --> 00:04:48,935
PROTEINS IN BLOOD MIGHT MEDIATE

121
00:04:48,935 --> 00:04:50,003
THE RELATIONSHIPS BETWEEN

122
00:04:50,003 --> 00:04:52,305
CONDITIONS LIKE CARDIO METABOLIC

123
00:04:52,305 --> 00:04:53,473
DISEASE, AUTOIMMUNE CONDITION,

124
00:04:53,473 --> 00:04:55,441
YOU KNOW AND THESE RISK FACTORS

125
00:04:55,441 --> 00:04:57,944
FOR DEMENTIA THAT ESSENTIALLY

126
00:04:57,944 --> 00:05:00,446
WILL INCREASE ONCE DEVELOPING

127
00:05:00,446 --> 00:05:01,281
DEMENTIA ACROSS THEIR LIFETIME

128
00:05:01,281 --> 00:05:07,187
AND HOW DOES THAT WORK, WELL, WE

129
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THINK THAT WHEN YOU DO HAVE A

130
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CLINICAL DISEASE, OR THIS COULD

131
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BE CLINICAL CONDITIONS THAT

132
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AREN'T DIAGNOSED OR NOTABLE OR

133
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CLINICAL PROCESSES LIKE CELLULAR

134
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AGING BUT ALL THESE CONDITIONS

135
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PART OF WHAT THEY DO IS THEY

136
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CHANGE THE EXPRESSION OF

137
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PROTEINS ACROSS DIFFERENT ORGAN

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SYSTEMS, ACROSS DEFINITE CELL

139
00:05:22,869 --> 00:05:25,271
TYPES AND THESE ALL FILTER INTO

140
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THE BLOOD OF SOME MORE THAN

141
00:05:26,573 --> 00:05:27,974
OTHERS, BUT THE IDEA IS THAT

142
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WHEN THEY MAKE IT INTO THE BLOOD

143
00:05:29,909 --> 00:05:32,111
STREAM THEY CAN ACROSS INTO THE

144
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CENTRAL NERVOUS SYSTEM THROUGH

145
00:05:33,980 --> 00:05:35,682
VARIOUS CONDUITS SO I WILL TALK

146
00:05:35,682 --> 00:05:37,417
ABOUT THESE MORE LATER, BUT

147
00:05:37,417 --> 00:05:38,484
THESE PROTEINS WE THINK

148
00:05:38,484 --> 00:05:40,353
INFLUENCE SOME OF THE TARGET

149
00:05:40,353 --> 00:05:42,789
CELLS WITHIN THE BRAIN ASK

150
00:05:42,789 --> 00:05:44,557
INFLUENCE BEHAVIOR, YOU KNOW

151
00:05:44,557 --> 00:05:45,091
DRIVE, DISEASE, ET CETERA.

152
00:05:45,091 --> 00:05:47,293
SO A NUMBER OF THESE PROTEINS

153
00:05:47,293 --> 00:05:47,794
HAVE BEEN IDENTIFIED.

154
00:05:47,794 --> 00:05:50,330
A LOT OF THEM AS YOU SEE HERE

155
00:05:50,330 --> 00:05:51,931
ARE CYTOKINES AND CHEMOKINES,

156
00:05:51,931 --> 00:05:54,801
THEY INCREASE WITH AGE OR

157
00:05:54,801 --> 00:05:56,302
DECREASE WITH AGE AND THEY HAVE

158
00:05:56,302 --> 00:05:57,503
SOME KNOWN EFFECT ON TARGET

159
00:05:57,503 --> 00:05:58,471
CELLS WITHIN THE BRAIN.

160
00:05:58,471 --> 00:06:00,240
WE THINK THERE'S MANY, MANY MORE

161
00:06:00,240 --> 00:06:04,444
PROTEINS OUT THERE INVOLVING

162
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[INDISCERNIBLE] THAT POTENTIALLY

163
00:06:05,178 --> 00:06:07,680
MIGHT BE USED AS BIOMARKERS BUT

164
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ALSO THERAPEUTIC TARGETS.

165
00:06:08,348 --> 00:06:18,591
SO WE GOT INTO THIS THE STUDIES

166
00:06:18,591 --> 00:06:18,958
 SOMA

167
00:06:18,958 --> 00:06:19,993
SCAN INTRODUCED THEIR PRODUCT.

168
00:06:19,993 --> 00:06:23,329
SO FOR THOSE THAT DON'T KNOW,

169
00:06:23,329 --> 00:06:25,398
SOMA SCAN IS A LARGE COMPANY

170
00:06:25,398 --> 00:06:32,272
THAT WILL ALLOW YOU TO MEASURE

171
00:06:32,272 --> 00:06:34,374
THINGS AND SO I WAS WORKING WITH

172
00:06:34,374 --> 00:06:37,410
A LARGE COHORT THAT ALLOWED US

173
00:06:37,410 --> 00:06:39,479
TO IMPLEMENT THE SOMA SCAN OF

174
00:06:39,479 --> 00:06:41,881
THIS LARGE GROUP OF PROTEOMICS

175
00:06:41,881 --> 00:06:45,685
AND WITH THAT, BEFORE THIS I WAS

176
00:06:45,685 --> 00:06:47,420
REALLY INTERESTED IN SYSTEMIC

177
00:06:47,420 --> 00:06:51,224
INFLAMMATION AS A FACTOR,

178
00:06:51,224 --> 00:06:52,392
PROTEINS, IL6, PROTEINS THAT

179
00:06:52,392 --> 00:06:54,394
HAPPEN TO BE MEASURED IN A

180
00:06:54,394 --> 00:06:56,429
COHORT AND RELATING THEM TO

181
00:06:56,429 --> 00:06:57,463
NEUROCOGNITIVE OUTCOME, WE WERE

182
00:06:57,463 --> 00:06:59,032
LOOKING AT 1 PROTEIN AT A TIME,

183
00:06:59,032 --> 00:07:01,601
WE WERE USING PROTEINS AGAIN OF

184
00:07:01,601 --> 00:07:03,436
CONVENIENCE AND WE WERE COMING

185
00:07:03,436 --> 00:07:07,206
TO CONCLUSIONS BASED ON A REALLY

186
00:07:07,206 --> 00:07:09,275
BIASED SELECTION OF POTENTIAL

187
00:07:09,275 --> 00:07:11,377
PROTEIN TARGETS, SO, YOU KNOW I

188
00:07:11,377 --> 00:07:13,446
WAS REALLY EXCITED WHEN WE HAD

189
00:07:13,446 --> 00:07:14,380
THIS UNBELIEVABLE OPPORTUNITY TO

190
00:07:14,380 --> 00:07:17,684
LOOK AT THOUSANDS OF PROTEINS,

191
00:07:17,684 --> 00:07:20,320
YOU KNOW MY INTEREST IN THE'MUNE

192
00:07:20,320 --> 00:07:20,987
DYSFUNCTION SPECIFICALLY, AND

193
00:07:20,987 --> 00:07:22,755
THERE WERE HUNDREDS OF PROTEINS,

194
00:07:22,755 --> 00:07:24,324
HUNDREDS OF IMMUNE PROTEINS ON

195
00:07:24,324 --> 00:07:25,725
THIS PANEL ALREADY, SO I WAS

196
00:07:25,725 --> 00:07:27,360
LIKE, OKAY, LET'S DO THIS AND WE

197
00:07:27,360 --> 00:07:32,598
WENT AND WE STARTED LOOKING AT

198
00:07:32,598 --> 00:07:34,500
THE SIGNATURE OF VARIOUS CENTRAL

199
00:07:34,500 --> 00:07:35,101
NERVOUS SYSTEM RELATED

200
00:07:35,101 --> 00:07:37,036
CONDITIONS AND THERE WAS A LOT

201
00:07:37,036 --> 00:07:38,604
OF, YOU KNOW SKEPTICISM

202
00:07:38,604 --> 00:07:41,040
INITIALLY ABOUT WHETHER OR NOT

203
00:07:41,040 --> 00:07:42,375
LOOKING AT BLOOD, PROTEOMICS WAS

204
00:07:42,375 --> 00:07:45,211
GOING TO GIVE US ANY INFORMATION

205
00:07:45,211 --> 00:07:47,347
ABOUT A CENTRAL NERVOUS SYSTEM

206
00:07:47,347 --> 00:07:48,881
CONDITION AND BLOOD BRAIN

207
00:07:48,881 --> 00:07:51,184
BARRIER, ET CETERA, WE DON'T

208
00:07:51,184 --> 00:07:53,786
REALLY THINK OF DEMENTIA AS

209
00:07:53,786 --> 00:07:54,821
BEING DRIVER BY STUFF IN THE

210
00:07:54,821 --> 00:07:56,122
BLOOD STREAM BUT THERE'S BEEN A

211
00:07:56,122 --> 00:07:57,957
LOT OF EVIDENCE TO SUPPORT THAT,

212
00:07:57,957 --> 00:07:59,492
AT LEAST TO SOME EXTENT THAT IT

213
00:07:59,492 --> 00:08:02,662
CAN BE, SO OUR FIRST PAPER WAS

214
00:08:02,662 --> 00:08:04,797
PUBLISHED IN 2021 IN NATURE

215
00:08:04,797 --> 00:08:06,866
ANDIGING WHICH LOOKED AT THESE

216
00:08:06,866 --> 00:08:09,402
5000 PROTEINS MEASURED BY THE

217
00:08:09,402 --> 00:08:11,137
SOMA SCAN PLATFORM AND RELATED

218
00:08:11,137 --> 00:08:13,473
THEM ACROSS A 5 YEAR FOLLOW UP

219
00:08:13,473 --> 00:08:13,706
PERIOD.

220
00:08:13,706 --> 00:08:15,875
SO WHAT WE FOUND WAS A NUMBER OF

221
00:08:15,875 --> 00:08:17,310
PROTEINS THAT WERE LINKED TO

222
00:08:17,310 --> 00:08:19,846
DEMENTIA WHICH WE CAN SAY MIGHT

223
00:08:19,846 --> 00:08:22,615
BE USED AS BIOMARKERS, WE WENT

224
00:08:22,615 --> 00:08:25,251
FURTHER AND DID CAUSAL INFERENCE

225
00:08:25,251 --> 00:08:26,686
USING MEN DEALIAN RANDOMIZATION,

226
00:08:26,686 --> 00:08:29,455
WE WERE ABLE TO IDIDN'TIFY

227
00:08:29,455 --> 00:08:30,089
POTENTIAL MECHANISTICALLY

228
00:08:30,089 --> 00:08:31,657
RELEVANT PROTEINS WHICH WE THINK

229
00:08:31,657 --> 00:08:33,426
MIGHT BE VIABLE DRUG TARGETS.

230
00:08:33,426 --> 00:08:35,294
NOW IN THIS PAPER WE WERE

231
00:08:35,294 --> 00:08:36,462
LOOKING IN OLDER ADULTS, AND

232
00:08:36,462 --> 00:08:39,465
THERE WAS A STRING OF PAPER

233
00:08:39,465 --> 00:08:42,135
USING O-LINK, USING SOMA

234
00:08:42,135 --> 00:08:43,970
KAN--KANA, USING MASS SPEC. THAT

235
00:08:43,970 --> 00:08:46,739
LOOKED AT THE PROTEOME IN BLOOD

236
00:08:46,739 --> 00:08:47,940
FOR FUTURE PREVALENT DEMENTIA

237
00:08:47,940 --> 00:08:51,210
BUT WE RECOGNIZE THAT DEMENTIA

238
00:08:51,210 --> 00:08:54,514
STARTS WELL, WELL BEFORE LATE

239
00:08:54,514 --> 00:08:54,714
LIFE.

240
00:08:54,714 --> 00:08:56,616
ALZHEIMER'S DISEASE, 1 FORM OF

241
00:08:56,616 --> 00:08:58,151
DEMENTIA STARTS DECADES BEFORE

242
00:08:58,151 --> 00:09:00,787
DEMENTIA ONSET SO YOU HAVE THIS

243
00:09:00,787 --> 00:09:01,954
PRECLINICAL PERIOD HERE WHICH

244
00:09:01,954 --> 00:09:05,458
OCCURS FOR YEARS BEFORE PEOPLE

245
00:09:05,458 --> 00:09:08,294
EXPRESS SYMPTOMS, NOW MILD

246
00:09:08,294 --> 00:09:10,696
COGNITIVE IMPAIRMENT IS THIS

247
00:09:10,696 --> 00:09:11,597
DEMENTIA [INDISCERNIBLE] AND

248
00:09:11,597 --> 00:09:14,600
THEN THIS CAN LAST FOR DECADES

249
00:09:14,600 --> 00:09:15,701
SO THE CONSENSUS IS THAT

250
00:09:15,701 --> 00:09:19,138
ALZHEIMER'S DISEASE WITH THE

251
00:09:19,138 --> 00:09:21,040
PATHOGENESIS STARTS IN MIDLIFE

252
00:09:21,040 --> 00:09:22,575
OR MITSD ADULTHOOD SO WE

253
00:09:22,575 --> 00:09:24,076
THOUGHT, OKAY, IF WE'RE REALLY

254
00:09:24,076 --> 00:09:26,412
GOING TO UNDERSTAND THE DISEASE

255
00:09:26,412 --> 00:09:28,714
BIOLOGY USING A PROTEOMIC LENS

256
00:09:28,714 --> 00:09:31,017
WE NEED TO ELECTRIC IN MIDDLE

257
00:09:31,017 --> 00:09:32,785
AGED ADULTS, SO THAT'S WHAT WE

258
00:09:32,785 --> 00:09:34,387
DID, WE WENT BACK TO THE SAME

259
00:09:34,387 --> 00:09:36,255
COHORT THAT WE DID OUR INITIAL

260
00:09:36,255 --> 00:09:39,659
STUDY IN AND MEASURE PROTEOME IN

261
00:09:39,659 --> 00:09:41,427
BLOOD 20 YEARS EARLIER THAT HAD

262
00:09:41,427 --> 00:09:42,495
BEEN BANKED AND WAS AVAILABLE

263
00:09:42,495 --> 00:09:44,964
AND SO THE COHORT THAT WE WORK

264
00:09:44,964 --> 00:09:46,566
WITH WAS THE ERIC STUDY, SO ERIC

265
00:09:46,566 --> 00:09:48,434
IS THE ABNORMAL GLUCOSE

266
00:09:48,434 --> 00:09:49,702
TOLERANCELER O CLEROSEIS RISK IN

267
00:09:49,702 --> 00:09:52,004
COMMUNITY STUDY AND THIS A

268
00:09:52,004 --> 00:09:54,440
MULTISITE COMMUNITY BASED COHORT

269
00:09:54,440 --> 00:09:55,341
THAT'S STILL ACTUALLY ONGOING

270
00:09:55,341 --> 00:10:00,813
BUT IT'S A STUDY THAT'S DRAWN

271
00:10:00,813 --> 00:10:02,982
ACROSS 4 UNITED STATES

272
00:10:02,982 --> 00:10:04,150
COMMUNITIES AND INITIALLY

273
00:10:04,150 --> 00:10:05,251
ENROLLED 16,000 INDIVIDUALS IN

274
00:10:05,251 --> 00:10:08,654
THE LATE 80S, SO THESE CONTINUED

275
00:10:08,654 --> 00:10:10,623
TO BE FOLLOWED AND WHAT WE WERE

276
00:10:10,623 --> 00:10:12,925
LUCKY ENOUGH TO DO IS TAKE BLOOD

277
00:10:12,925 --> 00:10:15,061
FROM THE THIRD VISIT WHICH

278
00:10:15,061 --> 00:10:16,629
OCCURRED IN 93 AND RELATE,

279
00:10:16,629 --> 00:10:21,033
MEASURE THE PROTEOME AGAIN WITH

280
00:10:21,033 --> 00:10:22,869
THIS 5000 SOMA SCAN PLATFORM AND

281
00:10:22,869 --> 00:10:24,270
RELATE THOSE TO 1 BY 1 TO

282
00:10:24,270 --> 00:10:26,339
SUBSIDIARY QUEBT OR FUTURE

283
00:10:26,339 --> 00:10:28,074
DEMENTIA REG, AND WE LOOK ACROSS

284
00:10:28,074 --> 00:10:30,309
THE FOLLOW UP TIME OF 25 YEARS

285
00:10:30,309 --> 00:10:32,445
IN THE STUDY, WE LOOKED ACROSS A

286
00:10:32,445 --> 00:10:34,380
SHORTER TERM, 15 YEARS AND THEN

287
00:10:34,380 --> 00:10:36,883
BEYOND 15 YEARS TO SEE HOW

288
00:10:36,883 --> 00:10:37,383
PROTEINS HAVE CHANGED.

289
00:10:37,383 --> 00:10:38,784
THIS IS FROM OUR FULL ANALYSIS

290
00:10:38,784 --> 00:10:40,586
AND THIS IS WITH ADJUSTMENT FOR

291
00:10:40,586 --> 00:10:42,355
CO VALID AND RELIABLEIATES,

292
00:10:42,355 --> 00:10:44,657
REALLY TRYING TO UNDERSTAND WHAT

293
00:10:44,657 --> 00:10:45,525
MECHANISTICALLY RELEVANT,

294
00:10:45,525 --> 00:10:46,759
THEY'RE NOT SIMPLY BIOMARKERS

295
00:10:46,759 --> 00:10:48,961
BUT YOU CAN SEE GD15 RISING WELL

296
00:10:48,961 --> 00:10:50,530
ABOVE THE REST AND THEN A NUMBER

297
00:10:50,530 --> 00:10:54,267
OF OTHER ABOUT 30 PROTEINS THAT

298
00:10:54,267 --> 00:10:55,868
PASS THE [INDISCERNIBLE] FOR ANY

299
00:10:55,868 --> 00:10:57,570
CORRECTED LEVEL OF STATISTICAL

300
00:10:57,570 --> 00:10:59,572
SIGNIFICANCE, SO WE TOOK A

301
00:10:59,572 --> 00:11:00,673
DEEPER DIVE INTO THIS SET OF

302
00:11:00,673 --> 00:11:01,841
PROTEIN ANDS THIS IS THE SET

303
00:11:01,841 --> 00:11:03,609
FROM THE FULL FOLLOW UP, WE DID

304
00:11:03,609 --> 00:11:04,477
FOLLOW UP WITHIN 15 YEARS WHICH

305
00:11:04,477 --> 00:11:07,680
WE THINK OF PROEN TOOS IS

306
00:11:07,680 --> 00:11:10,216
REGULATED CLOSER TO THE TIME OF

307
00:11:10,216 --> 00:11:13,819
DEMENTIA ONSET AND THEN BEYOND

308
00:11:13,819 --> 00:11:14,887
[INDISCERNIBLE] PROTEINS THAT

309
00:11:14,887 --> 00:11:16,989
ARE REGULATED WELL, WELL BEFORE

310
00:11:16,989 --> 00:11:17,356
DEMENTIA ONSET.

311
00:11:17,356 --> 00:11:18,791
LET ME BACK UP BECAUSE I WANT TO

312
00:11:18,791 --> 00:11:20,760
EMPHASIZE A FEW THINGS, AT BASE

313
00:11:20,760 --> 00:11:23,296
LINE, PEOPLE WERE IN THEIR 60S

314
00:11:23,296 --> 00:11:24,797
HERE AND NONDEMENTED WHEN WE

315
00:11:24,797 --> 00:11:25,765
MEASURED PROTEINS.

316
00:11:25,765 --> 00:11:27,466
SO WE'RE CONSIDERING THIS LIKE

317
00:11:27,466 --> 00:11:29,435
LATE MIDLIFE AND AGAIN PROTEINS

318
00:11:29,435 --> 00:11:32,204
WERE MEASURED BEFORE PEOPLE

319
00:11:32,204 --> 00:11:34,273
DEVELOP DEMENTIA, WE HAD ABOUT

320
00:11:34,273 --> 00:11:36,542
2000 DEMENTIA CASES OCCUR OVER

321
00:11:36,542 --> 00:11:38,344
THE 25 YEAR FOLLOW UP PERIOD.

322
00:11:38,344 --> 00:11:43,082
NOW 1 THING WE WANTED TO REALLY

323
00:11:43,082 --> 00:11:45,618
TRY TO DRILL DOWN ON IS WHETHER

324
00:11:45,618 --> 00:11:48,054
THESE PROTEINS WERE MIDLIFE

325
00:11:48,054 --> 00:11:49,088
BIOMARKERS, COULD WE FIND

326
00:11:49,088 --> 00:11:50,990
PROTEINS IN 40 AND 50 YEAR-OLDS

327
00:11:50,990 --> 00:11:54,093
THAT PREDICTED A CONDITION THAT

328
00:11:54,093 --> 00:11:55,628
WAS PREDOMINANTLY AFFECTED OLDER

329
00:11:55,628 --> 00:11:56,228
ADULTS.

330
00:11:56,228 --> 00:11:58,965
SO WE SPLIT THE SAMPLE IN HALF,

331
00:11:58,965 --> 00:12:00,199
PARTIC PAPTS BELOW AGE 60, AND

332
00:12:00,199 --> 00:12:01,968
COMPARED THAT OUT OF THE RATIO,

333
00:12:01,968 --> 00:12:05,071
THAT EFFECT SIZE, BETWEEN THOSE

334
00:12:05,071 --> 00:12:08,541
YOUNGER INDIVIDUALS BELOW 60 AND

335
00:12:08,541 --> 00:12:11,210
THE FULL SAMPLE AND REALLY THESE

336
00:12:11,210 --> 00:12:13,145
ESTIMATES STAYED FAIRLY SIMILAR

337
00:12:13,145 --> 00:12:14,447
AND SOMETIMES EVEN STRENGTHENED

338
00:12:14,447 --> 00:12:24,957
SO WE REALLY DO THINK WE HAVE

339
00:12:29,996 --> 00:12:30,129
IT.

340
00:12:30,129 --> 00:12:31,664
SO WE LOOK AT OUR TOP PROTEIN

341
00:12:31,664 --> 00:12:34,767
AND WE ASK WHAT ARE INVOLVE WIDE

342
00:12:34,767 --> 00:12:37,770
THEM, WE SEE THEY'RE RELEVANT TO

343
00:12:37,770 --> 00:12:38,804
PROTEIN COMPLEXIO STASIS AND

344
00:12:38,804 --> 00:12:41,007
FUNCTION AND OTHER BIOLOGIC

345
00:12:41,007 --> 00:12:42,074
PATHWAYS, IT AND THIS WE'RE

346
00:12:42,074 --> 00:12:44,243
HAPPY TO SEE BECAUSE IT IS

347
00:12:44,243 --> 00:12:45,645
SUPPORTED BY GWAS, IMMUNE

348
00:12:45,645 --> 00:12:47,346
DYSFUNCTION COMES OUT PROBABLY

349
00:12:47,346 --> 00:12:50,016
THE MOST, YOU KNOW STRONGLY

350
00:12:50,016 --> 00:12:53,352
ENRICHED PATHWAY, IF YOU LOOK AT

351
00:12:53,352 --> 00:12:54,920
GWAS HITS FOR ALZHEIMER'S

352
00:12:54,920 --> 00:12:56,355
DISEASE, AND WE'RE SEEING SOME

353
00:12:56,355 --> 00:12:58,024
REFLECTION OF THAT DUE TO

354
00:12:58,024 --> 00:13:00,726
PROTEOME, THAT'S LARGELY WHAT WE

355
00:13:00,726 --> 00:13:03,262
SAW IN SOME SYNAPTIC PROTEINS

356
00:13:03,262 --> 00:13:04,563
AND THAT MAKES SENSE AS WELL,

357
00:13:04,563 --> 00:13:06,165
BUT WHAT WAS A MORE INTERESTING

358
00:13:06,165 --> 00:13:09,468
WAY TO UNDERSTAND BIOLOGY OF THE

359
00:13:09,468 --> 00:13:10,536
PROTEOMIC SIGNATURE IN MY

360
00:13:10,536 --> 00:13:12,171
OPINION WAS THE APPROACH TO THE

361
00:13:12,171 --> 00:13:16,375
NETWORK ANALYSIS, MANY OF YOU

362
00:13:16,375 --> 00:13:21,847
ARE FAMILIAR WITH WGCNA, SO WE

363
00:13:21,847 --> 00:13:23,482
AMRI THAD TO OUR MIDDLE AGED

364
00:13:23,482 --> 00:13:23,983
ADULTS.

365
00:13:23,983 --> 00:13:25,985
SO WE CLUSTERED PENAL, WE

366
00:13:25,985 --> 00:13:28,587
CLUSTERED PROTEINS BASED ON A CO

367
00:13:28,587 --> 00:13:29,889
EXPRESSION OR ESSENTIALLY THE

368
00:13:29,889 --> 00:13:31,323
CORRELATION, IT IT'S A BIT MORE

369
00:13:31,323 --> 00:13:32,491
COMPLEX THAN THAT, WHEN WE LOOK

370
00:13:32,491 --> 00:13:35,628
AT GROUPS OF HIGHLY CORRELATED

371
00:13:35,628 --> 00:13:36,796
PROTEINS, WE FOUND 19 DIFFERENT

372
00:13:36,796 --> 00:13:39,365
GROUPS OR MODULES AND WE TOOK

373
00:13:39,365 --> 00:13:41,000
THE FIRST PRINCIPLE COMPONENT OF

374
00:13:41,000 --> 00:13:43,069
EACH OF MODULES AND USE THEM AS

375
00:13:43,069 --> 00:13:44,704
PREDICTERS BUT YOU CAN SEE THEM

376
00:13:44,704 --> 00:13:46,706
AS BEING USED HERE, THIS IS A

377
00:13:46,706 --> 00:13:48,808
BIG MODULE AND THIS IS A SMALL

378
00:13:48,808 --> 00:13:51,610
MODULE HERE AND SO WE RAINCHL IN

379
00:13:51,610 --> 00:13:52,511
SIZE FROM 28-2000.

380
00:13:52,511 --> 00:13:54,613
AND THESE ARE BIOLOGICALLY

381
00:13:54,613 --> 00:14:01,187
RELEVANT, SO WHAT WE DID,

382
00:14:01,187 --> 00:14:02,755
ANNOTATION, OR REPRESENTATION

383
00:14:02,755 --> 00:14:04,023
ANALYSIS STATISTICALLY, WHAT

384
00:14:04,023 --> 00:14:04,990
THESE MODELS REPRESENTED BUT WE

385
00:14:04,990 --> 00:14:08,728
ALSO LOOK AT EACH MODEL

386
00:14:08,728 --> 00:14:09,428
PREDICTED EACH ARREST.

387
00:14:09,428 --> 00:14:11,297
WE HAD 19 OF THEM AND WE HAD

388
00:14:11,297 --> 00:14:14,767
MODULES THAT WERE LEFT OVERS BUT

389
00:14:14,767 --> 00:14:15,935
WE HAD, 1, 2, 3, DIFFERENT

390
00:14:15,935 --> 00:14:18,938
MODELS THAT WERE PREDICTIVE OF

391
00:14:18,938 --> 00:14:20,639
25 DIFFERENT DEMENTIA RISK FOR

392
00:14:20,639 --> 00:14:22,408
ADJUSTING FOR OUR CO VARIANT,

393
00:14:22,408 --> 00:14:25,010
NOW WE SAW A SEPARATE MODULE

394
00:14:25,010 --> 00:14:28,314
WHEN WE LOOKED AT NEAR TERM

395
00:14:28,314 --> 00:14:30,483
DEMENTIA RISK WITHIN 15 YEARS.

396
00:14:30,483 --> 00:14:32,485
SO WE LEGALLY PINNED DOWN THE 4

397
00:14:32,485 --> 00:14:34,120
MODULES AND WE WERE ABLE TO

398
00:14:34,120 --> 00:14:36,889
UNDERSTAND THE BIOLOGY AGAIN

399
00:14:36,889 --> 00:14:38,491
THROUGH OVERREPRESENTATION AND

400
00:14:38,491 --> 00:14:40,659
ANALYSIS, BED THE DIRECTIONALITY

401
00:14:40,659 --> 00:14:42,528
BASED ON HOW THE INDIVIDUAL

402
00:14:42,528 --> 00:14:44,130
PROTEIN AND PATHWAY LOADED ON TO

403
00:14:44,130 --> 00:14:45,531
THE MODULE AND WE'RE ABLE TO

404
00:14:45,531 --> 00:14:50,503
MAKE SOME STATEMENTS ABOUT THE

405
00:14:50,503 --> 00:14:54,373
EVOLVING BIOLOGY LEADING UP TO

406
00:14:54,373 --> 00:14:57,176
DEMENTIA ONSET, SO WHAT I FOUND

407
00:14:57,176 --> 00:14:59,211
WAS INTERESTING WAS THE

408
00:14:59,211 --> 00:15:00,513
IMMUNOLOGIC SIGNATURE, A LOT OF

409
00:15:00,513 --> 00:15:04,550
MODELS HAVE BEEN PREDICTIVE FOR

410
00:15:04,550 --> 00:15:07,019
PROTEINS AND IMMUNE SPECIFIC

411
00:15:07,019 --> 00:15:08,287
PATHWAY, THINGS LIKE JAK STATS

412
00:15:08,287 --> 00:15:10,055
AND THE LANGUAGE THAT'S DOWN

413
00:15:10,055 --> 00:15:11,357
REGULATED AND OTHER IMMUNE

414
00:15:11,357 --> 00:15:14,226
ASSPECS OF FUNCTION WITH THE

415
00:15:14,226 --> 00:15:15,161
GENERAL IMMUNE RESPONSE,

416
00:15:15,161 --> 00:15:17,997
LYMPHOCYTE ACTIVATION AND OTHER

417
00:15:17,997 --> 00:15:20,666
MODELS THAT ARE UPREGULATED.

418
00:15:20,666 --> 00:15:23,202
SO THE COMPLEX IMMUNO DYNAMIC,

419
00:15:23,202 --> 00:15:24,703
AS PEOPLE GET CLOSER AND CLOSER

420
00:15:24,703 --> 00:15:28,274
TO DEMENTIA OBLIGATIONS SET AND

421
00:15:28,274 --> 00:15:30,209
IN--ONSET, AND IN MODEL 19 WE

422
00:15:30,209 --> 00:15:31,477
SEE MORE COAGULATION AND

423
00:15:31,477 --> 00:15:35,347
COMPLEMENT AMONG OTHER THINGS

424
00:15:35,347 --> 00:15:35,781
BEING DISREGULATED.

425
00:15:35,781 --> 00:15:38,017
SO WE'RE ABLE TO LEARN A LITTLE

426
00:15:38,017 --> 00:15:40,486
BIT ABOUT THE BIOLOGY WELLING UP

427
00:15:40,486 --> 00:15:41,086
TO DEMENTIA ONSET.

428
00:15:41,086 --> 00:15:43,389
WE DID A NUMBER OF OTHER THINGS

429
00:15:43,389 --> 00:15:53,933
WE APPLIED 2 SIMPLE MEN DEALIAN

430
00:15:54,900 --> 00:15:55,401
 DEALIAN

431
00:15:55,401 --> 00:15:55,734
RANDOMIZATION.

432
00:15:55,734 --> 00:15:58,370
THIS SIGNIFY VERSE SET OF

433
00:15:58,370 --> 00:16:00,773
BIOMARKERS GAZ BEYOND AMYLOID

434
00:16:00,773 --> 00:16:02,174
GOES BEYOND TAU, THAT I

435
00:16:02,174 --> 00:16:05,177
MENTIONED EARLIER AND HERE WE

436
00:16:05,177 --> 00:16:08,214
HAVE BIOMARKERS, IN DYSFUNCTION

437
00:16:08,214 --> 00:16:09,648
SYNAPTIC FUNCTION AND EXTRA

438
00:16:09,648 --> 00:16:11,083
CELLULAR MATE RICK ORGANIZATION

439
00:16:11,083 --> 00:16:13,285
AND VASCULAR PROCESSES THAT ARE

440
00:16:13,285 --> 00:16:14,987
PREDICTIVE OF DEMENTIA, AND WE

441
00:16:14,987 --> 00:16:17,156
THINK ARE YOU KNOW POTENTIALLY

442
00:16:17,156 --> 00:16:18,524
RELEVANT BY O MARKERS IN

443
00:16:18,524 --> 00:16:20,993
MIDLIFE, THEY GIVE US A SENSE OF

444
00:16:20,993 --> 00:16:21,961
DISEASE, HETEROGENEITY AND

445
00:16:21,961 --> 00:16:24,763
HOPEFULLY A WAY IN A MORE

446
00:16:24,763 --> 00:16:26,031
PERSONALIZED WAY UNDERSTAND

447
00:16:26,031 --> 00:16:26,365
WHAT'S DRIVING

448
00:16:26,365 --> 00:16:30,536
DEM-TEBURKEULOSEISIA RISK AS THE

449
00:16:30,536 --> 00:16:32,972
INDIVIDUAL LEVEL NOW WE

450
00:16:32,972 --> 00:16:34,006
UNDERSTAND,--FROM THIS WE GAINED

451
00:16:34,006 --> 00:16:35,975
A LOT OF INFORMATION ABOUT THE

452
00:16:35,975 --> 00:16:38,310
EARLY BIOLOGY, AT LEAST

453
00:16:38,310 --> 00:16:39,478
PERIPHERALLY AHEAD OF DEMENTIA

454
00:16:39,478 --> 00:16:42,248
ONSET BUT WE DON'T YET KNOW HOW

455
00:16:42,248 --> 00:16:43,482
WELL, QUANTITATIVELY THIS

456
00:16:43,482 --> 00:16:46,151
INDIVIDUAL PROTEINS OR THE

457
00:16:46,151 --> 00:16:47,119
COMBINATION PREDICT DEMENTIA

458
00:16:47,119 --> 00:16:50,155
RISK, LIKE DO WE HAVE A TOOL

459
00:16:50,155 --> 00:16:51,924
HERE THAT WE CAN USE FOR PEOPLE

460
00:16:51,924 --> 00:16:52,758
CONCERNED ABOUT THE DEMENTIA

461
00:16:52,758 --> 00:16:56,161
RISK IN THE POPULATION,

462
00:16:56,161 --> 00:16:59,298
PARTICULARLY MIDDLE AGED ADULTS

463
00:16:59,298 --> 00:17:00,766
WHICH IS KIND OF RISKY BUSINESS,

464
00:17:00,766 --> 00:17:04,637
YOU KNOW, YOU DON'T WANT TO

465
00:17:04,637 --> 00:17:06,372
MISPREDICT SOMEONE IN THEIR 40S

466
00:17:06,372 --> 00:17:08,307
AS BEING IMMINENTLY AT RISK FOR

467
00:17:08,307 --> 00:17:09,775
DEMENTIA AND HAVE A LARGE AND

468
00:17:09,775 --> 00:17:12,912
EKING 95 IMPACT ON THEIR LIFE.

469
00:17:12,912 --> 00:17:15,114
SO WE TESTED OUR--WE BUILT A

470
00:17:15,114 --> 00:17:20,019
PROTEIN RISK SCORE TO PREDICT 20

471
00:17:20,019 --> 00:17:21,220
YEAR RISK, USING THIS HERE AND

472
00:17:21,220 --> 00:17:24,957
CAME DOWN TO RUNNING A SIMILAR

473
00:17:24,957 --> 00:17:26,358
ANALYSIS, YOU KNOW WITHOUT THE

474
00:17:26,358 --> 00:17:28,727
ADJUSTMENT BECAUSE WE'RE

475
00:17:28,727 --> 00:17:30,129
INTERESTED IN APPROACHING

476
00:17:30,129 --> 00:17:31,864
PREDICTIVE POWER, AND WE USE IT

477
00:17:31,864 --> 00:17:34,700
WITHIN CROSS VALIDATION AND

478
00:17:34,700 --> 00:17:36,835
THAT, WE DERIVED THE OPTIMIZED

479
00:17:36,835 --> 00:17:40,072
25 PROTEIN MODULE AND THIS IS

480
00:17:40,072 --> 00:17:41,373
FROM A 70% TRAINING SET.

481
00:17:41,373 --> 00:17:43,342
SO WE'RE USING THE SAME COHORT,

482
00:17:43,342 --> 00:17:46,111
BUT THEN WE TUNED IT AND TESTED

483
00:17:46,111 --> 00:17:50,282
IT IN 15% AND 15%, THE REST OF

484
00:17:50,282 --> 00:17:51,850
THE COHORT AND SO FROM THIS WE

485
00:17:51,850 --> 00:17:53,852
GOT THE 25 PROTEIN COMPOSITES

486
00:17:53,852 --> 00:17:55,521
FOR WHICH YOU WILL SEE REFERRED

487
00:17:55,521 --> 00:17:58,424
TO AS THE DEMENTIA SOMA SIGNAL

488
00:17:58,424 --> 00:18:00,759
TEST OR THE SST, THAT'S

489
00:18:00,759 --> 00:18:02,828
PREDICTIVE TO AN EXTENT OF 20

490
00:18:02,828 --> 00:18:04,930
YEAR DEMENTIA, AND WE WERE ABLE

491
00:18:04,930 --> 00:18:07,299
TO DEFINE SOMEONE'S ABSOLUTE 20

492
00:18:07,299 --> 00:18:09,501
YEAR REZ AND PUT PEOPLE INTO 4

493
00:18:09,501 --> 00:18:11,103
RISK BIN ANDS THIS WAS WORK THAT

494
00:18:11,103 --> 00:18:13,539
WAS LED BY CLAIR PATTERSON AND

495
00:18:13,539 --> 00:18:18,177
MICHAEL DUG AN WHO IS A POST DOC

496
00:18:18,177 --> 00:18:19,078
IN MY LAB.

497
00:18:19,078 --> 00:18:24,283
SO HERE'S THE RESULTS FROM THE

498
00:18:24,283 --> 00:18:26,151
TRAINING AND VALIDATIONS SHOWN

499
00:18:26,151 --> 00:18:28,554
ON THE ROC CURVE BUT THE BOTTOM

500
00:18:28,554 --> 00:18:30,756
LINE THE TEST JUST 25 PROTEINS

501
00:18:30,756 --> 00:18:37,162
BY THEMSELVES, THE AUC, FOR

502
00:18:37,162 --> 00:18:39,898
DEMENTIA PREDICTION WAS .73, SO

503
00:18:39,898 --> 00:18:42,601
IT'S NOT EXCELLENT, IT'S LIKE

504
00:18:42,601 --> 00:18:42,835
OKAY.

505
00:18:42,835 --> 00:18:44,470
NOTHING TO WRITE HOME ABOUT BUT

506
00:18:44,470 --> 00:18:46,472
WE HAVE TO RECOGNIZE WHAT WE'RE

507
00:18:46,472 --> 00:18:47,172
PREDICTING WITH THAT 20 YEARS

508
00:18:47,172 --> 00:18:48,707
INTO THE FUTURE AND THERE'S A

509
00:18:48,707 --> 00:18:52,244
LOT OF COMPETING THINGS THAT CAN

510
00:18:52,244 --> 00:18:54,079
HAPPEN TO AN INDIVIDUAL OVER

511
00:18:54,079 --> 00:18:55,214
THOSE 20 YEAR PERIOD.

512
00:18:55,214 --> 00:18:57,282
SO IN THAT CONTEXT, IT'S OKAY,

513
00:18:57,282 --> 00:18:59,485
AGE OBVIOUSLY THE STRONGEST RISK

514
00:18:59,485 --> 00:19:05,491
DEMENTIA FACTOR RELEVANT BUT NOT

515
00:19:05,491 --> 00:19:06,258
SO CLINICALLY RELEVANT.

516
00:19:06,258 --> 00:19:09,061
HOW DO WE DO WHEN WE COMBINE AGE

517
00:19:09,061 --> 00:19:11,363
WITH THE SOMA SIGNAL TEST, WELL

518
00:19:11,363 --> 00:19:14,433
THEN WE GET INTO PREDICTABLE

519
00:19:14,433 --> 00:19:16,602
ACCURACY NUMBERS WHERE WE SEE AN

520
00:19:16,602 --> 00:19:18,237
APPOINTEE, SO WE THINK WITH

521
00:19:18,237 --> 00:19:19,638
THESE 25 PROTEINS PLUS KNOWING

522
00:19:19,638 --> 00:19:21,373
AN INDIVIDUAL'S AGE, WE CAN DO

523
00:19:21,373 --> 00:19:25,878
FAIRLY WELL IN PREDICTING YOUR

524
00:19:25,878 --> 00:19:28,881
20 YEAR DEMENTIA RISK AND THIS

525
00:19:28,881 --> 00:19:32,584
OUT  PERFORMS THE MAJOR DEMENTIA

526
00:19:32,584 --> 00:19:34,219
RISK GENE JUST IN COMPARISON BUT

527
00:19:34,219 --> 00:19:35,988
I WILL MENTION OTHERS LEALTER.

528
00:19:35,988 --> 00:19:39,725
SO I MENTIONED WE STRATIFIED

529
00:19:39,725 --> 00:19:43,662
PEOPLE INTO QUAR TILES, WE PUT

530
00:19:43,662 --> 00:19:45,397
PEOPLE AT MEDIUM LOW AND MEDE

531
00:19:45,397 --> 00:19:46,999
HIGH RISK BINS AND WE WERE ABLE

532
00:19:46,999 --> 00:19:50,102
TO SEE HOW MUCH MORE LIKELY YOU

533
00:19:50,102 --> 00:19:51,770
WERE TO DEVELOP DEMENTIA IF YOU

534
00:19:51,770 --> 00:19:53,572
WERE PUT IN THE HIGH RISK BIN

535
00:19:53,572 --> 00:19:56,742
COMPARED TO THE LOW RISK BIN AND

536
00:19:56,742 --> 00:19:58,844
THAT DIFFERENCE WAS ALMOST 10

537
00:19:58,844 --> 00:20:00,879
FOLD, 9-10 FOLD, WHERE YOU SEE

538
00:20:00,879 --> 00:20:02,948
HERE THE PERSPECTIVE PLOT, IF

539
00:20:02,948 --> 00:20:04,917
YOU WERE THE LOW RISK THEN,

540
00:20:04,917 --> 00:20:06,785
WELL, IF YOU WERE IN THE HIGH

541
00:20:06,785 --> 00:20:09,121
RISK BIN, YOU HAD 10 TIMES MORE

542
00:20:09,121 --> 00:20:11,090
HIGHER LIKELIHOOD OF DEVELOPING

543
00:20:11,090 --> 00:20:12,024
DEMENTIA OVER THE 20 YEAR PERIOD

544
00:20:12,024 --> 00:20:13,759
THAN SOMEONE IN THE LOW RISK,

545
00:20:13,759 --> 00:20:15,828
THEN, SO WE THINK THERE'S QUITE

546
00:20:15,828 --> 00:20:17,930
A BIT OF CERTAINTY AT LEAST

547
00:20:17,930 --> 00:20:20,666
ESPECIALLY IN THESE HIGH AND LOW

548
00:20:20,666 --> 00:20:24,970
RISK CATEGORIES OF PERSONS OF

549
00:20:24,970 --> 00:20:25,637
LESS CERTAINTY HERE.

550
00:20:25,637 --> 00:20:27,706
OKAY, SO WHAT ABOUT OTHER

551
00:20:27,706 --> 00:20:27,973
BENCHMARK.

552
00:20:27,973 --> 00:20:33,078
HOW WELL DOES IT DO AGAINST

553
00:20:33,078 --> 00:20:34,246
QUOTE-UNQUOTE GOLD DEMENTIA

554
00:20:34,246 --> 00:20:40,619
PREDICTORS OF RISK. 

555
00:20:40,619 --> 00:20:43,822
RIGHT NOW WE HAVE THIS IN THE

556
00:20:43,822 --> 00:20:45,023
PATHOGENESIS, WELL, ANOTHER

557
00:20:45,023 --> 00:20:46,191
EXCITING THING THAT'S HAPPENING

558
00:20:46,191 --> 00:20:47,426
IN ALZHEIMER'S DISEASES IS THESE

559
00:20:47,426 --> 00:20:49,027
PROTEINS HAVE BEEN, YOU KNOW

560
00:20:49,027 --> 00:20:51,463
MEASURABLE, NOW IN BLOOD, PRETTY

561
00:20:51,463 --> 00:20:53,098
ACCURATELY AND SO THERE'S A LOT

562
00:20:53,098 --> 00:20:55,868
OF EXCITEMENT ABOUT THE ABILITY

563
00:20:55,868 --> 00:20:57,836
TO PREDICT ALZHEIMER'S DISEASE

564
00:20:57,836 --> 00:20:59,905
OR IDENTIFY ALZHEIMER'S DEC

565
00:20:59,905 --> 00:21:00,973
USING BLOOD TESTS, YOU MAY HAVE

566
00:21:00,973 --> 00:21:02,040
HEARD ABOUT THIS IN YOUR OWN

567
00:21:02,040 --> 00:21:04,776
WORK OR IN THE LAY MEDIA, BUT WE

568
00:21:04,776 --> 00:21:07,112
TOOK SOME OF THESE, YOU KNOW AND

569
00:21:07,112 --> 00:21:09,014
ACKNOWLEDGED THESE ARE NOT THE

570
00:21:09,014 --> 00:21:09,815
STATE-OF-THE-ART NOW, BUT WHEN

571
00:21:09,815 --> 00:21:11,917
WE STARTED THIS STUDY, THEY

572
00:21:11,917 --> 00:21:16,021
WERE, THIS AMYLOID DATA MEASURE

573
00:21:16,021 --> 00:21:20,792
AND TAU, PTAU181, THIS IS A TAU

574
00:21:20,792 --> 00:21:22,528
PHOSPHO TYPE, AND WE COMPARED

575
00:21:22,528 --> 00:21:25,797
THEM TO OUR DEMENTIA SOMA SIGNAL

576
00:21:25,797 --> 00:21:26,064
TEST.

577
00:21:26,064 --> 00:21:29,968
YES, QUESTION?

578
00:21:29,968 --> 00:21:35,040
DID EMPLOY [INAUDIBLE QUESTION

579
00:21:35,040 --> 00:21:39,011
FROM AUDIENCE ] PREDICTIVE

580
00:21:39,011 --> 00:21:41,747
MODEL? 

581
00:21:41,747 --> 00:21:42,881
NO WE HAVEN'T.

582
00:21:42,881 --> 00:21:44,917
[INAUDIBLE QUESTION FROM

583
00:21:44,917 --> 00:21:46,418
AUDIENCE ] IT IS, IT IS BUT IT'S

584
00:21:46,418 --> 00:21:47,252
NOT SOMETHING, SO WE'RE TRYING

585
00:21:47,252 --> 00:21:51,990
TO HAVE A TOOL HERE THAT WE

586
00:21:51,990 --> 00:21:54,626
QUITE GENTLEMENLY IF IT MEETS A

587
00:21:54,626 --> 00:21:57,129
STANDARD, NOT NECESSARILY OUR

588
00:21:57,129 --> 00:21:58,430
STANDARD BUT FAMILY HISTORY IS 1

589
00:21:58,430 --> 00:21:59,631
OF THE THINGS LIKE A LOT OF

590
00:21:59,631 --> 00:22:01,466
PEOPLE DO HAVE ISSUES SAY YOUR

591
00:22:01,466 --> 00:22:03,669
PATIENT DIES AT 50, 60, YOU KNOW

592
00:22:03,669 --> 00:22:06,405
THEY MAY DIE BEFORE THEY HAVE A

593
00:22:06,405 --> 00:22:07,806
CHANCE TO EXPRESS THE

594
00:22:07,806 --> 00:22:08,874
DEMETROPOLITANNIA ITSELF, SO A

595
00:22:08,874 --> 00:22:10,409
LOT OF FAMILY HISTORY OF

596
00:22:10,409 --> 00:22:12,711
DEMENTIA THAT'S NOT NECESSARILY

597
00:22:12,711 --> 00:22:19,251
THERE,  ESSENTIALLY, YOU KNOW

598
00:22:19,251 --> 00:22:21,453
LIKE MY MOM'S FIERGT DIED AT 50

599
00:22:21,453 --> 00:22:25,390
SO WE DON'T KNOW IF HE WOULD

600
00:22:25,390 --> 00:22:26,158
HAVE DEVELOPED ALZHEIMERS, IT

601
00:22:26,158 --> 00:22:27,459
DOES IPT GREATER CREASE YOUR

602
00:22:27,459 --> 00:22:28,327
RISK FOR ALZHEIMER'S DISEASE AND

603
00:22:28,327 --> 00:22:33,232
A LOT OF THAT IS DRIVEN BY

604
00:22:33,232 --> 00:22:35,000
APO-E, POSSESSION WHICH IS THE

605
00:22:35,000 --> 00:22:35,567
MAJOR RISK JEAN.

606
00:22:35,567 --> 00:22:42,941
YOU CAN THINK OF THIS AS A

607
00:22:42,941 --> 00:22:44,710
PROXY, YEAH, SO YEAH, TO THAT

608
00:22:44,710 --> 00:22:46,678
EXTENT, LIKE WE TRY TO

609
00:22:46,678 --> 00:22:49,948
INCORPORATE THE BASE OF THE

610
00:22:49,948 --> 00:22:51,550
PREDICT OR AND WE DID OUT 

611
00:22:51,550 --> 00:22:54,486
PERFORM THAT AND WE DIDN'T FILL

612
00:22:54,486 --> 00:22:55,687
THEM UP BECAUSE WE WANTED THEM

613
00:22:55,687 --> 00:22:59,391
TO BE AS EASY AS POSSIBLE.

614
00:22:59,391 --> 00:23:03,829
SO HOW DID THE 2 COMPARED TO THE

615
00:23:03,829 --> 00:23:04,997
STATE-OF-THE-ART MEASURES OR

616
00:23:04,997 --> 00:23:05,931
FOREMOST STATE-OF-THE-ART

617
00:23:05,931 --> 00:23:06,865
MEASURES, SO IT DOES OUT 

618
00:23:06,865 --> 00:23:09,134
PERFORM EACH OF THEM AND IT OUT 

619
00:23:09,134 --> 00:23:10,168
PERFORMS THE COMBINATION, YOU

620
00:23:10,168 --> 00:23:12,070
SEE, WE'RE STILL HOVERING AT

621
00:23:12,070 --> 00:23:13,939
ABOUT .7 HERE WITH THE PROTEINS

622
00:23:13,939 --> 00:23:15,707
ALONE AND IT OUT  PERFORMS THE

623
00:23:15,707 --> 00:23:18,677
BIOMARKERS WHICH ARE THESE 4

624
00:23:18,677 --> 00:23:19,745
PROTEINS IN COMBINATION AND WHEN

625
00:23:19,745 --> 00:23:22,814
THEY'RE ALSO TOGETHER, WE GET A

626
00:23:22,814 --> 00:23:26,551
LITTLE BETTER AS WELL EMPLOY SO

627
00:23:26,551 --> 00:23:28,620
WE'RE BEATING AMYLOID, AND TAU

628
00:23:28,620 --> 00:23:31,923
ITSELF WHEN PREDICKING

629
00:23:31,923 --> 00:23:32,824
CLINICALLY RELEVANT DEMENTIA CAN

630
00:23:32,824 --> 00:23:34,493
WE THEN WANTED TO KNOW, OKAY,

631
00:23:34,493 --> 00:23:38,230
HOW WAS THE SCORE APPLIED TO

632
00:23:38,230 --> 00:23:40,599
OLDER ADULTS AND IT SEEMS TO DO

633
00:23:40,599 --> 00:23:48,206
BETTER THERE, WHEN YOU BRING THE

634
00:23:48,206 --> 00:23:50,742
SCORE AND APPLIED TO 60, 70, 80

635
00:23:50,742 --> 00:23:52,477
YEARS OLD, THOSE IN THE HIGH

636
00:23:52,477 --> 00:23:54,346
RISK BIN ARE ABOUT 13 TIMES

637
00:23:54,346 --> 00:23:56,214
HIGHER OR MORE LIKELY TO DEVELOP

638
00:23:56,214 --> 00:23:57,149
DEMENTIA OVER THIS 5 YEAR

639
00:23:57,149 --> 00:23:59,985
PERIOD, THAN THOSE IN THE LOW

640
00:23:59,985 --> 00:24:00,619
RISK BIN.

641
00:24:00,619 --> 00:24:02,554
SO WE'RE HAPPY TO SEE THAT AND

642
00:24:02,554 --> 00:24:04,156
THIS IS WITHOUT ANY

643
00:24:04,156 --> 00:24:07,426
RECALIBRATION OR THIS LATER LIFE

644
00:24:07,426 --> 00:24:09,394
PERIOD AND AGAIN IT OUT 

645
00:24:09,394 --> 00:24:10,228
PERFORMED, YOU SEE EVERYTHING A

646
00:24:10,228 --> 00:24:11,697
LITTLE BIT BETTER HERE BUT OUR

647
00:24:11,697 --> 00:24:13,265
MEASURES STILL OUT  PERFORMED

648
00:24:13,265 --> 00:24:15,400
THE STANDARD GOLD MEASURES AND

649
00:24:15,400 --> 00:24:17,636
IN COMBINATION, THEY DO REALLY

650
00:24:17,636 --> 00:24:17,836
WELL.

651
00:24:17,836 --> 00:24:20,172
SO WE TOOK IT OUT OF SAMPLE AND

652
00:24:20,172 --> 00:24:21,807
THE STUDY ARE AGING WHICH IS A

653
00:24:21,807 --> 00:24:24,876
COHORT WE HAVE AT NIA AND LOOKED

654
00:24:24,876 --> 00:24:29,047
AT IT WITH EBD O PHENOTYPES MRI

655
00:24:29,047 --> 00:24:30,549
AND SPECIFICALLY MEASURES OF

656
00:24:30,549 --> 00:24:32,150
VOLUME, AND YOU KNOW WHAT WE'RE

657
00:24:32,150 --> 00:24:33,685
SHOWING HERE IS THAT, YOU KNOW

658
00:24:33,685 --> 00:24:35,420
THIS RISK SCORE IS PREDICTIVE OF

659
00:24:35,420 --> 00:24:40,959
BOTH SMALL AND BRAIN VOLUME BUT

660
00:24:40,959 --> 00:24:42,027
ALSO BRAIN ATROPHY IF WE LOOK AT

661
00:24:42,027 --> 00:24:44,396
IT, AND IF WE LOOK TO SEE WHICH

662
00:24:44,396 --> 00:24:46,665
ASPECTS OF THE BRAIN IT ACTUALLY

663
00:24:46,665 --> 00:24:49,634
PREDICTIVE OF, IT'S MEDIAL

664
00:24:49,634 --> 00:24:50,369
TEMPORAL HIPPOCAMPAL REGION

665
00:24:50,369 --> 00:24:51,903
WHICH IS ACTUALLY WHERE WE SEE A

666
00:24:51,903 --> 00:24:54,139
LOT OF THE ATROPHY AND

667
00:24:54,139 --> 00:24:58,176
NEUROPATHOLOGY IN ALZHEIMER'S

668
00:24:58,176 --> 00:24:59,044
DISEASE.

669
00:24:59,044 --> 00:25:00,612
I WAS SPECIAL ASSURANCE THAT WE

670
00:25:00,612 --> 00:25:03,548
WERE BARKING UP THE RIGHT TRAIT.

671
00:25:03,548 --> 00:25:04,850
SO HOW PREDICTIVE WAS THE

672
00:25:04,850 --> 00:25:07,285
AMYLOID, SO THIS IS A KEY

673
00:25:07,285 --> 00:25:09,054
PROTEIN AGGREGATE IN ALZHEIMER'S

674
00:25:09,054 --> 00:25:10,322
DISEASE AND ACTUALLY THE TARGET

675
00:25:10,322 --> 00:25:12,624
OF SOME OF THESE THERAPIES,

676
00:25:12,624 --> 00:25:14,559
WELL, IT IS THE TARGET FOR THE 2

677
00:25:14,559 --> 00:25:16,628
THERAPIES THAT WERE MORE

678
00:25:16,628 --> 00:25:18,864
RECENTLY APPROVED TREATMENT FOR

679
00:25:18,864 --> 00:25:20,932
ALZHEIMER'S DISEASE, SO IT DOES

680
00:25:20,932 --> 00:25:22,667
OKAY BUT IT ACTUALLY UNDER 

681
00:25:22,667 --> 00:25:24,069
PERFORMS THE ACTUAL MEASURE OF

682
00:25:24,069 --> 00:25:26,138
AMYLOID, WHICH IS WHAT WE MIGHT

683
00:25:26,138 --> 00:25:27,105
EXPECT, IN COMBINATION THOUGH,

684
00:25:27,105 --> 00:25:30,208
IT DOES ACTUALLY DO QUIT WELL,

685
00:25:30,208 --> 00:25:31,943
YIELDS BETTER PREDICTION, FOR

686
00:25:31,943 --> 00:25:33,345
AMYLOID POSITIVE STATUS, BUT WE

687
00:25:33,345 --> 00:25:35,213
WOULDN'T PROPOSE TO USE IT TO

688
00:25:35,213 --> 00:25:36,014
MEASURE AMYLOID WHEN CAN YOU

689
00:25:36,014 --> 00:25:39,851
JUST MEASURE THE AMYLOID SOLUBLE

690
00:25:39,851 --> 00:25:41,019
AMYLOID LEVELS IN BLOOD ITSELF,

691
00:25:41,019 --> 00:25:42,888
SO I WILL SKIP THROUGH THIS

692
00:25:42,888 --> 00:25:44,189
SUMMARY, BUT SOME OF THE USE

693
00:25:44,189 --> 00:25:45,924
CASES ARE IMPORTANT TO TALK

694
00:25:45,924 --> 00:25:48,026
ABOUT, TRIAL ENRICHMENT IS A BIG

695
00:25:48,026 --> 00:25:50,529
DEAL FOR ALZHEIMER'S DISEASE, OR

696
00:25:50,529 --> 00:25:54,499
DEMENTIA DRUG TRIALS BECAUSE

697
00:25:54,499 --> 00:25:56,601
THE--YOU KNOW IT'S A VERY

698
00:25:56,601 --> 00:25:57,836
GRADUAL CONDITION, THE TRIALS

699
00:25:57,836 --> 00:26:01,173
HAVE TO BE VERY LONG AND VERY

700
00:26:01,173 --> 00:26:02,874
LARGE ESPECIALLY IF YOU START

701
00:26:02,874 --> 00:26:06,178
TREATING PEOPLE EARLY BEFORE

702
00:26:06,178 --> 00:26:09,014
THEY VISIT VERY SIGNIFICANT

703
00:26:09,014 --> 00:26:10,649
SYMPTOM, COGNITION TENDS TO BE

704
00:26:10,649 --> 00:26:15,420
THE END POINT THAT THE  FDA WILL

705
00:26:15,420 --> 00:26:17,389
APPROVE THE DRUG FOR, AND WE'RE

706
00:26:17,389 --> 00:26:21,660
INTERESTED IN USING FOR THEIR

707
00:26:21,660 --> 00:26:22,394
PHASE 3 PIVOTAL TRIAL.

708
00:26:22,394 --> 00:26:24,629
SO IF WE CAN FIND PEOPLE WHO ARE

709
00:26:24,629 --> 00:26:27,232
IMMINENTLY ABOUT TO DECLINE, OR

710
00:26:27,232 --> 00:26:30,368
ARE AT HIGHEST RISK FOR ACTUAL

711
00:26:30,368 --> 00:26:31,536
CLINICAL DEMENTIA ONSET THEN WE

712
00:26:31,536 --> 00:26:36,074
CAN ENRICH OUR TRIAL EVEN IF

713
00:26:36,074 --> 00:26:37,542
WE'RE ENROLLING COGNITIVE

714
00:26:37,542 --> 00:26:38,877
PEOPLE, EVEN IF THEY'RE IN THE

715
00:26:38,877 --> 00:26:41,413
HIGH RISK BEN, WE COULD SAY WITH

716
00:26:41,413 --> 00:26:42,881
ADDITIONAL CERTAINTY THAT THE

717
00:26:42,881 --> 00:26:44,983
PERSON WILL DECLINE AT THEIR

718
00:26:44,983 --> 00:26:45,917
GIIVE TRAJECTORY, LET'S PUT THE

719
00:26:45,917 --> 00:26:47,118
PERSON IN THE TRIAL AND SEE IF

720
00:26:47,118 --> 00:26:49,120
WE CAN SLOW THAT VERSUS THE

721
00:26:49,120 --> 00:26:49,921
PLACEBO.

722
00:26:49,921 --> 00:26:51,089
SO THIS WILL REDUCE SCREEN

723
00:26:51,089 --> 00:26:53,091
FAILURES AS WELL, AND YOU KNOW

724
00:26:53,091 --> 00:26:55,026
THINKING FURTHER ALONG, IT MAY

725
00:26:55,026 --> 00:26:57,295
BE ACTUALLY USE THE PROXY END

726
00:26:57,295 --> 00:26:58,697
POINT IF WE CAN'T OR DON'T HAVE

727
00:26:58,697 --> 00:27:01,967
ENOUGH TIME OR NOT POWERED TO

728
00:27:01,967 --> 00:27:03,101
MEASURE COGNITIVE CHANGES, OR

729
00:27:03,101 --> 00:27:04,302
TARGETING PEOPLE IN THE FIFTH

730
00:27:04,302 --> 00:27:06,371
DECADE OF LIFE, BUT WE DON'T

731
00:27:06,371 --> 00:27:07,539
EXPECT CHANGES, YOU MAY BE ABLE

732
00:27:07,539 --> 00:27:09,741
TO USE THIS AS A PROXY END POINT

733
00:27:09,741 --> 00:27:11,610
TO SEE IF, HEY, YOU'RE

734
00:27:11,610 --> 00:27:12,544
INTERVENTION ACTUALLY MOVES THE

735
00:27:12,544 --> 00:27:16,581
NEEDLE IN TERMS OF REDUCING

736
00:27:16,581 --> 00:27:19,818
DEMENTIA RISK, YOU KNOW FURTHER

737
00:27:19,818 --> 00:27:20,752
ALONG AS INDIVIDUALS AGE.

738
00:27:20,752 --> 00:27:22,954
SO NOW I'M GOING TO SWITCH GEARS

739
00:27:22,954 --> 00:27:25,457
AND TALK ABOUT ANOTHER

740
00:27:25,457 --> 00:27:27,959
APPLICATION, WHERE I MENTIONED

741
00:27:27,959 --> 00:27:30,328
EARLIER IN MY INTEREST IN THE

742
00:27:30,328 --> 00:27:32,697
IMMUNE SYSTEM AS IT RELATES TO

743
00:27:32,697 --> 00:27:33,598
ALZHEIMER'S DISEASE AND 1 OF THE

744
00:27:33,598 --> 00:27:37,369
THINGS THAT HAS BECOME FAIRLY

745
00:27:37,369 --> 00:27:38,637
APPARENT ESPECIALLY IN WAKE OF

746
00:27:38,637 --> 00:27:45,043
COVID IS THAT INFECTION AND

747
00:27:45,043 --> 00:27:47,412
IMMUNE ACTIVATION ISN'T SEVERE

748
00:27:47,412 --> 00:27:48,179
INFLAMMATORY INSULTS CAN AFFECT

749
00:27:48,179 --> 00:27:48,747
BRAIN FUNCTION.

750
00:27:48,747 --> 00:27:51,283
SO I WANTED TO UNDERSTAND THIS

751
00:27:51,283 --> 00:27:52,584
LINK WE'RE SEEING BETWEEN HAVING

752
00:27:52,584 --> 00:27:57,856
AN INFECTION AND RISK FOR

753
00:27:57,856 --> 00:28:00,258
DEMENTIA ONSET AND SO TO BE

754
00:28:00,258 --> 00:28:01,560
CLEAR THOUGH I'M TALKING ABOUT

755
00:28:01,560 --> 00:28:02,594
SEVERE INFECTIONS NOT YOUR

756
00:28:02,594 --> 00:28:03,428
COMMON COLD.

757
00:28:03,428 --> 00:28:06,231
SO REST ASSURED THAT, YOU KNOW

758
00:28:06,231 --> 00:28:07,599
CATCHING THE--WELL, I'M NOT

759
00:28:07,599 --> 00:28:09,367
GOING TO EVEN SAY THAT, CATCHING

760
00:28:09,367 --> 00:28:12,437
A COLD WILL NOT PUT YOU AT RISK

761
00:28:12,437 --> 00:28:13,939
FOR DEMENTIA BUT THERE IS

762
00:28:13,939 --> 00:28:15,440
EVIDENCE THAT THESE MAJOR

763
00:28:15,440 --> 00:28:16,441
INFECTIONS PARTICULARLY AMONG

764
00:28:16,441 --> 00:28:17,842
OLDER ADULLS SEEM TO BE RISK

765
00:28:17,842 --> 00:28:23,348
FACTORS, SO THIS IS JUST TO SHOW

766
00:28:23,348 --> 00:28:25,951
THAT IMMUNE ACTIVATION CAN

767
00:28:25,951 --> 00:28:27,519
INFLUENCE DEMENTIA RISK IN TERPS

768
00:28:27,519 --> 00:28:29,020
OF DIRECTIONALITY, THAT IS

769
00:28:29,020 --> 00:28:31,122
DEPENDENT ON THE CONTEXT BUT WE

770
00:28:31,122 --> 00:28:41,032
CAN--I CAN SEPARATE THESE IMMUNE

771
00:28:41,032 --> 00:28:43,535
EXPOSURES, DIET VERSUS ACUTE

772
00:28:43,535 --> 00:28:45,737
SURGERY, ACUTE INFECTION, TISSUE

773
00:28:45,737 --> 00:28:47,005
DAMAGE TO AN INJURY, THESE ALL

774
00:28:47,005 --> 00:28:48,440
HAVE IN COMMON THAT THEY

775
00:28:48,440 --> 00:28:52,711
STIMULATE THE IMMUNE SYSTEM, YOU

776
00:28:52,711 --> 00:28:56,014
KNOW P A MPs, ET CETERA, THEY

777
00:28:56,014 --> 00:28:57,882
STIMULATE THESE AND EVENTUALLY

778
00:28:57,882 --> 00:28:59,618
ADAPT TO THE IMMUNE CELLS AND WE

779
00:28:59,618 --> 00:29:02,487
THINK THROUGH VARIOUS PATHWAYS

780
00:29:02,487 --> 00:29:05,190
THEY CAN INFLUENCE THE BRAIN

781
00:29:05,190 --> 00:29:08,760
FUNCTION. 

782
00:29:08,760 --> 00:29:09,961
SO THIS HAS BEEN JUST THE

783
00:29:09,961 --> 00:29:11,596
PATHWAYS I TALK ABOUT, BUT AGAIN

784
00:29:11,596 --> 00:29:14,633
WE HAVE THIS INFLAMMATION,

785
00:29:14,633 --> 00:29:16,801
THINGS THAT ARE CHRONIC, ACUTE,

786
00:29:16,801 --> 00:29:19,237
AND WHAT THEY HAVE IN COMMON IS

787
00:29:19,237 --> 00:29:21,172
THE REGULATION, THESE ARE

788
00:29:21,172 --> 00:29:22,641
CYTOKINES, CHEMOKINES, THESE ARE

789
00:29:22,641 --> 00:29:27,245
THE 1S WE KNOW OF, OTHERS ARE

790
00:29:27,245 --> 00:29:28,079
IDENTIFYING PLENTY OF IMMUNE

791
00:29:28,079 --> 00:29:29,481
PROTEINS THAT TEND TO BE

792
00:29:29,481 --> 00:29:30,448
RELEVANT AS WELL, BUT THE IDEA

793
00:29:30,448 --> 00:29:33,652
IS THAT THEY CAN INFLUENCE BRAIN

794
00:29:33,652 --> 00:29:34,919
FUNCTION EITHER THROUGH CROSSING

795
00:29:34,919 --> 00:29:37,222
THE BLOOD BRAIN BIRRIER

796
00:29:37,222 --> 00:29:38,356
SURFACESSIER DIRECTLY,

797
00:29:38,356 --> 00:29:40,392
INDIRECTLY BY STIMULATING

798
00:29:40,392 --> 00:29:43,294
ENDOTHELIAL CELLS WHICH THEN CAN

799
00:29:43,294 --> 00:29:44,362
TRANSMIT SIGNALING TO MICROGLIAL

800
00:29:44,362 --> 00:29:46,297
OR ASTRO SIGHTS FOR EXAMPLE ON

801
00:29:46,297 --> 00:29:48,033
THE OTHER SIDE OF THE

802
00:29:48,033 --> 00:29:50,402
VASCULATURE, BUT ALSO THROUGH

803
00:29:50,402 --> 00:29:53,338
THESE THINGS CALL VENTRICULAR

804
00:29:53,338 --> 00:29:57,008
ORGANS LIKE THE PLEXUS WHERE

805
00:29:57,008 --> 00:29:59,477
THERE'S ACTUALLY PLACES STUFF IN

806
00:29:59,477 --> 00:30:00,545
THE BLOOD TO COMMUNICATE WITHIN

807
00:30:00,545 --> 00:30:03,381
THE BRAIN STEM AND THEN THROUGH

808
00:30:03,381 --> 00:30:05,784
THE VAGUS NERVE AS WELL.

809
00:30:05,784 --> 00:30:07,852
SO THERE IS, DESPITE BLOOD BRAIN

810
00:30:07,852 --> 00:30:11,222
BARRIER WHICH IS A REAL THING,

811
00:30:11,222 --> 00:30:12,757
THOSE CERTAINLY KEEP THE BRAIN

812
00:30:12,757 --> 00:30:14,893
PROTECTED FROM THE VARIOUSIATION

813
00:30:14,893 --> 00:30:16,795
AND CONTENTS OF BLOOD, THERE ARE

814
00:30:16,795 --> 00:30:19,130
STILL QUITE A FEW MECHANISMS FOR

815
00:30:19,130 --> 00:30:20,398
PROTEINS IN CIRCULATION TO

816
00:30:20,398 --> 00:30:21,666
INFLUENCE BRAIN FUNCTION AND I

817
00:30:21,666 --> 00:30:22,734
ALWAYS MENTION THIS TO PEOPLE,

818
00:30:22,734 --> 00:30:24,703
EVERY TIME YOU GET SICK, YOU

819
00:30:24,703 --> 00:30:26,971
FEEL DIFFERENTLY, YOU STOP

820
00:30:26,971 --> 00:30:28,606
EATING SO MUCH, YOU FEEL

821
00:30:28,606 --> 00:30:29,774
APATHETIC, YOU LOSE MOTIVATION,

822
00:30:29,774 --> 00:30:33,645
THAT'S AN EXAMPLE OF PROTEINS IN

823
00:30:33,645 --> 00:30:35,747
CIRCULATION, AND WHAT VPIL6 OR

824
00:30:35,747 --> 00:30:37,082
TNF ALPHA ACTUALLY INFLUENCING

825
00:30:37,082 --> 00:30:39,317
YOUR BEHAVIOR, AND THE

826
00:30:39,317 --> 00:30:41,086
BEHAVIORIAL INFLUENCE IS EXERTED

827
00:30:41,086 --> 00:30:42,487
THROUGH THE EFFECT ON THE BRAIN

828
00:30:42,487 --> 00:30:44,189
ITSELF, THIS HAPPENS TO US ALL

829
00:30:44,189 --> 00:30:47,592
THE TIME.

830
00:30:47,592 --> 00:30:49,828
YOU KNOW ACUTE INFLAMMATORY

831
00:30:49,828 --> 00:30:51,329
INSULT IS HAPPENING AT MUCH

832
00:30:51,329 --> 00:30:52,964
HIGHER LEVELS AND MANY FOLDS,

833
00:30:52,964 --> 00:30:55,266
AND HIGHER IN TERMS OF

834
00:30:55,266 --> 00:30:55,533
MAGNITUDE.

835
00:30:55,533 --> 00:30:57,435
BUT I'LL MOVE ON SO THERE'S BEEN

836
00:30:57,435 --> 00:31:00,438
QUITE A BIT OF EVIDENCE LINKING

837
00:31:00,438 --> 00:31:01,539
INFECTION HISTORY WITH DEMENTIA

838
00:31:01,539 --> 00:31:03,141
RISK, SO WE DID SOME WORK

839
00:31:03,141 --> 00:31:06,044
EARLIER SHOWING THAT HISTORY OF

840
00:31:06,044 --> 00:31:07,545
HOSPITALIZATION, ALSO CRITICAL

841
00:31:07,545 --> 00:31:08,346
ILLNESS AND INFECTION IN

842
00:31:08,346 --> 00:31:10,482
PARTICULAR SEEM TO BE ASSOCIATED

843
00:31:10,482 --> 00:31:13,451
WITH VOLUME LOSS IN THE FUTURE

844
00:31:13,451 --> 00:31:15,220
AND THEN THERE'S QUITE A BIT OF

845
00:31:15,220 --> 00:31:17,989
WORK SHOWING THAT HAVING HISTORY

846
00:31:17,989 --> 00:31:19,991
OF MAJOR INFLAMMATORY EVENTS

847
00:31:19,991 --> 00:31:20,992
LIKE CRITICAL ILLNESS,

848
00:31:20,992 --> 00:31:25,096
HOSPITALIZED INFECTION, YOU KNOW

849
00:31:25,096 --> 00:31:29,934
THESE THINGS AGAIN TEND TO

850
00:31:29,934 --> 00:31:34,405
INCREASE AND RISK WITHIN THE

851
00:31:34,405 --> 00:31:34,973
NEXT FEW DECADES.

852
00:31:34,973 --> 00:31:37,175
WAS THERE A QUESTION?

853
00:31:37,175 --> 00:31:38,209
NO?

854
00:31:38,209 --> 00:31:39,711
SO THIS IS 1 RECENT PAPER THAT I

855
00:31:39,711 --> 00:31:41,579
LIKE WHICH DID THIS REALLY WELL

856
00:31:41,579 --> 00:31:44,182
AND USED THE UK BIOBANK DATA, IT

857
00:31:44,182 --> 00:31:47,218
USED DATA FROM THE FINISHED

858
00:31:47,218 --> 00:31:48,353
MULTICOHORT SO 2 BIG LARGE

859
00:31:48,353 --> 00:31:53,458
STUDIES BUT THEY LOOK AT HISTORY

860
00:31:53,458 --> 00:31:55,627
OF ANY INFECTION, VIRAL

861
00:31:55,627 --> 00:31:57,228
INFECTION, HOW DOES THIS WORK

862
00:31:57,228 --> 00:32:01,866
FOR 4 DIFFERENT TIMES OF

863
00:32:01,866 --> 00:32:02,433
DEMENTIA AND IRRESPECT

864
00:32:02,433 --> 00:32:03,701
EVALUATION PROCESS OF WHETHER

865
00:32:03,701 --> 00:32:08,006
IT'S BACTERIAL OR VIRAL, HAVING

866
00:32:08,006 --> 00:32:10,308
AN INFECTION DOES INCREASE

867
00:32:10,308 --> 00:32:12,143
DEMENTIA RISK, PARTICULARLY

868
00:32:12,143 --> 00:32:14,779
VASCULAR DEMENTIA WHICH WAS IN

869
00:32:14,779 --> 00:32:16,514
PARKINSON'S DISEASE DEMENTIA, SO

870
00:32:16,514 --> 00:32:18,783
YOU KNOW WE FOCUS ON ALL COST

871
00:32:18,783 --> 00:32:22,520
DEMENTIA WHICH ARE STILL

872
00:32:22,520 --> 00:32:25,056
INCREASED POST INFECTION, BUT IT

873
00:32:25,056 --> 00:32:27,826
SEEMS LIKE THE VAST PART OF

874
00:32:27,826 --> 00:32:29,561
PATHOGENESIS IS PARKINSON'S IS

875
00:32:29,561 --> 00:32:30,361
THE MOST SUSCEPTIBLE HERE, BUT

876
00:32:30,361 --> 00:32:31,663
THE THING I WANT TO EMPHASIZE

877
00:32:31,663 --> 00:32:33,364
HERE IS THAT THIS STUDY LOOKEDDA

878
00:32:33,364 --> 00:32:36,801
THE LONG-TERM FOLLOW UP SO 10

879
00:32:36,801 --> 00:32:39,737
YEARS, 10 YEARS, 15 YEARS, SO

880
00:32:39,737 --> 00:32:42,140
MAY HAVE GONE TO 20 BECAUSE

881
00:32:42,140 --> 00:32:44,342
THERE'S ALWAYS THIS REVERSAL

882
00:32:44,342 --> 00:32:46,211
CAUSATION, PEOPLE AT RISK FOR

883
00:32:46,211 --> 00:32:47,378
DEMENTIA ESPECIALLY IF THEY'RE

884
00:32:47,378 --> 00:32:49,247
PROBABLY WITHIN YEARS OF

885
00:32:49,247 --> 00:32:50,915
DEVELOPING DEMENTIA OR PROBABLY

886
00:32:50,915 --> 00:32:52,350
MORE SUSCEPTIBLE TO INFECTIONS

887
00:32:52,350 --> 00:32:53,484
THEMSELVES, SO YOU HAVE TO

888
00:32:53,484 --> 00:32:56,888
SEPARATE OUT, IT'S DEMENTIA

889
00:32:56,888 --> 00:32:57,956
MAKING SOMEONE SUSCEPTIBLE IN

890
00:32:57,956 --> 00:33:01,392
DEMENTIA AND IF WE CAN LOOK AT

891
00:33:01,392 --> 00:33:03,461
INFECTION, 20 YEARS BEFORE

892
00:33:03,461 --> 00:33:05,797
DEMENTIA ONSET WE CAN SAY, OKAY,

893
00:33:05,797 --> 00:33:08,399
IT'S LIKELY NOT THE DEMENTIA OR

894
00:33:08,399 --> 00:33:09,434
THE DEMENTIA PATHOGENESIS THAT'S

895
00:33:09,434 --> 00:33:10,468
MAKE THANKSGIVING PERSON

896
00:33:10,468 --> 00:33:14,005
SUSCEPTIBLE TO AN INFECTION 20

897
00:33:14,005 --> 00:33:16,174
YEARS BEFORE THE DEMENTIA

898
00:33:16,174 --> 00:33:17,041
EXPRESSES ITSELF, IT'S MORE

899
00:33:17,041 --> 00:33:18,309
LIKELY THE OPPOSITE ISSUES THE

900
00:33:18,309 --> 00:33:19,711
IONIZATION FEKS MAY LAY THE

901
00:33:19,711 --> 00:33:22,647
GROUND WORK FOR DEMENTIA RISK.

902
00:33:22,647 --> 00:33:24,816
SO THIS COMES TO THE FOREFRONT

903
00:33:24,816 --> 00:33:27,552
OF OUR CONSCIOUSNESS WITH COVID,

904
00:33:27,552 --> 00:33:34,592
LONG COVID WE THINK IS AN

905
00:33:34,592 --> 00:33:37,462
EXAMPLE OF THIS SO HAD IS JUST

906
00:33:37,462 --> 00:33:39,063
SOME REALLY GOOD EXAMPLES OF

907
00:33:39,063 --> 00:33:40,398
THIS TOPIC FOR IT COHORT.

908
00:33:40,398 --> 00:33:42,533
THIS IS THE UK BIOBANK AS WELL,

909
00:33:42,533 --> 00:33:44,102
THIS IS A LONGITUDINAL ANALYSIS,

910
00:33:44,102 --> 00:33:46,371
AND THEY LOOK AT PEOPLE WITH A

911
00:33:46,371 --> 00:33:48,306
EFTHIMIOSY OF COVID INFECTION

912
00:33:48,306 --> 00:33:49,741
VERSUS THOSE WHO ARE--WHO DIDN'T

913
00:33:49,741 --> 00:33:54,345
HAVE A COVID INFECTION HISTORY

914
00:33:54,345 --> 00:33:55,847
AND THEY FOUND OVER TIME THOSE

915
00:33:55,847 --> 00:34:00,652
WITH A HISTORY OF SARS-COV-2 IN

916
00:34:00,652 --> 00:34:01,386
THESE HIGHLIGHTED AREAS OF THE

917
00:34:01,386 --> 00:34:03,154
BRAIN, SO WHEN THEY LOOK AT

918
00:34:03,154 --> 00:34:04,422
ACTUAL SEVERITY, LIKE IT'S OKAY,

919
00:34:04,422 --> 00:34:07,292
WE'RE GOING TO TAKE EVERYONE

920
00:34:07,292 --> 00:34:11,262
WITH AN INFECTION AND COMPARE

921
00:34:11,262 --> 00:34:11,729
HOSPITALIZED WITH

922
00:34:11,729 --> 00:34:12,397
NONHOSPITALLIZED INDIVIDUALS AND

923
00:34:12,397 --> 00:34:14,699
THEY FOUND EVEN FURTHER

924
00:34:14,699 --> 00:34:16,734
INCREASES IN VOLUME LOSS AMONG

925
00:34:16,734 --> 00:34:18,803
THOSE WITH MORE SEVERE INFECTION

926
00:34:18,803 --> 00:34:19,637
AND THE SEPARATION BETWEEN

927
00:34:19,637 --> 00:34:22,907
BASICALLY THE CASES AND CONTROLS

928
00:34:22,907 --> 00:34:25,643
SEEM TO WIDEN AS PEOPLE AGE.

929
00:34:25,643 --> 00:34:30,882
SO THIS AFFECT WAS MUCH STRONGER

930
00:34:30,882 --> 00:34:33,351
IN LATER SETS OF IN LIFE THAN IT

931
00:34:33,351 --> 00:34:34,619
WAS AMONG 40 AND 50 YEAR-OLDS AS

932
00:34:34,619 --> 00:34:36,220
I SLEEP APNEA AND OBESITYY HERE.

933
00:34:36,220 --> 00:34:38,790
SO THAT'S 1 EXAMPLE, HERE'S

934
00:34:38,790 --> 00:34:39,958
ANOTHER COVID EXAMPLE THAT I

935
00:34:39,958 --> 00:34:42,460
THINK IS ILLUSTRATIVE OF AN

936
00:34:42,460 --> 00:34:45,763
IMPORTANT POINT SO SARS-COV-2

937
00:34:45,763 --> 00:34:49,767
AND AVI NATH HAVE DONE THIS

938
00:34:49,767 --> 00:34:50,868
WORK, SARS-COV-2 IN MOST CASES

939
00:34:50,868 --> 00:34:52,570
DOES NOT ENTER THE BRAIN.

940
00:34:52,570 --> 00:34:55,106
SO MEN WITH HIGHER THEY LOOK AT

941
00:34:55,106 --> 00:34:57,175
CSS, OR SPINAL FLUID, I DON'T

942
00:34:57,175 --> 00:34:58,977
KNOW HOW MUCH AUTOPSIES THEY'VE

943
00:34:58,977 --> 00:34:59,911
DONE BUT THERE DOESN'T SEEM TO

944
00:34:59,911 --> 00:35:02,714
BE A LOT OF VIRUS IN THE BRAIN

945
00:35:02,714 --> 00:35:06,217
BUT THAT--AND THAT'S ILLUSTRATED

946
00:35:06,217 --> 00:35:09,620
BY THIS LACK OF ELEVATED CELL

947
00:35:09,620 --> 00:35:11,489
COUNT IN CEREBRAL SPINAL FLUID

948
00:35:11,489 --> 00:35:13,558
HERE, THIS IS JUST A CASE HERE,

949
00:35:13,558 --> 00:35:15,293
FROM VERY EARLY ON BEFORE THEY

950
00:35:15,293 --> 00:35:17,595
HAD BIG NUMBERS, BUT WHAT--WHAT

951
00:35:17,595 --> 00:35:22,200
IS APPARENT IN PEOPLE WITH

952
00:35:22,200 --> 00:35:24,836
SARS-COV-2 IS THEY HAVE SPIKES

953
00:35:24,836 --> 00:35:26,137
AND INFLAMMATION, THAT

954
00:35:26,137 --> 00:35:27,171
INFLAMMATION OUTSIDE THE CENTRAL

955
00:35:27,171 --> 00:35:30,908
NERVOUS SYSTEM IN THE BLOOD AS

956
00:35:30,908 --> 00:35:33,144
MEASURED HERE BY V-REACTIVE

957
00:35:33,144 --> 00:35:34,078
PROTEINS SO TYPICALLY 3 IS THE

958
00:35:34,078 --> 00:35:36,514
CUT OFF FOR AT LEAST CHRONIC

959
00:35:36,514 --> 00:35:37,382
INFLATION, LOW GRADE

960
00:35:37,382 --> 00:35:39,550
INFLAMMATION, BUT IF YOU HAVE A

961
00:35:39,550 --> 00:35:41,619
LEVEL ABOVE 3, IT'S NOT A GOOD

962
00:35:41,619 --> 00:35:42,453
THING, HERE EVERYBODY'S ABOVE A

963
00:35:42,453 --> 00:35:45,323
HUNDRED SO THIS IS AN ACUTE

964
00:35:45,323 --> 00:35:46,290
INFLAMMATORY EVENT AND WHEN I

965
00:35:46,290 --> 00:35:48,593
MENTION THIS IS LIKE MANY TIMES

966
00:35:48,593 --> 00:35:50,161
HIGHER MAGNITUDE THAN THE LOW

967
00:35:50,161 --> 00:35:51,396
GRADE INFORMATION THAT MAY ALSO

968
00:35:51,396 --> 00:35:54,098
BE A RISK FACTOR BUT BEYOND CRP,

969
00:35:54,098 --> 00:36:00,104
AND THIS IS IN BLOOD, WE SEE

970
00:36:00,104 --> 00:36:01,606
EVIDENT OF ACTIVATED IMMUNE

971
00:36:01,606 --> 00:36:04,575
CENTRAL IMMUNITY AND THE BETA 2

972
00:36:04,575 --> 00:36:05,743
MICROGLOBUE LYNN, SO THE TAKE

973
00:36:05,743 --> 00:36:07,378
AWAY HERE IS ALTHOUGH THE VIRUS

974
00:36:07,378 --> 00:36:09,914
DOESN'T ENTER THE BRAIN, THERE'S

975
00:36:09,914 --> 00:36:10,948
STILL A CENTRAL IMMUNE RESPONSE

976
00:36:10,948 --> 00:36:12,784
AND WE THINK THIS IS MEDIATED

977
00:36:12,784 --> 00:36:14,719
THROUGH THE PATHWAYS OF

978
00:36:14,719 --> 00:36:15,787
INTERVENTION, THOSE VARIOUS

979
00:36:15,787 --> 00:36:17,989
CONDUITS, SO WE RECENTLY

980
00:36:17,989 --> 00:36:19,390
PUBLISHED THIS PAPER IN NATURE

981
00:36:19,390 --> 00:36:20,925
AND AGING WHICH IS PRIOR TONING,

982
00:36:20,925 --> 00:36:25,730
WHAT IS THE MOLECULES THAT'S

983
00:36:25,730 --> 00:36:28,332
MEDIATE THIS RELATIONSHIP.

984
00:36:28,332 --> 00:36:28,900
YES?

985
00:36:28,900 --> 00:36:34,472
>> [INAUDIBLE QUESTION
FROM

986
00:36:34,472 --> 00:36:39,210
AUDIENCE ]

987
00:36:39,210 --> 00:36:39,911
>> YEAH, EXCELLENT
QUESTION.

988
00:36:39,911 --> 00:36:43,981
AND SO SOMETHING THAT WE LOOKED

989
00:36:43,981 --> 00:36:44,348
AT HERE.

990
00:36:44,348 --> 00:36:47,752
BUT IN THE PAPERS I SHOWED

991
00:36:47,752 --> 00:36:50,488
BEFORE THAT I MENTIONED COVID,

992
00:36:50,488 --> 00:36:52,223
THAT IS ALL PREPANDEMIC AND SO,

993
00:36:52,223 --> 00:36:53,891
YOU KNOW IF YOU TAKE PEOPLE WITH

994
00:36:53,891 --> 00:36:56,060
A HISTORY OF HOSPITALIZED

995
00:36:56,060 --> 00:36:57,728
INFECTION, WHETHER IT BE

996
00:36:57,728 --> 00:36:59,464
PNEUMONIA, SEPSIS, OR SOMETHING

997
00:36:59,464 --> 00:37:02,533
ELSE, THOSE SEEM TO BE RISK

998
00:37:02,533 --> 00:37:03,701
FACTORS AS WELL.

999
00:37:03,701 --> 00:37:05,303
AND SO MY--I STILL THINK THIS,

1000
00:37:05,303 --> 00:37:07,705
THERE MAY BE DIFFERENCES BETWEEN

1001
00:37:07,705 --> 00:37:10,174
COVID AND SOME OF THESE OTHER

1002
00:37:10,174 --> 00:37:12,243
MORE SEVERE COVID OR OTHER

1003
00:37:12,243 --> 00:37:13,744
SEVERE INFECTIONS IN TERMS OF

1004
00:37:13,744 --> 00:37:14,912
THE THE ACTUAL IMMUNE RESPONSE,

1005
00:37:14,912 --> 00:37:18,049
I THINK THERE A PATHWAY THAT

1006
00:37:18,049 --> 00:37:20,351
UNITES THEM AND REALLY

1007
00:37:20,351 --> 00:37:21,052
PERIPHERAL INFLAMMATION, IT

1008
00:37:21,052 --> 00:37:23,254
SEEMS TO BE LIKE A LOT OF

1009
00:37:23,254 --> 00:37:25,356
INTERFERON TYPE 1, TYPE 2

1010
00:37:25,356 --> 00:37:26,757
INTERFERON APGHTIVATION, SO I

1011
00:37:26,757 --> 00:37:32,563
THINK THEREYA MORE IN COMMON

1012
00:37:32,563 --> 00:37:33,831
THAN THE DIFFERENCES BETWEEN

1013
00:37:33,831 --> 00:37:35,032
THEM AND HERE, THIS PAPER, WE

1014
00:37:35,032 --> 00:37:36,434
LOOKED AT A NUMBER OF

1015
00:37:36,434 --> 00:37:38,836
INFECTIONS, NONE OF WHICH WERE

1016
00:37:38,836 --> 00:37:40,471
COVID, PROBABLY THE 1S THAT HAVE

1017
00:37:40,471 --> 00:37:43,307
BEEN AROUND FOR, WELL, YOU KNOW,

1018
00:37:43,307 --> 00:37:45,309
THAT WE'VE BEEN TREATING FOR A

1019
00:37:45,309 --> 00:37:46,511
LONG, LONG TIME, ACTUALLY LET ME

1020
00:37:46,511 --> 00:37:48,112
BACK UP, SO LET ME JUST GO

1021
00:37:48,112 --> 00:37:48,713
THROUGH THIS FRAMEWORK HERE

1022
00:37:48,713 --> 00:37:51,482
BECAUSE THIS IS WHAT THE STUDY

1023
00:37:51,482 --> 00:37:52,250
WAS BASED ON.

1024
00:37:52,250 --> 00:37:54,485
AND THIS WAS AGAIN LED BY

1025
00:37:54,485 --> 00:37:56,254
MICHAEL DUGG,A N, THE POST DOC

1026
00:37:56,254 --> 00:37:57,088
IN MY LAB.

1027
00:37:57,088 --> 00:37:58,623
THIS WAS MANYIERS OF WORK, WE

1028
00:37:58,623 --> 00:38:00,591
RECENTLY GOT THIS PUBLISHED AND

1029
00:38:00,591 --> 00:38:01,659
WE WERE SUPER EXCITED ABOUT IT

1030
00:38:01,659 --> 00:38:06,364
BUT THE IDEA THAT WAS THAT

1031
00:38:06,364 --> 00:38:07,398
INFLECTION INFLUENCES

1032
00:38:07,398 --> 00:38:08,065
NEURODEGENERATION BY INFLUENCING

1033
00:38:08,065 --> 00:38:09,400
THIS EXPRESSION OF IMMUNE

1034
00:38:09,400 --> 00:38:10,067
PROTEINS THROUGHOUT CIRCULATION

1035
00:38:10,067 --> 00:38:13,971
AND AGAIN THESE PROTEINS GO

1036
00:38:13,971 --> 00:38:16,240
THROUGH THE VARIOUS CONDUITS

1037
00:38:16,240 --> 00:38:17,508
INFLUENCE MOLECULAR CHANGES IN

1038
00:38:17,508 --> 00:38:19,810
THE BRAIN INCLUDING NEURAL

1039
00:38:19,810 --> 00:38:21,112
INFLAMMATION, PROMOTING AMYLOID

1040
00:38:21,112 --> 00:38:23,814
AND TAU WHICH I TALKED ABOUT AS

1041
00:38:23,814 --> 00:38:24,882
TETERMINANTS OF ALZHEIMER'S

1042
00:38:24,882 --> 00:38:27,018
DISEASE, AND EVENTUALLY YOU GET

1043
00:38:27,018 --> 00:38:27,618
BRAIN ATROPHY AND

1044
00:38:27,618 --> 00:38:28,986
NEURODEGENERATION AND A COG

1045
00:38:28,986 --> 00:38:30,388
95ATIVE SYMPTOMS THAT MANIFEST

1046
00:38:30,388 --> 00:38:31,589
WITH DEMENTIA SO THAT'S THE

1047
00:38:31,589 --> 00:38:35,092
FRAMEWORK AND WE SET OUT TO TEST

1048
00:38:35,092 --> 00:38:36,627
PRETTY MUCH EACH OF THESE ARROWS

1049
00:38:36,627 --> 00:38:38,162
IN THE STUDY, SO WE FIRST WENT

1050
00:38:38,162 --> 00:38:40,264
FROM THE BEGINNING TO THE VERY

1051
00:38:40,264 --> 00:38:43,100
END, IT DOES INFECTION, PEOPLE

1052
00:38:43,100 --> 00:38:46,103
WITH INFECTION HISTORY HAVE

1053
00:38:46,103 --> 00:38:47,038
EVIDENCE OF NEURODEGENERATION

1054
00:38:47,038 --> 00:38:48,773
AND THIS IS LONGITUDINAL BRAIN

1055
00:38:48,773 --> 00:38:51,275
VOLUME LOSS SO WE LOOK AT THAT

1056
00:38:51,275 --> 00:38:52,343
OF THE BALTIMORE LONGITUDINAL

1057
00:38:52,343 --> 00:38:54,312
STUDY OF AGING AND LOOK AT THIS

1058
00:38:54,312 --> 00:38:55,746
SET OF 10-15 INFECTION AND

1059
00:38:55,746 --> 00:38:57,815
LOOKED AT EACH 1 OF THEM IN

1060
00:38:57,815 --> 00:38:59,650
RELATION TO VOLUME LOSS AND

1061
00:38:59,650 --> 00:39:06,390
VARIOUS BRAIN REGIONS, AND

1062
00:39:06,390 --> 00:39:09,994
HERE'S JUST 2 INFECTIONS AS AN

1063
00:39:09,994 --> 00:39:12,396
EXAMPLE SO INFLUENCA WE SEE A

1064
00:39:12,396 --> 00:39:13,231
GENERAL TRANSFER, LIKE PEOPLE

1065
00:39:13,231 --> 00:39:17,034
WITH A HISTORY OF INFLUENZA TO

1066
00:39:17,034 --> 00:39:19,537
HAVE A STEEPER LOSS OF VOLUME

1067
00:39:19,537 --> 00:39:21,339
ACROSS VARIOUS BRAIN REGIONS,

1068
00:39:21,339 --> 00:39:22,807
THIS IS TOTAL BRAIN,

1069
00:39:22,807 --> 00:39:25,076
NONSIGNIFICANT IF YOU LOOK AT

1070
00:39:25,076 --> 00:39:27,545
TEMPORAL LOBE OR OCCIPITAL LOBE,

1071
00:39:27,545 --> 00:39:29,313
IT DOES CROSS THE THRESHOLD OF

1072
00:39:29,313 --> 00:39:31,082
SIGNIFICANCE AND THERE'S A TREND

1073
00:39:31,082 --> 00:39:32,016
THAT SUGGESTS IT'S NOT A GOOD

1074
00:39:32,016 --> 00:39:33,184
THING FOR THE BRAIN.

1075
00:39:33,184 --> 00:39:37,888
WE LOOK AT SKIN AND SUBCUTANEOUS

1076
00:39:37,888 --> 00:39:42,493
INFECTIONS, THINGS LIKE

1077
00:39:42,493 --> 00:39:43,427
CELLULITIS, INFECTIOUS SKIN,

1078
00:39:43,427 --> 00:39:45,429
YEAH, I GUESS, INFECTIONS OF THE

1079
00:39:45,429 --> 00:39:48,399
SKIN, AND THIS IS ACTUALLY--IT'S

1080
00:39:48,399 --> 00:39:52,069
INTERESTING WHAT FALLS IN THIS

1081
00:39:52,069 --> 00:39:55,339
CATEGORIES BUT IT'S BECOME VERY

1082
00:39:55,339 --> 00:39:56,774
RELEVANT AND CLEAR THAT THIS IS

1083
00:39:56,774 --> 00:39:58,175
SOMETHING THAT'S A CONSISTENT

1084
00:39:58,175 --> 00:39:59,710
RISK FACTOR FOR DEMENTIA AND IT

1085
00:39:59,710 --> 00:40:02,246
SURPRISED ALL OF US, BUT IF YOU

1086
00:40:02,246 --> 00:40:04,548
LOOK AT PEOPLE WITH A EFTHIMIOSY

1087
00:40:04,548 --> 00:40:06,384
OF SKIN AND SUBCUTANEOUS

1088
00:40:06,384 --> 00:40:09,020
INFECTIONS THEY SEEM TO BE

1089
00:40:09,020 --> 00:40:10,421
SUSCEPTIBLE TO TOTAL BRAIN LOSS

1090
00:40:10,421 --> 00:40:12,256
IN VOLUME GRAY MATTER WITH

1091
00:40:12,256 --> 00:40:13,758
DIRECTIONALITY ACROSS THE

1092
00:40:13,758 --> 00:40:16,294
REGIONS OF INTEREST, AND SO WE

1093
00:40:16,294 --> 00:40:18,329
LOOK BACK, WELL, MANY ADDITIONAL

1094
00:40:18,329 --> 00:40:19,730
INFECTION TYPES AND THESE ARE

1095
00:40:19,730 --> 00:40:22,933
THE 6 WHERE WE SAW AT LEAST 1

1096
00:40:22,933 --> 00:40:25,002
BRAIN REGION SHOW SOME

1097
00:40:25,002 --> 00:40:26,170
STATISTICAL SIGNIFICANCE SO WE

1098
00:40:26,170 --> 00:40:30,541
FOCUSED ON THESE 6 TYPES OF

1099
00:40:30,541 --> 00:40:31,809
INFECTIONS OF UPPER RESPIRATORY

1100
00:40:31,809 --> 00:40:33,177
INFECTIONS FROM THE VIRAL

1101
00:40:33,177 --> 00:40:35,646
INFECTION GROUP AND THE YOU HAD

1102
00:40:35,646 --> 00:40:37,415
HHV, THE HUMAN HERPES VIRUS

1103
00:40:37,415 --> 00:40:39,684
WHICH THERE'S BEEN QUITE A BIT

1104
00:40:39,684 --> 00:40:42,887
OF MIXED EVIDENT OF ITS ROLE OR

1105
00:40:42,887 --> 00:40:44,655
LACK THEREOF IN DEMENTIA SO

1106
00:40:44,655 --> 00:40:45,990
ESTABLISHING THESE 6 SECTIONS

1107
00:40:45,990 --> 00:40:47,258
WAS NOT CROSSED OFF ARE

1108
00:40:47,258 --> 00:40:49,026
ASSOCIATED AT LEAST IN OUR HANDS

1109
00:40:49,026 --> 00:40:53,764
WITH BRAIN ATROPHY, WE WANTED TO

1110
00:40:53,764 --> 00:40:55,299
SEE OKAY, ARE THEY ASSOCIATE

1111
00:40:55,299 --> 00:40:57,301
WIDE DEMENTIA RISK, SO WE WENT

1112
00:40:57,301 --> 00:41:00,171
TO THE BIOBANK, TO THE

1113
00:41:00,171 --> 00:41:01,372
MULTICATEGORY COHORT AND

1114
00:41:01,372 --> 00:41:03,641
CATEGORIZED THESE IN OUR INITIAL

1115
00:41:03,641 --> 00:41:05,843
TOEVERY COHORT AND FOUND

1116
00:41:05,843 --> 00:41:07,011
A--OKAY, THOSE INFECTIONS IN

1117
00:41:07,011 --> 00:41:08,813
ADDITION TO BEING ASSOCIATE WIDE

1118
00:41:08,813 --> 00:41:11,215
BRAIN VOLUME LOSS IN THE

1119
00:41:11,215 --> 00:41:12,149
BALTIMORE LONGITUDE FLAL STUDY

1120
00:41:12,149 --> 00:41:14,785
OF ANALLING ARE PREDICTABLE

1121
00:41:14,785 --> 00:41:16,253
DEMENTIA RISK OVER A 20 YEAR

1122
00:41:16,253 --> 00:41:18,789
FOLLOW UP PERIOD AND YOU IMAIF

1123
00:41:18,789 --> 00:41:19,023
BIOBANK.

1124
00:41:19,023 --> 00:41:20,691
SO SOME OF THESE WE DIDN'T HAVE

1125
00:41:20,691 --> 00:41:22,893
ENOUGH CASES TO LOOK AT BUT

1126
00:41:22,893 --> 00:41:24,295
ESSENTIALLY EACH OF THE

1127
00:41:24,295 --> 00:41:26,464
INFECTIONS WERE ASSOCIATED WITH

1128
00:41:26,464 --> 00:41:27,264
ALL CAUSE DEM-TEBURKEULOSEISIA

1129
00:41:27,264 --> 00:41:29,700
AND THEN WE SAW AGAIN--DEMENTIA

1130
00:41:29,700 --> 00:41:32,336
AND THEAN WE SAW AGAIN FOR THE

1131
00:41:32,336 --> 00:41:34,238
STUDY FOR THE VASCULAR DEMENTIA

1132
00:41:34,238 --> 00:41:36,006
COMPARED TO ALDZ JEIMER'S

1133
00:41:36,006 --> 00:41:36,240
DISEASE.

1134
00:41:36,240 --> 00:41:37,641
OKAY, SO WE ESTABLISHED THEN

1135
00:41:37,641 --> 00:41:39,510
THAT THESE INFECTIONS ARE

1136
00:41:39,510 --> 00:41:41,011
ASSOCIATED WITH ATROPHY, ARE

1137
00:41:41,011 --> 00:41:43,280
ASSOCIATED WITH DEMENTIA RISK.

1138
00:41:43,280 --> 00:41:45,850
SO THEN WE WANTED TO UNDERSTAND

1139
00:41:45,850 --> 00:41:47,651
WHAT--WHAT IS THE PROTEOMICS

1140
00:41:47,651 --> 00:41:48,586
SIGNATURES NAIFURE, LIKE WE'RE

1141
00:41:48,586 --> 00:41:50,421
REALLY AFTER THE PROTEOMIC

1142
00:41:50,421 --> 00:41:52,690
MEDIATORS HERE THAT MIGHT, YOU

1143
00:41:52,690 --> 00:41:54,358
KNOW LEAD SOMEONE WITH AN

1144
00:41:54,358 --> 00:42:00,498
INFECTION HISTORY TO DEVELOP

1145
00:42:00,498 --> 00:42:01,665
DEMENTIA RISK, AND AN IMPORTANT

1146
00:42:01,665 --> 00:42:02,967
POINT THIS IS INFECTION HISTORY

1147
00:42:02,967 --> 00:42:06,036
AND IT NOT NECESSARILY, WE'RE

1148
00:42:06,036 --> 00:42:07,438
NOT TAKING BLOOD IN THE ACUTE

1149
00:42:07,438 --> 00:42:08,839
PHASE SO THIS IS PEOPLE WITH,

1150
00:42:08,839 --> 00:42:13,344
YOU KNOW WHO MAY HAVE HAD AN

1151
00:42:13,344 --> 00:42:14,745
INFLUENZA EVENT 14 YEARS EARLIER

1152
00:42:14,745 --> 00:42:16,447
THAT WAS CAPTURED IN OUR STUDY,

1153
00:42:16,447 --> 00:42:17,748
YOU KNOW SOMETIME LATER WE

1154
00:42:17,748 --> 00:42:19,950
MEASURE THEIR BLOOD AND DID

1155
00:42:19,950 --> 00:42:21,585
PROTEOMIC ANALYSIS, AND I THINK

1156
00:42:21,585 --> 00:42:23,220
14 OR 10, SOMEWHERE AROUND THERE

1157
00:42:23,220 --> 00:42:24,855
MAY HAVE BEEN THE ACTUAL GAP

1158
00:42:24,855 --> 00:42:26,690
BETWEEN THE INFECTION, YOU KNOW

1159
00:42:26,690 --> 00:42:28,192
THE INDEMNIFICATION INFECTION

1160
00:42:28,192 --> 00:42:29,593
AND THE MEASUREMENT OF BLOOD IN

1161
00:42:29,593 --> 00:42:31,262
THE MEASUREMENT OF MRI SCANS,

1162
00:42:31,262 --> 00:42:37,868
THESE ARE REMOTE INFECTIONS.

1163
00:42:37,868 --> 00:42:39,870
SO WE LOOKED AT EACH OF OUR 6

1164
00:42:39,870 --> 00:42:44,508
INFECTIONS IN RELATION TO

1165
00:42:44,508 --> 00:42:47,111
HISTORY IN RELATION TO THE

1166
00:42:47,111 --> 00:42:48,546
PROTEOMICS SIGNATURE AND WHAT WE

1167
00:42:48,546 --> 00:42:50,481
SAW WAS INFLUENZA IN PARTICULAR

1168
00:42:50,481 --> 00:42:53,250
HAD A VERY STRONG PROTEOMICS

1169
00:42:53,250 --> 00:42:54,852
SIGNATURE THAT PEOPLE WITH A

1170
00:42:54,852 --> 00:42:58,823
HISTORY OF THE FLEW HAD A STRONG

1171
00:42:58,823 --> 00:43:00,925
OR HAD UP AND DOWN REGULATION OF

1172
00:43:00,925 --> 00:43:02,993
VARIOUS PROTEIN, SKIN AND

1173
00:43:02,993 --> 00:43:03,627
SUBCUTANEOUS INFECTIONS, THE

1174
00:43:03,627 --> 00:43:07,298
OTHER EXAMPLE, WE SAW A WEAKENED

1175
00:43:07,298 --> 00:43:08,032
PROTEOMICS SIGNATURE, THERE WERE

1176
00:43:08,032 --> 00:43:09,667
LESS OF THESE PEOPLE, IT WAS A

1177
00:43:09,667 --> 00:43:11,202
POWER ISSUE, AND WE SAW

1178
00:43:11,202 --> 00:43:13,704
INTERESTING PROTEINS AND SOME OF

1179
00:43:13,704 --> 00:43:21,045
WHICH WE SAW WERE ALREADY THERE

1180
00:43:21,045 --> 00:43:22,513
LIKE APO-E, LOOKING AT SIGNATURE

1181
00:43:22,513 --> 00:43:24,548
FOR ALL 6 AND SHOWING THAT HEY,

1182
00:43:24,548 --> 00:43:27,818
THERE ARE SOME PROTEINS THAT ARE

1183
00:43:27,818 --> 00:43:29,320
UPAND DOWN REGULATED

1184
00:43:29,320 --> 00:43:30,154
CONSISTENTLY ACROSS VARIOUS

1185
00:43:30,154 --> 00:43:32,089
INFECTION TYPE, WE WANTED--WE

1186
00:43:32,089 --> 00:43:33,858
THEN TRY TO UNDERSTAND, ARE

1187
00:43:33,858 --> 00:43:37,261
THESE PROTEIN, DO THESE PROTEINS

1188
00:43:37,261 --> 00:43:39,830
MEDIATE THIS RELATIONSHIP

1189
00:43:39,830 --> 00:43:40,664
BETWEEN INFECTION AND

1190
00:43:40,664 --> 00:43:43,400
NEURODEGENERATION, SO WE TRIED

1191
00:43:43,400 --> 00:43:45,369
TO FIND PROTEINS THAT WERE

1192
00:43:45,369 --> 00:43:47,972
DISREGULATED IN PEOPLE WITH AN

1193
00:43:47,972 --> 00:43:49,974
INFECTION HISTORY AND ASSOCIATED

1194
00:43:49,974 --> 00:43:50,774
WITH NEURODEGENERATION, AND THEN

1195
00:43:50,774 --> 00:43:56,847
FOR THOSE WE LOOKED AT THE  THE

1196
00:43:56,847 --> 00:43:57,882
MOLECULAR SIGNATURE AS WELL TO

1197
00:43:57,882 --> 00:44:01,886
SEE IF THEY WERE RELATED TO THE

1198
00:44:01,886 --> 00:44:02,753
BRAIN DEMENTIA UNDERLYING RISK.

1199
00:44:02,753 --> 00:44:04,154
SO WE'RE TRYING TO BRING IT ALL

1200
00:44:04,154 --> 00:44:04,421
TOGETHER.

1201
00:44:04,421 --> 00:44:06,624
SO THIS IS AN EXAMPLE OF THE

1202
00:44:06,624 --> 00:44:07,458
CANDIDATE PROTEIN WE IDENTIFIED

1203
00:44:07,458 --> 00:44:09,026
FOR 1 OF OUR INFECTIONS SO

1204
00:44:09,026 --> 00:44:10,294
LOOKING AT THE FLEW HERE FOR

1205
00:44:10,294 --> 00:44:13,931
WHICH WE HAD MANY CASES WE HAD

1206
00:44:13,931 --> 00:44:16,534
GOOD POWER, BUT EVERYTHING IN

1207
00:44:16,534 --> 00:44:19,103
THIS PLOT WAS WHAT WE CONSIDER A

1208
00:44:19,103 --> 00:44:19,703
CANDIDATE PROTEIN, CANDIDATE

1209
00:44:19,703 --> 00:44:23,140
MEANING IT WAS ASSOCIATED WITH

1210
00:44:23,140 --> 00:44:25,943
AN INFLUENZA HISTORY AND

1211
00:44:25,943 --> 00:44:28,012
ASSOCIATED WITH FUTURE EITHER,

1212
00:44:28,012 --> 00:44:29,880
FUTURE BRAIN ATROPHY, EITHER IN

1213
00:44:29,880 --> 00:44:32,616
A PROTECTIVE OR PATHOGENIC WAY.

1214
00:44:32,616 --> 00:44:34,785
SO, THESE PROTEINS FOR EXAMPLE

1215
00:44:34,785 --> 00:44:36,554
IN THIS TOP QUADRANT WERE

1216
00:44:36,554 --> 00:44:40,291
ELEVATED IN PEOPLE WITH A

1217
00:44:40,291 --> 00:44:42,026
HISTORY OF THE FLU AND

1218
00:44:42,026 --> 00:44:43,294
ASSOCIATED WITH BRAIN VOLUME

1219
00:44:43,294 --> 00:44:44,094
LOSS.

1220
00:44:44,094 --> 00:44:46,964
THESE PROTEINS IN IN QUADRANT

1221
00:44:46,964 --> 00:44:48,599
WERE DOWN REGULATED WITH PEOPLE

1222
00:44:48,599 --> 00:44:51,001
IN THE HISTORY AND ASSOCIATED

1223
00:44:51,001 --> 00:44:53,404
WITH LESS BRAIN VOLUME, AND

1224
00:44:53,404 --> 00:44:56,273
THESE ARE PATHOGENIC IN

1225
00:44:56,273 --> 00:44:57,875
PROPROTEINS RESPECTIVEY SO WE

1226
00:44:57,875 --> 00:44:59,610
MET BOALGT OF THOSE CRITERIA AND

1227
00:44:59,610 --> 00:45:01,946
WE WANTED TO UNDERSTAND THE

1228
00:45:01,946 --> 00:45:02,780
MOLECULAR SIGNATURE LINKED AT

1229
00:45:02,780 --> 00:45:04,982
THEM, AND WE LOOK AT THOSE IN

1230
00:45:04,982 --> 00:45:10,087
RELATION TO AMYLOID, AT TAU

1231
00:45:10,087 --> 00:45:11,355
WHICH ARE CANNONICLE ALZHEIMER'S

1232
00:45:11,355 --> 00:45:12,890
DISEASE AND THEN THE ACIDIC

1233
00:45:12,890 --> 00:45:15,259
PROTEIN WHICH IS A MARKER OF

1234
00:45:15,259 --> 00:45:16,527
REACTIVE NUCLEOSIS, SO SOME

1235
00:45:16,527 --> 00:45:19,063
INDICATE A TYPE OF NEURAL

1236
00:45:19,063 --> 00:45:19,897
INFLATION AND THE NEURAL LIGHT

1237
00:45:19,897 --> 00:45:22,299
WHICH IS A MEASURE OF AXONAL

1238
00:45:22,299 --> 00:45:24,935
DAMAGE WHICH IS NOT REALLY

1239
00:45:24,935 --> 00:45:28,739
DEMENTIA SPECIFIC BUT SENSITIVE

1240
00:45:28,739 --> 00:45:30,774
TO DISRUPTION AND NEURAL

1241
00:45:30,774 --> 00:45:31,942
FUNCTION OR NEURONAL INJURY, BUT

1242
00:45:31,942 --> 00:45:33,577
WE SAW AMONG OUR PROTECTIVE

1243
00:45:33,577 --> 00:45:35,446
PROTEINS AND EVERYTHING WITH THE

1244
00:45:35,446 --> 00:45:37,881
RED ARROW, IS LINKED TO

1245
00:45:37,881 --> 00:45:38,816
INFLUENZA, AND SOMEWHERE IN

1246
00:45:38,816 --> 00:45:40,818
HERE, BUT AMONG OUR PROTECTIVE

1247
00:45:40,818 --> 00:45:42,319
PROTEINS, WE SEE THAT THEY ALSO

1248
00:45:42,319 --> 00:45:44,955
SHOW THIS DOWN REGULATION, ARE

1249
00:45:44,955 --> 00:45:47,324
ASSOCIATED WITH DOWN REGULATION

1250
00:45:47,324 --> 00:45:49,393
OF P-TILE AND THIS UPREGULATION

1251
00:45:49,393 --> 00:45:50,260
OF THE 48-FROM--INTEGRATION

1252
00:45:50,260 --> 00:45:53,564
RATIO AND YOU CAN THINK OF IT IN

1253
00:45:53,564 --> 00:45:55,899
REVERSE, HIGH 48-40 MEANS LESS

1254
00:45:55,899 --> 00:45:56,734
CORTICALE AMYLOID, LESS AMYLOID

1255
00:45:56,734 --> 00:45:58,469
ON THE BRAIN SO THIS IS ALL

1256
00:45:58,469 --> 00:46:00,137
CONSISTENT WITH THE PICTURE OF

1257
00:46:00,137 --> 00:46:02,339
PROTECTION, IF WE ELECTRIC AT

1258
00:46:02,339 --> 00:46:03,307
OUR PATHOGENIC PROTEINS, WE

1259
00:46:03,307 --> 00:46:05,943
DON'T SEE A CONSISTENT PICTURE

1260
00:46:05,943 --> 00:46:07,611
IN TERMS OF THE MOLECULAR

1261
00:46:07,611 --> 00:46:08,912
PICTURE, SO A LOT OF STUFF THAT

1262
00:46:08,912 --> 00:46:11,148
WAS ASSOCIATED OR DEEMED

1263
00:46:11,148 --> 00:46:14,685
PATHOGENIC, IN RELATION TO

1264
00:46:14,685 --> 00:46:16,153
INFLUENZA AFFECT ON BRAIN

1265
00:46:16,153 --> 00:46:21,625
ATROPHY DIDN'T SO A RELATIONSHIP

1266
00:46:21,625 --> 00:46:24,628
WITH AMYLOID G OR TAU, IF SO

1267
00:46:24,628 --> 00:46:26,497
WE'RE STILL TRYING TO SHOW IF

1268
00:46:26,497 --> 00:46:28,332
THESE MECHANISMS ARE CAUSAL,

1269
00:46:28,332 --> 00:46:31,468
WHAT ARE THEIR EFFECTS?

1270
00:46:31,468 --> 00:46:35,039
SAME THING WITH SKIN, WE SAW 2

1271
00:46:35,039 --> 00:46:38,075
PATHEE GENIC, 1 PROTECTIVE AND

1272
00:46:38,075 --> 00:46:39,576
THESE ARE DISCORDANT, THEY'RE

1273
00:46:39,576 --> 00:46:41,111
UPREGULATIVE AND POST INFECTION

1274
00:46:41,111 --> 00:46:41,945
AND ALSO PROTECTIVE AND DIDN'T

1275
00:46:41,945 --> 00:46:43,147
KNOW WHAT TO MAKE OF THAT, WE

1276
00:46:43,147 --> 00:46:44,782
WERE ABLE TO TRY TO GET AT THE

1277
00:46:44,782 --> 00:46:47,184
CAUSAL QUESTION BY LOOKING AT

1278
00:46:47,184 --> 00:46:49,553
GENETIC OVERLAP, SO THIS MEN

1279
00:46:49,553 --> 00:46:50,354
DEALIAN RANDOMIZATION ANALYSIS,

1280
00:46:50,354 --> 00:46:52,923
SO WE DID A GWAS ON THE PROTEIN

1281
00:46:52,923 --> 00:46:56,627
LEVEL, WHERE WE MAY USE SOMEONE

1282
00:46:56,627 --> 00:46:57,561
ELSE'S QUANTITATIVE LOCI, I

1283
00:46:57,561 --> 00:46:58,896
FORGET BUT WE WERE ABLE TO LOOK

1284
00:46:58,896 --> 00:47:01,198
TO SEE IF THE PROTEIN

1285
00:47:01,198 --> 00:47:02,700
QUAWBTITATIVE TRAIT LOCI FOR

1286
00:47:02,700 --> 00:47:03,300
THESE INDIVIDUAL PROTEINS

1287
00:47:03,300 --> 00:47:05,436
OVERLAP WITH THE RISK VARIANCE

1288
00:47:05,436 --> 00:47:06,704
FOR ALZHEIMERAY DISEASE AND THAT

1289
00:47:06,704 --> 00:47:09,940
ALLOWS US TO BE--MAKE A STRONGER

1290
00:47:09,940 --> 00:47:11,575
CAUSAL INFERENCE AND FOR SOME OF

1291
00:47:11,575 --> 00:47:14,244
THE TEENS THAT WERE ACTUALLY

1292
00:47:14,244 --> 00:47:15,646
BEING IDENTIFIED AS RELEVANCE

1293
00:47:15,646 --> 00:47:17,147
AND SKIN AND CUE TAINIOUS

1294
00:47:17,147 --> 00:47:18,782
INFECTION, WE DID SEE EVIDENCE

1295
00:47:18,782 --> 00:47:21,985
FOR A CAUSALITY, THE OUTCOME

1296
00:47:21,985 --> 00:47:24,288
HERE BEING BRAIN ATROPHY SO BACK

1297
00:47:24,288 --> 00:47:26,957
TO OUR ORIGINAL MEASUREMENT OF

1298
00:47:26,957 --> 00:47:28,158
NEURODEGENERATION EMPLOY OKAY,

1299
00:47:28,158 --> 00:47:29,993
WE SAW THESE--WE SAW THE NUMBERS

1300
00:47:29,993 --> 00:47:30,828
THAT WERE ASSOCIATE WIDE

1301
00:47:30,828 --> 00:47:32,463
COGNITION AS WELL, IN THE SAME

1302
00:47:32,463 --> 00:47:36,100
COHORT, BUT I WANT TO, YOU KNOW

1303
00:47:36,100 --> 00:47:37,801
SPEND SOMETIME HERE BECAUSE THIS

1304
00:47:37,801 --> 00:47:39,837
IS 1 OF THE SUM RESULT OF OUR

1305
00:47:39,837 --> 00:47:42,005
ANALYSIS, WE TARTED WITH 7000

1306
00:47:42,005 --> 00:47:45,175
PROTEINS, HERE IN THE BLSA, AS

1307
00:47:45,175 --> 00:47:47,211
POTENTIAL CANDIDATES, WE FOCUSED

1308
00:47:47,211 --> 00:47:49,213
THEN DOWN ON 900 THAT WE KNOW

1309
00:47:49,213 --> 00:47:52,883
WHERE IMMUNE RELATED, SO WE LOOK

1310
00:47:52,883 --> 00:47:54,418
AT THOSE IMMUNE RELATED WITH A

1311
00:47:54,418 --> 00:47:55,586
HISTORY OF INFECTION AND FOUND

1312
00:47:55,586 --> 00:47:57,688
WHICH OF THOSE PROEN TOOS WERE

1313
00:47:57,688 --> 00:47:59,189
WITH INFECTION WERE ASSOCIATE

1314
00:47:59,189 --> 00:48:00,124
WIDE BRAIN ATROPHY, SO THROUGH

1315
00:48:00,124 --> 00:48:02,259
ALL THAT WE CAME DOWN ON THE

1316
00:48:02,259 --> 00:48:03,861
PROTEINS AS POTENTIAL MEDIATOR,

1317
00:48:03,861 --> 00:48:05,529
NOW THE FRAMEWORK WE HAVE NOW IS

1318
00:48:05,529 --> 00:48:09,733
THAT INFECTION, YOU KNOW, BOTH

1319
00:48:09,733 --> 00:48:10,934
INCREASES PATHOGENIC PROTEIN

1320
00:48:10,934 --> 00:48:12,402
EXPRESSION AND CIRCULATION,

1321
00:48:12,402 --> 00:48:13,337
DECREASES PROTECTIVE PROTEIN

1322
00:48:13,337 --> 00:48:14,304
EXPRESSION IN CIRCULATION, AND

1323
00:48:14,304 --> 00:48:16,273
FOR THESE PROTECTIVE PROTEINS,

1324
00:48:16,273 --> 00:48:19,443
WHICH ARE LABELED IN PINK DOWN

1325
00:48:19,443 --> 00:48:20,644
HERE SORRY LABELED IN PURPLE OR

1326
00:48:20,644 --> 00:48:22,379
BLUE OR WHATEVER THAT IS DOWN

1327
00:48:22,379 --> 00:48:24,548
HERE, FOR THESE PROTECTIVE

1328
00:48:24,548 --> 00:48:27,017
PROTEINS, WE SEE THAT THE

1329
00:48:27,017 --> 00:48:28,786
MOLECULAR CHANGES WHEN WE DOWN

1330
00:48:28,786 --> 00:48:31,855
REGULATE THEM, ARE THIS INCREASE

1331
00:48:31,855 --> 00:48:35,993
IN AMYLOID, INCREASE IF PTA, UU

1332
00:48:35,993 --> 00:48:38,195
AND WHICH ARE MONOMERIC OF

1333
00:48:38,195 --> 00:48:38,862
ALZHEIMER'S DISEASE AS WELL, SO

1334
00:48:38,862 --> 00:48:40,798
WE THINK THAT MIGHT BE WHAT'S

1335
00:48:40,798 --> 00:48:42,800
GOING OYOU HAVE A HISTORY OF

1336
00:48:42,800 --> 00:48:43,801
INFECTION, IT REDUCES THESE

1337
00:48:43,801 --> 00:48:53,277
IMMUNE PROTEINS THAT ARE

1338
00:48:53,277 --> 00:48:54,745
PROTECTIVE AND THAT LAYS THE

1339
00:48:54,745 --> 00:48:58,749
GLOWND WORK FOR THE P, TAU, AND

1340
00:48:58,749 --> 00:49:00,517
A HYPOTHESIS THAT MAY BE EQUALLY

1341
00:49:00,517 --> 00:49:02,719
OR MORE LIKELY IS THAT THERE'S

1342
00:49:02,719 --> 00:49:03,787
SOME COMMON IMMUNE TRAIT THAT

1343
00:49:03,787 --> 00:49:06,323
MAKES PEOPLE HAVE LOW LEVEL OF

1344
00:49:06,323 --> 00:49:08,959
THESE PROTECTIVE PROTEINS AND

1345
00:49:08,959 --> 00:49:09,793
MAKES SUSCEPTIBLE TO

1346
00:49:09,793 --> 00:49:10,227
NEURODEGENERATION.

1347
00:49:10,227 --> 00:49:14,198
SO YOU MAY BE BORN WITH THIS,

1348
00:49:14,198 --> 00:49:15,499
THIS IMMUNE TRAIT WHICH ACTUALLY

1349
00:49:15,499 --> 00:49:17,768
MAY BE PROTECTIVE IN EARLY LIFE

1350
00:49:17,768 --> 00:49:20,037
OR MAYBE MAKE YOU MORE OR LESS

1351
00:49:20,037 --> 00:49:25,642
SEZ SEPTORSIBLE TO CERTAIN

1352
00:49:25,642 --> 00:49:27,244
INFECTION EMPLOY BUT I GUESS IN

1353
00:49:27,244 --> 00:49:30,247
THIS CASE MORE SUSCEPTIBLE, AND

1354
00:49:30,247 --> 00:49:31,315
THOSE SEEMINGLY UNDERLYING

1355
00:49:31,315 --> 00:49:33,417
IMMUNE TRAITS IT MAY BE THAT YOU

1356
00:49:33,417 --> 00:49:34,251
DEVELOP ALZHEIMER'S DEC IN THE

1357
00:49:34,251 --> 00:49:38,021
FUTURE AND THESE PROTEINS,

1358
00:49:38,021 --> 00:49:38,989
PROTEOMIC EXPRESSIONS HERE MIGHT

1359
00:49:38,989 --> 00:49:40,424
JUST BE A SIGNATURE OF THAT

1360
00:49:40,424 --> 00:49:40,858
IMMUNE TRAIT.

1361
00:49:40,858 --> 00:49:47,698
WE'RE TRYING TO TEST THAT MORE

1362
00:49:47,698 --> 00:49:49,132
SPECIFICALLY NOW USING A NUMBER

1363
00:49:49,132 --> 00:49:51,501
OF METHODS AND THEN WE HAVE OUR

1364
00:49:51,501 --> 00:49:52,202
PATHOGENIC PROTEINS AND WE DON'T

1365
00:49:52,202 --> 00:49:54,538
KNOW WHAT THE MEDIAITOR IS HERE,

1366
00:49:54,538 --> 00:49:57,507
WE SEE THE PATHOGENIC, WE SEE

1367
00:49:57,507 --> 00:49:58,976
THEM ASSOCIATED AND UPREGULATED

1368
00:49:58,976 --> 00:50:00,544
POST INFECTION BUT THEY'RE NOT

1369
00:50:00,544 --> 00:50:02,079
ASSOCIATED WITH AMYLOID AND TAU,

1370
00:50:02,079 --> 00:50:03,614
SO THERE'S STILL WORK TO BE DONE

1371
00:50:03,614 --> 00:50:05,048
TO SORT OF COMPLETE THE PICTURE,

1372
00:50:05,048 --> 00:50:08,051
THERE MAY BE JUST A DIRECT

1373
00:50:08,051 --> 00:50:08,385
RELATIONSHIP.

1374
00:50:08,385 --> 00:50:10,888
SO JUST TO SUMMARIZE, WHEN WE DO

1375
00:50:10,888 --> 00:50:13,824
THINK WITH THE KEY INFLAMMATORY

1376
00:50:13,824 --> 00:50:17,594
EVENTS THERE'S THIS UPREGULATION

1377
00:50:17,594 --> 00:50:18,295
IN PURPLE MEDIATORS, THAT CAN

1378
00:50:18,295 --> 00:50:20,397
GET INTO THE BRAIN OR SIGNAL TO

1379
00:50:20,397 --> 00:50:28,338
THE BRAIN AND ACTUALLY YOU KNOW

1380
00:50:28,338 --> 00:50:29,439
DISREGULATION AMYLOID OR TAU AND

1381
00:50:29,439 --> 00:50:32,876
MAKE THEM MORE SUSCEPTIBLE TO

1382
00:50:32,876 --> 00:50:33,710
NEURODEGENERATION THAT MAY HAVE

1383
00:50:33,710 --> 00:50:34,544
NOT OCCURRED.

1384
00:50:34,544 --> 00:50:36,313
I WOULDN'T GO AS WISE AS SAYING

1385
00:50:36,313 --> 00:50:38,115
INFECTION, I WILL SAY TRIGGERS

1386
00:50:38,115 --> 00:50:39,283
DEMENTIA BUT WE DO HAVE EVIDENCE

1387
00:50:39,283 --> 00:50:44,755
HERE THAT IT CAN BE A RISK

1388
00:50:44,755 --> 00:50:44,988
FACTOR.

1389
00:50:44,988 --> 00:50:47,291
SO I'LL STOP THERE, THANKS

1390
00:50:47,291 --> 00:50:48,158
EVERYONE FOR LISTENING AND I'M

1391
00:50:48,158 --> 00:50:50,294
HAPPY TO TAKE QUESTIONS BUT

1392
00:50:50,294 --> 00:50:51,695
BEFORE THAT I WANT TO THANK THE

1393
00:50:51,695 --> 00:50:53,130
FOLKS IN MY LAB, PARTICULARLY

1394
00:50:53,130 --> 00:50:56,099
THOSE WHO WORK I REFERENCED HERE

1395
00:50:56,099 --> 00:50:58,168
AND THEN THE ARIC COLLABORATORS

1396
00:50:58,168 --> 00:50:59,403
AS WELL AND THE FOLKS THAT WORK

1397
00:50:59,403 --> 00:51:00,470
AT STUDIES OF MULTIPLE

1398
00:51:00,470 --> 00:51:01,471
ENDOCRINIA LOGIC.

1399
00:51:01,471 --> 00:51:02,673
THANKS FOR LISTENING AND I HOPE

1400
00:51:02,673 --> 00:51:12,716
YOU HAVE QUESTIONS.

1401
00:51:12,716 --> 00:51:13,850
>> WE HAVE 1 QUESTION FROM
ZOOM,

1402
00:51:13,850 --> 00:51:15,552
WHAT IS THE EFFECT OF AGEOT

1403
00:51:15,552 --> 00:51:16,820
ASSOCIATIONS BETWEEN INFECTIONS

1404
00:51:16,820 --> 00:51:18,689
AND THE AD BIOMARKERS IN.

1405
00:51:18,689 --> 00:51:21,858
>> WE DIDN'T LOOK AT AGE
AS A

1406
00:51:21,858 --> 00:51:23,827
MODIFIER OF THOSE RELATIONSHIPS

1407
00:51:23,827 --> 00:51:27,931
SPECIFICALLY, LET ME THINK ABOUT

1408
00:51:27,931 --> 00:51:28,131
THAT.

1409
00:51:28,131 --> 00:51:30,200
SO, YEAH, I MEAN THE SHORT

1410
00:51:30,200 --> 00:51:34,938
ANSWER IS QUEE DON'T KNOW.

1411
00:51:34,938 --> 00:51:36,440
IT SEEMS LIKE AGE MAKES THE

1412
00:51:36,440 --> 00:51:38,809
INFECTION ITSELF A STRONGER RISK

1413
00:51:38,809 --> 00:51:42,479
FACTOR FOR NEURODEGENERATION,

1414
00:51:42,479 --> 00:51:44,214
INFECTIONS IN THE COVID TABLE,

1415
00:51:44,214 --> 00:51:45,782
WE DIDN'T TEST THE INTERACTIONS

1416
00:51:45,782 --> 00:51:46,984
IN THE LAST PAPER I SHOWED BUT

1417
00:51:46,984 --> 00:51:49,052
IF YOU HAVE A SEVERE INFECTION

1418
00:51:49,052 --> 00:51:53,890
AND YOU'RE 70, IT SEEMS TO BE A

1419
00:51:53,890 --> 00:51:54,891
LOT MORE ON DEMENTIA RISK THAN

1420
00:51:54,891 --> 00:51:56,626
IF YOU HAVE A SEVERE INFECTION

1421
00:51:56,626 --> 00:51:59,796
IN THE LIFE, NOW HOW THAT

1422
00:51:59,796 --> 00:52:01,298
AFFECTS ERD BIOMARKERS, YOU KNOW

1423
00:52:01,298 --> 00:52:03,300
I ASSUME, YOU KNOW WE WOULD SEE

1424
00:52:03,300 --> 00:52:05,235
A SIMILAR PATTERN WHERE

1425
00:52:05,235 --> 00:52:06,403
INFECTIONS HAVING A STRONGER

1426
00:52:06,403 --> 00:52:08,438
EFFECT ON THOSE BIOMARKERS AT A

1427
00:52:08,438 --> 00:52:10,040
LATER LIFE THAN EARLIER IN LIFE

1428
00:52:10,040 --> 00:52:12,376
BUT WE DIDN'T TEST THAT

1429
00:52:12,376 --> 00:52:12,642
DIRECTLY.

1430
00:52:12,642 --> 00:52:16,113
>> I HAVE A QUESTION, SO
WHEN

1431
00:52:16,113 --> 00:52:17,514
YOU DID THIS INFECTION

1432
00:52:17,514 --> 00:52:19,616
CORRELATION, DID YOU LOOK AT THE

1433
00:52:19,616 --> 00:52:21,785
SIGNATURE PROTEIN YOU FOUND IN

1434
00:52:21,785 --> 00:52:22,586
THE OTHER STUDY?

1435
00:52:22,586 --> 00:52:30,293
DO THEY ALSO CORRELATE IN THIS? 

1436
00:52:30,293 --> 00:52:31,928
>> IN THE OTHER STUDY?

1437
00:52:31,928 --> 00:52:33,063
>> IN THE EARLIER STUDY
WHERE

1438
00:52:33,063 --> 00:52:35,298
YOU LOOK AT AGE RELATED.

1439
00:52:35,298 --> 00:52:38,235
>> YEAH, SO WE TOOK THE

1440
00:52:38,235 --> 00:52:39,169
INFECTION PROTEIN, PARTICULARLY

1441
00:52:39,169 --> 00:52:40,370
OUR CANDIDATES THAT WE

1442
00:52:40,370 --> 00:52:43,006
HIGHLIGHTED HERE AND THEN WE DID

1443
00:52:43,006 --> 00:52:44,274
ACTUALLY TAKE THEM BACK TO THE

1444
00:52:44,274 --> 00:52:46,476
FIRST I MENTIONED THE ARIC STUDY

1445
00:52:46,476 --> 00:52:48,245
IF THEY WERE THE DEMENTIA RISK

1446
00:52:48,245 --> 00:52:53,016
AND SO THAT IS SOMETHING WE DID 

1447
00:52:53,016 --> 00:52:54,117
SOME OF THEM, CERTAINLY NOT ALL

1448
00:52:54,117 --> 00:52:55,652
OF THEM, IT MAY HAVE BEEN LIKE A

1449
00:52:55,652 --> 00:52:56,953
THIRD THAT WERE SOABT WIDE

1450
00:52:56,953 --> 00:52:59,489
DEMENTIA EITHER IN THE FUTURE,

1451
00:52:59,489 --> 00:53:02,359
OR WERE ELEVATED IN PEOPLE WHO

1452
00:53:02,359 --> 00:53:03,393
CURRENTLY HAD DEMENTIA VERSUS

1453
00:53:03,393 --> 00:53:04,828
THOSE THAT WE DID AND IT WAS

1454
00:53:04,828 --> 00:53:06,797
LESS THAN WE ANTICIPATED AND YOU

1455
00:53:06,797 --> 00:53:09,900
KNOW WE WEREN'T SURE NECESSARILY

1456
00:53:09,900 --> 00:53:10,200
WHY.

1457
00:53:10,200 --> 00:53:12,569
>> I WAS THINKING THE
OTHER WAY

1458
00:53:12,569 --> 00:53:13,870
AROUND LIKE LOOKING AT THE

1459
00:53:13,870 --> 00:53:15,705
[INDISCERNIBLE] YOU PREDICTED IN

1460
00:53:15,705 --> 00:53:18,041
THE AGE RELATED STUDY ANDEE IF

1461
00:53:18,041 --> 00:53:19,276
THEY WERE ACTUALLY CORRELATED

1462
00:53:19,276 --> 00:53:21,812
HERE WITH THE [INDISCERNIBLE].

1463
00:53:21,812 --> 00:53:26,149
>> OH, NO, WE DIDN'T DO
THAT.

1464
00:53:26,149 --> 00:53:30,921
WE TRIED TO NARROW THEM MPLE SO

1465
00:53:30,921 --> 00:53:31,288
--NARROW

1466
00:53:31,288 --> 00:53:31,688
THEM.

1467
00:53:31,688 --> 00:53:34,024
SO PART OF THE STUDY I MENTIONED

1468
00:53:34,024 --> 00:53:35,392
WE DIDN'T NARROW THE SCOPE TO

1469
00:53:35,392 --> 00:53:36,760
OUR IMMUNE RELATED PROTEIN SO

1470
00:53:36,760 --> 00:53:38,061
SOME OF THE INITIAL PROTEIN FROM

1471
00:53:38,061 --> 00:53:41,932
THE INITIAL SET OF ANALYSIS,

1472
00:53:41,932 --> 00:53:43,033
IMMUNE RELATED BUT I WOULD SAY

1473
00:53:43,033 --> 00:53:45,702
MAYBE A FOURTH OF THEM WERE

1474
00:53:45,702 --> 00:53:48,839
INVOLVED IN OTHER YOU KNOW

1475
00:53:48,839 --> 00:53:54,211
ASPECTS OF BIOLOGY.

1476
00:53:54,211 --> 00:53:57,981
>> THANKS.

1477
00:53:57,981 --> 00:53:59,182
>> THANK YOU FOR A NICE
TALK.

1478
00:53:59,182 --> 00:54:03,286
I HAVE A QUESTION ABOUT THE DATA

1479
00:54:03,286 --> 00:54:07,691
PROCESSING, WHENEVER I SAW YOUR

1480
00:54:07,691 --> 00:54:09,092
DATA, THERE WAS 1 SENTENCE WHERE

1481
00:54:09,092 --> 00:54:14,297
THE RESULTS ARE JUST FOR THE

1482
00:54:14,297 --> 00:54:18,268
AGING [INDISCERNIBLE] AND I SAW

1483
00:54:18,268 --> 00:54:22,005
THE SAMPLE NUMBERS REALLY

1484
00:54:22,005 --> 00:54:23,507
GIGANTIC, I FEEL LIKE

1485
00:54:23,507 --> 00:54:27,043
[INDISCERNIBLE] PROCESS AND HOW

1486
00:54:27,043 --> 00:54:29,913
DID YOU DO IT FOR THE

1487
00:54:29,913 --> 00:54:31,381
ASSESSMENT?

1488
00:54:31,381 --> 00:54:33,984
>> I MISSED THE LAST
SENTENCE?

1489
00:54:33,984 --> 00:54:36,586
>> HOW DID YOU DO THE
ADJUSTMENT

1490
00:54:36,586 --> 00:54:39,856
FOR THE MRI ANALYSIS OR DEMENTIA

1491
00:54:39,856 --> 00:54:40,290
ANALYSIS OR BOTH?

1492
00:54:40,290 --> 00:54:46,196
>> THE LAST PART OF YOUR
DATA.

1493
00:54:46,196 --> 00:54:56,740
>> YEAH, SO THE ADJUSTMENT
SO

1494
00:54:57,207 --> 00:55:01,811
THIS SORT OF STUFF AND TRY TO

1495
00:55:01,811 --> 00:55:04,581
TAKE INTO ACCOUNT AGE AS BASED

1496
00:55:04,581 --> 00:55:06,316
DEMENTIA RISK FACTOR AND

1497
00:55:06,316 --> 00:55:07,684
SOMETHING THAT OBVIOUSLY

1498
00:55:07,684 --> 00:55:08,885
INFLUENCES PROTEOME, AND WE

1499
00:55:08,885 --> 00:55:10,053
TYPICALLY AJUST FOR THAT AND

1500
00:55:10,053 --> 00:55:12,622
IT'S A BIT AS A CONFOUNDER, WE

1501
00:55:12,622 --> 00:55:18,595
DO SETS, DO DEMOGRAPHIC FACTORS,

1502
00:55:18,595 --> 00:55:20,764
AND THIS MIGHT BE LITTLE--WE

1503
00:55:20,764 --> 00:55:23,533
CHANGE IT DEPENDING ON OUR

1504
00:55:23,533 --> 00:55:25,502
HYPOTHESIS BUT WE TYPICALLY WILL

1505
00:55:25,502 --> 00:55:28,038
JUST HAVE A COMMENT, CO VASCULAR

1506
00:55:28,038 --> 00:55:29,973
MORBIDITY THAT ARE THINGS AGAIN

1507
00:55:29,973 --> 00:55:32,842
THAT WE KNOW MAY NEED THE RISK

1508
00:55:32,842 --> 00:55:35,745
FACTORS THEMSELVES, AND THINGS

1509
00:55:35,745 --> 00:55:38,014
LIKE HYPERTENSION,

1510
00:55:38,014 --> 00:55:39,316
CARDIOVASCULAR DISEASE, AND

1511
00:55:39,316 --> 00:55:40,684
METABOLIC CONDITIONS LIKE

1512
00:55:40,684 --> 00:55:40,951
DIABETES.

1513
00:55:40,951 --> 00:55:42,919
THOSE SEEM TO MAKE IT INTO THE

1514
00:55:42,919 --> 00:55:43,253
MODEL.

1515
00:55:43,253 --> 00:55:48,491
AND THEN THE OTHER THING THAT

1516
00:55:48,491 --> 00:55:50,093
WE--THIS IS SOMEWHAT

1517
00:55:50,093 --> 00:55:51,361
CONTROVERSIAL IS KIDNEY

1518
00:55:51,361 --> 00:55:53,063
FUNCTION, WE OFTEN ADJUST FOR

1519
00:55:53,063 --> 00:55:54,564
THAT, IT MAY NOT BE REPRESENTED

1520
00:55:54,564 --> 00:55:56,733
HERE BUT WE KIND OF THINK KIDNEY

1521
00:55:56,733 --> 00:55:58,368
FUNCTION IN OLDER ADULLS SEEMS

1522
00:55:58,368 --> 00:56:07,911
TO INFLUENCE A LARGE SEGMENT OF

1523
00:56:07,911 --> 00:56:09,746
THE PROTEOME ITSELF.

1524
00:56:09,746 --> 00:56:11,047
AND DESCENT SIZE CHAIMPLES IN

1525
00:56:11,047 --> 00:56:12,215
THE RELATIONSHIP BETWEEN YOU

1526
00:56:12,215 --> 00:56:15,719
KNOW PROTEINS AND VARIOUS

1527
00:56:15,719 --> 00:56:15,986
OUTCOMES.

1528
00:56:15,986 --> 00:56:18,154
BUT WHAT THAT DOES ON THE FLIP

1529
00:56:18,154 --> 00:56:23,927
SIDE IS WE THINK THERE'S A

1530
00:56:23,927 --> 00:56:25,395
PROTEIN THAT IS ACTUALLY

1531
00:56:25,395 --> 00:56:28,398
RELEVANT TO OUR OUTCOME, LIKE

1532
00:56:28,398 --> 00:56:30,467
THE BETA 2 MICROGLOBUE LYNN, YOU

1533
00:56:30,467 --> 00:56:34,904
KNOW WE DON'T GET TO SEE THAT

1534
00:56:34,904 --> 00:56:35,605
ASSOCIATION BECAUSE WE ARE

1535
00:56:35,605 --> 00:56:39,242
TRYING TO GET RID OF THE

1536
00:56:39,242 --> 00:56:39,809
CONFOUNDING [INDISCERNIBLE]

1537
00:56:39,809 --> 00:56:41,244
REDUCE LOW FOR THE KIDNEY SO

1538
00:56:41,244 --> 00:56:44,581
THAT'S SOMETHING THAT WE DO BUT

1539
00:56:44,581 --> 00:56:46,149
NOT EVERYONE DOES BUT HA CAN BE

1540
00:56:46,149 --> 00:56:49,019
ADJUSTMENT AND WE WILL SOMETIMES

1541
00:56:49,019 --> 00:56:53,490
ADJUST FOR APO-E AS A MAJOR RISK

1542
00:56:53,490 --> 00:56:53,957
FACTOR.

1543
00:56:53,957 --> 00:56:59,462
>> THANK YOU.

1544
00:56:59,462 --> 00:56:59,796
>> YEAH?

1545
00:56:59,796 --> 00:57:04,567
>> DIRECTLY CORRELATED
WITH

1546
00:57:04,567 --> 00:57:05,435
INCREASED RISK?

1547
00:57:05,435 --> 00:57:07,404
>> YEAH, WE DID, LIKE
HAVING A

1548
00:57:07,404 --> 00:57:11,374
HISTORY OF 2 OR 3, YEAH, WE DID

1549
00:57:11,374 --> 00:57:12,909
LOOK AT STEP WIDE ASSOCIATIONS,

1550
00:57:12,909 --> 00:57:14,544
WE DIDN'T SEE MUCH IN OUR

1551
00:57:14,544 --> 00:57:16,279
ANALYSIS BUT I KNOW OTHER PEOPLE

1552
00:57:16,279 --> 00:57:22,285
HAVE, AND YOU KNOW WHETHER IT BE

1553
00:57:22,285 --> 00:57:23,987
THE DIVERSITY, IS IT MORE

1554
00:57:23,987 --> 00:57:27,891
PROBLEMATIC TO HAVE THE FLU HHV,

1555
00:57:27,891 --> 00:57:29,759
AND URI, VERSUS LIKE THE FLU 3

1556
00:57:29,759 --> 00:57:29,993
TIMES.

1557
00:57:29,993 --> 00:57:32,262
SO PEOPLE LOOK AT IT BOTH WAYS

1558
00:57:32,262 --> 00:57:35,365
AND THERE DOES TEND TO BE A STEP

1559
00:57:35,365 --> 00:57:39,803
WISE, MEAN IN THE EPIDEMIOLOGIC

1560
00:57:39,803 --> 00:57:43,206
WORK THIS DID SEEM TO BE

1561
00:57:43,206 --> 00:57:43,673
[INDISCERNIBLE] FACT.

1562
00:57:43,673 --> 00:57:44,974
BUT I DO THINK, WE KNOW THERE'S

1563
00:57:44,974 --> 00:57:47,711
PEOPLE OUT THERE WHO ARE JUST

1564
00:57:47,711 --> 00:57:49,579
SEEM TO ARE MORE SUSCEPTIBLE TO

1565
00:57:49,579 --> 00:57:56,753
THESE INFECTIONS AND I WONDER IF

1566
00:57:56,753 --> 00:57:58,388
A HYPOTHESIS IS SOME OF THESE

1567
00:57:58,388 --> 00:57:59,789
GENERATED ELTICS MAY MAKE THEM

1568
00:57:59,789 --> 00:58:01,157
MORE SUSCEPTIBLE TO THE

1569
00:58:01,157 --> 00:58:06,563
INFECTION WHICH MAY ALSO MAKE

1570
00:58:06,563 --> 00:58:09,032
THEM MORE SUSCEPTIBLE TO THE

1571
00:58:09,032 --> 00:58:11,234
BRAIN OR CAN'T CLEAR AS WELL OR

1572
00:58:11,234 --> 00:58:15,071
EFFICIENTLY SO THERE MAY BE AN

1573
00:58:15,071 --> 00:58:15,939
UNDERLYING IMMUNE TRAIT THAT

1574
00:58:15,939 --> 00:58:17,240
CONTRIBUTES TO THAT CONDITION

1575
00:58:17,240 --> 00:58:18,942
AND FROM THAT YOU WOULD SEE THE

1576
00:58:18,942 --> 00:58:29,486
STEP WISE RELATIONSHIP, I THINK.

1577
00:58:30,320 --> 00:58:32,055
NFOLKS, IF NO MORE QUESTIONS,

1578
00:58:32,055 --> 00:58:33,390
LET'S THANK DR. WALKER FOR

1579
00:58:33,390 --> 00:58:37,727
COMING OUT HERE TO GIVE THE

1580
00:58:37,727 --> 00:58:38,294
TALK.

1581
00:58:38,294 --> 00:58:38,995
[ APPLAUSE ]

1582
00:58:38,995 --> 00:58:49,439
>> THANKS FOR HAVING ME.