1 00:00:06,374 --> 00:00:08,310 GOOD AFTERNOON, EVERYBODY. 2 00:00:08,310 --> 00:00:10,712 WELCOME TO THE FIRST DIRECTOR'S 3 00:00:10,712 --> 00:00:13,248 SEMINAR OF 2025. 4 00:00:13,248 --> 00:00:15,450 HAPPY NEW YEAR, EVERYBODY HERE 5 00:00:15,450 --> 00:00:18,386 IN THE AUDIENCE, AND EVERYONE 6 00:00:18,386 --> 00:00:20,288 ONLINE ON VIDEOCAST. 7 00:00:20,288 --> 00:00:23,458 IT'S A REAL PLEASURE ALWAYS TO 8 00:00:23,458 --> 00:00:25,994 INTRODUCE THE SPEAKER FOR THE 9 00:00:25,994 --> 00:00:29,664 DIRECTOR'S SEMINAR SERIES, WHICH 10 00:00:29,664 --> 00:00:30,598 PRESENTS NEWLY TENURED 11 00:00:30,598 --> 00:00:33,168 INVESTIGATORS AT NIH, AND OUR 12 00:00:33,168 --> 00:00:38,373 SPEAKER TODAY IS DR. SONJA 13 00:00:38,373 --> 00:00:41,076 SCHOLZ FROM NINDS, WHO GOT HER 14 00:00:41,076 --> 00:00:44,980 MEDICAL DEGREE AT MEDICAL 15 00:00:44,980 --> 00:00:46,815 UNIVERSITY IN AUSTRIA AND WENT 16 00:00:46,815 --> 00:00:51,186 ON TO DO A Ph.D. AT UNIVERSITY 17 00:00:51,186 --> 00:00:52,554 COLLEGE LONDON. 18 00:00:52,554 --> 00:00:55,924 SHE DID HER Ph.D. IN 19 00:00:55,924 --> 00:00:59,394 NEUROGENOMICS AND THEN DID A 20 00:00:59,394 --> 00:01:00,729 POSTDOCTORAL FELLOWSHIP FIRST AT 21 00:01:00,729 --> 00:01:02,397 GEORGETOWN UNIVERSITY, AND THEN 22 00:01:02,397 --> 00:01:06,334 HERE AT NIH AT THE NATIONAL 23 00:01:06,334 --> 00:01:09,604 INSTITUTE ON AGING, WITH ANDY 24 00:01:09,604 --> 00:01:09,871 SINGLETON. 25 00:01:09,871 --> 00:01:11,373 AND REALLY THAT SET THE STAGE 26 00:01:11,373 --> 00:01:14,542 FOR THE WORK THAT SHE'S DONE AS 27 00:01:14,542 --> 00:01:16,277 AN INDEPENDENT INVESTIGATOR. 28 00:01:16,277 --> 00:01:19,681 SHE BECAME A TENURE TRACK 29 00:01:19,681 --> 00:01:22,083 INVESTIGATOR IN THE LASKER 30 00:01:22,083 --> 00:01:23,084 CLINICAL RESEARCH SCHOLARS 31 00:01:23,084 --> 00:01:29,324 PROGRAM, AND LAUNCHED HER 32 00:01:29,324 --> 00:01:30,158 LABORATORY IN NEURODEGENERATIVE 33 00:01:30,158 --> 00:01:32,360 DISEASE RESEARCH. 34 00:01:32,360 --> 00:01:34,162 JUST LAST YEAR WAS GRANTED 35 00:01:34,162 --> 00:01:38,400 TENURE AND BECAME A SENIOR 36 00:01:38,400 --> 00:01:38,967 INVESTIGATOR. 37 00:01:38,967 --> 00:01:41,936 ALL OF THAT IS THE SORT OF 38 00:01:41,936 --> 00:01:44,439 TANGIBLE DATA, THE STUFF YOU PUT 39 00:01:44,439 --> 00:01:46,641 IN A SPREADSHEET, BUT I WILL 40 00:01:46,641 --> 00:01:51,646 TELL YOU FOR ME AS A 41 00:01:51,646 --> 00:01:55,483 NEUROLOGIST, A NEUROSCIENTIST, 42 00:01:55,483 --> 00:01:59,654 REALLY THE SALIENT IMPORTANCE OF 43 00:01:59,654 --> 00:02:02,157 SONJA'S WORK HAS BEEN SHE 44 00:02:02,157 --> 00:02:04,893 SHIFTED THE PARADIGM THE WAY WE 45 00:02:04,893 --> 00:02:06,895 THINK ABOUT NEURODEGENERATIVE 46 00:02:06,895 --> 00:02:07,162 DISEASES. 47 00:02:07,162 --> 00:02:11,099 SHE HAS TAUGHT US THESE DISEASES 48 00:02:11,099 --> 00:02:15,036 MAY OUGHT BEST NOT THOUGHT OF AS 49 00:02:15,036 --> 00:02:21,209 DISCRETE CLINICAL ENTITIES, 50 00:02:21,209 --> 00:02:25,947 ALZHEIMER'S DISEASE, PARKINSON'S 51 00:02:25,947 --> 00:02:28,450 DISEASE, HUNTINGTON'S DISEASE, 52 00:02:28,450 --> 00:02:29,984 BUT RATHER ASSORTMENTS, 53 00:02:29,984 --> 00:02:35,223 DIFFERENT ASSORTMENTS OF, OF 54 00:02:35,223 --> 00:02:37,425 DEEP PHENOTYPIC CHARACTERISTICS 55 00:02:37,425 --> 00:02:39,928 THAT CO-SEGREGATE WITH 56 00:02:39,928 --> 00:02:42,130 ASSORTMENTS, AGAIN, OF GENOMIC 57 00:02:42,130 --> 00:02:42,664 ABNORMALITIES. 58 00:02:42,664 --> 00:02:45,633 SO THAT MOST OF THE PATIENTS 59 00:02:45,633 --> 00:02:51,005 WITH ANY OF THESE DISORDERS THAT 60 00:02:51,005 --> 00:02:52,207 INVOLVE AGGREGATION OF LARGE 61 00:02:52,207 --> 00:02:55,810 PROTEINS IN THE CENTRAL NERVOUS 62 00:02:55,810 --> 00:02:58,313 SYSTEM REALLY ARE SOMEWHERE IN 63 00:02:58,313 --> 00:03:00,849 THE CRACKS BETWEEN THE DISCRETE 64 00:03:00,849 --> 00:03:03,485 ENTITIES THAT HAVE BEEN 65 00:03:03,485 --> 00:03:07,956 CHARACTERIZED OVER THE YEARS. 66 00:03:07,956 --> 00:03:12,894 AND SO SONJA 'S TALK TODAY, WHIH 67 00:03:12,894 --> 00:03:15,730 I ALREADY MESSED UP BY HITTING 68 00:03:15,730 --> 00:03:19,134 SOME BUTTONS ON THIS -- LET ME 69 00:03:19,134 --> 00:03:22,070 JUST TRY TO GET THIS BACK FOR 70 00:03:22,070 --> 00:03:29,043 YOU. 71 00:03:29,043 --> 00:03:32,647 SORRY ABOUT THAT. 72 00:03:32,647 --> 00:03:34,716 THERE WE GO. 73 00:03:34,716 --> 00:03:37,585 EXCELLENT. 74 00:03:37,585 --> 00:03:42,390 SONJA'S TALK TODAY IS 75 00:03:42,390 --> 00:03:46,928 "UNLEACH LEASHING POTENTIAL OF 76 00:03:46,928 --> 00:03:51,499 GENOMICS WITH LEWY BODY DEMENTIA 77 00:03:51,499 --> 00:03:52,333 AND RELATED DISEASES." 78 00:03:52,333 --> 00:03:56,638 CONGRATULATIONS FROM ALL OF US 79 00:03:56,638 --> 00:03:57,172 AND WELCOME. 80 00:03:57,172 --> 00:03:58,373 [APPLAUSE] 81 00:03:58,373 --> 00:03:59,607 >> GOOD AFTERNOON, EVERYBODY. 82 00:03:59,607 --> 00:04:01,342 THANK YOU, DR. SCHOR, FOR THE 83 00:04:01,342 --> 00:04:01,910 KIND INTRODUCTION AND 84 00:04:01,910 --> 00:04:03,144 OPPORTUNITY TO SPEAK TO YOU 85 00:04:03,144 --> 00:04:04,612 TODAY, ALSO THANK YOU TO THE 86 00:04:04,612 --> 00:04:07,348 PEOPLE IN THE ROOM BRAVING THE 87 00:04:07,348 --> 00:04:08,683 COLD TEMPERATURES TODAY TO COME 88 00:04:08,683 --> 00:04:09,083 HERE. 89 00:04:09,083 --> 00:04:13,588 I'M GOING TO TALK TODAY ABOUT MY 90 00:04:13,588 --> 00:04:15,023 RECENT LAB'S RESEARCH EFFORTS 91 00:04:15,023 --> 00:04:17,659 TRYING TO USE MODERN GENOMICS 92 00:04:17,659 --> 00:04:22,897 TOOLS TO UNDERSTAND COMPLEX 93 00:04:22,897 --> 00:04:23,665 NEURODEGENERATIVE DISEASE. 94 00:04:23,665 --> 00:04:27,402 LEWY BODY IS THE TEMPLATE, THE 95 00:04:27,402 --> 00:04:28,436 MODEL THESE DAYS, BUT WHAT IS 96 00:04:28,436 --> 00:04:29,904 HAPPENING IS GOING ON IN OTHER 97 00:04:29,904 --> 00:04:30,872 DISEASES AS WELL. 98 00:04:30,872 --> 00:04:33,608 THERE'S HOPE TO BE OPTIMISTIC 99 00:04:33,608 --> 00:04:36,244 ABOUT THE FIELD. 100 00:04:36,244 --> 00:04:38,313 HERE ARE MY DISCLOSURES. 101 00:04:38,313 --> 00:04:40,448 SO THE MAIN ISSUES THAT I WANTED 102 00:04:40,448 --> 00:04:43,051 TO DISCUSS TODAY IS I WANT TO 103 00:04:43,051 --> 00:04:45,019 BASICALLY HIGHLIGHT, YOU KNOW, 104 00:04:45,019 --> 00:04:46,888 RECENT GENOMIC ADVANCES, AND HOW 105 00:04:46,888 --> 00:04:48,756 THESE GENOMIC ADVANCES ARE 106 00:04:48,756 --> 00:04:52,260 REALLY STARTING TO PAVE THE WAY 107 00:04:52,260 --> 00:04:55,863 FOR PRECISION MEDICINE, 108 00:04:55,863 --> 00:04:58,700 PRECISION NEUROLOGY 109 00:04:58,700 --> 00:04:59,033 INTERVENTIONS. 110 00:04:59,033 --> 00:05:00,235 MOLECULAR INSIGHTS WE'VE GAINED 111 00:05:00,235 --> 00:05:01,603 IN LEWY BODY DEMENTIA 112 00:05:01,603 --> 00:05:03,972 SPECIFICALLY, BUT I WANT TO 113 00:05:03,972 --> 00:05:07,575 HIGHLIGHT HOW THIS KNOWLEDGE CAN 114 00:05:07,575 --> 00:05:09,544 BE SEEN, HOW DO THEY RELATE TO 115 00:05:09,544 --> 00:05:10,144 OTHER DISEASES. 116 00:05:10,144 --> 00:05:12,714 AND THEN FROM THAT I WILL 117 00:05:12,714 --> 00:05:15,016 OUTLINE HOW WE CAN BEST USE THAT 118 00:05:15,016 --> 00:05:18,086 KNOWLEDGE IN THE CLINICAL 119 00:05:18,086 --> 00:05:20,455 CONTEXT TO BETTER DIAGNOSE, 120 00:05:20,455 --> 00:05:22,023 SUBSTRATIFY, ULTIMATELY TREAT 121 00:05:22,023 --> 00:05:23,658 THESE CHALLENGING CONDITIONS. 122 00:05:23,658 --> 00:05:26,194 AND SO I'M GOING TO GIVE 123 00:05:26,194 --> 00:05:26,494 BACKGROUND. 124 00:05:26,494 --> 00:05:27,829 I THINK IT'S FAIR TO SAY WE'RE 125 00:05:27,829 --> 00:05:31,399 LIVING IN A REALLY EXCITING 126 00:05:31,399 --> 00:05:32,734 TIME, SINCE THE FIRST DRAFT OF 127 00:05:32,734 --> 00:05:34,369 THE HUMAN GENOME HAS BEEN 128 00:05:34,369 --> 00:05:37,672 PUBLISHED IN THE EARLY 2000s, 129 00:05:37,672 --> 00:05:41,709 THERE HAS BEEN JUST A REVOLUTION 130 00:05:41,709 --> 00:05:43,678 OF GENOME INSIGHTS AND 131 00:05:43,678 --> 00:05:44,646 GENOMICALLY BASED TREATMENTS 132 00:05:44,646 --> 00:05:47,949 THAT ARE COMING TO THE PATIENTS. 133 00:05:47,949 --> 00:05:50,785 THESE ARE DISEASES THAT SUCH AS 134 00:05:50,785 --> 00:05:54,856 SPINAL MUSCULAR ATROPHY, LOU 135 00:05:54,856 --> 00:05:56,724 GEHRIG'S DISEASE, RARE UNUSUAL 136 00:05:56,724 --> 00:05:56,991 DISEASES. 137 00:05:56,991 --> 00:05:58,893 WHEN I TRAINED AS A PHYSICIAN I 138 00:05:58,893 --> 00:06:00,094 HONESTLY THOUGHT THAT TREATMENTS 139 00:06:00,094 --> 00:06:02,030 FOR THOSE DISEASES IS KIND OF 140 00:06:02,030 --> 00:06:03,298 SCIENCE FICTION. 141 00:06:03,298 --> 00:06:04,599 THIS IS ALREADY REALITY. 142 00:06:04,599 --> 00:06:07,435 SO THERE'S A LOT MORE HAPPENING 143 00:06:07,435 --> 00:06:09,304 NOW IN THE PRE-CLINICAL SPACE. 144 00:06:09,304 --> 00:06:11,906 AND FOR THE MOST PART WHAT'S 145 00:06:11,906 --> 00:06:14,742 COMING TO THE FOREFRONT ARE, YOU 146 00:06:14,742 --> 00:06:15,543 KNOW, THERAPIES FOR SO-CALLED 147 00:06:15,543 --> 00:06:18,813 MONOGENIC DISEASES WHERE YOU 148 00:06:18,813 --> 00:06:21,015 HAVE ONE MAJOR GENETIC DEFECT 149 00:06:21,015 --> 00:06:22,483 THAT EITHER CAUSES LOSS OF 150 00:06:22,483 --> 00:06:24,619 FUNCTION OR TOXIC GAIN OF 151 00:06:24,619 --> 00:06:28,222 FUNCTION AND USING THE VARIOUS 152 00:06:28,222 --> 00:06:30,458 STRATEGIES SUCH AS GENE 153 00:06:30,458 --> 00:06:32,860 REPLACEMENT WITH AAV VECTORS OR 154 00:06:32,860 --> 00:06:34,796 GENE TARGETED USING ASOs, OR 155 00:06:34,796 --> 00:06:36,230 GENE EDITING WHICH LOOKS VERY 156 00:06:36,230 --> 00:06:37,432 PROMISING, THESE ARE THE DISEASE 157 00:06:37,432 --> 00:06:38,966 WHERE IS WE HEAR A LOT NOW 158 00:06:38,966 --> 00:06:41,402 COMING INTO THE FDA PIPELINE. 159 00:06:41,402 --> 00:06:43,037 BUT OUR STORY DOESN'T STOP 160 00:06:43,037 --> 00:06:43,905 THERE. 161 00:06:43,905 --> 00:06:45,540 FOR THE MOST PART, THE PATIENTS 162 00:06:45,540 --> 00:06:48,476 THAT I SEE IN THE CLINIC, THOSE 163 00:06:48,476 --> 00:06:51,679 ARE PATIENTS WHO HAVE ADULT 164 00:06:51,679 --> 00:06:53,881 ONSET APPARENTLY SPORADIC 165 00:06:53,881 --> 00:06:54,182 CONDITIONS. 166 00:06:54,182 --> 00:06:56,918 AND SO, THE GENETIC STILL PLAYS 167 00:06:56,918 --> 00:06:58,486 A ROLE IN THOSE DISEASES 168 00:06:58,486 --> 00:07:00,888 ALTHOUGH IT'S MORE COMPLICATE. 169 00:07:00,888 --> 00:07:01,756 CONCEPTUALLY WE THINK ABOUT A 170 00:07:01,756 --> 00:07:04,258 LOT OF ADULT ONSET DISEASES AS 171 00:07:04,258 --> 00:07:05,593 POLYGENIC WHERE YOU HAVE RISK 172 00:07:05,593 --> 00:07:07,962 GENES THAT ARE COMING TOGETHER 173 00:07:07,962 --> 00:07:09,964 AND THAT IN AGGREGATE CAN DRIVE 174 00:07:09,964 --> 00:07:11,599 DISEASE, MAY NOT ALWAYS BE 175 00:07:11,599 --> 00:07:14,068 ENOUGH TO CAUSE IT BUT STILL CAN 176 00:07:14,068 --> 00:07:17,305 GIVE US A LOT OF INFORMATION 177 00:07:17,305 --> 00:07:18,406 ABOUT THE UNDERLYING 178 00:07:18,406 --> 00:07:19,807 PATHOPHYSIOLOGY, AND CAN ALSO 179 00:07:19,807 --> 00:07:22,343 REALLY HELP US DEVICE NEW 180 00:07:22,343 --> 00:07:22,810 TREATMENT STRATEGIES. 181 00:07:22,810 --> 00:07:25,513 SO FOR EXAMPLE BY IDENTIFYING 182 00:07:25,513 --> 00:07:26,914 CAUSAL RELATIONSHIP WITH OTHER 183 00:07:26,914 --> 00:07:28,883 DISEASES WE MAY BE ABLE TO 184 00:07:28,883 --> 00:07:30,218 REPURPOSE CERTAIN DRUGS THAT 185 00:07:30,218 --> 00:07:31,652 HAVE BEEN DEVELOPED, ONE DISEASE 186 00:07:31,652 --> 00:07:32,954 FOR ANOTHER. 187 00:07:32,954 --> 00:07:34,822 AND WE ALSO CAN REALLY IDENTIFY 188 00:07:34,822 --> 00:07:36,891 WHERE ARE THE PATHWAYS TO 189 00:07:36,891 --> 00:07:38,059 IMPORTANT NOTES WITHIN CELLULAR 190 00:07:38,059 --> 00:07:40,094 NETWORKS THAT SEEM TO BE ALWAYS 191 00:07:40,094 --> 00:07:40,428 DYSFUNCTIONAL. 192 00:07:40,428 --> 00:07:43,030 THOSE ARE THE ONES WE WANT TO GO 193 00:07:43,030 --> 00:07:44,365 AFTER FROM A THERAPEUTIC 194 00:07:44,365 --> 00:07:46,300 TRANSLATIONAL POINT OF VIEW. 195 00:07:46,300 --> 00:07:51,906 AND SO, THE MAIN KIND OF TOOLS 196 00:07:51,906 --> 00:07:53,674 WE'RE USING AS GENETICISTS ARE 197 00:07:53,674 --> 00:07:55,977 SEGREGATION ANALYSIS WHICH IS 198 00:07:55,977 --> 00:07:57,044 ESSENTIALLY WHAT WE'VE BEEN 199 00:07:57,044 --> 00:07:59,380 USING FOR A LONG TIME WHEN WE 200 00:07:59,380 --> 00:08:01,149 LOOK AT MENDELIAN DISEASES BUT 201 00:08:01,149 --> 00:08:03,217 NOWADAYS IT'S REALLY, YOU KNOW, 202 00:08:03,217 --> 00:08:06,621 A NUMBERS GAME WITH MODERN 203 00:08:06,621 --> 00:08:08,022 GENOMIC TOOLS, COMPUTATIONAL 204 00:08:08,022 --> 00:08:08,790 CAPABILITIES, ESSENTIALLY DOING 205 00:08:08,790 --> 00:08:10,124 ASSOCIATION TESTS. 206 00:08:10,124 --> 00:08:12,193 WE COMPARE LARGE CORDS OF CASES 207 00:08:12,193 --> 00:08:15,029 VERSUS CONTROLS AND TRY TO MAP 208 00:08:15,029 --> 00:08:17,331 OUT THAT PLOT WHERE WE 209 00:08:17,331 --> 00:08:19,400 ESSENTIALLY MAP OUT RISK GENES, 210 00:08:19,400 --> 00:08:20,935 HIGH IMPACT VERSUS LOWER IMPACT, 211 00:08:20,935 --> 00:08:22,937 AND EACH ONE OF THOSE CAN TELL 212 00:08:22,937 --> 00:08:25,773 US SOMETHING ABOUT THE 213 00:08:25,773 --> 00:08:26,974 UNDERLYING PATHOPHYSIOLOGY. 214 00:08:26,974 --> 00:08:29,610 OUR JOB DOESN'T STOP THERE. 215 00:08:29,610 --> 00:08:30,611 ONCE WE PINPOINT THERE'S 216 00:08:30,611 --> 00:08:32,880 SOMETHING IN THE GENOME THAT'S 217 00:08:32,880 --> 00:08:35,716 ASSOCIATED WITH OUR DISEASE OF 218 00:08:35,716 --> 00:08:38,386 INTEREST, WE CAN NOW USE MAPS 219 00:08:38,386 --> 00:08:41,022 ARE OR CATALOGS OF OTHER OMIC 220 00:08:41,022 --> 00:08:43,324 DATA, FOR EXAMPLE TRANSCRIPTION 221 00:08:43,324 --> 00:08:46,494 DATA, TO LOOK AT WHAT IS THE 222 00:08:46,494 --> 00:08:47,428 MOST LIKELY UNDERLYING GENE 223 00:08:47,428 --> 00:08:49,096 WITHIN THE LOCUS OF INTEREST AND 224 00:08:49,096 --> 00:08:51,098 WHAT'S IN SOME INSTANCES COULD 225 00:08:51,098 --> 00:08:52,233 BE THE POTENTIAL MECHANISM. 226 00:08:52,233 --> 00:08:56,003 IS IT A LOSS OF FUNCTION, IS IT 227 00:08:56,003 --> 00:08:57,738 AN INCREASE IN EXPRESSION, ET 228 00:08:57,738 --> 00:09:00,508 CETERA, SO WE'RE USING 229 00:09:00,508 --> 00:09:02,143 INCREASINGLY JUST BY 230 00:09:02,143 --> 00:09:03,377 COMPUTATIONAL MODELING A SYSTEMS 231 00:09:03,377 --> 00:09:05,012 BIOLOGY FRAMEWORK. 232 00:09:05,012 --> 00:09:06,280 AND WITHOUT EVEN HAVING TOUCHED 233 00:09:06,280 --> 00:09:08,950 AN ANIMAL MODEL OR CELL MODEL. 234 00:09:08,950 --> 00:09:11,786 THAT REALLY ACCELERATES OUR 235 00:09:11,786 --> 00:09:14,455 ABILITY TO BOIL DOWN TO THE MOST 236 00:09:14,455 --> 00:09:15,423 IMPORTANT MOLECULAR DEFECT. 237 00:09:15,423 --> 00:09:17,191 BUT THE OTHER THING THAT'S 238 00:09:17,191 --> 00:09:20,027 ACTUALLY QUITE ELEGANT IS WE CAN 239 00:09:20,027 --> 00:09:22,230 ALSO LEVERAGE GENOMIC TOOLS TO 240 00:09:22,230 --> 00:09:26,067 MAKE CAUSAL INFERENCES, NOT JUST 241 00:09:26,067 --> 00:09:27,168 USING ASSOCIATION TESTS BUT 242 00:09:27,168 --> 00:09:29,437 GENUINELY TELL US IF WE CAN TELL 243 00:09:29,437 --> 00:09:32,940 SOMETHING ABOUT A CAUSAL 244 00:09:32,940 --> 00:09:34,275 RELATIONSHIP, USING MODERN 245 00:09:34,275 --> 00:09:36,777 COMPUTATIONAL TOOLS SUCH AS 246 00:09:36,777 --> 00:09:38,312 MENDELIAN RANDOMIZATION STUDIES. 247 00:09:38,312 --> 00:09:39,947 I'LL SHOW EXAMPLES HOW WE 248 00:09:39,947 --> 00:09:40,915 LEVERAGED SOME OF THESE TOOLS 249 00:09:40,915 --> 00:09:41,716 THERE ARE. 250 00:09:41,716 --> 00:09:44,318 THERE'S A GROUP OF DISEASES THAT 251 00:09:44,318 --> 00:09:50,458 FALLS UNDER THE UMBRELLA OF 252 00:09:50,458 --> 00:09:51,259 ATYPICAL PARKINSON SYNDROME, 253 00:09:51,259 --> 00:09:52,159 UNDERSTUDIED NEURODEGENERATIVE 254 00:09:52,159 --> 00:09:58,833 DISEASE, ONE IS LEWY BODY 255 00:09:58,833 --> 00:10:01,002 DEMENTIA, WE SEE ABNORMAL 256 00:10:01,002 --> 00:10:02,370 DEPOSITION OF A PROTEIN CALLED 257 00:10:02,370 --> 00:10:06,040 ALPHA SIGH 258 00:10:06,040 --> 00:10:06,841 ALPHA-SYNUCLEIN. 259 00:10:06,841 --> 00:10:08,809 WHAT MAKES IT CHALLENGES IS 260 00:10:08,809 --> 00:10:10,278 CLINICAL VARIATIONS CAN BE 261 00:10:10,278 --> 00:10:11,746 VARIABLE EARLY ON, AS A 262 00:10:11,746 --> 00:10:13,514 CONSEQUENCE PATIENTS ARE OFTEN 263 00:10:13,514 --> 00:10:15,016 NOT RECOGNIZED UNTIL MUCH, MUCH 264 00:10:15,016 --> 00:10:16,684 FURTHER ALONG WHEN THEY ARE 265 00:10:16,684 --> 00:10:21,289 ALREADY QUITE DISABLED AND 266 00:10:21,289 --> 00:10:23,357 DEVASTATED BY THE CONDITION. 267 00:10:23,357 --> 00:10:24,892 TO BE EFFECTIVE, GENOMIC 268 00:10:24,892 --> 00:10:26,427 STUDIES, WE NEED LARGE COHORTS, 269 00:10:26,427 --> 00:10:28,062 THAT CAN BE DIFFICULT TO 270 00:10:28,062 --> 00:10:29,363 RECRUIT. 271 00:10:29,363 --> 00:10:30,898 BUT I WOULD ARGUE BEING AT THE 272 00:10:30,898 --> 00:10:31,899 NIH INTRAMURAL RESEARCH PROGRAM 273 00:10:31,899 --> 00:10:34,835 WHERE WE HAVE A MORE STABLE 274 00:10:34,835 --> 00:10:35,603 FUNDING ENVIRONMENT IT'S 275 00:10:35,603 --> 00:10:37,371 ACTUALLY A REAL IDEAL SCENARIO 276 00:10:37,371 --> 00:10:39,340 WHERE WE CAN BRING RESOURCES TO 277 00:10:39,340 --> 00:10:42,510 BEAR BOTH AT THIS LARGE TEAM 278 00:10:42,510 --> 00:10:43,477 SCIENCE EFFORT. 279 00:10:43,477 --> 00:10:45,913 THERE'S ALSO LACK OF PUBLIC 280 00:10:45,913 --> 00:10:46,681 GENOMIC RESOURCES, SOMETHING 281 00:10:46,681 --> 00:10:48,182 THAT WE'RE REALLY TRYING TO 282 00:10:48,182 --> 00:10:51,919 REMEDY AS MUCH AS POSSIBLE BY 283 00:10:51,919 --> 00:10:52,920 MAKING DATA RAPIDLY AVAILABLE TO 284 00:10:52,920 --> 00:10:55,623 ACCELERATE DISCOVERIES IN THESE 285 00:10:55,623 --> 00:10:56,958 UNDERSTUDIED DISEASES. 286 00:10:56,958 --> 00:11:02,597 AND HOPEFULLY HOPEFULLY EFFECT, 287 00:11:02,597 --> 00:11:03,364 SOME CHANGE. 288 00:11:03,364 --> 00:11:06,534 WE'RE GOING TO TALK MORE ABOUT 289 00:11:06,534 --> 00:11:08,603 LEWY BODY DEMENTIA, AN AREA OF 290 00:11:08,603 --> 00:11:08,869 INTEREST. 291 00:11:08,869 --> 00:11:11,706 LEWY BODY DEMENTIA, MANY OF YOU 292 00:11:11,706 --> 00:11:15,643 KNOW, IS AN ADULT ONSET 293 00:11:15,643 --> 00:11:18,045 DEVASTATING NEURODEGENERATIVE 294 00:11:18,045 --> 00:11:19,447 DISEASE, CHARACTERIZED BY 295 00:11:19,447 --> 00:11:24,385 COMPLEX CLINICAL FEATURES THAT 296 00:11:24,385 --> 00:11:27,355 INCLUDE PARKINSONISM, VISUAL 297 00:11:27,355 --> 00:11:28,756 HALLUCINATION, SLEEP DISORDERS, 298 00:11:28,756 --> 00:11:30,958 FLUCTUATIONS IN ATTENTION, ALSO 299 00:11:30,958 --> 00:11:33,394 AUTONOMIC NERVOUS SYSTEM 300 00:11:33,394 --> 00:11:33,694 INVOLVEMENT. 301 00:11:33,694 --> 00:11:36,564 IT VARIES FROM PERSON TO PERSON. 302 00:11:36,564 --> 00:11:38,633 WE'VE LEARNED THAT THESE 303 00:11:38,633 --> 00:11:39,567 PATIENTS HAVE ABNORMAL 304 00:11:39,567 --> 00:11:45,106 DEPOSITION OF THE 305 00:11:45,106 --> 00:11:46,407 ALPHA-SYNUCLEIN PROTEINS, IN THE 306 00:11:46,407 --> 00:11:48,809 FORM OF LEWY BODYs. 307 00:11:48,809 --> 00:11:51,112 60 TO 80%, THERE'S ALZHEIMER'S 308 00:11:51,112 --> 00:11:55,816 DISEASE CO-PATHOLOGY, FORM OF 309 00:11:55,816 --> 00:11:56,484 AMYLOID PLAQUE, AND 310 00:11:56,484 --> 00:11:58,019 NEUROFIBRILLARY TANGLES. 311 00:11:58,019 --> 00:11:58,653 WE'VE INCREASINGLY APPRECIATED 312 00:11:58,653 --> 00:12:00,221 THAT THERE IS A SUBSET OF 313 00:12:00,221 --> 00:12:03,924 PATIENTS THAT CLEARLY HAVE A 314 00:12:03,924 --> 00:12:04,525 FAMILY HISTORY. 315 00:12:04,525 --> 00:12:07,762 AND THERE SEEMS TO BE A GENETIC 316 00:12:07,762 --> 00:12:09,964 PREDISPOSITION, AT LEAST IN 317 00:12:09,964 --> 00:12:11,298 THOSE INDIVIDUALS THAT HAVE A 318 00:12:11,298 --> 00:12:14,568 FAMILY HISTORY, BUT EVEN IN 319 00:12:14,568 --> 00:12:15,670 THOSE THAT APPARENTLY SPORADIC, 320 00:12:15,670 --> 00:12:16,871 SO MAYBE ADDITIONAL GENETIC 321 00:12:16,871 --> 00:12:21,242 FACTORS THAT COULD PLAY A ROLE, 322 00:12:21,242 --> 00:12:23,210 IT'S AN AGED POPULATION, WE 323 00:12:23,210 --> 00:12:28,349 DIDN'T LIVE AS LONG, ANCESTORS 324 00:12:28,349 --> 00:12:29,684 DIDN'T SURVIVE AS LONG IN THE 325 00:12:29,684 --> 00:12:30,317 PAST. 326 00:12:30,317 --> 00:12:32,853 LEWY BODY IS PERCEIVED AS RARE 327 00:12:32,853 --> 00:12:37,892 BUT IT'S ACTUALLY THE SECOND 328 00:12:37,892 --> 00:12:40,394 MOST COMMON NEURODEGENERATIVE 329 00:12:40,394 --> 00:12:40,961 DEMENTIA AFTER ALZHEIMER'S, 330 00:12:40,961 --> 00:12:42,296 1.4 MILLION PEOPLE IN THE UNITED 331 00:12:42,296 --> 00:12:46,133 STATES ALONE, ABOUT 5% OF ALL 332 00:12:46,133 --> 00:12:47,668 DEMENTIA CASES, BUT MORE 333 00:12:47,668 --> 00:12:49,303 ESPECIALLY THE ONES THAT OVERLAP 334 00:12:49,303 --> 00:12:50,838 WITH ALZHEIMER'S DISEASE. 335 00:12:50,838 --> 00:12:52,907 AND BECAUSE WE HAVE THESE 336 00:12:52,907 --> 00:12:54,108 COMPLEX MOTOR AND NON-MOTOR 337 00:12:54,108 --> 00:12:56,377 FEATURES, IT IS A REALLY 338 00:12:56,377 --> 00:12:58,813 DEVASTATING DISEASE TO DEAL 339 00:12:58,813 --> 00:12:59,046 WITH. 340 00:12:59,046 --> 00:13:00,681 IT HAS HIGHEST COST OF ALL 341 00:13:00,681 --> 00:13:01,949 DEMENTIAS ASSOCIATED WITH IT. 342 00:13:01,949 --> 00:13:03,984 SO THERE'S A LOT OF NEED TO 343 00:13:03,984 --> 00:13:05,386 IMPROVE OUR UNDERSTANDING SO WE 344 00:13:05,386 --> 00:13:07,588 CAN DEVELOP TREATMENTS TO SLOW 345 00:13:07,588 --> 00:13:10,524 DOWN THE DISEASE PROCESS. 346 00:13:10,524 --> 00:13:12,626 AND SO THERE'S BEEN, YOU KNOW, A 347 00:13:12,626 --> 00:13:14,462 FAIR AMOUNT OF, YOU KNOW, 348 00:13:14,462 --> 00:13:16,664 OBSERVATIONAL STUDIES ALREADY 349 00:13:16,664 --> 00:13:18,099 THAT HAVE IMPLICATED THAT 350 00:13:18,099 --> 00:13:20,167 GENETICS IS PLAYING A ROLE. 351 00:13:20,167 --> 00:13:21,669 I MENTIONED FAMILY HISTORIES 352 00:13:21,669 --> 00:13:23,904 THAT HAVE BEEN OBSERVED. 353 00:13:23,904 --> 00:13:25,306 THEY ARE SUSPICIOUS. 354 00:13:25,306 --> 00:13:26,373 WE'VE SEEN SEVERAL FAMILIAL 355 00:13:26,373 --> 00:13:28,476 CASES AT THE NIH AS WELL. 356 00:13:28,476 --> 00:13:30,911 WE'VE NOTICED SIBLINGS OFTEN 357 00:13:30,911 --> 00:13:33,180 HAVE INCREASED RISK OF LEWY BODY 358 00:13:33,180 --> 00:13:35,583 DEMENTIA, ALSO INDICATIVE OF A 359 00:13:35,583 --> 00:13:37,151 HERITABLE CONTRIBUTION. 360 00:13:37,151 --> 00:13:38,552 AND THERE'S HERITABILITY WE CAN 361 00:13:38,552 --> 00:13:41,088 ESTIMATE BASED ON COMMON GENETIC 362 00:13:41,088 --> 00:13:41,555 VARIANTS. 363 00:13:41,555 --> 00:13:43,924 THERE MAY BE INTERESTING SEX 364 00:13:43,924 --> 00:13:44,391 DIFFERENCES. 365 00:13:44,391 --> 00:13:46,994 WE DEFINITELY SEE MEN MORE 366 00:13:46,994 --> 00:13:48,629 COMMONLY WITH THIS CONDITION 367 00:13:48,629 --> 00:13:49,730 THAN WOMEN. 368 00:13:49,730 --> 00:13:52,433 AND WHILE I -- YOU KNOW, I FOCUS 369 00:13:52,433 --> 00:13:54,568 IN ON THE GENETICS, IT DOESN'T 370 00:13:54,568 --> 00:13:56,937 MEAN GENETICS IS THE ANSWER TO 371 00:13:56,937 --> 00:13:57,238 EVERYTHING. 372 00:13:57,238 --> 00:13:59,140 IT'S AGE-RELATED DISEASE, 373 00:13:59,140 --> 00:14:00,241 THERE'S AGING, ENVIRONMENTAL 374 00:14:00,241 --> 00:14:01,642 FACTORS, THERE'S EPIGENETIC 375 00:14:01,642 --> 00:14:03,277 CHANGES, LIFESTYLE CHANGES THAT 376 00:14:03,277 --> 00:14:05,279 PROBABLY COME TOGETHER BUT THE 377 00:14:05,279 --> 00:14:06,714 LEAST GENETICS IS SOMETHING VERY 378 00:14:06,714 --> 00:14:10,651 TRACTABLE THAT WE CAN TEASE 379 00:14:10,651 --> 00:14:12,186 APART USING MODERN TECHNOLOGIES. 380 00:14:12,186 --> 00:14:14,755 AND SO VERY BRIEFLY LOOKING AT 381 00:14:14,755 --> 00:14:17,591 THE HISTORY OF LEWY BODY 382 00:14:17,591 --> 00:14:18,793 DEMENTIA, GENETICS, IT'S A 383 00:14:18,793 --> 00:14:23,931 RELATIVELY YOUNG FIELD, THREE 384 00:14:23,931 --> 00:14:24,832 DECADES SINCE WE OPERATIONALIZED 385 00:14:24,832 --> 00:14:26,867 THE CRITERIA FOR LEWY BODY 386 00:14:26,867 --> 00:14:28,135 DEMENTIA. 387 00:14:28,135 --> 00:14:31,138 AND THE FIRST COUPLE YEARS 388 00:14:31,138 --> 00:14:33,207 REALLY CONSISTED OF CANDIDATE 389 00:14:33,207 --> 00:14:38,479 GENE STUDIES, IN THIS CASE QUITE 390 00:14:38,479 --> 00:14:39,346 SUCCESSFUL. 391 00:14:39,346 --> 00:14:42,116 SO PARKINSON'S DISEASE AND 392 00:14:42,116 --> 00:14:44,618 ALZHEIMER'S DISEASE FIELD, 393 00:14:44,618 --> 00:14:45,419 INSIGHT ALLOWED CANDIDATE GENE 394 00:14:45,419 --> 00:14:47,788 STUDIES ON LEWY BODY DEMENTIA. 395 00:14:47,788 --> 00:14:49,190 SEVERAL GENES HAVE BEEN 396 00:14:49,190 --> 00:14:58,299 CONFIRMED AS BEING IMPORTANT IN 397 00:14:58,299 --> 00:15:00,701 LEWY BODY. 398 00:15:00,701 --> 00:15:02,570 IT WASN'T UNTIL IT CAME TO THE 399 00:15:02,570 --> 00:15:03,771 FOREFRONT WE'VE BEEN ABLE TO 400 00:15:03,771 --> 00:15:06,473 LOOK INTO THE BROADER SPORADIC 401 00:15:06,473 --> 00:15:07,474 FORMS OF LEWY BODY DEMENTIA, AND 402 00:15:07,474 --> 00:15:09,643 THIS IS WHAT I'M GOING TO SHOW 403 00:15:09,643 --> 00:15:10,010 YOU TODAY. 404 00:15:10,010 --> 00:15:12,746 SO ONE OF THE VERY FIRST 405 00:15:12,746 --> 00:15:14,615 PROJECTS CONSISTED OF EXOME 406 00:15:14,615 --> 00:15:17,384 SEQUENCING OF A PATHOLOGICALLY 407 00:15:17,384 --> 00:15:18,118 CONFIRMED COHORT. 408 00:15:18,118 --> 00:15:19,987 AND THIS WAS DRAWN FROM THE 409 00:15:19,987 --> 00:15:21,922 HOPKINS BRAIN BANK. 410 00:15:21,922 --> 00:15:24,258 WE WERE JUST ASTONISHED TO SEE 411 00:15:24,258 --> 00:15:26,794 ABOUT 25% OF ALL PATIENTS 412 00:15:26,794 --> 00:15:28,829 ACTUALLY HAD HIGH RISK OF 413 00:15:28,829 --> 00:15:29,430 PATHOGENIC MUTATION. 414 00:15:29,430 --> 00:15:37,071 IN ONE OF THOSE, THE THREE 415 00:15:37,071 --> 00:15:38,939 GENES, THOSE ARE IMPORTANT RISK 416 00:15:38,939 --> 00:15:39,139 GENES. 417 00:15:39,139 --> 00:15:40,708 WE HAD DIFFICULTY PUBLISHING 418 00:15:40,708 --> 00:15:41,709 BECAUSE NOBODY BELIEVED THAT IT 419 00:15:41,709 --> 00:15:44,178 WAS -- THAT THAT'S THE CASE, 420 00:15:44,178 --> 00:15:49,617 WE'RE SPOT ON. 421 00:15:49,617 --> 00:15:52,519 WE NOTICED APOE 4 PLAYS A ROLE, 422 00:15:52,519 --> 00:15:54,922 DEMONSTRATED THAT AND CLEARLY 423 00:15:54,922 --> 00:16:00,060 HAD MAJOR EFFECT ALSO ON 424 00:16:00,060 --> 00:16:00,327 SURVIVAL. 425 00:16:00,327 --> 00:16:02,563 WE COLLABORATED WITH 426 00:16:02,563 --> 00:16:04,098 INTERNATIONAL TEAM, FIRST GENOME 427 00:16:04,098 --> 00:16:04,999 WIDE ASSOCIATION STUDY, AGAIN 428 00:16:04,999 --> 00:16:07,268 CONFIRMING GENES THAT HAVE BEEN 429 00:16:07,268 --> 00:16:08,802 PREVIOUSLY IMPLICATED BASED ON 430 00:16:08,802 --> 00:16:12,172 CANDIDATE GENE WORK, GBA, SNCA, 431 00:16:12,172 --> 00:16:14,942 APOE AS IMPORTANT IN THE PATIENT 432 00:16:14,942 --> 00:16:15,576 POPULATION. 433 00:16:15,576 --> 00:16:16,810 WE REALIZED ONLY A SMALL 434 00:16:16,810 --> 00:16:18,345 FRACTION OF THE HERITABILITY 435 00:16:18,345 --> 00:16:19,980 THAT EXISTS COULD BE EXPLAINED 436 00:16:19,980 --> 00:16:20,648 AT THAT TIME. 437 00:16:20,648 --> 00:16:23,784 SO THAT WAS REALLY THE MAIN 438 00:16:23,784 --> 00:16:26,654 IMPETUS FOR US TO LAUNCH A 439 00:16:26,654 --> 00:16:27,922 GENOME SEQUENCING INITIATIVE. 440 00:16:27,922 --> 00:16:29,590 THIS WAS FUNDED THROUGH THE 441 00:16:29,590 --> 00:16:31,458 NATIONAL INSTITUTE ON AGING, SO 442 00:16:31,458 --> 00:16:33,527 A LARGE DEMENTIA GRANT. 443 00:16:33,527 --> 00:16:34,995 AND WE BASICALLY WENT THROUGH 444 00:16:34,995 --> 00:16:37,498 EVERY BRAIN BANK WE COULD 445 00:16:37,498 --> 00:16:39,667 IDENTIFY, ANYBODY WHO WAS 446 00:16:39,667 --> 00:16:42,503 WORKING IN THE FIELD, TO 447 00:16:42,503 --> 00:16:44,471 ASSEMBLE A COHORT OF 2600 CASES, 448 00:16:44,471 --> 00:16:48,275 AND ABOUT 4,000 NEUROLOGICALLY 449 00:16:48,275 --> 00:16:49,310 HEALTHY CONTROLS. 450 00:16:49,310 --> 00:16:52,446 OVER 2/3 WERE PATHOLOGICALLY 451 00:16:52,446 --> 00:16:53,514 CONFIRMED AND PERFORMED WHOLE 452 00:16:53,514 --> 00:16:56,550 GENOME SEQUENCING ON THEM USING 453 00:16:56,550 --> 00:16:59,887 A UNIFORM PIPELINE FOR SAMPLE 454 00:16:59,887 --> 00:17:04,525 PREPARATION SEQUENCING, AND 455 00:17:04,525 --> 00:17:05,225 ALIGNMENT, JOINT VARIANT, 456 00:17:05,225 --> 00:17:06,660 GENERALLY FOUNDATIONAL RESOURCE. 457 00:17:06,660 --> 00:17:08,529 ALL DATA WENT PUBLIC BEFORE WE 458 00:17:08,529 --> 00:17:10,698 HAD THE ANALYSIS OF THOSE DONE. 459 00:17:10,698 --> 00:17:12,066 THIS WAS SLIGHTLY STRESSFUL FOR 460 00:17:12,066 --> 00:17:14,802 ME AS A TENURE TRACKER, BUT WE 461 00:17:14,802 --> 00:17:16,537 WERE PLEASED THAT, YOU KNOW, 462 00:17:16,537 --> 00:17:18,072 EVERYTHING WAS REALLY WELL 463 00:17:18,072 --> 00:17:18,605 RECEIVED. 464 00:17:18,605 --> 00:17:20,274 WE SUBSEQUENTLY WERE ABLE TO 465 00:17:20,274 --> 00:17:21,775 PUBLISH SOME INTERESTING 466 00:17:21,775 --> 00:17:22,209 FINDINGS ON THAT. 467 00:17:22,209 --> 00:17:24,411 AND SO HERE IS A GENOME WIDE 468 00:17:24,411 --> 00:17:26,480 ASSOCIATION STUDY BASED ON OUR 469 00:17:26,480 --> 00:17:28,215 WHOLE GENOME SEQUENCING DATA, 470 00:17:28,215 --> 00:17:30,417 WHICH IMPLICATED FIVE GENOME 471 00:17:30,417 --> 00:17:40,861 WIDE SIGNIFICANT RISK LOCI 472 00:17:44,631 --> 00:17:50,804 INCLUDING GBA, SNCA, APOE, AND 473 00:17:50,804 --> 00:17:56,577 TWO OTHERS BN 1, AND 75 IS AN 474 00:17:56,577 --> 00:18:01,682 IMPORTANT RISK GENE IN 475 00:18:01,682 --> 00:18:02,816 PARKINSON'S DISEASE. 476 00:18:02,816 --> 00:18:04,518 LEWY BODY DEMENTIA GENETICALLY 477 00:18:04,518 --> 00:18:06,854 SPEAKING SEEMS TO SIT ALONG THE 478 00:18:06,854 --> 00:18:07,755 SPECTRUM BETWEEN PARKINSON'S 479 00:18:07,755 --> 00:18:08,455 DISEASE ON ONE HAND, ALZHEIMER'S 480 00:18:08,455 --> 00:18:11,492 DISEASE ON THE OTHER HAND. 481 00:18:11,492 --> 00:18:14,228 BUT WHEN WE DID SOME MORE FINE 482 00:18:14,228 --> 00:18:16,397 MAPPING OF SPECIFIC LOCI WE 483 00:18:16,397 --> 00:18:17,798 COULD APPRECIATE THERE WERE 484 00:18:17,798 --> 00:18:19,266 SUBTLE DIFFERENCES. 485 00:18:19,266 --> 00:18:23,203 FOR EXAMPLE, AT THE SNCA LOCUS, 486 00:18:23,203 --> 00:18:24,538 WHICH ENCLOUDS ALPHA-SYNUCLEIN 487 00:18:24,538 --> 00:18:27,274 PROTEIN THAT'S DEPOSITED IN 488 00:18:27,274 --> 00:18:28,809 THOSE LEWY BODIES, WE NOTICED 489 00:18:28,809 --> 00:18:31,111 OUR INDEX VARIANT IS AT THE FIVE 490 00:18:31,111 --> 00:18:36,817 PRIME END, WHICH OVERLAPS 491 00:18:36,817 --> 00:18:37,551 NON-CODING TRANSCRIPT, 492 00:18:37,551 --> 00:18:38,852 PARKINSON'S DISEASE THE MAIN 493 00:18:38,852 --> 00:18:41,055 SIGNAL WAS IN THE INTRONIC 494 00:18:41,055 --> 00:18:43,891 SEQUENCE, SO WHEN WE DID 495 00:18:43,891 --> 00:18:45,325 ADDITIONAL FUNCTIONAL GENOMIC 496 00:18:45,325 --> 00:18:47,828 MAPPING, WE COULD REALLY 497 00:18:47,828 --> 00:18:49,263 DEMONSTRATE THROUGH 498 00:18:49,263 --> 00:18:49,863 CO-LOCALIZATION ANALYSIS THAT 499 00:18:49,863 --> 00:18:54,701 THERE IS -- THAT INCREASED RISK 500 00:18:54,701 --> 00:18:58,105 OF SNCA-AS1 TRANSCRIPT THAT 501 00:18:58,105 --> 00:18:58,872 NATURALLY LOWERS EXPRESSION OF 502 00:18:58,872 --> 00:19:01,608 ALPHA 503 00:19:01,608 --> 00:19:03,043 ALPHA-SYNUCLEIN IS PROTECTIVE 504 00:19:03,043 --> 00:19:04,678 AND NEURONALLY SPECIFIC, AND 505 00:19:04,678 --> 00:19:08,615 FITS WITH THE MODEL THAT TOO 506 00:19:08,615 --> 00:19:09,650 HIGH EXPRESSION OF 507 00:19:09,650 --> 00:19:10,918 ALPHA-SYNUCLEIN IS TOXIC, EVEN 508 00:19:10,918 --> 00:19:13,654 AT MODEST LEVELS AS WE'RE SEEING 509 00:19:13,654 --> 00:19:16,390 HERE WITH THE LEWY BODY DEMENTIA 510 00:19:16,390 --> 00:19:16,723 GWAS. 511 00:19:16,723 --> 00:19:19,026 AND AS A CONSEQUENCE BECAUSE 512 00:19:19,026 --> 00:19:21,962 IT'S SUCH AN ATTRACTIVE TARGET 513 00:19:21,962 --> 00:19:23,063 THERE'S ALSO -- THERE ARE 514 00:19:23,063 --> 00:19:28,102 RESEARCH EFFORTS TO USE IT AS 515 00:19:28,102 --> 00:19:28,969 POTENTIAL THERAPEUTIC TARGET FOR 516 00:19:28,969 --> 00:19:30,070 THERAPY DEVELOPMENT. 517 00:19:30,070 --> 00:19:32,573 WE HAVE GENOME SEQUENCE DATA. 518 00:19:32,573 --> 00:19:35,075 AND THIS IS INCREDIBLY RICH. 519 00:19:35,075 --> 00:19:37,611 SO WE CAN LOOK AT COMMON 520 00:19:37,611 --> 00:19:40,781 VARIANTS, ALSO LOOK AT RARE 521 00:19:40,781 --> 00:19:41,281 VARIANTS. 522 00:19:41,281 --> 00:19:43,884 AND ONE OF THE GENES THAT WE 523 00:19:43,884 --> 00:19:47,287 NOTICED WHERE WE HAD SIGNIFICANT 524 00:19:47,287 --> 00:19:51,658 ENRICHMENT OF MUTATIONS WAS GBA, 525 00:19:51,658 --> 00:19:52,493 ENCODES A GENE THAT HAS 526 00:19:52,493 --> 00:19:54,928 PREVIOUSLY BEEN IMPLICATED IN 527 00:19:54,928 --> 00:19:56,463 LEWY BODY DEMENTIA. 528 00:19:56,463 --> 00:19:58,565 WE WERE ABLE TO REALLY SHOW THAT 529 00:19:58,565 --> 00:20:01,869 A PATIENT WITH LEWY BODY 530 00:20:01,869 --> 00:20:03,270 DEMENTIA VERY COMMONLY VARY 531 00:20:03,270 --> 00:20:05,239 VARIANTS OR MUTATIONS IN THAT 532 00:20:05,239 --> 00:20:06,006 GENE. 533 00:20:06,006 --> 00:20:08,609 IF WE SUM UP COMMON AND RARE 534 00:20:08,609 --> 00:20:10,911 VARIANTS THAT ARE PRESENT IN 535 00:20:10,911 --> 00:20:12,479 LEWY BODY DEMENTIA, IT'S ABOUT 536 00:20:12,479 --> 00:20:13,680 13% OF ALL PATIENTS. 537 00:20:13,680 --> 00:20:15,782 AND THAT MAKES THE REALLY 538 00:20:15,782 --> 00:20:17,951 INTERESTING PRIME TARGET ALSO 539 00:20:17,951 --> 00:20:21,355 FOR THERAPY DEVELOPMENT, USING 540 00:20:21,355 --> 00:20:23,323 CHAPERONES, SMALL MOLECULES, AND 541 00:20:23,323 --> 00:20:25,826 IN PARTICULAR HERE, MIH, ELLEN 542 00:20:25,826 --> 00:20:27,394 AT NHGRI HAS BEEN DIVERSITY IN 543 00:20:27,394 --> 00:20:28,061 THIS FIELD. 544 00:20:28,061 --> 00:20:31,231 WE MAY HEAR MORE ABOUT IT. 545 00:20:31,231 --> 00:20:33,367 AND BECAUSE IT IS AN IMPORTANT 546 00:20:33,367 --> 00:20:34,768 RISK GENE FOR PARKINSON'S 547 00:20:34,768 --> 00:20:36,603 DISEASE COULD BE RELEVANT FOR 548 00:20:36,603 --> 00:20:41,208 OTHER SPECTRUM OF PATIENTS 549 00:20:41,208 --> 00:20:42,409 SUFFERING FROM NEURODEGENERATIVE 550 00:20:42,409 --> 00:20:42,676 DISEASES. 551 00:20:42,676 --> 00:20:49,082 , YOU KNOW, WE CAN TAKE A MORE 552 00:20:49,082 --> 00:20:50,250 GLOBAL VIEW, CONSTRUCT CO-CALLED 553 00:20:50,250 --> 00:20:52,953 POLYGENIC RISK SCORES AND TRY TO 554 00:20:52,953 --> 00:20:54,922 LOOK AT THE RELATIONSHIP OF ONE 555 00:20:54,922 --> 00:20:56,857 DISEASE VERSUS ANOTHER. 556 00:20:56,857 --> 00:21:01,562 ON AVERAGE, USING GENETIC RISK 557 00:21:01,562 --> 00:21:04,431 SCORE FOR ALZHEIMER'S DISEASE, 558 00:21:04,431 --> 00:21:06,934 PARKINSON'S DISEASE, COMPARED TO 559 00:21:06,934 --> 00:21:10,671 LEWY BODY DEMENTIA CAN PROVE 560 00:21:10,671 --> 00:21:19,413 THERE'S OVERLAP IN GENETIC 561 00:21:19,413 --> 00:21:19,746 ARCHITECTURE. 562 00:21:19,746 --> 00:21:21,915 HIGHER RISK, REMAINS SIGNIFICANT 563 00:21:21,915 --> 00:21:26,320 IF YOU REMOVE HIGHEST RISK LOCI 564 00:21:26,320 --> 00:21:29,156 FOR EXAMPLE APOE, VARIANTS HAVE 565 00:21:29,156 --> 00:21:31,225 BEEN DESCRIBED IN OTHER RELATED 566 00:21:31,225 --> 00:21:31,892 NEURODEGENERATIVE DISEASES 567 00:21:31,892 --> 00:21:33,093 PROBABLY ALSO PLAYING A ROLE AND 568 00:21:33,093 --> 00:21:38,565 WE CAN ALREADY START TO 569 00:21:38,565 --> 00:21:41,602 APPRECIATE ENRICHMENT OF 570 00:21:41,602 --> 00:21:43,804 PATHWAYS THAT ARE CRUCIAL, 571 00:21:43,804 --> 00:21:48,408 RELEVANT FOR PROTEIN 572 00:21:48,408 --> 00:21:51,245 DEGRADATION, HANDLING. 573 00:21:51,245 --> 00:21:53,647 MOVING ON WE ALSO HAVE NOVEL 574 00:21:53,647 --> 00:21:56,950 WAYS OF LOOKING AT GENETIC 575 00:21:56,950 --> 00:21:57,284 INFORMATION. 576 00:21:57,284 --> 00:22:02,022 AND SO WE CAN LOOK AT VARIATIONS 577 00:22:02,022 --> 00:22:04,625 THAT ARE USUALLY NOT EASY TO 578 00:22:04,625 --> 00:22:06,627 CAPTURE, ONE CLASS IS SO-CALLED 579 00:22:06,627 --> 00:22:08,562 STRUCTURAL VARIANTS. 580 00:22:08,562 --> 00:22:10,964 THESE ARE BIGGER CHUNKS OF THE 581 00:22:10,964 --> 00:22:19,940 GENOME EITHER DUPLICATED, 582 00:22:19,940 --> 00:22:20,674 TRANSFERRED, INVERTED. 583 00:22:20,674 --> 00:22:23,577 THERE'S A REASON TO FOCUS ON THE 584 00:22:23,577 --> 00:22:25,846 VARIANTS, NOT ONLY AN IMPORTANT 585 00:22:25,846 --> 00:22:27,514 SOURCE OF EVOLUTION BUT WE'VE 586 00:22:27,514 --> 00:22:30,350 ALREADY LEARNED THAT STRUCTURAL 587 00:22:30,350 --> 00:22:34,054 VARIANTS ARE REALLY IMPORTANT IN 588 00:22:34,054 --> 00:22:34,821 COMPLEX NEUROPSYCHIATRIC 589 00:22:34,821 --> 00:22:37,257 CONDITIONS, SPECIFICALLY IN LEWY 590 00:22:37,257 --> 00:22:38,892 BODY DEMENTIA, MANY CASES, YOU 591 00:22:38,892 --> 00:22:41,161 KNOW, IF YOU HAVE DUPLICATIONS 592 00:22:41,161 --> 00:22:43,897 OF APP GENE OR SNCA GENE YOU'RE 593 00:22:43,897 --> 00:22:52,039 AT HIGH RISK FOR DEVELOPING LEWY 594 00:22:52,039 --> 00:22:53,707 BODY DEMENTIA, KNOWN RISK GENE 595 00:22:53,707 --> 00:22:55,475 FOR LEWY BODY DEMENTIA. 596 00:22:55,475 --> 00:22:59,413 AND SO WHAT WE THEN DID, WE USED 597 00:22:59,413 --> 00:23:02,649 MODERN COMPUTATIONAL PIPELINE TO 598 00:23:02,649 --> 00:23:05,218 MAP STRUCTURAL VARIANTS BASED ON 599 00:23:05,218 --> 00:23:09,156 WHOLE GENOME SEQUENCE DATA, A 600 00:23:09,156 --> 00:23:10,457 VERY INTENSE UNDERTAKING. 601 00:23:10,457 --> 00:23:13,093 BUT IN DOING SO WE WERE ABLE TO 602 00:23:13,093 --> 00:23:15,595 PERFORM THE VERY FIRST GENOME 603 00:23:15,595 --> 00:23:16,263 WIDE STRUCTURAL VARIANT 604 00:23:16,263 --> 00:23:21,668 ASSOCIATION STUDY IN LEWY BODY 605 00:23:21,668 --> 00:23:28,442 DEMENTIA, AND LO AND BEHOLD 606 00:23:28,442 --> 00:23:30,377 IDENTIFIED ANOTHER RISK GENE. 607 00:23:30,377 --> 00:23:40,921 THERE WAS A 300 BASE PAIR DELAYS 608 00:23:42,089 --> 00:23:43,423 IN TPCN1, ENDOLYSAL GENE, 1.4, 609 00:23:43,423 --> 00:23:45,726 IT'S A RISK GENE. 610 00:23:45,726 --> 00:23:49,463 WE VALIDATED, IT IS ACTUALLY 611 00:23:49,463 --> 00:23:51,998 QUITE PREVALENT IN OUR PATIENT 612 00:23:51,998 --> 00:23:52,332 POPULATION. 613 00:23:52,332 --> 00:23:54,101 THE INTERESTING THING IS THAT 614 00:23:54,101 --> 00:23:56,837 WHEN WE LOOK AT LITERATURE MORE 615 00:23:56,837 --> 00:23:59,439 CAREFULLY, IT HAS BEEN SUGGESTED 616 00:23:59,439 --> 00:24:01,641 AS A POSSIBLE RISK LOCUS FOR 617 00:24:01,641 --> 00:24:02,409 ALZHEIMER'S DISEASE. 618 00:24:02,409 --> 00:24:04,845 IT DIDN'T ACTUALLY REACH 619 00:24:04,845 --> 00:24:05,812 SIGNIFICANCE AT THAT TIME, AND 620 00:24:05,812 --> 00:24:08,315 SO WHAT WE DID THEN AS A NEXT 621 00:24:08,315 --> 00:24:10,951 STEP IS WE DID FINE MAPPING AT 622 00:24:10,951 --> 00:24:15,889 THE LOCUS, AT THE TPCN 1 LOCUS, 623 00:24:15,889 --> 00:24:18,525 COMPARING LEWY BODY DEMENTIA TO 624 00:24:18,525 --> 00:24:19,693 ALZHEIMER'S DISEASE, AND LEWY 625 00:24:19,693 --> 00:24:21,461 BODY DEMENTIA TO PARKINSON'S 626 00:24:21,461 --> 00:24:22,229 DISEASE. 627 00:24:22,229 --> 00:24:22,863 WITH ALZHEIMER'S DISEASE VERSUS 628 00:24:22,863 --> 00:24:25,098 LEWY BODY DEMENTIA WE SEE A 629 00:24:25,098 --> 00:24:27,367 STRONG CORRELATION, ESSENTIALLY 630 00:24:27,367 --> 00:24:29,770 SEE THE SAME RISK HAPLOTYPE 631 00:24:29,770 --> 00:24:31,638 SHOWING UP SUGGESTING AN 632 00:24:31,638 --> 00:24:33,507 IMPORTANT RISK LOCUS FOR 633 00:24:33,507 --> 00:24:34,908 ALZHEIMER'S DISEASE, 634 00:24:34,908 --> 00:24:36,443 SUBSEQUENTLY NOW ALSO BEEN 635 00:24:36,443 --> 00:24:36,777 CONFIRMED. 636 00:24:36,777 --> 00:24:39,212 BUT THIS IS IMPORTANT. 637 00:24:39,212 --> 00:24:41,281 BUT INTERESTINGLY DOES NOT PLAY 638 00:24:41,281 --> 00:24:43,016 A MAJOR ROLE IN PARKINSON'S 639 00:24:43,016 --> 00:24:43,250 DISEASE. 640 00:24:43,250 --> 00:24:45,352 SO THERE SEEMS TO BE PARTIAL 641 00:24:45,352 --> 00:24:48,188 OVERLAP OF ALZHEIMER'S DISEASE 642 00:24:48,188 --> 00:24:49,055 BUT NOT NECESSARILY WITH 643 00:24:49,055 --> 00:24:50,557 PARKINSON'S DISEASE FOR EVERY 644 00:24:50,557 --> 00:24:52,559 RISK LOCUS. 645 00:24:52,559 --> 00:24:55,395 AND SO WHAT I'M GETTING TO THAT 646 00:24:55,395 --> 00:24:57,364 IS INCREASINGLY WE'RE SEEING 647 00:24:57,364 --> 00:24:59,466 THAT ONE GENE CAN PLAY AN 648 00:24:59,466 --> 00:25:00,834 IMPORTANT ROLE IN MULTIPLE 649 00:25:00,834 --> 00:25:02,035 DIFFERENT DISEASES. 650 00:25:02,035 --> 00:25:02,736 I THINK ONCOLOGISTS ARE VERY 651 00:25:02,736 --> 00:25:10,277 MUCH USED TO THIS TYPE OF 652 00:25:10,277 --> 00:25:11,378 THINKING, FOR NEUROLOGISTS IT'S 653 00:25:11,378 --> 00:25:12,946 NEW CONCEPTUALLY. 654 00:25:12,946 --> 00:25:14,448 WE SEE NETWORKS THAT ARE 655 00:25:14,448 --> 00:25:16,550 AFFECTED, THAT ARE SHIFTING. 656 00:25:16,550 --> 00:25:19,286 AND THAT'S ACTUALLY REALLY GOOD 657 00:25:19,286 --> 00:25:19,953 NEWS, BECAUSE IT IMPLICATES THAT 658 00:25:19,953 --> 00:25:23,089 A LOT OF THESE REALLY 659 00:25:23,089 --> 00:25:23,790 DEVASTATING DISEASE HAVE SHARED 660 00:25:23,790 --> 00:25:25,625 BIOLOGY UNDER THE HOOD FROM A 661 00:25:25,625 --> 00:25:26,626 CELLULAR LEVEL. 662 00:25:26,626 --> 00:25:29,229 WE CAN LEVERAGE THAT TYPE OF 663 00:25:29,229 --> 00:25:31,531 KNOWLEDGE TO PRIORITIZE WHICH 664 00:25:31,531 --> 00:25:33,166 GENES WE SHOULD TARGET AND, YOU 665 00:25:33,166 --> 00:25:34,601 KNOW, PERHAPS YOU CAN REPURPOSE 666 00:25:34,601 --> 00:25:36,837 A DRUG THAT HAS BEEN DEVELOPED 667 00:25:36,837 --> 00:25:37,737 LET'S SAY FOR ALZHEIMER'S 668 00:25:37,737 --> 00:25:40,407 DISEASE NOW FOR LEWY BODY 669 00:25:40,407 --> 00:25:41,274 DEMENTIA, VICE VERSA. 670 00:25:41,274 --> 00:25:45,445 AND SO THERE'S ANOTHER EXAMPLE 671 00:25:45,445 --> 00:25:46,680 WHERE WE SAW PLEIOTROPIC GENE 672 00:25:46,680 --> 00:25:48,415 COME UP THAT WAS RATHER 673 00:25:48,415 --> 00:25:50,517 SURPRISING. 674 00:25:50,517 --> 00:25:52,619 WE LOOKED FOR KNOWN 675 00:25:52,619 --> 00:25:53,620 DISEASE-CAUSING MUTATIONS AND 676 00:25:53,620 --> 00:25:56,289 IDENTIFIED DAMAGING MUTATIONS IN 677 00:25:56,289 --> 00:25:57,724 THE GENE CALLED PROGRANULIN. 678 00:25:57,724 --> 00:26:00,327 IF YOU CARRY MUTATION IN THIS 679 00:26:00,327 --> 00:26:01,761 PARTICULAR GENE, YOU KNOW THE 680 00:26:01,761 --> 00:26:06,600 TEXT BOOK KNOWLEDGE IS YOU GET 681 00:26:06,600 --> 00:26:07,133 FRONTOTEMPORAL DEMENTIA, A 682 00:26:07,133 --> 00:26:09,102 DIFFERENT TYPE CHARACTERIZED BY 683 00:26:09,102 --> 00:26:12,072 ABNORMAL DEPOSITION OF A PROTEIN 684 00:26:12,072 --> 00:26:13,707 CALLED TDP-43. 685 00:26:13,707 --> 00:26:16,643 BUT LO AND BEHOLD WE SAW 686 00:26:16,643 --> 00:26:18,678 ENRICHMENT OF LOSS OF FUNCTION 687 00:26:18,678 --> 00:26:20,847 DISEASES, IN OUR LEWY BODY 688 00:26:20,847 --> 00:26:22,616 DEMENTIA PATIENTS. 689 00:26:22,616 --> 00:26:27,921 AND THERE WAS OTHER HINTS THAT 690 00:26:27,921 --> 00:26:30,123 PROGRANULIN COULD PLAY A ROLE 691 00:26:30,123 --> 00:26:33,460 BASED ON GWAS SIGNALS IDENTIFIED 692 00:26:33,460 --> 00:26:34,861 IN ALZHEIMER'S AND PARKINSON'S 693 00:26:34,861 --> 00:26:35,228 DISEASE. 694 00:26:35,228 --> 00:26:37,697 WHEN WE LOOKED AT THESE CASES 695 00:26:37,697 --> 00:26:40,000 CAREFULLY WE DEFINITELY COULD 696 00:26:40,000 --> 00:26:41,635 APPRECIATE YES THEY HAVE LEWY 697 00:26:41,635 --> 00:26:43,837 BODY DEMENTIA, THEY HAVE LEWY 698 00:26:43,837 --> 00:26:44,838 BODIES CLASSICAL FOR THE 699 00:26:44,838 --> 00:26:50,977 DISEASE, BUT THEY ALSO HAVE 700 00:26:50,977 --> 00:26:51,845 TDP-43 INCLUSIONS. 701 00:26:51,845 --> 00:26:54,581 WE'RE LEARNING SOME OF THESE 702 00:26:54,581 --> 00:26:55,916 CO-PATHOLOGIES THAT WE'RE OFTEN 703 00:26:55,916 --> 00:26:58,251 SEEING IN THESE PATIENTS IS 704 00:26:58,251 --> 00:27:00,987 ACTUALLY A MOLECULAR ETIOLOGY 705 00:27:00,987 --> 00:27:01,521 UNDERNEATH IT. 706 00:27:01,521 --> 00:27:05,525 AND ALTHOUGH THIS IS REALLY 707 00:27:05,525 --> 00:27:07,594 RARE, IT IS INTERESTING FROM A 708 00:27:07,594 --> 00:27:11,398 CLINICAL POINT OF VIEW BECAUSE A 709 00:27:11,398 --> 00:27:12,732 LOT OF TARGETED INTERVENTIONS 710 00:27:12,732 --> 00:27:15,135 FOR PROGRANULIN ARE ACTUALLY NOW 711 00:27:15,135 --> 00:27:16,670 ALREADY IN THE CLINICAL TRIALS 712 00:27:16,670 --> 00:27:17,103 PHASE. 713 00:27:17,103 --> 00:27:19,306 AND SO SOME OF THESE PATIENTS 714 00:27:19,306 --> 00:27:21,341 MAY REALLY BENEFIT FROM 715 00:27:21,341 --> 00:27:21,608 INCLUSION. 716 00:27:21,608 --> 00:27:23,543 AND THEY REALLY CAN LOOK LIKE 717 00:27:23,543 --> 00:27:24,344 BONA FIDE AND LEWY BODY 718 00:27:24,344 --> 00:27:27,280 DEMENTIA, IF YOU LOOK AT 719 00:27:27,280 --> 00:27:29,449 CLINICAL ON THE LEFT-HAND SIDE. 720 00:27:29,449 --> 00:27:32,519 THERE'S SO MANY LESSONS WE HAVE 721 00:27:32,519 --> 00:27:32,752 LEARNED. 722 00:27:32,752 --> 00:27:34,621 BUT ONE THING THAT WE REALLY 723 00:27:34,621 --> 00:27:36,556 WANTED TO DELVE INTO FURTHER 724 00:27:36,556 --> 00:27:38,758 BECAUSE WE HAVE THESE 725 00:27:38,758 --> 00:27:41,528 PATHOLOGICALLY REALLY WELL 726 00:27:41,528 --> 00:27:42,529 CHARACTERIZED CASES IS CAN WE 727 00:27:42,529 --> 00:27:46,900 EXPLAIN SOME OF THE 728 00:27:46,900 --> 00:27:48,001 CO-PATHOLOGIES AND OVERLAP WITH 729 00:27:48,001 --> 00:27:49,169 ALZHEIMER'S DISEASE A LITTLE BIT 730 00:27:49,169 --> 00:27:52,138 MORE CAREFULLY, SO WHAT WE DID 731 00:27:52,138 --> 00:27:54,674 IS WE TOOK PATHOLOGICALLY 732 00:27:54,674 --> 00:27:56,443 CONFIRMED CASES AND SUBDIVIDED 733 00:27:56,443 --> 00:27:57,978 INTO THOSE THAT HAVE RELATIVELY 734 00:27:57,978 --> 00:28:00,413 PURE LEWY BODY DEMENTIA AND 735 00:28:00,413 --> 00:28:03,083 THOSE THAT HAVE LEWY BODY 736 00:28:03,083 --> 00:28:04,084 DEMENTIA WITH ALZHEIMER'S 737 00:28:04,084 --> 00:28:05,285 DISEASE CO-PATHOLOGY. 738 00:28:05,285 --> 00:28:07,587 WHEN WE DO THAT WHAT WE SAW WAS 739 00:28:07,587 --> 00:28:08,455 QUITE INTERESTING. 740 00:28:08,455 --> 00:28:11,324 THE ONES THAT HAVE PURE LEWY 741 00:28:11,324 --> 00:28:13,126 BODY DEMENTIA IN OVER 80% OF 742 00:28:13,126 --> 00:28:18,999 CASES ARE MENTAL HEALTHS. 743 00:28:18,999 --> 00:28:20,867 ARE MALES. 744 00:28:20,867 --> 00:28:22,702 IT'S BEEN SEEN ACROSS 745 00:28:22,702 --> 00:28:23,737 POPULATIONS, THERE'S A REAL 746 00:28:23,737 --> 00:28:26,106 DIFFERENCE ACROSS THE SEXES. 747 00:28:26,106 --> 00:28:30,043 ONCE WE HAVE ALZHEIMER'S 748 00:28:30,043 --> 00:28:30,543 ALZHEIMER'S DISEASE 749 00:28:30,543 --> 00:28:31,544 CO-PATHOLOGY WE CAN APPRECIATE 750 00:28:31,544 --> 00:28:34,681 IN MANY CASES THOSE ARE THE 751 00:28:34,681 --> 00:28:37,183 INDIVIDUALS THAT CARRY THE APOE 752 00:28:37,183 --> 00:28:37,951 4 RISK ALLELE. 753 00:28:37,951 --> 00:28:40,353 SO THAT SEEMS TO BE A REALLY 754 00:28:40,353 --> 00:28:44,858 IMPORTANT DRIVER FOR THESE 755 00:28:44,858 --> 00:28:45,358 MULTI-PROTEINIC CHANGES 756 00:28:45,358 --> 00:28:45,725 HAPPENING. 757 00:28:45,725 --> 00:28:47,694 WHAT'S GOING ON WITH THE PURE 758 00:28:47,694 --> 00:28:48,094 CASES? 759 00:28:48,094 --> 00:28:49,763 SO WHEN WE LOOK AT THE PURE 760 00:28:49,763 --> 00:28:52,198 CASES, LOOK AT THE MOST COMMON 761 00:28:52,198 --> 00:28:53,733 RISK ALLELES, WHAT WE'RE SEEING 762 00:28:53,733 --> 00:28:55,902 IS THAT THOSE ARE VERY COMMONLY 763 00:28:55,902 --> 00:28:58,838 THE ONES THAT HAVE THE GBA RISK 764 00:28:58,838 --> 00:28:59,372 ALLELE. 765 00:28:59,372 --> 00:29:00,840 AND SO WHAT THIS SUGGESTS IS 766 00:29:00,840 --> 00:29:02,809 THAT SOME OF THESE HIGH RISK 767 00:29:02,809 --> 00:29:04,878 ALLELES THAT WE'RE APPRECIATING 768 00:29:04,878 --> 00:29:07,280 ARE REALLY TELLING US SOMETHING 769 00:29:07,280 --> 00:29:08,815 ABOUT DISEASE SUBTYPES THAT 770 00:29:08,815 --> 00:29:09,683 EXIST. 771 00:29:09,683 --> 00:29:17,023 ONE OF THE MORE APOE 4 DRIVEN 772 00:29:17,023 --> 00:29:18,792 BUT CO-PATHOLOGY AND ONE MALE 773 00:29:18,792 --> 00:29:20,960 DRIVEN AND PURE IN PRESENTATION, 774 00:29:20,960 --> 00:29:21,728 INTERESTING CLINICAL 775 00:29:21,728 --> 00:29:24,798 CORRELATIONS AS WELL. 776 00:29:24,798 --> 00:29:28,535 APOE 4 CARRIERS OFTEN HAVE 777 00:29:28,535 --> 00:29:31,371 SHORTER SURVIVAL, PURE DLB CASES 778 00:29:31,371 --> 00:29:33,440 HAVE PROMINENT CASES, THAT TELLS 779 00:29:33,440 --> 00:29:35,108 US SOMETHING ABOUT THE DISEASE 780 00:29:35,108 --> 00:29:38,878 AND ABOUT HOW WE SHOULD 781 00:29:38,878 --> 00:29:39,813 POTENTIALLY DEVELOP CLINICAL 782 00:29:39,813 --> 00:29:41,014 TRIALS. 783 00:29:41,014 --> 00:29:43,850 WE MAY HAVE TO SUBSTRATIFY 784 00:29:43,850 --> 00:29:46,586 PATIENT POPULATION TO RECOGNIZE 785 00:29:46,586 --> 00:29:48,121 THESE SUBTYPES. 786 00:29:48,121 --> 00:29:50,223 BUT BECAUSE WE'RE SEEING SO 787 00:29:50,223 --> 00:29:51,458 INTERESTING SEX DIFFERENCES 788 00:29:51,458 --> 00:29:52,959 ACROSS OUR PATIENT POPULATION WE 789 00:29:52,959 --> 00:29:57,330 WERE ALSO WONDERING IF WE CAN 790 00:29:57,330 --> 00:29:58,531 PERHAPS IDENTIFY GENETIC FACTORS 791 00:29:58,531 --> 00:30:00,667 THAT COULD PLAY A ROLE THAT MAY 792 00:30:00,667 --> 00:30:04,471 PLAY A ROLE, YOU KNOW, IN 793 00:30:04,471 --> 00:30:06,639 EXPLAINING WHY WOMEN VERSUS MEN 794 00:30:06,639 --> 00:30:07,540 HAVE DIFFERENT RISKS. 795 00:30:07,540 --> 00:30:09,275 SO THIS IS, YOU KNOW, REALLY 796 00:30:09,275 --> 00:30:11,578 JUST THE TIP OF THE ICEBERG, IN 797 00:30:11,578 --> 00:30:13,012 MY HUMBLE OPINION. 798 00:30:13,012 --> 00:30:17,484 WE DID A SO-CALLED CHROMOSOME X 799 00:30:17,484 --> 00:30:19,786 WIDE ASSOCIATION STUDY WHERE WE 800 00:30:19,786 --> 00:30:22,622 SUBDIVIDED COHORT IN MALES ONLY 801 00:30:22,622 --> 00:30:24,557 VERSUS MALE CONTROLS, FEMALE 802 00:30:24,557 --> 00:30:27,193 ONLY CASES VERSUS FEMALE ONLY 803 00:30:27,193 --> 00:30:27,460 CONTROLS. 804 00:30:27,460 --> 00:30:29,629 AND THEN CONDITIONED IT BASED ON 805 00:30:29,629 --> 00:30:32,165 THE HIGH RISK APOE 4 ALLELE. 806 00:30:32,165 --> 00:30:39,839 BUT WE WERE ABLE TO IDENTIFY 807 00:30:39,839 --> 00:30:42,108 ANOTHER RISK SIGNAL IN, ONLY 808 00:30:42,108 --> 00:30:45,512 SEEN IN FEMALES WITH THIS 809 00:30:45,512 --> 00:30:45,745 DISEASE. 810 00:30:45,745 --> 00:30:47,914 SO THIS IS AN INTERESTING 811 00:30:47,914 --> 00:30:50,884 PATHWAY THAT WE'RE SEEING WHICH 812 00:30:50,884 --> 00:30:53,086 IS THE MAP K PATHWAY, MULTIPLE 813 00:30:53,086 --> 00:30:56,356 FUNCTIONS, PLAYs AN IMPORTANT 814 00:30:56,356 --> 00:30:59,092 ROLE IN NEUROINFLAMMATORY 815 00:30:59,092 --> 00:31:01,561 PROCESSES, IN RESPONSE TO 816 00:31:01,561 --> 00:31:03,630 PROTEIN DEPOSITS, AND BASED ON 817 00:31:03,630 --> 00:31:05,565 OUR FINDINGS MAY PLAY A 818 00:31:05,565 --> 00:31:09,169 PARTICULAR IMPORTANT ROLE IN 819 00:31:09,169 --> 00:31:14,774 WOMEN WITH THE DISEASE. 820 00:31:14,774 --> 00:31:16,309 PERHAPS WHY WOMEN HAVE MORE 821 00:31:16,309 --> 00:31:17,744 CO-PATHOLOGIES AND DON'T READ 822 00:31:17,744 --> 00:31:19,579 THE TEXT BOOKS AS WE SAY BECAUSE 823 00:31:19,579 --> 00:31:22,215 THEY PRESENT WITH MORE COMPLEX 824 00:31:22,215 --> 00:31:22,649 FEATURES. 825 00:31:22,649 --> 00:31:24,417 SO GENOMICS IS FUN BUT THERE ARE 826 00:31:24,417 --> 00:31:27,587 OTHER LINES OF EVIDENCE THAT CAN 827 00:31:27,587 --> 00:31:29,656 REALLY HELP US UNDERSTAND THE 828 00:31:29,656 --> 00:31:30,223 DISEASE. 829 00:31:30,223 --> 00:31:31,090 WHERE WE'VE BEEN WORKING 830 00:31:31,090 --> 00:31:32,292 CAREFULLY OVER THE LAST COUPLE 831 00:31:32,292 --> 00:31:34,093 YEARS TRYING TO MARRY THE TWO OF 832 00:31:34,093 --> 00:31:34,594 THEM TOGETHER. 833 00:31:34,594 --> 00:31:39,732 AND SO HERE IS AN EXAMPLE OF HOW 834 00:31:39,732 --> 00:31:42,035 WE HAVE STUDIED -- USED 835 00:31:42,035 --> 00:31:44,304 EPIDEMIOLOGICAL DATA TOGETHER 836 00:31:44,304 --> 00:31:47,774 WITH OUR MOLECULAR DATA TO GAIN 837 00:31:47,774 --> 00:31:48,975 IMPORTANT INSIGHTS INTO WHICH 838 00:31:48,975 --> 00:31:50,677 DRUGS COULD BE POTENTIALLY 839 00:31:50,677 --> 00:31:51,477 REPURPOSE AND USED FOR TREATMENT 840 00:31:51,477 --> 00:31:52,912 OF LEWY BODY DEMENTIA. 841 00:31:52,912 --> 00:31:56,316 SO THIS IS A STUDY THAT I'VE 842 00:31:56,316 --> 00:32:06,826 DONE IN COLLABORATION WITH DR. 843 00:32:07,427 --> 00:32:08,461 RUTH PFEIFFER, USED MEDICARE 844 00:32:08,461 --> 00:32:09,896 DATABASE TO EXTRACT PATIENTS 845 00:32:09,896 --> 00:32:11,731 WITH LEWY BODY DEMENTIA AND 846 00:32:11,731 --> 00:32:13,266 MATCHED CONTROLS. 847 00:32:13,266 --> 00:32:14,467 THOSE NUMBERS ARE SPECTACULAR. 848 00:32:14,467 --> 00:32:16,436 I THINK AS FAR AS I KNOW THAT'S 849 00:32:16,436 --> 00:32:18,638 THE LARGEST STUDY OF LEWY BODY 850 00:32:18,638 --> 00:32:21,074 DEMENTIA ANYBODY HAS EVER DONE. 851 00:32:21,074 --> 00:32:22,775 AND THE EXCITING THING IS WE HAD 852 00:32:22,775 --> 00:32:25,745 A LOT OF, YOU KNOW, ANCESTRY 853 00:32:25,745 --> 00:32:27,947 DIVERSE CASES AS WELL, SO ABOUT 854 00:32:27,947 --> 00:32:31,050 20% OF OUR COHORT WERE FROM 855 00:32:31,050 --> 00:32:32,352 DIVERSE ANCESTRY INDIVIDUALS. 856 00:32:32,352 --> 00:32:35,722 AND WHAT WE ESSENTIALLY DID WAS 857 00:32:35,722 --> 00:32:37,423 WE LOOKED AT INDIVIDUALS WHO 858 00:32:37,423 --> 00:32:39,692 WERE DIAGNOSED WITH LEWY BODY 859 00:32:39,692 --> 00:32:41,661 DEMENTIA, BUT THEN LOOKED THREE 860 00:32:41,661 --> 00:32:43,162 YEARS PRIOR TO THAT, WHAT WERE 861 00:32:43,162 --> 00:32:45,598 THE DRUGS THEY WERE TAKING FOR 862 00:32:45,598 --> 00:32:46,900 ANY KIND OF ETIOLOGY, AND WERE 863 00:32:46,900 --> 00:32:49,202 ANY OF THOSE DRUGS ASSOCIATED 864 00:32:49,202 --> 00:32:50,737 WITH DECREASED RISK FOR 865 00:32:50,737 --> 00:32:51,371 DEVELOPING THE DISEASE, 866 00:32:51,371 --> 00:32:56,743 ESSENTIALLY WE DID A LARGE SCALE 867 00:32:56,743 --> 00:33:00,146 VERY BROADLY ADJUSTED LOGISTIC 868 00:33:00,146 --> 00:33:01,681 REGRESSION ANALYSIS. 869 00:33:01,681 --> 00:33:03,416 ONE THING THAT STOOD OUT 870 00:33:03,416 --> 00:33:05,385 CARDIOVASCULAR DISEASE RISK 871 00:33:05,385 --> 00:33:07,020 MANAGEMENT DRUGS WERE 872 00:33:07,020 --> 00:33:07,654 CONSISTENTLY ASSOCIATED WITH 873 00:33:07,654 --> 00:33:09,422 DECREASED RISK FOR LEWY BODY 874 00:33:09,422 --> 00:33:10,089 DEMENTIA. 875 00:33:10,089 --> 00:33:12,392 I THINK IT CAPTURES SOMETHING 876 00:33:12,392 --> 00:33:15,261 ABOUT THERE'S A BROADER 877 00:33:15,261 --> 00:33:15,929 METABOLIC DYSFUNCTION ONGOING 878 00:33:15,929 --> 00:33:18,097 BEFORE PEOPLE DEVELOP OR GET TO 879 00:33:18,097 --> 00:33:20,400 THE DIAGNOSIS, THAT MAY BE 880 00:33:20,400 --> 00:33:20,667 TREATABLE. 881 00:33:20,667 --> 00:33:23,236 SO THIS IS POTENTIALLY DISEASE 882 00:33:23,236 --> 00:33:32,011 MODIFICATION AT OUR FINGERS 883 00:33:32,011 --> 00:33:32,845 TIPS. 884 00:33:32,845 --> 00:33:33,680 ANTI-DIABETICS, 885 00:33:33,680 --> 00:33:34,280 ANTI-HYPERTENSIVE, CHOLESTEROL 886 00:33:34,280 --> 00:33:38,651 LOWERING MEDICATION, A FEW 887 00:33:38,651 --> 00:33:41,754 OUTLIERS, REVERSE CAUSE 888 00:33:41,754 --> 00:33:43,056 INDICATION, PEOPLE WITH 889 00:33:43,056 --> 00:33:47,226 PRODROMAL FEATURES SUCH AS 890 00:33:47,226 --> 00:33:48,428 TREMOR. 891 00:33:48,428 --> 00:33:49,829 EPIDEMIOLOGICAL DATA ARE MESSY, 892 00:33:49,829 --> 00:33:51,364 REAL WORLD ELECTRONIC HEALTH 893 00:33:51,364 --> 00:33:53,800 RECORDS DATA, WE WANTED TO SEE 894 00:33:53,800 --> 00:33:56,502 IF WE CAN LEVERAGE GENOMIC 895 00:33:56,502 --> 00:33:58,037 INFORMATION TO CONFIRM THAT 896 00:33:58,037 --> 00:34:00,440 THESE OBSERVATIONS ARE REAL, 897 00:34:00,440 --> 00:34:01,641 THERE'S NOT CONFOUNDING THAT'S 898 00:34:01,641 --> 00:34:03,609 DRIVING THIS. 899 00:34:03,609 --> 00:34:06,779 WE WENT TO OUR VERY CAREFUL AND 900 00:34:06,779 --> 00:34:08,214 DEEPLY PHENOTYPED GENOME 901 00:34:08,214 --> 00:34:10,316 SEQUENCING DATASETS. 902 00:34:10,316 --> 00:34:11,751 WE LEVERAGED A METHODOLOGY THAT 903 00:34:11,751 --> 00:34:14,587 ALLOWS US TO DRAW CAUSAL 904 00:34:14,587 --> 00:34:14,921 RELATIONSHIPS. 905 00:34:14,921 --> 00:34:17,657 SO IN ESSENCE YOU TAKE THE 906 00:34:17,657 --> 00:34:20,293 GENOME WIDE ASSOCIATION STUDIES, 907 00:34:20,293 --> 00:34:20,994 SUMMARY STATISTICS FROM 908 00:34:20,994 --> 00:34:25,531 CARDIOVASCULAR DISEASE TRAITS 909 00:34:25,531 --> 00:34:27,400 SUCH AS HYPERTENSION, DIABETES, 910 00:34:27,400 --> 00:34:31,337 LDL CHOLESTEROL LEVELS, AND SEE 911 00:34:31,337 --> 00:34:32,038 HOW THEY ARE CORRELATED. 912 00:34:32,038 --> 00:34:35,942 AND SO WHEN WE LOOK AT THAT WE 913 00:34:35,942 --> 00:34:36,843 COULD CLEARLY APPRECIATE THAT 914 00:34:36,843 --> 00:34:39,545 THERE WAS A GENETIC OVERLAP IN 915 00:34:39,545 --> 00:34:41,514 THE GENETIC ARCHITECTURE OF 916 00:34:41,514 --> 00:34:42,382 THESE CARDIOVASCULAR DISEASE 917 00:34:42,382 --> 00:34:47,553 TRAITS AND LEWY BODY DEMENTIA. 918 00:34:47,553 --> 00:34:49,455 AND BASED ON THE MIXER MODELING 919 00:34:49,455 --> 00:34:51,958 COULD DEMONSTRATE THIS IS A 920 00:34:51,958 --> 00:34:54,861 CAUSAL RELATIONSHIP, SO WE SEE 921 00:34:54,861 --> 00:34:56,863 LEFT DEFLECTION ON THE LEFT-HAND 922 00:34:56,863 --> 00:34:59,399 KIND OF PLOT, WHICH IS THE 923 00:34:59,399 --> 00:35:00,700 SIGNATURE FOR CAUSAL 924 00:35:00,700 --> 00:35:01,034 RELATIONSHIPS. 925 00:35:01,034 --> 00:35:06,072 AND SO WHAT THIS MEANS IS THAT 926 00:35:06,072 --> 00:35:06,672 CARDIOVASCULAR DISEASE TRAITS 927 00:35:06,672 --> 00:35:09,442 ARE REALLY PART OF THE DISEASE 928 00:35:09,442 --> 00:35:11,110 PHENOTYPE, REALLY IS EXCITING 929 00:35:11,110 --> 00:35:13,813 BECAUSE THESE ARE ALL MODIFIABLE 930 00:35:13,813 --> 00:35:14,814 RISK FACTORS. 931 00:35:14,814 --> 00:35:18,217 SO THIS IS -- POTENTIAL DISEASE 932 00:35:18,217 --> 00:35:21,454 MODIFICATION AT OUR FINGERTIPS 933 00:35:21,454 --> 00:35:24,557 RIGHT NOW, IN LINE WITH EVIDENCE 934 00:35:24,557 --> 00:35:26,726 WE'VE SEEN IN ALZHEIMER'S AND 935 00:35:26,726 --> 00:35:27,460 PARKINSON'S DISEASE, RISK 936 00:35:27,460 --> 00:35:30,096 FACTORS ARE A MAJOR DRIVER FOR 937 00:35:30,096 --> 00:35:30,963 NEURODEGENERATION, SO THIS IS 938 00:35:30,963 --> 00:35:32,865 SOMETHING WE NEED TO THINK ABOUT 939 00:35:32,865 --> 00:35:37,470 MORE CAREFULLY IN THE CLINIC AS 940 00:35:37,470 --> 00:35:43,376 WE TREAT PATIENTS AND TRY TO 941 00:35:43,376 --> 00:35:45,044 DESIGN CLINICAL TRIALS. 942 00:35:45,044 --> 00:35:47,313 WE TAKE A SNAPSHOT WITH RESPECT 943 00:35:47,313 --> 00:35:49,649 TO LEWY BODY DEMENTIA, SO 944 00:35:49,649 --> 00:35:50,950 DEFINITELY THE DISEASE THAT 945 00:35:50,950 --> 00:35:52,718 OVERLAPS IN ITS ARCHITECTURE 946 00:35:52,718 --> 00:35:54,554 WITH OTHER NEURODEGENERATIVE 947 00:35:54,554 --> 00:35:58,858 CONDITIONS SUCH AS ALZHEIMER'S 948 00:35:58,858 --> 00:35:59,525 DISEASE, FRONTOTEMPORAL, 949 00:35:59,525 --> 00:36:00,293 VASCULAR DEMENTIA, PARKINSON'S 950 00:36:00,293 --> 00:36:01,828 DISEASE, AND MANY RISK GENES 951 00:36:01,828 --> 00:36:06,132 THAT I PUT NICELY THERE ON THE 952 00:36:06,132 --> 00:36:08,067 SO-CALLED PLOT HAS BEEN 953 00:36:08,067 --> 00:36:09,235 DESCRIBED IN THESE DISEASES. 954 00:36:09,235 --> 00:36:12,438 I THINK A NICER WAY TO 955 00:36:12,438 --> 00:36:14,307 DEMONSTRATE WHAT THEY ARE IS BY 956 00:36:14,307 --> 00:36:17,243 LOOKING AT THE CELLULAR 957 00:36:17,243 --> 00:36:21,380 FUNCTIONS, PATHWAYS THEY MAP TO. 958 00:36:21,380 --> 00:36:24,150 ONE IMPORTANT PATHWAY, ONE 959 00:36:24,150 --> 00:36:25,451 IMPORTANT FUNCTION, IS 960 00:36:25,451 --> 00:36:26,285 ENDOLYSOSOMAL FUNCTIONS, WE 961 00:36:26,285 --> 00:36:27,854 OFTEN SEE DYSFUNCTION IN THE 962 00:36:27,854 --> 00:36:30,256 PATHWAY, IN THE LEWY BODY 963 00:36:30,256 --> 00:36:32,258 DEMENTIA PATIENT POPULATION. 964 00:36:32,258 --> 00:36:35,094 ANOTHER IMPORTANT PATHWAY IS 965 00:36:35,094 --> 00:36:37,663 AMYLOID PATHWAY, SO THAT'S 966 00:36:37,663 --> 00:36:42,969 AMYLOID PRECURSOR PROTEIN OFTEN 967 00:36:42,969 --> 00:36:43,736 DEPOSITED IN ALZHEIMER'S DISEASE 968 00:36:43,736 --> 00:36:47,340 AND LEWY BODY, SHOWING UP IN 969 00:36:47,340 --> 00:36:49,308 LEWY BODY DEMENTIA PATIENT 970 00:36:49,308 --> 00:36:49,609 POPULATION. 971 00:36:49,609 --> 00:36:51,744 GENES THAT ARE PLAYING AN 972 00:36:51,744 --> 00:36:53,713 IMPORTANT ROLE IN 973 00:36:53,713 --> 00:36:54,180 NEUROTRANSMISSION AND 974 00:36:54,180 --> 00:36:55,348 NEUROINFLAMMATION, SO THIS THING 975 00:36:55,348 --> 00:36:58,751 IS SOMETHING THAT WE'RE SEEING 976 00:36:58,751 --> 00:37:02,054 AGAIN AND AGAIN, USUALLY THE SUM 977 00:37:02,054 --> 00:37:04,257 OF THE PARTS IS GENE IN CONCERT 978 00:37:04,257 --> 00:37:09,495 WITH AGING THAT WE THINK IS 979 00:37:09,495 --> 00:37:12,465 TIPPING THE CELL INTO DISEASE 980 00:37:12,465 --> 00:37:13,332 ULTIMATELY RESULTING IN 981 00:37:13,332 --> 00:37:13,966 NEURODEGENERATION. 982 00:37:13,966 --> 00:37:15,201 WHAT ARE WE GOING TO DO WITH 983 00:37:15,201 --> 00:37:15,768 THAT? 984 00:37:15,768 --> 00:37:17,103 IT'S A NICE ACADEMIC EXERCISE, 985 00:37:17,103 --> 00:37:18,304 TO FIGURE THESE THINGS OUT, BUT 986 00:37:18,304 --> 00:37:21,340 AT THE END OF THE DAY THESE ARE 987 00:37:21,340 --> 00:37:21,807 DEVASTATING DISEASES. 988 00:37:21,807 --> 00:37:23,276 SO WE WANT TO GET TO A POINT 989 00:37:23,276 --> 00:37:25,978 WHERE WE WANT TO DO SOMETHING 990 00:37:25,978 --> 00:37:26,612 ABOUT IT. 991 00:37:26,612 --> 00:37:30,216 AND SO ALREADY WE'RE USING 992 00:37:30,216 --> 00:37:33,386 GENETICS IN FAMILIAL CASES TO, 993 00:37:33,386 --> 00:37:34,587 YOU KNOW, IMIMPROVE COUNSELING 994 00:37:34,587 --> 00:37:36,022 OF PATIENTS AND FAMILIES. 995 00:37:36,022 --> 00:37:38,324 IT ALLOWS US TO ENROLL PATIENTS 996 00:37:38,324 --> 00:37:40,626 IN CLINICAL TRIALS, REALLY 997 00:37:40,626 --> 00:37:41,794 TARGETS CERTAIN GENETIC FORMS OF 998 00:37:41,794 --> 00:37:45,097 THE DISEASE, BUT REALLY HELPS US 999 00:37:45,097 --> 00:37:46,199 ALSO WITH DISEASE MODELING, A 1000 00:37:46,199 --> 00:37:48,301 LOT OF OUR PATIENTS PROVIDING, 1001 00:37:48,301 --> 00:37:50,036 FOR EXAMPLE, BLOOD SAMPLES THAT 1002 00:37:50,036 --> 00:37:52,104 CAN BE CONVERTED INTO STEM CELLS 1003 00:37:52,104 --> 00:37:54,273 AND WE CAN DO A LOT OF IN VITRO 1004 00:37:54,273 --> 00:37:56,275 MODELS NOW PROVING A LOT OF 1005 00:37:56,275 --> 00:37:57,176 THESE INTERESTING OBSERVATIONS 1006 00:37:57,176 --> 00:38:01,547 IN A DISH, ACCELERATING 1007 00:38:01,547 --> 00:38:03,282 THERAPEUTIC DEVELOPMENT. 1008 00:38:03,282 --> 00:38:07,220 BUT EVEN FOR THE NON-FAMILIAL 1009 00:38:07,220 --> 00:38:08,554 CASES THERE'S IMPORTANT INSIGHT 1010 00:38:08,554 --> 00:38:13,459 WE ALREADY GAINED THAT REALLY 1011 00:38:13,459 --> 00:38:15,728 ARE INSPIRING US, TRANSLATIONAL 1012 00:38:15,728 --> 00:38:17,597 IMPLICATIONS IN OUR GRASP. 1013 00:38:17,597 --> 00:38:18,931 WE'VE IDENTIFIED IMPORTANT 1014 00:38:18,931 --> 00:38:21,567 GENES, IMPORTANT PATHWAYS, MANY 1015 00:38:21,567 --> 00:38:23,102 ARE SHARED, WITH OTHER DISEASES, 1016 00:38:23,102 --> 00:38:25,838 THAT REALLY TELLS US SOMETHING 1017 00:38:25,838 --> 00:38:28,007 ABOUT OPPORTUNITIES TO TREAT A 1018 00:38:28,007 --> 00:38:30,509 BROADER SPECTRUM OF CONDITIONS. 1019 00:38:30,509 --> 00:38:32,945 WE ARE SMARTER NOW IN TERMS OF 1020 00:38:32,945 --> 00:38:34,247 RECOGNIZING DISEASE SUBTYPES 1021 00:38:34,247 --> 00:38:38,050 THAT WE CAN DEFINE GENETICALLY 1022 00:38:38,050 --> 00:38:39,485 SIMPLE PCR GENOTYPING, NOTHING 1023 00:38:39,485 --> 00:38:41,787 SPECIAL ABOUT IT, THAT CAN 1024 00:38:41,787 --> 00:38:42,888 PERHAPS HELP US IDENTIFY 1025 00:38:42,888 --> 00:38:47,126 INTERESTING SIGNALS AS MAY HAVE 1026 00:38:47,126 --> 00:38:49,462 BEEN MISSED IN CLINICAL TRIALS. 1027 00:38:49,462 --> 00:38:51,097 WE CAN USE MOLECULAR DATA TO 1028 00:38:51,097 --> 00:38:52,798 REPURPOSE AND HIGHLIGHT DRUGS 1029 00:38:52,798 --> 00:38:54,066 THAT CAN BE USED. 1030 00:38:54,066 --> 00:38:58,004 I THINK OVERALL THIS IS A VERY 1031 00:38:58,004 --> 00:38:59,905 IMPORTANT DEVELOPMENT BECAUSE 1032 00:38:59,905 --> 00:39:01,741 GENOMICS INCREASINGLY IS REALLY 1033 00:39:01,741 --> 00:39:03,042 ACCELERATING THE DRUG 1034 00:39:03,042 --> 00:39:03,609 DEVELOPMENT PIPELINE. 1035 00:39:03,609 --> 00:39:05,578 THERE'S A LOT OF ADVANCES 1036 00:39:05,578 --> 00:39:06,879 ALREADY IN OTHER FIELDS THAT ARE 1037 00:39:06,879 --> 00:39:09,715 A LITTLE BIT FURTHER ALONG, HAVE 1038 00:39:09,715 --> 00:39:10,383 BIGGER NUMBERS, BUT WE'RE 1039 00:39:10,383 --> 00:39:12,685 STARTING TO CATCH UP. 1040 00:39:12,685 --> 00:39:13,819 SO, FOR EXAMPLE, STATINS, 1041 00:39:13,819 --> 00:39:15,855 MILLIONS OF PEOPLE TAKE STATINS 1042 00:39:15,855 --> 00:39:17,390 FOR HIGH CHOLESTEROL LEVELS, 1043 00:39:17,390 --> 00:39:19,392 REALLY HAS BEEN BASED ON A 1044 00:39:19,392 --> 00:39:21,093 GENETIC DISCOVERY, NOW THIS IS 1045 00:39:21,093 --> 00:39:22,862 REALLY A GAME CHANGER. 1046 00:39:22,862 --> 00:39:26,032 AND SO WE'RE VERY HOPEFUL THAT A 1047 00:39:26,032 --> 00:39:28,100 LOT OF THESE DISCOVERIES, 1048 00:39:28,100 --> 00:39:30,269 INSIGHTS, WILL ULTIMATELY RESULT 1049 00:39:30,269 --> 00:39:32,571 IN NEW THERAPIES. 1050 00:39:32,571 --> 00:39:34,874 AND, YOU KNOW, THERE'S GOOD 1051 00:39:34,874 --> 00:39:39,912 REASON TO BE OPTIMISTIC, A THIRD 1052 00:39:39,912 --> 00:39:40,680 OF FDA-APPROVED DRUGS ALREADY 1053 00:39:40,680 --> 00:39:42,114 HAVE GENETIC SUPPORT AND THAT 1054 00:39:42,114 --> 00:39:43,649 NUMBER IS REALLY INCREASING AS 1055 00:39:43,649 --> 00:39:46,285 WE'RE GETTING BETTER WITH OUR 1056 00:39:46,285 --> 00:39:47,787 GENETIC MODELING, AND THE MORE 1057 00:39:47,787 --> 00:39:49,322 GENETIC EVIDENCE WE HAVE, THE 1058 00:39:49,322 --> 00:39:53,959 HIGHER THE SUCCESS RATE IS. 1059 00:39:53,959 --> 00:39:55,361 AND SO, YES, WHILE A LOT OF 1060 00:39:55,361 --> 00:39:56,996 THINGS ARE PUSHING INTO THE 1061 00:39:56,996 --> 00:39:58,464 CLINIC, WE STILL HAVE TO DO A 1062 00:39:58,464 --> 00:39:59,632 LOT OF WORK. 1063 00:39:59,632 --> 00:40:02,935 THERE ARE THINGS WE HAVEN'T 1064 00:40:02,935 --> 00:40:05,237 REALLY STUDIED EXTENSIVELY. 1065 00:40:05,237 --> 00:40:06,105 THINGS LIKE SOMATIC MUTATIONS, 1066 00:40:06,105 --> 00:40:09,175 SO IN ORDER TO CAPTURE THAT WE 1067 00:40:09,175 --> 00:40:12,111 HAVE TO DO DEEP SEQUENCING TO 1068 00:40:12,111 --> 00:40:13,045 PICK THEM OUT. 1069 00:40:13,045 --> 00:40:19,251 THERE ARE VARIANTS WHERE WE ARE 1070 00:40:19,251 --> 00:40:20,886 UNDERPOWERED. 1071 00:40:20,886 --> 00:40:24,957 OURS IS THE LARGE FOR LEWY BODY, 1072 00:40:24,957 --> 00:40:26,692 SMALL FOR GENOMICS, WE NEED TO 1073 00:40:26,692 --> 00:40:27,693 EXPAND INTERACTIONS FROM ONE 1074 00:40:27,693 --> 00:40:29,495 GENE TO ANOTHER THAT WE COULDN'T 1075 00:40:29,495 --> 00:40:30,229 MODEL STATISTICALLY. 1076 00:40:30,229 --> 00:40:32,732 THERE ARE OTHER TYPES OF GENETIC 1077 00:40:32,732 --> 00:40:34,667 VARIANTS THAT WE CAN'T REALLY 1078 00:40:34,667 --> 00:40:36,736 MAP VERY WELL. 1079 00:40:36,736 --> 00:40:46,445 SO, FOR EXAMPLE, TELL TELOMERE 1080 00:40:46,445 --> 00:40:48,047 REGION, COULD PLAY AN IMPORTANT 1081 00:40:48,047 --> 00:40:50,483 ROLE, WE MAY BE MISSING A LOT. 1082 00:40:50,483 --> 00:40:51,584 I'M A GENETICIST. 1083 00:40:51,584 --> 00:40:53,319 I ADMIT THE ENVIRONMENT IS STILL 1084 00:40:53,319 --> 00:40:54,520 VERY IMPORTANT AND THOSE 1085 00:40:54,520 --> 00:40:55,621 INTERACTIONS IS SOMETHING WE 1086 00:40:55,621 --> 00:40:58,124 HAVE TO THINK ABOUT MORE 1087 00:40:58,124 --> 00:40:58,657 CAREFULLY. 1088 00:40:58,657 --> 00:41:00,426 THERE MAY BE OTHER THINGS WE 1089 00:41:00,426 --> 00:41:03,529 HAVEN'T YET THOUGHT B I DON'T 1090 00:41:03,529 --> 00:41:04,063 -- 1091 00:41:04,063 --> 00:41:05,164 THOUGHT ABOUT. 1092 00:41:05,164 --> 00:41:06,932 I DON'T CLAIM ALL THE ANSWERS 1093 00:41:06,932 --> 00:41:08,000 WE'RE. 1094 00:41:08,000 --> 00:41:09,668 WE'VE MORE THAN DOUBLED COHORT 1095 00:41:09,668 --> 00:41:10,970 SIZE, CURRENTLY ALIGNING THE 1096 00:41:10,970 --> 00:41:12,004 GENOMES. 1097 00:41:12,004 --> 00:41:14,807 WE HAVE REALLY DOUBLED DOWN IN 1098 00:41:14,807 --> 00:41:16,008 TRYING TO INCREASE DIVERSITY. 1099 00:41:16,008 --> 00:41:19,078 A LOT OF BRAIN BANKS HAVE A 1100 00:41:19,078 --> 00:41:20,379 BIASED COLLECTION, WE DON'T HAVE 1101 00:41:20,379 --> 00:41:22,782 A LOT OF DIVERSITY IN THEM. 1102 00:41:22,782 --> 00:41:25,985 I'VE BEEN PARTNERING WITH A LOT 1103 00:41:25,985 --> 00:41:29,188 OF PROGRAM DIRECTORS FOR PDPP 1104 00:41:29,188 --> 00:41:32,591 AND ALL BRAIN BANKS TO GET LEWY 1105 00:41:32,591 --> 00:41:34,460 BODY CASES FROM ANCESTRY DIVERSE 1106 00:41:34,460 --> 00:41:34,994 INDIVIDUALS. 1107 00:41:34,994 --> 00:41:37,396 AND WE'RE TRYING TO REALLY 1108 00:41:37,396 --> 00:41:39,999 EXPAND OUR FOUNDATIONAL GENOMIC 1109 00:41:39,999 --> 00:41:40,566 RESOURCES, ALSO LEVERAGE 1110 00:41:40,566 --> 00:41:44,036 RESOURCES THAT OTHERS ARE 1111 00:41:44,036 --> 00:41:46,071 GENERATING LIKE TRANSCRIPTOMIC 1112 00:41:46,071 --> 00:41:46,739 CATALOGS THAT DON'T HAVE TO BE 1113 00:41:46,739 --> 00:41:48,874 FROM MY PATIENT OF INTEREST. 1114 00:41:48,874 --> 00:41:50,743 I CAN USE COMMON VARIANTS AND 1115 00:41:50,743 --> 00:41:52,478 CAN PREDICT WHAT THEY ARE DOING 1116 00:41:52,478 --> 00:41:56,315 BASED ON CATALOGS OF COMMON 1117 00:41:56,315 --> 00:41:57,016 VARIANTS. 1118 00:41:57,016 --> 00:41:57,750 AND INCREASINGLY USING 1119 00:41:57,750 --> 00:42:00,719 COMPUTATIONAL TOOLS WE CAN USE 1120 00:42:00,719 --> 00:42:03,756 MULTI-OMIC DATA INTEGRATION TO 1121 00:42:03,756 --> 00:42:06,158 REALLY INTERPRET OUR FINDINGS IN 1122 00:42:06,158 --> 00:42:07,059 SYSTEMS BIOLOGY FRAMEWORK. 1123 00:42:07,059 --> 00:42:09,895 AND WE HAVE DONE SIMILAR THINGS 1124 00:42:09,895 --> 00:42:12,097 NOW WITH OTHER DISEASES, FOR 1125 00:42:12,097 --> 00:42:13,265 EXAMPLE MULTIPLE SYSTEM ATROPHY, 1126 00:42:13,265 --> 00:42:16,135 AND WE'RE NOT THE ONLY ONES 1127 00:42:16,135 --> 00:42:20,439 WORKING AND ACCELERATING THE 1128 00:42:20,439 --> 00:42:22,408 FIELD, ABLE TO PINPOINT 1129 00:42:22,408 --> 00:42:23,609 MOLECULAR UNDERPINNINGS IN 1130 00:42:23,609 --> 00:42:25,811 AGE-RELATED DISEASES EVEN IN 1131 00:42:25,811 --> 00:42:31,283 THOSE THAT ARE SPORADIC, SO 1132 00:42:31,283 --> 00:42:31,817 SUSCEPTIBILITY GENES, GENE 1133 00:42:31,817 --> 00:42:32,918 MODIFIERS STILL PLAYING A ROLE, 1134 00:42:32,918 --> 00:42:34,353 THAT KNOWLEDGE IS WORTHWHILE. 1135 00:42:34,353 --> 00:42:36,655 IT'S WORTH THE EFFORT OF TRYING 1136 00:42:36,655 --> 00:42:38,524 TO PUT IT TOGETHER. 1137 00:42:38,524 --> 00:42:40,159 WE NOW HAVE CAPABILITIES TO 1138 00:42:40,159 --> 00:42:41,927 STUDY THESE DISEASES IN THE 1139 00:42:41,927 --> 00:42:45,631 BROADER COMPLEX, SIDE BY SIDE, 1140 00:42:45,631 --> 00:42:47,399 COMPARISONS, LOOKING AT OVERLAP 1141 00:42:47,399 --> 00:42:48,434 IN ARCHITECTURES. 1142 00:42:48,434 --> 00:42:50,669 AND, YOU KNOW, THIS IS ALREADY 1143 00:42:50,669 --> 00:42:54,073 REALLY GEARING UP TOWARDS 1144 00:42:54,073 --> 00:42:55,174 GETTING TOWARDS TRANSLATIONAL 1145 00:42:55,174 --> 00:42:55,708 APPLICATIONS. 1146 00:42:55,708 --> 00:42:59,211 SO WHERE WE ARE RIGHT NOW IS 1147 00:42:59,211 --> 00:42:59,845 WE'RE STILL GATHERING MOLECULAR 1148 00:42:59,845 --> 00:43:03,282 KNOWLEDGE BUT WE'RE ALREADY 1149 00:43:03,282 --> 00:43:05,351 USING GENETICS INCREASINGLY TO 1150 00:43:05,351 --> 00:43:08,053 HELP US WITH THE DIAGNOSTIC 1151 00:43:08,053 --> 00:43:08,354 IMPRESSION. 1152 00:43:08,354 --> 00:43:11,423 WE'RE USING IT AS A BIOMARKER TO 1153 00:43:11,423 --> 00:43:12,658 SUBSTRATIFY INDIVIDUALS, AND, 1154 00:43:12,658 --> 00:43:14,193 YOU KNOW, WE ALREADY, YOU KNOW, 1155 00:43:14,193 --> 00:43:16,729 ARE COMING UP WITH BETTER WAYS 1156 00:43:16,729 --> 00:43:18,697 TO POTENTIALLY DO GENE THERAPY 1157 00:43:18,697 --> 00:43:20,332 TRIALS AND WHAT GENES AND 1158 00:43:20,332 --> 00:43:21,867 TARGETS WE SHOULD USE AND 1159 00:43:21,867 --> 00:43:23,402 HOPEFULLY BY PUTTING THESE 1160 00:43:23,402 --> 00:43:24,703 EFFORTS TOGETHER KEEPING WORKING 1161 00:43:24,703 --> 00:43:26,438 ON THAT PATH, WE CAN GET TO THE 1162 00:43:26,438 --> 00:43:27,873 POINT WHERE WE CAN GET THE RIGHT 1163 00:43:27,873 --> 00:43:29,141 THERAPY TO THE RIGHT PATIENT AT 1164 00:43:29,141 --> 00:43:30,943 THE RIGHT POINT OF TIME AND MAKE 1165 00:43:30,943 --> 00:43:32,578 A REAL DIFFERENCE IN THE LIVES 1166 00:43:32,578 --> 00:43:36,215 OF PATIENTS WHO ARE DEVASTATED 1167 00:43:36,215 --> 00:43:38,284 BY THESE SERIOUS 1168 00:43:38,284 --> 00:43:40,286 NEURODEGENERATIVE DISEASES. 1169 00:43:40,286 --> 00:43:42,454 KEY MESSAGE, THERE'S BEEN 1170 00:43:42,454 --> 00:43:44,957 MASSIVE ADVANCES IN GENOMICS. 1171 00:43:44,957 --> 00:43:46,058 AND WE'RE FINALLY REALLY 1172 00:43:46,058 --> 00:43:49,261 STARTING TO GET A HANDLE AT 1173 00:43:49,261 --> 00:43:50,329 THESE COMPLEX NEURODEGENERATIVE 1174 00:43:50,329 --> 00:43:52,631 DISEASE THAT HAVE UNTIL NOW HAVE 1175 00:43:52,631 --> 00:43:56,168 BEEN VERY DIFFICULT TO TACKLE. 1176 00:43:56,168 --> 00:44:00,506 AND SO USING EXAMPLE OF LEWY 1177 00:44:00,506 --> 00:44:02,942 BODY DEMENTIA IT'S A COMPLEX 1178 00:44:02,942 --> 00:44:06,211 DISEASE, INTERSECTS WITH OTHER 1179 00:44:06,211 --> 00:44:07,479 AGE-RELATED NEURODEGENERATIVE 1180 00:44:07,479 --> 00:44:08,747 DISEASES, MANY PLEIOTROPIC GENES 1181 00:44:08,747 --> 00:44:11,016 AND THESE ARE REALLY INTERESTING 1182 00:44:11,016 --> 00:44:11,917 FROM A THERAPEUTIC TARGETING 1183 00:44:11,917 --> 00:44:13,652 POINT OF VIEW. 1184 00:44:13,652 --> 00:44:15,654 AND INCREASINGLY WE'RE EXPANDING 1185 00:44:15,654 --> 00:44:17,623 OUR EFFORTS TO REALLY GET 1186 00:44:17,623 --> 00:44:18,924 TOWARDS TRANSLATIONAL GENOMICS 1187 00:44:18,924 --> 00:44:21,160 AND BRING THOSE THERAPIES TO THE 1188 00:44:21,160 --> 00:44:21,460 PATIENTS. 1189 00:44:21,460 --> 00:44:23,963 AND SO ALL OF WHAT I DO HERE IS 1190 00:44:23,963 --> 00:44:25,064 TEAM SCIENCE. 1191 00:44:25,064 --> 00:44:26,365 THERE'S NOTHING THAT REALLY AM 1192 00:44:26,365 --> 00:44:27,399 DOING HERE. 1193 00:44:27,399 --> 00:44:30,436 SO I OWE A LOT OF GRATITUDE TO 1194 00:44:30,436 --> 00:44:33,038 THE MANY PEOPLE WHO HAVE BEEN 1195 00:44:33,038 --> 00:44:33,939 CONTRIBUTING. 1196 00:44:33,939 --> 00:44:36,976 I CANNOT FIT EVERYBODY ON THE 1197 00:44:36,976 --> 00:44:38,444 SLIDE HERE. 1198 00:44:38,444 --> 00:44:40,179 BUT I ALSO WANT TO SAY SPECIAL 1199 00:44:40,179 --> 00:44:41,814 THANKS TO THE PATIENTS AND 1200 00:44:41,814 --> 00:44:44,316 FAMILIES WHO WORK WITH US, WHILE 1201 00:44:44,316 --> 00:44:46,752 THEY ARE FACING VERY DIFFICULT 1202 00:44:46,752 --> 00:44:47,052 SITUATIONS. 1203 00:44:47,052 --> 00:44:47,753 WE'LL KEEP GOING. 1204 00:44:47,753 --> 00:44:50,022 SO THANK YOU VERY MUCH FOR YOUR 1205 00:44:50,022 --> 00:44:50,222 TIME. 1206 00:44:50,222 --> 00:44:52,524 AND I'M HAPPY TO TAKE A COUPLE 1207 00:44:52,524 --> 00:44:53,425 OF QUESTIONS RIGHT NOW. 1208 00:44:53,425 --> 00:45:01,533 [APPLAUSE] 1209 00:45:01,533 --> 00:45:04,803 1210 00:45:04,803 --> 00:45:06,672 >> IF YOU HAVE A QUESTION PLEASE 1211 00:45:06,672 --> 00:45:09,274 GO TO THE MICROPHONE SO THE 1212 00:45:09,274 --> 00:45:15,114 OUTSIDE WORLD CAN HEAR. 1213 00:45:15,114 --> 00:45:16,081 THANK YOU. 1214 00:45:16,081 --> 00:45:18,851 >> BY THE TIME A PATIENT 1215 00:45:18,851 --> 00:45:21,053 DEVELOPS COGNITIVE DYSFUNCTION, 1216 00:45:21,053 --> 00:45:23,756 THE NEURODEGENERATION IS ALSO 1217 00:45:23,756 --> 00:45:24,256 ADVANCED. 1218 00:45:24,256 --> 00:45:25,190 HOMEOSTATIC MECHANISMS THAT THE 1219 00:45:25,190 --> 00:45:29,662 BODY HAS HAVE BEEN OVERWHELMED. 1220 00:45:29,662 --> 00:45:35,067 WHAT CAN YOU DO TO IDENTIFY THE 1221 00:45:35,067 --> 00:45:42,307 GENETIC RISK BEING ACTUALLY 1222 00:45:42,307 --> 00:45:45,344 TRANSLATED INTO NEUROPATHOLOGY 1223 00:45:45,344 --> 00:45:47,646 IN PRE-CLINICAL PHASE? 1224 00:45:47,646 --> 00:45:49,615 >> YEAH, SO THERE'S A LOT OF 1225 00:45:49,615 --> 00:45:51,050 DISCUSSIONS OBVIOUSLY. 1226 00:45:51,050 --> 00:45:52,384 WE NEED TO IDEALLY IDENTIFY 1227 00:45:52,384 --> 00:45:55,854 DISEASE AS EARLY AS POSSIBLE. 1228 00:45:55,854 --> 00:45:59,258 AND SO INCREASINGLY, WE'RE 1229 00:45:59,258 --> 00:46:01,694 UTILIZING BIOMARKERS THAT CAN 1230 00:46:01,694 --> 00:46:02,895 DETECT ABNORMALLY DEPOSITED 1231 00:46:02,895 --> 00:46:04,396 PROTEIN. 1232 00:46:04,396 --> 00:46:07,032 EITHER IN THE CSF USING 1233 00:46:07,032 --> 00:46:10,469 DEAGGREGATION ASSAYS SUCH AS RT 1234 00:46:10,469 --> 00:46:17,042 QUICK, WE CAN ALSO USE SKIN 1235 00:46:17,042 --> 00:46:19,745 BIOPSIES, STILL TRYING TO 1236 00:46:19,745 --> 00:46:21,180 UNDERSTAND HOW LONG PATHOLOGICAL 1237 00:46:21,180 --> 00:46:25,117 PROTEIN DEPOSITS EXIST IN THE 1238 00:46:25,117 --> 00:46:26,351 PRESYMPTOMATIC SPACE. 1239 00:46:26,351 --> 00:46:28,654 WITH SKIN BIOPSIES WE'RE SEEING 1240 00:46:28,654 --> 00:46:29,855 INDIVIDUALS VERY YOUNG, 1241 00:46:29,855 --> 00:46:32,191 NEUROLOGICALLY HEALTHY, IT'S 1242 00:46:32,191 --> 00:46:34,860 VERY DIFFICULT TO SAY WHAT IS 1243 00:46:34,860 --> 00:46:35,861 YOUR PROGNOSIS, BUT THOSE ARE 1244 00:46:35,861 --> 00:46:38,831 THE INDIVIDUALS WE WOULD LIKE TO 1245 00:46:38,831 --> 00:46:41,567 FOLLOW VERY CAREFULLY. 1246 00:46:41,567 --> 00:46:43,435 IT'S THE COMBINATION OF VERY 1247 00:46:43,435 --> 00:46:46,305 CLINICAL ASSESSMENT WITH NEW 1248 00:46:46,305 --> 00:46:48,373 BIOMARKERS, NEW IMAGING MARKERS, 1249 00:46:48,373 --> 00:46:51,443 POTENTIALLY ALSO NEW PET LIGANDS 1250 00:46:51,443 --> 00:46:52,478 SPECIFIC TO SYNUCLEIN IN THE 1251 00:46:52,478 --> 00:46:54,613 PIPELINE WE WILL BE ABLE TO 1252 00:46:54,613 --> 00:46:55,948 IDENTIFY THESE INDIVIDUALS AND 1253 00:46:55,948 --> 00:46:58,817 TRY TO GET THEM INTO CLINICAL 1254 00:46:58,817 --> 00:47:01,720 TRIALS, DISEASE MODIFYING, PUT 1255 00:47:01,720 --> 00:47:02,488 THEM ON DISEASE-MODIFYING 1256 00:47:02,488 --> 00:47:02,721 AGENTS. 1257 00:47:02,721 --> 00:47:05,891 MAY NOT BE A CURE BUT EVEN A 1258 00:47:05,891 --> 00:47:07,192 SLOWING DOWN OF THE DISEASE 1259 00:47:07,192 --> 00:47:13,866 WOULD BE WORTH THE EFFORT. 1260 00:47:13,866 --> 00:47:15,300 >> SO, THIS WORK IS AMAZING. 1261 00:47:15,300 --> 00:47:17,503 I LOVE IT, RIGHT? 1262 00:47:17,503 --> 00:47:19,238 SO WE'VE GOT -- WE'RE BREAKING 1263 00:47:19,238 --> 00:47:22,007 THIS IDEA OF GENE TO DISEASE. 1264 00:47:22,007 --> 00:47:24,076 AND EXTREMELY WILL SAY GENES ARE 1265 00:47:24,076 --> 00:47:28,447 REAL BUT DISEASES MIGHT NOT BE, 1266 00:47:28,447 --> 00:47:29,414 BEING DELIBERATELY PROVOCATIVE 1267 00:47:29,414 --> 00:47:31,917 THERE. 1268 00:47:31,917 --> 00:47:32,117 RIGHT. 1269 00:47:32,117 --> 00:47:35,087 LET'S TAKE THE EXAMPLE OF APOE, 1270 00:47:35,087 --> 00:47:37,189 HOW WE COULD TACKLE THIS. 1271 00:47:37,189 --> 00:47:43,996 MAYBE APOE IS A PROCESS OF 1272 00:47:43,996 --> 00:47:51,737 DEMENTIA IRRESPECTIVE OF 1273 00:47:51,737 --> 00:47:55,140 TAUOPATHY, HOW COULD WE TACKLE 1274 00:47:55,140 --> 00:48:02,247 THAT? 1275 00:48:02,247 --> 00:48:04,817 I'D LOVE TO HEAR YOUR THOUGHTS 1276 00:48:04,817 --> 00:48:06,185 ON THAT. 1277 00:48:06,185 --> 00:48:07,085 >> YEAH, IN PARTICULAR APOE I 1278 00:48:07,085 --> 00:48:09,054 THINK IS A VERY EXCITING 1279 00:48:09,054 --> 00:48:10,389 POTENTIAL TARGET FOR THERAPY 1280 00:48:10,389 --> 00:48:13,759 DEVELOPMENT, IT'S BEEN 1281 00:48:13,759 --> 00:48:18,430 IMPLICATED IN VASCULAR, LEWY 1282 00:48:18,430 --> 00:48:19,998 BODY, ALZHEIMER'S, A BIG ONE, 1283 00:48:19,998 --> 00:48:26,338 REFLECTIVE OF THE FACT THERE'S A 1284 00:48:26,338 --> 00:48:28,207 BROAD METABOLIC DYSFUNCTION WITH 1285 00:48:28,207 --> 00:48:28,807 AGING. 1286 00:48:28,807 --> 00:48:34,012 BASED ON THE ANIMAL MODELS, FOR 1287 00:48:34,012 --> 00:48:35,414 EXAMPLE, WORKING WITH RON 1288 00:48:35,414 --> 00:48:37,683 CRYSTAL'S LAB, YOU CAN ACTUALLY 1289 00:48:37,683 --> 00:48:40,219 TARGET THE APOE 4 ALLELE AND 1290 00:48:40,219 --> 00:48:42,287 INSERT, FOR EXAMPLE, USING GENE 1291 00:48:42,287 --> 00:48:43,956 THERAPIES AND APOE 2 ALLELE AND 1292 00:48:43,956 --> 00:48:45,958 SLOW DOWN THE DISEASE PROCESS. 1293 00:48:45,958 --> 00:48:47,559 SO THAT'S ONE OF THE ANIMAL 1294 00:48:47,559 --> 00:48:52,030 MODELS THAT'S REALLY VERY 1295 00:48:52,030 --> 00:48:52,431 EXCITING. 1296 00:48:52,431 --> 00:48:55,234 THERE'S ALSO POTENTIAL FOR 1297 00:48:55,234 --> 00:48:57,870 ENGINEERING, SO AS YOU KNOW 1298 00:48:57,870 --> 00:49:00,906 THERE'S CHRIST CHURCH VARIANT 1299 00:49:00,906 --> 00:49:04,743 THAT IMPARTS RESILIENCE TO 1300 00:49:04,743 --> 00:49:05,844 AMYLOID PATHOLOGY, THEY HAVE 1301 00:49:05,844 --> 00:49:07,246 PATHOLOGY BUT DON'T DEVELOP 1302 00:49:07,246 --> 00:49:09,214 DEMENTIA, FOR SOME REASON DON'T 1303 00:49:09,214 --> 00:49:12,284 GET THE NEURODEGENERATION. 1304 00:49:12,284 --> 00:49:13,952 SO PERHAPS BIOENGINEERING THESE 1305 00:49:13,952 --> 00:49:15,687 CHRISTCHURCH VARIANT WE MAY BE 1306 00:49:15,687 --> 00:49:18,323 ABLE TO STOP THE DISEASE PROCESS 1307 00:49:18,323 --> 00:49:20,192 IN THOSE HIGH RISK INDIVIDUALS 1308 00:49:20,192 --> 00:49:26,098 WITH LET'S SAY APOE 4 ALLELE, 1309 00:49:26,098 --> 00:49:27,966 IT'S SO PREVALENT, SO COMMON, SO 1310 00:49:27,966 --> 00:49:29,801 MANY FUNCTIONS, I COULD SEE IT 1311 00:49:29,801 --> 00:49:32,571 WHEN PEOPLE ENTER MIDDLE AGE, 1312 00:49:32,571 --> 00:49:34,873 UNFORTUNATELY AFFECTS ME, WOULD 1313 00:49:34,873 --> 00:49:38,777 GET SCREENED FOR, THAT MAY 1314 00:49:38,777 --> 00:49:41,179 INDIVIDUALIZE FOLLOW-UP 1315 00:49:41,179 --> 00:49:41,780 TREATMENT FOR HYPERLIPIDEMIA, 1316 00:49:41,780 --> 00:49:42,848 VASCULAR RISK FACTORS PART OF 1317 00:49:42,848 --> 00:49:45,284 THE DISEASE PROCESS. 1318 00:49:45,284 --> 00:49:49,521 I COULD SEE THERE ARE TARGETED 1319 00:49:49,521 --> 00:49:51,123 GENE THERAPIES FOR APOE COMING 1320 00:49:51,123 --> 00:49:54,359 AND BASED ON METABOLIC 1321 00:49:54,359 --> 00:49:56,461 DYSFUNCTIONS. 1322 00:49:56,461 --> 00:49:57,763 THANK YOU, GREAT QUESTION. 1323 00:49:57,763 --> 00:49:58,263 >> FANTASTIC. 1324 00:49:58,263 --> 00:50:00,165 I JUST LOVED IT. 1325 00:50:00,165 --> 00:50:01,600 ESPECIALLY YOUR THIRD HALF ON 1326 00:50:01,600 --> 00:50:04,102 THE DRUG STUFF. 1327 00:50:04,102 --> 00:50:05,437 A SIMPLE QUESTION. 1328 00:50:05,437 --> 00:50:07,372 SOME DRUGS, THREE CONDITIONS 1329 00:50:07,372 --> 00:50:11,376 THAT ARE ASSOCIATED WITH THE 1330 00:50:11,376 --> 00:50:13,912 VASCULAR, HYPERTENSION, 1331 00:50:13,912 --> 00:50:15,981 DIABETES, HIGH LDL, SO THERE IS 1332 00:50:15,981 --> 00:50:16,648 ALREADY A CLASSIC COMPOUND, I 1333 00:50:16,648 --> 00:50:18,884 DON'T KNOW IF IT HAS SHOWN ON 1334 00:50:18,884 --> 00:50:20,886 THE SCREEN. 1335 00:50:20,886 --> 00:50:31,363 PREF A STATIN LOWERS LDL AND 1336 00:50:35,968 --> 00:50:37,302 ANTI-INFLAMMATORY DISEASES, 1337 00:50:37,302 --> 00:50:37,869 WHICH COMPONENT IS CAUSING 1338 00:50:37,869 --> 00:50:39,838 DISEASE, DID YOU SEE DIFFERENCE 1339 00:50:39,838 --> 00:50:44,343 IN YOUR WHOLE -- YOU HAD 2500 1340 00:50:44,343 --> 00:50:45,877 PEOPLE, WERE SOME ALREADY ON A 1341 00:50:45,877 --> 00:50:46,745 STATIN FOR EXAMPLE AND DID THEY 1342 00:50:46,745 --> 00:50:48,947 HAVE LESS THAN THE ONES THAT 1343 00:50:48,947 --> 00:50:49,281 DIDN'T? 1344 00:50:49,281 --> 00:50:52,751 YOU KNOW WHAT I MEAN? 1345 00:50:52,751 --> 00:50:55,620 >> SO IN OUR LDD COHORT WE 1346 00:50:55,620 --> 00:50:57,589 DIDN'T HAVE THE DRUG 1347 00:50:57,589 --> 00:50:57,889 INFORMATION. 1348 00:50:57,889 --> 00:51:02,194 THE ONES WE GENOME SEQUENCED, SO 1349 00:51:02,194 --> 00:51:02,861 WE MADE INTERESTING OBSERVATIONS 1350 00:51:02,861 --> 00:51:06,064 IN THE DATA SOCIETY AND -- 1351 00:51:06,064 --> 00:51:07,666 DATASET, ONE OF THE STRONGEST 1352 00:51:07,666 --> 00:51:10,068 ASSOCIATED DUGS THAT CAME UP WAS 1353 00:51:10,068 --> 00:51:18,176 AN ANTI-HYPERTENSIVE NOT 1354 00:51:18,176 --> 00:51:21,780 COMMONLY PRESCRIBED, CARVELALOL, 1355 00:51:21,780 --> 00:51:22,914 A BETA BLOCKER. 1356 00:51:22,914 --> 00:51:24,216 WHAT'S GOING ON THERE? 1357 00:51:24,216 --> 00:51:28,653 IT IS A VERY POTENT ANTIOXIDANT 1358 00:51:28,653 --> 00:51:31,390 AS WELL. 1359 00:51:31,390 --> 00:51:33,191 MORE POTENT THAN VITAMIN E. 1360 00:51:33,191 --> 00:51:37,229 I WONDER WHETHER WE'RE TARGETING 1361 00:51:37,229 --> 00:51:39,031 BY HAPPENSTANCE TWO PROCESSES. 1362 00:51:39,031 --> 00:51:41,633 THERE ARE MORE DRUG REPURPOSING 1363 00:51:41,633 --> 00:51:43,802 PIPELINES WE CAN APPLY WITH 1364 00:51:43,802 --> 00:51:44,469 BIGGER COHORT. 1365 00:51:44,469 --> 00:51:46,138 WE'RE STILL ON THE LOWER END 1366 00:51:46,138 --> 00:51:47,873 WHERE WE CAN SPECIFICALLY LOOK 1367 00:51:47,873 --> 00:51:51,843 AT THESE RELATIONSHIPS AND THESE 1368 00:51:51,843 --> 00:51:54,012 PATHWAYS, AND THESE DIRTY DRUGS 1369 00:51:54,012 --> 00:51:58,517 THAT HIT MULTIPLE PATHWAYS ARE 1370 00:51:58,517 --> 00:52:00,152 THE ONES MOST INTERESTING FOR 1371 00:52:00,152 --> 00:52:00,452 REPURPOSING. 1372 00:52:00,452 --> 00:52:02,454 >> A SECOND THOUGHT CAN YOU TELL 1373 00:52:02,454 --> 00:52:03,355 WELL IN ADVANCE WHEN SOMETHING 1374 00:52:03,355 --> 00:52:10,328 IS GOING TO BE A PROBLEM, LIKE 1375 00:52:10,328 --> 00:52:12,097 FOR ELEVATED SUGARS, BY THE TIME 1376 00:52:12,097 --> 00:52:14,366 YOU COME TO 110 YOU KNOW YOU'RE 1377 00:52:14,366 --> 00:52:15,467 GOING TO DO DIABETES AND YOU 1378 00:52:15,467 --> 00:52:17,869 NEED TO DO SOMETHING FAST. 1379 00:52:17,869 --> 00:52:19,838 YOU NEED SOMETHING SIMPLE, WELL, 1380 00:52:19,838 --> 00:52:21,706 NOT SIMPLE, BUT YOU KNOW WHAT I 1381 00:52:21,706 --> 00:52:21,907 MEAN. 1382 00:52:21,907 --> 00:52:22,908 IF THERE WAS ONE OR TWO 1383 00:52:22,908 --> 00:52:24,810 BIOMARKERS, I LIKE THE WAY 1384 00:52:24,810 --> 00:52:25,444 YOU'RE TALKING ABOUT BIOMARKERS, 1385 00:52:25,444 --> 00:52:28,213 ONE OR TWO THINGS THAT WILL TELL 1386 00:52:28,213 --> 00:52:29,815 YOU A MARKER, THAT WILL TELL 1387 00:52:29,815 --> 00:52:31,049 YOU, YES, YOU HAVE THAT PROBLEM, 1388 00:52:31,049 --> 00:52:35,620 THIS IS GOING TO OCCUR IF YOU 1389 00:52:35,620 --> 00:52:36,621 DON'T GO ON THIS, WHATEVER, ARE 1390 00:52:36,621 --> 00:52:39,991 WE CLOSE TO THAT YET? 1391 00:52:39,991 --> 00:52:42,127 >> SOMETHING WE WOULD LIKE TO 1392 00:52:42,127 --> 00:52:42,594 DO. 1393 00:52:42,594 --> 00:52:43,962 I MEAN, I'M OPTIMISTIC WE'RE 1394 00:52:43,962 --> 00:52:46,731 GETTING TO THAT POINT. 1395 00:52:46,731 --> 00:52:48,767 ESPECIALLY THE PROTEOMICS FIELD 1396 00:52:48,767 --> 00:52:49,868 RAPIDLY ADVANCING, REALLY 1397 00:52:49,868 --> 00:52:50,202 EXCITING. 1398 00:52:50,202 --> 00:52:53,171 YOU CAN PICK UP 1399 00:52:53,171 --> 00:52:53,939 NEURODEGENERATION QUITE EARLY 1400 00:52:53,939 --> 00:52:57,109 ON, LET'S SAY THROUGH MEASURING 1401 00:52:57,109 --> 00:52:58,076 NEUROFILAMENT, WE CAN START TO 1402 00:52:58,076 --> 00:53:00,512 PICK IT UP BUT I DON'T YET HAVE 1403 00:53:00,512 --> 00:53:03,682 THE ANSWER AS TO HOW SPECIFIC IT 1404 00:53:03,682 --> 00:53:05,650 IS AND HOW GOOD IT IS FOR 1405 00:53:05,650 --> 00:53:07,219 DISEASE PREDICTION. 1406 00:53:07,219 --> 00:53:08,286 MAY BE MULTI-MODAL BIOMARKERS 1407 00:53:08,286 --> 00:53:12,691 THAT WE'LL HAVE TO DEVELOP. 1408 00:53:12,691 --> 00:53:15,660 OTHER DISEASES ARE FURTHER 1409 00:53:15,660 --> 00:53:19,364 ALONG, PARKINSON'S DISEASE, YOU 1410 00:53:19,364 --> 00:53:20,899 KNOW, DIFFERENT PANELS OF 1411 00:53:20,899 --> 00:53:23,735 PROTEINS THAT CAN PREDICT THE 1412 00:53:23,735 --> 00:53:25,270 DISEASE BUT I THINK LEWY BODY 1413 00:53:25,270 --> 00:53:26,605 DEMENTIA WE'RE JUST GETTING 1414 00:53:26,605 --> 00:53:27,139 THERE. 1415 00:53:27,139 --> 00:53:29,441 BUT WE HAVE THE TECHNOLOGIES NOW 1416 00:53:29,441 --> 00:53:30,609 AND WE'RE PULLING EVERYTHING 1417 00:53:30,609 --> 00:53:31,209 TOGETHER. 1418 00:53:31,209 --> 00:53:33,178 THIS IS A REALLY IMPORTANT POINT 1419 00:53:33,178 --> 00:53:35,914 TO LOOK AT PREDICTION. 1420 00:53:35,914 --> 00:53:36,581 >> THANK YOU. 1421 00:53:36,581 --> 00:53:38,550 >> MICHAEL, WOULD IT BE OKAY IF 1422 00:53:38,550 --> 00:53:41,286 I SLIP IN AND ONLINE QUESTION? 1423 00:53:41,286 --> 00:53:43,655 WE HAVE SEVERAL ONLINE 1424 00:53:43,655 --> 00:53:43,922 QUESTIONS. 1425 00:53:43,922 --> 00:53:46,758 THE FIRST ONE WAS DO THESE 1426 00:53:46,758 --> 00:53:48,059 DUPLICATION OR TRANSLOCATION OF 1427 00:53:48,059 --> 00:53:48,727 LEWY BODY DEMENTIA GENES OCCUR 1428 00:53:48,727 --> 00:53:50,829 AT BIRTH OR DO THEY OCCUR DURING 1429 00:53:50,829 --> 00:53:52,898 THE HUMAN LIFE CYCLE? 1430 00:53:52,898 --> 00:53:55,233 AND HOW CAN THESE MUTATIONS 1431 00:53:55,233 --> 00:53:56,835 CAUSE ONLY PHENOTYPE ONLY IN OLD 1432 00:53:56,835 --> 00:54:01,106 PEOPLE, WHY DOES IT NOT OCCUR 1433 00:54:01,106 --> 00:54:01,339 EARLIER. 1434 00:54:01,339 --> 00:54:04,042 >> GREAT QUESTION. 1435 00:54:04,042 --> 00:54:06,478 I CAN ANSWER EVERY ASPECT BUT 1436 00:54:06,478 --> 00:54:08,213 THESE ARE GERMLINE MUTATIONS 1437 00:54:08,213 --> 00:54:12,050 THAT PEOPLE CARRY AS THEY ARE 1438 00:54:12,050 --> 00:54:13,251 BORN ALREADY. 1439 00:54:13,251 --> 00:54:15,554 AND WHY IS THERE, YOU KNOW, 1440 00:54:15,554 --> 00:54:17,389 DECREASED PENETRANCE AND WHY DO 1441 00:54:17,389 --> 00:54:19,291 SOME OF THESE RISK GENES NOT 1442 00:54:19,291 --> 00:54:20,392 CAUSE DISEASE EARLIER, THAT'S A 1443 00:54:20,392 --> 00:54:21,927 QUESTION WE ASK A LOT. 1444 00:54:21,927 --> 00:54:24,095 WE DON'T ALWAYS HAVE THE RIGHT 1445 00:54:24,095 --> 00:54:25,564 KIND OF ANSWERS. 1446 00:54:25,564 --> 00:54:28,033 I THINK IT'S PROBABLY PART OF 1447 00:54:28,033 --> 00:54:29,701 THE NORMAL AGING PROCESS THAT A 1448 00:54:29,701 --> 00:54:32,103 LOT OF THESE PATHWAYS WE HAVE A 1449 00:54:32,103 --> 00:54:33,605 LOT OF RESILIENCE BUILT IN, BUT 1450 00:54:33,605 --> 00:54:35,740 AS WE'RE AGING A LOT OF THESE 1451 00:54:35,740 --> 00:54:36,841 PATHWAYS START TO BECOME 1452 00:54:36,841 --> 00:54:38,777 IMPAIRED AND IF YOU ALREADY HAVE 1453 00:54:38,777 --> 00:54:40,745 A HIGH RISK GENE PERHAPS IN 1454 00:54:40,745 --> 00:54:43,081 CONJUNCTION WITH OTHER RISK 1455 00:54:43,081 --> 00:54:43,748 FACTORS MAYBE DIABETES, 1456 00:54:43,748 --> 00:54:45,350 HYPERTENSION, THAT MAY BE ENOUGH 1457 00:54:45,350 --> 00:54:48,186 TO TIP YOU INTO DISEASE. 1458 00:54:48,186 --> 00:54:50,288 BUT THERE MAY BE OTHER 1459 00:54:50,288 --> 00:54:52,891 PROTECTIVE FACTORS THAT COULD 1460 00:54:52,891 --> 00:54:53,792 EXPLAIN WHY THERE'S DECREASED 1461 00:54:53,792 --> 00:54:54,259 PENETRANCE. 1462 00:54:54,259 --> 00:54:59,097 WE DON'T HAVE ALL THE ANSWERS AS 1463 00:54:59,097 --> 00:55:00,832 OF YET. 1464 00:55:00,832 --> 00:55:01,099 >> OKAY. 1465 00:55:01,099 --> 00:55:01,533 >> TERRIFIC TALK. 1466 00:55:01,533 --> 00:55:02,367 THANK YOU. 1467 00:55:02,367 --> 00:55:04,903 I HAD A QUESTION ABOUT ANIMAL 1468 00:55:04,903 --> 00:55:05,136 MODELS. 1469 00:55:05,136 --> 00:55:07,739 YOU MENTIONED TOWARDS THE END 1470 00:55:07,739 --> 00:55:09,741 THAT THE GENOMICS REALLY INFORMS 1471 00:55:09,741 --> 00:55:11,142 DEVELOPMENT OF NEW MODELS. 1472 00:55:11,142 --> 00:55:13,211 AND ONE OF THE ISSUES IT SEEMS 1473 00:55:13,211 --> 00:55:17,282 TO ME IN THIS DISEASE WHICH IS A 1474 00:55:17,282 --> 00:55:20,085 CONTINUUM OF NEURODEGENERATIVE 1475 00:55:20,085 --> 00:55:22,754 DISEASES IS THE EFFECT OF ADDING 1476 00:55:22,754 --> 00:55:26,458 A BUNCH OF MUTATIONS, MAYBE 1477 00:55:26,458 --> 00:55:26,925 ENVIRONMENTAL FACTORS, 1478 00:55:26,925 --> 00:55:27,993 STOCHASTIC IN WHAT DISEASE YOU 1479 00:55:27,993 --> 00:55:28,760 GET? 1480 00:55:28,760 --> 00:55:32,030 IN OTHER WORDS TO SOME EXTENT 1481 00:55:32,030 --> 00:55:33,698 RANDOM, DEPENDING ON WHAT 1482 00:55:33,698 --> 00:55:35,934 HAPPENS FIRST, OR IS IT 1483 00:55:35,934 --> 00:55:37,435 DETERMINISTIC, IF YOU ADD GENE 1484 00:55:37,435 --> 00:55:38,970 XYZ YOU ALWAYS GET LEWY BODY 1485 00:55:38,970 --> 00:55:40,939 DEMENTIA, AND SO ON? 1486 00:55:40,939 --> 00:55:43,975 ARE THERE ANY GOOD ANIMAL MODELS 1487 00:55:43,975 --> 00:55:45,543 TO TEST THAT QUESTION? 1488 00:55:45,543 --> 00:55:48,947 >> SO A LOT OF ANIMAL MODELS 1489 00:55:48,947 --> 00:55:50,482 ARE ESSENTIALLY BASED ON THE 1490 00:55:50,482 --> 00:55:52,851 FAMILIAL FORMS OF THE DISEASE. 1491 00:55:52,851 --> 00:55:55,954 AND MANY OF THEM ARE ALSO 1492 00:55:55,954 --> 00:55:58,890 INCLUDING MUTATIONS THAT 1493 00:55:58,890 --> 00:56:01,493 OVEREXPRESS LET'S SAY 1494 00:56:01,493 --> 00:56:02,927 ALPHA-SYNUCLEIN OR INCREASE 1495 00:56:02,927 --> 00:56:03,795 LIKELIHOOD OF PROTEIN 1496 00:56:03,795 --> 00:56:04,929 DEPOSITION. 1497 00:56:04,929 --> 00:56:09,834 SO IN A WAY, THESE ARE REALLY 1498 00:56:09,834 --> 00:56:10,468 TOXICS CELLULAR ENVIRONMENTS, I 1499 00:56:10,468 --> 00:56:12,570 DON'T KNOW TO WHICH EXTENT THEY 1500 00:56:12,570 --> 00:56:14,739 REFLECT WHAT'S GOING ON IN A 1501 00:56:14,739 --> 00:56:16,941 SPORADIC CASE WITH A MORE 1502 00:56:16,941 --> 00:56:18,910 AGE-RELATED DISEASE SO IT'S VERY 1503 00:56:18,910 --> 00:56:20,545 DIFFICULT TO COMMENT ON 1504 00:56:20,545 --> 00:56:22,414 ENVIRONMENTAL FACTORS THAT MAY 1505 00:56:22,414 --> 00:56:23,481 PLAY A MILDER ROLE. 1506 00:56:23,481 --> 00:56:26,818 BUT AT LEAST IN GENETIC MODELS 1507 00:56:26,818 --> 00:56:28,887 YOU DO SEE, YOU KNOW, PROTEIN 1508 00:56:28,887 --> 00:56:31,489 DEPOSITION, YOU DO SEE 1509 00:56:31,489 --> 00:56:34,693 NEUROINFLAMMATION VERY EARLY ON. 1510 00:56:34,693 --> 00:56:37,696 WE SEE, YOU KNOW, THE NEURONAL 1511 00:56:37,696 --> 00:56:40,365 CELL POPULATIONS VERY MUCH 1512 00:56:40,365 --> 00:56:42,634 AFFECTED BUT INCREASINGLY ABLE 1513 00:56:42,634 --> 00:56:45,637 TO APPRECIATE GLIAL CELLS ARE 1514 00:56:45,637 --> 00:56:46,705 STARTING TO MALFUNCTION SO 1515 00:56:46,705 --> 00:56:48,473 MICROGLIAL DYSFUNCTION IS 1516 00:56:48,473 --> 00:56:50,342 SOMETHING WE CLEARLY APPRECIATE. 1517 00:56:50,342 --> 00:56:53,378 UNFORTUNATELY WE DON'T REALLY 1518 00:56:53,378 --> 00:56:57,982 HAVE GOOD DATA ON OLIGO 1519 00:56:57,982 --> 00:57:01,186 DENDRITIC BUT WORK ON 1520 00:57:01,186 --> 00:57:03,054 MULTI-SYSTEM ATROPHY 1521 00:57:03,054 --> 00:57:04,189 REAPPRECIATE SYNUCLEIN BIOLOGY 1522 00:57:04,189 --> 00:57:05,824 AND OLIGO NUCLEAR BIOLOGY ARE 1523 00:57:05,824 --> 00:57:06,257 RELATED. 1524 00:57:06,257 --> 00:57:07,459 WE'RE STILL TRYING TO IDENTIFY 1525 00:57:07,459 --> 00:57:10,195 WHAT IS THE BEST MODEL FOR OUR 1526 00:57:10,195 --> 00:57:12,597 DISEASE OF INTEREST, AND SOME IS 1527 00:57:12,597 --> 00:57:16,201 ARTIFICIAL BUT AT LEAST WE'RE 1528 00:57:16,201 --> 00:57:18,169 STARTING TO DISENTANGLE SOME OF 1529 00:57:18,169 --> 00:57:20,672 THE CRUCIAL STEPS OF PROTEIN 1530 00:57:20,672 --> 00:57:21,473 DEPOSITION, REALLY AN EARLY 1531 00:57:21,473 --> 00:57:25,410 EVENT THAT IS HAPPENING IN THESE 1532 00:57:25,410 --> 00:57:25,710 INDIVIDUALS. 1533 00:57:25,710 --> 00:57:26,845 >> YOU'RE LIMITED TO THE MOUSE 1534 00:57:26,845 --> 00:57:27,379 AT THIS POINT? 1535 00:57:27,379 --> 00:57:33,184 OR YOU'RE THINKING ABOUT OTHER 1536 00:57:33,184 --> 00:57:33,752 MODELS, NON-HUMAN PRIMATE? 1537 00:57:33,752 --> 00:57:35,587 >> YEAH, THERE ARE GROUPS THAT 1538 00:57:35,587 --> 00:57:37,689 ARE WORKING ON MACAQUES NOW. 1539 00:57:37,689 --> 00:57:41,292 SO THAT IS ONE ANIMAL MODEL THAT 1540 00:57:41,292 --> 00:57:42,494 ESPECIALLY FOR DRUG DEVELOPMENT 1541 00:57:42,494 --> 00:57:45,130 PIPELINE MAY BE MORE RELEVANT 1542 00:57:45,130 --> 00:57:47,632 BUT MOST IS REALLY FOCUSED ON 1543 00:57:47,632 --> 00:57:48,400 MOUSE MODELS. 1544 00:57:48,400 --> 00:57:51,236 THERE HAS BEEN A FAMILIAL 1545 00:57:51,236 --> 00:57:56,307 OCCURRENCE OF LEWY BODY DEMENTIA 1546 00:57:56,307 --> 00:57:57,308 IN PARROTS. 1547 00:57:57,308 --> 00:57:59,244 PARROTS APPARENTLY CAN ALSO GET 1548 00:57:59,244 --> 00:57:59,511 DEMENTIA. 1549 00:57:59,511 --> 00:58:04,949 IF SOMEBODY WANTS TO UNDERTAKE A 1550 00:58:04,949 --> 00:58:05,784 STUDY ON PARROTS -- 1551 00:58:05,784 --> 00:58:08,553 >> CAN I SLIP IN ANOTHER? 1552 00:58:08,553 --> 00:58:09,654 THANK YOU. 1553 00:58:09,654 --> 00:58:15,994 HERE'S ANOTHER QUESTION FROM 1554 00:58:15,994 --> 00:58:16,461 ONLINE. 1555 00:58:16,461 --> 00:58:17,929 HAVE YOU LOOKED AT ALCOHOL AND 1556 00:58:17,929 --> 00:58:19,697 SUBSTANCE USE DISORDERS IN THE 1557 00:58:19,697 --> 00:58:21,499 LEWY BODY DEMENTIA PATIENT 1558 00:58:21,499 --> 00:58:23,568 COHORT THAT YOU ANALYZED, AND 1559 00:58:23,568 --> 00:58:26,204 HOW THESE DISORDERS COMPARE WITH 1560 00:58:26,204 --> 00:58:27,539 CBD THAT YOU MENTIONED 1561 00:58:27,539 --> 00:58:29,607 CORRELATED WITH LEWY BODY 1562 00:58:29,607 --> 00:58:29,874 DEMENTIA? 1563 00:58:29,874 --> 00:58:30,575 >> GREAT QUESTION. 1564 00:58:30,575 --> 00:58:35,213 SHORT ANSWER WE HAVEN'T LOOKED 1565 00:58:35,213 --> 00:58:36,548 AT OTHER COMORBIDITIES THAT 1566 00:58:36,548 --> 00:58:40,051 COULD PLAY A ROLE SO ALCOHOL IS 1567 00:58:40,051 --> 00:58:41,586 CERTAINLY A MAIN TOXIN. 1568 00:58:41,586 --> 00:58:43,788 AND SO I CAN'T REALLY COMMENT AS 1569 00:58:43,788 --> 00:58:45,757 TO WHICH EXTENT IT MAY PLAY A 1570 00:58:45,757 --> 00:58:45,957 ROLE. 1571 00:58:45,957 --> 00:58:48,693 CERTAINLY NOT HEALTHY AS 1572 00:58:48,693 --> 00:58:51,329 NEUROLOGISTS, I SAY THE LESS 1573 00:58:51,329 --> 00:58:52,564 ALCOHOL, THE BETTER. 1574 00:58:52,564 --> 00:58:55,967 BUT IT'S PROBABLY NOT THE ONLY 1575 00:58:55,967 --> 00:58:56,668 ANSWER. 1576 00:58:56,668 --> 00:58:58,970 SO HEALTH AND LIFESTYLE FACTORS 1577 00:58:58,970 --> 00:59:00,004 IS STILL SOMETHING EVERYBODY 1578 00:59:00,004 --> 00:59:01,873 SHOULD STICK TO AS MUCH AS 1579 00:59:01,873 --> 00:59:02,140 POSSIBLE. 1580 00:59:02,140 --> 00:59:03,408 >> THANK YOU FOR YOUR TALK. 1581 00:59:03,408 --> 00:59:05,343 IT WAS REALLY INTERESTING. 1582 00:59:05,343 --> 00:59:07,979 I WANTED TO ASK YOU FIRST ABOUT 1583 00:59:07,979 --> 00:59:11,382 THE -- WHEN YOU SHOWED -- 1584 00:59:11,382 --> 00:59:13,251 ANALYZING THE GENOMIC NETWORKS 1585 00:59:13,251 --> 00:59:15,653 FOR TRYING TO CHARACTERIZE SOME 1586 00:59:15,653 --> 00:59:18,056 PATIENTS AS HAVING PURE LEWY 1587 00:59:18,056 --> 00:59:21,092 BODY DEMENTIA VERSUS MORE 1588 00:59:21,092 --> 00:59:21,526 ALZHEIMER'S-LIKE OR 1589 00:59:21,526 --> 00:59:22,527 DEMENTIA-LIKE, IF YOU WERE TO 1590 00:59:22,527 --> 00:59:25,163 JUST TRY TO CHARACTERIZE THE 1591 00:59:25,163 --> 00:59:27,232 NETWORK BASED ON GENOMICS ITSELF 1592 00:59:27,232 --> 00:59:30,602 AND NOT THINKING ABOUT THE 1593 00:59:30,602 --> 00:59:31,936 ALZHEIMER'S OR DEMENTIA, HOW 1594 00:59:31,936 --> 00:59:32,804 MANY DIFFERENT SUBTYPES COULD 1595 00:59:32,804 --> 00:59:34,138 YOU KIND OF SEE? 1596 00:59:34,138 --> 00:59:36,241 THE SECOND PART OF MY QUESTION 1597 00:59:36,241 --> 00:59:38,810 WAS ALSO WHAT ROLE DO YOU THINK 1598 00:59:38,810 --> 00:59:40,478 THAT VIRAL INFECTIONS, IF ANY, 1599 00:59:40,478 --> 00:59:43,648 MIGHT PLAY IN THE PROGRESSION, 1600 00:59:43,648 --> 00:59:48,119 LIKE IN ACTUALLY -- EITHER IN 1601 00:59:48,119 --> 00:59:49,354 EITHER INFECTIOUS VIRUS OR 1602 00:59:49,354 --> 00:59:52,190 LATENT VIRUS, THAT MIGHT BECOME 1603 00:59:52,190 --> 00:59:53,291 ACTIVE AS THE IMMUNE SYSTEM 1604 00:59:53,291 --> 00:59:55,894 BREAKS DOWN AS PEOPLE AGE? 1605 00:59:55,894 --> 00:59:58,396 >> YEAH, GREAT QUESTIONS. 1606 00:59:58,396 --> 00:59:59,531 WE HAVEN'T BROKEN DOWN THE 1607 00:59:59,531 --> 01:00:00,698 NETWORK FURTHER. 1608 01:00:00,698 --> 01:00:02,700 WE'VE LOOKED FROM DIFFERENT 1609 01:00:02,700 --> 01:00:03,201 ANGLES. 1610 01:00:03,201 --> 01:00:05,103 BUT WHEN IT COMES TO VIRAL 1611 01:00:05,103 --> 01:00:08,373 INFECTION, THAT'S A REALLY HOTLY 1612 01:00:08,373 --> 01:00:09,674 DEBATED TOPIC. 1613 01:00:09,674 --> 01:00:12,977 I THINK COLLABORATING WITH STEVE 1614 01:00:12,977 --> 01:00:14,646 JACOBSON AT NINDS, TO GET AT 1615 01:00:14,646 --> 01:00:18,216 THAT, WE USED OUR COHORT OF DATA 1616 01:00:18,216 --> 01:00:22,820 TO LOOK AT VIRAL SEQUENCES THAT 1617 01:00:22,820 --> 01:00:26,424 MAY BE INTEGRATED IN LEWY BODY 1618 01:00:26,424 --> 01:00:30,495 DEMENTIA AND IN ALZHEIMER'S 1619 01:00:30,495 --> 01:00:30,728 DISEASE. 1620 01:00:30,728 --> 01:00:33,364 WE DIDN'T SEE ANYTHING 1621 01:00:33,364 --> 01:00:35,967 ASSOCIATED WITH ALZHEIMER'S 1622 01:00:35,967 --> 01:00:37,569 DISEASE WE DID SEE INCREASE IN 1623 01:00:37,569 --> 01:00:40,905 VIRAL SEQUENCES IN LEWY BODY 1624 01:00:40,905 --> 01:00:42,307 DEMENTIA, IN RARE INSTANCES, 1625 01:00:42,307 --> 01:00:47,478 ALSO IN MULTIPLE SYSTEM ATROPHY, 1626 01:00:47,478 --> 01:00:50,782 ANOTHER SYNUCLEINOPATHY. 1627 01:00:50,782 --> 01:00:51,983 IT'S JUST AN OBSERVATION, 1628 01:00:51,983 --> 01:00:53,051 WHETHER THIS IS SECONDSARY 1629 01:00:53,051 --> 01:00:56,988 BECAUSE CHROMATIN IS OPENING UP, 1630 01:00:56,988 --> 01:00:57,755 WILDLY TRANSCRIBED, VIRAL 1631 01:00:57,755 --> 01:00:59,290 SEQUENCES BECOME ACTIVE, OR IS 1632 01:00:59,290 --> 01:01:02,493 IT IN ANY WAY CAUSALLY RELATED. 1633 01:01:02,493 --> 01:01:05,763 THE CONCERN IS THOSE INDIVIDUALS 1634 01:01:05,763 --> 01:01:09,500 THAT HAVE VIRAL REACTIVATION 1635 01:01:09,500 --> 01:01:10,568 THAT MAY EXACERBATE INFLAMMATORY 1636 01:01:10,568 --> 01:01:12,670 PROCESS AND COULD BECOME A 1637 01:01:12,670 --> 01:01:13,638 RUNAWAY DISEASE MECHANISM, 1638 01:01:13,638 --> 01:01:14,973 THAT'S A VERY INTERESTING 1639 01:01:14,973 --> 01:01:15,273 QUESTION. 1640 01:01:15,273 --> 01:01:17,709 THANK YOU. 1641 01:01:17,709 --> 01:01:19,477 1642 01:01:19,477 --> 01:01:20,678 >> I'M GOING TO TRY ANOTHER ONE 1643 01:01:20,678 --> 01:01:23,414 THAT I THINK SOMEBODY IS JUST 1644 01:01:23,414 --> 01:01:24,616 MESSING WITH ME HERE. 1645 01:01:24,616 --> 01:01:27,051 THANK YOU FOR SHARING YOUR WORK. 1646 01:01:27,051 --> 01:01:30,154 SEVERAL OF THE RARE PEDIATRIC 1647 01:01:30,154 --> 01:01:34,926 LYSOSOMAL DISEASES, e.g. 1648 01:01:34,926 --> 01:01:40,431 NEURONAL LIPO FUSION OSIS, PICK 1649 01:01:40,431 --> 01:01:44,602 DISEASE TYPEC HAVE N 1650 01:01:44,602 --> 01:01:46,671 EURODEGENERATIVE FEATURES, DO 1651 01:01:46,671 --> 01:01:48,840 THESE COME UP OR OPPORTUNITIES 1652 01:01:48,840 --> 01:01:53,511 TO LOOK FOR GENES CODING FOR 1653 01:01:53,511 --> 01:01:54,545 LYSOSOMAL GENES. 1654 01:01:54,545 --> 01:01:56,280 >> THEY ARE SOMETHING WE NEED TO 1655 01:01:56,280 --> 01:01:59,684 LOOK -- HAVE BEEN LOOKING AT 1656 01:01:59,684 --> 01:01:59,984 CAREFULLY. 1657 01:01:59,984 --> 01:02:03,054 SO PROGRANULIN IS ONE EXAMPLE 1658 01:02:03,054 --> 01:02:04,155 FOR LYSOSOMAL GENE, WE SEE 1659 01:02:04,155 --> 01:02:04,555 ENRICHMENT. 1660 01:02:04,555 --> 01:02:09,527 WE'VE LOOKED AT A COUPLE OTHERS. 1661 01:02:09,527 --> 01:02:15,667 SO FOR EXAMPLE NEWMAN PICC 1662 01:02:15,667 --> 01:02:17,502 DISEASE, WE CAN'T DO PROOF 1663 01:02:17,502 --> 01:02:19,170 THERE'S ASSOCIATION WITH LEWY 1664 01:02:19,170 --> 01:02:21,439 BODY DEMENTIA, I ALSO HAVE TO 1665 01:02:21,439 --> 01:02:23,875 ADMIT WE HAVE LIMITED POWER. 1666 01:02:23,875 --> 01:02:26,177 SOME OF THESE ALLELES ARE RARE, 1667 01:02:26,177 --> 01:02:27,712 AND COULD STILL PLAY A ROLE, 1668 01:02:27,712 --> 01:02:32,316 THERE'S A LOT OF ALLELIC 1669 01:02:32,316 --> 01:02:32,650 HETEROGENEITY. 1670 01:02:32,650 --> 01:02:33,785 , FOR EXAMPLE, IN PARKINSON'S 1671 01:02:33,785 --> 01:02:35,687 DISEASE, IN THE PARKINSON'S 1672 01:02:35,687 --> 01:02:37,355 DISEASE COMMUNITY, WHAT'S BEEN 1673 01:02:37,355 --> 01:02:39,524 SHOWN ON AVERAGE YOU SEE 1674 01:02:39,524 --> 01:02:41,626 ENRICHMENT OF DAMAGING MUTATIONS 1675 01:02:41,626 --> 01:02:43,261 IN PARKINSON'S DISEASE DISEASE, 1676 01:02:43,261 --> 01:02:44,562 IN THE LYSOSOMAL GENES. 1677 01:02:44,562 --> 01:02:47,398 WE SEE IT FOR A FEW OF THE GENES 1678 01:02:47,398 --> 01:02:48,933 BUT GLOBALLY IT JUST HASN'T BEEN 1679 01:02:48,933 --> 01:02:49,367 SIGNIFICANT. 1680 01:02:49,367 --> 01:02:50,501 IT COULD JUST BE BECAUSE IT'S 1681 01:02:50,501 --> 01:02:51,703 TOO RARE. 1682 01:02:51,703 --> 01:02:54,305 THERE'S TOO MUCH ALLELIC 1683 01:02:54,305 --> 01:02:56,174 HETEROGENEITY TO HAVE SUFFICIENT 1684 01:02:56,174 --> 01:02:57,742 POWER, BUT THOSE PATHWAYS ARE 1685 01:02:57,742 --> 01:03:02,680 CERTAINLY IMPORTANT IN LEWY BODY 1686 01:03:02,680 --> 01:03:03,047 DEMENTIA. 1687 01:03:03,047 --> 01:03:04,449 >> I'M BEING TOLD THAT THERE ARE 1688 01:03:04,449 --> 01:03:05,149 OTHER ONLINE QUESTIONS. 1689 01:03:05,149 --> 01:03:07,685 THANK YOU BUT WE DON'T HAVE 1690 01:03:07,685 --> 01:03:11,222 TIME. 1691 01:03:11,222 --> 01:03:14,492 >> I'M SUCH A KILL-JOY IN THIS 1692 01:03:14,492 --> 01:03:14,692 THING. 1693 01:03:14,692 --> 01:03:16,661 SONJA, THANK YOU FOR A WONDERFUL 1694 01:03:16,661 --> 01:03:17,228 LECTURE. 1695 01:03:17,228 --> 01:03:20,064 AND IN FAIRNESS TO OUR 1696 01:03:20,064 --> 01:03:21,899 COLLEAGUES ON VIDEOCAST, WE'RE 1697 01:03:21,899 --> 01:03:24,335 BEYOND THE TOP OF THE HOUR. 1698 01:03:24,335 --> 01:03:27,505 BUT THANK YOU AGAIN. 1699 01:03:27,505 --> 01:03:28,606 JUST A WONDERFULLY LUCID 1700 01:03:28,606 --> 01:03:30,608 PRESENTATION ON A VERY, VERY 1701 01:03:30,608 --> 01:03:30,975 COMPLEX SUBJECT. 1702 01:03:30,975 --> 01:03:33,010 >> THANK YOU SO MUCH FOR HAVING 1703 01:03:33,010 --> 01:03:34,746 ME. 1704 01:03:34,746 --> 01:03:35,012 THANK YOU. 1705 01:03:35,012 --> 01:03:45,012 [APPLAUSE]