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8/9/2019 Precision Medicine and Dementia
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Precision Medicine
Dementia
Precision Medicine
Dementia
Ronald C. Petersen, Ph.D., M.D.
Alzheimer’s Disease Research
Center Mayo Clinic College of Medicine
Rochester, MN
Precision MedicineRochester, MN
May 18, 21!
Ronald C. Petersen, Ph.D., M.D.
Alzheimer’s Disease Research
Center Mayo Clinic College of Medicine
Rochester, MN
Precision MedicineRochester, MN
May 18, 21!
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DisclosuresDisclosures
•
Pfizer, "nc. and #anssen Alzheimer"mm$nothera%y & Chair DMC
• Roche& Cons$ltant
•
Merc', "nc.& Cons$ltant• (enentech& Cons$ltant
• )$nding• National "nstit$te on Aging&
• *1 A(+8+
• P! A(1+!-
• *1 A(118
•
Pfizer, "nc. and #anssen Alzheimer"mm$nothera%y & Chair DMC
• Roche& Cons$ltant
•
Merc', "nc.& Cons$ltant• (enentech& Cons$ltant
• )$nding• National "nstit$te on Aging&
• *1 A(+8+
• P! A(1+!-
• *1 A(118
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/erminology/erminology
• Dementia
• 0iomar'ers
• (enetics• Prediction
• Preention
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DementiaDementia
• Alzheimer’s disease
• )rontotem%oral loar degeneration
• Dementia 3ith 4e3y odies
• Mild cognitie im%airment
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Dementia Dementia
15
AD asc$lar dementiaAD asc$lar dementiaAlzheimer’s
disease 6AD7
Alzheimer’s
disease 6AD7
!5
85
asc$lar dementiaasc$lar dementia
85)ronto9
tem%oraldementia
)ronto9tem%oraldementia
+5
:ther :ther
!5
D40D4015
AD ; dementia 3ith4e3y odies 6D407
AD ; dementia 3ith4e3y odies 6D407
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FTD and PPAGenetics
• The majority of patients with FTD or PPA do
not have any known genetic cause of their illness
• However, some do, and the information that
follows will hopefully help in making decisions
regarding
• Genetic testing to aid in the diagnosis• Genetic testing to aid in future planning• Genetic testing to aid in family planning
• The majority of patients with FTD or PPA do
not have any known genetic cause of their illness
• However, some do, and the information that
follows will hopefully help in making decisions
regarding
• Genetic testing to aid in the diagnosis• Genetic testing to aid in future planning• Genetic testing to aid in family planning
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FTD and PPAGenetics
! affected "y FTD or PPA #or Parkinson$s disease or
A%&'
! affected "y FTD or PPA #or Parkinson$s disease or
A%&'
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FTD and PPAGenetics
&poradic, and pro"a"ly not related to any genetic
mutation
&poradic, and pro"a"ly not related to any genetic
mutation
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FTD and PPAGenetics
(hile there is some ) family history of neurologic
disease, this person pro"a"ly does not have anygenetic cause
(hile there is some ) family history of neurologic
disease, this person pro"a"ly does not have any
genetic cause
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FTD and PPAGenetics
There is ) family history of neurologic disease in one
side of the family affecting multiple first*degree
relatives, so this person is more likely to have a
genetic cause
There is ) family history of neurologic disease in one
side of the family affecting multiple first*degree
relatives, so this person is more likely to have a
genetic cause
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FTD and PPA+linical &yndromes
Corticobasal
Syndrome
svPPASemantic
variant
)/D9Motor
Ne$ron
Disease
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FTD 1otor -euron
Disease"ALS
Progressive
Supranuclear
Palsy
C9ORF72
GRN
FUS
OPTN
PNF1
naPPA
-on%luent"
agrammatic
variant
Corticobasal
Syndrome
svPPA
Semantic
variant
lvPPA
Logopenic
variant
Behavioral
Variant FTD
ALS
C9ORF72
GRN
TARDBP
FUS
VCP
SporadicGRN
C9ORF72
MAPT-unclear
MAPT
GRN
MAPT
C9ORF72
C9ORF 72
GRN
MAPT
VCP
CHMP2B2AD3
GRN
PA0S
Progressive
apra,ia
o% speech
Sporadic
SOD1
TARDBP
UBQLN2
VCP
FTD and PPAGenetic verview
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Alzheimer’s Disease(enetics
Alzheimer’s Disease(enetics
• Deterministic ariants
>no3n genes
?o$ng onset
!5 ris'
• (enes 3ith moderate effects
•(enes that infl$ence leels of %roteins
• 4ate onset @ r$ns in familiesB
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Alzheimer’s DiseaseAlzheimer’s Disease
• *s$ally grad$al memory loss
• :ther cognitie f$nctions im%aired
•4oss of aility to do daily f$nctions
• Pathologically
Pla$es @ amyloid %rotein
/angles @ ta$ %rotein
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CP2+8+-9 1
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CP2+8+-9 2
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CP2+8+-9
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19/7445675 F)8 9 :5:;no%man,($y M. Mc>hann, Reisa A. =%erling, Maria C. Carrillo,
0ill /hies, Creighton F. Phel%s
Al- and Dementia, ./00
Fy%othetical Model of Dynamic 0iomar'ersFy%othetical Model of Dynamic 0iomar'ers
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Fy%othetical Model of Dynamic 0iomar'ersof the Alzheimer’s Pathological Cascade
Fy%othetical Model of Dynamic 0iomar'ersof the Alzheimer’s Pathological Cascade
>ac+ et al? Lancet -eurol 5676
-ormal B
i o m a r + e r m a
g n i t u d e
A /a$9meditated ne$ronal inG$ry and dysf$nction
0rain str$ct$re Abnormal
Clinical disease stage
Cognitively normal C/ Dementia
Memory
Clinical f$nction
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Prealence of Pi0 PH/ in NormalsPrealence of Pi0 PH/ in Normals
Rowe et al: 2010
P r e v a l e n c e ( % )
Age (years)
Prevalence
of pla1uesin H+
~15 yr
Prevalence
of AD
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0iomar'ers for AD0iomar'ers for AD
•Harly iomar'ers
Amyloid de%osition
PH/ imaging
C=) amyloid• 4ater iomar'ers
Ne$rodegeneration
=tr$ct$ral MR")D( PH/
C=) ta$
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Ne$roimaging in ADNe$roimaging in AD
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Ne$roimaging in ADNe$roimaging in AD
• =tr$ct$ral MR"
• )$nctional imaging)D( PH/
• Molec$lar imaging
Amyloid PH/ imaging
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=tr$ct$ral "maging in AD=tr$ct$ral "maging in AD
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=tr$ct$ral MR"& Atro%hy and AD
=tageControl, , ) MC", 2, ) AD, -, )
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4567: F)8 9 :5@=15
MR" (ray Matter DifferencesCognitiely Normal s. AD Dementia
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)$nctional "maging in AD)$nctional "maging in AD
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4567: F)8 9 :5@=1:6
)D( PH/ DifferencesCognitiely Normal s. AD Dementia
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Molec$lar Ne$roimagingMolec$lar Ne$roimaging
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02-155-940 02-310-847 06-209-892
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Ne3est "maging Modality
/a$ PH/ scanning
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Criteria A%%roachCriteria A%%roach
• Clinical criteria
• 0iomar'ers
• Molec$lar ne$ro%athology 6Amyloid7
C=) A0-2Amyloid imaging
• Meas$res of ne$ronal inG$ry
6Ne$rodegeneration7=tr$ct$ral, e.g., MR"
)$nctional, e.g., )D( PH/
C=) ta$
• Clinical criteria
• 0iomar'ers
• Molec$lar ne$ro%athology 6Amyloid7
C=) A0-2Amyloid imaging
• Meas$res of ne$ronal inG$ry
6Ne$rodegeneration7=tr$ct$ral, e.g., MR"
)$nctional, e.g., )D( PH/
C=) ta$
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Mild Cognitie "m%airmentMild Cognitie "m%airment
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Alzheimer’s Disease =%ectr$mAlzheimer’s Disease =%ectr$m
MC" D$e to AD
Preclinical AD
Dementia D$e to AD
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©2012 MFMER | 21!50"#"0
Mild Cognitie "m%airment
Ronald C. Petersen, MD, PhD
N Hngl # Med 211&+-92229-
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:6@1
Case
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:6@1
! y
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:6@1
! y
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:6@1
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:6@1
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©2012 MFMER | 21!50"#"$
MC" D$e to AD
Diagnostic category
0iomar'er%roaility of AD
etiologyA
6PH/ or C=)7Ne$ronal inG$ry6ta$, )D(, sMR"7
MC" *ninformatie Conflicting<indeterminant or $naailale
MC" d$e to AD @intermediateli'elihood
"ntermediate"ntermediate
Positie*ntested
*ntestedPositie
MC" d$e to AD @high li'elihood
Fighest Positie Positie
MC" @ $nli'ely d$e toAD
4o3est Negatie Negatie
Alert et al& 211
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2008
Mayo MCI Subject
!
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5""566; FD' Scan
Parietal temporal hypometabolism
2'lobal FD' AD score o% 77 is abnormal3
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:6@1
Clinical Progression 2 yr later
• (etting lost
• )re$ent forgetting
•Not driing
• Des%ondent
• Needs assistance
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:6@1
!! y
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:6@1
!! yis$al Re%rod$ctions& 2
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2008 (-0.31) 2010 (-0.91)
Mayo MCI Subject
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"7"5676 FD' Scan
Progressive hypometabolism 8atio 76;
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"7"5676 P/B Scan
Progressive
8atio 5
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©2012 MFMER | 21!50"#5!
Dementia D$e to AD
Diagnostic category
0iomar'er%roaility of AD
etiologyA
6PH/ or C=)7Ne$ronal inG$ry6ta$, )D(, sMR"7
Proale ADdementia
*ninformatie<aailale
Conflicting<indeterminant or $naailale
Proale AD 3itheidence of %ath AD "ntermediateFighest QPositie PositiePositie
Possile ADdementia aty%ical3ith %ath
Figh considersecondary
Positie Positie
Dementia $nli'elyAD
4o3est Negatie Negatie
Mc>hann et al& 211
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:6@1
Do the Criteria Eor' in the
(eneral Po%$lationQ
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Mayo Clinic
=t$dy of Aging
Mayo Clinic
=t$dy of Aging
CP12+!-191-
Po%$lation9ased st$dy of !;
628 actie7 nondemented
%ersons age !98 years in:lmsted Co$nty, MN
Po%$lation9ased st$dy of !;
628 actie7 nondemented
%ersons age !98 years in:lmsted Co$nty, MN
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Mayo Clinic =t$dy of Aging
F*< ! follow*up
2- + 8 1 12 1-
:ct.
)9* Cycle 2
)9* Cycle
Hnrollment
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)9* Cycle !Data analysis
Re%lencohort
Re%lencohort
Re%lencohort
Re%lencohort
)9* Cycle +Data analysis
)9* Cycle Data analysis
Mayo Clinic =t$dy of Aging
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)9* L follo39$%
2- + 8 1 12 1-
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)9* Cycle 2
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Hnrollment
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nL2
S year olds
211 12 1 1-
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S! year olds
)9* Cycle !
)9* Cycle +
)9* Cycle
)9* Cycle 2
)9* Cycle
Hnrollment
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Mayo Clinic =t$dy of AgingMayo Clinic =t$dy of Aging
• Rene3ed thro$gh 21
• Contin$ing to recr$it non9dementedTT
98 y
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CP1+-92
Hal$ationHal$ation
N$rse
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Reso$rces Ac$iredReso$rces Ac$ired
•!; non9demented s$Gects
!5 cognitiely normal
2-5 MC"
• ! $antitatie MR" scans
• V ! DNA sam%les
•
V ! frozen %lasma
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Contin$ation of MC=AContin$ation of MC=A
• Add ne3 s$Gects to cohort
• Contin$e ann$al clinical follo39$%s
• Contin$e serial MR"
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C ff
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:6@:;:1
NormalNormal MC"MC" ADAD
Disease9modifying
thera%y
Disease9modifying
thera%y
DiagnosticDiagnostic
CostCost
Cost L A 6$ntreated7Cost L A 6$ntreated7
Cost 0 W XCost 0 W X
Cost 0 ; C W XCost 0 ; C W X
Cost Difference Analysis
6Cost saings L X76Cost saings L X7
6Cost L A76Cost L A7
6Cost L C76Cost L C7
6Cost L 076Cost L 07
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=o, 3here are 3eQ=o, 3here are 3eQ
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"s Precision Medicine Eor'ing in ADQ"s Precision Medicine Eor'ing in ADQ
Criteria gie $s frame3or'
Clinical feat$res %l$s iomar'ers cane $ite acc$rate
0etter in sym%tomatic %hases, MC"and dementia
(enetics direct $s
*ltimately, yes, $t 3or' to do
Mayo Clinic AD ResearchMayo Clinic AD Research
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