Precision Medicine and Dementia

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


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

2.!

2

1.!

1

.!

4 o 3

4 o 3

F i g h

F i g h

CNCN aMC"aMC" ADAD

00-863-895 01-873-114

CNCN aMC"aMC"

P"0 HIam%les @ )$ll =%ectr$mP"0 HIam%les @ )$ll =%ectr$m

1-!92


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4567: F)8 9 :5@=1:

Amyloid 6Pi07 PH/ DifferencesCognitiely Normal s. AD Dementia


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Ne3est "maging Modality

/a$ PH/ scanning


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4567: F)8 9 :567;:1:@

J18)K9/8 PH/ 6891 Min P"7

+hien et al 2 Al-heimer$s Disease 34456, ./0.7 8ia et al Al-heimer$s 9 Dementia, ./0. #in

press'7 :hang et al 2 Al-heimer$s Disease 30;/0, ./0.

FC

6!+ yr7

MC"

6MM=H L 2+7

AD

6MM=H L 217

AD

6MM=H L 7


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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

! y


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:6@1

! y


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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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4567: F)8 9 :5@:=1@5

Mayo Clinic =t$dy of Aging

F*< ! follow*up

2- + 8 1 12 1-

:ct.

)9* Cycle 2

)9* Cycle

Hnrollment

)9* Cycle -

)9* Cycle !Data analysis

Re%lencohort

Re%lencohort

Re%lencohort

Re%lencohort

)9* Cycle +Data analysis

)9* Cycle Data analysis



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4567: F)8 9 :567;:1@:


)9* L follo39$%

2- + 8 1 12 1-

:ct

)9* Cycle 2

)9* Cycle

Hnrollment

)9* Cycle -

nL2

S year olds

211 12 1 1-

nL2

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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Rochester 0rad 0oee

Dae >no%man

Cliff #ac'

Daniel Dr$ach

al 4o3e

0o "ni'

Mary Mach$lda

Michelle Miel'e

Rose$d Roerts

Ealter Rocca=hane Pan'ratz

>eGal >antarci

#oe Parisi

Hric /angalos

#ac'sonilleNeill (raff9Radford

=tee ?o$n'in

Dennis Dic'son

#ohn 4$cas

/anis )erman

Rosa Radema'ers

Nil$fer /aner9Hr'etin

4en Petr$celli

(oG$in 0$

:tto Pedraza

=cottsdaleRic' Caselli

0ryan Eoodr$ff

?onas (eda


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/han' ?o$/han' ?o$


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Precision Medicine and Dementia