MCI Petersen Miami Final

8/13/2019 MCI Petersen Miami Final

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Imaging Biomarkers inPredicting MCI and Dementia

Ronald C. Petersen, Ph.D., M.D.

Alzheimers Disease Research

Center

Mayo Clinic College of Medicine

Rochester, MN

Mild Cognitive Impairment Symposium

Miami

January 18, 2014


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Disclosures

Pfizer, Inc. and Janssen AlzheimerImmunotherapy : Chair DMC

Roche: Consultant

Merck: Consultant

Funding National Institute on Aging:

U01 AG006786 P50 AG016574 U01 AG011378


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2012 MFMER | 3238583-3

Introduction to the Recommendationsfrom the National Institute on

Aging-Alzheimers Association

Workgroups on Diagnostic Guidelinesfor Alzheimers Disease

Clifford R. Jack, Jr, Marilyn S. Albert, David S. Knopman,Guy M. McKhann, Reisa A. Sperling, Maria C. Carrillo,

Bill Thies, Creighton H. Phelps

Alz and Dementia, 2011


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ypo e ca o e o ynam c omar ersof the Alzheimers Pathological Cascade

Jack et al: Lancet Neurol 2010

NormalB

iomarkerma

gnitude

ATau-meditated neuronal injury and dysfunctionBrain structureAbnormal

Clinical disease stage

Cognitively normal MCI Dementia

Memory

Clinical function


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Criteria Approach

Clinical criteria

Biomarkers

Molecular neuropathology

CSF AB42Amyloid imaging

Measures of neuronal injuryStructural, e.g., MRI

Functional, e.g., FDG PET

CSF tau


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Alzheimers Disease Spectrum

MCI Due to AD

Preclinical AD

Dementia Due to AD


7/602012 MFMER | 3238583-7

The Diagnosis of DementiaDue to Alzheimers Disease:

Recommendations from the National Institute onAging-Alzheimers Association Workgroups on

Diagnostic Guidelines for Alzheimers Disease

Guy M. McKhann, David S. Knopman, Howard Chertkow,Bradley T. Hyman, Clifford R. Jack, Jr, Claudia H. Kawas,William E. Klunk, Walter J. Koroshetz, Jennifer J. Manly,

Richard Mayeux, Richard C. Mohs, John C. Morris,

Martin N. Rossor, Philip Scheltens, Maria C. Carrillo, Bill Theis,Sandra Weintraub, Creighton H. Phelps



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Dementia Due to AD

Diagnostic category

Biomarkerprobability of AD

etiologyA

(PET or CSF)Neuronal injury(tau, FDG, sMRI)

Probable ADdementia

Uninformative/available

Conflicting/indeterminant or unavailable

Probable AD withevidence of path AD

IntermediateHighest

?Positive

PositivePositive

Possible ADdementia atypicalwith path

High considersecondary

Positive Positive

Dementia unlikelyAD

Lowest Negative Negative

McKhann et al: 2011


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MCI Due to AD

Preclinical AD

Dementia Due to AD


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The Diagnosis of Mild CognitiveImpairment Due to Alzheimers Disease:Recommendations from the National Institute on

Aging-Alzheimers Association Workgroups onDiagnostic Guidelines for Alzheimers Disease

Marilyn S. Albert, Steven T. DeKosky, Dennis Dickson, Bruno Dubois,Howard H. Feldman, Nick C. Fox, Anthony Gamst, David M.

Holtzman, William J. Jagust, Ronald C. Petersen, Peter J. Snyder,

Maria C. Carrillo, Bill Thies, Creighton H. Phelps



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MCI Due to AD

Diagnostic category

Biomarkerprobability of AD

etiologyA

(PET or CSF)Neuronal injury(tau, FDG, sMRI)

MCI Uninformative Conflicting/indeterminant or unavailable

MCI due to ADintermediatelikelihood

IntermediateIntermediate

PositiveUntested

UntestedPositive

MCI due to ADhigh likelihood

Highest Positive Positive

MCIunlikely dueto AD

Lowest Negative Negative

Albert et al: 2011


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MCI Due to AD

Preclinical AD

Dementia Due to AD


13/602012 MFMER | 3238583-13

Toward Defining the PreclinicalStages of Alzheimers Disease:

Recommendations from the National Institute onAging-Alzheimers Association Workgroups on

Diagnostic Guidelines for Alzheimers Disease

Reisa A. Sperling, Paul S. Aisen, Laurel A. Beckett, David A. Bennett,Suzanne Craft, Anne M. Fagan, Takeshi Iwatsubo, Clifford R. Jack, Jr,

Jeffrey Kaye, Thomas J. Montine, Denise C. Park, Eric M. Reiman,Christopher C. Rowe, Eric Siemers, Yaakov Stern, Kristine Yaffe,

Maria C. Carrillo, Bill Thies, Marcelle Morrison-Bogorad,Molly V. Wagster, Creighton H. Phelps



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Preclinical AD

Diagnosticcategory

A(PET or CSF) Neuronal injury Clinical

Stage 1 Positive Negative Negative

Stage 2 Positive Positive Negative

Stage 3 Positive Positive Positive

Stage 0 Negative Negative Negative

Sperling et al: 2011


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Preclinical Stage1 2 3

NIA-AA Preclinical AD Staging in Relation toOur Hypothetical Model of Biomarkers

NormalB

iomarkerma

gnitude

A Neuronalinjury Cognitivesymptoms

Abnormal



Cut points

0


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Do the Criteria Work?

Mayo Clinic Study of Aging (MCSA)


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Mayo Olmsted County

Study of Aging

(U01 AG006786)

CP1265413-14


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Mayo Clinic

Study of Aging

CP1265413-14

Population-based study of 3000-

4000 nondemented persons age

50-89 years in Olmsted County, MN


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Mayo Clinic Study of Aging

F-U = follow-up

2004 06 08 10 12 14

Oct.

F-U Cycle 2

F-U Cycle 3

Enrollment

F-U Cycle 4

F-U Cycle 5Data analysis

Replencohort

Replencohort

Replencohort

Replencohort




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F-U = follow-up

2004 06 08 10 12 14

Oct

F-U Cycle 2

F-U Cycle 3

Enrollment

F-U Cycle 4

n=2000

70 year olds

2011 12 13 14

n=2000

50 year olds

F-U Cycle 5

F-U Cycle 6

F-U Cycle 7

F-U Cycle 2

F-U Cycle 3

Enrollment


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CP1333643-2

Evaluation

Nurse/SC interview

ParticipantFamily history

Current medicationsDemographic information

Memory & orientationMedical history &risk assessment

Neuropsychiatric inventoryStudy partner

Clinical dementia ratingFunctional

assessment (FAQ)

Consent form

Blood draw

Clinical evaluation

Neurological evaluation

Consensus conference

Neurological history

Short test of mental status

Modified Hachinski scale

Prime MD (physician form)

Neurological examinationand modified UPDRS

Cognitive assessment

MemoryLogical memory (delayed)

Visual reprod (delayed)AVLT

Executive functionTrails A & B

Digit symbol substitution

VisuospatialPicture completion

Block designLanguage

Boston naming testCategory fluency


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Resources Acquired

4000 non-demented subjects3000 cognitively normal

800 MCI

2500 quantitative MRI scans

~ 4000 DNA samples

~ 4000 frozen plasma/serum samplesplus annual samples

Clinical and performance measures


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Extension of MCSA

Add new subjects older cohort

Add 1000+ subjects younger cohort

Continue annual clinical follow-ups

Continue serial MRI scans Collect annual plasma/serum

Perform 800 CSFs Perform 1200 FDG-PET scans

Perform 1200 PiB PET scans


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So, How Do the Criteria Fare inthe General Population?


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MCI Due to AD


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Assessing Biomarkers in theCommunity

Biomarker negativeAmyloid neg

FDG PET/MRI neg

Amyloid positive Neurodeg negAmyloid pos

FDG PET/MRI neg

Amyloid pos Neurodeg posAmyloid pos

FDG PET/MRI pos

Neurodegen onlyAmyloid neg

FDG PET/MRI pos


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2013 MFMER | 3270183-27

All MCI MCSAPopulation Frequencies

0

10

20

30

40

50

Petersen et al: Ann Neuro, 2013

%

Biomneg

Amyloidonly

Amyloid +neurodeg

Neurodegonly

sNAP


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MCSA aMCIAnnual Rates of Change

Petersen et al: Ann Neuro, 2013

NL

MCI

Biom

neg

Dementia

42%

50% 8%NL

MCI

Amyloid

positive

Dementia

64%

36% 0%

NL

MCI

Amyloid

+

Neurodegen

Dementia

78%

5% 17%NL

MCI

Neurodegen

only

(sNAP)

Dementia

42%

36% 22%


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2014 MFMER | 3320580-29

0

20

40

60

80

100

0 2 4 6 8

Risk of Dementia FollowingReversion to Normal

Years of follow-up

Cumulativein

cidence

ofdementia(%)

MCI with reversion vs normalHR = 6.6; P


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2013 MFMER | 3270183-30

aMCI

0

10

20

30

40

50

60

Petersen et al: Ann Neuro , 2013

MCSA

ADNI

%

Biomneg

Amyloidonly

Amyloid +neurodeg

Degenerativeonly


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Preclinical AD


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Preclinical AD

Diagnosticcategory

A(PET or

CSF)Neuronal

injury Clinical

Stage 1 Positive Negative Negative

Stage 2 Positive Positive Negative

Stage 3 Positive Positive Positive

Stage 0 Negative Negative Negative

Sperling et al: 2011


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Pre-clinical NormalPopulation Frequencies

Jack et al., Ann Neurol, 2012

%


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NIA-AA Preclinical AD Stagingin Relation to Our Hypothetical Model

of BiomarkersPreclinical Stage

1 2 3

Normal

Biomarkermagnitude

A Neuronalinjury

Cognitivesymptoms

Abnormal



Cut points

0

43% 16% 12% 3%

Jack et al: Lancet Neuro, 2010


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2014 MFMER | 3320580-35

Preclinical Alzheimers Diseaseand Its Outcome

A Longitudinal Cohort Study

Stephanie J. B. Vos; Chengjie Xiong; Pieter Jelle Visser;

Mateusz S. Jasielec; Jason Hassenstab;Elizabeth A. Grant; Nigel J. Cairns; John C. Morris;David M. Holtzman; Anne M. Fagan

Lancet Neurology 12:957, Oct 2013


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2014 MFMER | 3320580-36

Lancet Neurology 12:957, Oct 2013

Preclinical Alzheimers Disease

and Its Outcome:A Longitudinal Cohort Study


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2014 MFMER | 3320580-37

Pre-Clinical AD StagesNeuroimaging vs CSF

0

10

20

30

40

50Jack et al: MCSA, 2012

%

Vos et al: 2013

Stage 0 Stage 1 Stage 2 Stage 3 SNAP Uncl

Petersen, L Neur 2013


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Stage 0 Stage 1 Stage 2 Stage 3 SNAP0

10

20

30

40

50

%

2012 MFMER | 3205603-38

Preclinical Progression to MCI/DementiaMayo Clinic Study of Aging

Knopman et al., 2012


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2013 MFMER | 3309417-39

0.0

0.2

0.4

0.6

0.8

1.0

0 2 4 6 8 10 12 14

Progression to CDR >/= 0.5by Preclinical Alzheimers Disease Stage

Vos et al: Lancet Neurol 12:957, 2013

Follow-up (years)

NormalStage 1

Stage 2

Stage 3

SNAP Group

Cumulativei

ncidence

probab

ility

St 3

St 2

St 1

SNAPNL


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Amyloid-first and Neurodegeneration-first Profiles Characterize Incident

Amyloid PET Positivity

Clifford R. Jack, Jr., Heather J. Wiste, Stephen D.Weigand, David S. Knopman, Val Lowe, Prashanthi

Vemuri, Michelle M. Mielke, David T. Jones, Matthew L.Senjem, Jeffrey L. Gunther, Brian E. Gregg, Vernon S.

Pankratz, Ronald C. Petersen

Neurology, 2013; 81: 1732-1740


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Figure 1. Flow chart.

The CN groups in blue are the focus of this paper.


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Jack et al, Neurology, 2013


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2013 MFMER | 3266631-43

Changes in Imaging and ClinicalMeasures By Amyloid Status


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2013 MFMER | 3263944-44


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2013 MFMER | 3266631-45

Figure 1.

Linear trend of performance on the verbal memory composite (A) and the visual memory

composite (B) for HA-A, HA-A+, MCI-A, MCI-A+, and AD-A+ groups, from baseline

to 36 months.

Lim YY et al, Brain 2013.


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2013 MFMER | 3266631-46


Role of amyloid status in progressionfrom healthy control to MCI in the

general population

Role of Amyloid in Predicting


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2013 MFMER | 3266631-47

Role of Amyloid in PredictingProgression in Imaging and Cognitive

Biomarkers

Amyloid positive vs. amyloid negative

Imaging biomarkers

PiB PET

FDG PET

MR ventricular volume

Cognitive measures

Global 4 cognitive domains


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BASELINECHARACTERISTICSOFSUBJECTSWITHSERIALDATACharacteristic Serial Cognitive Data

(n = 484)Serial Imaging Scans

(n = 200)Age, years, median (IQR) 78 (75, 82) 78 (75, 82)Male, no. (%) 269 (56) 121 (60)APOE e4 carrier, no (%) 120 (25) 57 (28)Education, years, median (IQR) 14 (12, 16) 14 (12, 16)Short Test Score, median (IQR) 35 (34, 37) 35 (33, 37)Cognitive domain z-scores, median (IQR)

Global 0.75 (0.16, 1.25) 0.71 (0.13, 1.23)Memory 0.70 (0.02, 1.38) 0.70 (-0.04, 1.32)Language 0.50 (-0.02, 1.02) 0.47 (-0.04, 0.99)Attention 0.59 (-0.00, 1.11) 0.59 (0.02, 0.99)Visuospatial 0.64 (0.02, 1.22) 0.61 (0.00, 1.20)

PIB ratio, median (IQR) 1.38 (1.31, 1.63) 1.38 (1.30, 1.61)FDG ratio, median (IQR) 1.40 (1.30, 1.50) 1.40 (1.30, 1.50)Hippocampal volume, cm3, median (IQR) 7.0 (6.4, 7.5) 7.0 (6.4, 7.5)Hippocampal volume/TIV, median (IQR) 0.47 (0.43, 0.52) 0.47 (0.42, 0.52)Number of follow-up visits, %

1 261 (54) 171 (86)2 181 (37) 28 (14)3 29 (6) 1 (0)4 10 (2) 0 (0)5 3 (1) 0 (0)


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2014 MFMER | 3320580-49

0.0 0.5 1.0 1.5 2.0

Change in STMS by PiB Over Time

Time (years)

ShortTestof

Mental

Status

2.92.7

2.5

2.3

2.1

1.9

1.7

1.5

1.3

Age=75, PIB-Age=75, PIB+


PIB, P=0.002


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2014 MFMER | 3320580-50

0.0 0.5 1.0 1.5 2.0

Change in Global Cognition by PiB OverTime

Time (years)

Globalz-s

core



PIB, P=0.02

0.0

-0.5

1.0

0.5

1.5

2.0


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2014 MFMER | 3320580-51

0.0 0.5 1.0 1.5 2.0

Change in Attention by PiB Over Time

Time (years)

Attentionz-score



PIB, P=0.005

0.0

-0.5

1.0

0.5

1.5

2.0

ApoE and PiB


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2014 MFMER | 3320473-52

Annual change

APOE4+, PIB+

APOE4+, PIB-

APOE4-, PIB+

APOE4-, PIB-

ApoE and PiBCognitive Measures

Global z-score Attention z-score Short Test MentalStatus

-0.1 0.0 0.1 -0.1 0.0 0.1 -1.0 -0.5 0.0 0.5


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2014 MFMER | 3320580-53

0.0 0.5 1.0 1.5 2.0

Change in PiB Levels by PiB Over Time

Time (years)

PiBratio

2.92.7

2.5

2.3

2.1

1.9

1.7

1.5

1.3



PIB, P0.001


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2014 MFMER | 3320580-54

0.0 0.5 1.0 1.5 2.0

Change in Ventricular Volume by PiBOver Time

Time (years)

Ventricularvolume(cm3)

40



PIB, P=0.001

30

60

50

ApoE and PiB


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2014 MFMER | 3320473-55

Annual change

APOE4+, PIB+

APOE4+, PIB-

APOE4-, PIB+

APOE4-, PIB-

ApoE and PiBImaging Biomarkers

PIB Ventricular volume

0.01 0.01 0.03 00.05 1 2 3 4


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2014 MFMER | 3320473-56

Education, PBI by ApoE Interaction andHippocampal Volume

0 1 2 3 4 5 6

Hazard ratio

Education (12 vs 16 yr)

Among ApoE4 - / PIB +

Among ApoE4+ / PIB +

PIB + ApoE4 + vs PiBApoE4-

Among PiB + APOE4 +

Among PiB - APOE4+

HV/TIV (P25 vs P75)

Evolving Field on Biomarkers


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Evolving Field on Biomarkers

Pre-clinical

Amyloid alone slow progressionAmyloid plus neurodegeneration

Amyloid plus ApoE4 additive

MCIAmyloid alone slow progression

Amyloid plus neurodegeneration

Mayo Clinic AD Research


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y

RochesterBrad Boeve

Dave Knopman

Cliff Jack

Val Lowe

Bob Ivnik

Mary MachuldaMichelle Mielke

Rosebud Roberts

Walter Rocca

Shane PankratzJenny Whitwell

Kejal Kantarci

Joe Parisi

Eric Tangalos

JacksonvilleNeill Graff-Radford

Steve Younkin

Dennis Dickson

John Lucas

Tanis Ferman

Rosa RademakersNilufer Taner-Erketin

Len Petrucelli

Guojin Bu

Otto Pedraza

ScottsdaleRick Caselli

Bryan Woodruff

Yonas Geda


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Thank You


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Documents

MCI Petersen Miami Final