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Dementia
Ronald C. Petersen, Ph.D., M.D.
Alzheimers Disease Research
Center
Mayo Clinic College of Medicine
Rochester, MN
Precision Medicine
Rochester, MN
May 18, 2015
Disclosures
Pfizer, Inc. and Janssen Alzheimer
Immunotherapy : Chair DMC
Roche: Consultant
Merck, Inc.: Consultant
Genentech: Consultant
Funding
National
National Institute
Institute on Aging:
U01
U01 AG006786
AG006786
P50
P50 AG016574
AG016574
U01
U01 AG011378
AG011378
Terminology
Dementia
Biomarkers
Genetics
Prediction
Prevention
Dementia
Alzheimers disease
Frontotemporal lobar degeneration
Dementia with Lewy bodies
Mild cognitive impairment
Dementia
Alzheimers
disease (AD)
AD vascular dementia
10%
8%
Vascular
dementia
8%
53%
Frontotemporal
dementia
6%
5%
10%
Other
DLB
AD + dementia with
Lewy bodies (DLB)
PAOS
Progressive
apraxia
of speech
Behavioral
Variant FTD
FTD-Motor
Neuron
Disease/ALS
Decreased
comprehensio
Segmenting
n
slow speech
& recognition
Sound
of objects
distortions
& people
Cognitive loss
Disinhibition
Inflexibility
Decreased
insight
Cognitive loss
Behavior impairment
Motor symptoms
ALS
svPPA
Semantic
variant
Motor symptoms
Upper and/or lower
Motor neuron pathways
naPPA
Nonfluent/
agrammatic
variant
lvPPA
Logopenic
variant
Grammar errors
Short phrases
Haulting
Spontaneous but
speech
slow speech
Corticobasal
output
Syndrome
Word retrieval
problems
Cognitive loss
Behavioral impairment
Asymmetric rigidity
Apraxia
Eye movement
Disturbances, falls,
parkinsonism
Progressive
Supranuclear
Palsy
Behavioral
Variant FTD
C9ORF72
GRN
TARDBP
FUS
VCP
ALS
C9ORF72
GRN
FUS
OPTN
PNF1
PAOS
Progressive
apraxia
of speech
C9ORF72
GRN
MAPT
VCP
CHMP2B
SOD1
TARDBP
UBQLN2
VCP
Sporadic
svPPA
Semantic
variant
Sporadic
naPPA
Nonfluent/
agrammatic
variant
GRN
C9ORF72
MAPT-unclear
lvPPA
Logopenic
variant
(AD)
GRN
GRN
MAPT
C9ORF72
MAPT
Corticobasal
Syndrome
Progressive
Supranuclear
Palsy
Alzheimers Disease
Alzheimers Disease
Genetics
Deterministic variants
Known genes
Young onset
50% risk
Alzheimers Disease
CP926864- 31
CP926864- 29
CP926864- 30
Biomarker magnitude
Abnormal
A
Tau-meditated neuronal injury and dysfunction
Brain structure
Memory
Clinical function
Normal
Cognitively normal
MCI
Dementia
Prevalence (%)
Prevalence
of plaques
in HC
~15 yr
Prevalence
of AD
Age (years)
Rowe et al: 2010
Biomarkers for AD
Early biomarkers
Amyloid deposition
PET imaging
CSF amyloid
Later biomarkers
Neurodegeneration
Structural MRI
FDG PET
CSF tau
Neuroimaging in AD
Neuroimaging in AD
Structural MRI
Functional imaging
FDG PET
Molecular imaging
Amyloid PET imaging
Structural Imaging in AD
MCI, 72, F
AD, 74, F
Functional Imaging in AD
Molecular Neuroimaging
PIB Idealized
CN
aMCI
AD
3
2.5
2
00-863-895
02-310-847
06-209-892
1.5
1
0.5
0
Low
CN
00-863-895
High
CN
02-155-940
aMCI
3
2.5
2
1.5
1
0.5
0
01-873-114
aMCI
02-310-847
AD
06-209-892
3001475-2
HC
(56 yr)
MCI
(MMSE = 26)
AD
(MMSE = 21)
AD
(MMSE = 7)
Chien et al: J Alzheimers Disease 34:457, 2012; Xia et al: Alzheimers & Dementia, 2012 (in
press); Zhang et al: J Alzheimers Disease 31:601, 2012
2013 MFMER | 3270183-36
Criteria Approach
Clinical criteria
Biomarkers
Molecular neuropathology (Amyloid)
CSF AB42
Amyloid imaging
MCI Due to AD
Dementia Due to AD
Case
3047674-4
53 y/o woman
3047674-4
53 y/o woman
3047674-4
53 y/o woman
STMS: 37/38
VIQ: 107, PIQ: 97
Attention/Executive
Trails A and B: 50th %ile
Stroop: 50th %ile
Language
Fluency: 90th %ile
BNT: 59/60
3047674-4
53 y/o woman
Visuospatial
Rey O copy: 50th %ile
JLO: 50th %ile
Memory
Logical Memory: 17/10
Visual Reproductions: 64/21
AVLT: 7,6,11,10,8; DR 3
3047674-4
MCI Due to AD
Diagnostic category
MCI
Biomarker
probability of AD
etiology
Uninformative
A
(PET or CSF)
Neuronal injury
(tau, FDG, sMRI)
Conflicting/
indeterminant or unavailable
MCI due to AD
intermediate
likelihood
Intermediate
Intermediate
Positive
Untested
Untested
Positive
MCI due to AD
high likelihood
Highest
Positive
Positive
Lowest
Negative
Negative
2008
MCI Due to AD
Diagnostic category
MCI
Biomarker
probability of AD
etiology
Uninformative
A
(PET or CSF)
Neuronal injury
(tau, FDG, sMRI)
Conflicting/
indeterminant or unavailable
MCI due to AD
intermediate
likelihood
Intermediate
Intermediate
Positive
Untested
Untested
Positive
MCI due to AD
high likelihood
Highest
Positive
Positive
Lowest
Negative
Negative
Getting lost
Frequent forgetting
Not driving
Despondent
Needs assistance
3047674-5
55 y/o woman
STMS: 32/38
VIQ: 107, PIQ: 97
Attention/Executive
Trails A and B: 25th %ile
Stroop: 30th %ile
Language
Fluency: 60th %ile
BNT: 50/60
3047674-5
55 y/o woman
Visuospatial
Rey O copy: 30th %ile
JLO: 25th %ile
Memory
Logical Memory: 12/5
Visual Reproductions: 32/15
AVLT: 3,4,3,5,4; DR 0
3047674-5
2008 (-0.31)
2010 (-0.91)
Dementia Due to AD
Diagnostic category
Probable AD
dementia
Probable AD with
evidence of path AD
Biomarker
probability of AD
etiology
Uninformative/
available
A
(PET or CSF)
Neuronal injury
(tau, FDG, sMRI)
Conflicting/
indeterminant or unavailable
Intermediate
Highest
?
Positive
Positive
Positive
Possible AD
dementia atypical
with path
High consider
secondary
Positive
Positive
Dementia unlikely
AD
Lowest
Negative
Negative
3047674-6
Mayo Clinic
Study of Aging
Population-based study of 5000+
(2800 active) nondemented
persons age 50-89 years in
Olmsted County, MN
CP1265413-14
06
08
10
14
12
Oct.
Enrollment
F-U Cycle 2
F-U Cycle 3
F-U Cycle 4
F-U Cycle 5
Data analysis
F-U Cycle 6
Data analysis
Replen
cohort
Replen
cohort
Replen
cohort
Replen
cohort
F-U Cycle 7
Data analysis
F-U = follow-up
2013 MFMER | 3263944-62
06
08
10
14
12
Oct
Enrollment
F-U Cycle 2
F-U Cycle 3
F-U Cycle 4
F-U Cycle 5
F-U Cycle 6
n=2000
F-U Cycle 7
50 year olds
2011
12
13
14
Enrollment
F-U Cycle 2
n=2000
F-U Cycle 3
F-U = follow-up
2013 MFMER | 3270183-63
Evaluation
Consent
Consent form
form
Blood
Blood draw
draw
Clinical
Clinical evaluation
evaluation
Nurse/SC
Nurse/SC interview
interview
Neurological
Neurological evaluation
evaluation
Participant
Participant
Family
Family history
history
Current
medications
Current medications
Demographic
Demographic information
information
Memory
Memory &
& orientation
orientation
Medical
Medical history
history &
&
risk
assessment
risk assessment
Neuropsychiatric
Neuropsychiatric inventory
inventory
Study
Study partner
partner
Clinical
dementia
Clinical dementia rating
rating
Functional
Functional
assessment
assessment (FAQ)
(FAQ)
Neurological
Neurological history
history
Short
Short test
test of
of mental
mental status
status
Modified
Hachinski
scale
Modified Hachinski scale
Prime
Prime MD
MD (physician
(physician form)
form)
Neurological
Neurological examination
examination
and
and modified
modified UPDRS
UPDRS
Consensus
Consensus conference
conference
Cognitive
Cognitive assessment
assessment
Memory
Memory
Logical
Logical memory
memory (delayed)
(delayed)
Visual
Visual reprod
reprod (delayed)
(delayed)
AVLT
AVLT
Executive
Executive function
function
Trails
A
Trails A &
&B
B
Digit
symbol
substitution
Digit symbol substitution
Visuospatial
Visuospatial
Picture
Picture completion
completion
Block
Block design
design
Language
Language
Boston
Boston naming
naming test
test
Category
Category fluency
fluency
CP1333643-2
Resources Acquired
Continuation of MCSA
DiseaseDiseasemodifying
modifying
therapy
therapy
(Cost
(Cost savings
savings == X)
X)
Diagnostic
Diagnostic
Cost
(Cost
(Cost == B)
B)
(Cost
(Cost == C)
C)
Normal
MCI
AD
3046383-6
Jacksonville
Brad Boeve
Neill Graff-Radford
Dave Knopman
Steve Younkin
Cliff Jack
Dennis Dickson
Daniel Drubach
John Lucas
Val Lowe
Tanis Ferman
Bob Ivnik
Rosa Rademakers
Mary Machulda
Nilufer Taner-Erketin
Michelle Mielke
Len Petrucelli
Rosebud Roberts
Gojuin Bu
Walter Rocca
Otto Pedraza
Shane Pankratz
Scottsdale
Kejal Kantarci
Joe Parisi
Eric Tangalos
Rick Caselli
Bryan Woodruff
Yonas Geda
Thank You