Population-based
Neuropathology:
classification of disease
biomarker
discovery tool
Thomas J. Montine, MD, PhD
Alvord Professor and Chair
Department of Pathology
University of Washington
Disclosures:
Consultant to: Eisai, Amgen, BMS
No off-label medications
No medical devices
Neuropathology of Dementia
Risk of disease vs. Actual disease
Extent vs. Causes of functional impairment
Classification of Disease
Risk
Genetics
Previous life events
Likelihood of initiation or progression
disease in the future.
Clinical Data
Actual
degree & character of
functional impairment
Mild
Dementia or
Impairment Parkinsonian
Normal
Laboratory Data
disease type &
burden
Chronic Disease
Model
“Laboratory data”
None
+
++
+++
No
Disease
Latency
Prodrome
Full
Expression
can be neuropath, lab med, and neuroimaging
“Clinical data” can be signs, symptoms, and neuropsych findings
Neuropathology of Dementia
Chronic disease model of dementia
Classification of Disease
Aging, Genetics, Environment
Injury &
Response
to Injury
AD AD
≈45%
VBIVBI
≈33%
LBDLBD
≈10%
Proteinopathy
Mito Stress
COGNITIVELY
NORMAL
Glial activation
Etc.
LATENT DISEASE
Repair &
Functional
Compensation
P
R
O
D
R
O
M
E
D
E
M
E
N
T
I
A
Neuropathology of Dementia
Dementia stage
Classification of Disease
Neuropathology of Dementia
Chronic disease model of dementia
Aging, Genetics, Environment
Injury &
Response
to Injury
AD AD
≈45%
VBIVBI
≈33%
LBDLBD
≈10%
Proteinopathy
Mito Stress
COGNITIVELY
NORMAL
Glial activation
Etc.
LATENT DISEASE
Repair &
Functional
Compensation
P
R
O
D
R
O
M
E
D
E
M
E
N
T
I
A
Neuropathology of Dementia
ACT
Aging, Genetics, Environment
HAAS
Nun Study
Injury &
OBAS
Cumulative
Relative Frequency
1.00
AD AD
≈45%
0.75
P
Response
R
to Injury
O
D
R
RepairCN
&
O
Functional
LCF M
Compensation
E
Dementia
Proteinopathy
Mito Stress
COGNITIVELY
NORMAL
Glial activation
Etc.
0.50
VBIVBI
≈33%
0.25
LBDLBD
≈10%
0.00
Chronic disease model of dementia
LATENT DISEASE
0
1
2
3
4
5
6
7
8
Summary Neuropathology Score
D
E
M
E
N
T
I
A
9
Neuropathology of Dementia
Summary
Classification of Disease
Aging, Genetics, Environment
P
R
O
Proteinopathy
D
Mito Stress
VBIVBI
≈33% COGNITIVELY
NORMAL
Glial activation
R
Etc.
Repair &
O
Functional
3 chronic diseases account for vast majority Compensaof dementia M
LBD
LBD
≈10% convergence at all stages of impairment
Idiosyncratic
tion
E
LATENT DISEASE
Progressive aggregate disease vs. functional impairment
Apparent resilience and hightened vulnerability
AD AD
≈45%
•
•
•
•
Injury &
Response
to Injury
D
E
M
E
N
T
I
A
and of
hippocampal
sclerosis (HS) as designated. We recommend that enumeration of
Neuropathology
Dementia
microvascular lesions (MVLs)
for clinico-pathologic
correlations
of cognitive
impairment
2012
NIA-AA revised
Guidelines
for Neuropath
Evaluation
andDisease
dementia be limited to the six regions shaded green. Other lesions should be
Classification of
sampled as appropriate.
AD Neuropathologic Change
Region
A
B
C
Stain for
Stain for
Stain for
A! /amyloid
NFTs
NPs [41]
plaques [57]
[14,15]
Medulla including DMV
Pons including LC
3º: if 2º is +
Midbrain including SN
Cerebellar cortex and dentate n.
Thalamus and subthalamic n.
Hippocampus and EC
H&E
1º: IHC or H&E
3
1º: IHC or H&E
3
1º: IHC or H&E
3
VBI
VBI
MVL
2º: if 1° is +
Consider
4
MVL
1
1
2º: if 1º is +
2
Yes
Consider
4
2º: IHC in at least
HS
one if 1º +
VBI
1º: IHC
1
Superior & middle temporal gyri
Inferior parietal lobule
VBI
VBI
Amygdala
1
Occipital cortex (BA 17 & 18)
WM at ACA, MCA, and PCA
watershed
Stain for LBs
3º: if 2º is +
Cingulate, anterior
Middle frontal gyrus
VBI & HS
1
Basal ganglia at level of AC with
basal nucleus of Meynert
LBD
1
1
1º
2
1º
2
1º
2
Consider
4
Yes
Yes
Yes
Yes
Yes
Yes
Yes
Consider
3
2º: IHC in at least
one if 1º +
4
VBI
MVL
MVL
MVL
MVL
Consider
4
Table 3. “ABC”
for Level
of AD Neuropathologic
Change. AD
Table 2.Score
“ABC” Score
for AD Neuropathologic
Change
“A”
Thalchange
Phase for is evaluated
“B”
Braak
and an
Braak
neuritic
neuropathologic
with
“ABC”“C”scoreCERAD
(Table
2): A! /amyloid
NFT Stage [14,15]
A! plaques [57]
plaque score [41]
plaques (A), NFT stage (B), and neuritic plaque score (C). The combination of A,
0
0
0
None
0
None
B, and C scores
is1 or
designated
“Low”,
Intermediate”
or “High” AD
1
2
1 as “Not”,I or
II
1
Sparse
2
3
2
III or
2 neuropathologic
Moderate
neuropathologic
change.
“Intermediate”
orIV“High” AD
change
3
4 or 5
3
V or VI
3
Frequent
(black background) is considered sufficient explanation for dementia.
B1
AD Neuropathologic Change
A2
C3
0 or 1
2
3
0
0
Not4
Not4
Not4
0 or 1
Low
Low
Low5
2 or 37
Low
Intermediate
Intermediate5
Any C
Low6
Intermediate
Intermediate5
0 or 1
Low6
Intermediate
Intermediate5
2 or 3
Low6
Intermediate
High
1
2
3
Neuropathology of Dementia
2012 NIA-AA revised Guidelines for Neuropath Evaluation
Classification of Disease
Isssue
1997
2012
Clinical Dx of dementia
required for NP Dx of AD
Yes
No
NP assessment based on
Braak for NFTs & CERAD
for Neuritic plaques
These plus Thal phase for
Ab regional accumulation
NP assessment of commonly
co-morbid diseases
Little guidance
Explicit
Minimum regions to sample
and stains to be used
Silent
Explicit
Reporting and CPC
Silent
Guidelines
Neuropathology of Dementia
Biomarkers
CSF tau and Ab42
Volunteers for lumbar puncture: OHSU, UCSD, & UW ADC
Spectrum of Normal Cognition to Dementia
Clinical Lab evidence for AD is rare in cognitively
normal volunteers younger than 50 yr-old
≈ 20% of cognitively normal volunteers > 50 yrold have laboratory evidence of AD
• Have poorer cognitive function at baseline
• Have much greater risk of converting to MCI
or AD in next 3 to 4 years
LP within 3 wk of
cognitive testing
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Time (min)
Discovery Tool
Histelide
• Molecular-specific regional quantification
• IHC
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Neuropathology of Dementia
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Neuropathology of Dementia
Histelide
• Molecular-specific
regional quantification
P #"
• IHC
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Discovery Tool
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G9#
0.6
0.4
0.2
0.0
0.6
0.4
0.2
0.0
Control
AD
: ; <(<<<>#
0.8
0.6
0.4
: ; <(<=#
0.2
0.0
Braak Stage
VVI
0.8
SIGM (Absorbance/cm2)
^#"
SIGM (Absorbance/cm2)
: ;Braak
<(<<<>#Stage
V-VI
II I
-I
V
III-IV
I- I
I
I-II
ne
None
#"
No
SIGM (Absorbance/cm2)
0.8
Neuropathology of Dementia
Discovery Tool
MFG PHF-tau
2.0
Histelide
• Molecular-specific regional quantification
• IHC
PHF-tau Not Dementia (n = 161)
PHF-tau Dementia (n = 176)
1.5
1.0
0.5
0.0
0.0
0.5
1.0
1.5
MFG Abeta42
2.0
2.5
Neuropathology of Dementia
Histelide
• Molecular-specific regional quantification
• IHC
Discovery Tool
Abeta42 Dementia
PHF-tau Dementia
Abeta42 Not Dementia
PHF-tau Not Dementia
MFG Histelide
2.5
2.0
1.5
1.0
0.5
0.0
0
20
40
60
80
Last CASI (< 2 yr from Death)
100