PET neuroimaging approaches to characterizing underlying molecular pathology in neurodegenerative disease Susan M Landau, PhD Helen Wills Neuroscience Institute University of California, Berkeley Lawrence Berkeley National Lab
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PET neuroimaging approaches to characterizing underlying molecular pathology in neurodegenerative disease
Susan M Landau, PhD
Helen Wills Neuroscience Institute University of California, Berkeley
Lawrence Berkeley National Lab
Cortexyme
NeuroVision
Disclosures
Detection of b-amyloid (Ab) and tau pathology in Alzheimer’s diseaseTime course of changes
Regional specificity
NIA-AA Research Framework
Practical considerations for PET in clinical trials
Future imaging biomarkers in neurodegenerative diseasesa-synuclein, inflammation, synaptic density, vascular disease, TDP-43
Overview
Age Related Neuropathology
b-amyloid plaques (Ab)
Neurofibrillary
Tangles (tau)
Ab plaques
0
A
B
C
NFTs
0
I/II
III/IV
V/VI
In vivo Measurement of Ab and Tau with PET Imaging
Ab PET Imaginge.g. [11C] PIB,
[18F] florbetapir, [18F] florbetaben, [18F] flutemetamol
Fibrillar Ab
Ab and tau
Paired helical
filament tau
Tau PET Imaginge.g. [18F] flortaucipir (AV1451),
[18F] MK-6240, [18F] GTP1, [18F] PI-2620
Alzheimer’s
Disease
Normal Aging
(Amyloid Negative)
Normal Aging
(Amyloid Positive)
Ab PET imaging in aging and dementia
~30% of cognitively normal people in
their 70s and above have substantial Ab
accumulation by PET
b-amyloid Cognitive Declineand
Dementia
Amyloid Hypothesis: AD Biomarker progression
Neurodegeneration:
Tau pathology
Synaptic dysfunction
Metabolic decline
Brain atrophy
Regional specificity
Amyloid PET
Florbetapir SUVR:
cortical sumary region mean/
whole cerebellum mean
Freq
uen
cy
Florbetapir Cortical SUVR
Cortical Ab accumulation over the disease trajectory
32% florbetapir+
35% florbetapir+
48% florbetapir+
65% florbetapir+
86% florbetapir+
Normal
Late MCI
AD
Total N=1064
Subjective Memory
Complaint
Early MCI
La Joie et al. Alz & Dementia (in press)
Ab PET imaging – postmortem associations
Cortical Ab PET retention is highly associated with Ab plaques at autopsy in 179 diverse cases
Elevated Ab predicts ADAS-cog decline in MCI and AD
And in cognitively normal individuals
In cognitively normal, Ab- individuals, negative but increasing Ab is associated with memory
decline
Cortical Ab accumulation predicts cognitive decline
Landau et al Neurology 2016
Donohue et al JAMA
2017
Landau et al Neurology 2018
Villemagne et al. Lancet Neurol (2013)Jack et al. Neurology (2013)
-0.025
0.000
0.025
0.050
0.8 1.0 1.2Florbetapir Cortical Summary SUVR
Flo
rbeta
pir
SU
VR
an
nu
al
ch
an
ge
N
SMC
EMCI
LMCI
AD
3
Time course of changes
Rate of Aβ accumulation is not constant throughout the disease trajectory
Regional specificity
Braak I/IIMedial temporal
Braak III/IVInferolateral temporal/
limbic
Braak V/VINeocortical
(extra-temporal)
Amyloid PET
Florbetapir SUVR:
cortical sumary region mean/
whole cerebellum mean
Tau PET
Flortaucipir SUVRs:
Braak stage-based region means/
cerebellar grey matter mean
Tau increases with impairment and elevated Ab
Medial temporal AV1451 Neocortical (extra-temporal) AV1451Inferolateral temporal/limbic AV1451
Ab -
Ab +Ab -
Ab +
Ab -
Ab +
Unimpaired Impaired Unimpaired Impaired Unimpaired Impaired
=
Higher tau is linked to poorer cognition for Ab+ individuals
Co-occurrence of Ab and tau are linked to cognitive decline
Ab-
Ab+
Ab-
Ab+
Higher tau is linked to retrospective cognitive decline in Ab+ individuals
Jack et al. Alz & Dementia 2018
2018 NIA-AA Research Framework
Jack et al. Alz & Dementia 2018
2018 NIA-AA Research Framework
Jack et al. Alz & Dementia 2018Hippocampal Volume FDG metaROI
Ab PET
Abnormal (+) Abnormal (+)
Abnormal (+)
Normal (-) Normal (-)
Normal (-)
Distributions differ across A, T, N biomarkers
Determining standardized cut-points for positivity is challenging
Abnormal (+)Normal (-)
Tau PET
Medial temporal AV1451 Neocortical (extra-temporal) AV1451Inferolateral temporal/limbic AV1451
Ab -
Ab +Ab -
Ab +
Ab -
Ab +
90% upper threshold of 141
Ab- normals
Unimpaired Impaired Unimpaired Impaired Unimpaired Impaired
19%
29%
Ab-
High FTP
Ab+
Low FTP
Lowe et al. Brain 2018Maass et al. NeuroImage 2017
Atypical/EOAD ADNI LOAD
Tau increases with impairment and elevated Ab
Longitudinal tau PET
Jack et al. Brain 2018
Still early!
PET in Clinical Trials: Practical considerations
Cross-sectional PET(Subject selection)
Longitudinal PET(Target Engagement)
Participant burden and cost
Multiple PET scans (+ MRI?)
Radiation exposure
PET vs blood-based vs CSF markers
Multisite studies
Different scanners
Different tracers
Identification of intervention “sweet spot”
(biomarker-specific)
Scan cost
Scanner changes
Scan-rescan variability;
Longitudinal changes are usually small
Ligand-specific methodological challenges
Determining a followup time period with
adequate power (biomarker-specific)
Amyloid clearance
Klein et al. AAIC 2018
Baseline
3 months
6 months
LY3002813 (N3pG)
Gantanerumab
Jack et al. Alz & Dementia 2018
2018 NIA-AA Research Framework
Rabinovici et al Alz & Dem 2017
Beyond amyloid and tau
[A] Plasma or retinal amyloid[T] New tau PET ligands[N] Neurofilament light, Synaptic density ([C11] UCB-J)
[V] Vascular disease[I] Inflammation[S] a-synuclein
TDP-43
Biomarker targets in development
Jack et al. Alz & Dementia 2018
Upcoming imaging biomarkers
Chen et al. JAMA Neurol 2018
Synaptic density with [11C] UCB-J
Parbo et al. Neurobiol Dis 2018
Neuroinflammation with
[11C]–(R)-PK11195
PET markers of a-synuclein and TDP-43 in development
CerebrovascularDisease
AgeGenetics(ApoE)
Other pathology(a-synuclein, TDP-43)
b-amyloid Cognitive Declineand
DementiaNeurodegeneration:
Tau pathology
Synaptic dysfunction
Metabolic decline
Brain atrophy
Lifestyle andenvironment
Recent Ab and tau PET work has emphasized detection of earliest pathological AD changes, and associations with cognitive decline
Research framework relies on amyloid [A], tau [T], and neurodegenerative [N] biomarkers to identify and stage AD pathological changes
PET has been used successfully in clinical trials for participant selection and tracking of target engagement despite methodological challenges
In vivo characterization of other comorbid pathology is a key developing area
ADNI collaborators
Michael Weiner
Robert Koeppe
Duygu Tosun
Chester Mathis
Eric Reiman
Kewei Chen
Leslie Shaw
John Trojanowski
Clifford Jack
Danielle Harvey
Laurel Beckett
Andrew Saykin
Paul Aisen
Ronald Petersen
Michael Donohue
Arthur Toga
Karen Crawford
UC Berkeley
Bill Jagust
Suzanne Baker
Deniz Korman
Gil Rabinovici
Renaud La Joie
Tessa Harrison
ADNI sponsors
Thank you
ADNI participants & staff
0.5 2.01.2
MCI: 80yo maleAb- (4 scans)ApoE4-CDR-sb=0.5ADAS-cog=12Braak III/IV = 1.72
Ab-High FTP
MCI: 78yo male Ab+ (4 scans)ApoE4-CDR-sb=1.0ADAS-cog=6Braak III/IV = 1.14
Ab+ Low FTP
MCI: 83yo male Ab+ (4 scans)ApoE4+CDR-sb=1.5ADAS-cog=9Braak III/IV = 1.35
Ab+ Low FTP
A
B
C
Example [18F] flortaucipir tau PET cases
High vs low FTP groups
Inferolateral temporal/limbic AV1451
Unimpaired Impaired
Ab -
Ab +
Non-AD dementiaPossible AD with
comorbid pathology
Primary Age Related
Tauopathy (PART)Typical MCI/AD
Low FTP
High FTP
Ab –(N=80)
Ab +(N=71)
Non-AD dementia Possible AD with comorbid pathology
Primary Age Related Tauopathy
(PART)
Typical MCI/AD
81% 29%
19% 71%
Flortaucipir is variable among impaired (MCI / AD) individuals
Schneider et al Brain 2016
Non-AD dementiaPossible AD with
comorbid pathology
Primary Age Related
Tauopathy (PART)Typical MCI/AD
Low
FTP
High
FTP
Ab – Ab +
Non-AD dementia Possible AD with comorbid pathology
Primary Age Related Tauopathy
(PART)
Typical MCI/AD
81% 29%
19% 71%
- Fewer AD-specific biomarker
characteristics
- Mostly male
- Cerebrovascular or TDP-43 pathology
may account for cognitive symptoms (e.g. Schneider et al Brain 2016)
Understanding the characteristics of “atypical tau” individuals will be important for effective selection of participants for clinical trials of tau-modifying treatments
Greater hippocampal
atrophy + hypometabolism
supports a medial temporal
predominant role that could
be AD-independent
Tau PET variability
Whitwell et al Ann Neurol 2018Ossenkoppele et al JAMA 2018
Ab-
Ab+
Distribution of suprathreshold (>1.4 SUVR) voxels
10% 80%50%
% subjects with suprathreshold voxels
Unimpaired (N/SMC) Impaired (Early/Late MCI, AD)
Fan et al. Brain 2018
Considerable overlap within the low tau range among individuals across the disease spectrum (in LOAD)
Conversely, high neocortical tau in unimpaired subjects has also been reported (e.g. Lowe et al. Brain 2018) PART
Medial temporal AV1451
Ab -
Ab +
Resembles MAPT406W mutation pattern
All Unimpaired (N/SMC)Entire AV1451 range p=0.04“Normal” AV1451 range ns
All Impaired (EMCI/LMCI/AD)Entire AV1451 range p<0.001“Normal” AV1451 range ns
Ab-
Ab+
FDG comparison
Impaired Ab+ : High inferotemporal/limbic FTP < Low FTP
Impaired Ab- : High inferotemporal/limbic FTP < Low FTP
3.0 7.0
p<0.001 uncorr
N=57 N=23
N=13 N=56
High vs low FTP group comparison
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