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pathology in neurodegenerative disease Susan M Landau, PhD Helen - - PowerPoint PPT Presentation
pathology in neurodegenerative disease Susan M Landau, PhD Helen - - PowerPoint PPT Presentation
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 Disclosures
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Detection of b-amyloid (Ab) and tau pathology in Alzheimer’s disease Time course of changes Regional specificity NIA-AA Research Framework Practical considerations for PET in clinical trials Future imaging biomarkers in neurodegenerative diseases a-synuclein, inflammation, synaptic density, vascular disease, TDP-43
Overview
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Age Related Neuropathology
b-amyloid plaques (Ab) Neurofibrillary Tangles (tau)
Ab plaques
A B C
NFTs
I/II III/IV V/VI
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In vivo Measurement of Ab and Tau with PET Imaging
Ab PET Imaging
e.g. [11C] PIB, [18F] florbetapir, [18F] florbetaben, [18F] flutemetamol
Fibrillar Ab Ab and tau Paired helical filament tau
Tau PET Imaging
e.g. [18F] flortaucipir (AV1451), [18F] MK-6240, [18F] GTP1, [18F] PI- 2620
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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
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b-amyloid
Cognitive Decline and Dementia
Amyloid Hypothesis: AD Biomarker progression
Neurodegeneration: Tau pathology Synaptic dysfunction Metabolic decline Brain atrophy
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Regional specificity
Amyloid PET
Florbetapir SUVR: cortical sumary region mean/ whole cerebellum mean
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Frequency 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
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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
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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
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Villemagne et al. Lancet Neurol (2013) Jack et al. Neurology (2013)
- 0.025
0.000 0.025 0.050 0.8 1.0 1.2 Florbetapir Cortical Summary SUVR Florbetapir SUVR annual change
Time course of changes
Rate of Aβ accumulation is not constant throughout the disease trajectory
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Regional specificity
Braak I/II Medial temporal Braak III/IV Inferolateral temporal/ limbic Braak V/VI Neocortical (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
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Tau increases with impairment and elevated Ab
Medial temporal AV1451 Neocortical (extra-temporal) AV1451 Inferolateral temporal/limbic AV1451
Ab - Ab + Ab - Ab + Ab - Ab +
Unimpaired Impaired Unimpaired Impaired Unimpaired Impaired
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=
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
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Jack et al. Alz & Dementia 2018
2018 NIA-AA Research Framework
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Jack et al. Alz & Dementia 2018
2018 NIA-AA Research Framework
Jack et al. Alz & Dementia 2018
Hippocampal 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
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Medial temporal AV1451 Neocortical (extra-temporal) AV1451 Inferolateral 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 2018 Maass et al. NeuroImage 2017 Atypical/EOAD ADNI LOAD
Tau increases with impairment and elevated Ab
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Longitudinal tau PET
Jack et al. Brain 2018
Still early!
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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)
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Amyloid clearance
Klein et al. AAIC 2018 Baseline 3 months 6 months
LY3002813 (N3pG) Gantanerumab
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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
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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
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Cerebrovascular Disease Age Genetics (ApoE) Other pathology (a-synuclein, TDP-43)
b-amyloid
Cognitive Decline and Dementia Neurodegeneration: Tau pathology Synaptic dysfunction Metabolic decline Brain atrophy Lifestyle and environment
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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
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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
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0.5 2.0 1.2
MCI: 80yo male Ab- (4 scans) ApoE4- CDR-sb=0.5 ADAS-cog=12 Braak III/IV = 1.72
Ab- High FTP
MCI: 78yo male Ab+ (4 scans) ApoE4- CDR-sb=1.0 ADAS-cog=6 Braak III/IV = 1.14
Ab+ Low FTP
MCI: 83yo male Ab+ (4 scans) ApoE4+ CDR-sb=1.5 ADAS-cog=9 Braak III/IV = 1.35
Ab+ Low FTP A B C
Example [18F] flortaucipir tau PET cases
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High vs low FTP groups
Inferolateral temporal/limbic AV1451
Unimpaired Impaired
Ab - Ab +
Non-AD dementia Possible 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%
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Flortaucipir is variable among impaired (MCI / AD) individuals
Schneider et al Brain 2016
Non-AD dementia Possible 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
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Tau PET variability
Whitwell et al Ann Neurol 2018 Ossenkoppele et al JAMA 2018
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Ab- Ab+
Distribution of suprathreshold (>1.4 SUVR) voxels
10% 80% 50% % subjects with suprathreshold voxels
Unimpaired (N/SMC) Impaired (Early/Late MCI, AD)
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Fan et al. Brain 2018
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Cons Consid iderable overla rlap p with thin in the he low tau au rang ange am among ind ndiv ivid iduals s acr acros
- ss
s the he di dise sease sp spect ctrum (i (in n LOAD) D) Con Conversely ly, hi high gh ne neoc
- cortic
tical tau au in n unim unimpair ired su subje bjects ts has has al also so be been n repo port rted (e (e.g.
- g. Lowe et al
- al. Br
Brain in 20 2018 18) PART
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Medial temporal AV1451
Ab - Ab +
Resembles MAPT406W mutation pattern
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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