Imaging Biomarkers for Dementia:
Visualising neuropathology in vivo
John O’Brien, DM
Professor of Old Age Psychiatry
Department of Psychiatry
University of Cambridge
Why do we need in vivo biomarkers
for the dementias?
 Diagnosis: on clinical grounds alone is not
always accurate, and early diagnosis is
especially challenging
 Biopsy not popular - and autopsy a bit late
 Stratification: for appropriate targeting of
diagnostics and therapeutics
 Prognostic marker
 Surrogate outcome marker for therapeutic
trials
Key issues with biomarkers
 Reliability and validity
 Relation to underlying pathology
 Diagnostic accuracy
 Temporal change and relation to other markers
and clinical symptoms
 Sensitivity to change
 Cost, availability and acceptability (scan v LP)
 Clinical utility “why bother”
 When to use them
Control
AD
Sens for AD around 80%, spec for controls 80%
Spec lower for other dementias (esp FTD)
Strongest pathological correlate is tau / tangle pathology
Strongest relationship of MR atrophy
is with underlying tau/ tangle pathology
Assessment of MTA on multislice CT
Kappa 0.86 between CT and MRI ratings
Wattjes M et al. Radiology 2009
Blood flow SPECT images (Tc-HMPAO)
Con
AD
FTD
DLB
Sens for AD 65-85%, spec 72-87% for other dementias
Similar changes seen with FDG PET
FDG PET may have higher sensitivity (75-99%) but few direct
comparisons
Davidson and O’Brien. In J Ger Psych 2013
NIHR funded SUSPECTED-AD Study
FDG PET scan
of control
HMPAO SPECT scan
of same control
Imaging amyloid in the
human brain with PIB
Thioflavin-T derivative
Klunk WE et al. Ann Neurol 2004
Imaging is correlated with amyloid
pathology at autopsy
29 subjects underwent Florbetapir (AV-45) PET
Mean 99 days before death
Clark CM et al. JAMA 2011; Lancet Neurol 2013
Amyloid imaging in dementia
Villemagne VL et al. J Nucl Med 2011
 Reduced CSF Abeta and raised
tau/ptau associated with AD
 84 labs, CoV high (20–30%)
“The overall variability remains too
high to allow assignment of universal
biomarker cut-off values for a specific
intended use”
Mattsson N et al. Alzheimers Dement 2013
Core diagnostic criteria
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Gradual and progressive change in memory function reported by
patients or an informant over more than 6 months
Objective evidence of significantly impaired episodic memory
Plus one or more of the supportive features
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Medial temporal lobe atrophy on MR
Bilateral temporal/parietal changes on PET/SPECT
Amyloid positive PET imaging
Abnormal CSF biomarkers (reduced A beta 42; raised tau / p-tau)
International Working Group (IWG)
Dubois B et al. Lancet Neurol 2007; Dubois B et al. Lancet Neurol 2010
Mild cognitive impairment due to AD
Biomarkers with high likelihood MCI due to AD
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Positive A-beta biomarker (Amyloid PET or CSF) AND
Positive biomarker for neuronal injury (MRI, FDG PET, CSF tau)
Biomarkers with intermediate likelihood MCI due to AD
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Positive A-beta biomarker OR
Positive biomarker for neuronal injury
Situations where biomarkers are uninformative
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Biomarker information unavailable
Results ambiguous or conflicting
Biomarkers suggesting AD unlikely
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A-beta and neuronal injury biomarkers negative
ADD Workgroup; Albert MS et al. Alzheimers Dement 2011
Relationship between AD biomarkers (?)
Jack CR et al. Lancet Neurol 2013
Amyloid β deposition, neurodegeneration, and
cognitive decline in sporadic Alzheimer’s
disease: A prospective cohort study
Villemagne VL et al. Lancet Neurol 2013
Amyloid PET uptake reaches a plateau
Jack et al, 2014; www.neurology.org.
Amyloid-first and neurodegeneration-first
profiles characterise incident amyloid
PET positivity
 Controls from the Mayo Study of Ageing
 Incidence of amyloid positivity 13% / year
 In 58% of cases, amyloid positivity predated
other changes (MRI and FDG-PET)
 However, in 42% it occurred after these
other changes
 Suggests two different pathways to
AD are possible
Jack CR et al. Neurology 2013
50 MCI subjects, of whom 20 developed dementia at 2 years
Most accurate MRI + PIB (76% sens, 90% spec)
Trzepacz PT et al. Neurobiol Aging 2014
Other potential biomarkers for AD
 Structural MR
 Cortical thickness
 High-resolution MRI
 Serial MR
 MR spectroscopy, blood flow, diffusion imaging
 Resting state BOLD and task-driven fMRI
 Quantitative EEG / MEG
 Inflammatory markers
 Blood biomarkers (including proteomics)
 Markers for tau, neurochemistry and synuclein
Novel PET markers of Tau
Early clinical PET imaging
results with the novel PHF-tau
radioligand [F-18]-T807
Chien DT et al. J Alzheimers Dis 2013
Imaging of tau pathology in a
tauopathy mouse model and in
Alzheimer patients compared to
normal controls (C-PBB3_
Maruyama M et al. Neuron 2013
Dopaminergic imaging
in Lewy body
dementia
Sens 80%
Spec 90%
Marker of
dopaminergic
loss, not
diagnosis
Colloby SJ et al. Brain 2012
Key issues with biomarkers
 Reliability and validity
 Relation to underlying pathology
 Diagnostic accuracy
 Temporal change and relation to other
markers and clinical symptoms
 Sensitivity change
 Cost, availability and acceptability (LP)
 Clinical utility “why bother”
 When to use them
Evidence-based indications
for PET-CT: 18F-Florbetapir
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Use in highly selected patients where:
– Alzheimer’s dementia (AD) is a possible diagnosis but this remains
uncertain after comprehensive evaluation by a dementia expert and
conventional imaging work-up, and
– Knowledge of the presence or absence of amyloid is expected to
increase diagnostic certainty and influence patient management
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Appropriate uses: unexplained dementia, unusual
clinical presentation, very young age of onset
Inappropriate uses: established AD, in those with
no cognitive impairment or as a screening test
November 2013
Conclusions
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The last decade has seen a transformational
change in the development and validation of
biomarkers in AD and other dementias
Translation to clinical practice is already
occurring, but highly variable, and not without
controversy
Several new initiatives:
– G8 summit and UK leadership
– UK Dementia platform
– NIHR translational research collaboration: deep and
frequent phenotyping study
– PREVENT study
Thank you!