Imaging tau and other molecular

markers in dementia

John O’Brien

Professor of Old Age Psychiatry

Department of Psychiatry

University of Cambridge

Imaging in Dementia

• Computed tomography (CT)

• Magnetic resonance imaging (MRI)

• Perfusion (HMPAO) SPECT

• Glucose (FDG) PET

• Dopamine (FP-CIT) SPECT (for Lewy body

dementia)

• Amyloid (PIB, florbetapir, flutemetamol, flurbetaben)

PET

• Research (Tau, inflammation, receptor)

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

Why image molecular imaging markers in

dementia?

• Subject stratification for studies

• Understanding pathophysiology – including

temporal relationship between changes

• Demonstrate target engagement in therapeutic

studies

• Outcome measure for disease modifying studies

• Improve diagnosis of challenging cases

McKhann et al, 1984

Is there a downside?

• Cost

• Availability and distribution

• 11Carbon v 18Fluorine

• Need careful validation

• Injection

• Radiation dose – 4-7 mSv

Radiation dose

• Average exposure in the UK/yr 2.7 mSv

• CT scan head 1 mSv

• CT scan chest 6.6 mSv

• Living in Cornwall/yr 7.8 mSv

• F-Amyloid PET scan 7 mSv

• Industry limits/ yr 20 mSv

• To cause radiation sickness 1000 mSv

Glucose (FDG) PET scans

Healthy Control Mild AD subject

Dopaminergic imaging, a biomarker for

Lewy body dementia

C-PBB3

• Phase 2 study of diagnosis (DLB v AD).

Sens 78% Spec 90%

• Phase 3 Study (GE Healthcare funded).

Similar diagnostic accuracy in 40 sites

• Autopsy validation

• Use in possible cases

• Pooled data analysis

Licensed for clinical use in dementia in EU (2006)

Normal

DLB

Walker et al, 2002; O’Brien et al, 2004; McKeith et al, 2007;

O’Brien et al, 2009; Colloby et al, 2012; Walker et al, 2014; O’Brien et al, 2014

Amyloid imaging in Dementia

Villemagne et al, 2011

CPIB – research tool

Now F-amyloid compounds

for clinical use

Amyloid PET imaging

Negative scan:

normal

Positive scan:

amyloid

Flurbetapir

(Amyvid)

Flutametamol

(Vizamyl

Flurbetaben

(NeuraCeq)

Time course of biomarker changes in DIAN

study

Bateman et al, NEJM, 2016

Sevigny et al, Nature, 2016

ARIA:

5% - Placebo

6% - 1mg

13% - 3mg

37% - 6mg

47% - 10mg

Novel PET markers of Tau

Chien DT et al. J Alzheimers Dis 2013;34:457-68. Maruyama M et al. Neuron 2013;79:1094-108.

C-PBB3

Radioligand [F-18]-T807

(now AV 1451)

Imaging of tau pathology with C-

PBB3 in a tauopathy mouse

model and in Alzheimer patients

compared to normal controls

C-PBB3

WIBIC imaging of AV1451 (tau) in AD

C-PBB3

Control AD

Tau deposition (AV 1451) mirrors clinical

phenotype in AD

C-PBB3

Ossenkoppele et al, 2016

Tau deposition (AV 1451) correlates with

tau in CSF

C-PBB3

Gordon et al, 2016

AD and the FTD spectrum

TAU TDP-43

AD

Mean AV-1451 uptake in Controls

0.8

-0.5

BPND

0.8

-0.5

Mean AV-1451 uptake in AD/MCI+

BPND

Mean AV-1451 uptake in PSP

0.8

-0.5

BPND

Tau imaging with AV1451 in AD and PSP

Clearly differentiates AD from PSP with

differences in keeping with known and distinct

regional distributions

Passamonti, Vázquez Rodríguez et al, Brain 2017

AD and the FTD spectrum

TAU TDP-43

AD

C-PBB3

MATP

case

Bevan-Jones, Cope et al, 2016

Tau (AV 1451) imaging in DLB

Kantarci et al, 2017

DLB (n=19) v

Controls (n=95)

DLB (n=19) v

AD (n=19)

Tau imaging in DLB

Kantarci et al, 2017

Conclusions

• CT, MR, perfusion SPECT and Glucose PET are

established clinical tools

• Molecular imaging for dopamine transporter a

diagnostic tool for DLB

• Amyloid imaging licensed, but not currently

funded

• Tau imaging developing as a research tool, still

needs further study and validation, likely to be

clinical tool in the future

Thank you!