Neuroimaging in trials in AD Neuroimaging in trials in AD Nick Fox - - PowerPoint PPT Presentation

Neuroimaging in trials in AD Neuroimaging in trials in AD

Nick Fox Nick Fox Dementia Research Centre Dementia Research Centre Institute of Neurology, Queen Square Institute of Neurology, Queen Square University College London University College London

Disclosures & Acknowledgements Disclosures & Acknowledgements

• Work of the members of the Dementia Research

Work of the members of the Dementia Research Centre (DRC) Centre (DRC)

• The DRC has conducted image analysis for a

The DRC has conducted image analysis for a number of companies and has been a clinical number of companies and has been a clinical site for sponsored trials site for sponsored trials

• I have advised these and other companies and

I have advised these and other companies and also the NIH and FDA also the NIH and FDA

• I am a member of the MRI

I am a member of the MRI-

• core of ADNI

core of ADNI (Alzheimer’s disease neuroimaging initiative) (Alzheimer’s disease neuroimaging initiative) – – ADNI members have generously shared slides ADNI members have generously shared slides and data for this meeting: including and data for this meeting: including

– – Jagust Jagust, Weiner, Jack, Foster, , Weiner, Jack, Foster, Reiman Reiman, , Klunk Klunk

Overview Overview

• Why neuroimaging?

Why neuroimaging?

• Focus on ph2/3 issues

Focus on ph2/3 issues

• Roles of imaging in AD trials

Roles of imaging in AD trials

– – Defining target/study populations Defining target/study populations – – Safety Safety – – Measuring progression Measuring progression

• Assessing disease

Assessing disease-

• modification

modification

– – Problems and potential Problems and potential

Why neuroimaging? Why neuroimaging?

• Inaccessibility of brain

Inaccessibility of brain

– – To assess pathology To assess pathology – – Drug delivery Drug delivery

• Complexity of brain response

Complexity of brain response

– – Systems biology Systems biology

• Limitation of clinical measures

Limitation of clinical measures

• Lack simple biomarkers

Lack simple biomarkers

• Imaging allows objective repeated

Imaging allows objective repeated assessment assessment – – no practice effects! no practice effects!

Roles: define study population Roles: define study population – – exclusion/inclusion and stratification exclusion/inclusion and stratification

• Is this the correct pathology?

Is this the correct pathology?

– – AD AD vs vs non AD non AD e.g e.g vascular or FTD pathology vascular or FTD pathology

• Know what we are treating

Know what we are treating – – adjust if need adjust if need

– – Stage/severity: more homogenous populations? Stage/severity: more homogenous populations? – – Subtypes of AD Subtypes of AD – – e.g e.g biparietal (PCA) variant biparietal (PCA) variant

• Open an early therapeutic window

Open an early therapeutic window – – “enriched “enriched MCI” MCI” -

• e

early or preclinical arly or preclinical

• r presymptomatic AD
• r presymptomatic AD

Imaging established role in Imaging established role in excluding excluding

• ther pathology
• ther pathology

MR- FLAIR MR –T1- volume

More rigour assessing vascular path, focal More rigour assessing vascular path, focal atrophy FTD not just tumours etc atrophy FTD not just tumours etc

Inclusion criteria for AD Inclusion criteria for AD and opening an earlier therapeutic and opening an earlier therapeutic window: predicting AD window: predicting AD

A number of imaging features are A number of imaging features are predictive of AD pathology predictive of AD pathology

• Medial temporal lobe atrophy on MRI

Medial temporal lobe atrophy on MRI

• Increased rates of atrophy on serial

Increased rates of atrophy on serial MRI (>90% MRI (>90% sens sens/specificity: AD /specificity: AD vs vs C) C)

• Hypometabolism

Hypometabolism on PET/SPECT

• n PET/SPECT
• Amyloid imaging

Amyloid imaging

Hippocampus reduced by 20% in early AD

0.0007 0.0012 0.0017 0.0022 0 5 1 1 5 2

Hippocampus/TIV

Control AD

0, n=68 1, n=370 2, n=244 3 or 4, n=208

MTA

10 20 30 40 50 60 70

ADAS-COG/MCI

In vivo Amyloid Imaging with In vivo Amyloid Imaging with Pittsburgh Compound B (PIB) Pittsburgh Compound B (PIB)

N S NH11CH3 HO

PET Imaging - [11C]6-OH-BTA-1 (PIB)

N S N CH3 CH3 H3C CH

+

6 1

Histology - Thioflavin T

Amyloid Plaques Courtesy of Bill Jagust

Structure/Function: Topography Molecules: Proteomic Specificity

Alzheimer’s Disease Normal FDG PIB

Courtesy of Bill Jagust

MCI non MCI non-

• converter PIB

converter PIB MCI converter PIB MCI converter PIB

Archer, Okello, Brooks, Rossor

Imaging measures of drug effect Imaging measures of drug effect

• Safety

Safety

– – Haemorrhage Haemorrhage – – Inflammation Inflammation

• Unrelated adverse events

Unrelated adverse events

• Efficacy

Efficacy

Registration of serial MRI allows clear recognition of new lesions

5761aa 5761ba

Imaging markers of disease Imaging markers of disease-

• modification

modification

• Measure a feature of disease that

Measure a feature of disease that should predict clinical response should predict clinical response (imaging change being necessary and (imaging change being necessary and sufficient to predict that response) sufficient to predict that response)

– – Associated with disease pathology Associated with disease pathology – – Progresses with clinical progression Progresses with clinical progression – – On the pathogenic pathway On the pathogenic pathway

• Clinically meaningful

Clinically meaningful

AD: brain volume vs time

86 88 90 92 94 96 98 100 500 1000 1500 Days from first scan

%

Therapy

Need to maximise efficiency and Need to maximise efficiency and interpretability of trials in AD interpretability of trials in AD

• Clinical scales

Clinical scales -

• high variance drives

high variance drives sample sizes sample sizes

2 2

SD Variance : Note effect) treatment ed (Anticipat group each in rate atrophy

• f

Variance trial

• f

Size = ∝

Milameline Milameline trial trial in AD in AD

Jack et al, Neurology

Estimated sample size (per arm) needed Estimated sample size (per arm) needed to show a 50% effect on progression to show a 50% effect on progression

• ver 1 year
• ver 1 year
• ADAS

ADAS-

• Cog

Cog score score 320 320

• MMSE

MMSE score score 241 241

• Hippocampal

Hippocampal volume volume 21 21

Imaging Imaging – – disease modification markers disease modification markers

• Structural MRI

Structural MRI

– – Hippocampi, entorhinal cortex Hippocampi, entorhinal cortex – – Whole brain, ventricles Whole brain, ventricles – – Cortical thickness Cortical thickness

• Functional

Functional -

• PET/SPECT

PET/SPECT

• Molecular

Molecular -

• Amyloid imaging

Amyloid imaging – – PIB PIB

• Spectroscopy, diffusion, MTR,

Spectroscopy, diffusion, MTR, fMRI fMRI … …

Time 0 18months 36months H Serial coronal MRI of an individual with initially mild AD

• 5

5 10 15 Rate of atrophy % year -1

Manual Semi-automated HBSI Automated HBSI

Rate of atrophy % year –1

0.3 %/y +/- 0.9 %/y 4.6%/y +/- 3.0 %/y

Controls AD

Hippocampal rates of atrophy

• 1

1 2 3 4

Controls AD

Rate of brain atrophy in early-onset AD

%/yr

2.8% (+/ 2.8% (+/-

• 1)

1) 0.2% (+/ 0.2% (+/-

• 0.3)

0.3)

AD: brain volume vs time

86 88 90 92 94 96 98 100 500 1000 1500 Days from first scan

%

Therapy

Mean and sd of rate (between subject)

Previously Estimated Number of AD Patients per Treatment Group Previously Estimated Number of AD Patients per Treatment Group Needed to Detect an Effect with 80% Power in One Year Needed to Detect an Effect with 80% Power in One Year Treatment Effect Treatment Effect 20% 20% 30% 30% 40% 40% 50% 50% Frontal Frontal 85 85 38 38 22 22 14 14 Parietal Parietal 217 217 97 97 55 55 36 36 Temporal Temporal 266 266 119 119 68 68 44 44 Cingulate Cingulate 343 343 153 153 87 87 57 57

Alexander et al, Am J Psychiatry 2002

P=0.01 (two P=0.01 (two-

• tailed, uncorrected for multiple comparisons)

tailed, uncorrected for multiple comparisons)

.

Engler, H. et al. Brain 2006 129:2856-66

PIB retention stable over 2 years

healthy controls (HC) and Alzheimer patients at baseline (AD 1) and follow-up (AD 2)

Disease modification: differing Disease modification: differing views and difficult issues views and difficult issues

“an effect on the underlying disease pathophysiological progression” “a long-lasting(> 18 months) effect on disability” Surrogates need to capture “full effects Surrogates need to capture “full effects

• f an intervention”
• f an intervention”

Conclusions Conclusions

• Imaging has an under used role in inclusion as well as

Imaging has an under used role in inclusion as well as exclusion for trial exclusion for trial

• Safety imaging markers increasingly important

Safety imaging markers increasingly important

• Imaging may provide evidence to show effect on brain

Imaging may provide evidence to show effect on brain structure, metabolism or amyloid load structure, metabolism or amyloid load – – to understand to understand effect of intervention effect of intervention

• Evidence for

Evidence for modification modification is more difficult: is more difficult:

– – Robust, multiple markers & multiple time points Robust, multiple markers & multiple time points – – To support clinical endpoint effects To support clinical endpoint effects

Trials will increasingly need to incorporate these markers Trials will increasingly need to incorporate these markers in a considered evidence in a considered evidence-

• based manner

based manner