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 – – no practice effects! no practice effects! assessment
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” - - e early or preclinical arly or preclinical MCI” or presymptomatic AD or presymptomatic AD
Imaging established role in excluding excluding Imaging established role in other pathology other 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% sens sens/specificity: AD /specificity: AD vs vs C) C) MRI (>90% • Hypometabolism Hypometabolism on PET/SPECT on PET/SPECT • • Amyloid imaging Amyloid imaging •
Hippocampus reduced by 20% in early AD 0.0022 Hippocampus/TIV 0.0017 70 0.0012 60 Control AD 50 0.0007 ADAS-COG/MCI 0 5 1 1 5 2 40 30 20 10 0 0, n=68 1, n=370 2, n=244 3 or 4, n=208 MTA
In vivo Amyloid Imaging with In vivo Amyloid Imaging with Pittsburgh Compound B (PIB) Pittsburgh Compound B (PIB) 1 6 H 3 C S CH 3 N + CH 3 N CH Histology - Thioflavin T Amyloid Plaques PET Imaging - [ 11 C]6-OH-BTA-1 (PIB) HO S NH 11 CH 3 N Courtesy of Bill Jagust
Structure/Function: Topography Molecules: Proteomic Specificity Alzheimer’s Normal Disease FDG PIB Courtesy of Bill Jagust
MCI converter PIB MCI non- -converter PIB converter PIB MCI converter PIB MCI non 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 100 % 98 96 94 92 90 Therapy 88 86 0 500 1000 1500 Days from first scan
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 Variance of atrophy rate in each group Size of trial ∝ 2 (Anticipat ed treatment effect) 2 Note : Variance SD =
Milameline trial trial in AD in AD Milameline 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 over 1 year over 1 year • ADAS ADAS- -Cog Cog score score 320 320 • • MMSE MMSE score score 241 241 • • Hippocampal Hippocampal volume volume 21 21 • Jack et al, Neurology
Imaging – – disease modification markers disease modification markers Imaging • 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 … … •
H Time 0 18months 36months Serial coronal MRI of an individual with initially mild AD
15 Hippocampal rates of atrophy Rate of atrophy % year –1 10 Rate of atrophy % year -1 Manual Semi-automated HBSI Automated HBSI 5 0 0.3 %/y +/- 0.9 %/y 4.6%/y +/- 3.0 %/y -5 AD Controls
Rate of brain atrophy in early-onset AD %/yr 4 3 2 0.2% (+/- -0.3) 0.3) 2.8% (+/- -1) 1) 0.2% (+/ 2.8% (+/ 1 0 -1 Controls AD
AD: brain volume vs time 100 Mean and sd of rate % 98 (between subject) 96 94 92 90 Therapy 88 86 0 500 1000 1500 Days from first scan
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% 30% 40% 50% 20% 30% 40% 50% Frontal 85 38 22 14 Frontal 85 38 22 14 Parietal 217 97 55 36 Parietal 217 97 55 36 Temporal 266 119 68 44 Temporal 266 119 68 44 Cingulate Cingulate 343 343 153 153 87 87 57 57 P=0.01 (two- -tailed, uncorrected for multiple comparisons) tailed, uncorrected for multiple comparisons) P=0.01 (two Alexander et al, Am J Psychiatry 2002
PIB retention stable over 2 years healthy controls (HC) and Alzheimer patients at baseline (AD 1) and follow-up (AD 2) Engler, H. et al. Brain 2006 129:2856-66 .
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 of an intervention” of an intervention”
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