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Alzheimer’s Disease Neuroimaging Initiative (ADNI)

Ronald C. Petersen, PhD, MD Co-Director, Clinical Core Mayo Clinic College of Medicine Rochester, MN Alzheimer’s Disease International Toronto March 28, 2011. Alzheimer’s Disease Neuroimaging Initiative (ADNI). Pfizer, Inc. (Wyeth): Chair, DMC

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Alzheimer’s Disease Neuroimaging Initiative (ADNI)

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  1. Ronald C. Petersen, PhD, MD Co-Director, Clinical Core Mayo Clinic College of Medicine Rochester, MN Alzheimer’s Disease International Toronto March 28, 2011 Alzheimer’s Disease Neuroimaging Initiative (ADNI)

  2. Pfizer, Inc. (Wyeth): Chair, DMC Janssen Alzheimer’s Immunotherapy Program (Elan): Chair, DMC Elan Pharmaceuticals: Consultant GE Healthcare: Consultant Funding: National Institute on Aging U01 AG006786, P50 AG 016574, R01 AG011378, R01 AG034676 and the Robert and Clarice Smith and Abigail Van Buren Alzheimer’s Disease Research Program Disclosures

  3. FUNDED BY NATIONAL INSTITUTE ON AGING NIBIB,NIMH,NINR,NINDS,NCRR,NIDA and CIHR M. Weiner, P. Aisen, R Petersen, C. Jack, W. Jagust, J Trojanowski, L. Shaw, A. Toga, L. Beckett, D. Harvey, C Mathis, A. Gamst. R. Green, A Saykin, J Morris, L Thal (D) Neil Buckholz, David Lee, Mark Schmidt Industry Scientific Advisory Board (ISAB) And Site PIs, Study Coordinators and 821 subjects enrolled in 58 Sites in US and Canada

  4. ADNI Structure • Executive Committee • Clinical Core • MRI Core • PET Core • Biomarker Core • Biostatistics Core • Informatics Core • Genetics Core • Neuropathology Core

  5. GOALS OF ADNI • Validate biomarkers as measures of change • Validate biomarkers as diagnostics or predictors: symptomatic and presymptomatic • Optimize biomarker methods • Standardize biomarker methods • Establish a world-wide network for clinical AD studies and treatment trials

  6. ADNI • Naturalistic study of AD progression • 200 NORMAL 4 yrs • 400 MCI 4 yrs • 200 AD 2 yrs • Visits every 6 months • 57 sites • Clinical, blood, LP • Cognitive Tests • 1.5T MRI • Some also have • 3.0T MRI (25%) • FDG-PET (50%) • PiB-PET (approx 100) All data in public database: UCLA/LONI/ADNI: No embargo of data

  7. CSF abeta42 Function (ADL) MRI hippocampal volume Amyloid imaging CSF Tau Cognitive performance FDG PET AD Progression Abnormal Normal Time Pre-symptomatic EMCI LMCI Dementia Jack et al: Lancet Neurology, 2010

  8. CSF abeta42 Function (ADL) MRI hippocampal volume Amyloid imaging CSF Tau Cognitive performance FDG PET AD Progression Abnormal Normal Time Pre-symptomatic EMCI LMCI Dementia Jack et al: Lancet Neurology, 2010

  9. CSF abeta42 Function (ADL) MRI hippocampal volume Amyloid imaging CSF Tau Cognitive performance FDG PET AD Progression Abnormal Normal Time Pre-symptomatic EMCI LMCI Dementia Jack et al: Lancet Neurology, 2010

  10. CSF abeta42 Function (ADL) MRI hippocampal volume Amyloid imaging CSF Tau Cognitive performance FDG PET AD Progression Abnormal Normal Time Pre-symptomatic EMCI LMCI Dementia Jack et al: Lancet Neurology, 2010

  11. CSF abeta42 Function (ADL) MRI hippocampal volume Amyloid imaging CSF Tau Cognitive performance FDG PET AD Progression Abnormal Normal Time Pre-symptomatic EMCI LMCI Dementia Jack et al: Lancet Neurology, 2010

  12. Paul Aisen, UCSD Ron Petersen, Mayo Clinic Clinical Core

  13. ADNI Conversion Rates 15 NL 229 MCI 398 AD 192 12+2 158+2 215 225 192 3003446-26

  14. ADNI Withdrawal Rates p<0.001 P<0.001 3003446-26

  15. ADAS Cog 11 3003731-7

  16. ADAS Cog Change 3003731-8

  17. Clinical groups are performing as expected MCI to AD rates are accelerating from 16%/yr to 24%/yr Significant variability in clincal instruments Opportunity for imaging and fluid biomarkers to define subsets Summary

  18. POWER CALCULATIONS • Hypothetical clinical trial • Two arms: Treatment and Placebo • Estimate the sample size/arm required to detect a significant treatment effect • 1 year trial • 25% slowing of rate of change • two-sided tests, alpha=0.05, 80% power • 23 ADNI publications on longitudinal change

  19. POWER OF CLINICAL/COGNITIVE TESTS25% CHANGE 1YR STUDY (2 ARM) : AD (155 Subjects)

  20. POWER OF CLINICAL/COGNITIVE TESTS25% CHANGE 1YR STUDY (2 ARM) :MCI (355 Subjects)

  21. MRI CORE Clifford Jack MD Mayo Clinic 60 publications on MRI

  22. FREESURFER PARCELATION

  23. Mean Cortical Thickness Change over 12 Months Diagnosed as AD +2% Diagnosed as NC -2% Lateral View Medial View Holland et al.

  24. Normal and MCI had similar WMH distributions; increased WMH burden in AD with suggestions of anterior-posterior progression Baseline White Matter Hyperintensities Normal MCI AD

  25. 1.5T MRI Comparisons - AD (n=69)

  26. PET CORE William Jagust UC Berkeley 12 papers on PET

  27. Normal Aging vs. Alzheimer’s DiseaseFDG PET Normal AD

  28. FDG-PET ANALYSIS Jagust Lab Composite ROI - Based on published coordinates

  29. Statistical ROI of12-Month CMRgl declines Defined using data from 27 training-set patients using bootstrap with replacement Number of AD patients per group needed in a 12-month multi-center RCT to detect a 25% treatment effect with power=80%, p=0.05 & no need to correct for multiple comparisons FDG PET ADAS-COG11 MMSE 61 612 493 Characterized in 29 test-set patients (excluding HiRez & HRRT scanners) Reiman et al Banner Alzheimer Institute

  30. PET Comparisons - AD (n=36)

  31. PET Comparisons - MCI (n=81)

  32. First Conclusion • In general atrophy, measured by MRI is a more sensitive and robust measure of rate of change • Hippocampus, ventricles, not that different • With the exception of Eric Reiman’s statistically generated ROI, PET measures have less statistical power to detect a slowing of change than MRI • BUT PET may be more sensitive to detect a treatment effect which improves function!!!

  33. Biomarker Core John Trojanowski, U Penn Les Shaw, U Penn

  34. BIOMARKERS John Trojanowski, Les Shaw, U Penn. 24 papers on biomarkers p<0.0001, for each of the 5 biomarker tests for AD vs NC and for MCI vs NC. For AD vs MCI:p<0.005, Tau; p<0.01, Ab1-42; p<0.01, P-Tau 181P; p<0.0005, Tau/Ab1-42; p<0.005, P-Tau 181P/Ab1-42. Mann-Whitney test

  35. Survival analyses for ADNI MCI subjects: progression to AD for BASELINE CSF biomarkers > or < cutpoints Ab42<192 pg/mL t-tau/Ab42>0.39 As of June 28, 2010 riskTAA2>0.34

  36. Lower CSF Aβ1-42 is Associated with Increased Rates of Atrophy in MCI Consistent with the view that MCI patients with low CSF Aβ1–42 have the AD

  37. ADNI: HC atrophy and CSF Aβ

  38. PiB Imaging Chet Mathis, U Pitt

  39. PIB Imaging:Chet Mathis FDG PIB

  40. Follow-Up of PIB-Positive ADNI MCI’s ADNI PiB MCI’s N = 65, 12 mo. follow-up PiB(-)18 Converters to AD3 PiB(+)47 Converters to AD21

  41. Follow-Up of ADNI PiB Controls ADNI PiB Ctrl’s N = 19, 12 mo. follow-up PiB(-)10 Converters to MCI0 PiB(+)9 Converters to MCI2

  42. Penn Autopsy Sample (56 AD, 52 Cog normal) 192 pg/ml PIB vs CSF Biomarkers: A Total N = 55 (11 Control, 34 MCI, 10 AD)

  43. PREDICTING TIME TO CONVERSION • Time to conversion from MCI to AD (using Cox proportional hazards) is predicted by • Baseline ADAS-cog • FAQ • Use of acetylcholinesterase inhibitors • Baseline biomarkers: hippocampus, FDG PET, PIB PET, CSF

  44. PREDICTING RATE OF ADAS COG-11 CHANGE • In controls: Hippocampal volume • In MCI: ApoE, CSF AB and tau, FDG PET, PIB PET, hippocampal and ventricular volumes • In AD: CSF tau and FDG PET

  45. PREDICTING FUTURE RATE OF HIPPOCAMPAL ATROPHY • Controls: CSF AB and tau • MCI: APOE, CSF AB and tau, FDG and PIB PET • AD: CSF AB and tau

  46. INFORMATICS CORE Arthur Toga UCLA

  47. ADNI Extensions • ADNI GO • ADNI 2 • World Wide ADNI

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