Structural MRI as a Biomarker of Disease Progression in AD

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Structural MRI as a Biomarker of Disease
Progression in AD

• Department of Diagnostic Radiology
• and MRI Research Lab

Presented by Clifford Jack, M.D. at the November
18, 2002 Peripheral and Central Nervous System
Drugs Advisory Committee Meeting
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Indirect measures of disease can be valid
biomarkers of progression

• provided a plausible biologic link exists between
  change in the marker and progression of the
  disease itself
• changes in the marker are empirically proven to
  track with independent measures of progression

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Applicable MR Measurements

• Structural MRI (linkcell loss to atrophy)
• MR Spectroscopy
• Functional MRI
• Proton Diffusion
• Perfusion
• Relaxometry
• Magnetization Transfer
• Amyloid Plaque Imaging

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The Rate of Medial Temporal Lobe Atrophy in
Typical Aging and Alzheimers Disease

• Neurology 199851993-999

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Objectives

• To determine the annualized rates of volume
  change of the hippocampus and temporal horn in
  cognitively normal elderly control subjects and
  individually matched AD patients
• To test the hypothesis that these rates were
  different

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Characterization Of Subjects
Controls(n24) Cases (n24) Mean
SD Mean SD Age 81.04 3.78 yrs 80.42
4.02 yrs Education 14.75 2.51 yrs 13.21
2.83 yrs MMSE 28.79 1.28 20.74
4.60 DRS 137.38 4.69 108.48
14.35 Interval Between MRI 1.96 0.75 yrs 1.89
0.68 yrs Studies
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Annual Percent Volume Change

• Controls (n24) Cases (n-24)
  P-value
• Mean ? SD Mean ? SD
• Hippocampal -1.6?1.4 -4.0?1.9
  lt0.001
• Temporal Horn 6.2?7.69 14.2?8.5
  0.002
• Rank sum test of difference between cases and
  controls

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Conclusion

• Reasonable 1st step expected differences in
  rates between AD and controls were observed, but
  it did not prove that changes in imaging tracked
  with changes in independent measures of disease
  progression
• Rates were approximately 2.5 times greater in AD
  than in individually age and gender matched
  control

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Rates of Hippocampal Atrophy in Normal Aging,
Mild Cognitive Impairment, and Alzheimer's
Disease

• Neurology, 200055484-489

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ObjectiveTransition Analysis

• To test the hypothesis that change on imaging
  (rates of hippocampal atrophy) match clinical
  change
• Use clinical transition (or lack of) as gold
  standard independent measures of progression

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Methods

• 129 subjects from the ADRC/ADPR who met
  established criteria for normal controls, mild
  cognitive impairment (MCI), or probable AD at
  entry
• Controls and MCI patients could either remain
  cognitively stable or could decline
• MRI at initial FU clinical assessment

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Descriptive Information
Age at 1st MMSE Duration between
MRI baseline and
followup MRI in years Normal-Stable
80.4 6.4 28 1.6 3.0
0.5 (N48) (62, 97) (23, 30) (2.0,
3.9) Normal-Decliner 82.3 5.8 28 1.7
3.3 0.4 (N10) (76, 95) (25, 30)
(2.7, 4.0) MCI-Stable 77.9 8.0 24 1.9
2.9 0.5 (N25) (60, 92) (23, 30)
(2.1, 4.0) MCI-Decliner 77.3 8.0 24
3.2 2.9 0.6 (N18) (64, 94) (18,
30) (2.1, 3.9) AD 73.8
11.3 22 4.3 2.9 0.5 (N28) (51,
93) (14, 29) (2.1, 3.9)
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PERCENT ANNUAL CHANGE IN HIPPOCAMPAL VOLUME BY
FOLLOWUP CLINICAL GROUP

• Normal-Stable (N 48) -1.7 0.9
• Normal-Decliner (N 10) -2.8 1.7
• MCI-Stable (N 25) -2.5 1.5
• MCI-Decliner (N 18) -3.7 1.5
• AD (N 28) -3.5 1.8

Values in table represent mean SD (range)
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Conclusion

• Rates of hippocampal atrophy match the change in
  cognitive status (or lack of) over time in
  elderly persons who lie along the cognitive
  continuum from normal to MCI to AD
• Validation of change in MRI volume as a biomarker
  of Dz progression

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Rates of Atrophy by Technique and by Clinical
Group
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Objective

• Are some techniques better measures of
  progression than others at different disease
  stages?
• To compare the annualized rates of atrophy by
  technique among clinical groups (normal -stable,
  normal-converter, MCI -stable, MCI-converter,
  AD-slow progressor, and AD-fast progressor)

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Structures Measured Rates of Change

• Hippocampus
• Entorhinal Cortex (ERC)
• Whole Brain
• Ventricle

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Whole Brain
Ventricle GROUP Ann ch GMM
GMM HF ERC Normal Stable
Mean -0.4 1.8 -1.5
-2.7 Normal Converter Mean
-0.7 3.3 -3.1 -5.3 MCI Stable
Mean -0.4 2.8 -1.8
-4.8 MCI Converter Mean
-0.9 4.0 -4.0 -6.8 AD Slow
Progressor Mean -1.3 4.2 -3.5
-7.2 AD Fast Progressor Mean
-1.6 6.6 -5.2 -10.2 SDSD
0.8 2.3 3.0 4.7
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(Mean1-Mean2) Whole Brain
Ventricle (SD1SD1)(SD2SD2) GMM GMM
HF ERC Normal Stable vs.
0.37 0.92 0.88
0.83 Normal Converter
MCI Stable
vs 0.87 0.56 1.00
0.38 MCI Converter

AD Slow Progressor vs
0.25 0.72 0.42
0.41 AD Fast Progressor
Normal Stable
vs 1.32 1.95 1.22
1.52 AD Fast Progressor

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Conclusions

• Structural MRI rates consistently follow expected
  correlations with clinical status and clinical
  transition support for use as biomarker of Dz
  progression
• Appears to be some stage specific Dx sensitivity

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Multi-Site Studies

• Milamilene
• Objective To assess the technical feasibility of
  using MRI measurements as a surrogate end point
  for disease progression in a therapeutic trial of
  Milamilene for AD

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Methods

• 52 week controlled trial of Milameline, a
  muscarinic receptor agonist, N450
• therapeutic trial itself was not completed
• MRI arm of the study was continued
• 192 subjects from 38 different centers underwent
  2 MRI with 1 yr interval
• hippocampal and temporal horn volume

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Change from Baseline in Behavioral/Cognitive and
MRI Variables
Annual Raw Annual Percent
Change Change Decliners (N192)
(N192) ADAS-Cog 4.1
16.4 65.1 MMSE -1.9 -8.4
65.1 GDS 0 0.0 38.5 Total
Hippocampal mm3 -221 -4.9
99.0 Total Temporal Horn Volume mm3 616
16.1 85.4
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Power Calculations

• Per arm for 50 effect size (rate reduction over
  1 yr.)
• ADAS-Cog 320
• MMSE 241
• hippocampal volume 21
• temporal horn volume 54

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Conclusions

• Technical feasibility documented
• Decline over time was more consistently seen with
  imaging measures than behavioral/cognitive
  measures (plt0.001)
• Power calculations sample sizes imagingltlt
  behavioral/cognitive

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Structural MRI as a Biomarker

• In the absence of a positive therapeutic trial
  that incorporated imaging, the best available
  evidence supporting the validity of MRI as a
  biomarker of progression would be multiple
  natural history studies that consistently
  demonstrate concordant MRI and clinical changes

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Acknowledgments

• R01 AG11378
• R01 AG19142
• AG16574 ADRC
• AG06786 ADPR

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Mayo ADRC and ADPR

• Ronald C. Petersen, M.D., Ph.D. Dorla Burton
• Ruth H. Cha, M.S. Dianne Fitch
• Peter C. OBrien, Ph.D. Nancy Haukom
• Steven D. Edland, Ph.D. Kris Johnson
• Robert Ivnik Ph.D. Martha Mandarino
• Glenn E. Smith, Ph.D. Joan
  McCormick
• Bradly F. Boeve, M.D. Sheryl Ness
• Eric G. Tangalos, M.D. Kathy Wytaske
  David Knopman MD

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MILAMILENE Parke-Davis

• M. Slomkowski, Pharm.D.
• S. Gracon, D.V.M.
• T. M. Hoover, Ph.D.

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MR LAB

• Maria Shiung
  Kejal Kantarci
• Jeff Gunter
• Yuecheng Xu
• Mira Senkacova
• Kelly Stewart
• Marina Davtian