MR SPECTROCOPY AND MRI TO MEASURE TREATMENT OF NEURODEGENERATION

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MR SPECTROCOPYAND MRITO MEASURE TREATMENT OF
NEURODEGENERATION

• MICHAEL W. WEINER
• Professor of Radiology, Medicine, Psychiatry, and
  Neurology, U.C.S.F.

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MR SURROGATES FOR AD

• What is needed
• Specificity measure of neurodegeneration
• Sensitivity maximum statistical power to
  determine treatment effects
• MRS, perfusion MRI, structural MRI

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MAGNETIC RESONANCE SPECTROSCOPY (MRS)MEASURES
METABOLITES

• N-acetyl aspartate ( NAA) a neuronal marker
• Measure of neuronal number/density
• Sensitive to changes of neuronal metabolism
• Choline metabolites membranes
• Creatine energy metabolism
• Myo-inositol proposed as a glial marker

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Multislice 1 H MRSI (TE 135ms)
MRI
NAA
B
A
Cr
Cho
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Comparison of NAA in Hippocampus and Frontal
Lobe
1.4

1.2


1
NAA
0.8
0.6
AD
SIVD
CI
AD
SIVD
CI
HC
HC
0.4
0.2
0
Frontal Lobe
Hp
Hippocampus
p lt 0.05
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Rates of Cortical NAA and Cho Changes
Control (15) CI (12) AD (11)
NAA
Cho
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LONGITUDINAL MRS

• Pfefferbaum et al (Lancet 2001) found a NAA
  decrease of 12/yr
• Krishnan et al found that donepezil increased NAA
  and improved cognition
• Satlin (AJP 1997) found xanomeline decreased
  Cho/Cr
• Conclusion Insufficient data concerning MRS as
  an outcome measure for AD

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PULSED ARTERIAL SPIN LABELED PERFUSION MRI
Model
EPISTAR - QUIPPS II
MRI slices
AlternationTag/Sat
E. Wong et al. Magn Reson Med. 1998 39702-8
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MULTISLICE PERFUSION DATA
Normal (892)
AD (1022)
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Regional Cerebral Blood Flow in Normal Aging and
AD
In Units of ml/100mg tissue/min
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STRUCTURAL MRI

• Brain atrophy has face validity as a measure of
  neurodegeneration
• Different measures of brain atrophy
• Whole brain, hippocampus, temporal horn
• Reported on different groups of subjects
• Difficult to compare methods

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Atrophy Rates in Normal Aging and AD
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Relationship between Atrophy Rates and Memory in
AD
DLR Delayed List Recall at baseline Includes
AD patients with DLR gt 0
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Sample Size for 20 treatment effectOne year
trial
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CONCLUSION

• Structural MRI has high power to detect
  longitudinal change in AD
• Structural MRI is a relatively specific, measure
  of neurodegeneration
• Not affected by brain activity or metabolism
• PET, MRS are sensitive to activity/metabolism
• Structural MRI correlates with cognition
• MUCH MORE WORK NEEDED!

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CONCLUSION

• MRI is useful in Phase II
• MRI is an unvalidated surrogate
• Not a primary outcome for Phase III
• However, structural MRI is currently useful to
• Provide confirmatory evidence of effect
• Provide evidence of disease modification

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WHAT IS NEEDED

• Standards for MRI, MRS, PET so that studies can
  be compared
• Correlations of imaging data with
  cognition/function/pathology
• Data from multiple sites for powering of future
  trials

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WHAT IS NEEDED II

• A longitudinal multi-site observational
  (non-treatment) trial of Controls, MCI, AD using
• MRI, PET
• Cognition
• Biomarkers
• Supported by NIA together with Pharma

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ACKNOWLEDGEMENTS

• VA Norbert Schuff, Antao Du, Colin Studholme,
  Valerie Cardenes Nickelson,Geon-Ho Jahng
• UCSF Joel Kramer, Bruce Miller, Kristine Yaffe
• SIVD PPG Helena Chui, William Jagust, Bruce
  Reed, Dan Mungas
• National Institutes of Aging, VA