1. MR SPECTROCOPY AND MRI TO MEASURE TREATMENT OF NEURODEGENERATION MICHAEL W. WEINER Professor of Radiology, Medicine, Psychiatry, and Neurology, U.C.S.F.

2. MR SURROGATES FOR AD What is needed: –Specificity: measure of neurodegeneration –Sensitivity: maximum statistical power to determine treatment effects MRS, perfusion MRI, structural MRI

3. 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

4. Multislice 1 H MRSI (TE = 135ms) B - gray matter A - white matter MRINAA CrCho A B

5. Comparison of [NAA] in Hippocampus and Frontal Lobe [NAA] Hp Hippocampus * p < 0.05 Frontal Lobe * HC AD SIVDCI 1.4 1.2 1 0.8 0.6 0.4 0.2 0 HC AD SIVDCI * *

6. Rates of Cortical NAA and Cho Changes NAA Cho Control (15) CI (12) AD (11)

7. 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

8. PULSED ARTERIAL SPIN LABELED PERFUSION MRI MRI slices Alternation Tag/Sat EPISTAR - QUIPPS II* Model *E. Wong et al. Magn Reson Med. 1998; 39:702-8

9. MULTISLICE PERFUSION DATA Normal (#892) AD (#1022)

10. Regional Cerebral Blood Flow in Normal Aging and AD In Units of [ml/100mg tissue/min]

11. 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

12. Atrophy Rates in Normal Aging and AD

13. Relationship between Atrophy Rates and Memory in AD* *DLR = Delayed List Recall at baseline; Includes AD patients with DLR > 0

14. Sample Size for 20% treatment effect One year trial

15. 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!

16. 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

17. 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

18. 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

19. 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