# Presentation: 786421

## MR SPECTROCOPYAND MRITO MEASURE TREATMENT OF NEURODEGENERATION

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

## MR SURROGATES FOR AD

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

## 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

## Multislice 1 H MRSI (TE = 135ms)

- MRI

- NAA

- Cr

- Cho

**A**

**B**

## Comparison of [NAA] in Hippocampus and Frontal Lobe

- [NAA]

- Hp

- Hippocampus

- * p < 0.05

- Frontal Lobe

- *

- HC

- AD

-  SIVD

- CI

- 1.4

- 1.2

- 1

- 0.8

- 0.6

- 0.4

- 0.2

- 0

- HC

- AD

-  SIVD

- CI

- *

- *

## Rates of Cortical NAA and Cho Changes 

- NAA

- Cho

- Control (15)
- CI (12)
- AD (11)

## 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**

## PULSED ARTERIAL SPIN LABELED PERFUSION MRI

- PULSED ARTERIAL SPIN LABELED PERFUSION MRI

- MRI slices

- AlternationTag/Sat

- EPISTAR - QUIPPS II*

- Model

- *E. Wong et al. Magn Reson Med. 1998; 39:702-8

**Notes:**
Here is a brief review of the method. 
We used QUippSII sequence 

## MULTISLICE PERFUSION DATA

- Normal (#892)

- AD (#1022)

## Regional Cerebral Blood Flow in Normal Aging and AD 

**Regional Cerebral Blood Flow in Normal Aging and AD **

**In Units of [ml/100mg tissue/min]**

## 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

## Atrophy Rates in Normal Aging and AD

## Relationship between Atrophy Rates and Memory in AD* 

- Relationship between Atrophy Rates and Memory in AD*

- *DLR = Delayed List Recall at baseline; Includes AD patients with DLR > 0

## Sample Size for 20% treatment effectOne year trial

## 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!**

## 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***

## 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

## 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

## 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