# Presentation: 047248

## Presented 

- by
- William Jagust, M.D.
- at the
- November 18, 2002
- Peripheral and Central Nervous System
- Advisory Committee
- meeting

## Why is PET a Good Potential Surrogate Marker in AD?

**PET is a good assay for tissue biochemistry and physiology that is related to disease process**
**PET is highly related to cognitive function and predictive of cognitive decline**
**PET is sensitive, reliable, and valid as a marker for AD pathology**
**PET provides statistically powerful measures of decline**

## PET Tracers Relevant to AD

**Radioligands that bind to acetylcholinesterase**
**	****Reflect cholinergic function**
**Radioligands that bind to amyloid**
**	****Reflect unknown characteristics of amyloid pathology**
**Fluorodeoxyglucose**
**	****Synaptic activity**

## Cholinergic Ligands in AD

**Kuhl et al, Neurology 1999**

## Markers of Alzheimer’s Disease:

**AD1**

**AD2**

**C**

**Markers of Alzheimer’s Disease:**
**Temporal-Parietal Hypometabolism**

## Posterior Cingulate Hypometabolism

## FDG PET and AD Diagnosis

**Hoffman et al., J Nucl Med 2000 (N=22)**
**Pathologically confirmed AD**
**	****sensitivity 90%, specificity 65%**
**Silverman et al., JAMA 2001**
**Progressive dementia (N=146)**
**	****sensitivity 93%, specificity 76%**
**Pathologically confirmed AD (N=138)**
**	****sensitivity 94%, specificity 73%**

## FDG-PET Predicts Decline

**Baseline PET predicts MMSE change in AD patients (Jagust et al., 1996)**
**Baseline PET predicts decline from memory-impairment to dementia (Minoshima et al, 1997)**
**Baseline PET predicts memory decline in nondemented ApoE4 carriers (Small et al, 2000)**
**Baseline PET predicts decline from normal to MCI (DeLeon et al., 2001)**

## PET Metabolic Rates Predict Rate of Decline in AD

- <date/time>

**PET Metabolic Rates Predict Rate of Decline in AD**

**MMSE**
**Change**

**Post Temp Ctx rCMRglc**
**        ****(mg/100g/min)**

**r=0.58**

## Regional Glucose Metabolism is Correlated with Cognitive Function

**Regional Glucose Metabolism is Correlated with Cognitive Function**

**left temporal lobe**

**left hippocampus**

**Delayed Recall**

## 2-year Glucose Metabolic Decline in Asymptomatic ApoE 4 Heterozygotes

**2-year ****Glucose Metabolic Decline in Asymptomatic ApoE 4 Heterozygotes**

**Reiman et al., PNAS 2001**

## Slide 12

## Asymptomatic Subjects Per Treatment Group to Detect a Drug Effect in Two YearsPost Cingulate rCMRglc, 80% Power, p = 0.01, two tailed

**Estimated Drug Treatment Effect**

**Number of Subjects**

**Reiman et al, PNAS 2001**

## AD Patients per Treatment Group to Detect a Drug Effect in 1 yearFrontal rCMRglc, 80% Power, p = 0.01, two tailed

**Estimated Drug Treatment Effect**

**Number of Subjects**

**Reiman et al**

## FDG-PET as a Surrogate: PositivesLink between PET and clinical decline

**PET predicts clinical decline**
**Biologically plausible – “on the pathway for AD”**
**	****sensitive and specific for pathology**
**	****related to pathology, synaptic function**
**	****correlated with cognition**
**Statistically powerful**

## FDG-PET as a Surrogate: NegativesLink Between PET and Disease Modification

**Problem**
**Inability to distinguish symptomatic from disease-modifying drug effects**
**Solutions**
**Randomized start or withdrawal design**
**Use PET tracers that reflect basic biology of AD: amyloid imaging agents**
**Assess PET in symptomatic drug treatments**

## Technical Considerations

**Standardization of multisite acquisition**
**	****state**
**	****input function**
**	****attenuation correction**
**	****resolution**
**Standardization of data analysis**
**	****quantitation: metabolic rates, ratios**
**	****regions-of-interest, atlas and voxel-based**

## Summary

**FDG PET shows potential as a surrogate but clearly has not been confirmed**
**Very sensitive in detecting decline, and statistically powerful**
**Strong links with clinical symptoms and pathology, questions on disease modification**
**Incorporation of PET in clinical trials will help address questions**