The role of neuroimaging in dementia is no longer limited to diagnosis. Investigators are now showing that neuroimaging is useful for monitoring the progression of brain changes, and for monitoring the efficacy of drugs that might slow down the progression of Alzheimer’s disease.

One of the earliest changes that occur in Alzheimer’s disease is atrophy of the medial temporal lobe. Within the medial temporal lobe are two structures: the hippocampus and the entorhinal cortex. These structures degenerate very early in the disease. This effect appears to be very strongly correlated with the cognitive deficits in Alzheimer’s disease and the future rate of decline. Therefore, measurements of these brain structures might be useful as a surrogate marker to gauge the degree of brain degeneration and to predict rate of decline in patients with Alzheimer’s disease.

Modern imaging techniques allow investigators to measure the volumes of brain structures with a high degree of accuracy and validity. Therefore, there is increasing interest in using these measurements as an outcome measure in clinical trials of neuroprotective drugs. In stroke, multiple sclerosis and other diseases, magnetic resonance imaging is already established as an outcome measure in clinical trials.

Magnetic resonance (MR) spectroscopy is one imaging technique under development for outcome measures in Alzheimer’s clinical trials. This imaging technique measures a brain chemical called N-acetyl-aspartate. There is of a lot of interest in this metabolite because it is only found inside nerve cells. Investigators consider it as a marker of a living nerve cell. As nerve cells die, the levels of N-acetyl-aspartate declines. Therefore, a measurement of the amount of N-acetyl-aspartate in a particular brain region is a good indicator of how many living nerve cells there are in a region and how well they are functioning.

Dr. Doraiswamy presented results of the first randomized, controlled trial in which investigators looked at the effect of an Alzheimer’s disease treatment on magnetic resonance imaging markers in the brain.

This trial included 77 patients with mild to moderate probably Alzheimer’s disease. Scores on the Mini-Mental State Exam ranged from 10 to 26. These patients received 24 weeks of donepezil or placebo, followed by a 6-week washout period.

All patients underwent magnetic resonance imaging of the brain at baseline and every 6 weeks during the trial. In addition, they underwent evaluation with the cognitive subscale of the Alzheimer’s Disease Assessment Scale (ADAS-cog) at baseline and every 6 weeks thereafter. In addition, investigators measured hippocampal volumes at baseline and week 24.

Data from the ADAS-cog evaluations showed that patients receiving donepezil did substantially better than placebo at every time point. The mean difference at the end of 24 weeks was approximately 3 points. Dr. Doraiswamy said this was similar to results of larger randomized multicenter trials, pointing to the validity of this smaller trial.

The imaging findings of this study suggest that donepezil increased levels of N-acetyl-aspartate between weeks 6 and 18 in a variety of brain regions (white, periventricular, and subcortical gray matter). However, the difference in N-acetyl-aspartate levels versus placebo was not significant at the 24- or 30-week evaluations.

Data on hippocampal volumes were somewhat surprising to investigators. Some expected to see no significant differences between hippocampal volumes in donepezil versus placebo. This was because of the small size and short duration of the trial. However, they found that hippocampal volumes declined by 8.2% from baseline to 24 weeks in the placebo group. By comparison, volumes declined by only 0.37%. This difference was statistically significant (p < 0.01).

Findings like this could have important implications for the development of Alzheimer’s disease treatments. Until now, the treatment of symptoms has been the main indication for Alzheimer’s disease drugs. If neuroimaging can conclusively prove that drugs slow the rate of brain atrophy, the drug may receive an indication for slowing the progression of Alzheimer’s disease. In the future, clinical trial investigators will increasingly use imaging markers alongside clinical markers as outcome measures in patients with dementia.