Imaging the Living Brain - Alzheimer's

Cortical Thinning

Researchers continue to search for imaging biomarkers (brain changes visible by MRI or other imaging methods) that can predict who will develop Alzheimer's. Scientists at Massachusetts General Hospital, Boston, and Rush University Medical Center, Chicago, identified a signature of structural changes in the brains of cognitively normal older people that strongly predicted which of them would develop Alzheimer's (Dickerson et al., 2011). They had previously identified nine regions of the cerebral cortex that thinned out in people with mild Alzheimer's.

In this study of 65 cognitively normal study participants, the researchers identified a subgroup who showed significant thinning in the same cortical areas. They determined that this group was more than three times more likely to develop Alzheimer's dementia over the next 10 years. The cortical thinning signature appears to predict risk for Alzheimer's more accurately than shrinkage of the hippocampus, a more commonly studied MRI biomarker for the disorder.

Beta-Amyloid Imaging

Positron emission tomography (PET) imaging of brain beta-amyloid is increasingly used in research for detecting early stages of Alzheimer's. Pittsburgh Compound B, or PiB, is the radioactive agent commonly used in PET imaging to light up amyloid levels in the brain. However, the use of PiB imaging is largely restricted to major research centers due to PiB's short half-life: its signal fades by half within 20 minutes, so it must be made onsite. A team led by researchers at Avid Radiopharmaceuticals reported results with a new beta-amyloid tracer, florbetapir (also known as Amyvid), which has a much longer half-life of 110 minutes (Clark et al., 2011).

The researchers analyzed florbetapir-PET images from nearly 30 people who died within several months after their PET scans were done, and they also performed post mortem analyses of the brains to look for Alzheimer's pathology. About half of the group had Alzheimer's confirmed at autopsy. The researchers found a 96 percent agreement in determining the presence of Alzheimer's pathology between the florbetapir-PET images and post mortem results. At this time, florbetapir is approved by the U.S. Food and Drug Administration to help rule out Alzheimer's as a cause of memory and behavior changes.

Acetylcholine is an important neurotransmitter critical to attention and memory. In Alzheimer's disease, brain cells that produce acetylcholine are known to die. Research has shown that as the disorder progresses, neurons lose their stores of choline acetyltransferase (ChAT), the enzyme that produces acetylcholine. The loss of ChAT activity is associated with cognitive impairment. Indeed, University of Pittsburgh, PA, researchers studied the precuneus region, which plays a role in attention and memory.

The researchers found reduced ChAT in the precuneus region at autopsy in people with Alzheimer's but not in those with MCI (Ikonomovic et al., 2011). In addition, this decline occurred only after significant beta-amyloid had accumulated in the precuneus. This finding suggests that the window of time immediately following the onset of amyloid accumulation in the precuneus may be a particularly critical period for drugs that enhance acetylcholine production.

Imaging Brain Glucose Uptake

Cognitive tests are frequently used to evaluate new therapeutics in clinical trials. However, a volunteer's performance on a cognitive test may vary depending on the conditions under which the test is administered, and some test results may not accurately reflect their ability to carry out everyday tasks and social activities.

Investigators at the University of California, Berkeley, found that FDG-PET imaging, which measures glucose metabolism in the brain, was a more reliable tool than a commonly used cognitive test for monitoring Alzheimer's progression (Landau et al., 2011). The researchers studied more than -00 volunteers enrolled in ADNI over 2 years. Individuals who had low brain glucose metabolism at the start of the study were more likely to show subsequent cognitive and functional decline. Moreover, statistical analyses indicated that FDG-PET data would be more sensitive than the ADAS-Cog, a cognitive test frequently used for assessing drug treatments.