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fter age 50, the majority of us will have trouble remembering where we left the house keys 10 minutes ago. But for some, these short-term memory problems are just the first stage in a progression toward Alzheimer's disease.

Doctors have not been able to distinguish between short-term memory loss associated with early Alzheimer's disease and those "senior moments" that occur during normal aging. If doctors could diagnose people who are more likely to get Alzheimer's, those identified could be targeted for new treatments that might prevent the dementia. And the "worried well" would be relieved they are not at risk.

In a study led by Dr. Scott Small, Irving Assistant Professor of Neurology, a group of P&S researchers report they can differentiate between memory decline due to either normal aging or what might become Alzheimer's disease in the hippocampus. The research, which used a new application of functional MRI (fMRI), was published Jan. 18 in the online version of Annals of Neurology.

Dr. Small's group focused on the hippocampus because brain biopsies from people with early stage Alzheimer's only show plaques and tangles characteristic of the disease in this region of the brain. As the disease progresses, the pathology spreads to the rest of the brain. The hippocampus also is involved in short-term memory processing. Dr. Small's group asked if they could characterize subregions in the hippocampus where function either declined with age or from a disease process.

To see the subregions the investigators employed an improved fMRI, an imaging technique that detects oxygenated hemoglobin as blood flows through the brain. Classical fMRI measures transient changes in the amount of oxyhemoglobin when the brain is engaged in a task (more oxygen means better function), but can find changes only in large structures. Dr. Small's technique measures more permanent changes in oxyhemoglobin levels, allowing him to see smaller structures in the brain.

Using his new technique, Dr. Small studied how well four subregions in the hippocampus—the entorhinal cortex, the subiculum, the dentate gyrus, and the CA1—functioned in 70 people ranging from 20 to 88 years of age. The researchers measured the function of each subregion by the amount of oxyhemoglobin detected while the brain was not engaged in a task, what the researchers called resting oxygen. Brain regions with diminished functional integrity will have lower resting oxygen compared with regions that are functionally intact.

Dr. Small then tried to find a disease-related pattern in the resting oxygen levels in each subregion. He separated the 70 subjects into two groups, young and old, and drew a graph of the distribution of resting oxygen levels in each group (see diagram). When normal processes are at work, resting oxygen levels will be distributed normally in each group, taking on the shape of the familiar bell curve. But if disease affects resting oxygen, only some people in the population will have the condition, and the shape of the curve will be skewed. The researchers looked for this distortion—measured by a greater width of the curve—in the older group when they compared the curves of the old and young.

In two subregions—the dentate gyrus and the subiculum—resting oxygen was lower in the older group on average, but the width of the curves stayed the same. The similar shaped curves indicate that even though function in these two subregions declines with age, the decline is due to normal processes. Because the decline is normal, Dr. Small says it's unlikely older people with low resting oxygen in these two subregions will get Alzheimer's disease.

But the two other subregions show a different pattern. In the entorhinal cortex, average resting oxygen also declined with age, but the width of the curve increased, indicating a disease process causes the shift. In CA1, both disease and normal aging seemed to play a role in declining levels.

Dr. Small found that diminished function in the hippocampus was associated with memory decline because he had given each of the subjects in the study memory tests. Thirty of the older subjects were tested annually for five years. He found that 18 seniors who showed diminished oxygen levels in at least one of four hippocampal subregions were less likely to remember words in the test than the other 12, who had the same resting oxygen as the younger people. fMRIs showed seven of the 18 seniors had dysfunction in the entorhinal cortex.

Since brain biopsies also suggest the entorhinal cortex is the first hippocampus subregion affected by Alzheimer's disease, Dr. Small thinks low resting oxygen here may be among the first signs of Alzheimer's. Dr. Small is continuing to use his fMRI technique to monitor the hippocampal regions of the 30 older people from the study. He predicts that seven people with the diminished resting oxygen in the entorhinal cortex are more likely to progress to Alzheimer's during the next few years. He also is recruiting more elderly people into the study to replicate the findings of the Annals study.

If he can reproduce results and changes in the entorhinal region predict who will get Alzheimer's, the technique could someday be used to diagnose the disease when patients first notice memory loss, not years later when they are suffering from dementia. Earlier diagnosis should allow the development of new drugs to be used earlier in the disease. Current drugs are not very effective at treating Alzheimer's disease.

Researchers are studying other neuroimaging techniques to diagnose Alzheimer's, but none are ready for the clinic. PET scans, for example, show brain abnormalities when the patient already has dementia but cannot pick up physiological changes in subregions, such as in the entorhinal cortex where minor memory loss is the first sign of the disease.

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