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PROGRESSION TO
ALZHEIMER’S DEMENTIA CAN BE PREDICTED
NEW YORK CITY—The relatively recent discovery of a prodromal phase in Alzheimer’s disease has naturally prompted interest in providing treatment during that phase to stop dementia before it starts. This cannot happen, however, until someone determines how to identify people with prodromal Alzheimer’s disease who are at high risk for dementia—a feasible task, according to Marilyn S. Albert, PhD, because the clinical features of prodromal Alzheimer’s disease are reasonably well documented.
Investigators led by Dr. Albert, who is a Professor of Psychology in the Department of Psychiatry at Harvard Medical School in Boston, have already made substantial progress in that area, showing that it may be possible to accurately predict Alzheimer’s dementia with a combination of neuropsychological and neuroimaging tests. Dr. Albert reported her group’s findings at the 127th Annual Meeting of the American Neurological Association.
ONGOING FOLLOW-UP OF ELDERLY SUBJECTS
The investigators have been closely following 165 elderly adults for six years through regularly scheduled interviews, neuropsychological testing, genetic analyses of blood samples, and magnetic resonance imaging (MRI) and single photon emission computed tomography (SPECT) scans of the brain. The intent, related Dr. Albert, was to distinguish brain and cognitive changes that would allow the investigators to identify prodromal Alzheimer’s disease and to determine if any of the various tests correlated with subsequent dementia.
To qualify for inclusion in the study, the subjects had to report a progressive memory decline, and the decline had to be confirmed by an individual close to them. Of the cohort, 123 participants had a Clinical Dementia Rating of 0.5, suggesting questionable or prodromal Alzheimer’s disease; 42 had a Clinical Dementia Rating of 0 (normal cognition) and were therefore in the control group.
The two groups scored the same on the Mini-Mental State Examination (MMSE), however, indicating that there were no differences in terms of mental status. They were also equal in age (early 70s) and education.
NEUROPSYCHOLOGICAL TEST RESULTS
While some of the controls displayed measurable cognitive decline during follow-up, none of them progressed to Alzheimer’s disease. Compared to subjects with prodromal Alzheimer’s disease who did not subsequently develop dementia, those who did were slightly older and had lower MMSE scores at baseline; these differences were not statistically significant, however, Dr. Albert reported.
Of the 10 memory and executive function tests that the investigators administered, four were especially accurate in a cross-sectional analysis; three of the tests assessed memory and one gauged executive function. “Just using those four tests, we could differentiate 89% of the people who subsequently developed Alzheimer’s disease from the people who were controls,” Dr. Albert said.
For making the most clinically relevant distinctionæwho among those with prodromal Alzheimer’s disease will develop dementia—the four tests showed a bit less accuracy (80%).
In longitudinal analysis, executive function decline at baseline was the strongest dementia predictor among subjects with prodromal Alzheimer’s disease; surprisingly, memory loss alone did not predict dementia in these subjects. Thus, the investigators hypothesized that Alzheimer’s disease is apt to occur within a few years in questionable cases involving reduced executive function. “But if all you have is memory impairment, it is unlikely that you are going to develop Alzheimer’s disease within a few years,” said Dr. Albert.
A SECOND SURPRISE
MRI scanning produced another unexpected finding in the prodromal Alzheimer’s disease group. Those who developed full-blown Alzheimer’s disease during follow-up showed gradual and significant volume reductions in the entorhinal cortex, but not in the hippocampus, before or at diagnosis of Alzheimer’s disease. Why is that unusual? In previous investigations, the hippocampus has shown such steady neuronal loss on MRI but in Dr. Albert’s study the loss was not apparent until Alzheimer’s disease was fully established.
Unfortunately, none of the volume reductions that she and her co-investigators observed in the entorhinal cortex or hippocampus were sufficient to identify prodromal Alzheimer’s disease cases at high risk for dementia. The investigators found that they could accurately discriminate these cases from controls, however, when they looked at the combined volumes of the entorhinal cortex, superior temporal sulcus, and anterior cingulate. As with neuropsychological testing, accuracy declined somewhat when the researchers used the shrinkage in these regions to differentiate prodromal Alzheimer’s disease cases at low and high risk for dementia.
Accuracy dramatically increased, however, when the investigators combined MRI with SPECT images, actually superimposing MRI scans of the entorhinal cortex, superior temporal sulcus, and anterior cingulate onto SPECT scans of the same brain regions. Importantly, the ability to identify prodromal Alzheimer’s disease cases at high risk for dementia also increased dramatically with this technique.
Correlations were observed between the volumes of the three brain regions scanned and relevant neuropsychological test scores, Dr. Albert noted. There was, for example, such a statistical relationship between the volume of the entorhinal cortex and scores on tests of executive function.
NONGENETIC PREDICTOR
Although research has linked homozygosity for the apolipoprotein E (APOE) e4 allele to an increased risk of Alzheimer’s disease, the presence or absence of this genotype was not useful in predicting dementia in Dr. Albert’s cohort. “Even when we add APOE status to neuropsychological measures, MRI, or SPECT, it does not improve discrimination,” she reported.
Nonetheless, she and her colleagues are hopeful that their study and similar investigations will lead to specific diagnostic measures for Alzheimer’s disease and to specific indices of the progression of the disease. “It is very likely that, within the next few years, the kinds of measures that I have [described] will be used in clinical trials and hopefully will lead to better treatments for Alzheimer’s disease,” Dr. Albert concluded.
NR
—Timothy Begany
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