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REGION OF CORTICAL HYPOMETABOLISM COULD HELP PREDICT EARLY-ONSET ALZHEIMER DISEASE

MIAMI BEACH—Results of an imaging study using FDG (fluorine-18-labeled deoxyglucose) PET supports the concept that some of the brain changes in mild cognitive impairment (MCI) anticipate patterns seen in Alzheimer disease (AD), said Pablo Martinez-Lage, MD, of the Memory Disorders Unit in the Department of Neurology at the University of Navarra in Pamplona, Spain.

The study, presented here at the AAN Annual Meeting in April, showed that parietal and left temporal metabolism was significantly reduced in those with MCI compared with controls but still higher than in AD. In AD, they also found subnormal activity in the posterior cingulate gyrus and frontal lobe; this pattern was not observed in mild cognitive impairment, he said.

“This finding in Alzheimer disease patients has been reported previously,” Dr. Martinez-Lage said, “but we were surprised to observe that metabolism was not reduced in the posterior cingulate region in MCI, so it seems to be a later feature of progressive disease,” Dr. Martinez-Lage said.

“We found a region of hypometabolism in AD that has not been previously described in the base of the brain, an area that may include the nucleus basalis of Meynert. The neurons of this cholinergic nucleus start to degenerate in the early stages of AD. If this is confirmed, we could try to detect which patients with MCI are in the earliest stages of AD,” he said.

IMAGING PROTOCOLS

The FDG-PET study included three groups of patients: 24 with MCI, 30 with mild AD, and 28 normal controls. FDG-PET, which involves injecting radiolabeled glucose followed by PET scan, was used to study metabolic activity in various regions of the brain.

All regions in AD patients showed hypometabolism compared with controls. In the MCI, the level of hypometabolism in parietal and left temporal regions was intermediate between AD patients and controls. Posterior cingulate hypometabolism was observed in AD patients, but not in MCI.

“The next step will be to determine the prognostic values of these markers in MCI – that is, will patients with these markers go on to develop AD or not? We are not there yet,” Dr. Martinez-Lage said.

FDG PET is not widely available in the US. However, Dr. Martinez-Lage said that medical insurers in the US now reimburse for use of FDG-PET in the differential diagnosis of AD versus other kinds of dementia – “but not for MCI or early diagnosis of AD.”

GROWING BODY OF EVIDENCE

Commenting on the study, David Knopman, MD, Professor of Neurology at Mayo Clinical College of Medicine in Rochester, MN, said biomarkers, including FDG-PET, are being tested to predict with greater precision which individuals with MCI progress within a year or two to AD. And, he said, the study provided important information toward that end.

A noteworthy aspect of the paper by Dr. Martinez-Lage and colleagues is that they demonstrated differences between patients with MCI and early AD, he continued. “FDG-PET may provide a biological marker of the stage of the disease.”

But Dr. Knopman noted that that Dr. Martinez-Lage conducted a cross-sectional study showing patients at a particular moment in time. Longitudinal data are needed to determine features that are associated with progression to AD over time, he said.

Figure

Dr. Pablo Martinez-Lage: “We found a region of hypometabolism in AD that has not been previously described in the base of the brain, an area that may include the nucleus basalis of Meynert. The neurons of this cholinergic nucleus start to degenerate in the early stages of AD. If this is confirmed, we could try to detect which patients with MCI are in the earliest stages of AD.”

“Generally speaking, establishing the prognostic value of a biomarker takes a large number of subjects who are studied serially over several years. The results presented by Dr. Martinez-Lage represent the first step in that process,” Dr. Knopman said.

MORE PIECES OF THE PUZZLE

This study offers another piece of data suggesting that MCI is an intermediate stage between being normal and having AD, said Ronald Petersen, MD, Professor of Neurology and Director of the Mayo Alzheimer's Disease Research in Rochester, MN.

“The findings of this study showed patterns that tended toward AD but are not the same as fully developed AD,” he noted.

Dr. Petersen said the FDG-PET data are compatible with the clinical picture of MCI, structural data from neuroimaging, biomarker data, and neuropathology studies – all of which show changes in patients with mild cognitive impairment that are similar to those in AD, but of lesser magnitude.

Structural data from neuroimaging studies show that patients with MCI have atrophy of the hippocampus and entorhinal cortex, but not to the degree seen in AD. Changes in two biomarkers from the CSF are in the same direction as in AD, but of lesser magnitude in patients with MCI. These markers are amyloid beta – a marker of amyloid involvement – and tau, a marker of neurofibrillary tangles. In AD, amyloid beta is decreased and tau is increased. In mild cognitive impairment, these changes are less marked but in the same direction, Dr. Petersen continued.

“All of these lines of evidence coalesce to show that mild cognitive impairment is an intermediate stage on the road to AD,” Dr. Petersen commented.

Dr. Petersen said that FDG-PET may be able to detect metabolic changes in patients in the earliest stages of mild cognitive impairment, before clinical changes are apparent. Also, FDG-PET could serve as a marker for response to treatment; if the metabolic patterns improve, that would mean the treatment is working.

“It is not unreasonable to assume that FDG-PET could be useful in these ways, but at present, this is a ‘wish list,’” he said.