The jury is still out on the ability of brain biomarkers to predict Alzheimer’s disease in people with mild cognitive impairment, according to a study published May 20 online in Annals of Neurology.
The study was a field test of the National Institute on Aging-Alzheimer’s Association (NIA-AA) diagnostic guidelines for mild cognitive impairment (MCI) from Alzheimer’s disease, which propose that the presence of two neuroimaging biomarkers – amyloid and neurodegeneration – makes it highly likely that MCI will progress to Alzheimer’s, and that the presence of one, if the other is untested, conveys an intermediate risk (Alzheimers Dement. 2011;7:270-9).
The investigators found both of the markers in 46% of 212 MCI patients, one of the findings that led them to conclude that the "NIA-AA criteria apply to most MCI subjects in both the community and clinical trials settings" and that the "the proposed addition of biomarkers to the clinical diagnosis of MCI is largely valid."
However, they also found that "a sizeable proportion of subjects had conflicting biomarkers" that didn’t fit neatly into the model and require further exploration (Ann. Neurol. 2013 May 20 [doi: 10.1002/ana.23931]).
"Do these biomarkers work? Maybe, yes. Time will tell," lead investigator Dr. Ronald C. Petersen told an audience May 9 at Northwestern University in Chicago, explaining the findings."Conflicting markers are a problem. We clearly need more data," said Dr. Peterson, who is director of the Alzheimer’s Disease Research Center at the Mayo Clinic in Rochester, Minn.
His team enrolled 154 MCI patients from the Mayo Clinic Study of Aging (MCSA), a longitudinal study of patients without dementia, aged 70-89 years at enrollment, who are randomly selected from Olmsted County, Minn. In addition, 58 amnestic MCI patients (median age, 75 years) were enrolled from the Alzheimer’s Disease Neuroimaging Initiative-1 (ADNI-1), a longitudinal, multisite observational study into the early detection of Alzheimer’s. After their initial evaluation, the MCSA patients were reassessed at 15 months and the ADNI-1 patients at 12 months.
Among the findings inconsistent with the proposed NIA-AA mode, "29% of the MCSA subjects and 17% of the ADNI-1 subjects had evidence for neurodegeneration without amyloid deposition," the authors wrote. The model would suggest that "by the time of symptomatic impairment with MCI, both amyloid and neurodegeneration should be present," they noted.
Adding to the complexity, they also found that the neurodegeneration-positive but amyloid-negative group "had the highest rate of progression to dementia" on follow-up in the MCSA (7/36) cohort and the second highest in the ADNI-1 (2/10) cohort, bringing into question the salience of amyloid.
"These are very preliminary numbers; we don’t put a lot of faith in them," said Dr. Petersen. The final validation of the use of biomarkers will come from longitudinal studies.
Even so, biomarker research "is starting to tell us a pattern," he said. The cumulative acquisition of markers with clinical symptoms "does portend the likelihood that somebody is going to progress. But we have to sort out" the details, he said.
The presence of amyloid was assessed by Pittsburgh Compound B-PET scans; neurodegenerative findings were assessed by fluorodeoxyglucose PET scans and MRI measures of hippocampal volume. "We considered a subject positive for evidence of neurodegeneration if one or both measures" were positive, the investigators noted.
Dr. Petersen is the chair of Pfizer’s data monitoring committee, the chair of Janssen Alzheimer Immunotherapy’s data monitoring committee, and a consultant to Elan and GE Healthcare. The study was funded by the National Institute on Aging, the Robert H. and Clarice Smith and Abigail van Buren Alzheimer’s Disease Research Program, and other sources.