Compared to biomarkers, functional and cognitive measures seem to better predict conversion from mild cognitive impairment to Alzheimer’s disease.
A decline on the Functional Assessment Questionnaire and the Trail Making Test, part B, was significantly more accurate in predicting 12-month conversion than were any of the biomarkers assessed in a subanalysis of the Alzheimer’s Disease Neuroimaging Initiative (ADNI), according to Jesus Gomar, Ph.D., and his colleagues. Their report was published in the September issue of Archives of General Psychiatry.
Functional and cognitive changes might be more useful than biomarkers at predicting conversion, because they are the ones upon which the diagnosis of Alzheimer’s is based, wrote Dr. Gomar of Centro de Investigation Biomedica en Red de Salud Mental, Barcelona, and his coauthors.
The finding suggests that diagnostic conversion reflects not so much a physical progression of disease as a large functional decline, the investigators noted.
"Different biomarkers and behavioral markers may have differentially predictive values at different times in disease progression," the authors wrote. "That is, biomarkers are dynamic and they will vary in their informativeness depending on when they are measured. ... They may be most informative in the very early prodromal stages, a perspective that has been incorporated into proposed diagnosis criteria for preclinical [Alzheimer’s]" (Arch. Gen. Psych. 2011;68:961-9).
The substudy included 517 subjects who were studied over a 2-year period: 204 with mild cognitive impairment (MCI) who did not convert to AD, 116 with MCI who did convert, and 197 controls.
There was not a significant age difference between the groups. However, there were some significant baseline differences in function and cognitive status, including the Mini Mental State Exam (MMSE), the Clinical Dementia Rating (CDR) sum of boxes score, and the Functional Assessment Questionnaire (FAQ).
For all of these measures, nonconverters scored significantly worse at baseline than did converters. The mean MMSE score was 27.3 for nonconverters vs. 26.6 for converters. The mean CDR score was 1.46 in nonconverters vs. 1.84 in converters. And the mean FAQ score was 2.72 in nonconverters vs. 5.76 in converters.
Also, a significant difference was found in the prevalence of the apolipoprotein epsilon 4, the genetic variant that confers an increased risk of Alzheimer’s. Among the nonconverters, 45% carried the gene, compared with 66% of those who converted.
The study also assessed numerous biomarkers, including whole brain, ventricle, temporal and hippocampal volume; cortical thickness at different brain regions; and the tau /Ab42 ratio in cerebrospinal fluid. The nonconverters and converters had significantly different measures on all of these areas.
However, in a multivariate logistic regression model, only three measures were significantly associated with conversion over a 2-year period: delayed logistical memory, delayed auditory verbal learning recall, and left middle temporal lobe cortical thickness. Taken together, the positive predictive value of the markers was 65%, and the negative predictive value, 75%.
"In effect, it appeared to us that many MCI patients may already have met cognitive criteria for AD, and the diagnostic trigger had little to do with a shift in the disease trajectory," the authors said. "In addition to this possibility, we suggest that a second smaller factor in conversion may reflect compromises in executive and cognitive control functions that reduce compensatory potential."
When examining conversion within 12 months, only two cognitive factors were significantly associated with 12-month progression: The baseline- to 12-month FAQ difference score and the baseline- to 12-month Trails B score.
"Remarkably, they accounted for nearly 50% of the predictive variance," the authors said. For this combination, the area under the curve was 0.85, with a specificity of 93% and a sensitivity of 52%.
Dr. Gomar reported no financial conflicts. Two other study authors reported financial relationships with Merck, GlaxoSmithKline, and Applied Neurosciences. The ADNI substudy was sponsored by the Litwin0Zucker Alzheimer’s Center and the Instituto de Salud Carlos III.