A multicenter study has found that CSF biomarkers can identify incipient Alzheimer’s disease with good accuracy, but less accurately than has been reported from single-center studies, according to a report in the July 22/29 JAMA.
Niklas Mattsson, MD, of Sahlgrenska University Hospital in Mölndal, Sweden, and colleagues, sought to determine the diagnostic accuracy of CSF beta-amyloid1-42 (Aβ 42), total tau protein (T-tau), and tau phosphorylated at position threonine 181 (P-tau) in predicting incipient Alzheimer’s disease in patients with mild cognitive impairment (MCI). A cross-sectional study of patients with Alzheimer’s disease and controls to identify cut points was followed by a prospective cohort study of patients with MCI; in total, 750 persons with MCI, 529 with Alzheimer’s disease, and 304 controls were recruited from 12 centers throughout Europe and the United States from 1990 to 2007. Those with MCI were followed up for two years, or until symptoms progressed to clinical dementia. Sensitivity, specificity, positive and negative likelihood ratios of CSF, Aβ 42, T-tau, and P-tau for identifying incipient Alzheimer’s disease were the main outcome measures.
“During follow-up, 330 cases with MCI showed progression of cognitive symptoms to clinical dementia,” Dr. Mattsson and colleagues stated. “Of these, 271 were diagnosed as having Alzheimer’s disease (ie, had incipient Alzheimer’s disease at baseline), and 59 with other types of dementia, including 28 with vascular dementia, 14 with dementia with Lewy bodies, 7 with frontotemporal dementia, and 10 with neurologic diseases and dementia.” Of those with MCI, 420 did not progress to dementia during follow-up.
The annual rate of Alzheimer’s disease diagnosis was approximately 11% in the first four study years in the MCI sample. The median time to conversion was 24 months among patients with Alzheimer’s disease, compared with 30 months for vascular dementia patients, 12 months for patients with dementia with Lewy bodies, 22 months in frontotemporal dementia patients, and 36 months in patients with other dementias.
Intercenter assay differences complicated comparisons. “Substantial differences in CSF Aβ 42 levels were seen, while differences in T-tau and P-tau were much smaller,” Dr. Mattsson and his team commented.
The cutoff equation achieved sensitivity of 83% when the investigators compared patients with MCI and incipient Alzheimer’s disease (specificity of 88%, positive likelihood ratio of 7.0, negative likelihood ratio of 0.17). When only patients with MCI were observed, the specificity was 72% (positive likelihood ratio of 3.0, negative likelihood ratio of 0.24, positive predictive value of 62%, and negative predictive value of 88%). “The relative risk for incipient Alzheimer’s disease in MCI patients with a positive result on this equation was 5.2,” Dr. Mattsson and colleagues stated. “When testing the equation for patients with MCI who had incipient Alzheimer’s disease vs those who had developed specific other dementias, the specificity varied between 57% and 86% for the different follow-up diagnoses.”