Multicenter assessment of CSF-phosphorylated tau for the prediction of conversion of MCI

Abstract

Background: The measurement of hyperphosphorylated tau (p-tau) in CSF has been proposed as a biomarker candidate for the prediction of Alzheimer disease (AD) in patients with mild cognitive impairment (MCI). However, a standard quantitative criterion of p-tau has not been evaluated. Objective: To assess in a multicenter study the predictive accuracy of an a priori defined criterion of tau phosphorylated at threonine 231 (p-tau₂₃₁) for the prediction of conversion from MCI to AD during a short-term observation interval. Methods: The study included 43 MCI converters, 45 stable MCI (average follow-up interval = 1.5 years), and 57 healthy controls (at baseline only). Subjects were recruited at four international expert sites in a retrospective study design. Cox regression models stratified according to center were used to predict conversion status. Bootstrapped 95% CIs of classification accuracy were computed. Results: Levels of p-tau₂₃₁ were a significant predictor of conversion (B = 0.026, p = 0.001), independent of age, gender, Mini-Mental State Examination, and ApoE genotype. For an a priori–defined cutoff point (27.32 pg/mL), sensitivity ranged between 66.7 and 100% and specificity between 66.7 and 77.8% among centers. The bootstrapped mean percentage of correctly classified cases was 79.95% (95% CI = 79.9 to 80.00%). Post hoc defined cutoff values yielded a mean bootstrapped classification accuracy of 80.45% (95% CI = 80.24 to 80.76%). Conclusions: An a priori defined cutoff value of p-tau₂₃₁ yields relatively stable results across centers, suggesting a good feasibility of a standard criterion of p-tau₂₃₁ for the prediction of Alzheimer disease.