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

From the Department of Psychiatry (M.E., K.B., S.J.T., H.H.), Institute of Anaesthesiology (B.H.), Ludwig-Maximilian University, Munich, Germany; Discipline of Psychiatry and Trinity College Institute of Neuroscience (TCIN) (M.E., H.H.), School of Medicine, Trinity College Dublin, Trinity Centre for Health Sciences, The Adelaide and Meath Hospital Incorporating The National Children’s Hospital (AMiNCH), Dublin, Ireland; VU University Medical Centre Amsterdam (P.S., F.H.B, N.S.M.S.), The Netherlands; Department of Psychiatry (J.S., P.S.), Section of Geriatric Psychiatry, University of Heidelberg, Germany; Applied NeuroSolutions (R.P.Z., J.F.D., D.J.K.), Vernon Hills, IL; Department of Neurobiology (N.A.), Caring Sciences and Society, Department of Geriatric Medicine, Karolinska University Hospital, Huddinge, Sweden; and Department of Neuroscience and Physiology (A.W, K.B.), Sahlgren’s Academy at Göteborg University, Sahlgren’s University Hospital, Mölndal, Sweden.

Address correspondence and reprint requests to Professor Harald Hampel or Dr. Michael Ewers, Discipline of Psychiatry, School of Medicine, Trinity College Dublin, Trinity Centre for Health Sciences, The Adelaide and Meath Hospital, Incorporating The National Children’s Hospital (AMiNCH), Tallaght, Dublin 24, Ireland Harald.Hampel{at}tcd.ie or ewersm{at}tcd.ie

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.

Abbreviations: AD = Alzheimer disease; ANCOVA = analysis of covariance; CERAD = Consortium to Establish a Registry for Alzheimer’s Disease; MCI = mild cognitive impairment; MMSE = Mini-Mental State Examination; ROC = receiver operating characteristic.

Disclosure: Drs. J.F. DeBernardis, D.J. Kerkman, and R.P. Zinkowski are employees of Applied NeuroSolutions Inc., Vernon Hills, IL, and have stocks and stock options.

Received October 9, 2006. Accepted in final form June 7, 2007.

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