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Original Contribution
August 2002

Differential Diagnosis of Alzheimer Disease With Cerebrospinal Fluid Levels of Tau Protein Phosphorylated at Threonine 231

Author Affiliations

From the Dementia Research Section and Memory Clinic, Alzheimer Memorial Center, Geriatric Psychiatry Branch, Department of Psychiatry (Drs Buerger, Teipel, Padberg, Möller, and Hampel), and the Department of Anesthesiology (Dr Hofmann-Kiefer), Ludwig-Maximilian University, Munich, Germany; the Molecular Geriatrics Corporation, Vernon Hills, Ill (Drs Zinkowski, DeBernardis, Kerkman, and Kohnken and Ms McCulloch); the Department of Neuroscience and Neurology, University Hospital, University of Kuopio, Kuopio, Finland (Drs Tapiola and Pirttilä); the Department of Geriatric Medicine, Tohoku University School of Medicine, Sendai, Japan (Dr Arai); the Unit of Neurochemistry, Department of Clinical Neuroscience, University of Göteborg, Sahlgren's University Hospital, Mölndal, Sweden (Dr Blennow); the Department of Rehabilitation, Pitea River Valley Hospital, Pitea, Sweden (Dr Andreasen); the Division of Pediatric Neurology, Children's Hospital Medical Center, Cincinnati, Ohio (Dr Schapiro); the Brain Physiology and Metabolism Section, National Institute on Aging, National Institutes of Health, Bethesda, Md (Dr Rapoport); and the Department of Pathology, Albert Einstein College of Medicine, Bronx, NY (Dr Davies). Dr Andreasen is now affiliated with the Division of Geriatric Medicine, Karolinska Institutet, Neurotec, Huddinge University Hospital, Stockholm, Sweden.

Arch Neurol. 2002;59(8):1267-1272. doi:10.1001/archneur.59.8.1267

Background  Phosphorylation of tau protein at threonine 231 (using full-length tau, 441 amino acids, for the numbering scheme) (p-tau231) occurs specifically in postmortem brain tissue of patients with Alzheimer disease (AD) and can be sensitively detected in cerebrospinal fluid (CSF).

Objectives  To determine to what extent CSF levels of p-tau231 distinguish patients with AD from control subjects and from patients with other dementias, and to investigate whether p-tau231 levels are a better diagnostic marker than levels of total tau protein (t-tau) in CSF.

Design and Setting  Cross-sectional, multicenter, memory clinic–based studies.

Participants  One hundred ninety-two patients with a clinical diagnosis of AD, frontotemporal dementia (FTD), vascular dementia, Lewy body dementia, or other neurological disorder and healthy controls.

Main Outcome Measures  Levels of CSF tau proteins as measured with enzyme-linked immunosorbent assays.

Results  Mean CSF levels of p-tau231 were significantly elevated in the AD group compared with all other groups. Levels of p-tau231 did not correlate with dementia severity in AD, and discriminated with a sensitivity of 90.2% and a specificity of 80.0% between AD and all non-AD disorders. Moreover, p-tau231 levels improved diagnostic accuracy compared with t-tau levels when patients with AD were compared with healthy controls (P = .03) and demented subjects (P<.001), particularly those with FTD (P<.001), but not those with vascular and Lewy body dementias. Sensitivity levels between AD and FTD were raised by p-tau231 compared with t-tau levels from 57.7% to 90.2% at a specificity level of 92.3% for both markers.

Conclusion  Increased levels of CSF p-tau231 may be a useful, clinically applicable biological marker for the differential diagnosis of AD, particularly for distinguishing AD from FTD.