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Katharina Buerger, MD; Raymond Zinkowski, PhD; Stefan J. Teipel, MD; Tero Tapiola, MD; Hiroyuki Arai, MD, PhD; Kaj Blennow, MD, PhD; Niels Andreasen, MD, PhD; Klaus Hofmann-Kiefer, MD; John DeBernardis, PhD; Daniel Kerkman, PhD; Cheryl McCulloch, BS; Russell Kohnken, PhD; Frank Padberg, MD; Tuula Pirttilä, MD, PhD; Marc B. Schapiro, MD; Stanley I. Rapoport, PhD; Hans-Jürgen Möller, MD; Peter Davies, PhD; Harald Hampel, MD

Arch Neurol. 2002;59:1267-1272.

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.

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.

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