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A Comparative Cerebrospinal Fluid Study

Harald Hampel, MD; Katharina Buerger, MD; Raymond Zinkowski, PhD; Stefan J. Teipel, MD; Alexander Goernitz, MD; Niels Andreasen, MD, PhD; Magnus Sjoegren, MD; John DeBernardis, PhD; Daniel Kerkman, PhD; Koichi Ishiguro, PhD; Hideto Ohno, PhD; Eugeen Vanmechelen, PhD; Hugo Vanderstichele, PhD; Cheryl McCulloch, BS; Hans-Jürgen Möller, MD; Peter Davies, PhD; Kaj Blennow, MD, PhD

Arch Gen Psychiatry. 2004;61:95-102.

Background  Abnormal hyperphosphorylation of the microtubule-associated protein tau and its incorporation into neurofibrillary tangles are major hallmarks of the pathogenesis of Alzheimer disease (AD). Different tau phosphoepitopes can be sensitively detected in cerebrospinal fluid (CSF).

Objective  To compare the diagnostic accuracy of CSF concentrations of tau proteins phosphorylated at 3 pathophysiologically important epitopes (p-tau) to discriminate among patients with AD, nondemented control subjects, and patients with other dementias.

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

Participants  One hundred sixty-one patients with a clinical diagnosis of AD, frontotemporal dementia, dementia with Lewy bodies, or vascular dementia and 45 nondemented controls (N = 206).

Main Outcome Measures  Levels of tau protein phosphorylated at threonine 231 (p-tau₂₃₁), threonine 181 (p-tau₁₈₁), and serine 199 (p-tau₁₉₉). The CSF p-tau protein levels were measured using 3 different enzyme-linked immunosorbent assays.

Results  The mean CSF levels of the studied p-tau proteins were significantly elevated in patients with AD compared with the other groups. Applied as single markers, p-tau₂₃₁and p-tau₁₈₁ reached specificity levels greater than 75% between AD and the combined non-AD group when sensitivity was set at 85% or greater. Statistical differences between the assay performances are presented. Particularly, discrimination between AD and dementia with Lewy bodies was maximized using p-tau₁₈₁at a sensitivity of 94% and a specificity of 64%, and p-tau₂₃₁ maximized group separation between AD and frontotemporal dementia with a sensitivity of 88% and a specificity of 92%. Combinations of the 3 markers did not add discriminative power compared with the application as single markers.

Conclusions  The p-tau proteins in CSF come closest to fulfilling the criteria of a biological marker of AD. There is a tendency for p-tau proteins to perform differently in the discrimination of primary dementia disorders from AD.

From the Dementia Research Section and Memory Clinic, Alzheimer Memorial Center and Geriatric Psychiatry Branch, Department of Psychiatry, Ludwig-Maximilian University, Munich, Germany (Drs Hampel, Buerger, Teipel, Goernitz, and Möller); Applied NeuroSolutions Inc, Vernon Hills, Ill (Drs Zinkowski, DeBernardis, and Kerkman and Ms McCulloch); Karolinska Institute, Neurotec, Division of Geriatric Medicine, Huddinge University Hospital, Stockholm, Sweden (Dr Andreasen); the Department of Clinical Neuroscience, Unit of Neurochemistry, University of Göteborg, Sahlgren's University Hospital, Mölndal, Sweden (Drs Sjoegren and Blennow); Mitsubishi Kagaku Institute of Life Sciences, Tokyo, Japan (Dr Ishiguro); Mitsubishi Kagaku Medical, Tokyo (Dr Ohno); Innogenetics NV, Gent, Belgium (Drs Vanmechelen and Vanderstichele); and the Department of Pathology, Albert Einstein College of Medicine, Bronx, NY (Dr Davies). Drs Hampel and Davies are consultants for Applied NeuroSolutions Inc. Drs Zinkowski, DeBernardis, Kerkman, and Davies have stock and employee stock options and Ms McCulloch has employee stock options from Applied NeuroSolutions Inc.

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