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Review
. 2015 Jan;11(1):58-69.
doi: 10.1016/j.jalz.2014.02.004. Epub 2014 May 3.

Clinical utility of cerebrospinal fluid biomarkers in the diagnosis of early Alzheimer's disease

Kaj Blennow  1 , Bruno Dubois  2 , Anne M Fagan  3 , Piotr Lewczuk  4 , Mony J de Leon  5 , Harald Hampel  2
Affiliations
Review

Clinical utility of cerebrospinal fluid biomarkers in the diagnosis of early Alzheimer's disease

Kaj Blennow et al. Alzheimers Dement. 2015 Jan.

Abstract

Several potential disease-modifying drugs for Alzheimer's disease (AD) have failed to show any effect on disease progression in clinical trials, conceivably because the AD subjects are already too advanced to derive clinical benefit from treatment and because diagnosis based on clinical criteria alone introduces a high misdiagnosis rate. Thus, well-validated biomarkers for early detection and accurate diagnosis are crucial. Low cerebrospinal fluid (CSF) concentrations of the amyloid-β (Aβ1-42) peptide, in combination with high total tau and phosphorylated tau, are sensitive and specific biomarkers highly predictive of progression to AD dementia in patients with mild cognitive impairment. However, interlaboratory variations in the results seen with currently available immunoassays are of concern. Recent worldwide standardization efforts and quality control programs include standard operating procedures for both preanalytical (e.g., lumbar puncture and sample handling) and analytical (e.g., preparation of calibration curve) procedures. Efforts are also ongoing to develop highly reproducible assays on fully automated instruments. These global standardization and harmonization measures will provide the basis for the generalized international application of CSF biomarkers for both clinical trials and routine clinical diagnosis of AD.

Keywords: Alzheimer's disease; Biomarkers; Cerebrospinal fluid; Mild cognitive impairment; Tau protein; β-Amyloid.

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Conflict of interest statement

Conflicts of interest: All authors participated in the international Expert Committee meeting (held in April 2012) and were involved in the discussions regarding development and validation of CSF diagnostic assays, which form the basis of this publication. This meeting was held with the unrestricted support of Roche Diagnostics International Ltd. The authors take full responsibility for the manuscript and the industrial partner did not advise or interfere with its content. Each of the authors contributed to the writing, critical review and revision of the article, and approved the final version. K.B. has served as a consultant for Innogenetics, Kyowa Hakko Kirin Pharma, Pfizer, and Roche. H.H. declares no competing financial interests related to the present article. During the last 2 years (2011–2013), he has received lecture honoraria, research grants, and/or travel funding, participated in scientific advisory boards and/or as a consultant to diagnostic and biotechnology companies involved in the manufacture and marketing of biomarkers and/or diagnostics for cognitive impairment and Alzheimer’s disease including Roche Diagnostics, GE Healthcare, Avid, Eli Lilly and Company, GlaxoSmithKline-Biologicals, Jung-Diagnostics, Thermo Fisher Scientific Clinical Diagnostics, and Cytox. H.H. is the coinventor in pending patent submissions relating to biological markers and/or diagnostics and has not received any royalties. A.M.F. is a member of the US Alzheimer’s Disease Advisory Board for Lilly USA. P.L. has received consultation honoraria from Innogenetics and IBL International. Through collaboration with New York University, M.J.de.L. holds patents on PETand MRI image analysis techniques that have been commercially licensed.

Figures

Fig. 1
Fig. 1
The hypothetical model for biomarkers during the development of AD. The figure shows the relation between time (x-axis) and degree of biomarker abnormality (y-axis). Biomarkers for cortical Aβ deposition include CSF Aβ42 and amyloid PET imaging. Neurodegeneration is measured by FDG PET (lowered glucose metabolism in cortical neurons and glial cells) and structural MRI (atrophy), which are drawn concordantly (dark dashed line). Cognitive impairment is illustrated as a zone (dark gray–filled area) with low- and high-risk borders. By definition, all curves converge at the top right-hand corner of the plot, the point of maximum abnormality. CSF, cerebrospinal fluid; Aβ, amyloid β; PET, positron emission tomography; MRI, magnetic resonance imaging; FDG, fluorodeoxyglucose; MCI, mild cognitive impairment. (Adapted from The Lancet Neurology, Vol. 12, Jack CR Jr, Knopman DS, Jagust WJ, Petersen RC, Weiner MW, Aisen PS, et al., Tracking pathophysiological processes in Alzheimer’s disease: an updated hypothetical model of dynamic biomarkers., 207-16,2013, with permission from Elsevier.)
See this image and copyright information in PMC

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