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

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.

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.)