Variability of CSF Alzheimer's disease biomarkers: implications for clinical practice

• Published in: PloS one 2014-06, Vol.9 (6), p.e100784-e100784
• Main Authors: Vos, Stephanie J B, Visser, Pieter Jelle, Verhey, Frans, Aalten, Pauline, Knol, Dirk, Ramakers, Inez, Scheltens, Philip, Rikkert, Marcel G M Olde, Verbeek, Marcel M, Teunissen, Charlotte E
• Format: Article
• Language: English
• Subjects: Alzheimer Disease - cerebrospinal fluid; Alzheimer Disease - diagnosis; Alzheimer's disease; Amyloid; Amyloid beta-Peptides - cerebrospinal fluid; Biological markers; Biology and Life Sciences; Biomarkers; Biomarkers - cerebrospinal fluid; Cerebrospinal fluid; Classification; Clinical medicine; Cognition & reasoning; Cognitive ability; Dementia; Diagnostic systems; Enzyme-linked immunosorbent assay; Enzymes; Humans; Immunoassays; Laboratories; Measurement methods; Medicine and Health Sciences; Mental health; Neurodegenerative diseases; Neurology; Neuropsychology; Neurosciences; Psychiatry; Quality control; Reproducibility of Results; Studies; Tau protein; tau Proteins - cerebrospinal fluid; Variability
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0100784

Cerebrospinal fluid (CSF) biomarkers are increasingly being used for diagnosis of Alzheimer's disease (AD). We investigated the influence of CSF intralaboratory and interlaboratory variability on diagnostic CSF-based AD classification of subjects and identified causes of this variation. We measured CSF amyloid-β (Aβ) 1-42, total tau (t-tau), and phosphorylated tau (p-tau) by INNOTEST enzyme-linked-immunosorbent assays (ELISA) in a memory clinic population (n = 126). Samples were measured twice in a single or two laboratories that served as reference labs for CSF analyses in the Netherlands. Predefined cut-offs were used to classify CSF biomarkers as normal or abnormal/AD pattern. CSF intralaboratory variability was higher for Aβ1-42 than for t-tau and p-tau. Reanalysis led to a change in biomarker classification (normal vs. abnormal) of 26% of the subjects based on Aβ1-42, 10% based on t-tau, and 29% based on p-tau. The changes in absolute biomarker concentrations were paralleled by a similar change in levels of internal control samples between different assay lots. CSF interlaboratory variability was higher for p-tau than for Aβ1-42 and t-tau, and reanalysis led to a change in biomarker classification of 12% of the subjects based on Aβ1-42, 1% based on t-tau, and 22% based on p-tau. Intralaboratory and interlaboratory CSF variability frequently led to change in diagnostic CSF-based AD classification for Aβ1-42 and p-tau. Lot-to-lot variation was a major cause of intralaboratory variability. This will have implications for the use of these biomarkers in clinical practice.