TY - JOUR
T1 - Variability of CSF Alzheimer's Disease Biomarkers: Implications for Clinical Practice
AU - Vos, Stephanie J. B.
AU - Visser, Pieter Jelle
AU - Verhey, Frans
AU - Aalten, Pauline
AU - Knol, Dirk
AU - Ramakers, Inez
AU - Scheltens, Philip
AU - Rikkert, Marcel G. M. Olde
AU - Verbeek, Marcel M.
AU - Teunissen, Charlotte E.
PY - 2014/6/24
Y1 - 2014/6/24
N2 - Background: Cerebrospinal fluid (CSF) biomarkers are increasingly being used for diagnosis of Alzheimer's disease (AD). Objective: We investigated the influence of CSF intralaboratory and interlaboratory variability on diagnostic CSF-based AD classification of subjects and identified causes of this variation. Methods: We measured CSF amyloid-beta (A beta) 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. Results: CSF intralaboratory variability was higher for A beta 1-42 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 A beta 1-42, 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 Ab1-42 and t-tau, and reanalysis led to a change in biomarker classification of 12% of the subjects based on A beta 1-42, 1% based on t-tau, and 22% based on p-tau. Conclusions: Intralaboratory and interlaboratory CSF variability frequently led to change in diagnostic CSF-based AD classification for A beta 1-42 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.
AB - Background: Cerebrospinal fluid (CSF) biomarkers are increasingly being used for diagnosis of Alzheimer's disease (AD). Objective: We investigated the influence of CSF intralaboratory and interlaboratory variability on diagnostic CSF-based AD classification of subjects and identified causes of this variation. Methods: We measured CSF amyloid-beta (A beta) 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. Results: CSF intralaboratory variability was higher for A beta 1-42 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 A beta 1-42, 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 Ab1-42 and t-tau, and reanalysis led to a change in biomarker classification of 12% of the subjects based on A beta 1-42, 1% based on t-tau, and 22% based on p-tau. Conclusions: Intralaboratory and interlaboratory CSF variability frequently led to change in diagnostic CSF-based AD classification for A beta 1-42 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.
U2 - 10.1371/journal.pone.0100784
DO - 10.1371/journal.pone.0100784
M3 - Article
C2 - 24959687
SN - 1932-6203
VL - 9
JO - PLOS ONE
JF - PLOS ONE
IS - 6
M1 - e100784
ER -