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

Stephanie J B Vos,Pauline Aalten,Inez Ramakers,Marcel M Verbeek,Philip Scheltens,Dirk Knol,Pieter Jelle Visser,Marcel G M Olde Rikkert,Frans Verhey,Charlotte E Teunissen,Gianluigi Zanusso

doi:10.1371/journal.pone.0100784

Stephanie J B Vos, Pauline Aalten + Show 9 more

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https://doi.org/10.1371/journal.pone.0100784

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Abstract

BackgroundCerebrospinal fluid (CSF) biomarkers are increasingly being used for diagnosis of Alzheimer’s disease (AD).ObjectiveWe investigated the influence of CSF intralaboratory and interlaboratory variability on diagnostic CSF-based AD classification of subjects and identified causes of this variation.MethodsWe 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.ResultsCSF 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.ConclusionsIntralaboratory 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.

Highlights

Amyloid-b (Ab) 1-42, total tau (t-tau), and phosphorylated tau (p-tau) proteins in cerebrospinal fluid (CSF) are well-established biomarkers for Alzheimer’s disease (AD) [1,2,3], and are increasingly being used for diagnosis in clinical practice
It was hypothesized that change of diagnosis would be lower for analyses performed in the same laboratory than for analyses performed in different laboratories because Cerebrospinal fluid (CSF) intralaboratory variability has been reported to be lower than interlaboratory variability (2.3–25% vs. 13–38%) [5,6,7]
Intralaboratory Variability CSF Ab1-42 and t-tau levels were higher and p-tau levels were lower after reanalysis in the same laboratory (p,0.05 for all analysis, Figure 1A, Figure S2A)

Summary

Introduction

Amyloid-b (Ab) 1-42, total tau (t-tau), and phosphorylated tau (p-tau) proteins in cerebrospinal fluid (CSF) are well-established biomarkers for Alzheimer’s disease (AD) [1,2,3], and are increasingly being used for diagnosis in clinical practice. Previous studies reported considerable intra- or interlaboratory variability of CSF analyses [4,5,6,7], which may influence the diagnostic classification. We hypothesized that the change of diagnosis would be largest for classification of subjects based on CSF Ab1-42, as previous studies showed larger variability for CSF Ab1-42 than for t-tau and p-tau [5,6,7]. Cerebrospinal fluid (CSF) biomarkers are increasingly being used for diagnosis of Alzheimer’s disease (AD)

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