Abstract
BackgroundOngoing efforts within the Alzheimer’s disease (AD) field have focused on improving the intra- and inter-laboratory variability for cerebrospinal fluid (CSF) biomarkers. Fully automated assays offer the possibility to eliminate sample manipulation steps and are expected to contribute to this improvement. Recently, fully automated chemiluminescence enzyme immunoassays for the quantification of all four AD biomarkers in CSF became available. The aims of this study were to (i) evaluate the analytical performance of the Lumipulse G β-Amyloid 1-42 (restandardized to Certified Reference Materials), β-Amyloid 1-40, total Tau, and pTau 181 assays on the fully automated LUMIPULSE G600II; (ii) compare CSF biomarker results of the Lumipulse G assays with the established manual ELISA assays (INNOTEST®) from the same company (Fujirebio); and (iii) establish cut-off values and the clinical performance of the Lumipulse G assays for AD diagnosis.MethodsIntra- and inter-assay variation was assessed in CSF samples with low, medium, and high concentrations of each parameter. Method comparison and clinical evaluation were performed on 40 neurological controls (NC) and 80 patients with a diagnosis of probable AD supported by a follow-up ≥ 3 years and/or positive amyloid PET imaging. A small validation cohort of 10 NC and 20 AD patients was also included to validate the cut-off values obtained on the training cohort.ResultsThe maximal observed intra-assay and inter-assay coefficients of variation (CVs) were 3.25% and 5.50%, respectively. Method comparisons revealed correlation coefficients ranging from 0.89 (for Aβ40) to 0.98 (for t-Tau), with those for Aβ42 (0.93) and p-Tau (0.94) in-between. ROC curve analysis showed area under the curve values consistently above 0.85 for individual biomarkers other than Aβ40, and with the Aβ42/40, Aβ42/t-Tau, and Aβ42/p-Tau ratios outperforming Aβ42. Validation of the cut-off values in the independent cohort showed a sensitivity ranging from 75 to 95% and a specificity of 100%. The overall percentage of agreement between Lumipulse and INNOTEST was very high (> 87.5%).ConclusionsThe Lumipulse G assays show a very good analytical performance that makes them well-suited for CSF clinical routine measurements. The good clinical concordance between the Lumipulse G and INNOTEST assays facilitates the implementation of the new method in routine practice.
Highlights
Ongoing efforts within the Alzheimer’s disease (AD) field have focused on improving the intra- and inter-laboratory variability for cerebrospinal fluid (CSF) biomarkers
The aims of this study were to (i) evaluate the analytical performance of the Lumipulse G β-Amyloid 1-42, βAmyloid 1-40, total Tau, and pTau 181 assays on the fully automated LUMIPULSE G600II platform; (ii) compare CSF biomarker results of the Lumipulse G assays with the established manual enzyme-linked immunosorbent assays (ELISA) assays (INNOTEST® βAMYLOID(1-42), INNOTEST β-AMYLOID(1-40), INNOTEST hTAU Ag, and INNOTEST PHOSPHO-TAU(181P)); and (iii) establish cut-offs and the clinical performance of the Lumipulse G assays for AD diagnosis
The female-to-male ratio was similar in both groups, and the percentage of Apolipoprotein E (ApoE)-ε4 carriers in AD patients was over 53%, considerably higher than what we have previously shown in a Portuguese control population [42]
Summary
Ongoing efforts within the Alzheimer’s disease (AD) field have focused on improving the intra- and inter-laboratory variability for cerebrospinal fluid (CSF) biomarkers. In CSF, a combination of low levels of the 42-aminoacid isoform of amyloid beta (Aβ42) and high levels of total tau (t-Tau) and phosphorylated tau (p-Tau) is thought to reflect the two widely accepted pathophysiological hallmarks of AD: amyloid plaques and neurofibrillary tangles [2]. In clinical practice, these biomarkers are useful to detect or exclude AD, to make a prognosis at the Mild Cognitive Impairment (MCI) stage, and to guide patients’ management, in atypical and clinically challenging cases [3, 4]. When an effective drug for AD is available, CSF biomarkers will become even more important in guiding the diagnosis and management of clinical cases
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