Abstract
Cerebrospinal fluid (CSF) biomarkers can enhance the early and accurate etiologic detection of Alzheimer’s disease (AD) even when symptoms are very mild, but are not yet widely available for clinical testing. There are a number of reasons for this, including the need for an experienced operator, the use of instruments mostly reserved for research, and low cost-effectiveness when patient samples do not completely fill each assay plate. Newer technology can overcome some of these issues through automated assays of a single patient sample on existing clinical laboratory platforms, but it is not known how these newer automated assays compare with previous research-based measurements. This is a critical issue in the clinical translation of CSF AD biomarkers because most cohort and clinicopathologic studies have been analyzed on older assays. To determine the correlation of CSF beta-amyloid 1–42 (Aβ42) measures derived from the automated chemiluminescent enzyme immunoassay (CLEIA, on Lumipulse® G1200), a bead-based Luminex immunoassay, and a plate-based enzyme-linked immunoassay enzyme-linked immunosorbent assay (ELISA), we analyzed 30 CSF samples weekly on each platforms over 3 weeks. We found that, while CSF Aβ42 levels were numerically closer between CLEIA and ELISA measurements, levels differed between all three assays. CLEIA-based measures correlated linearly with the two other assays in the low and intermediate Aβ42 concentrations, while there was a linear correlation between Luminex assay and ELISA throughout all concentrations. For repeatability, the average intra-assay coefficient of variation (CV) was 2.0%. For intermediate precision, the inter-assay CV was lower in CLEIA (7.1%) than Luminex (10.7%, p = 0.009) and ELISA (10.8%, p = 0.009), primarily due to improved intermediate precision in the higher CSF Aβ42 concentrations. We conclude that the automated CLEIA generated reproducible CSF Aβ42 measures with improved intermediate precision over experienced operators using Luminex assays and ELISA, and are highly correlated with the manual Aβ42 measures.
Highlights
Cerebrospinal fluid (CSF) levels of proteins and peptides associated with neuritic plaques and neurofibrillary tangles can enhance the accurate etiologic diagnosis of Alzheimer’s disease (AD) (Shaw et al, 2009; Jack et al, 2010, 2018)
Immunoassays targeting Aβ42, t-Tau, and p-Tau181 have predominated the landscape of CSF AD biomarker analysis to date, mass spectrometry-based assays are under development (Pannee et al, 2016)
Regression analysis showed that a quadratic – rather than linear – relationship better converted measures from enzyme linked immunosorbent assays (ELISA) and Luminex to chemiluminescent enzyme immunoassay (CLEIA) due to relatively higher CLEIA measures than ELISA/Luminex measures in the high concentration range [Figure 1, Aβ42CLEIA = 63.32 + 0.32Aβ42ELISA + 0.001Aβ42ELISA2, Aβ42CLEIA = 100 + 0.92Aβ42Luminex + 0.002Aβ42Luminex2 ]
Summary
Cerebrospinal fluid (CSF) levels of proteins and peptides associated with neuritic plaques and neurofibrillary tangles can enhance the accurate etiologic diagnosis of Alzheimer’s disease (AD) (Shaw et al, 2009; Jack et al, 2010, 2018) These markers –beta-amyloid peptides (Aβ38, Aβ40, Aβ42), (Adamczuk et al, 2015; Olsson et al, 2016; Howell et al, 2017) total and phosphorylated tau (Arai et al, 2000; Hampel et al, 2004; Fagan et al, 2009) – are measured in research. Automated Analysis of CSF Aβ42 and commercial laboratories around the world, but there remain key obstacles in their broader application These include the need to purchase a research-based assay platform, preanalytical and analytical variability, (Fourier et al, 2015; Leitao et al, 2015) and the need for experienced operators. We selected 30 human CSF samples representing a range of physiologic Aβ42 levels, characterized the correlation between CSF Aβ42 measurements from different assay types, and assessed the repeatability and intermediate precision of each assay
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