Derivation of cutoffs for the Elecsys^® amyloid β (1–42) assay in Alzheimer's disease

Abstract

Introduction An Elecsys® Amyloid β (Aβ [1–42]) immunoassay cutoff for classification of patients with Alzheimer's disease was investigated. Methods Cerebrospinal fluid samples collected from patients with mild-to-moderate Alzheimer's disease were analyzed by Elecsys® immunoassays: (1) Aβ (1–42), (2) total tau, and (3) phosphorylated tau. Cutoffs (Aβ [1–42] and ratios with tau) were estimated by method comparison between AlzBio3 ( n = 206), mixture modeling ( n = 216), and concordance with florbetapir F 18 imaging-based classification ( n = 75). Results A 1065-pg/mL (95% confidence interval: 985–1153) Elecsys® Aβ (1–42) cutoff provided 94% overall percentage agreement with AlzBio3. Comparable cutoff estimates (95% confidence interval) were derived from mixture modeling (equally weighted: 1017 [949–1205] pg/mL; prevalence weighted: 1172 [1081–1344] pg/mL) and concordance with florbetapir F 18 imaging (visual read: 1198 [998–1591] pg/mL; automated: 1198 [1051–1638] pg/mL). Discussion Based on three approaches, a 1100-pg/mL Elecsys® Aβ (1–42) cutoff is suitable for clinical trials with similar populations and preanalytical handling.

Evolution of Alzheimer's Disease Cerebrospinal Fluid Biomarkers in Early Parkinson's Disease

“…Moreover, low baseline CSF Aβ 42 in this PD cohort was, overall, associated with lower baseline levels of CSF t-tau and p-tau, rather than higher levels of CSF tau as in preclinical and clinical AD cohorts. 16 Table 4), which is opposite than expected; however, there was heterogeneity in values with higher overall range in these analytes than seen in PD. Our observed frequency of 31% of early PD with positive AD CSF biomarker profile is similar to autopsy data in end-stage PD, 1 but lower than a previous study using a CSF p-tau/Aβ 42 ratio to designate AD positive profile.…”

“…Biorepository Core Laboratories to the University of Pennsylvania (Penn) Biomarker Research Laboratory for measurement of CSF Aβ 42 , total-tau (t-tau) and phosphorylated tau at threonine 181 position (p-tau) using Elecsys electrochemiluminescence immunoassays on the cobas e 601 analysis platform (Roche Diagnostics) as described. 16,18 The analytical measurement range for the Aβ 42 assay was 200 to 1,700 pg/mL, the t-tau assay was 80 to 1,300 pg/mL, and the p-tau 181 assay: 8 to 120 pg/ mL. Roche extrapolated values above the upper technical limit from the calibration curve, 1,700 pg/mL, in 96 measurements of Aβ 42 .…”

“…To characterize the AD CSF profile of patients with PD and HCs we applied a cut off point for amyloid-positivity established in AD. 16 To mitigate differences in pre-analytical factors between PPMI and AD cohorts that influence CSF Aβ 42 levels, 24 we used the transformation formula from Shaw et al 25 For longitudinal analyses we focused on core AD CSF biomarkers (Aβ 42 , t-tau, and p-tau), rather than ratios of these analytes, to more directly test biomarker associations. To assess the difference in mean change from baseline for each AD CSF analyte between the patients with PD and control groups, we used rank-based linear mixed models (LMMs) with adjustment for age, sex, and the baseline value of the CSF outcome.…”

“…Finally, we examined cross-sectional profiles of patients with presumed amyloid-positivity in patients with PD and HCs at baseline using an established cut off point in AD. 16 We found at baseline, relative equal frequencies of pathologically low CSF Aβ 42 indicative of amyloidosis (+A) in patients with PD (31.5%) and HCs (27.7%; Table 4) with no differences in demographics between PD + A and PD with normal CSF Aβ 42 (−A) or HC + A and HC -A; however, there were lower CSF t-tau, p-tau, and aSyn levels in PD + A vs PD -A (effect size = 0.29-0.45; p < 0.0001). In contrast, there was no difference in CSF p-tau between HC + A and HC -A, but CSF p-tau was lower in PD + A than HC + A (effect size = 0.19; p < 0.03), suggesting a divergent interaction between AD CSF biomarkers in PD compared with controls (see Table 4).…”

“…One obstacle to longitudinal CSF studies is interand intra-assay variation, 15 which could reduce the sensitivity to detect changes between repeated measurements from an individual over time in longitudinal biomarker studies. The Roche Elecsys analytical platform is fully automated with high reliability for measurement of AD CSF biomarkers [16][17][18] and was previously validated with a reference measurement procedure approved by the Joint Committee for Traceability in Laboratory Medicine for CSF Aβ 42 . 19 Parkinson Progression Markers Initiative (PPMI 20 ) is a unique multicenter international observational study collecting long term annual detailed harmonized clinical measures and biomarkers in a large cohort of newly diagnosed drug-naïve PD.…”