ABSTRACT
BACKGROUND: Ongoing 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 ß-Amyloid 1-42 (restandardized to Certified Reference Materials), ß-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. METHODS: Intra- 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. RESULTS: The 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 Aß40) to 0.98 (for t-Tau), with those for Aß42 (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 Aß40, and with the Aß42/40, Aß42/t-Tau, and Aß42/p-Tau ratios outperforming Aß42. 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%). CONCLUSIONS: The 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.
Subject(s)
Alzheimer Disease/diagnosis , Amyloid beta-Peptides/cerebrospinal fluid , Peptide Fragments/cerebrospinal fluid , tau Proteins/cerebrospinal fluid , Aged , Alzheimer Disease/cerebrospinal fluid , Biomarkers/cerebrospinal fluid , Enzyme-Linked Immunosorbent Assay/methods , Female , Humans , Male , Middle AgedABSTRACT
OBJECTIVE: To determine the cutoffs that optimized the agreement between 18 F-Florbetapir positron emission tomography (PET) and Aß1-42, Aß1-40, tTau, pTau and their ratios measured in cerebrospinal fluid (CSF) on the LUMIPULSE G600II instrument, we quantified the levels of these four biomarkers in 94 CSF samples from participants of the Sant Pau Initiative on Neurodegeneration (SPIN cohort) using the Lumipulse G System with available 18 F-Florbetapir imaging. METHODS: Participants had mild cognitive impairment (n = 35), AD dementia (n = 12), other dementias or neurodegenerative diseases (n = 41), or were cognitively normal controls (n = 6). Levels of Aß1-42 were standardized to certified reference material. Amyloid scans were assessed visually and through automated quantification. We determined the cutoffs of CSF biomarkers that optimized their agreement with 18 F-Florbetapir PET and evaluated concordance between markers of the amyloid category. RESULTS: Aß1-42, tTau and pTau (but not Aß1-40) and the ratios with Aß1-42 had good diagnostic agreement with 18 F-Florbetapir PET. As a marker of amyloid pathology, the Aß1-42/Aß1-40 ratio had higher agreement and better correlation with amyloid PET than Aß1-42 alone. INTERPRETATION: CSF biomarkers measured with the Lumipulse G System show good agreement with amyloid imaging in a clinical setting with heterogeneous presentations of neurological disorders. Combination of Aß1-42 with Aß1-40 increases the agreement between markers of amyloid pathology.
