Dataset Information

Validation of Immunoassay-Based Tools for the Comprehensive Quantification of A?40 and A?42 Peptides in Plasma.

ABSTRACT: Recent advances in neuroimaging and cerebrospinal fluid (CSF) biomarker assays have provided evidence of a long preclinical stage of Alzheimer's disease (AD). This period is being increasingly targeted for secondary prevention trials of new therapies. In this context, the interest of a noninvasive, cost-effective amyloid-? (A?) blood-based test does not need to be overstated. Nevertheless, a thorough validation of these bioanalytical methods should be performed as a prerequisite for confident interpretation of clinical results. The aim of this study was to validate ELISA sandwich colorimetric ABtest40 and ABtest42 for the quantification of A?40 and A?42 in human plasma. The validation parameters assessed included precision, accuracy, sensitivity, specificity, recovery, and dilution linearity. ABtest40 and ABtest42 proved to be specific for their target peptide using A? peptides with sequence similar to the target. Mean relative error in the quantification was found to be below 7.5% for both assays, with high intra-assay, inter-assay, and inter-batch precision (CV <9.0% on average). Sensitivity was assessed by determination of the limit of quantification fulfilling precision and accuracy criteria; it was established at 7.60 pg/ml and 3.60 pg/ml for ABtest40 and ABtest42, respectively. Plasma dilution linearity was demonstrated in PBS; however, dilution in a proprietary formulated buffer significantly increased the recovery of both A?40 and A?42 masked by matrix interactions, allowing a more comprehensive assessment of the free and total peptide levels in the plasma. In conclusion, both assays were successfully validated as tools for the quantification A?40 and A?42 in plasma.

SUBMITTER: Perez-Grijalba V

PROVIDER: S-EPMC5044780 | biostudies-literature | 2016 Sep

REPOSITORIES: biostudies-literature

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Validation of Immunoassay-Based Tools for the Comprehensive Quantification of Aβ40 and Aβ42 Peptides in Plasma.

Pérez-Grijalba Virginia V Fandos Noelia N Canudas Jesús J Insua Daniel D Casabona Diego D Lacosta Ana M AM Montañés María M Pesini Pedro P Sarasa Manuel M

Journal of Alzheimer's disease : JAD 20160901 2

Recent advances in neuroimaging and cerebrospinal fluid (CSF) biomarker assays have provided evidence of a long preclinical stage of Alzheimer's disease (AD). This period is being increasingly targeted for secondary prevention trials of new therapies. In this context, the interest of a noninvasive, cost-effective amyloid-β (Aβ) blood-based test does not need to be overstated. Nevertheless, a thorough validation of these bioanalytical methods should be performed as a prerequisite for confident in ...[more]

PMID: 27567833

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Project description:Key Points Question Is plasma amyloid-?42/40 (A?42/40) associated with cognitive decline among community-dwelling older adults with memory concerns? Findings In this cohort study of 483 participants from a randomized clinical trial, low plasma A?42/40 ratio was significantly associated with more pronounced decline in composite cognitive score and Mini Mental State Examination score over time. Meaning In this study, low plasma A?42/40 was associated with more pronounced decline in cognitive function over time, suggesting that this marker may be used to identify people at risk of cognitive decline and as an alternative to more complex and expensive measures. This cohort study investigates the associations between plasma amyloid-?42/40 and cognitive decline over time among community-dwelling older adults with subjective memory concerns. Importance Plasma measurement of amyloid-? (A?) peptides has been associated with cognitive function, but evidence of its ability to identify cognitive decline is still scarce. Objective To investigate the associations between plasma A?42/40 and cognitive decline over time among community-dwelling older adults with subjective memory concerns. Design, Setting, and Participants This multicenter cohort study used data from volunteers in the 5-year study Multidomain Alzheimer Preventive Trial (MAPT). Participants were aged 70 years or older and observed for a median (interquartile range) of 3.9 (2.0-4.0) years. Recruitment of participants started in May 2008 and ended in February 2011. Follow-up ended in April 2016. Data analysis was conducted from April to October 2020. Exposure Plasma A?42 and A?40 were measured at 12 months for 448 participants (92.8%) and at 24 months for the rest. The moment of A? assessment was defined as the baseline for this study. Main Outcomes and Measures Cognitive function was assessed at 12, 24, 36, 48, and 60 months by a composite cognitive score based on 4 tests; Mini Mental State Examination (MMSE); Clinical Dementia Rating, sum of boxes; and Alzheimer Disease Cooperative Study–Activities of Daily Living. Mixed-effect linear regressions were performed. Results A total of 483 participants (median [IQR] age, 76.0 [73.0-80.0]; 286 [59.2%] women) were analyzed. Of them, 161 (33.3%) were classified as low plasma A?42/40 (?0.107). After adjusting for age, sex, education, body mass index, Geriatric Depression Scale score, apolipoprotein E ?4 genotype, and MAPT intervention groups, low plasma A?42/40 was associated with more pronounced decline in composite cognitive score (adjusted between-group mean difference: ?0.20, 95% CI, ?0.34 to ?0.07; P?=?.004) and decline in MMSE score (adjusted between-group mean difference: ?0.59; 95% CI, ?1.07 to ?0.11; P?=?.02) during the follow-up period compared with the group with an A?42/40 ratio greater than 0.107. Conclusions and Relevance In this study, low plasma A?42/40 was associated with more pronounced decline in cognitive function (measured by multiple outcomes) over time. Findings suggest that plasma A?42/40 may be used to identify people at risk of cognitive decline, being an alternative to more complex and expensive measures, such as positron emission tomography imaging or cerebrospinal fluid measurement.

Project description:ImportanceBlood-based tests for brain amyloid-β (Aβ) pathology are needed for widespread implementation of Alzheimer disease (AD) biomarkers in clinical care and to facilitate patient screening and monitoring of treatment responses in clinical trials.ObjectiveTo compare the performance of plasma Aβ42/40 measured using 8 different Aβ assays when detecting abnormal brain Aβ status in patients with early AD.Design, setting, and participantsThis study included 182 cognitively unimpaired participants and 104 patients with mild cognitive impairment from the BioFINDER cohort who were enrolled at 3 different hospitals in Sweden and underwent Aβ positron emission tomography (PET) imaging and cerebrospinal fluid (CSF) and plasma collection from 2010 to 2014. Plasma Aβ42/40 was measured using an immunoprecipitation-coupled mass spectrometry developed at Washington University (IP-MS-WashU), antibody-free liquid chromatography MS developed by Araclon (LC-MS-Arc), and immunoassays from Roche Diagnostics (IA-Elc); Euroimmun (IA-EI); and Amsterdam University Medical Center, ADx Neurosciences, and Quanterix (IA-N4PE). Plasma Aβ42/40 was also measured using an IP-MS-based method from Shimadzu in 200 participants (IP-MS-Shim) and an IP-MS-based method from the University of Gothenburg (IP-MS-UGOT) and another immunoassay from Quanterix (IA-Quan) among 227 participants. For validation, 122 participants (51 cognitively normal, 51 with mild cognitive impairment, and 20 with AD dementia) were included from the Alzheimer Disease Neuroimaging Initiative who underwent Aβ-PET and plasma Aβ assessments using IP-MS-WashU, IP-MS-Shim, IP-MS-UGOT, IA-Elc, IA-N4PE, and IA-Quan assays.Main outcomes and measuresDiscriminative accuracy of plasma Aβ42/40 quantified using 8 different assays for abnormal CSF Aβ42/40 and Aβ-PET status.ResultsA total of 408 participants were included in this study. In the BioFINDER cohort, the mean (SD) age was 71.6 (5.6) years and 49.3% of the cohort were women. When identifying participants with abnormal CSF Aβ42/40 in the whole cohort, plasma IP-MS-WashU Aβ42/40 showed significantly higher accuracy (area under the receiver operating characteristic curve [AUC], 0.86; 95% CI, 0.81-0.90) than LC-MS-Arc Aβ42/40, IA-Elc Aβ42/40, IA-EI Aβ42/40, and IA-N4PE Aβ42/40 (AUC range, 0.69-0.78; P < .05). Plasma IP-MS-WashU Aβ42/40 performed significantly better than IP-MS-UGOT Aβ42/40 and IA-Quan Aβ42/40 (AUC, 0.84 vs 0.68 and 0.64, respectively; P < .001), while there was no difference in the AUCs between IP-MS-WashU Aβ42/40 and IP-MS-Shim Aβ42/40 (0.87 vs 0.83; P = .16) in the 2 subcohorts where these biomarkers were available. The results were similar when using Aβ-PET as outcome. Plasma IPMS-WashU Aβ42/40 and IPMS-Shim Aβ42/40 showed highest coefficients for correlations with CSF Aβ42/40 (r range, 0.56-0.65). The BioFINDER results were replicated in the Alzheimer Disease Neuroimaging Initiative cohort (mean [SD] age, 72.4 [5.4] years; 43.4% women), where the IP-MS-WashU assay performed significantly better than the IP-MS-UGOT, IA-Elc, IA-N4PE, and IA-Quan assays but not the IP-MS-Shim assay.Conclusions and relevanceThe results from 2 independent cohorts indicate that certain MS-based methods performed better than most of the immunoassays for plasma Aβ42/40 when detecting brain Aβ pathology.

Dataset Information

Validation of Immunoassay-Based Tools for the Comprehensive Quantification of A?40 and A?42 Peptides in Plasma.

Publications

Validation of Immunoassay-Based Tools for the Comprehensive Quantification of Aβ40 and Aβ42 Peptides in Plasma.

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