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      Clinical validation of the Lumipulse G cerebrospinal fluid assays for routine diagnosis of Alzheimer’s disease

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          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 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.

          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 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%).

          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.

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          Most cited references30

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          Advantages and disadvantages of the use of the CSF Amyloid β (Aβ) 42/40 ratio in the diagnosis of Alzheimer’s Disease

          The cerebrospinal fluid (CSF) biochemical markers (biomarkers) Amyloidβ 42 (Aβ42), total Tau (T-tau) and Tau phosphorylated at threonine 181 (P-tau181) have proven diagnostic accuracy for mild cognitive impairment and dementia due to Alzheimer’s Disease (AD). In an effort to improve the accuracy of an AD diagnosis, it is important to be able to distinguish between AD and other types of dementia (non-AD). The concentration ratio of Aβ42 to Aβ40 (Aβ42/40 Ratio) has been suggested to be superior to the concentration of Aβ42 alone when identifying patients with AD. This article reviews the available evidence on the use of the CSF Aβ42/40 ratio in the diagnosis of AD. Based on the body of evidence presented herein, it is the conclusion of the current working group that the CSF Aβ42/40 ratio, rather than the absolute value of CSF Aβ42, should be used when analysing CSF AD biomarkers to improve the percentage of appropriately diagnosed patients.
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            Development of a functional measure for persons with Alzheimer's disease: the disability assessment for dementia.

            This article describes the development of an assessment of functional disability for use with proxy-respondents of community-dwelling persons who have Alzheimer's disease as well as a study testing its reliability. Panels composed of health care professionals and caregivers of persons with Alzheimer's disease were used to develop the Disability Assessment for Dementia (DAD). Fifty-nine caregivers participated in the refinement of the content and the testing of reliability. The DAD includes 40 items: 17 related to basic self-care and 23 to instrumental activities of daily living. It demonstrated a high degree of internal consistency (Cronbach's alpha = .96) and excellent interrater (N = 31, ICC = .95) and test-retest (N = 45, ICC = .96) reliability. In addition, it was found not to have gender bias. This instrument may help clinicians and caregivers of the population with Alzheimer's disease make decisions regarding the choice of suitable interventions.
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              Unbiased Approach to Counteract Upward Drift in Cerebrospinal Fluid Amyloid-β 1–42 Analysis Results

              Low cerebrospinal fluid (CSF) amyloid-β 1-42 (Aβ 1-42) concentrations indicate amyloid plaque accumulation in the brain, a pathological hallmark of Alzheimer disease (AD). Innotest assay values of Aβ 1-42 have gradually increased over the past 2 decades, which might lead to misclassification of AD when a single cutpoint for abnormality is used. We propose an unbiased approach to statistically correct for drift.
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                Author and article information

                Contributors
                maria.joao.leitao@cnc.uc.pt
                anidss887@gmail.com
                isabeljsantana@gmail.com
                Olmedo@fujirebio.com
                Alicia.Nadal@fujirebio.com
                Nathalie.Le.Bastard@fujirebio.com
                351-239-836244 , ines.baldeiras@sapo.pt
                Journal
                Alzheimers Res Ther
                Alzheimers Res Ther
                Alzheimer's Research & Therapy
                BioMed Central (London )
                1758-9193
                23 November 2019
                23 November 2019
                2019
                : 11
                : 91
                Affiliations
                [1 ]ISNI 0000000106861985, GRID grid.28911.33, Laboratory of Neurochemistry, Neurology Department, , Centro Hospitalar e Universitário de Coimbra, ; 3000-075 Coimbra, Portugal
                [2 ]ISNI 0000 0000 9511 4342, GRID grid.8051.c, Center for Neuroscience and Cell Biology, , University of Coimbra, ; 3004-504 Coimbra, Portugal
                [3 ]ISNI 0000000106861985, GRID grid.28911.33, Dementia Clinic, Neurology Department, , Centro Hospitalar e Universitário de Coimbra, ; 3000-075 Coimbra, Portugal
                [4 ]ISNI 0000 0000 9511 4342, GRID grid.8051.c, Faculty of Medicine, , University of Coimbra, ; 3000-548 Coimbra, Portugal
                [5 ]GRID grid.435322.1, Fujirebio, Iberia, S.I, ; Barcelona, Spain
                [6 ]Fujirebio Europe N.V, Ghent, Belgium
                Author information
                http://orcid.org/0000-0002-8106-7308
                Article
                550
                10.1186/s13195-019-0550-8
                6875031
                31759396
                282ae3d5-28bd-4ac9-b94c-6481f6c13be2
                © The Author(s). 2019

                Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License ( http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver ( http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.

                History
                : 22 August 2019
                : 28 October 2019
                Categories
                Research
                Custom metadata
                © The Author(s) 2019

                Neurology
                alzheimer’s disease,cerebrospinal fluid,biomarkers,chemiluminescent enzyme-automated immunoassay

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