Elecsys® Total-Tau and Phospho-Tau (181P) CSF assays: Analytical performance of the novel, fully automated immunoassays for quantification of tau proteins in human cerebrospinal fluid

Lifke, Valeria; Kollmorgen, Gwendlyn; Manuilova, Ekaterina; Oelschlaegel, Tobias; Hillringhaus, Lars; Widmann, Monika; Arnim, Christine A. F. Von; Otto, Markus; Christenson, Robert H.; Powers, Jennifer; Shaw, Leslie M.; Hansson, Oskar; Doecke, James D.; Li, Qiao Xin; Teunissen, Charlotte E.; Tumani, Hayrettin; Blennow, Kaj

doi:10.1016/j.clinbiochem.2019.05.005

Cited by 73 publications

(53 citation statements)

References 35 publications

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“…Core AD biomarkers that exceeded detectable limits were imputed at the limit threshold: Aβ 42 lower limit is 200, upper limit is 1700, pTau 181 lower limit is 8, upper limit is 120, tTau lower limit is 80 upper limit is 1300. In cases in which CSF analyte values exceeded upper or lower detection limits, 9,11 the value of the threshold was imputed; 44 values were imputed for Aβ 42 (N <LL = 3, N >UL = 41), and 20 for pTau 181 (N <LL = 19, N >UL = 1). Ten CU participants had missing values for core AD biomarker values due to sample abnormalities.…”

Section: Resultsmentioning

confidence: 99%

An examination of a novel multipanel of CSF biomarkers in the Alzheimer's disease clinical and pathological continuum

Hulle

Jonaitis

Betthauser

et al. 2020

Alzheimer's & Dementia

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118

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Introduction This study examines the utility of a multipanel of cerebrospinal fluid (CSF) biomarkers complementing Alzheimer's disease (AD) biomarkers in a clinical research sample. We compared biomarkers across groups defined by clinical diagnosis and pTau181/Aβ42 status (+/−) and explored their value in predicting cognition. Methods CSF biomarkers amyloid beta (Aβ)42, pTau181, tTau, Aβ40, neurogranin, neurofilament light (NfL), α‐synuclein, glial fibrillary acidic protein (GFAP), chitinase‐3‐like protein 1 (YKL‐40), soluble triggering receptor expressed on myeloid cells 2 (sTREM2), S100 calcium binding protein B (S100B), and interleukin 6 (IL6), were measured with the NeuroToolKit (NTK) for 720 adults ages 40 to 93 years (mean age = 63.9 years, standard deviation [SD] = 9.0; 50 with dementia; 54 with mild cognitive impairment [MCI], 616 unimpaired). Results Neurodegeneration and glial activation biomarkers were elevated in pTau181/Aβ42+ MCI/dementia participants relative to all pTau181/Aβ42‐ participants. Neurodegeneration biomarkers increased with clinical severity among pTau181/Aβ42+ participants and predicted worse cognitive performance. Glial activation biomarkers were unrelated to cognitive performance. Discussion The NTK contains promising markers that improve the pathophysiological characterization of AD. Neurodegeneration biomarkers beyond tTau improved statistical prediction of cognition and disease stages.

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Section: Resultsmentioning

confidence: 99%

An examination of a novel multipanel of CSF biomarkers in the Alzheimer's disease clinical and pathological continuum

Hulle

Jonaitis

Betthauser

et al. 2020

Alzheimer's & Dementia

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118

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“…The Elecsys® assay has now been a part of the Alzheimer's Association QC program since 2014, with mean CVs being as low as 4% as compared to~15% for ELISA methods [47]. Novel assays on the Elecsys® instrument for P-tau and T-tau have also recently been described [26,48,49] and have so far performed well in the Alzheimer's Association QC program [44]. Similar automated platforms for AD biomarkers have since been launched, including those from Euroimmun [50], and Fujirebio (LUMIPULSE®) [51][52][53][54], and have shown superior performance in the QC program [44].…”

Section: Phase 2: Secondary Aimmentioning

confidence: 99%

2020 update on the clinical validity of cerebrospinal fluid amyloid, tau, and phospho-tau as biomarkers for Alzheimer’s disease in the context of a structured 5-phase development framework

Leuzy

Ashton

Mattsson‐Carlgren

et al. 2021

Eur J Nucl Med Mol Imaging

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Purpose In the last decade, the research community has focused on defining reliable biomarkers for the early detection of Alzheimer’s disease (AD) pathology. In 2017, the Geneva AD Biomarker Roadmap Initiative adapted a framework for the systematic validation of oncological biomarkers to cerebrospinal fluid (CSF) AD biomarkers—encompassing the 42 amino-acid isoform of amyloid-β (Aβ42), phosphorylated-tau (P-tau), and Total-tau (T-tau)—with the aim to accelerate their development and clinical implementation. The aim of this work is to update the current validation status of CSF AD biomarkers based on the Biomarker Roadmap methodology. Methods A panel of experts in AD biomarkers convened in November 2019 at a 2-day workshop in Geneva. The level of maturity (fully achieved, partly achieved, preliminary evidence, not achieved, unsuccessful) of CSF AD biomarkers was assessed based on the Biomarker Roadmap methodology before the meeting and presented and discussed during the workshop. Results By comparison to the previous 2017 Geneva Roadmap meeting, the primary advances in CSF AD biomarkers have been in the area of a unified protocol for CSF sampling, handling and storage, the introduction of certified reference methods and materials for Aβ42, and the introduction of fully automated assays. Additional advances have occurred in the form of defining thresholds for biomarker positivity and assessing the impact of covariates on their discriminatory ability. Conclusions Though much has been achieved for phases one through three, much work remains in phases four (real world performance) and five (assessment of impact/cost). To a large degree, this will depend on the availability of disease-modifying treatments for AD, given these will make accurate and generally available diagnostic tools key to initiate therapy.

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“…In this study, we aimed at characterizing the pattern of changes in phosphorylated tau in the preclinical stage of the Alzheimer’s continuum . For this purpose, we measured a set of novel CSF p‐tau biomarkers in the ALFA+ study (a cohort of CU individuals, some of whom are in the preclinical stage of the Alzheimer’s continuum ) and compared them with the well‐established Elecsys ® Mid‐p‐tau181 assay [targeting mid‐region (Mid) tau fragments phosphorylated at threonine‐181 (Lifke et al , 2019)], used herein as the reference assay. The set of novel p‐tau biomarkers studied include (Fig EV1): (a) N‐p‐tau181 [targeting tau forms phosphorylated at threonine‐181 and containing the N‐terminal (N) epitope 6‐18], (b) N‐p‐tau217 (targeting tau forms phosphorylated at threonine‐217 as well as containing the N‐terminal epitope 6–18) and (c) Mid‐p‐tau231 (targeting Mid tau fragments phosphorylated at threonine‐231).…”

Section: Introductionmentioning

confidence: 99%

Novel tau biomarkers phosphorylated at T181, T217 or T231 rise in the initial stages of the preclinical Alzheimer’s continuum when only subtle changes in Aβ pathology are detected

et al. 2020

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In Alzheimer's disease (AD), tau phosphorylation in the brain and its subsequent release into cerebrospinal fluid (CSF) and blood is a dynamic process that changes during disease evolution. The main aim of our study was to characterize the pattern of changes in phosphorylated tau (p-tau) in the preclinical stage of the Alzheimer's continuum. We measured three novel CSF p-tau biomarkers, phosphorylated at threonine-181 and threonine-217 with an Nterminal partner antibody and at threonine-231 with a mid-region partner antibody. These were compared with an automated midregion p-tau181 assay (Elecsys) as the gold standard p-tau measure. We demonstrate that these novel p-tau biomarkers increase more prominently in preclinical Alzheimer, when only subtle changes of amyloid-b (Ab) pathology are detected, and can accurately differentiate Ab-positive from Ab-negative cognitively unimpaired individuals. Moreover, we show that the novel plasma N-terminal p-tau181 biomarker is mildly but significantly increased in the preclinical stage. Our results support the idea that early changes in neuronal tau metabolism in preclinical Alzheimer, likely in response to Ab exposure, can be detected with these novel p-tau assays.

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Elecsys® Total-Tau and Phospho-Tau (181P) CSF assays: Analytical performance of the novel, fully automated immunoassays for quantification of tau proteins in human cerebrospinal fluid

Cited by 73 publications

References 35 publications

An examination of a novel multipanel of CSF biomarkers in the Alzheimer's disease clinical and pathological continuum

An examination of a novel multipanel of CSF biomarkers in the Alzheimer's disease clinical and pathological continuum

2020 update on the clinical validity of cerebrospinal fluid amyloid, tau, and phospho-tau as biomarkers for Alzheimer’s disease in the context of a structured 5-phase development framework

Novel tau biomarkers phosphorylated at T181, T217 or T231 rise in the initial stages of the preclinical Alzheimer’s continuum when only subtle changes in Aβ pathology are detected

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