Dataset Information

Diagnostic Values of Cerebrospinal Fluid T-Tau and A??? using Meso Scale Discovery Assays for Alzheimer's Disease.

ABSTRACT: Meso Scale Discovery (MSD) recently established electrochemiluminescence-based assays to measure cerebrospinal fluid (CSF) levels of total tau (t-tau) and amyloid-? 1-42 peptide (A?42) that can aid in the diagnosis of Alzheimer's disease (AD). The goal of this investigation is to independently evaluate this platform and establish cut-off values of these biomarkers for AD diagnosis.To validate the analytical and clinical performance of the MSD t-tau and A?42 kits and propose diagnostic cut-off values for the field.The analytical performance of the CSF t-tau and A?42 assays was determined, followed by assessment of diagnostic performance of CSF t-tau, A?42, and t-tau/A?42 in three clinically characterized cohorts.Both MSD assays demonstrated consistent and stable analytical performance, as well as resistance to several important pre-analytic variables. Diagnostically, t-tau/A?42 performed the best.Our results independently confirm the analytical and clinical performance of the MSD CSF t-tau and A?42 assays. Based on a large, multi-center, clinically-diagnosed cohort, we propose for the first time candidate diagnostic cut-offs for MSD measured CSF t-tau, A?42, and t-tau/A?42. However, these values needs to be refined as more subjects are included and the assays are tested by other laboratories.

SUBMITTER: Pan C

PROVIDER: S-EPMC4517668 | biostudies-literature | 2015

REPOSITORIES: biostudies-literature

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Diagnostic Values of Cerebrospinal Fluid T-Tau and Aβ₄₂ using Meso Scale Discovery Assays for Alzheimer's Disease.

Pan Catherine C Korff Ané A Galasko Douglas D Ginghina Carmen C Peskind Elaine E Li Ge G Quinn Joseph J Montine Thomas J TJ Cain Kevin K Shi Min M Zhang Jing J

Journal of Alzheimer's disease : JAD 20150101 3

<h4>Background</h4>Meso Scale Discovery (MSD) recently established electrochemiluminescence-based assays to measure cerebrospinal fluid (CSF) levels of total tau (t-tau) and amyloid-β 1-42 peptide (Aβ42) that can aid in the diagnosis of Alzheimer's disease (AD). The goal of this investigation is to independently evaluate this platform and establish cut-off values of these biomarkers for AD diagnosis.<h4>Objective</h4>To validate the analytical and clinical performance of the MSD t-tau and Aβ42 k ...[more]

PMID: 25613100

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Project description:ObjectiveThe primary study objective of this retrospective academic memory clinic-based observational longitudinal study was to investigate the prognostic value of a cerebrospinal fluid (CSF)-based ATN classification for subsequent cognitive decline during the 3 years following lumbar puncture in a clinical, real-life setting. The secondary objective was to investigate the prognostic value of CSF biomarkers as continuous variables.MethodsData from 228 patients (median age 67 (47-85) years), who presented at the Neurology Memory Clinic UZ/KU Leuven between September 2011 and December 2016, were included with a follow-up period of up to 36 months. Patients underwent a CSF AD biomarker test for amyloid-beta 1-42 (Aβ42), hyperphosphorylated tau (p181-tau) and total tau (t-tau) in the clinical work-up for diagnostic reasons. Patients were divided into ATN classes based on CSF biomarkers: Aβ42 for amyloid (A), p181-tau for tau (T), and t-tau as a measure for neurodegeneration (N). Based on retrospective data analysis, cognitive performance was evaluated by Mini Mental State Examination (MMSE) scores every 6 months over a period up to 36 months following the lumbar puncture. The statistical analysis was based on linear mixed-effects modeling (LME).ResultsThe distribution in the current clinical sample was as follows: A-/T-/N- 32.02%, A+/T-/N- 33.33%, A+/T+/N+ 17.11%, A+/T-/N+ 11.84%, A-/T-/N+ 4.39%, A-/T+/N+ 1.32% (3 cases), with no cases in the A-/T+/N- and A+/T+/N- class. Hence, the latter 3 classes were excluded from further analyses. The change of MMSE relative to A-/T-/N- over a 36-month period was significant in all four ATN classes: A+/T+/N+ = - 4.78 points on the MMSE; A-/T-/N+ = - 4.76; A+/T-/N+ = - 2.83; A+/T-/N- = - 1.96. The earliest significant difference was seen in the A+/T+/N+ class at 12 months after baseline. The effect of ATN class on future cognitive decline was confirmed for a different set of CSF thresholds. All individual baseline CSF biomarkers including the Aβ42/t-tau ratio showed a significant correlation with subsequent cognitive decline, with the highest correlation seen for Aβ42/t-tau.ConclusionATN classification based on CSF biomarkers has a statistically significant and clinically relevant prognostic value for the course of cognitive decline in a 3-year period in a clinical practice setting.

Project description:BackgroundAlzheimer's disease is characterized by an abnormal increase of phosphorylated tau (pTau) species in the CSF. It has been suggested that emergence of different pTau forms may parallel disease progression. Therefore, targeting multiple specific pTau forms may allow for a deeper understanding of disease evolution and underlying pathophysiology. Current immunoassays measure pTau epitopes separately and may capture phosphorylated tau fragments of different length depending on the non-pTau antibody used in the assay sandwich pair, which bias the measurement.MethodsWe developed the first antibody-free mass spectrometric method to simultaneously measure multiple phosphorylated epitopes in CSF tau: pT181, pS199, pS202, pT205, pT217, pT231, and pS396. The method was first evaluated in biochemically defined Alzheimer's disease and control CSF samples (n = 38). All seven pTau epitopes clearly separated Alzheimer's disease from non-AD (p < 0.001, AUC = 0.84-0.98). We proceeded with clinical validation of the method in the TRIAD (n = 165) and BioFINDER-2 cohorts (n = 563), consisting of patients across the full Alzheimer's disease continuum, including also young controls (< 40 years), as well as patients with frontotemporal dementia and other neurodegenerative disorders.ResultsIncreased levels of all phosphorylated epitopes were found in Alzheimer's disease dementia and Aβ positron emission tomography-positive patients with mild cognitive impairment compared with Aβ-negative controls. For Alzheimer's disease dementia compared with Aβ-negative controls, the best biomarker performance was observed for pT231 (TRIAD: AUC = 98.73%, fold change = 7.64; BioFINDER-2: AUC = 91.89%, fold change = 10.65), pT217 (TRIAD: AUC = 99.71%, fold change = 6.33; BioFINDER-2: AUC = 98.12%, fold change = 8.83) and pT205 (TRIAD: AUC = 99.07%, fold change = 5.34; BioFINDER-2: AUC = 93.51%, fold change = 3.92). These phospho-epitopes also discriminated between Aβ-positive and Aβ-negative cognitively unimpaired individuals: pT217 (TRIAD: AUC = 83.26, fold change = 2.39; BioFINDER-2: AUC = 91.05%, fold change = 3.29), pT231 (TRIAD: AUC = 86.25, fold change = 3.80; BioFINDER-2: AUC = 78.69%, fold change = 3.65) and pT205 (TRIAD: AUC = 71.58, fold change = 1.51; BioFINDER-2: AUC = 71.11%, fold change = 1.70).ConclusionsWhile an increase was found for all pTau species examined, the highest fold change in Alzheimer's disease was found for pT231, pT217 and pT205. Simultaneous antibody-free measurement of pTau epitopes by mass spectrometry avoids possible bias caused by differences in antibody affinity for modified or processed forms of tau, provides insights into tau pathophysiology and may facilitate clinical trials on tau-based drug candidates.

Dataset Information

Diagnostic Values of Cerebrospinal Fluid T-Tau and A??? using Meso Scale Discovery Assays for Alzheimer's Disease.

Publications

Diagnostic Values of Cerebrospinal Fluid T-Tau and Aβ₄₂ using Meso Scale Discovery Assays for Alzheimer's Disease.

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