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Associations of fully automated Elecsys CSF and novel plasma biomarkers with Alzheimer's disease neuropathology
Author(s) -
Grothe Michel J.,
Moscoso Alexis,
Ashton Nicholas J,
Zetterberg Henrik,
Blennow Kaj,
Schöll Michael
Publication year - 2021
Publication title -
alzheimer's and dementia
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 6.713
H-Index - 118
eISSN - 1552-5279
pISSN - 1552-5260
DOI - 10.1002/alz.053735
Subject(s) - neuropathology , medicine , pathology , cerebrospinal fluid , dementia , biomarker , neurogranin , disease , senile plaques , alzheimer's disease , autopsy , amyloid (mycology) , oncology , biology , kinase , biochemistry , protein kinase c , microbiology and biotechnology
Background The development of fully automated analysis platforms for cerebrospinal fluid (CSF) biomarkers of Alzheimer’s disease (AD) and recent advances in blood‐derived biomarkers signify major steps towards a widespread clinical use of fluid‐based biomarkers. We aimed to study AD CSF biomarkers analyzed by fully automated Elecsys immunoassays in comparison to neuropathologic gold standards, and compare their accuracy to plasma phosphorylated tau (p‐tau181) and neurofilament light (NfL) measured using novel Simoa assays. Method We compared ante‐mortem Elecsys‐derived CSF biomarkers to standardised post‐mortem assessments of AD and non‐AD neuropathologic changes in 45 participants from the Alzheimer’s Disease Neuroimaging Initiative autopsy cohort. In a subset of 26 participants, we also analyzed ante‐mortem levels of plasma p‐tau181 and NfL. Reference biomarker values were obtained from 146 amyloid‐PET‐negative healthy controls (HC)([18F]Florbetapir‐PET <12 Centiloids). Result All CSF biomarkers clearly distinguished pathology‐confirmed AD dementia patients (N=27) from HC (AUCs=0.86‐1.00). CSF total‐tau (t‐tau), p‐tau181, and their ratios with Aβ 1‐42 , also accurately distinguished pathology‐confirmed AD from non‐AD dementia (N=8; AUCs=0.94‐0.97)(Fig. 1). In pathology‐specific analyses, intermediate‐to‐high Thal amyloid phases were best detected by CSF Aβ1‐42 (AUC[95% CI]=0.91[0.81‐1]), while intermediate‐to‐high CERAD neuritic plaques and Braak tau stages were best detected by CSF p‐tau181 (AUC=0.89[0.79‐0.99] and 0.88[0.77‐0.99], respectively)(Fig. 2). Optimal Elecsys CSF biomarker cut‐offs were derived at 1097/229/19 pg/ml for Aβ 1‐42 , t‐tau, and p‐tau181. In the plasma subsample, both plasma p‐tau181 (AUC=0.91[0.86‐0.96]) and NfL (AUC=0.93[0.87‐0.99]) accurately distinguished pathology‐confirmed AD (N=14) from HC. However, only p‐tau181 distinguished AD from non‐AD dementia cases (N=4; AUC=0.96[0.88‐1.00])(Fig. 1), and showed a similar, though weaker, pathologic specificity for neuritic plaques (AUC=0.75[0.52‐0.98]) and Braak stage (AUC=0.71[0.44‐0.98]) as CSF p‐tau181. No CSF or plasma biomarker was sensitive to the presence of Lewy body or TDP‐43 pathology, but Elecsys CSF Aβ 1‐42 levels detected the presence of cerebral amyloid angiopathy (AUC=0.84[0.73‐0.96]). Conclusion We demonstrate for the first time that the fully automated Elecsys CSF biomarkers detect AD neuropathologic changes with very high discriminative accuracy in vivo , and we report corresponding pathology‐based cut‐offs for these standardized biomarker measurements. Preliminary findings in a smaller subsample also support the use of plasma p‐tau181 as an easily accessible and scalable biomarker of AD pathology.