Diagnostic value of plasma p-tau181, NfL and GFAP in a clinical setting cohort of prevalent neurodegenerative dementias

Abstract Background. Increasing evidence support the clinical implementation of plasma biomarkers of neurodegeneration and neuroinflammation for the screening and diagnosis of patients with dementia. However, confirmatory studies are required to demonstrate their usefulness in the real-world clinical setting, in which co-existence of multiple pathologies in dementia is common.Methods. We evaluated plasma and cerebrospinal fluid (CSF) samples from consecutive patients with frontotemporal dementia (FTD) (n=59), progressive supranuclear palsy (PSP) (n=31), corticobasal syndrome (CBS) (29), dementia with Lewy bodies (DLB) (49), and Alzheimer disease (AD) (n=97). Plasma samples from 60 healthy controls were also analysed. We measured neurofilament light chain (NfL), phospho-tau181 (p-tau181), and glial fibrillary acid protein (GFAP) using Simoa (all plasma biomarkers and CSF GFAP), CLEIA (CSF p-tau181), and ELISA (CSF NfL) assays. To assess the effect of AD and Lewy body co-pathologies, we stratified the non-AD groups according to the A/T/N classification and the results of the CSF alpha-synuclein real-time quaking-induced conversion assay.Results. We found good correlations between CSF and plasma biomarkers for NfL (rho=0.651, p<0.001) and p-tau181 (rho=0.637, p<0.001). Plasma NfL was significantly higher in disease groups than in HC, and showed a greater increase in FTD than in AD [44.9 (28.1-68.6) vs. 21.9 (17.0-27.9) pg/ml, p<0.001]. Conversely, plasma p-tau and GFAP levels were significantly higher in the AD than in FTD [3.2 (2.4-4.3) vs. 1.1 (0.7-1.6) pg/ml, p<0.001; 404.7 (279.7-503.0) vs. 198.2 (143.9-316.8) pg/ml, p<0.001]. GFAP also allowed discriminating disease groups from HC. In the distinction between FTD and AD, plasma p-tau showed better accuracy (AUC 0.964) than NfL (AUC 0.791) and GFAP (AUC 0.818). In DLB and CBS, CSF amyloid positive (A+) subjects had higher plasma p-tau181 and GFAP levels than A- individuals.Conclusions. In a clinical setting, we confirm the high diagnostic value of plasma p-tau181 for distinguishing FTD from AD, and plasma NfL for discriminating degenerative dementias from HC. Plasma GFAP alone combines the value of distinguishing both AD from FTD and neurodegenerative dementias from HC, but with a lower accuracy than p-tau181 and NfL. In CBS and DLB, both plasma ptau181 and GFAP levels are significantly influenced by amyloid co-pathology.