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

Abstract

Background Increasing evidence supports the use of plasma biomarkers of neurodegeneration and neuroinflammation to screen and diagnose patients with dementia. However, confirmatory studies are required to demonstrate their usefulness in the clinical setting. 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) (n = 29), dementia with Lewy bodies (DLB) (n = 49), Alzheimer disease (AD) (n = 97), and suspected non-AD physiopathology (n = 51), as well as plasma samples from 60 healthy controls (HC). 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. Additionally, we stratified patients according to the A/T/N classification scheme and the CSF α-synuclein real-time quaking-induced conversion assay (RT-QuIC) results. Results We found good correlations between CSF and plasma biomarkers for NfL (rho = 0.668, p < 0.001) and p-tau181 (rho = 0.619, 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-tau181 and GFAP levels were significantly higher in 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-tau181 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. CSF RT-QuIC showed positive α-synuclein seeding activity in 96% DLB and 15% AD patients with no differences in plasma biomarker levels in those stratified by RT-QuIC result. Conclusions In a single-center clinical cohort, 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 differentiates AD from FTD and neurodegenerative dementias from HC but with lower accuracy than p-tau181 and NfL. In CBS and DLB, plasma p-tau181 and GFAP levels are significantly influenced by beta-amyloid pathology.

Diagnostic performance of plasma Aβ1-42, Aβ1-40and pTau181in the LUMIPULSE automated platform for the detection of Alzheimer disease

“…The performance of plasma markers to discriminate patients with AD from cognitively unimpaired participants, patients with other dementias and with not degenerative dementias has been assessed in previous studies using other analytical platforms, with AUCs ranging from 0.70 to 0.96 for pTau 181 [7,17,[23][24][25][26][27], and from 0.64 to 0.86 for Aβ 1-/Aβ 1-40 [5,8,10]. Most of the studies reported better accuracies with the use of composite measures that combined two or more markers and/or clinical or genetic information.…”

Differences between ante mortem Alzheimer's disease biomarkers in predicting neuropathology at autopsy

“…2 Biomarker evidence consistent with AD in the previous study required at least one modality of an abnormal amyloid marker, but not tau measure, [3][4][5] or defined based on differentiating between clinical diagnosis of AD and controls. 6,7 However, the limitation of the former is that individuals with only abnormal amyloid pathology may not have AD because some individuals who had ante mortem abnormal amyloid markers but normal tau markers were not found to have AD at autopsy. 8 The limitation of the latter is that clinical diagnosis may not be consistent with the pathological diagnosis and may not accurately reflect the presence of AD neuropathology.…”

Elevated plasma p-tau181 levels unrelated to Alzheimer’s disease pathology in amyotrophic lateral sclerosis

“…Moreover, reliable assays that can detect p-tau and NfL in blood have become available, paving the way for more widespread use of these biomarkers in clinical practice 7 8. In particular, the measurement of blood p-tau is increasingly considered a realistic, cost-effective and non-invasive assay that will help the diagnostic process for patients with cognitive decline 7 9 10. Nevertheless, whether plasma measures of these biomarkers exclusively reflect their cerebrospinal fluid (CSF) concentration or are also influenced by peripheral sources remains to be fully explored.…”