Background: Amyotrophic lateral sclerosis (ALS) is a fatal central nervous system neurodegenerative disease, but the relationships among genetic mutations, plasma biomarkers, glymphatic system and clinical variables remain unclear.
Methods: This study retrospectively collected data from April 2015 to November 2024 from the Department of Neurology of First Affiliated Hospital, Fujian Medical University, China. ALS patients (including genetic ALS (gALS) and sporadic ALS (sALS)), Alzheimer's disease (AD) patients, and healthy controls (HC) were included. Plasma glial fibrillary acidic protein (GFAP), neurofilament light chain (NfL), phosphorylated tau 181 (p-tau181), amyloid-beta 42 (Aβ42) and amyloid-beta 40 (Aβ40) concentrations were measured using ultrasensitive single molecule array (Simoa). All ALS individuals underwent genetic screening. The ALS Functional Rating Scale-Revised (ALSFRS-R) was used to assess motor function. The choroid plexus volume (CPV) and enlarged perivascular spaces (EPVS) were used to assess glymphatic function.
Results: Firstly, we found that plasma levels of NfL (p < 0.001) and p-tau181 (p < 0.001) were significantly higher in ALS than in HC. Compared with sALS, gALS had a significantly higher plasma ptau181 (p < 0.05), Aβ42/40 ratio (p < 0.001). Secondly, gALS had more severe glymphatic dysfunction than sALS (p < 0.05), plasma GFAP (ρ = 0.57, p < 0.05) and p-tau181 (ρ = 0.58, p < 0.05) in gALS showed significant correlations with CPV. Thirdly, plasma GFAP was significantly associated with motor function (ρ = -0.35, p < 0.01) and its progression rate (ρ = 0.24, p < 0.05) in gALS.
Conclusions: The gALS exhibit a more severe and complex biomarker profile than sALS, in which plasma GFAP showed a significant correlation in disease progression.
Keywords: Amyotrophic lateral sclerosis; Astrocyte; Biomarker; Genetic ALS; Glymphatic system; Protein aggregation.
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