CSF Aβ, Tau, Axonal, Synaptic, Glial, Neural, and Inflammatory Biomarkers in Patients With Sporadic Amyotrophic Lateral Sclerosis

BACKGROUND AND OBJECTIVES: Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disorder with multifactorial pathophysiologic mechanisms, yet reliable CSF biomarkers for the diagnosis of ALS are lacking. The aim of this study was to systematically identify CSF protein alterations in patients with sporadic ALS and to develop an effective CSF protein panel to aid in ALS diagnosis. METHODS: This observational study was conducted at Qilu Hospital, Cheeloo College of Medicine, Shandong University. Using proximity extension assay, single-molecule array, and ELISA, approximately 200 proteins involved in different pathogenic events, including axonal damage, neuronal damage, glial responses, synaptic dysfunction, β-amyloid (Aβ) pathology, tau pathology, and neuroinflammation, were measured in the CSF. Moreover, Xtreme gradient boosting and logistic regression models were applied to develop a CSF protein panel to distinguish patients with sporadic ALS from disease controls (DCs), and the diagnostic performance was verified in an independent cohort. RESULTS: A total of 180 participants were included, comprising 109 patients with sporadic ALS (mean age 56.7 ± 11.9 years, 58.7% male), 30 DCs (56.9 ± 12.6 years, 56.7% male), and 41 healthy controls (HCs, 57.1 ± 12.4 years, 63.4% male). Compared with HCs, patients with ALS had significantly elevated CSF levels of neurofilament light chain, chitinase proteins including chitotriosidase (CHIT1), and 55 other proteins, whereas CSF Aβ40, Aβ42, and GAP43 levels were significantly lower. Moreover, we identified a 3-protein CSF panel (CHIT1, N-CDase, and PDGF-R-alpha) that effectively distinguished patients with ALS from DCs, achieving an area under the curve of 0.927 (95% CI 0.883-0.971) in the original cohort and 0.912 (95% CI 0.841-0.985) in the replication cohort. DISCUSSION: Using a combined approach, we comprehensively investigated CSF protein alterations in a cohort of newly diagnosed patients with ALS and provided further in vivo evidence supporting the presence of mixed copathologies in patients with ALS. Moreover, we developed a 3-protein CSF biomarker panel that effectively distinguished patients with ALS from DCs and validated its performance in an independent cohort. However, considering the relatively small cohort and lack of multiple comparison adjustments, further validation in larger, multicenter studies is warranted.