Value of synaptic proteins as biomarkers in amyotrophic lateral sclerosis

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ID: 318731
2026
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Abstract
Abstract Amyotrophic lateral sclerosis is a heterogenous and rapidly progressing neurodegenerative disorder with limited treatment options. Therefore, there is a critical need for biomarkers that capture the diverse pathophysiological mechanisms underlying disease onset and progression. Emerging evidence suggests that synaptic dysfunction is an early disease mechanism in amyotrophic lateral sclerosis. Using homebrew immunoassays, we explored a panel of pre- and post-synaptic proteins in cerebrospinal fluid of patients with amyotrophic lateral sclerosis (N = 57) and controls (N = 36). The potential value as a biomarker was explored by correlating cerebrospinal fluid levels with clinical parameters and established biomarkers for amyotrophic lateral sclerosis. Higher levels of Neurogranin (NRGN) (p = 0.003) and Vesicle-associated membrane protein 2 (VAMP2) (p = 0.014) were observed in patients with amyotrophic lateral sclerosis compared to controls. VAMP2, Synaptosome-associated protein 25kDa (SNAP25) and β-synuclein (SNCB) correlated with individual relative disease stage, but none of the biomarkers correlated with disease progression rate. High levels of SNAP25 predicted worse survival in a univariate and stepwise multivariable analysis, but significance did not persist upon including Neurofilament light chain (NfL) levels. Synaptic proteins did not correlate with cerebrospinal fluid levels of neurofilaments or biomarkers of neuroinflammation, suggesting that they reflect different pathological mechanisms in amyotrophic lateral sclerosis. Our findings warrant further investigation to determine whether increased cerebrospinal fluid levels of synaptic proteins reflect synaptic breakdown or active release of synaptic proteins. This will help elucidate how synaptic dysfunction or damage contributes to elevated levels of synaptic markers in amyotrophic lateral sclerosis, and its underlying value as biomarker.
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Authors Frederik Hobin, Shreyasee Das, Charlotte Lambrechts, Charlotte De Rocker, Jonas Dubin, Fouke Ombelet, Joke De Vocht, Nikita Lamaire, Eugeen Vanmechelen, Koen Poesen, Philip Van Damme
Journal Brain communications
Year 2026
DOI
10.1093/braincomms/fcag247
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