Background: Recently, several serum biomarkers have been proposed in Neuromyelitis Optica Spectrum Disorders (NMOSD) to monitor disease activity. Objective: The objective of the study is to evaluate the longitudinal clinical value of serum biomarkers in patients with NMOSD. Methods: We prospectively recruited consecutive NMOSD patients with anti-aquaporin-4 antibody and obtained serum samples at enrollment, after 6–12 months of follow-up (main period), and at attacks. Using single-molecule array assays, we evaluated longitudinal changes of serum neurofilament light chain (NfL), glial fibrillary acidic protein (GFAP), and GFAP/NfL levels. Results: Overall, 64 patients (58 women) were enrolled (age: 51 years, disease duration: 6.7 years) and 133 samples were obtained. Among patients who did not develop new attacks during the main period ( n = 62), serum levels of NfL, GFAP, and GFAP/NfL were significantly decreased over time in patients with attacks (<2 months) at enrollment ( n = 14 (23%)), whereas serum NfL and GFAP levels gradually increased in the others ( n = 48 (77%)). During the study, five (8%) patients developed new attacks; only serum GFAP levels increased consistently upon these events compared with baseline levels. To differentiate attacks from remissions, serum GFAP levels showed the largest area under the receiver operating characteristic curve (0.876, 95% confidence interval: 0.801–0.951). Conclusion: Among NfL, GFAP, and GFAP/NfL, serum GFAP might be the most appropriate for monitoring NMOSD longitudinally, which warrants future confirming studies.

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