Effects of physical exercise on neurofilament light chain in multiple sclerosis and other neurological disorders: A systematic review

BACKGROUND: Neurofilament light chain (NfL) is a well-established biomarker of axonal damage and neurodegeneration, with critical relevance in multiple sclerosis (MS) and other neurological disorders. This systematic review primarily aims to assess the impact of physical exercise on circulating NfL concentrations in people with MS, while secondarily exploring its effects across other neurological conditions. METHODS: Five databases (PubMed, Scopus, Web of Science, EBSCO, and Cochrane) were searched according to PRISMA guidelines (PROSPERO: CRD420261294977). The search was conducted from inception until February 27, 2026. Methodological quality was assessed using RoB 2.0, ROBINS-I, and the PEDro scale. Articles were graded for evidence and recommendation levels using the Oxford Centre for Evidence-Based Medicine (OCEBM) criteria. RESULTS: Fifteen articles were analyzed, involving a total sample of 765 patients (484 women). The sample predominantly comprised patients with MS (n = 368), followed by secondary groups with Alzheimer's disease (AD; n = 305), vascular cognitive impairment (VCI; n = 58), Huntington's disease (HD; n = 31), and Parkinson's disease (PD; n = 3). In MS, significant reductions in NfL were found following resistance training, Pilates, and high-intensity interval training (HIIT). Conversely, prolonged moderate-to-high intensity aerobic exercise yielded no significant effects on NfL in AD, VCI, HD, or MS. Findings for PD remain preliminary, though HIIT appears to induce acute, transient NfL reductions. CONCLUSION: Physical exercise, specifically resistance training, Pilates, and HIIT, may be associated with reduced NfL concentrations in patients with MS, suggesting a potential neuroprotective role. In contrast, current evidence for other neurological disorders (AD, premanifest HD, PD, and VCI) remains preliminary or non-significant. Exercise modality and intensity appear to be key variables; notably, resistance-based programs also induced additional reductions in GFAP and tau protein.