Serum neurofilament light chain and the 2024 McDonald criteria for multiple sclerosis: a retrospective cohort study

BACKGROUND: The 2024 McDonald criteria broaden the definition of multiple sclerosis (MS), enabling diagnosis in individuals with asymptomatic MRI findings or clinical presentations not meeting the 2017 criteria. We assessed whether these criteria identify such cases using independent laboratory/imaging biomarkers and whether these biomarkers predict subsequent disease activity. METHODS: Participants with asymptomatic MRI findings or clinical presentations not meeting the 2017 criteria were included and stratified according to the 2024 criteria. Serum neurofilament light chain (sNfL) and 3T brain MRI measures-including normalised brain volumes, T2 lesion load (T2LL), cortical lesion (CL) and paramagnetic rim lesion (PRL)-were compared between McDonald2024-positive and McDonald2024-negative groups, and with age/sex matched McDonald2017-positive cases according to the 2017 criteria; predictors of disease activity were assessed using penalised-Cox regression. FINDINGS: A total of 141 participants were included: 95 not meeting the 2017 criteria (n = 64 asymptomatic MRI findings; n = 31 clinical presentations), stratified as McDonald2024-positive (n = 46) or McDonald2024-negative (n = 49), and 46 McDonald2017-positive cases. McDonald2024-positive vs. McDonald2024-negative cases showed higher age-corrected sNfL Z-scores (median 0.28[IQR 0.76] vs. -0.12[0.82], p = 0.003/pFDR = 0.006), reduced normalised thalamic volume (mean 0.009±[SD]0.0007 vs. 0.010 ± 0.0007, p = 0.003/pFDR = 0.006), and higher CL (1[4] vs. 0[0], p < 0.001/pFDR < 0.001) and PRL (1[1] vs. 0[0], p < 0.001/pFDR = 0.003) counts (differences remaining significant after age/sex, disease duration and T2LL adjustments). Biomarker profiles were comparable between McDonald2024-positive and McDonald2017-positive cases. Penalised-Cox regression (n = 52) identified sNfL Z-score and PRL presence as the most consistently selected predictors of disease activity, with higher bootstrap stability for sNfL (0.84) than PRL (0.76), and good model discrimination (C-index = 0.71). INTERPRETATION: The 2024 McDonald criteria identify individuals not meeting the 2017 criteria who already exhibit MS-like neuroinflammatory/neurodegenerative pathological changes. These are reflected by laboratory and imaging biomarkers, including sNfL, which may predict subsequent disease activity and complement current diagnostic frameworks to support early clinical decision-making. FUNDING: King Baudouin Foundation; Cliniques Universitaires Saint-Luc; Fondation Charcot Stichting; Fund for Scientific Research (FNRS); ECTRIMS; Biogen; Sanofi.