Macro- and microstructural changes in the upper cervical spinal cord and their clinical correlates in multiple sclerosis

Background Spinal cord (SC) damage is central to multiple sclerosis (MS) progression but remains difficult to quantify with conventional magnetic resonance imaging (MRI). Objectives To characterize upper cervical SC pathology using quantitative MRI (qMRI) and assess longitudinal changes and predictors of clinical progression and fluid biomarker trajectories. Methods We conducted a prospective study including people with MS (PwMS) and healthy controls (HCs). Participants underwent brain 3T-MRI, clinical assessments, and serum biomarker analyses at baseline and 2 years, with clinical follow-up to a median of 3.0 years. SC lesion burden, morphometry, quantitative T1 (qT1), and magnetization transfer saturation (MTsat) metrics were derived. Results We enrolled 183 PwMS and 100 HCs at baseline, with follow-up for a subset. PwMS showed widespread SC macro/microstructural damage compared with HCs, with qT1 at C1-C4 and MTsat at C4 providing the highest discrimination (model-area under the curve = 0.81). Disability was most strongly associated with cross-sectional area at C1–C2, and qT1 at C1, C2, and C4 ( R 2 = 0.49). Baseline SC metrics predicted disability worsening and progression independent of relapse activity, with lower transverse diameters at C3–C4 as key predictors (model-HRs = 0.59–0.69), and worsening serum glial fibrillary acidic protein but not serum neurofilament light chain. Conclusion Upper cervical SC morphometry and qMRI capture clinically relevant pathology and are linked to disease evolution, supporting their potential prognostic value in MS.