To identify MRI predictors of upper cervical cord (UCC)-grey matter (GM) cross-sectional area (CSA) reduction in multiple sclerosis (MS) phenotypes.

UCC-GM atrophy is one of the most relevant MRI predictors of disability in MS, but its pathophysiology is poorly understood, with possible contributions from segmental, suprasegmental cord and corticospinal tract (CST) lesions/degeneration, and intrinsic GM demyelination/neural loss.

139 (44 early [disease duration ≤5 years], 37 late [disease duration >5 years] relapsing-remitting [RR], 18 primary progressive [PP] and 40 secondary progressive [SP]) MS patients and 53 healthy controls (HC) underwent neurological examination and 3T MRI with sequences for assessing lesions, atrophy and diffusion-tensor metrics in brain and UCC. UCC-GM atrophy was measured with a high-resolution phase-sensitive inversion recovery sequence at C2-C3 intervertebral level. Percentage lesion volumes (pT2-LV) and diffusion tensor-metrics were quantified for CST, suprasegmental lateral funiculi and dorsal columns (at C1 and C2 vertebral levels), and UCC segmental compartments (C2-C3 intervertebral level). MRI predictors of UCC-GM atrophy were identified with age-, sex- and disease duration-adjusted step-wise linear models.

UCC-GM CSA was similar in early RRMS vs HC, reduced in late RRMS vs former groups, and in PPMS and SPMS vs late RRMS. UCC-GM CSA was the most relevant MRI predictor of Expanded Disability Status Scale score in late RRMS, PPMS and SPMS. Independent predictors of UCC-GM CSA were: suprasegmental lateral column pT2-LV, segmental dorsal column pT2-LV and normalized brain volume (NBV) in all MS patients (R2=0.42); suprasegmental lateral column pT2-LV and NBV in late RRMS patients (R2=0.39); suprasegmental lateral column pT2-LV, brain CST pT2-LV and segmental GM pT2-LV in SPMS patients (R2=0.36); brain GM volume and suprasegmental lateral column pT2-LV in PPMS patients (R2=0.65).

UCC-GM atrophy pathophysiology is different among MS phenotypes, with predominant contribution of WM lesions in RRMS, GM lesions in SPMS and diffuse GM neurodegeneration in PPMS.