To perform a multiparametric assessment of cortical, deep (D) grey matter (GM), cerebellar and cervical cord damage and determine their relative contributions to the main clinical disability milestones of multiple sclerosis (MS).

In MS, inflammation and neurodegeneration involve several cortical and subcortical central nervous system structures.

3T brain and cervical cord T₂- and 3D T₁-weigthed images were acquired from 198 MS patients (139 relapsing-remitting [RR] MS, 59 progressive [P] MS) and 67 healthy controls (HC) at three European sites. Brain and cervical cord lesion burden, cortical thickness (CTh), whole-GM, DGM and cerebellar volumetry, as well as cord cross-sectional area (CSA) were quantified. Random forest analyses identified predictors of the expanded disability status scale (EDSS) score and determined the main contributors to different disability milestones (EDSS=3.0, 4.0 and 6.0).

Compared to HC, MS patients had widespread atrophy in all investigated compartments (p=range <0.001-0.05). In MS patients, lower cord CSA, higher number of cord lesions and reduced whole-GM volume predicted the EDSS score (out-of-bag R2=0.59, p range=<0.001-0.003). The main determinants of an EDSS score=3.0 were reduced cord CSA, higher brain lesion volume and thalamic atrophy, together with smaller whole-GM and cerebellar volumes (out-of-bag accuracy=0.81, p range=<0.001-0.04). Conversely, reaching an EDSS score=4.0 was mainly predicted by reduced whole-GM volume and cord area, reduced CTh of the frontal and sensorimotor cortices, a higher number of cord lesions and higher cerebellar and DGM atrophy (out-of-bag accuracy=0.84, p range=<0.001-0.04). Finally, a lower cord CSA (p=0.001) and higher number of cord lesions (p=0.003) were the only predictors of EDSS=6.0 (out-of-bag accuracy=0.83).

Random forest analyses identified the peculiar contribution of each CNS compartment to different EDSS milestones. While lesion burden, brain GM and thalamic atrophy were the main determinants of EDSS=3.0 and 4.0, cervical cord damage was predominant to explain an EDSS=6.0.