Spinal cord versus brain imaging biomarkers of multiple sclerosis trajectory combining 7T and 3T MRI

In multiple sclerosis, different types of lesions and their localization can have varying effects on clinical disability and disease progression. Ultra-high field 7-Tesla MRI improves the visualization of cortical, especially subpial, lesions and of white matter lesions with a paramagnetic rim that are associated with smoldering inflammation. Spinal cord atrophy is also a critical determinant of clinical disability in multiple sclerosis, but its importance relative to paramagnetic rim and cortical lesions in predicting neurological disability and its progression remains unclear. In this longitudinal study, we aimed to identify the most relevant predictors of both the baseline Expanded Disability Status Scale status and 4-year progression independent of relapse activity in a heterogeneous multiple sclerosis cohort. One-hundred-twelve patients (83 relapsing-remitting and 29 secondary progressive; mean age 42.3 years, mean disease duration 9.8 years) underwent 7-Tesla T2* susceptibility-weighted images to segment paramagnetic rim lesions, non-rim white matter lesions and cortical lesions; 3-Tesla T1-weighted brain MRI images extended to the C2-C3 spinal cord were employed to obtain brain volumes and the spinal cord C2-C3 cross-sectional area using FreeSurfer and Spinal Cord Toolbox. Clinical disability was assessed through the Expanded Disability Status Scale at baseline and, in 97/112 patients (86.6%), after a mean follow-up of 4.0 years. The association between imaging metrics and clinical outcome was evaluated using correlations and regression models, corrected for age, sex, treatment class and clinical follow-up time. The main predictors of baseline Expanded Disability Status Scale were cortical lesion (β = 2.9 × 10^-4, P = 0.001), non-rim white matter lesion (β = 1.2 × 10^-4, P < 0.001) volumes, brain white matter volume (β = -15.68, P = 0.017) and C2-C3 cross-sectional area (β = -0.68, P = 0.003). At follow-up, 23/97 patients (24%) experienced progression independent of relapse activity. Progression independent of relapse activity was associated with paramagnetic rim lesion volume (odds ratio = 1.0006 per mm³ increase, P = 0.030), cortical lesion volume (odds ratio = 1.0005 per mm³ increase, P = 0.011) and brain white matter volume (odds ratio = 0.97 × 10^-20, P < 0.001). However, a stepwise logistic regression model assessing clinical, lesion and atrophy variables identified cortical lesion volume as the strongest independent predictor of progression independent of relapse activity (odds ratio = 1.0006 per mm³ increase, P = 0.005). In multiple sclerosis, different imaging biomarkers contribute differently to current disability and progression independent of relapse activity. Spinal cord atrophy mainly explains the current Expanded Disability Status Scale, while brain white matter atrophy and paramagnetic rim lesions provide additional insights into future disability trajectory. Among all markers, cortical lesions emerged as the main driver for progression independent of relapse activity.