PROJECT SUMMARY There is ever-growing evidence that African Americans (AAs) with multiple sclerosis (MS) present with a more severe disease course than Caucasian-Americans (CAs) with MS. It has been reported that clinical disability outcomes are worse, and inflammatory and MRI biomarkers significantly more unfavourable in AAs MS patients than in their CAs counterparts. Although genetic and environmental risk factors are likely to play a role, it is unclear why AAs MS patients experience a more disabling effect of the disease even after controlling for education, income, and insurance status. Two previous MRI studies have suggested that the more severe course is associated with the higher white matter (WM) lesion accumulation rather than with greater whole brain atrophy. However, these studies were limited by the retrospective or cross-sectional design and by the lack of assessment of regional cortical and sub-cortical gray matter (GM) volume. Moreover, potential differences in brain GM cortical lesion (CL) count and in area/volume of the spinal cord (SC) between MS patients of AA and CA ancestry have not been investigated up to date. Brain GM atrophy and CLs as well as SC atrophy occur since the early stages of MS and are independent predictors of physical disability and cognitive impairment suggesting their prominent role in determining the extent and pace of disease progression. Therefore, we propose a prospective, longitudinal brain and cervical SC MRI study of MS patients of AA and CA ancestry focused on the assessment of atrophy of strategic anatomical regions such as the thalamus and SC, on the assessment of diffuse microscopic WM tissue damage in the corpus callosum and SC and the assessment of cortical GM focal inflammation. We will also investigate the relationship between brain and SC MRI metrics and neurological and cognitive impairment at baseline and follow-up. This research is innovative because it proposes the first prospective clinical and MRI study of AAs MS patients with a longitudinal design to investigate the pathophysiology of the disease in MS patients of AA ancestry and to identify short- and medium-term predictors of disease and disability progression. The proposed research is significant because it will advance our understanding of the pathophysiology of neurodegeneration in MS and will provide accurate tools to better (i) understand the mechanisms leading to worse physical and cognitive disability in AAs MS patients; (ii) identify predictors of more aggressive disease progression in MS patients of AA descent, and (iii) help tailor therapeutic development and clinical interventions based on this knowledge.