Project Summary People with multiple sclerosis (PwMS) with an insidious clinical decline independent of inflammatory disease activity (progression) often have a greater extent of spinal cord (SC) involvement. There is a critical need to understand how injury of clinically eloquent SC motor and sensory tracts can lead to variable functional impairment ranging from being asymptomatic to a bedridden state. Strong correlations between disability worsening and a progressive disease course have been observed with 1) focal atrophy with some lateral SC lesions and 2) upper cervical SC atrophy reflecting global SC lesion burden. These findings suggest that axonal loss is a key driver of disability and is variably lost as a consequence of lesions. In postmortem tissue, we determined that T2*-weighted intensity can be used to discriminate demyelinated hyperintense lesions from myelinated lesions (intermediate hyperintensity). Approximately a third of T2* lesions were intermediate intensity characterized by swollen dystrophic axons with thinner myelin and activated/phagocytic microglia/macrophages. This led to our hypothesis that intermediate lesions represent secondary neurodegenerative changes (Wallerian degeneration) distal to a demyelinated lesion. Our aims determine whether 1) intermediate lesions can be detected distinctly from hyperintense lesions in vivo and whether they are distal to hyperintense lesions using 7T MRI; and 2) differences in detection of intermediate lesions between 7T and 3T. We are particularly well positioned to perform this work as we have demonstrated T2* can be thresholded to discriminate between lesion subtypes by MRI-pathology and have similar sequences already available in a pre-existing 3T MRI dataset and prospectively on 7T. The 52% improved detection of 7T lesions compared to 3T and our ability to pre-screen PwMS with known focal cervical SC lesions at our Center, will optimize the potential for successful execution of our aims. Ultimately, the data generated from this proposal will identify the ability of 7T and 3T to detect potential neurodegenerative changes distal to demyelination to ask what patient characteristics lead to a greater likelihood of Wallerian degeneration (intermediate lesions) or axonal loss (atrophy) and whether therapeutic interventions can prevent these processes.