This research proposal aims to investigate the role of cerebral perfusion in the development of lesion burden and disease progression in multiple sclerosis (MS). Are well perfused regions of the brain are more likely to recover from inflammatory and/or demyelinating activity? Would such propensity translate into an anatomical prevalence of lesion persistence? The clinical disease course, prognosis, and response to treatment in patients with multiple sclerosis (MS) are highly variable and difficult to predict. The clinical subtypes of relapsing-remitting (RR) and secondary progressive (SP) are considered the early and late phases respectively of the MS disease course. Yet progression within these phases and conversion between them can vary greatly among individuals, and the pathological differences are poorly characterized. We hypothesize that sustained tissue damage results from lesion development in regions of anatomical and physiological susceptibility in which the environment is restrictive or prohibitive to normal reparative processes (e.g. resolution of inflammation, remyelination). We will specifically test if well perfused regions of the brain are more likely to recover from MS damage and therefore result in fewer persistent lesions over the course of disease progression. To this end, we will compare the spatial distribution of lesions in early (RR) and late (SP) MS patients and characterize lesion distribution in these two groups as a function of normal cerebral perfusion. The proposed work will be carried out on a retrospective dataset of a large cohort of MS patients stratified by clinical subtype (n = 1,607 RR, n = 495 SP). This project will provide important information regarding the spatial specificity of white matter lesions in the early and late stages of MS and how these distributions relate to the normal pattern of healthy perfusion.