Cortical Demyelination and Repair in Early Multiple Sclerosis.

PROJECT SUMMARY/ABSTRACT Multiple Sclerosis (MS) is an immune-mediated, demyelinating disorder of the central nervous system (CNS) and a leading cause of disability in young adults. MS white matter lesions are easily visible on clinical magnetic resonance imaging (MRI) and are the target of current treatments. However, white matter lesions are poor

predictors of disability, and prevention of white matter lesion formation does not stop gradual disability worsening in later stages of disease, when white matter lesion formation is rare. Cortical lesions are also common in MS, can be extensive, and are associated with disability and disability worsening over time. Cortical lesions are

thought to form due to overlying meningeal inflammation and thus they may respond differently to treatment than white matter lesions, in which inflammatory mediators come from parenchymal veins. Here we propose to further our understanding of MS cortical lesion formation and repair in early MS, the immunological mechanisms

underlying these processes, and the impact of these processes on the clinical course of disease. New MRI methods applied at ultra-high field strength (7 tesla, T), some of which we helped to develop, now allow us to sensitively visualize cortical lesions in vivo and track their formation and repair. With these methods, we

and others have demonstrated that cortical lesions are common, even early in disease, and are associated with disability. We have also found that cortical lesion burden, but not white matter lesion burden, predicts subsequent worsening of motor disability. Our recent data demonstrate that cortical lesion formation is rare in longstanding

disease, and so we hypothesize that cortical lesions form early in disease and then lead to subsequent gradual worsening of disability over time. Here, we propose to follow a cohort of adults with newly diagnosed MS for 3-years with 7T MRI (including 0.5mm3 T1 and motion and B0-corrected T2* weighted imaging), motor and cognitive

evaluation, and blood collection at baseline, year 1, and year 3. A subset of participants will also undergo cerebrospinal fluid (CSF) collection at baseline. We will determine how cortical and white matter demyelination are related in early MS and their relative contributions to physical and cognitive disability and disability worsening

over time (Aim 1). Using annual MRI data as well as data from short interval MRI follow-up (baseline, month 3, month 6) in a subset of participants, we will measure changes in cortical lesions over time and characterize cortical lesion growth, repair, and chronic inflammation (Aim 2). Finally, we will use single cell transcriptomics,

proteomics, and flow cytometry in blood and CSF to determine how cortical lesion burden is related to immune activation in the periphery and the CNS (Aim 3). This work will lead to key advances in our understanding of the pathophysiology, natural history, and clinical implications of cortical lesions in early MS, which will be essential the future development and testing of

treatments targeting cortical lesion formation and repair.