PROJECT ABSTRACT AND SUMMARY Multiple Sclerosis (MS) is a devastating and incurable neurological disease characterized by recurrent bouts of acute immune-mediated inflammation as well as insidious neurodegeneration of the central nervous system. MRI is the most important tool to diagnose and assess MS, allowing visualization of the hallmark pathology as T2-hyperintense inflammatory lesions. After an acute phase, most MS lesions quickly become quiescent; however in about 40% of patients, some remain chronically active. These “smoldering” lesions can be identified on susceptibility-sensitive MRI by their paramagnetic rim, which has been shown on histopathology to be composed of iron-enriched, pro-inflammatory microglia and macrophages; these activated glial cells are hypothesized to accelerate and perpetuate the inflammatory processes ultimately causing neurodegeneration. However, the definitive identification and clinical consequences of these “paramagnetic rim lesions” (PRL) remains unknown. Additionally, the possibility of treating these PRLs using contemporary disease- modifying therapies (DMT) is an important clinical question. This project aims to first determine the presence of these lesions on clinically-available 3T MRI using a susceptibility-sensitive T2-star phase sequence, in a retrospective longitudinal cohort of MS patients. The presence of PRLs will be examined for associations with other known markers of neurodegeneration including slow lesion expansion, the appearance of new cortical lesions, and the whole brain atrophy rate. The effects of DMT will also be assessed by examining the details of individual treatment histories in relation to PRLs. Next, in a prospective longitudinal cohort we aim to use an advanced MRI technique called quantitative susceptibility mapping to determine the quantitative PRL iron concentration as a correlate of inflammatory severity, and observe the objective rates of iron change in MS patients on different DMTs. The candidate plans to devote his career to the investigation of neurodegeneration and its links to neuroinflammation. Career goals include the creation, validation, and translation of MRI biomarkers using novel sequences. As part of this project, the candidate will be training in the development and use of susceptibility-protocol multimodal structural MRI, as well as learning advanced statistical modeling tools necessary to handle complex -and often incomplete- longitudinal clinical datasets. Overall this project involves a novel translational approach to explore hypotheses connecting smoldering inflammation to pathophysiological manifestations of neurodegeneration that we see as clinicians caring for our patients with MS.