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.