PROJECT SUMMARY / ABSTRACT: Multiple sclerosis is a chronic, debilitating disease of the central nervous system characterized by neuroinflammation, focal demyelination, gliosis, axonal degeneration, and neuronal loss. As remyelination is both highly variable and associated with improvement of symptoms, therapies that foster remyelination represent an opportunity for repair prior to irreversible damage and decline. Given the importance of myelination, magnetic resonance imaging (MRI) biomarkers of myelin integrity have been developed for use in clinical trials. Unfortunately, these biomarkers reflect static levels of myelin and cannot predict demyelination or remyelination processes. Recent studies have suggested that remyelination relies on adequate tissue perfusion. While altered perfusion has been reported in MS, the relationship between perfusion and myelin has not been fully characterized in vivo. Furthermore, whether perfusion MRI biomarkers can predict downstream myelin repair remains an outstanding question. This proposal aims to overcome this challenge by investigating the role of perfusion in demyelination and remyelination using MRI biomarkers. The development of biomarker assays to quantitatively probe both perfusion and myelin content may predict regenerative potential and evaluate emerging therapies that promote neuroprotection and remyelination. To assay perfusion changes, a multi-contrast spin- and gradient-echo (SAGE) MRI method enables evaluation of hemodynamic measures at distinct vascular scales (i.e., total vascular and microvascular regimes). Given the known microvascular component of MS, the ability to specifically quantify microvascular function may provide a more specific indicator of underlying pathology. Myelin content can be assayed using a selective inversion recovery (SIR) method that provides quantitative and reliable measures of myelin. The objective of this study is to determine whether vascular function is indicative of lesion demyelination and remyelination. More specifically, this project aims to a) establish the relationship between perfusion and myelin in persons with relapsing-remitting MS (pwMS) and in healthy controls; b) establish normative values in healthy controls and test-retest repeatability in both healthy controls and pwMS with stable disease; and c) assess whether lesion perfusion predicts demyelination and remyelination in pwMS with active lesions. If successful, this approach will establish the role of microvascular changes as a precursor of disease and prognosticator of outcomes, as well as provide potential treatment targets related to preventing microvascular dysfunction and its downstream effects. The development of robust MRI biomarker assays that quantitatively probe both perfusion and myelin content could more reliably, and with greater biospecificity, assess regenerative potential and therapeutic response, thus filling a critical gap in both patient care and clinical trials designed to ev...