Multiple sclerosis (MS) is a central nervous system (CNS) autoimmune disorder characterized by chronic inflammation, axonal demyelination, and neuronal degeneration. The complex pathophysiology of MS is mediated by autoreactive T cells that ultimately invade and attack the CNS by traversing the blood-brain barrier (BBB), resulting in persistent irreversible axonal damage and physical disability. Magnetic resonance imaging (MRI) metrics contribute substantially to the diagnosis and management of MS, providing critical information regarding disease activity in addition to serving as secondary endpoint measures for clinical trials evaluating MS therapies. Traditional MRI techniques (e.g., contrast enhanced [CE] T1-weighted imaging, spin-echo [SE] T2-weighted imaging [T2-WI]) have proven effective for detecting the presence of macroscopic white matter (WM) MS lesions but are limited by the inability to effectively delineate microscopic tissue damage occurring in normal-appearing white matter (NAWM) and microscopic and macroscopic tissue damage in normal-appearing gray matter (NAGM). Furthermore, the brain-lesion burden on traditional MRI scans correlates only modestly with clinical disease progression. Thus, a need exists to use alternative non-conventional MRI techniques and approaches that more accurately monitor clinical disease activity and efficacy of disease-modifying therapies.