Spinal cord tract-specific myelin water fraction and heterogeneity indices predict five-year disease progression in multiple sclerosis

Multiple sclerosis (MS) is a chronic demyelinating disease of the central nervous system that affects both the brain and spinal cord, producing focal lesions as well as diffuse pathology in normal-appearing white matter (NAWM). In the spinal cord, these microstructural abnormalities are strongly linked to motor dysfunction and long-term disability, yet sensitive biomarkers capable of capturing early myelin damage remain limited. Improving our understanding of how spinal cord myelin integrity relates to clinical progression may help identify individuals at greater risk for deterioration and guide earlier intervention. Myelin water imaging (MWI) is a quantitative MRI technique that provides histologically validated measures of myelin content. From MWI data, the mean myelin water fraction (MWF), its spatial variability (Standard Deviation, SD), and the myelin heterogeneity index (MHI = SD / MWF) can be derived, offering complementary insights into both the degree and uniformity of myelin integrity. In this thesis, we applied MWI to investigate cervical spinal cord myelin abnormalities across major white-matter tracts—including the dorsal, lateral, and ventral corticospinal pathways—in people with MS. In cross-sectional analysis, we observed lower NAWM MWF and higher MHI in MS compared to controls, with the strongest differences localized to the dorsal and lateral columns. Importantly, lower baseline NAWM MWF, particularly in the dorsal column, related to five-year EDSS worsening. Building on these findings, we examined whether early myelin trajectories over one year could forecast future clinical outcomes. We found that relapsing-remitting MS experienced greater myelin deterioration and diffuse NAWM deterioration across all tracts, which contributed to the risk of EDSS worsening, though only the ventral CST showed a linear relationship with progression. Overall, our results suggest that diffuse NAWM injury across the cervical cord is a contributor to accumulating disability. Together, Chapters 2 and 3 demonstrate that MWI-derived markers capture clinically meaningful myelin pathology in MS and may serve as sensitive biomarkers of progression risk.