Multi-compartment Myelin Streamline Decomposition reveals tract-specific and global brain network myelination in Multiple Sclerosis

Multiple Sclerosis (MS) disrupts white matter (WM) tract organization, affecting brain networks and neurological function. Current methods lack the capacity to directly quantify tract- and network specific myelin-sensitive measures with clinical outcomes. This cross-sectional study (122 MS patients, 72 females, median age 48.5 years, median EDSS 3.0) applied multi-compartment Myelin Streamline Decomposition (MySD), an advanced MRI technique for assessing myelin-sensitive measures of WM bundles and networks in the presence of focal lesions. Patients underwent 3T MRI with magnetization transfer (MT)-weighted and multi-shell diffusion imaging. These data enabled multi-compartment MySD reconstruction to generate myelin-sensitive tract measures for the corticospinal tract (CST) and cingulum bundle (CB) and MVF-derived myelin-sensitive network properties. Associations were tested between tract-specific measures and five network measures with disability (Expanded Disability Status Scale (EDSS)), information processing speed (Symbol Digit Modalities Test) and neuroaxonal damage (serum neurofilament light chain), adjusting for covariables. Primary FDR-corrected analyses were considered for the left/right CST with EDSS and left/right CB with SDMT. All remaining analyses were considered exploratory. While primary CST-EDSS associations did not reach significance, a subgroup analysis revealed an association between myelin-sensitive tract measure of the left CST with SDMT z-scores (β = 0.57, p = 0.001, R 2 Adj = 0.21). Sensitivity analysis demonstrated correlations between myelin-sensitive tract measure of the left CST with mean strength (ρ = 0.38, p < 0.001) and efficiency (ρ = 0.33, p < 0.001). Lower myelin-sensitive tract measures of the CST related to poorer cognitive performance. Multi-compartment MySD enables exploration of myelin-sensitive proxies and clinical outcomes in MS.