Diffusion Basis Spectrum Imaging of Tissue Microstructure and Early Treatment in Multiple Sclerosis

OBJECTIVE: Conventional MRI cannot resolve the coexisting pathological processes within multiple sclerosis tissue. Diffusion Basis Spectrum Imaging decomposes the diffusion signal into fiber, cell, and hindered ratios indexing axonal integrity, cellularity, and extracellular space, respectively. We asked how these ratios differ between early relapsing and established non-relapsing disease, change with early treatment, and relate to disability, and secondarily, whether lesions form reproducible microstructural subtypes. METHODS: Thirty-seven participants underwent multi-shell diffusion MRI: 11 healthy controls, 15 treatment-naïve relapsing, and 11 non-relapsing patients. Thirteen were rescanned ~3 months after starting high-efficacy disease-modifying therapy. Metrics were extracted from normal-appearing gray and white matter and lesions (core, rim, and perilesional white matter); Gaussian mixture model clustering of per-lesion fiber, cell, and hindered ratios identified lesion subtypes. RESULTS: Treatment-naïve relapsing patients showed reduced normal-appearing white matter fiber (p = 0.04) and elevated hindered ratios (p = 0.02) versus controls. Lesions had lower fiber and cell ratios and higher hindered ratio than within-subject normal-appearing white matter (all p < 0.001). After treatment, lesional fiber ratio increased (p = 0.01) while lesional and gray matter cell ratios declined (both p = 0.02). Lesional cell ratio was higher in relapsing than non-relapsing patients at the core (p = 0.03) and rim (p = 0.04) but not perilesionally; treatment-related improvement was similar across compartments. Clustering yielded four reproducible subtypes (edematous-hypocellular, moderately cellular, actively inflamed, structurally preserved); the inflamed subtype predominated in relapsing and the edematous-hypocellular in non-relapsing disease. INTERPRETATION: Diffusion basis spectrum imaging distinguishes relapsing from non-relapsing disease by lesion-body cellularity and detects treatment-related changes in fiber and cell compartments. Reproducible, hypothesis-generating lesion subtypes support its use for in vivo lesion phenotyping.