Subtype and stage inference of tract-level diffusion abnormalities in amyotrophic lateral sclerosis

Amyotrophic Lateral Sclerosis (ALS) shows substantial heterogeneity in clinical presentation and white matter involvement, but conventional diffusion tensor imaging analyses provide limited information on whether tract-level abnormalities follow distinct patient level patterns.

This retrospective secondary analysis included 73 patients with ALS and 30 healthy controls. Fractional anisotropy (FA) and mean diffusivity (MD) from 11 predefined tracts were used as SuStaIn biomarkers, with healthy controls providing the normative reference for Z-score standardization. SuStaIn subtypes and stages were examined against Amyotrophic Lateral Sclerosis Functional Rating Scale-Revised (ALSFRS-R), King's stage, and peak width of skeletonized mean diffusivity (PSMD).

The three-subtype model classified patients into cingulate callosal motor mixed subtype (n = 34), hippocampal cingulum posterior projection subtype (n = 32), and posterior callosal projection, MD predominant subtype (n = 7). Exploratory comparisons showed lower PSMD in subtype 0 than subtypes 1 and 2 (both p = 0.026), lower ALSFRS-R in subtype 2 than subtype 1 (p = 0.026), and higher SuStaIn stage in subtype 2 than subtype 0 (p = 0.025). Higher SuStaIn stage correlated with higher King's stage (rho = 0.318, p = 0.006) and lower ALSFRS-R (rho = - 0.289, p = 0.013). After adjustment, higher SuStaIn stage remained associated with lower ALSFRS-R (β = - 0.333, p = 0.013) and more advanced King's stage (odds ratio = 1.181, p < 0.001).

Tract-level diffusion SuStaIn identified anatomically interpretable patterns of white matter involvement in ALS and provided patient-level stage estimates associated with clinical disease burden.