Superficial white matter microstructural impairments correlate with functional alterations and disease severity in...

White matter (WM) damage is a key pathophysiological process in amyotrophic lateral sclerosis (ALS). However, alterations in superficial WM (SWM) have not been systematically explored. This study aimed to assess SWM microstructural changes in early-stage ALS and their associations with cortical functional alterations and disease severity.

Forty-two early-stage ALS patients and 48 healthy controls were included. Disease severity was evaluated using the revised ALS Functional Rating Scale (ALSFRS-R). The SWM was identified by sampling voxels along the cortical surface, maintaining a fixed distance (2 mm) from the gray matter/WM interface and removing deep white matter regions. SWM microstructural impairments were evaluated via neurite orientation dispersion and density imaging. Functional disturbances in the cortical regions corresponding to impaired SWM were measured by assessing regional homogeneity (ReHo) that reflects local synchronization of neuronal activity.

Patients showed a decreased neurite density index (NDI) in specific SWM regions, primarily including the bilateral precentral gyrus, supplementary motor area, paracentral lobule, and postcentral gyrus (family-wise error-corrected P < 0.05). Additionally, significant ReHo reductions were observed in cortical regions corresponding to compromised SWM. Both SWM NDI and cortical ReHo values significantly correlated with the ALSFRS-R score. Cortical ReHo alterations mediated the relationship between the SWM NDI value and the ALSFRS-R score (mediation effect = 0.103). SWM NDI assessments effectively identified ALS (area under the curve = 0.725-0.926).

Our findings highlight the SWM disruption as a crucial neurobiological substrate involved in early-stage ALS neuropathological mechanisms.