Reduced medial periventricular diffusion markers are associated with depressive symptoms and social deficits in ASD

The glymphatic system is a candidate mechanism in autism spectrum disorder (ASD), linked to altered cerebrospinal fluid (CSF) dynamics, perivascular space (PVS) enlargement, and neuroinflammation, yet its relation to brain structure and clinical outcomes remains unexamined. We analyzed multimodal MRI (T2 FLAIR, T1, diffusion) in 58 adult males (29 ASD, 29 TD) from ABIDE-II, quantifying regional DTI-ALPS indices, free water metrics, white matter hyperintensities, and PVS and CSF volumes. ASD showed a more pronounced anterior peak in the DTI-ALPS anterior-to-posterior profile (group × position: β = 0.0020, p < .001), though this attenuated under random slopes (p = .160); scalar indices showed no group differences. Within ASD, medial DTI-ALPS was the sole marker associating with both depression (r = -0.51) and social communication (r = -0.56), while tissue radial diffusivity was the strongest correlate of depressive symptoms (p < .001). Left basal ganglia PVS correlated negatively with medial DTI-ALPS (partial r = -0.58, p = .005), and mediation showed PVS related to social functioning only indirectly, via medial DTI-ALPS. Regional associations persisted after free-water correction, consistent with a tissue-microstructural basis. These ASD-specific findings suggest dissociable microstructural and neurofluid mechanisms in mood and social dysfunction.