Neuroclearance dysfunction in autism with sleep disorder: MRI evidence and mediation by systemic iron deficiency.

BACKGROUND

Sleep disturbances are highly prevalent in children with autism spectrum disorder (ASD) and exacerbate neurodevelopmental impairments. Yet, the mechanistic link between sleep disruption, brain fluid clearance, and systemic trace element status remains unclear.

METHODS

We enrolled 230 children with ASD (114 with sleep disorder, ASD-SD; 116 without, ASD-nSD) and 110 typically developing controls. Neuroclearance function was quantified using diffusion kurtosis imaging along the perivascular space (DKI-ALPS), free water fraction (FW), and perivascular space volume fraction (PVSVF). Serum iron (Fe), lead (Pb), and magnesium (Mg) were measured. Group comparisons, correlations, ROC analysis, and mediation modeling assessed relationships among sleep, iron status, and neuroclearance.

RESULTS

ASD-SD children exhibited significantly reduced ALPS indices and elevated FW compared with ASD-nSD and controls, indicating impaired perivascular clearance. Serum Fe was markedly lower in ASD-SD, whereas Pb was elevated; Mg showed no significant differences. ALPS indices strongly correlated with Fe levels (r = 0.75-0.95). Mediation analysis revealed that iron deficiency partially reduced ALPS via increased FW, supporting a hypothesized "Fe deficiency → cerebral edema → impaired neuroclearance" pathway. Combined ALPS and serum Fe distinguished ASD-SD from ASD-nSD and controls with high accuracy (AUC up to 0.94).

CONCLUSION

Children with ASD and comorbid sleep disorder exhibit pronounced neuroclearance dysfunction linked to systemic iron deficiency. The combination of DKI-ALPS and serum Fe shows potential as a candidate biomarker for ASD-SD, highlighting a potential cascade from sleep disruption to impaired neuroclearance and suggesting targeted interventions integrating iron supplementation and sleep optimization.