Dual glymphatic roles in first-episode schizophrenia and clinical high-risk for psychosis: Evidence from diffusion...

Emerging evidence has implicated glymphatic dysfunction in schizophrenia-spectrum disorders (SSD), yet its role during early stages of the disease remains unclear. To clarify its involvement in pathophysiological mechanisms in the early illness course, we evaluated glymphatic function in first-episode SSD (FES) and clinical high-risk for psychosis (CHR-P) populations using diffusion-tensor image analysis along perivascular space (DTI-ALPS) index, testing whether it would exhibit progressive deterioration or transient compensatory adaptation.

We examined 55 FES patients, 23 individuals with CHR-P and 30 healthy controls (HCs). ANCOVAs were conducted on the global and bilateral DTI-ALPS indices across the three groups, adjusting for age, sex, and head motion. Partial correlation analyses further examined associations between DTI-ALPS index and measures on severity of various symptom dimensions, functioning, and cognitive performance of FES and CHR-P samples.

After controlling for covariates, group comparisons revealed that FES patients showed significantly lower global and bilateral DTI-ALPS indices than HCs, while CHR-P did not differ from HCs. Antipsychotic dosage and FES diagnostic subtypes showed no significant differences in DTI-ALPS indices. Correlation analyses showed that, after correction for multiple comparisons, ALPS indices showed no significant correlations with symptoms or cognitive performance. But in the uncorrected analyses, the FES and CHR-P groups showed opposite patterns of correlations with symptoms and cognition.

These findings indicate that glymphatic dysfunction is a prominent feature of FES, while early signs of dysfunction may already be present during the prodromal stage. DTI-ALPS index show potential as a stage-specific marker pending longitudinal validation and replication.