Distinct patterns of putative glymphatic function between early-onset and adult-onset first-episode schizophrenia:...

Schizophrenia exhibits high heterogeneity, with early-onset (EOS) and adult-onset (AOS) potentially involving distinct pathophysiological mechanisms. We investigated the patterns of putative glymphatic function in first-episode schizophrenia across different onset types to explore this heterogeneity, with a focus on differences in glymphatic-related perivascular diffusion characteristics.

This study enrolled 195 first-episode schizophrenia patients (EOS, n = 103; AOS, n = 92) and 191 matched healthy controls (younger controls [yHC], n = 62; older controls [oHC], n = 129). Diffusion tensor imaging indices along the perivascular space (DTI-ALPS) were computed as indirect markers of putative glymphatic-related fluid dynamics. We first explored the interaction effects of disease and onset-age on bilateral and mean ALPS. Further analyses included multiple linear regression models adjusting for confounding factors of illness duration and antipsychotic dosage, and partial correlation analyses with symptom subdimensions and cognitive function.

Significant disease and onset-age interaction effects were observed in the right and mean ALPS indices. Simple effect analysis revealed that the interactions were primarily driven by the significant differences between AOS and both oHC and EOS. Specifically, AOS patients exhibited significantly lower right and mean ALPS indices compared to both oHC and EOS groups. Notably, lower right ALPS in AOS patients were associated with greater hallucination severity, whereas no significant associations between DTI-ALPS indices and cognitive measures survived multiple comparison correction.

Differences in DTI-ALPS indices in first-episode schizophrenia varied by onset-age, with more pronounced alterations occurring in AOS patients, particularly within the right hemisphere, partly explaining the onset-age heterogeneity of schizophrenia.