Putative glymphatic function and free water in schizophrenia: A 7T DTI study across psychosis stages

Schizophrenia is characterized by impaired brain health, including gray matter reductions and cognitive dysfunction, with vascular and glymphatic dysfunction emerging as key contributors. The glymphatic system, which clears metabolic waste via perivascular pathways, is measurable using Diffusion Tensor Imaging-Along the Perivascular Space (DTI-ALPS) and its dysfunction is suspected to increase extracellular free water (FW). Prior studies reported potential glymphatic impairment in schizophrenia, but its relationship to the stage of illness and impact on interstitial fluid dynamics remains unclear. This study employed ultra-high field (7-Tesla) DTI to quantify DTI-ALPS and FW in white and gray matter in 125 subjects, including clinical high-risk (CHR), untreated first-episode psychosis (FEP), established schizophrenia (>3 years), and healthy controls (HC). We investigated: (1) the presence of DTI-ALPS alterations in CHR and its relative magnitude across disease stages; (2) its association with symptom severity; (3) its correlation with FW; and (4) its relationship to likely origins of neuroanatomical progression in schizophrenia from the hippocampal region. Compared with HC, the established, FEP and CHR all showed lower DTI-ALPS (p < 0.01 for all, Hedge's g = 0.73-1.13) and higher white matter FW (p < 0.05 for all, g = 0.59-1.57). Lower DTI-ALPS was correlated with higher FW, longer duration of untreated psychosis, and was selectively pronounced in the FEP subgroup, whose structural changes may originate from the hippocampal region. Our findings suggested that the putative glymphatic dysfunction indexed by DTI-ALPS predates antipsychotics, drives interstitial fluid accumulation, and contributes to schizophrenia's structural and clinical progression, offering mechanistic insights into its pathophysiology.