Glymphatic System Dysfunction Underlying Schizophrenia Is Associated With Cognitive Impairment

Abstract Background and Hypothesis Despite the well-documented structural and functional brain changes in schizophrenia, the potential role of glymphatic dysfunction remains largely unexplored. This study investigates the glymphatic system’s function in schizophrenia, utilizing diffusion tensor imaging (DTI) to analyze water diffusion along the perivascular space (ALPS), and examines its correlation with clinical symptoms. Study Design A cohort consisting of 43 people with schizophrenia and 108 healthy controls was examined. We quantified water diffusion metrics along the x-, y-, and z-axis in both projection and association fibers to derive the DTI-ALPS index, a proxy for glymphatic activity. The differences in the ALPS index between groups were analyzed using a 2-way ANCOVA controlling for age and sex, while partial correlations assessed the association between the ALPS index and clinical variables. Study Results People with schizophrenia showed a significantly reduced DTI-ALPS index across the whole brain and within both hemispheres (F = 9.001, P = .011; F = 10.024, P = .011; F = 5.927, P = .044; false discovery rate corrected), indicating potential glymphatic dysfunction in schizophrenia. The group by cognitive performance interaction effects on the ALPS index were not observed. Moreover, a lower ALPS index was associated with poorer cognitive performance on specific neuropsychological tests in people with schizophrenia. Conclusion Our study highlights a lower ALPS index in schizophrenia, correlated with more pronounced cognitive impairments. This suggests that glymphatic dysfunction may contribute to the pathophysiology of schizophrenia, offering new insights into its underlying mechanisms.