271. Glymphatic system dysfunction, accelerated brain aging, and inflammation in major psychiatric disorders: a transdiagnostic DTI-ALPS study

Abstract

Abstract Background Major psychiatric disorders, including Schizophrenia (SZ), Bipolar Disorder (BD), and Major Depressive Disorder (MDD), are increasingly recognized as conditions associated with accelerated biological aging and cognitive decline. The glymphatic system, a glial-dependent perivascular network, mediated by aquaporin-4 (AQP4) channels, plays a critical role in clearing metabolic waste and soluble proteins from the central nervous system. Impairment in this clearance system—evaluated non-invasively via the Diffusion Tensor Image Analysis along the Perivascular Space (DTI-ALPS) index—may exacerbate neuroinflammation and neurodegeneration. However, the relationship between glymphatic function, structural brain aging, systemic inflammation, and cognitive deficits across these disorders remains unclear. Aims & Objectives This study aims to investigate whether glymphatic dysfunction serves as a transdiagnostic mechanism linking inflammation to accelerated brain aging. Method A total of 796 participants were recruited, including patients with Schizophrenia (n=82), Bipolar Disorder (n=262), Major Depressive Disorder (n=256), and Normal Controls (NC, n=196). All participants underwent magnetic resonance imaging (MRI) to calculate the DTI-ALPS index, representing glymphatic function, and to assess the "Brain Age GAP" (the deviation between predicted brain age and chronological age). Systemic inflammation was evaluated using plasma levels of soluble IL-6 receptor (sIL-6R), C-reactive protein (CRP), and tumor necrosis factor receptor 1 (TNFR1). Cognitive function was assessed using the Wisconsin Card Sorting Test (WCST) and the Digit Symbol Substitution Test (DSST). Statistical analyses, including ANOVA and Pearson correlations, were conducted to compare groups and evaluate relationships between variables. Results Biochemically, the SCZ group showed significantly elevated levels of pro-inflammatory cytokines (IL-6sR, CRP, TNFR1) compared to other groups (p<0.0001). Crucially, lower ALPS scores and higher brain age gaps were significantly correlated with higher levels of inflammation (TNFR1, sIL-6R) and poorer cognitive performance on the WCST and DSST. The data indicates a gradient of severity where Schizophrenia patients present the most distributed structural aging and glymphatic dysfunction, followed by mood disorders, relative to controls. Discussion & Conclusions These findings suggest that glymphatic system dysfunction is a pivotal pathophysiological factor in major psychiatric disorders, particularly Schizophrenia. The significant correlation between reduced ALPS index, elevated inflammation, and accelerated brain aging supports the hypothesis that inefficient intracranial waste clearance may exacerbate neuroinflammatory processes, leading to structural brain changes and cognitive decline. The results highlight the potential utility of the DTI-ALPS index as a biomarker for monitoring brain health and suggest that therapeutic strategies enhancing glymphatic clearance could potentially mitigate neuroprogression and cognitive deterioration in psychiatric populations.