Glymphatic Dysfunction and Related Brain Structure Changes in Major Depressive Disorder: Effects of Glymphatic Function in Mediating Neuroinflammation

Objective The glymphatic system, responsible for cerebrospinal fluid flow and waste clearance, is increasingly implicated in the pathophysiology of major depressive disorder (MDD) through its influence on neuroinflammation. This study investigated the association between glymphatic dysfunction, systemic inflammation, and brain volume changes in patients with MDD.Methods Glymphatic function was assessed using the diffusion tensor image analysis along the perivascular space (DTI-ALPS) index in 176 patients with MDD and 178 controls. Inflammatory cytokine levels, including plasma C-reactive protein (CRP) levels, were measured in 68 patients with MDD and 54 controls. Depressive symptoms were evaluated using the Hamilton Depression Rating Scale. Statistical analyses included a multivariate analysis of covariance and Pearson’s partial correlations adjusted for covariates. Mediation analysis examined the relationships between CRP, glymphatic function, and brain volume.Results Patients with MDD showed reduced glymphatic function compared to healthy controls. Reduced DTI-ALPS indices were correlated with higher CRP levels and increased ventricular volumes, including the choroid plexus. CRP levels were negatively correlated with DTI-ALPS indices and right choroid plexus volumes. Mediation analysis indicated that glymphatic dysfunction partially mediated the relationship between elevated CRP levels and decreased choroid plexus volume in patients with MDD.Conclusion This study found that in MDD, glymphatic dysfunction is associated with higher CRP and mediates the link between systemic inflammation and right choroid plexus volume. Given sample size and limited covariate control, these results are preliminary and need confirmation in larger longitudinal cohorts. Even so, impaired glymphatic function may represent a therapeutic target.