Sex-specific role of systemic inflammation in moderating the association between choroid plexus volume and depressive severity: findings from sBEAD cohort.

BACKGROUND: Accumulating evidence implicates peripheral inflammation and glymphatic dysfunction in adult major depressive disorder (MDD), but whether glymphatic impairment exists in adolescent MDD and how it interacts with systemic inflammation remains unknown. METHODS: Data were derived from the Symptomatic Trajectory and Biomarkers of Early Adolescent MDD (sBEAD) study. The sample comprised 461 adolescents with MDD and 253 healthy controls. Multimodal magnetic resonance imaging-derived markers of glymphatic function, including the diffusion tensor imaging along the perivascular space index, free water fraction, perivascular space volume, and choroid plexus (CP) volume, were investigated, as well as their interaction with peripheral inflammatory and oxidative stress indices. RESULTS: Compared with healthy controls, adolescents with MDD exhibited a significantly elevated diffusion tensor imaging along the perivascular space index, increased free water fraction, and higher systemic immune-inflammation index (SII) levels. Notably, the SII significantly moderated the relationship between CP volume and depression severity: greater CP volume was associated with more severe depression in patients with high SII levels, whereas this association was absent under low SII levels. This moderating effect was significant in female patients, whereas no such effect was detected in males. CONCLUSIONS: These findings provide evidence of a synergistic interaction between systemic inflammation and brain clearance pathways in adolescent MDD, highlighting a potential sex-dependent mechanism that may inform targeted interventions for affected subpopulations.