Abnormal coupling between glymphatic activity and brain structure-function in adolescents with major depressive...

Suicide is the second leading cause of adolescent death, with major depressive disorder (MDD) heightening suicidality risk. Emerging evidence suggests glymphatic dysfunction and neuroinflammation may play critical roles. This study investigated glymphatic function and its associations with brain structure-function in adolescents with MDD and comorbid suicidality (MDD-S).

We analyzed multimodal MRI data from 46 adolescents with MDD-S (12-19 years) and 30 healthy controls (HC, 12-19 years). Glymphatic function was assessed using the diffusion tensor image analysis along the perivascular space (DTI-ALPS) index. Cortical thickness and amplitude of low-frequency fluctuations (ALFF) were also evaluated. Between-group differences were tested using vertex-wise general linear models (GLMs).

MDD-S patients showed a significantly elevated DTI-ALPS index than HC (1.517 ± 0.1790 for HC vs. 1.430 ± 0.1535 for MDD-S; F = 4.773; P = 0.032). While no significant group differences were found in cortical thickness or ALFF alone, interaction analyses revealed significant group × DTI-ALPS effects on cortical thickness and ALFF: (1) MDD-S exhibited weaker correlations between DTI-ALPS and cortical thickness in the bilateral superior temporal gyrus, left fusiform gyrus, and right anterior insular cortex compared to HC. (2) For ALFF in the right precuneus, the MDD-S showed a strong positive correlation, contrasting with HC's significant negative correlation.

These findings suggest abnormal coupling between glymphatic activity and brain structure-function in MDD-S adolescents, providing novel insights into the neuropathophysiology of suicidality in MDD. While DTI-ALPS index may contribute to suicidality assessment, its clinical utility as a biomarker requires further validation.