Assessment of glymphatic system function in young major depressive disorder using multimodal MRI.

OBJECTIVES

To assess glymphatic system function in young major depressive disorder (MDD) patients using multimodal MRI and explore associations between imaging parameters and clinical severity.

METHODS

First-episode, treatment-native young MDD patients (December 2023 to January 2025) were divided into mild, moderate, and severe subgroups based on HAMD-24 scores. Age and sex matched healthy controls (HCs) were recruited. Clinical data and MRI scans were collected. Glymphatic parameters-perivascular space (PVS) volume, diffusion tensor image analysis along the perivascular space (DTI-ALPS) index, and global blood oxygen level-dependent cerebrospinal fluid (gBOLD-CSF) coupling coefficient-were compared between groups and across MDD severity subgroups. Spearman correlation analysis assessed associations with HAMD-24 scores and clinical data; to avoid extreme-group bias, analyses were performed in the whole sample and replicated within the MDD subgroup. Binary logistic regression identified independent MDD-related factors, with variance inflation factor (VIF) testing for multicollinearity. Receiver operating characteristic (ROC) curves evaluated diagnostic performance. The combined model was validated using stratified 10-fold cross-validation and 1000 permutation tests.

RESULTS

A total of 81 young MDD patients (20 mild, 29 moderate, 32 severe) and 61 HCs were included. (1) MDD patients showed lower DTI-ALPS index (P < 0.001), larger PVS volume (P < 0.001), and higher gBOLD-CSF coupling coefficient (P = 0.014) than HCs. (2) With increasing severity, DTI-ALPS index decreased, PVS volume increased, and gBOLD-CSF coupling coefficient increased. Pairwise comparisons (Bonferroni): severe vs. mild/moderate differed in all parameters (all P < 0.05); moderate vs. mild differed in PVS volume and gBOLD-CSF (both P < 0.05), but not in DTI-ALPS (P > 0.05). (3) DTI-ALPS index correlated negatively with HAMD-24 scores (r = -0.37, P < 0.001); PVS volume (r = 0.66-0.74) and gBOLD-CSF (r = 0.59) correlated positively (all P < 0.001). Results within the MDD subgroup were consistent (all P < 0.001). (4) DTI-ALPS index and PVS volume were independently associated factors with MDD (both P < 0.001). The combined model achieved an AUC of 0.88 (sensitivity 0.91, specificity 0.77), outperforming single indicators. Cross-validation yielded an AUC of 0.87; permutation tests confirmed significance (P = 0.001).

CONCLUSION

Young MDD patients have impaired glymphatic function. PVS, DTI-ALPS, and gBOLD-CSF correlate with severity. The combination of DTI-ALPS index and PVS volume has high diagnostic value and may serve as a non-invasive imaging biomarker for young MDD.