Integrative Profiling of Glymphatic Dysfunction in Adolescent Subthreshold Depression

ObjectiveSubthreshold depression (StD) in adolescence is a potent risk factor for major depressive disorder, yet its neurobiological mechanisms remain unclear. The glymphatic system, a brain-wide waste clearance pathway, has been implicated in psychiatric disorders but has not been investigated integratively in StD. This study aimed to characterize glymphatic function in adolescents with StD using a multimodal neuroimaging approach. MethodsA total of 107 adolescents (71 with StD and 36 healthy controls) underwent multimodal MRI. Glymphatic function was assessed using three complementary metrics: the diffusion tensor imaging analysis along the perivascular space (DTI-ALPS) index for clearance capacity, BOLD-CSF coupling for neurovascular-driven circulation, and Hurst exponent for CSF flow dynamics. An integrated Mahalanobis Distance (MD) was calculated to quantify individual deviation from the healthy glymphatic profile. ResultsCompared with healthy controls, adolescents with StD exhibited significant reductions in the left DTI-ALPS index and global BOLD-CSF coupling (p < 0.05). No significant group differences were found in structural volumes of the choroid plexus or perivascular spaces. The integrated MD metric significantly differentiated StD from controls and demonstrated stronger associations with clinical severity than single biomarkers. Specifically, glymphatic dysfunction was significantly correlated with greater depressive symptom severity, sleep disturbances, and general psychopathology. ConclusionsAdolescents with StD exhibit distinct, lateralized impairments in glymphatic clearance and neurovascular driving mechanisms. These findings provide early physiological evidence for a dimensional model of depression, suggesting that glymphatic dysfunction is present before diagnostic criteria for major depression are met. The multivariate MD metric offers a sensitive biomarker for tracking early pathophysiological changes and potential intervention targets.