Integrative profiling of glymphatic dysfunction in adolescent subthreshold depression

Subthreshold depression (StD) in adolescence is clinically important, but its neurobiological substrates remain unclear. We examined whether adolescents with StD show multimodal MRI alterations related to glymphatic function.

We recruited 107 adolescents (71 StD, 36 healthy controls). Six glymphatic-related biomarkers were assessed: choroid plexus volume, BOLD-CSF coupling, CSF Hurst exponent, ALPS index, perivascular space volume, and basal forebrain cholinergic nucleus volume. Group differences were tested using age- and sex-adjusted ANCOVA. Biomarker-clinical associations were examined using partial correlations with biomarker-wise Bonferroni correction across five primary clinical scales. Mahalanobis distance (MD) quantified multivariate deviation from the healthy-control glymphatic profile.

Compared with controls, adolescents with StD showed reduced BOLD-CSF coupling (F = 4.14, p = 0.044) and lower left ALPS (F = 9.12, p = 0.003). Three associations survived Bonferroni correction: lower left ALPS was associated with greater insomnia severity (p_Bonf = 0.021) and self-rated depressive symptoms (p_Bonf = 0.016), and lower CSF Hurst exponent with higher PHQ-9 scores (p_Bonf = 0.029). MD was higher in StD (F = 6.17, p = 0.01) and showed the strongest clinical association with PHQ-9 severity (r = 0.403, p = 0.001).

Adolescents with StD exhibit a multivariate glymphatic-related MRI profile involving altered BOLD-CSF coupling, reduced left ALPS, and clinically relevant deviations across biomarkers. These findings provide preliminary evidence that glymphatic-related MRI alterations may represent a neurobiological feature of adolescent StD and support multimodal integration over reliance on any single indirect marker.