Assessing glymphatic function in major depressive disorder using DTI-ALPS and AQP4-related miRNAs

Major Depressive Disorder (MDD) is associated with sleep disturbances, which may affect glymphatic function. The Diffusion Tensor Imaging–Along the Perivascular Space (DTI-ALPS) index provides a non-invasive measure of glymphatic activity. This study investigated glymphatic function in MDD and its relation with Aquaporin-4 (AQP4) targeting miR-196b.

Participants included 29 MDD patients in acute depressive episode (MDD-Dep), 15 MDD patients in remission (MDD-Rem), and 26 healthy controls (HC) aged 18-45 years. ALPS indices were calculated from 3Tesla-Magnetic Resonance Imaging (MRI) scans acquired at two institutions. Group differences were assessed using a General Linear Model (Univariate) controlling for age, sex and MRI-acquisition site/protocol. An age and sex matched subset of the cohort (15 MDD-Dep, 15 HC) was used for miR-196b analysis. Correlation and regression analyses were performed.

MDD-Dep showed significantly lower bilateral and left ALPS indices than both HC (p=0.028; p=0.046, respectively) and MDD-Rem (p=0.049; p=0.006, respectively). Right ALPS index did not have significant differences. In correlation analyses, while ALPS_Right had negative nominal association with Hamilton Depression Rating Scale (HDRS); and ALPS_Left with Percieved Stress Scale (PSS), none survived Benjamini-Hochberg correction. miR-196b expression did not differ between MDD-Dep and HC, but was significantly associated with ALPS_bilateral (r=-0.542, FDR-adjusted p=0.021) and ALPS_Left (r=-0.543, FDR-adjusted p=0.021), confirmed through regressions (ALPS_bilateral: β=-0.546, p=0.007; ALPS_Left: β=-0.557, p=0.005).

Lower ALPS indices in MDD-dep and the association between miR-196b and ALPS index suggest a relationship between glymphatic activity and clinical state. Given the multi-central, cross-sectional design, findings should be cautiously interpreted and confirmed in more balanced longitudinal cohorts.