Reduced cerebral cortex thickness is related to overexpression of exosomal miR-146a-5p in medication-free patients with major depressive disorder

BACKGROUND: Previous studies have confirmed that miR-146a-5p overexpression suppresses neurogenesis, thereby enhancing depression-like behaviors. However, it remains unclear how miR-146a-5p dysregulation produces in vivo brain structural abnormalities in patients with major depressive disorder (MDD). METHODS: In this case–control study, we combined cortical morphology analysis of magnetic resonance imaging (MRI) and miR-146a-5p quantification to investigate the neuropathological effect of miR-146a-5p on cortical thickness in MDD patients. Serum-derived exosomes that were considered to readily cross the blood-brain barrier and contain miR-146a-5p were isolated for miRNA quantification. Moreover, follow-up MRI scans were performed in the MDD patients after 6 weeks of antidepressant treatment to further validate the clinical relevance of the relationship between miR-146a-5p and brain structural abnormalities. RESULTS: In total, 113 medication-free MDD patients and 107 matched healthy controls were included. Vertex-vise general linear model revealed miR-146a-5p-dependent cortical thinning in MDD patients compared with healthy individuals, i.e., overexpression of miR-146a-5p was associated with reduced cortical thickness in the left orbitofrontal cortex (OFC), anterior cingulate cortex, bilateral lateral occipital cortices (LOCs), etc. Moreover, this relationship between baseline miR-146a-5p and cortical thinning was nonsignificant for all regions in the patients who had received antidepressant treatment, and higher baseline miR-146a-5p expression was found to be related to greater longitudinal cortical thickening in the left OFC and right LOC. CONCLUSIONS: The findings of this study reveal a relationship between miR-146a-5p overexpression and cortical atrophy and thus may help specify the in vivo mediating effect of miR-146a-5p dysregulation on brain structural abnormalities in patients with MDD.