Neurobiological factors related to differential cortical abnormalities in youth-onset and adult-onset major depressive disorder.

BACKGROUND: Age of onset is considered a key factor for the heterogeneity in major depressive disorder (MDD). Differential cortical thickness (CT) alteration patterns between youth-onset and adult-onset MDD have been evident, yet the neurobiological factors associated with such divergence remain unknown. METHODS: CT alteration patterns in youth-onset and adult-onset MDD were derived from the Enhancing NeuroImaging Genetics through Meta-Analysis. We interrogated whether the structural connectome constrains MDD-related CT alterations, followed by identifying likely epicentre regions and examining the hub vulnerability hypothesis. Using the neurotransmitter, transcriptome, and mitochondria atlases, we further explored the neurochemical basis, genetic architecture, and molecular energetic landscape related to the CT alterations. RESULTS: The structural connectome constrained CT alterations in both youth-onset and adult-onset MDD, but the constraint effect was greater in adult-onset MDD. The epicentres were divergent for youth-onset (lateral prefrontal cortex) and adult-onset (orbitofrontal cortex, anterior and middle cingulate gyrus) MDD. The association between CT alterations and connectome degree centrality confirmed the hub vulnerability hypothesis in youth-onset MDD. Moreover, we found common and distinct neurotransmitter systems linked to CT alterations in youth-onset and adult-onset MDD. Transcriptomic contextualization demonstrated that CT alterations in adult-onset MDD were related to gene categories primarily involving synapse, neuron, synaptic transmission, and ion channel activity, yet those in youth-onset MDD were not related to gene expression. Additionally, associations between mitochondrial features and CT alterations were found in adult-onset MDD but not in its youth-onset counterpart. CONCLUSIONS: Our findings may illuminate the neurobiological factors related to the spatial patterning of cortical abnormalities in youth-onset and adult-onset MDD.