Molecular and Transcriptional Signatures of Gray Matter Volume Alterations Associated With Depressive Symptoms in Mild Cognitive Impairment

Depressive symptoms are common in individuals with mild cognitive impairment (MCI) and may contribute to an increased risk of dementia. However, the neuroanatomical correlates and underlying pathophysiological mechanisms of depressive symptoms in MCI remain largely unknown. We aimed to elucidate alterations in gray matter volume and the related molecular and genetic bases in MCI patients with depressive symptoms. A total of 177 participants were enrolled, comprising 57 MCI patients with depressive symptoms (D-MCI), 60 MCI patients without depressive symptoms (nD-MCI), and 60 healthy controls (HCs). Gray matter morphological differences among groups were examined using voxel-based morphometry. The associations between depressive symptom-related morphological alterations and functional characteristics, neurotransmitter distributions, and gene expression profiles were further investigated. Group comparisons revealed depressive symptom-related morphological alterations in the inferior frontal gyrus, precentral gyrus, and anterior cingulate cortex, with the associated functional terms strongly linked to "emotions" and "affective." These alterations were further correlated with serotonergic, dopaminergic, and GABAergic systems and the expression of specific genes implicated in synaptic function and excitatory neurons. This study demonstrated the molecular and transcriptional underpinnings of brain morphological alterations linked to depressive symptoms in MCI, which may provide deeper insight into this condition.