Neurobiological architecture of first-episode, drug-naive late-life depression: Insights from multimodal MRI,...

To elucidate the neurobiological architecture of late-life depression (LLD) by integrating macroscopic multimodal MRI with microscopic transcriptomic and neurochemical mapping.

We analyzed 39 first-episode, drug-naive LLD patients and 41 matched healthy controls (HC) using structural MRI, diffusion kurtosis imaging, and resting-state fMRI. Data were processed to extract gray matter volume (GMV), white matter diffusion metrics (FA, MD, AD, RD), and functional indices (fALFF, DC), with group differences evaluated under rigorous multiple-comparison corrections. To elucidate molecular underpinnings, partial least squares (PLS) regression was applied to link neuroimaging t-maps with Allen Human Brain Atlas gene expression profiles. Spatial correlations between neuroimaging statistical maps and PET-derived neurotransmitter receptor density maps were further examined to identify neurochemical substrates.

LLD patients exhibited localized gray matter volume (GMV) reductions in the right fusiform gyrus and limbic structures, widespread microstructural white matter degradation across fronto-limbic tracts, and increased functional amplitude and network centrality centered on the medial prefrontal cortex (mPFC). Transcriptomic decoding linked these macroscopic anomalies to gene sets enriched for mitochondrial metabolism, calcium signaling, and synaptic organization. Furthermore, spatial correlation analyses uniquely revealed that structural atrophy was predominantly associated with the glutamatergic system, whereas functional and network alterations aligned most robustly with the opioid system.

Our findings support a multi-scale neurobiological model of LLD, wherein distinct molecular deficits in bioenergetics, glutamatergic excitotoxicity, and opioid neurotransmission underlie macroscopic structural and functional network failures. This integrative framework identifies specific neurochemical systems as prime mechanistic substrates and potential therapeutic targets for the cognitive-emotional dysregulation characteristic of LLD.