Molecular Basis Underlying Changes of Brain Entropy and Couplings in Late-life Depression

INTRODUCTION: Late-life depression (LLD) with high prevalence accelerates cognitive impairment and becomes a risk factor for dementia, yet the pathogenesis of LLD is still largely unclear. Delineating the neuromolecular mechanism of LLD is of great significance to its etiology, early diagnosis, and precision treatment. METHODS: This study included 35 patients with LLD and 41 age-matched healthy controls (HCs). Brain entropy (BEN) and functional connectivity (FC) were used to assess the abnormalities in brain functional system irregularity and couplings in LLD, using resting-state functional magnetic resonance imaging. Additionally, transcriptome and neurotransmitter data were employed to investigate the neuromolecular mechanisms underlying these changes. RESULTS: Compared with HCs, patients with LLD exhibited significantly reduced BEN in the temporoparietal junction (TPJ) and decreased FC between TPJ and the middle frontal gyrus (MFG). Moreover, the changes of BEN were closely associated with the genes' expression profiles, which were involved in endocannabinoid, adrenergic, oxytocin, and cGMP-PKG signaling, glutamatergic, GABAergic, dopaminergic, cholinergic, serotonergic synapses, long-term potentiation, and long-term depression. We also found that the changes of BEN and FC were correlated with neurotransmitterreceptor distribution patterns of serotonin, histamine, acetylcholine, and dopamine. DISCUSSION: Reduced BEN of TPJ in LLD indicates impaired regional information-processing complexity, potentially driving persistent cognitive deficits and abnormal negative-emotion handling, even in early LLD without overt clinical symptoms. Decreased TPJ-MFG FC disrupts brain network synchronization, weakening MFG-mediated emotion regulation and cognition, and possibly elevating the risk of suicidal ideation. Some genes, such as PRKACA/PRKACB, GNAI1, MAPK-ERK, PLA2G4A, and LXN, along with neurotransmitter receptors, contribute to a more comprehensive understanding of LLD. Altered brain entropy and connectivity in the TPJ-MFG circuit and related neurobiomolecules may underlie the pathogenesis of LLD and provide predictive value for its diagnosis and treatment. CONCLUSION: Our study highlights the important role of the TPJ-MFG circuit in the neuropathology of LLD and links the macroscopic functional abnormalities with transcriptome and neurotransmitter to establish the molecular basis. Our findings contribute to understanding the neurobiological basis of LLD and may facilitate future precision therapy.