Multiscale neurobiological architecture of functional synchronization abnormalities in primary angle-closure glaucoma: an imaging-transcriptomics study.
BACKGROUND Primary angle-closure glaucoma (PACG) induces widespread central nervous system remodeling. However, the molecular, cellular, and neurochemical architectures driving macroscopic functional synchronization abnormalities in PACG remain unexplored. METHODS We employed a multiscale imaging-transcriptomics framework. Resting-state functional MRI was used to evaluate regional homogeneity (ReHo) in 44 PACG patients and 57 healthy controls. Voxel-wise ReHo alterations were spatially linked to whole-brain gene expression profiles from the Allen Human Brain Atlas, canonical cell-type-specific expression data, and multimodal PET neurotransmitter maps. RESULTS PACG patients exhibited decreased ReHo in the primary visual cortex and compensatory increases across widespread subcortical and higher-order associative cortices. These macroscopic ReHo alterations significantly covaried with a specific transcriptional profile characterized by the upregulation of stress response and extracellular matrix remodeling pathways, alongside the downregulation of synaptic transmission. Cellular enrichment analysis revealed that these transcriptomic signatures were highly specifically localized to the neurovascular and glial axis (astrocytes, endothelial cells, and oligodendrocytes) rather than neuronal lineages. Furthermore, the ReHo abnormality map was significantly coupled with the spatial distribution of multiple neurotransmitters, particularly dopamine, gamma-aminobutyric acid, and serotonin receptors. CONCLUSION This study provides multidimensional evidence that PACG-induced functional synchronization alterations are tightly constrained by underlying transcriptomic gradients, glial-vascular networks, and neurochemical architectures, reinforcing the conceptualization of PACG as a systemic central neurodegenerative disease.