Cingulate Gradient Dysfunction in End‐Stage Renal Disease: Associations With Clinical Phenotypes and Exploratory Transcriptomic Signatures

AIMS: The cingulate cortex is highly vulnerable in end-stage renal disease (ESRD) patients, but whether ESRD disrupts its functional gradient and the links to clinical phenotypes and underlying molecular mechanisms remain unclear. METHODS: We prospectively enrolled clinical and resting-state functional MRI data from 125 participants (77 ESRD patients, 48 healthy controls) to explore cingulate gradient alterations. Associations between cingulate gradients and canonical functional networks, clinical phenotypes, and meta-analytic behavioral domains were analyzed. A gene expression decoding analysis based on the Allen Human Brain Atlas was performed to advance understanding of how molecular mechanisms relate to hierarchical changes in ESRD. RESULTS: Across global, network, and regional scales, patients with ESRD showed significant cingulate gradient dysfunction, with these anomalies exhibiting associations across multiple functional domains. Notably, serum urea and hemoglobin levels were correlated with cingulate gradient dysfunction. Spatially, these alterations correlated with genes enriched in neurodegenerative processes. Excitatory and inhibitory neurons' specific transcriptional changes account for most of the observed correlation with ESRD-specific cingulate gradient alterations. CONCLUSION: Our findings highlight ESRD-related cingulate gradient dysfunction and its links to clinical phenotypes and gene expression profiles, providing critical insights into the neurodegenerative underpinnings of cerebral dysfunction in ESRD.