Cerebral Blood Flow-Related Cognitive Impairment Is Mediated by Functional Connectivity in End-Stage Renal Disease Patients Undergoing Hemodialysis CBF–FC Mediation of Cognitive Impairment in Hemodialysis ESRD

Introduction: Cognitive impairment (CI) is highly prevalent in patients with end-stage renal disease (ESRD) undergoing hemodialysis and is associated with increased morbidity and mortality. Although altered cerebral blood flow (CBF) and disrupted functional connectivity (FC) have been independently reported in ESRD, whether neurovascular alterations mechanistically contribute to CI remains unclear. We aim to investigate whether abnormalities in CBF and FC mediate CI in ESRD patients undergoing hemodialysis. Methods: Patients with ESRD receiving maintenance hemodialysis and matched healthy controls (HCs) underwent arterial spin labeling (ASL) to quantify CBF and resting-state functional magnetic resonance imaging (rs-fMRI) to assess FC. Cognitive performance was evaluated using the adjusted Montreal Cognitive Assessment (MoCA). Between-group differences in regional CBF and whole-brain FC were analyzed. Mediation models were constructed to examine whether altered FC mediated the association between regional CBF and cognitive performance. Results: ESRD patients demonstrated significantly increased standardized CBF (zCBF) predominantly within default mode network (DMN)-related regions compared with HCs. Higher normalized zCBF values in the right posterior cingulate gyrus (PCG.R) and left precuneus were observed in patients with CI and were negatively correlated with MoCA scores. Whole-brain FC analyses revealed decreased connectivity between DMN nodes and limbic structures, particularly reduced connectivity between the PCG.R and left amygdala in the ESRD-CI group. Mediation analysis showed that FC partially mediated the association between regional CBF alterations and MoCA scores, with the FC between the right posterior cingulate gyrus and left amygdala accounting for 35.7% of the total effect. Conclusions: These findings reveal a significant association between altered cerebral hemodynamic patterns, characterized by increased regional zCBF and impaired functional integration within DMN-limbic circuits, and cognitive dysfunction in ESRD patients undergoing hemodialysis. Although the cross-sectional design precludes definitive causal inferences, the observed mediation patterns suggest a potential relationship linking cerebral hemodynamic alterations, functional connectivity changes, and cognitive decline. These findings may guide future longitudinal and interventional investigations to further clarify these relationships.