Preoperative Cholinergic Signatures Drive Segregated Brain Architecture in Postoperative Delirium

Delirium affects up to 50% of hospitalised, older patients and is linked to increased risk of death and long-term cognitive decline. Age-related changes in the ascending arousal system (AAS), including cholinergic and noradrenergic nuclei, may contribute to delirium vulnerability. Static and dynamic functional connectivity, across cortical and subcortical regions, was extracted from preoperative resting-state fMRI from 120 older adults (aged > 65 years old). Participants who developed delirium showed more segregated brain networks, cholinergic hyperconnectivity and noradrenergic hypoconnectivity. Dynamic patterns from these systems separated groups in low-dimensional space, suggesting altered temporal network dynamics. Normative maps of cholinergic gene expression density were associated with increased network segregation. These results suggest that aging-related AAS alterations—particularly compensatory cholinergic overactivity—may drive network changes that increase delirium risk. This work provides new insights into the neural mechanisms linking aging, arousal system dysfunction, and brain network disruption in delirium, mandating re-appraisal of leading delirium theories.