PROJECT SUMMARY/ABSTRACT Delirium occurs in up to 50% of patients after cardiac surgery and is associated with cognitive decline and Alzheimer’s disease and related dementias (ADRD). However, the underlying mechanisms for these complications are elusive. Further, the extent to which events in the early postoperative period increase risk for delirium, cognitive decline, and ADRD is unclear. The goal of this proposal is to examine cerebrovascular contributions to delirium / cognitive decline, with a focus on cerebral perfusion in the cardiac surgery intensive care unit (ICU). Given the wide variations in blood pressure in the ICU, coupled with the high prevalence of cerebrovascular disease, cerebral malperfusion in the ICU may contribute to delirium and cognitive decline. Current practice of targeting empiric mean arterial pressure (MAP) goals in the perioperative period may be inadequate for individual patients. Our group has championed a more personalized method based on cerebral autoregulation monitoring. Through the process of cerebral autoregulation, the brain is regulated to maintain a constant cerebral blood flow across a range of MAP. However, when MAP exceeds limits of autoregulation or when autoregulation is impaired, compensatory mechanisms fail and inadequate or excessive cerebral blood flow results. Our work in the cardiac surgery operating room has shown several results that emphasize the importance of individualizing blood pressure goals. First, the MAPs at the limits of autoregulation vary widely in patients, and both impaired autoregulation and MAP outside the limits of autoregulation are associated with organ injury. Second, in a recent trial, targeting MAP to be >lower limit of autoregulation during cardio- pulmonary bypass vs. usual care reduced delirium by 28% and improved memory scores at 1- and 12-months. To date, the majority of research has been conducted in the operating room during cardiopulmonary bypass. However, our preliminary data suggests that the early phase of ICU care may be equally important. In a small pilot study, we found that in the ICU, the extent of MAP outside the limits of autoregulation, as well as impaired autoregulation, were associated with delirium. Importantly, cognitive change was not assessed in this pilot and mechanisms for these findings are unclear. These results motivate the proposed observational study, which will examine whether (a) MAP outside the limits of autoregulation and (b) impaired autoregulation in the ICU are associated with delirium after cardiac surgery (Aim 1) and cognitive change from baseline at 1- and 12- months (Aim 2). In an exploratory mechanistic aim (Aim 3), we will characterize whether perioperative brain injury mediates or baseline neurodegeneration moderates the association of cerebral autoregulation characteristics and delirium and cognitive decline. The results of this study will more precisely characterize the role of cerebral malperfusion in the ICU with delirium ...