Investigation of a Novel Biomarker of Postoperative Delirium

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PROJECT SUMMARY / ABSTRACT Delirium commonly occurs following acute illness, surgery, or hospitalization, and often initiates a cascade of events culminating in loss of independence, increased morbidity and mortality, and high healthcare costs. We note that patients who experience delirium are at higher risk of being diagnosed with cognitive impairments that approximate Alzheimer’s disease and related dementias to suggest a shared causal pathway. Thus, the underlying pathophysiology of delirium, which remains unclear, is expected to also benefit our understanding of Alzheimer’s disease and related dementias. Studies suggest that a maladaptive systemic and neuroinflammatory response is on the delirium causal pathway. Consistent with this hypothesis, high levels of inflammatory markers such as interleukin-6 and C-reactive protein levels have been associated with delirium. However, these inflammatory markers are upregulated in most if not all patients following surgery, including individuals that do not develop postoperative delirium. Thus, the identification of biomarkers that can accurately and selectively identify patients predisposed to develop delirium are greatly needed. In preliminary studies, we identified a significant increase in serum levels of a novel growth factor, in patients that developed postoperative delirium following cardiopulmonary bypass compared to age- and sex-matched non-delirious patients. We hypothesize that temporal expression of specific metabolic proteins and steady-state metabolite levels during the perioperative period may predict patients that will develop postoperative delirium. In Specific Aim 1, we will perform a prospective cohort study of patients (n=95) undergoing cardiac surgery to characterize the temporal regulation of a panel of metabolic regulating proteins perioperatively. We will relate its regulation to the patients’ underlying behavioral and cognitive state. In Specific Aim 2, we will investigate systemic metabolite levels and mitochondrial function throughout the perioperative period to determine if changes in systemic bioenergetics are predictive of the development of cognitive dysfunction following surgery. Taken together, our Aims will investigate metabolic regulation as a novel pathway important in development of postoperative delirium and provide valuable additional insights into the pathophysiological mechanisms underlying neurocognitive dysfunction, and perhaps, Alzheimer’s disease and related dementias. The impact of delirium in this population will likely rise over time, as an increasingly older population continues to undergo cardiac surgery. Thus, studies validating any potential novel biomarker(s) to accurately guide delirium treatment and prevention strategies is vital to improve perioperative care in this increasingly at-risk older population.