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.