Geroscience metabolites beta-hydroxybutyrate and NAD+ linking inflammation and neuroenergetic failure in delirium

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PROJECT SUMMARY Delirium is a geriatric syndrome of fluctuating confusion that is a common complication of surgery and hospitalization in older adults, and is associated with increased risk of death, disability, and dementia. People with Alzheimer's Disease and Related Dementias (ADRD) are at especially high risk for delirium. The pathophysiology of delirium is not well understood, but is thought to include neuroinflammation and brain energetic disruption. These features also link delirium to ADRD. Impaired cerebral glucose metabolism is a chronic feature of ADRD, and an acute feature of delirium. Similarly, chronic neuroinflammation is thought to be an important contributor to ADRD, and acute inflammation is associated with delirium. In this translational project we propose to test an innovative molecular link between acute-on-chronic brain inflammation and metabolic dysfunction, using cell systems, mouse models, and biospecimens from a human delirium cohort. Ketone bodies provide a non-glucose energy source for the brain during fasting, and ketone body metabolism remains intact in ADRD even with impaired glucose metabolism. We recently found that disrupted glucose metabolism is an important driver of behavioral changes in mouse models of delirium. We also recently showed that a ketogenic diet improves memory in both aging mice and an ADRD mouse model. We developed an innovative toolkit of compounds and genetic models to mechanistically study ketone bodies experimentally. We hypothesize that energetic support from ketone bodies might help compensate for inflammation-induced neuronal impairments in glucose metabolism. We also elucidated a new mechanism linking inflammation to metabolism, showing that activation of peripheral macrophages induces enzymes that degrade the key metabolic mediator NAD+. Inflammation-driven NAD+ depletion occurs chronically in aging and ADRD, and may occur acutely in delirium. We will use an inflammation model of delirium with normal mice and two ADRD models to test if ketone bodies or NAD+ can rescue acute delirium-like behavioral changes, and identify the relevant mechanisms (Aim 1). We will use cultured cells and an in vivo brain inflammation model to determine if activated microglia deplete NAD+ similarly to macrophages, and whether preventing this also rescues delirium-like behaviors (Aim 2). Finally, we will use cerebrospinal fluid samples from a large clinical study of postoperative delirium to determine how endogenous ketone body and NAD+ levels differ between patients with vs. without delirium (Aim 3). This collaborative project links basic science expertise in ketone body and NAD+ biology relevant to ADRD, with basic and clinical research expertise in delirium. It will open a new area of mechanistic study on inflammation-induced metabolic deficits in delirium, guiding development of translational interventions.