Biological signatures of neurodegeneration and aging associated with delirium in older adults following hip fracture surgery

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PROJECT SUMMARY/ABSTRACT Delirium is a life-threatening acute disturbance in mental status affecting more than 2.6 million hospitalized adults in the United States annually. Delirium is associated with many poor clinical outcomes, including decline in physical function, new or accelerated cognitive impairment, and death. Delirium is significantly more common in older adults, and those with mild cognitive impairment (MCI), Alzheimer's Disease, or Alzheimer's Disease Related Dementias (AD/ADRD). While delirium prevention efforts are critically important, they fail to prevent approximately 60% of cases. Insufficient knowledge of the underlying pathophysiology of delirium dramatically hinders advances in personalized delirium risk assessment, prevention, and impedes the development of delirium treatments, which do not currently exist. The complex association between delirium, cognitive impairment, and advanced age is largely established by epidemiologic studies rather than the identification of biological markers. There is growing evidence for plasma biomarkers, such as tau phosphorylated at two sites (pTau181, pTau217) and neurofilament light chain (NfL), to distinguish healthy controls from those with AD, which is an important innovation from cerebrospinal fluid testing. While advanced age is a major risk factor for both delirium and AD/ADRD, this is based on chronological age – the number of years alive. However, aging is increasingly understood to be driven by biological mechanisms that are more or less advanced in different individuals. This biological age can be distinguished from chronological age, and the difference between biological and chronologic age is “age acceleration,” which is associated with increased risk of chronic disease, including AD. One specific mechanism of biological aging is the accumulation of senescent cells in a state of cell cycle arrest that is associated with increased risk of chronic disease. This proposal is the first application of plasma pTau181, pTau217 and signatures of biological aging (age acceleration, cellular senescence) in delirious patients. The goal of this project is to identify whether elevated preoperative measures of pTau181, pTau217, NfL, and age acceleration in blood, and intraoperative measures of senescent cell burden in tissue, are associated with postoperative delirium in 100 older adults undergoing hip fracture surgery in order to advance our understanding of the pathologic drivers of delirium. We will also quantify whether these biomarkers are affected by external stressors (e.g., hip fracture surgery with anesthesia). This project will shed light on the pathological basis for the observed association between delirium, neurodegeneration and aging, and lay the foundation for my development as an early-stage clinician- investigator at the intersection of neurology and geriatrics. Findings from this study will provide the basis for a future career development award application to investigate how these markers of neurodegeneration and aging influence the trajectory of post-operative cognitive decline in older adults who develop delirium.