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

项目总结/摘要 谵妄是一种危及生命的急性精神状态紊乱，影响超过260万住院患者 美国成年人每年。谵妄与许多不良临床结局相关，包括下降 在身体功能，新的或加速的认知障碍，和死亡。谵妄明显比 常见于老年人和轻度认知障碍（MCI）、阿尔茨海默病或阿尔茨海默病患者 疾病相关性痴呆（AD/ADRD）。虽然谵妄预防工作至关重要，但它们未能 预防约60%的病例。对谵妄的潜在病理生理学了解不足 极大地阻碍了个性化谵妄风险评估，预防的进展，并阻碍了 发展目前尚不存在的谵妄治疗方法。谵妄和精神错乱， 认知障碍和高龄在很大程度上是由流行病学研究而不是 生物标志物的识别。越来越多的证据表明，血浆生物标志物，如tau蛋白， 在两个位点磷酸化（pTau 181，pTau 217）和神经丝轻链（NfL），以区分健康的 这是脑脊液检测的一项重要创新。而高级 年龄是谵妄和AD/ADRD的主要危险因素，这是基于实际年龄- 年活着。然而，越来越多的人认为衰老是由生物机制驱动的， 在不同的个体中不那么先进。这个生物学年龄可以与实足年龄区分开来， 生物学年龄和生理年龄之间的差异是“年龄加速”，这与增加 慢性疾病，包括AD。生物衰老的一个具体机制是 衰老细胞处于细胞周期停滞状态，这与慢性疾病风险增加有关。这 该提案是首次应用血浆pTau 181、pTau 217和生物衰老的标志（age 加速，细胞衰老）。本项目的目标是确定是否升高 术前测量pTau 181、pTau 217、NfL和血液中的年龄加速，以及术中测量 组织中衰老细胞负荷的增加与100例老年人术后谵妄有关， 髋部骨折手术，以提高我们对谵妄病理驱动因素的理解。我们还将 量化这些生物标志物是否受到外部应激源的影响（例如，髋部骨折手术， 麻醉）。该项目将阐明观察到的 谵妄，神经退化和衰老，并为我作为早期临床医生的发展奠定基础- 神经学和老年病学交叉学科的研究员这项研究的结果将为以下方面提供基础： 未来职业发展奖申请，以调查这些神经退行性疾病和衰老的标志物 影响发生谵妄的老年人术后认知能力下降的轨迹。

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.