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

项目摘要/摘要 精神错乱是一种危及生命的急性精神状态障碍，影响着260多万住院患者 美国的成年人每年都有。精神错乱与许多不良的临床结果有关，包括衰退。 在身体功能方面，新的或加速的认知障碍，以及死亡。精神错乱明显比 常见于老年人和患有轻度认知障碍(MCI)、阿尔茨海默病或阿尔茨海默氏症的人 疾病相关性痴呆(AD/ADRD)。虽然预防精神错乱的努力至关重要，但它们未能 预防约60%的病例。对精神错乱的潜在病理生理学认识不足 极大地阻碍了个性化精神错乱风险评估和预防的进展，并阻碍了 开发目前尚不存在的精神错乱治疗方法。精神错乱和精神错乱之间的复杂联系 认知障碍和高龄在很大程度上是由流行病学研究确定的，而不是 生物标志物的鉴定。越来越多的证据表明存在血浆生物标记物，如tau。 两个位点(pTau181，pTau217)和神经丝轻链(NFL)的磷酸化，以区分健康 来自AD患者的对照，这是脑脊液检测的一项重要创新。在先进的同时 年龄是精神错乱和AD/ADRD的主要危险因素，这是基于时间顺序的年龄-- 活着的几年。然而，人们越来越多地理解衰老是由更多或更多的生物机制驱动的 在不同的个体中不那么先进。这一生物年龄可以与时间年龄区分开来，而 生物学年龄和实际年龄之间的差异是“年龄加速”，这与年龄增加有关 患慢性病的风险，包括阿尔茨海默病。生物衰老的一个特殊机制是体内 衰老的细胞处于细胞周期停滞状态，这与慢性病风险增加有关。这 建议首次应用血浆pTau181、pTau217和标记生物老化(AGE 神志不清患者的症状有加速、细胞衰老等。该项目的目标是确定是否提升了 血中pTau181、pTau217、NFL和AGE加速的术前措施和术中措施 组织中衰老细胞负荷的增加与100名老年人接受手术后的妄想有关 髋部骨折手术，以促进我们对精神错乱的病理驱动因素的了解。我们还将 量化这些生物标志物是否受外部应激源的影响(例如，髋部骨折手术 麻醉)。该项目将阐明观察到的两者之间联系的病理基础 精神错乱、神经退化和衰老，并为我作为一名早期临床医生的发展奠定了基础- 神经学和老年病学交叉学科的研究人员。这项研究的发现将为 未来职业发展奖申请，以调查这些神经退行性变和衰老的标志 影响患有精神错乱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.