The Role of the Aging Brain-Heart-Immune Axis in Postoperative Delirium

老化的脑-心-免疫轴在术后谵妄中的作用

• 批准号: 10517672
• 负责人: Leah Acker
• 金额: $ 16.1万
• 依托单位: DUKE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-09-15 至 2024-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10517672
• 关键词: Acute; Affect; Alzheimer' s Disease; Alzheimer' s disease related dementia; Alzheimer' s disease risk; American; Anesthesia procedures; Anti-Cholinergics; Anti-Inflammatory Agents; Anxiety; Applications Grants; Attention; Biological Markers; Brain; Caring; Clinic; Clinical Trials; Cognitive; Cognitive deficits; Conscious; Data; Data Set; Day Surgery; Dehydration; Delirium; Dementia; Elderly; Environment; Evaluation; Family; Foundations; Friends; Future; Geriatrics; Goals; Habilitation; Health Care Costs; Heart; Hour; Immune; Impaired cognition; Incidence; Inflammation; Inflammatory; Intervention; Intervention Trial; Left; Link; Measurement; Measures; Mediating; Modification; Mus; Negative Finding; Neuronal Injury; Neurons; Operative Surgical Procedures; Outcome; Pathogenesis; Patients; Perioperative; Play; Postoperative Period; Preoperative Care; Recovery of Function; Reflex action; Research; Risk; Role; Sampling; Serum; Stress; Surgical Models; Syndrome; Testing; Training; Vagus nerve structure; Work; aging brain; arm; base; career; experience; follow-up; heart rate monitor; heart rate variability; immune function; improved; inflammatory marker; mortality; neuroinflammation; novel; novel marker; older patient; postoperative delirium; prevent; prospective; screening; standard measure; stressor; systemic inflammatory response; therapy development; vagus nerve stimulation; wound healing

ABSTRACT Postoperative delirium (POD) is a syndrome of acute fluctuating changes in attention and consciousness that affects up to 50% of surgery patients 65 and older, increases the risk for Alzheimer's disease (AD) and AD-related dementias (ADRD), and accelerates dementia progression. Yet, interventions for POD are limited because its pathophysiologic mechanisms are poorly understood. The vagus nerve mediates the brain-heart-immune axis, which allows the brain to suppress systemic inflammation via the cholinergic anti-inflammatory reflex. Advanced age, preoperative stressors, the condition requiring surgery, and surgery and anesthesia themselves all decrease vagal tone. Without sufficient vagal tone to keep inflammation in check, excessive inflammation will result, including neuroinflammation. Excessive postoperative inflammation is thought to play a role in POD pathogenesis. Furthermore, excessive postoperative inflammation can injure neurons, providing a plausible mechanistic link between POD and AD+ADRD. Thus, there is a critical need to evaluate the role of the brain-heart-immune axis in POD among older adults. To interrogate the aging brain-heart-immune axis as a possible contributor to POD pathogenesis, heart rate variability (HRV), the standard measure of vagal tone, will be measured before general surgery in 100 patients 65 and older. Specifically, the prospective, observational HIPPIE - HRV In POD and Postoperative Inflammatory Endpoints - study will quantify the relationship between preoperative vagal tone and (1) POD incidence and (2) postoperative increase in serum biomarkers of inflammation and neuronal injury. Successful completion of the HIPPIE study will demonstrate the involvement of the brain-heart-immune axis in POD pathogenesis and will provide novel biomarker(s) of POD risk. Furthermore, a mechanistic link between POD and the brain-heart-immune axis is anticipated to provide strong scientific justification for future trials of vagal tone enhancement as an intervention for POD. Finally, this work will provide a rich new perioperative geriatric data set including measurements of the previously unexplored perioperative brain-heart-immune axis. The data, experience, and training from this proposal will lay the foundation of a successful career in geriatrics research.

抽象的 术后谵妄（POD）是一种注意力和注意力急剧波动变化的综合征。 意识影响高达 50% 的 65 岁及以上手术患者，增加了手术风险 阿尔茨海默病 (AD) 和 AD 相关痴呆 (ADRD)，并加速痴呆 进展。然而，POD 的干预措施是有限的，因为其病理生理机制是 不太了解。 迷走神经介导脑-心-免疫轴，使大脑能够抑制 通过胆碱能抗炎反射引起全身炎症。高龄，术前 压力源、需要手术的病症以及手术和麻醉本身都会减少 迷走神经音。没有足够的迷走神经张力来控制炎症，炎症过度 会导致包括神经炎症。术后过度炎症被认为发挥了作用 在 POD 发病机制中发挥作用。此外，术后过度炎症也会损伤 神经元，提供 POD 和 AD+ADRD 之间合理的机制联系。因此，有一个 迫切需要评估脑-心-免疫轴在老年人 POD 中的作用。 为了探究老化的脑-心-免疫轴是否是 POD 发病机制的一个可能因素， 心率变异性（HRV）是迷走神经张力的标准测量值，将在一般检查前进行测量 对 100 名 65 岁及以上的患者进行了手术。具体来说，前瞻性、观察性的嬉皮士 - HRV 在 POD 和术后炎症终点中 - 研究将量化两者之间的关系 术前迷走神经张力和 (1) POD 发生率和 (2) 术后血清升高 炎症和神经元损伤的生物标志物。成功完成嬉皮士研究将 证明脑-心-免疫轴参与 POD 发病机制，并将 提供 POD 风险的新生物标志物。此外，POD 和 脑-心-免疫轴预计将为未来的试验提供强有力的科学依据 迷走神经张力增强作为 POD 的干预措施。最后，这项工作将提供丰富的新内容 围手术期老年数据集，包括先前未探索的测量值 围术期脑-心-免疫轴。该提案中的数据、经验和培训将 为老年病学研究的成功职业生涯奠定基础。