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

摘要 术后神志不清(POD)是一种注意力和注意力急剧波动的综合征。 影响多达50%65岁及以上手术患者的意识会增加患上 阿尔茨海默病(AD)和AD相关痴呆(ADRD)，并加速痴呆 进步。然而，对POD的干预是有限的，因为它的病理生理机制是 人们对此知之甚少。 迷走神经调节大脑-心脏-免疫轴，从而允许大脑抑制 通过胆碱能抗炎反射的全身性炎症。高龄，术前 应激源、需要手术的情况以及手术和麻醉本身都在减少 迷走神经。没有足够的迷走神经张力来控制炎症，过度的炎症 会导致包括神经炎症在内的。术后过度的炎症被认为起了作用。 在POD发病机制中的作用。此外，术后过度的炎症可能会造成伤害。 神经元，在POD和AD+ADRD之间提供了一种看似合理的机制联系。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。 为了询问老化的大脑-心脏-免疫轴是否可能导致POD的发病， 心率变异性(HRV)，迷走神经张力的标准测量，将在一般情况下之前进行测量 手术治疗了100名65岁及以上的患者。具体地说，前瞻性的、观察性的嬉皮士-HRV POD和术后炎症终点--研究将量化两者之间的关系 术前迷走神经张力与(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的发病和意志 提供POD风险的新生物标志物(S)。此外，POD和POD之间的机械联系 大脑-心脏-免疫轴有望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，这项工作将提供一个丰富的新 围手术期老年数据集，包括以前未探索的 围手术期脑-心-免疫轴。本计划书中的数据、经验和培训将 为在老年病学研究领域取得成功奠定基础。

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.