Investigation of a Novel Biomarker of Postoperative Delirium

项目摘要/摘要 精神错乱通常发生在急性疾病、手术或住院之后，并经常引发一连串的 最终导致丧失独立性、发病率和死亡率增加以及医疗费用高昂的事件。我们 请注意，经历精神错乱的患者被诊断为认知障碍的风险更高， 与阿尔茨海默氏症和相关痴呆症相似，以表明共同的因果关系。因此， 精神错乱的潜在病理生理学目前仍不清楚，预计也将有助于我们对 阿尔茨海默病和相关痴呆症。研究表明，适应不良的全身性和神经炎性 反应发生在精神错乱的起因路径上。与这一假设一致的是，高水平的炎症标志物 如白介素6和C反应蛋白水平与精神错乱有关。然而，这些 术后炎性标志物在大多数患者(如果不是所有患者)中上调，包括个别患者。 不会发展为术后精神错乱。因此，能够准确和选择性地识别生物标志物 识别容易发展为精神错乱的患者是非常必要的。在初步研究中，我们发现了一种 术后神志不清患者血清中一种新的生长因子水平显著升高 体外循环后与年龄和性别匹配的非神志不清患者进行比较。我们假设 特定代谢蛋白和稳态代谢物水平的时间表达 围手术期可能预示着患者将发展为术后精神错乱。在具体目标1中，我们 将对接受心脏手术的患者(n=95)进行前瞻性队列研究，以确定 围手术期一组代谢调节蛋白的时间调节。我们将把它的监管与 患者潜在的行为和认知状态。在特定目标2中，我们将研究全身代谢物 整个围手术期的水平和线粒体功能，以确定全身性 生物能量学可以预测手术后认知功能障碍的发展。总而言之，我们的 AIMS将研究代谢调节作为一种新的途径，在术后精神障碍的发展中起重要作用 并为神经认知的病理生理机制提供了有价值的补充见解 功能障碍，也许还有阿尔茨海默病和相关的痴呆症。精神错乱对这一人群的影响 随着日益老龄化的人口继续接受心脏手术，这一数字可能会随着时间的推移而上升。因此，研究 验证任何潜在的新生物标记物(S)以准确指导妄想的治疗和预防策略 对于改善这一日益高危的老年人口的围手术期护理至关重要。

PROJECT SUMMARY / ABSTRACT Delirium commonly occurs following acute illness, surgery, or hospitalization, and often initiates a cascade of events culminating in loss of independence, increased morbidity and mortality, and high healthcare costs. We note that patients who experience delirium are at higher risk of being diagnosed with cognitive impairments that approximate Alzheimer’s disease and related dementias to suggest a shared causal pathway. Thus, the underlying pathophysiology of delirium, which remains unclear, is expected to also benefit our understanding of Alzheimer’s disease and related dementias. Studies suggest that a maladaptive systemic and neuroinflammatory response is on the delirium causal pathway. Consistent with this hypothesis, high levels of inflammatory markers such as interleukin-6 and C-reactive protein levels have been associated with delirium. However, these inflammatory markers are upregulated in most if not all patients following surgery, including individuals that do not develop postoperative delirium. Thus, the identification of biomarkers that can accurately and selectively identify patients predisposed to develop delirium are greatly needed. In preliminary studies, we identified a significant increase in serum levels of a novel growth factor, in patients that developed postoperative delirium following cardiopulmonary bypass compared to age- and sex-matched non-delirious patients. We hypothesize that temporal expression of specific metabolic proteins and steady-state metabolite levels during the perioperative period may predict patients that will develop postoperative delirium. In Specific Aim 1, we will perform a prospective cohort study of patients (n=95) undergoing cardiac surgery to characterize the temporal regulation of a panel of metabolic regulating proteins perioperatively. We will relate its regulation to the patients’ underlying behavioral and cognitive state. In Specific Aim 2, we will investigate systemic metabolite levels and mitochondrial function throughout the perioperative period to determine if changes in systemic bioenergetics are predictive of the development of cognitive dysfunction following surgery. Taken together, our Aims will investigate metabolic regulation as a novel pathway important in development of postoperative delirium and provide valuable additional insights into the pathophysiological mechanisms underlying neurocognitive dysfunction, and perhaps, Alzheimer’s disease and related dementias. The impact of delirium in this population will likely rise over time, as an increasingly older population continues to undergo cardiac surgery. Thus, studies validating any potential novel biomarker(s) to accurately guide delirium treatment and prevention strategies is vital to improve perioperative care in this increasingly at-risk older population.