Investigation of a Novel Biomarker of Postoperative Delirium

术后谵妄的新型生物标志物的研究

• 批准号: 10452901
• 负责人: Oluwaseun Johnson-Akeju
• 金额: $ 21万
• 依托单位: MASSACHUSETTS GENERAL HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-06-15 至 2024-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10452901
• 关键词: AFP gene; ANGPTL3 gene; ANGPTL4 gene; Acute; Acute Disease; Affect; Age; Alzheimer' s disease related dementia; Attention; Awareness; Behavioral; Bioenergetics; Biological; Biological Markers; Blood; Blood Circulation; C-reactive protein; Cardiac Surgery procedures; Cardiopulmonary Bypass; Cells; Chronic; Cognition; Cognitive; Cognitive deficits; Critical Illness; Day Surgery; Delirium; Development; Diagnosis; Diagnostic Procedure; Event; FABP1 gene; FGF19 gene; Fibroblast Growth Factor; Functional disorder; Genes; Goals; Growth Factor; Health Care Costs; Hospitalization; Human; Impaired cognition; Individual; Inflammation Mediators; Inflammatory; Interleukin-6; Investigation; Laboratories; Measures; Metabolic; Metabolism; Mitochondria; Modeling; Morbidity - disease rate; Neurocognitive; Nutrient; Older Population; Operative Surgical Procedures; Outcome; Oxidative Stress; Pathway interactions; Patients; Perioperative; Perioperative Care; Population; Postoperative Period; Predisposition; Prevention; Prevention strategy; Prospective cohort study; Proteins; Proteomics; Public Health; Regulation; Reporting; Risk; Role; Serum; Severities; Stimulus; Testing; Time; Whole Blood; Work; biomarker identification; brain dysfunction; cognitive change; cognitive development; cognitive recovery; experience; fibroblast growth factor 21; fibroblast growth factor 23; high risk; improved; inflammatory marker; insight; metabolomics; mitochondrial dysfunction; mortality; neurocognitive disorder; neuroinflammation; novel; novel marker; older patient; postoperative delirium; prognostic; prospective; protein expression; resilience; respiratory; response; sex; treatment strategy

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.

项目概要/摘要 谵妄通常发生在急性疾病、手术或住院之后，并且常常引发一系列的反应 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。 请注意，经历过谵妄的患者被诊断为认知障碍的风险较高， 近似阿尔茨海默病和相关的痴呆症表明有一个共同的因果途径。 谵妄的潜在病理生理学目前尚不清楚，预计也将有助于我们了解 阿尔茨海默病和相关痴呆症研究表明，系统适应不良和神经炎症。 反应与谵妄因果途径一致，炎症标志物水平高。 例如白细胞介素 6 和 C 反应蛋白水平与谵妄有关。 大多数（如果不是全部）患者术后炎症标志物都会上调，包括接受过手术的个体 因此，生物标志物的鉴定可以准确且选择性地进行。 在初步研究中，我们非常需要识别出容易发生谵妄的患者。 发生术后谵妄的患者中一种新型生长因子的血清水平显着增加 体外循环后与年龄和性别匹配的非谵妄患者进行比较。 特定代谢蛋白的时间表达和稳态代谢水平 围手术期可以预测患者术后发生谵妄的情况，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，以表征 围手术期一组代谢调节蛋白的时间调节我们将其调节与 在具体目标 2 中，我们将研究患者的潜在行为和认知状态。 水平和线粒体功能在整个围手术期以确定是否发生全身变化 总而言之，生物能量学可以预测手术后认知功能障碍的发展。 目标将研究代谢调节作为术后谵妄发展中重要的新途径 并为神经认知的病理生理机制提供有价值的额外见解 功能障碍，也许还有阿尔茨海默病和相关的痴呆症。谵妄对这一人群的影响。 随着时间的推移，随着越来越多的老年人继续接受心脏手术，这一数字可能会上升。 验证任何潜在的新型生物标志物以准确指导谵妄的治疗和预防策略是 对于改善风险日益增加的老年人群的围手术期护理至关重要。