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.

项目摘要 /摘要 del妄通常是在急性疾病，手术或住院后发生的，并且经常发起级联 事件最终导致失去独立性，发病率和死亡率增加以及高昂的医疗保健成本。我们 请注意，经历ir妄的患者被诊断出患有认知障碍的风险更高 近似阿尔茨海默氏病和相关痴呆症提示共享因果途径。那， 尚不清楚的妄想的基本病理生理学也有望使我们对 阿尔茨海默氏病和相关痴呆症。研究表明，适应不良的全身性和神经炎症性 反应在del妄因果途径上。与这一假设一致，高水平的炎症标记 例如白介素6和C反应蛋白水平与del妄有关。但是，这些 在手术后，大多数（即使不是所有患者），包括DO 不发展术后del妄。那就是可以准确，有选择性地的生物标志物的识别 非常需要识别易于发展del妄的患者。在初步研究中，我们确定了 在术后del妄的患者中，新型生长因子的血清水平显着升高 与年龄和性别匹配的非轻率患者相比，心肺旁路途径是相比的。我们假设 特定代谢蛋白和稳态代谢物水平的暂时表达 围手术期可能会预测会发展术后del妄的患者。在特定目标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 定期对一组代谢调节蛋白进行临时调节。我们将将其调节与 患者的基本行为和认知状态。在特定目标2中，我们将研究系统性代谢物 在整个周期期间的水平和线粒体功能，以确定全身性的变化 生物能学可以预测手术后认知功能障碍的发展。总的来说，我们的 AIMS将研究代谢调节，这是在术后del妄发展中重要的新途径 并为神经认知基础的病理生理机制提供宝贵的额外见解 功能障碍，也许是阿尔茨海默氏病和相关痴呆症。 ir妄对这个人群的影响 随着年龄较大的人群继续进行心脏手术，可能会随着时间的流逝而上升。那，研究 验证任何潜在的新型生物标志物以准确指导del妄治疗和预防策略是 在这种越来越高的老年人群中，至关重要的是至关重要。