The Role of Inflammation in the Pathophysiology of Delirium and its Associated Long-Term Cognitive Decline

炎症在谵妄的病理生理学及其相关的长期认知衰退中的作用

• 批准号: 10405118
• 负责人: EDWARD R MARCANTONIO
• 金额: $ 46.95万
• 依托单位: HEBREW REHABILITATION CENTER FOR AGED
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-09-15 至 2025-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10405118
• 关键词: Address; Aging; Alzheimer' s disease related dementia; Biological Markers; Biological Specimen Banks; Blood; Blood - brain barrier anatomy; Brain; C-reactive protein; Cells; Cerebrospinal Fluid; Cerebrospinal Fluid Proteins; Collection; Cytometry; Delirium; Dementia; Development; Disease; Elderly; Enrollment; Enzyme-Linked Immunosorbent Assay; Epidemiology; Fluorescence-Activated Cell Sorting; Functional disorder; Immune; Immune response; Impaired cognition; Inflammation; Inflammatory; Inflammatory Response; Interdisciplinary Study; Intervention; Laboratories; Link; Measures; Methods; Modeling; Neuronal Injury; Operative Surgical Procedures; Outcome; Participant; Patients; Phenotype; Plasma; Population; Postoperative Period; Preventive; Probability Samples; Proteins; Proteomics; Protocols documentation; Replacement Arthroplasty; Research Personnel; Risk; Role; Sampling; Schedule; Series; Spinal Anesthesia; Systems Biology; Techniques; Time; Validation; Work; base; biomarker discovery; biomarker panel; clinical diagnosis; cohort; cost; crosslink; cytokine; differential expression; experience; functional disability; improved; improved outcome; indexing; mortality; neuroinflammation; neuron loss; next generation; novel; older patient; postoperative recovery

ABSTRACT The pathophysiology of delirium and the mechanisms underlying its epidemiological association with long-term cognitive decline (LTCD) remain largely unknown. This important gap limits development of preventive and disease-modifying therapies. To address this gap, we conducted the “Biomarker Discovery for Delirium” project within the P01 “Interdisciplinary Study of Delirium and Its Long Term Outcomes”. Our results support a model for delirium in which a predisposing, pre-inflammatory state results in a heightened inflammatory response to surgery, leading to blood-brain barrier breakdown, microglial activation and neuro-inflammation, resulting in neuronal injury and death. This model is intriguing, as inflammation could be the mechanism underlying the epidemiological link between delirium, LTCD, and Alzheimer's Disease and Related Dementias (ADRD). For the P01 renewal, Delirium, Dementia, and the Vulnerable Brain: An Integrative Approach, our project will leverage banked specimens from the first cycle's Successful Aging after Elective Surgery study (SAGES I), which enrolled and followed 560 participants undergoing major scheduled surgery, and collected plasma at 4 time points relative to surgery. We add banked specimens from the Healthier Postoperative Recovery study (HiPOR), which enrolled 242 participants undergoing total joint replacements under spinal anesthesia using a similar protocol to SAGES I, with the additional collection of preoperative cerebrospinal fluid (CSF). Further, we will collect new blood and CSF samples from a probability sample of 128 SAGES I participants, and from a new cohort of 400 older patients undergoing total joint replacement under spinal anesthesia (SAGES II). We will use two state-of-the-art approaches, SOMAscan, a next generation proteomics platform, to discover new inflammatory proteins (Aim 1), and CyTOF, a single-cell mass cytometry platform, to characterize circulating immune cells that regulate inflammation (Aim 2). We will also extend our prior work by examining CSF in addition to plasma, and by quantifying a novel inflammatory index (Aim 3). Using these techniques, we will compare inflammatory proteins and cells in patients who do and do not develop delirium, and in those who have slower and faster rates of LTCD following delirium. Importantly, we will also independently validate all SOMAscan and CyTOF results using standard laboratory methods. Our current Project represents the next in a series of systematic studies extending important findings from the first P01 cycle, and leading to more detailed understanding of the full inflammatory protein profile associated with delirium and LTCD, including markers in the CSF, plus origins of the inflammatory response from immune cells. The Aims also represent an initial step toward development of blood and CSF protein, and cytometry-based biomarker panels to refine prediction of delirium and LTCD. Importantly, the proposed work will improve our understanding of the pathophysiology of delirium and its association with ADRD, ultimately leading to targeted interventions to improve outcomes of hospitalized older adults with vulnerable brains.

抽象的 del妄的病理生理和其流行病学与长期相关的机制 认知能力下降（LTCD）在很大程度上仍然未知。这一重要差距限制了预防性和 疾病改良疗法。为了解决这一差距，我们进行了“ del妄的生物标志物发现”项目 在P01“ ir妄及其长期结果的跨学科研究”中。我们的结果支持模型 对于del妄，易感性，炎症状态导致对 手术，导致血脑屏障分解，小胶质细胞激活和神经炎症，导致 神经元损伤和死亡。该模型很有趣，因为炎症可能是该机制 del妄，LTCD和阿尔茨海默氏病与相关痴呆症（ADRD）之间的流行病学联系。为了 P01更新，del妄，痴呆和脆弱的大脑：一种综合方法，我们的项目将 在选修手术研究（SAGES I）之后，第一个周期成功衰老的杠杆标本， 招募并跟随560名参加大型手术的参与者，并在4时收集血浆 时间点相对于手术。我们从更健康的术后恢复研究中添加了库存标本 （髋），招募了242名参与者使用A 与圣人I相似的方案，术前脑脊液（CSF）的额外收集。此外，我们 将从我参与者的概率样本中收集新的血液和CSF样本，并从一个参与者中收集 在脊柱麻醉下进行总关节置换的400名老年患者的新队列（SAGES II）。我们 将使用两种最先进的方法，即下一代蛋白质组学平台Somascan来发现新的 炎性蛋白（AIM 1）和单细胞质量细胞仪平台Cytof，以表征循环 调节炎症的免疫细胞（AIM 2）。我们还将通过检查CSF来扩展我们的先前工作 除了血浆，并通过量化新型炎症指数（AIM 3）。使用这些技术，我们将 比较在做和不发展ir妄的患者中的炎性蛋白和细胞，以及 del妄后，LTCD的速度较慢，更快。重要的是，我们还将独立验证所有 Somascan和Cytof使用标准实验室方法。我们当前的项目代表下一个 一系列系统的研究将重要发现从第一个P01周期扩展出来，并导致更多 详细了解与del妄和LTCD相关的完整炎症蛋白特征，包括 CSF中的标记，以及免疫细胞炎症反应的起源。目标也代表 迈向血液和CSF蛋白的开发的第一步，以及基于细胞术的生物标志物面板以完善 del妄和LTCD的预测。重要的是，拟议的工作将提高我们对 del妄的病理生理及其与ADRD的关联，最终导致针对性的干预措施 改善住院的老年人的脆弱大脑的结果。