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

基本信息

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
项目类别：
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&apos 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

项目摘要

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.

抽象的谵妄的病理生理学及其与长期流行病学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和治疗的发展。为了弥补这一差距，我们开展了“谵妄生物标志物发现”项目。在 P01“谵妄及其长期结果的跨学科研究”中，我们的结果支持一个模型。用于谵妄，其中易发的炎症前状态导致炎症反应手术，导致血脑屏障破坏、小胶质细胞激活和神经炎症，从而导致这个模型很有趣，因为炎症可能是神经元损伤和死亡的机制。谵妄、LTCD 和阿尔茨海默病及相关痴呆 (ADRD) 之间的流行病学联系。 P01 更新、谵妄、痴呆和脆弱大脑：综合方法，我们的项目将利用来自第一个周期选择性手术后成功衰老研究 (SAGES I) 的储存样本，该项目招募并跟踪了 560 名接受大型预定手术的参与者，并于 4 点收集了血浆。我们添加了来自健康术后恢复研究的储存样本。 (HiPOR)，该项目招募了 242 名参与者，他们在脊髓麻醉下使用与 SAGES I 类似的方案，额外收集术前脑脊液 (CSF)。将从 128 名 SAGES I 参与者的概率样本以及来自由 400 名老年患者组成的新队列在脊髓麻醉下接受全关节置换术 (SAGES II)。将使用两种最先进的方法，SOMAscan（下一代蛋白质组学平台）来发现新的炎症蛋白（目标 1）和 CyTOF（一种单细胞质谱流式分析平台）来表征循环调节炎症的免疫细胞（目标 2）我们还将通过检查脑脊液来扩展我们之前的工作。除了血浆，并通过量化新的炎症指数（目标 3），我们将使用这些技术。比较发生和未发生谵妄的患者以及发生谵妄的患者的炎症蛋白和细胞谵妄后 LTCD 的发生率会变慢或变快重要的是，我们还将独立验证所有这些。 SOMAscan 和 CyTOF 结果使用标准实验室方法。我们当前的项目代表了下一个项目。一系列系统研究扩展了第一个 P01 周期的重要发现，并导致更多详细了解与谵妄和 LTCD 相关的完整炎症蛋白谱，包括脑脊液中的标记物以及免疫细胞炎症反应的起源也代表了一个目标。迈向开发血液和脑脊液蛋白质以及基于细胞计数的生物标志物组合的第一步重要的是，所提出的工作将提高我们对谵妄和 LTCD 的理解。谵妄的病理生理学及其与 ADRD 的关联，最终导致有针对性的干预改善大脑脆弱的住院老年人的治疗结果。