Delirium, Dementia, and the Vulnerable Brain: An Integrative Approach

谵妄、痴呆和脆弱的大脑：综合方法

• 批准号: 10405113
• 负责人: SHARON K. INOUYE
• 金额: $ 271.63万
• 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/10405113
• 关键词: Address; Aging; Alzheimer' s Disease; Alzheimer' s disease pathology; Alzheimer’s disease biomarker; Area; Brain; Cerebrospinal Fluid; Cessation of life; Clinical Trials; Cognitive; Data; Delirium; Dementia; Development; Diffusion Magnetic Resonance Imaging; Elderly; Enrollment; Ensure; Evaluation; Evoked Potentials; Frequencies; Functional disorder; Future; Health Care Costs; Impaired cognition; Impairment; Individual; Inflammation; Infrastructure; Investigation; Journals; Lead; Life; Longitudinal Studies; Longterm Follow-up; Measures; Methodology; Nature; Observational Study; Operative Surgical Procedures; Outcome; Paper; Pathway interactions; Patients; Prevention strategy; Probability Samples; Productivity; Prospective cohort; Publishing; Resources; Risk Marker; Role; Running; Sampling; Series; Source; Spinal Anesthesia; Statistical Data Interpretation; Structure; Transcranial magnetic stimulation; base; clinically relevant; cognitive performance; cohort; cost; crosslink; data management; disability; follow-up; innovation; mild cognitive impairment; neuroimaging marker; novel; pre-clinical; preventive intervention; programs; prospective; recruit; supportive environment; treatment response

ABSTRACT Delirium is a common, costly, life-threatening, and potentially preventable problem for older persons, yet its pathophysiology remains poorly understood. The development of delirium is considered to be a marker of brain vulnerability; however, its relationship to dementia remains unclear. During the first cycle, we successfully completed 4 projects centered around a cohort of >560 older surgical patients (SAGES I), which documented: an accelerated trajectory of long-term cognitive decline following delirium (Project 1); and important risk markers for delirium, related to inflammation (Project 2), structural dysconnectivity (Project 3), and impairment in global cognitive performance (Project 4). These important findings have paved the way for us to move forward to extend our pathophysiologic understanding through innovative probes of brain vulnerability. We now propose a series of 5 interlinked projects applying innovative approaches to deepen our exploration of pathophysiologic pathways potentially contributing to delirium and its associated cognitive decline. We will examine the role of inflammation with state-of-the-art approaches in Project 2; Alzheimer's disease (AD) biomarkers (cerebrospinal fluid, CSF) in Project 1,and neuroimaging markers in Project 3); and measures of brain plasticity/connectivity (transcranial magnetic stimulation and evoked potentials) in Project 5. These approaches were chosen based on their innovation, potential to probe vulnerability, and ability to advance our mechanistic understanding. Project 4 will identify and validate predictors of complicated delirium, i.e., delirium associated with long-term cognitive decline. All of these studies will utilize both the original SAGES I cohort, and a new prospectively enrolled cohort, SAGES II (N=400), which will include CSF sampling obtained prior to spinal anesthesia. All projects will be supported by our effective infrastructure of 3 cores: Administrative (Core A), Field (Core B), and Data Management and Statistical Analysis (Core C). This Program Project renewal proposal brings together an expert, interdisciplinary group in a supportive environment to address a highly clinically relevant area in an integrated and coordinated fashion. The proposal is truly innovative with novel pathophysiologic approaches, extensive cross-linking aims, and multiple methodologic innovations. Furthermore, the large, well-defined cohort created in the first cycle (SAGES I) presents an unprecedented opportunity to explore long-term the relationship of delirium, cognitive decline, and Alzheimer's disease, lending some urgency to this renewal. The highly integrated nature of all the projects could not be achieved without this program project infrastructure, representing a major strength and source of efficiency. This infrastructure provides the capacity to execute five projects and cross-linking aims, expanding the breadth of our pathophysiologic investigation in far-reaching directions. Ultimately, this project holds tremendous potential to advance our understanding of delirium, its attendant complications, and to develop more effective strategies for prevention and treatment.

抽象的 对于老年人来说，谵妄是一种常见的、昂贵的、危及生命且可能可以预防的问题，但它 病理生理学仍然知之甚少。谵妄的发展被认为是大脑的一个标志 脆弱性；然而，它与痴呆症的关系仍不清楚。在第一个周期中，我们成功地 围绕超过 560 名老年外科患者 (SAGES I) 完成了 4 个项目，其中记录了： 谵妄后长期认知能力下降的加速轨迹（项目 1）；和重要风险 谵妄标志物，与炎症（项目 2）、结构性脱节（项目 3）和损伤相关 整体认知表现（项目 4）。这些重要的发现为我们的行动铺平了道路 通过对大脑脆弱性的创新探索来扩展我们对病理生理学的理解。 我们现在提出一系列 5 个相互关联的项目，应用创新方法来深化我们的 探索可能导致谵妄及其相关认知的病理生理途径 衰退。我们将在项目 2 中采用最先进的方法研究炎症的作用；阿尔茨海默氏症 项目1中的疾病（AD）生物标志物（脑脊液，CSF），以及项目3中的神经影像标志物）；和 项目 5 中大脑可塑性/连接性的测量（经颅磁刺激和诱发电位）。 选择这些方法是基于其创新性、探测漏洞的潜力以及发现漏洞的能力。 增进我们对机制的理解。项目 4 将识别并验证复杂谵妄的预测因子， 即与长期认知能力下降相关的谵妄。所有这些研究都将利用原始 SAGES I 队列和一个新的前瞻性入组队列 SAGES II (N=400)，其中将包括脑脊液采样 在脊髓麻醉之前获得。所有项目都将得到我们有效的 3 核基础设施的支持： 行政（核心 A）、现场（核心 B）以及数据管理和统计分析（核心 C）。 该计划项目更新提案汇集了专家、跨学科小组，提供支持 以综合和协调的方式解决高度临床相关领域的环境。提案 具有真正的创新性，具有新颖的病理生理学方法、广泛的交联目标和多种 方法论创新。此外，在第一个周期（SAGES I）中创建的大型、定义明确的队列 提供了一个前所未有的机会来探索谵妄、认知能力下降和精神错乱之间的长期关系。 阿尔茨海默病给这种复兴带来了一些紧迫感。所有项目的高度集成性 如果没有该计划，项目基础设施就不可能实现，它代表了主要力量和来源 效率。该基础设施提供了执行五个项目和交叉链接目标的能力，扩大了 我们病理生理学研究的广度具有深远的意义。最终，这个项目 推进我们对谵妄及其伴随并发症的理解并开发 更有效的预防和治疗策略。