Development and Testing of a Framework of Social Determinants of Health for Delirium Tailored to Older Adults

摘要 谵妄是一种常见的，昂贵的，危及生命的，并可能预防老年人的问题，但其 病理生理学仍然知之甚少。谵妄的发展被认为是大脑 然而，它与痴呆症的关系仍然不清楚。在第一个周期中，我们成功地 完成了4个项目，以>560名老年手术患者（SAGES I）为中心，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）、结构性连接障碍（项目3）和损伤相关 在全球认知表现（项目4）。这些重要的发现为我们 我们期待通过创新的大脑脆弱性探针来扩展我们对病理生理学的理解。 我们现在提出了一系列5个相互关联的项目，采用创新的方法来深化我们的 探索可能导致谵妄及其相关认知障碍的病理生理学途径 下降我们将在项目2中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）和项目3中的神经影像学标志物）;以及 在项目5中测量大脑可塑性/连通性（经颅磁刺激和诱发电位）。 这些方法的选择是基于它们的创新性、探测脆弱性的潜力以及 促进我们对机械的理解。项目4将确定和验证复杂性谵妄的预测因子， 也就是说，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的 SAGES I队列和一个新的前瞻性入组队列SAGES II（N=400），将包括CSF采样 在脊髓麻醉之前获得。所有项目都将得到我们三个核心的有效基础设施的支持： 行政（核心A）、外地（核心B）和数据管理和统计分析（核心C）。 该计划项目更新提案汇集了一个支持性的跨学科专家小组， 环境，以综合和协调的方式解决高度临床相关的领域。该提案 是真正的创新与新的病理生理学方法，广泛的交联目标， 方法创新。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，探索长期的关系谵妄，认知能力下降， 老年痴呆症，给这种更新增加了一些紧迫性。所有项目的高度集成性 如果没有这个计划项目基础设施，就无法实现，这是一个主要的力量和来源， 效率这一基础设施提供了执行五个项目和交叉目标的能力， 我们的病理生理学研究的广度在深远的方向。最终，这个项目 巨大的潜力，以促进我们的理解谵妄，其伴随的并发症，并发展 更有效的预防和治疗策略。

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.