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

摘要 精神错乱对老年人来说是一种常见的、代价高昂的、危及生命的、可能可以预防的问题，但其 病理生理学仍然知之甚少。精神错乱的发展被认为是大脑的一个标志。 然而，它与痴呆症的关系尚不清楚。在第一个周期中，我们成功地 完成了4个项目，以560名老年外科患者(SAGE I)为中心，记录了： 精神错乱后长期认知衰退的加速轨迹(项目1)；和重大风险 精神错乱的标记物，与炎症(项目2)、结构连接障碍(项目3)和损害有关 全球认知表现(项目4)。这些重要发现为我们下一步行动铺平了道路 希望通过对大脑脆弱性的创新探测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，应用创新的方法来深化我们的 可能导致妄想症及其相关认知的病理生理途径的探讨 拒绝。我们将在项目2中用最先进的方法检查炎症的作用；阿尔茨海默氏症 疾病(AD)生物标志物(项目1中的脑脊液、脑脊液，以及项目3中的神经影像标志物)；以及 在项目5中测量大脑的可塑性/连通性(经颅磁刺激和诱发电位)。 选择这些方法的依据是它们的创新性、探测漏洞的潜力以及 推进我们的机械性认识。项目4将确定和验证复杂精神错乱的预测因素， 即与长期认知衰退相关的精神错乱。所有这些研究都将利用原始的 SAGES I队列，以及一个新的预期招募的队列SAGS II(N=400)，其中将包括脑脊液采样 是在脊椎麻醉前获得的。所有项目都将得到我们由3个核心组成的有效基础设施的支持： 行政(核心A)、外地(核心B)以及数据管理和统计分析(核心C)。 此计划项目续订建议将专家、跨学科小组聚集在一起，以提供支持 环境，以综合和协调的方式处理高度临床相关的领域。这项建议 是真正的创新，具有新颖的病理生理方法、广泛的交叉目标和多种 方法论创新。此外，在第一个周期中创建的大的、定义明确的队列(SAGES I) 提供了一个前所未有的机会来长期探索精神错乱、认知衰退和 阿尔茨海默氏症，为这种更新增添了一些紧迫感。所有项目的高度集成性 如果没有该计划项目基础设施，就无法实现，这是 效率。这一基础设施提供了执行五个项目和交叉链接目标的能力， 我们在深远方向上的病理生理调查的广度。最终，这个项目保持了 极大的潜力促进我们对精神错乱及其伴随的并发症的理解，并发展 更有效的预防和治疗战略。

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.