Amyloid PET and blood biomarker supplement to the Delirium Program Project

摘要 对老年人来说，精神错乱是一种常见的、代价高昂的、危及生命的、可能可以预防的问题。这个 精神错乱的发展被认为是大脑脆弱的标志；然而，它与 痴呆症和阿尔茨海默病及相关痴呆(AD/ADRD)仍不清楚。在父程序中 项目续期赠款，我们正在进行一系列5个相互关联的项目，采用创新的方法 深化我们对可能导致精神错乱及其相关的病理生理途径的探索 认知能力下降。我们正在研究淀粉样蛋白标志物在项目1、3和5的主要目标中的作用，以及在 交叉链接所有项目的目标。在我们最初的提案中，我们建议使用脑脊液(CSF) 在我的队列中的一个子样本(n=128)和所有新的SAGE中，用于量化淀粉样蛋白状态的生物标志物 SAGE II队列(n=350-400)；然而，大约25%-30%的参与者不符合或将不符合医疗条件 没有接受脑脊液采样(由于他们自己或他们的外科医生的偏好)。我们将完成《圣贤2》 明年入选队列，预计约有80-90名参与者，而脑脊液淀粉样蛋白状态不会 已经确定了。 在本补编中，我们请求支持2个子项目：(1)增加30[F18]Florbetapir(“淀粉样蛋白”) 正电子发射断层扫描(PET)测量未接受治疗的SAGES II参与者的淀粉样蛋白状态 接受脑脊液采样；(2)神经退行性变的新生物标志物(p-tau 181和GFAP)在 储存的血浆来自整个SAGE I队列(n=560)。这项补充资料将加强 以多种方式规划项目。首先，淀粉样蛋白-PET将使我们能够确保我们可以评估淀粉样蛋白状态 大多数高危参与者没有接受脑脊液采样，并达到了最初的目的。第二，PET 成像可以定位异常升高的大脑淀粉样蛋白，这将提供联系的机会 淀粉样蛋白成像措施，以各种MRI和电生理措施，我们正在获得。第三, 生物标记物分析将使我们能够验证其他潜在的基于血液的精神错乱预测指标， 严重的精神错乱和术后认知能力下降(与我们最初的目标一致)，这将带来风险 用于对未来的患者进行临床试验和监测治疗反应的标记物。 因此，获得额外的扫描和分析将确保实现我们最初的目标和 还可以通过与 最初的目标。这一补充将真正支持计划项目，并使其能够实现其目标 促进我们对精神错乱及其与AD/ADRD的关系的理解，并最终发展出更多 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. The development of delirium is considered to be a marker of brain vulnerability; however, its relationship to dementia and Alzheimer’s disease and related dementias (AD/ADRD) remains unclear. In the parent Program Project renewal grant, we are now conducting 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 are examining the role of amyloid markers in primary aims of Projects 1, 3, and 5, and in cross-linking aims across all projects. In our original proposal, we proposed using cerebrospinal fluid (CSF) biomarkers to quantify amyloid status in a subsample (n=128) of the SAGES I cohort, and in all of the new SAGES II cohort (n=350-400); however, about 25-30% of the participants are either medically ineligible or will not receive CSF sampling (due to their own or their surgeon’s preference). We will be completing SAGES II cohort enrollment in the next year, and anticipate about 80-90 participants where CSF amyloid status will not have been determined. In this supplement, we request support for 2 Sub-Projects: (1) addition of 30 [F18] Florbetapir (“Amyloid”) Positron Emission Tomography (PET) scans to measure amyloid status in SAGES II participants who did not receive CSF sampling; (2) measurement of novel biomarkers for neurodegeneration (p-tau 181 and GFAP) in stored plasma from the entire SAGES I cohort (n=560). This supplement will enhance the impact of the Program Project in several ways. First, amyloid-PET will allow us to assure we can assess amyloid status for most high-risk participants who do not receive CSF sampling, and to achieve the original aims. Second, PET imaging allows abnormally elevated cerebral amyloid to be localized, which will offer opportunities to relate amyloid imaging measures to the variety of MRI and electrophysiological measures we are obtaining. Third, the biomarker assays would allow us to validate additional potential blood-based predictors of delirium, delirium severity, and post-operative cognitive decline (aligned with our original aims), which would provide risk markers to stratify future patients for clinical trials and to monitor response to treatment. Thus, obtaining the additional scans and assays will ensure the achievement of our original aims and will also magnify the overall impact of the Program Project, through modifications that are well-aligned with the original aims. This supplement will truly bolster the Program Project, and allow it to achieve its goals of advancing our understanding of delirium and its relationship to AD/ADRD, and ultimately, to develop more effective strategies for prevention and treatment.