Amyloid PET and blood biomarker supplement to the Delirium Program Project

摘要 对于老年人来说，谵妄是一种常见的、昂贵的、威胁生命的、潜在的可预防的问题。的 谵妄的发展被认为是大脑脆弱性的标志;然而，它与 痴呆和阿尔茨海默病及相关痴呆（AD/ADRD）的发病机制尚不清楚。在父程序中 项目更新赠款，我们现在正在进行一系列的5个相互关联的项目，采用创新的方法 为了加深我们对可能导致谵妄及其相关疾病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记物在项目1、3和5的主要目标中的作用， 将所有项目的目标相互联系起来。在我们最初的建议中，我们建议使用脑脊液（CSF） 在SAGES I队列的子样本（n=128）中，以及在所有新的 SAGES II队列（n=350-400）;然而，约25-30%的受试者在医学上不合格或将 不接受CSF采样（由于他们自己或他们的外科医生的偏好）。我们将完成SAGES II 队列招募在明年，并预计约80-90名参与者，其中CSF淀粉样蛋白状态将不会 已经确定。 在本补充文件中，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SAGES II参与者的淀粉样蛋白状态， 接受CSF采样;（2）测量神经变性的新生物标志物（p-tau 181和GFAP）， 来自整个SAGES I队列的储存血浆（n=560）。这一补充将加强 项目以多种方式进行。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， 大多数未接受CSF采样的高危受试者，并达到最初的目的。二、PET 影像学检查可以定位异常升高的大脑淀粉样蛋白，这将提供机会， 淀粉样蛋白成像测量与我们所获得的各种MRI和电生理测量相比较。第三、 生物标志物测定将允许我们验证谵妄的其他潜在的基于血液的预测因子， 谵妄严重程度和术后认知下降（与我们最初的目标一致），这将提供风险 这些标记物用于对未来的患者进行临床试验分层，并监测对治疗的反应。 因此，获得额外的扫描和分析将确保实现我们最初的目标， 还通过与计划项目相一致的修改，扩大计划项目的整体影响， 最初的目标。这一补充将真正支持该计划项目，并使其能够实现其目标， 推进我们对谵妄及其与AD/ADRD关系的理解，并最终发展更多 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. 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.