Amyloid PET and blood biomarker supplement to the Delirium Program Project

淀粉样蛋白 PET 和血液生物标志物对谵妄计划项目的补充

• 批准号: 10430721
• 负责人: SHARON K. INOUYE
• 金额: $ 22.73万
• 依托单位: HEBREW REHABILITATION CENTER FOR AGED
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-08-01 至 2023-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10430721
• 关键词: Achievement; Aging; Alzheimer' s Disease; Alzheimer' s disease related dementia; Alzheimer’s disease biomarker; Amyloid; Amyloid beta-42; Biological Assay; Biological Markers; Blood; Brain; Cells; Cerebrospinal Fluid; Cerebrum; Cessation of life; Classification; Clinical; Clinical Trials; Cognitive; Cognitive aging; Cytometry; Data; Delirium; Dementia; Development; Doctor of Medicine; Doctor of Philosophy; Early identification; Elderly; Electroencephalography; Electrophysiology (science); Enrollment; Ensure; Functional disorder; Future; Glial Fibrillary Acidic Protein; Goals; Grant; Health Care Costs; Hospitalization; Immune; Impaired cognition; Impairment; Incidence; Individual; Inflammation; Inflammatory; Knowledge; Life; Magnetic Resonance Imaging; Measurement; Measures; Mediating; Medical; Modeling; Modification; Monitor; Nerve Degeneration; Nursing Homes; Operative Surgical Procedures; Outcome; Parents; Participant; Pathway interactions; Patients; Pattern; Phenotype; Physiology; Plasma; Positron-Emission Tomography; Postoperative Period; Prevention strategy; Probability; Probability Samples; Proteins; Proteomics; Recording of previous events; Risk; Risk Marker; Role; Sampling; Scanning; Series; Severities; Spinal Anesthesia; Surgeon; Testing; Text; Validation; amyloid imaging; base; cerebral atrophy; cognitive performance; cohort; cost; crosslink; disability; effective intervention; follow-up; high risk; imaging biomarker; indexing; inflammatory marker; innovation; magnetic resonance imaging biomarker; multimodality; network dysfunction; neuroimaging; neuroimaging marker; neuropathology; neurophysiology; novel; novel marker; postoperative delirium; pre-clinical; predictive modeling; predictive test; preference; preventive intervention; programs; prospective; tau Proteins; tau-1; treatment response

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.

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。这 谵妄的发生被认为是大脑脆弱性的标志；然而，它与 痴呆症和阿尔茨海默病及相关痴呆症（AD/ADRD）仍不清楚。在父程序中 项目更新拨款，我们现在正在开展一系列应用创新方法的 5 个相互关联的项目 加深我们对可能导致谵妄及其相关疾病的病理生理学途径的探索 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，以及 所有项目的交叉链接目标。在我们最初的提案中，我们建议使用脑脊液 (CSF) 用于量化 SAGES I 队列子样本 (n=128) 以及所有新研究中淀粉样蛋白状态的生物标志物 SAGES II 队列（n=350-400）；然而，大约 25-30% 的参与者要么因健康原因不符合资格，要么不愿意 不接受脑脊液采样（由于他们自己或外科医生的偏好）。我们将完成 SAGES II 明年队列入组，预计大约 80-90 名参与者的脑脊液淀粉样蛋白状态不会 已确定。 在本补充文件中，我们请求支持 2 个子项目：(1) 添加 30 [F18] Florbetapir（“淀粉样蛋白”） 正电子发射断层扫描 (PET) 扫描可测量 SAGES II 参与者的淀粉样蛋白状态，而这些参与者没有 接受脑脊液采样； (2) 神经退行性变的新型生物标志物（p-tau 181 和 GFAP）的测量 储存来自整个 SAGES I 队列 (n=560) 的血浆。该补充文件将增强该计划的影响 以多种方式进行项目计划。首先，淀粉样蛋白-PET 将使我们能够确保能够评估淀粉样蛋白的状态： 大多数高风险参与者没有接受CSF采样，并达到最初的目的。二、PET 成像可以定位异常升高的脑淀粉样蛋白，这将提供将异常升高的脑淀粉样蛋白联系起来的机会 淀粉样蛋白成像测量我们正在获得的各种 MRI 和电生理测量。第三， 生物标志物检测将使我们能够验证其他潜在的基于血液的谵妄预测因子， 谵妄的严重程度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 用于对未来患者进行临床试验分层并监测治疗反应的标记物。 因此，获得额外的扫描和化验将确保实现我们最初的目标，并将 还通过与项目计划相一致的修改，扩大了计划项目的整体影响 最初的目标。该补充文件将真正支持该计划项目，并使其实现以下目标： 增进我们对谵妄及其与 AD/ADRD 关系的理解，并最终开发更多 有效的预防和治疗策略。