Blood-based biomarkers of neuronal injury and Alzheimer's disease: predictors of delirium and long-term cognitive decline, and potential shared pathophysiology

神经元损伤和阿尔茨海默病的血液生物标志物：谵妄和长期认知能力下降的预测因子，以及潜在的共同病理生理学

• 批准号: 9436265
• 负责人: TAMARA G FONG
• 金额: $ 21.8万
• 依托单位: HEBREW REHABILITATION CENTER FOR AGED
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-09-30 至 2019-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9436265
• 关键词: Address; Aging; Alzheimer' s Disease; Amyloid beta-Protein; Area; Biological Markers; Blood; Blood specimen; Brain; Case-Control Studies; Cerebrospinal Fluid; Cognition; Cognitive; Complex; Confusion; Delirium; Dementia; Development; Disease; Disease Marker; Disease Outcome; Enrollment; Functional disorder; Funding; Goals; Health Care Costs; Hospitalization; Immunoassay; Impaired cognition; Incidence; Lead; Light; Link; Matched Case-Control Study; Measures; Medical History; MicroRNAs; Nerve Degeneration; Neuronal Injury; Neurons; Older Population; Onset of illness; Operative Surgical Procedures; Orthopedic Surgery procedures; Outcome; Participant; Pathologic Processes; Patient Schedules; Patients; Performance; Periodicity; Persons; Phase; Physical Function; Plasma; Postoperative Period; Prospective cohort; Proteins; Psychometrics; Research; Resources; Risk; Risk Marker; Severities; Spinal Anesthesia; Time; Total Hip Replacement; Untranslated RNA; aged; axon injury; base; biobank; blood-based biomarker; candidate identification; candidate marker; cognitive function; cohort; cost effective; effective therapy; functional disability; high reward; high risk; innovation; knee replacement arthroplasty; mild cognitive impairment; neurofilament; novel; postoperative delirium; potential biomarker; pre-clinical; predictive marker; prospective; protein biomarkers; tau Proteins; treatment strategy

Project Summary/Abstract Alzheimer's disease (AD) and delirium are common causes of cognitive impairment in older populations that can each lead to functional disability, loss of independence, and higher healthcare costs. While AD and delirium may occur independently, they frequently coexist, resulting synergistically in poorer outcomes. The relationship between AD and delirium is complex, with AD patients at greater risk to develop delirium, and patients with delirium at risk for developing accelerated cognitive decline. Whether delirium is a marker of vulnerability to AD, unmasks unrecognized AD, accelerates preclinical AD, or can itself cause permanent neuronal damage and lead to AD are all poorly understood, and addressing these issues is a high-priority area for aging research. The goals of this R21/R33 phased innovation project is to provide “proof of concept” for the interrelationship between delirium and AD by exploring potential shared biomarkers between these two conditions. In the R21 phase, we will leverage resources from the NIA-funded Successful Aging after Elective Surgery (SAGES study, P01AG031720), a cohort of 560 persons aged ≥ 70 years without dementia, 24% of whom developed delirium postoperatively, and who have undergone ≥ 48 months of periodic detailed cognitive and functional assessments. In a matched parallel case-control study (n=110), candidate biomarkers of neuronal injury, specifically the proteins tau and neurofilament light, and microRNAs (miR), small non-coding RNAs that have been demonstrated to become dysregulated in pathological processes including AD, will be measured in biobanked plasma from SAGES. This will allow for efficient identification of candidate blood-based biomarkers that are predictive of postoperative delirium or long-term cognitive decline (LTCD). In the R33, phase, a new prospective cohort (n=125) of patients scheduled to undergo elective orthopedic surgery under spinal anesthesia will be enrolled to confirm and expand the findings from the R21 phase. As in SAGES, the patients in the R33 cohort will have a comprehensive baseline assessment of medical history, physical and cognitive functioning, and blood sampling, and will be followed prospectively for 12 months from their initial hospitalization with periodic assessments. Cerebrospinal fluid (CSF) will be collected during induction of spinal anesthesia at the time of surgery, and delirium will be assessed daily during hospitalization. Biomarkers from CSF and blood will be used to predict delirium incidence, severity, and cognitive decline. We expect that one or more candidate biomarkers will have utility as a delirium risk, disease, and/or outcome biomarker. Discovery of such biomarkers will contribute to understanding of the interconnection between delirium and dementia; demonstration of a lack of a connection would provide important information as well. Defining the relationship . between neuronal injury and AD-related biomarkers and delirium would advance the pathophysiologic understanding of AD and delirium, and may ultimately aid in the identification of potential targets for effective treatment strategies for both conditions

项目总结/摘要 阿尔茨海默病（AD）和谵妄 是老年人认知障碍的常见原因， 每一种都可能导致功能性残疾、丧失独立性和更高的医疗费用。虽然AD和 谵妄可能独立发生，但它们经常共存，协同作用导致不良结局。的 AD关系 谵妄是复杂的，AD患者发生谵妄的风险更大， 谵妄患者有发生认知能力加速下降的风险。 谵妄是否是 易患AD，暴露未识别的AD，加速临床前AD，或本身可导致永久性 神经元损伤和导致AD都知之甚少，解决这些问题是一个高度优先领域 用于衰老研究该R21/R33分阶段创新项目的目标是为 通过探索谵妄和AD之间潜在的共享生物标志物， 条件在R21阶段，我们将利用来自NIA资助的“选择性后成功老龄化”项目的资源， 手术（SAGES研究，P01 AG 031720），一个包含560名年龄≥ 70岁无痴呆患者的队列，24%的 术后发生谵妄，并且接受了≥ 48个月的定期详细认知 功能评估。在一项匹配的平行病例对照研究（n=110）中， 神经元损伤，特别是蛋白质tau和神经丝轻，和microRNA（miR），小的非编码 已被证明在包括AD在内的病理过程中变得失调的RNA将被 在SAGES的生物库血浆中测量。这将允许有效地识别候选的基于血液的 预测术后谵妄或长期认知下降（LTCD）的生物标志物。在R33中， 阶段，一个新的前瞻性队列（n=125）的患者计划接受择期骨科手术， 将入组脊髓麻醉，以确认和扩展R21期的发现。在SAGES中， R33队列中的患者将对病史、体格检查和 认知功能和血液采样，以及 将 从他们最初的研究开始， 住院并定期评估。将在脊髓诱导期间收集脑脊液（CSF） 手术时麻醉，住院期间每天评估谵妄。生物标志物 CSF和血液将用于预测谵妄发生率、严重程度和认知能力下降。我们预计， 更多的候选生物标志物将具有作为谵妄风险、疾病和/或结果生物标志物的效用。发现 这些生物标志物将有助于理解谵妄和痴呆之间的相互联系; 缺乏联系的证明也将提供重要的信息。定义关系 . 神经元损伤和AD相关生物标志物之间的联系，谵妄将促进病理生理学 了解AD和谵妄，并可能最终有助于确定有效治疗的潜在靶点。 针对这两种情况的治疗策略