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

项目摘要/摘要 阿尔茨海默病(AD)和精神错乱 是老年人认知障碍的常见原因 每一种都可能导致功能残疾、丧失独立性和更高的医疗成本。而AD和 精神错乱可以独立发生，它们经常共存，协同作用导致较差的预后。这个 AD之间的关系 精神错乱是复杂的，AD患者发展为精神错乱的风险更大，而且 精神错乱患者有发展为认知功能减退加速的风险。 精神错乱是否是 AD的漏洞，未屏蔽未识别的AD，加速临床前AD，或本身可能导致永久性 神经元损伤和导致阿尔茨海默病的机制都知之甚少，解决这些问题是一个高度优先的领域 用于衰老研究。这个R21/R33阶段性创新项目的目标是为 通过探讨精神分裂症和阿尔茨海默病之间潜在的共同生物标志物来探讨两者的相互关系 条件。在R21阶段，我们将利用NIA资助的选修后成功老化项目的资源 外科(SAGS研究，P01AG031720)，对560名年龄在≥70岁但没有痴呆的人进行了队列调查，24%的人 术后出现精神错乱，并接受≥48个月定期详细认知的患者 和功能评估。在一项配对的平行病例对照研究中(n=110)，候选生物标志物 神经元损伤，特别是tau和神经丝光蛋白，以及microRNAs(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 在来自圣人的生物库血浆中进行测量。这将允许有效地识别基于血液的候选 预测术后精神错乱或长期认知功能衰退(LTCD)的生物标志物。在R33中， 阶段，新的预期队列(n=125)的患者计划在以下条件下接受选择性骨科手术 脊椎麻醉将被纳入以确认和扩大R21阶段的发现。与圣人一样，圣人 R33队列中的患者将接受全面的基线评估，包括病史、体检和 认知功能和血液样本，以及 将会是 从最初的12个月开始前瞻性地跟踪调查 住院接受定期评估。在脊髓诱导过程中收集脑脊液(CSF)。 手术时的麻醉和住院期间的精神错乱将每天进行评估。生物标志物来自 脑脊液和血液将被用来预测精神错乱的发生率、严重程度和认知能力下降。我们期待着这一次或 更多的候选生物标记物将作为精神错乱的风险、疾病和/或结果的生物标记物。发现了 这些生物标志物将有助于理解精神错乱和痴呆症之间的相互联系； 证明缺乏联系也将提供重要的信息。定义关系 。 神经元损伤与AD相关生物标志物和精神障碍之间的关系将促进AD的病理生理 了解阿尔茨海默病和精神错乱，并最终可能有助于确定有效的潜在目标 针对这两种情况的治疗策略

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