The Role of Brain Beta-Amyloid and Tau Protein in POD and POCD

大脑 β-淀粉样蛋白和 Tau 蛋白在 POD 和 POCD 中的作用

• 批准号: 9130078
• 负责人: Zhongcong Xie
• 金额: $ 22.12万
• 依托单位: MASSACHUSETTS GENERAL HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-09-01 至 2019-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9130078
• 关键词: Adverse event; Alzheimer' s Disease; Amyloid; Amyloid beta-Protein; Anesthesia procedures; Anesthetics; Beds; Biochemistry; Biological Markers; Brain; Brain imaging; Caring; Cerebrospinal Fluid; Clinical; Data; Delirium; Dementia; Elderly; Enzyme-Linked Immunosorbent Assay; Funding; Future; Geriatrics; Grant; Health; Human; Impaired cognition; Incidence; Individual; Inflammation; Intervention; Investigation; Isoflurane; Knowledge; Lead; Magnetic Resonance Imaging; Measures; Medical Care Costs; Methods; Microglia; Morbidity - disease rate; Neurofibrillary Tangles; Operative Surgical Procedures; Outcome; Participant; Pathogenesis; Patient Care; Patients; Perioperative; Pilot Projects; Pittsburgh Compound-B; Plasma; Positron; Positron-Emission Tomography; Postoperative Complications; Postoperative Period; Proteins; Protocols documentation; Recruitment Activity; Research; Research Personnel; Role; Safety; Scanning; Senile Plaques; Severities; Side; Spinal Anesthesia; Stress; Support System; System; Testing; Time; Total Hip Replacement; Translational Research; Work; cognitive testing; design; high risk; innovation; innovative technologies; interest; knee replacement arthroplasty; mortality; natural hypothermia; neurocognitive test; neuroinflammation; post-operative cognitive dysfunction; postoperative delirium; retention rate; tau Proteins; tau phosphorylation; trend

 DESCRIPTION (provided by applicant): Postoperative delirium (POD) and postoperative cognitive dysfunction (POCD) are the two most common postoperative complications in older adults, and increase perioperative morbidity, mortality, and cost of medical care. However, at the present time, both POD and POCD are clinical phenomena and their pathogenesis is largely unknown. This gap in knowledge has impeded the progress of research to develop targeted interventions for POD and POCD. We have shown that low pre-operative Aß/Tau ratio in cerebrospinal fluid (CSF), a biomarker of Alzheimer's disease, may identify individuals at high risk of POD and POCD. However, the direct association between brain Aß, Tau, and neuroinflammation (e.g., microglia activation) levels with POD/POCD remains to be investigated. Our co-investigator Dr. Johnson has developed the innovative technology of measuring brain Tau [(F-18)T807] and Aß (Pittsburgh compound B) levels by using positron emission tomographic imaging. We have developed methods to assess POD/POCD and to measure CSF levels of Aß and Tau. Taken together, the proposed research is aimed at establishing a system/protocol that will help us for a potential larger scale study to investigate the association of brain, CSF, and plasma Aß and/or Tau levels, and brain microglia activation level, with the incidence and severity of POD and POCD. Our overall hypothesis is that high pre-operative brain Aß and Tau levels, and high postoperative neuroinflammation represent markers of brain vulnerability under perioperative stress, leading to POD and POCD. We will employ bed-side cognitive tests, bench-side enzyme-linked immunosorbent assays, and brain imaging to accomplish two Specific Aims: (1) to conduct a pilot study determining the feasibility and safety of our system/protocol in 24 participants; (2) to obtain preliminary effect size estimates of the association of brain Aß, Tau, and/or microglia activation levels with POD/POCD in the recruited 24 participants. The outcomes from the proposed studies will provide crucial information in regard to a future definitive study, including: (1) eligible:recruit ratio; (2) retetion rates; (3) safety; and (4) preliminary effect sizes for the associations of interest. The results fom our pilot study will guide us in determining whether we should apply for the R01; and if so, how many participants are needed. The proposed studies are highly innovative and significant, because the anticipated results would lead to an R01 study, which could illustrate that high brain Aß, Tau, and/or microglia activation levels are associated with POD and POCD. These findings would suggest that we should avoid or treat perioperative factors (e.g., anesthetic isoflurane, hypothermia, and severe inflammation) which may cause Aß accumulation, Tau phosphorylation, and/or neuroinflammation, leading to POD and POCD. Ultimately, the proposed R21-supported system/protocol study and the future R01-supported confirmative/ definitive research could lead to better anesthesia and surgery care for older adults.

 描述(申请人提供)：术后精神障碍(POD)和术后认知功能障碍(POCD)是老年人最常见的两种术后并发症，增加了围手术期的发病率、死亡率和医疗费用。然而，目前POD和POCD都是临床现象，其发病机制很大程度上还不清楚。这种知识上的差距阻碍了为POD和POCD制定有针对性的干预措施的研究进展。我们已经证明，作为阿尔茨海默病的生物标志物，术前脑脊液(CSF)中较低的Aü/Tau比率可以识别POD和POCD的高危个体。然而，脑Aü、Tau和神经炎症(如小胶质细胞激活)水平与POD/POCD之间的直接联系仍有待研究。我们的合作研究员Johnson博士开发了一项创新技术，通过使用正电子发射断层成像来测量大脑Tau[(F-18)T807]和A？(匹兹堡化合物B)水平。我们已经开发了评估POD/POCD和测定脑脊液中Aü和Tau水平的方法。综上所述，这项拟议的研究旨在建立一个系统/方案，帮助我们进行潜在的更大规模的研究，以调查脑、脑脊液和血浆Aü和/或Tau水平以及脑小胶质细胞激活水平与POD和POCD的发生率和严重程度的关系。我们的总体假设是，术前高水平的脑Aü和Tau，以及术后高水平的神经炎症是围术期应激下脑部脆弱的标志，从而导致POD和POCD。我们将使用床边认知测试、工作台边酶联免疫吸附分析和脑成像来实现两个特定目标：(1)在24名参与者中进行一项初步研究，以确定我们的系统/方案的可行性和安全性；(2)在招募的24名参与者中，获得大脑Aü、Tau和/或小胶质细胞激活水平与POD/POCD之间的关联的初步效果大小估计。拟议研究的结果将为未来的最终研究提供关键信息，包括：(1)合格：招募比率；(2)退学率；(3)安全性；(4)感兴趣的协会的初步效果大小。我们的试验研究结果将指导我们决定是否应该申请R01；如果应该，需要多少参与者。拟议的研究具有很高的创新性和重要意义，因为预期的结果将导致R01研究，该研究可能表明高水平的脑Aü、Tau和/或小胶质细胞激活水平与POD和POCD相关。这些发现提示我们应该避免或处理围手术期因素(如麻醉、异氟醚、体温过低和严重炎症)，这些因素可能导致A？蓄积、Tau磷酸化和/或神经炎症，从而导致POD和POCD。最终，建议的R21支持的系统/方案研究和未来R01支持的确认性/确定性研究可能会为老年人带来更好的麻醉和手术护理。