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（由申请人提供）：术后谵妄（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，会增加围手术期发病率、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尚不清楚。这种知识差距阻碍了针对 POD 和 POCD 制定针对性干预措施的研究进展。我们已经证明，术前脑脊液 (CSF) 中 Aß/Tau 比率较低（阿尔茨海默病的生物标志物）可能会识别出 POD 和 POCD 高风险个体。然而，大脑 Aß、Tau 和神经炎症（例如小胶质细胞激活）水平与 POD/POCD 之间的直接关联仍有待研究。我们的合作研究员 Johnson 博士开发了利用正电子发射断层扫描成像测量脑 Tau [(F-18)T807] 和 Aß（匹兹堡化合物 B）水平的创新技术。我们开发了评估 POD/POCD 以及测量 CSF Aß 和 Tau 水平的方法。总而言之，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，以调查大脑、脑脊液、血浆 Aß 和/或 Tau 水平以及大脑小胶质细胞激活水平与 POD 和 POCD 的发生率和严重程度之间的关系。我们的总体假设是，术前大脑 Aß 和 Tau 水平较高以及术后神经炎症水平较高是围手术期应激下大脑脆弱性的标志，从而导致 POD 和 POCD。 我们将采用床边认知测试、台式酶联免疫吸附测定和脑成像来实现两个具体目标：(1) 进行一项试点研究，确定我们的系统/方案在 24 名参与者中的可行性和安全性； (2) 在招募的 24 名参与者中获得大脑 Aß、Tau 和/或小胶质细胞激活水平与 POD/POCD 关联的初步效应大小估计。拟议研究的结果将为未来的最终研究提供重要信息，包括：（1）合格：招聘比率； (2) 保留率； （三）安全； (4) 相关关联的初步效应大小。我们试点研究的结果将指导我们决定是否应该申请 R01；如果需要，需要多少参与者。拟议的研究具有高度创新性和意义，因为预期结果将导致 R01 研究，该研究可以说明大脑中高 Aß、Tau 和/或小胶质细胞激活水平与 POD 和 POCD 相关。这些发现表明我们应该避免或治疗围手术期因素（例如麻醉异氟烷、体温过低和严重炎症），这些因素可能导致 Aß 积累、Tau 磷酸化和/或神经炎症，从而导致 POD 和 POCD。最终，拟议的 R21 支持的系统/方案研究和未来 R01 支持的验证性/确定性研究可能会为老年人带来更好的麻醉和手术护理。