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

 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，并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，其发病机制在很大程度上是未知的。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，脑脊液（CSF）中的低术前Akt/Tau比率（阿尔茨海默病的生物标志物）可能会识别出POD和POCD高风险的个体。然而，脑中的Akt、Tau和神经炎症之间的直接关联（例如，小胶质细胞活化）水平与POD/POCD的关系仍有待研究。我们的合作研究者约翰逊博士开发了通过使用正电子发射断层扫描成像测量脑Tau [（F-18）T807]和April（匹兹堡化合物B）水平的创新技术。我们已经开发了评估POD/POCD和测量CSF中的Akt和Tau水平的方法。综上所述，拟议的研究旨在建立一个系统/方案，这将有助于我们进行一项潜在的更大规模的研究，以调查脑、CSF和血浆中的Akt和/或Tau水平以及脑小胶质细胞活化水平与POD和POCD的发生率和严重程度的相关性。我们的总体假设是，高术前脑ApoE和Tau水平和高术后神经炎症代表围手术期应激下脑脆弱性的标志，导致POD和POCD。 我们将采用床边认知测试、实验室酶联免疫吸附测定和脑成像来实现两个特定目的：（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名参与者中获得脑ApoE、Tau和/或小胶质细胞激活水平与POD/POCD相关性的初步效应量估计。拟议研究的结果将为未来的确定性研究提供关键信息，包括：（1）合格招募率;（2）保留率;（3）安全性;（4）相关性的初步效应量。我们的试验研究结果将指导我们决定是否应该申请R 01;如果是的话，需要多少人参加。拟议的研究具有高度创新性和重要性，因为预期的结果将导致R 01研究，这可能说明高脑April，Tau和/或小胶质细胞激活水平与POD和POCD相关。这些发现表明，我们应该避免或处理围手术期因素（例如，麻醉剂异氟烷、体温过低和严重炎症），其可引起Ablast积聚、Tau磷酸化和/或神经炎症，导致POD和POCD。最终，拟议的R21支持的系统/方案研究和未来的R 01支持的确认性/确定性研究可能会为老年人提供更好的麻醉和手术护理。

 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.