The Role of Alzheimer's-associated Abeta 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）是老年人手术后最常见的两种并发症，并大大增加围手术期的发病率、死亡率和医疗费用。然而，目前POD和POCD均为临床现象，其神经发病机制在很大程度上尚不清楚。这种知识上的差距阻碍了有针对性的预防和治疗策略的发展，这些策略旨在解决POD和POCD的潜在机制。2-淀粉样蛋白（A2）积累和神经炎症（如小胶质细胞激活和脑细胞因子积累）与认知功能障碍和谵妄有关，与我们的中心假设一致，我们的初步研究表明，术前脑脊液（CSF）中高IL-6水平和低A2水平与POD和术后记忆障碍有关。提示大脑中高水平的A2和细胞因子可能在POD和POCD的神经发病机制中起作用。因此，本研究旨在通过验证脑内高水平的A2和IL-6是围手术期应激下脑易感性标志物，从而导致POD和POCD的假设，来确定POD和POCD的神经发病机制。我们将采用床侧认知测试和台侧生化分析来实现三个特定目的：(1)研究脊髓麻醉下预定全髋关节和膝关节置换术后1、2和3天测量的术前CSF A2和IL-6水平与POD的关系，CSF将在脊髓麻醉时收集，因此不会对参与者造成额外的风险；(2)确定同一人群术后7天、3个月和1年测定的术前CSF A2和IL-6水平与POCD的关系；(3)开展匹兹堡化合物B正电子发射层析成像测量脑淀粉样蛋白量和脊髓导管采集术后即刻脑脊液的可行性研究。我们将使用经过验证和标准化的方法评估POD和POCD，并使用ELISA测量CSF A2、IL-6和皮质醇水平。本项目将为POD和POCD的神经发病机制提供重要信息，具有高度创新性和重要意义。预期的结果将为POD和POCD的针对性预防和治疗策略的设计提供信息，因此有可能最终为老年人提供更好的麻醉和手术护理。我们的建议符合国家老龄研究所的主要使命，即减轻老年人的疾病和残疾负担。

DESCRIPTION (provided by applicant): Post-operative delirium (POD) and Post-operative cognitive dysfunction (POCD) are the two most common post-operative complications in older adults, and substantially increase peri-operative morbidity, mortality and cost of medical care. However, at present time, both POD and POCD are clinical phenomena and their neuropathogeneisis is largely unknown. This gap in knowledge has impeded development of targeted prevention and treatment strategies designed to address the underlying mechanisms of POD and POCD. Consistent with our central hypotheses that 2-Amyloid protein (A2) accumulation and neuroinflammation (e.g., microglia activation and brain cytokine accumulation) are linked with cognitive dysfunction and delirium, our preliminary studies have shown that high IL-6 levels and low A2 levels in the immediate pre-operative cerebrospinal fluid (CSF) are associated with POD and post-operative memory impairment, which suggest that high levels of A2 and cytokine in the brain may play a role in POD and POCD neuropathogenesis. Thus, the proposed research is aimed at determining the neuropathogenesis of POD and POCD by testing a hypothesis that high levels of A2 and IL-6 in the brain represent markers of brain vulnerability under peri-operative stress, leading to POD and POCD. We will employ bed-side cognitive tests and bench-side biochemistry analysis to accomplish three Specific Aims: (1) to investigate the association of pre-operative CSF A2 and IL-6 levels with POD measured 1, 2 and 3 days after scheduled total hip and knee replacement surgery conducted under spinal anesthesia, the CSF will be collected when spinal anesthesia is performed and therefore poses no added risk to the participants; (2) to determine the association of pre-operative CSF A2 and IL-6 levels with POCD measured 7 days, 3 months, and 1 year after surgery in the same population; (3) to perform feasibility studies of using positron emission tomographic imaging with Pittsburgh Compound B to measure brain amyloid amount and of using spinal catheter to collect immediate pre- and post-operative CSF. We will assess POD and POCD using validated and standardized methods, and measure CSF A2, IL-6 and cortisol levels with ELISA. The proposed project will provide important information regarding the neuropathogenesis of POD and POCD, and therefore is highly innovative and significant. The anticipated results will inform the design of targeted prevention and treatment strategies for POD and POCD and therefore have the potential to ultimately lead to better anesthesia and surgery care for older adults. Our proposal meets with the major mission of the National Institute of Aging to reduce the burdens of illness and disability in the elderly.