The Significance of Perioperative Changes in CSF tau levels in the Elderly

 描述（由申请人提供）：Tau是在神经元轴突中发现的微管相关蛋白，并且在神经元损伤后释放。脑脊液（CSF）tau水平升高可预测阿尔茨海默病的发展，CSF tau水平升高也可预测蛛网膜下腔出血和创伤性脑损伤后结局恶化。我们已经发现手术和麻醉后患者的CSF tau水平增加，并且许多研究者已经发现麻醉和手术增加tau水平并导致动物模型中的记忆缺陷（6-8）。总之，这些发现表明CSF tau水平的变化也可能与我们患者麻醉和手术后的神经认知变化相关。事实上，多项研究发现，神经认知变化（即术后谵妄和认知功能障碍）发生在相当一部分 这些疾病的主要危险因素是年龄>60岁。术后谵妄和认知功能障碍是老年患者的主要并发症：它们与执行IADL的能力下降、生活质量下降、提前退出劳动力市场和1年死亡率增加相关。然而，术后谵妄和/或认知功能障碍的潜在病理生理学尚不清楚，这阻碍了我们治疗的能力。 这些症状和改善患者的结果。在本申请中，我们将扩展我们的初步工作，通过确定这些围手术期CSF tau增加的长期轨迹，以及它们是否与老年手术患者与年龄匹配的对照组的谵妄，认知功能障碍或功能性神经连接改变相关，证明麻醉和手术后CSF tau水平显著增加。我们还将获得这些患者与对照组的CSF tau水平、IADL和生活质量变化之间关系的数据。这项研究是第一项具有充分把握度的前瞻性临床研究，旨在确定围手术期CSF tau水平变化的长期轨迹，并将这些变化与认知功能、脑连接和功能状态的变化相关联。了解这些关系可以帮助制定策略，以防止麻醉和手术对老年人的不良影响，并改善美国每年接受围手术期护理的60岁以上患者的神经认知功能。

 DESCRIPTION (provided by applicant): Tau is a microtubule-associated protein found in neuronal axons, and is released after neuronal injury. Increased cerebrospinal fluid (CSF) tau levels predict the development of Alzheimer's disease, and increased CSF tau levels also predict worsened outcomes after subarachnoid hemorrhage and traumatic brain injury. We have found increased CSF tau levels in patients after surgery and anesthesia, and numerous investigators have found that anesthesia and surgery increase tau levels and cause memory deficits in animal models (6-8). Taken together, these findings suggest the possibility that changes in CSF tau levels may also be associated with neurocognitive changes after anesthesia and surgery in our patients. Indeed, multiple studies have found neurocognitive changes (i.e. post-operative delirium and cognitive dysfunction) occur in a substantial fraction of patients after surgery and anesthesia, and a major risk factor for these disorders is age >60. Post-operative delirium and cognitive dysfunction are major complications in elderly patients: they are associated with decreased ability to perform IADLs, decreased quality of life, early exit from the work force, and increased one year mortality. Yet, the underlying pathophysiology of post-operative delirium and/or cognitive dysfunction is unclear, which impedes our ability to treat these syndromes and improve patient outcomes. In this application, we will extend our preliminary work demonstrating significant increases in CSF tau levels after anesthesia and surgery by determining the long-term trajectory of these perioperative CSF tau increases, and whether they are associated with delirium, cognitive dysfunction, or altered functional neural connectivity in elderly surgical patients vs age-matched controls. We will also obtain data on the relationship between changes in CSF tau levels, IADLs and quality of life in these patients' vs controls. This study is the first, adequately powered prospective clinical study to determine the long-term trajectory of perioperative changes in CSF tau levels, and to correlate these changes with changes in cognitive function, brain connectivity and functional status. Understanding these relationships could help develop strategies to prevent adverse effects of anesthesia and surgery in the elderly and to improve neurocognitive function for the millions of patients over age 60 who undergo perioperative care each year in the United States.