Tau/pTau as Biomarkers of Anesthesia/Surgery-Associated Neurocognitive Outcomes in Children

项目摘要/摘要。 每年，美国有数百万儿童在麻醉下接受手术。新近人口 研究表明，在较早的时间多次接受麻醉和手术的儿童 年龄可能会增加患神经认知障碍的风险。因此当务之急是履行 这一新领域的研究：麻醉/手术相关的神经认知功能障碍 在孩子们身上。到目前为止，还没有用于识别神经认知障碍的生物标记物存在，这一差距在 知识阻碍了研究的进展。为了解决这一问题，我们提议建立 麻醉/手术相关的儿童神经认知障碍的生物标志物。与 Tau蛋白是婴幼儿缺氧缺血性脑病脑损伤的标志物 和脑积水，我们的初步研究表明，多次暴露于麻醉剂七氟醚 增加血液中牛磺酸水平，并导致幼鼠神经认知障碍。因此，假设 建议的研究是，儿童的Tau和磷酸化Tau水平升高，并发展神经认知 麻醉下进行多次但不是单一手术后的损害。我们将在两个队列中检验这一假设 3至5岁儿童：(1)20名接受重建手术修复烧伤疤痕的儿童 谁会因为多次接触铅的历史而出现神经认知功能障碍？ 用于治疗烧伤的麻醉/手术；以及(2)20名儿童首次接受疝修补术 谁可能不会因为缺乏接触史而出现神经认知功能障碍 麻醉/手术。在目标1中，我们将使用NIH工具箱和创新的纳米束技术来确定 治疗前后的神经认知结果以及血Tau和磷酸化Tau水平 麻醉/手术。我们还将收集符合条件的信息：招募比率、保留率、协议安全和 功率计算。在目标2中，我们将检测10名儿童尿液、粪便和唾液中的Tau和磷酸化Tau 在AIM 1中招募的参与者。总的来说，这些高风险但高影响的前瞻性队列研究 儿童将为申请R01赠款提供重要信息，以进一步建立Tau或 磷酸化Tau作为麻醉/手术相关神经认知功能障碍的生物标志物 孩子们。生物标志物的建立将有助于诊断麻醉/手术相关的 神经认知损害，识别神经毒性麻醉药，并确定干预结果(S)。 这些研究工作最终将带来更安全的麻醉/手术护理和更好的术后结果 为儿童准备的。因此，这些努力与融资机会公告的目标是一致的 PAR-18-214：提高儿科或产科患者现有药物的安全性和有效性。

Project Summary/Abstract. Each year, millions of children in the United States have surgery under anesthesia. Recent population studies have suggested that children who undergo multiple exposures to anesthesia and surgery at an earlier age could have an increased risk for developing neurocognitive impairment. It is therefore urgent to perform studies in this new and still under-investigated area: anesthesia/surgery-associated neurocognitive impairment in children. Thus far, no biomarker for identifying neurocognitive impairment currently exists and this gap in knowledge impedes the progress of the research. To address this issue, we have made a proposal to establish the biomarker for anesthesia/surgery-associated neurocognitive impairment in children. Consistent with the notion that Tau protein is a marker of brain injury in infants and children with hypoxic ischemic encephalopathy and hydrocephalus, our preliminary studies showed that multiple exposures to the anesthetic sevoflurane increased blood Tau levels and induced neurocognitive impairment in young mice. Thus, the hypothesis of the proposed study is that children have elevated Tau and phosphorylated Tau levels and develop neurocognitive impairment after multiple, but not single, surgeries under anesthesia. We will test this hypothesis in two cohorts of children between 3 and 5 year-old: (1) 20 children undergoing reconstruction surgery to repair burn scars who will likely develop the neurocognitive impairment due to the histories of multiple exposures to anesthesia/surgery used to treat the burn; and (2) 20 children having hernia repair surgery for the first time who will likely NOT develop the neurocognitive impairment due to a lack of history of exposure to anesthesia/surgery. In Aim 1, we will use the NIH Toolbox and innovative nanobeam technology to determine neurocognitive outcomes as well as blood Tau and phosphorylated Tau levels before and after the anesthesia/surgery. We will also collect information of eligible:recruit ratio, retention rates, protocol safety, and power calculation. In Aim 2, we will measure Tau and phosphorylated Tau in urine, feces and saliva of 10 participants recruited in Aim 1. Taken together, these high risk but high impact prospective cohort studies in children would provide important information for the application of the R01 grant to further establish Tau or phosphorylated Tau as the biomarker of the anesthesia/surgery-associated neurocognitive impairment in children. The establishment of the biomarker will help diagnose the anesthesia/surgery-associated neurocognitive impairment, identify neurotoxic anesthetics, and determine the outcomes of intervention(s). These research works will ultimately lead to safer anesthesia/surgery care and better postoperative outcomes for children. Therefore, these efforts are consistent with the goal of the funding opportunity announcement PAR-18-214: to improve the safety and effectiveness of current drugs for pediatric or obstetric patients.