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

项目概要/摘要。 每年，美国有数百万儿童在麻醉下接受手术。最近人口 研究表明，在较早的时间接受多次麻醉和手术的儿童， 年龄可能会增加神经认知障碍的风险。因此，迫切需要执行 麻醉/手术相关神经认知功能障碍这一新领域的研究仍在研究之中 小儿到目前为止，目前还不存在用于识别神经认知障碍的生物标志物，并且在神经认知障碍的诊断中存在这种差距。 知识阻碍了研究的进展。为解决这一问题，我们提出了一项建议， 儿童麻醉/手术相关神经认知障碍的生物标志物。符合 Tau蛋白是缺氧缺血性脑病婴儿和儿童脑损伤的标志物 和脑积水，我们的初步研究表明， 增加血液Tau水平并诱导幼年小鼠的神经认知障碍。因此， 一项拟议的研究是，儿童的Tau和磷酸化Tau水平升高， 多次（而不是单次）麻醉手术后的损伤。我们将在两个队列中检验这一假设 3 - 5岁儿童：（1）20名接受修复烧伤疤痕重建手术的儿童 他们可能会因为多次暴露于 20例首次行疝修补术的患儿 由于缺乏接触史， 麻醉/手术。在目标1中，我们将使用美国国立卫生研究院和创新的纳米束技术来确定 神经认知结果以及血液Tau和磷酸化Tau水平之前和之后， 麻醉/手术。我们还将收集合格的信息：招募率、保留率、方案安全性和 功率计算在目标2中，我们将测量10名受试者的尿液、粪便和唾液中的Tau和磷酸化Tau。 目标1中招募的参与者。总之，这些高风险但高影响的前瞻性队列研究， 儿童将为申请R 01补助金提供重要信息，以进一步建立Tau或 磷酸化Tau作为麻醉/手术相关神经认知障碍的生物标志物， 孩子生物标志物的建立将有助于诊断麻醉/手术相关性 神经认知障碍，识别神经毒性麻醉剂，并确定干预的结果。 这些研究工作将最终导致更安全的麻醉/手术护理和更好的术后结果 是为了带孩子因此，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当前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.