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

Tau/pTau 作为儿童麻醉/手术相关神经认知结果的生物标志物

基本信息

批准号：
9758066
负责人：
Zhongcong Xie
金额：
$ 21.8万
依托单位：
MASSACHUSETTS GENERAL HOSPITAL
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-05-01 至 2021-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9758066
关键词：
5 year old Address Age Anesthesia procedures Anesthetics Animals Area Biological Markers Blood Boston Brain Caring Catheters Child Childhood Cicatrix Clinical Research Communities Data Diagnosis Discipline of obstetrics Effectiveness Enrollment Exposure to Feasibility Studies Feces Funding Opportunities Future General Hospitals Goals Grant Health Hemorrhage Hernia Hour Hydrocephalus Impaired cognition Impairment Intervention Intravenous Knowledge Lead Massachusetts Measures Medical Mission Modeling Mus National Institute of Child Health and Human Development Neurocognitive Neurocognitive Deficit Neurons Operative Surgical Procedures Outcome Participant Patient Recruitments Patients Pediatric Hospitals Pharmaceutical Preparations Population Study Postoperative Period Prospective cohort study Protocols documentation Reconstructive Surgical Procedures Recording of previous events Research Risk Safety Saliva Salvia Sampling System Technology Testing Time United States United States National Institutes of Health Urine Venous Work cohort design high risk improved infant brain injury innovation interest neonatal hypoxic-ischemic brain injury neurocognitive test neurotoxic new technology recruit repaired retention rate sevoflurane tau Proteins tau-1

项目摘要

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.

项目摘要/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，早期接受多次麻醉和手术的儿童年龄可能会增加发生神经认知障碍的风险。因此当务之急是执行这个新的且尚未得到充分研究的领域的研究：麻醉/手术相关的神经认知障碍在儿童中。迄今为止，尚不存在用于识别神经认知障碍的生物标志物，并且这一差距知识阻碍了研究的进展。为了解决这个问题，我们提出了建立儿童麻醉/手术相关神经认知障碍的生物标志物。符合 Tau 蛋白是患有缺氧缺血性脑病的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，多次暴露于麻醉剂七氟醚增加年轻小鼠的血液 Tau 水平并诱导神经认知障碍。因此，假设拟议的研究表明，儿童的 Tau 蛋白和磷酸化 Tau 蛋白水平升高，并发展出神经认知能力多次而非单次麻醉下手术后的损伤。我们将在两个队列中测试这个假设 3至5岁儿童：（1）20名儿童接受烧伤疤痕重建手术由于多次暴露史而可能出现神经认知障碍的人用于治疗烧伤的麻醉/手术；（2）20名首次进行疝气修复手术的儿童由于缺乏暴露史而可能不会出现神经认知障碍的人麻醉/手术。在目标 1 中，我们将使用 NIH 工具箱和创新纳米束技术来确定神经认知结果以及治疗前后的血液 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：招募率、保留率、协议安全性和功率计算。在目标 2 中，我们将测量 10 名患者的尿液、粪便和唾液中的 Tau 蛋白和磷酸化 Tau 蛋白目标 1 中招募的参与者。总而言之，这些高风险但高影响力的前瞻性队列研究儿童将为申请 R01 赠款以进一步建立 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们。生物标志物的建立将有助于诊断麻醉/手术相关的疾病神经认知障碍，识别神经毒性麻醉剂，并确定干预的结果。这些研究工作最终将带来更安全的麻醉/手术护理和更好的术后结果对于儿童。因此，这些努力与融资机会公告的目标是一致的 PAR-18-214：提高现有药物对儿科或产科患者的安全性和有效性。