Blood-Biomarkers and Risk Factors of Acute Brain Injury associated with Neurodisability in Ugandan Children [BRAIN-Child]

乌干达儿童神经功能障碍相关的急性脑损伤的血液生物标志物和危险因素 [BRAIN-Child]

• 批准号: 10682592
• 负责人: Paul Bangirana
• 金额: $ 17.48万
• 依托单位: INDIANA UNIV-PURDUE UNIV AT INDIANAPOLIS
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-08-15 至 2024-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10682592
• 关键词: Acute; Acute Brain Injuries; Address; Adult; African; Age; Astrocytes; Attention; Biological Markers; Blood; Brain Hypoxia-Ischemia; Brain Injuries; Cerebral Malaria; Child; Childhood; Childhood Injury; Cognition; Cognitive; Collaborations; Communities; Complication; Consult; Country; Data; Disease; Educational workshop; Fostering; Functional disorder; Future; Glial Fibrillary Acidic Protein; Glucose; Goals; Human Resources; Impaired cognition; Income; Infrastructure; Injury; Interdisciplinary Study; Knowledge; Malaria; Memory; Methods; Neurocognitive Deficit; Neuronal Injury; Neurons; Neuropsychology; Outcome; Patient-Focused Outcomes; Proteins; Research; Research Design; Resources; Risk; Risk Factors; Role; Short-Term Memory; Site; Students; Supervision; Survivors; Technology; Therapeutic Intervention; Training; Training Support; Traumatic Brain Injury; UCHL1 gene; Uganda; Universities; Work; Youth; biomarker identification; brain parenchyma; burden of illness; cell injury; cerebral microvasculature; cognitive function; disability; endothelial dysfunction; follow-up; global health; low and middle-income countries; malaria infection; member; mild traumatic brain injury; mortality; nervous system disorder; new therapeutic target; pediatric traumatic brain injury; prevent; prognostic tool; risk mitigation; risk prediction; screening; symposium; tau Proteins; virtual

ABSTRACT Neurocognitive impairment (NCI) is a common complication of acute brain injury in two unrelated nervous system disorders: cerebral malaria (CM) and traumatic brain injury (TBI). In children ages 5–15 years, six of the top 15 causes of mortality and disability are injury-related, and 95% of these occur in low- and middle- income countries (LMICs). The burden of TBI in LMICs is not fully known but is estimated at three times more than in high-income countries. Meanwhile, the high burden of pediatric CM is borne almost exclusively by African nations. Thus, there is a global need for reliable, noninvasive prognostic tools that can predict the risk of future NCI as early as possible after acute brain injury. Biomarkers of brain injury—proteins expressed in the brain parenchyma (by neurons and astrocytes)—can be useful prognostic tools in brain injury. Neuronal injury markers tau and UCH- L1, and astrocyte injury marker GFAP can predict NCI after moderate/severe TBI; likewise, tau and UCH-L1 are elevated in CM and predict future NCI. Further, the pathophysiologies of CM and TBI have overlapping features: injury to the brain’s microvasculature leads to hypoxia/ischemia with glucose abnormalities, cellular injury, and endothelial dysfunction. These effects interact to complicate acute brain injury resulting in impaired cognitive functions. Our group has led studies identifying biomarkers and risk factors of pediatric CM in an LMIC setting, but no such research has been conducted for pediatric TBI to understand brain injury in children at risk of NCI after TBI. To address this gap in knowledge, we propose a study to: (1) screen a specific set of blood biomarkers implicated in NCI after CM for their roles in NCI after TBI in Uganda and (2) build on the successful work on CM and NCI by members of our research team within Global Health Uganda and Makerere University, expanding infrastructure and personnel to conduct research on NCI after TBI. We hypothesize that blood biomarkers of acute brain injury and risk factors including glucose abnormalities, cellular injury, and endothelial dysfunction may help identify children at risk of NCI after acute TBI. Our research and collaboration aims are as follows: Research aim 1 will determine if biomarkers and risk factors of brain injury elevated in pediatric CM are elevated in pediatric TBI. We will determine if children with moderate/severe TBI (N=80) have elevated biomarkers compared to mild TBI (N=120) or controls (N=100) and if the biomarkers are associated with known risk factors of brain injury. Aim 2 will determine if elevated brain injury biomarkers in pediatric TBI correlate with NCI at 6- month follow-up, to be assessed using: (1) K-ABC for overall cognition and working memory, (2) TOVA for attention, and (3) BNIS-C for cognitive function screening. Our capacity building aim will expand capacity for interdisciplinary NCI research in Uganda by supporting training in neuropsychological methods that apply to NCI after pediatric TBI. This study will fill a key gap in knowledge regarding biomarkers and risk factors of acute brain injury associated with NCI after pediatric TBI in a malaria-endemic setting, while simultaneously building global collaborations and capacity for sustained neuropsychological research in diverse nervous system disorders.

摘要 神经认知功能障碍（NCI）是急性脑损伤后常见的并发症 疾病：脑疟疾（CM）和创伤性脑损伤（TBI）。在5-15岁的儿童中，前15名中有6名 死亡和残疾的原因与伤害有关，其中95%发生在中低收入国家 （中低收入国家）。低收入国家的创伤性脑损伤负担尚不完全清楚，但估计是高收入国家的三倍。 国家与此同时，儿科CM的高负担几乎完全由非洲国家承担。因此 全球需要可靠的、非侵入性的预后工具，可以在早期预测未来NCI的风险。 可能是急性脑损伤后脑损伤的生物标志物-脑实质中表达的蛋白质（通过 神经元和星形胶质细胞）-可以是脑损伤中有用的预后工具。神经元损伤标记物tau和UCH- L1和星形胶质细胞损伤标记物GFAP可以预测中度/重度TBI后的NCI;同样，tau和UCH-L1也可以预测中度/重度TBI后的NCI。 CM升高并预测未来的NCI。此外，CM和TBI的病理生理学具有重叠的特征： 脑微血管系统的损伤导致缺氧/缺血，伴有葡萄糖异常、细胞损伤， 内皮功能障碍这些影响相互作用，使急性脑损伤复杂化，导致认知功能受损。 功能协调发展的我们的团队领导了在LMIC环境中确定儿科CM的生物标志物和风险因素的研究， 但是还没有对儿童TBI进行这样的研究，以了解有NCI风险的儿童的脑损伤 脑外伤后。为了解决这一知识差距，我们提出了一项研究：（1）筛选一组特定的血液生物标志物 在乌干达TBI后NCI中的作用，以及（2）在CM成功工作的基础上， 我们的研究团队成员在全球卫生乌干达和马凯雷雷大学，扩大 基础设施和人员在TBI后对NCI进行研究。我们假设， 急性脑损伤和危险因素，包括血糖异常、细胞损伤和内皮功能障碍 可能有助于识别急性TBI后NCI风险的儿童。我们的研究和合作目标如下： 研究目的1将确定儿童CM中升高的脑损伤生物标志物和风险因素是否升高 儿科创伤性脑损伤我们将确定中度/重度TBI儿童（N=80）的生物标志物是否升高 与轻度TBI（N=120）或对照组（N=100）相比，如果生物标志物与已知的风险因素相关， 脑损伤目标2将确定儿童TBI中升高的脑损伤生物标志物是否与6- 10岁时的NCI相关。 随访1个月，使用以下方法进行评估：（1）K-ABC用于总体认知和工作记忆，（2）TOVA用于 （3）BNIS-C用于认知功能筛查。我们的能力建设目标将扩大能力， 通过支持适用于NCI的神经心理学方法的培训，在乌干达进行跨学科的NCI研究 在小儿创伤性脑损伤后这项研究将填补有关急性脑损伤的生物标志物和危险因素的知识空白。 在疟疾流行的环境中，儿童TBI后与NCI相关的损伤，同时建立全球 在不同的神经系统疾病的持续神经心理学研究的合作和能力。