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.

抽象的 神经认知障碍（NCI）是两个无关神经系统中急性脑损伤的常见并发症 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个 死亡率和残疾的原因是与伤害有关的，其中95％在低收入国家和中等收入国家中发生 （LMIC）。 LMIC中TBI的Burnen尚不完全清楚，但估计是高收入的三倍 国家。同时，小儿广告的高燃烧几乎完全由非洲国家诞生。那，那里 全球需要可靠的无创预后工具，可以预测未来NCI的风险 急性脑损伤后可能。脑损伤的生物标志物 - 在脑实质中表达的蛋白质（通过 神经元和星形胶质细胞） - 在脑损伤中可能是有用的预后工具。神经元损伤标记tau和Uch- L1和星形胶质细胞损伤标记GFAP可以预测中度/重度TBI后NCI；同样，tau和uch-l1是 CM升高并预测未来的NCI。此外，CM和TBI的病理生理具有重叠的特征： 大脑微举行的损伤导致缺氧/缺血异常，葡萄糖异常，细胞损伤和 内皮功能障碍。这些影响与复杂的急性脑损伤相互作用，导致认知受损 功能。我们的小组领导的研究确定了在LMIC环境中的小儿CM的生物标志物和危险因素， 但是，尚未针对小儿TBI进行此类研究，以了解NCI风险的儿童的脑损伤 在TBI之后。为了解决知识的这一差距，我们提出了一项研究：（1）筛选一组特定的血液生物标志物 CM之后在NCI实施，因为其在乌干达TBI之后在NCI中的角色和（2）在CM上成功的工作建立 我们的NCI由我们的全球健康乌干达和马克雷尔大学的研究团队成员扩展 在TBI之后，基础设施和人员对NCI进行研究。我们假设该血液生物标志物的 急性脑损伤和危险因素，包括葡萄糖异常，细胞损伤和内皮功能障碍 急性TBI后可能有助于识别有NCI风险的儿童。我们的研究和协作目的如下： 研究目标1将确定小儿CM升高的生物标志物和脑损伤的危险因素是否升高 在小儿TBI中。我们将确定中度/重度TBI（n = 80）的儿童是否具有升高的生物标志物 与轻度TBI（n = 120）或对照（n = 100）相比，如果生物标志物与已知危险因素相关 脑损伤。 AIM 2将确定小儿TBI中脑损伤生物标志物的升高是否与6--的NCI相关 每月随访，将使用：（1）K-ABC进行整体认知和工作记忆，（2）TOVA 注意，（3）BNIS-C进行认知功能筛选。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，乌干达的NCI跨学科研究 小儿TBI之后。这项研究将填补有关生物标志物和急性大脑危险因素知识的关键空白 小儿TBI后与NCI相关的伤害在疟疾末端环境中，同时建立全球 在多种神经系统疾病中持续的神经心理学研究的合作和能力。