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）是两个不相关神经系统急性脑损伤的常见并发症 疾病：脑型疟疾（CM）和创伤性脑损伤（TBI）。在 5-15 岁儿童中，前 15 名中有 6 名 死亡和残疾的原因与伤害有关，其中 95% 发生在低收入和中等收入国家 （中低收入国家）。中低收入国家的 TBI 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的沉重负担几乎全部由非洲国家承担。因此，有 全球都需要可靠、无创的预后工具，能够尽早预测未来 NCI 的风险 急性脑损伤后可能发生。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）——可以成为脑损伤的有用预后工具。神经元损伤标志物 tau 和 UCH- L1、星形胶质细胞损伤标志物GFAP可预测中/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 的病理生理学具有重叠的特征： 大脑微血管损伤导致缺氧/缺血，并伴有葡萄糖异常、细胞损伤和 内皮功能障碍。这些影响相互作用，使急性脑损伤复杂化，导致认知受损 功能。我们的小组领导了研究，以确定中低收入国家儿童 CM 的生物标志物和危险因素， 但尚未针对儿科 TBI 进行此类研究，以了解有 NCI 风险的儿童的脑损伤 TBI 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 后参与 NCI 的 CM 后，他们在 NCI 中发挥了作用，并且 (2) 在 CM 的成功工作基础上继续发展 和 NCI 由我们乌干达全球健康和马凯雷雷大学研究团队的成员负责，扩大 TBI 后对 NCI 进行研究的基础设施和人员。我们假设血液生物标志物 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 可能有助于识别急性 TBI 后有 NCI 风险的儿童。我们的研究和合作目标如下： 研究目标 1 将确定儿科 CM 中升高的脑损伤生物标志物和危险因素是否升高 在儿科 TBI 中。我们将确定患有中度/重度 TBI 的儿童 (N=80) 的生物标志物是否升高 与轻度 TBI (N=120) 或对照 (N=100) 相比，以及生物标志物是否与已知危险因素相关 脑损伤。目标 2 将确定儿童 TBI 中脑损伤生物标志物升高是否与 6-NCI 相关 一个月的随访，使用以下方法进行评估：(1) K-ABC 总体认知和工作记忆，(2) TOVA (3) BNIS-C 用于认知功能筛查。我们的能力建设目标是扩大能力 通过支持适用于 NCI 的神经心理学方法培训，在乌干达开展跨学科 NCI 研究 儿童 TBI 后。这项研究将填补急性脑生物标志物和危险因素方面的知识空白 疟疾流行环境下儿童 TBI 后与 NCI 相关的损伤，同时建立全球 对各种神经系统疾病进行持续神经心理学研究的合作和能力。