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)是两个不相关神经系统急性脑损伤的常见并发症 疾病：脑性疟疾(CM)和创伤性脑损伤(TBI)。在5-15岁的儿童中，排名前15的人中有6人 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。 (LMIC)。低收入中等收入国家的TBI负担尚不完全清楚，但估计是高收入人群的三倍。 国家。与此同时，儿童CM的高负担几乎完全由非洲国家承担。因此，在那里 是全球对可靠的、非侵入性的预后工具的需求，这种工具最早可以预测未来NCI的风险 有可能发生在急性脑损伤后。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)-在脑损伤中可以作为有用的预后工具。神经元损伤标记物tau和Uch- L1，星形胶质细胞损伤标记物GFAP可以预测中、重度颅脑损伤后的NCI；同样，tau和UCH-L1也是 在CM中升高并预测未来的NCI。此外，CM和TBI的病理生理有重叠的特征： 脑微血管损伤导致缺氧/缺血，伴有血糖异常，细胞损伤，以及 内皮功能障碍。这些影响相互作用，使急性脑损伤复杂化，导致认知障碍。 功能。我们小组领导了一项研究，确定了LMIC环境下儿童CM的生物标记物和危险因素， 但是，还没有对儿童脑外伤进行这样的研究，以了解有非脑损伤风险的儿童的脑损伤。 在TBI之后。为了解决这一知识差距，我们建议进行一项研究，以：(1)筛选一组特定的血液生物标记物 在乌干达的TBI之后，他们在NCI中所扮演的角色，以及(2)在CM方面的成功工作的基础上，参与了CM之后的NCI 和NCI，由我们在全球健康乌干达和Makerere大学的研究团队成员提供，扩展 基础设施和人员，开展脑损伤后NCI的研究。我们假设血液中的生物标志物 急性脑损伤及其危险因素，包括血糖异常、细胞损伤和内皮功能障碍 可能有助于确定急性颅脑损伤后有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患者脑损伤的生物标志物和危险因素是否升高 在儿科脑外伤中。我们将确定中/重度脑外伤(N=80)的儿童是否有升高的生物标志物 与轻度脑外伤(N=120)或对照组(N=100)相比，如果生物标记物与已知危险因素相关 脑损伤的症状。目的2将确定儿童脑损伤生物标志物升高是否与6-6岁的NCI相关。 一个月的随访，使用：(1)K-ABC用于总体认知和工作记忆，(2)TOVA用于 注意；(3)BNIS-C用于认知功能筛查。我们的能力建设目标将扩大 乌干达的跨学科NCI研究，通过支持适用于NCI的神经心理学方法的培训 儿科颅脑损伤后。这项研究将填补关于急性脑损伤生物标志物和危险因素知识的一个关键空白。 在疟疾流行环境中，儿童脑外伤后与NCI相关的损伤，同时建立全球 在不同神经系统疾病的持续神经心理学研究方面的合作和能力。