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.

PROJECT NARRATIVE Neurocognitive impairment (NCI) is a common complication following traumatic brain injury (TBI) in all age ranges, worldwide. There is no current research that identifies blood-biomarkers of brain injury or risk factors including glucose abnormalities, cellular injury, and endothelial dysfunction in children at risk of NCI after TBI in resource limited low- and middle-income countries. This project will fill that gap by exploring whether a set of biomarkers can be used in pediatric TBI to determine if these biomarkers can predict NCI at 6-months, and embed this work within a framework to expand interdisciplinary research capacity in Uganda.