Severe Malaria And Risk to The Brain (SMART Brain)

PROJECT SUMMARY/ABSTRACT Cerebral malaria (CM) and severe malarial anemia (SMA), which together affect >1 million children annually, are associated with long-term neurodevelopmental impairment (NDI). Our data show that some systemic factors are associated with NDI in CM and SMA (e.g., endothelial dysregulation, acute kidney injury), but

others are associated with NDI CM alone (e.g., inflammatory cytokines). Our findings suggest that both shared and unique systemic pathways contribute to NDI in CM vs. SMA. While our studies to date have advanced understanding of systemic pathways that may lead to NDI in children with CM or SMA, the central nervous

system (CNS) pathways that contribute to NDI in children after CM or SMA remain unknown. In children with CM, the relationship of CNS findings to NDI has rarely been assessed, while in children with SMA, there is a paucity of CNS testing. Without data on how CNS pathways relate to NDI after CM or SMA, optimal

interventions to prevent or mitigate NDI cannot be developed. The central hypotheses of this study are that the contribution of systemic factors to NDI in CM or SMA is mediated by CNS factors, and that the specific factors and relative contributions of factors differ in CM and SMA. The proposed study will leverage investment by

Indiana University (IU) in an IU-Global Health Uganda Center for Child Neurodevelopment in Jinja, Uganda. IU will donate a Hyperfine mobile MRI and BrainAmp EEG to the Center, and provide training in MRI, EEG and TCD testing. The specific aims of this study are to: 1) identify CNS risk factors for neurodevelopment

impairment (NDI) after CM vs. SMA; 2) establish systemic risk factors for NDI after CM vs. SMA; and 3) define the pathways by which systemic and CNS factors contribute to NDI after CM vs. SMA. We will conduct the study in a cohort of 620 children 6 months to 4-years of age (120 children with CM, 300 with SMA, 100 with

uncomplicated malaria and 100 community children) who will be followed for 12 months after disease/ enrollment and have neurodevelopmental testing at 12-month follow-up. CNS pathways will be evaluated through bedside MRI testing with the Hyperfine Swoop MRI, quantitative EEG and evoked response potential

testing, and transcranial Doppler ultrasound evaluation of cerebral blood flow patterns. Systemic pathways identified in prior studies as associated with brain injury, long-term neurodevelopment or both will be tested for reproducibility. Finally, established and novel statistical models will be used to identify systemic and CNS risk

factors and mediation pathways for long-term NDI. We expect that unique systemic and CNS pathways will lead to NDI in CM compared to SMA. Identification of these pathways will allow for targeted interventions to prevent NDI in the millions of children with CM or SMA. The study will constitute a major advance in the

understanding of the pathophysiology of brain injury and recovery in severe malaria, and provide critical new information on brain biology that will inform studies of other childhood CNS diseases.