Malaria is a leading cause of morbidity and mortality in children in sub-Saharan Africa, causing >1 million deaths annually. Our studies at Mulago Hospital, Kampala, Uganda document that 21.6% of children >5 years of age who survive CM have cognitive deficits 6 months after hospitalization. However, the effects of CM on cognition in younger children have not been prospectively characterized, and the underlying question of what leads to cognitive deficits in children with CM remains unanswered. The central hypothesis of this study is that specific immunologic/inflammatory and genetic factors lead to cognitive and neurologic deficits in a subset of children with CM.
Our specific aims are to: 1) Establish the areas, frequency and severity of cognitive and neurologic function affected by cerebral malaria in children of different ages (18 months-4 years, 5-12 years). We will compare areas, frequency and age-adjusted levels of cognitive and neurologic deficits in children with CM in 2 age groups (18 mo-4 years, 5-12 years) to healthy children and children with severe malarial anemia in these age groups, at discharge and in follow-up. Cognitive function in the areas of attention, reasoning, memory, motor function and language will be assessed. 2) Identify the immunologic/inflammatory and genetic factors associated with cognitive and neurologic deficits in children with cerebral malaria.We will compare the presence/level of specific risk factors in children with CM age 18 months-12 years to the presence/level of cognitive and neurologic deficits at discharge and in follow-up. To test that the genetic and plasma/ leukocyte inflammatory factors are specific for CM, they will also be assessed in children with severe malarial anemia (without CNS involvement) and in community controls. We will assess: a) markers of the components of endovascular inflammation (e.g. plasma levels of VCAM-1. ICAM-1, endothelial microparticles, endothelin-1, reactive oxygen (ROS) and nitrogen (RNS) species, and pro- and anti- inflammatory cytokines, and leukocyte heme oxygenase-1 (HO-1) expression;b) markers of central nervous system inflammation (e.g., CSF levels of ROS and RNS, pro- and anti-inflammatory cytokines, quinolinic and kynurenic acid, and tau and neuron- specific enolase),;and c) genetic polymorphisms in apolipoprotein-E and HO-1, which may affect cognition through alterations in CNS immune responses. We expect that this study will constitute a major advance in the knowledge of CM pathogenesis and long-term outcomes, and will lead to clinical trials of interventions to prevent cognitive and neurologic sequelae in children with CM. We also expect this study will provide insights and hypothesis generating information for researchers involved in investigating the many other types of non- traumatic brain injury and recovery in the developed and developing world.

Public Health Relevance

The present study will assess how frequently children develop cognitive impairment after cerebral malaria, and what factors might lead to this impairment. We believe that our study findings will be the first step in developing interventions to prevent the brain injury that causes cognitive impairment. The study therefore has the potential to lead to the prevention of brain injury in hundreds of thousands of children in sub-Saharan Africa.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS055349-05
Application #
8261923
Study Section
Special Emphasis Panel (ZRG1-ICP2-B (51))
Program Officer
Hirtz, Deborah G
Project Start
2008-04-15
Project End
2014-01-14
Budget Start
2012-04-01
Budget End
2014-01-14
Support Year
5
Fiscal Year
2012
Total Cost
$529,735
Indirect Cost
$104,548
Name
University of Minnesota Twin Cities
Department
Pediatrics
Type
Schools of Medicine
DUNS #
555917996
City
Minneapolis
State
MN
Country
United States
Zip Code
55455
Idro, Richard; Kakooza-Mwesige, Angelina; Asea, Benjamin et al. (2016) Cerebral malaria is associated with long-term mental health disorders: a cross sectional survey of a long-term cohort. Malar J 15:184
Brand, Nathan R; Opoka, Robert O; Hamre, Karen E S et al. (2016) Differing Causes of Lactic Acidosis and Deep Breathing in Cerebral Malaria and Severe Malarial Anemia May Explain Differences in Acidosis-Related Mortality. PLoS One 11:e0163728
Bangirana, Paul; Opoka, Robert O; Boivin, Michael J et al. (2016) Neurocognitive domains affected by cerebral malaria and severe malarial anemia in children. Learn Individ Differ 46:38-44
Shabani, Estela; Opoka, Robert O; Bangirana, Paul et al. (2016) The endothelial protein C receptor rs867186-GG genotype is associated with increased soluble EPCR and could mediate protection against severe malaria. Sci Rep 6:27084
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Hanisch, Benjamin R; Bangirana, Paul; Opoka, Robert O et al. (2015) Thrombocytopenia May Mediate Disease Severity in Plasmodium falciparum Malaria Through Reduced Transforming Growth Factor Beta-1 Regulation of Proinflammatory and Anti-inflammatory Cytokines. Pediatr Infect Dis J 34:783-8
Shabani, Estela; Opoka, Robert O; Idro, Richard et al. (2015) High plasma erythropoietin levels are associated with prolonged coma duration and increased mortality in children with cerebral malaria. Clin Infect Dis 60:27-35
Cusick, Sarah E; Opoka, Robert O; Lund, Troy C et al. (2014) Vitamin D insufficiency is common in Ugandan children and is associated with severe malaria. PLoS One 9:e113185
Bangirana, Paul; Opoka, Robert O; Boivin, Michael J et al. (2014) Severe malarial anemia is associated with long-term neurocognitive impairment. Clin Infect Dis 59:336-44
Bangirana, Paul; Menk, Jeremiah; John, Chandy C et al. (2013) The association between cognition and academic performance in Ugandan children surviving malaria with neurological involvement. PLoS One 8:e55653

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