Plasmodium falciparum malaria is a major cause of mortality and morbidity in the developing world and cerebral malaria (CM), its most severe form, accounts for the majority of malaria-associated deaths. The pathophysiology and the molecular mechanisms underlying this complex neurologic syndrome are still poorly understood, which has hindered the development of effective adjunct therapies. For this exploratory project, we will leverage our International Center of Excellence for Malaria Research in India to expand the unique ongoing MRI investigations in both adults and pediatric CM patients admitted at Ispat General Hospital (IGH) in Rourkela, and apply advanced magnetic resonance imaging techniques in the first comprehensive vascular imaging analysis of its kind. Novel findings suggest that reversible cerebral vasoconstriction syndrome (RCVS) alone or in combination with posterior reversible encephalopathy syndrome (PRES) may play a role in the pathophysiology of CM. Here, we propose to investigate the occurrence, frequency and amplitude of cerebral vasoconstriction in CM patients at IGH by combining for the first time serial vascular imaging including time-of-flight and phase-contrast magnetic resonance angiography , as well as cerebral perfusion measurements and assessment of subtle blood-brain barrier disruption. By comparing our imaging results with plasma levels of endothelin-1 (ET-1), angiopoietin-1(Ang-1), Ang-2 and free heme in our patients, we will evaluate their clinical relevance as biomarkers of RCVS in CM. The primary outcome of this project will be a better understanding of the different pathogenetic processes involved in pediatric and adult CM, which will guide the development of new adjunct therapies.
Cerebral malaria (CM), the most severe complication of Plasmodium falciparum infection, is often fatal and represents a major public health burden. A recent case-study suggests that cerebral vasoconstriction contributes to the pathogenesis of CM. We aim to leverage our ongoing magnetic resonance imaging study in India to apply a new range of advanced neuroimaging techniques to map out and quantify cerebral vasoconstriction for the first time in a cohort of CM patients, and evaluate the clinical relevance of known vasoconstrictors and endothelial permeability factors as biomarkers of this phenomenon. .
