Determining Mechanisms of Cerebral Blood Flow and Metabolism Derangements in Pediatric Cerebral Malaria (FLOW) - Project Summary Cerebral malaria (CM), even with effective anti-malarial drugs, results in >450,000 deaths annually, with pediatric case fatality rates ranging from 15-30%. This equates to >1300 dead children on any given day. Long-term neurologic sequelae are identified in 30-50% of survivors. The neuropathogenesis of CM is unclear and under-investigated, but an improved understanding is necessary to develop efficacious therapies that improve outcomes. We have, in two different populations of African children with CM, identified five distinct patterns of abnormal Transcranial Doppler Ultrasound (TCD) cerebral blood flow velocities and waveforms, each with differing risks of neurologic morbidity or mortality. In a small cohort of children with CM, we have also determined that multiple different types of disrupted flow- metabolism coupling and cerebral metabolic dysfunction (luxury perfusion, misery perfusion, ischemia, mitochondrial dysfunction) occurred in 85% of patients with CM. We hypothesize that in children with CM, due to parasite and/or host factors, altered bioavailability of various vasoactive peptides results in altered cerebrovascular tone/cerebral blood flow, flow metabolism uncoupling, and cerebral metabolic dysfunction, with different combinations of abnormalities inherently associated with differing kinds and risk of neurologic injury. This project will establish altered cerebral blood flow (CBF) and metabolism as mechanistic contributors to neurologic injury in CM for the first time. Using non-targeted metabolomics, we will also determine putative peptides contributing to the different categories of abnormal CBF and metabolism. These peptides may then act as biomarkers of underlying mechanisms of injury or as therapeutic targets. Using the large amounts of data that will be captured in the proposed work, machine learning/cluster analysis will, also for the first time, determine endotypes of CM. This work is innovative in that we will establish new mechanisms of neurologic injury in CM, identify associated vasoactive peptides, and develop a novel framework that is a necessary step towards the delivery of precision medicine in CM. Additionally, the work is innovative in that we will further develop and validate a portable, non-invasive approach to measure CBF, cerebral metabolic rate of oxygen consumption, and oxygen extraction fraction, an approach that may have widespread implications for patient neuromonitoring during any acute neurocritical illness across all settings.
