Cerebral Metabolic Reduction in Severe Malaria: Fluorodeoxyglucose-Positron Emission Tomography Imaging in a Primate Model of Severe Human Malaria With Cerebral Involvement

Abstract

Cerebral metabolic changes in Japanese macaques (Macaca fuscata) infected with Plasmodium coatneyi, a primate model of severe human malaria with cerebral involvement, were directly evaluated by fluorodeoxyglucose-positron emission tomography (FDG-PET). We observed diffuse and heterogeneous reduction of metabolism in the cerebral cortex in the acute phase of malaria infection. Neuropathologic examination showed preferential sequestration of parasitized red blood cells in the cerebral microvasculature. However, hemorrhagic change or necrosis was not observed in hematoxylin and eosin-stained and Nissl-stained brain tissues. This suggests that reduction of cerebral metabolism occurs before parenchymal changes appear in the brain. This may be one reason why more than half of the patients with cerebral malaria have no neurologic sequelae after recovery.

Reduced cerebral blood flow and N-acetyl aspartate in a murine model of cerebral malaria

“…Since blood flow and blood volume are generally coupled (Grubb et al 1974) the observed blood flow decreases in the current study would be consistent with cytokine-induced vasoconstriction. Studies of cerebral malaria in primate models suggest a decrease in glucose metabolism, even in the absence of changes in brain parenchyma (Sugiyama et al 2004). Thus, a decrease in blood flow could also reflect decreased cerebral metabolism since under normal conditions oxygen delivery and extraction are coupled (Marrett and Gjedde 1997).…”

Altered Regulation of Akt Signaling with Murine Cerebral Malaria, Effects on Long-Term Neuro-Cognitive Function, Restoration with Lithium Treatment

“…A little-recognized effect of CM is the metabolic dysfunction that occurs as a result of this vasculopathy and the neuronal damage which ensues. Primate studies of CM have demonstrated metabolic abnormalities in brains of infected animals with impairment in glucose uptake preceding parenchymal damage or manifestations of ECM [16]. Our previous studies in a murine model of CM demonstrating that n-acetyl aspartate (NAA), an inverse indicator of both of neuronal loss and recent or ongoing neuronal injury/dysfunction [17]–[19], is decreased in the brains of mice with CM reflects this impairment of metabolic function in affected neurons [20].…”

The Role of Animal Models for Research on Severe Malaria

“…In contrast to the PbA mouse model, the presence of cerebral microvascular iRBC sequestration through cytoadhesion in cerebral blood vessels is proven for these two macaque monkeys, and they therefore offer an alternative for examining the association of parasite-specific adhesive events in the brain with disease and underlying pathogenic mechanism(s). These models also offer the potential to use more sophisticated approaches for neuroimaging, such as functional MRI [66], which has been applied to HCM [67], [68] and in initial studies of P. coatneyi malaria [69].…”