Abstract
BackgroundOne-fourth of children with cerebral malaria (CM) retain cognitive sequelae up to 2 years after acute disease. The kynurenine pathway of the brain, forming neuroactive metabolites, e.g. the NMDA-receptor antagonist kynurenic acid (KYNA), has been implicated in long-term cognitive dysfunction in other CNS infections. In the present study, the association between the kynurenine pathway and neurologic/cognitive complications in children with CM was investigated.MethodsCerebrospinal fluid (CSF) concentrations of KYNA and its precursor kynurenine in 69 Ugandan children admitted for CM to Mulago Hospital, Kampala, Uganda, between 2008 and 2013 were assessed. CSF kynurenine and KYNA were compared to CSF cytokine levels, acute and long-term neurologic complications, and long-term cognitive impairments. CSF kynurenine and KYNA from eight Swedish children without neurological or infectious disease admitted to Astrid Lindgren’s Children’s Hospital were quantified and used for comparison.ResultsChildren with CM had significantly higher CSF concentration of kynurenine and KYNA than Swedish children (P < 0.0001 for both), and CSF kynurenine and KYNA were positively correlated. In children with CM, CSF kynurenine and KYNA concentrations were associated with coma duration in children of all ages (P = 0.003 and 0.04, respectively), and CSF kynurenine concentrations were associated with worse overall cognition (P = 0.056) and attention (P = 0.003) at 12-month follow-up in children ≥5 years old.ConclusionsCSF KYNA and kynurenine are elevated in children with CM, indicating an inhibition of glutamatergic and cholinergic signaling. This inhibition may lead acutely to prolonged coma and long-term to impairment of attention and cognition.
Highlights
One-fourth of children with cerebral malaria (CM) retain cognitive sequelae up to 2 years after acute disease
Informed consent was obtained from parents or guardians of study participants. 269 children with CM were enrolled in the study, of whom 69 had sufficient Cerebrospinal fluid (CSF) sample to be tested for kynurenine and kynurenic acid (KYNA) levels after aliquots were made for other testing, including pro- and anti-inflammatory cytokine testing and testing for nitric oxide levels
The included children had slightly longer coma duration, a slightly lower percentage of females, and higher levels of CSF IFN-γ and tumour necrosis factor (TNF) compared to the full study cohort (Table 1)
Summary
One-fourth of children with cerebral malaria (CM) retain cognitive sequelae up to 2 years after acute disease. The kynurenine pathway of the brain, forming neuroactive metabolites, e.g. the NMDA-receptor antagonist kynurenic acid (KYNA), has been implicated in long-term cognitive dysfunction in other CNS infections. Cerebral malaria (CM) is estimated to occur in as many as 500,000 children a year, with a high mortality and post-discharge morbidity [1]. The mechanisms that lead to the clinical presentation of CM are not entirely understood, sequestration of infected erythrocytes in cerebral capillaries and post-capillary venules and inflammatory responses in the central nervous system (CNS) both appear to play a role [2]. Tryptophan degradation along the kynurenine pathway is largely regulated by cytokines and give rise to the neuroactive kynurenic acid (KYNA), a compound that blocks the glycine co-agonist site of the N-methyl-d-aspartic acid receptor (NMDAR) as well as the cholinergic α7 nicotinic receptor (α7nAChR) [10] (Fig. 1). NMDAR, as well as α7nAChR, have an established role in cognitive functions,
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