Plasma angiopoietin-2 is associated with age-related deficits in cognitive sub-scales in Ugandan children following severe malaria

Abstract

Background Elevated angiopoietin-2 (Angpt-2) concentrations are associated with worse overall neurocognitive function in severe malaria survivors, but the specific domains affected have not been elucidated. Methods Ugandan children with severe malaria underwent neurocognitive evaluation a week after hospital discharge and at 6, 12 and 24 months follow-up. The relationship between Angpt-2 concentrations and age-adjusted, cognitive sub-scale z-scores over time were evaluated using linear mixed effects models, adjusting for disease severity (coma, acute kidney injury, number of seizures in hospital) and sociodemographic factors (age, gender, height-for-age z-score, socio-economic status, enrichment in the home environment, parental education, and any preschool education of the child). The Mullen Scales of Early Learning was used in children < 5 years and the Kaufman Assessment Battery for Children 2nd edition was used in children ≥ 5 years of age. Angpt-2 levels were measured on admission plasma samples by enzyme-linked immunosorbent assay. Adjustment for multiple comparisons was conducted using the Benjamini–Hochberg Procedure of False Discovery Rate. Results Increased admission Angpt-2 concentration was associated with worse outcomes in all domains (fine and gross motor, visual reception, receptive and expressive language) in children < 5 years of age at the time of severe malaria episode, and worse simultaneous processing and learning in children < 5 years of age at the time of severe malaria who were tested when ≥ 5 years of age. No association was seen between Angpt-2 levels and cognitive outcomes in children ≥ 5 years at the time of severe malaria episode, but numbers of children and testing time points were lower for children ≥ 5 years at the time of severe malaria episode. Conclusion Elevated Angpt-2 concentration in children with severe malaria is associated with worse outcomes in multiple neurocognitive domains. The relationship between Angpt-2 and worse cognition is evident in children < 5 years of age at the time of severe malaria presentation and in selected domains in older years.

Pathophysiology of Acute Kidney Injury in Malaria and Non-Malarial Febrile Illness: A Prospective Cohort Study

“…Irrespective of infection etiology, plasma Angpt-2 levels were elevated in severe AKI. These results are consistent with Angpt-2 as a marker of disease severity in critical illness [4,[25][26][27]30,[34][35][36]. Angpt-2 levels have been implicated in both severe malaria and sepsis-associated AKI [30,37].…”

Malaria Related Neurocognitive Deficits and Behavioral Alterations

“…Among children up to five years old, a greater risk for the development of impairment in motor skills, receptive and expressive language, visual reception and social interaction has been identified ( Brim et al., 2017 ; Ouma et al., 2021 ). Multiple seizures, prolonged coma and intracranial hypertension during CM appear to be related to the risk of neurological sequelae including epilepsy ( Idro et al., 2004 ; Idro et al., 2006 ; Kariuki et al., 2011 ).…”

Cerebrospinal fluid biomarkers provide evidence for kidney-brain axis involvement in cerebral malaria pathogenesis

“…Although this study focused specifically on CSF markers, previous studies from the larger cohort have shown widespread endothelial activation associated with AKI. Specifically, increases in Angiopoietin-2, associated with increased vascular permeability and AKI, was associated with increased BBB dysfunction and worse cognitive outcomes across the age spectrum ( Ouma et al, 2020 , 2021 ). Increased BBB dysfunction associated with increased systemic endothelial activation is a likely mechanism by which uremic solutes and other host and parasite proteins cross the BBB leading to oxidative stress, inflammation, and brain injury.…”