Association of Plasma Tau With Mortality and Long-term Neurocognitive Impairment in Survivors of Pediatric Cerebral Malaria and Severe Malarial Anemia

Datta, Dibyadyuti; Bangirana, Paul; Opoka, Robert O.; Conroy, Andrea L.; Co, Katrina; Bond, Caitlin; Zhao, Yi; Kawata, Keisuke; Saykin, Andrew J.; John, Chandy C.

doi:10.1001/jamanetworkopen.2021.38515

Cited by 21 publications

(32 citation statements)

References 43 publications

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“…The mechanisms of long-term neurological impairment are unknown. Elevated levels of tau in cerebral spinal fluid and increased transcriptions of genes linked to Alzheimer’s disease may be involved [ 289 , 290 ]. In a recent study, examination of the retina revealed that leaks from endothelial cell tight junctions were associated with neurological disability, whereas larger haemorrhagic breaches in the endothelium were associated with brain swelling and death [ 291 ].…”

Section: Molecular Basis Of Severe Disease Phenotypes and Symptomsmentioning

confidence: 99%

Pathogenicity and virulence of malaria: Sticky problems and tricky solutions

Walker¹,

Rogerson

2023

Virulence

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Infections with Plasmodium falciparum and Plasmodium vivax cause over 600,000 deaths each year, concentrated in Africa and in young children, but much of the world’s population remain at risk of infection. In this article, we review the latest developments in the immunogenicity and pathogenesis of malaria, with a particular focus on P. falciparum , the leading malaria killer. Pathogenic factors include parasite-derived toxins and variant surface antigens on infected erythrocytes that mediate sequestration in the deep vasculature. Host response to parasite toxins and to variant antigens is an important determinant of disease severity. Understanding how parasites sequester, and how antibody to variant antigens could prevent sequestration, may lead to new approaches to treat and prevent disease. Difficulties in malaria diagnosis, drug resistance, and specific challenges of treating P. vivax pose challenges to malaria elimination, but vaccines and other preventive strategies may offer improved disease control.

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Section: Molecular Basis Of Severe Disease Phenotypes and Symptomsmentioning

confidence: 99%

Pathogenicity and virulence of malaria: Sticky problems and tricky solutions

Walker¹,

Rogerson

2023

Virulence

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“…The association of plasma sST2 levels with levels of plasma tau in children with CM [ 43 ] was of particular interest, because it provides a potential pathway through which IL-33/sST2 might lead to long-term neurocognitive impairment. A recent study in this same study cohort demonstrated that plasma tau concentrations were associated with cognitive deficits in children with CM but not SMA [ 44 ], suggesting that long-term neurocognitive impairment may be occurring by a different mechanism in children with CM than SMA. Similarly, in the current study, plasma sST2 levels in children with CM but not in children with SMA were associated with worse cognitive outcomes, despite children in both severe malaria groups demonstrating elevated levels of plasma sST2, suggesting that the ST2 pathway may be more important in brain injury in CM compared to SMA.…”

Section: Discussionmentioning

confidence: 99%

“…In brief, for children <5 years of age, cognitive ability was assessed by the Mullen Scales of Early Learning [36], attention by the Early Childhood Vigilance Test [37], and associative memory by the Color Object Association Test [38]. In children ≥5 years, overall cognitive ability was assessed by the summary mental processing index of the Kaufman Assessment Battery for Children, second edition (KABC-II) [39], attention by the Test of Variables of Attention (D prime measure primary outcome) [40], and working memory by the sequential processing subtest of the K-ABC-II (44). To account for differences in child age, we converted each raw score into a z-score using scores of the community control children.…”

Section: Methodsmentioning

confidence: 99%

Elevated Plasma Soluble ST2 Levels are Associated With Neuronal Injury and Neurocognitive Impairment in Children With Cerebral Malaria

Fernander

Adogamhe

Datta

et al. 2022

PAI

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Background: Murine experimental cerebral malaria studies suggest both protective and deleterious central nervous system effects from alterations in the interleukin-33 (IL-33)/ST2 pathway. Methods: We assessed whether soluble ST2 (sST2) was associated with neuronal injury or cognitive impairment in a cohort of Ugandan children with cerebral malaria (CM, n=224) or severe malarial anemia (SMA, n=193). Results: Plasma concentrations of sST2 were higher in children with CM than in children with SMA or in asymptomatic community children. Cerebrospinal fluid (CSF) sST2 levels were elevated in children with CM compared with North American children. Elevated plasma and CSF ST2 levels in children with CM correlated with increased endothelial activation and increased plasma and CSF levels of tau, a marker of neuronal injury. In children with CM who were ≥5 years of age at the time of their malaria episode, but not in children <5 years of age, elevated risk factor-adjusted plasma levels of sST2 were associated with worse scores for overall cognitive ability and attention over a 2-year follow-up. Conclusions: The study findings suggest that sST2 may contribute to neuronal injury and long-term neurocognitive impairment in older children with CM.

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“…in 2020: they found that higher CSF tau levels correlated with younger age, increased disease severity (evidenced by low glucose, kidney injury, and prolonged coma death) and an elevated CSF-to-plasma albumin ratio, a marker of BBB breakdown ( Datta et al., 2020 ). In 2021, they demonstrated that plasma tau is also raised in children with CM and is linked to mortality and long-term neurocognitive impairment in children under five ( Datta et al., 2021 ).…”

Section: Biomarkersmentioning

confidence: 99%

Diagnosis of cerebral malaria: Tools to reduce Plasmodium falciparum associated mortality

Muppidi

Wright²,

Wassmer³

et al. 2023

Front. Cell. Infect. Microbiol.

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Cerebral malaria (CM) is a major cause of mortality in Plasmodium falciparum (Pf) infection and is associated with the sequestration of parasitised erythrocytes in the microvasculature of the host’s vital organs. Prompt diagnosis and treatment are key to a positive outcome in CM. However, current diagnostic tools remain inadequate to assess the degree of brain dysfunction associated with CM before the window for effective treatment closes. Several host and parasite factor-based biomarkers have been suggested as rapid diagnostic tools with potential for early CM diagnosis, however, no specific biomarker signature has been validated. Here, we provide an updated review on promising CM biomarker candidates and evaluate their applicability as point-of-care tools in malaria-endemic areas.

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Association of Plasma Tau With Mortality and Long-term Neurocognitive Impairment in Survivors of Pediatric Cerebral Malaria and Severe Malarial Anemia

Cited by 21 publications

References 43 publications

Pathogenicity and virulence of malaria: Sticky problems and tricky solutions

Pathogenicity and virulence of malaria: Sticky problems and tricky solutions

Elevated Plasma Soluble ST2 Levels are Associated With Neuronal Injury and Neurocognitive Impairment in Children With Cerebral Malaria

Diagnosis of cerebral malaria: Tools to reduce Plasmodium falciparum associated mortality

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