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

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

doi:10.1001/jamanetworkopen.2021.38515

Abstract

Cerebral malaria (CM) and severe malarial anemia (SMA) are associated with persistent neurocognitive impairment (NCI) among children in Africa. Identifying blood biomarkers of acute brain injury that are associated with future NCI could allow early interventions to prevent or reduce NCI in survivors of severe malaria. To investigate whether acutely elevated tau levels are associated with future NCI in children after CM or SMA. This prospective cohort study was conducted at Mulago National Referral Hospital in Kampala, Uganda, from March 2008 to October 2015. Children aged 1.5 to 12 years with CM (n = 182) or SMA (n = 162) as well as community children (CC; n = 123) were enrolled in the study. Data analysis was conducted from January 2020 to May 2021. CM or SMA. Enrollment plasma tau levels were measured using single-molecule array detection technology. Overall cognition (primary) and attention and memory (secondary) z scores were measured at 1 week and 6, 12, and 24 months after discharge using tools validated in Ugandan children younger than 5 years or 5 years and older. A total of 467 children were enrolled. In the CM group, 75 (41%) were girls, and the mean (SD) age was 4.02 (1.92) years. In the SMA group, 59 (36%) were girls, and the mean (SD) age was 3.45 (1.60) years. In the CC group, 65 (53%) were girls, and the mean (SD) age was 3.94 (1.92) years. Elevated plasma tau levels (>95th percentile in CC group; >6.43 pg/mL) were observed in 100 children (55%) with CM and 69 children (43%) with SMA (P < .001). In children with CM who were younger than 5 years, elevated plasma tau levels were associated with increased mortality (odds ratio [OR], 3.06; 95% CI, 1.01-9.26; P = .048). In children with CM who were younger than 5 years at both CM episode and follow-up neurocognitive testing, plasma tau levels (log10 transformed) were associated with worse overall cognition scores over 24-month follow-up (β = -0.80; 95% CI, -1.32 to -0.27; P = .003). In children with CM who were younger than 5 years at CM episode and 5 years or older at follow-up neurocognitive testing, plasma tau was associated with worse scores in attention (β = -1.08; 95% CI, -1.79 to -0.38; P = .003) and working memory (β = -1.39; 95% CI, -2.18 to -0.60; P = .001). In this study, plasma tau, a marker of injury to neuronal axons, was elevated in children with CM or SMA and was associated with mortality and persistent NCI in children with CM younger than 5 years.

Highlights

Injury to neuronal axons can occur in acute disorders, such as traumatic brain injury (TBI),[1] and in infections, such as cerebral malaria (CM),[2] where it is associated with persistent neurocognitive impairment (NCI).[3,4] Injury to a child’s brain when complex neural networks are being formed and structured can have lasting consequences, yet there are limited studies of axonal injury in children
In children with CM who were younger than 5 years, elevated plasma tau levels were associated with increased mortality
In children with CM who were younger than 5 years at both CM episode and follow-up neurocognitive testing, plasma tau levels were associated with worse overall cognition scores over 24-month follow-up (β = −0.80; 95% CI, −1.32 to −0.27; P = .003)

Summary

Introduction

Injury to neuronal axons can occur in acute disorders, such as traumatic brain injury (TBI),[1] and in infections, such as cerebral malaria (CM),[2] where it is associated with persistent neurocognitive impairment (NCI).[3,4] Injury to a child’s brain when complex neural networks are being formed and structured can have lasting consequences, yet there are limited studies of axonal injury in children. Identifying biomarkers that can gauge the initial severity of injury and predict NCI in infectionmediated brain injury, as in CM, is critical to interrupting future NCI among the millions of affected children in malaria-endemic countries.[5]. CM occurs in Plasmodium falciparum infection with coma when infected erythrocytes sequester in the brain microvasculature, leading to ischemic and/or hypoxic injury,[6,7] hemolysis and cellular damage,[7,8] inflammation,[9,10] coagulation,[11] and endothelial and/or blood-brain barrier dysfunction.[8] CM is associated with persistent NCI in survivors.[12] Severe malarial anemia (SMA), defined as hemoglobin levels of 5 g/dL or less (to convert to grams per liter, multiply by 10) with P falciparum infection, is the most common form of severe malaria in children in Africa.[13] children with SMA do not have acute neurologic deficits, they do develop long-term NCI.[14] Several infectioninduced pathophysiologic features of CM and SMA overlap with other neurologic disorders. In TBI, coagulopathy, elevated cellular injury marker lactate dehydrogenase,[15,16] and increased expression of endothelial/blood-brain barrier dysfunction markers[17,18] complicate focal axonal injury, which can impair cognitive functions.[19]

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