Malarial Impact on Neurobehavioral Development (MIND)

摘要 据估计，脑型疟疾（CM）和严重疟疾性贫血（SMA）影响了50多万儿童和1-5 每年在撒哈拉以南非洲分别有100万儿童。我们对乌干达儿童的研究 表明CM和SMA与显著的神经行为损害（NBI）相关。我们的数据 提示：1）CM和SMA相关的NBI的发病机制不同; 2）CM和SMA导致的NBI比SMA更大。 其他形式的严重疟疾; 3）NBI持续至少2年;和4）几种宿主免疫应答 在≥5岁的儿童中，这些因素与NBI相关，但在<5岁的儿童中不相关。回顾性 研究表明，NBI在CM后长达9年，但没有关于NBI持续时间的前瞻性研究。 CM后NBI超过2年，或其他形式严重的慢性认知或心理健康后遗症 疟疾，如SMA。我们前瞻性地在3项评估NB后遗症的研究中招募了> 1，700名儿童， 严重的疟疾这些研究提供了一个独特的队列，以评估5种主要形式的 严重疟疾对长期认知和心理健康的影响。我们建议对其中约1,100名儿童进行研究4-20 严重疟疾发作10年后，回答3个关键问题：1）严重疟疾的NB后遗症 从儿童期持续到成年期，它们是否因严重疟疾的形式而有所不同？2)什么是长- 这些后遗症的长期功能和经济成本？3)长期NBI的风险因素是什么， 有些因素只有在孩子长大并获得特定的认知技能时才能识别？这项研究的中心 假设是：1）严重疟疾后的NBI因严重疟疾类型和发病年龄而异; 2）这些 损伤具有重大的社会、经济和生活质量成本; 3）损伤的风险因素可能 只有在5岁以后才变得明显。我们的研究有三个目的。目的1是确定持续时间和年龄- 严重疟疾从儿童期到成年早期的神经行为后遗症的具体表现。 目的2是确定重症疟疾神经行为后遗症的功能和经济成本。目标3 是为了确定预测长期神经行为的代谢，免疫和寄生因素， 严重疟疾后的功能障碍。我们预测，与疟疾相关的严重NBI将持续到2020年。 青少年和年轻的成年人，导致巨大的社会和经济成本， 损伤的风险因素只有在孩子长大后才能检测出来，并且可以检测出更高的水平。 skills.确定年轻时存在的风险因素将有助于早期干预。我们希望这项研究 将构成对神经行为、功能和社会经济的理解的重大进步。 严重疟疾的成本，并形成重点干预措施的基础， 数百万患有严重疟疾的儿童的神经行为障碍。

ABSTRACT Cerebral malaria (CM) and severe malarial anemia (SMA) are estimated to affect >500,000 children and 1-5 million children, respectively, in sub-Saharan Africa annually. Our research studies in Ugandan children have demonstrated that CM and SMA are associated with significant neurobehavioral impairment (NBI). Our data suggest that: 1) the pathogenesis of CM and SMA-related NBI differs; 2) CM and SMA lead to greater NBI than other forms of severe malaria; 3) NBI persists for at least 2 years; and 4) several host immune response factors are associated with NBI in children ≥5 years of age but not in children <5 years of age. Retrospective studies suggest NBI is present up to 9 years after CM, but there are no prospective studies on the duration of NBI after CM beyond 2 years, or on chronic cognitive or mental health sequelae of other forms of severe malaria such as SMA. We prospectively enrolled >1,700 children in 3 studies that assessed NB sequelae of severe malaria. These studies provide a unique cohort in which to assess the effects of the 5 major forms of severe malaria on long-term cognition and mental health. We propose to study ~1,100 of these children 4-20 years after their severe malaria episode, to answer 3 key questions: 1) Do NB sequelae of severe malaria persist through childhood into adulthood, and do they differ by form of severe malaria? 2) What are the long- term functional and economic costs of these sequelae? 3) What are the risk factors for long-term NBI, and are some factors identifiable only as children grow older and acquire specific cognitive skills? The study’s central hypotheses are that: 1) NBI after severe malaria differs by type of severe malaria and age at episode; 2) these impairments have significant social, economic and quality of life costs; and 3) risk factors for impairment may become apparent only after 5 years of age. Our study has 3 Aims. Aim 1 is to establish the duration and age- specific manifestations of neurobehavioral sequelae of severe malaria from childhood to early adulthood. Aim 2 is to determine the functional and economic costs of neurobehavioral sequelae of severe malaria. Aim 3 is to identify the metabolic, immunologic and parasitic factors predictive of long-term neurobehavioral and functional impairment after severe malaria. We predict that severe malaria-related NBI will persist into adolescence and young adulthood, leading to substantial societal and economic costs, and that a number of risk factors for impairment will be detectable only as the child gets older and can be tested for higher level skills. Identification of risk factors present at a young age will allow for early intervention. We expect the study will constitute a major advance in the understanding of the neurobehavioral, functional and socioeconomic costs of severe malaria, and form the basis for focused interventions that can prevent or decrease neurobehavioral impairment in the millions of children who suffer from severe malaria.