Burden and Risk of Neurological and Cognitive Impairment in Pediatric Sickle Cell Anemia in Uganda (BRAIN SAFE II)

摘要 中风通常发生在镰状细胞性贫血（SCA）的儿童中， 脑血管病（SCV）损伤。SCV还可导致神经认知障碍。可识别 中风风险与脑动脉血流异常有关， 经颅多普勒超声（TCD）。大多数SCA儿童生活在非洲。我们的假设是 1）贫血，炎症和营养不良的负担更高，使非洲儿童容易患上 SCA比西方更大的SCV负担; 2）在乌干达，HU治疗将预防，稳定 或提高SCV及其效果。我们建议：在目标1中，进行开放标签、单组 一项临床试验，旨在测试羟基脲治疗对一组患有以下疾病的儿童的三年影响： 乌干达2-9岁SCA患者的三个临床重要结局：TCD异常， 神经认知障碍和首次中风基线评估后，所有受试者将 开始每日约20 mg/kg的羟基脲治疗。每种疾病的频率和严重程度的变化 通过重复这三项测试，将结果与年龄调整的基线测试结果进行比较 在18个月和36个月时;在目标2中，使用 在基线和36个月时，在该队列随机选择的33%子集中进行MRI和MRA; 目的3我们将评估贫血、C反应蛋白和营养不良状态的生物标志物的变化 在羟基脲治疗期间，随着时间的推移，与基线水平相比，并确定其 与脑损伤的发展和其他发现的关系。我们提议的干预 与羟基脲是唯一的非洲为基础的试验，以广泛预防或改善的表现， SCV.

Abstract Stroke commonly occurs in children with sickle cell anemia (SCA) due to development of sickle cerebral vasculopathy (SCV) injury. SCV also can cause neurocognitive impairment. Identifiable stroke risk is associated with abnormal cerebral abnormal arterial blood flow detected by transcranial Doppler ultrasound (TCD). Most children with SCA live in Africa. Our hypotheses are that: 1) Higher burden of anemia, inflammation and malnutrition predispose African children with SCA to greater burden of SCV than in the West; 2) in Uganda, HU therapy will prevent, stabilize or improve SCV and its effects. We propose to: in Aim 1 to perform an open label, single arm clinical trial to test the three-year impact of hydroxyurea treatment for a cohort of children with SCA ages 2-9 years in Uganda on each of three clinically important outcomes: abnormal TCD, neurocognitive impairment, and first stroke. Following baseline assessments, all subjects will begin hydroxyurea therapy at about 20mg/kg daily. Changes in the frequency and severity of each outcome will be compared with age-adjusted baseline test results by repeating these three tests at 18 and 36 months; in Aim 2 to evaluate the impact of HU on structural vascular injury using MRI and MRA in a randomly selected 33% subset of this cohort at baseline and at 36 months; in Aim 3 we will assess changes to biomarkers of anemia, C-reactive protein and malnutrition status during hydroxyurea therapy, over time, compared with baseline levels, and determine their relationship to the development of brain injury and the other findings. Our proposed intervention with hydroxyurea is the only Africa-based trial to broadly prevent or ameliorate manifestations of SCV.