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，这是由于镰状细胞贫血的发展 脑血管病(SCV)损伤。SCV还会导致神经认知障碍。可识别的 中风风险与检测到的异常脑动脉血流有关 经颅多普勒超声(TCD)。大多数患有SCA的儿童生活在非洲。我们的假设是 1)更高的贫血、炎症和营养不良的负担使非洲儿童容易患上 SCA给SCV带来比西方更大的负担；2)在乌干达，HU疗法将预防、稳定 或改善SCV及其效果。我们建议：在目标1中执行开放标签，单臂 测试羟基脲治疗对一组儿童的三年影响的临床试验 在乌干达，SCA年龄2-9岁，有三种临床重要结局：TCD异常， 神经认知障碍和首次中风。在基线评估之后，所有受试者将 开始羟基尿素治疗，每天大约20毫克/公斤。每种疾病的发生频率和严重程度的变化 通过重复这三项测试，将结果与年龄调整后的基线测试结果进行比较 在18个月和36个月；目的2评估HU对结构性血管损伤的影响 在基线和36个月时随机选择该队列中33%的子集进行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，与基线水平进行比较，并确定其 与脑损伤的发展及其他发现的关系。我们建议的干预措施 羟基脲是唯一一项广泛预防或改善糖尿病表现的非洲试验 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.