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

摘要 尽管镰状细胞性贫血(SCA)儿童的卒中预防策略潜在有效 通过风险筛查和实施有针对性的干预，约25%的12岁以下儿童 临床上出现“无症状性脑梗塞”(SCI)--这是一种基于MRI的诊断，与 神经学上明显的中风。SCIS可能会损害认知功能和学习成绩， 并增加明显中风的风险。此外，筛查中风风险和减少SCA 通过改变疾病治疗而造成的脑血管损伤在亚健康人群中并不普遍 撒哈拉非洲(SSA)。在我们目前在乌干达的羟基脲(HU)试验中，“大脑安全II” (BS2)“(1R01HD09655)，我们假设HU治疗超过2.5年可能预防或 稳定SCA相关的脑损伤，包括认知功能障碍。基线MRI-MRA 在随机抽样(N=90)中进行成像，证实有1个以上的脑梗塞 60%，多数患者TCD正常。儿科非影像筛查的替代模式 SCA脑血管损伤--例如使用基于血液的生物标记物--是有针对性的 干预，特别是对SSA的干预。在一项初步研究中，使用了我们之前交叉采集的血液样本- 横断面研究，我们评估了4个基于血液的脑生物标记物，它们用于非SCA 成人用于检测脑损伤，例如中风。其中一个生物标志物水平是神经丝状光线 链(NFL)与MRI检测到的脑梗塞显著相关，即使在患有 中风风险的正常筛查。在补充资金的情况下，在90名政制事务局局长的参与者中 在登记时，我们建议：目标1.复制和更好地描述我们的研究结果 登记时NFL水平较高的参与者：(A)MRI检测到的总体脑梗塞 在有或没有正常中风风险筛查(重复)和(B)受损的亚组中 神经认知(特征)；目的2.量化NFL和其他3个大脑的纵向变化 在HU治疗期间的生物标志物，并评估与脑血管损伤和 与基线相比，试验中点和完成时的认知损害。联谊会 NFL和其他脑生物标志物与SCA脑血管损伤之间的关系将进一步支持 风险筛查和核磁共振成像的血液替代品的研究及其潜在用途 评估干预措施对SCA儿童脑血管健康的影响。

Abstract Despite potentially effective stroke prevention strategy for children with sickle cell anemia (SCA) through risk screening and implementing targeted intervention, about 25% under age 12 develop clinically "silent cerebral infarcts" (SCI) - an MRI-based diagnosis not associated with neurologically apparent strokes. SCIs may impair cognitive function and school performance, and increase risk for overt stroke. Moreover, screening for stroke risk and reduced SCA cerebrovascular injury through disease-altering therapies are not widely available in Sub- Saharan Africa (SSA). In our current trial in Uganda of hydroxyurea (HU), “BRAIN SAFE II (BS2)” (1R01HD09655), we hypothesize that HU therapy over 2.5 years may prevent or stabilize SCA-associated brain injury, including cognitive dysfunction. Baseline MRI-MRA imaging performed in a random sub-sample (N= 90), demonstrated >1 cerebral infarcts in over 60%, of whom most had normal TCD. Alternative non-imaging screening modalities for pediatric SCA cerebrovascular injury – e.g. using blood-based biomarkers - are needed for targeted intervention, especially in SSA. In a pilot study using blood samples from our prior cross- sectional study, we assessed 4 blood-based brain biomarkers which are used in non-SCA adults for detecting brain injury, e.g. stroke. One of these biomarker levels, neuro-filament light chain (NfL), was significantly associated with MRI-detected infarcts, even among children with normal screening for stroke risk. With supplemental funding, in the 90 SCA participants with MRI-imaging at enrollment, we propose to: AIM 1. Replicate and better characterize our findings of higher NfL levels in participants at enrollment with: (a) MRI-detected cerebral infarcts overall and in sub-groups with or without normal stroke risk screening (replicate) and (b) Impaired neurocognition (characterize); AIM 2. Quantify longitudinal changes in NfL and the 3 other brain biomarkers while on HU therapy, and assess the relationship to cerebrovascular injury and cognitive impairment at trial midpoint and completion compared to baseline. Associations between NfL and other brain biomarkers and SCA cerebrovascular injury would support further investigation into blood-based alternatives to risk screening and MRI imaging, and potential use in assessing impact of interventions on cerebrovascular health in children with SCA.