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

乌干达儿童镰状细胞贫血症的神经和认知障碍的负担和风险 (BRAIN SAFE II)

• 批准号: 10855068
• 负责人: Nancy S. Green
• 金额: $ 13.24万
• 依托单位: GLOBAL HEALTH UGANDA, LTD
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-09-11 至 2024-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10855068
• 关键词: Adult; Africa; Africa South of the Sahara; Age; Award; Axon; Biological Assay; Biological Markers; Blood; Blood specimen; Brain; Brain Infarction; Brain Injuries; British; Cells; Central Nervous System; Cephalic; Cerebral Infarction; Cerebrovascular Circulation; Cerebrum; Child; Childhood; Childhood Injury; Clinical; Clinical Trials; Cross-Sectional Studies; Cytoplasmic Protein; Diagnosis; Disease; Enrollment; Evaluation; Evaluation Studies; Funding; Hematology; Hemoglobin concentration result; Image; Impaired cognition; Impairment; Infarction; Injury; Intervention; Investigation; Light; Magnetic Resonance Imaging; Malnutrition; Manuscripts; Modality; Neurocognition; Neurocognitive Deficit; Neurologic; Neurons; Oral; Participant; Performance; Pilot Projects; Plasma; Prevention strategy; Prospective Studies; Risk; Role; Sampling; Schools; Siblings; Sickle Cell Anemia; Socioeconomic Status; Stroke; Stroke prevention; Subgroup; Testing; Uganda; Universities; biomarker panel; blood-based biomarker; brain based; caregiver education; cerebrovascular; cerebrovascular health; clinical predictors; clinically relevant; cognitive function; hydroxyurea; neurofilament; novel; prevent; prospective; prospective test; screening; sex; standardize measure; stroke risk; success; targeted imaging

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.

摘要 尽管镰状细胞性贫血（SCA）儿童的卒中预防策略可能有效， 通过风险筛查和实施针对性干预，约25%的12岁以下儿童 临床上发展为“无症状性脑梗死”（SCI）--一种基于MRI的诊断， 神经学上明显的中风SCI可能会损害认知功能和学校表现， 并增加明显中风的风险此外，筛查中风风险和降低SCA 通过改变疾病的疗法治疗脑血管损伤在亚热带地区并不普遍， 撒哈拉非洲。在我们目前在乌干达进行的羟基脲（HU）试验中， (BS2)“（1 R 01 HD 09655），我们假设HU治疗超过2.5年可以预防或 稳定SCA相关的脑损伤，包括认知功能障碍。基线MRI-MRA 在随机子样本（N= 90）中进行的成像显示超过1例脑梗死。 TCD正常者占60%。儿科非影像学筛查的替代方式 SCA脑血管损伤-例如使用基于血液的生物标志物-需要靶向 干预，特别是在撒哈拉以南非洲。在一项初步研究中，使用了我们先前交叉的血液样本- 在一项横断面研究中，我们评估了在非SCA中使用的4种基于血液的脑生物标志物， 成人用于检测脑损伤，例如中风。其中一种生物标志物，神经丝光 链（NfL）与MRI检测到的梗死显著相关，即使在患有 正常的中风风险筛查有了补充资金，在90名SCA参与者中， 入组时的MRI成像，我们建议：AIM 1。复制并更好地描述我们的发现 在入组时，参与者的NfL水平较高：（a）MRI检测的脑梗死总体 以及在进行或不进行正常中风风险筛查的亚组中（重复）和（B）受损 神经认知（表征）; AIM 2.量化NfL和其他3个大脑的纵向变化 生物标志物，并评估与脑血管损伤的关系， 与基线相比，试验中点和完成时的认知损害。协会 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 对风险筛查和MRI成像的血液替代品及其潜在用途的研究 评估干预措施对SCA儿童脑血管健康的影响。

项目成果

The Consortium on Newborn Screening in Africa for sickle cell disease: study rationale and methodology.

非洲新生儿筛查联盟的镰状细胞疾病：研究理由和方法论。

• DOI: 10.1182/bloodadvances.2022007698
• 发表时间: 2022-12-27
• 期刊: Blood advances
• 影响因子: 7.5
• 作者: Green NS;Zapfel A;Nnodu OE;Franklin P;Tubman VN;Chirande L;Kiyaga C;Chunda-Liyoka C;Awuonda B;Ohene-Frempong K;Inusa BPD;Ware RE;Odame I;Ambrose EE;Dogara LG;Oron AP;Willett C;Thompson AA;Berliner N;Coetzer TL;Novelli EM
• 通讯作者: Novelli EM