Clinical and Neuroimaging Phenotypes of Neurodevelopmental Disorders inPediatric Sickle Cell Disease

摘要_ 镰状细胞病（SCD）是一种遗传性血液病，具有几种神经和发育障碍。 并发症虽然在神经系统疾病的筛查和治疗方面取得了进展， 并发症，特别是明显的缺血性卒中和无症状性脑梗死，SCD儿童仍然 在没有明显脑损伤的情况下，随着时间的推移，认知能力会恶化。SCD儿童和注意力 缺陷多动障碍（ADHD），既往无卒中或无症状性脑梗死病史，定义为 隐源性ADHD是这一脆弱人群中研究不足但很重要的一个子集。我们 假设隐源性ADHD与白色物质损伤和血浆生物标志物相关 脑损伤我们将通过以下具体目标来探讨这一假设。 目的1：确定SCD患者中隐源性ADHD的临床危险因素。 通过对儿童SCD神经发育和血液学患者的回顾性病历审查， 临床，我们将比较儿童SCD和隐源性ADHD的临床特点， SCD，既往无卒中、无症状性脑梗死或ADHD和其他神经发育障碍病史。 目的2：建立隐源性ADHD和白色脑损伤之间的联系。 我们将招募20名8至12岁患有SCD和隐源性ADHD的儿童和20名患有SCD的儿童 无中风、无症状性脑梗死或ADHD和其他神经发育障碍病史， 参与病例对照研究。受试者将接受神经发育和神经心理学检查 评估，神经影像学方案，包括DTI，动脉自旋标记，氧提取分数，和 容积成像和血样抽取。 目的3：建立隐源性ADHD和血浆生物标志物之间的关联。 使用目标2中的研究对象组的血液样本，我们将测量各种 神经元和神经胶质蛋白标志物，以鉴定神经损伤的潜在血浆生物标志物蛋白。我们 将蛋白质水平与DTI结果以及神经心理学测量进行比较。 拟议的工作将确定一个临床和神经影像学表型的儿童SCD和隐源性 注意力缺陷多动障碍，建立这一人口的一部分，脑损伤的频谱中看到的儿科SCD。校长 研究者将需要接受SCD血液学管理和神经影像学方面的额外培训 获取和分析技术，以完成拟议的项目。未来的研究将涉及使用DTI 作为疾病严重程度的衡量标准，预测认知结果，并监测临床治疗的反应。 试验研究和目标2中建立的研究组的纵向评估，以确定其 神经系统并发症

ABSTRACT _____ ________________________ ______________ _____ _ Sickle cell disease (SCD) is an inherited blood disorder with several neurological and developmental complications. While there has been progress in terms of screening and treatment of neurological complications, particularly in terms of overt ischemic stroke and silent cerebral infarct, children with SCD still have worsening cognition over time in the absence of obvious brain injury. Children with SCD and attention deficit hyperactivity disorder (ADHD) and no prior history of stroke or silent cerebral infarct, defined as cryptogenic ADHD, represent an understudied yet important subset of this vulnerable population. We hypothesize that cryptogenic ADHD is associated with white matter injury and plasma biomarkers associated with brain injury. We will explore this hypothesis through the following Specific Aims. Aim 1: Identify clinical risk factors of cryptogenic ADHD in SCD. Through a retrospective chart review of patients from pediatric SCD neurodevelopmental and hematology clinics, we will compare the clinical characteristics of children with SCD and cryptogenic ADHD to children with SCD and no prior history of stroke, silent cerebral infarct, or ADHD and other neurodevelopmental disorders. Aim 2: Establish associations between cryptogenic ADHD and white matter brain injury. We will recruit 20 children 8 to 12 years of age with SCD and cryptogenic ADHD and 20 children with SCD without a prior history of stroke, silent cerebral infarct, or ADHD and other neurodevelopmental disorders to participate in a case control study. Subjects will undergo neurodevelopmental and neuropsychological evaluations, neuroimaging protocols including DTI, arterial spin labeling, oxygen extraction fraction, and volumetric imaging, and blood sample draw. Aim 3: Establish associations between cryptogenic ADHD and plasma biomarkers. Using the blood samples from the group of research subjects in Aim 2, we will measure the levels of various neuronal and glial protein markers to identify potential plasma biomarker proteins of neurological injury. We will compare the protein levels to DTI findings as well as neuropsychological measures. The proposed work will define a clinical and neuroimaging phenotype of children with SCD and cryptogenic ADHD, establishing this population as part of the spectrum of brain injury seen in pediatric SCD. The Principal Investigator will require additional training in the hematological management of SCD and neuroimaging acquisition and analysis techniques to complete the proposed projects. Future research will involve use of DTI as a measure of disease severity, predict cognitive outcomes, and monitor response to treatment in clinical trials research and longitudinal assessment of the research group established in Aim 2 to establish their risk of future neurological complications.