MR-Derived Cerebral Blood Flow and Oxygen Metabolism to Stratify Stroke Risk in Pediatric Sickle Cell Disease

 描述（由申请人提供）：作为最常见的遗传性血液病，镰状细胞病（SCD）影响400个非洲裔美国人中的一个。这种疾病改变了红细胞的形状，导致全身性的多器官效应，使中位预期寿命降低到40岁。在其并发症中，缺血性中风是常见的和致残的，始于婴儿期-“显性”中风导致急性神经功能缺损，而“隐性”中风表现为智力下降。预防中风的筛查方法--经颅多普勒超声（TCD）有助于选择SCD儿童，这些儿童将受益于输血治疗，作为减少中风发生的一种手段。然而，不幸的是，筛查机制有几个局限性，包括它对预测那些有无症状中风风险的人不敏感。此外，近一半的儿童继续有复发性显性中风，无症状中风，和/或进行性血管病变，尽管筛选和输血。因此，需要一种改进的生物标志物来对SCD儿童的卒中风险进行分层。在这个建议中，我们假设，大脑的血流动力学和代谢代偿反应，以减少血液中的氧含量在SCD将揭示机制，导致缺血性中风。我们将确定MR衍生的脑血流量（CBF）和氧提取分数（OEF），作为这种血流动力学和代谢应激的指标，是否可以提供新的工具来分层SCD儿童的卒中风险，以便治疗可以个性化，确定那些风险最高的患者进行更积极的治疗，同时避免那些风险较低的患者出现任何不必要的治疗不良反应。我们假设在脑组织水平上测量CBF和OEF比TCD测量血流速度更敏感和特异。在过去的15年里，我们已经开发出一种新的，非侵入性的MR方法来测量脑OEF在体素水平。到目前为止，OEF只能通过PET成像测量，因此由于辐射风险，从未在SCD儿童中进行过研究。目标1.确定与同胞对照组相比，SCD儿童的CBF和OEF是否增加，表明卒中风险升高。目标2。确定在SCD儿童血管病变亚组中，半球CBF和OEF是否表现出最大变化，表明受累血管区域卒中风险非常高。目标3。为了确定输血 治疗使CBF和OEF正常化，从而减少血液动力学和代谢应激，作为降低中风风险的手段。目标4。确定在3年随访MRI中，CBF和/或OEF升高预测未来卒中的效果是否优于TCD。

 DESCRIPTION (provided by applicant): As the most common inherited blood disorder, sickle cell disease (SCD) affects one in 400 African-Americans. The disorder alters the shape of the red blood cell, leading to systemic, multi-organ effects, reducing the median life expectancy to 40 years. Among its complications, ischemic stroke is common and disabling, beginning in infancy - "overt" strokes cause acute neurological deficits and "silent" strokes manifest as intellectual decline. A screening method to prevent strokes, transcranial Doppler ultrasound (TCD), is helpful for selecting SCD children who will benefit from transfusion therapy as a means to reduce stroke occurrence. Unfortunately, however, the screening mechanism has several limitations including its insensitivity for predicting those at risk for silent strokes. Moreover, nearly half of children continue to have recurrent overt strokes, silent strokes, and/or progressive vasculopathy, despite screening and being placed on transfusions. Thus, an improved biomarker for stratifying stroke risk in SCD children is needed. In this proposal, we hypothesize that the brain's hemodynamic and metabolic compensatory responses to reduced blood oxygen content in SCD will reveal mechanisms leading to ischemic stroke. We will determine if MR-derived cerebral blood flow (CBF) and oxygen extraction fraction (OEF), as metrics of this hemodynamic and metabolic stress, may provide novel tools to stratify stroke risk in SCD children so that treatment may be individualized, identifying those at highest risk for more aggressive therapies, while sparing those at lower risk any unnecessary adverse effects of treatment. We hypothesize that measurements of CBF and OEF at the brain- tissue level will be more sensitive and specific for stroke risk than blunt measures of blood velocity as measured by TCD. Over the past 15 years, we have developed a novel, noninvasive MR approach to measure brain OEF at the voxel-level. Until now, OEF could only be measured by PET imaging, and thus has never been studied in SCD children due to the risks of radiation. Aim1. To determine if CBF and OEF are increased in SCD children compared to sibling controls indicating an elevated stroke risk. Aim2. To determine if hemispheric CBF and OEF demonstrate greatest alteration in the subset of SCD children with vasculopathy indicating a very high risk of stroke in the territory of the affected vessel. Aim3. To determine if transfusion therapy normalizes CBF and OEF, thereby reducing hemodynamic and metabolic stress as a means to reduce stroke risk. Aim 4. To determine if elevated CBF and/or OEF predict future stroke on 3 year follow-up MRI better than TCD.