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

 描述(申请人提供)：作为最常见的遗传性血液疾病，镰状细胞病(SCD)影响每400名非裔美国人中的一人。这种疾病会改变红细胞的形状，导致全身、多器官的影响，使人的平均预期寿命减少到40岁。在其并发症中，缺血性中风是常见的和致残的，从婴儿期就开始--“显性”中风会导致急性神经功能障碍，而“无症状”中风则表现为智力下降。一种预防中风的筛查方法，即经颅多普勒超声(TCD)，有助于选择将受益于输血治疗的SCD儿童作为减少中风发生的手段。然而，不幸的是，筛查机制有几个局限性，包括它对预测有无症状中风风险的人不敏感。此外，尽管进行了筛查和输液，近一半的儿童仍有反复发作的显性卒中、无症状卒中和/或进行性血管病变。因此，需要一种改进的生物标志物来分层SCD儿童的卒中风险。在这项建议中，我们假设SCD患者的脑血流动力学和代谢代偿反应对血氧含量降低的反应将揭示导致缺血性卒中的机制。我们将确定MR衍生的脑血流量(CBF)和氧摄取分数(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对SCD儿童的中风风险进行分层，以便个体化治疗，识别那些风险最高的人进行更积极的治疗，同时避免那些风险较低的人避免治疗的任何不必要的不良影响。我们假设，在脑组织水平上测量CBF和OEF将比TCD测量的钝性血流速度对中风风险更敏感和特异。在过去的15年里，我们开发了一种新的、非侵入性的磁共振方法来测量体素水平的大脑OEF。到目前为止，OEF只能通过PET成像来测量，因此由于辐射的风险，从未在SCD儿童中进行研究。目的：1.为了确定SCD儿童的CBF和OEF是否比兄弟姐妹对照组增加，表明中风风险增加。AIM2.为了确定大脑半球CBF和OEF是否在有血管病变的SCD儿童亚组中表现出最大的变化，表明在受影响血管区域中风的风险非常高。Aim3.以确定输血是否 治疗使CBF和OEF正常化，从而减少血流动力学和代谢压力，作为降低中风风险的一种手段。目的4.确定脑血流量升高和/或OEF升高在3年随访MRI上是否比经颅多普勒更好地预测未来卒中。

 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.