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

MR 衍生的脑血流和氧代谢对儿童镰状细胞病的中风风险进行分层

• 批准号: 9122484
• 负责人: Andria Lee Ford
• 金额: $ 53.49万
• 依托单位: WASHINGTON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-08-15 至 2020-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9122484
• 关键词: Acute; Adult; Adverse effects; Affect; Affinity; African American; Applications Grants; Biological Markers; Blood; Brain; Cerebral Infarction; Cerebrovascular Circulation; Cerebrum; Child; Childhood; Chronic; Disease; Doppler Ultrasound; Drops; Enrollment; Erythrocytes; Etiology; Financial compensation; Functional disorder; Future; Health; Hematological Disease; Hemolytic Anemia; Imaging Techniques; Impaired cognition; Infarction; Inherited; Ischemic Stroke; Lead; Life Expectancy; MRI Scans; Magnetic Resonance Imaging; Measurement; Measures; Metabolic; Metabolic stress; Metabolism; Methods; Morbidity - disease rate; Neurologic; Organ; Oxygen; Patients; Perfusion; Physiology; Positron-Emission Tomography; Preventive therapy; Radiation; Recurrence; Risk; Shapes; Siblings; Sickle Cell Anemia; Stratification; Stroke; Stroke prevention; Testing; Time; Tissues; Transfusion; Vascular Diseases; aggressive therapy; artery occlusion; brain tissue; disability; falls; follow-up; hemodynamics; high risk; improved; infancy; insight; meetings; middle cerebral artery; mortality; new therapeutic target; novel; prevent; response; screening; tool

 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.

 描述（由申请人提供）：作为最常见的遗传性血液疾病，镰状细胞病 (SCD) 影响着四分之一的非裔美国人。这种疾病会改变红细胞的形状，导致全身性、多器官效应，使中位预期寿命缩短至 40 岁。在其并发症中，缺血性中风很常见并且会致残，从婴儿期开始——“明显”中风会导致急性神经功能缺损，而“无症状”中风则表现为智力下降。经颅多普勒超声 (TCD) 是一种预防中风的筛查方法，有助于选择可受益于输血治疗以减少中风发生的 SCD 儿童。然而不幸的是，这种筛查机制有一些局限性，包括它对预测无症状中风风险的人不敏感。此外，尽管进行了筛查和输血，但近一半的儿童仍然患有复发性明显中风、无症状中风和/或进行性血管病变。因此，需要一种改进的生物标志物来对 SCD 儿童的中风风险进行分层。在这项提议中，我们假设大脑对 SCD 中血氧含量降低的血流动力学和代谢代偿反应将揭示导致缺血性中风的机制。我们将确定 MR 衍生的脑血流量 (CBF) 和氧提取分数 (OEF) 作为血流动力学和代谢应激的指标，是否可以提供新颖的工具来对 SCD 儿童的卒中风险进行分层，以便实现个体化治疗，识别风险最高的患者，以采取更积极的治疗，同时避免风险较低的患者受到任何不必要的治疗副作用。我们假设，与 TCD 测量的血流速度相比，脑组织水平上的 CBF 和 OEF 测量对于中风风险更加敏感和特异。在过去 15 年里，我们开发了一种新颖的无创 MR 方法来测量体素水平的大脑 OEF。迄今为止，OEF 只能通过 PET 成像来测量，因此由于存在辐射风险，从未在 SCD 儿童中进行过研究。目标1。确定与兄弟姐妹对照相比，SCD 儿童的 CBF 和 OEF 是否增加，表明中风风险升高。目标2。确定患有血管病变的 SCD 儿童的半球 CBF 和 OEF 是否表现出最大的改变，表明受影响血管区域中风的风险非常高。目标3。判断是否输血 治疗使 CBF 和 OEF 正常化，从而减少血流动力学和代谢应激，从而降低中风风险。目标 4. 确定升高的 CBF 和/或 OEF 在 3 年随访 MRI 中是否比 TCD 更好地预测未来卒中。