Longitudinal Neuroimaging in Sturge-Weber Syndrome

这项研究计划的总体目标是了解早期大脑的机制， 损伤，识别临床进展的早期影像学标志物，并引入新的 儿童Sturge-Weber综合征的诊断方法和治疗靶点 综合征（SWS）。在第一个供资周期，我们的纵向方法， 对SWS结构和代谢异常的评估使我们能够确定 疾病进展的时间框架和白色物质变化在认知功能中的作用 下降纵向设计还使我们能够证明以下成像相关性： 进行性神经认知缺陷，也表明代谢异常， 有时是可逆的，这表明有机会进行早期治疗干预。 最近的研究还表明，软脑膜血管瘤可能不是静态病变， 并且血管异常的重塑可导致蛋白质合成增加。期间 在上一个资助期，我们实施了几种新的成像方式， 现在我们可以测量脑灌注，有更高的灵敏度检测血管 畸形和白色物质的变化，并可以测量蛋白质的合成。这些 初步研究为SWS的病理生理学提供了新的见解， 导致了新的假设在这个提议中被测试。我们将结合联合收割机几种先进的 MRI和PET技术，包括：（1）动态灌注加权成像（PWI）;（2） 扩散张量成像（DTI）;（3）磁敏感加权成像（SWI）;（4）PET 脑葡萄糖代谢扫描。此外，我们亦会研究如何使用 [11 C]亮氨酸PET评估血管瘤及其周围蛋白质合成异常 大脑区域。我们提出三个目的：（1）评价早期脑血流动力学 变化及其对幼儿代谢和临床进展的意义 单侧SWS。(2)了解皮质和白色物质损伤在 神经认知结局（包括癫痫发作、运动缺陷和认知障碍） 儿童SWS (3)为了确定是否增加蛋白质合成的区域， 血管瘤是疾病进展严重程度的预测因子。拟议的研究将 确定可用于临床诊断的先进成像标记物 早期识别受损和有风险的大脑区域，并预测临床结果。 这些成像技术将有助于选择新的治疗方法的患者 影响SWS病理学的各个方面以停止或减少进展过程， 并监测治疗效果。此外，拟议的研究将有助于 更广泛的医学界通过（i）建立临床使用和评估功能 和临床相关的先进的MRI和PET技术在儿童，和（ii）更好地 了解慢性缺血导致的进行性脑损伤的机制。该研究项目将应用先进的神经成像技术，包括各种 磁共振成像（MRI）和正电子发射断层扫描（PET）方法， 一种前瞻性的纵向方式，结合神经心理学测试， 了解Sturge-Weber综合征儿童早期脑损伤的机制。 这些结果有望引入新的，更准确的诊断测试， 确定新的治疗靶点，以改善这种通常具有破坏性的疾病的结果。

The overall goal of this research proposal is to understand mechanisms of early brain injury, identify early imaging markers of clinical progression, and introduce new diagnostic approaches as well as therapeutic targets in children with Sturge-Weber syndrome (SWS). During the first cycle of funding, our longitudinal approach to the assessment of structural and metabolic abnormalities in SWS allowed us to define the time frame of disease progression and the role of white matter changes in cognitive decline. The longitudinal design also allowed us to demonstrate imaging correlates of progressive neuro-cognitive deficit, and also showed that the metabolic abnormalities are sometimes reversible, suggesting an opportunity for early therapeutic interventions. Recent studies also suggest that leptomeningeal angiomas may not be static lesions, and remodeling of vessel abnormalities may lead to increased protein synthesis. During the previous funding period, we implemented several novel imaging modalities which now allow us to measure brain perfusion, have higher sensitivity for detecting vascular malformations and white matter changes, and can measure protein synthesis. These preliminary studies have provided new insights in the pathophysiology of SWS and have led to new hypotheses to be tested in this proposal. We will combine several advanced MRI and PET techniques, including: (1) dynamic perfusion weighted imaging (PWI); (2) diffusion tensor imaging (DTI); (3) susceptibility weighted imaging (SWI), and (4) PET scanning of cerebral glucose metabolism. In addition, we will explore the use of [11C]leucine PET to assess abnormal protein synthesis in the angioma and surrounding brain regions. We propose three aims: (1) To evaluate early cerebral hemodynamic changes and their significance for metabolic and clinical progression in young children with unilateral SWS. (2) To understand the role of cortical and white matter damage in neurocognitive outcome (including seizures, motor deficit and cognitive impairment) in children with SWS. (3) To determine whether increased protein synthesis in the region of the angioma is a predictor for severity of disease progression. The proposed studies will identify advanced imaging markers that can be used clinically to make the diagnosis early and identify damaged and ¿at-risk¿ brain regions, and also predict clinical outcome. These imaging techniques will help select patients for novel therapeutic approaches affecting various aspects of pathology in SWS to halt or diminish the progressive course, and also monitor therapeutic effects. In addition, the proposed studies will serve the wider medical community by (i) establishing the clinical use and evaluate the functional and clinical correlates of advanced MRI and PET techniques in children, and (ii) better understanding mechanisms of progressive brain damage due to chronic ischemia. This research project will apply advanced neuroimaging techniques, including various magnetic resonance imaging (MRI) and positron emission tomography (PET) methods, in a prospective, longitudinal fashion, combined with neuro-psychology testing, to understand mechanisms of early brain injury in children with Sturge-Weber syndrome. The results are expected to introduce novel, more accurate diagnostic tests and also identify new therapeutic targets to improve the outcome of this often devastating disease.