Longitudinal Neuroimaging in Sturge-Weber Syndrome

描述(申请人提供)：这项研究计划的总体目标是了解脑损伤的机制和临床进展，以及引入新的成像生物标记物和治疗靶点，以治疗单侧斯特奇-韦伯综合征(SWS)。在第一个资助周期中，我们对SWS的结构、代谢和神经认知异常的纵向评估方法确定了疾病进展的时间框架和神经认知缺陷的成像相关性。我们继续研究的主要重点是了解导致SWS患者神经和认知结果高度可变的具体机制，尽管最初的大脑参与有限。我们的一般假设是脑血管畸形，而不是传统的认为是静态的，在进展性病程的患者中经历了增殖性转化。这一假说是基于我们新的初步数据，即在切除的组织中，血管瘤表现出[11C]亮氨酸PET蛋白合成增加，血管内皮细胞增殖标记物和血管生成蛋白异常表达。在第一个发现周期中的第二个主要发现是，由于MR灌注加权成像(PWI)测量的灌注变化超出了MR结构和PET葡萄糖代谢异常的范围，有证据表明大脑皮质存在灌注/代谢不匹配。最后，我们发现在我们的样本SWS儿童中，白质体积丢失和水扩散异常与认知障碍有关。为了研究这些疾病进展的机制，我们将结合先进的MRI和PET技术，以及切除组织的免疫组织化学研究，以达到三个目标：(1)研究血管瘤区域蛋白质合成、增殖活性增加和血管生成因子的表达，并确定PET测量的蛋白质合成增加是否与单侧SWS儿童进行性认知和神经功能障碍有关。(2)评价早期脑血流动力学改变及其对代谢和神经功能进展的意义。(3)评价脑白质弥散异常及其对认知功能的影响。拟议的研究有望确定SWS的新治疗靶点。最重要的是，增生性软脑膜血管瘤可能适用于抗血管瘤治疗，这将是SWS临床治疗的一个主要突破。应用的先进成像技术还可以用于监测未来旨在预防缺血性皮质损伤和脑白质损伤的治疗试验。此外，拟议的研究将服务于更广泛的医学界，建立临床应用，评估先进的MRI和PET技术在儿童中的功能和临床相关性，并更好地了解慢性脑缺血造成的进行性脑损伤的机制。公共卫生相关性：该研究项目的目标是了解斯特奇-韦伯综合征儿童的疾病进展机制。我们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，结合切除的脑和血管瘤组织的免疫组织化学研究，研究软脑膜血管瘤的增殖性变化和异常血管生成，以及潜在皮质和白质的结构、灌注和代谢变化。结果将引入新的、更准确的诊断测试，并确定新的治疗目标，以改善这种往往具有破坏性的疾病的结果。

DESCRIPTION (provided by applicant): The overall goal of this research proposal is to understand mechanisms of brain injury and clinical progression, as well as introduce new imaging biomarkers and therapeutic targets in children with unilateral Sturge-Weber syndrome (SWS). During the first cycle of funding, our longitudinal approach to the assessment of structural, metabolic and neuro-cognitive abnormalities in SWS defined the time frame of disease progression and imaging correlates of neuro-cognitive deficit. The main focus of our continuing studies is to understand the specific mechanisms leading to highly variable neurological and cognitive outcomes in SWS despite limited initial brain involvement. Our general hypothesis is that the cerebral vascular malformation, rather than the traditional view as being static, undergoes proliferative transformation in patients with a progressive course. This hypothesis is based upon our novel preliminary data that the angioma shows increased protein synthesis on [11C]leucine PET and abnormal expression of proliferation markers and angiogenic proteins in vascular endothelial cells in resected tissues. The second major finding during the first cycle of finding was evidence for a perfusion/metabolic mismatch in the cortex, due to perfusion changes measured by MR Perfusion Weighted Imaging (PWI) extending beyond the MR structural and PET glucose metabolic abnormalities. Finally, we found that white matter volume loss and abnormal water diffusion were related to cognitive deficits in our sample of children with SWS. To study these mechanisms of disease progression, we will combine advanced MRI and PET techniques, as well as immunohistochemistry studies from resected tissue to address three aims: (1) To study protein synthesis, increased proliferative activity and expression of angiogenic factors in the region of the angioma, and to determine if increased protein synthesis measured by PET is associated with progressive cognitive and neurological deficits in children with unilateral SWS. (2) To evaluate early cerebral hemodynamic changes and their significance for metabolic and neurological progression. (3) To evaluate white matter diffusion abnormalities and their contribution to cognitive outcome. The proposed studies are expected to identify novel therapeutic targets in SWS. Most importantly, proliferative leptomeningeal angiomas may be amenable to anti-angioma therapies, which would be a major breaktrough in the clinical management of SWS. The applied advanced imaging techniques can also be used to monitor future therapeutic trials aimed at preventing ischemic cortical damage and white matter injury. In addition, the proposed studies will serve the wider medical community by establishing the clinical use and evaluate the functional and clinical correlates of advanced MRI and PET techniques in children, and better understanding mechanisms of progressive brain damage due to chronic ischemia. PUBLIC HEALTH RELEVANCE: The goal of this research project is to understand mechanisms of disease progression in children with Sturge-Weber syndrome. We will apply advanced neuroimaging techniques, including various magnetic resonance imaging (MRI) and positron emission tomography (PET) methods, combined with immunohistochemistry studies of resected brain and angioma tissues, to study proliferative changes and abnormal angiogenesis in the leptomeningeal angioma, as well as structural, perfusion, and metabolic changes in the underlying cortex and white matter. The results will introduce novel, more accurate diagnostic tests and also identify new therapeutic targets to improve the outcome of this often devastating disease.