Longitudinal Neuroimaging in Sturge-Weber Syndrome

描述（由申请人提供）：斯特奇-韦伯综合征（SWS）是一种散发的神经皮肤疾病，其特征是面部port-wine port-wine stain （PWS）和小脑膜血管瘤（LMA）。SWS最常（85%）影响一个半球，具有进行性但可变的临床病程，因此为研究早期单侧进行性脑病变的神经认知影响提供了独特的临床模型。70-75%的单侧SWS患儿会出现癫痫发作和神经系统症状（运动缺陷和视野损害）。目前，SWS没有治愈或特异性治疗方法。在NIH的支持和全国范围内的患者招募下，我们建立了一个针对SWS儿童的临床研究项目，以了解疾病的病理生理和寻找新的治疗范例。在第一个资助周期中，我们描述了自然病程，并确定了最可能发生进行性脑损伤的关键年龄窗口（<4岁）。在第二个资助周期中，我们已经确定了两种与癫痫发生和血管生成相关的机制，作为早期疾病进展的两种潜在驱动因素。在这个重新提交的更新建议中，我们专注于通过针对这些机制来改变早期疾病进程来开发新的治疗范例。在Aim 1中，我们将研究癫痫发作前患有SWS的幼儿，并将测试谷氨酸（GLU，大脑中主要的兴奋性氨基酸）磁共振波谱和弥散张量成像，以评估严重癫痫、认知和运动功能低下以及脑损伤的风险。这些数据将导致预防性抗癫痫药物试验和由高级MRI指导的早期运动干预。在Aim 2中，我们将研究针对癫痫手术切除儿童LMA中检测到的异常血管生成的药物试验的可行性。主要目的是通过磁共振成像和切除脑组织研究LMA和深侧支血管，比较它们的增殖活性和血管生成潜力。我们还将把最近发现的GNAQ基因活化体细胞突变定位到LMA。在设计临床试验之前，这些数据将提供有关抗血管生成药物（如心得安，它导致了最近婴儿血管瘤治疗的范式转变）潜在不良反应风险的关键信息。最后，在Aim 3中，我们将使用前瞻性收集的SWS儿童的临床和影像学数据，证明单侧脑损伤程度（通过葡萄糖代谢PET成像测量）与认知功能（IQ）之间存在非线性（u型）关系。这表明单侧皮质大面积损伤（约占受影响半球的60%）的患者对侧功能重组有效。我们将重新测试先前入组的SWS患儿，他们继续接受抗癫痫药物治疗或随后手术切除（由于难治性癫痫发作），并评估他们的长期神经认知结果，以确定手术治疗如何改变长期神经认知轨迹。这些数据将为未来的临床决策提供急需的指导，通过影像学和临床变量来预测谁将从预期的长期认知结果中受益最多的手术患者选择。

DESCRIPTION (provided by applicant): Sturge-Weber syndrome (SWS) is a sporadic neurocutaneous disorder characterized by a facial port-wine port-wine stain (PWS) and leptomeningeal angioma (LMA). SWS most often (85%) affects one hemisphere and has a progressive but variable clinical course, thus providing a unique clinical model to study the neurocognitive effects of an early, unilateral progressive brain lesion. 70-75% of children with unilateral SWS will develop seizures and neurological symptoms (motor deficit and visual field impairment). Currently, SWS has no cure or specific treatment. With NIH support and nationwide patient recruitment, we have built a clinical research program for children with SWS, in order to understand disease pathophysiology and find new treatment paradigms. In the first funding cycle, we have described the natural disease course and identified a critical age window (<4 years) when progressive brain damage most likely occurs. In the second funding cycle, we have identified two mechanisms, related to epileptogenesis and angiogenesis, as two potential drivers of early disease progression. In this resubmission renewal proposal we focus on developing novel treatment paradigms by targeting these mechanisms to alter early disease course. In Aim 1, we will study young children with SWS, before onset of epilepsy, and will test glutamate (GLU, a major excitatory amino acid in the brain) MR spectroscopy and Diffusion Tensor Imaging for assessing risk for severe epilepsy, poor cognitive and motor functions and brain damage. The data will lead to a preventive antiepileptic drug trial and early motor intervention guided by advanced MRI. In Aim 2, we will study the feasibility of a drug trial targeting abnormal angiogenesis detected in the LMA resected from children undergoing epilepsy surgery. The main goal is to study LMA and deep collateral vessels both by MR imaging and in resected brain tissues to compare their proliferative activity and angiogenetic potential. We will also localize the recently discovered activation somatic mutation in the GNAQ gene to the LMA. These data will provide critical information on the risk of potential adverse effects of antiangiogenic agents (such as propranolol, which has led to a recent paradigm shift in the treatment of infantile hemangiomas) before a clinical trial is designed. Finally, in Aim 3, we will use our prospectively collected clinical and imaging data in previously enrolled SWS children, demonstrating a non- linear (U-shaped) relation between the extent of unilateral brain damage (measured by glucose metabolism PET imaging) and cognitive functions (IQ). This suggested effective contralateral functional reorganization in those with extensive (>60% of the affected hemisphere) unilateral cortical damage. We will retest previously enrolled children with SWS, who continued antiepileptic drug treatment or underwent subsequent surgical resection (due to intractable seizures), and assess their long-term neurocognitive outcome to determine how surgical treatment altered long-term neurocognitive trajectory. These data will provide a much-needed guidance for future clinical decision-making in surgical patient selection using imaging and clinical variables to predict who will benefit most from surgery in terms of expected long-term cognitive outcome.