Longitudinal Neuroimaging in Sturge-Weber Syndrome

描述(由申请者提供)：斯特奇-韦伯综合征(SWS)是一种散发性神经皮肤病，特征是面部葡萄酒酒渍(PWS)和软脑膜血管瘤(LMA)。SWS最常累及一侧大脑半球(85%)，其临床病程为进展性但多变的，因此提供了一种独特的临床模型来研究早期单侧进行性脑损害的神经认知效应。70%-75%的单侧SWS儿童会出现癫痫发作和神经症状(运动障碍和视野障碍)。目前，系统性红斑狼疮尚无治愈或特效治疗方法。在NIH的支持下，在全国范围内招募患者，我们为SWS儿童建立了一个临床研究计划，以了解疾病的病理生理学，并找到新的治疗范式。在第一个资助周期中，我们描述了自然疾病的病程，并确定了进行性脑损伤最有可能发生的关键年龄窗口(&lt；4岁)。在第二个资金周期中，我们确定了与癫痫发生和血管生成相关的两种机制，作为早期疾病进展的两个潜在驱动因素。在这份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病程来开发新的治疗范例。在目标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)磁共振波谱和扩散张量成像，以评估严重癫痫、认知和运动功能低下以及脑损伤的风险。这些数据将导致在先进核磁共振的指导下进行预防性抗癫痫药物试验和早期运动干预。在目标2中，我们将研究一项针对癫痫手术儿童LMA中发现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脑组织切片研究LMA和深部侧支血管，以比较它们的增殖活性和血管生成潜力。我们还将最近发现的GNAQ基因激活体细胞突变定位到LMA。在设计临床试验之前，这些数据将提供关于抗血管生成药物(如心得安，这导致最近婴儿血管瘤治疗模式转变)潜在不良反应风险的关键信息。最后，在目标3中，我们将使用我们在以前登记的SWS儿童中前瞻性收集的临床和成像数据，证明单侧脑损伤的程度(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。这表明在那些广泛(60%的受累半球)单侧皮质损伤的患者中，有效的对侧功能重组。我们将重新测试之前登记的SWS儿童，这些儿童继续接受抗癫痫药物治疗或随后接受手术切除(由于顽固性癫痫发作)，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。这些数据将为未来外科患者选择的临床决策提供急需的指导，使用成像和临床变量来预测从预期的长期认知结果来看，谁将从手术中受益最大。

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.