Longitudinal Neuroimaging in Sturge-Weber Syndrome

斯特奇-韦伯综合征的纵向神经影像学

• 批准号: 8690418
• 负责人: CSABA JUHASZ
• 金额: $ 33.25万
• 依托单位: WAYNE STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-07-01 至 2019-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8690418
• 关键词: Adverse effects; Affect; Age; Angiogenesis Inhibitors; Antiepileptic Agents; Blood Vessels; Blood Volume; Blood flow; Brain; Brain Injuries; Cerebral hemisphere; Child; Clinical; Clinical Research; Clinical Trials; Cognitive; Contralateral; Corticospinal Tracts; Data; Databases; Deep Hemangioma; Diffusion Magnetic Resonance Imaging; Disease; Disease Progression; Early treatment; Endothelin; Enrollment; Epilepsy; Epileptogenesis; Excision; Excitatory Amino Acids; Face; Feasibility Studies; Frequencies; Functional disorder; Funding; Future; GNAQ gene; Gene Frequency; Gene Mutation; Glutamates; Goals; Hemangioma; Image; Impairment; Intervention; Intractable Epilepsy; Ipsilateral; Label; Lead; Lesion; Magnetic Resonance Imaging; Magnetic Resonance Spectroscopy; Measures; Mental Retardation; Methods; Modeling; Motor; Neurocognitive; Neurocutaneous Syndromes; Neurologic; Oncogenic; Operative Surgical Procedures; Outcome; Oxygen; Patient Recruitments; Patient Selection; Patients; Pharmaceutical Preparations; Port-Wine Stain; Positioning Attribute; Positron-Emission Tomography; Preventive; Process; Propranolol; Resected; Risk; Safety; Seizures; Severities; Shapes; Somatic Mutation; Staging; Strawberry nevus; Sturge-Weber Syndrome; Symptoms; Testing; Time; Tissues; United States National Institutes of Health; Vascular Endothelial Growth Factors; Veins; Venous; Visual Fields; Wine; angiogenesis; antiangiogenesis therapy; base; brain surgery; brain tissue; clinical decision-making; cognitive function; design; follow-up; glucose metabolism; high risk; improved; motor deficit; mutant; neuroimaging; novel; pre-clinical; programs; prophylactic; public health relevance; spectroscopic imaging

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.

描述（由申请人提供）：Sturge-weber综合征（SWS）是一种零星的神经性疾病，其特征在于面部港口港口港口葡萄酒染色（PWS）和瘦脑动脉瘤（LMA）。 SWS最常见（85％）会影响一个半球，并且具有渐进型但可变的临床过程，因此提供了独特的临床模型来研究早期，单侧进行性脑损伤的神经认知作用。有70-75％的单侧SWS儿童会出现癫痫发作和神经系统症状（运动缺陷和视野障碍）。目前，SWS没有治愈或特定的治疗方法。在NIH支持和全国患者招募的情况下，我们为SWS儿童建立了一项临床研究计划，以了解疾病的病理生理学并找到新的治疗范例。在第一个融资周期中，我们描述了自然疾病过程，并确定了当前脑部损伤很可能发生的关键年龄窗口（<4岁）。在第二个融资周期中，我们确定了两种与癫痫发生和血管生成有关的机制，是早期疾病进展的两个潜在驱动因素。在此重新提出的提案中，我们专注于通过针对这些机制来改变早期疾病过程来开发新的治疗范例。在AIM 1中，我们将在癫痫发作之前研究患有SWS的幼儿，并将测试谷氨酸（GLU，大脑中的主要兴奋性氨基酸）MR Spotroscopicy和Spotroscopicy和扩散张量张量成像，以评估严重癫痫，较差的认知和运动功能和运动功能和大脑损害的严重癫痫风险。数据将导致预防性抗癫痫药试验和以高级MRI为指导的早期运动干预。在AIM 2中，我们将研究针对从接受癫痫手术的儿童切除的LMA异常血管生成的药物试验的可行性。主要目标是通过MR成像和切除的脑组织研究LMA和深层侧支血管，以比较其增殖活性和血管生成潜力。我们还将在GNAQ基因中将最近发现的激活体突变定位到LMA。这些数据将提供有关抗血管生成剂的潜在不良影响风险（例如普萘洛尔，这导致婴儿血管瘤治疗的最新范式转移）的关键信息。最后，在AIM 3中，我们将在先前入学的SWS儿童中使用前瞻性收集的临床和成像数据，这表明单侧脑损伤的程度（通过葡萄糖代谢PET成像）和认知功能（IQ）之间存在非线性（U形）关系。这表明在广泛（> 60％受影响半球）单侧皮质损伤的人中有效的对侧功能重组。我们将重新测试先前入学的SWS儿童，他们继续抗癫痫药治疗或接受了随后的手术切除（由于诱发性癫痫发作），并评估其长期神经认知结果，以确定手术如何改变长期神经认知轨迹。这些数据将提供急需的指导，用于使用成像和临床变量在手术患者选择中的未来临床决策中，以预测谁将从手术中受益于预期的长期认知结果。