Longitudinal Neuroimaging in Sturge-Weber Syndrome

斯特奇-韦伯综合征的纵向神经影像学

基本信息

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
项目类别：
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

项目摘要

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）：斯特奇-韦伯综合征（SWS）是一种散发性神经皮肤疾病，其特征是面部葡萄酒色斑（PWS）和软脑膜血管瘤（LMA）。 SWS 最常（85%）影响一侧半球，并具有进行性但可变的临床病程，从而提供了一种独特的临床模型来研究早期单侧进行性脑病变的神经认知影响。 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 尚无治愈方法或特异性治疗方法。在 NIH 的支持和全国范围内的患者招募下，我们为 SWS 儿童建立了临床研究项目，以了解疾病的病理生理学并寻找新的治疗范例。在第一个资助周期中，我们描述了自然疾病过程，并确定了最有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。在这个重新提交更新提案中，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，并测试谷氨酸（GLU，大脑中的一种主要兴奋性氨基酸）MR 波谱和扩散张量成像，以评估严重癫痫、认知和运动障碍的风险功能和脑损伤。这些数据将导致预防性抗癫痫药物试验和由先进 MRI 引导的早期运动干预。在目标 2 中，我们将研究针对从接受癫痫手术的儿童切除的 LMA 中检测到的异常血管生成进行药物试验的可行性。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，这些数据将提供有关抗血管生成药物（例如普萘洛尔，最近导致婴儿血管瘤治疗范式转变）潜在不良反应风险的关键信息。最后，在目标 3 中，我们将使用我们在先前入组的 SWS 儿童中前瞻性收集的临床和影像数据，证明单侧脑损伤程度（通过葡萄糖代谢 PET 成像测量）与认知之间存在非线性（U 形）关系。功能（智商）。这表明对于那些具有广泛（> 60％受影响半球）单侧皮质损伤的患者，可以进行有效的对侧功能重组。我们将重新测试先前入组的 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。这些数据将为未来手术患者选择的临床决策提供急需的指导，使用影像学和临床变量来预测谁将从手术中获得预期的长期认知结果获益最多。