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：
8059584
负责人：
CSABA JUHASZ
金额：
$ 28.89万
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 2013-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8059584
关键词：
Address Affect Age Angiogenic Factor Angiogenic Proteins Biological Markers Blood Vessels Brain Brain Hemangioma Brain Injuries Brain region Cerebrum Child Chronic Clinical Clinical Management Clinical Markers Cognitive Cognitive deficits Communities Data Diagnostic tests Diffusion Diffusion Magnetic Resonance Imaging Disease Disease Progression Frequencies Functional disorder Funding Future Glucose Goals Health Hemangioma Image Imaging Techniques Immunohistochemistry Impaired cognition Ischemia Lesion Leucine Magnetic Resonance Imaging Measures Medical Metabolic Methods Monitor Neurologic Outcome Patients Pattern Perfusion Perfusion Weighted MRI Positron-Emission Tomography Predisposition Proliferation Marker Protein Biosynthesis Research Project Grants Research Proposals Resected Role Sampling Seizures Severities Sturge-Weber Syndrome Techniques Testing Therapeutic Intervention Therapy Clinical Trials Time Tissues Vascular Endothelial Cell Weight angiogenesis base calcification deep vein design early onset follow-up glucose metabolism hemodynamics imaging modality improved insight longitudinal design malformation motor deficit neuroimaging new therapeutic target novel novel diagnostics prevent therapeutic target water diffusion white matter white matter change white matter damage white matter injury

项目摘要

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.

描述（由申请人提供）：该研究建议的总体目标是了解脑损伤和临床进展的机制，并引入单侧Sturge-Weber综合征（SWS）儿童的新成像生物标志物和治疗靶标。在资金的第一个周期中，我们纵向评估SWS中结构，代谢和神经认知异常的方法定义了疾病进展的时间范围和神经认知赤字的成像相关性。我们继续研究的主要重点是了解尽管最初的大脑参与度有限，但导致SWS的高度可变的神经系统和认知结果的特定机制。我们的总体假设是，脑血管畸形，而不是传统观点是静态的，而是在患有渐进疗程的患者中经历了增殖。该假设是基于我们新的初步数据，即血管瘤显示了在干燥组织中血管内皮细胞中增殖标记和血管生成蛋白的[11C]亮氨酸PET和血管生成蛋白异常表达上的蛋白质合成的增加。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）测得的灌注变化，其灌注/代谢不匹配的证据表明，超出了MR结构和PET葡萄糖代谢异常。最后，我们发现白质体积损失和水扩散异常与我们的SWS儿童样本中的认知缺陷有关。为了研究这些疾病进展的这些机制，我们将结合先进的MRI和PET技术，以及从切除的组织中的免疫组织化学研究，以解决三个目的：（1）研究蛋白质合成，增加的活性和增加的血管生成因子的增殖活性和血管生成因子在血管瘤区域中的血管生成因子的表达以及与蛋白质相关的蛋白质相关，并确定与蛋白质相关的依从性，并确定与petsis的渐进性有关SWS。（2）评估早期脑血液动力学变化及其对代谢和神经系统进展的重要性。（3）评估白质扩散异常及其对认知结果的贡献。拟议的研究有望确定SWS中的新型治疗靶标。最重要的是，增生性瘦脑脑血管瘤可能适合抗血管瘤疗法，这将是SWS临床管理的主要破裂。应用的先进成像技术也可用于监测旨在防止缺血性皮质损伤和白质损伤的未来治疗试验。此外，拟议的研究将通过建立临床使用并评估儿童晚期MRI和PET技术的功能和临床相关性来为更广泛的医学界提供服务，并更好地理解慢性缺血引起的渐进性脑损伤机制。公共卫生相关性：该研究项目的目的是了解Sturge-Weber综合征儿童疾病进展的机制。我们将采用先进的神经影像学技术，包括各种磁共振成像（MRI）和正电子发射断层扫描（PET）方法，结合了切除的脑和血管瘤组织的免疫组织化学研究，以研究瘦脑血管瘤的增殖变化和血管生成的增殖变化和异常血管生成，以及结构性的白细胞，以及综合性的变化，并在综合效率下进行了综合性变化。结果将引入新颖，更准确的诊断测试，并确定新的治疗靶标，以改善这种经常毁灭性疾病的结果。