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: 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
• 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

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）：本研究计划的总体目标是了解脑损伤和临床进展的机制，并为单侧斯特奇-韦伯综合征（SWS）儿童引入新的成像生物标志物和治疗靶点。在第一个资助周期中，我们对 SWS 的结构、代谢和神经认知异常进行纵向评估，确定了疾病进展的时间范围以及神经认知缺陷的影像学相关性。我们持续研究的主要重点是了解导致 SWS 神经学和认知结果高度可变的具体机制，尽管最初的大脑参与有限。我们的一般假设是，脑血管畸形并非传统观点认为是静态的，而是在进行性病程的患者中经历增殖性转化。这一假设基于我们新的初步数据，即血管瘤在 [11C]亮氨酸 PET 上显示蛋白质合成增加，以及切除组织中血管内皮细胞中增殖标志物和血管生成蛋白的异常表达。第一个发现周期中的第二个主要发现是皮质灌注/代谢不匹配的证据，这是由于 MR 灌注加权成像 (PWI) 测量的灌注变化超出了 MR 结构和 PET 葡萄糖代谢异常范围。最后，我们发现，在我们的 SWS 儿童样本中，白质体积减少和水扩散异常与认知缺陷有关。为了研究这些疾病进展的机制，我们将结合先进的 MRI 和 PET 技术，以及切除组织的免疫组织化学研究，以实现三个目标：（1）研究蛋白质合成、增殖活性增加和血管生成因子的表达。血管瘤，并确定 PET 测量的蛋白质合成增加是否与单侧 SWS 儿童的进行性认知和神经功能缺陷有关。 (2)评估早期脑血流动力学变化及其对代谢和神经进展的意义。 (3) 评估白质扩散异常及其对认知结果的贡献。拟议的研究预计将确定 SWS 的新治疗靶点。最重要的是，增殖性软脑膜血管瘤可能适合抗血管瘤治疗，这将是 SWS 临床治疗的重大突破。所应用的先进成像技术还可用于监测未来旨在预防缺血性皮质损伤和白质损伤的治疗试验。此外，拟议的研究将通过建立临床应用并评估先进 MRI 和 PET 技术在儿童中的功能和临床相关性，以及更好地了解慢性缺血引起的进行性脑损伤的机制，为更广泛的医学界服务。公共健康相关性：该研究项目的目标是了解斯特奇-韦伯综合征儿童疾病进展的机制。我们将应用先进的神经影像技术，包括各种磁共振成像（MRI）和正电子发射断层扫描（PET）方法，结合切除的脑和血管瘤组织的免疫组织化学研究，研究软脑膜血管瘤的增殖变化和异常血管生成，以及底层皮层和白质的结构、灌注和代谢变化。研究结果将引入新颖、更准确的诊断测试，并确定新的治疗靶点，以改善这种往往具有毁灭性的疾病的治疗结果。