MRI Biomarkers of Patients with Tuberous Sclerosis Complex and Autism

描述(申请人提供)：结节性硬化症和自闭症结节性硬化症患者的MRI生物标记物(TSC)是一种常染色体显性遗传病，其特征是存在良性肿瘤，称为错构瘤，几乎可以影响身体的每个器官系统，包括大脑。患有TSC的个体的预后根据特定症状的严重程度而不同。虽然在儿童时期确诊的人可能会出现严重的症状，但成年后确诊的男性和女性可能会出现轻微的疾病形式。TSC患者的神经功能障碍的原因是一个关键的未解决的问题。我们的关键假设是自闭症谱系障碍(ASD)在TSC患者中的发展是白质发育和成熟异常的结果。这一假设得到了轴突连接错误和髓鞘过少的动物模型结果的支持，以及对TSC患者进行的扩散成像研究证实了与异常连接和髓鞘丧失一致的脑结构变化。这表明不良的认知/社会/行为结果可能是由于脑白质连通性和微结构完整性的改变，而不是TSC中最明显的脑部异常的皮质结节。TSC是一种遗传性疾病，其大脑发育异常的遗传学基础已为人所熟知，目前已有脑修饰药物治疗。确定伴有和不伴有ASD的TSC的脑异常的能力对于TSC治疗ASD的药物治疗的发展至关重要。我们的总体目标是通过对健康对照组、无TSC的ASD患者以及伴有和不伴有ASD的TSC患者的高级MRI评估，确定与ASD相关的脑变化。我们建议招募一组5-10岁的儿童，并进行全面的磁共振成像、图像分析和认知表型鉴定。我们建议对这些儿童进行为期五年的纵向研究。我们建议开发和评估一套定量解剖和弥散磁共振测量方法，以确定白质、皮质和皮质下灰质以及错构瘤的特征。为了提高MRI测量的准确性和可靠性，我们将在我们最近的工作基础上开发用于这些对象的MRI分析的新算法，实现应用这些算法的开源软件工具，并将这些工具与传统分析策略进行比较验证。我们将把成像数据和这些软件工具分发给成像社区。主要结果将是首次发展出区分对照组、无TSC的ASD患者、无ASD的TSC患者和有ASD的TSC患者的能力。

DESCRIPTION (provided by applicant): MRI Biomarkers of Patients with Tuberous Sclerosis Complex and Autism Tuberous sclerosis complex (TSC) is an autosomal dominant disease characterized by the presence of benign tumors, called hamartomas, which can affect virtually every organ system of the body, including the brain. The prognosis for individuals with TSC varies in accordance with the severity of the specific symptoms. While severe manifestations may be seen in individuals diagnosed in childhood, mild forms of the disease may be observed in men and women diagnosed in adulthood. The cause of neurological deficits in TSC patients is a key unresolved question. Our key hypothesis is that the development of autistic spectrum disorders (ASD) in TSC patients is a consequence of abnormal white matter development and maturation. This hypothesis is supported by both animal model findings of axonal miswiring and hypomyelination, and studies with TSC patients using diffusion imaging that have identified brain structural changes consistent with aberrant connectivity and loss of myelination. These suggest that adverse cognitive/social/behavioral outcomes may be due to alterations in white matter connectivity and microstructural integrity, not the cortical tubers that are the most obviou brain abnormalities in TSC. TSC is a genetic disorder with a well understood genetic basis for abnormal brain development, for which brain modifying drug therapy is currently available. The ability to characterize brain abnormalities in TSC with and without ASD will be crucial to the development of a drug therapy for ASD in TSC. Our overall objective is to identify the brain changes that are associated with ASD in patients with TSC, by the evaluation of advanced MRI of healthy controls, ASD patients without TSC, and TSC patients with and without ASD. We propose to recruit a cohort of children, aged 5-10 years old, and to carry out comprehensive MRI, image analysis and cognitive phenotyping. We propose to study these children longitudinally for five years. We propose to develop and evaluate a set of quantitative anatomic and diffusion MRI measures that characterize white matter, cortical and subcortical gray matter, and harmatomas. In order to improve the accuracy and reliability of the MRI measures, we will develop novel algorithms for MRI analysis of these subjects building on our own recent work, implement open source software tools to apply these algorithms, and validate these tools in comparison to conventional analysis strategies. We will distribute the imaging data and these software tools to the imaging community. The primary outcome will be the development for the first time of a capability discriminate between controls, patients with ASD without TSC, TSC patients without ASD and TSC patients with ASD.