MRI Biomarkers of Patients with Tuberous Sclerosis Complex and Autism

描述（由申请人提供）：多发性硬化症和自闭症多发性硬化症（TSC）患者的MRI生物标志物是一种常染色体显性遗传疾病，其特征为存在称为错构瘤的良性肿瘤，其几乎可以影响身体的每个器官系统，包括大脑。TSC患者的预后根据具体症状的严重程度而变化。虽然在儿童时期诊断的个体中可能会出现严重的表现，但在成年期诊断的男性和女性中可能会观察到轻度形式的疾病。TSC患者神经功能缺损的原因是一个尚未解决的关键问题。我们的主要假设是TSC患者自闭症谱系障碍（ASD）的发展是异常白色物质发育和成熟的结果。这一假设得到了轴突布线错误和髓鞘形成不足的动物模型结果以及使用弥散成像对TSC患者进行的研究的支持，这些研究已经确定了与异常连接和髓鞘形成丧失一致的脑结构变化。这些结果表明，不良的认知/社会/行为结果可能是由于白色物质连接和微结构完整性的改变，而不是TSC中最明显的大脑异常皮质结节。TSC是一种遗传性疾病，其具有异常脑发育的充分理解的遗传基础，目前可对其进行脑修饰药物治疗。描述TSC伴和不伴ASD的脑异常的能力对于开发TSC中ASD的药物治疗至关重要。我们的总体目标是通过对健康对照、无TSC的ASD患者以及有和无ASD的TSC患者进行高级MRI评估，确定与TSC患者中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MRI、图像分析和认知表型分析。我们建议对这些儿童进行为期五年的纵向研究。我们建议开发和评价一套定量解剖和扩散MRI措施，表征白色物质，皮质和皮质下灰质，和错构瘤。为了提高MRI测量的准确性和可靠性，我们将在我们自己最近的工作基础上开发用于这些主题的MRI分析的新算法，实现开源软件工具来应用这些算法，并与传统分析策略相比验证这些工具。我们将把成像数据和这些软件工具分发给成像社区。主要结局将是首次开发区分对照、ASD无TSC患者、TSC无ASD患者和TSC伴ASD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.