MRI Biomarkers of Patients with Tuberous Sclerosis Complex and Autism

结节性硬化症（TSC）是一种常染色体显性疾病，其特征是存在被称为错构瘤的良性肿瘤，它几乎可以影响身体的每个器官系统，包括大脑。TSC患者的预后因具体症状的严重程度而异。虽然在儿童时期确诊的个体可能出现严重症状，但在成年后确诊的男性和女性中可能出现轻度症状。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。这一假设得到了两方面的支持：一是动物模型发现轴突连接错误和髓鞘形成不足；二是利用弥散成像技术对TSC患者进行研究，发现大脑结构变化与异常连接和髓鞘形成缺失一致。这些结果表明，不良的认知/社会/行为结果可能是由于白质连通性和微观结构完整性的改变，而不是皮层结节，这是TSC中最明显的大脑异常。TSC是一种遗传性疾病，具有良好的大脑异常发育的遗传基础，目前可用于脑修饰药物治疗。在伴有或不伴有ASD的TSC中表征大脑异常的能力对于开发针对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者、无TSC的ASD患者以及伴有和不伴有ASD的TSC患者进行高级MRI评估，确定TSC患者与ASD相关的大脑变化。我们建议招募一组5-10岁的儿童，进行全面的MRI、图像分析和认知表型分析。我们建议对这些孩子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MRI测量方法，以表征白质、皮层和皮层下灰质和损伤瘤。为了提高MRI测量的准确性和可靠性，我们将在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。研究的主要结果将是首次建立一种区分对照组、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.