MRI Biomarkers of Patients with Tuberous Sclerosis Complex and Autism

结节性硬化症和自闭症患者的 MRI 生物标志物

• 批准号: 8705058
• 负责人: SIMON K WARFIELD
• 金额: $ 71.65万
• 依托单位: BOSTON CHILDREN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-08-01 至 2018-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8705058
• 关键词: 10 year old; Adult; Affect; Age; Algorithms; Anatomy; Animal Model; Atrophic; Autistic Disorder; Behavioral; Benign; Biological Markers; Brain; Brain Hamartoma; Cells; Characteristics; Child; Childhood; Cognitive; Communication; Communities; Data; Development; Diagnosis; Diffusion; Diffusion Magnetic Resonance Imaging; Disease; Enrollment; Ethnic group; Evaluation; Exhibits; Frequencies; Genetic; Hamartoma; Hereditary Disease; Image; Image Analysis; Incidence; Individual; Intellectual functioning disability; Intervention; Language; Longitudinal Studies; Magnetic Resonance Imaging; Measures; Modeling; Monitor; Mutation; Neurologic; Non-Malignant; Outcome; Pathway interactions; Patients; Pharmaceutical Preparations; Pharmacotherapy; Phenotype; Quality of life; Race; Recruitment Activity; Rewards; Risk; Seizures; Severities; Social support; Software Tools; Symptoms; TSC1 gene; TSC2 gene; Technology; Therapeutic; Thick; Time; Tuberous sclerosis protein complex; Woman; Work; aged; autism spectrum disorder; base; body system; brain tissue; cohort; disorder control; gray matter; improved; men; myelination; neuropsychological; novel; open source; outcome forecast; primary outcome; prospective; public health relevance; relating to nervous system; research study; response; sex; social; social communication; tool; tumor; white matter

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.

描述（由申请人提供）：结节性硬化症复合物和自闭症结节性硬化症复合物（TSC）患者的MRI生物标志物是一种常染色体显性疾病，其特征是存在良性肿瘤的存在，称为Hamartomas，它几乎会影响包括大脑在内的每个器官。 TSC患者的预后根据特定症状的严重程度而有所不同。虽然在童年时期被诊断出的个体中可以看到严重的表现，但在成年期被诊断出的男性和女性中可能会观察到这种疾病的轻度形式。 TSC患者神经缺陷的原因是一个关键的未解决问题。我们的关键假设是TSC患者自闭症频谱疾病（ASD）的发展是白质发育和成熟异常的结果。轴突误导和低司启示的动物模型发现以及使用TSC患者使用扩散成像的研究来支持这一假设，这些发现已经确定了与异常连通性和髓鞘丧失一致的大脑结构变化。这些表明，不利的认知/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TSC中最明显的脑异常的皮质块茎。 TSC是一种遗传疾病，具有众所周知的脑发育异常的遗传基础，目前可以为此提供大脑修饰药物治疗。具有和不具有ASD的TSC中脑异常的表征能力对于开发TSC中ASD的药物治疗至关重要。我们的总体目标是通过评估健康对照组，没有TSC的ASD患者以及患有和没有ASD的TSC患者的高级MRI，确定与TSC患者相关的大脑变化。我们建议招募一群5-10岁的儿童，并进行全面的MRI，图像分析和认知表型。我们建议纵向研究这些儿童五年。我们建议开发和评估一组定量解剖和扩散的MRI测量，这些测量表征了白质，皮质和皮层灰质以及Harmatomas。为了提高MRI措施的准确性和可靠性，我们将开发新的算法，用于根据我们自己的最新工作来建立这些主题，实施开源软件工具以应用这些算法，并与常规分析策略相比验证这些工具。我们将将成像数据和这些软件工具分发给成像社区。主要结果将是能力的首次开发，在对照组，无TSC的患者，无ASD和TSC患者ASD患者的TSC患者之间进行区分。