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）：结节性硬化症和自闭症患者的 MRI 生物标志物 结节性硬化症 (TSC) 是一种常染色体显性遗传疾病，其特征是存在称为错构瘤的良性肿瘤，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有所不同。虽然在儿童时期诊断的个体中可能会出现严重的症状，但在成年后诊断的男性和女性中可能会观察到轻微的疾病形式。 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，TSC 患者患自闭症谱系障碍 (ASD) 是白质发育和成熟异常的结果。这一假设得到了轴突错误和髓鞘形成不足的动物模型研究结果的支持，以及使用弥散成像对 TSC 患者进行的研究，这些研究已经确定了与异常连接和髓鞘形成缺失一致的大脑结构变化。这些表明不良的认知/社会/行为结果可能是由于白质连接性和微结构完整性的改变，而不是 TSC 中最明显的大脑异常的皮质结节。 TSC 是一种遗传性疾病，其导致大脑发育异常的遗传基础已被充分了解，目前可采用大脑修饰药物治疗。表征患有和不患有 ASD 的 TSC 大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 患者以及患有或不患有 ASD 的 TSC 患者进行先进 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，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扩散 MRI 测量方法，以表征白质、皮质和皮质下灰质以及错构瘤。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受试者 MRI 分析的新算法，实施开源软件工具来应用这些算法，并与传统分析相比验证这些工具策略。我们将向成像社区分发成像数据和这些软件工具。主要成果将是首次开发区分对照、无 TSC 的 ASD 患者、无 ASD 的 TSC 患者和患有 ASD 的 TSC 患者的能力。