Early Biomarkers of Autism Spectrum Disorders in infants with Tuberous Sclerosis

结节性硬化症婴儿自闭症谱系障碍的早期生物标志物

• 批准号: 8730738
• 负责人: Darcy Krueger
• 金额: $ 346.36万
• 依托单位: BOSTON CHILDREN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-09-01 至 2017-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8730738
• 关键词: Affect; Age; Alabama; Anatomy; Animal Model; Autistic Disorder; Axon; Basic Science; Behavioral; Biological Markers; Biology; Birth; Brain; Child; Clinic; Clinical; Clinical Data; Clinical Management; Clinical Sciences; Clinical Treatment; Clinical assessments; Cognitive; Cognitive deficits; Collaborations; Comorbidity; Complex; Coupled; Data; Data Coordinating Center; Defect; Development; Diagnosis; Disease; Early Diagnosis; Education; Electroencephalography; Epilepsy; Etiology; Evaluation; FDA approved; Frequencies; Future; General Population; Genes; Genetic; Hereditary Disease; High Frequency Oscillation; High Prevalence; Human; Human Resources; Hyperactive behavior; Image; Impaired cognition; Individual; Infant; Interdisciplinary Study; Intervention; Lead; Leadership; Life; Longevity; Magnetic Resonance Imaging; Measures; Methodology; Modality; Molecular; Morbidity - disease rate; Mutation; Natural History; Neurodevelopmental Disorder; Neurofibromatoses; Neurologic; Pathway interactions; Patients; Pediatric Hospitals; Pharmaceutical Preparations; Physiological; Population Study; Radial; Rare Diseases; Recording of previous events; Recruitment Activity; Relative Risks; Reporting; Research; Research Infrastructure; Research Personnel; Research Training; Risk; Seizures; Signal Pathway; Site; Study models; Technology; Testing; Time; Toddler; Training; Training and Education; Tuberous Sclerosis; Tuberous sclerosis protein complex; Universities; Variant; Work; age group; autism spectrum disorder; base; clinical phenotype; design; disability; early childhood; effective therapy; experience; genetic analysis; high risk; human FRAP1 protein; improved; infancy; mTOR Inhibitor; mTOR inhibition; medical specialties; mouse model; myelination; neuron development; novel; operation; prevent; programs; prospective; public health relevance; relating to nervous system; small molecule; success; tool; treatment trial; white matter

DESCRIPTION (provided by applicant): Autism Spectrum Disorders (ASD) has complex and varying etiologies. A lack of understanding regarding the underlying molecular and cellular mechanisms is a key barrier in finding effective treatments. Single-gene disorders that have a high prevalence of ASD provide unique opportunities to investigate the underlying biology and test treatments for autism. Tuberous Sclerosis Complex (TSC) is a genetic disorder in which approximately 50% of individuals are also affected with ASD. Importantly, TSC can be diagnosed before or at the time of birth, and thus infants with TSC allow us to observe prospectively the natural history of ASD and develop better tools for early detection of autism. On a molecular level, TSC disease manifestations result from the aberrant hyperactivity of mTOR that is caused by mutation in one of two TSC genes. Pharmacologic mTOR inhibition to correct the cellular defects in TSC is no longer a hope for the future, but rather an exciting reality with proven efficacy against various TSC disease manifestations. To determine the potential benefit these agents may have in treating or preventing ASD, it is imperative to identify early markers of autism in infants with TSC, so as to not put young children who will not develop ASD at unnecessary risk. Accumulating clinical and basic science evidence suggests that aberrant white matter connectivity represents a rational candidate as a biomarker in TSC. TSC mouse models demonstrate defects in the specification, guidance, and myelination of axons. More importantly, several groups have reported abnormalities in the normal-appearing white matter of TSC patients that can be identified by MR imaging, and loss of white matter microstructural integrity is associated with neurological and cognitive deficits. Furthermore, there is preliminary data indicating that white matter integrity can be improved by treatment with mTOR inhibitors in both animal models and in TSC patients. Taken together, these findings lead to the hypothesis that longitudinal assessment of white matter integrity and neural connectivity in TSC infants, through advanced MRI and EEG analysis, can be used as an early biomarker of subsequent ASD in this genetic disease. This proposal aims to establish a consortium of five Children's Hospitals that are geographically-distributed throughout the US to recruit TSC patients in the first year of life to test this hypothesis. State of the art imaging with 3Tesla MR scanners, advanced EEG technology, validated neurodevelopmental assessment tools, genetic analysis, and standardized clinical measures through age 36 months will be utilized. The clinical consortium will be supported by a centralized Data Coordinating Center with experience in another rare disease (neurofibro- matosis). Collaboration with Leadership Education in Neurodevelopmental and Related Disabilities (LEND) programs at each center will provide additional interdisciplinary research training and education expertise in ASD and TSC. As a result of the research outlined in this proposal, better understanding of brain connectivity and it relationship to ASD in TSC will pave the way for new interventions for this and related causes of autism.

描述（由申请人提供）：自闭症谱系障碍（ASD）具有复杂且不同的病因。缺乏对潜在分子和细胞机制的了解是寻找有效治疗的关键障碍。 ASD高患病率的单基因疾病为研究自闭症的基本生物学和测试治疗提供了独特的机会。结节性硬化症复合物（TSC）是一种遗传疾病，其中大约50％的个体也受ASD影响。重要的是，可以在出生之前或出生时诊断出TSC，因此TSC的婴儿可以使我们能够前瞻性地观察ASD的自然历史，并开发出更好的自闭症早期检测工具。在分子水平上，TSC疾病的表现是由MTOR的异常多动症引起的，这是由两个TSC基因之一突变引起的。药理学MTOR抑制纠正TSC中细胞缺陷的抑制不再是对未来的希望，而是一种令人兴奋的现实，具有对各种TSC疾病表现的可靠疗效。为了确定这些代理在治疗或预防ASD的潜在利益，必须识别 TSC婴儿的自闭症早期标记，以便不让不会出于不必要的风险而发展ASD的幼儿。积累的临床和基础科学证据表明，异常的白质连通性代表了作为TSC中生物标志物的理性候选人。 TSC鼠标模型在轴突的规范，引导和髓鞘中表现出缺陷。更重要的是，有几个小组报告了可以通过MR成像鉴定的TSC患者正常同名白质的异常，而白质微观结构完整性的丧失与神经和认知缺陷有关。此外，有初步数据表明，在动物模型和TSC患者中用MTOR抑制剂治疗可以改善白质完整性。综上所述，这些发现导致了以下假设：通过先进的MRI和EEG分析，可以将TSC婴儿中白质完整性和神经连接性的纵向评估用作这种遗传疾病中随后ASD的早期生物标志物。该提案旨在建立一个由五个儿童医院组成的财团，这些财产在美国整个美国都被地理分布，以在生命的第一年招募TSC患者，以检验这一假设。使用3TESLA MR扫描仪，先进的脑电图技术，经过验证的神经发育评估工具，遗传分析和标准化的临床指标的最先进的成像。临床财团将由具有另一种罕见疾病（神经纤维结构）经验的集中数据协调中心支持。在每个中心与神经发育和相关残疾计划（LEND）计划（LEND）方案的领导力教育的合作将为ASD和TSC提供其他跨学科研究培训和教育专业知识。由于该提案中概述的研究，对大脑连通性及其与TSC中ASD的关系的更好理解将为这项自闭症的新干预措施铺平道路。