Growth and Development of the Striatum in Huntington's Disease

描述（由申请人提供）：本提案是一项独特研究的竞争性更新，该研究测量亨廷顿病（HD）风险儿童纹状体的体积、功能和发育。HD是一种由DNA三联体重复序列（CAG）扩增引起的神经退行性疾病，表现为认知、行为和运动改变。平均发病年龄为40岁。这种疾病最终会影响大部分大脑区域，但主要病理位于纹状体。退行性变是疾病过程中的一个关键因素，但过去几年的研究支持了HD病理的一个关键因素是大脑发育异常的观点。该基金于2009年资助，通过研究有患HD风险的儿童（父母一方患有HD的儿童）来调查这一假设。由于HD是一种常染色体显性遗传病，每个孩子都有50%的遗传机会。对高危参与者进行基因分型，并将基因扩增组（GE）与基因未扩增组（GNE）进行比较；第三组为健康对照儿童（HC）（家庭无HD）。评估包括核磁共振成像和运动功能、认知技能和行为的测量。目前的提案旨在通过对纹状体的生长和发育进行更彻底的评估来扩展我们的研究。原始研究使用结构磁共振成像（sMRI）评估体积，使用扩散张量成像（DTI）评估白质完整性。结果（见进展报告）表明纹状体体积不足，丘脑和小脑相对保留或扩大；和多道分数各向异性异常（FA）。新方案将增加：1)纹状体静息状态功能连接MRI （fcMRI）评估，2)纹状体完整性的分子测量（1)磁共振波谱（MRS），以及3）通过“加速纵向”格式评估大脑结构的发育轨迹（6-18岁之间的生长）。补偿机制，如小脑和丘脑的过度生长也将被调查。功能评估将包括认知和运动技能的测量。从这一建议中获得的信息可能是确定神经保护干预措施的最早可能时间框架的关键。

DESCRIPTION (provided by applicant): This proposal is a competitive renewal for a unique study that measures the volume, function, and development of the striatum in children at risk for Huntington's Disease (HD). HD is a neurodegenerative disease caused by a DNA triplet repeat (CAG) expansion and manifests in cognitive, behavioral, and motor changes. Average age of onset is 40 yrs. The disease eventually affects most brain regions, yet the primary pathology is located in the striatum. Degeneration is a key component in the disease process, yet research in the past few years has supported the notion that a crucial component of the pathoetiology of HD is abnormal brain development. The grant was funded in 2009 to investigate this hypothesis by the study of children at risk for HD (those with a parent with HD). As HD is an autosomal dominant disease, each child has a 50% chance of inheritance. The at-risk participants are genotyped and those who are gene-expanded (GE) are compared to those who are gene non-expanded (GNE); a 3rd comparison group is healthy control children (HC) (no HD in family). Assessments include MRI and measures of motor function, cognitive skills, and behavior. The current proposal is designed to extend our studies by conducting a more thorough evaluation of the growth and development of the striatum. The original study evaluated volumes using structural Magnetic Resonance Imaging (sMRI) and white matter integrity using Diffusion Tensor Imaging (DTI). Results (shown in progress report) indicate volume deficits in the striatum with relative sparing or enlargement of the thalamus and cerebellum; and abnormal fractional anisotropy (FA) in multiple tracks. The new protocol will add: 1) evaluation of striatal resting state functional connectivity MRI (fcMRI), 2) Molecular measures of striatal integrity using (1)H magnetic resonance spectroscopy (MRS), and 3) the evaluation of developmental trajectories (growth between ages 6-18 years) of brain structure via an 'accelerated longitudinal' format. Compensatory mechanisms such as overgrowth of the cerebellum and thalamus will also be investigated. Functional assessment will include measures of cognition and motor skill. Information gained from this proposal could be key to identifying the earliest possible time-frame for neuroprotective interventions.