Brain Structure and Function in Children at Risk for Huntington's Disease

描述（由申请人提供）：亨廷顿病（HD）是一种常染色体显性遗传疾病，表现为认知、精神和运动体征和症状的三联征。这种疾病传统上被概念化为“纹状体神经退行性疾病”。然而，最近的证据挑战了这一概念。多项证据表明，除了退行性过程之外，这种疾病的病因可能还存在一个重要的发育因素。例如，我们实验室的研究表明，HD基因阳性但尚未表现出疾病的成年受试者（症状前基因携带者或PSGC）的大脑结构发生显着变化，具体表现为颅内容积减少、大脑白质体积减少、大脑皮层体积增加。这些变化支持了这些受试者大脑发育异常的可能性。越来越多的研究评估 PSGC 与非基因携带者 (NGC) 的比较，支持这样的观点：PSGC 不仅具有如上所述的大脑结构变化，而且在认知、运动和精神症状方面也有微妙但显着的缺陷。因此，尽管大脑变化和症状在诊断之前就已经存在，但它们是什么时候开始的呢？这些变化是否有可能从出生时就存在，然后在疾病过程中不断进展？为了更好地了解这种脑部疾病的发育方面，当前的研究建议评估有患 HD 风险的儿童（6-12 岁）的大脑结构和功能。将使用磁共振成像（MRI）对整个大脑进行定量测量来评估大脑结构，包括大脑和小脑体积等一般测量以及大脑皮层、大脑白质和皮质下核（尾状核、壳核、丘脑）等区域测量。将通过认知测试、神经学评估和行为评估来评估大脑功能。 PSGC 受试者将与 NGC 受试者进行比较。 PSGC 中大脑结构和/或功能的变化将为这种疾病具有重要发育成分的观点提供重要支持。如果得到证实，HD 的发育模型可以识别退化之前功能失调的疾病途径。这可能会导致干预技术能够针对并保护这些途径，从而预防疾病。公共健康相关性：这是“亨廷顿舞蹈病风险儿童的大脑结构和功能”提案 (1RO1 NS055903-01) 的修订申请。该研究旨在评估有亨廷顿舞蹈病风险的儿童（6 - 12 岁）的大脑结构（使用磁共振成像）和大脑功能（使用认知和行为评估）。基因阳性组的大脑结构和/或功能的变化将为这种疾病具有重要发育成分的观点提供了重要支持。

DESCRIPTION (provided by applicant): Huntington's disease (HD) is an autosomal dominant disease manifested in a triad of cognitive, psychiatric, and motor signs and symptoms. This disease has classically been conceptualized as a "neurodegenerative disease of the striatum". However, recent evidence challenges this concept. Several lines of evidence have suggested that in addition to the degenerative process, there may be an important developmental component to the etiology of this disease. For example, studies in our laboratory show that adult subjects who are gene positive for HD but have not yet manifested the illness (presymptomatic gene carriers or PSGCs) have significant changes in the structure of their brain, specifically, decreased intracranial volume, decreased volume of cerebral white matter, and increased volume of cerebral cortex. These changes support the possibility that these subjects may have had abnormal brain development. A growing body of research evaluating PSGCs compared to Non-Gene Carriers (NGCs) supports the notion that PSGCs not only have structural brain changes as described above, they also have subtle but significant deficits in cognitive, motor, and psychiatric symptoms. Thus, although brain changes and symptoms are present prior to diagnosis, when do they begin? Is it possible that these changes are present from birth and then progress during the course of the disease process? In an effort to better understand the developmental aspects of this brain disease, the current study proposes to evaluate brain structure and function in children (ages 6-12) who are at risk for developing HD. Brain structure will be evaluated using Magnetic Resonance Imaging (MRI) with quantitative measures of the entire brain, including general measures such as cerebrum and cerebellar volume as well as regional measures such as cerebral cortex, cerebral white matter, and subcortical nuclei (caudate, putamen, thalamus). Brain function will be assessed by cognitive tests, neurologic evaluation, and behavioral assessment. Subjects that are PSGCs will be compared to subjects who are NGCs. Changes in brain structure and/or function in the PSGCs would lend significant support to the notion that this disease has an important developmental component. If proven, a developmental model of HD could identify disease pathways that are dysfunctional prior to degeneration. This could lead to intervention techniques that could target and protect these pathways, preventing the disease. PUBLIC HEALTH RELEVANCE: This is a revised application for the proposal "Brain Structure and Function in Children at Risk for Huntington's Disease (1RO1 NS055903-01). The study is designed to evaluate the brain structure (using Magnetic Resonance Imaging) and brain function (using cognitive and behavioral assessment) of children (ages 6 - 12 years) at risk for Huntington's Disease. Changes in brain structure and/or function in the gene positive group would lend significant support to the notion that this disease has an important developmental component.