Longitudinal Assessment of Brain Structure and Function in Juvenile Onset Huntington's Disease

项目概要： 亨廷顿氏病（HD）是一种遗传性神经退行性疾病， 亨廷顿基因的三核苷酸CAG重复区（HTT）。大多数HD患者不存在 症状持续到平均40-50岁，这被称为成人发病HD（AOHD）。 HD患者在21岁之前接受运动诊断的比例要小得多， 被称为青少年发病HD（JOHD）。尽管JOHD患者具有相同的核心三联征， 认知、行为和运动症状，存在不同于AOHD的独特临床特征。 具体来说，与AOHD患者相比，JOHD患者的舞蹈病较少，通常表现为 僵硬和运动迟缓。然而，由于罕见，关于症状的数据很少 特征，神经生物学和JOHD的进展。大规模的观察性研究已经 在AOHD中进行，这拓宽了我们对HD的理解，并为 开发和开展临床试验。JOHD患者已被排除在临床试验之外， 病人和他们的家人感到绝望，被科学界抛弃。大规模， 对JOHD患者的纵向研究对于我们更好地理解这种破坏性的疾病至关重要。 随着治疗策略在AOHD中的进展，为那些感到落后的患者提供希望。 我们在这里提出了有史以来第一次全面的，临床和神经影像学研究JOHD。大学的 在爱荷华州，我们进行了一项试点纵向临床和神经影像学研究，以了解 JOHD。我们将JOHD受试者与年龄和性别匹配的对照组进行了比较。此外，我们还比较了 从大型PREDICT-HD研究中随时间变化为AOHD受试者。我们的试点结果是惊人的： 首先，认知的标准测量和运动功能障碍的标准测量（联合亨廷顿的 疾病评定量表或UHDRS）显示随时间推移显著下降，支持这些 准确追踪疾病。这包括UDRS的“运动功能减退”分项评分， 与JOHD受试者相关。第二，JOHD患者即使在非常严重的 运动开始后的早期阶段。然而，纹状体和其他皮质下结构继续退化， 这表明它们可用于疾病进展的定量测量。第三，纹状体体积是 与临床症状密切相关，与UHDRS表现出很强的相关性，认知症状是 与丘脑体积有关。第四，在所有这些观察中，进展的速度更快 与AOHD患者相比，JOHD患者的变异较小。这些发现表明JOHD可能是一种 临床试验的上级组。

PROJECT SUMMARY: Huntington's disease (HD) is a genetic neurodegenerative disorder caused by an abnormal expansion of a trinucleotide CAG repeat region of the huntingtin gene (HTT). The majority of patients with HD do not present with symptoms until the age of 40-50 years old, on average, which is referred to as Adult-Onset HD (AOHD). A much smaller percentage of patients with HD receive a motor diagnosis prior to the age of 21, which is referred to as Juvenile-Onset HD (JOHD). Although patients with JOHD have the same core triad of cognitive, behavior, and motor symptoms, there are unique clinical characteristics that are distinct from AOHD. Specifically, patients with JOHD have less chorea compared to patients with AOHD, often presenting with rigidity and bradykinesia. However due to the rarity, there is a paucity of data regarding the symptom characterization, the neurobiology, and the progression of JOHD. Large-scale observational studies have been performed in AOHD, which have broadened our understanding of HD and opened the doors for the development and conduct of clinical trials. Patients with JOHD have been excluded from clinical trials, leaving patients and their families feeling hopeless and abandoned by the scientific community. Large-scale, longitudinal studies in patients with JOHD are critical to bettering our understanding of this devastating disease and providing hope to patients who have felt left behind as therapeutic strategies advance in AOHD. We propose here the first ever comprehensive, clinical and neuroimaging study of JOHD. At the University of Iowa, we have performed a pilot longitudinal clinical and neuroimaging study to understand the progression of JOHD. We compared JOHD subjects to age and sex matched controls. In addition, we compared rate of change over time to AOHD subjects from the large PREDICT-HD study. Results from our pilot are striking: First, standard measures of cognition, and standard measures of motor dysfunction (United Huntington's Disease Rating Scale or UHDRS) show significant decline over time, supporting the notion that these measures accurately track disease. This includes a `hypokinesis' sub-score of the UDRS that is particularly relevant for JOHD subjects. Second, patients with JOHD demonstrate impressive striatal atrophy even in very early stages after motor onset. However, the striatum and other subcortical structures continue to degenerate, suggesting that they can be used for quantitative measures of disease progression. Third, striatal volume is closely related to clinical symptoms, showing strong correlations to the UHDRS, and cognitive symptoms are associated with thalamus volume. Fourth, in all of these observations, the rate of progression is faster and less variable in JOHD compared to patients with AOHD. These findings suggest JOHD may be a superior group for clinical trials.