Neurobiological Predictors of Huntington's Disease

描述(由申请人提供)：Forecate-HD是一项对亨廷顿病(HD)高危人群进行的30个地点的国际观察性研究。Forecast-HD利用了神经退行性疾病中HD的两个独特方面，即提前知道谁会患上这种疾病，以及知道所有受影响的人都有相同的病因(Huntingtin基因的CAG扩增)。Forecast-HD已经成为世界范围内努力的一部分，并提供了一个前所未有的机会来检查早期HD的病理生理学和神经生物学。我们寻求更新这个项目，以最大限度地发挥这一资源的影响，并测试新的和改进的假设，以推进HD的临床试验。Forecast-HD的最终目标是充分定义HD的神经生物学，以便在高危人群出现可诊断的疾病症状之前，对潜在的疾病修改疗法进行临床试验。通过识别在这一早期阶段有用的疾病状态标记物，预测-HD将使测试可能延迟或预防疾病表现的假定的神经保护疗法成为可能。Forecast-HD已经成功招募了1000多名健康的参与者，他们之前曾接受过HD扩展的基因测试。每年对血浆、脑成像、认知能力、精神症状和功能能力的测量与其他人口统计学、临床和遗传信息相一致。我们已经确定了比传统运动诊断早15年出现的疾病标志。Forecast-HD申请的5年纵向延续将产生六个产品：(1)描述从传统临床诊断点之前10-20年到之后0-3年的早期纵向功能、认知、运动和精神变化过程。(2)确定可能作为有用的生物标志物和临床试验替代终点的候选生物和神经影像标志物。如果开发得当，Predicate-HD中确定的标志物可以用来大幅减少未来临床试验所需的受试者数量，和/或在研究中对受试者进行分层选择。(3)HD早期神经功能损害测量的精细化和标准化，包括传统临床诊断的角度。(4)提供一个队列，以供亚样本自愿参加候选疗法的早期(第一阶段和第二阶段)试验以及第三阶段疗效试验。(5)检查现有化合物的安全性和耐受性，以及它们对症状前队列中新开发的疾病状态标志物的影响。(6)基础设施的创新和全球合作，以作为其他神经退行性疾病临床试验的典范和催化剂。

DESCRIPTION (provided by applicant): PREDICT-HD is an international 30-site observational study of persons at-risk for Huntington's disease (HD). PREDICT-HD capitalizes on two unique aspects of HD among neurodegenerative disorders the ability to know in advance who will develop the disease and the knowledge that all affected individuals have the same etiology (a CAG expansion in the huntingtin gene). PREDICT-HD has become part of a world-wide effort and offers an unprecedented opportunity to examine the pathophysiology and neurobiology of early HD. We seek renewal of this project to maximize the impact of this resource and test new and refined hypotheses to advance clinical trials in HD. The ultimate goal of PREDICT-HD is to define the neurobiology of HD sufficiently to allow clinical trials of potential disease-modifying therapies before at-risk individuals have diagnosable symptoms of the disease. By identifying disease state markers that are useful during this early period, PREDICT-HD will make it possible to test putative neuroprotective therapies that could delay or prevent the manifestations of disease. PREDICT-HD has successfully recruited over 1000 healthy participants who had previously undergone genetic testing for the HD expansion. Annual measures of plasma, brain imaging, cognitive performance, psychiatric symptoms, and functional capacity are obtained in concert with other demographic, clinical and genetic information. We have already identified markers of disease that are present 15 years prior to traditional motor diagnosis. The requested 5-year longitudinal continuation of PREDICT-HD will result in six products: (1) Characterization of the early longitudinal course of functional, cognitive, motor, and psychiatric change in the period encompassing 10-20 years before to 0-3 years after the traditional point of clinical diagnosis. (2) Identification of candidate biological and neuroimaging markers that have potential as useful biomarkers and possibly as surrogate endpoints in clinical trials. Developed appropriately, markers identified in PREDICT-HD could be used to reduce dramatically the number of subjects needed in future clinical trials, and/or to stratify subjects for selection in studies. (3) Refinement and standardization of the measurement of neurological and functional impairment in the earliest stages of HD development, including the point of traditional clinical diagnosis. (4) Provision of a cohort from which sub samples may volunteer for early (phase I and II) trials of candidate therapies as well as phase III efficacy trials. (5) Examination of available compounds for safety and tolerability and of their impact on newly developed disease state markers in this presymptomatic cohort. (6) Innovations in infrastructure and worldwide collaboration to serve as a model and catalyst for clinical trials in other neurodegenerative diseases.