Neurobiological Predictors of Huntington's Disease

描述（由申请人提供）：PREDICT-HD是一项针对亨廷顿舞蹈病（HD）高危人群的国际30点观察性研究。PREDICT-HD利用了HD在神经退行性疾病中的两个独特方面：能够提前知道谁将会患上这种疾病，以及所有受影响的个体具有相同的病因（亨廷顿蛋白基因中的CAG扩增）。PREDICT-HD已经成为全球努力的一部分，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。我们寻求这个项目的更新，以最大限度地发挥这一资源的影响，并测试新的和完善的假设，以推进HD的临床试验。PREDICT-HD的最终目标是充分定义HD的神经生物学，以便在高危个体出现可诊断的疾病症状之前进行潜在的疾病改善疗法的临床试验。通过识别在早期阶段有用的疾病状态标记，PREDICT-HD将使测试可能延迟或预防疾病表现的假定神经保护疗法成为可能。PREDICT-HD已成功招募了1000多名健康参与者，他们此前曾接受过HD扩增基因检测。每年测量血浆、脑成像、认知表现、精神症状和功能能力，并结合其他人口统计学、临床和遗传信息。我们已经确定了比传统的运动诊断早15年的疾病标记。要求对PREDICT-HD进行5年的纵向延续，将产生6个产品：(1)在传统临床诊断前10-20年至后0-3年期间，对功能、认知、运动和精神变化的早期纵向病程进行表征。(2)确定候选生物学和神经影像学标记物，这些标记物有可能成为有用的生物标记物，并可能作为临床试验的替代终点。如果发展得当，在PREDICT-HD中发现的标记物可用于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)细化和标准化HD早期神经和功能损害的测量，包括传统的临床诊断点。(4)提供一个队列，其中子样本可以自愿参加候选疗法的早期（I期和II期）试验以及III期疗效试验。(5)检查可用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记物的影响。(6)基础设施创新和全球合作，为其他神经退行性疾病的临床试验提供模式和催化剂。

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.