Prospective Neuroimaging in Huntington's Disease

描述（由申请人提供）：症状性亨廷顿病（HD）实验治疗的最重要目标是开发能够减缓进展的疾病修饰（神经保护）疗法。快速发展的基础和转化研究已经确定了许多潜在的神经保护靶点，基于这些靶点的治疗正在为临床试验创造一个不断扩大的管道。然而，临床试验并没有接近跟上已经有一些理由的化合物，以及安全性和耐受性的可能性，并且差距正在迅速扩大。在HD临床试验中开发和使用生物标志物具有提高化合物及其靶点评估的速率和准确性的巨大潜力。由于HD基本上是一种进行性神经退行性疾病，因此神经成像测量作为疾病进展的直接测量方法具有很大的前景，还可以提供必要的灵敏度和特异性，以帮助评估II期和III期临床试验中的疾病改善。在当前的资助期间，我们使用最先进的神经成像工具来显示HD中的局部脑萎缩是早期和进行性的，并且与包括TFC在内的临床特征相对应。我们还将这些工具用作HD受试者中高剂量肌酸（一种主要候选神经保护剂）的初步研究中的药效学生物标志物。我们发现，高剂量肌酸减缓脑萎缩，减少氧化应激的措施，并可能减缓认知能力下降。我们正在寻求验证我们的神经成像工具，在一项受资助的安慰剂对照，双盲III期临床试验中，将大剂量肌酸作为疾病进展的生物标志物。如果肌酸能减缓进展和脑萎缩，这将是证明神经成像作为疾病改善的药效学生物标志物的价值的关键一步。公共卫生相关性：如果通过TFC测量，肌酸减缓了HD的临床进展，我们将了解神经成像测量作为药效学生物标志物的表现;它将为神经成像作为II期研究中潜在神经保护疗效的有用指标奠定基础;它将是最终将神经成像作为III期研究中潜在次要或替代终点的第一步。即使没有疗效，我们将了解如何区域大脑参与的基础上复杂的神经病学和过程的HD。

DESCRIPTION (provided by applicant): The most important goal of experimental therapeutics for symptomatic Huntington's disease (HD) is to develop disease-modifying (neuroprotective) therapies able to slow progression. Rapidly advancing basic and translational research has identified numerous potential targets for neuroprotection and treatments based on them are creating an expanding pipeline for clinical trials. However, clinical trials are not close to keeping up with compounds for which there is already some rationale, as well as likelihood of safety and tolerability, and the gap is quickly widening. The development and use of biomarkers in clinical trials for HD have profound potential to increase the rate and accuracy with which compounds, and by implication their targets, can be assessed. Since HD is fundamentally a progressive neurodegenerative disease, neuro-imaging measures hold great promise as direct measures of disease progression that may also provide the necessary sensitivity and specificity to help assess disease modification in Phase II and Phase III clinical trials. During the current funding period, we used state-of-the-art neuro-imaging tools to show that regional brain atrophy in HD is early and progressive, and corresponds to clinical features, including the TFC. We also used these tools as a pharmacodynamic biomarker in a pilot study of high-dose Creatine, a leading candidate neuroprotective agent, in HD subjects. We found that high dose Creatine slowed brain atrophy, reduced measures of oxidative stress, and may have slowed cognitive decline. We are seeking to validate our neuro-imaging tools in a funded placebo-controlled, double-blind Phase III clinical trial of high-dose creatine as a biomarker of disease progression. Should Creatine slow progression and slow brain atrophy, it will be a crucial step in demonstrating the value of neuro-imaging as a pharmacodynamic biomarker of disease modification. PUBLIC HEALTH RELEVANCE: If Creatine slows the clinical progression of HD as measured by the TFC, we will learn how well neuro-imaging measures perform as pharmacodynamic biomarkers; it will set the stage for neuro-imaging as a useful indicator of potential neuroprotective efficacy in Phase II studies; it will be a first step towards eventually qualifying neuro-imaging as a potential secondary or surrogate endpoint in Phase III studies. Even without efficacy, we will learn how regional brain involvement underlies the complex symptomatology and course of HD.