Prospective Neuroimaging in Huntington's Disease

描述（由申请人提供）：针对症状性亨廷顿舞蹈病（HD）的实验疗法的最重要目标是开发能够减缓疾病进展的疾病改善（神经保护）疗法。快速推进的基础研究和转化研究已经确定了许多神经保护的潜在靶点，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渠道。然而，临床试验并不能跟上已经有一些基本原理的化合物，以及安全性和耐受性的可能性，而且差距正在迅速扩大。生物标志物在HD临床试验中的开发和使用具有极大的潜力，可以提高评估化合物及其靶点的比率和准确性。由于HD本质上是一种进行性神经退行性疾病，神经影像学测量作为疾病进展的直接测量具有很大的前景，也可能提供必要的敏感性和特异性，以帮助评估II期和III期临床试验中的疾病改变。在目前的资助期内，我们使用了最先进的神经成像工具来显示HD的区域性脑萎缩是早期和进行性的，并且与临床特征相对应，包括TFC。我们还将这些工具用作HD受试者高剂量肌酸（一种主要的候选神经保护剂）的先导研究的药效学生物标志物。我们发现高剂量肌酸可以减缓脑萎缩，减少氧化应激，并可能减缓认知能力下降。我们正在寻求在一项资助的安慰剂对照、双盲III期临床试验中验证我们的神经成像工具，该试验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，它将是证明神经成像作为疾病改变的药效学生物标志物价值的关键一步。公共卫生相关性：如果肌酸通过TFC测量减缓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效果如何；它将为神经成像在II期研究中作为潜在神经保护功效的有用指标奠定基础；这将是最终将神经成像作为III期研究潜在的次要或替代终点的第一步。即使没有疗效，我们也将了解局部脑受累是如何导致HD的复杂症状和病程的。

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.