Prospective Neuroimaging in Huntington's Disease

项目负责人/主要研究者（最后、第一、中间）：罗萨斯、赫米尼亚·戴安娜 摘要： 症状性亨廷顿病（HD）的实验性治疗的最重要目标是 开发能够减缓疾病进展的疾病修饰（神经保护）疗法。快速推进 基础和转化研究已经确定了许多潜在的神经保护靶点， 基于它们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论基础的化合物，以及 安全性和耐受性的可能性，并且差距正在迅速扩大。开发使用为 HD临床试验中的生物标志物具有极大的潜力，可以提高HD的发生率和准确性， 可以评估哪些化合物以及它们的靶点。由于HD基本上是一种 进行性神经退行性疾病，神经影像学措施具有很大的希望， 疾病进展的测量，也可以提供必要的敏感性和特异性， 帮助评估II期和III期临床试验中的疾病改变。在目前的资金 在此期间，我们使用了最先进的神经成像工具来显示HD的局部脑萎缩是早期的， 并且是进行性的，并且对应于临床特征，包括TFC。我们还使用这些工具作为 一种药效学生物标志物，在一项高剂量肌酸的试点研究中， 神经保护剂。我们发现大剂量肌酸可以减缓脑萎缩 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 在一项受资助的安慰剂对照、双盲III期临床试验中验证我们的神经成像工具， 高剂量肌酸作为疾病进展的生物标志物。肌酸应该减缓进展， 缓慢的脑萎缩，这将是证明神经成像作为一种 疾病改善的药效学生物标志物。 PHS 398/2590（Rev. 11/07）

Program Director/Principal Investigator (Last, First, Middle): Rosas, Herminia Diana Abstract: 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. PHS 398/2590 (Rev. 11/07) Page Continuation Format Page