Characterization of White Matter in Huntington's Disease Using Diffusion MRI

描述（由申请人提供）：这项为期两年的辅助拨款申请涉及亨廷顿病（HD），这是一种遗传性和进行性神经系统疾病，其特征是运动、认知和行为功能逐渐下降。目前尚无治愈HD的方法，了解受影响脑区早期疾病进展对于开发新的治疗干预措施至关重要。最近的研究已经确定了皮质-纹状体白色物质通路，其连接纹状体与运动皮质，作为HD运动功能障碍学的关键。然而，目前的扩散MRI分析方法不足以正确表征HD诱导的该通路中的病理变化。因此，该辅助拨款申请的目的是将我们的新型高级弥散MRI生物标志物和分析方法定位于皮质-纹状体通路。通过将这些新的生物标志物检测到的异常与皮质-纹状体束的特定部分相关联，将有可能精确地绘制白色束变性和运动功能障碍之间的关系。这将有助于我们进一步了解HD运动功能恶化的神经病理学基础。这项拨款提案的核心是预测HD数据库。该数据集包含大脑成像数据和一组全面的临床相关性，这些数据来自一个非常大的患有预显（前驱）HD的个体样本，选择这些个体是为了从其最早的体征开始追踪HD病理学。该提案将联合收割机的优势与我们的尖端神经成像技术相结合，该技术可检测和测量白色组织的几种新型结构和生理特性。因此，本研究的主要创新之处在于使用我们的新方法对弥散MRI数据进行分析，以在体内表征HD中皮质-纹状体通路的白色物质连接发生的变化。这些新方法结合起来，不仅能够量化白色物质的病理变化，而且能够将这些变化的纵向演变与特定运动功能障碍的演变相关联。这些生物标志物将增强对表现前HD的理解，并将使更好地监测疾病进展和靶向潜在早期治疗的能力成为可能。

DESCRIPTION (provided by applicant): This ancillary grant application for two years of funding addresses Huntington's disease (HD), a genetic and progressive neurological disorder characterized by a gradual decline in motor, cognitive and behavioral functions. No cure for HD currently exists, and an understanding of disease progression at early stages in the affected brain areas is important for the development of new therapeutic interventions. Recent research has identified the cortico-striatal white matter pathway, which connects the striatum to the motor cortex, as key to HD motor function symptomatology. Current methods of analysis in diffusion MRI, however, are insufficient to properly characterize the pathological changes in this pathway induced by HD. The purpose of this ancillary grant application is therefore to target our novel advanced diffusion MRI biomarkers and analysis methods to the cortico-striatal pathway. By associating abnormalities detected with these novel biomarkers to specific parts of the cortico-striatal tract, it will be possible to precisely map the relationship between white matter tract degeneration and motor dysfunction. This will help advance our understanding of the neuropathological basis of motor deterioration in HD. At the center of this grant proposal is the PREDICT-HD database. This dataset contains brain imaging data and a comprehensive set of clinical correlates from a very large sample of individuals with pre-manifest (prodromal) HD, who were selected to allow for tracing HD symptomatology from its very earliest signs. This proposal will combine the strengths of PREDICT-HD with our cutting-edge neuroimaging technology, which detects and measures several novel types of structural and physiological properties of white matter tissue. The principal innovation in this grant is therefore the use of our novel methods of analysis of diffusion MRI data to characterize in vivo the changes occurring in the white matter connections of the cortico-striatal pathways in HD. Applied together, these new methods will have the ability to not only to quantify pathological changes in white matter, but also to correlate the longitudinal evolution of these changes to the evolution of specific motor dysfunctions. These biomarkers will enhance understanding of pre-manifest HD and will make possible the ability to better monitor disease progression and to target potential early treatments.