Cognitive and functional brain changes in preclinical Huntington's disease (HD)

描述（由申请人提供）：亨廷顿氏病（HD）是一种遗传性脑疾病，在中年表现为由于纹状体细胞死亡和相关回路中断导致的运动、认知和情感系统的缓慢进行性功能障碍。遗传突变包括多聚谷氨酰胺（CAG）重复序列数量的扩增，重复序列数量与HD发作相关，至少占年龄变异性的50%。目前正在努力更好地了解HD的发病机制，并获得更离散的估计其发病。在另一项研究中，我们正在评估具有HD基因突变但尚未表现出疾病临床体征（以下称为HD前）的人。正在进行结构MRI和全面的神经心理学和精神病学评估，以在传统的运动症状出现之前发现细微的疾病。我们小组的初步工作表明，结合使用成像和认知挑战任务可以检测早期功能障碍。使用认知激活磁共振成像（或功能性MRI），我们希望增加我们的正常基底神经节功能的理解，并允许我们监测和表征HD基底神经节病理的发展。将入组60例HD前受试者和30例健康对照受试者，并在间隔30个月的两个时间点进行纵向检查。MRI会议将包括解剖扫描，以评估对基底神经节功能敏感的四项认知任务的大脑结构和功能性MRI（fMRI）：时间辨别，概念推理，运动计时和反应抑制。具体的目的是检查功能磁共振成像在识别HD前参与者的神经功能障碍的敏感性，并确定基于DMA的疾病发作估计和随着时间的推移脑功能障碍指数之间的关联。该项目将促进我们对HD的神经生物学以及皮质纹状体回路在介导认知功能中的作用的理解。

DESCRIPTION (provided by applicant): Huntington's disease (HD) is a genetic brain disease that reveals itself in mid-life with slowly progressive dysfunction of motor, cognitive and emotional systems due to cell death in the striatum and related circuitry disruption. The genetic mutation consists of an expansion in the number of polyglutamine (CAG) repeats and the number of repeats is associated with HD onset, accounting for at least 50% of the variability in age. Efforts are underway to better understand the pathogenesis of HD and to derive more discrete estimates of its onset. In another study we are evaluating persons who have the gene mutation for HD, but do not yet demonstrate the clinical signs of illness (hereafter referred to pre-HD). Structural MRI and comprehensive neuropsychological and psychiatric assessments are being conducted to detect subtle disease before traditional motor symptoms appear. Preliminary work from our group suggests that a combined use of imaging and cognitive challenge tasks allow detection of early dysfunction. Using cognitive-activated magnetic resonance imaging (or functional MRI) we hope to increase our understanding of normal basal ganglia function and allow us to monitor and characterize the development of basal ganglia pathology in HD. Sixty pre-HD and thirty healthy control subjects will be enrolled and examined longitudinally at two time points separated by a 30-month interval. The MRI sessions will include anatomical scans to assess brain structure and functional MRI (fMRI) of four cognitive tasks sensitive to basal ganglia function: time discrimination, conceptual reasoning, motor timing, and response inhibition. The specific aims are to examine the sensitivity of fMRI in identifying neural dysfunction in pre-HD participants and to determine the association between DMA-based estimations of disease onset and indices of brain dysfunction over time. The proposed project will advance our understanding of the neurobiology of HD as well as the role of corticostriatal circuitry in mediating cognitive functions.