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

描述(申请人提供)：亨廷顿病(HD)是一种遗传性脑部疾病，在中年时出现运动、认知和情绪系统的缓慢进行性功能障碍，原因是纹状体细胞死亡和相关的电路中断。基因突变包括聚谷氨酰胺(CAG)重复数的扩大，重复数与HD发病有关，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，并得出对其发病的更离散的估计。在另一项研究中，我们正在评估那些具有HD基因突变，但尚未表现出疾病临床症状的人(以下称为HD前)。正在进行结构核磁共振以及全面的神经心理学和精神病学评估，以在传统运动症状出现之前发现细微疾病。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到早期功能障碍。利用认知激活磁共振成像(或功能磁共振成像)，我们希望增加我们对正常基底节功能的了解，并使我们能够监测和描述HD基底节病理的发展。60名HD前受试者和30名健康对照组受试者将在间隔30个月的两个时间点进行纵向检查。MRI课程将包括解剖扫描，以评估大脑结构和对基底节功能敏感的四项认知任务的功能磁共振成像(FMRI)：时间辨别、概念推理、运动计时和反应抑制。具体目的是检查功能磁共振成像在识别HD前参与者神经功能障碍方面的敏感性，并确定基于DMA的疾病发病估计与随时间推移的脑功能障碍指数之间的关联。这个拟议的项目将促进我们对HD的神经生物学以及皮质纹状体回路在调节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.