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

临床前亨廷顿病 (HD) 的认知和功能性大脑变化

• 批准号: 7424036
• 负责人: Jane S Paulsen
• 金额: $ 38.19万
• 依托单位: UNIVERSITY OF IOWA
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-05-15 至 2012-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7424036
• 关键词: Accounting; Address; Age; Basal Ganglia; Biological; Brain; Brain Diseases; CAG repeat; Cell Death; Clinical; Clinical Data; Cognitive; Complex; Corpus striatum structure; Data; Development; Diagnosis; Discrimination; Disease; Disruption; Early Diagnosis; Emotional; Enrollment; Functional Magnetic Resonance Imaging; Functional disorder; Gene Mutation; Genetic; Goals; Huntington Disease; Image; Impairment; Individual; Knowledge; Literature; Magnetic Resonance Imaging; Measures; Mediating; Monitor; Motor; Neurobiology; Neuronal Dysfunction; Neurophysiology - biologic function; Neuropsychological Tests; Numbers; Onset of illness; Participant; Pathogenesis; Pathology; Pattern; Performance; Persons; Range; Rate; Reaction Time; Relative (related person); Research; Role; Scanning; Structure; Symptoms; System; Testing; Time; Trinucleotide Repeats; Validation; Work; base; clinical phenotype; cognitive function; disorder control; human disease; indexing; middle age; morphometry; neural circuit; neuropsychological; polyglutamine; pre-clinical; prospective; relating to nervous system; size

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.

描述（由申请人提供）：亨廷顿病（HD）是一种遗传性脑部疾病，由于纹状体细胞死亡和相关电路破坏，在中年时会出现运动、认知和情感系统缓慢进行性功能障碍。基因突变包括聚谷氨酰胺 (CAG) 重复次数的增加，重复次数与 HD 发病相关，至少占年龄变异的 50%。人们正在努力更好地了解 HD 的发病机制，并对其发病情况进行更离散的估计。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症状的人（以下称为 HD 前期）。正在进行结构性核磁共振以及全面的神经心理学和精神病学评估，以便在传统运动症状出现之前发现微妙的疾病。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），我们希望增加对正常基底神经节功能的了解，并使我们能够监测和表征 HD 基底神经节病理的发展。将招募 60 名 HD 前受试者和 30 名健康对照受试者，并在相隔 30 个月的两个时间点进行纵向检查。 MRI 课程将包括评估大脑结构的解剖扫描和对基底神经节功能敏感的四种认知任务的功能 MRI (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 fMRI 在识别 HD 前期参与者神经功能障碍方面的敏感性，并确定基于 DMA 的疾病发作估计与随时间变化的脑功能障碍指数之间的关联。该项目将增进我们对 HD 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。