Basal Ganglia Shape Analysis and Circuitry in Huntington's Disease

描述（由申请人提供）：亨廷顿病（HD）是一种进行性、致死性、神经退行性疾病，伴有运动障碍、精神病特征和认知功能下降。神经退行性变是区域异质性的，优先损失纹状体中型多棘神经元，但在其他地区的显着萎缩。这就引出了一个问题，即这种局部变性模式是否与回路有关，反映了受影响神经元的解剖学连接，或者相反，是多灶性的。为了解决这个问题，我们将对基底神经节进行统计形状分析，并检查连接萎缩区域和受影响皮质区域的白色物质结构。我们假设，将有异质性萎缩在选定的皮质下区域，形状分析可能会发现一些局部变化早期，整体体积变化显着之前。我们假设区域苍白球萎缩与特定的局部基底神经节连接相关，但区域纹状体萎缩与区域皮质萎缩预测的连接不完全相关。我们还将进行白色物质结构的补充分析。具体而言，目标1将进行横截面统计形状分析（尾状核、壳核、丘脑、海马、丘脑核和苍白球）; Aim 2将对特定皮质下灰质区域进行纵向形状分析（如上所列），351例受试者在2个时间点进行扫描; Aim 3将对白色物质结构进行分析，以确定受影响最严重的纹状体区域是否接受来自最受影响的皮质，以及最受影响的苍白球区域是否接受来自最受影响的纹状体区域的投射。 公共卫生相关性：在前驱期和早期症状性亨廷顿氏病（HD）中鉴定的萎缩的特定子区域将有助于确定HD中的神经变性是否遵循连接脑结构的基于回路的通路（类似于朊病毒病，并且如针对阿尔茨海默氏病和帕金森氏病的假设），或者是多灶性的。这些数据对于规划直接针对大脑的干预措施非常重要，因此与HD治疗直接相关。

DESCRIPTION (provided by applicant): Huntington disease (HD) is a progressive, fatal, neurodegenerative disease, with movement disorder, psychiatric features, and cognitive decline. The neurodegeneration is regionally heterogeneous with preferential loss of striatal medium spiny neurons, but with significant atrophy in other regions. This leads to the question whether this pattern of regional degeneration is circuit related, reflecting the anatomic connections of the affected neurons, or by contrast is multifocal. To address this question, we will perform statistical shape analysis of basal ganglia and examine white matter structures connecting atrophied regions with affected cortical regions. We hypothesize that there will be heterogeneous atrophy in selected subcortical regions, and that shape analysis may detect some localized changes early, before overall volumes change significantly. We hypothesize that regional globus pallidus atrophy will correlate with specific local basal ganglia connections, but that regional striatal atrophy will not entirely correlate with connections predicted by regional cortical atrophy. We will also perform complementary analysis of white matter structures. Specifically Aim 1 will perform cross- sectional statistical shape analysis (caudate, putamen, thalamus, hippocampus, nucleus accumbens and globus pallidus) in 351 subjects with and without prodromal HD; Aim 2 will perform longitudinal shape analysis on specific subcortical gray matter regions (as listed above) for 351 subjects with scans at 2 time points; and Aim 3 will perform analysis of white matter structures in to determine whether the regions of striatum most affected receive projections from the regions of cortex most affected, and whether the regions of globus pallidus most affected receive projections from the regions of striatum most affected. PUBLIC HEALTH RELEVANCE: Specific sub-regions of atrophy identified in prodromal and early symptomatic Huntington's Disease (HD) will help determine whether neurodegeneration in HD follows a circuit-based pathway connecting brain structures (similar to prion disease, and as hypothesized for Alzheimer's and Parkinson's disease), or is multifocal. These data will be important for planning interventions, which directly target the brain and thus will be directly relevant for HD therapeutics.