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、精神特征和认知能力下降。神经退行性变具有区域异质性，纹状体中棘神经元优先丧失，但其他区域显著萎缩。这就引出了这样一个问题：这种区域退化模式是否与回路相关，反映了受影响神经元的解剖连接，或者相反是多灶性的。为了解决这个问题，我们将对基底节区进行统计形状分析，并检查连接萎缩区域和受影响皮质区域的白质结构。我们假设在选定的皮质下区域存在异质性萎缩，并且形状分析可以在整体体积显著变化之前早期发现一些局部变化。我们假设区域苍白球萎缩与特定的局部基底神经节连接有关，但区域纹状体萎缩与区域皮质萎缩预测的连接并不完全相关。我们还将对白质结构进行补充分析。具体来说，Aim 1将对351名患有和不患有前驱HD的受试者进行横断面统计形状分析（尾状核、壳核、丘脑、海马、伏隔核和苍白球）；目标2将在两个时间点对351名受试者进行扫描，对特定的皮层下灰质区域（如上所述）进行纵向形状分析；Aim 3将对脑中的白质结构进行分析，以确定纹状体最受影响的区域是否接收到来自皮层最受影响区域的投影，以及苍白球最受影响的区域是否接收到来自纹状体最受影响区域的投影。

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.