Imaging and Genetics in Huntington's Disease

描述（由申请人提供）：PREDICT-HD研究收集了具有亨廷顿舞蹈病（HD）标记的健康受试者的令人印象深刻的样本，以及没有该标记的对照样本。分析认知、精神和运动机能随着时间在这个示例提供了证据,前驱期前临床诊断HD:在许多领域的测量,受试者超过15年远离他们发病的年龄预测显示与控制,很少或根本没有区别虽然受试者在9 - 1年窗口中已经显示出重要如果微妙的下降,和9年内发病的年龄预测显示出很大的损失。虽然这是对HD前驱期的有影响力的澄清，但需要进一步澄清；根据亨廷顿基因中CAG重复数计算的发病年龄在重复数高时非常精确，但在重复数低时可能导致几十年的大窗口期。在这项辅助研究中，我们将多变量技术（如平行独立成分分析（pICA））应用于预测样本的组合结构和遗传成像数据。在目标1中，使用横断面技术，我们将确定与疾病相关的灰质损失模式共同变化的遗传谱。在目标2中，使用纵向样本，我们将确定与运动和认知功能丧失相关的大脑结构和遗传概况。在目标3中，我们将确保PREDICT团队接受这些技术的培训，并能够将其应用于其正在进行的数据收集，并且将结果纳入其数据管理系统。该建议的结论将CAG重复序列的影响置于来自较大基因组的遗传影响的初始背景中。我们利用脑成像措施来确定HTT遗传网络中加速或提供疾病发作恢复力的相关基因型概况。

DESCRIPTION (provided by applicant): The PREDICT-HD study has collected an impressive sample of healthy subjects with the marker for Huntington's Disease (HD), and a sample of controls without that marker. The analyses of cognitive, psychiatric, and motor function over time in this sample has provided evidence for a prodromal phase preceding clinical diagnosis of HD: In many of the domains being measured, subjects who are more than 15 years away from their predicted age of onset show little or no difference from controls, while subjects in the 9- 1 year window are already showing significant if subtle declines, and within 9 years of the predicted age of onset are showing large losses. While this is an impactful clarification of the prodromal phase of HD, it needs to be further clarified; the predicted age of onset as calculated by the number of CAG repeats in the Huntington gene is very precise when the number of repeats is high, but can lead to a very large window of several decades when the number is low. In this ancillary study, we apply multivariate techniques such as parallel independent components analysis (pICA) to the combined structural and genetic imaging data from the PREDICT sample. In Aim 1, using a cross-sectional technique we will identify the genetic profiles which covary with disease-related patterns of gray matter loss. In Aim 2, using a longitudinal sample we will identify the brain structure and genetic profiles which correlate with loss of motor and cognitive function. In Aim 3, we will ensure that the PREDICT team is trained on these techniques and can apply them to its ongoing data collection, and that the results are incorporated into their data management system. The conclusion of this proposal places the effect of the CAG repeats within an initial context of genetic influences from the larger genome. We leverage the brain imaging measures to identify relevant profiles of genotypes within the HTT genetic network which accelerate or provide resilience to disease onset.