Imaging and Genetics in Huntington's Disease

描述（由申请人提供）：PREDICT-HD研究收集了一个令人印象深刻的具有亨廷顿氏病（HD）标志物的健康受试者样本，以及一个没有该标志物的对照样本。对该样本随时间推移的认知、精神和运动功能的分析为HD临床诊断前的前驱期提供了证据：在许多正在测量的领域中，距离预测发病年龄超过15年的受试者与对照组几乎没有差异，而9- 1年窗口中的受试者已经显示出显著的轻微下降，而在预测发病年龄的9年内，则显示出大量的损失。虽然这是对HD前驱期的一个有影响力的澄清，但需要进一步澄清;当重复数高时，通过亨廷顿基因中CAG重复数计算的预测发病年龄非常精确，但当重复数低时，可能导致数十年的非常大的窗口。在这项辅助研究中，我们应用多变量技术，如并行独立成分分析（pICA）的组合结构和遗传成像数据的预测样本。在目标1中，我们将使用横断面技术确定与疾病相关的灰质丢失模式协变的遗传特征。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特征。在目标3中，我们将确保预测小组接受这些技术的培训，并能将其应用于正在进行的数据收集，并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。我们利用脑成像测量来确定HTT遗传网络中加速或提供疾病发作恢复力的基因型的相关概况。

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.