Functional Connectivity in Premanifest Huntington's Disease

描述（由申请人提供）：由于功能成像研究相对缺乏，因此尚不了解亨廷顿病（prHD）表现前阶段微妙认知变化的脑机制。初步证据表明，区域性脑激活的改变可能对prHD的早期变化敏感。然而，由于认知依赖于大脑区域之间的通信，大脑网络的功能连接可能是早期病理学的更重要的中间表型。拟议的prHD纵向调查将检查从静息状态测量的功能连接MRI（fcMRI）。静息状态fcMRI与认知能力相关，作为纵向研究的生物标志物具有优势，但在prHD中很少受到关注。该项目的主要目标是使用fcMRI连接来识别prHD中大脑网络的最早变化并纵向跟踪它们。 拟议的研究将采用两种不同但互补的分析方法来研究fcMRI，因为某些方法可能对疾病相关变化更敏感。将在对照组和prHD个体之间比较网络中的连接强度，prHD个体根据其疾病进展的基因特征分为三组。参与者将连续三年或四年每年接受研究。目的1将使用感兴趣区域（ROI）方法识别prHD的敏感fcMRI标记物。种子ROI的选择将通过任务激活的功能磁共振成像测试来确定，该测试探测不同额纹状体网络的功能。主要的假设是，种子的连接强度将逐渐减弱，因为prHD个体接近诊断。目的2将从复杂网络分析中识别prHD的敏感fcMRI标记物，其表征全脑网络的组织特征和信息处理能力。主要的假设是，组织，处理效率，和/或区域之间的功能相互作用将逐渐减弱prHD个人接近诊断。目标3将确定在基线时确定的fcMRI标记物是否对三到四年期间的纵向下降敏感。主要的假设是，连接标记的纵向变化将出现在脑形态和认知功能的变化之前。 本提案还将研究fcMRI是否部分依赖于脑组织的结构完整性。每个目标将包括一个子目标，其中高角度扩散加权成像和结构MRI将确定纤维束连接性和体积/变薄的损失 与基线时特定网络的连接性改变相关。将评价fcMRI和纵向变化的结构标志物的相对灵敏度。我们还将确定fcMRI连接标记物是否选择性地与基线认知能力和认知的纵向变化相关。总之，提出的多管齐下的方法有望促进对prHD大脑网络的新理解。

DESCRIPTION (provided by applicant): Brain mechanisms underlying subtle cognitive changes in the premanifest stage of Huntington disease (prHD) are not understood due to a relative dearth of functional imaging studies. Preliminary evidence suggests that alterations in regional brain activation may be sensitive to very early changes in prHD. However, as cognition depends on communication among brain regions, functional connectivity of brain networks may be a more important intermediate phenotype of early pathology. The proposed longitudinal investigation of prHD will examine functional connectivity MRI (fcMRI) measured from a resting state. Resting state fcMRI correlates with cognitive abilities and has advantages as a biomarker for longitudinal studies, yet has received scant attention in prHD. The primary goal of this projec is to use fcMRI connectivity to identify the earliest changes in brain networks in prHD and to track them longitudinally. The proposed study will employ two different, but complimentary analytic approaches to study fcMRI, as some approaches may be more sensitive to disease-relevant changes. Connectivity strength in networks will be compared between a control group and prHD individuals who are stratified into three groups based on their genetic signature of disease progression. Participants will have been studied annually for three or four consecutive years. Aim 1 will identify sensitive fcMRI markers of prHD using a region-of-interest (ROI) method. The selection of seed ROI will be informed by task-activated fMRI on tests that probe for functioning in different frontostriatal networks. The main hypothesis is that connectivity strength of seeds will be progressively weakened as prHD individuals approach diagnosis. Aim 2 will identify sensitive fcMRI markers of prHD from complex network analysis, which characterizes organizational features and information- processing capabilities of whole-brain networks. The main hypothesis is that the organization, processing efficiency, and/or functional interactions between regions will progressively weaken as prHD individuals approach diagnosis. Aim 3 will determine if fcMRI markers identified at baseline are sensitive to longitudinal decline across a three to four year period. The main hypothesis is that longitudinal changes in connectivity markers will emerge prior to changes in brain morphometry and cognitive functioning. The present proposal will also examine if fcMRI partially depends on the structural integrity of brain tissue. Each aim will include a sub-aim wherein high angular diffusion weighted imaging and structural MRI will determine if a loss in fiber-tract connectivity and volume/thinning correlate with altered connectivity in specific networks at baseline. The relative sensitivity of fcMRI and structural markers of longitudinal change will be evaluated. We will also determine if fcMRI connectivity markers selectively correlate with cognitive abilities at baseline and longitudinal changes in cognition. Altogether, the proposed multipronged approach is expected to promote a new understanding of brain networks in prHD.