Functional Connectivity in Premanifest Huntington's Disease

描述（由申请人提供）：由于功能成像研究的相对缺乏，亨廷顿病（prHD）表现前阶段微妙认知变化的脑机制尚不清楚。初步证据表明，局部脑活动的改变可能对prHD的早期变化很敏感。然而，由于认知依赖于大脑区域之间的交流，大脑网络的功能连接可能是早期病理更重要的中间表型。拟议的prHD纵向研究将检查静息状态下测量的功能连接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中却很少受到关注。该项目的主要目标是利用功能性磁共振成像连接来识别prHD患者大脑网络的最早变化，并对其进行纵向追踪。拟议的研究将采用两种不同但互补的分析方法来研究fcMRI，因为一些方法可能对疾病相关的变化更敏感。网络中的连通性强度将在对照组和prHD个体之间进行比较，prHD个体根据其疾病进展的遗传特征分为三组。参与者将连续三到四年每年接受一次研究。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fMRI在不同额纹状体网络功能的测试中得到通知。主要假设是，随着prHD个体接近诊断，种子的连通性强度将逐渐减弱。目标2将从复杂网络分析中识别prHD的敏感fcMRI标记，复杂网络分析表征了全脑网络的组织特征和信息处理能力。主要假设是，随着prHD个体接近诊断，组织、处理效率和/或区域之间的功能相互作用将逐渐减弱。目的3将确定在基线时识别的fcMRI标记物是否对三到四年的纵向下降敏感。主要的假设是，连接标记的纵向变化将先于大脑形态和认知功能的变化出现。目前的提案还将检查功能磁共振成像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将确定纤维束连通性是否丧失和体积/变薄

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. PUBLIC HEALTH RELEVANCE: Changes in the brain in Huntington disease (HD) begin long before a person is diagnosed, during a preclinical stage. To measure the effectiveness of potential treatments for HD, it is necessary to identify measurement tools that reliably detect changes in the brain during the preclinical stage where treatments are more likely to be successful. The primary goal of this project is to use a neuroimaging technique, namely functional connectivity MRI, to identify the earliest changes in brain connections in preclinical HD and to track these changes longitudinally.