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)显性前期微妙认知变化背后的大脑机制尚不清楚。初步证据表明，区域大脑激活的变化可能对早发性早发性脑发育迟缓的变化敏感。然而，由于认知依赖于脑区之间的交流，脑网络的功能连通性可能是早期病理学更重要的中间表型。拟议的PrHD纵向研究将检查从静息状态测量的功能连接性MRI(FcMRI)。静息状态的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。这个项目的主要目标是使用fcMRI连接来识别PrHD患者大脑网络的最早变化，并纵向跟踪它们。这项拟议的研究将使用两种不同的、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。网络中的连接强度将在对照组和PrHD个体之间进行比较，后者根据他们疾病进展的遗传特征被分成三组。参与者将连续三到四年每年接受研究。目的1将使用感兴趣区域(ROI)方法识别PrHD的敏感fcMRI标志物。种子ROI的选择将由任务激活的fMRI在测试中提供信息，这些测试探测不同额纹状体网络的功能。主要的假说是，随着遗传性早衰症患者接近诊断，种子的连接强度将逐渐减弱。目的2将从复杂网络分析中识别出PRHD的敏感fcMRI标记，该标记表征了全脑网络的组织特征和信息处理能力。主要的假设是，随着PRHD患者接近诊断，区域之间的组织、处理效率和/或功能相互作用将逐渐减弱。目标3将确定基线确定的fcMRI标志物是否对三到四年期间的纵向下降敏感。主要的假设是，连接性标记的纵向变化将先于大脑形态测量和认知功能的变化出现。目前的建议还将检查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，其中高角扩散加权成像和结构磁共振将确定纤维束连通性和体积/变薄的损失 与基准线上特定网络中的连接改变相关。将评估fcMRI和结构标记物的相对敏感度。我们还将确定fcMRI连接标记是否选择性地与基线时的认知能力和认知的纵向变化相关。总之，拟议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.