Evolution of memory related fMRI activation over the course of MCI and AD

描述（由申请人提供）：这是R 01-AG 02745的竞争性更新申请，旨在表征阿尔茨海默病（AD）所致轻度认知损害（MCI）过程中功能性磁共振成像（fMRI）活动的记忆相关变化。我们已经非常成功地实现了我们的目标，在第一个资助周期，招募了140多个老科目，并在高影响力的期刊上发表了40多篇科学手稿。我们已经证明了分布式记忆网络中功能中断的特征模式：1）具有良好的重测重现性; 2）与PiB-PET成像估计的淀粉样蛋白沉积相关; 3）预测快速认知衰退; 4）在MCI过程中保持动态。R 01的下一阶段将建立在我们先前的发现基础上，并利用我们强大的多学科研究人员团队，将我们的发现转化为可行的措施，以跟踪MCI的进展，并在AD早期症状阶段的“概念验证”临床试验中检测早期有效信号。此外，我们建议利用一种新的多模态成像技术的组合来探索异常fMRI活动的机制基础。目标1将建立在我们的fMRI工作与面名范例，开发和验证简短的临床版本的面名联想记忆考试（FNAME），早期AD病理学的影响是敏感的，并将跟踪进展的连续MCI。目的二是探讨记忆任务功能磁共振成像与静息态功能连接的关系，使其在多中心临床试验中更具可行性。我们预测，早期任务相关的多动症将在静息状态下的功能断开之前，并预测其进展。目的3将检验这样的假设，即观察到的活动过度是早期兴奋性毒性的指标，其将预测突触失败、神经元损失和快速临床衰退。我们将采用一种新的PET配体（18-F-PEB）的代谢型谷氨酸受体，mGluR 5，这已经牵连在学习和兴奋性毒性，结合11-C-PiB淀粉样蛋白成像，18-F-FDG葡萄糖代谢，纵向功能和结构成像，以阐明在早期AD的过程中进行性记忆障碍的神经机制。

DESCRIPTION (provided by applicant): This is a competing renewal application of R01-AG02745 to characterize memory related changes in functional magnetic resonance imaging (fMRI) activity over the course of mild cognitive impairment (MCI) due to Alzheimer's disease (AD). We have been very successful in accomplishing our Aims over the first funding cycle of this grant, recruiting over 140 older subjects and publishing over 40 scientific manuscripts in high impact journals. We have demonstrated a characteristic pattern of functional disruption in a distributed memory network that: 1) has good test-retest reproducibility; 2) is associated with amyloid-¿ deposition as estimated with PiB-PET imaging; 3) predicts rapid cognitive decline, and 4) remains dynamic over the course of MCI. The next phase of this R01 will build on our previous discoveries, and leverage our strong group of multi- disciplinary investigators, to translate our findings into measures that are feasible to track progression of MCI and detect an early signal of efficacy in "Proof of Concept" clinical trials for early symptomatic stages of AD. n addition, we propose to probe the mechanistic underpinnings of aberrant fMRI activity, utilizing a novel combination of multi-modality imaging techniques. Aim 1 will build on our fMRI work with face-name paradigms to develop and validate short clinical versions of the face-name associative memory exam (FNAME) that are sensitive to the effects of early AD pathology and will track progression over the continuum of MCI. Aim 2 will investigate the relationship between memory task fMRI and resting state functional connectivity that will be more feasible in multi-center clinical trials. We predict that early task-related hyperactivity will precede and predict progression of functional disconnection during the resting state. Aim 3 will test the hypothesis that the observed hyperactivity is an indicator of early excitotoxicity that will predict synaptic failure, neuronal loss and rapid clinical decline. We will employ a novel PET ligand (18-F-PEB) for the metabotropic glutamate receptor, mGluR5, which has been implicated in both learning and in excitotoxicity, in combination with 11-C-PiB amyloid imaging, 18-F-FDG glucose metabolism, with longitudinal functional and structural imaging to elucidate the neural mechanisms underlying progressive memory impairment over the course of early AD.