Age and genetic influence on fcMRI networks in autosomal dominant and sporadic AD

 描述(申请人提供)：这是一份重新提交的K23指导性以患者为导向的研究职业发展奖的申请。在培训方面，申请者的目标是利用K23资助期完成功能和图像分析方面的重点培训， 神经病理学、老年病学、神经心理学和生物统计学。这种培训将通过导师、有限数量的正式教学以及一个雄心勃勃的项目的完成来进行，该项目有望为未来作为独立调查人员的研究奠定基础。功能连通性磁共振成像(FcMRI)是一种非侵入性的方法，可以评估复杂行为背后的解剖分布神经网络的完整性。在阿尔茨海默病(AD)中，默认模式网络(DMN)的fcMRI已显示出在临床和基础研究中作为生物标志物的巨大前景，因为(1)DMN的fcMRI在前驱症状和临床明显的AD中显著减少，(2)DMN是AD早期淀粉样蛋白沉积的部位之一。然而，使用fcMRI作为早期AD生物标志物受到正常衰老中连接性重叠变化的限制，这反过来又限制了识别 早期阿尔茨海默病受试者参加临床试验。为了解决这一局限性，我们提出了一系列研究，使用fcMRI通过关注两个独特受试者群体中六个描述良好的皮质网络的退化模式，来消除正常衰老与早期AD的歧义。这些研究的中心假设是，早期AD和衰老将表现出不同的网络退化模式，与衰老相比，早期AD认知网络(特别是默认模式和注意网络)的退化优先。我们通过比较有和没有AD病理证据的年轻和老年受试者来检验这一假设，利用来自主要遗传性阿尔茨海默病(DIAD)的年轻受试者的新可用的数据，这些数据来自显性遗传性阿尔茨海默病网络(DIAN)。值得注意的是，哈佛老龄化脑研究跟踪的DIAD人群与年龄较大的高危和有症状的患者的比较代表了一个独特的机会来区分年龄和AD病理，因为DIAD携带者在很小的时候就开始患病(通常在30多岁和40岁出头)。此外，利用我们的老年受试者的tau负荷的PET数据(来自F18-T807PET，一种新开发的tau放射性配体)，我们将探索淀粉样蛋白和tau病理在改变的fcMRI中的相对贡献。这些研究将起到双重作用：(1)通过识别区分衰老和AD的fcMRI变化模式，优化fcMRI作为AD生物标志物的使用；(2)为区分衰老和AD的系统水平病理生理学提供新的见解。此外，这些研究将比较主要遗传性AD和散发性AD中网络退化的时间和模式，并为解释目前在(至少)三个主要AD预防试验中收集的fcMRI数据提供关键背景，这些试验是在散发性AD和显性遗传性AD的风险较大的老年人中收集的。

 DESCRIPTION (provided by applicant): This is a resubmitted application for a K23 Mentored Patient-Oriented Research Career Development Award. In terms of training, the applicant's goal is to utilize the K23 funding period to complete focused training in functional and image analysis, neuropathology, geriatrics, neuropsychology, and biostatistics. This training will take place through mentorship, a limited number of formal didactics, and through the completion of an ambitious project that will hopefully set the stage for future studies as an independent investigator. Functional connectivity MRI (fcMRI) is a non-invasive method to assess the integrity of anatomically distributed neural networks underlying complex behaviors. In Alzheimer's disease (AD), fcMRI of the default mode network (DMN) has shown great promise as a biomarker in clinical and basic research studies, as (1) profound decreases in DMN fcMRI are seen in prodromal and clinically evident AD and (2) the DMN is among the sites of early amyloid deposition in AD. However, using fcMRI as an early AD biomarker is limited by the overlapping changes in connectivity seen in normal aging, which, in turn, limits the identification of early AD subjects to enroll in clinical trials. To address this limitation, we propose a series f studies that use fcMRI to disambiguate normal aging from early AD by focusing on the pattern of degeneration across six well-described cortical networks in two unique subject populations. The central hypothesis of these studies is that early AD and aging will show distinct patterns of network degradation, with preferential degradation of cognitive networks (especially the Default Mode and Attention Networks) in early AD as compared to aging. We test this hypothesis by comparing young and old subjects with and without evidence of AD pathology, leveraging newly available data from young subjects with dominantly inherited AD (DIAD) drawn from the Dominantly-Inherited Alzheimer's Network (DIAN). Notably, the comparison of the DIAD population and older at-risk and symptomatic patients followed in the Harvard Aging Brain Study represents a unique opportunity to disentangle age and AD pathology, as DIAD carriers have disease onset at a young age (often in the late 30s and early 40s). In addition, using PET data on tau burden in our older subjects (from F18-T807 PET, a newly-developed tau radioligand), we will explore the relative contributions of amyloid and tau pathologies to altered fcMRI. These studies will serve the dual purpose of (1) optimizing the use of fcMRI as an AD biomarker by identifying patterns of fcMRI change that distinguish aging and AD, and (2) provide novel insight into the systems-level pathophysiology that distinguishes aging and AD. Further, these studies will compare the timing and pattern of network degradation in dominantly-inherited vs. sporadic AD and provide critical context for the interpretation of fcMRI data currently being gathered in (a least) three major AD prevention trials in older individuals at-risk for sporadic AD and dominantly-inherited AD.