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

年龄和遗传对常染色体显性和散发性 AD 中 fcMRI 网络的影响

• 批准号: 9265410
• 负责人: JASMEER P CHHATWAL
• 金额: $ 20.09万
• 依托单位: MASSACHUSETTS GENERAL HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-08-15 至 2020-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9265410
• 关键词: Address; Affect; Age; Aging; Alzheimer disease prevention; Alzheimer' s Disease; Alzheimer' s disease risk; American; Amyloid; Amyloid deposition; Anatomy; Attention; Basic Science; Behavior; Biological Markers; Biological Neural Networks; Biometry; Brain; Clinical; Clinical Research; Clinical Trials; Cognitive; Complex; Data; Dementia; Disease; Disease Marker; Early identification; Elderly; Enrollment; Functional Imaging; Functional disorder; Funding; Future; Genetic; Geriatrics; Goals; Hippocampus (Brain); Image; Image Analysis; Imaging Techniques; Individual; Inherited; Intervention; Magnetic Resonance Imaging; Measures; Memory; Memory Loss; Mentored Patient-Oriented Research Career Development Award; Mentorship; Methods; Motor; Mutation; Neurons; Neuropsychology; Neurosciences; Onset of illness; Outcome Measure; Participant; Pathology; Patients; Pattern; Population; Positron-Emission Tomography; Prevention trial; Research Personnel; Risk; Sampling; Sensory; Series; Site; Specificity; Synapses; System; Techniques; Testing; Training; age effect; age related; aging brain; cognitive change; fluorodeoxyglucose positron emission tomography; imaging biomarker; insight; mild cognitive impairment; mutation carrier; nervous system disorder; neural correlate; neuron loss; neuropathology; non-invasive imaging; normal aging; novel; pre-clinical; public health relevance; radioligand; research study; secondary outcome; tau Proteins

 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.

 描述（由申请人提供）：这是重新提交的 K23 指导患者导向研究职业发展奖申请。在培训方面，申请人的目标是利用K23资助期限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。这种培训将通过指导、有限数量的正式教学以及完成一个雄心勃勃的项目来进行，该项目有望为未来作为独立研究者的研究奠定基础。 功能连接 MRI (fcMRI) 是一种非侵入性方法，用于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 作为临床和基础研究中的生物标志物显示出了巨大的前景，因为 (1) 在前驱期和临床明显的 AD 中观察到 DMN fcMRI 的大幅下降，(2) DMN 是 AD 早期淀粉样蛋白沉积的位点之一。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 AD 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，通过关注两个独特受试者群体中六个明确描述的皮质网络的退化模式，使用 fcMRI 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 的认知网络（特别是默认模式和注意力网络）优先退化。我们通过比较有或没有 AD 病理学证据的年轻和年长受试者，利用来自显性遗传性阿尔茨海默病网络 (DIAN) 的显性遗传性 AD (DIAD) 年轻受试者的最新数据来检验这一假设。值得注意的是，哈佛大脑老化研究中对 DIAD 人群与老年高危和有症状患者进行的比较代表了一个解开年龄和 AD 病理学的独特机会，因为 DIAD 携带者在年轻时发病（通常在 30 岁末和 40 岁出头）。此外，利用老年受试者 tau 负荷的 PET 数据（来自 F18-T807 PET，一种新开发的 tau 放射性配体），我们将探讨淀粉样蛋白和 tau 病理学对 fcMRI 改变的相对贡献。这些研究将达到双重目的：(1) 通过识别区分衰老和 AD 的 fcMRI 变化模式来优化 fcMRI 作为 AD 生物标志物的使用，(2) 为区分衰老和 AD 的系统级病理生理学提供新的见解。此外，这些研究将比较显性遗传性 AD 与散发性 AD 中网络退化的时间和模式，并为解释目前在（至少）三项主要 AD 预防试验中收集的 fcMRI 数据提供关键背景，这些试验针对有散发性 AD 和显性遗传性 AD 风险的老年人。