Linking basal forebrain and entorhinal cortex vulnerability to preclinical Alzheimer's disease

项目摘要 阿尔茨海默病(AD)的病理开始出现在大脑中，并在发病前导致认知能力下降 临床症状。众所周知，基底前脑(BF)易受早期tau的影响。 积累，但早期临床前AD的神经影像研究主要集中在tau积累上 在颞叶，开始于内嗅皮层(ERC)，随后记忆力下降。最重要的是 当前提案的目标是重新激发人们对BF研究的兴趣，特别是对认知健康的老年人 可以观察到最早的、临床前AD的病理变化。更好的更广泛的含义 了解临床前阿尔茨海默病是如何在大脑中展开的，这是在 在干预措施最有效的时候出现症状。 研究项目：在这项建议中，BF和ERC将被并列检查，以测试假设 在这两个地区，共同的临床前AD过程正在展开。BF和ERC中的萎缩和tau积聚 包括这些变化有多密切相关，以及是否有证据表明 这些更改的排序(例如，BF优先或ERC优先)。BF tau负荷和萎缩的认知后果 将被评估并与与ERC tau和萎缩相关的记忆变化进行比较。中的具体差距 将通过探索BF和ERC体积/萎缩与PET生物标记物和 纵向、特定于领域的认知(目标1)，确定基于种子的功能连接模式 BF和ERC与tau病理负担和扩散有关(目标2)，并建立相关的基因表达 跨BF、ERC和相连区域的关系，以确定可能支撑其 AD漏洞(目标3)。这些实验将有助于发现高炉和 ERC，并阐明BF在临床前AD中的作用，包括与广泛性认知功能下降的关系。 应聘者发展和环境：这项提议将促进应聘者的最终职业目标 建立一个独立的研究计划，采用多模式、创新的方法来表征认知 衰老与临床前阿尔茨海默病在K奖期间，候选人将扩展她在神经成像方面的专业知识 通过集成新的PET示踪剂和数据集，同时在几个关键领域获得新的专业知识，实现临床前AD 研究领域：BF和胆碱能系统的解剖，基因表达数据的分析 神经影像数据和基于因果推断的高级统计方法。应聘者的训练 计划概述了她利用实验室和加州大学伯克利分校更广泛的丰富资源的方法 社区，包括访问独特的数据集、社区建设研讨会和务虚会以及世界知名的 许多学科的教职员工。候选人组建的不同的合作者和顾问团队 因为这个项目将确保她成功地利用她无与伦比的环境获得 独立。

Project Summary Alzheimer’s disease (AD) pathology begins to emerge in the brain and drives cognitive decline before the onset of clinical symptoms. It has been known for decades that the basal forebrain (BF) is vulnerable to early tau accumulation, and yet neuroimaging research of early, preclinical AD has largely focused on tau accumulation in the temporal lobe, beginning in entorhinal cortex (ERC), and subsequent memory decline. An overarching goal of the current proposal is to reinvigorate interest in BF research, especially in cognitively healthy older adults where the earliest, preclinical AD pathological changes can be observed. The broader implication of a better understanding of how preclinical AD unfolds across the brain is the opportunity to detect the disease before the emergence of symptoms when interventions can be most effective. Research Project: In this proposal, BF and ERC will be examined side-by-side to test the hypothesis that a common, preclinical AD process is unfolding in both regions. Atrophy and tau accumulation in BF and ERC will be explored, including how tightly correlated these changes are and whether there is evidence of temporal ordering of these changes (e.g., BF first or ERC first). Cognitive consequences of BF tau burden and atrophy will be assessed and compared to memory changes associated with ERC tau and atrophy. Specific gaps in the field will be addressed by exploring relationships of BF and ERC volume/atrophy with PET biomarkers and longitudinal, domain-specific cognition (Aim 1), determining how patterns of seed-based functional connectivity of BF and ERC relate to tau pathology burden and spread (Aim 2), and establishing correlated gene expression relationships across BF, ERC and connected regions to identify common pathways that may underlie their vulnerability to AD (Aim 3). These experiments will help uncover common drivers of AD vulnerability in BF and ERC and elucidate the role of BF in preclinical AD, including associations with generalized cognitive decline. Candidate Development and Environment: This proposal will promote the candidate’s ultimate career goal to build an independent research program that takes multimodal, innovative approaches to characterizing cognitive aging and preclinical AD. During the K award, the candidate will extend her expertise in neuroimaging of preclinical AD by integrating novel PET tracers and datasets while also acquiring new expertise in several key areas: the anatomy of the BF and cholinergic system, analysis of genetic expression data in concert with neuroimaging data and advanced statistical approaches grounded in causal inference. The candidate’s training plan outlines her approach to engage the rich resources available in her lab and the broader UC Berkeley community, including access to unique datasets, community-building seminars and retreats and world-renowned faculty across many disciplines. The diverse team of collaborators and advisors the candidate has assembled for this project will ensure she is successful in leveraging her unparalleled environment toward gaining independence.