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

项目概要 阿尔茨海默病 (AD) 病理学开始在大脑中出现，并在发病前导致认知能力下降 的临床症状。几十年来，人们都知道基底前脑 (BF) 很容易受到早期 tau 蛋白的影响。 然而，早期临床前 AD 的神经影像学研究主要集中在 tau 积累上 颞叶，从内嗅皮层（ERC）开始，随后记忆力下降。一个总体的 当前提案的目标是重新激发人们对 BF 研究的兴趣，尤其是认知健康的老年人 可以观察到最早的临床前 AD 病理变化。更好的更广泛的含义 了解临床前 AD 如何在大脑中展开是在发病前发现疾病的机会 当干预措施最有效时出现症状。 研究项目：在本提案中，BF 和 ERC 将被并列检验，以检验以下假设： 常见的临床前 AD 过程正在这两个地区展开。 BF 和 ERC 中的萎缩和 tau 蛋白积累将 进行探索，包括这些变化的相关性如何，以及是否有时间证据 这些更改的顺序（例如，BF 优先或 ERC 优先）。 BF tau 负担和萎缩的认知后果 将进行评估并与 ERC tau 和萎缩相关的记忆变化进行比较。具体差距 该领域将通过探索 BF 和 ERC 体积/萎缩与 PET 生物标志物的关系来解决 纵向、特定领域的认知（目标 1），确定基于种子的功能连接模式 BF 和 ERC 与 tau 病理负担和扩散相关（目标 2），并建立相关基因表达 BF、ERC 和连接区域之间的关系，以确定可能构成其基础的共同路径 AD 的脆弱性（目标 3）。这些实验将有助于揭示 BF 和 AD 脆弱性的常见驱动因素 ERC 并阐明 BF 在临床前 AD 中的作用，包括与全身认知能力下降的关联。 候选人发展与环境：该提案将促进候选人的最终职业目标 建立一个独立的研究项目，采用多模式、创新的方法来表征认知 衰老和临床前AD。在 K 奖期间，候选人将扩展她在神经影像学方面的专业知识 通过整合新型 PET 示踪剂和数据集，同时获取几个关键领域的新专业知识，进行临床前 AD 领域：BF 和胆碱能系统的解剖、基因表达数据的分析 基于因果推理的神经影像数据和高级统计方法。候选人的培训 计划概述了她利用实验室和更广泛的加州大学伯克利分校可用的丰富资源的方法 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 跨多个学科的教师。候选人组建的多元化合作者和顾问团队 对于这个项目将确保她成功地利用她无与伦比的环境来获得 独立性。

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.