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

将基底前脑和内嗅皮层的脆弱性与临床前阿尔茨海默病联系起来

• 批准号: 10506801
• 负责人: Theresa M. Harrison
• 金额: $ 13.13万
• 依托单位: UNIVERSITY OF CALIFORNIA BERKELEY
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-08-15 至 2027-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10506801
• 关键词: Acetylcholinesterase Inhibitors; Address; Affect; Alzheimer disease detection; Alzheimer' s Disease; Alzheimer' s disease model; Alzheimer' s disease pathology; Amyloid beta-Protein; Anatomy; Area; Atlases; Atrophic; Automobile Driving; Biological Markers; Brain; Clinical; Cognition; Cognitive; Cognitive aging; Communities; Data; Data Set; Deposition; Development; Discipline; Disease; Early Diagnosis; Elderly; Ensure; Environment; Episodic memory; Ethnic group; Faculty; Flowcharts; Gene Expression; Genes; Genetic; Goals; Human; Impaired cognition; Intervention; K-Series Research Career Programs; Link; Magnetic Resonance Imaging; Measures; Mediating; Memory; Memory Loss; Modality; Modeling; Ontology; Participant; Pathogenesis; Pathologic; Pathology; Pathway interactions; Pattern; Phenotype; Positron-Emission Tomography; Pre-Clinical Model; Process; Research; Research Project Grants; Resources; Rest; Role; Seeds; Side; Site; Structure; Symptoms; Synapses; System; Systems Analysis; Technical Expertise; Temporal Lobe; Testing; Thick; Tracer; Training; Work; basal forebrain; basal forebrain cholinergic neurons; base; career; causal model; cholinergic; cohort; community building; effective intervention; entorhinal cortex; experimental study; genetic analysis; innovation; interest; multimodality; neuroimaging; neuroinflammation; novel; pre-clinical; programs; racial and ethnic; tau Proteins; tau aggregation; training opportunity

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.

项目摘要 阿尔茨海默病（AD）病理开始出现在大脑中，并在发病前驱动认知能力下降 临床症状。几十年来，人们已经知道基底前脑（BF）容易受到早期tau蛋白的影响。 积累，但早期、临床前AD的神经影像学研究主要集中在tau积累上 从内嗅皮层（ERC）开始的颞叶，以及随后的记忆衰退。一个总体 当前提案的目标是重新激发对BF研究的兴趣，特别是在认知健康的老年人中 其中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疾病发生前检测疾病的机会。 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将被并排检查，以测试假设， 共同的，临床前AD过程在这两个地区展开。BF和ERC中的萎缩和tau积累将 研究，包括这些变化的紧密相关性，以及是否有证据表明 这些改变的排序（例如，BF优先或ERC优先）。BF tau负荷和萎缩的认知后果 将评估并与ERC tau和萎缩相关的记忆变化进行比较。《公约》中的具体差距 通过探索BF和ERC体积/萎缩与PET生物标志物的关系， 纵向，特定领域的认知（目标1），确定如何模式的种子为基础的功能连接 BF和ERC与tau病理负荷和扩散相关（目的2），并建立相关基因表达 BF、ERC和相关区域之间的关系，以确定可能构成其 易受AD影响（目标3）。这些实验将有助于揭示BF中AD漏洞的常见驱动因素， ERC和阐明BF在临床前AD中的作用，包括与广泛性认知功能减退的相关性。 候选人的发展和环境：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计划，采取多模态，创新的方法来表征认知 老化和临床前AD。在K奖期间，候选人将扩展她在神经成像方面的专业知识， 通过整合新型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， 领域：BF和胆碱能系统的解剖学，基因表达数据的分析， 神经影像数据和基于因果推理的先进统计方法。候选人的培训 计划概述了她的方法，利用丰富的资源，在她的实验室和更广泛的加州大学伯克利分校 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 跨学科的教师。候选人组建的由合作者和顾问组成的多元化团队 这个项目将确保她成功地利用她无与伦比的环境， 独立