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 阿尔茨海默氏病（AD）病理学开始在大脑中出现，并在发作前驱动认知能力下降 临床症状。数十年来，基本的前脑（BF）很容易受到早期tau的影响 积累，但对早期临床前AD的神经影像学研究主要集中在TAU积累上 在临时叶中，从内嗅皮层（ERC）开始，随后记忆下降。总体 当前建议的目标是重振对BF研究的兴趣，尤其是在认知健康的老年人中 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 了解临床前广告如何在整个大脑中展开是有机会检测疾病之前的 当干预措施最有效时，症状的出现。 研究项目：在此提案中，将对BF和ERC进行检查，以检验以下假设。 在两个区域中，临床前广告过程都在展开。 BF和ERC中的萎缩和Tau积累将 探索，包括这些变化的密切相关性以及是否有临时证据 这些更改的排序（例如，首先是BF或ERC）。 BF Tau Burnen和萎缩的认知后果 将评估并将其与与ERC TAU和萎缩相关的记忆变化进行比较。特定差距 将通过探索BF和ERC量/萎缩与PET生物标志物的关系来解决领域 纵向，域特异性认知（AIM 1），确定基于种子的功能连接的模式如何 BF和ERC与Tau病理学和扩散有关（AIM 2），并建立相关基因表达 BF，ERC和连接区域之间的关系，以确定可能是其基础的共同途径 AD的脆弱性（AIM 3）。这些实验将有助于发现BF中AD脆弱性的共同驱动因素和 ERC并阐明了BF在临床前AD中的作用，包括与认知能力下降的关联。 候选人的发展和环境：该建议将促进候选人的最终职业目标 建立一个独立的研究计划，该计划采用多模式，创新的方法来表征认知 老化和临床前广告。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 临床前广告通过整合新颖的宠物示踪剂和数据集，同时还可以在多个关键中获取新的专业知识 区域：BF和胆碱能系统的解剖结构，对遗传表达数据的分析与 基于因果推断的神经影像学和高级统计方法。候选人的培训 计划概述了她在实验室和更广泛的UC Berkeley中参与丰富资源的方法 社区，包括访问独特的数据集，社区建设的半身和务虚会以及世界知名度 许多学科的教师。合作者和顾问的潜水团队候选人已经组装了 因为这个项目将确保她成功地利用自己无与伦比的环境来获得 独立。