Elevated locus coeruleus metabolism as mechanism driving Alzheimer's disease pathology

蓝斑代谢升高是阿尔茨海默氏病病理的驱动机制

• 批准号: 10478080
• 负责人: Heidi Irma Jacobs
• 金额: $ 21.69万
• 依托单位: MASSACHUSETTS GENERAL HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-09-01 至 2024-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10478080
• 关键词: Affect; Age; Alzheimer' s Disease; Alzheimer' s disease pathology; Amyloid beta-Protein; Anatomy; Animals; Automobile Driving; Autopsy; Brain; Brain Injuries; Brain Stem; Cells; Cerebrospinal Fluid; Clinical Trials; Cognition; Cognitive; Cognitive deficits; Data; Databases; Detection; Development; Diagnostic; Diffusion Magnetic Resonance Imaging; Disease; Disease Progression; Distant; Early Diagnosis; Early treatment; Evolution; Exhibits; Fiber; Functional disorder; Funding; Goals; Human; Impaired cognition; Individual; Longitudinal cohort; Measures; Medial; Mediating; Mediation; Metabolism; Methodology; Methods; Mission; Modeling; Neocortex; Norepinephrine; Pathology; Pattern; Persons; Phase; Positron-Emission Tomography; Public Health; Research; Resolution; Risk; Site; Temporal Lobe; Therapeutic; Time; Tracer; United States National Institutes of Health; Work; abeta accumulation; aging brain; base; brain metabolism; cohort; connectome; density; fluorodeoxyglucose; fluorodeoxyglucose positron emission tomography; improved; in vivo; individual patient; innovation; insight; locus ceruleus structure; longitudinal dataset; mild cognitive impairment; multimodality; neocortical; neuroimaging; novel; success; symptomatology; tau Proteins; tau aggregation; white matter

ABSTRACT: The neuropathologic hallmarks of Alzheimer's disease (AD) are accumulations of beta-amyloid (Aβ) and tau proteins, that each have their own typical topography during disease progression. The fact that this anatomic pattern of pathology progression occurs along regions that are anatomically connected, suggests that pathology spreads via connectivity. Disappointing results from recent therapeutic efforts targeting Aβ in the prodromal phase of AD indicate the importance of intervening early and prelude an exciting opportunity: by focusing on mechanisms related to initial propagation of pathology, disease progression may be halted in the earliest stage, prior to irreversible damage has affected the brain. Autopsy data indicated that the locus coeruleus (LC) is one of the first regions affected by tau: by age 40, tau aggregation in the LC can be detected in 80% of the individuals, prior to neocortical Aβ or tau. At age 50, almost 50% of the individuals harbor tau pathology in the transentorhinal cortex (TEC), suggesting that tau has progressed from the LC to the TEC. The scientific premise supporting the current study emerges from animal and our cerebrospinal fluid (CSF) work, demonstrating that elevated metabolism of the LC may be driving tau hyperphosphorylation, and propagation to distant, connected regions, and triggering cognitive decline. The overall goal of this proposal is to examine LC metabolism and its relation to progression of tau across all stages of the AD continuum, and to model connectivity as mechanism related to progression of tau and cognitive decline. To achieve this, we will resolve two methodological barriers that so far hampered human in vivo assessment of these relationships: 1) measuring LC metabolism while taking into account the resolution of 18F-Fluorodeoxy-glucose PET and 2) identify tracts connecting the LC to the TEC among many crossing brainstem fibers. Combining these state-of- the-art novel methods with longitudinal data of Aβ, tau (PET and CSF) and cognition in two NIA-funded, rich multi-modal longitudinal datasets, the Harvard Aging Brain Study and the Alzheimer Disease Neuroimaging Initiative, will allow us to examine the following aims: Aim 1) To examine the evolution of LC metabolism as a function of Ab/tau stages or diagnostic groups, and its relationship to tau accrual over time; Aim 2A) To identify and validate tracts connecting the LC to the TEC in a consistent way across both cohorts; and examine LC-TEC tract integrity across the AD continuum; and Aim 2B) To model the successive mediation by lower LC- TEC connectivity and tau accrual on the relationship between LC metabolism and cognitive decline. Together, these aims improve our understanding of the mechanistic underpinnings of initial tau propagation, as well as its relevance for cognition. The proposed research is innovative and can have a substantial impact on our understanding of the pathophysiology of AD, and can also result in a significant breakthrough for the field by shifting detection to earlier time points and providing new targets or strategies for therapeutic approaches administered early in the disease trajectory, when brain damage is not yet extensive.

摘要：阿尔茨海默氏病的神经病理学标志（AD）是β-淀粉样蛋白的积累 （Aβ）和tau蛋白，每个蛋白在疾病进展过程中都有自己的典型地形。事实 这种病理进展的解剖学模式发生在解剖学上的区域。 该病理通过连通性传播。最近针对Aβ的治疗努力令人失望的结果 AD的前驱阶段表明，早期干预和前奏的重要性是一个令人兴奋的机会： 通过关注与病理初始传播相关的机制，疾病进展可以停止 最早的阶段在不可逆转的损害之前影响了大脑。尸检数据表明该基因座 Coeruleus（LC）是受Tau影响的第一个区域之一：到40岁，可以在LC中检测到LC中的Tau聚集 80％的个体，在新皮层Aβ或TAU之前。在50岁时，几乎50％ 跨肾上腺皮质（TEC）中的病理学表明Tau已从LC发展到TEC。 支持当前研究的科学前提来自动物和我们的脑脊液（CSF）工作， 证明LC的新陈代谢升高可能正在驱动Tau高磷酸化，并传播 遥远，连接的区域，并触发认知能力下降。该提议的总体目标是检查 LC代谢及其与Tau在AD连续阶段的各个阶段的关系，并建模 连通性作为与tau进展和认知下降有关的机制。为了实现这一目标，我们将解决 到目前为止，有两个方法论障碍阻碍了对这些关系的体内评估：1） 考虑到18F-氟脱氧葡萄糖PET和2的分辨率，测量LC代谢和2） 识别许多跨越脑干纤维中LC连接到TEC的区域。结合这些最新 ART新方法具有Aβ，TAU（PET和CSF）的纵向数据，并在两个NIA资助的富含NIA资助的 多模式纵向数据集，哈佛大学衰老大脑研究和阿尔茨海默氏病神经影像学 主动性将使我们能够检查以下目的：目标1）检查LC代谢的演变 随着时间的流逝，AB/TAU阶段或诊断组的功能及其与Tau cock的关系；目标2a） 识别和验证将LC连接到TEC的区域以一致的方式连接到TEC；并检查 lc-tec道的完整性跨广告连续性； AIM 2B）通过较低的LC-进行成功调解 TEC连通性和TAU对LC代谢与认知能力下降之间关系的重音。一起， 这些目标提高了我们对初始tau传播的机械基础的理解，以及 它与认知的相关性。拟议的研究具有创新性，可以对我们的 了解AD的病理生理学，也可以通过 将检测转移到较早的时间点，并为治疗方法提供新的目标或策略 当脑损伤尚未广泛时，在疾病轨迹的早期进行管理。