Locus Coeruleus Biomarker Development for Early Detection of Alzheimers Disease in Humans

用于早期检测人类阿尔茨海默病的蓝斑生物标记物开发

• 批准号: 10380028
• 负责人: Anne Shively Berry
• 金额: $ 16.25万
• 依托单位: BRANDEIS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-04-01 至 2024-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10380028
• 关键词: Acceleration; Address; Affect; Age; Aging; Alzheimer disease detection; Alzheimer' s Disease; Alzheimer' s disease pathology; Alzheimer' s disease patient; Anti-Inflammatory Agents; Back; Basic Science; Blood - brain barrier anatomy; Brain; Brain region; Catecholamines; Cell Density; Cell Nucleus; Chronology; Clinical; Cognition; Cognitive; Data Set; Detection; Development; Diagnosis; Disease; Disease Progression; Dopamine; Early Diagnosis; Early identification; Elderly; Financial compensation; Foundations; Health; Human; Image; Individual; Individual Differences; Infrastructure; Injury; Magnetic Resonance; Magnetic Resonance Imaging; Maintenance; Measures; Medial; Mediating; Memory; Mental disorders; Metabolism; Methods; Midbrain structure; Modeling; Nerve Degeneration; Neuromodulator; Norepinephrine; Oxidative Stress; Parkinson Disease; Participant; Pathologic; Pathology; Patients; Pattern; Performance; Play; Positron-Emission Tomography; Process; Property; Radioactive Tracers; Reporting; Research; Research Personnel; Resolution; Role; Signal Transduction; Sleep; Source; Stress; Structure; Substantia nigra structure; Symptoms; System; Temporal Lobe; Testing; Therapeutic Intervention; Tyrosine; Validation; abnormally phosphorylated tau; amyloid pathology; biomarker development; cognitive neuroscience; efficacy testing; healthy aging; hyperphosphorylated tau; imaging approach; imaging biomarker; imaging modality; in vivo; interest; locus ceruleus structure; mild cognitive impairment; multimodal neuroimaging; neurochemistry; neuroimaging; neuromelanin; neuroregulation; norepinephrine system; pars compacta; predictive marker; resilience; targeted treatment; tau Proteins; tau aggregation; theories; tool; young adult

Project Summary The advent of neuroimaging methods for measuring locus coeruleus (LC) structural integrity has generated intense interest from scientific fields focused on Alzheimer’s disease (AD), psychiatric disorders, as well as basic cognitive neuroscience. The LC is the brain’s primary generator of the neuromodulator norepinephrine (NE) and is one of the first brain regions to accumulate hyperphosphorylated tau protein, a hallmark pathological agent in AD. The ability to use magnetic resonance (MR) imaging to assess LC integrity opens up exciting possibilities for earliest detection of disease acceleration, and may also provide an MR measure that captures information about individual differences in neurochemical function. The ability to study neurochemical systems in vivo in humans is limited, with imaging approaches using radioactive tracers being the most established (e.g. positron emission tomography (PET)). However, due to the burden to subjects, as well as the infrastructural challenges, PET imaging is not a tool many researchers use despite the central role neuromodulatory systems like NE play in basic cognition and disease. We will take initial steps towards testing the validity of LC MR measures for predicting NE function by examining the correspondence between a neuromelanin-sensitive MR measure of LC integrity and a PET measure of catecholamine (norepinephrine/dopamine) synthesis capacity ([18F]Fluoro-l-m-tyrosine (FMT)) within subject in healthy young and older adults (Aim 1). Accumulating evidence in healthy aging, AD, and Parkinson’s disease suggests the catecholamine system responds to injury and shows compensatory capacity. Next, we will test the hypothesis that with advancing age, catecholamine synthesis goes up (Aim 2). Finally, to test the utility of LC neuroimaging measures as forecasters of the advancement of tau pathology, we will explore whether neuromelanin-sensitive MR and [18F]FMT predict the accumulation of tau in the medial temporal lobe using tau-sensitive [18F]flortaucipir imaging (Aim 3). Together, this research takes critical steps in establishing MR approaches as sensitive to neurochemical function, examines intriguing mechanisms of neurochemical compensation, and provides empirical testing of models of pathological spread in AD.

项目摘要 用于测量基因座（LC）结构的神经影像学方法的冒险 诚信引起了专注于阿尔茨海默氏症的科学领域的浓厚兴趣 疾病（AD），精神疾病以及基本的认知神经科学。 LC是 大脑的主要发电机神经调节剂去甲肾上腺素（NE），是一种 累积高磷酸化tau蛋白的第一个大脑区域，标志 AD中的病理剂。使用磁共振（MR）成像评估的能力 LC完整性为最早发现疾病加速的令人兴奋的可能性开辟了可能性， 并可能提供MR测量，以捕获有关个人的信息 神经化学功能的差异。在体内研究神经化学系统的能力 在人类中，有限 建立（例如，正电子发射断层扫描（PET））。但是，由于烧伤 受试者以及基础设施挑战，宠物成像不是许多工具 研究人员使用任务的核心角色神经调节系统，例如NE在基本中播放 认知和疾病。我们将采取初步步骤测试LC MR的有效性 通过检查A之间的对应关系来预测NE功能的措施 LC完整性的神经素素敏感的MR测量和PET测量 儿茶酚胺（去甲肾上腺素/多巴胺）的合成能力（[18F]氟-l-m-M-酪氨酸 （FMT））在健康的年轻和老年人中受试者（AIM 1）。积累证据 在健康衰老中，广告和帕金森氏病都表明了儿茶酚胺系统 对伤害的反应并显示出补偿能力。接下来，我们将检验假设 随着年龄的增长，Catecholamine合成增加（AIM 2）。最后，测试 LC神经影像措施的实用性，作为Tau病理发展的预测者， 我们将探讨神经苯胺敏感的MR和[18F] FMT是否预测 使用tau敏感的[18F] flortaucipir在内侧临时叶片中积聚tau 成像（目标3）。这项研究共同采取了关键步骤来建立MR 对神经化学功能敏感的方法，考试有趣的机制 神经化学补偿，并提供病理模型的经验测试 在广告中传播。

项目成果

Locus coeruleus catecholamines link neuroticism and vulnerability to tau pathology in aging.

• DOI: 10.1016/j.neuroimage.2022.119658
• 发表时间: 2022-11
• 期刊: NEUROIMAGE
• 影响因子: 5.7
• 作者: Parent, Jourdan H.;Ciampa, Claire J.;Harrison, Theresa M.;Adams, Jenna N.;Zhuang, Kailin;Betts, Matthew J.;Maass, Anne;Winer, Joseph R.;Jagust, William J.;Berry, Anne S.
• 通讯作者: Berry, Anne S.

Interactive effects of locus coeruleus structure and catecholamine synthesis capacity on cognitive function.

• DOI: 10.3389/fnagi.2023.1236335
• 发表时间: 2023
• 期刊: Frontiers in aging neuroscience
• 影响因子: 4.8