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

基本信息

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
项目类别：
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&apos s Disease Alzheimer&apos s disease pathology Alzheimer&apos 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

项目摘要

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.

项目概要用于测量蓝斑 (LC) 结构的神经影像学方法的出现诚信引起了以阿尔茨海默氏症为重点的科学领域的强烈兴趣疾病（AD）、精神疾病以及基础认知神经科学。大脑是神经调节剂去甲肾上腺素 (NE) 的主要生成器，也是其中之一第一个积累过度磷酸化 tau 蛋白的大脑区域，这是一个标志 AD 中的病理因素使用磁共振 (MR) 成像进行评估的能力。 LC 完整性为尽早检测疾病加速提供了令人兴奋的可能性，并且还可以提供 MR 测量来捕获有关个人的信息神经化学功能的差异。研究体内神经化学系统的能力。对人类的影响是有限的，使用放射性示踪剂的成像方法是最有效的建立（例如正电子发射断层扫描（PET））然而，由于负担由于基础设施的挑战，PET 成像并不是一种工具尽管像 NE 这样的神经调节系统在基础研究中发挥着核心作用，但研究人员仍然使用我们将采取初步措施来测试 LC MR 的有效性。通过检查之间的对应关系来预测 NE 功能的措施神经黑色素敏感的 MR 测量 LC 完整性和 PET 测量儿茶酚胺（去甲肾上腺素/多巴胺）合成能力（[18F]氟-l-m-酪氨酸（FMT））在健康年轻人和老年人中进行（目标 1）。在健康老龄化、阿尔茨海默病和帕金森病中，儿茶酚胺系统表明对伤害做出反应并显示出补偿能力接下来，我们将检验该假设。随着年龄的增长，儿茶酚胺的合成会增加（目标 2）。 LC 神经影像学测量作为 tau 病理学进展预测的实用性，我们将探讨神经黑色素敏感的 MR 和 [18F]FMT 是否可以预测使用 tau 敏感的 [18F]flortaucipir 在内侧颞叶积聚 tau 总之，这项研究在建立 MR 方面迈出了关键的一步。方法对神经化学功能敏感，检查了有趣的机制神经化学补偿，并提供病理模型的经验测试传播于公元

项目成果

期刊论文数量（3）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

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.