Investigating whole-body innate immune activation in Alzheimer's disease using PET imaging and immune profiling

使用 PET 成像和免疫分析研究阿尔茨海默病的全身先天免疫激活

• 批准号: 10352311
• 负责人: Aisling Chaney
• 金额: $ 10.75万
• 依托单位: STANFORD UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-02-15 至 2022-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10352311
• 关键词: Address; Age; Alzheimer' s Disease; Alzheimer' s disease brain; Alzheimer' s disease model; Alzheimer' s disease patient; Alzheimer' s disease risk; Astrocytes; Autopsy; Biological Markers; Blood; Blood Platelets; Bone Marrow; Brain; Cells; Clinical; Clinical assessments; Cognitive; Complex; Data; Development; Diabetes Mellitus; Diagnosis; Disease; Disease Progression; Endothelial Cells; Environment; Faculty; Funding; Genes; Goals; Gold; Heart; Human; Image; Immune; Immune Targeting; Immune response; Immunology; Immunomodulators; Infection; Inflammation; Inflammatory; Inflammatory Response; Innate Immune Response; Investigation; Knowledge; Link; Magnetic Resonance Imaging; Measures; Mentors; Methods; Microglia; Monitor; Multiple Sclerosis; Mus; Myelogenous; Myeloid Cells; Neuraxis; Neuroimmune; Neurosciences; Obesity; Outcome; Pathogenesis; Patients; Peripheral; Phase; Phenotype; Play; Positron-Emission Tomography; Proteins; Protocols documentation; Radiology Specialty; Reporting; Research Personnel; Resources; Risk; Role; Severity of illness; Specificity; Spleen; Techniques; Therapeutic; Time; Tissues; Tracer; Training; Transgenic Organisms; Viral; Work; base; brain tissue; clinical application; cohort; comorbidity; disorder control; genome-wide; immune activation; immune function; immunological status; immunoregulation; improved; in vivo; innovation; insight; interest; lymph nodes; macrophage; member; mild cognitive impairment; molecular imaging; mouse model; multidisciplinary; nervous system disorder; neuroinflammation; novel; patient population; pre-clinical; receptor; response; screening; skills; spatiotemporal; specific biomarkers; systemic inflammatory response; tenure track; therapeutically effective; tool; treatment strategy; uptake

Project Summary/Abstract The emerging role of inflammation in the pathogenesis of Alzheimer’s disease (AD) is shifting how the field is approaching its treatment, with growing interest in the development of immunomodulatory therapeutics. The appropriate therapeutic window and patient population for such treatment strategies remains to be determined. Importantly, current understanding of inflammation in AD has largely arose from brain tissues studied in isolation. However, it has become clear that peripheral inflammatory responses may influence both AD risk and disease progression. Here, I propose to use whole-body positron emission tomography (PET) of the translocator protein 18kDa (TSPO) and triggering receptor on myeloid cells 1 (TREM1) and complementary immune profiling techniques to non-invasively assess peripheral and central inflammation in Alzheimer’s disease. This project aims to use parallel preclinical (Aim 1) and clinical approaches (Aims 2 & 3) to increase the fundamental understanding of inflammation in disease while actively improving clinical assessment. Our specific aims are (1) to characterize distinct peripheral and central myeloid cell responses and investigate the effects of systemic inflammation on neuroinflammation in the 5XFAD mouse model of AD; (2) to develop a clinically feasible approach to quantify whole-body TSPO-PET uptake in AD patients; and (3) to study whole-body immune signatures associated with disease severity in AD and mild cognitive impairment patients using whole-body TSPO-PET and blood-based immune profiling. The innovation of this work lies in the whole-body approach for the investigation of inflammation in AD, which has yet to be investigated. TREM1-PET is the first tool to specifically image proinflammatory peripheral myeloid cells in vivo. Preclinical investigation using TREM1-PET and clinical application of whole-body TSPO-PET imaging in patients will provide novel insights into the complex neuroimmune interactions involved in AD pathogenesis. The significance of this work is that enhanced understanding of whole-body innate immune responses in AD has the potential to not only improve diagnosis and disease monitoring, but also to develop and screen for effective disease modifying therapeutics. Additionally, these methods can be applied to impact our understanding of inflammation across a broad range of inflammatory and neurological disorders.

项目概要/摘要 炎症在阿尔茨海默病 (AD) 发病机制中的新作用正在改变该领域的研究方式 接近其治疗，人们对免疫调节疗法的开发越来越感兴趣。这 这种治疗策略的适当治疗窗和患者群体仍有待确定。 重要的是，目前对 AD 炎症的理解很大程度上来自于单独研究的脑组织。 然而，很明显，外周炎症反应可能会影响 AD 风险和疾病 进展。在这里，我建议使用易位蛋白的全身正电子发射断层扫描（PET） 18kDa (TSPO) 和骨髓细胞触发受体 1 (TREM1) 以及互补免疫分析 非侵入性评估阿尔茨海默氏病周围和中枢炎症的技术。 该项目旨在使用并行的临床前（目标 1）和临床方法（目标 2 和 3）来提高 对疾病炎症的基本了解，同时积极改进临床评估。我们的具体 目的是 (1) 表征不同的外周和中枢骨髓细胞反应并研究 AD 5XFAD 小鼠模型中全身炎症对神经炎症的影响； (2) 临床开发 量化 AD 患者全身 TSPO-PET 摄取的可行方法； (3)研究全身免疫 使用全身与 AD 和轻度认知障碍患者的疾病严重程度相关的特征 TSPO-PET 和血液免疫分析。 这项工作的创新之处在于研究 AD 炎症的全身方法， 尚待调查。 TREM1-PET 是第一个专门对促炎性外周骨髓细胞进行成像的工具 体内的细胞。 TREM1-PET的临床前研究和全身TSPO-PET的临床应用 患者成像将为 AD 中复杂的神经免疫相互作用提供新的见解 发病。这项工作的意义在于增强了对全身先天免疫的理解 AD 的反应不仅有可能改善诊断和疾病监测，而且有可能发展和 筛选有效的疾病缓解疗法。此外，这些方法可以用来影响我们 了解各种炎症和神经系统疾病的炎症。