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

项目总结/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发展方向。 随着人们对免疫调节疗法的发展越来越感兴趣，的 用于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炎症的理解主要来自孤立研究的脑组织。 然而，外周炎症反应可能影响AD的风险和疾病， 进展在这里，我建议使用转运蛋白的全身正电子发射断层扫描（PET） 18 kDa（TSPO）和髓样细胞上的触发受体1（TREM 1）和互补免疫谱 非侵入性评估阿尔茨海默病外周和中枢炎症的技术。 该项目旨在使用平行的临床前（目标1）和临床方法（目标2和3）来增加 对疾病炎症的基本认识，同时积极改善临床评估。我们的具体 目的是（1）表征不同的外周和中央髓样细胞反应，并研究 在AD的5XFAD小鼠模型中，全身炎症对神经炎症的影响;（2）开发临床上用于治疗AD的系统性炎症模型。 量化AD患者全身TSPO-PET摄取的可行方法;（3）研究全身免疫 与AD和轻度认知障碍患者疾病严重程度相关的特征， TSPO-PET和基于血液的免疫分析。 这项工作的创新之处在于研究AD炎症的全身方法， 还有待调查TREM 1-PET是第一种特异性成像促炎性外周骨髓的工具 体内细胞使用TREM 1-PET的临床前研究和全身TSPO-PET的临床应用 对患者的成像将为AD中涉及的复杂神经免疫相互作用提供新的见解 发病机制这项工作的意义在于加深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， 筛选有效的疾病改善治疗剂。此外，这些方法可以应用于影响我们的 在广泛的炎症和神经系统疾病的炎症的理解。

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.