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

项目摘要/摘要 炎症在阿尔茨海默病(AD)发病机制中的作用正在改变这一领域的方式 随着对免疫调节疗法的发展越来越感兴趣，对其治疗方法也越来越感兴趣。这个 这种治疗策略的适当治疗窗口和患者群体仍有待确定。 重要的是，目前对阿尔茨海默病炎症的了解主要源于孤立研究的脑组织。 然而，外周炎症反应可能会影响AD的风险和疾病，这一点已经变得很清楚 进步。在这里，我建议使用全身正电子发射断层扫描(PET)的转位蛋白 18 kDa(TSPO)和触发髓系细胞受体1(TREM1)与补体免疫 非侵入性评估阿尔茨海默病外周和中枢炎症的技术。 该项目旨在使用并行的临床前方法(目标1)和临床方法(目标2和3)，以增加 在积极改进临床评估的同时，对疾病中的炎症有基本的了解。我们的特定 目的是(1)表征不同的外周和中央髓系细胞反应，并研究 全身性炎症对5XFAD小鼠AD模型神经炎症的影响；(2)临床研究 量化AD患者全身TSPO-PET摄取的可行途径；以及(3)全身免疫研究 全身检查显示AD和轻度认知障碍患者的症状与疾病严重程度相关 TSPO-PET和基于血液的免疫分析。 这项工作的创新之处在于对AD炎症的全身研究方法，即 还有待调查。TREM1-PET是第一个特异性成像促炎外周髓系的工具 体内的细胞。TREM1-PET临床前研究及全身TSPO-PET的临床应用 对患者的成像将为AD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，提高了对全身先天免疫的认识 对AD的反应不仅有可能改善诊断和疾病监测，而且还可能发展和 筛选有效的疾病修饰疗法。此外，这些方法可以应用于影响我们的 了解广泛的炎症性和神经系统疾病中的炎症。

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.