Characterisation of longitudinal peripheral immune cellular changes in vascular dementia

中风是全世界死亡和残疾的一个主要原因。在中风幸存者中，最令人痛苦的并发症之一是痴呆症，在五年内，多达三分之一的人会出现这种情况，并对生活质量产生重大影响。炎症和免疫通路失调与脑血管疾病的病理生理学密切相关，也与痴呆和认知障碍有关。先天免疫细胞，如小胶质细胞和单核细胞，在脑损伤反应中起着关键作用，被认为可以调节随后参与恢复和修复的途径。我们最近对急性中风患者的外周血髓细胞室进行了详细的免疫表型分析，并确定了树突状细胞和单核细胞亚群的特异性变化。在初步研究中，我们的合作者已经证明，中风急性期外周先天细胞的特异性变化与随后的认知障碍相关。我们的主要假设是，中风后急性期的先天免疫改变形成了慢性适应性不良的神经免疫反应，损害了长期的大脑结构和功能完整性，并导致血管性痴呆的发展。该项目的主要目的是研究卒中后外周血免疫状态与患者血管性痴呆发展之间的关系，重点关注髓系亚群。该项目将与一项正在进行的急性缺血性卒中患者前瞻性队列研究（stroke-impact; https://stroke-impact.org/）保持一致，包括纵向随访、连续血液采样、血液生物库和临床评估，该研究由著名的Leducq基金会跨大西洋卓越网络奖（https://www.fondationleducq.org/）资助。将抽取一系列血液样本，使用最先进的多色流式细胞术、RNA测序和相关血浆炎症标志物的免疫测定来评估骨髓亚群的免疫表型和功能。计算免疫学算法将应用于流式细胞分析和单细胞RNA测序。将探讨与基线临床因素以及认知和功能结果的关系。将提供转化神经科学、免疫学和生物信息学方面的综合培训。这项工作将与卒中影响网络内的临床前研究并行，并受益于与领先的卒中研究实验室的互动。将有机会访问我们的合作小组，展示数据并学习新兴技术和技巧。该项目将为中风后免疫系统如何随着时间的推移而改变以及这与认知轨迹和可能的治疗或预防目标之间的关系提供新的见解。

Stroke is a major cause of death and disability worldwide. In stroke survivors one of the most distressing complications is dementia, which occurs in up to a third of individuals within five years and impacts significantly on quality of life. Dysregulated inflammatory and immune pathways are strongly implicated in the pathophysiology of cerebrovascular disease and have also been linked to dementia and cognitive impairment. Innate immune cells, such as microglia and monocytes, play a key role in the response to brain injury and are thought to modulate subsequent pathways involved in recovery and repair. We have recently undertaken detailed immunophenotyping of the peripheral blood myeloid compartment in acute stroke patients, and identified specific changes in dendritic cell and monocyte subsets. In preliminary studies, our collaborators have demonstrated that specific changes in peripheral innate cells in the acute phase of stroke correlate with subsequent cognitive impairment. Our overarching hypothesis is that innate immune alterations in the acute phase after stroke shape chronic maladaptive neuroimmune responses that compromise long-term structural and functional brain integrity, and contribute to the development of vascular dementia.The main aim of this project is to Investigate the association between peripheral blood immune status after stroke, with a focus on myeloid sub-sets, and development of vascular dementia in patients. The project will align with an ongoing prospective cohort study of patients with acute ischemic stroke (Stroke-IMPaCT; https://stroke-impact.org/), with longitudinal follow-up, serial blood sampling, blood bio-banking, and clinical assessments, funded by a prestigious Leducq Foundation Transatlantic Network of Excellence Award (https://www.fondationleducq.org/). Serial blood samples will be drawn for evaluation of immunophenotype and function of myeloid subsets using state of the art multicolour flow cytometry, RNA sequencing and immunoassay of related plasma inflammatory markers. Computational immunology algorithms will be applied to the flow cytometric analyses and single-cell RNA sequencing. Relationships with baseline clinical factors and both cognitive and functional outcomes will be explored. Comprehensive training will be provided in translational neuroscience, immunology and bioinformatics. The work will parallel pre-clinical studies within the Stroke IMPaCT network and benefit from interactions with leading stroke research laboratories. There will be opportunities to visit our collaborating groups to present data and learn emerging technologies and techniques. This project will provide novel insights into how the immune system is altered over time after stroke and how this relates to cognitive trajectory and possible therapeutic or preventative targets.