Characterisation of longitudinal peripheral immune cellular changes in vascular dementia

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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.