Vascular cognitive impairment (VCI) refers to cognitive dysfunction primarily caused by cerebrovascular disease and its risk factors, encompassing a spectrum from mild cognitive impairment to dementia with mixed pathologies. Despite significant progress in VCI research, its pathological mechanisms and treatment strategies remain incompletely understood. Recent data from neutrophil studies suggest that chronic inflammatory processes, including chronic liver injury, significantly impact neurological disorders. Systemic inflammation and neutrophil activation are increasingly recognized as predictors and risk factors for cognitive impairment across a range of neurological disorders. Neutrophils originate from hematopoietic processes in the bone marrow, and myeloid-biased hematopoiesis-a shift toward increased production of myeloid lineage cells-has been strongly implicated in the pathogenesis of numerous chronic diseases. However, its role in vascular cognitive impairment (VCI) remains unknown.
Based on current knowledge, this research proposes three key questions:
(1) Does chronic liver injury trigger long-lasting epigenetic modification in hematopoietic cells?
(2) How does aberrant hematopoiesis contribute to neuroinflammation and vascular cognitive impairment (VCI)?
(3) Can targeting myeloid cells-mediated pathways mitigate VCI progression!
There are four objectives in this research!
(1) Validate aberrant hematopoiesis in chronic liver injury models.
(2) Characterize neutrophil trafficking to the brain and their role in neuroinflammation.
(3) Identify key inflammatory mediators linking trained neutrophils to VCI, such as neutrophil extracellular traps.
(4) Develop neutrophil-targeted therapeutic interventions in preclinical models.
This research leverages the UK Biobank’s large-scale biomedical database to investigate the relationship between neutrophil activation and VCI risk and progression.
