The association of vascular and systemic inflammation with cerebrovascular diseases and its related outcomes
Inflammation has been implicated as a risk factor for cerebrovascular diseases. There are evidences that anti-inflammatory drugs potentially improve stroke outcomes. However, several key questions shall be addressed to further understand the causal association of inflammation with cerebrovascular diseases. First, although there exist evidences supporting causal relationship between inflammation and stroke, the association between the genetic predisposition to either systemic and vascular inflammation and the related outcomes of stroke are unknown. Second, the causal relationship between inflammation and SVD/carotid stenosis are rarely studied. Last, previous studies did not comprehensively examine the role of both vascular and systemic inflammation in developing cerebrovascular diseases. It is unclear how the inflammation mediates or moderates the cerebrovascular outcomes such dementia, recurrence of stroke or mortality. The project primarily aims to investigate the association between vascular and systemic inflammation and cerebral vascular diseases including stroke, cerebral small vessel diseases and carotid stenosis. Particularly, the study is set to explore the causal relationship between the genetically determined circulating levels of inflammatory biomarkers (homocysteine, neopterin, ICAM-1, VCAM-1, E-selectin, P-selectin, VEGF, CRP, IL-6, TNF-!, fibrinogen, etc), genetic underpinnings relating to susceptibility of infection and immunoinflammatory diseases and the cerebrovascular diseases. Last, the study observes the mediating or moderating effects of inflammation on the vascular outcomes. This project is expected to last for 36 months. The findings may deepen the understanding in biological mechanisms of cerebrovascular and their related outcomes, and may guide anti-inflammatory strategies to prevent and treat cerebrovascular diseases.
The project primarily aims to investigate the association between systemic inflammation (indicated by peripheral inflammatory biomarkers, chronic infections and chronic immunoinflammatory disorders), vascular inflammation (biomarkers of endothelial dysfunction) and cerebral vascular diseases including stroke, cerebral small vessel diseases (SVD), and carotid atherosclerosis. Particularly, this study intends to employ the Mendelian Randomization to study the causal relationship between genetically determined circulating levels of inflammatory biomarkers (homocysteine, neopterin, ICAM-1, VCAM-1, E-selectin, P-selectin, VEGF, CRP, IL-6, TNF-!, fibrinogen, etc) and the abovementioned cerebrovascular diseases. In addition, this study investigates how the genetic underpinnings relating to the susceptibility of infection and immunoinflammatory diseases (systemic lupus erythematosus, rheumatoid arthritis, multiple sclerosis, etc) determine the risk of cerebrovascular diseases.
The second aim of this study is to explore whether these systemic inflammations moderate or mediate the vascular outcomes including mortality, recurrence of stroke, vascular cognitive impairment or dementia, and depressive symptoms in patients with cerebrovascular diseases.
The study extends its aims as follow:
This study also aims to investigate the potential impacts of environmental (air pollution, noise, diet, life events, etc) and lifestyle factors (physical activity, grip strength, commuting, etc) on the risks of multiple chronic diseases, in particular, neuropsychiatric diseases (stroke, depression, dementia, etc) and as well as brain health as indicated by brain imaging markers or cognitive tests. Moreover, the study hypothesizes that the low- grade chronic inflammation, along with the chronic diseases or triggered by both physical and mental dysfunctions, plays a role in moderating or mediating the relationship between the life course factors (air pollution, noise, diet, life events, etc) and the outcomes of the disease. To testify the above hypotheses, the current study will further employ cox or logistic/linear regressions to examine the associations between the environmental and lifestyle factors and neuropsychiatric diseases as well as other related chronic diseases. Furthermore, the study applies mediation analyses to investigate the role of chronic inflammation in mediating the above-mentioned relationship. With these works done, the study hopes to describe the critical role of chronic inflammation in bridging the relationship between multiple risk factors and chronic diseases or brain health.
The study further extends its aims as follow:
Amongst the various lifestyle risk factors, this study is further particularly interested in the detrimental effects of life events (childhood/adolescent/adult adverse experiences) and sleep/circadian behaviors on the incidence and prognosis of cerebrovascular, cardiometabolic diseases, dementia, and their underlying neuroinflammation and neuroimaging mechanisms as previously described. We hypothesize that 1) the abnormality of the brain networks responsible for emotional processing like salience network, and the inflammation may act as the mechanisms linking lifestyle factors or events and the sparse vascular events by using multimodal brain MRI data and cardiac MRI data with mediation analyses; 2) the genetic risk scores of diseases may stratify the risks of life stress on the outcomes of cerebrovascular, cardiometabolic diseases, dementia. These works are expected to clarify the mechanisms and susceptibility underlying life stress on cerebrovascular, cardiometabolic diseases, dementia, and suggest potential interventions and preventive strategies.