Chronic Cerebral Hypoperfusion Induces Cognitive Impairment And Aggravates The Progression Of Cardiac And Renal Dysfunction

Objective: Vascular contributions to vascular cognitive impairment(VCI)and dementia are major health problems worldwide.Heart-kidney deficit and dementia frequently coexist,but little is known whether VCI induces cardiac and kidney deficit absent from primary heart and kidney deficit.The purpose of this study was to investigate the effect of VCI on white matter(WM)injury and cognitive impairment,as well as how VCI affects heart and kidney function at 2 and 8 months after bilateral common carotid artery stenosis(BCAS)in a mouse model of VCI.Methods: Adult male C57BL/6J(8-months)mice were subjected to Sham and BCAS surgery using micro-coils with inner diameter of 0.16 mm.Cognitive functional tests and cardiac function were measured before mice were sacrificed at 2 months post BCAS(2mo-BCAS)and at 8 months post BCAS(8mo-BCAS),respectively.Novel object recognition(NOR)test,odor test and Morris water maze test were employed to test cognitive function,blood pressure was recorded.Echocardiogram was used to measure the cardiac function,and 24 h urine was collected to measure albumin.The brains,hearts and kidneys were then harvested for histological and immunohistochemical staining.Significant statistics were determined as p<0.05.Results: Compared to Sham group,mice in 2mo-BCAS and 8mo-BCAS group both exhibit significantly: 1)increased cognitive deficits identified by decreasing the novel NOR test,odor test and Morris water maze test.2)increased white matter injury by decreasing Luxol fast blue density in CC and striatum as well as increased axonal injury in striatum by Bielschowsky silver staining 3)decreased the expression of synaptophysin on cortex and striatum.4)decreased left ventricular ejection fraction(LVEF)and fractional shortening(FS)measured by echocardiogram.5)increased heart IBA-1,CD45,and CD86 expression as well as cardiac fibrosis indicated by picrosirius red(PSR)staining.6)increased kidney IBA-1and MCP-1 as well as renal fibrosis indicated by picrosirius red(PSR)staining.Compared to 8mo-Sham group,enhanced expression for the cognitive impairment associative cytokines of APN、CHI3L1、IGFBP2、IGFBP-6、RBP4、OPN and REG3 G in 8mo-BCAS group.Compared to Sham group,mice in 2mo-BCAS did not affect the level of albumin in urine,but 8moBCAS significantly increased the level of albumin in urine.Compared to 2mo-BCAS,8mo-BCAS mice exhibit significantly: 1)worse cognitive function of odor test and Morris water maze test.2)worse axonal/WM injury.3)worse LVEF and FS.4)increased heart IBA-1,CD45,and CD86 expression.5)higher level of albumin in urine.6)increased kidney IBA-1and MCP-1 expression as well as renal fibrosis.Conclusions: Our data indicate that BCAS not only induces progressive long-term cognitive impairment and WM/axonal damage,but also induces progressive cardiac and renal dysfunction compared to sham control mice.