| PART ONEFramingham stroke risk factors and cognitive impairment:a community-based studyObjective Previous studies have demonstrated that single vascular risk factor (VRF) such as high blood pressure or diabetes mellitus can increase the risk of cognitive impairment independent of stroke events and detectable cerebral lesions. However, the presence of multiple vascular risk factors might have synergistic effect. The objective of this study was to examine the relationship between aggregative Framingham Stroke Risk Profile (FSRP) and cognitive function in a Chinese community-based sample, and to explore which cognitive domains are more vulnerable to VRFs.Methods Participants were184adults aged50years and over of the Chinese Stroke Screening Registration Project, a prospective cohort study. A modified version of the Framingham Stroke Risk Profile (incorporating age, sex, systolic blood pressure, antihypertensive medication, diabetes, smoking status, cardiovascular disease, and atrial fibrillation) was used to assess10-year risk of stroke. Linear regression models were used to determine the cross-sectional relationship of stroke risk to global cognitive function and performance in multiple cognitive domains, including global cognitive function, working memory, attention, executive function, immediate and delayed memory. The regression analyses were adjusted for white matter hyperintensities (WMHs) volume and presence of lacunes. Bayes discriminant analysis was used to identify the combined effect of each VRF important for discrimination the risk of cognitive impairment. Subjects were divided into low-(<10%), medium-(10-20%), and high-risk(>20%) groups according to their FSRP scores. Clinical research registration number:ChiCTR-RNC-12002205.Results As Framingham ten-year stroke risk increased, the global cognitive function, executive function and memory significantly declined. Compared with low-risk group, the executive function (assessed by Digit Symbol Test) and delayed recall (assessed by RAVLT) were significantly impaired in both the medium-risk group (P=0.034and P=0.014respectively) and high-risk group (P<0.01and P<0.01respectively). The scores in global cognitive tests, the Trail Making Tests B and the Digit Span Backward Tests were also significantly lower in high-risk group (P<0.01, P=0.026and P=0.044respectively), but not in the medium-risk group. After adjusted for WMHs volume and presence of lacunes, there was a significant negative correlation between FSRP score and cognitive performance, including global cognitive test (r=-0.451, P=0.001), executive function(r=-0.311, P=0.025), working memory (r=-0.309, P=0.026) and delayed memory (r=-0.352, P=0.01). Bayes discriminant analysis showed that systolic pressure, presence of diabetes, age and current smoking were the major factors leading to cognitive impairment. The overall prediction accuracy was85.2%.Conclusion In individuals free from a history of stroke, high vascular risk factors burden was associated with worse cognitive function in multiple domains, mainly the executive function and delayed memory. PART TWOAbnormal levels of brain metabolites may mediate cognitive impairment in stroke-free patients with cerebrovascular risk factorsObjective Conventional vascular risk factors (VRFs) are associated with cognitive impairment independent of stroke and detectable cerebral lesions. We used proton magnetic resonance spectroscopy (1H-MRS) to examine the hypothese that abnormal levels of brain metabolites may mediate the relationship between VRFs and cognitive impairment.Methods A group of54stroke-free subjects with various VRFs underwent comprehensive cognitive assessments and1H-MRS scan of the left hippocampus and prefrontal cortex. We indirectly measured the concentrations of N-acetyl-aspartate (NAA), Choline (Cho), Inositol (Ins), Creatine (Cr) and total concentrations of glutamate plus glutamine (Glx). VRFs were quantified by Framingham Stroke Risk Profile (FSRP) score. Subjects were divided into low-(<10%), medium-(10-20%), and high-risk(>20%) groups according to their FSRP scores. Pearson and partial correlation analysis were used to investigate the correlation between FSRP scores and cognitive performance along with the brain metabolism. Written informed consent was obtained from all participants. Clinical research registration number: ChiCTR-RNC-12002205.Results Compared with subjects in low-risk group, high-risk group subjects had significantly poor performances on the tasks of working memory (3.9±1.0versus4.8±1.1, P<0.05), delayed recall (7.1±1.5versus9.1±1.5, P<0.01) and executive function (27.8±6.2versus37.1±6.5, P<0.01). In high-risk group, hippocampal Glx/Cr ratios (1.21±0.25versus1.48±0.22, P<0.01) and prefrontal NAA/Cr ratios (1.33±0.14versus1.66±0.33, P<0.01) were significantly lower than those in low-risk group. Higher FSRP score was significantly associated with lower Glx/Cr ratio in hippocampus (r=-0.332, P=0.016) and with lower NAA/Cr ratio in prefrontal cortex (r=-0.287, P=0.039). Lower prefrontal NAA/Cr ratios were associated with executive dysfunction (r=0.327, P=0.016), and lower hippocampal Glx/Cr ratios were associated with impaired delayed recall (r=0.419, P=0.002). There were no significant differences in Cho/Cr and Ins/Cr ratios across the three groups. All associations were adjusted for WMHs volume and presence of lacunes. Conclusion Abnormal concentrations of brain metabolites and decreased glutamate plus glutamine concentration may play an important role in the pathophysiology of VRF-associated cognitive impairment. Brain metabolites detected by1H-MRS may serve as important markers for monitoring vascular risk factors burden. PART THREEBlood brain barrier dysfunction may mediate cognitive impairment in stroke-free patients with cerebrovascular risk factorsObjective Blood brain barrier (BBB) dysfunction is the common pathological and physiological basis for various central nervous system diseases. In this study, we used dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) to examine the hypothese that increased BBB permeability may mediate the relationship between vascular risk factors and cognitive impairment.Methods his is a small sample pilot study. A group of22stroke-free subjects from PART ONE study underwent a series of cognitive assessments and3.0Tesla DCE-MRI scan (Sequence:T1-mapping with partial inversion recovery, TAPIR). The left hippocampus and frontal subcortical white matter were chosen as the volume of interests. Participants were divided into low-(<10%), and high-risk(>20%) groups according to their FSRP scores. The Vascular volume index was defined as the peak value of signal enhancement at30seconds, and the BBB permeability index was defined as the ratio between late enhancements at the180seconds to the peak value at30seconds. Pearson and partial correlation analysis were used to investigate the correlation between BBB permeability index and FSRP scores along with cognitive performance. Written informed consent was obtained from all participants. Clinical research registration number:ChiCTR-RNC-12002205.Results Compared with subjects in low-risk group, high-risk group subjects were elder (74.3±3.7versus56.7±6.9, P<0.01), and had significantly higher systolic pressure (143.5±16.0versus129.0±13.0, P=0.032), and had more serious white matter lesions (1.5±2.2versus7.1±3.8, P<0.05). In high-risk group, left hippocampal Vascular volume index (0.238±0.17versus0.264±0.16, P<0.05) was significantly lower than that in low-risk group, and left hippocampal BBB permeability index was higher in high-risk group than that in low-risk group (0.74±0.07versus0.69±0.04, P<0.05). Higher FSRP score was significantly associated with higher BBB permeability index (r=0.576, P=0.006) and with lower Vascular volume index (r=-0.626, P=0.002) in left hippocampus. Lower left hippocampal BBB permeability index was associated with delayed recall test score (r=-0.596, P=0.002). In the level of left frontal subcortical white matter, there were no significant differences in BBB permeability index between the two groups. All associations were adjusted for white matter hyperintensities volume and presence of lacunes.Conclusion Blood brain barrier dysfunction is a form of brain damage associated with vascular risk factors, and may mediate the cognitive impairment associated with vascular risk factors. DCE-MRI is a useful technique to detect sublte blood brain barrier dysfunction in the early-stage of cognitive impairment. |
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