Study On Makers Associated With Clinical Risk Assessment Of Cerebral Small Vessel Disease And Its Relationship With Prognosis Of Acute Ischemic Stroke

BackgroundSmall vessel disease(SVD)refers to a series of manifestations caused by various lesions of small vessels in the brain.Typical SVD imaging features including enlarged perivascular spaces(EPVS),lacunes,white matter hyperintensities(WMH)and cerebral microbleeds(CMB).With the increase of SVD lesion number and the combination of lesion types,SVD was associated with cognitive impairment,dementia,depression,motor dysfunction,increased risk of stroke and poor prognosis after stroke.The pathogenesis of SVD is still not fully understood,to explore the makers of clinical risk assessment related to SVD can provide a certain basis for the mechanism research of SVD.Although there is no specific targeted therapy for SVD at present,several studies have found that effective control of risk factors and treatment measures can delay the occurrence and development of SVD.Therefore,early identification of SVD and timely control of risk factors are important.At present,the discovery of SVD mainly rely on MRI,but MRI is not a routine item in the physical examination of the elderly population.Therefore,it is of great significance to search for easily accessible and inexpensive makers of SVD in clinical practice to help determine candidates for MRI examination and to provide timely clinical decision for early detection of SVD.It is critical for delaying the progress of SVD and even reversing the damage to prevent or delay the devastating clinical consequences of SVD.Stroke is one of the important devastating clinical consequences of SVD.About a quarter of acute ischemic strokes are caused by SVD.However,stroke is the leading cause of death and disability worldwide,and approximately 25-74%of stroke survivors require some assistance in life or are totally dependent on caregivers.Therefore,it is necessary to explore the influencing factors of the prognosis of stroke.The features of SVD could affect the prognosis of ischemic stroke,which can significantly increase the risk of stroke recurrence,death,disability and adverse clinical outcomes.However,previous studies mainly focused on the effect of individual feature of SVD on the prognosis of ischemic stroke.As the SVD features are correlated with each other,it is suggested that SVD should be considered as a whole brain disease instead of considering each feature separately.At present,the relationship between total SVD burden and functional outcome after acute ischemic stroke is not clear,and whether total SVD burden is superior to single feature in predicting functional outcome after ischemic stroke has not been reported.Explore the predictive value of SVD on functional prognosis of acute ischemic stroke is of great value to help develop rehabilitation strategies for stroke survivors,guide clinical practice to improve the prognosis and clinical management of stroke patients.Therefore,this study will be conducted from the following two parts.The first part is to explore the easily obtained makers associated with clinical risk assessment of SVD.The second part explored the relationship between SVD and functional outcome after acute ischemic stroke.Part One The makers associated with clinical risk assessment of cerebral SVDChapter One Screening of the makers associated with clinical risk assessment of cerebral SVDObjectives:Screening the makers associated with clinical risk assessment of imaging manifestations of SVD from the laboratory examination indicators that easily available in clinical practice to provides new clues for early detection and early management of SVD,and also helps to explore the pathogenesis of SVD.Methods:Consecutive SVD patients over 60 years who were admitted to the department of neurology of the first affiliated hospital of Chongqing medical university between November 2017 and November 2018 were collected.Fasting blood samples were collected within 12 hours after admission for testing of laboratory indexes.MRI was used to evaluate the SVD features.The receiver operating characteristic(ROC)curve was used to measure the evaluation value of each laboratory index on the features of SVD.Results:1.A total of 413 SVD patients aged over 60 years were included,173(41.9%)had lacunes and 387(93.7%)had WMH.Among EPVS,366(88.6%)patients had mild EPVS and 47(11.4%)patients had severe EPVS in basal ganglia(BG);316(76.5%)had mild EPVS and 97(23.5%)had severe EPVS in central semiovale(CS).2.The makers associated with clinical risk assessment of lacune are glomerular filtration rate(eGFR),Cystain C(Cys C),creatinine,homocysteine and white blood cell count.Among which,renal function indexes have the larger predictive value.3.The makers associated with clinical risk assessment of WMH are total cholesterol(TC)/high-density lipoprotein cholesterol(HDL-C),non-high-density lipoprotein cholesterol(Non-HDL-C)/HDL-C,Apolipoprotein B(Apo B)/Apolipoprotein A-I(Apo A-I),Apo B/HDL-C,Cys C,low-density lipoprotein cholesterol(LDL-C)/HDL-C,eGFR,Apo B,Non-HDL-C,creatinine,etc.Among them,the ratios of blood lipid were of greatest value in predicting WMH,which was only significant in women.4.The makers associated with clinical risk assessment of BG-EPVS included the product of triglycerides and glucose(TyG)index and ZJU index,while the makers associated with clinical risk assessment of CS-EPVS were hemoglobin level and uric acid level.Conclusions:1.Among the makers associated with clinical risk assessment of lacune,the prediction value of renal function indexes(eGFR,Cys C and creatinine)were relatively large.2.Among the makers associated with clinical risk assessment of WMH,blood lipid ratios had the largest predictive value,which was only significant in women.3.The makers associated with clinical risk assessment of BG-EPVS included TyG index and ZJU index,while the maker with greater predictive value for CS-EPVS was hemoglobin level.Chapter Two The makers associated with clinical risk assessment of EPVSObjectives:According to the screening results of the makers associated with clinical risk assessment of EPVS in chapter one,the makers with the greatest evaluation value of BG-EPVS and CS-EPVS were further analyzed.It can help to understand the risk factors and pathogenesis of EPVS and help to prevent subsequent events such as stroke and cognitive decline.Methods:BG-EPVS and CS-EPVS were divided into two groups:mild(score≤1)and severe(score>1).ZJU index and TyG index were calculated.Logistics regression models were used to analyze the relationship between ZJU index and TyG index and risk of EPVS.ROC curve was used to evaluate the clinical predictive value of ZJU index and TyG index on EPVS.Logistics regression models were used to analyze the relationship between hemoglobin level and the severity of EPVS as well as the predominance of EPVS.The other methods are the same as chapter one.Results:1.The makers associated with clinical risk assessment of BG-EPVS1.1 Among the enrolled 413 SVD patients aged≥60 years,a total of 324 patients with complete data of ZJU index and TyG index were included in the statistical analysis,287(88.6%)were mild BG-EPVS,and 37(11.4%)were severe BG-EPVS.There were 246 cases(75.9%)with mild CS-EPVS and 78 cases(24.1%)with severe CS-EPVS.1.2 The levels of ZJU index and TyG index in severe BG-EPVS group were significantly higher than those in mild BG-EPVS group(P<0.05),while there were no differences between two groups of CS-EPVS(P>0.05).Further stratified analysis revealed that the relationship between BG-EPVS and ZJU index and TyG index existed only in males.1.3 ZJU index and TyG index were grouped according to quartile interval respectively.In men,Quartile 3(OR:2.93,95%CI:1.24-4.32)and Quartile 4(OR:3.79,95%CI:1.53-5.82)of the ZJU index were significantly correlated with the risk of severe BG-EPVS after adjusted for potential confounding factors.Similarly,Quartile 3(OR:2.34,95%CI:1.19-3.83)and Quartile 4(OR:4.02,95%CI:1.85-6.17)of the TyG index were significantly correlated with the risk of severe BG-EPVS(P<0.05).1.4 ROC analysis showed that in men,the predictive value of ZJU index and TyG index on high degree of BG-EPVS were higher than FPG and AST,and the AUC of TyG index(0.664,95%CI:0.597-0.727,P=0.002)was the highest.Further analysis showed that the sensitivity and specificity of TyG index were higher than that of ZJU index.1.5 The recognition rate of high-TyG combined with high-ZJU for high degree of BG-EPVS was 89.2%,which is higher than that of high-TyG(73.0%)and high-ZJU alone(67.6%,P<0.05).2.The makers associated with clinical risk assessment of CS-EPVS2.1 Among the enrolled 413 SVD patients aged≥60 years,a total of 401 patients with complete data of blood routine examination were included in the statistical analysis,356(88.8%)were mild BG-EPVS and 45(11.2%)were severe BG-EPVS.There were 307 cases with mild CS-EPVS(76.6%)and 94 cases with severe CS-EPVS(23.4%).2.2 The hemoglobin level of severe CS-EPVS group was significantly higher than that of mild CS-EPVS group(P=0.008).The incidence of severe CS-EPVS increased significantly from tertile 1(T1)to tertile 3(T3)of hemoglobin(P=0.017).Compared with T1 of hemoglobin,T3 of hemoglobin was independently associated with high degree of CS-EPVS(OR:2.24,95%CI:1.09-4.59).2.3 The proportion of T3 hemoglobin increased significantly from the BG-EPVS dominant group to the CS-EPVS dominant group(P=0.012).In multinomial logistic regression models,compared with T1 of hemoglobin,T3 of hemoglobin was associated with higher odds of BG-EPVS<CS-EPVS pattern(OR:2.576,95%CI:1.004-6.608).Conclusions:1.The makers associated with clinical risk assessment of BG-EPVS1.1 ZJU index and TyG index were associated with the risk of BG-EPVS.The risk of severe BG-EPVS in the highest ZJU index group was 3.79 times than that in the lowest group,and the risk of severe BG-EPVS in the highest TyG index group was 4.02 times than that in the lowest group.1.2 In males,the predictive value of TyG index on high degree of BG-EPVS was higher than ZJU index,and the sensitivity and specificity were higher than ZJU index.The risk assessment value of high degree of BG-EPVS was highest when combined with the two indexes.2.The makers associated with clinical risk assessment of CS-EPVS2.1 Patients in the T3 of hemoglobin had a 2.24 times higher risk of developing severe CS-EPVS than those in the T1 of hemoglobin.2.2 Higher hemoglobin level was independently associated with higher odds of CS-EPVS predominance pattern.Chapter Three The makers associated with clinical risk assessment of lacunesObjectives:According to the screening results of the makers associated with clinical risk assessment of lacunes in chapter one,the relationship between renal function indexes and lacunes was further analyzed.In order to explore the risk factors related to lacune and to provide a basis for the mechanism study of lacune.Methods:The number of lacune was recorded and divided into 3 groups:no lacune,single lacune and multiple lacunes.ROC curve was used to evaluate the clinical predictive value of renal function indexes on lacunes.The relationship between Cys C and risk of lacunes was analyzed by logistics regression.The other methods are the same as chapter two.Results:1.Among the enrolled 413 SVD patients aged≥60 years,a total of 264 patients with complete data of renal function indexes were included in the statistical analysis,156(59.1%)have no lacune and 108(40.9%)have at least one lacune.Further graded according to the number of lacune,there are 24 patients with single lacune(9.1%)and 84 patients with multiple lacunes(31.8%).2.Among the renal function indexes,Cys C and creatinine levels showed a significantly increased trend from non-lacune group to multiple-lacunes group(P<0.001),while eGFR levels showed a decreased trend(P<0.001).3.ROC curve analysis showed that Cys C,eGFR and creatinine have predictive value for multiple lacunes,with the highest predictive value of Cys C(AUC:0.732,95%CI:0.670-0.794,P<0.001).In the prediction of multiple lacunes,Cys C had the highest sensitivity and creatinine had the highest specificity.4.Compared with Quartile 1 of Cys C,Quartile3(OR:4.586,95%CI:1.161-18.113)and Quartile 4(OR:5.714,95%CI:1.468-22.240)were significantly correlated with increased risk of multiple lacunes.Conclusions:1.Among renal function indexes,Cys C had the largest predictive value on multiple lacunes,which was higher than eGFR and creatinine.2.Compared with Quartile 1 of Cys C,patients in Quartile 3 group and Quartile 4 group had increased risk of multiple lacunes,independent of traditional cerebral-vascular risk factors such as age,hypertension and diabetes etc.Chapter Four The makers associated with clinical risk assessment of WMHObjectives:Based on the screening of makers associated with clinical risk assessment of WMH in chapter one,the relationship between blood lipid indexes and the risk of WMH was further explored and analyzed.Methods:The presence of WMH was measured according to the Fazekas scale.Logistics regression models were used to analyze the relationship between blood lipid indexes and the risk of VMH.ROC curve analysis was used to evaluate the clinical predictive value of lipid ratio indexes on WMH.The other methods are the same as chapter two.Results:1.The enrolled 413 SVD patients aged≥60 years were included in the statistical analysis,387(93.7%)had WMH,and 26(6.3%)had no WMH.2.In women,the levels of Apo B and Non-HDL-C in individual lipid indexes were significantly higher in the WMH group(P<0.05).Among lipid ratio indexes,TC/HDL-C,LDL-C/HDL-C,Non-HDL-C/HDL-C,Apo B/HDL-C and Apo B/Apo A-I levels were significantly higher in WMH group than that in non-WMH group(P<0.05).However,in men,there were no significant differences between the two groups(P>0.05).3.In women,among individual lipid indexes,Non-HDL-C and Apo B are independent risk factors for WMH(P<0.05);while in lipid ratio indexes,TC/HDL-C,LDL-C/HDL-C,Non-HDL-C/HDL-C,Apo B/HDL-C and Apo B/Apo A-I are associated with increased risk of WMH(P<0.05).4.ROC curve analysis showed that the predictive value of lipid ratio indexes was higher than that of individual lipid indexes in women.Among lipid ratio indexes,TC/HDL-C and Non-HDL-C/HDL-C have the highest predictive value.5.Lipid indexes were dichotomized by the optimal cutoff point.Logistics regression analysis found that the lipid ratio indexes(TC/HDL-C≥3.84,LDL/HDL-C≥2.51,Non-HDL-C/HDL-C≥2.84,Apo B/Apo A-I≥0.45 and Apo B/HDL-C≥0.83)and individual lipid indexes(Apo B≥0.94 and Non-HDL-C≥3.17)can significantly increase the risk of WMH(P<0.05).Conclusions:1.The clinical correlation between lipid index and WMH was only found in women.Individual lipid indexes(Non-HDL-C and Apo B)and lipid ratio indexes(TC/HDL-C,LDL-C/HDL-C,Non-HDL-C/HDL-C,Apo B/HDL-C and Apo B/Apo A-I)were independent risk factors of WMH.2.Among lipid ratios,TC/HDL-C and Non-HDL-C/HDL-C have the largest clinical predictive value of WMH.Part Two The prediction value of SVD on functional outcome after acute ischemic strokeObjectives:To investigate the relationship between SVD and functional outcome at 90 days after acute ischemic stroke,and whether the total SVD burden is superior to individual SVD feature in prediction of functional outcome.In order to help develop rehabilitation strategies for stroke survivors and guide clinical practice to improve prognosis.Methods:From April 2017 to January 2018,consecutive patients with acute ischemic stroke who underwent baseline MRI scan were evaluated.The functional outcome was assessed using the modified Rankin Scale(mRS)at 90 days and defined as:i)excellent outcome(mRS≤1);ii)good outcome(mRS≤2).Brain MRI was performed and assessed for lacunes,WMH and EPVS.The total SVD burden was calculated based on lacunes,WMH,EPVS and then summed up to generate an ordinal "total SVD burden"(range 0-3).Bivariate logistic regression models were used to identify the association between SVD and functional outcome.Results:1.A total of 416 patients were included in the final analysis,44.0%,33.4%,19.2%and 3.4%of the patients had 0,1,2 and 3 features of SVD respectively.The 90-day mRS score and the proportion of poor functional outcome in patients with increasing SVD burden increased significantly(P<0.001).2.In regard to individual SVD feature,lacunes(OR:0.48,95%CI:0.32-0.71)and WMH(OR:0.53,95%CI:0.34-0.82)were negatively associated with excellent outcome and good outcome,independent of other SVD features.3.As to the total burden of SVD,3 SVD features had strongest negative associations with functional outcomes(excellent outcome,OR:0.13,95%CI:0.03-0.48;good outcome,OR:0.18,95%CI:0.06-0.54).After adjustment for potential confounders,a high SVD burden(3 features,OR:0.07,95%CI:0.01-0.41)and the score of total SVD burden(OR:0.64,95%CI:0.44-0.93)remained negatively associated with excellent outcome.4.Further analysis of different location of WMH found that mild,moderate and severe periventricular white matter hyperintensities(PVWMH)were significantly associated lower odds of excellent outcome and good outcome(P<0.05),while only severe deep white matter hyperintensities(DWMH)was negatively correlated with excellent outcome(P<0.05).Conclusions:1.In regard to individual SVD feature,lacune and WMH were negatively associated with functional outcome.2.Total SVD burden is superior to individual SVD feature in prediction of functional outcome with the 3 SVD features had strongest negative associations.3.PVWMH had stronger association with functional outcome than DWMH,suggesting that PVWMH are more sensitive than DWMH in predicting poor functional outcome after stroke.