The Pathophysiology Of Cognitive Impairment And The Application Of Lipidomics To Biomarker Research In Maintenance Dialysis Patients

BackgroundCognitive impairrment(CI)is prevalent and devastating in dialysis patients.The pathophysiology was not completely clear,which may relate with vascular injury.Cerebral small vessel disease(CSVD),especially cerebral lacunar infarcts,white matter hyperintensities(WMHs),microbleeds,and cerebral atrophy may contribute to CI.Atherosclerosis is a risk factor of CI,but the association of CI with the non-invasive indicators of atherosclerosis,including carotid Intima-media thickness(cIMT),and pulse wave velocity(PWV),in dialysis patients were not understood.Lipid metabolism is vital for cardiovascular diseases.The disorder of lipid metabolism in dialysis patients is prominent,but the relation of lipids with cardiovascular diseases in dialysis patients is still controversial.Whether the classic lipid components that affect cardiovascular outcome in the general population also have effect in dialysis patients.Whether the lipid metabolism is involved in CI in dialysis patients.The study aimed to find biomarkers of CI in dialysis patients by lipidomics method.Objectives1.To evaluate the prevalence of CI in the multicenter dialysis patients,and the association between CI and depression,activity daily living ability.2.To explore the influence of vascular injury on CI in dialysis patients,including the relationship between CSVD and CI,the relationship between CIMT,PWV,and CI,the relationship between ultrafiltration volume(UV)and cognition.3.To find the predictive markers of CI,adverse cardiovascular and cerebrovascular outcome,and death in hemodialysis patient.MethodsPart ?.The prevalence,harm and mechanism of cognitive impairment in maintenance dialysis patientsFrom July 2013 to July 2014,the patients with chronic kidney disease(CKD)4-5 stages and regular maintenance dialysis patients were enrolled from 4 centers.The demographic,clinical and laboratory data,cognitive function,depression state and quality of life questionnaire at baseline were recorded.The global cognitive function was evaluated by the Chinese version of the Mini Mental State Examination(MMSE)and Montreal Cognitive Assessment(MoCA).The specific cognitive domain included memory,language and executive function.The study evaluated the prevalence of Cl,and the relationship between cognition and depression,daily living ability.The study explored the relationship between dialysis mode,dialysis adequacy,and cognition.Part ?.The mechanism of vascular damage of CI in dialysis patientsThe dialysis patients in Peking Union Medical College Hospital followed(PUMCH)were followed for further exploration1.The CSVD in dialysis patientsThis cross-sectional controlled study enrolled dialysis patients and matched normal serum creatinine controls.Brain MRI were used to assess CVSD in all participants.The presence and location of different features of CSVD in the dialysis patients,including lacunes,microbleeds(CMBs),and white matter hyperintensities(WMHs),were evaluated and compared with controls.Logistic regression were used to investigate the risk factors for CSVD2.The association between CSVD and CI in dialysis patientsThe dialysis patients underwent brain MR examination for assessment of lacunar infarctions,WMHs,and microbleeds.Participants with microbleeds were categorized into 3 groups:lobar group,deep group,and mixed group.The quantitative volume of gray matter,white matter and cerebrospinal fluid was obtained by voxel-based morphometry study.The study analysised the relationship between CSVD,brain volume and CI.3.The association between cardiovascular injury and CI in dialysis patientsThe cIMT,and PWV were assessed at baseline.The study explored their relationship with cognition,and whether CSVD mediate the relationship between CIMT,PWV and CI.4.The association between UV and cognition,CSVD in hemodialysis patientsThe UV of hemodialysis patients were recorded once a week in past 12 months before baseline.If the dialysis vintage is less than 1 year,all dialysis period weer recorded.The relationship between UV and cognition,CSVD was analysised.Part ?.The application of lipidomics to biomarker research in dialysis patientsBaseline plasma and haemocytes of PUMCH hemodialysis patients were collected at baseline.All lipidomic analyses were performed on an Exion LC-system coupled with a QTRAP 6500 PLUS system(Sciex).Principal component analysis,orthogonal project to late structures discriminant analysis,and t-test were used to analyze the differences between the with and without cognitive decline,adverse cardio-cerebral vascular outcome and death groups.ResultsPart ?.The prevalence and negatively effect of CI in dialysis patients1.340 patients were enrolled at baseline,including 55 patients with CKD 4-5 stage without dialysis and 285 patients with maintenance dialysis(including 200 hemodialysis patients and 85 peritoneal dialysis patients).The prevalence of CI in dialysis patients was 18.6%(according to MMSE)and 67.7%(according to MoCA),and the executive function was worse than those in CKD 4-5 patients.2.The CI correlated with depression and daily living ability decline3.The peritoneal dialysis patients presented worse memory function than hemodialysis patients.Dialysis adequacy didn't relate with cognition.Part ?.The mechanism of vascular damage of CI in dialysis patients1.The CSVD in dialysis patientsThere was a significant increased prevalence of CSVD in dialysis patients.Compared to controls,the age of CSVD lesions detected was significantly smaller in dialysis patients for three features of CSVD.2.The association between CSVD and CI in dialysis patientsThe incidence of lacunes,WMHs,and microbleeds was 28.6%,38.1%,and 32.8%respectively.The cognition of patients with different CSVD was worse than those without CSVD.Brain parenchymal fraction and white matter fraction were positively correlated with cognitive function.The prevalence of any microbleed was 32.8%(62/189),and 31 subjects(16.4%)suffered deep microbleeds.There was a significant association between deep microbleeds and impaired global cognitive function,memory,language ability and executive function.3.Cardiovascular injury and CI in dialysis patients(1)cIMT:73 dialysis patients in PUMCH cohort had received ultrasound cIMT measurement 54.8%(40/73)were diagnosed as increased cIMT.Greater cIMT was an independent risk factor of impairment of global cognitive function,memory and executive function.The mediation analysis results showed CI was mediated by brain parenchymal fraction.(2)PWV:171 dialysis patients in PUMCH cohort had received PWV measurement.Linear regression analysis showed that PWV was related to the decreased executive function after adjusting confounders.The brain parenchymal fraction mediated the association.4.The relationship between UV and cognition,CSVD in hemodialysis patientsThere was no correlation between UV and cognition.UV was closely associated with the risk of lacunes,WMHs and microbleeds.Part ?.The application of lipidomics to biomarker research in hemodialysis patients45 plasma samples and 117 hemocytes samples were collected.539 kinds of lipid metabolites were detected in plasma,237 kinds of lipid were detected in erythrocytes1.Compared with remained MMSE scores group,decreased MMSE scores group presented higher level of plasma PA 32:1(P=0.004,FC=1.76),PA 38:5(P=0.013,FC=1.54),CE-17:1(P=0.017,FC=1.54),and lower level of plasma DAG 40:6(18:0/22:6)(P=0.039,FC=0.34),PE 36:4(18:1/18:3)(P=0.041,FC=0.55).There was no significant difference in erythrocytes lipids between the two groups.2.Compared with remained MoCA scores group,decreased MoCA scores group presented higher level of plasma LacCer d18:1/18:0(P=0.003,FC=1.78),LPE 18:2(P=0.022,FC=1.79),GM3 d18:1/20:1(P=0.029,FC=1.73),PE 36:3(18:1/18:2)(P=0.029,FC=1.50),LPE 18:1(P=0.040,FC=1.60),lower level of plasma PI 38:5(18:0/20:5)(P=0.036,FC=0.64),and higher level of erythrocytes GM3 d18:0/20:0(P=0.043,FC=1.59)3.Compared with the patients without follow-up cardio-cerebrovascular events,the patients with these events presented higher level of plasma PS 34:2 and TAG 44:1(16:1),lower level of plasma TAG 52:6(16:2),TAG 58:9(22:5),LPS 18:0,and lower level of erythrocytes Cer d18:1/20:0,Cer d18:1/18:0 and cerd18:1/21:04.Compared with the survival group,the death group presented higher level of plasma GM3 d18:1/25:0,and lower level of plasma TAG 50:4(16:2),TAG 52:6(16:1),TAG 54:7(18:3),TAG 54:7(18:2),TAG 54:7(20:5),TAG 56:8(18:2),TAG 50:3(16:2),TAG 58:9(22:5),PE 42:1p,PA 38:6Conclusion1.CI was common and negatively affects depression and quality of life in dialysis patients.2.CSVD was related to CI in dialysis patients.Deep microbleeds was the most common microbleeds in dialysis patients,which was related to CI3.The IMT and PWV involved CI in dialysis patients,which was mediated by brain parenchymal fraction.4.The UV of hemodialysis patients was related to the risk of CSVD5.Lipidomics identified some biomarkers to predict cognitive decline,adverse cardio-cerebrovascular outcome and death in hemodialysis patients.