Study On Risk Factors And Metabolomics Of Cognitive Impairment In Parkinson's Disease

Part One Analysis of Related Factors of Cognitive Impairmentin Parkinson's DiseaseObjective: To investigate the prevalence of cognitive impairment in patients with Parkinson's Disease,and to analyze related factors of different degrees of cognitive impairment in PD.Methods: A cross-sectional study was carried out.During the period from Jan.2011 to Dec.2013,237 cases were collected in PD clinic,Department of Neurology,Changzheng Hospital,Shanghai.All met UK Parkinson's Disease Society Brain Bank clinical diagnostic criteria.Cognitive functions were assessed using Mental State Examination Scale(MMSE)and Clinical Dementia Rating Scale(CDR).Hoehn-Yahr(H-Y)stage was used for evaluation of motor symptoms of PD.Depression and anxiety were assessed with the Hamilton Depression Scale(HAMD)-17 and Hamilton Anxiety Scale(HAMA).Related factors of cognitive impairment(PD-CI),dementia(PDD)and mild cognitive impairment(PD-MCI)of Parkinson's Disease were analyzed with logistic univariate and stepwise regression model,respectively.Results: 93 of the 237 cases(39.24%)were PD-CI,5(2.11%)were PDD,and 88(37.13%)were PD-MCI.Logistic univariate was used to analyze the associations of PD-CI that were hypertension,stroke,other systemic diseases,family history of PD,bradykinesia,dysarthria,dysphagia,Rapid Eye Movement(REM)Sleep Behavior Disorder(RBD),fatigue,pain,hyposmia,dizziness,salivation,constipation,urinary dysfunction,depression and anxiety(P < 0.05).Stepwise regression analysis showed that PD-CI mainly was associated with hypertension,family history of PD,dysarthria,urinary dysfunction and depression(P < 0.05).Among which dysarthria was the maximum correlation(OR=2.43,95%CI:1.22~4.84).Univariate and stepwise regression analysis showed that all factors were independent of PDD(P>0.05).Through the analysis of univariate regression(P < 0.05),the related factors of PD-MCI are mostly consistent with those of PD-CI except vascular factors(hypertension and stroke).Stepwise regression analysis showed that main related factors of PD-MCI were family history of PD,dysarthria,urinary dysfunction,depression and pain.The maximum correlated factor among them was also dysarthria(OR=2.77,95%CI:1.53~5.04).Conclusion: Multiple factors,including vascular factors,other systemic diseases,PDmotor and nonmotor symptoms,and PD genetic factors,are associated with cognitive impairment of PD,while vascular factors have little effect on mild cognitive impairment of PD.Dysarthria is the maximum correlation with different degrees of cognitive impairment of PD.Part Two Risk Factors of Parkinson's Disease Dementia: anOutpatient-based Nested Case-control StudyObjective: To observe the incidence density(ID)of Parkinson's disease dementia(PDD),and analyze risk factors of PDD in outpatients with Parkinson's disease after 2years' follow-up.Methods: 1:4 matched nested case-control study.A total of 219 outpatients were enrolled in the dynamic and open cohort study during the period from Jan.2011 to Dec.2013.Each of them had a semi-annual follow-up.Various exposures were collected from these patients to carry out and complete the assessment of their cognitive function.Univariate and multivariate conditional logistic regression models were used to analyze the relationship between various exposures and PDD.Results: During the follow-up period,17 cases were diagnosed as PDD,and person-year incidence of PDD was 3995 cases per 100,000.Univariate analysis indicated that high BMI,high Schwab and England Activities of Daily Living Scale(SC-ADLS)score,and exercise training were protective factors of PDD,while dysarthria,dysphagia,paresthesia,urinary dysfunction,psychiatric symptoms,duration of PD diagnosis,H-Y staging,side effects of dopamine agonists,and hospitalization were risk factors of PDD.Multivariate analysis,adjusted for mutual confounding effects of motor and non-motor symptoms of PD,showed that only psychiatric symptoms were the risk factors of PDD(OR=32.61,95%CI:2.71~392.81).Multivariate analysis,adjusted for the confounding effect between PD duration of diagnosis and H-Y stage,the latter was significant(OR=2.60,95%CI:1.04~6.55).Multivariate analysis,adjusted for confounding factors of the side effects of dopamine agonists and hospitalization,psychiatric symptoms were still the risk factors of PDD(OR=27.47,95%CI:3.05~247.19).Multivariate analysis,adjusted for confounding factors of exercise training and BMI,high SE-ADLS score was still the protective factor of PDD(OR=0.93,95%CI:0.89~0.98).Multivariate analysis,adjusted for the mutual confounding effects between psychiatric symptoms and protective factors,psychiatric symptoms were independent risk factors of PDD(OR=17.27,95%CI:1.71~174.31),and high SE-ADLS score was the only protection for PDD(OR= 0.94,95%CI:0.89~0.99).Conclusion: ID of PDD is relatively low.The risk factors of PDD are multiple.The protective factors of PDD include high BMI,high Schwab-England score and exercise training,among which high Schwab-England score is the most significant.The independent risk factors of PDD are psychiatric symptoms.Part Three Study on the Plasmic Metabolomics of Cognitive Impairment in Parkinson's DiseaseObjective: Respectively comparing the plasmic metabolomics between cognitive impairment of PD(PD-CI)and Alzheimer's disease(AD),PD-CI and normal cognition of PD(PD-NC),to observe the different metabolites between the two groups,analyze the characteristics of metabolomics of PD-CI,and search for the metabolic markers of PD-CI.Methods: The case control study was carried out.Age,gender,and the degree of education were matched respectively between PD-CI and AD,PD-CI and PD-NC groups.MMSE total score was also matched between PD-CI and AD group.Each group included20 cases.Peripheral blood plasma of the cases was collected.The extraction and derivatization of metabolites were performed and then analyzed,using Gas Chromatography-Time of Flight Mass Spectrometry(GC/TOFMS).Multivariate statistical analysis,including Principal Component Analysis(PCA),Partial Least SquaresDiscriminant Analysis(PLS-DA),and Orthogonal Partial Least Squares-Discriminatory Analysis(OPLS-DA),was performed using SIMCA-P+13.0 software after the pretreatment of metabolomics data by R software.Different metabolic products between 2 groups were chosen according to the criteria: Variable Importance in the Projection(VIP>1)to analyze the first principal component in OPLS-DA model;P value <0.05 using student's t test.After compounds were screened and identified,the metabolic pathways from the databases were searched to analyze the metabolic changes.Results:Comparing PD-CI and AD group,57 species(VIP>1,P < 0.05)of different metabolites were screened out.Given a similarity value>700 for the compound identification accuracy,a total of 18 compounds,including 8 kinds of amino acids,citric acid and other metabolites,were identified.Compared withAD,these metabolic compounds of PD-CI were all up-regulated(fold change>1,Log-fold change>0).Comparing PD-CI and PD-NC group,16 species(VIP>1,P < 0.05)of different metaboliteswere screened out.Given a similarity value>700 for the compound identification accuracy,a total of 5 compounds,including 4 kinds of Long Chain Fatty Acids(LCFAs),were identified.Compared withPD-NC,LCFAs of PD-CI were all down-regulated(Fold change<1,Log-fold change<0).Conclusion: Plasmicmetabolites of PD-CI have some features.Compared with AD,PD-CI has a higher level of amino acids and citric acid,for neurotransmitter imbalance and abnormality of energy metabolism in patients with PD-CI might be more serious.Compared withPD-NC,PD-CI has a lower level ofLCAFs,for with the progression of cognitive impairment in PD,?-synuclein pathology might aggravate the disorder of lipid metabolism.