Diagnostic Utility Of Fluid Biomarkers In Multiple System Atrophy:Meta-analysis And Reprospective Analysis

Part Ⅰ Diagnostic utility of fluid biomarkers in multiple system atrophy: meta-analysisObjective: Multiple system atrophy(MSA)is an adult onset,progressive neurodegenerative disease.However,no reliable biomarker is currently available to guide clinical diagnosis and help to determine the prognosis.In recent years,several biomarkers have been identified and assessed in multiple studies for their diagnostic value of MSA;however,these studies remain controversial.Method: Pub Med,Web of Science,Cochrane and Embase during 1984–2019 were searched until 2019 measuring CSF and peripheral blood levels of different biomarkers in patients with MSA compared with PD and healthy controls.The results of the combination of the experimental and the control groups were expressed by MD and 95%CI(95% confidence interval).The levels of FLT3 in the CSF and α-syn in the plasma showed high levels of heterogeneity in the comparison of MSA and healthy controls(HCs),thus using random-effect model for these two biomarkers and fixed-effect model for other biomarkers with low levels of heterogeneity for calculation.Results: We included 28 studies with 1223 MSA patients,1600 PD patients and 1868 HC subjects estimating 11 biomarkers.Six biomarkers were significantly different in the CSF of MSA patients compared with HCs: α-syn(Hedges g-183.37;95%CI-213.35 to-153.40;P<0.00001),NFL(Hedges g3.13;95%CI 0.87 to 5.38;P=0.007),p-tau(Hedges g-7.90;95%CI-11.67 to-4.14;P<0.00001),t-tau(Hedges g-6.89;95%CI-9.85 to-3.93;P<0.00001),Aβ42(Hedges g-71.66;95%CI-106.21 to-37.10;P<0.00001)and FLT3(Hedges g-20.23;95%CI-23.59 to-16.86;P=0.04).The blood levels of three biomarkers in MSA patients also differed compared with HCs: α-syn(Hedges g 3.13;95%CI 0.87 to 5.38;P=0.007),HCY(Hedges g 3.51;95%CI2.63 to 4.40;P<0.00001),UA(Hedges g-45.96;95%CI-63.66 to-28.97;P<0.00001)and Co Q10(Hedges g-251.89;95%CI-361.78 to-142.01;P<0.0001).Conclusions: We found that compared with PD patients and HCs,α-syn,NFL and t-tau in the CSF were potential biomarkers for MSA diagnosis.Another seven biomarkers are available to distinguish MSA patients from HCs: p-tau,Aβ42 and FLT3 in CSF;and α-syn,UA,HCY and COQ10 in plasma.It is unlikely that CRP and YKL-40 are suitable for MSA diagnosis.Part Ⅱ The Diagnostic utility of Urea and homocysteine in multiple system atrophy: reprospective analysisObjective: Multiple system atrophy(MSA)is a rare fatal neurodegenerative disease.It progress faster and early clinical manifestations are similar as other neurodegenerative diseases,including Parkinson’s disease(PD),consequently,the diagnosis and treatment in initial stage are limited.Therefore,we designed this reprospective study to clarify the clinical manifestation,blood levels of biomarkers to gain a better understanding of MSA,hoping to shed a light on the diagnosis and treatment for MSA at early stage.Method: 50 MSA patients,50 PD patients and 50 healthy controls(HCs)were enrolled from 2012 to 2019 at Department of Neurology,Shenjing Hospital,China Medical University.Clinical manifestation and biochemical results of homocysteine(HCY)and uric acid(UA)were collected in detail.The t test,multinomial logistic regression and Analysis of Variance(ANOVA)were conducted to compare the HCY,UA levels between MSA patients,PD patients and HCs.The relationship between HCY,UA levels and age,gender and subtypes were conducted by t test.Results: The levels of HCY in MSA patients were significantly higher and the levels of UA in MSA patients were significantly lower than HCs,but no significant difference in HCY and UA levels between MSA and PD patients were found(UA:MSA/ HCs P=0.038;MSA/PD P=0.980 HCY: MSA/ HCs P=0.036;MSA/PD P=0.548).Multivariate analysis shows the correlation of Hcy and MSA(P < 0.05),but not for UA(P=0.064).HCY was an indendpent factor for MSA(P=0.003),especially in male populations(P=0.044).Conclusions: The increased level of HCY and the decreased level of UA are significantly different in the comparison between MSA patients and HCs.No significant difference was found for UA and HCY between MSA patients and PD patients.