The Study Of Biochemical Markers In Patients With Amyotrophic Lateral Sclerosis

Part 1 Biomarkers and its correlation with clinical features and survival in patients with amyotrophic lateral sclerosisObjective:To investigate the levels of serum creatinine(SCr),uric acid(UA)and creatine kinase(CK)in patients with amyotrophic lateral sclerosis(ALS)and their correlation with the clinical characteristics and survival prognosis of ALS.Methods:The clinical data and levels of SCr,serum UA and CK were collected from 322 patients with sporadic ALS registered in Peking Union Medical College Hospital from January 1,2014 to May 31,2017.The disease progression and survival of the patients were regularly followed up.One-way ANOVA,correlation analysis and multiple regression analysis were used to explore the correlation of SCr,UA,CK levels with ALS clinical features,including the patients' sex,age,disease duration,body weight and height index(BMI),site of onset,spreading pattern,muscle strength,muscular atrophy,ALSFRS-R score and the progression of disease.Kaplan-Meier curve and Cox proportional hazards regression model were used to analyze the correlation between biochemical markers and survival prognosis of ALS patients.Results:322 ALS patients were enrolled in this study,including 171 males and 151 females,with an average age of 54.70±10.71 years old.The mean SCr level in 312 ALS patients was 58.74± 13.64 ?mol/L.The SCr level was related to the patients' sex,muscle strength(r=0.287,p<0.001),muscle atrophy(r=-0.216,p<0.001),ALSFRS-R score(r=0.284,p<0.001)and the decline rate of ALSFRS-R score before visiting(r=-0.227,p<0.001).It was not related to the patients' disease duration,site of onset,spreading pattern or the decline rate of ALSFRS-R score during the follow-up.The baseline SCr level was independently correlated with the survival of ALS patients after adjustment for potential confounders.There was an 2.9%reduction in risk of reaching a survival endpoint during the study per ?mol/L increase in SCr level(HR=0.971,95%CI:0.952-0.991,p=0.004).The mean serum UA level in 247 ALS patients was 305.47±86.19?mol/L.The serum UA level was related to patients' sex,age(r=-0.152,p=0.019),BMI(r=0.266,p<0.001)and SCr level(r=0.263,p<0.001),but it was not related to the site of onset,the spreading pattern,disease duration,muscle strength,the muscular atrophy score,the ALSFRS-R score or its rate of decline.There was a 45.1%reduction in risk of death in ALS patients with a higher level of serum UA(UA>5.13mg/dL)compared with patients with a lower level of serum UA(UA<5.13mg/dL)(HR=0.549,95%CI:0.301-1.000,p=0.05).Baseline serum CK was raised in 43%of participants.The median CK level was 160(95,255)U/L,and 99%of patients had a baseline serum CK level less than 1000 U/L.CK levels were significantly higher in males than in females[204(169)versus 117(111)U/L,p<0.001]and in patients with limb onset ALS than in those with bulbar onset ALS(p<0.001).CK levels were also correlated with SCr level(p = 0.011)and the spontaneous potential score on electromyography(EMG)(p = 0.032),but not correlated with age,disease duration,or BMI.Log CK was independently correlated with the survival of ALS patients(HR = 0.457,95%confidence interval 0.221-0.947,p=0.035)after adjusting for age,sex,site of onset,serum Cr,and BMI.Conclusions:The SCr level was positively correlated with ALS patients' muscle strength,muscular atrophy score,ALSFRS-R score and the survival prognosis,which allows it to be a promising biomarker in monitoring disease progression.The serum UA level was not related to any characteristic of ALS,but higher level of serum UA might have a protective effect on ALS and lead to a longer survival.Serum CK levels of ALS patients were correlated with sex,site of onset,SCr level and spontaneous activity in EMG.Serum CK might be an independent prognostic factor for survival of ALS patients.Part 2 Relationship between serum creatinine,creatine kinase level and skeletal muscle mass in patients with amyotrophic lateral sclerosisObjective:The study aimed to explore whether the serum creatinine(SCr)and creatine kinase(CK)levels correlate with the skeletal muscle mass in patients with amyotrophic lateral sclerosis(ALS)and whether it contributes to the mechanisms of SCr decline and CK elevation in ALS patients.Methods:40 sporadic ALS patients without dysphagia and 34 age-and sex-matched healthy controls were enrolled in our hospital from April 1,2017 to December 30,2017.The subjects' demographic data and clinical features were collected.All subjects underwent SCr and serum CK level tests and the skeletal muscle mass assessment by dual energy X-ray absorptiometry(DXA).Results:There were 40 ALS patients(male:female=28:12)and 34 healthy controls(male:female=21:13)in total.No significant differences were found in gender,age,height,weight and BMI between the two groups.The SCr level in ALS patients(0.69±0.12 mg/dL)was lower than that in healthy controls(0.75±0.14mg/dL,p<0.001).However,after adjusting for the appendicular lean soft tissue(ALST)mass,the SCr levels between the two groups were no longer statistically different,and so as the SCr level between male and female ALS patients.Most importantly,the relationship between SCr level and ALST mass in ALS patients was comparable with that in healthy controls.The CK level is correlated with the ALST mass(r=-0.429,p=0.023)in male patients with ALS,but not in female ALS patients(p=0.243)or healthy controls.Conclusions:The relationship between SCr level and skeletal muscle mass in ALS patients is comparable with that in healthy people.The decrease of muscle mass could be the main cause of SCr decline in ALS patients.There may be a gender difference involved in the mechanism of CK elevation and its relationship with muscle mass in ALS patients.Part 3 Cerebrospinal fluid uric acid level in patients with amyotrophic lateral sclerosisObjective:To test the cerebrospinal fluid uric acid(CSF-UA)level in patients with amyotrophic lateral sclerosis(ALS),and investigate the correlation between CSF-UA level and clinical features.Methods:18 sporadic ALS patients and 18 age-and sex-matched controls were enrolled in the department of neurology in Peking Union Medical College Hospital(PUMCH).CSF and blood samples were collected for testing UA level using high performance liquid chromatography(HPLC).CSF albumin index(CSF-Alb/serum-Alb)was tested simultaneously.Results:A total of 18 ALS patients(male:female=9:9)and 18 controls(male:female=11:7)were included.The mean CSF-UA level in ALS patients(46.40±12.56?g/mL)was not significantly different from that in the control group(42.68±10.77?g/mL,p=0.347).CSF-UA level in ALS did not correlate with the patients'gender,disease duration,ALSFRS-R score or disease progression rate.The CSF-UA/S-UA ratio was nearly at the same level as the CSF albumin index.Conclusions:The CSF-UA level in ALS patients was not different from that in the control group,and there is no indication for its clinical application.