【作者】 杨静；

【导师】 陈雪平；

【作者基本信息】 四川大学 ， 神经病学， 2022， 硕士

【摘要】 目的:肌萎缩侧索硬化(Amyotrophic lateral sclerosis,ALS)是一种致死性的神经变性病,目前可能的致病机制有很多,但它的自身免疫起源假说受到的关注较少,但免疫现象似乎仍然参与其中。本研究旨在探讨抗糖脂抗体与ALS患者的疾病严重程度的相关性,以及抗糖脂抗体是否能作为预测ALS患者的死亡风险的指标。材料和方法:本研究包括横断面研究和前瞻性队列研究,纳入2019年6月至2022年1月就诊于四川大学华西医院住院部的ALS患者。由神经专科医生对患者进行查体。肌萎缩侧索硬化功能评定量表修正版(amyotrophic lateral sclerosis functional rating scale revised,ALSFRS-R)用于评估疾病严重程度。24条目的汉密尔顿抑郁评定量表(Hamilton Depression Rating Scale-24,HDRS-24)用于评估患者抑郁情况。汉密尔顿焦虑评定量表(Hamilton Anxiety Rating Scale,HARS)用于评估患者焦虑情况。蒙特利尔认知评估量表(Montreal Cognitive Assessment,Mo CA)评定患者认知情况。使用酶联免疫吸附试验(Enzyme linked immunesorbent assay,ELISA)检测患者血清和/或脑脊液中的12种抗糖脂抗体(anti-glycolipid antibodies,AGAbs)是否阳性。在血清或脑脊液中检测到抗体的为AGAbs阳性组,未检测到则为AGAbs阴性组。横断面研究纳入133名ALS患者。前瞻性队列研究的结局指标是死亡事件(包括死亡、气管插管、气管切开)的发生,对纳入的120名ALS患者进行随访,直到死亡事件发生或最后一次随访时间,即2022年3月1日为终点。使用多因素线性回归分析AGAbs对疾病进程的影响,使用多变量Cox比例风险回归模型来探究AGAbs是否能作为ALS死亡的预测指标。结果:(1)横向研究纳入133名患者,AGAbs阳性组54例,AGAbs阴性组79例。其中AGAbs阳性组和阴性组的性别比,就诊年龄、BMI、起病部位、病程、初始进展率均未见差异。单个抗体阳性和多个抗体阳性组在年龄、性别、BMI、起病部位、病程、初始进展率和查体体征上未见明显差异。抗GM2抗体阳性患者年龄较大(p=0.022),抗GD1b抗体阳性患者的就诊时运动功能评分较阴性组分值高(p=0.014),阳性组的初始功能评分下降率较低(p=0.037),抗GM1/GD1a/GD1b复合抗体阳性组的肌张力升高出现率较低(p=0.035)。其余抗体是否阳性的组间在人口学和临床特征表现上均未见明显差异。(2)纵向队列纳入120名患者,其中AGAbs阳性49例,AGAbs阴性71例。两组的平均就诊年龄、病程、随访时间上未见明显差异,但抗体阳性组的终末疾病严重情况较阴性组重,ALSFRS-R评分较低(p=0.014),疾病进展较快(p=0.010),阳性组使用IVIg治疗的比例更大(p<0.001)。多因素线性回归结果显示,AGAbs阳性组的疾病进展速度更快(p=0.015),延髓起病的ALS患者疾病进展更快(p=0.004)。另外,抗sulfatide抗体、抗GM1抗体、抗GM2抗体这三种抗体阳性表达与疾病进展更快相关。纳入66人进行Cox生存分析,AGAbs阳性组和阴性组各33人,平均病程分别是22.58±9.89月,29.18±15.52月,AGAbs阳性组生存时间更短(p=0.040),但两组的生存曲线有交叉,AGAbs阳性与否不能作为ALS的预测指标。结论:AGAbs阳性预示ALS疾病进展更快,其中抗sulfatide抗体、抗GM1抗体、抗GM2抗体阳性均预示ALS疾病进展更快。AGAbs阳性组的生存时间更短。更多还原

【Abstract】 Objective:Amyotrophic lateral sclerosis(ALS)is a fatal neurodegenerative disease.At present,there are many possible pathogenic mechanisms,but the hypothesis of the origin of autoimmune has received less attention,but the immune phenomenon still seems to be involved.The purpose of this study is to explore the correlation between anti-glycolipid antibodies and the severity of disease in patients with ALS,and whether anti-glycolipid antibodies can be used as an index to predict the risk of death of patients with ALS.Materials and Methods:This study includes cross-sectional study and prospective cohort study,including ALS patients who visited the Inpatient Department of West China Hospital from June2019 to January 2022.The patients were examined by neurologists.The amyotrophic lateral sclerosis functional rating scale revised(ALSFRS-R)was used to evaluate the severity of the disease.The 24-item Hamilton Depression Rating Scale-24(HDRS-24)was used to evaluate patients’ depression.Hamilton Anxiety Rating Scale(HARS)was used to evaluate patients’ anxiety.The Montreal Cognitive Assessment(Mo CA)was used to evaluate the cognitive status of patients.Enzyme linked immunesorbent assay(ELISA)was used to detect whether 12 kinds of anti-glycolipid antibodies(AGAbs)in serum and/or cerebrospinal fluid were positive.The AGAbs positive group was detected antibodies in serum or cerebrospinal fluid,but the AGAbs negative group was not detected antibodies.A cross-sectional study included 133 ALS patients.The outcome index of prospective cohort study is the occurrence of death events(including death,tracheal intubation and tracheotomy).120 ALS patients were followed up until the death event occurred or the last follow-up time,that was,March 1,2022,which was the end point.Multivariate linear regression was used to analyze the influence of AGAbs on the disease process,and multivariate Cox proportional hazard regression model was used to explore whether AGAbs could be used as a predictor of ALS death.Results:(1)A total of 133 patients were included in the cross-sectional study,including54 patients in AGAbs positive group and 79 patients in AGAbs negative group.Among them,there was no difference in sex ratio,age of seeing a doctor,BMI,onset site,course of disease,and initial progression rate between AGAbs positive group and negative group.There was no significant difference in age,sex,BMI,onset site,course of disease,initial progression rate and physical signs between single antibody positive and multiple antibody positive groups.Patients with anti-GM2 antibody positive were older(p=0.022).In anti-GD1 b antibody positive group,the patients’ scores of motor function were higher than those of negative group(p=0.014),and the decrease rate of initial function score was lower(p=0.037).The increase of muscle tone of positive group with anti-GM1/GD1a/GD1 b compound antibodies was lower(p=0.035).There was no significant difference in demography and clinical features between the other antibody positive groups.(2)A longitudinal cohort of 120 patients were enrolled,including 49 patients with AGAbs positive and 71 patients with AGAbs negative.There was no significant difference in the average age of seeing a doctor,course of disease and follow-up time between the two groups,but the terminal disease severity in the antibody positive group was more serious than that in the negative group,with lower ALSFRS-R score(p=0.014)and faster disease progress(p=0.010).And the proportion of IVIg treatment in the positive group was larger(P < 0.001).The results of multiple linear regression showed that the disease progression of AGAbs positive group was faster(p=0.015),and the disease progression of ALS patients with medulla oblongata onset was faster(p=0.004).In addition,the positive expression of anti-sulfatide antibody,anti-GM1 antibody or anti-GM2 antibody was related to the faster progression rate of the disease.Sixty-six subjects were included in Cox survival analysis,with 33 subjects in AGAbs positive group and 33 subjects in negative group.The average course of disease was22.58±9.89 months and 29.18±15.52 months,respectively.The survival time of AGAbs positive group was shorter(p=0.040),but the survival curves of the two groups crossed,and whether AGAbs was positive or not could not be used as a predictor of ALS.Conclusion:AGAbs positive indicates faster progression of ALS,among which anti-sulfatide antibody,anti-GM1 antibody and anti-GM2 antibody all indicate faster progression of ALS.The survival time of AGAbs positive group is shorter.更多还原