JNNP:较高的血液高密度脂蛋白和载脂蛋白A1水平与肌萎缩侧索硬化风险降低相关

2021-09-24 MedSci原创 MedSci原创

除了占不到15%病例的少数单基因变异外,神经退行性疾病肌萎缩侧索硬化症(ALS)发展的确切因素尚不清楚。目前主要理论有:神经毒性物质累积;自由基使神经细胞膜受损;神经生长因子缺乏,使神经细胞无法持续生

除了占不到15%病例的少数单基因变异外,神经退行性疾病肌萎缩侧索硬化症(ALS)发展的确切因素尚不清楚。目前主要理论有:神经毒性物质累积;自由基使神经细胞膜受损;神经生长因子缺乏,使神经细胞无法持续生长、发育。

许多流行病学研究都考虑了代谢因素在ALS发展中的作用。相对心血管健康和较低的病前体重指数(BMI)与ALS发病风险增加相关。体力活动与ALS发病风险增加不一致,有人认为剧烈运动更具特异性,可能与ALS易感性有因果关系。糖尿病似乎会调节ALS的发病风险,这种关系因年龄而异。高水平的低密度脂蛋白胆固醇(LDL)载脂蛋白A1与后续ALS的风险增加相关,孟德尔随机研究也提供了一些脂质生物标记物水平与ALS之间因果关系的证据。

ALS的许多流行病学研究都是基于病例对照研究,这些研究具有转诊、回忆偏差的内在风险,这些问题可以通过前瞻性队列研究部分规避。本研究旨在研究代谢因素与ALS的关系,包括脂质和碳水化合物代谢的血液标志物、体育锻炼和BMI。本文发表在《神经病学,神经外科学和精神病学杂志》上()。

参与者在2006年3月至2010年10月期间接受了初步评估,跟踪时间中位数为11.9年。参与者提供了人口统计和健康信息,以及捐赠的血液,供生化分析。测量指标包括血液总胆固醇、高密度脂蛋白胆固醇(HDL)、低密度脂蛋白、甘油三酯、载脂蛋白A1(apoA1),载脂蛋白B(apoB)、HbA1c和肌酐。根据自我报告的每周步行、中等强度和剧烈活动计算超额代谢当量任务(MET)小时数。获得住院患者健康记录,获得抽样后某个时间点的ALS诊断(HES APC,英格兰),苏格兰发病率记录(SMR01)和威尔士患者件数据(PEDW),以及死亡证明联系。吸烟被建模为一个连续变量,即每天报告的吸烟包数乘以吸烟年数。

组合模型中包含的变量的Schoenfeld残差

在R中进行统计分析。分析中仅包括偶发ALS病例,即在抽样后诊断为ALS的参与者,在基线研究访视时未报告ALS诊断,或在抽样前通过医学联系确定诊断。主要分析包括符合这些标准的所有ALS事件病例的数据。神经元丢失的可检测标记物,例如,神经丝和几丁质酶蛋白的增加已被证明至少在1小时内发生 致病性遗传变异携带者出现症状的年份。为了针对神经退行性变前几年发生的代谢变化,因此,仅使用基线研究访问后5年以上与ALS诊断相关的参与者的数据进行二次分析。

采用研究登记的Cox比例风险模型进行ALS诊断的时间-事件分析。数据以危险比(HR)和CI表示。高密度脂蛋白比率、甘油三酯和载脂蛋白A1和B被选为公认的脂质心血管风险生物标记物,此外,纳入了测量体力活动(过量MET)的变量以及HbA1c形式的血糖控制,因为它们与ALS风险相关。包括吸烟、心血管疾病、脑血管疾病和他汀类药物的使用,以控制变量。建立模型,控制初次就诊时的年龄和性别。还构建了组合模型,包括人口统计学变量、心脑血管疾病、吸烟和他汀类药物的使用,以及所有ALS事件病例和从登记开始5年以上诊断为ALS患者的过量MET和血液生物标记物。由于载脂蛋白A1与高密度脂蛋白和载脂蛋白B与低密度脂蛋白高度相关,因此构建了包含载脂蛋白A1和载脂蛋白B以及高密度脂蛋白和低密度脂蛋白的单独模型。

低密度脂蛋白和高密度脂蛋白胆固醇、载脂蛋白B和载脂蛋白A1与ALS的诊断的关系

数据 对409名参与者进行了分析。共有343名参与者在随访期间被诊断为ALS,粗略的发病率为5.85/100 000/年。构建Cox比例风险模型,检查个体代谢标志物与ALS事件的关联,控制年龄和性别。生物标志物或代谢参数水平上升。结合所有ALS病例,高密度脂蛋白(HR 0.84,,p=0.010)和高载脂蛋白A1(HR 0.83,p=0.005)与ALS后续诊断风险降低相关。高密度脂蛋白(HR1.17)与ALS风险增加相关。排除首次就诊后5年内诊断的参与者的模型在关联程度和方向上与纳入所有参与者的模型基本一致。高密度脂蛋白(HR 0.81,p=0.022)和高载脂蛋白A1(HR 0.83,p=0.043)与ALS风险降低相关。高总胆固醇:高密度脂蛋白(HR1.19,p=0.022)与ALS风险增加相关。

结合HDL和LDL以及载脂蛋白A1和载脂蛋白B、HbA1c、甘油三酯、过量蛋氨酸、BMI、血清肌酐、性别和年龄构建组合模型。考虑到血管疾病与ALS风险和血脂水平的相关性,冠状动脉和脑血管疾病被作为协变量加入,吸烟与高密度脂蛋白胆固醇水平和ALS风险和他汀类药物使用相关,用于治疗高胆固醇血症,并与ALS的高风险和低风险相关。由于总胆固醇与LDL高度相关,因此排除了总胆固醇。高密度脂蛋白和载脂蛋白A1水平与ALS风险较低相关。

总之,高密度脂蛋白、载脂蛋白A1和低密度脂蛋白水平与肌萎缩侧索硬化风险之间的关联有有助于症状前生物标记物的探索和治疗靶向性。

Thompson AGTalbot KTurner MR Higher blood high density lipoprotein and apolipoprotein A1 levels are associated with reduced risk of developing amyotrophic lateral sclerosis

 

 

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ApoC-III存在于Lp(a)和主动脉瓣小叶中。与Lp(a)结合的ApoCIII-Lp(a)复合物、OxPL-apoB或OxPL-apo(a)水平升高可以识别AS进展快速和AVR/心源性死亡率高的轻-中度AS患者。

JAMA:血脂管理不止是胆固醇和甘油三酯?还有一个指标越来越受关注

随着新兴证据的不断涌现,在血脂管理中,除了人们熟悉的胆固醇和甘油三酯,另一个指标——载脂蛋白B100(apoB)也开始受到更多重视。这是为什么呢?

Clin Chem:利用EuBIVAS群体的生物变异模型分析脂蛋白(a)、载脂蛋白B-100和载脂蛋白a-i的性能指标

随着人们越来越关注脂蛋白(a) (Lp[a])浓度作为降低风险的目标,以及越来越多其对心血管疾病(CVD)风险影响的临床证据,严格的分析性能指标(APS)和Lp(a)的准确度目标就显得越来越来越重要。

JACC:脂蛋白与家族性高胆固醇血症的相关性研究

脂蛋白(a)是一种致动脉粥样硬化的低密度脂蛋白样颗粒,其循环水平在很大程度上由遗传学决定,家族性高胆固醇血症(FH)患者的脂蛋白(a)升高,但原因尚不清楚。本研究比较了临床和遗传学上确诊为FH的个体间

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NEUROPATHOLOGY AND APPLIED NEUROBIOLOGY:肌萎缩侧索硬化症中外周血的RNA测序揭示了不同的分子亚型

本文发现表明,外周血RNA-seq可以识别诊断生物标志物并区分ALS患者的分子亚型,然而,其预后价值需要进一步研究。

2023AANEM:依达拉奉对肌萎缩侧索硬化症病程的影响

在接受依达拉奉和利鲁唑治疗的患者中,ALSFRS-R评分和FVC的下降幅度较低,但在统计学上并不显著。

好文推荐 | 小胶质细胞髓样细胞触发受体2及其可溶形式在肌萎缩侧索硬化症中的研究进展

小胶质细胞作为CNS内主要的免疫细胞,在肌萎缩侧索硬化症疾病进展过程中发挥着重要的作用,现将小胶质细胞TREM2、sTREM2及其在ALS中的研究进行综述。

影像诊断 | 一个病例了解肌萎缩侧索硬化症MR表现!

肌萎缩侧索硬化是一种好发于中老年人的神经系统变性疾病,由于大脑皮层、脑干、脊髓前角运动神经元退化和死亡,肌肉逐渐无力、萎缩,最后,大脑完全丧失控制随意运动的能力。

Nature子刊:雷帕霉素治疗肌萎缩侧索硬化症的随机、双盲、安慰剂对照试验

研究表明雷帕霉素治疗具有良好的耐受性,并且为ALS患者提供了令人放心的安全性结果。

Brain:遗传性和散发性肌萎缩侧索硬化症队列中存在不同的神经炎症特征

根据ALS-FTSD队列之间和队列内部存在的不同分子特征定制治疗方法十分重要。