Routine blood biochemical biomarkers in amyotrophic lateral sclerosis: Systematic review and cohort analysis

Introduction: Blood biochemical biomarkers, including urate, creatinine, albumin, and creatine kinase, have been shown to be useful in ALS. To provide further information about the roles of these four biomarkers roles we performed a systematic review. In addition, we also performed a new study of the role of these biomarkers in predicting survival, using data from our local ALS cohort. Methods: (1) Using established databases and other sources, we searched for papers about the use of urate, creatinine, albumin, and creatine kinase as biomarkers in ALS. Included articles were reviewed for information about biomarker levels in ALS and controls, association with markers of functional decline, and survival. (2) For our local ALS cohort, we performed survival analysis, Cox-proportionate-hazard ratio and ROC curves to investigate the use of these biomarkers in predicting survival. Results: (1) For systematic review, 104 papers were included. There was some variability in the findings. For urate, there was evidence of decreased levels in ALS, with higher levels associated ith longer survival. For creatinine, there was evidence of decreased levels in ALS, and higher levels correlated with longer survival. For albumin, some reports of reduced levels in ALS, but no consistent association with survival. For creatine kinase, some reports of increased levels in ALS, with inconsistent association with survival. (2) For the local ALS cohort there was evidence that urate and creatinine were associated with survival, but no significant association with survival. There was less evidence for albumin and CK. Discussion: This study provides support for further studies of these readily available biochemical measurement as bioamerkers in ALS.引言：血液生化生物标志物，包括尿酸（urate）、肌酐（creatinine）、白蛋白（albumin）以及肌酸激酶（creatine kinase），已被证实可应用于肌萎缩侧索硬化症（Amyotrophic Lateral Sclerosis, ALS）的相关研究。为进一步阐明这四种生物标志物的作用机制，我们开展了一项系统综述。此外，我们还利用本地ALS队列数据，开展了一项关于上述生物标志物预测患者生存情况的新研究。方法：（1）通过已构建的数据库及其他数据源，我们检索了以尿酸、肌酐、白蛋白、肌酸激酶作为ALS生物标志物的相关文献。对纳入的文献进行系统梳理，提取其关于ALS患者与对照人群的生物标志物水平、生物标志物与功能衰退指标的关联以及生存相关性的相关信息。（2）针对本研究的本地ALS队列，我们采用生存分析、Cox比例风险比（Cox-proportionate-hazard ratio）以及受试者工作特征（Receiver Operating Characteristic, ROC）曲线，探究上述生物标志物在预测患者生存情况中的应用价值。结果：（1）系统综述部分共纳入104篇文献，研究结果存在一定异质性。针对尿酸，现有证据表明ALS患者体内尿酸水平降低，且较高的尿酸水平与更长的生存期相关。针对肌酐，现有证据表明ALS患者体内肌酐水平降低，且较高的肌酐水平与更长的生存期呈正相关。针对白蛋白，部分研究报道ALS患者体内白蛋白水平降低，但未发现其与生存期存在一致的关联。针对肌酸激酶，部分研究报道ALS患者体内肌酸激酶水平升高，但其与生存期的关联结果并不一致。（2）针对本地ALS队列的分析结果显示，尿酸与肌酐水平与患者生存期存在关联，但白蛋白与肌酸激酶（CK）与生存期未呈现显著关联，相关证据亦较为有限。讨论：本研究为进一步将这些易于检测的生化指标作为ALS的生物标志物开展相关研究提供了理论支持。