The Bradford Hill model evaluates the causal inference of one variable on another by assessing whether evidence of the suspected causal variable aligns with a set of nine criteria proposed by Bradford Hill, each representing fundamental tenets of a causal relationship. The aim of this study was to use the Bradford Hill model of causation to assess the level of empirical evidence supporting our hypotheses that alterations to iron and copper levels, and iron- and copper-associated proteins and genes, contribute to Parkinson’s disease etiology. We conducted a systematic review of all available articles published to September 2019 in four online databases. 8437 articles matching search criteria were screened for pre-defined inclusion and exclusion criteria. 181 studies met study criteria and were subsequently evaluated for study quality using established quality assessment tools. Studies meeting criteria for moderate to high quality of study design (n = 155) were analyzed according to the Bradford Hill model of causation. Evidence from studies considered of high quality (n = 73) supported a causal role for iron dysregulation in Parkinson’s disease. A causal role for copper dysregulation in Parkinson’s disease was also supported by high quality studies, although substantially fewer studies investigated copper in this disorder (n = 25) compared with iron. The available evidence supports an etiological role for iron and copper dysregulation in Parkinson’s disease, substantiating current clinical trials of therapeutic interventions targeting alterations in brain levels of these metals in Parkinson’s disease.

Bradford Hill 模型通过评估可疑因果变量的证据是否符合 Bradford Hill 提出的一组九个标准来评估一个变量对另一个变量的因果推论，每个标准代表因果关系的基本原则。本研究的目的是使用 Bradford Hill 因果关系模型来评估支持我们假设的经验证据水平，即铁和铜水平以及铁和铜相关蛋白和基因的改变有助于帕金森病的病因学。我们对四个在线数据库中截至 2019 年 9 月发表的所有可用文章进行了系统审查。根据预定义的包含和排除标准筛选了 8437 篇符合搜索条件的文章。181 项研究符合研究标准，随后使用既定的质量评估工具对研究质量进行了评估。符合中等至高质量研究设计标准的研究（n  = 155) 根据 Bradford Hill 因果关系模型进行分析。来自高质量研究 ( n  = 73) 的证据支持帕金森病中铁失调的因果关系。高质量的研究也支持铜失调在帕金森病中的因果作用，尽管 与铁相比，研究铜在这种疾病中的研究 ( n = 25) 的研究要少得多。现有证据支持铁和铜失调在帕金森病中的病因学作用，证实了目前针对帕金森病中这些金属脑水平改变的治疗干预临床试验。