Amr H. Abdeen, Benjamin G. Trist and Kay L. Double. Empirical evidence for biometal dysregulation in Parkinson’s disease from a systematic review and Bradford Hill analysis. npj Parkinson’s disease. 8, 83 (2022)

The first observation of biometal dysregulation in Parkinson's disease was demonstrated almost 100 years ago, but the extent to which biometals, including iron and copper, contribute to disease pathogenesis remain unknown. Sir Austin Bradford Hill proposed a model comprised of nine criteria to examine the causal inference between an underlying factor and an observed. These criteria were carefully developed during his investigation of a perceived causal association between tobacco smoking and lung cancer. We applied the Bradford Hill model to empirical evidence for biometal dysregulation in Parkinson's disease to assess the evidence for an etiological role for iron and copper dysregulation in Parkinson's disease. Assessment of data derived from clinical and post-mortem studies support the idea that iron dysregulation is causally associated with Parkinson's disease. While fewer studies report copper levels in Parkinson’s disease brain, our analysis of available data is consistent with a causal role for copper alterations in Parkinson's disease. The available evidence therefore supports an aetiological 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.