Association of peripheral and CSF zinc levels with Parkinson's disease: A systematic review and meta-analysis

The possible involvement of numerous chemical elements in the pathogenesis of neurodegenerative diseases has long been studied by researchers, yet no clear consensus regarding the concentration of Zinc (Zn) and the onset of Parkinson's disease (PD) has emerged. The objective of this study was to conduct a robust meta-analysis to clarify the association between Zn levels across different biological matrices and Parkinson's disease. A comprehensive literature search was conducted across six databases up to April 2024. We included 29 case-control studies reporting Zn concentrations in serum, plasma, and cerebrospinal fluid (CSF) and performed subgroup analyses by biological matrix, continent, and detection method to extend and update previous meta-analyses on this topic. Statistical meta-analysis was performed using STATA v18 software, calculating the weighted mean difference (WMD) and 95 % CIs using a random-effects REML model. Heterogeneity was assessed using the I2 statistic, and publication bias was tested using Begg's and Egger's tests. This meta-analysis pooled data from 29 unique studies. The analysis of Zn in serum (N=22 data points) revealed a statistically significant reduction in PD patients (WMD=-108.23 μg/L, 95% CI: [-205.27, -11.18], p=0.03), with extreme heterogeneity (I²=99.43%). A similar significant deficit was found in plasma (WMD=-258.15 μg/L, 95% CI: [-481.20, -35.11], p=0.02). In contrast, Zn levels in CSF (N=8 studies) showed no statistically significant overall difference (WMD=-15.88 μg/L, 95% CI: [-36.21, 4.46], p=0.13), exhibiting the highest heterogeneity (I2=99.91%). All pooled estimates were characterized by extremely high heterogeneity (I²>99 %), primarily driven by the Asian subgroup and methodological differences, indicating substantial between-study variability and the need for cautious interpretation. Begg's and Egger's tests did not suggest substantial publication bias in serum or plasma, but CSF findings should be interpreted with caution. Our research demonstrates a significant association between lower Zn levels in the peripheral circulation (serum and plasma) and susceptibility to PD, suggesting that Zn deficiency may contribute to oxidative stress in PD but without establishing a causal relationship. Our findings reiterate the necessity of large-scale longitudinal cohort studies to validate this association, address the issue of reverse causation, and rigorously evaluate whether correcting Zn deficiency has any therapeutic value in the prevention or progression of PD.