Review article
Environmental risk factors and Parkinson's disease: An umbrella review of meta-analyses

https://doi.org/10.1016/j.parkreldis.2015.12.008Get rights and content

Highlights

  • We assessed the strength of the evidence linking 75 environmental risk factors with Parkinson's disease.

  • Physical activity and constipation presented Class I evidence for an association.

  • Head injury, anxiety or depression, beta-blockers, smoking, and serum uric acid presented Class II evidence for an association.

  • The majority of the examined meta-analyses had large or very large heterogeneity, many had signals of bias, and confounding or reverse causation was a common explanation.

  • Data from more prospective studies and investigation of sources of heterogeneity are needed to better understand the association between the risk factors and PD.

Abstract

Background

Parkinson's disease is a neurological disorder with complex pathogenesis implicating both environmental and genetic factors. We aimed to summarise the environmental risk factors that have been studied for potential association with Parkinson's disease, assess the presence of diverse biases, and identify the risk factors with the strongest support.

Methods

We searched PubMed from inception to September 18, 2015, to identify systematic reviews and meta-analyses of observational studies that examined associations between environmental factors and Parkinson's disease. For each meta-analysis we estimated the summary effect size by random-effects and fixed-effects models, the 95% confidence interval and the 95% prediction interval. We estimated the between-study heterogeneity expressed by I2, evidence of small-study effects and evidence of excess significance bias.

Results

Overall, 75 unique meta-analyses on different risk factors for Parkinson's disease were examined, covering diverse biomarkers, dietary factors, drugs, medical history or comorbid diseases, exposure to toxic environmental agents and habits. 21 of 75 meta-analyses had results that were significant at p < 0.001 by random-effects. Evidence for an association was convincing (more than 1000 cases, p < 10−6 by random-effects, not large heterogeneity, 95% prediction interval excluding the null value and absence of hints for small-study effects and excess significance bias) for constipation, and physical activity.

Conclusion

Many environmental factors have substantial evidence of association with Parkinson's disease, but several, perhaps most, of them may reflect reverse causation, residual confounding, information bias, sponsor conflicts or other caveats.

Introduction

Parkinson's disease (PD) is the second most common neurodegenerative disorder, after Alzheimer's disease [1]. The prevalence of PD is rising steadily with age, reaching 1903 per 100,000 in those older than age 80 [2] and it is expected to impose an increasing social and economic burden on societies as population ages [1]. Approximately 630,000 people in the United States had been diagnosed with PD in 2010, with diagnosed prevalence likely to double by 2040 [3]. In the United States, the economic burden of PD exceeded $14.4 billion in 2010 (approximately $22,800 per patient) and it is projected to grow substantially over the next few decades [3].

PD risk is determined by the complex interplay and composite effects of both genetic and non-genetic risk factors [4]. Substantial progress has been made on deciphering genetic risk factors for PD [5], [6]. To our knowledge, there is no previous attempt to summarize the evidence from existing meta-analyses on non-genetic risk factors for PD. We performed an umbrella review of the evidence across existing systematic reviews and meta-analyses of observational studies. Our aim is to provide an overview of the range and validity of the reported associations of diverse environmental risk factors with PD by evaluating whether there is evidence for biases in this literature. Finally we pinpoint which of the previously studied associations that have been synthesized in meta-analyses have the strongest evidence for association.

Section snippets

The concept of umbrella review

We conducted an umbrella review, a systematic collection and evaluation of multiple systematic reviews and meta-analyses performed on a specific research topic [7]. An umbrella review synthesizes the large number of existing systematic reviews and meta-analyses on risk factors rather than performing these systematic reviews from scratch. The methods of the umbrella review are standardized and follow the same principles as a previous umbrella review on risk factors for multiple sclerosis [8].

Search strategy and eligibility criteria

We

Results

Overall, 979 articles were searched and 38 articles were eligible (Fig. 1). The eligible papers were published between 2005 and 2015 (median, 2013; IQR, 2012-2014). 21 articles were excluded in full text screening, because a larger meta-analysis was available. The aforementioned 21 articles examined smoking (n = 9) [28], [29], [30], [31], [32], [33], [34], [35], [36], pesticides (n = 5) [37], [38], [39], [40], [41], physical activity (n = 2) [42], [43], coffee (n = 3) [34], [44], [45], farming

Discussion

We provide an overview and appraisal of environmental risk factors that have been associated with PD. Overall, 75 risk factors have been studied for an association with the disease, including biomarkers, dietary factors, drugs, exposure to toxic environmental agents, habits and medical history or comorbid diseases. Two factors (constipation, physical activity) presented Class I evidence for an association with PD. Several other putative risk factors (head injury, anxiety or depression,

Author contributions

VB and LB had the original idea for the manuscript and all authors contributed to design the study. VB, LB performed the analyses and all authors interpreted the results. VB, LB and JPAI wrote the first draft of the manuscript. All authors critically reviewed, wrote and approved the final version.

Conflict of interest

The authors declare that there are no conflicts of interest.

Acknowledgment statement

There was no funding source for this study. All authors had full access to all the study data. The corresponding author had final responsibility for the decision to submit for publication.

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  • Cited by (0)

    Editor's Comment: Bellou and her colleagues have employed a systematic umbrella strategy review for evaluation of previously published meta-analyses and systematic reviews for the assessment of the environmental risk factors that could be potentially associated with Parkinson's disease. They describe and discuss several risk factors with potential associations. However, they also caution about many caveats in these studies that render these associations essentially unproven. They point out that more studies are needed to understand the association between environmental risk factors and Parkinson's disease.

    Zbigniew K. Wszolek, Editor-in-Chief, Department of Neurology, Mayo Clinic, 4500 San Pablo Road, Jacksonville, FL 32224, USA.

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