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Parkinson’s disease (PD) is the second most common neurodegenerative disorder. People with PD, their families, scientists, health care providers, and the general public are increasingly interested in identifying environmental contributors to PD risk.
In June 2007, a multidisciplinary group of experts gathered in Sunnyvale, California, USA, to assess what is known about the contribution of environmental factors to PD.
We describe the conclusions around which they came to consensus with respect to environmental contributors to PD risk. We conclude with a brief summary of research needs.
PD is a complex disorder, and multiple different pathogenic pathways and mechanisms can ultimately lead to PD. Within the individual there are many determinants of PD risk, and within populations, the causes of PD are heterogeneous. Although rare recognized genetic mutations are sufficient to cause PD, these account for < 10% of PD in the U.S. population, and incomplete penetrance suggests that environmental factors may be involved. Indeed, interplay among environmental factors and genetic makeup likely influences the risk of developing PD. There is a need for further understanding of how risk factors interact, and studying PD is likely to increase understanding of other neurodegenerative disorders.
Parkinson’s disease (PD) is the second most common neurodegenerative disorder. The likelihood of developing PD increases with age. PD is rare before age 50. The average age of onset is in the mid- to late 60s (Bower et al. 1999; de Rijk et al. 1995; Marras and Tanner 2002; Van den Eeden et al. 2003). As the U.S. population ages, prevalence of this disabling disorder is expected to rise dramatically (Dorsey et al. 2007). Unfortunately, few valid data that address changes in PD incidence or prevalence over time are available. In fact, active case-finding efforts in communities detect as many as 10–40% of cases of PD for the first time, suggesting that underestimation of PD prevalence is common (de Pedro-Cuesta 1991; de Rijk et al. 1997).
The symptoms of PD are slowly progressive. Well-recognized clinical features of PD are slowed movements, tremor, rigidity, and difficulties with gait and balance. However, other features commonly occur, including changes in olfaction, autonomic function, cognitive function, affect, sleep, and energy level (Alves et al. 2005; Burn et al. 2006; Pfeiffer 1998; Stern et al. 1994).
In PD, specific neuronal populations degenerate. Neurodegeneration occurs in concert with the deposition of aggregates of the protein alpha synuclein in neuronal cell bodies and processes (Spillantini et al. 1998). The classical focus has been on dopamine-releasing cells in the substantia nigra, because dopamine replacement can partially correct some of the motor features of PD. It has long been known, however, that many other neuronal populations are also affected in PD. Recently, converging epidemiologic and pathologic data suggest that years or even decades before the onset of these classical features of PD, neurons outside of the central nervous system may be injured (Abbott et al. 2005, 2007; Braak et al. 2004; Langston 2006; Ross et al. 2008). If this is correct, current concepts of PD will need revision. Clarification may provide exciting new opportunities for treatment and intervention.
In the 1980s, the observation that intravenous exposure to 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) caused parkinsonism in humans offered important insights into environmental triggers (Langston et al. 1983). Even though relatively uncommon genetic mutations are sufficient to cause some cases of PD, twin studies conclude that the contribution of genetic makeup to the risk of most cases of PD is limited (Tanner et al. 1999; Wirdefeldt et al. 2004). Moreover, studies of uncommon genetic forms of PD have shown that changes in the structure of proteins that can lead to neural dysfunction, and death can also be caused independently by some environmental toxicants (Lee 2003; Purisai et al. 2005; Uversky et al. 2001; Vila et al. 2000). As a result, a general view has evolved that the vast majority of cases of PD are caused by environmental factors interacting with genetic makeup.
People with PD, their families, scientists, health care providers, and the general public are increasingly interested in identifying environmental contributors to PD with an eye toward not only more effective treatments but also prevention. What percentage of cases involves preventable causes? What precautionary interventions would be warranted and effective, and when must they be implemented? Can individuals destined to develop neurologic dysfunction due to PD be identified before typical motor symptoms manifest?
The current scientific literature does not provide conclusive answers to most of these and other relevant questions. But indications from epidemiology, basic neurobiology, and toxicology increasingly support the conclusion that a large portion of the risk of developing PD may be attributable to environmental exposures. Therefore, the risk of PD is theoretically reducible to the extent that some cases may be preventable.
Responding to these questions and concerns, a multidisciplinary group of experts gathered in Sunnyvale, California, USA, 26–28 June 2007, to assess what is known about the contribution of environmental factors to PD. Participants included toxicologists, epidemiologists, geneticists, neuroscientists, and medical practitioners. They were joined by representatives of PD advocacy groups and people with PD to review the state of environmental health science as it pertains to PD.
The purposes of the meeting were as follows:
Participants recognized the existence of various syndromes that may share some clinical and neurobiologic features with classic PD. Sometimes the term “parkinsonism” is used to refer to these syndromes. They often involve more extensive (or less specific) brain injury than is typically seen in classic PD and can be degenerative or nondegenerative (e.g., carbon monoxide–induced parkinsonism, carbon tetrachloride–induced parkinsonism, vascular parkinsonism). However, boundaries between PD and parkinsonism are evolving concepts. For this reason, participants were not asked to discuss and come to a consensus definition of PD.
Participants did not attempt to rank specific pathogenic mechanisms with respect to their relative importance in PD causation. Nonetheless, various combinations of alpha synuclein deposition, mitochondrial dysfunction, proteosome dysfunction, oxidative stress, and inflammation arose in discussions of potential contributors in causal pathways.
Participants were also not asked to address and did not consider a) an exhaustive list of toxicants that have been associated with PD (examples of toxicants not considered include organic solvents, electromagnetic fields); or b) factors that may influence the progression of PD (as differentiated from causes of onset of PD).
Over the course of the meeting, the following core points of consensus were identified, which we offer in this summary to acquaint scientists, medical professionals, public health advocates, and policy makers with the current state of understanding in the field, as seen by conference participants, and to help in identifying fruitful research strategies.
Based on existing evidence, we are confident of the following:
PD risk factors are categorized according to the terminology of the Institute of Medicine (IOM) for strength of evidence. IOM committees sometimes classify the evidence of association between exposure to a specific agent and a specific health outcome into five previously established categories, as set forth below. The group of experts gathered in Sunnyvale decided to use these categories as a means of describing their evaluation of the state of the evidence with respect to the influence of various factors on PD risk. Criteria for inclusion in each category are described at the outset.
Participants felt that these categories for describing the strength of evidence pertaining to individual risk factors were useful even though not based here on a systematic evidence-based literature review. Risk factors were assigned to the various categories based on consensus opinion of those attending the conference. Moreover, within each category there is no attempt to list the entries in any particular order.
In this IOM category, evidence from available studies is sufficient to conclude that there is a positive association. A consistent positive association has been observed between exposure to a specific agent and a specific health outcome in human studies in which chance and bias, including confounding, could be ruled out with reasonable confidence. For example, several high-quality studies report consistent positive associations, and the studies are sufficiently free of bias, including adequate control for confounding.
Conference participants are confident of the associations but uncertain about the causal relationships or pathways by which smoking and coffee consumption might have a neuroprotective effect. Various biologic mechanisms have been proposed. For example, nicotine in cigarettes and caffeine in coffee are hypothesized to be agents that may confer a lower PD risk. However, noncausal explanations for these associations are also plausible (Hernan et al. 2002), uncertainties remain, and no consensus has been achieved. Nonetheless, further investigation into the biologic mechanisms by which female sex, cigarette smoking, and coffee consumption lower PD risk is warranted and may result in important insights into the etiology and progression of PD.
In this IOM category, evidence from available studies suggests an association between exposure to a specific agent and a specific health outcome in human studies, but the body of evidence is limited by the inability to rule out chance and bias, including confounding, with confidence. For example, at least one high-quality study reports a positive association that is sufficiently free of bias, including adequate control for confounding. Other corroborating studies provide support for the association, but they were not sufficiently free of bias, including confounding. Alternatively, several studies of less quality show consistent positive associations, and the results are probably not due to bias, including confounding.
Available scientific studies suggest an association between a number of different factors and PD risk. Here, the data are limited but tend to point toward a valid association with PD risk. Causal mechanisms explaining the associations, if they exist, are not well understood.
In this IOM category, evidence from available studies is of insufficient quantity, quality, or consistency to permit a conclusion regarding the existence of an association between exposure to a specific agent and a specific health outcome in humans.
In this IOM category, evidence from available studies is consistent in not showing a positive association between exposure to a specific agent and a specific health outcome after exposure of any magnitude. A conclusion of no association is inevitably limited to the conditions, magnitudes of exposure, and length of observation in the available studies. The possibility of a very small increase in risk after exposure studied cannot be excluded.
In this IOM category, if the entire committee did not agree on a conclusion, then the association was not assigned a category.
In addition to known risk factors for PD, conference participants identified a number of others in need of further investigation. Even for those that are well established, however, there is a need for additional information about mechanisms by which they influence PD risk. Moreover, in addition to individual risk factors, conference participants recognized a need for further understanding of how risk factors interact as they contribute to the multiple pathogenic pathways that may ultimately result in PD.
We acknowledge with gratitude the support of the John Merck Fund and the Jenifer Altman Foundation.
D.D. has received research support from the National Institutes of Health (NIH), the Michael J. Fox Foundation, and the Backus Foundation. S.G. has been compensated for consulting with General Electric Corporation. S.J. has received research support from the Department of Defense, from a group of current and former manufacturers of welding products, and the Michael J. Fox Foundation. J.W.L. has received research support from the Department of Defense, the Michael J. Fox Foundation, the Parkinson's Disease Foundation, former and current welding products manufacturers group, and Omeros; he has been compensated for consulting with Merck-Serono, Jaiji Pharmaceuticals, Teva, and Vernalis. B.R. has received research support and/or has consulted for the NIH, Department of Defense, Acadia, Envivo, Novartis, Vernalis, Link, Medivation, Boehringer Ingelheim, Teva, and Edison Pharmaceuticals. G.W.R. has received research support from Boehringer Ingelheim, the National Institute for Neurological Disorders and Stroke, National Institute on Aging, Department of Defense, and former and current welding products manufacturers group. C.M.T. has received research support from the NIH, Department of Defense, Michael J. Fox Foundation, Parkinson's Disease Foundation, former and current welding products manufacturers group, and has consulted for Luncbeck Pharmaceuticals. The other authors declare they have no competing financial interests.