By Caroline M. Tanner, M.D., Ph.D.
Originally published in the Spring 2011 issue of PDF's Newsletter, News & Review.
Scientists generally agree that most cases of Parkinson’s disease (PD) result from some combination of nature and nurture — the interaction between a person’s underlying genetic make-up and his or her life activities and environmental exposures. A simple way to describe this is that “genetics loads the gun and environment pulls the trigger.” In this formulation, “environment” has a very broad meaning — that is, it refers to any and all possible causes other than those that are genetic in origin.
The interactions between genes and environment can be quite complex. Some environmental exposures may lower the risk of PD, while others may increase it. Similarly, some people have inherited a genetic makeup that makes them more or less susceptible to the effects of toxicants, or poisonous agents, than others. The effect of a combined exposure can be greater — or lower — than a single exposure. All of this means that the particular combination of factors leading to PD is likely to be unique for each person. These combinations, in different ways, may trigger a common series of biological changes that will ultimately lead to the disease.
Scientists are beginning to tease apart the non-genetic factors that influence PD risk. In particular, epidemiologists are working to identify differences in the experiences of people who develop PD, compared to those who do not. But identifying these risk factors can be difficult. And when we do identify them, they serve only as clues. They do not provide a direct explanation for the cause of Parkinson’s, so scientists must supplement these population studies with laboratory experiments.
The following is a list of some of the risk factors for which we have found some evidence of an association with PD. For the most part, it is too soon to make recommendations for how to prevent Parkinson’s based on this research. However, these results may help us to understand the causes of PD, and provide direction for future research and therapy development.
Potential Risk Factors
Age. About one percent of people over age 60 have Parkinson's disease, compared with just 0.001 percent of people 45 or younger.
Gender. Parkinson’s is more common in men than in women. It is not known whether this is due to genetic factors, hormones or differences in behavior.
Head Injury. Traumatic brain injury — injury that results in amnesia or loss of consciousness — has been associated with an increased risk of developing Parkinson’s years after the injury. Laboratory studies suggest that such injury may provoke inflammation in the brain, which could lead to the development of PD.
Area of Residence. There are differences in the geographic distribution of PD. These could be due to differences in environmental factors, some of which are referenced below, and differences in genetic risk factors. Alternatively, they could be traced to differences in the methods that are used to count people with PD. While studies are too few to provide definitive patterns, some have been suggested. For example, Parkinson’s prevalence is higher in the Inuit population in Denmark than it is among other Danes, possibly reflecting a greater dietary intake among the Inuits of persistent organic pollutants such as polychlorinated biphenyls, or PCBs (see page 7). In the agricultural California central valley, living in a home near to fields where the pesticides paraquat and maneb were used was associated with PD in one report. Another study reported greater incidence of PD in urban areas with high levels of industrial emissions of the metal manganese, and possibly copper (see more on page 7).
Occupation. Certain occupational categories or job titles have been associated with a higher incidence of PD, but results have been inconsistent. The relationship between welding (the process of fusing substances, usually metals) and PD has been a recent focus of controversy. In some reports for example, studies of people who are referred for medicolegal evaluation (an examination to determine the legal aspects of a workplace) welding has been suggested to cause Parkinson’s symptoms or earlier onset of PD.
However, in most other studies, including several in large national occupational and disease registries, welding has not been associated with PD risk.
A higher frequency of PD has been associated with many other occupations, but only a few occupations have been associated with PD in multiple studies, including agricultural and industrial workers. By contrast, lower rates of Parkinson’s are associated with shift work and jobs involving vigorous physical work. While we can hypothesize that the agricultural or industrial jobs may involve greater exposure to toxicant chemicals, further study in other populations is needed to understand if certain occupations are actually associated with a higher risk of PD. Some of the studies investigating specific toxicant exposures are described in the next sections.
Pesticide Exposure. Of all the chemical exposures that have been linked to Parkinson’s, pesticides have been reported the most consistently. Recent research has shown higher rates of Parkinson’s among people who were exposed to pesticides over a long period of time as part of their work. Investigating other types of pesticide exposure, such as home use, is more challenging. However, hobby gardening and home pesticide use have each been associated with PD in one report. Although few studies have identified specific pesticides as leading to PD, those that have been so identified include the insecticides rotenone and permethrin (used in clothing and mosquito netting to kill mosquitos); organochlorines such as beta-hexachlorocyclohexane (beta-HCH — used in the United States from the 1950s to the 1970s); and the herbicides paraquat and 2,4- dichlorophenoxyacetic acid (2,4-D). It is important to note that most people who are exposed to these pesticides do not go on to develop Parkinson’s. The herbicide 2,4-D is one of the chemicals making up Agent Orange, used as a defoliant during the Vietnam war era. Although Agent Orange has not been proven to cause PD, the US Department of Veterans Affairs has ruled that veterans with PD who served in Vietnam between January 9, 1962 and May 7, 1975 are eligible to receive disability compensation from the Veterans Administration.
Exposure to Metals. Occupational exposures to various metals have been suggested to be related to the development of PD. But long-term exposure to metals is not easily measured, and the results of studies measuring PD risk and specific metals have been inconsistent. For example, high dose manganese exposure, a metal mentioned earlier, is known to cause a form of parkinsonism called manganism. Whether there is a relationship between manganese exposure and PD has been a point of interest, with focus on welders who may be exposed to it. A recent review concluded that manganese is an unlikely cause of Parkinsonism in the US population of welders. Direct measurement of lead levels in bone and blood serum suggests a link between PD and lead exposure, with greater risk associated with greater lifetime exposure.
Solvents and Polychlorinated Biphenyls (PCBs). Trichloroethylene (TCE) is a solvent used in many industries and is the most common organic contaminant in groundwater. Occupational exposure to TCE was found to be associated with Parkinson’s among workers whose factory jobs resulted in long-term (eight to 33 years) exposure to the solvent. In a study of discordant twins (that is, twin pairs in which just one of the members had PD), the twin who had been occupationally exposed to TCE was more likely to develop Parkinson’s than the one who had not. This link has also been observed in experiments in the laboratory.
Polychlorinated biphenyls (PCBs), mentioned earlier, are persistent organic pollutants that were used in industrial processes until the late 1970s. PCBs have been found in relatively high concentrations in the brains of people who had PD. Occupational exposure to PCBs has been associated with greater risk of Parkinson’s in women, but not in men, and those women who were exposed have shown evidence of injury to their dopamine systems (the systems disrupted in PD).
Genetic Predisposition. Often, a person’s genetic makeup will help to determine the effect of an environmental exposure. For example, agricultural workers exposed to pesticides were at an increased risk of PD only if they also had inherited a reduced ability to metabolize toxicants. In another study, head injury was associated with a higher risk of Parkinson’s only in people with one form of a particular gene; in people without this particular gene variant, head injury was not associated with a higher risk of PD. Increasingly, epidemiologists and geneticists are working together to identify combinations of genes and environmental exposures that are related to PD.
Potential Protective Factors
Scientists have also found certain factors that may actually reduce the risk of developing Parkinson’s. As with risk factors, not enough is known about these and they should not be tried without the counsel of a doctor.
Coffee and tea. Drinking coffee or tea has been associated with a lower risk of Parkinson’s, most markedly so in men. Caffeine has direct effects on the brain, and some of these effects may help to cause a lower risk of PD.
Uric acid or urate. This chemical occurs naturally in blood. High levels, associated with diets high in certain foods, such as meats, can cause gout and kidney stones. However, researchers have found that men with uric acid levels in the high end of the normal range have a lower incidence of Parkinson’s. Men with PD who have uric acid in the high normal range have a slower rate of PD progression. In women, who typically have lower urate levels, the same effects are not established. A drug that increases blood urate is being studied in a clinical trial in PD.
Anti-inflammatory drugs. Several studies have shown that people who regularly take anti-inflammatory drugs such as ibuprofen have a lower risk of Parkinson’s. Inflammation is thought to play a role in causing Parkinson’s, and reducing inflammation may explain the reduced PD risk.
Smoking. Many studies have associated cigarette smoking with a decreased risk of PD. Researchers hypothesize that nicotine may block the damaging processes causing PD, but the exact effects are not known. A clinical trial to study nicotine in PD is planned.
Cholesterol levels. Some studies have suggested that the use of statins — drugs that are used to lower cholesterol levels — is associated with reduced PD risk. However, in other studies an association was also found between low blood cholesterol levels and increased PD risk. Understanding cholesterol metabolism may provide clues to the molecular mechanisms that cause PD.
Vitamin D. People with higher vitamin D levels were at lower risk of PD in one study. Vitamin D has many beneficial effects that, theoretically, could help to prevent PD, and Vitamin D receptors (recognition sites) are found in the brain areas damaged in PD.
Exercise. Greater physical activity has been associated with lower risk of Parkinson’s. Studies in animals also support this.
The Search for Proof
Observational studies cannot prove that an association is truly a cause of PD. This is because the kinds of studies that could pin down exact answers cannot be carried out on people. Instead, we must conduct experiments in the laboratory and then project the results of these tests as best we can to what happens in people. However, laboratory experiments can never give us the full picture of PD risk in humans. The final test can only be done through an iterative process, taking the clues gained from observations of human populations into the laboratory, and then bringing the laboratory results back again to the human population. Plausibility in the human framework provides the ultimate test for results from laboratory research. Our hope is that understanding environmental risk factors will lead to a better understanding not only of the causes of PD, but of other neurodegenerative disorders as well.
Dr. Tanner is the Director of Clinical Research at the Parkinson's Institute and Clinical Center.