Herbicide Exposure/TBI Combination Triples Parkinson's Risk

Pauline Anderson

November 13, 2012

Both a traumatic brain injury and exposure to the herbicide paraquat increase the risks of developing Parkinson's disease (PD), but the combination of the 2 triples the risk, a new study suggests.

The study is important because it shows what epidemiologists have known for years: that risk factors should be looked at in combination, and in vulnerable populations, study author Beate Ritz, MD, PhD, chair, Department of Epidemiology, Center for Occupational and Environmental Health, Fielding School of Public Health, University of California at Los Angeles, told Medscape Medical News.

"For example, someone who has already suffered a head injury might need to stay away from the next neuro toxic agent more than his neighbor does" because that head injury may have made him more vulnerable to an additional insult, said Dr. Ritz.

The study was published in the November 13 issue of Neurology.

Widely Used Herbicide

The study included 357 patients diagnosed with incident idiopathic PD within the previous 3 years and 754 controls, living in 3 mostly rural agricultural counties of California from 2002 to 2011.

From medical history interviews, researchers determined whether participants had ever had a TBI, defined as a head injury with loss of consciousness for more than 5 minutes. They documented the age at the time of the event and whether the participant was hospitalized for the injury.

Investigators also calculated paraquat exposure of each participant up to 1999 (before PD was diagnosed in most patients) using a sophisticated geographic information system that takes advantage of California pesticide records.

From addresses and amounts of pesticide applied per acre (within 500 meters of a workplace or home), researchers estimated an average study period exposure. Participants were considered exposed to the pesticide if they had an average study period exposure greater than 0 at both work and at home.

After adjusting for age, sex, smoking status, race, county, and educational level, the study found a 100% increased risk of developing PD among those who had experienced a TBI (adjusted odds ratio [aOR], 2.00; 95% confidence interval [CI],1.28 - 3.14). The effect estimate was stronger for women (aOR, 2.61; 95% CI,1.32 - 5.16) than for men (aOR, 1.71; 95% CI, 0.94 - 3.11).

TBI induces an inflammatory cascade and accumulation of α-synuclein and tau, 2 proteins that are major components of the hallmark PD Lewy bodies. TBI may also contribute to PD by disrupting the blood-brain barrier and mitochondrial function.

Up to 41% of the study population had been exposed to paraquat. The study found that exposed participants had close to a 40% higher chance of developing PD than those not exposed (aOR, 1.36; 95% CI, 1.02 - 1.81).

In animals, paraquat, one of the most widely used herbicides in the world, has been shown to cause dopamine neurons to die, said Dr. Ritz.

More Than Additive

Adding the risks from the 2 exposures resulted in more than an additive risk. Study participants who had experienced a TBI and been exposed to paraquat had a 3-fold increased risk of having PD compared with those who had never experienced a TBI or been exposed to the pesticide (aOR, 3.01; 95% CI, 1.51 - 6.01).

The physiologic process triggered by a head injury may increase the vulnerability of neurons to insults from neurotoxic pesticides, with the combination increasing the risk for PD more than each exposure on its own, said Dr. Ritz.

As she explained, we are all born with a certain number of dopamine neurons and have to lose 60% to 80% of these neurons before we become parkinsonian. A TBI may increase the vulnerability of dopaminergic neurons to additional insults because the neurons that are left have to work overtime to compensate for the earlier insult, said Dr. Ritz.

"When you have one thing happen and a certain number of neurons die, the other neurons may become more vulnerable to the next hit. You could imagine this biologically because those neurons have to work harder; have to do their dead comrades' job."

Or, in the case of long-term pesticide exposure, the dopamine neurons are continually trying to "defend themselves against injury," a situation that causes the neurons to be constantly stressed and more vulnerable to attack, said Dr. Ritz.

Confirms Animal Research

The current study results mimic those produced in laboratory animals and confirm the researchers' previous findings but with a larger control group and inclusion of exposures both at residences and workplaces. They previously reported a 2- to 3-fold increase in risk of developing PD with exposure to specific types or classes of pesticides, especially for combined exposure to paraquat and maneb, and for persons who carry genetic polymorphisms in susceptibility genes.

A limitation of the study was its inability to address temporality of TBI and paraquat exposure because pesticide records were available only after 1974. Some study participants had experienced TBI at a young age, when pesticide exposures were not yet recorded in the California system. (In animal models, the 2 exposures had to be within a certain time frame, said Dr. Ritz.)

The results may not apply to regions with low pesticide exposure. And because TBI information was collected through interviews, a bias may have been introduced as a result of differential recall.

PD, which affects 1% to 2% of the population older than age 65 years, is the second most common neurodegenerative disorder after Alzheimer's disease.

Two-hit Scenarios Common

Commenting on the findings for Medscape Medical News, Anna DePold Hohler, MD, associate professor of neurology, Boston University School of Medicine, Massachusetts, and member of the American Academy of Neurology, said the results were interesting but not surprising.

"Two-hit scenarios are common in neurological disease," she said.

Although cumulative injury and the length and quantity of parquet exposure may increase the risk of developing PD, the underlying genetic predisposition to PD may also be a factor in determining who will go on to develop the disease, said Dr. Hohler.

The study findings "provide a source of inspiration" for future research, she added. They suggest, for example, that it may be possible to track high-risk individuals for longitudinal study and biomarker analysis to better understand the earliest phases of PD, said Dr. Hohler. "This knowledge can be leveraged into the neuroprotective treatments of the future."

Studies that address the etiology of PD are particularly useful in understanding the mechanism of disease in order to develop a cure, she said.

This work was supported by the National Institute of Environmental Health Science and the National Institute of Neurological Disorders and Stroke; in addition, initial pilot funding was provided from the National Institutes of Health and a pilot grant by the American Parkinson Disease Association. Dr. Ritz and Dr. Hohler have disclosed no relevant financial relationships.

Neurology. 2012;79:2061-2066. Abstract