Gene Variants May Affect PD Risk After Pesticide Exposure

Daniel M. Keller, PhD

October 20, 2020

The likelihood of developing Parkinson's disease (PD) is associated with prior exposure to occupational pesticides, both with regard to sporadic cases of PD and among patients who have a GBA genetic risk variant for PD, a new study suggests. This association was not as strong for the LRRK2 risk variant for PD.

Pesticide exposure was also associated with cognitive decline, especially for carriers of the GBA variant, the researchers noted.

"Environmental exposures may have differential effects in different genotypes" and may predispose people with PD to different symptom burden, the investigators, with lead author Ethan Brown, MD, of the University of California, San Francisco (UCSF), concluded.

About 10% to 15% of cases of PD are associated with genetic variants, with GBA and LRRK2 variants being two prominent risk factors. Although these genes are associated with increased risk of developing PD, people who carry them do not necessarily develop the disease. Other risk factors, including environmental and lifestyle factors, are thought to play a role.

The study, presented at the Movement Disorder Society 23rd International Congress of Parkinson's Disease and Movement Disorders (Virtual) 2020, included two cohorts of patients, one with PD, and one without.

The Parkinson's Progression Marker Initiative (PPMI) is a longitudinal study of people with PD and includes genetic subtypes. Assessments are performed in person and include thorough motor and nonmotor evaluations. The study compared patients who had idiopathic PD with healthy control persons; people with PD who carryied the LRRK2 G2019S mutation with unaffected carriers; and people with PD who carried GBA mutations with carriers of the GBA mutation who did not have PD.

In the second cohort, Fox Insight (FI), participants self-report PD symptoms online. Using these reports, the investigators compared the frequency of pesticide exposure for people with PD to the frequency for persons without PD. Across all subgroups in PPMI and FI, participants ranged in age from 57 to 66 years.

A second set of analyses looked for correlations between pesticide exposure and cognitive impairment in people with PD for both cohorts. For the PPMI cohort, changes in cognitive abilities were determined on the basis of the Montreal Cognitive Assessment (MoCA) as well as by characterization of cognitive impairment by the investigator.

For the FI cohort, judgment of subjective cognitive impairment was based on the Non-Motor Symptom Questionnaire (NMSQ), the taking of medication for cognitive impairment, and the Penn Parkinson's Daily Activity Questionnaire (PDAQ), which measures functional cognitive impairment.

The investigators found that occupational pesticide exposure conferred risk for idiopathic PD, as did GBA mutations

"Significant differences between occupational pesticide exposure was higher in people with PD in almost every group, although it wasn't significantly so in the LRRK2 group," Brown reported in a narrated poster presentation. "It's occurred with all different types of pesticides," he said.

Among the PPMI cohort, pesticide exposure conferred a 3.9-fold increased risk (adjusted odds ratio [aOR] after adjusting for age and sex) for developing idiopathic PD compared with healthy control persons.

Similarly, for people with a GBA mutation, pesticide exposure was associated with a significantly increased risk for PD (aOR = 4.2). The same was not true for people carrying the LRRK2 G2019S mutation. For these persons, pesticide exposure had no effect on the risk for PD.

"The fact that we did not see as significant a difference of LRRK2 indicates that there may be an interaction between pesticides and GBA in particular, or it may just be indicative of how strong the penetrance of LRRK2 is," Brown suggested. If LRRK2 penetrance is high enough, environmental exposures may be less of a determining factor.

In the FI cohort, occupational pesticide exposure was moderately associated with increased risk of developing PD (aOR = 1.5).

In both the PPMI and FI cohorts, home pesticide exposure was common, ranging from 72% to 91% of the people in the various subgroups in each cohort, but it was not associated with an increased risk of developing PD. The investigators speculated that exposure may have been too low to increase risk and that recall bias may also have been a factor.

"In Fox Insight, people with pesticide exposure were more likely to report subjective cognitive impairment either through the NMSQ or through reporting taking medications for cognitive impairment," Brown reported (aOR = 1.51; 95% CI, 1.22 – 1.87).

Also in this cohort, people with a GBA mutation and PD who were exposed to pesticides were more likely to score lower (worse outcome) on the PDAQ compared with those with no exposure (mean scores, 48 vs 54; P = .043).

In PPMI at 5 years, trends toward impaired cognition were seen for people with idiopathic PD who were exposed to pesticides, but the trends did not reach statistical significance. For MoCA, scores decreased by 1.44; for nonexposed individuals, there was an increase of 0.299 (P = .059).

Exposed individuals were also more often characterized as having mild cognitive impairment (24% vs 11%; aOR = 2.64; 95% CI, 0.63 – 9.77).

Strong Evidence

Ray Dorsey, MD, professor of neurology at the University of Rochester, in Rochester, New York, commented to Medscape Medical News that Caroline Tanner, MD, PhD, and Samuel Goldman, MD, MPH, leaders of the UCSF group, have been prominent in defining the role of pesticides in the development of PD.

"Many pesticides are neurotoxins, many are fat soluble, many target the same parts of cells, mitochondria, that we know are damaged in Parkinson's disease, and many laboratory animals when exposed to these develop the behavioral and pathological hallmarks of Parkinson's disease," Dorsey summarized.

For environmental risk factors, one generally looks to find a dose-response relationship. In the present study, "the fact that individuals who presumably had higher doses were more likely to develop disease actually supports the finding," he said. Furthermore, "we know there are genetic-environmental interactions, and this study provides some additional information regarding those interactions."

Dorsey is a coauthor of the recently published book Ending Parkinson's Disease: A Prescription for Action (from which all proceeds go to efforts to end PD). The book makes the case that environmental factors are of major importance in the development of PD, "the world's fastest growing brain disease." The lifetime risk is about 1 in 15; by comparison, the risk of dying in a car accident is about 1 in 100, he said.

"So we drive safe cars. We wear seat belts, and we don't drink and drive, and we use airbags. What are we doing to prevent ourselves from developing Parkinson's disease?" he asked.

Besides Tanner and Goldman, he said Alexis Elbaz, MD, PhD, at INSERM in Paris, France, and others have shown an almost perfect correlation between the amount of pesticides used in certain communities and the rates of PD.

Many of these substances have been banned in other countries, but use of some of these is increasing in the United States. Dorsey suggests developing safer alternatives as well as using organic growing methods when appropriate.

"If 32 countries, including China, come up with using pesticides other than paraquat, why can't the United States?" he asked. Scientists have "been telling us for decades that certain pesticides are linked and are contributing to Parkinson's disease. We should listen."

Data used in the study were obtained from projects funded by the Michael J. Fox Foundation for Parkinson's Research and its funding partners. Brown receives research support from the Michael J. Fox Foundation and the Gateway Institute for Brain Research Inc, and he has received research support from Biogen Inc within the past year. He receives compensation for serving as Neurology section editor of the NEJM Knowledge+. He has received compensation for consulting for Oscar Health and Rune Labs Inc within the past 2 years. Dorsey has received honoraria for speaking at American Academy of Neurology courses, the American Neurological Association, and the University of Michigan; has received compensation for consulting services from 23andMe, Abbott, Abbvie, American Well, Biogen, BrainNeuroBio, Clintrex, Curasen Therapeutics, DeciBio, Denali Therapeutics, GlaxoSmithKline, Grand Rounds, Karger, Lundbeck, MC10, MedAvante and medical-legal services, Mednick Associates, the National Institute of Neurological Disorders and Stroke, Olson Research Group, Optio, Origent Data Sciences, Inc, Otsuka, Prilenia, Putnam Associates, Roche, Sanofi, Shire, Spark, Sunovion Pharma, Teva, Theravance, UCB and Voyager Therapeutics; research support from Abbvie, Acadia Pharmaceuticals, AMC Health, Biosensics, Burroughs Wellcome Fund, Davis Phinney Foundation, Duke University, Food and Drug Administration, GlaxoSmithKline, Greater Rochester Health Foundation, Huntington Study Group, Michael J. Fox Foundation, National Institutes of Health/National Institute of Neurological Disorders and Stroke, National Science Foundation, Nuredis Pharmaceuticals, Patient-Centered Outcomes Research Institute, Pfizer, Prana Biotechnology, Raptor Pharmaceuticals, Roche, Safra Foundation, Teva Pharmaceuticals, University of California Irvine; editorial servicesfor Karger Publications; and has ownership interestswith Grand Rounds (second opinion service).

International Congress of Parkinson's Disease and Movement Disorders (MDS) 2020: Presented September 12, 2020.

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