Movement Disorders Moment: Environmental and Biologic Risk and Protective Factors Associated with Parkinson Disease

Parkinson disease (PD) is a common neurodegenerative disorder in older people, and the prevalence is expected to double to 12.9 million from 2015 to 2040, creating a substantial burden on health care systems.¹ Over the past several decades, recognition of the contribution of environmental and biologic factors to the risk of PD has been growing. Known risk factors associated with PD include toxins, traumatic brain injury (TBI), cancer, illicit substances, and cardiovascular risk factors. Protective factors associated with PD include smoking, exercise, medication, and nutrition. Many ongoing epidemiologic studies are focused on identifying modifiable environmental risk factors that could be targeted as preventative measures.¹ The challenge is determining how to interpret the studies because of varying study designs and inconsistencies among conclusions. We provide a concise summary of the evidence for environmental and biologic risk factors as well as protective factors for PD.

Environmental Risk Factors

Pesticides

A variety of environmental toxins have been implicated in increasing the risk of PD,² including paraquat, organochlorine pesticides, and rotenone. Paraquat has been the topic of much debate recently, with the Environmental Protection Agency (EPA) reaffirming its safety after being sued by a number of agricultural and public health groups because of mounting concerns about its association with PD.³ Tanner and colleagues⁴ reported that pesticides such as paraquat and rotenone (the latter of which is used to create an experimental model of PD in rats) were significantly associated with the risk of PD. Organochlorines, which comprise a large group of compounds, including many banned pesticides (eg, dichlorodiphenyltrichloroethane [DDT], dieldrin, chlordane, lindane) and industrial compounds, such as polychlorinated biphenyls (PCBs), have been associated with a higher risk of PD.² In addition, living in rural areas and those with high rates of farming and drinking well water can result in higher exposure to pesticides and an associated increased risk of PD.¹

Trichloroethylene

Trichloroethylene (TCE), an industrial compound often used as a degreaser, to decaffeinate tea and coffee, and in dry cleaning, has been associated with a 500% increased risk of PD.⁵ Goldman and colleagues⁶ reported that Marines stationed at Camp Lejeune had a 70% higher risk of PD compared with Veterans stationed at other locations, perhaps because of higher levels of TCE exposure at that site. TCE has been used to reproduce pathologic features of PD in multiple animal studies.⁵

Dairy Intake

Multiple studies have suggested a relationship between dairy intake and risk of PD, with increasing volume of intake leading to increased risk. A meta-analysis of prospective studies⁷ reported that the risk of PD increased 40% in participants with the highest intake, and Domenighetti and colleagues⁸ found a significant association between a specific single nucleotide polymorphism in men and 70% increased risk of PD per serving of dairy.

Air Pollution

Air pollution has frequently been cited as a potential risk factor for PD as well as other neurodegenerative disorders, such as Alzheimer disease and amyotrophic lateral sclerosis.⁹ The potential mechanisms by which these pollutants can increase risk include neuronal toxicity, systemic or central nervous system inflammation, and alterations in the gut ecosystem and microbiome.¹⁰ Because many pollutant exposures occur simultaneously, parsing out specific contributors has proven difficult.

Biologic Risk Factors

Traumatic Brain Injury

The relationship between TBI and PD became an increased area of interest after the professional boxer Muhammad Ali was diagnosed with early-onset PD in the early 1980s. Systematic reviews have shown significantly higher risk of PD in former soccer and American football players.¹¹ Most available studies on TBI examine risk after a single serious head injury, and there is no consistent definition of head trauma among these studies. Despite these limitations, there seems to be an association between head injury and risk of PD. The pathophysiology is possibly secondary to breakdown of the blood–brain barrier, brain inflammation, disruption of mitochondrial function, increased glutamate release, or α-synuclein accumulation in the brain.¹²

Cancer

Several epidemiologic studies have shown a decreased risk of smoking-related cancers in PD, but whether this is attributable to ascertainment biases related to reduced cancer screening after a PD diagnosis is unclear.¹³ Some studies have shown an increased risk of melanoma, skin, breast, and prostate cancer among people with PD.¹³ Among these, the link between PD and melanoma is well-established. There is an increased susceptibility of developing PD in individuals with melanoma, as well as of developing melanoma in individuals with PD.¹⁴ Studies show that melanoma and PD have shared genetic susceptibility factors; environmental risk factors, such as pesticide exposure; and embryonic origins, as levodopa is involved in the synthesis of both dopamine and melanin.¹⁴

Illicit Substance Use

Amphetamine, methamphetamine, and cocaine use are associated with increased risk of PD. Epidemiologic studies show a 3-fold increased risk of PD with use of amphetamine-type stimulants.¹⁵ Theories regarding links between methamphetamine use and PD include neurotoxicity to the dopaminergic neurons from chronic use as well as increased release of dopamine from neurons.¹⁵ Because substance abuse increases the risk of premature death, abusers may not reach older ages, when PD is more common. Cocaine also has been hypothesized to increase risk of PD as it causes downregulation of postsynaptic dopamine neurons, but clinical studies are lacking.

Cardiovascular Risk Factors

Body Mass Index. Studies on body mass index (BMI) and PD have shown conflicting results in observational studies as well as meta-analyses. Some studies have shown low BMI to be associated with increased risk of PD, others have shown no effect of BMI on PD, and some have shown obesity to be associated with increased risk of PD.¹⁶ Whether the discrepancy in data is attributable to racial or ethnic differences, fat distribution, or other associated metabolic conditions is unclear.

Diabetes and Metabolic Syndrome. The role of diabetes in PD remains controversial. Multiple cohort studies have shown that prediabetes and diabetes increase the risk of PD 27% to 37%.¹⁷ However, case-control studies have not found this association.¹⁷ Some proposed mechanisms include exposure of neurons to increased metabolic stress, neuronal dysfunction, and neuronal death attributable to hyperglycemia. This possible association has led the Movement Disorder Society to consider diabetes a risk factor for PD. In cohort studies, metabolic syndrome has been associated with increased risk of PD, but further studies are needed to validate this finding.¹⁷

Protective Factors

Smoking

Smoking has consistently been found to be inversely associated with the risk of developing PD. Mappin-Kasirer and colleagues¹⁸ reported on a 65-year follow-up of 30,000 male British physicians. They found that current smokers had a 30% to 40% lower risk of PD compared with nonsmokers, depending on which survey was used to determine smoking habits. These observations are being used to guide research into potential neuroprotective strategies that might mimic the effects of nicotine without the harmful consequences of smoking.¹⁹

Exercise

Exercise has been increasingly recognized as a possible protective factor in reducing the risk of PD. A systematic review and meta-analysis of 8 studies including more than 500,000 participants found a significantly reduced PD risk with the highest levels of total or moderate to vigorous physical activity (relative risk 0.79 and 0.71, respectively), in men more than women.²⁰ The proposed mechanisms behind this protective effect include improved mitochondrial function, increased neurotrophic factors, reduction in neuroinflammation, and enhanced autophagy.

Medications

Medications that have been investigated for a role in PD include ibuprofen, statins, inhibitors of the renin-angiotensin system, and glycolysis-enhancing drugs. Some meta-analyses have demonstrated that NSAID exposure is associated with lower incidence of PD, but others have not shown this association.²¹ There are also significantly mixed data with regard to the association of statin therapy with the risk of PD.²² Some studies show a protective role of statins; some found no association of PD risk with statin use; and 1 observational study showed an increased risk of PD with statin use.²² There are limited studies showing decreased risk of PD with renin–angiotensin receptor blockers²³ and glycolysis-enhancing drugs.²⁴

Nutrition

Diet. The Mediterranean diet has been found to be associated with reduction in PD age at onset, slower progression, improvement of motor symptoms, and reduced prodromal risk of PD progression in multiple cohort and cross-sectional studies.¹⁷ In a randomized controlled trial (RCT) including 35 participants with PD, adherence to the Mediterranean diet resulted in improved cognitive function.¹⁷ The Mediterranean diet has an anti-inflammatory effect, improves gut microbiota, and reduces oxidative stress, α-synuclein aggregation, and early neuronal degeneration. In another RCT, the ketogenic diet was shown to improve symptoms in PD.¹⁷ However, this was a short-term study, and thus its results need to be interpreted with caution. A low protein diet was shown to reduce motor symptoms in 6 people with PD.¹⁷

Caffeine and Resveratrol. Caffeine has been shown to improve cognition, exert a protective effect, and decrease dyskinesia in PD in multiple animal studies.¹⁷ A meta-analysis showed that caffeine intake decreased risk and progression of PD, but an RCT with 60 participants with PD did not find that caffeine improved motor symptoms.¹⁷ A meta-analysis demonstrated that drinking black tea was associated with decreased PD risk.¹⁷ Resveratrol, found in red wine, has also been shown to have a neuroprotective effect in animal studies, but clinical human studies are lacking.¹⁷

Probiotics. Gut microbiome dysbiosis has been implicated in the pathogenesis of PD. This has raised interest in whether microbiota improvement could have a protective effect in PD. An RCT showed that 12 weeks of probiotic consumption resulted in improvement in Unified Parkinson’s Disease Rating Scale scores.¹⁷ However, the microbial environment within an individual differs depending on many factors, including diet, geographic location, hygiene, and nutritional factors throughout the individual’s life. Thus, this study cannot be generalized.

Vitamins. The role of vitamins in prevention of oxidative stress and neuroinflammation in PD is a vibrant area of interest.²⁵ Multiple meta-analyses have shown that individuals with vitamin D, vitamin B6, or vitamin B12 deficiency are at increased risk of developing PD, but thus far, vitamin D and B12 supplementation has not been shown to have any benefit.^17,25 A cohort study including more than 5000 participants with PD found high dietary intake of thiamine to be associated with reduced risk of PD.^17,25 Vitamin C has been proposed as a possible biomarker in PD, as individuals with PD have reduced vitamin C plasma levels, but whether supplementation improves outcomes is unclear.^17,25 Vitamin E deficiency has been shown to be associated with increased PD risk, and an RCT including 60 participants with PD showed clinical benefit with supplementation.^17,25 Although vitamin levels have been implicated in the pathogenesis of PD, the beneficial effect of vitamin replacement remains controversial. Regarding minerals, iron has been the most studied, but the data are unclear and further studies are required.

Urates. Uric acid levels are determined by many factors, including sex, diet, physical activity, and medications. A low uric acid level is associated with development of PD as well as progression of disease.²⁶ Initially, uric acid was thought to be an antioxidant, but recent research has suggested that low uric acid level could be a result—not a cause—of the disease,²⁶ attributable to mitochondrial dysfunction, reduced physical activity, and changes in the gut microbiome. Interventional studies have trialed improvement of uric acid levels using oral inosine, but showed no clinical benefit.²⁶

Conclusion

This brief summary presents the most common risk factors and protective factors of PD (Figure). Optimizing risk factors in the prodromal phase of PD might be more effective than targeting disease mechanisms after the onset of disease. As the prevalence of PD continues to rise, there is an urgent need for high-quality studies and exposome analysis to elucidate potential causative factors and strengthen the evidence, with the goal of developing more effective approaches to prevent PD.