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Association of NO2 and Other Air Pollution Exposures With the Risk of Parkinson Disease

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>> From the JAMA Network, this is JAMA Neurology Author Interviews, conversations with authors exploring the latest clinical research, reviews, and opinions featured in JAMA Neurology. 

Dr. Cynthia Armand: I'm Dr. Cynthia Armand, Assistant Professor of Neurology at the Montefiore Medical Center Albert Einstein College of Medicine.  I'd like to welcome Dr. Sun Ju Chung.  He's a Professor of Neurology at the University of Ulsan College of Medicine and Asan Medical Center in Seoul, South Korea.  He also is the Editor-in-Chief of the Journal of Movement Disorders.  Dr. Chung, welcome to the JAMA Neurology Author Interviews Podcast. 

 Dr. Sun Ju Chung: Thank you so much for having me, Dr. Armand.  I'm really pleased to talk to you today. 

Dr. Armand: Excellent, I'm so excited to have you here.  You are the senior author of an original investigation looking into the association of nitrogen dioxide and other air-pollution exposures with the risk of Parkinson disease.  Can you tell us a little bit about your background and your work with Parkinson disease? 

Dr. Chung: I'm a movement specialized and over the last 20 years I was interested in genetics in movement disorders and Parkinson disease, but the Parkinson disease a common complex disease.  So, in addition to genetic factors, environment factors is also important.  So I want to study some environmental factors related to Parkinson disease. 


Dr. Armand: Right, so like you just said, we know that Parkinson disease is a complex, heterogeneous, chronically progressive neurodegenerative disorder and it affects millions of people.  What do we know about this epidemiology, in terms of age of onset and incidence and areas of where it may be more prevalent? 


Dr. Chung: There are more than 6 million patients with Parkinson disease in the world, maybe 10 million patients with Parkinson disease, and the prevalence of Parkinson is almost similar in all of the world.  Some European people, they have more high frequency.  Regarding age at onset, in our data, the mean age at onset of Parkinson disease is 60 years old.  In general, about 90% of all patient Parkinson disease is sporadic Parkinson disease, that is, idiopathic.  The remaining familial or monogenic PD patients are caused by genetic mutations.  In particular, all those PD patients are more likely to have a single gene mutation compared with late-onset PD patients.  In contrast, late-onset PD patients are more likely to have environmental risk factors. 


Dr. Armand: Right, that makes a lot of sense.  When you say late onset versus early onset, what's the age cutoff? 


Dr. Chung: Actually, that is somewhat arbitrary.  We usually say when the age of onset below 50 years that the early age at onset, and when you have Parkinson disease over 60 years old, then you have late-onset Parkinson disease. 


Dr. Armand: Now, there have been so many advances that have been made over the past 15 years in regards to different categories in Parkinson disease research, risk factors, cause, pathophysiology, treatment, and I would place your study in the realm of risk factors, cause and effect.  And you talked to us a little bit about your inspiration in terms of looking at environmental factors, genetic factors that we already know about.  What can you tell us about how you developed the study, and were there other studies out there that you pulled from in order to design your study? 


Dr. Chung: Yeah, as now we don't know clear etiology and pathogenesis of Parkinson disease, but we think that genetic factors and environment factors and aging factors may co-contribute to the development of Parkinson disease together.  Some PD patients may have predominant genetic factors.  Some PD patients may have more contribution from environmental factors, and some patients may have similar, both genetic and environmental risk factors.  So there may be heterogeneity, in terms of etiology and pathogenesis for Parkinson disease in each individual.  Over the last 20 years, we found that mutations in about 20 genes, including SNCA, LRRK2, Parkin, DJ1, PINK1, and et cetera that causes Parkinson disease.  And we also know that there are more than 90 genetic variations that are associated with the risk of Parkinson disease. 

In terms of environmental factors, we know there are pesticides, herbicides, and some metals, such as manganese, associated with the risk of Parkinson disease.  And interesting, smoking and coffee drinking has been reported to have protective effect.  But we think that the other environment factors may contribute to the development of Parkinson disease.  One of the possible environmental factors is air pollution, because air pollution is responsible for shortening people's lives worldwide on a large scale, and the world is facing an air-pollution pandemic.  According to World Health Organization, air pollution kills an estimated 7 million people worldwide every year.  Seoul is the capital and largest city in South Korea and has a population of 10 million people.  Like many metropolitan cities, Seoul has air-quality problem with various types of pollutants suspended in the air that can cause or can be a risk factor for several diseases, including Parkinson disease.  So we aim to investigate the association between air pollution and the risk of Parkinson disease. 


Dr. Armand: So that makes your setting, Seoul, Korea ideal for a type of study like this, and it might even make the results more generalizable, correct? 


Dr. Chung: Yes, I think so. 


Dr. Armand: Alright, so tell us about your study design. 


Dr. Chung: Okay.  Our study used a very large-scale, nationwide population-based cohort data from the National Health Insurance Service of South Korea.  Approximately 97% of Korean residents are covered by this National Health Insurance Service and the rest are covered by a medical aid program.  National Health Insurance Service built the National Sample Cohort Version 2.0 by selecting a representative 1 million Korean individuals, considering age, sex, comorbidity, and socioeconomic state using a systemic stratified sampling method.  Our study suggests the inclusion criteria that included individuals who lived in Seoul consecutively from year 2002 to 2006.  We selected only individuals who lived in Seoul consecutively in this study period because the air-pollution data was the most systemically and reliably collected in Seoul compared to other cities. Exclusion criteria included individuals who were less than 40 years old and individuals who were already diagnosed with Parkinson disease until 2006.  Primary outcome was new diagnosis of Parkinson disease by 2015.  For air-pollution-exposure measurement, we used the data from the Seoul Research Institute of Public Health and Environment.  That institution provided us hourly monitored data of air pollution from 25 monitoring sites, one for each district in Seoul. 


Dr. Armand: Wow, that's a large, large area of coverage. 

Dr. Chung: Yes. 

Dr. Armand: How many districts are there? 

Dr. Chung: Twenty-five. 

Dr. Armand: Wow. 

Dr. Chung: Yeah, so every district. 


Dr. Armand: So within your inclusion-exclusion criteria, was there any monitoring of whether or not individuals smoked or drank caffeine, because I know you mentioned that earlier about those being protective from developing Parkinson disease? 


Dr. Chung: Yeah, so we have data about socioeconomic status and social behavior, smoking, alcohol drinking, and coffee drinking, so we put it as a confounding variable in the analysis. 


Dr. Armand: Oh, that's great.  So that was accounted for.  Good.  Now before we get into the results, I wanted to talk about the air pollutants that you looked at.  Do we have any evidence of one type of air pollutant being more potent or associated more so with development of Parkinson disease?  Is there evidence out there prior to you doing this study? 


Dr. Chung: Yeah, initially we were very much interested in the nitrogen dioxide, then particulate matter 2.5, PM 2.5, because there's a few studies that suggest the association between nitrogen dioxide and PM 2.5.  And there are several papers, those air pollution pollutant associated with other diseases, such as lung disease, the heart disease, so we are first very much interested in nitrogen dioxide, and PM 2.5. 


Dr. Armand: I see.  Now, tell us about your results.  What did you find? 


Dr. Chung: Our main result was that exposure to nitrogen dioxide was associated with an increase in risk of Parkinson disease.  Hazard ratio for highest versus lowest quartile 1.41, but there was no significant associations between exposure to PM 2.5, PM 10, ozone, sulfide dioxide, or carbon monoxide and Parkinson disease incidence. 


Dr. Armand: Was that surprising to you? 


Dr. Chung: We first expected there may be some correlation between the nitrogen dioxide exposure and Parkinson disease, so actually, we confirmed our hypothesis after the study. 


Dr. Armand: Now, looking at your hypothesis and looking at these results, I can't help but tie in the pathophysiology, here, because we know in Parkinson disease there's degeneration of the nigrostriatal neurons and do we know what the pathophysiology is behind, or the proposed pathophysiology of nitrogen dioxide and its contribution to Parkinson disease? 


Dr. Chung: Yeah, it's very interesting.  Nitrogen dioxide is a pervasive air pollutant.  If you inhale nitrogen dioxide, at first, nitrogen dioxide may have poisonous effect on the olfactory nerve, if the olfactory nerve's the anatomic exposure to airborne pollutants.  Interestingly, alpha-synuclein pathology of Parkinson disease starts from the olfactory bulb as well as in dorsal motor nucleus of vagus, medulla oblongata.  So nitrogen dioxide may have a direct effect on the brain beginning from the olfactory nerve and spreading to the central-lobe system.  Secondary inhalation of nitrogen dioxide may increase systemic proinflammatory cytokines, such as interleukin 1-beta, 6, and 8, and TNF alpha.  These proinflammatory cytokines may be related to neuroinflammation in brain.  It's very important, considering mechanism of Parkinson disease or other neurological diseases. Third, nitrogen dioxide can be delivered to brain after passing through blood-brain barrier and it may cause reduced production of ATP and increase the production of reactive oxygen species, as demonstrated in animal studies using rat.  This may, in turn, cause mitochondrial-membrane damage, energy-production defect, and mitochondrial biogenesis inhibition.  As you know, mitochondrial dysfunction is very critical pathogenetic mechanism the development and progression of Parkinson disease, and I think other potential mechanisms may be involved in nitrogen-dioxide-mediated neurotoxicity, so for the study [inaudible] important test chances. 


Dr. Armand: Right, right. I mean, that's pretty extensive.  Do we know, I'm just curious, do we know of any other neurologic or bodily effects of nitrogen dioxide, aside from Parkinson disease?


Dr. Chung: There are a few studies conducted related to the nitrogen dioxide exposure to [inaudible], but we have data of some neurologicial diseases.  For example, nitrogen dioxide has been reported to be associated with Alzheimer disease or vascular dementia. Ischemic and hemorrhagic strokes and amyotrophic lateral sclerosis.  I think other neurologicial diseases may be related to nitrogen dioxide exposure, so we need to further investigate this issue. 


Dr. Armand: Right.  What are the main sources of nitrogen dioxide in the environment? 


Dr. Chung: Nitrogen dioxide is highly poisonous, one of the group of highly reactive gases known as nitrogen oxides.  Nitrogen dioxide primarily gets in the air from the burning of fuel.  In reality, the primary source of nitrogen dioxide are high-temperature combustion processes in cars and power plants, as well as in chemical manufacturing processes.  So in outdoors, the major source of nitrogen dioxide is the emissions from motor vehicles.  Furthermore, nitrogen dioxide is most often generated by diesel vehicles that do not meet the latest diesel emission standards.  Since diesel vehicles also raise fine dust in addition to nitrogen dioxide, many countries are discussing policies for these vehicles.  That may be one of the reasons why Green New Deal projects of several countries plans to invest in electric cars to reduce air pollution, especially for nitrogen dioxide. 


Dr. Armand: Yeah, in a study like this, we have patients who may have individuals in their family who have Parkinson disease and there may be questions about, how do I lower my risk and how do I live, where do I live?  How do you counsel a patient like that, especially with your results that you find here today? 


Dr. Chung: That's a very difficult question because we have some real issues for living in a certain area, in a certain region, but we need to be careful about the exposure to the air pollution, especially for nitrogen dioxide, when you consider the development of Parkinson disease.  So in every environment, we need to avoid some exposures, nitrogen dioxide from cars or the pollutions area.  That's the problem because it will be possible, if the government policy should protect air pollutions as a huge plan, national energy plan. 


Dr. Armand: Right, I would think a study like this, even having follow-up studies would call for some sort of standard on emissions and regulations and keeping that up to par in order to help sway what happens in our bodies and neurological development or degeneration. 


Dr. Chung: Yes, I think so.  I think that the further study should cover that study about the exact pathogenesis of the nitrogen-dioxide-induced neurotoxicity, because this is the study of association between nitrogen dioxide and Parkinson disease, but we don't know exactly about detailed pathogens mechanism of nitrogen dioxide in the development of Parkinson disease.  So we need to further study about the exact pathogenetic mechanism between air pollution and Parkinson disease, including nitrogen dioxide and other possible air pollutants.  Because in this study, we didn't find any significant association between other air pollutant and Parkinson disease, but in some countries, that air pollutant may be associated with Parkinson disease because the certain air pollutant levels are very high, compared with other countries.  So there may be some regional factors related to the air pollution. 


Dr. Armand: Dr. Chung, would you be willing to collaborate on a scientist or a researcher who's listening to this podcast in a different country and saying, hey, let's take our results.  Let's do the same study in your location and put it together and make this larger?  Would you be willing to do that, because we can do a call for action right now? 


Dr. Chung: Yeah, I love to collaborate with other scientists, there, researchers in the world, because these environmental studies did big samples and various areas of sampling.  So I want to collaborate with the scientists and clinical researchers in other areas in the world.  It's a good idea. 


Dr. Armand: Yeah.  You heard it here first, and if anyone wants to collaborate with Dr. Chung, you can comment, and we can get something going.  This is really important, Dr. Chung.  I think you and your colleagues are contributing to the advancement of our understanding of Parkinson disease and it's really important to get the word out there.  And then, this really helps with counseling our patients and taking care of them and looking into the future, brighter for neurologic disease and how we think about them. 


Dr. Chung: Yeah, absolutely. 


Dr. Armand: Dr. Chung, is there anything else that you wanted to highlight in your study before we close out today? 


Dr. Chung: Yeah, as I mentioned earlier, Parkinson disease is a common complex disease.  There are some genetic risk factors and environmental risk factors.  In previous studies, researchers and scientists are interested in the one risk factors, predominantly genetic factors or environmental factors.  So we missed some other related factors, such as, in certain patients may have a strong environment factors, but we investigate the genetic factors for that patient, and some patients have strong genetic factors, but we study the environment risk factors.  So I think it is necessary to combine the genetic factors and environment factors study together to investigate the exact or heterogeneous etiology or risk factors for Parkinson disease in each individual.  I (have been) involved in genetic studies over the last 20 years, but in some patient, the environmental factor is very important compared with the genetic factors. So we need to find out other risk factors.  For example, this type of air pollution should be a potential risk factors for Parkinson disease, like in other neurologicial disease.  So I think we have a broader eye to find out the heterogeneous etiology of Parkinson disease. 


Dr. Armand: Absolutely.  Dr. Chung, I really appreciate the time you spent with me today and our listeners and really strong work on you and your colleagues' contribution to the advancement of our knowledge about Parkinson disease. 


Dr. Chung: Thank you so much.  And I would like to really appreciate all efforts of my coinvestigators of this study, yeah. 


Dr. Armand: Awesome.  And don't forget to follow up our chat with a more in-depth look at Dr. Chung and his collaborators' work on jamanetwork.com.  For more of our podcasts, visit us at jamanetworkaudio.com.  You can subscribe there or wherever you listen to your podcasts.  I'm Dr. Cynthia Armand.  Until next time.  

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