Pesticide exposure and dream-enacting behavior

[00:01:13] Dr. Chen Honglei:
Thank you, Hugo, for the kind introduction. And also it's a great pleasure to speak to the movement disorder community about our research.
 

[00:01:22] Dr. Hugo Morales:
I would like to use your expertise on the topic and first discuss the association between the pesticide exposure and Parkinson's disease. We know that there are multiple pathophysiological mechanisms that have been explored in Parkinson's, which include genetic environmental factors. But how much do we know about the risks of PD attributed to pesticide exposure?
 

[00:01:48] Dr. Chen Honglei:
That's a really good question. As you know, as I know, that pesticides are likely among the environmental contributors to Parkinson's disease. This has been supported by both epidemiological studies and also animal experimental studies. This study is also implies that specific pesticides may contribute to the etiology of Parkinson's and are different mechanisms.

And these pesticides include organochlorines, botanical pesticides, and Paraquat, among many others. However, there is a question that we know very little about when, where, and how pesticides make contribute to the development of the disease. I think this is a very important question to ask, because as we know that Parkinson's disease mostly affects older adults— the so-called late- onset sporadic Parkinson's. And in these individuals, it's very likely that the disease may take decades to develop before it can be clinically diagnosed.

And during this stage, many environmental factors may come into play either initiating the disease etiology, or modifying its progression to its clinical phenotype. And we learned in the past 20 years that during the tests, the so-called prodromal stage of Parkinson's disease, many non-motor symptoms such as poor olfaction, REM sleep, behavior disorder or RBD, which we studied in this particular study, and the other symptom constipation, among many others, may gradually develop during the prodromal stage of PD, prior to the disease motor onset. Therefore I'm particularly interested that by studying the pesticide exposures in relation to the onset of these intermediate symptoms, the prodromal symptoms, they may learn more about how and when, and where pesticides may play roles in the etiology of Parkinson's disease. And in the end, this may turn out to be very important because of the disease prevention purposes, and also for the purpose of delaying the disease onset.
 

[00:04:02] Dr. Hugo Morales:
It's very interesting that your research is focusing on the prodromal aspects of neurodegeneration, which you mentioned that's very helpful to know and stratify patients according to different risks in order to get these potential treatments to prevent neurodegeneration.

And in your paper, that is something that hasn't been shown before. You found an association between pesticide exposure in dream-enacting behavior, but before going into more detailed description of your results, can you tell us briefly about the methodology in this study, and how did you select this cohort?
 

[00:04:43] Dr. Chen Honglei:
Oh, absolutely. In this particular study, we analyzed data from about 11,000 farmers in the United States. And these farmers reported whether they had any the so-called unusually high pesticide exposure event, like accidental spills. This will be the, you know, meter, spills, at their enrollment and survey into our study in 1993 to 1997. And then about 20 years later, 2013 and 2015, at a follow-up survey, we ask whether they had had any dream-enacting behaviors in the past. In this study, we use a dream-enacting behavior as a surrogate for REM sleep behavior disorder. As you know, the REM sleep, RBD clinical diagnosis, require PSG sleep studies, which almost impossible in large epidemiological studies.

So we use the dream-enacting behavior as a surrogate outcome, and we conducted multi-variable logistic regression to examine whether the high pesticide exposure event was associated with higher odds of reporting the dream-enacting behaviors about to decades later.

We are particularly interested in this study for the reasons that this is a study among US farmers. So they know very well about their pesticide exposure, and the use a pesticide at much higher levels than the general population. So they are basically a high risk group for neurodegeneration by their exposure status.
 

[00:06:21] Dr. Hugo Morales:
How many of these patients reported to have these dream-enacting behaviors? And how did you characterize that this association in terms of how much exposure, if it's only one high-exposure event or multiple ones. Tell us about that.
 

[00:06:39] Dr. Chen Honglei:
Oh, that's a really good question. I think about close to 9% of the farmers reported ever having a dream-enacting behavior. And we also know that the PSG confirmed RBD in the the general population typically will be one to 2%. The data is still fairly limited, but that's probably the best estimate we can get.

And the eight to 9% is much higher than that. So, you know, there are going to be some RBD mimics and also going to be some reporting errors. The question we asked is basically the one item screener that had developed clinically by Dr. Ron Postuma in Canada.

In terms of the high pesticide exposure event, we ask at multiple surveys and the question we asked was, " have you ever had any high pesticide exposure event in the past?" We asked when this exposure occurred in the 1970s, 1980s, 1990s. We asked about which part of your body was exposed? Your face, your nose, your hand, or your body trunk.

We ask you more details than, you know, my classifications for the body parts. And also we ask after the event, how quickly, how many minutes or how many hours, delay you had before you actually cleaned it up using water and soap. We also ask which pesticides were involved in the event.

And then we focused on the highest exposure event, because in the farmers, they might have multiple events. And we ask the details for the highest exposure event.
 

[00:08:18] Dr. Hugo Morales:
And also you explore some of the differences between respiratory and digestive tract versus skin exposures. Was there any difference between these exposures in terms of increased risk of reporting these dream-enacting behaviors?
 

[00:08:36] Dr. Chen Honglei:
Yeah, that's a good question, but that's also a good leeway to talk about the results. Overall, we found that a history of a yearly high pesticide exposure event was associated with a higher odds of reporting dream-enacting behaviors 20 years later among these farmers and compared to farmers who did not report any high pesticide exposure event in their farming experience.

Those who reported a event were about 75% more likely to report dream-enacting behaviors two decades later. And, interestingly, we observed the association appeared to be stronger when there was a longer delay in washing with water and soap after the event.

And when the exposure involved the respiratory or the digestive tract as compared to the skin only, the respiratory and digestive you can consider is through the nose and the gut, which is more internal exposures as compared to skin only, which is the external exposures, indeed suggest some difference between these two routes of exposures. And I think this another novelty of our analysis.

However, the difference did not reach statistical significance, because think about how people can classify. Unfortunately a high- pesticide exposure event it's very difficult to correctly recall. "Okay, I inhaled. Okay, I ingested some." As compared to, "Oh, it's only got to my face. I don't think I inhaled any of those." So reporting errors can play a big role in the analysis.
 

[00:10:17] Dr. Hugo Morales:
And in terms of the pesticides used, was there any difference or hint to any major risk regarding the type of pesticides, either insecticides, fungicides, herbicides?
 

[00:10:33] Dr. Chen Honglei:
So we asked the participant to report what kind of pesticide was involved in the highest-exposure event, asking people to recall certain details. Maybe a few decades earlier can be a difficult task, but nevertheless most people were able to call the pesticide involved.

And we analyze the associations, and most of them show positive associations. And we did find significant associations for the two organochlorine insecticides, the DDT and Linden, both implicated in Parkinson's disease etiology in the past. We also found for organophosphate insecticides, and some of those also implicated in Parkinson's disease etiology in the past. Interestingly of the herbicides we looked at, we found two herbicides. Particularly we found a positive association with paraquat. It's not a hugely strong association. But this is also consistent with the findings for Parkinson's disease.

And finally we found fungicide, as a group, is associated with the dream-enacting behaviors. But we do not have the sample size to look into specific fungicides.
 

[00:11:50] Dr. Hugo Morales:
I find very interesting that you focus in on dream-enacting behaviors as a surrogate of RBD. And in the past, you have explored this association with other prodromal symptoms, such as hyposmia and constipation. Is this something that you will explore in this cohort that you gathered? Sort of characterize the prodromal spectrum of PD with these patients?
 

[00:12:17] Dr. Chen Honglei:
Thank you for asking about the history of my research. I've been studying epidemiology of Parkinson's disease for the past 20 years.

Initially I focused analyzing the disease clinical diagnosis at outcome, but over time, as you kind of implicated, I began to get more and more interested in studying the prodromal stage of the disease. Basically that's inspired by the publications of the Braak hypothesis. And also the later dual-hit hypothesis is in terms of Parkinson's disease etiology. And I think environmental epidemiology, which is my research area, has a big role to play in this research, because the implications of these two hypotheses, as far as environmental epidemiology is concerned, is the nose and the gut. And these are the two anatomic sides that our body interacts with the environment. And it happens to be the GI dysfunction and also the poor olfaction, the prodromal symptoms of Parkinson's disease, and probably related to other neurodegenerative diseases as well.

So about three years ago, I began to get more and more interested in studying Prodromal PD, which by itself is very difficult, given the complexity and the lack of knowledge. So we began to add the prodromal symptoms into large cohorts. They have their regular follow-up surveys, including this agricultural health study. We add expressions about RBD, the REM sleep behavior disorder. We add questions about olfaction, constipation, so on and so forth. And we did publish both occupational exposures to pesticide in the yearly high pesticide event in relation to self reported olfaction a couple of years ago. Then the findings of olfaction and high-pesticide exposure event is very much like that for the dream-enacting behavior and the results support that pesticides may play a role in the early stage of the disease development. The findings are very preliminary and are from one single group. So I'm really interested to see independent replications.
 

[00:14:34] Dr. Hugo Morales:
Yeah, that's very interesting how two different research studies dovetails very well with the prodromal aspects of PD or neurodegeneration associated with pesticide exposure.

Just one last comment: In terms of the prodromal risk classification, we have the PD prodromal calculator that you can enter all the risk factors and forecast the probability of prodromal PD — possible, probable. And one of the things that comes out there is that it's just exposure to pesticides. It doesn't say either. high-risk exposure. It only says more than a hundred times exposure to pesticides, but doesn't say which type of it.

Do you think with your research, those scores or risk factors need to be recalibrated, or do we need more studies to support your findings?
 

[00:15:27] Dr. Chen Honglei:
That's another great question. We are very interested in applying the research criteria for prodromal PD in our cohort — study whether a pesticide or other environmental factors are actually related to the prodromal spore of Parkinson's disease. But as you kind of indicated, the calculator was based on mostly cross-sectional data perspective.

But to study Prodromal Parkinson's, you need prospective longitudinal data because the risk and also the association are likely to be dynamic. The closer to the disease diagnosis, maybe the association is stronger between the predictors of the predominant symptoms in the disease.

And another thing is how to best define each of the risk factors of the prodromal symptoms. For example, in this population, almost everyone is exposed capacity aside by the definition of the calculator, probably they all got is exposure as "yes," but on the other hand, these individuals have very different exposures. And also very different exposures to specific pesticides. I think it's hugely difficult to take care of every little detail in calculating the prodromal probability of developing Parkinson's disease using the calculator. But it will be still possible that as the new data come into the literature in the future, I hope that that calculator can be updated over time. So, as new data coming out, the calculator probably can be improved. And longitudinal cohort data will be really important.
 

[00:17:09] Dr. Hugo Morales:
Thank you, Dr. Chen, for providing your insight on the topic and discussing the results or your paper. And I'll invite all the listeners to read paper reported by Dr. Chen, again, entitled, "High Pesticide Exposure Events and Dream-Enacting Behaviors Among US Farmers," published in Movement Disorders.