Microstructural changes in the substantia nigra of asymptomatic agricultural workers

Abstract

Parkinson's disease (PD) is marked by the loss of dopamine neurons in the substantia nigra (SN). Although the exact etiology is unknown, sporadic PD is hypothesized to be a result of genetic susceptibility interacting with environmental insult. Epidemiological studies suggest that pesticide exposure is linked to higher PD risk, but there are no studies demonstrating SN changes with chronic pesticide exposure in human subjects. Thus, high resolution T2-weighted magnetic resonance imaging (MRI) and diffusion tensor (DTI) images were obtained from 12 agricultural workers with chronic pesticide exposure, 12 controls, and 12 PD subjects. Neither controls, nor pesticide-exposed subjects, had any parkinsonian symptoms. Exposure history to pesticides was assessed by a structured questionnaire. DTI measures in the SN, including fractional anisotropy (FA), mean diffusivity (MD), axial diffusivity (AD), and radial diffusivity (RD), were obtained for all subjects and compared among groups. Compared to controls, PD patients showed the expected significant changes in all DTI measurements in the SN. The pesticides-exposed subjects, compared to controls, had significantly lower FA values (p=0.022, after multiple comparisons correction), but no significant differences in RD, MD, or AD measures. The study is the first to demonstrate microstructural changes in the SN of human subjects with chronic pesticide exposure. The changes detected by MRI may mark “one of the hits” leading to PD, and underlie the increased risk of PD in pesticide users found in epidemiological studies. Further human studies assisted by these imaging markers may be useful in understanding the etiology of PD.

Parkinsonism Signs and Symptoms in Agricultural Pesticide Handlers in Washington State

“…The mean and standard deviation were 0.76 (1.95), which is somewhat lower than a recent study of 12 paraquat exposed workers with UPDRS3 scores of 3.5 (1.8), as might be expected given that those workers were older than ours on average (55.8 years). 10 Similarly in our study, UPDRS2 score (which captures symptoms that are common in PS but not unique to PS) was 0.29 on average (standard deviation [SD] 0.52) as compared to 0.7 (SD 0.9) in the paraquat study. Taken together these results are generally negative because of the limited extent of PS signs observed.…”

“…The lack of association did not appear to be due to low statistical power because there was no suggestion of a positive association with years working as a pesticide applicator. Du et al (2014) 10 likewise did not observe an association between UPDRS scores and total years exposed to pesticides. However, because applying pesticides might be difficult to do with signs of PS we cannot rule out a healthy worker survivor effect, which would most likely bias these associations down, even past null.…”

“…Examination by a movement disorders specialist is a key strength of this study because some signs of PS, such as rigidity, are difficult for other clinicians to assess and would not likely be well-reported by study participants themselves. Previous studies have examined 12 paraquat-exposed workers 10 and 50 maneb-exposed workers. 11 Because the 38 workers in our study applied pesticides in apple orchards in Washington State these workers potentially had some exposure to both the herbicide paraquat and mancozeb, 12 a fungicide similar to maneb that contains the neurotoxicant manganese.…”

“…Taken together these results are generally negative because of the limited extent of PS signs observed. On the other hand, Du et al (2014) 10 conducted a brain imaging study and despite low UPDRS2 and UPDRS3 scores observed that workers exposed to pesticides (including but not limited to paraquat) had microstructural differences in the substantia nigra region of the brain when compared to age-matched subjects without occupational pesticide exposure. Those unexposed comparison workers (n = 12) had a mean UPDRS2 of 0.1 (SD 0.3), which is somewhat lower than in our sample despite being older on average (53.9 years).…”

“…However, because PD likely develops over the course of many years, signs and symptoms of PS may be apparent long before diagnosis. Studies in which pesticide-exposed workers have been examined for signs of PS have been limited to workers exposed to paraquat 10 or maneb. 11 In this study, we examined agricultural pesticide handlers from apple orchards in central Washington State, where insecticides such as chlorpyrifos are much more commonly used.…”