Our study suggests a combined effect of 2 environmental exposures, TBI and paraquat exposure, on PD development that is larger than each component effect. These results in humans are supported by findings from a recent animal study in which the combination of experimental head trauma and subthreshold paraquat doses led to increased nigrostriatal dopaminergic neuron loss, and greater induction of α-synuclein accumulation and inflammation compared with experimental head trauma treatment alone.12
Our results for TBI and PD are consistent with findings from previous studies that reported head injuries as being associated with PD.3,6,7,9,10
A twin study reported a 4-fold increased risk for developing PD among subjects self-reporting a prior head injury (OR = 3.8, 95% CI = 1.3–11). Two case-control studies assessed head injuries based on medical record review rather than participant recall.3,8
One of these was a small study (196 patients with PD) that found associations for subjects with severe head injury requiring hospitalization, but included only 9 head trauma hospitalizations.3
The other very large medical record linkage study conducted in Denmark reported a 50% increase in risk of developing PD after hospital treatment for head injuries within 10 years prior to a PD diagnosis.8
This is consistent with our estimate for subject reports of head injuries requiring hospitalization (AOR = 1.77, 95% CI = 0.99–3.17).
Our new results for ambient paraquat exposure confirm our previous findings, but with a larger control group, and including exposures both at residences and workplaces.23
A previous study in Taiwan reported occupational paraquat exposure to increase PD risk (OR = 3.2, 95% CI = 2.41–4.31).24
More recently, a cohort study in the United States also reported ever being exposed to paraquat as being associated with PD (OR = 2.5, 95% CI = 1.4–4.7).25
Although the effect estimates for PD and paraquat from these 2 studies are greater than ours (AOR = 1.36, 95% CI = 1.02–1.81), these results cannot easily be compared to our findings, due to differences in the types of exposure, i.e., occupational vs ambient paraquat exposures.
Similar to most previous studies, we collected TBI information through interviews, which might introduce bias due to differential recall by cases compared with controls. However, a previous head trauma and PD study6
observed perfect agreement between self-reports and medical record retrieval of information regarding head injuries in a subset of their sample. These authors also suggested that differential recall for head injuries is most likely for events that occur closer in time to PD onset. When we excluded TBI reports close to PD onset, we observed similar size associations, suggesting no differences in recall depending on PD diagnosis. A major strength of our study is the availability of our GIS-based modeling system for long-term ambient residential and workplace paraquat exposures, using California pesticide use records. This exposure assessment tool avoids differential recall bias for historical exposure; however, nondifferential misclassification of exposure cannot be ruled out (e.g., due to geocoding errors and uncertainties concerning pesticide drift).
There are a number of biological mechanisms that may explain the associations we observed. TBI is known to induce an inflammatory cascade and accumulation of α-synuclein and tau, 2 proteins that are major components of Lewy bodies.26–31
Furthermore, TBI may contribute to PD through disruption of the blood–brain barrier and mitochondrial function.32–35
Most recently, a pooled epidemiologic study36
observed an association (OR = 3.5, 95% CI = 1.4–9.2) between head injury and PD, but only among carriers of the α-synuclein (SNCA) Rep1 promoter risk allele, which has been previously associated with an increased risk of PD.36–38
In experimental animal studies, paraquat exposure can induce reactive oxygen species production in the brain, which may lead to loss of nigral dopaminergic neurons.39,40
This, combined with recent experimental animal data,12
suggests that the physiologic process triggered by a head injury may increase the vulnerability of neurons to insults from neurotoxic pesticides, with the combination increasing the risk of PD more than each exposure on its own.
A recent animal study that examined the combined effects of TBI (first exposure) and low-dose paraquat exposure (subsequent exposure) in rats observed a synergistic effect of both exposures on nigrostriatal dopaminergic neuron loss with exposure to paraquat 3 and 6 days after TBI; however, this synergistic effect was not observed when paraquat was administered 21 and 22 weeks after TBI.12
In the present study, we were unable to address temporality of TBI and paraquat exposures, since pesticide records were only available after 1974. Many of our study participants reported TBIs that had occurred at a young age (mean = 27 years; range = 2–82), i.e., during a period when pesticide exposures were not yet recorded in the California system. Another limitation of our study is that we were unable to examine the effect measure modification by gender since the relatively small number of cases exposed to both agents did not provide sufficient statistical power for gender stratification.
Furthermore, our population-based case-control study was conducted in California's rural Central Valley, an area with substantial agricultural pesticide use. The high prevalence of pesticide exposure in this population provided sufficient statistical power to examine interactions between paraquat exposure and TBI on PD risk. However, study results may not be generalizable to populations with low pesticide exposure.
While both TBI and paraquat exposures weakly or moderately increased PD risk, the magnitude of the combined effect estimate was stronger than the sum of the TBI and PD effects alone, indicating a positive interaction on an additive scale. Our data suggest that multiple environmental factors may act together to increase the risk of PD beyond the effect of each risk factor alone, and that some individuals might be developing PD due to an accumulation of multiple exposures.