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ABSTRACT: BACKGROUND: We previously demonstrated that carriers of the "slower metabolizer" MM genotype of paraoxonase (PON1) who were also exposed to ambient organophosphate (OP) pesticides at their residences were at increased risk of developing Parkinson's disease (PD). Here, with a larger sample size, we extend our previous investigation to consider additional sources of ambient exposure and examined two additional functional PON1 variants. METHODS: From 2001 to 2011, we enrolled incident cases of idiopathic PD and population controls living in central California. We genotyped three well-known functional PON1 SNPs: two exonic polymorphisms (PON1L55M and PON1Q192R) and the promoter region variant (PON1C-108T). Ambient exposures to diazinon, chlorpyrifos, and parathion at residential and workplace addresses were assessed using a validated geographic information system-based model incorporating records of agricultural pesticide applications in California. RESULTS: The odds ratio (OR) for Caucasians exposed to OPs at either residential or workplace addresses varied by PON1 genotype; for exposed carriers of the "faster" metabolizer genotypes, ML or LL, we estimated lower odds ratios (range, 1.20-1.39) than for exposed carriers of the "slower" metabolizer genotype MM (range, 1.78-2.45) relative to unexposed carriers of the faster genotypes. We observed similarly increased ORs for exposure across PON1Q192R genotypes, but no differences across PON1C-108T genotypes. The largest ORs were estimated for exposed carriers of both PON1192QQ and PON155MM (OR range, 2.84-3.57). CONCLUSIONS: Several functional PON1 variants may act together to modify PD risk for ambient OP exposures. While either PON1L55M or PON1Q192R may be sufficient to identify increased susceptibility, carriers of both slow metabolizer variants seem most susceptible to OP exposures.
Environment international 04/2013; 56C:42-47. · 4.79 Impact Factor
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ABSTRACT: OBJECTIVES: Traumatic brain injury (TBI) increased risk of Parkinson disease (PD) in many but not all epidemiologic studies, giving rise to speculations about modifying factors. A recent animal study suggested that the combination of TBI with subthreshold paraquat exposure increases dopaminergic neurodegeneration. The objective of our study was to investigate PD risk due to both TBI and paraquat exposure in humans. METHODS: From 2001 to 2011, we enrolled 357 incident idiopathic PD cases and 754 population controls in central California. Study participants were asked to report all head injuries with loss of consciousness for >5 minutes. Paraquat exposure was assessed via a validated geographic information system (GIS) based on records of pesticide applications to agricultural crops in California since 1974. This GIS tool assesses ambient pesticide exposure within 500 m of residences and workplaces. RESULTS: In logistic regression analyses, we observed a 2-fold increase in risk of PD for subjects who reported a TBI (adjusted odds ratio [AOR] 2.00, 95% confidence interval [CI] 1.28-3.14) and a weaker association for paraquat exposures (AOR 1.36, 95% CI 1.02-1.81). However, the risk of developing PD was 3-fold higher (AOR 3.01, 95% CI 1.51-6.01) in study participants with a TBI and exposure to paraquat than those exposed to neither risk factor. CONCLUSIONS: While TBI and paraquat exposure each increase the risk of PD moderately, exposure to both factors almost tripled PD risk. These environmental factors seem to act together to increase PD risk in a more than additive manner.
Neurology 11/2012; 79(20):2061-2066. · 8.31 Impact Factor
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ABSTRACT: Due to the heavy and expanding agricultural use of neurotoxic pesticides suspected to affect dopaminergic neurons, it is imperative
to closely examine the role of pesticides in the development of Parkinson’s disease (PD). We focus our investigation on pesticide
use in California’s heavily agricultural central valley by utilizing a unique pesticide use reporting system. From 2001 to
2007, we enrolled 362 incident PD cases and 341 controls living in the Central Valley of California. Employing our geographic
information system model, we estimated ambient exposures to the pesticides ziram, maneb, and paraquat at work places and residences
from 1974 to 1999. At workplaces, combined exposure to ziram, maneb, and paraquat increased risk of PD three-fold (OR: 3.09;
95% CI: 1.69, 5.64) and combined exposure to ziram and paraquat, excluding maneb exposure, was associated with a 80% increase
in risk (OR:1.82; 95% CI: 1.03, 3.21). Risk estimates for ambient workplace exposure were greater than for exposures at residences
and were especially high for younger onset PD patients and when exposed in both locations. Our study is the first to implicate
ziram in PD etiology. Combined ambient exposure to ziram and paraquat as well as combined ambient exposure to maneb and paraquat
at both workplaces and residences increased PD risk substantially. Those exposed to ziram, maneb, and paraquat together experienced
the greatest increase in PD risk. Our results suggest that pesticides affecting different mechanisms that contribute to dopaminergic
neuron death may act together to increase the risk of PD considerably.
KeywordsCase–control study–Geographic information systems (GIS)–Paraquat–Parkinson’s disease–Pesticide–Ziram
European Journal of Epidemiology 04/2012; 26(7):547-555. · 4.71 Impact Factor
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ABSTRACT: Currently, there are no reported genetic predictors of motor symptom progression in Parkinson's disease (PD). In familial PD, disease severity is associated with higher α-synuclein (SNCA) expression levels, and in postmortem studies expression varies with SNCA genetic variants. Furthermore, SNCA is a well-known risk factor for PD occurrence. We recruited Parkinson's patients from the communities of three central California counties to investigate the influence of SNCA genetic variants on motor symptom progression in idiopathic PD. We repeatedly assessed this cohort of patients over an average of 5.1 years for motor symptom changes employing the Unified Parkinson's Disease Rating Scale (UPDRS). Of 363 population-based incident PD cases diagnosed less than 3 years from baseline assessment, 242 cases were successfully re-contacted and 233 were re-examined at least once. Of subjects lost to follow-up, 69% were due to death. Adjusting for covariates, risk of faster decline of motor function as measured by annual increase in motor UPDRS exam score was increased 4-fold in carriers of the REP1 263bp promoter variant (OR 4.03, 95%CI:1.57-10.4). Our data also suggest a contribution to increased risk by the G-allele for rs356165 (OR 1.66; 95%CI:0.96-2.88), and we observed a strong trend across categories when both genetic variants were considered (p for trend = 0.002). Our population-based study has demonstrated that SNCA variants are strong predictors of faster motor decline in idiopathic PD. SNCA may be a promising target for therapies and may help identify patients who will benefit most from early interventions. This is the first study to link SNCA to motor symptom decline in a longitudinal progression study.
PLoS ONE 01/2012; 7(5):e36199. · 4.09 Impact Factor
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ABSTRACT: Due to the heavy and expanding agricultural use of neurotoxic pesticides suspected to affect dopaminergic neurons, it is imperative to closely examine the role of pesticides in the development of Parkinson's disease (PD). We focus our investigation on pesticide use in California's heavily agricultural central valley by utilizing a unique pesticide use reporting system. From 2001 to 2007, we enrolled 362 incident PD cases and 341 controls living in the Central Valley of California. Employing our geographic information system model, we estimated ambient exposures to the pesticides ziram, maneb, and paraquat at work places and residences from 1974 to 1999. At workplaces, combined exposure to ziram, maneb, and paraquat increased risk of PD three-fold (OR: 3.09; 95% CI: 1.69, 5.64) and combined exposure to ziram and paraquat, excluding maneb exposure, was associated with a 80% increase in risk (OR:1.82; 95% CI: 1.03, 3.21). Risk estimates for ambient workplace exposure were greater than for exposures at residences and were especially high for younger onset PD patients and when exposed in both locations. Our study is the first to implicate ziram in PD etiology. Combined ambient exposure to ziram and paraquat as well as combined ambient exposure to maneb and paraquat at both workplaces and residences increased PD risk substantially. Those exposed to ziram, maneb, and paraquat together experienced the greatest increase in PD risk. Our results suggest that pesticides affecting different mechanisms that contribute to dopaminergic neuron death may act together to increase the risk of PD considerably.
European Journal of Epidemiology 04/2011; 26(7):547-55. · 4.71 Impact Factor
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ABSTRACT: Although of great interest and suggested in prior reports, possible α-synuclein (SNCA) gene-environment interactions have not been well investigated in humans.
We used a population-based approach to examine whether the risk of Parkinson's disease (PD) depended on the combined presence of SNCA variations and two important environmental factors, pesticide exposures and smoking.
Similar to recent meta- and pooled analyses, our data suggest a lower PD risk in subjects who were either homozygous or heterozygous for the SNCA REP1 259 genotype, and a higher risk in subjects who were either homozygous or heterozygous for the REP1 263 genotype, especially among subjects with an age of onset ≤68 years. More importantly, while analyses of interactions were limited by small cell sizes, risk due to SNCA variations seemed to vary with pesticide exposure and smoking, especially in younger onset cases, suggesting an age-of-onset effect.
Neuroepidemiology 01/2010; 35(3):191-5. · 2.31 Impact Factor
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ABSTRACT: Investigators have hypothesized that consuming pesticide-contaminated well water plays a role in Parkinson's disease (PD), and several previous epidemiologic studies support this hypothesis.
We investigated whether consuming water from private wells located in areas with documented historical pesticide use was associated with an increased risk of PD.
We employed a geographic information system (GIS)-based model to estimate potential well-water contamination from agricultural pesticides among 368 cases and 341 population controls enrolled in the Parkinson's Environment and Genes Study (PEG). We separately examined 6 pesticides (diazinon, chlorpyrifos, propargite, paraquat, dimethoate, and methomyl) from among 26 chemicals selected for their potential to pollute groundwater or for their interest in PD, and because at least 10% of our population was exposed to them.
Cases were more likely to have consumed private well water and to have consumed it on average 4.3 years longer than controls (p = 0.02). High levels of possible well-water contamination with methomyl [odds ratio (OR) = 1.67; 95% confidence interval (CI), 1.00-2.78]), chlorpyrifos (OR = 1.87; 95% CI, 1.05-3.31), and propargite (OR = 1.92; 95% CI, 1.15-3.20) resulted in approximately 70-90% increases in relative risk of PD. Adjusting for ambient pesticide exposures only slightly attenuated these increases. Exposure to a higher number of water-soluble pesticides and organophosphate pesticides also increased the relative risk of PD.
Our study, the first to use agricultural pesticide application records, adds evidence that consuming well water presumably contaminated with pesticides may play a role in the etiology of PD.
Environmental Health Perspectives 12/2009; 117(12):1912-8. · 7.04 Impact Factor
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ABSTRACT: Human, animal and cell models support a role for pesticides in the etiology of Parkinson disease. Susceptibility to pesticides may be modified by genetic variants of xenobiotic enzymes, such as paraoxonase, that play a role in metabolizing some organophosphates.
We examined associations between Parkinson disease and the organophosphates diazinon, chlorpyrifos, and parathion, and the influence of a functional polymorphism at position 55 in the coding region of the PON1 gene (PON1-55). From 1 January 2001 through 1 January 2008, we recruited 351 incident cases and 363 controls from 3 rural California counties in a population-based case-control study. Participants provided a DNA sample, and residential exposure to organophosphates was determined from pesticide usage reports and a geographic information system (GIS) approach. We assessed the main effects of both genes and pesticides in unconditional logistic regression analyses, and evaluated the effect of carrying a PON1-55 MM variant on estimates of effects for diazinon, chlorpyrifos, and parathion exposures.
Carriers of the variant MM PON1-55 genotype exposed to organophosphates exhibited a greater than 2-fold increase in Parkinson disease risk compared with persons who had the wildtype or heterozygous genotype and no exposure (for diazinon, odds ratio = 2.2 [95% confidence interval = 1.1-4.5]; for chlorpyrifos, 2.6 [1.3-5.4]). The effect estimate for chlorpyrifos, was more pronounced in younger-onset cases and controls (<or=60 years) (5.3 [1.7-16]). No increase in risk was noted for parathion.
The increase in risk we observed among PON1-55 variant carriers for specific organophosphates metabolized by PON1 underscores the importance of considering susceptibility factors when studying environmental exposures in Parkinson disease.
Epidemiology (Cambridge, Mass.) 11/2009; 21(1):87-94. · 5.51 Impact Factor
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ABSTRACT: Attempts at cell-based dopamine replacement therapy in Parkinson disease (PD) have included surgical implantation of adrenal medullary, fetal mesencephalic, and cultured human mesencephalic tissue grafts. Trials involving putamenal implantation of human retinal pigment epithelial (RPE) cells in PD have also been performed. Neuropathologic findings in humans undergoing RPE cell implantation have not heretofore been reported. We describe the brain autopsy findings from a subject enrolled in a clinical trial of RPE cells in gelatin microcarriers for treatment of PD, and suggest factors which may have impacted cell survival.
A 68-year-old man underwent bilateral surgical implantation of 325,000 RPE cells in gelatin microcarriers (Spheramine) but died 6 months after surgery. The left cerebral hemisphere was examined. Routine postmortem formalin fixation was performed and standard, as well as immunohistochemical methods used to highlight senile plaque and Lewy body pathologic changes, iron deposition, cellular inflammation, and reactive astrocytosis in implant regions. Manual cell counts were done of RPE cells.
Hematoxylin-eosin and alpha-synuclein immunostains confirmed the diagnosis of PD. Needle tracts with matrix material and RPE cells were observed in the context of local inflammatory and astrocytic reactive change. A total of 118 cells were counted (estimated 0.036% survival).
Retinal pigment epithelial cells are seen in human brain 6 months postimplantation, but overall survival of implanted cells appeared poor.
Neurology 10/2009; 73(14):1095-102. · 8.31 Impact Factor
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ABSTRACT: Research suggests that independent and joint effects of genetic variability in the dopamine transporter (DAT) locus and pesticides may influence Parkinson's disease (PD) risk.
In 324 incident PD patients and 334 population controls from our rural California case-control study, we genotyped rs2652510, rs2550956 (for the DAT 5' clades), and the 3' variable number of tandem repeats (VNTR). Using geographic information system methods, we determined residential exposure to agricultural maneb and paraquat applications. We also collected occupational pesticide use data. Employing logistic regression, we calculated odds ratios (ORs) for clade diplotypes, VNTR genotype, and number of susceptibility (A clade and 9-repeat) alleles and assessed susceptibility allele-pesticide interactions.
PD risk was increased separately in DAT A clade diplotype carriers [AA vs. BB: OR = 1.66; 95% confidence interval (CI), 1.08-2.57] and 3' VNTR 9/9 carriers (9/9 vs. 10/10: OR = 1.8; 95% CI, 0.96-3.57), and our data suggest a gene dosing effect. Importantly, high exposure to paraquat and maneb in carriers of one susceptibility allele increased PD risk 3-fold (OR = 2.99; 95% CI, 0.88-10.2), and in carriers of two or more alleles more than 4-fold (OR = 4.53; 95% CI, 1.70-12.1). We obtained similar results for occupational pesticide measures.
Using two independent pesticide measures, we a) replicated previously reported gene-environment interactions between DAT genetic variants and occupational pesticide exposure in men and b) overcame previous limitations of nonspecific pesticide measures and potential recall bias by employing state records and computer models to estimate residential pesticide exposure.
Our results suggest that DAT genetic variability and pesticide exposure interact to increase PD risk.
Environmental Health Perspectives 07/2009; 117(6):964-9. · 7.04 Impact Factor
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ABSTRACT: Evidence from animal and cell models suggests that pesticides cause a neurodegenerative process leading to Parkinson's disease (PD). Human data are insufficient to support this claim for any specific pesticide, largely because of challenges in exposure assessment. The authors developed and validated an exposure assessment tool based on geographic information systems that integrated information from California Pesticide Use Reports and land-use maps to estimate historical exposure to agricultural pesticides in the residential environment. In 1998-2007, the authors enrolled 368 incident PD cases and 341 population controls from the Central Valley of California in a case-control study. They generated estimates for maneb and paraquat exposures incurred between 1974 and 1999. Exposure to both pesticides within 500 m of the home increased PD risk by 75% (95% confidence interval (CI): 1.13, 2.73). Persons aged < or =60 years at the time of diagnosis were at much higher risk when exposed to either maneb or paraquat alone (odds ratio = 2.27, 95% CI: 0.91, 5.70) or to both pesticides in combination (odds ratio = 4.17, 95% CI: 1.15, 15.16) in 1974-1989. This study provides evidence that exposure to a combination of maneb and paraquat increases PD risk, particularly in younger subjects and/or when exposure occurs at younger ages.
American journal of epidemiology 04/2009; 169(8):919-26. · 5.59 Impact Factor
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Jeff Bronstein,
Paul Carvey,
Honglei Chen,
Deborah Cory-Slechta,
Donato DiMonte,
John Duda,
Paul English,
Samuel Goldman,
Stephen Grate,
Johnni Hansen, [......],
George W Ross,
Ted Schettler,
Michael Schwarzschild,
Bill Scott,
Richard Seegal,
Andrew Singleton,
Kyle Steenland,
Caroline M Tanner,
Stephen Van Den Eeden,
Marc Weisskopf
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ABSTRACT: Parkinson's disease (PD) is the second most common neurodegenerative disorder. People with PD, their families, scientists, health care providers, and the general public are increasingly interested in identifying environmental contributors to PD risk.
In June 2007, a multidisciplinary group of experts gathered in Sunnyvale, California, USA, to assess what is known about the contribution of environmental factors to PD.
We describe the conclusions around which they came to consensus with respect to environmental contributors to PD risk. We conclude with a brief summary of research needs.
PD is a complex disorder, and multiple different pathogenic pathways and mechanisms can ultimately lead to PD. Within the individual there are many determinants of PD risk, and within populations, the causes of PD are heterogeneous. Although rare recognized genetic mutations are sufficient to cause PD, these account for < 10% of PD in the U.S. population, and incomplete penetrance suggests that environmental factors may be involved. Indeed, interplay among environmental factors and genetic makeup likely influences the risk of developing PD. There is a need for further understanding of how risk factors interact, and studying PD is likely to increase understanding of other neurodegenerative disorders.
Environmental Health Perspectives 01/2009; 117(1):117-21. · 7.04 Impact Factor
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ABSTRACT: K(+) channels are differentially expressed throughout oligodendrocyte (Olg) development. K(V)1 family voltage-sensitive K(+) channels have been implicated in proliferation and migration of Olg progenitor cell (OPC) stage, and inward rectifier K+ channels (K(IR))4.1 are required for OPC differentiation to myelin-forming Olg. In this report we have identified a Shaw family K(+) channel, K(V)3.1, that is involved in proliferation and migration of OPC and axon myelination. Application of anti-K(V)3.1 antibody or knockout of Kv3.1 gene decreased the sustained K(+) current component of OPC by 50% and 75%, respectively. In functional assays block of K(V)3.1-specific currents or knockout of Kv3.1 gene inhibited proliferation and migration of OPC. Adult Kv3.1 gene-knockout mice had decreased diameter of axons and decreased thickness of myelin in optic nerves compared with age-matched wild-type littermates. Additionally, K(V)3.1 was identified as an associated protein of Olg-specific protein (OSP)/claudin-11 via yeast two-hybrid analysis, which was confirmed by coimmunoprecipitation and coimmunohistochemistry. In summary, the K(V)3.1 K(+) current accounts for a significant component of the total K(+) current in cells of the Olg lineage and, in association with OSP/claudin-11, plays a significant role in OPC proliferation and migration and myelination of axons.
AJP Cell Physiology 11/2006; 291(4):C687-98. · 3.54 Impact Factor
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ABSTRACT: Deep Brain Stimulation (DBS) of the ventro-intermedius nucleus of the thalamus is the treatment of choice for drug-refractory essential tremor (ET). This study evaluated the effectiveness of thalamic stimulation in improving the patient's quality of life through activities of daily living.
Sixteen ET patients completed a health questionnaire, the "Tremor Activities of Daily Living Scale" (TADLS) measured by the patient, a 10-item subset of the TADLS measured by the clinician, and the Fahn-Tolosa-Marin tremor rating scale (TRS). Each patient was evaluated with the stimulator on and off with the average evaluation occurring 13 months after surgery. Additionally, improvements on the TADLS were compared to electrode positioning on the axial plane and stimulation parameters.
There was a 44.0% improvement in the patient-rated TADLS, a 45.2% improvement in the clinician-rated TADLS, and a 33.9% improvement in the TRS. The average electrode location was 5.65 mm anterior to the posterior commissure (AC-PC), 13.4 mm lateral from the midline, and 2.0 mm below the AC-PC line. The average stimulation parameters were 2.74 Volts, 160 Hertz, and 119 microsec. There was no correlation between improvements on the TADLS, electrode location, and stimulation parameters. Of the 16 patients, 10 patients would repeat the surgery, two were unsure, and four would not repeat the surgery.
Tremor is significantly controlled with DBS and activities of daily living are highly correlated with patient satisfaction. The degree of improvement in the four patients who would not repeat the surgery was outweighed by the negative factors associated with the surgery.
Surgical Neurology 07/2003; 59(6):479-84; discussion 484-5. · 1.67 Impact Factor
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Jeff Bronstein,
Paul Carvey,
Honglei Chen,
Deborah Cory-Slechta,
Donato DiMonte,
John Duda,
Paul English,
Stephen Grate,
Johnni Hansen,
Jane Hoppin, [......],
Bill Scott,
Richard Seegal,
Andrew Singleton,
Kyle Steenland,
Caroline M Tanner,
Stephen Van Den Eeden,
Samuel Goldman,
George W. Ross,
Michael Alan Schwarzschild,
Marc G Weisskopf
[show abstract]
[hide abstract]
ABSTRACT: Background: Parkinson’s disease (PD) is the second most common neurodegenerative disorder. People with PD, their families, scientists, health care providers, and the general public are increasingly interested in identifying environmental contributors to PD risk. Methods: In June 2007, a multidisciplinary group of experts gathered in Sunnyvale, California, USA, to assess what is known about the contribution of environmental factors to PD. Results: We describe the conclusions around which they came to consensus with respect to environmental contributors to PD risk. We conclude with a brief summary of research needs. Conclusions: PD is a complex disorder, and multiple different pathogenic pathways and mechanisms can ultimately lead to PD. Within the individual there are many determinants of PD risk, and within populations, the causes of PD are heterogeneous. Although rare recognized genetic mutations are sufficient to cause PD, these account for < 10% of PD in the U.S. population, and incomplete penetrance suggests that environmental factors may be involved. Indeed, interplay among environmental factors and genetic makeup likely influences the risk of developing PD. There is a need for further understanding of how risk factors interact, and studying PD is likely to increase understanding of other neurodegenerative disorders.
