Beate Ritz

Parkinson's Disease and Residential Exposure to Maneb and Paraquat From Agricultural Applications in the Central Valley of California

Evidence from animal and cell models suggests that pesticides cause a neurodegenerative process leading to Parkinsons 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.

Effect of air pollution on preterm birth among children born in Southern California between 1989 and 1993.

We evaluated the effect of air pollution exposure during pregnancy on the occurrence of preterm birth in a cohort of 97,518 neonates born in Southern California. We used measurements of carbon monoxide (CO), nitrogen dioxide, ozone, and particulate matter less than 10 &mgr;m (PM10) collected at 17 air-quality-monitoring stations to create average exposure estimates for periods of pregnancy. We calculated crude and adjusted risk ratios (RRs) for premature birth by period-specific ambient pollution levels. We observed a 20% increase in preterm birth per 50-&mgr;g increase in ambient PM10 levels averaged over 6 weeks before birth [RRcrude = 1.20; 95% confidence interval (CI) = 1.09–1.33] and a 16% increase when averaging over the first month of pregnancy (RRcrude = 1.16; 95% CI = 1.06–1.26). PM10 effects showed no regional pattern. CO exposure 6 weeks before birth consistently exhibited an effect only for the inland regions (RRcrude= 1.13; 95% CI = 1.08–1.18 per 3 parts per million), and during the first month of pregnancy, the effect was weak for all stations (RRcrude = 1.04; 95% CI = 1.01–1.09 per 3 parts per million). Exposure to increased levels of ambient PM10 and possibly CO during pregnancy may contribute to the occurrence of preterm births in Southern California.

Nonsteroidal anti-inflammatory drugs may protect against Parkinson disease

Objective: Markers of neuroinflammation, including activated microglia and increased levels of circulating proinflammatory cytokines, have been observed in the brains and CSF of patients with Parkinson disease (PD). Yet the link between anti-inflammatory agents and PD in humans remains uncertain, despite indications that neuroinflammation may contribute to cell death in the PD brain and experimental evidence of anti-inflammatory agents such as nonsteroidal anti-inflammatory drugs (NSAIDs) exerting neuroprotective effects in animal models. Methods: Using a population-based approach, we studied NSAID use among 293 incident idiopathic PD cases and 286 age-, race-, and gender-matched controls from three rural California counties. Results: Our data suggested a decreased risk of PD among regular (≥2 pills/week for at least 1 month) aspirin NSAID users (OR, 0.80; 95% CI, 0.56 to 1.15). A stronger protective effect was observed for regular nonaspirin NSAID users (OR, 0.52; 95% CI, 0.35 to 0.79), particularly those who reported 2 or more years of use (OR, 0.44; 95% CI, 0.26 to 0.74). The aspirin effect estimates differed by gender, showing a protective effect only in women, especially among long term (≥24 months) regular users (OR, 0.51; 95% CI, 0.26 to 1.02). Conclusion: Our study contributes to the growing body of literature suggesting a protective role for nonsteroidal anti-inflammatory drugs (NSAIDs) in Parkinson disease (PD). Given our results and the biologic plausibility of a neuroprotective function for NSAIDs there is a pressing need for further studies elucidating the protective role such drugs may play in PD. GLOSSARY: MPTP = 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine; NSAIDs = nonsteroidal anti-inflammatory drugs; PD = Parkinson disease.

Clinical Characteristics in Early Parkinson’s Disease in a Central California Population-Based Study

There is considerable variation in the phenotypic appearance of individuals with idiopathic Parkinsons disease (PD), which may translate into differences in disease progression in addition to underlying disease etiology. In this publication, we report on the demographic and clinical characteristics of 162 individuals diagnosed with clinically probable PD from January 1998 to June 2003 who resided in predominantly rural communities in central California. The majority of the subjects were Caucasian, male, and between 60 and 79 years of age. The akinetic–rigid and tremor‐dominant subtypes were more common than the mixed subtype. The majority of subjects displayed motor signs of rigidity (92.0%), bradykinesia (95.7%), and gait problems (87.0%), whereas less than half (43.3%) of the subjects displayed a tremor. Three fourths of patients received a Hoehn and Yahr Scale score of Stage 2 or higher. One third of the patients were treated with levodopa, and patients under 60 years of age were more likely to be treated with dopamine agonists. Within 3 years after first diagnosis, 13% of subjects showed some signs of depression and 17% of subjects met criteria for mild dementia. Among our subjects, 17.3% reported a family history of PD in first‐ or second‐degree relatives,15.4% a family history of essential tremor, and 14.2% of Alzheimers disease. This study represents the most extensive phenotypic description of rural U.S. residents in the initial stages of PD who were recruited in a population‐based manner; future follow‐up may provide valuable information regarding the prognostic indication of these symptoms/signs and improve our understanding of the underlying etiology of PD.

Exposure to particulate matter and adverse birth outcomes: a comprehensive review and meta-analysis

Increasing number of studies have investigated the impact of maternal exposure to air pollution during pregnancy and adverse birth outcomes, particularly low birth weight (LBW, <2,500xa0g at birth) and preterm birth (PTB, <37 completed weeks of gestation). We performed a comprehensive review of the peer-reviewed literature and a meta-analysis to quantify the association between maternal exposure to particulate matter with aerodynamic diameter 2.5 and 10xa0μm (PM2.5 and PM10) during pregnancy and the risk of LBW and PTB. We identified 20 peer-reviewed articles providing quantitative estimate of exposure and outcome that met our selection criteria. There was significant heterogeneity between studies, particularly for findings related to PM10 exposure (LBW, I-squared 54%, pu2009=u20090.01; PTB, I-squaredu2009=u200973%, pu2009<u20090.01). Results from random-effect meta-analysis suggested a 9% increase in risk of LBW associated with a 10-μg/m3 increase in PM2.5 (combined odds ratios (OR), 1.09; 95% confidence interval (CI), 0.90–1.32), but our 95% CI included the null value. We estimated a 15% increase in risk of PTB for each 10-μg/m3 increase in PM2.5 (combined OR, 1.15; CI, 1.14–1.16). The magnitude of risk associated with PM10 exposure was smaller (2% per 10-μg/m3 increase) and similar in size for both LBW and PTB, neither reaching formal statistical significance. We observed no significant publication bias, with pu2009>u20090.05 based on both Beggs and Eggers bias tests. Our results suggest that maternal exposure to PM, particularly PM2.5 may have adverse effect on birth outcomes. Additional mechanistic studies are needed to understand the underlying mechanisms for this association.

Aldehyde dehydrogenase inhibition as a pathogenic mechanism in Parkinson disease

Parkinson disease (PD) is a neurodegenerative disorder particularly characterized by the loss of dopaminergic neurons in the substantia nigra. Pesticide exposure has been associated with PD occurrence, and we previously reported that the fungicide benomyl interferes with several cellular processes potentially relevant to PD pathogenesis. Here we propose that benomyl, via its bioactivated thiocarbamate sulfoxide metabolite, inhibits aldehyde dehydrogenase (ALDH), leading to accumulation of the reactive dopamine metabolite 3,4-dihydroxyphenylacetaldehyde (DOPAL), preferential degeneration of dopaminergic neurons, and development of PD. This hypothesis is supported by multiple lines of evidence. (i) We previously showed in mice the metabolism of benomyl to S-methyl N-butylthiocarbamate sulfoxide, which inhibits ALDH at nanomolar levels. We report here that benomyl exposure in primary mesencephalic neurons (ii) inhibits ALDH and (iii) alters dopamine homeostasis. It induces selective dopaminergic neuronal damage (iv) in vitro in primary mesencephalic cultures and (v) in vivo in a zebrafish system. (vi) In vitro cell loss was attenuated by reducing DOPAL formation. (vii) In our epidemiology study, higher exposure to benomyl was associated with increased PD risk. This ALDH model for PD etiology may help explain the selective vulnerability of dopaminergic neurons in PD and provide a potential mechanism through which environmental toxicants contribute to PD pathogenesis.

Statin use and the risk of Parkinson disease

Objective: To investigate associations between statin (3-hxydroxy-3-methylglutaryl-coenzyme A reductase inhibitor) use and Parkinson disease (PD). Methods: We used a population-based design to recruit 312 incident idiopathic PD cases and 342 controls from three rural California counties. Results: We observed a higher frequency of statin use among controls vs cases (OR 0.45; 95% CI 0.29 to 0.71) and a strong dose-response relation. The strongest protective association between statin use and PD was observed in long-term (≥5 years) users (OR 0.37; 95% CI 0.18 to 0.78). There was no difference by gender or age. We noted 60 to 70% risk reductions for each individual statin except pravastatin. Conclusion: Ascribing causality to these associations is premature and further studies are needed to confirm a potential neuroprotective role for statins in PD. GLOSSARY: B-D test = Breslow-Day test; NO = nitric oxide; PD = Parkinson disease; PEG = Parkinsons Environment and Genes.

Well-Water Consumption and Parkinson’s Disease in Rural California

Introduction 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. Objectives We investigated whether consuming water from private wells located in areas with documented historical pesticide use was associated with an increased risk of PD. Methods 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. Results 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. Conclusion 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.

Lack of replication of thirteen single-nucleotide polymorphisms implicated in Parkinson’s disease: a large-scale international study

BACKGROUNDnA genome-wide association study identified 13 single-nucleotide polymorphisms (SNPs) significantly associated with Parkinsons disease. Small-scale replication studies were largely non-confirmatory, but a meta-analysis that included data from the original study could not exclude all SNP associations, leaving relevance of several markers uncertain.nnnMETHODSnInvestigators from three Michael J Fox Foundation for Parkinsons Research-funded genetics consortia-comprising 14 teams-contributed DNA samples from 5526 patients with Parkinsons disease and 6682 controls, which were genotyped for the 13 SNPs. Most (88%) participants were of white, non-Hispanic descent. We assessed log-additive genetic effects using fixed and random effects models stratified by team and ethnic origin, and tested for heterogeneity across strata. A meta-analysis was undertaken that incorporated data from the original genome-wide study as well as subsequent replication studies.nnnFINDINGSnIn fixed and random-effects models no associations with any of the 13 SNPs were identified (odds ratios 0.89 to 1.09). Heterogeneity between studies and between ethnic groups was low for all SNPs. Subgroup analyses by age at study entry, ethnic origin, sex, and family history did not show any consistent associations. In our meta-analysis, no SNP showed significant association (summary odds ratios 0.95 to 1.08); there was little heterogeneity except for SNP rs7520966.nnnINTERPRETATIONnOur results do not lend support to the finding that the 13 SNPs reported in the original genome-wide association study are genetic susceptibility factors for Parkinsons disease.

An effective and efficient approach for manually improving geocoded data

BackgroundThe process of geocoding produces output coordinates of varying degrees of quality. Previous studies have revealed that simply excluding records with low-quality geocodes from analysis can introduce significant bias, but depending on the number and severity of the inaccuracies, their inclusion may also lead to bias. Little quantitative research has been presented on the cost and/or effectiveness of correcting geocodes through manual interactive processes, so the most cost effective methods for improving geocoded data are unclear. The present work investigates the time and effort required to correct geocodes contained in five health-related datasets that represent examples of data commonly used in Health GIS.ResultsGeocode correction was attempted on five health-related datasets containing a total of 22,317 records. The complete processing of these data took 11.4 weeks (427 hours), averaging 69 seconds of processing time per record. Overall, the geocodes associated with 12,280 (55%) of records were successfully improved, taking 95 seconds of processing time per corrected record on average across all five datasets. Geocode correction improved the overall match rate (the number of successful matches out of the total attempted) from 79.3 to 95%. The spatial shift between the location of original successfully matched geocodes and their corrected improved counterparts averaged 9.9 km per corrected record. After geocode correction the number of city and USPS ZIP code accuracy geocodes were reduced from 10,959 and 1,031 to 6,284 and 200, respectively, while the number of building centroid accuracy geocodes increased from 0 to 2,261.ConclusionThe results indicate that manual geocode correction using a web-based interactive approach is a feasible and cost effective method for improving the quality of geocoded data. The level of effort required varies depending on the type of data geocoded. These results can be used to choose between data improvement options (e.g., manual intervention, pseudocoding/geo-imputation, field GPS readings).