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BACKGROUND: We recently reported an increased risk of Parkinson's disease (PD) in service members who resided at Marine Base Camp Lejeune, North Carolina, when water supplies were contaminated with trichloroethylene and other volatile organic compounds (VOCs). Prior studies suggest that environmental exposures may affect PD phenotype or progression, but this has not been reported for VOCs. OBJECTIVE: The objective of this study was to test whether PD progression is faster in individuals exposed to VOCs in water at Camp Lejeune. METHODS: A cohort of 172,128 marines residing at Camp Lejeune between 1975 and 1985 was previously assembled. We identified individuals with PD in Veterans Health Administration and Medicare databases between 2000 and 2021. Using estimates derived by the US Agency for Toxic Substances and Disease Registry, we classified individuals as exposed or unexposed to VOCs in residential water. We used Kaplan-Meier and Cox regression models to test differences between exposed and unexposed groups in the time from PD diagnosis until psychosis, fracture, fall, or death. RESULTS: Among 270 persons with PD, 177 (65.6%) were exposed to VOCs in residential water. Median cumulative exposure was 4970 µg/L-months, >50-fold the permissible level. Time until psychosis, fracture, and fall were all shorter in the exposed group, with adjusted hazard ratios (HRs) exceeding 2: psychosis HR, 2.19 (95% confidence interval [CI]: 0.99-4.83); fracture HR, 2.44 (95% CI: 0.91-6.55); and fall HR, 2.64 (95% CI: 0.97-7.21). A significant dose response was observed for time to fall (P trend, 0.032). No differences were observed for time until death. CONCLUSIONS: PD progression may be faster in persons exposed to trichloroethylene and other VOCs in water decades earlier. © 2024 The Author(s). Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society. This article has been contributed to by U.S. Government employees and their work is in the public domain in the USA.
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BACKGROUND: Environmental exposure to trichloroethylene (TCE), a carcinogenic dry-cleaning chemical, may be linked to Parkinson's disease (PD). OBJECTIVE: The objective of this study was to determine whether PD and cancer were elevated among attorneys who worked near a contaminated site. METHODS: We surveyed and evaluated attorneys with possible exposure and assessed a comparison group. RESULTS: Seventy-nine of 82 attorneys (96.3%; mean [SD] age: 69.5 [11.4] years; 89.9% men) completed at least one phase of the study. For comparison, 75 lawyers (64.9 [10.2] years; 65.3% men) underwent clinical evaluations. Four (5.1%) of them who worked near the polluted site reported PD, more than expected based on age and sex (1.7%; P = 0.01) but not significantly higher than the comparison group (n = 1 [1.3%]; P = 0.37). Fifteen (19.0%), compared to four in the comparison group (5.3%; P = 0.049), had a TCE-related cancer. CONCLUSIONS: In a retrospective study, diagnoses of PD and TCE-related cancers appeared to be elevated among attorneys who worked next to a contaminated dry-cleaning site. © 2024 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.
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Neoplasias , Enfermedad de Parkinson , Tricloroetileno , Masculino , Humanos , Anciano , Femenino , Enfermedad de Parkinson/epidemiología , Enfermedad de Parkinson/etiología , Enfermedad de Parkinson/diagnóstico , Estudios Retrospectivos , Tricloroetileno/análisisRESUMEN
PURPOSE: Cardiac autonomic dysfunction in idiopathic Parkinson's disease (PD) manifests as reduced heart rate variability (HRV). In the present study, we explored the deceleration capacity of heart rate (DC) in patients with idiopathic PD, an advanced HRV marker that has proven clinical utility. METHODS: Standard and advanced HRV measures derived from 7-min electrocardiograms in 20 idiopathic PD patients and 27 healthy controls were analyzed. HRV measures were compared using regression analysis, controlling for age, sex, and mean heart rate. RESULTS: Significantly reduced HRV was found only in the subcohort of PD patients older than 60 years. Low- frequency power and global HRV measures were lower in patients than in controls, but standard beat-to-beat HRV markers (i.e., rMSSD and high-frequency power) were not significantly different between groups. DC was significantly reduced in the subcohort of PD patients older than 60 years compared to controls. CONCLUSIONS: Deceleration-related oscillations of HRV were significantly reduced in the older PD patients compared to healthy controls, suggesting that short-term DC may be a sensitive marker of cardiac autonomic dysfunction in PD. DC may be complementary to traditional markers of short-term HRV for the evaluation of autonomic modulation in PD. Further study to examine the association between DC and cardiac adverse events in PD is needed to clarify the clinical relevance of DC in this population.
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Enfermedad de Parkinson , Disautonomías Primarias , Sistema Nervioso Autónomo , Desaceleración , Frecuencia Cardíaca , Humanos , Enfermedad de Parkinson/complicacionesRESUMEN
During the 1990s, we estimated the genetic contribution to Parkinson's disease risk in a large, population-based twin registry. Because many unaffected twins were still alive, previous concordance estimates were based on incomplete information. Ninety-five percent of twins are now deceased. Here, we update concordance and heritability through 2015 using National Death Index data. In total, we identified 30 concordant and 193 discordant pairs. Proband-wise concordance was 0.20 in monozygotic and 0.13 in dizygotic pairs. Heritability was 0.27 overall, 0.83 in pairs diagnosed ≤50, and 0.19 in pairs diagnosed >50. High concordance in dizygotic twins suggests shared effects of early childhood environment. Ann Neurol 2019;85:600-605.
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Enfermedades en Gemelos/genética , Predisposición Genética a la Enfermedad/genética , Enfermedad de Parkinson/genética , Gemelos Dicigóticos/genética , Gemelos Monocigóticos/genética , Adulto , Anciano , Anciano de 80 o más Años , Enfermedades en Gemelos/epidemiología , Femenino , Estudios de Seguimiento , Predisposición Genética a la Enfermedad/epidemiología , Humanos , Masculino , Persona de Mediana Edad , Enfermedad de Parkinson/epidemiología , Sistema de Registros , Factores de RiesgoRESUMEN
BACKGROUND: The penetrance of leucine rich repeat kinase 2 (LRRK2) mutations is incomplete and may be influenced by environmental and/or other genetic factors. Nonsteroidal anti-inflammatory drugs (NSAIDs) are known to reduce inflammation and may lower Parkinson's disease (PD) risk, but their role in LRRK2-associated PD is unknown. OBJECTIVES: The objective of this study is to evaluate the association of regular NSAID use and LRRK2-associated PD. METHODS: Symptomatic ("LRRK2-PD") and asymptomatic ("LRRK2-non-PD") participants with LRRK2 G2019S, R1441X, or I2020T variants (definitely pathogenic variant carriers) or G2385R or R1628P variants (risk variant carriers) from 2 international cohorts provided information on regular ibuprofen and/or aspirin use (≥2 pills/week for ≥6 months) prior to the index date (diagnosis date for PD, interview date for non-PD). Multivariate logistic regression was used to evaluate the relationship between regular NSAID use and PD for any NSAID, separately for ibuprofen and aspirin in all carriers and separately in pathogenic and risk variant groups. RESULTS: A total of 259 LRRK2-PD and 318 LRRK2-non-PD participants were enrolled. Regular NSAID use was associated with reduced odds of PD in the overall cohort (odds ratio [OR], 0.34; 95% confidence interval [CI], 0.21-0.57) and in both pathogenic and risk variant carriers (ORPathogenic , 0.38; 95% CI, 0.21-0.67 and ORRiskVariant , 0.19; 95% CI, 0.04-0.99). Similar associations were observed for ibuprofen and aspirin separately (ORIbuprofen , 0.19; 95% CI, 0.07-0.50 and ORAspirin , 0.51; 95% CI, 0.28-0.91). CONCLUSIONS: Regular NSAID use may be associated with reduced penetrance in LRRK2-associated PD. The LRRK2 protein is involved in inflammatory pathways and appears to be modulated by regular anti-inflammatory use. Longitudinal observational and interventional studies of NSAID exposure and LRRK2-PD are needed to confirm this association. © 2020 International Parkinson and Movement Disorder Society.
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Enfermedad de Parkinson , Antiinflamatorios no Esteroideos/uso terapéutico , Predisposición Genética a la Enfermedad , Humanos , Proteína 2 Quinasa Serina-Treonina Rica en Repeticiones de Leucina/genética , Mutación/genética , Enfermedad de Parkinson/tratamiento farmacológico , Enfermedad de Parkinson/genética , PenetranciaRESUMEN
BACKGROUND: Parkinson's Disease (PD) is a clinically diagnosed neurodegenerative disorder that affects both motor and non-motor neural circuits. Speech deterioration (hypokinetic dysarthria) is a common symptom, which often presents early in the disease course. Machine learning can help movement disorders specialists improve their diagnostic accuracy using non-invasive and inexpensive voice recordings. METHOD: We used "Parkinson Dataset with Replicated Acoustic Features Data Set" from the UCI-Machine Learning repository. The dataset included 44 speech-test based acoustic features from patients with PD and controls. We analyzed the data using various machine learning algorithms including Light and Extreme Gradient Boosting, Random Forest, Support Vector Machines, K-nearest neighborhood, Least Absolute Shrinkage and Selection Operator Regression, as well as logistic regression. We also implemented a variable importance analysis to identify important variables classifying patients with PD. RESULTS: The cohort included a total of 80 subjects: 40 patients with PD (55% men) and 40 controls (67.5% men). Disease duration was 5 years or less for all subjects, with a mean Unified Parkinson's Disease Rating Scale (UPDRS) score of 19.6 (SD 8.1), and none were taking PD medication. The mean age for PD subjects and controls was 69.6 (SD 7.8) and 66.4 (SD 8.4), respectively. Our best-performing model used Light Gradient Boosting to provide an AUC of 0.951 with 95% confidence interval 0.946-0.955 in 4-fold cross validation using only seven acoustic features. CONCLUSIONS: Machine learning can accurately detect Parkinson's disease using an inexpensive and non-invasive voice recording. Light Gradient Boosting outperformed other machine learning algorithms. Such approaches could be used to inexpensively screen large patient populations for Parkinson's disease.
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Enfermedad de Parkinson , Trastornos de la Voz , Algoritmos , Estudios de Cohortes , Femenino , Humanos , Aprendizaje Automático , Masculino , Enfermedad de Parkinson/complicaciones , Enfermedad de Parkinson/diagnóstico , Máquina de Vectores de Soporte , Trastornos de la Voz/etiologíaRESUMEN
There is evidence from observational studies for a role of a number of environmental exposures and lifestyle habits in modulating the risk for Parkinson's disease. Environmental and lifestyle associations, if causal, represent opportunities for Parkinson's disease prevention or disease modification at individual and population levels. In the past decade, additional evidence has been published that improves causal inference and/or enhances our understanding of the complexity of these associations. A number of gene-environment interactions have been elucidated, and our understanding of the roles of physical activity, pesticide and other chemical exposures, dietary habits, emotional stress, head injury, and smoking has been refined. In the next decade, better techniques will help us to close the gaps in our knowledge, including taking into account Parkinson's disease heterogeneity and gene and risk factor interactions in observational studies. To do this, larger datasets, global consortia, genomewide environment interaction studies, prospective studies throughout the lifespan, and improvements in the methodology of clinical trials of physical activity will be key. Despite the caveats of observational studies, a number of low-risk and potentially high-yield recommendations for lifestyle modification could be made to minimize the individual and societal burdens of Parkinson's disease, including dietary modifications, increasing physical activity, and head injury avoidance. Furthermore, a reduction in pesticide use could have a major impact on global health related to and beyond Parkinson's disease. Given the increasing prevalence of this disorder, formulating and promoting these recommendations should be a high priority. © 2019 International Parkinson and Movement Disorder Society.
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Ambiente , Interacción Gen-Ambiente , Estilo de Vida , Enfermedad de Parkinson/etiología , Exposición a Riesgos Ambientales , Humanos , Enfermedad de Parkinson/genéticaRESUMEN
PURPOSE: Cardiac autonomic dysfunction manifests as reduced heart rate variability (HRV) in idiopathic Parkinson's disease (PD), but no significant reduction has been found in PD patients who carry the LRRK2 mutation. Novel HRV features have not been investigated in these individuals. We aimed to assess cardiac autonomic modulation through standard and novel approaches to HRV analysis in individuals who carry the LRRK2 G2019S mutation. METHODS: Short-term electrocardiograms were recorded in 14 LRRK2-associated PD patients, 25 LRRK2-non-manifesting carriers, 32 related non-carriers, 20 idiopathic PD patients, and 27 healthy controls. HRV measures were compared using regression modeling, controlling for age, sex, mean heart rate, and disease duration. Discriminant analysis highlighted the feature combination that best distinguished LRRK2-associated PD from controls. RESULTS: Beat-to-beat and global HRV measures were significantly increased in LRRK2-associated PD patients compared with controls (e.g., deceleration capacity of heart rate: p = 0.006) and idiopathic PD patients (e.g., 8th standardized moment of the interbeat interval distribution: p = 0.0003), respectively. LRRK2-associated PD patients also showed significantly increased irregularity of heart rate dynamics, as quantified by Rényi entropy, when compared with controls (p = 0.002) and idiopathic PD patients (p = 0.0004). Ordinal pattern statistics permitted the identification of LRRK2-associated PD individuals with 93% sensitivity and 93% specificity. Consistent results were found in a subgroup of LRRK2-non-manifesting carriers when compared with controls. CONCLUSIONS: Increased beat-to-beat HRV in LRRK2 G2019S mutation carriers compared with controls and idiopathic PD patients may indicate augmented cardiac autonomic cholinergic activity, suggesting early impairment of central vagal feedback loops in LRRK2-associated PD.
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Enfermedad de Parkinson/complicaciones , Enfermedad de Parkinson/genética , Enfermedad de Parkinson/fisiopatología , Disautonomías Primarias/etiología , Anciano , Femenino , Frecuencia Cardíaca/fisiología , Humanos , Proteína 2 Quinasa Serina-Treonina Rica en Repeticiones de Leucina/genética , Masculino , Persona de Mediana Edad , Mutación , Nervio Vago/fisiopatologíaRESUMEN
The National Academy of Sciences-National Research Council (NAS-NRC) Twin Registry is one of the oldest, national population-based twin registries in the USA. It comprises 15,924 White male twin pairs born in the years 1917-1927 (N = 31.848), both of whom served in the armed forces, chiefly during World War II. This article updates activities in this registry since the most recent report in Twin Research and Human Genetics (Page, 2006). Records-based data include information from enlistment charts and Veterans Administration data linkages. There have been three major epidemiologic questionnaires and an education and earnings survey. Separate data collection efforts with the NAS-NRC registry include the National Heart, Lung, and Blood Institute (NHLBI) subsample, the Duke Twins Study of Memory in Aging and a clinically based study of Parkinson's disease. Progress has been made on consolidating the various data holdings of the NAS-NRC Twin Registry. Data that had been available through the National Academy of Sciences are now freely available through National Archive of Computerized Data on Aging (NACDA).
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Envejecimiento/genética , Sistemas de Registros Médicos Computarizados , Memoria , Sistema de Registros , Gemelos/genética , Anciano de 80 o más Años , Femenino , Humanos , Masculino , National Academies of Science, Engineering, and Medicine, U.S., Health and Medicine Division , Estados Unidos , United States Department of Veterans AffairsRESUMEN
Parkinson's disease (PD) is a chronic, progressive, disabling neurodegenerative disorder that begins in mid to late life and is characterized by motor impairment, autonomic dysfunction, and, in many, psychological and cognitive changes. Recent advances have helped delineate pathogenetic mechanisms, yet the cause of PD in most individuals is unknown. Although at least 15 genes and genetic loci have been associated with PD, identified genetic causes are responsible for only a few percent of cases. Epidemiologic studies have found increased risk of PD associated with exposure to environmental toxicants such as pesticides, solvents, metals, and other pollutants, and many of these compounds recapitulate PD pathology in animal models. This review summarizes the environmental toxicology of PD, highlighting the consistency of observations across cellular, animal, and human studies of PD pathogenesis.
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Exposición a Riesgos Ambientales/efectos adversos , Sustancias Peligrosas/toxicidad , Enfermedad de Parkinson/epidemiología , Enfermedad de Parkinson/patología , Contaminación del Aire/efectos adversos , Animales , Modelos Animales de Enfermedad , Interacción Gen-Ambiente , Humanos , Metales Pesados/toxicidad , Enfermedad de Parkinson/etiología , Enfermedad de Parkinson/genética , Plaguicidas/toxicidad , Bifenilos Policlorados/toxicidad , Solventes/toxicidadRESUMEN
BACKGROUND: Heart rate variability is reduced in idiopathic PD, indicating cardiac autonomic dysfunction likely resulting from peripheral autonomic synucleinopathy. Little is known about heart rate variability in leucine-rich repeat kinase 2-associated PD. OBJECTIVES: This study investigated heart rate variability in LRRK2-associated PD. METHODS: Resting electrocardiograms were obtained from 20 individuals with LRRK2-associated PD, 37 nonmanifesting carriers, 48 related noncarriers, 26 idiopathic PD patients, and 32 controls. Linear regression modelling compared time and frequency domain values, adjusting for age, sex, heart rate, and disease duration. RESULTS: Low-frequency power and the ratio of low-high frequency power were reduced in idiopathic PD versus controls (P < .008, P < .029 respectively). In contrast, individuals with LRRK2-associated PD were not statistically different from controls in any parameter measured. Furthermore, all parameters trended toward being higher in LRRK2-associated PD when compared with idiopathic PD. CONCLUSIONS: Heart rate variability may remain intact in LRRK2-associated PD, adding to a growing literature supporting clinical-pathologic differences between LRRK2-associated and idiopathic PD. © 2017 International Parkinson and Movement Disorder Society.
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Cardiopatías/etiología , Frecuencia Cardíaca/genética , Proteína 2 Quinasa Serina-Treonina Rica en Repeticiones de Leucina/genética , Mutación/genética , Enfermedad de Parkinson/genética , Enfermedad de Parkinson/fisiopatología , Anciano , Electrocardiografía , Femenino , Estudios de Asociación Genética , Glicina/genética , Cardiopatías/genética , Humanos , Masculino , Persona de Mediana Edad , Serina/genética , Índice de Severidad de la EnfermedadRESUMEN
Increased gut permeability, inflammation, and colonic α-synuclein pathology are present in early Parkinson's disease (PD) and have been proposed to contribute to PD pathogenesis. Peptidoglycan is a structural component of the bacterial cell wall. Peptidoglycan recognition proteins (PGRPs) maintain healthy gut microbial flora by regulating the immune response to both commensal and harmful bacteria. We tested the hypothesis that variants in genes that encode PGRPs are associated with PD risk. Participants in two independent case-control studies were genotyped for 30 single-nucleotide polymorphisms (SNPs) in the four PGLYRP genes. Using logistic regression to estimate odds ratios (OR) and 95% confidence intervals (CI) adjusted for potential confounding variables, we conducted analyses in each study, separately and pooled. One SNP failed the assay, and three had little to no variation. The ORs were similar in both study populations. In pooled analyses, three of seven PGLYRP2 SNPs (rs3813135, rs733731, rs892145), one of five PGLYRP3 SNPs (rs2987763), and six of nine PGLYRP4 SNPs (rs10888557, rs12063091, rs3006440, rs3006448, rs3006458, and rs3014864) were significantly associated with PD risk. Association was strongest for PGLYRP4 5'untranslated region (UTR) SNP rs10888557 (GG reference, CG OR 0.6 [95%CI 0.4-0.9], CC OR 0.15 [95%CI 0.04-0.6]; log-additive P-trend, 0.0004). Common variants in PGLYRP genes are associated with PD risk in two independent studies. These results require replication, but they are consistent with hypotheses of a causative role for the gut microbiota and gastrointestinal immune response in PD.
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Proteínas Portadoras/genética , Predisposición Genética a la Enfermedad/genética , Enfermedad de Parkinson/genética , Polimorfismo de Nucleótido Simple/genética , Adulto , Anciano , Anciano de 80 o más Años , Estudios de Casos y Controles , Femenino , Estudios de Asociación Genética , Genotipo , Humanos , Modelos Logísticos , Masculino , Microbiota/genética , Persona de Mediana Edad , Oportunidad RelativaRESUMEN
Although the causes of Parkinson's disease (PD) are thought to be primarily environmental, recent studies suggest that a number of genes influence susceptibility. Using targeted case recruitment and online survey instruments, we conducted the largest case-control genome-wide association study (GWAS) of PD based on a single collection of individuals to date (3,426 cases and 29,624 controls). We discovered two novel, genome-wide significant associations with PD-rs6812193 near SCARB2 (p = 7.6 × 10(-10), OR = 0.84) and rs11868035 near SREBF1/RAI1 (p = 5.6 × 10(-8), OR = 0.85)-both replicated in an independent cohort. We also replicated 20 previously discovered genetic associations (including LRRK2, GBA, SNCA, MAPT, GAK, and the HLA region), providing support for our novel study design. Relying on a recently proposed method based on genome-wide sharing estimates between distantly related individuals, we estimated the heritability of PD to be at least 0.27. Finally, using sparse regression techniques, we constructed predictive models that account for 6%-7% of the total variance in liability and that suggest the presence of true associations just beyond genome-wide significance, as confirmed through both internal and external cross-validation. These results indicate a substantial, but by no means total, contribution of genetics underlying susceptibility to both early-onset and late-onset PD, suggesting that, despite the novel associations discovered here and elsewhere, the majority of the genetic component for Parkinson's disease remains to be discovered.
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Sitios Genéticos/genética , Estudio de Asociación del Genoma Completo , Internet , Enfermedad de Parkinson/genética , Bases de Datos Factuales , Predisposición Genética a la Enfermedad , Herencia/genética , Humanos , Polimorfismo de Nucleótido Simple/genética , Medición de RiesgoRESUMEN
Alzheimer's disease, Parkinson's disease, and motor neuron disease, the most common of the late-life neurodegenerative disorders, are in most cases thought to have complex etiologies. Common features among these disorders include insidious onset, pathological findings of protein aggregates and selected neuronal degeneration, and resulting characteristic clinical syndromes. The number of elders in the United States, including aging veterans, is increasing. Investigation of causes and preventive interventions for neurodegenerative disorders is increasingly relevant. Recent epidemiological and laboratory studies suggest that exposures years or decades before diagnosis can trigger the processes that ultimately result in a neurodegenerative disease. If this is correct, preventive measures may be needed in midlife or earlier. This article will focus on putative risk factors relevant to military service.
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Enfermedad de Alzheimer/epidemiología , Esclerosis Amiotrófica Lateral/epidemiología , Personal Militar , Exposición Profesional/efectos adversos , Enfermedad de Parkinson/epidemiología , Enfermedad de Alzheimer/fisiopatología , Esclerosis Amiotrófica Lateral/fisiopatología , Animales , Interacción Gen-Ambiente , Predisposición Genética a la Enfermedad , Humanos , Enfermedad de Parkinson/fisiopatología , Factores de RiesgoRESUMEN
INTRODUCTION: Between 1953 and 1987, over one million Veterans were exposed to contaminated water at Marine Corps Base Camp Lejeune, North Carolina. We examined the relationship between toxicant exposure and subsequent disability ratings in female veterans. MATERIALS AND METHODS: Comparisons were made between females stationed at Camp Lejeune and from Marine Corps Base Camp Pendleton, California who were not known to have been exposed to these toxicants, between 1975 and 1985, using data from the Agency for Toxic Substances and Diseases Registry and VA data. RESULTS: A total of 4,491 (52%) females from Camp Lejeune and 2,811 (47%) from Camp Pendleton used VA health care between October 1, 1999 and February 17, 2021. Approximately 51% of Camp Lejeune females were exposed to toxicants. More than half (50.6% and 53.9% from Lejeune and Pendleton, respectively) had a disability rating ≥10%. Females who were Black, Hispanic, officers, or had longer duration in camp were more likely to have a disability rating, whereas females exposed to toxicants were less likely to have a disability rating. When the regression was redone examining the predictors of disability due to any of 8 presumptive conditions associated with toxicant exposure, the only significant variable was having been at Camp Lejeune (odds ratio [OR], 2.5, 95% CI, 1.3-4.7). Toxicant exposure was not significant when only Camp Lejeune females were included in the model. CONCLUSION: Little attention has been given to female veterans exposed to toxicants at Camp Lejeune. Although we did not find an association between exposure and disability ratings, reliance on service-connected disability codes and small numbers were limitations. Further examination using international code of diseases diagnostic codes may be warranted.
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Post-traumatic stress disorder (PTSD) may be a risk factor for Parkinson's disease (PD). We examined the relation between PTSD and PD in a cohort of 158,122 Veterans who had any Veterans Health Administration (VHA) or Medicare health care utilization between 10/1/1999- 2/17/2021. Using a nested case-control design we matched 10 controls to each Veteran with PD by sex, race, and rank. In conditional logistic regression models adjusted for camp and smoking, a PTSD diagnosis was significantly associated with PD (ORâ=â1.35; pâ=â0.0002); odds were higher if PTSD was coded before PD (ORâ=â1.53, pâ<â0.0001). PTSD may be a risk factor for PD.
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Background: The penetrance of common genetic risk variants for Parkinson's disease (PD) is low. Pesticide exposure increases PD risk, but how exposure affects penetrance is not well understood. Objective: To determine the relationship between occupational pesticide exposure and PD in people with LRRK2 and GBA risk variants. Methods: Participants of the Parkinson's Progression Markers Initiative (PPMI) with a LRRK2-G2019âS or GBA risk variant provided information about occupational pesticide exposure. We compared exposure in carriers with and without PD. Among carriers with PD, we used Cox proportional hazard models to compare time-to impairment in balance, cognition, and activities of daily living (ADLs) between participants with and without prior occupational pesticide exposure. Results: 378 participants with a risk variant provided exposure information; 176 with LRRK2-G2019âS (54 with and 122 without PD) and 202 with GBA variants (47 with and 155 without PD). Twenty-six participants reported pesticide exposure. People with a GBA variant and occupational pesticide exposure had much higher odds of PD (aOR: 5.4, 95% CI 1.7-18.5, pâ<â0.01). People with a LRRK2 variant and a history of occupational pesticide exposure had non-significantly elevated odds of PD (aOR 1.3, 95% CI 0.4-4.6, pâ=â0.7). Among those with PD, pesticide exposure was associated with a higher risk of balance problems and cognitive impairment in LRRK2-PD and functional impairment in GBA-PD, although associations were not statistically significant. Conclusions: Occupational pesticide exposure may increase penetrance of GBA-PD and may be associated with faster symptom progression. Further studies in larger cohorts are necessary.
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Glucosilceramidasa , Proteína 2 Quinasa Serina-Treonina Rica en Repeticiones de Leucina , Exposición Profesional , Enfermedad de Parkinson , Plaguicidas , Humanos , Proteína 2 Quinasa Serina-Treonina Rica en Repeticiones de Leucina/genética , Femenino , Enfermedad de Parkinson/genética , Masculino , Glucosilceramidasa/genética , Exposición Profesional/efectos adversos , Plaguicidas/efectos adversos , Anciano , Persona de Mediana Edad , Penetrancia , Actividades Cotidianas , Disfunción Cognitiva/etiología , Disfunción Cognitiva/genética , Disfunción Cognitiva/inducido químicamenteRESUMEN
OBJECTIVE: Several case reports have linked solvent exposure to Parkinson disease (PD), but few studies have assessed associations with specific agents using an analytic epidemiologic design. We tested the hypothesis that exposure to specific solvents is associated with PD risk using a discordant twin pair design. METHODS: Ninety-nine twin pairs discordant for PD ascertained from the National Academy of Sciences/National Research Council World War II Veteran Twins Cohort were interviewed regarding lifetime occupations and hobbies using detailed job task-specific questionnaires. Exposures to 6 specific solvents selected a priori were estimated by expert raters unaware of case status. RESULTS: Ever exposure to trichloroethylene (TCE) was associated with significantly increased risk of PD (odds ratio [OR], 6.1; 95% confidence interval [CI] 1.2-33; p = 0.034), and exposure to perchloroethylene (PERC) and carbon tetrachloride (CCl(4) ) tended toward significance (respectively: OR, 10.5; 95% CI, 0.97-113; p = 0.053; OR, 2.3; 95% CI, 0.9-6.1; p = 0.088). Results were similar for estimates of exposure duration and cumulative lifetime exposure. INTERPRETATION: Exposure to specific solvents may increase risk of PD. TCE is the most common organic contaminant in groundwater, and PERC and CCl(4) are also ubiquitous in the environment. Our findings require replication in other populations with well-characterized exposures, but the potential public health implications are substantial.
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Enfermedades en Gemelos/epidemiología , Exposición Profesional/efectos adversos , Enfermedad de Parkinson/epidemiología , Enfermedad de Parkinson/etiología , Solventes/toxicidad , Adulto , Anciano , Anciano de 80 o más Años , Tetracloruro de Carbono/toxicidad , Estudios de Cohortes , Femenino , Humanos , Masculino , Persona de Mediana Edad , Oportunidad Relativa , Factores de Riesgo , Tetracloroetileno/toxicidad , GemelosRESUMEN
OBJECTIVE: To test the hypothesis that variability in SNCA Rep1, a polymorphic dinucleotide microsatellite in the promoter region of the gene encoding α-synuclein, modifies the association between head injury and Parkinson's disease (PD) risk. METHODS: Participants in the Farming and Movement Evaluation (FAME) and the Study of Environmental Association and Risk of Parkinsonism using Case-Control Historical Interviews (SEARCH), 2 independent case-control studies, were genotyped for Rep1 and interviewed regarding head injuries with loss of consciousness or concussion prior to Parkinson's disease (PD) diagnosis. Logistic regression modeling adjusted for potential confounding variables and tested interaction between Rep1 genotype and head injury. RESULTS: Consistent with prior reports, relative to medium-length Rep1, short Rep1 genotype was associated with reduced PD risk (pooled odds ratio [OR], 0.7; 95% confidence interval [CI], 0.5-0.9), and long Rep1 with increased risk (pooled OR, 1.4; 95% CI, 0.95-2.2). Overall, head injury was not significantly associated with PD (pooled OR, 1.3; 95% CI, 0.9-1.8). However, head injury was strongly associated with PD in those with long Rep1 (FAME OR, 5.4; 95% CI, 1.5-19; SEARCH OR, 2.3; 95% CI, 0.6-9.2; pooled OR, 3.5; 95% CI 1.4-9.2, p-interaction = 0.02). Individuals with both head injury and long Rep1 were diagnosed 4.9 years earlier than those with neither risk factor (p = 0.03). INTERPRETATION: While head injury alone was not associated with PD risk, our data suggest head injury may initiate and/or accelerate neurodegeneration when levels of synuclein are high, as in those with Rep1 expansion. Given the high population frequency of head injury, independent verification of these results is essential.
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Traumatismos Craneocerebrales/epidemiología , Traumatismos Craneocerebrales/genética , Repeticiones de Microsatélite/genética , Enfermedad de Parkinson/epidemiología , Enfermedad de Parkinson/genética , alfa-Sinucleína/genética , Adulto , Anciano , Anciano de 80 o más Años , Estudios de Casos y Controles , Estudios de Cohortes , Traumatismos Craneocerebrales/sangre , Femenino , Variación Genética , Humanos , Masculino , Persona de Mediana Edad , Enfermedades Neurodegenerativas/sangre , Enfermedades Neurodegenerativas/epidemiología , Enfermedades Neurodegenerativas/genética , Enfermedad de Parkinson/diagnóstico , Estudios Prospectivos , alfa-Sinucleína/biosíntesis , alfa-Sinucleína/sangreRESUMEN
Introduction: Early diagnosis of Parkinson's disease (PD) is important to identify treatments to slow neurodegeneration. People who develop PD often have symptoms before the disease manifests and may be coded as diagnoses in the electronic health record (EHR). Methods: To predict PD diagnosis, we embedded EHR data of patients onto a biomedical knowledge graph called Scalable Precision medicine Open Knowledge Engine (SPOKE) and created patient embedding vectors. We trained and validated a classifier using these vectors from 3,004 PD patients, restricting records to 1, 3, and 5 years before diagnosis, and 457,197 non-PD group. Results: The classifier predicted PD diagnosis with moderate accuracy (AUC = 0.77 ± 0.06, 0.74 ± 0.05, 0.72 ± 0.05 at 1, 3, and 5 years) and performed better than other benchmark methods. Nodes in the SPOKE graph, among cases, revealed novel associations, while SPOKE patient vectors revealed the basis for individual risk classification. Discussion: The proposed method was able to explain the clinical predictions using the knowledge graph, thereby making the predictions clinically interpretable. Through enriching EHR data with biomedical associations, SPOKE may be a cost-efficient and personalized way to predict PD diagnosis years before its occurrence.