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Objective: Survival of patients with monogenic Parkinson's disease may depend on the causative genes associated with the disease. In this study, we compare survival of patients with Parkinson's disease according to the presence of SNCA, PRKN, LRRK2, or GBA mutations. Methods: Data from the French Parkinson Disease Genetics national multicenter cohort study were used. Patients with sporadic and familial Parkinson's disease were recruited between 1990 and 2021. Patients were genotyped for the presence of mutations in the SNCA, PRKN, LRRK2, or GBA genes. Vital status was collected from the National death register for participants born in France. Hazard ratios (HRs) and 95% confidence intervals (CIs) were computed using multivariable Cox proportional hazards regression. Results: Of the 2,037 patients with Parkinson's disease, 889 had died after a follow‐up of up to 30 years. Patients with PRKN (n = 100, HR = 0.41; p = 0.001) and LRRK2 mutations (n = 51, HR = 0.49; p = 0.023) had longer survival than those without any mutation, whereas patients with SNCA (n = 20, HR = 9.88; p < 0.001) or GBA mutations (n = 173, HR = 1.33; p = 0.048) had shorter survival. Interpretation: Survival differs across genetic forms of Parkinson's disease, with higher mortality for patients with SNCA or GBA mutations, and lower mortality for those with PRKN or LRRK2 mutations. Differences in severity and disease progression among monogenic forms of Parkinson's disease likely explain these findings, which has important consequences for genetic counselling and choice of end points for future clinical trials for targeted therapies. ANN NEUROL 2023;94:123–132 [ABSTRACT FROM AUTHOR]

Sporadic Creutzfeldt-Jakob disease (sCJD) is the most common form of prion diseases. The causes of sCJD are still unknown and exogenous factors may play a role. Worldwide, the number of patients with sCJD has progressively increased over time. This increase can be partly explained by increasing life expectancy and better case ascertainment, but a true increase in the number of sCJD cases cannot be excluded. We estimated mortality rates from sCJD in France (1992–2016) and studied variation in mortality rates by age, period, and time. We included all cases aged 45–89 years old who died with a probable/definite sCJD diagnosis based on the French national surveillance network. We used age-period-cohort (APC) Poisson regression models to study variation in mortality rates by sex, age, period, and time. A total of 2475 sCJD cases aged 45–89 years were included. Mortality rates increased with age, reached a peak between 75 and 79 years, and decreased thereafter. Mortality rates were higher in women than men at younger ages and lower at older ages. The full APC model with a sex×age interaction provided the best fit to the data, thus in favour of sex, age, period, and cohort effects on mortality rates. In particular, mortality rates increased progressively with successive birth cohorts. Based on 25 years of active surveillance in France, we show evidence for sex, age, period, and cohort effects on sCJD mortality. The identification of cohort effects suggests that environmental exposures may play a role in sCJD etiology. [ABSTRACT FROM AUTHOR]

This study retrospectively compared all‐cause and cause‐specific mortality in French male professional football players with data from France's national population. Altogether, 6114 individuals born in Metropolitan France or in one of its overseas territories who played at least one competitive match in France's professional football championships between January 1, 1968 and December 31, 2015, were identified and followed up for vital status obtained from a national reference database until December 31, 2015. Data on all‐cause and cause‐specific mortality were subsequently compared to the expected number of deaths for the national population after standardization for the year, age, and sex. Ratios between observed and expected deaths provided standardized mortality ratios (SMR) along with 95% confidence intervals (95% CI). Linear trends were investigated using the Poisson trend test. Altogether, 662 player deaths were observed. All‐cause mortality overall was lower than that of the national population (SMR: 0.69, 95% CI 0.64–0.75). An excess of deaths from dementia was observed in the players (SMR: 3.38, 95% CI: 2.49–4.50) whereas mortality from diseases of the nervous (SMR: 0.64, 95% CI: 0.35–1.08) and cardiovascular systems (SMR: 0.82, 95% CI: 0.70–0.96), and cancer (SMR: 0.67, 95% CI: 0.58–0.76) was lower. Lower overall mortality and that owing to common cardiovascular and cancer‐related diseases were reported in French professional football players compared to France's national population. In line with previous studies, however, excess mortality from dementia was observed in the players. Career length was not associated with all‐cause or cause‐specific mortality. Prospective matched‐cohort studies are necessary to identify the neurologic impact of participation in professional football. [ABSTRACT FROM AUTHOR]

Background: Dementia onset in those aged <65 years (young onset dementia, YOD) has dramatic individual and societal consequences. In the context of population aging, data on YOD are of major importance to anticipate needs for planning and allocation of health and social resources. Few studies have provided precise frequency estimates of YOD. The aim of this study is to provide YOD prevalence and incidence estimates in France and to study the contribution of comorbidities to YOD incidence.Methods and Findings: Using data from the French national health data system (Système National des Données de Santé, SNDS) for 76% of the French population aged 40 to 64 years in 2016 (n = 16,665,795), we identified all persons with dementia based on at least 1 of 3 criteria: anti-Alzheimer drugs claims, hospitalization with the International Classification of Diseases-10th Revision (ICD-10) dementia codes (F00 to F03, G30, G31.0, G31.1, or F05.1), or registration for free healthcare for dementia. We estimated prevalence rate (PR) and incidence rate (IR) and estimated the association of comorbidities with incident YOD. Sex differences were investigated. We identified 18,466 (PRstandardized = 109.7/100,000) and 4,074 incident (IRstandardized = 24.4/100,000 person-years) persons with prevalent and incident YOD, respectively. PR and IR sharply increased with age. Age-adjusted PR and IR were 33% (95% confidence interval (CI) = 29 to 37) and 39% (95% CI = 31 to 48) higher in men than women (p < 0.001 both for PR and IR). Cardio- and cerebrovascular, neurological, psychiatric diseases, and traumatic brain injury prevalence were associated with incident YOD (age- and sex-adjusted p-values <0.001 for all comorbidities examined, except p = 0.109 for antihypertensive drug therapy). Adjustment for all comorbidities explained more than 55% of the sex difference in YOD incidence. The lack of information regarding dementia subtypes is the main limitation of this study.Conclusions: We estimated that there were approximately 24,000 and approximately 5,300 persons with prevalent and incident YOD, respectively, in France in 2016. The higher YOD frequency in men may be partly explained by higher prevalence of cardiovascular and neurovascular diseases, substance abuse disorders, and traumatic brain injury and warrants further investigation. [ABSTRACT FROM AUTHOR]

BACKGROUND/OBJECTIVES: The associations of reproductive history and motor function are controversial. DESIGN: Prospective cohort study with 10 years of follow‐up. SETTING: Three French cities between 1999 and 2011. PARTICIPANTS: A total of 3043 community‐dwelling women from the Three‐City Dijon study population. MEASUREMENTS: We examined the cross‐sectional and longitudinal association of age at menopause, artificial menopause, and parity with walking speed (WS) using linear regression and linear mixed models, respectively. Cox proportional models were used to examine the association of characteristics of reproductive life with disability. RESULTS: Mean baseline WS was 143.8 cm/s. Artificial menopause was associated with slower WS at baseline (β = −3.29; 95% confidence interval [CI] = −5.83 to −0.74; P =.01). Reproductive life characteristics had no effect on change in WS. Increasing age at menopause was associated with reduced disability risk (hazard ratio [HR] for 5‐year increase = 0.92; 95% CI = 0.87‐0.99; P =.02), while parity increased disability risk (HR for ≥3 vs 0 children = 1.53; 95% CI = 1.22‐1.93; P <.01). CONCLUSION: These findings show that early age at menopause and higher parity have a deleterious effect on motor function that persists in older people. J Am Geriatr Soc 68:585–594, 2020 [ABSTRACT FROM AUTHOR]

Background: Since the 2011 French guidance updates, cholinesterase inhibitors and memantine are considered optional in the management of dementia and leave physicians free to prescribe based on their clinical expertise. Objectives: The aims of this study were to analyze the influence of these recent guidance updates on the prescription rates of these drugs and to quantify the impact of potential changes on healthcare expenditures. Methods: Patients over 65 years old from a representative sample of a national administrative claims database, the French national health insurance database, were retrospectively included from 2006 to 2014. Trends of annual prescription rates were tested using adjusted segmented regression analysis. Drug costs with and without prescribers' behavioral changes were estimated. Results: A total of 119,731 individuals were included and followed during the study period. Among them, 5514 individuals were treated for dementia. According to the unadjusted segmented regression model, there was a significant increase in prescription rates between 2006 and 2010, from 2.23% (95% confidence interval 2.13-2.34) to 2.73% (95% confidence interval 2.62-2.84) of the study population. Since 2011, the trend has reversed with a significant decrease until 2014, from 2.64% (95% confidence interval 2.54-2.75) to 1.92% (95% confidence interval 1.84-2.01). In the multivariate analysis, we also found a gradual decline since 2011, particularly for patients aged 65-69 years and with one or more other chronic diseases. Cost savings associated with prescribers' behavioral changes were estimated at €108 million. Conclusion: Drugs prescribed for dementia are on a declining trend with important cost savings, and this was concomitant with guidance updates that left physicians to rely on their clinical expertise while managing dementia. [ABSTRACT FROM AUTHOR]

Objective: There are no estimates of the nationwide incidence of motor neuron disease (MND) in France. We used the French health insurance information system to identify incident MND cases (2012–2014), and compared incidence figures to those from three external sources.Methods: We identified incident MND cases (2012–2014) based on three data sources (riluzole claims, hospitalisation records, long-term chronic disease benefits), and computed MND incidence by age, gender, and geographic region. We used French mortality statistics, Limousin ALS registry data, and previous European studies based on administrative databases to perform external comparisons.Results: We identified 6553 MND incident cases. After standardisation to the United States 2010 population, the age/gender-standardised incidence was 2.72/100,000 person-years (males, 3.37; females, 2.17; male:female ratio = 1.53, 95% CI1.46–1.61). There was no major spatial difference in MND distribution. Our data were in agreement with the French death database (standardised mortality ratio = 1.01, 95% CI = 0.96–1.06) and Limousin ALS registry (standardised incidence ratio = 0.92, 95% CI = 0.72–1.15). Incidence estimates were in the same range as those from previous studies.Conclusions: We report French nationwide incidence estimates of MND. Administrative databases including hospital discharge data and riluzole claims offer an interesting approach to identify large population-based samples of patients with MND for epidemiologic studies and surveillance. [ABSTRACT FROM PUBLISHER]

Background: Use of antidepressants is seen to be a risk factor for type 2 diabetes, even though the underlying mechanisms remain unclear. We examined whether antidepressant use was associated with change in fasting plasma glucose, glycated haemoglobin (HbA1c), β-cell function (HOMA2-%B) and insulin sensitivity (HOMA2-%S) over time.Methods: Participants in the French D.E.S.I.R. cohort study included over 4700 men (48.1%) and women, free of diabetes, aged 30-65 years at baseline in 1994-96 (D.E.S.I.R. 0), who were followed for 9 years at 3-yearly intervals (D.E.S.I.R. 3, 1997-99; 6, 2000-02; 9, 2003-05). Antidepressant use, fasting plasma glucose, HbA1c, HOMA2-%B and HOMA2-%S were assessed concurrently at four medical examinations. Linear mixed models were used to examine the cross-sectional and longitudinal associations of time-dependent antidepressant use with changes in these four biological parameters.Results: Mean fasting plasma glucose and HbA1c increased whereas HOMA2-%B and HOMA2-%S decreased over the follow-up. In a fully adjusted model, there were no differences in: mean fasting plasma glucose (β = 0.01 mmol/l, P = 0.702); HbA1c (β = 0.01 %, P = 0.738); HOMA2-%B (β = 0.00, P = 0.812); or HOMA2-%S (β =-0.01, P = 0.791) at baseline (1994-96) between antidepressant users and non-users. The interaction term with time also suggested no differences in the annual change in: fasting plasma glucose (β = 0.00 mmol/l, P = 0.322); HbA1c (β = 0.00 %, P = 0.496); HOMA2-%B (β = 0.00, P = 0.609); or HOMA2-%S (β = 0.00, P = 0.332) between antidepressant users and non-users. Similar associations were observed in analyses of type and cumulative use of antidepressants over follow-up.Conclusion: Our longitudinal data show that use of antidepressants is not associated with altered glucose metabolism, suggesting that the association between antidepressant use and diabetes reported by previous studies may not be causal. Detection bias or clinical ascertainment bias may account for much of this apparent association. [ABSTRACT FROM AUTHOR]

BACKGROUND: Pesticides have been associated with Parkinson's disease (PD), but there are few data on important exposure characteristics such as dose--effect relations. It is unknown whether associations depend on clinical PD subtypes. OBJECTIVES: We examined quantitative aspects of occupational pesticide exposure associated with PD and investigated whether associations were similar across PD subtypes. METHODS: AS part of a French population-based case--control study including men enrolled in the health insurance plan for farmers and agricultural workers, cases with clinically confirmed PD were identified through antiparkinsonian drug claims. Two controls were matched to each case. Using a comprehensive occupational questionnaire, we computed indicators for different dimensions of exposure (duration, cumulative exposure, intensity). We used conditional logistic regression to compute odds ratios (ORs) and 95% confidence intervals (CIs) among exposed male farmers (133 cases, 298 controls). We examined the relation between pesticides and PD subtypes (tremor dominant/non-tremor dominant) using polytomous logistic regression. RESULTS: There appeared to be a stronger association with intensity than duration of pesticide exposure based on separate models, as well as a synergistic interaction between duration and intensity (p-interaction = 0.04). High-intensity exposure to insecticides was positively associated with PD among those with low-intensity exposure to fungicides and vice versa, suggesting independent effects. Pesticide exposure in farms that specialized in vineyards was associated with PD (OR = 2.56; 95% CI: 1.31, 4.98). The association with intensity of pesticide use was stronger, although not significantly (p-heterogeneity = 0.60), for tremor-dominant (p-trend < 0.01) than for non-tremor--dominant PD (p-trend = 0.24). CONCLUSIONS: This study helps to better characterize different aspects of pesticide exposure associated with PD, and shows a significant association of pesticides with tremor-dominant PD in men, the most typical PD presentation. [ABSTRACT FROM AUTHOR]

Pesticides are ubiquitous neurotoxicants, and several lines of evidence suggest that exposure may be associated with depression. Epidemiologic evidence has focused largely on organophosphate exposures, while research on other pesticides is limited. We collected detailed pesticide use history from farmers recruited in 1998–2000 in France. Among 567 farmers aged 37–78 years, 83 (14.6%) self-reported treatment or hospitalization for depression. On the basis of the reported age at the first such instance, we used adjusted Cox proportional hazards models to estimate hazard ratios and 95% confidence intervals for depression (first treatment or hospitalization) by exposure to different pesticides. The hazard ratio for depression among those who used herbicides was 1.93 (95% confidence interval (CI): 0.95, 3.91); there was no association with insecticides or fungicides. Compared with nonusers, those who used herbicides for <19 years and ≥19 years (median for all herbicide users, 19 years) had hazard ratios of 1.51 (95% CI: 0.62, 3.67) and 2.31 (95% CI: 1.05, 5.10), respectively. Similar results were found for total hours of use. Results were stronger when adjusted for insecticides and fungicides. There is widespread use of herbicides by the general public, although likely at lower levels than in agriculture. Thus, determining whether similar associations are seen at lower levels of exposure should be explored. [ABSTRACT FROM PUBLISHER]

The incidence and mortality of motor neuron disease (MND) increase with age and appear to have increased with time. The examination of period and cohort effects using age-period-cohort (APC) models can help characterize temporal trends. Our objective was to describe mortality from MND in France (1968-2007), and to examine the role of age, period of death, and birth-cohort on changes in mortality. The number of people who died from MND and population statistics (1968-2007) were extracted from French national records. Annual standardized (age/sex) mortality ratios (SMRs) were computed. Using Poisson regression, APC models examined the relationship between mortality rates and age, period of death, and birth-cohort in subjects aged 40-89 years. Deviance/degrees-of-freedom ratios evaluated model fit; ratios close to one indicated adequate fit. Between 1968 and 2007, 38,863 individuals died from MND (mortality rate = 1.74/100,000); 37,624 were aged 40-89 years. SMRs increased from 54 (95% CI = 49-59) in 1968 to 126 (120-132) in 2007. Male-to-female ratios declined from 1.80 in 1968 to 1.45 in 2007. Changing mortality rates were best explained by cohort effects (deviance/degrees-of-freedom = 1.09). The relative risk of dying from MND increased markedly for persons born between 1880 and 1920, and more slowly after 1920. In conclusion, mortality rates for MND increased between 1968 and 2007, and more rapidly in women than men. This increase was better explained by the birth-cohort of individuals than by period effects. Changing environmental exposures may be a possible explanation and these findings warrant the continued search for environmental risk factors for MND. [ABSTRACT FROM AUTHOR]

Drug claims databases are increasingly available and provide opportunities to investigate epidemiologic questions. The authors used computerized drug claims databases from a social security system in 5 French districts to predict the probability that a person had Parkinson's disease (PD) based on patterns of antiparkinsonian drug (APD) use. Clinical information for a population-based sample of persons using APDs in 2007 was collected. The authors built a prediction model using demographic variables and APDs as predictors and investigated the additional predictive benefit of including information on dose and regularity of use. Among 1,114 APD users, 320 (29%) had PD and 794 (71%) had another diagnosis as determined by study neurologists. A logistic model including information on cumulative APD dose and regularity of use showed good performance (c statistic = 0.953, sensitivity = 92.5%, specificity = 86.4%). Predicted PD prevalence (among persons aged ≥18 years) was 6.66/1,000; correcting this estimate using sensitivity/specificity led to a similar figure (6.04/1,000). These data demonstrate that drug claims databases can be used to estimate the probability that a person is being treated for PD and that information on APD dose and regularity of use improves models’ performances. Similar approaches could be developed for other conditions. [ABSTRACT FROM PUBLISHER]

The article presents insights on a meta-analysis of studies which examined the link between Parkinson's disease (PD) and pesticide exposure in France. Topics covered include the occurrence of cases of Parkinsonism following intravenous injection of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), the main limitation of the studies and the discovery of an association with some organochlorine insecticides.

Walking speed (WS) represents an objective measure of motor function and health. We aimed to develop usual (UWS) and fast WS (FWS) norms for the general population using a regression-based approach, while considering age, sex, height, and education. Cross-sectional analysis of a population-based study. French Constances study (45-69 years). UWS/FWS were measured over 3 m (dynamic start) using photoelectric cells. We addressed selection effects (related to survey sampling and nonresponse) and missing data using a combination of inverse probability weighting (IPW) and multiple imputation (MI). Norms by sex, age, height, and education (

The article presents a prospective cohort study which investigated the relationship between slow walking speed and cardiovascular death in older people living in the community in Dijon, France. The study population, who were recruited from 1999 to 2001, involved nursing home residents between the ages of 65 to 85. Medical history of the patients include Parkinson's disease, dementia and disabling stroke. An overview of the research findings is presented. Also noted are bias, confounding and other reasons for caution.

Objective: To examine the relationship between a Parkinson's disease (PD) polygenic risk score (PRS) and impulse control disorders (ICDs) in PD.Background: Genome wide association studies (GWAS) have brought forth a PRS associated with increased risk of PD and younger disease onset. ICDs are frequent adverse effects of dopaminergic drugs and are also more frequent in patients with younger disease onset. It is unknown whether ICDs and PD share genetic susceptibility.Methods: We used data from a multicenter longitudinal cohort of PD patients with annual visits up to 6 years (DIG-PD). At each visit ICDs, defined as compulsive gambling, buying, eating, or sexual behavior were evaluated by movement disorders specialists. We genotyped DNAs using the Megachip assay (Illumina) and calculated a weighted PRS based on 90 SNPs associated with PD. We estimated the association between PRS and prevalence of ICDs at each visit using Poisson generalized estimating equations, adjusted for dopaminergic treatment and other known risk factors for ICDs.Results: Of 403 patients, 185 developed ICDs. Patients with younger age at onset had a higher prevalence of ICDs (p < 0.001) as well as higher PRS values (p = 0.06). At baseline, there was no association between the PRS and ICDs (overall, p = 0.84). The prevalence of ICDs increased over time similarly across the quartiles of the PRS (overall, p = 0.88; DA users, p = 0.99).Conclusion: Despite younger disease onset being associated with both higher PRS and ICD prevalence, our findings are not in favor of common susceptibility genes for PD and ICDs. [ABSTRACT FROM AUTHOR]

Background: The benefit of ideal cardiovascular health (CVH) on health-related outcomes in middle-aged patients is firmly established. In the growing elderly population, the high prevalence of comorbidities and medications for chronic diseases may offset such benefit.Objectives: This study analyzed the association of ideal CVH with mortality, incident coronary heart disease, and stroke events in elderly individuals from the community.Methods: Between 1999 and 2001, 9,294 men and women, noninstitutionalized and aged 65 years and over were examined, and thereafter followed up for the occurrence of vascular events and mortality within the Three-City Study. Hazard ratios (HRs) were estimated by Cox proportional hazard model and compared subjects with 3 to 4 and subjects with 5 to 7 ideal metrics with those with 0 to 2 ideal metrics, respectively.Results: The mean age was 73.8 ± 5.3 years, and 36.7% were men. Only 5% of the participants had ≥5 metrics at the ideal level. After a median follow-up of 10.9 years and 8.6 years, respectively 1,987 deaths and 680 adjudicated coronary heart disease or stroke events had occurred. In multivariate analysis, the risk of mortality and of vascular events decreased across the categories of ideal metrics. In particular, in subjects with ≥5 metrics at the ideal level (compared with those with ≤2), there was a 29% (hazard ratio [HR]: 0.71; 95% confidence interval [CI]: 0.55 to 0.90) decreased risk of all-cause mortality and 67% (HR: 0.33; 95% CI: 0.19 to 0.57) for coronary heart disease and stroke combined (p for trend <0.001).Conclusions: Even in the elderly, higher CVH status is highly beneficial regarding mortality and vascular event risks. [ABSTRACT FROM AUTHOR]

Background Vitamin D is thought to contribute to brain health, but it is unclear whether low vitamin D levels are associated with increased incidence of Parkinson's disease (PD). Using ultraviolet B (UV-B) as a surrogate for vitamin D levels, we conducted a nationwide ecologic study in France in order to examine the association of UV-B with PD incidence. Methods We used French national drug claims databases to identify PD cases using a validated algorithm. UV-B data from the solar radiation database were derived from satellite images. We estimated PD incidence (2010–2012) at the canton level (small administrative French unit) and used multilevel Poisson regression to examine its association with UV-B (2005 annual average), after adjustment for age, sex, deprivation index, density of neurologists, smoking, proportion of agricultural land, and vitamin D supplementation. Results Analyses are based on 69,010 incident PD patients. The association between UV-B and PD incidence was quadratic (P<0.001) and modified by age (P<0.001). Below 70y, incidence was higher in the bottom quintile (relative risk, RR Q1:45-49y =1.18, 95% CI=1.08–1.29) compared with the middle UV-B quintile, and lower in the top quintile (RR Q5:45-49y =0.85 [0.77–0.94]). An opposite pattern was observed in older subjects (RR Q1:85-89y =0.92 [0.89–0.96]; RR Q5:85-89y =1.06 [1.02–1.11]). Analysis based on continuous UV-B yielded similar conclusions. Conclusions In this nationwide study, there was an age-dependent quadratic association between UV-B and PD incidence. This study suggests that reasonable UV-B exposure is associated with lower PD risk in younger persons and that future studies should examine dose-response relations and take age into account. [ABSTRACT FROM AUTHOR]

Abstract: Levodopa induces long-term motor complications in Parkinson’s disease (PD). Therapeutic strategies that prevent motor complications are needed. Our aim was to evaluate the impact of recommendations of a French consensus conference published in 2000 on initial PD therapy. We identified 308 PD patients as part of a population-based study performed within the Mutualité Sociale Agricole in five French districts (2007). Neurologists confirmed PD diagnosis. We compared initial therapy in 102 patients treated before 12/31/2000 to that of 206 patients treated afterwards. Initial treatment was in agreement with the recommendations if dopamine agonists were used in patients <60 years (n = 49) and levodopa in patients ≥70 years (n = 133). Agreement with the recommendations increased after 2000 (66.0%) compared to before (46.3%, p = 0.025). For patients <60 years, agreement increased (64.0% vs 20.2%, p = 0.017) while it remained stable (66.4% vs 70.6%, p = 0.73) in patients ≥70 years. The publication of recommendations has influenced initial treatment choices for PD in France. [Copyright &y& Elsevier]

Previous studies showed positive associations between milk intake and Parkinson's disease (PD) in men but not in women, but few studies were available in women. Due to the long prodromal PD phase, reverse causation represents a major threat to investigations of diet in PD; cohort studies with a long follow-up are needed. We investigated associations between intake of milk and other dairy products with PD incidence in women from the E3N cohort study (1993-2018). PD diagnoses were validated using medical records and drug claim databases. Diet was assessed via a dietary questionnaire. Hazard ratios (HR) were estimated using multivariable Cox regression models. Exposures were lagged by 5y in main analyses and longer lags in sensitivity analyses. We examined the impact of adjustment for premotor symptoms (constipation/depression). During a mean follow-up of 18.8y, 845 of 71,542 women developed PD. Main analyses showed a J-shaped association between total milk intake and PD (P-non linearity = 0.045), with a significant linear positive association among drinkers (HR/1-SD = 1.09, 95% CI = 1.01-1.18, P = 0.024), that was explained in secondary analyses by a different pattern of association for plain milk (alone or with cereals) and milk added to drinks (tea/coffee/chicory). PD incidence increased significantly with plain milk consumption (HR/1-SD = 1.08 [1.02-1.14], P = 0.014). A U-shaped relation was observed for milk added to drinks (P-non linearity = 0.038), with lower PD incidence in women with moderate consumption (HR = 0.77 [0.61-0.97], P = 0.030) and no difference between non-drinkers and those with the highest consumption (HR = 0.98 [0.79-1.21], P = 0.848). Findings were similar in analyses using longer lags and adjusted for constipation/depression. Consumption of other dairy products was not associated with PD. A J-shaped association between total milk intake and PD was explained by a different pattern of association for plain milk intake and milk added to drinks. Reverse causation is unlikely to explain a positive association of plain milk with PD incidence in women. The U-shaped relation for milk added to drinks could be explained by an interaction between milk and coffee/tea/chicory. Further studies are warranted to elucidate the underlying mechanisms., (© 2024. Springer Nature B.V.)

Background: Exposure assessment represents a major challenge for studies on the relation between pesticides and health., Objective: We developed a method combining information from crop-exposure matrices (CEMs) and land use data, in order to compute indices of environmental and occupational pesticide exposure. We illustrate our approach using French data (1979-2010)., Methods: We used CEMs for five crops (straw cereals, grain corn, corn fodder, potatoes, vineyards) that describe use (annual probability, frequency, intensity) of pesticide subgroups, chemical families, and active substances by region and time since 1960. We combined these data with land use data from agricultural censuses (1979, 1988, 2000, 2010) to compute indices of environmental and occupational pesticide exposure in cantons (small French administrative units). Indices of environmental exposure were calculated based on the area of each crop in the cantons, while indices of occupational exposure depended on combinations of crops in each farm from the cantons. To illustrate our approach, we selected a pesticide group (herbicides), chemical family of herbicides (phenoxyacetic acids), and active substance from the phenoxyacetic acids chemical family (2,4-D)., Results: The estimated proportion of the area of crops with CEMs and of farms sprayed with herbicides was close to 100% between 1979-2010, but the estimated average annual number of applications increased. There were decreasing time-trends for phenoxyacetic acids and 2,4-D over the same period for all indices of exposure. There was a high use of herbicides throughout France in 2010, except in the South coast. For phenoxyacetic acids and 2,4-D, the spatial distribution was heterogeneous for all indices of exposure, with the highest values in the Centre and North regions., Impact Statement: Assessment of pesticide exposure is a key issue for epidemiological studies on their association with health outcomes. However, it presents some unique challenges, particularly for retrospective exposure and the investigation of chronic diseases. We present a method to compute indices of exposure by combining information from crop-exposure matrices for five crops and land use data. Specificities of environmental and occupational exposure are addressed using different methods. These methods are applied to pesticides used in agriculture in France for five crops (3 groups, 91 chemical families, 197 active substances) to produce indices at a small geographic scale from 1979 to 2010 for the whole metropolitan France. Besides using these indices in French epidemiological studies, our approach could be relevant for other countries., (© 2023. The Author(s), under exclusive licence to Springer Nature America, Inc.)

Objective: The objective of this study was to evaluate the association between occupational exposure to solvents and cognitive performance in middle-aged and early-ageing participants, taking into account the working environment., Methods: In the French Cohorte des consultants des Centres d'examens de santé (CONSTANCES) cohort, 41 854 participants aged 45- 69 years completed a self-reported, lifetime occupational exposure questionnaire. Exposure to solvents (gasoline for hand washing, trichloroethylene, white spirit, cellulosic thinner) was first considered as a binary variable (exposed/not exposed). We computed number of solvent types to which participants were exposed, solvent exposure time and delay since last exposure. Cognitive performance was assessed and analysed in reference to norms of neuropsychological battery previously established in CONSTANCES according to age, sex and education. Multiple linear and modified Poisson regression were used to estimate the associations between solvent exposure and cognitive performance adjusting for individual and environmental characteristics, and working conditions (night shift, repetitive and noisy work)., Results: Men had a greater risk of global cognitive impairment when they were exposed to gasoline (relative risk (RR)=1.12, 95% CI 1.03 to 1.22), white spirit (RR=1.14, 95% CI 1.05 to 1.25) or cellulosic thinner (RR=1.17, 95% CI 1.06 to 1.31) at the workplace, even after adjusting for confounders. Women exposed to white spirit or exposed for more than 20 years had poorer global cognitive performance., Conclusion: These findings strengthen our understanding of the detrimental effect of solvent exposure on cognitive health not only in men but also in women for the first time, in a large general population middle-aged and early-ageing sample from France, taking into account working conditions., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2020. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Objectives: Previous studies have reported controversial findings regarding the association of testosterone with mortality in older men. This heterogeneity might be partially explained by comorbidities and the presence of metabolic syndrome, as well as differential associations according to causes of death., Methods: We used data from a random subsample of the Three-City study, in which hormone levels were measured in 338 men ≥65 years without metabolic syndrome who were followed-up for 12 years. Vital status was determined for all participants from different sources. We used inverse-probability-weighted Cox regression to estimate the hazard ratios (HRs) of cause-specific mortality and 95% confidence intervals (CIs)., Results: Over the follow-up period, 130 men died (30 from cardiovascular disease, 45 from cancer, 55 from other causes). The association of testosterone with mortality showed significant heterogeneity across causes of death (p=0.027 and p=0.022 for total and bioavailable testosterone, respectively). Higher testosterone levels were associated with increased cardiovascular mortality (HR for 1-standard deviation increase, 1.86; 95% CI, 1.28 to 2.71 and 1.50; 95% CI, 1.04 to 2.17 for total and bioavailable testosterone, respectively). By contrast, there were no significant associations of testosterone with mortality from cancer and other causes., Conclusions: Our data suggest that the association of testosterone with mortality in men without metabolic syndrome might be differential according to the cause of death. These findings may partially explain the heterogeneity across studies on the relationship between testosterone levels and mortality.

Objective: The objective was to evaluate the association between restless legs syndrome (RLS) with generalized anxiety disorder (GAD), major depression disorder (MDD), dysthymia, and GAD-depression comorbidity. Secondary aims were to examine the association between RLS with the cognitive-affective and somatic-vegetative disturbances experienced as part of depression and GAD., Methods: This was a cross-sectional study of 1493 elderly participants (median age 80.6 years, 64% women) from Dijon, France. Probable RLS was assessed using the minimal diagnostic criteria of the International Restless Legs Study Group and RLS symptom frequency and treatment. Participants underwent structured interviews for MDD, dysthymia, and GAD. Participants also completed the Center for Epidemiological Studies-Depression scale (CES-D). The association between RLS and psychiatric disorders, their criterion symptoms, or symptom factors was examined using logistic regression., Results: The point prevalence of probable RLS in this sample was 8.2%. Probable RLS was associated with isolated GAD (odds ratio [OR] 2.17, 95% confidence interval [CI] 1.01-4.68) and comorbid GAD-any depression disorder (OR 3.26, 95% CI 1.14-9.29), but not MDD or dysthymia. Probable RLS was also associated with the GAD criterion worry most days and feeling tense, and the CES-D factors representing depressed affect, somatic symptoms, and positive affect., Conclusions: Probable RLS was associated with GAD-depression comorbidity as well as isolated GAD. The findings challenge previous reports linking RLS solely with MDD, suggesting the association is partly driven by GAD-depression comorbidity., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Background: Previous studies on the number of Parkinson's disease (PD) patients in the future based on projections of population size underestimated PD burden because they did not take into account the improvement of life expectancy over time., Objective: The objective of this study was to assess PD progression from 2010 to 2030 in France in terms of prevalent patient numbers, prevalence rates, lifetime risk, and life expectancy with PD, accounting for projections of overall mortality and increased risk of death of PD patients., Methods: To provide projections of PD burden, we applied a multistate approach considering age and calendar time to incidence and prevalence rates of PD (France 2010) based on drug claims and national demographic data., Results: The number of PD patients will increase by ∼65% between 2010 (n = 155,000) and 2030 (n ∼ 260,000), mainly for individuals older than 65 years; the prevalence rate of PD after age 45 will increase from 0.59% in 2010 to ∼0.80% in 2030. We project an extension of ∼3 years of the life expectancy of PD patients at 65 years between 2010 (women, 14.8 years; men, 13.0 years) and 2030 (women, 17.8 years; men, 16.1 years), and a relative increase of about 10% of the lifetime risk of PD at 45 years between 2010 (women, 5.5%; men, 6.0%) and 2030 (women, 6.3%; men, 7.4%)., Conclusions: The number of PD patients is predicted to grow substantially in future years as a consequence of population aging and life expectancy improvement. The assessment of the future PD burden is an important step for planning resources needed for patient care in aging societies. © 2018 International Parkinson and Movement Disorder Society., (© 2018 International Parkinson and Movement Disorder Society.)

Objective: To examine the relation of age with male-to-female (M/F) ratios and incidence rates of motor neuron disease (MND) in a French nationwide study and meta-analysis of incidence studies., Methods: We used data from the French National Health Insurance databases. Patients with incident MND (2010-2014) were identified based on drug claims (riluzole), hospitalization records, death records, and long-term chronic disease benefits. We estimated age-specific M/F incidence ratios using Poisson regression. Poisson, Gompertz, and multistep models were used to model the relation between age and incidence. We performed a meta-analysis (n = 28 studies) and used meta-regression to examine the relation of age with incidence rates and ratios., Results: In France, we identified 10,848 patients with incident MND (6,021 men, 4,827 women). Incidence was higher in men than in women in all age groups. M/F ratios were significantly different across age groups and followed a quadratic trend ( p < 0.001). Between 20 and 49 years, the average M/F ratio was 2.26 (95% confidence interval [CI] = 1.96-2.62); it was 1.41 (95% CI = 1.35-1.47) between 50 and 84 years, and 1.88 (95% CI = 1.64-2.17) after 85 years. Incidence was lower in women than men at younger ages, but increased more steeply in women than men. Similar patterns were observed in the meta-analysis of incidence studies, especially in 19 higher-quality studies., Conclusion: The relation between age and M/F incidence ratios of MND follows a quadratic U-shaped pattern with an abrupt drop after the fifth decade. The change in M/F ratios before and after menopause suggests that reproductive/hormonal protective factors have a role in women and should prompt further studies to explore this hypothesis., (© 2018 American Academy of Neurology.)

Background: Parkinson's disease (PD) is 1.5 times more frequent in men than women. Whether age modifies this ratio is unclear. We examined whether male-to-female (M-F) ratios change with age through a French nationwide prevalence/incidence study (2010) and a meta-analysis of incidence studies., Methods: We used French national drug claims databases to identify PD cases using a validated algorithm. We computed M-F prevalence/incidence ratios overall and by age using Poisson regression. Ratios were regressed on age to estimate their annual change. We identified all PD incidence studies with age/sex-specific data, and performed a meta-analysis of M-F ratios., Results: On the basis of 149 672 prevalent (50% women) and 25 438 incident (49% women) cases, age-standardised rates were higher in men (prevalence=2.865/1000; incidence=0.490/1000 person-years) than women (prevalence=1.934/1000; incidence=0.328/1000 person-years). The overall M-F ratio was 1.48 for prevalence and 1.49 for incidence. Prevalence and incidence M-F ratios increased by 0.05 and 0.14, respectively, per 10 years of age. Incidence was similar in men and women under 50 years (M-F ratio <1.2, p>0.20), and over 1.6 (p<0.001) times higher in men than women above 80 years (p trend <0.001). A meta-analysis of 22 incidence studies (14 126 cases, 46% women) confirmed that M- F ratios increased with age (0.26 per 10 years, p trend=0.005)., Conclusions: Age-increasing M-F ratios suggest that PD aetiology changes with age. Sex-related risk/protective factors may play a different role across the continuum of age at onset. This finding may inform aetiological PD research., (Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/)

Obesity, whose prevalence is increasing, is associated with poor functional status at older ages. However, much of this evidence is cross-sectional with little known about longitudinal associations. We examined associations of body mass index (BMI), and change in BMI, with change in objective [walking speed (WS)] and self-reported (disability) measures of motor decline. Analyses included participants (65-85 years) from the Dijon center of the Three-City study (France) with up to five WS (N = 4007) and six disability assessments (N = 4478) over 11 years. Data were analyzed using regression models for repeated measures. Mean baseline WS was 153 cm/s. Compared to normal weight persons, obese participants at baseline walked slower and reported more disability; they also experienced 45% faster WS decline (-18.63 vs. -12.85 cm/s/10 years, P = 0.002). Participants who lost or gained weight had 47% (-18.85 cm/s/10 years, P < 0.001) and 33% (-17.08 cm/s/10 years, P = 0.002) respectively greater WS decline than participants in the normal BMI change category. 24% of participants reported disability at least once during the follow-up, those who lost or gained weight had a 1.63 and 1.34 respectively higher odds of disability than participants in the normal BMI change category (P = 0.001). Associations remained after adjustment for covariates. In conclusion, obesity is associated with worse motor performances, a higher risk of disability, and faster motor decline. Our results underline the interest of repeated BMI and motor assessments to identify those at higher risk of disability.

Background: Restless legs syndrome has been speculated to be linked to cognitive impairment through vascular risk factors or through its effect on sleep deprivation. Previous studies on the association between restless legs syndrome and cognitive function have been inconclusive. We performed a cross-sectional analysis of the association between restless legs syndrome and cognitive function using data from a large population-based study of elderly individuals residing in France., Methods: We used information from 2070 individuals from the Dijon, France center of the Three-City study who had available information on restless legs syndrome and cognitive functioning measures. Restless legs syndrome was assessed using the 4 minimal diagnostic criteria of the International Restless Legs Study Group. During the same wave in which restless legs syndrome status was assessed, cognitive functions also were assessed using 4 tests: Isaacs' test of verbal/category fluency, the Benton Visual Retention Test, the Trail Making Test B, and the Mini-Mental State Examination. We created a summary global cognitive score by summing the z scores for the 4 tests and used analysis of covariance to explore the association between restless legs syndrome and cognitive function., Results: We did not observe any statistically significant differences in any cognitive z-score between those with restless legs syndrome and those without restless legs syndrome. The mean global z-score after multivariate adjustment was -0.003 (SE 0.173) for those with restless legs syndrome and -0.007 (SE 0.129) for those without restless legs syndrome (P-value = .98)., Conclusion: Data from this large, population-based study do not suggest that restless legs syndrome is associated with prevalent cognitive deficits in elderly individuals., (Copyright © 2015 Elsevier Inc. All rights reserved.)

Objectives: To determine whether fast gait speed at study baseline and change in gait speed had independent associations with disability onset., Design: Cohort study with 11-year follow-up (1999-2010)., Setting: Three-City Study center, Dijon, France., Participants: Community-dwelling individuals aged 65 to 85 (N = 3,814, 61% female)., Measurements: Fast gait speed (over 6 m) was assessed up to five times and disability (mobility (Rosow-Breslau scale), instrumental activities of daily living (IADLs; Lawton-Brody scale), basic activities of daily living (ADLs; Katz scale)) six times. A hierarchical disability indicator was constructed; participants were considered disabled if they reported difficulties with mobility and IADLs or with mobility, IADLs, and ADLs. The association between baseline fast gait speed and its slope of change and disability incidence was examined using joint models for longitudinal and time-to-event data., Results: Over follow-up, 628 participants (68% women) developed disability. Mean fast gait speed at baseline was 1.54 m/s, and annual decline was 0.017 m/s. The hazard ratio of disability per standard deviation (SD) (-0.22 m/s) slower baseline fast gait speed was 1.77 (95% confidence interval (CI) = 1.60-1.94) and for one-SD (-0.013 m/s) faster annual decline was 1.38 (95% CI = 1.10-1.73) when both parameters were included in a sex- and age-adjusted model. All associations remained statistically significant in multivariable models, except for slope of change when chronic conditions were added to the model; of chronic conditions, dyspnea was the main contributor., Conclusion: Accelerated decline in fast gait speed was associated with disability independent of baseline fast gait speed. These results confirm the importance of measuring gait speed repeatedly in elderly adults to identify those at higher risk of disability and the need to identify determinants of decline, because they are likely to be targets for prevention and treatment to reduce disability risk., (© 2015, Copyright the Authors Journal compilation © 2015, The American Geriatrics Society.)

Background: Vascular risk factors contribute to motor decline in the elderly persons. We investigated the relationship between lipid-lowering drugs (LLDs) use and decline in walking speed (WS) in older adults., Methods: Data on 4,009 community-dwelling men and women, aged ≥65 years at baseline, are drawn from the Dijon (France) center of the Three-City study. "Fast" WS was assessed over 6 m at baseline and at 4, 6, 8, and 10 years of follow-up. Mixed linear models were used to determine the relationship between LLDs and change in WS over the follow-up., Results: At baseline, 1,295 (32%) participants used LLDs (statins, n = 643; fibrates, n = 652); mean fast WS was 152.9cm/s and not significantly different between LLDs users and nonusers. In models adjusted for age, sex, cholesterol level, and other covariates, WS decline was 25% slower in LLDs users (difference with nonusers: 0.58cm/s/y, 95% CI: 0.30, 0.86; p < .001). Both fibrates and statins were associated with slower decline, but only the effect of statins was robust in analyses that took missing values into account. The beneficial effect was more pronounced in those on LLDs continuously over the follow-up., Conclusion: Fast WS declined less in those on LLDs, suggesting that the effect of LLDs, statins in particular, extend beyond that on cardiovascular disease in the elderly persons. However, these effects were modest and their clinical relevance is unclear.

Objective: The reserve hypothesis accounts for the lack of direct relationship between brain pathology and its clinical manifestations. Research has mostly focused on cognition; our objective is to examine whether the reserve hypothesis applies to motor function. We investigated whether education, a marker of reserve, modifies the association between white matter lesions (WMLs), a marker of vascular brain damage, and maximum walking speed (WS), an objective measure of motor function. We also examined the cross-sectional and longitudinal association between education and WS., Methods: Data are from 4,010 participants aged 65-85 years in the longitudinal Three-City-Dijon Study with up to 4 WS measures over 10 years. We examined the interaction between education and WMLs for baseline WS. We studied the association between education and repeated WS measures using linear mixed models, and the role of covariates in explaining the education-WS association., Results: Education was strongly associated with baseline WS; the difference in mean WS between the high and low education groups (0.145 m/s, 95% confidence interval = 0.125-0.165) was equivalent to 7.4 years of age. WMLs were associated with slow WS only in the low education group (p interaction = 0.026). WS declined significantly over time (-0.194 m/s/10 years, 95% confidence interval = -0.206, -0.182), but education did not influence rate of decline. Anthropometric characteristics, parental education, general health, and cognition had the strongest role in explaining the baseline education-WS association., Conclusions: Participants with more education were less susceptible to WMLs' effect on motor function. Higher education was associated with better motor performances but not with motor decline. These results are consistent with the passive reserve hypothesis.

Incidence of dementia increases sharply with age and, because of the increase in life expectancy, the number of dementia cases is expected to rise dramatically over time. Some studies suggest that controlling some modifiable risk factors for dementia like diabetes or hypertension could lower its incidence. However, as treating these vascular factors would also reduce mortality risk, the actual impact of such public-health intervention on dementia prevalence is not known. Accounting for the impact of dementia and risk factors on mortality, the aim of this work was (1) to compute projections of age- and-sex specific prevalence of dementia in France from 2010 to 2030, (2) to evaluate how public-health interventions targeting risk factors for dementia could change these projections. Age-and-sex specific incidence of dementia and mortality of demented subjects were estimated from the Paquid population-based cohort using a semi-parametric illness-death model. Future global mortality rates and population sizes were obtained from national demographic projections. Under the assumption that life expectancy will increase by 3.5 years for men and 2.8 years for women by 2030, the number of subjects with dementia was estimated to increase by about 75% from 2010 to 2030 with a 200% increase after 90 years of age. Therapeutic intervention on the whole population reducing high blood pressure prevalence would lead to a decrease in both dementia incidence rates and mortality and would have a modest impact on the number of dementia cases. On the other hand, a preventive dementia treatment targeting ApoE4 carriers would probably not improve survival and hence would decrease dementia prevalence by 15-25%.

Objective: To describe the clinical features at first evaluation that best predict survival of the amyotrophic lateral sclerosis (ALS) population from the Salpêtrière Hospital between 1995 and 2009., Methods: Data are collected and entered into a clinical database from all patients seen at the Paris ALS Center. Variables analyzed were demographic and baseline information, strength testing (manual muscle testing; 1995-2009), the revised ALS Functional Rating Scale (ALSFRS-R; 2002-2009) and survival status. The χ(2) test and ANOVA assessed differences in variables by region and across time period. Univariate and multivariate Cox proportional hazards models determined which variables best predicted survival. Flexible modeling of continuous predictors (splines) assessed trends in survival for different variables., Results: 3,885 patients with ALS were seen in 1995-2009, of whom 2,037 had ALSFRS-R scores. Age, weight, strength, and site of onset varied by region of residence. The proportion of patients living outside Paris, the time to first visit, patient age, and motor function differed across time periods. In Cox models, site of onset, time to first visit greater than 18 months, strength and the year of visit after 2006 predicted survival (all p values <0.0001). Compared to patients first seen between 1999 and 2002, the hazard ratio of death was 1.04 (95% CI = 0.95-1.14) for 2003-2006, and 0.76 (95% CI = 0.66-0.87) after 2006, while adjusting for other predictors of survival. The use of noninvasive ventilation increased during 2004-2008 from 16 to 51% of patients., Conclusions: Older age, bulbar onset, shorter delay to first visit and poor motor function at first visit predicted shorter survival rates in this large center-based sample from France, showing marked consistency across time and region of residence. Survival improved after 2006, concurrent with increasing rates of noninvasive ventilation use. Clinicopathologic correlation could better define subgroups, but identification of etiologies may be needed to elucidate individual forms of ALS with unique survival patterns., (Copyright © 2012 S. Karger AG, Basel.)

Objective: Neuroleptics and neuroleptic-like drugs are known to induce parkinsonism, which may reveal underlying Parkinson disease (PD) in some cases. We assessed the long-term risk of developing PD after past exposure to these drugs, in a 15-year prospective population-based elderly cohort study., Methods: We used the Cox proportional hazards model to assess the relation between past exposure to neuroleptics and the risk of developing incident PD. All incident cases of parkinsonism were identified by standardized procedure and validated by a committee of experts., Results: Of 2,991 subjects followed, 117 developed parkinsonism and 43 developed probable PD during follow-up, of whom 22.2% and 32.6%, respectively, had been exposed to neuroleptics, compared to 16.6% for subjects without parkinsonism. About a third of subjects presented transient parkinsonism during drug exposure. After adjustment for gender and past occupation, past exposure to neuroleptics was associated with incident PD (relative risk, 3.16; 95% confidence interval [CI], 1.65-6.04). The relative risk was 3.65 (95% CI, 1.41-9.45) for benzamides and 2.59 (95% CI, 1.23-5.43) for phenothiazines. The population-attributable fraction of the risk for developing PD was 8.2% for benzamides and 12.2% for phenothiazines., Conclusions: In a French elderly cohort, the risk of probable PD was increased by 3.2-fold after exposure to neuroleptics. This finding suggests the necessity of limiting the use of such drugs in elderly people.

The aim of this work was to determine whether survival changed during 2002-2009 at a French amyotrophic lateral sclerosis (ALS) center. We included all patients with ALS who were seen consecutively at the center from January 2002-May 2009. Participants were followed from date of first visit through death, date of censoring, or December 31, 2009, whichever occurred first. Cox proportional hazard models computed hazard ratios (HR; 95% confidence interval CI) of death, and flexible modeling of continuous predictors (splines) assessed trends in survival. We analyzed a total of 2,037 ALS patients, of whom 1,471 died before the end of follow-up. Median survival was 2.83 years from onset and 1.65 years from first visit. Compared to patients first seen before 2004, the HR of death was 0.97 (95% CI = 0.85-1.11, p = 0.6721) for patients first seen in 2004-2005, 0.96 (95% CI = 0.83-1.10, p = 0.5125) for 2006-2007, and 0.56 (95% CI = 0.46-0.69, p < 0.0001) after 2007, while adjusting for other survival predictors. Spline analysis confirmed that survival remained stable during 2002-2006, then markedly improved. The proportion of patients receiving non-invasive ventilation (NIV) increased from 16 (2004) to 51% (2008). At this large ALS center, survival improved after 2006. Because more aggressive use of NIV was the principal therapeutic adaptation, our data suggest that better survival resulted from improved respiratory care.

Two genome-wide association studies (GWASs) recently highlighted the HLA-DRA and HLA-DRB5 genes as associated with Parkinson disease (PD). However, because HLA-DRA displays a low level of polymorphisms and HLA-DRB5 is only present in approximately 20% of the population, these findings are difficult to interpret. Our aims were: (1) to replicate and investigate in greater detail the association between PD and the HLA-DR region; (2) to identify PD-associated HLA alleles; and (3) to perform a meta-analysis of our top finding. As part of 2 French population-based case-control studies of PD including highly ethnically homogeneous participants, we investigated the association between PD and 51 Single-nucleotide polymorphisms (SNPs) in the HLA-DR region. HLA-DRB1 alleles were imputed using the HLA(*) IMP software. HLA typing was performed in a subsample of the participants. We performed a meta-analysis of our top finding based on 4 GWAS data sets. Among 499 cases and 1123 controls, after correction for multiple testing, we found an association with rs660895 (OR/minor allele, 0.70; 95% CI, 0.57-0.87) within the HLA-DRB1 gene, which encodes the most polymorphic HLA-DR chain (DRβ). A meta-analysis (7996 cases, 36455 controls) confirmed this association (OR, 0.86; 95% CI, 0.82-0.91; P < .0001). SNP-based imputation of HLA alleles showed an inverse association between PD and the HLA-DRB1(*) 04 allele. We replicated an association between PD and the HLA-DR region and provided further insight into the loci and alleles involved. The highly polymorphic HLA-DRB1 locus contains rs660895, which represents a more legitimate candidate than previous ones. Our finding is in agreement with the hypothesis of an immune component in PD pathophysiology., (Copyright © 2012 Movement Disorder Society.)

Retrospective assessment of pesticide exposure is complex; however, patterns of pesticide use strongly depend on farming type, which is easier to assess than pesticide exposure. Our aim was to estimate Parkinson's disease (PD) prevalence in five French districts in 2007 among affiliates of Mutualité Sociale Agricole (MSA) and to investigate the relation between PD prevalence and farming type. We identified PD cases from administrative files as persons who used levodopa and/or benefited from free health care for PD. Densities of 16 farming types were defined at the canton of residence level (1988 French agricultural census). We used logistic regression to study the relation between PD prevalence and density of farming types and a semi-Bayes approach to deal with correlated exposures. We identified 1,659 PD cases, yielding an age- and sex-standardized PD prevalence of 3.01/1,000. Prevalence increased with age and was higher in men than women. We found a higher PD prevalence among affiliates living in cantons characterized by a higher density of farms specialized in fruits and permanent crops (multivariable semi-Bayes model: OR(4+5 vs 1+2+3 quintiles) = 1.21, 95% CI = 1.08-1.36; test for trend, P = 0.035). In France, farms specialized in fruits and permanent crops rank first in terms of insecticide use per hectare. Our findings are consistent with studies reporting an association between PD and insecticide use and show that workers in farms specialized in fruits or permanent crops may be an occupational group at higher PD risk., (Copyright © 2010 Movement Disorder Society.)

Objective: We studied the relation between Parkinson disease (PD) and professional exposure to pesticides in a community-based case-control study conducted in a population characterized by a high prevalence of exposure. Our objective was to investigate the role of specific pesticide families and to perform dose-effect analyses., Methods: PD cases (n = 224) from the Mutualité Sociale Agricole (France) were matched to 557 controls free of PD affiliated with the same health insurance. Pesticide exposure was assessed using a 2-phase procedure, including a case-by-case expert evaluation. Analyses of the relation between PD and professional exposure to pesticides were first performed overall and by broad category (insecticides, fungicides, herbicides). Analyses of 29 pesticide families defined based on a chemical classification were restricted to men. Multiple imputation was used to impute missing values of pesticide families. Data were analyzed using conditional logistic regression, both using a complete-case and an imputed dataset., Results: We found a positive association between PD and overall professional pesticide use (odds ratio [OR] = 1.8, 95% confidence interval [CI] = 1.1-3.1), with a dose-effect relation for the number of years of use (p = 0.01). In men, insecticides were associated with PD (OR = 2.2, 95% CI = 1.1-4.3), in particular organochlorine insecticides (OR = 2.4, 95% CI = 1.2-5.0). These associations were stronger in men with older onset PD than in those with younger onset PD, and were characterized by a dose-effect relation in the former group., Interpretation: Our results support an association between PD and professional pesticide exposure, and show that some pesticides (ie, organochlorine insecticides) may be more particularly involved.

Myeloperoxidase (MPO) has been shown to contribute to several diseases and more particularly to atherosclerosis through excessive ROS production via the MPO/H(2)O(2)/Cl(-) oxidation system. The aim of this study was to determine whether there is an association between MPO polymorphisms and brain infarction (BI), one of the main consequences of atherosclerosis. We investigated MPO G-463A and G-129A polymorphisms in 450 patients with BI confirmed by magnetic resonance imaging (MRI) and 450 controls of the GENIC (Génétique de l'Infarctus Cérébral) Study. Genotype determination of MPO was performed by polymerase chain reaction and allele-specific oligonucleotide hybridization (ASO). Genotype distributions for each of both MPO polymorphisms were found to be similar between cases and controls overall, and according to etiologic subtypes or gender. The frequency of the A allele of the G-463A polymorphism was 22% (95% confidence interval, 19.4 to 24.9) and the frequency of the A allele of the G-129A polymorphism was 6.8% (95% confidence interval, 5.3 to 8.6). The odds ratio (OR) for BI in carriers of the A allele of the G-129A polymorphism was 0.92 (95% confidence interval, 0.61 to 1.39), and the OR for BI in carriers of the A allele of the G-463A polymorphism was 1.15 (95% confidence interval, 0.88 to 1.52). No association between the main risk factors for BI such as hypertension, cholesterol, diabetes and MPO polymorphisms was found. In analyses restricted to cases, we identified an association between the A allele of the G-129A polymorphism and the size of the brain infarct (P=0.01). Furthermore, the A allele of the G-463A polymorphism was associated with a poorer functional short-term outcome as evaluated by the Rankin score (P=0.02). In conclusion, MPO polymorphisms were associated with the extent of brain damage and the functional outcome rather than with the risk of developing a BI.