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Background and ObjectivesPrevious studies on the relationship between body mass index (BMI) and Parkinson disease (PD) provided inconsistent results, likely due to reverse causation explained by weight loss during the prodromal phase. We examined the association of BMI and abdominal adiposity with PD incidence using lagged analyses to address the potential for reverse causation and compared BMI trajectories in patients before diagnosis and matched controls.MethodsWe used data from the E3N cohort study of French women with a 29-year follow-up (1990–2018). BMI (kg/m2) was computed based on self-reported weight and height up to 11 times; up to 6 waist circumference (WC) and hip circumference measures were available. PD diagnoses were validated based on medical records and drug claim databases. Multivariable time-varying Cox proportional hazards models were used to estimate hazard ratios (HRs) and 95% CIs according to BMI categories (underweight 2; normal = [18.5–25.0[ kg/m2; overweight = [25.0–30.0[ kg/m2; obese ≥30.0 kg/m2). Exposures were lagged by 5 years in main analyses; we used longer lags (10 and 20 years) in sensitivity analyses. We examined trajectories of BMI categories within a nested case-control study using multivariable generalized estimating equations multinomial logistic models.ResultsOf 96,702 women (baseline age = 40–65 years), 1,164 developed PD. PD incidence was lower (HR = 0.76, 95% CI = 0.59–0.98,p= 0.032) among women with obesity compared with those with normal BMI. There was a similar association in analyses using longer lag times (20 years, 598 cases, HR = 0.52, 95% CI = 0.30–0.88,p= 0.016). A similar pattern was seen for WC and waist-height ratio but not waist-hip ratio. Trajectories of BMI categories (1,196 patients and 23,876 controls) showed that obesity was less frequent in patients with PD before diagnosis than in controls, with a statistically significant difference 29 years before. In addition, the frequency of obesity decreased 5–10 years before diagnosis in patients.DiscussionIn this large cohort of women with a long follow-up, obesity was associated with a lower hazard of PD, even when measured 20 years before diagnosis, in agreement with Mendelian randomization studies. Our analyses underscore the importance of lagged analyses to account for reverse causation. These findings warrant further investigations to understand the mechanisms underlying this inverse association.

ObjectiveTo 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.MethodsWe 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.ResultsIn 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.ConclusionThe 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.

ObjectiveTo investigate whether cigarette smoking interacts with genes involved in individual susceptibility to xenobiotics for the risk of Parkinson disease (PD).MethodsTwo French population-based case-control studies (513 patients, 1,147 controls) were included as a discovery sample to examine gene-smoking interactions based on 3,179 single nucleotide polymorphisms (SNPs) in 289 genes involved in individual susceptibility to xenobiotics. SNP–by–cigarette smoking interactions were tested in the discovery sample through an empirical Bayes (EB) approach. Nine SNPs were selected for replication in a population-based case-control study from California (410 patients, 845 controls) with standard logistic regression and the EB approach. For SNPs that replicated, we performed pooled analyses including the discovery and replication datasets and computed pooled odds ratios and confidence intervals (CIs) using random-effects meta-analysis.ResultsNine SNPs interacted with smoking in the discovery dataset and were selected for replication. Interactions of smoking with rs4240705 in the RXRA gene and rs1900586 in the SLC17A6 gene were replicated. In pooled analyses (logistic regression), the interactions between smoking and rs4240705-G and rs1900586-G were 1.66 (95% CI 1.28–2.14, p = 1.1 × 10−4, p for heterogeneity = 0.366) and 1.61 (95% CI 1.17–2.21, p = 0.003, p for heterogeneity = 0.616), respectively. For both SNPs, while smoking was significantly less frequent in patients than controls in AA homozygotes, this inverse association disappeared in G allele carriers.ConclusionsWe identified and replicated suggestive gene-by-smoking interactions in PD. The inverse association of smoking with PD was less pronounced in carriers of minor alleles of both RXRA-rs4240705 and SLC17A6-rs1900586. These findings may help identify biological pathways involved in the inverse association between smoking and PD.

ObjectiveTo investigate the longitudinal dose-effect relationship between dopamine replacement therapy and impulse control disorders (ICDs) in Parkinson disease (PD).MethodsWe used data from a multicenter longitudinal cohort of consecutive patients with PD with ≤5 years' disease duration at baseline followed up annually up to 5 years. ICDs were evaluated during face-to-face semistructured interviews with movement disorder specialists. Generalized estimating equations and Poisson models with robust variance were used to study the association between several time-dependent definitions of dopamine agonist (DA) use, taking dose and duration of treatment into account, and ICDs at each visit. Other antiparkinsonian drugs were also examined.ResultsAmong 411 patients (40.6% women, mean age 62.3 years, average follow-up 3.3 years, SD 1.7 years), 356 (86.6%) took a DA at least once since disease onset. In 306 patients without ICDs at baseline, the 5-year cumulative incidence of ICDs was 46.1% (95% confidence interval [CI] 37.4–55.7, DA ever users 51.5% [95% CI 41.8–62.1], DA never users 12.4% [95% CI 4.8–30.0]). ICD prevalence increased from 19.7% at baseline to 32.8% after 5 years. ICDs were associated with ever DA use (prevalence ratio 4.23, 95% CI 1.78–10.09). Lifetime average daily dose and duration of treatment were independently associated with ICDs with significant dose-effect relationships. Similar analyses for levodopa were not in favor of a strong association. ICDs progressively resolved after DA discontinuation.ConclusionIn this longitudinal study of patients with PD characterized by a high prevalence of DA treatment, the 5-year cumulative incidence of ICDs was ≈46%. ICDs were strongly associated with DA use with a dose-effect relationship; both increasing duration and dose were associated with ICDs. ICDs progressively resolved after DA discontinuation.ClinicalTrials.gov identifier:NCT01564992.

OBJECTIVE: To examine the association between alcohol consumption in midlife and subsequent cognitive decline. METHODS: Data are from 5,054 men and 2,099 women from the Whitehall II cohort study with a mean age of 56 years (range 44-69 years) at first cognitive assessment. Alcohol consumption was assessed 3 times in the 10 years preceding the first cognitive assessment (1997-1999). Cognitive tests were repeated in 2002-2004 and 2007-2009. The cognitive test battery included 4 tests assessing memory and executive function; a global cognitive score summarized performances across these tests. Linear mixed models were used to assess the association between alcohol consumption and cognitive decline, expressed as z scores (mean = 0, SD = 1). RESULTS: In men, there were no differences in cognitive decline among alcohol abstainers, quitters, and light or moderate alcohol drinkers (

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.

Objective: To study the validity of information provided by case and control subjects (or their proxies) about PD among their first-degree relatives. Methods: Secondary cases of PD were assessed both through a single informant (family history method) and through the study of each relative (family study method). The family study method was considered as the standard for comparison, and the sensitivity and specificity of the family history method were studied. Results: A total of 133 population-based case subjects and their 655 relatives were recruited, and 119 population-based control subjects and their 511 relatives. Sensitivity was 68% (95% CI = 47 to 85) for cases and 45% (95% CI = 17 to 77) for controls. Specificity was 99% (95% CI = 98 to 99) for cases and 100% (95% CI = 99 to 100) for controls. The odds ratio (OR) for family history of PD was 4.34 (95% CI = 1.63 to 11.58, p = 0.003) using the family history method and 1.86 (95% CI = 0.78 to 4.44, p = 0.16) using the family study method. The former significant OR more than doubled the latter not significant OR (relative bias = 133%). Bias was more pronounced for proxy interviews and for women informants, and when the relatives were siblings, were living, and were examined or had medical record documentation. Conclusions: Case subjects with PD (or their proxies) are more aware of PD among their first-degree relatives than control subjects (or their proxies); however, they overreport PD in relatives who are not affected. This causes a substantial family information bias.

International audience; 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. 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. 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. 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.

International audience; OBJECTIVE: To investigate the association of Parkinson disease (PD) with education and occupations using a case-control study design. METHODS: The authors used the medical records-linkage system of the Rochester Epidemiology Project to identify all subjects who developed PD in Olmsted County, MN, from 1976 through 1995. Each incident case was matched by age (+/-1 year) and sex to a general population control. The authors collected information about education and occupations using two independent sources of data: a review of the complete medical records in the system and a telephone interview. Occupations were coded using the 1980 Standard Occupational Classification. RESULTS: Subjects with 9 or more years of education were at increased risk of PD (OR = 2.0; 95% CI = 1.1 to 3.6; p = 0.02), and there was a trend of increasing risk with increasing education (test for linear trend, p = 0.02; medical records data). Physicians were at significantly increased risk of PD using both sources of occupational data. By contrast, four occupational groups showed a significantly decreased risk of PD using one source of data: construction and extractive workers (e.g., miners, oil well drillers), production workers (e.g., machine operators, fabricators), metal workers, and engineers. These associations with increased or decreased risk did not change noticeably after adjustment for education. CONCLUSION: Subjects with higher education and physicians have an increased risk of Parkinson disease (PD), while subjects with some occupations presumed to involve high physical activity have a decreased risk of PD.

To investigate the familial aggregation of PD in a large collaborative population-based case-control study.Most previous case-control studies of the familial aggregation of PD have been hospital- or clinic-based.We included 219 prevalent cases ascertained in three European populations (centers), using a two-phase design consisting of screening and examination by a neurologist. Each case was matched by age, sex, and center to three controls drawn from the same populations (n = 657). Presence of PD among first-degree relatives (parents and siblings) was determined using the family history approach for 175 cases and 481 controls.Overall, a positive family history (at least one parent or sibling affected by PD) was reported in 10.3% of patients and 3.5% of controls (odds ratio [OR] = 3.2; 95% confidence interval [CI] = 1.6 to 6.6). A similar association was observed when analyses were restricted to nondemented patients and controls (OR = 3.9; 95% CI = 1.7 to 8.7) or to newly diagnosed patients (OR = 3.3; 95% CI = 0.9 to 11.9). We found a significant trend of increasing risk with increasing number of affected relatives (p = 0.003). Analyses stratified by age showed a stronger association for younger PD patients (OR = 7.6; 95% CI = 1.5 to 38.9) than for older patients (OR = 2.5; 95% CI = 1.1 to 5.7).In this large sample of prevalent PD patients and population-matched controls, PD significantly aggregates in families, with the strength of the association being age-dependent. Therefore, familial factors, which can be genetic, environmental, or both, play a role in PD.

Objective: To investigate the familial aggregation of PD in a large collaborative population-based case-control study.Background: Most previous case-control studies of the familial aggregation of PD have been hospital- or clinic-based.Methods: We included 219 prevalent cases ascertained in three European populations (centers), using a two-phase design consisting of screening and examination by a neurologist. Each case was matched by age, sex, and center to three controls drawn from the same populations (n = 657). Presence of PD among first-degree relatives (parents and siblings) was determined using the family history approach for 175 cases and 481 controls.Results: Overall, a positive family history (at least one parent or sibling affected by PD) was reported in 10.3% of patients and 3.5% of controls (odds ratio [OR] = 3.2; 95% confidence interval [CI] = 1.6 to 6.6). A similar association was observed when analyses were restricted to nondemented patients and controls (OR = 3.9; 95% CI = 1.7 to 8.7) or to newly diagnosed patients (OR = 3.3; 95% CI = 0.9 to 11.9). We found a significant trend of increasing risk with increasing number of affected relatives (p = 0.003). Analyses stratified by age showed a stronger association for younger PD patients (OR = 7.6; 95% CI = 1.5 to 38.9) than for older patients (OR = 2.5; 95% CI = 1.1 to 5.7).Conclusions: In this large sample of prevalent PD patients and population-matched controls, PD significantly aggregates in families, with the strength of the association being age-dependent. Therefore, familial factors, which can be genetic, environmental, or both, play a role in PD.