Association Between education and walking speed: counterfactual mediation analysis in favor of a motor reserve hypothesis.

We quantified the extent to which the association between education and fast walking speed (FWS) is explained by 17 mediators (cardiovascular risk factors/diseases, comorbidities, health behaviours, socio-professional characteristics, cognition), and examined whether mediators interact with education, in favor of a reserve hypothesis. Cross-sectional analyses are based on Constances (population-based study of French adults 45-69y). 3m-FWS was measured using photoelectric cells. Education was categorized as lower/higher. After multiple imputation of missing values, we used counterfactual mediation models for multiple mediators allowing for education×mediator interactions, to estimate the total effect (TE), total indirect effect (TIE), and mediated interaction (IMD) of lower education on FWS. Analyses are based on 71,222 participants (52.6% women; mean age=57.2y; 27.2% higher education; mean FWS=180.2cm/s). In joint mediation analyses, the TE of lower education was -8.19cm/s (95% confidence interval [CI]=-8.87;-7.51), with a TIE of -5.76cm/s (95%CI=-6.10;-5.41; proportion mediated=70.3%, 95%CI=65.6;75.0). The IMD was negative (-2.52, 95%CI=-3.31;-1.72); 30.8% of the TE and 43.8% of the TIE were attributable to the IMD. Several mediators explain a large part of the association between lower education and slower FWS. The detrimental effect of mediators was more pronounced in participants with lower than in those with higher education, in agreement with a reserve hypothesis.

Genome-wide determinants of mortality and motor progression in Parkinson's disease.

There are 90 independent genome-wide significant genetic risk variants for Parkinson's disease (PD) but currently only five nominated loci for PD progression. The biology of PD progression is likely to be of central importance in defining mechanisms that can be used to develop new treatments. We studied 6766 PD patients, over 15,340 visits with a mean follow-up of between 4.2 and 15.7 years and carried out genome-wide survival studies for time to a motor progression endpoint, defined by reaching Hoehn and Yahr stage 3 or greater, and death (mortality). There was a robust effect of the APOE ε4 allele on mortality in PD. We also identified a locus within the TBXAS1 gene encoding thromboxane A synthase 1 associated with mortality in PD. We also report 4 independent loci associated with motor progression in or near MORN1, ASNS, PDE5A, and XPO1. Only the non-Gaucher disease causing GBA1 PD risk variant E326K, of the known PD risk variants, was associated with mortality in PD. Further work is needed to understand the links between these genomic variants and the underlying disease biology. However, these may represent new candidates for disease modification in PD.

Healthy lifestyle change and all-cause and cancer mortality in the European Prospective Investigation into Cancer and Nutrition cohort.

BACKGROUND: Healthy lifestyles are inversely associated with the risk of noncommunicable diseases, which are leading causes of death. However, few studies have used longitudinal data to assess the impact of changing lifestyle behaviours on all-cause and cancer mortality. METHODS: Within the European Prospective Investigation into Cancer and Nutrition (EPIC) cohort, lifestyle profiles of 308,497 cancer-free adults (71% female) aged 35-70 years at recruitment across nine countries were assessed with baseline and follow-up questionnaires administered on average of 7 years apart. A healthy lifestyle index (HLI), assessed at two time points, combined information on smoking status, alcohol intake, body mass index, and physical activity, and ranged from 0 to 16 units. A change score was calculated as the difference between HLI at baseline and follow-up. Associations between HLI change and all-cause and cancer mortality were modelled with Cox regression, and the impact of changing HLI on accelerating mortality rate was estimated by rate advancement periods (RAP, in years). RESULTS: After the follow-up questionnaire, participants were followed for an average of 9.9 years, with 21,696 deaths (8407 cancer deaths) documented. Compared to participants whose HLIs remained stable (within one unit), improving HLI by more than one unit was inversely associated with all-cause and cancer mortality (hazard ratio [HR]: 0.84; 95% confidence interval [CI]: 0.81, 0.88; and HR: 0.87; 95% CI: 0.82, 0.92; respectively), while worsening HLI by more than one unit was associated with an increase in mortality (all-cause mortality HR: 1.26; 95% CI: 1.20, 1.33; cancer mortality HR: 1.19; 95% CI: 1.09, 1.29). Participants who worsened HLI by more than one advanced their risk of death by 1.62 (1.44, 1.96) years, while participants who improved HLI by the same amount delayed their risk of death by 1.19 (0.65, 2.32) years, compared to those with stable HLI. CONCLUSIONS: Making healthier lifestyle changes during adulthood was inversely associated with all-cause and cancer mortality and delayed risk of death. Conversely, making unhealthier lifestyle changes was positively associated with mortality and an accelerated risk of death.

Norms for Usual and Fast Walking Speed in Adults 45-69 Years Old From the French General Population: Constances Study.

OBJECTIVES: 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. DESIGN: Cross-sectional analysis of a population-based study. SETTING AND PARTICIPANTS: French Constances study (45-69 years). METHODS: 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 (

Combining crop-exposure matrices and land use data to estimate indices of environmental and occupational exposure to pesticides.

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.

Association of Physical Activity and Parkinson Disease in Women: Long-term Follow-up of the E3N Cohort Study.

BACKGROUND AND OBJECTIVES: Previous cohort studies reported that a single measure of physical activity (PA) assessed at baseline was associated with lower Parkinson disease (PD) incidence, but a meta-analysis suggested that this association was restricted to men. Because of the long prodromal phase of the disease, reverse causation could not be excluded as a potential explanation. Our objective was to study the association between time-varying PA and PD in women using lagged analyses to address the potential for reverse causation and to compare PA trajectories in patients before diagnosis and matched controls. METHODS: We used data from the Etude Epidémiologique auprès de femmes de la Mutuelle Générale de l'Education Nationale (1990-2018), a cohort study of women affiliated with a national health insurance plan for persons working in education. PA was self-reported in 6 questionnaires over the follow-up. As questions changed across questionnaires, we created a time-varying latent PA (LPA) variable using latent process mixed models. PD was ascertained using a multistep validation process based on medical records or a validated algorithm based on drug claims. We set up a nested case-control study to examine differences in LPA trajectories using multivariable linear mixed models with a retrospective timescale. Cox proportional hazards models with age as the timescale and adjusted for confounders were used to estimate the association between time-varying LPA and PD incidence. Our main analysis used a 10-year lag to account for reverse causation; sensitivity analyses used 5-, 15-, and 20-year lags. RESULTS: Analyses of trajectories (1,196 cases and 23,879 controls) showed that LPA was significantly lower in cases than in controls throughout the follow-up, including 29 years before diagnosis; the difference between cases and controls started to increase ∼10 years before diagnosis (p interaction = 0.003). In our main survival analysis, of 95,354 women free of PD in 2000, 1,074 women developed PD over a mean follow-up of 17.2 years. PD incidence decreased with increasing LPA (p trend = 0.001), with 25% lower incidence in those in the highest quartile compared with the lowest (adjusted hazard ratio 0.75, 95% CI 0.63-0.89). Using longer lags yielded similar conclusions. DISCUSSION: Higher PA level is associated with lower PD incidence in women, not explained by reverse causation. These results are important for planning interventions for PD prevention.

The role of environmental factors on sporadic Creutzfeldt-Jakob disease mortality: evidence from an age-period-cohort analysis.

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.

Differences in Survival across Monogenic Forms of Parkinson's Disease.

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.

Statin Use and Incidence of Parkinson's Disease in Women from the French E3N Cohort Study.

BACKGROUND: Statins represent candidates for drug repurposing in Parkinson's disease (PD). Few studies examined the role of reverse causation, statin subgroups, and dose-response relations based on time-varying exposures. OBJECTIVES: We examined whether statin use is associated with PD incidence while attempting to overcome the limitations described previously, especially reverse causation. METHOD: We used data from the E3N cohort study of French women (follow-up, 2004-2018). Incident PD was ascertained using multiple sources and validated by experts. New statin users were identified through linked drug claims. We set up a nested case-control study to describe trajectories of statin prescriptions and medical consultations before diagnosis. We used time-varying multivariable Cox proportional hazards regression models to examine the statins-PD association. Exposure indexes included ever use, cumulative duration/dose, and mean daily dose and were lagged by 5 years to address reverse causation. RESULTS: The case-control study (693 cases, 13,784 controls) showed differences in case-control trajectories, with changes in the 5 years before diagnosis in cases. Of 73,925 women (aged 54-79 years), 524 developed PD and 11,552 started using statins in lagged analyses. Ever use of any statin was not associated with PD (hazard ratio [HR] = 0.87, 95% confidence interval [CI] = 0.67-1.11). Alternatively, ever use of lipophilic statins was significantly associated with lower PD incidence (HR = 0.70, 95% CI = 0.51-0.98), with a dose-response relation for the mean daily dose (P-linear trend = 0.02). There was no association for hydrophilic statins. CONCLUSION: Use of lipophilic statins at least 5 years earlier was associated with reduced PD incidence in women, with a dose-response relation for the mean daily dose. © 2023 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Characteristics of reproductive history, use of exogenous hormones and walking speed among women: Data from the CONSTANCES French Cohort Study.

OBJECTIVE: To investigate the cross-sectional associations of reproductive history and use of exogenous hormones with fast walking speed (WS) in women. STUDY DESIGN: Between 2012 and 2020, 33,892 French women aged 45 years or more, recruited at health centers, underwent physical function tests and self-reported information on reproductive history and use of exogenous hormones. Linear mixed models with the center as random intercept were used to estimate the association of exposures with WS. MAIN OUTCOME MEASURES: Fast WS. RESULTS: Mean WS was 172.2 cm/s. WS increased with age at menarche (ß+1y = 0.23, 95 % confidence interval = 0.05 to 0.40), age at first birth (ß+1y = 0.20, 95 % CI = 0.13 to 0.27) and duration of breastfeeding (ßfor ≥10 vs ≤5months = 1.38; 95 % CI = 0.39 to 2.36). In addition, parity was quadratically associated with WS, with women with 3 children having the highest WS (p for U-shaped relationship < 0.01). Menopausal status had no impact on WS but age at menopause was positively associated with WS (ß+5y = 0.52, 95 % CI = 0.17 to 0.87) and partly explained the deleterious impact of artificial menopause on WS. WS increased with reproductive lifetime duration (ß+5y = 0.49, 95 % CI = 0.16 to 0.83) and decreased with time since onset of menopause (ß+5y = -0.65, 95 % CI = -0.99 to -0.31). By contrast, there was no association of WS with oral contraception and postmenopausal hormone therapy. CONCLUSION: Our findings suggest that reproductive life characteristics may be associated with WS and timing of exposure could play a role.

Long-term air pollution exposure and Parkinson's disease mortality in a large pooled European cohort: An ELAPSE study.

BACKGROUND: The link between exposure to ambient air pollution and mortality from cardiorespiratory diseases is well established, while evidence on neurodegenerative disorders including Parkinson's Disease (PD) remains limited. OBJECTIVE: We examined the association between long-term exposure to ambient air pollution and PD mortality in seven European cohorts. METHODS: Within the project 'Effects of Low-Level Air Pollution: A Study in Europe' (ELAPSE), we pooled data from seven cohorts among six European countries. Annual mean residential concentrations of fine particulate matter (PM2.5), nitrogen dioxide (NO2), black carbon (BC), and ozone (O3), as well as 8 PM2.5 components (copper, iron, potassium, nickel, sulphur, silicon, vanadium, zinc), for 2010 were estimated using Europe-wide hybrid land use regression models. PD mortality was defined as underlying cause of death being either PD, secondary Parkinsonism, or dementia in PD. We applied Cox proportional hazard models to investigate the associations between air pollution and PD mortality, adjusting for potential confounders. RESULTS: Of 271,720 cohort participants, 381 died from PD during 19.7 years of follow-up. In single-pollutant analyses, we observed positive associations between PD mortality and PM2.5 (hazard ratio per 5 µg/m3: 1.25; 95% confidence interval: 1.01-1.55), NO2 (1.13; 0.95-1.34 per 10 µg/m3), and BC (1.12; 0.94-1.34 per 0.5 × 10-5m-1), and a negative association with O3 (0.74; 0.58-0.94 per 10 µg/m3). Associations of PM2.5, NO2, and BC with PD mortality were linear without apparent lower thresholds. In two-pollutant models, associations with PM2.5 remained robust when adjusted for NO2 (1.24; 0.95-1.62) or BC (1.28; 0.96-1.71), whereas associations with NO2 or BC attenuated to null. O3 associations remained negative, but no longer statistically significant in models with PM2.5. We detected suggestive positive associations with the potassium component of PM2.5. CONCLUSION: Long-term exposure to PM2.5, at levels well below current EU air pollution limit values, may contribute to PD mortality.

Reproductive characteristics, use of exogenous hormones and Parkinson disease in women from the E3N study.

Despite experimental studies suggesting a disease-modifying role of oestrogens, results from epidemiological studies on the relation of reproductive characteristics and hormonal exposures with Parkinson disease in women are conflicting. We used the data from the E3N cohort study including 98 068 women aged 40-65 years in 1990 followed until 2018. Parkinson disease was ascertained using a validation process based on drug claim databases and medical records. Reproductive characteristics and hormonal exposures were self-reported (11 questionnaires). Associations of exposures with Parkinson disease incidence were investigated using time-varying Cox proportional hazards regression with a 5-year exposure lag and age as the timescale adjusted for confounders. We identified 1165 incident Parkinson disease cases during a mean follow-up of 22.0 years (incidence rate = 54.7 per 100 000 person-years). Parkinson disease incidence was higher in women with early (<12 years, HR = 1.21, 95% CI = 1.04-1.40) or late age at menarche (≥14 years, HR = 1.18, 95% CI = 1.03-1.35) than in women with menarche at 12-13 years. Nulliparity was not associated with Parkinson disease, but Parkinson disease incidence increased with the number of children in parous women (P-trend = 0.009). Women with artificial (surgical, iatrogenic) menopause were at greater risk than women with natural menopause (HR = 1.28, 95% CI = 1.09-1.47), especially when artificial menopause occurred at an early age (≤45.0 years). Postmenopausal hormone therapy tended to mitigate greater risk associated with artificial or early menopause (≤45.0 years). While fertility treatments were not associated with Parkinson disease overall, ever users of clomiphene were at greater Parkinson disease risk than never users (HR = 1.81, 95% CI = 1.14-2.88). Other exposures (breastfeeding, oral contraceptives) were not associated with Parkinson disease. Our findings suggest that early and late age at menarche, higher parity, and artificial menopause, in particular at an early age, are associated with increased Parkinson disease incidence in women. In addition, there was some evidence that use of exogenous hormones may increase (fertility treatments) or decrease (postmenopausal hormone therapy) Parkinson disease incidence. These findings support the hypothesis that hormonal exposures play a role in the susceptibility to neurodegenerative diseases. If confirmed, they could help to identify subgroups at high risk for Parkinson disease.

Body Mass Index, Abdominal Adiposity, and Incidence of Parkinson Disease in French Women From the E3N Cohort Study.

BACKGROUND AND OBJECTIVES: Previous 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. METHODS: We 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 <18.5 kg/m2; 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. RESULTS: Of 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. DISCUSSION: In 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.

Mitochondrial haplogroups and cognitive progression in Parkinson's disease.

Mitochondria are a culprit in the onset of Parkinson's disease, but their role during disease progression is unclear. Here we used Cox proportional hazards models to exam the effect of variation in the mitochondrial genome on longitudinal cognitive and motor progression over time in 4064 patients with Parkinson's disease. Mitochondrial macro-haplogroup was associated with reduced risk of cognitive disease progression in the discovery and replication population. In the combined analysis, patients with the super macro-haplogroup J, T, U# had a 41% lower risk of cognitive progression with P = 2.42 × 10-6 compared to those with macro-haplogroup H. Exploratory analysis indicated that the common mitochondrial DNA variant, m.2706A>G, was associated with slower cognitive decline with a hazard ratio of 0.68 (95% confidence interval 0.56-0.81) and P = 2.46 × 10-5. Mitochondrial haplogroups were not appreciably linked to motor progression. This initial genetic survival study of the mitochondrial genome suggests that mitochondrial haplogroups may be associated with the pace of cognitive progression in Parkinson's disease over time.

Association between the LRP1B and APOE loci and the development of Parkinson's disease dementia.

Parkinson's disease is one of the most common age-related neurodegenerative disorders. Although predominantly a motor disorder, cognitive impairment and dementia are important features of Parkinson's disease, particularly in the later stages of the disease. However, the rate of cognitive decline varies among Parkinson's disease patients, and the genetic basis for this heterogeneity is incompletely understood. To explore the genetic factors associated with rate of progression to Parkinson's disease dementia, we performed a genome-wide survival meta-analysis of 3923 clinically diagnosed Parkinson's disease cases of European ancestry from four longitudinal cohorts. In total, 6.7% of individuals with Parkinson's disease developed dementia during study follow-up, on average 4.4 ± 2.4 years from disease diagnosis. We have identified the APOE ε4 allele as a major risk factor for the conversion to Parkinson's disease dementia [hazard ratio = 2.41 (1.94-3.00), P = 2.32 × 10-15], as well as a new locus within the ApoE and APP receptor LRP1B gene [hazard ratio = 3.23 (2.17-4.81), P = 7.07 × 10-09]. In a candidate gene analysis, GBA variants were also identified to be associated with higher risk of progression to dementia [hazard ratio = 2.02 (1.21-3.32), P = 0.007]. CSF biomarker analysis also implicated the amyloid pathway in Parkinson's disease dementia, with significantly reduced levels of amyloid ß42 (P = 0.0012) in Parkinson's disease dementia compared to Parkinson's disease without dementia. These results identify a new candidate gene associated with faster conversion to dementia in Parkinson's disease and suggest that amyloid-targeting therapy may have a role in preventing Parkinson's disease dementia.

Comparison of manual and automated measures of walking speed: Distance and pace matter.

BACKGROUND: Walking speed (WS) represents a global marker of individual health and provides a simple and objective measure of motor performances for use in clinical and research settings. WS is most often measured over relatively short distances at usual (UWS) or fast (FWS) pace, using manual (e.g., stopwatch) or automated methods (e.g., photoelectric cells). As the time needed to walk over these distances is very short, we hypothesized that measurement error related to manual compared to automated WS measures is more pronounced for shorter distances and FWS and investigated the reliability and agreement of WS in a subsample of the Constances cohort at two paces and over two distances. METHODS: We recruited 100 community-dwelling participants (50 % women) aged 45-70y (mean = 56.1y). WS was measured manually (stopwatches) and using photoelectric cells, at two paces (UWS/FWS) and over two distances (3 m/5 m). Agreement was examined using Bland and Altman plots and intraclass correlation coefficients (ICC). RESULTS: Participants were on average 169.8 cm tall, and their mean body mass index was 25.4 kg/m2. Agreement between manual stopwatches and photoelectric cells was excellent (ICCs between 0.92 and 0.97), but it was lower for smaller distances, with significantly lower ICCs over 3 m compared to 5 m both for UWS (differenceICC = -0.04) and FWS (differenceICC = -0.05). Bias of manual measures was constant for UWS and increased with increasing FWS. There were inter-rater effects, with better agreement for UWS and 5 m compared to FWS and 3 m. CONCLUSIONS: Both distance and pace have an influence on the reliability of WS measures using manual timing methods. Our findings also suggest the presence of rater effects and better agreement for 5 m and UWS. These findings are helpful for the design of studies that include manual measures of WS, especially FWS, in order to reduce measurement error and suggest that longer distances are preferable.

Identifying Protective Drugs for Parkinson's Disease in Health-Care Databases Using Machine Learning.

BACKGROUND: Available treatments for Parkinson's disease (PD) are only partially or transiently effective. Identifying existing molecules that may present a therapeutic or preventive benefit for PD (drug repositioning) is thus of utmost interest. OBJECTIVE: We aimed at detecting potentially protective associations between marketed drugs and PD through a large-scale automated screening strategy. METHODS: We implemented a machine learning (ML) algorithm combining subsampling and lasso logistic regression in a case-control study nested in the French national health data system. Our study population comprised 40,760 incident PD patients identified by a validated algorithm during 2016 to 2018 and 176,395 controls of similar age, sex, and region of residence, all followed since 2006. Drug exposure was defined at the chemical subgroup level, then at the substance level of the Anatomical Therapeutic Chemical (ATC) classification considering the frequency of prescriptions over a 2-year period starting 10 years before the index date to limit reverse causation bias. Sensitivity analyses were conducted using a more specific definition of PD status. RESULTS: Six drug subgroups were detected by our algorithm among the 374 screened. Sulfonamide diuretics (ATC-C03CA), in particular furosemide (C03CA01), showed the most robust signal. Other signals included adrenergics in combination with anticholinergics (R03AL) and insulins and analogues (A10AD). CONCLUSIONS: We identified several signals that deserve to be confirmed in large studies with appropriate consideration of the potential for reverse causation. Our results illustrate the value of ML-based signal detection algorithms for identifying drugs inversely associated with PD risk in health-care databases. © 2022 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Machine Learning-Based Prediction of Impulse Control Disorders in Parkinson's Disease From Clinical and Genetic Data.

Goal: Impulse control disorders (ICDs) are frequent non-motor symptoms occurring during the course of Parkinson's disease (PD). The objective of this study was to estimate the predictability of the future occurrence of these disorders using longitudinal data, the first study using cross-validation and replication in an independent cohort. Methods: We used data from two longitudinal PD cohorts (training set: PPMI, Parkinson's Progression Markers Initiative; test set: DIGPD, Drug Interaction With Genes in Parkinson's Disease). We included 380 PD subjects from PPMI and 388 PD subjects from DIGPD, with at least two visits and with clinical and genetic data available, in our analyses. We trained three logistic regressions and a recurrent neural network to predict ICDs at the next visit using clinical risk factors and genetic variants previously associated with ICDs. We quantified performance using the area under the receiver operating characteristic curve (ROC AUC) and average precision. We compared these models to a trivial model predicting ICDs at the next visit with the status at the most recent visit. Results: The recurrent neural network (PPMI: 0.85 [0.80 - 0.90], DIGPD: 0.802 [0.78 - 0.83]) was the only model to be significantly better than the trivial model (PPMI: ROC AUC = 0.75 [0.69 - 0.81]; DIGPD: 0.78 [0.75 - 0.80]) on both cohorts. We showed that ICDs in PD can be predicted with better accuracy with a recurrent neural network model than a trivial model. The improvement in terms of ROC AUC was higher on PPMI than on DIGPD data, but not clinically relevant in both cohorts. Conclusions: Our results indicate that machine learning methods are potentially useful for predicting ICDs, but further works are required to reach clinical relevance.

A retrospective analysis of all-cause and cause-specific mortality rates in French male professional footballers.

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.