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.

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.

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.