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Abstract: Background: Vascular risk factors are associated with increased risk of cognitive impairment and dementia, but their association with motor function, another key feature of aging, has received little research attention. We examined the association between trajectories of the Framingham general cardiovascular disease risk score (FRS) over midlife and motor function later in life. Methods: A total of 5376 participants of the Whitehall II cohort study (29% women) who had up to four repeat measures of FRS between 1991–1993 (mean age=48.6years) and 2007–2009 (mean age=65.4years) and without history of stroke or coronary heart disease in 2007–2009 were included. Motor function was assessed in 2007–2009 through objective tests (walking speed, chair rises, balance, finger tapping, grip strength). We used age- and sex-adjusted linear mixed models. Results: Participants with poorer performances for walking speed, chair rises, and balance in 2007–2009 had higher FRS concurrently and also in 1991–1993, on average 16years earlier. These associations were robust to adjustment for cognition, socio-economic status, height, and BMI, and not explained by incident mobility limitation prior to motor assessment. No association was found with finger tapping and grip strength. Conclusions: Cardiovascular risk early in midlife is associated with poor motor performances later in life. Vascular risk factors play an important and under-recognized role in motor function, independently of their impact on cognition, and suggest that better control of vascular risk factors in midlife may prevent physical impairment and disability in the elderly. [Copyright &y& Elsevier]

Background: A genome-wide association study identified 13 single-nucleotide polymorphisms (SNPs) significantly associated with Parkinson's disease. Small-scale replication studies were largely non-confirmatory, but a meta-analysis that included data from the original study could not exclude all SNP associations, leaving relevance of several markers uncertain.Methods: Investigators from three Michael J Fox Foundation for Parkinson's Research-funded genetics consortia-comprising 14 teams-contributed DNA samples from 5526 patients with Parkinson's disease and 6682 controls, which were genotyped for the 13 SNPs. Most (88%) participants were of white, non-Hispanic descent. We assessed log-additive genetic effects using fixed and random effects models stratified by team and ethnic origin, and tested for heterogeneity across strata. A meta-analysis was undertaken that incorporated data from the original genome-wide study as well as subsequent replication studies.Findings: In fixed and random-effects models no associations with any of the 13 SNPs were identified (odds ratios 0.89 to 1.09). Heterogeneity between studies and between ethnic groups was low for all SNPs. Subgroup analyses by age at study entry, ethnic origin, sex, and family history did not show any consistent associations. In our meta-analysis, no SNP showed significant association (summary odds ratios 0.95 to 1.08); there was little heterogeneity except for SNP rs7520966.Interpretation: Our results do not lend support to the finding that the 13 SNPs reported in the original genome-wide association study are genetic susceptibility factors for Parkinson's disease. [ABSTRACT FROM AUTHOR]

We applied the incidence rates of parkinsonism and Parkinson''s disease (PD) from Olmsted County, MN (1976–1990) to a hypothetical cohort undergoing the mortality rates observed in Minnesota, and computed the lifetime risk and the remaining lifetime risk of developing parkinsonism and PD. These risks were compared to cumulative incidences that do not take competing risks of death into account. The lifetime risk of developing parkinsonism from birth was 4.4% for men and 3.7% for women (ratio = 1.2). The corresponding risk of developing PD was 2.0% for men and 1.3% for women (ratio = 1.5). Because of the opposite effect of higher incidence and higher mortality rates in men, the lifetime risks were only slightly higher in men than in women. Lifetime cumulative incidences were consistently higher than lifetime risks; this difference was more pronounced in men and in older subjects. Lifetime risk estimates are useful in clinical practice, epidemiologic research, and public health. [Copyright &y& Elsevier]

Background: Several genes have been implicated in the pathogenesis of Parkinson's disease (PD). The aim of this study was to define the clinical symptoms and age-associated cumulative incidence of the most frequent mutation associated with PD, LRRK2 Gly2019Ser. Methods: 238 patients with sporadic PD and 371 unrelated control participants from the Arab-Berber population were screened at the Institut National de Neurologie, Tunis. Symptoms of PD were assessed using the Hoehn and Yahr scale, the unified Parkinson's disease rating scale, and the Epworth scale. Genotyping for LRRK2 6055G-->A, which causes the Gly2019Ser mutation, was done in all participants, and the age-specific cumulative incidence of PD was calculated by Kaplan-Meier analysis. Findings: 30% of patients with PD in this case-control sample were carriers of LRRK2 Gly2019Ser. The age of onset of symptoms and the clinical presentation of patients with LRRK2 Gly2019Ser were similar to those of patients with idiopathic PD. Carriers of LRRK2 Gly2019Ser were 22.6 times (95% CI 10.2-50.1) more likely to be affected by PD than non-carriers. Tremor was the predominant symptom in LRRK2 Gly2019Ser carriers (92% [homozygotes] vs 75% [heterozygotes] vs 69% [non-carriers]; Cochran-Armitage trend test p=0.0587). Disease severity, response to treatment, and disease duration were similar among LRRK2 Gly2019Ser homozygotes, heterozygotes, and non-carriers (p=0.85). Disease penetrance in LRRK2 Gly2019Ser carriers ranged from less than 20% in those younger than 50 years to greater than 80% at 70 years. Interpretation: The LRRK2 Gly2019Ser mutation in patients with PD is a useful aid to diagnosis. LRRK2 Gly2019Ser penetrance can vary but in most carriers PD seems an inevitable consequence of ageing. LRRK2 Gly2019Ser considerably increases susceptibility to neuronal degeneration, although the process might be mediated by many triggers. By contrast, idiopathic PD is rare before 50 years and the prevalence only increases to 4% in the oldest members of the population. Funding: GlaxoSmithKline; National Institutes of Health; and Mayo Foundation. [ABSTRACT FROM AUTHOR]

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 (

Abstract: The best validated susceptibility variants for Parkinson's disease are located in the α-synuclein (SNCA) and microtubule-associated protein tau (MAPT) genes. Recently, a protective p.N551K-R1398H-K1423K haplotype in the leucine-rich repeat kinase 2 (LRRK2) gene was identified, with p.R1398H appearing to be the most likely functional variant. To date, the consistency of the protective effect of LRRK2 p.R1398H across MAPT and SNCA variant genotypes has not been assessed. To address this, we examined 4 SNCA variants (rs181489, rs356219, rs11931074, and rs2583988), the MAPT H1-haplotype–defining variant rs1052553, and LRRK2 p.R1398H (rs7133914) in Caucasian (n = 10,322) and Asian (n = 2289) series. There was no evidence of an interaction of LRRK2 p.R1398H with MAPT or SNCA variants (all p ≥ 0.10); the protective effect of p.R1398H was observed at similar magnitude across MAPT and SNCA genotypes, and the risk effects of MAPT and SNCA variants were observed consistently for LRRK2 p.R1398H genotypes. Our results indicate that the association of LRRK2 p.R1398H with Parkinson's disease is independent of SNCA and MAPT variants, and vice versa, in Caucasian and Asian populations. [Copyright &y& Elsevier]

• The study examined the cross-sectional association between characteristics of reproductive history, use of exogenous hormones and fast walking speed among >30,000 French women aged 45 to 69 years. • Age at menarche, age at first birth and duration of breastfeeding were positively associated with fast walking speed. • There was a quadratic association of fast walking speed with parity among parous women. • Among menopausal women, age at menopause was positively associated with fast walking speed. • Fast walking speed increased with reproductive lifetime duration and decreased with time since onset of menopause. • There was no association of fast walking speed with oral contraception and postmenopausal hormone therapy. To investigate the cross-sectional associations of reproductive history and use of exogenous hormones with fast walking speed (WS) in women. 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. Fast WS. Mean WS was 172.2 cm/s. WS increased with age at menarche (β +1y = 0.23, 95 % confidence interval = 0.05 to 0.40), age at first birth (β +1y = 0.20, 95 % CI = 0.13 to 0.27) and duration of breastfeeding (β for ≥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 (β +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 (β +5y = 0.49, 95 % CI = 0.16 to 0.83) and decreased with time since onset of menopause (β +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. Our findings suggest that reproductive life characteristics may be associated with WS and timing of exposure could play a role. [ABSTRACT FROM AUTHOR]

We examined the effect of salivary cortisol on cognitive performance and decline in 3229 adults (79% men), mean age 61 years. Six saliva samples over the day along with a cognition test battery were administered twice in 5 years. In fully-adjusted cross-sectional analyses from 2002 to 2004, higher waking cortisol was associated with higher reasoning score (β = 0.08, 95% confidence interval: 0.01, 0.15) but this finding was not replicated using data from 2007 to 2009. Over the mean 5 years follow-up there was decline in all cognitive tests but this decline did not vary as a function of cortisol levels; the exception was among APOE e4 carriers where a flatter diurnal slope and higher bedtime cortisol were associated with faster decline in verbal fluency. Changes in cortisol measures between 2002/2004 and 2007/2009 or chronically elevated levels were not associated with cognitive performance in 2007/2009. These results, based on a large sample of community-dwelling adults suggest that variability in hypothalamic-pituitary-adrenal function is not a strong contributor to cognitive aging. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Objective: To examine the longitudinal relation of dopamine agonists (DA) use with body mass index (BMI) change and weight gain in Parkinson's disease (PD).Methods: In a cohort of 356 patients with PD annually followed up to 6 years, BMI, antiparkinsonian drugs use, and impulse control disorders (ICDs) were assessed at each visit. DA dose trajectories were estimated using latent class mixed models. The association of DA use with BMI change and weight gain was examined using latent-process mixed models and time-dependent Cox models respectively, while adjusting for disease severity and levodopa (LD) use.Results: In the mixed model, BMI (kg/m2) increased over the follow-up in DA users (betaDA×time = 0.13, 95% CI = 0.02, 0.24) compared to non-users, while it decreased in LD users (betaLD×time = -0.26, 95% CI = -0.38, -0.13). We identified three trajectories of average daily DA dose over the follow-up. Patients in the high trajectory gained more weight than patients who never used DA (P = .001) and in the low (P = .02) or moderate (P = .04) trajectories. The incidence of weight gain of ≥6 kg was 2.10-fold (95% CI = 1.03, 4.28) higher in DA users compared to non-users, while LD users were less likely to gain weight (HR = 0.60, 95% CI = 0.33, 1.11). Associations decreased in analyses adjusted for compulsive eating or ICDs.Conclusion: Weight increased in DA users over 6 years, and DA use was associated with increased incidence of weight gain. These associations were partially explained by compulsive eating. Alternatively, weight decreased in LD users. These findings warrant careful monitoring of compulsive eating and weight in PD patients. [ABSTRACT FROM AUTHOR]

To examine the relationship between a Parkinson's disease (PD) polygenic risk score (PRS) and impulse control disorders (ICDs) in PD. 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. 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. 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). 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. • Younger Parkinson's disease onset is associated with the risk for impulse control disorders. • A polygenic risk score for Parkinson's disease is higher in young onset patients. • This study did not find an association between a PD polygenic risk score and ICDs. [ABSTRACT FROM AUTHOR]

Introduction: The management of impulse control disorders (ICDs) in Parkinson's disease (PD) relies on their early identification, allowing adjustment of antiparkinsonian treatment before these manifestations lead to major social, financial or legal consequences. The Questionnaire for Impulsive-Compulsive Disorders in Parkinson's Disease-Rating Scale (QUIP-RS) is an English-developed and -validated PD-specific rating scale constructed to support the rating of ICDs and related disorders and the assessment of changes in symptom severity over time, but it has not to date been validated in French.Methods: We conducted an observational, multicenter, cross-sectional study among a subset of patients (n = 280) from the Drug Interacting with Genes in PD (DIG-PD) cohort, aiming to assess psychometric properties of the French version of QUIP-RS: acceptability, internal consistency, factor analysis, reproductibility and hypotheses testing. In addition to this scale, the following measures were applied: MDS-Unified Parkinson's Disease Rating Scale, Mini-Mental State Examination, Frontal Assessment Behavior, and Ardouin Scale of Behavior in Parkinson's Disease (ASBPD).Results: Cronbach's alpha coefficient was 0.72 and ranged from 0.25 to 0.55. Regarding test-retest reliability and inter-rater reliability, the Lin concordance coefficient for items was higher than 0.58. The correlations between QUIP-RS and ASBPD were moderate to high except for dopaminergic addiction and hobbyism (r = 0.41 and 0.40 respectively, p < 0.001). No clinically significant correlation was found between QUIP-RS total score (and items) and other scales.Conclusion: The French version of the QUIP-RS appears to be a valid, reliable, and precise instrument for the assessment of ICDs and related disorders in PD. REGISTRATION NUMBER: clinicaltrials.gov number NCT01564992. [ABSTRACT FROM AUTHOR]

Background: Cognitive decline is a debilitating manifestation of disease progression in Parkinson's disease. We aimed to develop a clinical-genetic score to predict global cognitive impairment in patients with the disease.Methods: In this longitudinal analysis, we built a prediction algorithm for global cognitive impairment (defined as Mini Mental State Examination [MMSE] ≤25) using data from nine cohorts of patients with Parkinson's disease from North America and Europe assessed between 1986 and 2016. Candidate predictors of cognitive decline were selected through a backward eliminated Cox's proportional hazards analysis using the Akaike's information criterion. These were used to compute the multivariable predictor on the basis of data from six cohorts included in a discovery population. Independent replication was attained in patients from a further three independent longitudinal cohorts. The predictive score was rebuilt and retested in 10 000 training and test sets randomly generated from the entire study population.Findings: 3200 patients with Parkinson's disease who were longitudinally assessed with 27 022 study visits between 1986 and 2016 in nine cohorts from North America and Europe were assessed for eligibility. 235 patients with MMSE ≤25 at baseline and 135 whose first study visit occurred more than 12 years from disease onset were excluded. The discovery population comprised 1350 patients (after further exclusion of 334 with missing covariates) from six longitudinal cohorts with 5165 longitudinal visits over 12·8 years (median 2·8, IQR 1·6-4·6). Age at onset, baseline MMSE, years of education, motor exam score, sex, depression, and β-glucocerebrosidase (GBA) mutation status were included in the prediction model. The replication population comprised 1132 patients (further excluding 14 patients with missing covariates) from three longitudinal cohorts with 19 127 follow-up visits over 8·6 years (median 6·5, IQR 4·1-7·2). The cognitive risk score predicted cognitive impairment within 10 years of disease onset with an area under the curve (AUC) of more than 0·85 in both the discovery (95% CI 0·82-0·90) and replication (95% CI 0·78-0·91) populations. Patients scoring in the highest quartile for cognitive risk score had an increased hazard for global cognitive impairment compared with those in the lowest quartile (hazard ratio 18·4 [95% CI 9·4-36·1]). Dementia or disabling cognitive impairment was predicted with an AUC of 0·88 (95% CI 0·79-0·94) and a negative predictive value of 0·92 (95% 0·88-0·95) at the predefined cutoff of 0·196. Performance was stable in 10 000 randomly resampled subsets.Interpretation: Our predictive algorithm provides a potential test for future cognitive health or impairment in patients with Parkinson's disease. This model could improve trials of cognitive interventions and inform on prognosis.Funding: National Institutes of Health, US Department of Defense. [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]

Frailty is common and associated with poorer outcomes in the elderly, but its role as potential cardiovascular disease (CVD) risk factor requires clarification. We thus aimed to meta-analytically evaluate the evidence of frailty and pre-frailty as risk factors for CVD. Two reviewers selected all studies comparing data about CVD prevalence or incidence rates between frail/pre-frail vs. robust. The association between frailty status and CVD in cross-sectional studies was explored by calculating and pooling crude and adjusted odds ratios (ORs) ±95% confidence intervals (CIs); the data from longitudinal studies were pooled using the adjusted hazard ratios (HRs). Eighteen cohorts with a total of 31,343 participants were meta-analyzed. Using estimates from 10 cross-sectional cohorts, both frailty and pre-frailty were associated with higher odds of CVD than robust participants. Longitudinal data were obtained from 6 prospective cohort studies. After a median follow-up of 4.4 years, we identified an increased risk for faster onset of any-type CVD in the frail (HR = 1.70 [95%CI, 1.18–2.45]; I 2 = 66%) and pre-frail (HR = 1.23 [95%CI, 1.07–1.36]; I 2 = 67%) vs. robust groups. Similar results were apparent for time to CVD mortality in the frail and pre-frail groups. In conclusion, frailty and pre-frailty constitute addressable and independent risk factors for CVD in older adults. [ABSTRACT FROM AUTHOR]

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. 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). 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 (difference ICC = −0.04) and FWS (difference ICC = −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. 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. • Although agreement between manual and automated measures of walking speed was excellent, it was lower for 3 m than 5 m. • Reliability decreased with increasing fast walking speed, so that measurement error was higher for those who walk faster. • Longer distances are preferable in studies using manual measures of walking speed, especially for fast walking speed. [ABSTRACT FROM AUTHOR]

Abstract: We investigated the relationship of anthropometric markers of obesity with quantitative magnetic resonance imaging markers of brain aging, including measures of total brain volume (TBV), gray matter volume (GMV), hippocampal volume, white matter hyperintensity volume (WMHV), and brain infarcts, and examined causality using Mendelian randomization (MR). Analyses were performed in 1779 individuals (60.4% women, 72.8 ± 4.1 years of age) from the 3C-Dijon population-based cohort study (N = 1555 for the MR). Larger waist-to-hip-ratio (WHR) and waist circumference (WC) were associated with lower TBV (p = 0.0001 and p = 0.005), and lower GMV (p = 0.0008 and p = 0.003), independently of age, gender, body mass index (BMI), and vascular risk factors. Higher BMI, WC, and WHR were associated with larger WMHV and WC with brain infarcts, before adjusting for vascular risk factors only. We used MR to investigate the inverse relationship between WHR and GMV. One valid instrumental variable was available in women only (rs6905288), which was associated with GMV (p = 0.015). Age and BMI-adjusted effect estimates from the MR analysis confirmed the inverse association between GMV and WHR and are in favor of a causal association. [Copyright &y& Elsevier]

Abstract: Middle-aged subjects report subjective cognitive complaints (SSCs) but whether these are meaningfully related to health remains unknown. We examined the association between SCCs, both amnestic and non-amnestic, and mortality in a middle-aged population after taking into account the role of depression. 15,510 participants (26.2% women), mean age 57.9 years in 2002, from the French GAZEL study provided data on 3 measures of SCCs: memory complaints, cognitive symptoms (forgetfulness, difficulties in recalling memories, retaining new information, mental calculation, in language, and orientation) and whether they sought medical advice for SCCs. All-cause mortality was assessed between 2002 and 2012. Over the follow-up 56.3% participants reported memory problems, 62.6% cognitive complaints, 22.3% sought medical advice and 651 died. All SCCs were strongly associated (odds ratio 2.08–6.35) with depression which was itself associated with greater mortality (HR = 1.77, 95% CI: 1.50, 2.09). In analyses adjusted for age, sex, education, marital status and depression difficulty in mental calculation (HR = 1.30, 95% CI: 1.08, 1.60) and seeking medical advice for cognitive symptoms (HR = 1.41, 95% CI: 1.18, 1.68) were significantly associated with mortality, while memory complaints did not carry increased risk (HR = 0.93, 95% CI: 0.79, 1.09). All SCCS were strongly associated with depression but not all carried excess risk of mortality. [Copyright &y& Elsevier]

Summary: Background: Background The leucine-rich repeat kinase 2 gene (LRRK2) harbours highly penetrant mutations that are linked to familial parkinsonism. However, the extent of its polymorphic variability in relation to risk of Parkinson''s disease (PD) has not been assessed systematically. We therefore assessed the frequency of LRRK2 exonic variants in individuals with and without PD, to investigate the role of the variants in PD susceptibility. Methods: LRRK2 was genotyped in patients with PD and controls from three series (white, Asian, and Arab–Berber) from sites participating in the Genetic Epidemiology of Parkinson''s Disease Consortium. Genotyping was done for exonic variants of LRRK2 that were identified through searches of literature and the personal communications of consortium members. Associations with PD were assessed by use of logistic regression models. For variants that had a minor allele frequency of 0·5% or greater, single variant associations were assessed, whereas for rarer variants information was collapsed across variants. Findings: 121 exonic LRRK2 variants were assessed in 15 540 individuals: 6995 white patients with PD and 5595 controls, 1376 Asian patients and 962 controls, and 240 Arab–Berber patients and 372 controls. After exclusion of carriers of known pathogenic mutations, new independent risk associations were identified for polymorphic variants in white individuals (M1646T, odds ratio 1·43, 95% CI 1·15–1·78; p=0·0012) and Asian individuals (A419V, 2·27, 1·35–3·83; p=0·0011). A protective haplotype (N551K-R1398H-K1423K) was noted at a frequency greater than 5% in the white and Asian series, with a similar finding in the Arab–Berber series (combined odds ratio 0·82, 0·72–0·94; p=0·0043). Of the two previously reported Asian risk variants, G2385R was associated with disease (1·73, 1·20–2·49; p=0·0026), but no association was noted for R1628P (0·62, 0·36–1·07; p=0·087). In the Arab–Berber series, Y2189C showed potential evidence of risk association with PD (4·48, 1·33–15·09; p=0·012). Interpretation: The results for LRRK2 show that several rare and common genetic variants in the same gene can have independent effects on disease risk. LRRK2, and the pathway in which it functions, is important in the cause and pathogenesis of PD in a greater proportion of patients with this disease than previously believed. These results will help discriminate those patients who will benefit most from therapies targeted at LRRK2 pathogenic activity. Funding: Michael J Fox Foundation and National Institutes of Health. [Copyright &y& Elsevier]

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]

Abstract: We aimed at associating common osteopontin (OPN) gene variants with cardiovascular disease phenotypes.We scanned the OPN gene in 190 chromosomes from myocardial infarction (MI) patients and identified five variants in the promoter, three synonymous and one non-synonymous variant. All variants were investigated in case–control studies for MI (ECTIM: 990 cases, 900 controls) and brain infarction (BI) (GÉNIC: 466 cases, 444 controls). Promoter variants were functionally analyzed by bandshift assays, the coding D147D [T/C] by Western blot. Allele D147D C was independently and significantly associated with lower apoB levels (P =0.044 [ECTIM] P =0.03 [GENIC]), its allele frequency was significantly lower in patients with BI compared to controls (OR [95% CI] 0.39 [0.20–0.74], P =0.004), and C allele carriers had a significantly lower frequency of presence of carotid plaques (P =0.02). Bandshifts with HepG2 and Ea.hy926 nuclear proteins did not reveal any functionality of promoter variants, whereas the OPN-441C-containing construct resulted in reduced OPN protein expression in Western blots, complying with its potential protective effect on the phenotypes studied.We here provide evidence that a portion of the OPN locus is likely to associate with cardiovascular disease-related phenotypes. However, further experiments are warranted to clarify the functional role of OPN variants. [Copyright &y& Elsevier]

Myeloperoxidase (MPO) has been shown to contribute to several diseases and more particularly to atherosclerosis through excessive ROS production via the MPO/H2O2/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 (Ge´ne´tique de l'Infarctus Ce´re´bral) 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. [Copyright &y& Elsevier]

Genetics has proven to be a powerful approach in neurodegenerative diseases research, resulting in the identification of numerous causal and risk variants. Previously, we introduced the NeuroX Illumina genotyping array, a fast and efficient genotyping platform designed for the investigation of genetic variation in neurodegenerative diseases. Here, we present its updated version, named NeuroChip. The NeuroChip is a low-cost, custom-designed array containing a tagging variant backbone of about 306,670 variants complemented with a manually curated custom content comprised of 179,467 variants implicated in diverse neurological diseases, including Alzheimer's disease, Parkinson's disease, Lewy body dementia, amyotrophic lateral sclerosis, frontotemporal dementia, progressive supranuclear palsy, corticobasal degeneration, and multiple system atrophy. The tagging backbone was chosen because of the low cost and good genome-wide resolution; the custom content can be combined with other backbones, like population or drug development arrays. Using the NeuroChip, we can accurately identify rare variants and impute over 5.3 million common SNPs from the latest release of the Haplotype Reference Consortium. In summary, we describe the design and usage of the NeuroChip array and show its capability for detecting rare pathogenic variants in numerous neurodegenerative diseases. The NeuroChip has a more comprehensive and improved content, which makes it a reliable, high-throughput, cost-effective screening tool for genetic research and molecular diagnostics in neurodegenerative diseases. [ABSTRACT FROM AUTHOR]

Background: Background The leucine-rich repeat kinase 2 gene (LRRK2) harbours highly penetrant mutations that are linked to familial parkinsonism. However, the extent of its polymorphic variability in relation to risk of Parkinson's disease (PD) has not been assessed systematically. We therefore assessed the frequency of LRRK2 exonic variants in individuals with and without PD, to investigate the role of the variants in PD susceptibility.Methods: LRRK2 was genotyped in patients with PD and controls from three series (white, Asian, and Arab-Berber) from sites participating in the Genetic Epidemiology of Parkinson's Disease Consortium. Genotyping was done for exonic variants of LRRK2 that were identified through searches of literature and the personal communications of consortium members. Associations with PD were assessed by use of logistic regression models. For variants that had a minor allele frequency of 0·5% or greater, single variant associations were assessed, whereas for rarer variants information was collapsed across variants.Findings: 121 exonic LRRK2 variants were assessed in 15 540 individuals: 6995 white patients with PD and 5595 controls, 1376 Asian patients and 962 controls, and 240 Arab-Berber patients and 372 controls. After exclusion of carriers of known pathogenic mutations, new independent risk associations were identified for polymorphic variants in white individuals (M1646T, odds ratio 1·43, 95% CI 1·15-1·78; p=0·0012) and Asian individuals (A419V, 2·27, 1·35-3·83; p=0·0011). A protective haplotype (N551K-R1398H-K1423K) was noted at a frequency greater than 5% in the white and Asian series, with a similar finding in the Arab-Berber series (combined odds ratio 0·82, 0·72-0·94; p=0·0043). Of the two previously reported Asian risk variants, G2385R was associated with disease (1·73, 1·20-2·49; p=0·0026), but no association was noted for R1628P (0·62, 0·36-1·07; p=0·087). In the Arab-Berber series, Y2189C showed potential evidence of risk association with PD (4·48, 1·33-15·09; p=0·012).Interpretation: The results for LRRK2 show that several rare and common genetic variants in the same gene can have independent effects on disease risk. LRRK2, and the pathway in which it functions, is important in the cause and pathogenesis of PD in a greater proportion of patients with this disease than previously believed. These results will help discriminate those patients who will benefit most from therapies targeted at LRRK2 pathogenic activity.Funding: Michael J Fox Foundation and National Institutes of Health. [ABSTRACT FROM AUTHOR]

Objective Physical activity is critically important for successful aging, but its effect on adiposity markers at older ages is unclear as much of the evidence comes from self-reported data on physical activity. We assessed the associations of questionnaire-assessed and accelerometer-assessed physical activity with adiposity markers in older adults. Design/Setting/Participants This was a cross-sectional study on 3940 participants (age range 60-83 years) of the Whitehall II study who completed a 20-item physical activity questionnaire and wore a wrist-mounted accelerometer for 9 days in 2012 and 2013. Measurements Total physical activity was estimated using metabolic equivalent hours/week for the questionnaire and mean acceleration for the accelerometer. Time spent in moderate-and-vigorous physical activity (MVPA) was also assessed by questionnaire and accelerometer. Adiposity assessment included body mass index, waist circumference, and fat mass index. Fat mass index was calculated as fat mass/height² (kg/m²), with fat mass estimated using bioimpedance. Results Greater total physical activity was associated with lower adiposity for all adiposity markers in a dose-response manner. In men, the strength of this association was 2.4 to 2.8 times stronger with the accelerometer than with questionnaire data. In women, it was 1.9 to 2.3 times stronger. For MVPA, questionnaire data in men suggested no further benefit for adiposity markers past 1 hour/week of activity. This was not the case for accelerometer-assessed MVPA where, for example, compared with men undertaking <1 hour/week of accelerometer-assessed MVPA, waist circumference was 3.06 (95% confidence interval 2.06–4.06) cm lower in those performing MVPA 1–2.5 hours/week, 4.69 (3.47–5.91) cm lower in those undertaking 2.5–4 hours/week, and 7.11 (5.93–8.29) cm lower in those performing ≥4 hours/week. Conclusions The association of physical activity with adiposity markers in older adults was stronger when physical activity was assessed by accelerometer compared with questionnaire, suggesting that physical activity might be more important for adiposity than previously estimated. [ABSTRACT FROM AUTHOR]

Abstract: Sepiapterin reductase (SPR) gene is an enzyme which catalyses the final step of tetrahydrobiopterin synthesis (BH4) and was implicated in Parkinson''s disease (PD) pathogenesis as a candidate gene for PARK3 locus. A number of studies yielded association of the PARK3 locus with PD, and SPR knockout mice were shown to display parkinsonian features. To evaluate the role of SPR gene polymorphisms in diverse populations in PD, we performed collaborative analyses in the Genetic Epidemiology of Parkinson Disease (GEO-PD) Consortium. A total of 5 single nucleotide polymorphisms (3 in the promoter region and 2 in the 3′ untranslated region [UTR]) were genotyped. Fixed as well as random effect models were used to provide summary risk estimates of SPR variants. A total of 19 sites provided data for 6547 cases and 9321 controls. Overall odds ratio estimates varied from 0.92 to 1.01. No overall association with the SPR gene using either fixed effect or random effect model was observed in the studied population. I2 Metric varied from 0% to 36.2%. There was some evidence for an association for participants of North European/Scandinavian descent with the strongest signal for rs1876487 (odds ratio = 0.82; p value = 0.003). Interestingly, families which were used to map the PARK3 locus, have Scandinavian ancestry suggesting a founder effect. In conclusion, this large association study for the SPR gene revealed no association for PD worldwide. However, taking the initial mapping of the PARK3 into account, the role of a population-specific effect warrants consideration in future studies. [Copyright &y& Elsevier]

Abstract: High-profile studies have provided conflicting results regarding the involvement of the Omi/HtrA2 gene in Parkinson''s disease (PD) susceptibility. Therefore, we performed a large-scale analysis of the association of common Omi/HtrA2 variants in the Genetic Epidemiology of Parkinson''s disease (GEO-PD) consortium. GEO-PD sites provided clinical and genetic data including affection status, gender, ethnicity, age at study, age at examination (all subjects); age at onset and family history of PD (patients). Genotyping was performed for the five most informative SNPs spanning the Omi/HtrA2 gene in approximately 2–3kb intervals (rs10779958, rs2231250, rs72470544, rs1183739, rs2241028). Fixed as well as random effect models were used to provide summary risk estimates of Omi/HtrA2 variants. The 20 GEO-PD sites provided data for 6378 cases and 8880 controls. No overall significant associations for the five Omi/HtrA2 SNPs and PD were observed using either fixed effect or random effect models. The summary odds ratios ranged between 0.98 and 1.08 and the estimates of between-study heterogeneity were not large (non-significant Q statistics for all 5 SNPs; I 2 estimates 0–28%). Trends for association were seen for participants of Scandinavian descent for rs2241028 (OR 1.41, p =0.04) and for rs1183739 for age at examination (cut-off 65 years; OR 1.17, p =0.02), but these would not be significant after adjusting for multiple comparisons and their Bayes factors were only modest. This largest association study performed to define the role of any gene in the pathogenesis of Parkinson''s disease revealed no overall strong association of Omi/HtrA2 variants with PD in populations worldwide. [Copyright &y& Elsevier]