Postmenopausal Hormone Therapy and Risk of Stroke: Impact of the Route of Estrogen Administration and Type of Progestogen.

BACKGROUND AND PURPOSE: The benefit/risk analysis of hormone therapy in postmenopausal women is not straightforward and depends on cardiovascular disease. Evidence supports the safety of transdermal estrogens and the importance of progestogens for thrombotic risk. However, the differential association of oral and transdermal estrogens with stroke remains poorly investigated. Furthermore, there are no data regarding the impact of progestogens. METHODS: We set up a nested case-control study of ischemic stroke (IS) within all French women aged 51 to 62 years between 2009 and 2011 without personal history of cardiovascular disease or contraindication to hormone therapy. Participants were identified using the French National Health Insurance database, which includes complete drug claims for the past 3 years and French National hospital data. We identified 3144 hospitalized IS cases who were matched for age and zip code to 12 158 controls. Conditional logistic regression was used to estimate odds ratios (OR) and 95% confidence intervals (95% CI). RESULTS: Compared with nonusers, the adjusted ORs of IS were1.58 (95% CI, 1.01-2.49) in oral estrogen users and 0.83 (0.56-1.24) in transdermal estrogens users (P<0.01). There was no association of IS with use of progesterone (OR, 0.78; 95% CI, 0.49-1.26), pregnanes (OR, 1.00; 95% CI, 0.60-1.67), and nortestosterones (OR, 1.26; 95% CI, 0.62-2.58), whereas norpregnanes increased IS risk (OR, 2.25; 95% CI, 1.05-4.81). CONCLUSIONS: Both route of estrogen administration and progestogens were important determinants of IS. Our findings suggest that transdermal estrogens might be the safest option for short-term hormone therapy use.

A meta-analysis of genome-wide association studies identifies ORM1 as a novel gene controlling thrombin generation potential.

Thrombin, the major enzyme of the hemostatic system, is involved in biological processes associated with several human diseases. The capacity of a given individual to generate thrombin, called the thrombin generation potential (TGP), can be robustly measured in plasma and was shown to associate with thrombotic disorders. To investigate the genetic architecture underlying the interindividual TGP variability, we conducted a genome-wide association study in 2 discovery samples (N = 1967) phenotyped for 3 TGP biomarkers, the endogenous thrombin potential, the peak height, and the lag time, and replicated the main findings in 2 independent studies (N = 1254). We identified the ORM1 gene, coding for orosomucoid, as a novel locus associated with lag time variability, reflecting the initiation process of thrombin generation with a combined P value of P = 7.1 × 10(-15) for the lead single nucleotide polymorphism (SNP) (rs150611042). This SNP was also observed to associate with ORM1 expression in monocytes (P = 8.7 × 10(-10)) and macrophages (P = 3.2 × 10(-3)). In vitro functional experiments further demonstrated that supplementing normal plasma with increasing orosomucoid concentrations was associated with impaired thrombin generation. These results pave the way for novel mechanistic pathways and therapeutic perspectives in the etiology of thrombin-related disorders.

Parkinson disease male-to-female ratios increase with age: French nationwide study and meta-analysis.

BACKGROUND: Parkinson's disease (PD) is 1.5 times more frequent in men than women. Whether age modifies this ratio is unclear. We examined whether male-to-female (M-F) ratios change with age through a French nationwide prevalence/incidence study (2010) and a meta-analysis of incidence studies. METHODS: We used French national drug claims databases to identify PD cases using a validated algorithm. We computed M-F prevalence/incidence ratios overall and by age using Poisson regression. Ratios were regressed on age to estimate their annual change. We identified all PD incidence studies with age/sex-specific data, and performed a meta-analysis of M-F ratios. RESULTS: On the basis of 149 672 prevalent (50% women) and 25 438 incident (49% women) cases, age-standardised rates were higher in men (prevalence=2.865/1000; incidence=0.490/1000 person-years) than women (prevalence=1.934/1000; incidence=0.328/1000 person-years). The overall M-F ratio was 1.48 for prevalence and 1.49 for incidence. Prevalence and incidence M-F ratios increased by 0.05 and 0.14, respectively, per 10 years of age. Incidence was similar in men and women under 50 years (M-F ratio <1.2, p>0.20), and over 1.6 (p<0.001) times higher in men than women above 80 years (p trend <0.001). A meta-analysis of 22 incidence studies (14 126 cases, 46% women) confirmed that M- F ratios increased with age (0.26 per 10 years, p trend=0.005). CONCLUSIONS: Age-increasing M-F ratios suggest that PD aetiology changes with age. Sex-related risk/protective factors may play a different role across the continuum of age at onset. This finding may inform aetiological PD research.

Carotid plaque as a predictor of dementia in older adults: the Three-City Study.

BACKGROUND: The contribution of carotid atherosclerosis to incident dementia remains unclear. We examined the association between carotid plaques (CP) and common carotid intima media thickness (CCA-IMT) with incident dementia and its subtypes, and their added value for dementia risk prediction. METHODS: At baseline, 6025 dementia-free subjects aged 65-86 years underwent bilateral carotid ultrasonography measures of CP and plaque-free CCA-IMT. Subjects were followed-up over 7 years for the detection of dementia. RESULTS: After a mean 5.4 years of follow-up, 421 subjects developed dementia including 272 Alzheimer's disease and 83 vascular/mixed dementia (VaD). Only CP were independently related to VaD (HR(≥2 sites with plaques) = 1.92; 95% confidence interval or CI = 1.13-3.22) and improved VaD risk prediction (continuous Net Reclassification Index = 30.1%; 95% CI = 8.4-51.7) beyond known dementia risk factors. Accounting for stroke or competing risk by death marginally modified the results. CONCLUSION: In older adults, CP are independent predictors of incident VaD and may improve VaD risk prediction.

Estrogen receptor polymorphisms and incident dementia: the prospective 3C study.

BACKGROUND: Genetic variation in the estrogen receptor (ESR) may be associated with the incidence of Alzheimer's disease (AD), but this association could be modified by genetic and environmental factors. METHODS: The association between five ESR α (ESR1) and ß (ESR2) polymorphisms with 7-year dementia incidence was examined among 6959 older men and women from the Three City Study using multivariate-adjusted Cox regression models with delayed entry. Gender, the apolipoprotein E (APOE) ε4 allele, and hormone treatment were considered as potential effect modifiers of this association. RESULTS: Among women, the CC genotype of ESR1rs2234693 was specifically associated with a small increased risk of AD (adjusted hazard ratio [HR]: 1.54, 95% confidence interval [CI]: 1.03-2.28, P = .03). However, women with this genotype had a substantially increased risk of AD associated with the APOE ε4 allele (adjusted HR: 3.24, 95% CI: 1.81-5.79 for women rs2234693 CC; compared with HR: 1.87, 95% CI: 1.37-2.56 for all women). There was also evidence of a nominally significant interaction between the ESR1 and ESR2 polymorphisms on the risk of all dementias (P = .04). Hormone treatment did not modify these associations, and there were no significant associations in men. CONCLUSIONS: Although there was only weak support for a gender-specific association between the common ESR1rs2234693 polymorphism and AD, this polymorphism may act as an effect modifier, modifying the association between an ESR2 polymorphism and dementia, as well as the risk of AD associated with the APOE ε4 allele.

Low testosterone and the risk of dementia in elderly men: Impact of age and education.

OBJECTIVE: The objective of this study was to examine the association of plasma estradiol and testosterone with risk for dementia in elderly men. METHODS: Within the population based Three-City study, including 3650 men age 65 years and older, a case-cohort design was set up after 4-years of follow-up. Baseline plasma levels of total 17-ß estradiol (Total-E2), total testosterone (total-T) and bioavailable testosterone (bio-T) were measured for all cases of incident dementia (n=105) and for a random sample of the cohort (n=413). Cox regression models were used to estimate multivariate steroid sex hormone-associated hazard ratios (HR) and 95% confidence intervals of dementia. RESULTS: There was a reverse J-shaped relationship between total-T and risk for dementia (P=.007). Compared with the median tertile, the HRs associated with total-T in the lower and upper tertile were increased (HR, 2.33; P=.026; HR, 1.9, P=.126; respectively). Low bio-T was associated with a greater risk for dementia (HR for one standard deviation of decreasing log(bio-T), 1.29; 95% confidence interval, 1.03-1.62). An interaction was found between bio-T and age (P<.0001), and bio-T and education (P=.044). Risk for dementia associated with low bio-T was greater in older men (80 years or older) than in younger men (younger than 80 years; HR, 3.11; P=.011 vs. HR, 1.07, P=.715, respectively) and in men with high level of education compared with those with low level of education (HR, 2.32; P=.0002 vs. HR, 0.95; P=.790, respectively). No significant association was found between Total-E2 and dementia. CONCLUSIONS: Low levels of testosterone are associated with a risk for dementia in elderly men. The association between low bio-T and dementia may be more relevant to men 80 years or older and men with a high level of education.

Endogenous oestradiol as a positive correlate of plasma fibrinogen among older postmenopausal women: a population-based study (the Three-City cohort study).

BACKGROUND: Plasma fibrinogen is a strong predictor of ischaemic arterial disease in women. Sex steroid hormones including hormone therapy may play an important role in the development of cardiovascular disease. However, whether endogenous sex steroid hormones influence the plasma fibrinogen concentrations among postmenopausal women remains unclear. OBJECTIVES: To investigate the association of plasma fibrinogen levels with endogenous sex steroid hormones and sex hormone binding globulin (SHBG) among postmenopausal women. METHODS: We used data from the French prospective Three-City cohort study that included 9294 noninstitutionalized men and women over 65 years of age. Total 17ß-oestradiol (E2, pg/ml), total testosterone (T, ng/ml), SHBG (nm) and fibrinogen (g/l) were measured in stored plasmas in a subcohort of 602 randomly selected postmenopausal women who used neither hormone medication nor anticoagulation therapy. Multivariate linear regression models were used to estimate the regression coefficients assessed in fibrinogen unit by 1 SD increase in log-distribution of sex steroid hormones and SHBG. RESULTS: E2 but neither T nor SHBG was positively associated with plasma fibrinogen levels (ß = 0·148, P < 0·001). Adjustment for cardiovascular risk factors including diabetes made no substantial change to the results (ß = 0·145, P < 0·001). The association of fibrinogen with E2 was stronger among women with body mass index over 25 kg/m(2) compared with those with normal weight (ß = 0·156, P < 0·001 and ß = 0·092, P = 0·02, respectively, P for interaction = 0·04). CONCLUSION: E2 emerges as a positive and independent correlate of plasma fibrinogen among postmenopausal women, especially in subjects who are overweight. These findings suggest a deleterious effect of endogenous oestrogens on cardiovascular risk profile among postmenopausal women.

Increased thrombin generation is associated with acute ischemic stroke but not with coronary heart disease in the elderly: the Three-City cohort study.

OBJECTIVE: A high thrombin generation level has been associated with the risk of venous thrombosis. Whether changes in this biomarker are relevant to arterial disease remains unknown. We investigated the association of thrombin generation with coronary heart disease (CHD) and acute ischemic stroke (AIS) in the elderly. METHODS AND RESULTS: We used data from the Three-City study, a prospective cohort including 9294 subjects aged >65 years. After 4 years of follow-up, a case-cohort study was established. Using the calibrated automated thrombography method, endogenous thrombin potential and peak height were measured in plasma samples of all CHD and AIS cases and a random sample of 1177 controls. We did not find any significant association between thrombin generation and CHD. In multivariate analyses, high levels of endogenous thrombin potential and peak height were associated with an increased risk of AIS (hazard ratio=1.16 [95% CI, 0.90 to 1.50] and 1.31 [95% CI, 1.01 to 1.69] for a 1 SD increase, respectively). Data also suggested that these associations might be more important in women (hazard ratio=1.55 [95% CI, 1.05 to 2.33] and 1.71 [95% CI, 1.11 to 2.63], respectively) than in men (P for interaction=0.04 and 0.08, respectively). CONCLUSION: Thrombin generation emerges as an independent predictor of AIS, particularly in women. Hypercoagulability may have an important role in the pathogenesis of AIS.

Multiple imputation for estimating hazard ratios and predictive abilities in case-cohort surveys.

BACKGROUND: The weighted estimators generally used for analyzing case-cohort studies are not fully efficient and naive estimates of the predictive ability of a model from case-cohort data depend on the subcohort size. However, case-cohort studies represent a special type of incomplete data, and methods for analyzing incomplete data should be appropriate, in particular multiple imputation (MI). METHODS: We performed simulations to validate the MI approach for estimating hazard ratios and the predictive ability of a model or of an additional variable in case-cohort surveys. As an illustration, we analyzed a case-cohort survey from the Three-City study to estimate the predictive ability of D-dimer plasma concentration on coronary heart disease (CHD) and on vascular dementia (VaD) risks. RESULTS: When the imputation model of the phase-2 variable was correctly specified, MI estimates of hazard ratios and predictive abilities were similar to those obtained with full data. When the imputation model was misspecified, MI could provide biased estimates of hazard ratios and predictive abilities. In the Three-City case-cohort study, elevated D-dimer levels increased the risk of VaD (hazard ratio for two consecutive tertiles = 1.69, 95%CI: 1.63-1.74). However, D-dimer levels did not improve the predictive ability of the model. CONCLUSIONS: MI is a simple approach for analyzing case-cohort data and provides an easy evaluation of the predictive ability of a model or of an additional variable.

Postmenopausal hormone therapy and risk of idiopathic venous thromboembolism: results from the E3N cohort study.

OBJECTIVE: Oral estrogen therapy increases venous thromboembolism risk among postmenopausal women. Although recent data showed transdermal estrogens may be safe with respect to thrombotic risk, the impact of the route of estrogen administration and concomitant progestogens is not fully established. METHODS AND RESULTS: We used data from the E3N French prospective cohort of women born between 1925 and 1950 and biennially followed by questionnaires from 1990. Study population consisted of 80 308 postmenopausal women (average follow-up: 10.1 years) including 549 documented idiopathic first venous thromboembolism. Hazard ratios (HR) and 95% confidence intervals (CI) were estimated using Cox proportional models. Compared to never-users, past-users of hormone therapy had no increased thrombotic risk (HR=1.1; 95% CI: 0.8 to 1.5). Oral not transdermal estrogens were associated with increased thrombotic risk (HR=1.7; 95% CI: 1.1 to 2.8 and HR=1.1; 95% CI: 0.8 to 1.8; homogeneity: P=0.01). The thrombotic risk significantly differed by concomitant progestogens type (homogeneity: P<0.01): there was no significant association with progesterone, pregnanes, and nortestosterones (HR=0.9; 95% CI: 0.6 to 1.5, HR=1.3; 95% CI: 0.9 to 2.0 and HR=1.4; 95% CI: 0.7 to 2.4). However, norpregnanes were associated with increased thrombotic risk (HR=1.8; 95% CI: 1.2 to 2.7). CONCLUSIONS: In this large study, we found that route of estrogen administration and concomitant progestogens type are 2 important determinants of thrombotic risk among postmenopausal women using hormone therapy. Transdermal estrogens alone or combined with progesterone might be safe with respect to thrombotic risk.

A subtest of the MMSE as a valid test of episodic memory? Comparison with the Free and Cued Reminding Test.

BACKGROUND/AIMS: Episodic memory impairment is known to be the core of Alzheimer's disease (AD) dementia syndrome and one of the earliest domains to decline. However, episodic memory tests are long and expensive. METHODS: In a sample of the French Three-City Study (n = 1,516), we aimed at validating a subtest of the Mini-Mental State Examination (MMSE) specifically measuring episodic memory. We focused on the correlation between 7 MMSE subscores and 4 scores of the Free and Cued Selective Reminding Test (FCSRT) evaluating episodic memory. We performed linear regressions and principal component analyses to identify which MMSE subscores were better correlated with the FCSRT scores. Thereafter, we conducted validation analyses on the whole sample (n = 9,077). RESULTS: We found that subscores for orientation to time and the 3-word recall task were well correlated with FCSRT scores. The summation of these 2 subscores was more strongly associated with dementia and AD than the FCSRT scores and the total MMSE score. CONCLUSION: Orientation to time and the 3-word recall task might provide a good measure of episodic memory. Making the evaluation of episodic memory faster and cheaper, this finding can be of direct interest for practitioners and epidemiologists.

Non-pharmacological management of behavioural symptoms in nursing homes.

BACKGROUND: Behavioural and psychological symptoms of dementia (BPSD) are often reported in institutions for the elderly. OBJECTIVE: To evaluate the effectiveness of a staff education intervention to manage BPSD in older people with a diagnosis of dementia. METHODS: The trial was conducted in 16 nursing homes; 306 patients with a diagnosis of dementia and presenting BPSD were selected. Nursing homes were randomly allocated to an intervention group or a control group. An 8-week staff education and training programme was conducted in the nursing homes in the intervention group. The main outcome measures were the Cohen-Mansfield Agitation Inventory (CMAI) and an Observation Scale (OS) score. Assessments were done at baseline (W0), at the end of the 'intervention' period (W8) and 12 weeks after (W20). RESULTS: There was a significant decrease in the global CMAI score between baseline and W8 (-7.8; p > 0.01) and between baseline and W20 (-6.5; p > 0.01) in the intervention group but not in the control group. Results of mixed linear models showed that the CMAI global score, the CMAI physically non-aggressive behaviours subscale score and verbally non-aggressive behaviours subscale score significantly decreased in the intervention group (p < 0.001) although there was no significant evolution in the control group. Direct assessment with the OS produced the same pattern of results, with a significant decrease only in the intervention group. CONCLUSION: The intervention reduced BPSD in severely demented nursing home residents and this effect was still present 3 months after the end of the programme.

Synergism between oral estrogen therapy and cytochrome P450 3A5*1 allele on the risk of venous thromboembolism among postmenopausal women.

CONTEXT: Hormone therapy increases the risk of venous thromboembolism (VTE) among postmenopausal women. This effect may be modulated by the expression of cytochromes P450 3A5 (CYP3A5) and 1A2 (CYP1A2) which are involved in the hepatic metabolism of estrogens. OBJECTIVE: The objective was to investigate the impact of CYP3A5 and CYP1A2 genetic polymorphisms on the association of VTE with hormone therapy. DESIGN: We conducted a case-control study. SETTING: This study was conducted in eight French hospital centers and in the general population. PATIENTS: CYP3A5 and CYP1A2 genotypes were evaluated among 195 cases with a first documented episode of idiopathic VTE and 533 controls matched for center, age, and admission date. OUTCOME MEASURE: The outcome measure was hormone therapy by route of estrogen administration. RESULTS: Overall, oral but not transdermal estrogen increased VTE risk [odds ratio (OR) = 4.5, 95% confidence interval (CI) = 2.6-7.6, and OR = 1.2, 95% CI = 0.8-1.8, respectively]. The allele frequency of CYP3A5*1 was 9 and 10% among cases and controls (OR = 1.0; 95% CI = 0.6-1.5) and that of CYP1A2*1F was 72 and 71% among cases and controls (OR = 1.5; 95% CI = 0.8-2.8). Compared with nonusers, OR for VTE in users of oral estrogen was 3.8 (95% CI = 2.1-6.7) among patients without CYP3A5*1 allele and 30.0 (95% CI = 4.4-202.9) among patients with this allele (test for interaction P = 0.04). By contrast, there was no significant interaction between CYP3A5*1 allele and transdermal estrogen on VTE risk. There is no interaction between CYP1A2 genetic polymorphism and hormone therapy on VTE risk. CONCLUSIONS: Women with CYP3A5*1 allele using oral estrogen can define a subgroup at high VTE risk. Additional data are needed to assess the relevance of this genetic biomarker in the medical management of menopause.

Clustering and switching processes in semantic verbal fluency in the course of Alzheimer's disease subjects: results from the PAQUID longitudinal study.

Reduced semantic fluency performances have been reported in the preclinical phase of Alzheimer's disease (AD). To investigate the cognitive processes underlying this early deficit, this study analyzed the verbal production of predemented subjects for the animals category with the qualitative parameters related to clustering (i.e. the ability to generate words belonging to semantic subcategories of animals) and switching (i.e. the ability to shift from one subcategory to another) proposed by Troyer. This qualitative analysis was applied to the PAQUID (Personnes Agées QUID) cohort, a 17-year longitudinal population-based study. The performances on the animal verbal fluency task of 51 incident cases of possible and probable AD were analyzed at the onset of dementia, 2 years and 5 years before dementia onset. Each case was matched for age, sex and education to two control subjects leading to a sample of 153 subjects. The mean cluster size and the raw number of switches were compared in the two samples. The results revealed a significantly lower switching index in the future AD subjects than in the elderly controls including 5 years before dementia incidence. A significant decline in this parameter was evidenced all along the prodromal phase until the clinical diagnosis of dementia. In contrast, the mean cluster size could not discriminate the two groups. Therefore the results support the hypothesis that impaired shifting abilities - rather than semantic memory storage degradation - could explain the early decline in semantic fluency performance occurring in the predementia phase of AD.

Vasodilators and nootropics as predictors of dementia and mortality in the PAQUID cohort.

OBJECTIVES: To assess the effects of treatment for memory impairment and the Ginkgo biloba extract (EGb 761) on dementia, mortality, and survival without dementia. DESIGN: Prospective community-based cohort study. SETTING: France. PARTICIPANTS: Three thousand five hundred thirty-four subjects aged 65 and older. MEASUREMENTS: Information on drug consumption was obtained by interview and visual assessment of patients' medicine chests. Active screening of dementia was performed every 2 years over a 13-year period. The independent effects of treatment for memory impairment and the Ginkgo biloba extract on the risks of dementia and death were estimated using Cox proportional hazards models, adjusted for potentially confounding factors (including comorbidities). RESULTS: The initial consumption of Ginkgo biloba did not modify the risk of dementia (relative risk (RR)=1.16, 95% confidence interval (CI)=0.84-1.60), whereas the consumption of other treatments for memory impairment was associated with a higher risk of dementia (RR=1.35, 95% CI=1.11-1.63). Subjects who took Ginkgo biloba had a significantly lower risk of mortality in the long term (RR=0.76, 95% CI=0.62-0.93), even after adjustment for potentially confounding factors. The initial consumption of treatment for memory impairment other than Ginkgo biloba did not modify the risk of mortality. CONCLUSION: These results suggest that treatment with EGb 761 may increase the probability of survival in the elderly population. These findings need to be corroborated and further assessed using randomized, controlled trials.

Evaluation of a program to reduce motor-vehicle collisions among young adults in the county of Landes, France.

The aim of this study was to evaluate the impact of a prevention program called "Atout-Route", based on the concept of commitment. The program was implemented in March 2000, to reduce the number of drivers under the age of 25 years involved in motor-vehicle collisions in the county of Landes (southwestern France). Using data from the regional observatory of road safety, we defined a target and three control groups similar on age or location. We used Poisson and quasi-Poisson regression to estimate whether the observed evolution of motor-vehicle collisions, after the program was implemented, was different in the targeted group than in the three control groups. The number of motor-vehicle collisions decreased everywhere and in every age group. The effect of the prevention program was not statistically significant (relative risk=0.89; 95% confidence interval 0.74-1.07). Our results are compatible with a positive effect of the program. The possible dilution of its effect by national road safety actions implemented since 2000, and our early assessment are possible reasons for the non-significant observation.

High plasma estradiol interacts with diabetes on risk of dementia in older postmenopausal women.

OBJECTIVE: We aimed to investigate the impact of endogenous estradiol (E2) on dementia and to evaluate the contribution of vascular risk factors and inflammatory and blood coagulation markers to this association. METHODS: Using data from a French population-based prospective study (the Three-City Study) including 5,644 postmenopausal women aged 65 years or older, we investigated the association of endogenous total-E2 and bioavailable-E2 and total-testosterone with the 4-year incidence of all-cause dementia. We further focused on the role of dementia and cardiovascular risk factors as well as inflammation (C-reactive protein, fibrinogen) and hypercoagulability (fibrin d-dimers, thrombin generation) in these associations. We used a case-cohort design consisting of a random subcohort of 562 women not using hormone therapy and 132 incident dementia cases. RESULTS: Adjusted Cox proportional hazards models showed a J-shaped relationship between total-E2 and risk of dementia (p = 0.001). Total-E2 values in the lower and upper quartiles were associated with an increased dementia risk (adjusted hazard ratio [HR] [95% confidence interval] = 2.2 [1.1-4.5] and HR = 2.4 [1.2-5.2], respectively). Importantly, the risk associated with higher E2 levels was dramatically increased in women with diabetes compared with nondiabetic women (adjusted HR associated with the upper E2 quartile = 14.2 [1.60-123] and HR = 3.4 [0.1-147], respectively, p interaction <0.05). Similar results were found for bioavailable-E2. Adjustment for inflammatory and blood coagulation markers did not modify our results. No significant association was found for total-testosterone. CONCLUSION: High E2 level is an independent predictor of incident dementia, particularly in postmenopausal women with diabetes.

A new operational definition of frailty: the Frailty Trait Scale.

OBJECTIVES: To provide a new instrument to diagnose frailty, the Frailty Trait Scale (FTS), that allows a more precise assessment and monitoring of individuals. DESIGN: Prospective population-based cohort study. SETTING: The Toledo Study for Healthy Aging, Spain. PARTICIPANTS: A total of 1972 men and women aged 65 years or older. MEASUREMENTS: We identified 7 frailty dimensions (energy balance-nutrition, physical activity, nervous system, vascular system, strength, endurance, and gait speed) represented by 12 items. Each item was pondered based on the quintiles of its distribution in the study population. Validity was evaluated by testing its association with factors related to frailty and its predictive value for adverse events. This predictive capacity was further compared with the capacity of 2 well-established frailty models (the frailty phenotype and the Frailty Index). RESULTS: FTS score was associated with several comorbidities and biomarkers classically associated with frailty. The FTS was associated with the incidence of hospitalization and mortality (hazard ratio associated with a score in the highest quartile [versus the first quartile] = 2.3, 95% confidence interval [CI] 1.6-3.4, and 2.5, 95% CI 1.8-3.6, respectively). Compared with Fried et al's definition, the FTS showed a better predictor for hospitalization in persons younger than 80 (area under the curve [AUC] = 0.65 vs 0.62, P = .01), and for mortality in the oldest group (AUC = 0.77 vs 0.72, P = .02). FTS showed similar predictive value to the Frailty Index. CONCLUSION: FTS associates with many of the factors linked to frailty and has a similar predictive capacity to that provided by the classical instruments. Its characteristics offer some advantages over them, with potential utility in research and clinical practice.

Association between endothelial dysfunction and frailty: the Toledo Study for Healthy Aging.

Cardiovascular disease (CVD), both clinical and subclinical, has been proposed as one of the mechanisms underlying frailty. However, there is no evidence addressing the relationship between the earliest stage of CVD (endothelial dysfunction) and frailty. The goal of the study was to analyze the association between endothelial dysfunction, evaluated by asymmetric dimethylarginine (ADMA) levels, and frailty. We used data from the Toledo Study for Healthy Aging, a prospective Spanish cohort study. Biological samples were obtained and ADMA levels were determined using an enzyme immunoassay method. Logistic regression was used to estimate the odds ratio (OR) and 95 % confidence intervals of frailty associated with ADMA. Adjustments were made for age, gender, cardiovascular risk factors, and presence of atherosclerotic disease (assessed by ankle­brachial index; ABI). One thousand two hundred eighty-seven community-dwelling elderly were included. One hundred seven (8.3 %) were identified as frail, 542 (42.1 %) as pre-frail, and 638 (49.6 %) as non-frail. ADMAvalues were higher in frail subjects than in non-frail ones. In addition, an interaction between the presence of atherosclerotic disease and ADMA on the odds of frailty (p=0.045) was detected. After adjustments for age, classical cardiovascular risk factors, and ABI, the risk of frailty was associated with increasing levels of ADMA in subjects without atherosclerotic disease [OR for 1 standard deviation increase in ADMA=1.14 (1.01­1.28), p=0.032] but not in those with atherosclerotic disease. In our study, endothelial dysfunction, assessed by ADMA levels, is associated with frailty. These findings provide additional support for a relevant role of vascular system since its earliest stage in frailty.