Grip Strength, Gait Speed and Plasma Markers of Neurodegeneration in Asymptomatic Middle-aged and Older Adults.

BACKGROUND: Pragmatic biomarkers of preclinical dementia would allow for easy and large-scale screening of risk in populations. Physical function measures like grip strength and gait speed are potential predictive biomarkers but their relationship with plasma markers of Alzheimer's Disease and neurodegeneration have not been elucidated. OBJECTIVES: To examine association between physical function measures and plasma markers of Alzheimer's Disease (AD) and neurodegeneration. DESIGN: Cross-sectional and longitudinal analyses. SETTING: Community-based cohort in the city of Framingham, Massachusetts. PARTICIPANTS: 2336 participants of the Framingham Heart Study Offspring cohort with an average age of 61. MEASUREMENTS: Plasma Aß40 and Aß42 were measured in 1998-2001 (Exam-7) and plasma total tau measured 5 years later (Exam-8). Grip strength, fast walk speed and chair stand speed were measured at both exams. Quantification of Aß isoforms in plasma was performed using INNO-BIA assays and plasma total-tau was measured using Quanterix Simoa HD-1 assay. Confounder-adjusted linear regression models examined associations between physical function and plasma markers, Results: Grip strength at Exam-7 was associated with plasma Aß40 (ß -0.006, p-value 0.032) at Exam-7 and plasma total-tau (ß -0.010, p-value 0.001) at Exam-8. Grip strength and fast walk speed at Exam-8 were associated with plasma total-tau at Exam-8 (GS: ß -0.009, p 0.0005; FWS: ß -0.226, p-value <0.0001). Chair stand speed was not associated with plasma markers; Aß42 was not associated with function. CONCLUSION: Grip strength and fast walk speed are associated with plasma markers of neurodegeneration in dementia-free middle aged and older individuals. Both these measures could be used as potential screening tools for identifying individuals at a higher risk for AD and related dementias alongside other validated markers.

Genome-wide analysis of mitochondrial DNA copy number reveals loci implicated in nucleotide metabolism, platelet activation, and megakaryocyte proliferation.

Mitochondrial DNA copy number (mtDNA-CN) measured from blood specimens is a minimally invasive marker of mitochondrial function that exhibits both inter-individual and intercellular variation. To identify genes involved in regulating mitochondrial function, we performed a genome-wide association study (GWAS) in 465,809 White individuals from the Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) consortium and the UK Biobank (UKB). We identified 133 SNPs with statistically significant, independent effects associated with mtDNA-CN across 100 loci. A combination of fine-mapping, variant annotation, and co-localization analyses was used to prioritize genes within each of the 133 independent sites. Putative causal genes were enriched for known mitochondrial DNA depletion syndromes (p = 3.09 × 10-15) and the gene ontology (GO) terms for mtDNA metabolism (p = 1.43 × 10-8) and mtDNA replication (p = 1.2 × 10-7). A clustering approach leveraged pleiotropy between mtDNA-CN associated SNPs and 41 mtDNA-CN associated phenotypes to identify functional domains, revealing three distinct groups, including platelet activation, megakaryocyte proliferation, and mtDNA metabolism. Finally, using mitochondrial SNPs, we establish causal relationships between mitochondrial function and a variety of blood cell-related traits, kidney function, liver function and overall (p = 0.044) and non-cancer mortality (p = 6.56 × 10-4).

Large trans-ethnic meta-analysis identifies AKR1C4 as a novel gene associated with age at menarche.

STUDY QUESTION: Does the expansion of genome-wide association studies (GWAS) to a broader range of ancestries improve the ability to identify and generalise variants associated with age at menarche (AAM) in European populations to a wider range of world populations? SUMMARY ANSWER: By including women with diverse and predominantly non-European ancestry in a large-scale meta-analysis of AAM with half of the women being of African ancestry, we identified a new locus associated with AAM in African-ancestry participants, and generalised loci from GWAS of European ancestry individuals. WHAT IS KNOWN ALREADY: AAM is a highly polygenic puberty trait associated with various diseases later in life. Both AAM and diseases associated with puberty timing vary by race or ethnicity. The majority of GWAS of AAM have been performed in European ancestry women. STUDY DESIGN, SIZE, DURATION: We analysed a total of 38 546 women who did not have predominantly European ancestry backgrounds: 25 149 women from seven studies from the ReproGen Consortium and 13 397 women from the UK Biobank. In addition, we used an independent sample of 5148 African-ancestry women from the Southern Community Cohort Study (SCCS) for replication. PARTICIPANTS/MATERIALS, SETTING, METHODS: Each AAM GWAS was performed by study and ancestry or ethnic group using linear regression models adjusted for birth year and study-specific covariates. ReproGen and UK Biobank results were meta-analysed using an inverse variance-weighted average method. A trans-ethnic meta-analysis was also carried out to assess heterogeneity due to different ancestry. MAIN RESULTS AND THE ROLE OF CHANCE: We observed consistent direction and effect sizes between our meta-analysis and the largest GWAS conducted in European or Asian ancestry women. We validated four AAM loci (1p31, 6q16, 6q22 and 9q31) with common genetic variants at P < 5 × 10-7. We detected one new association (10p15) at P < 5 × 10-8 with a low-frequency genetic variant lying in AKR1C4, which was replicated in an independent sample. This gene belongs to a family of enzymes that regulate the metabolism of steroid hormones and have been implicated in the pathophysiology of uterine diseases. The genetic variant in the new locus is more frequent in African-ancestry participants, and has a very low frequency in Asian or European-ancestry individuals. LARGE SCALE DATA: N/A. LIMITATIONS, REASONS FOR CAUTION: Extreme AAM (<9 years or >18 years) were excluded from analysis. Women may not fully recall their AAM as most of the studies were conducted many years later. Further studies in women with diverse and predominantly non-European ancestry are needed to confirm and extend these findings, but the availability of such replication samples is limited. WIDER IMPLICATIONS OF THE FINDINGS: Expanding association studies to a broader range of ancestries or ethnicities may improve the identification of new genetic variants associated with complex diseases or traits and the generalisation of variants from European-ancestry studies to a wider range of world populations. STUDY FUNDING/COMPETING INTEREST(S): Funding was provided by CHARGE Consortium grant R01HL105756-07: Gene Discovery For CVD and Aging Phenotypes and by the NIH grant U24AG051129 awarded by the National Institute on Aging (NIA). The authors have no conflict of interest to declare.

Associations of objective physical activity with insulin sensitivity and circulating adipokine profile: the Framingham Heart Study.

The purpose of this study was to explore the relation of physical activity (PA) and sedentary time (SED) to insulin sensitivity and adipokines. We assessed PA and SED using Actical accelerometers and insulin resistance (HOMA-IR) in 2109 participants (free of type 1 and 2 diabetes mellitus) from Framingham Generation 3 and Omni 2 cohorts (mean age 46 years, 54% women). Systemic inflammation (C-reactive protein [CRP]) and circulating adipokines were measured 6 years earlier. Steps per day, moderate-to-vigorous PA (MVPA) and SED per wear time (%SED) were predictor variables in multivariable regression analyses, with HOMA-IR, CRP and circulating adipokines as outcome measures. We reported that higher MVPA and more steps per day were associated with lower HOMA-IR, adjusting for %SED (ß = -0.036, P = 0.002; ß = -0.041, P = 0.005). Steps were inversely associated with CRP, but were directly associated with insulin-like growth factor (IGF)-1 levels (ß = -0.111, P = 0.002; ß = 3.293, P = 0.007). %SED was positively associated with HOMA-IR (ß = 0.033, P < 0.0001), but non-significant after adjusting for MVPA (P = 0.13). %SED was associated with higher ratio of leptin/leptin receptor (sOB-R) and higher adipocyte fatty acid-binding protein (FABP)4 (ß = 0.096, P < 0.0001; ß = 0.593, P = 0.002). Our findings suggest differential influences of PA vs. SED on metabolic pathways, with PA modulating insulin resistance and inflammation, whereas SED influences FABPs.

Gene transcripts associated with muscle strength: a CHARGE meta-analysis of 7,781 persons.

Lower muscle strength in midlife predicts disability and mortality in later life. Blood-borne factors, including growth differentiation factor 11 (GDF11), have been linked to muscle regeneration in animal models. We aimed to identify gene transcripts associated with muscle strength in adults. Meta-analysis of whole blood gene expression (overall 17,534 unique genes measured by microarray) and hand-grip strength in four independent cohorts (n = 7,781, ages: 20-104 yr, weighted mean = 56), adjusted for age, sex, height, weight, and leukocyte subtypes. Separate analyses were performed in subsets (older/younger than 60, men/women). Expression levels of 221 genes were associated with strength after adjustment for cofactors and for multiple statistical testing, including ALAS2 (rate-limiting enzyme in heme synthesis), PRF1 (perforin, a cytotoxic protein associated with inflammation), IGF1R, and IGF2BP2 (both insulin like growth factor related). We identified statistical enrichment for hemoglobin biosynthesis, innate immune activation, and the stress response. Ten genes were associated only in younger individuals, four in men only and one in women only. For example, PIK3R2 (a negative regulator of PI3K/AKT growth pathway) was negatively associated with muscle strength in younger (<60 yr) individuals but not older (≥ 60 yr). We also show that 115 genes (52%) have not previously been linked to muscle in NCBI PubMed abstracts. This first large-scale transcriptome study of muscle strength in human adults confirmed associations with known pathways and provides new evidence for over half of the genes identified. There may be age- and sex-specific gene expression signatures in blood for muscle strength.

The heritability of circulating testosterone, oestradiol, oestrone and sex hormone binding globulin concentrations in men: the Framingham Heart Study.

OBJECTIVE: Circulating testosterone, oestradiol and oestrone concentrations vary considerably between men. Although a substantial proportion of this variation may be attributed to morbidity and behavioural factors, these cannot account for its entirety, suggesting genetic inheritance as a potential additional determinant. The analysis described here was intended to estimate the heritability of male circulating total testosterone (TT), calculated free testosterone (cFT), oestrone (E1), oestradiol (E2) and sex hormone binding globulin (SHBG), along with the genetic correlation between these factors. DESIGN: Cross-sectional, observational analysis of data from male members of the Offspring and Generation 3 cohorts of the Framingham Heart Study. Data were collected in the years 1998-2005. PARTICIPANTS: A total of 3367 community-dwelling men contributed to the analysis, including 1066 father/son and 1284 brother pairs among other family relationships. MEASUREMENTS: Levels of serum sex steroids (TT, E1 and E2) were measured by liquid chromatography-tandem mass spectrometry, SHBG by immunofluorometric assay and cFT by mass action equation. Heritability was obtained using variance components analysis with adjustment for covariates including age, diabetes mellitus, body mass index and smoking status. RESULTS: Age-adjusted heritability estimates were 0·19, 0·40, 0·40, 0·30 and 0·41 for cFT, TT, E1, E2 and SHBG, respectively. Adjustment for covariates did not substantially attenuate these estimates; SHBG-adjusted TT results were similar to those obtained for cFT. Genetic correlation coefficients (ρG ) indicated substantial genetic association between TT and cFT (ρG = 0·68), between TT and SHBG (pG = 0·87), between E1 and E2 (ρG = 0·46) and between TT and E2 (ρG = 0·48). CONCLUSION: Circulating testosterone, oestradiol and oestrone concentrations exhibit substantial heritability in adult men. Significant genetic association between testosterone and oestrogen levels suggests shared genetic pathways.

Development and validation of an ankle brachial index risk model for the prediction of cardiovascular events.

BACKGROUND: The ankle brachial index (ABI) is related to risk of cardiovascular events independent of the Framingham risk score (FRS). The aim of this study was to develop and evaluate a risk model for cardiovascular events incorporating the ABI and FRS. DESIGN: An analysis of participant data from 18 cohorts in which 24,375 men and 20,377 women free of coronary heart disease had ABI measured and were followed up for events. METHODS: Subjects were divided into a development and internal validation dataset and an external validation dataset. Two models, comprising FRS and FRS + ABI, were fitted for the primary outcome of major coronary events. RESULTS: In predicting events in the external validation dataset, C-index for the FRS was 0.672 (95% CI 0.599 to 0.737) in men and 0.578 (95% CI 0.492 to 0.661) in women. The FRS + ABI led to a small increase in C-index in men to 0.685 (95% CI 0.612 to 0.749) and large increase in women to 0.690 (95% CI 0.605 to 0.764) with net reclassification improvement (NRI) of 4.3% (95% CI 0.0 to 7.6%, p = 0.050) and 9.6% (95% CI 6.1 to 16.4%, p < 0.001), respectively. Restricting the FRS + ABI model to those with FRS intermediate 10-year risk of 10 to 19% resulted in higher NRI of 15.9% (95% CI 6.1 to 20.6%, p < 0.001) in men and 23.3% (95% CI 13.8 to 62.5%, p = 0.002) in women. However, incorporating ABI in an improved newly fitted risk factor model had a nonsignificant effect: NRI 2.0% (95% CI 2.3 to 4.2%, p = 0.567) in men and 1.1% (95% CI 1.9 to 4.0%, p = 0.483) in women. CONCLUSIONS: An ABI risk model may improve prediction especially in individuals at intermediate risk and when performance of the base risk factor model is modest.

Association of heat shock proteins with all-cause mortality.

Experimental mild heat shock is widely known as an intervention that results in extended longevity in various models along the evolutionary lineage. Heat shock proteins (HSPs) are highly upregulated immediately after a heat shock. The elevation in HSP levels was shown to inhibit stress-mediated cell death, and recent experiments indicate a highly versatile role for these proteins as inhibitors of programmed cell death. In this study, we examined common genetic variations in 31 genes encoding all members of the HSP70, small HSP, and heat shock factor (HSF) families for their association with all-cause mortality. Our discovery cohort was the Rotterdam study (RS1) containing 5,974 participants aged 55 years and older (3,174 deaths). We assessed 4,430 single nucleotide polymorphisms (SNPs) using the HumanHap550K Genotyping BeadChip from Illumina. After adjusting for multiple testing by permutation analysis, three SNPs showed evidence for association with all-cause mortality in RS1. These findings were followed in eight independent population-based cohorts, leading to a total of 25,007 participants (8,444 deaths). In the replication phase, only HSF2 (rs1416733) remained significantly associated with all-cause mortality. Rs1416733 is a known cis-eQTL for HSF2. Our findings suggest a role of HSF2 in all-cause mortality.

The ratio of visceral to subcutaneous fat, a metric of body fat distribution, is a unique correlate of cardiometabolic risk.

AIMS/HYPOTHESIS: The anatomic location of excess body fat has an impact on associated cardiometabolic morbidity, and visceral adipose tissue (VAT) is more pathogenic than subcutaneous adipose tissue (SAT). However, VAT or SAT alone provides little information regarding the relative distribution of body fat. We hypothesised that the propensity to store energy in VAT relative to SAT depots may be a correlate of cardiometabolic risk, and tested this hypothesis using the VAT/SAT ratio as a metric of fat distribution. METHODS: We investigated associations of the VAT/SAT ratio with cardiometabolic traits in 3,223 participants (48% women) from the Framingham Heart Study. Fat depots were quantified by multidetector computed tomography (CT) scanning. RESULTS: In women and men, higher VAT/SAT ratio was associated (p < 0.05) with most assessed cardiovascular risk factors reflecting blood pressure, dyslipidaemia and insulin resistance. Additional adjustment for BMI did not materially change the findings in women, and generally strengthened associations in men. Further adjustment for VAT attenuated some associations in women, but those with lower HDL-cholesterol, higher triacylglycerol (both p < 0.0001) and higher prevalence of hypertension (p = 0.02), diabetes (p = 0.01) and the metabolic syndrome (p = 0.005) remained significant. Similarly, in men, associations with higher systolic (p = 0.006) and diastolic blood pressure (p = 0.03), higher fasting glucose (p = 0.0005), lower HDL-cholesterol and higher triacylglycerol (both p < 0.0001) and higher prevalence of diabetes (p = 0.006) remained significant. CONCLUSIONS/INTERPRETATION: VAT/SAT ratio is a correlate of cardiometabolic risk, above and beyond BMI and VAT. The propensity to store fat viscerally versus subcutaneously may be a unique risk factor independent of absolute fat volumes.

Clinical correlates of sex steroids and gonadotropins in men over the late adulthood: the Framingham Heart Study.

Low serum concentrations of sex steroids and gonadotropins in men have been associated with increased cardiometabolic risk and mortality, but the clinical correlates of these hormones in men over late adulthood are less clearly understood. We analysed up to five serial measurements of total testosterone (TT), dehydroepiandrosterone sulphate (DHEAS), follicle stimulating hormone (FSH), luteinizing hormone (LH) and total estradiol (EST) in older men in the original cohort of the Framingham Heart Study to determine the short- (2-years; 1,165 person-observations in 528 individuals) and long-term (up to 10-years follow-up; 2520 person-observations in 835 individuals with mean baseline age: 71.2 years) clinical correlates of these sex steroids and gonadotropins using multilevel modelling and Generalized Estimating Equations. Age, body mass index and pre-existing type 2 diabetes were inversely related to long-term TT concentrations, whereas higher systolic blood pressure showed a positive association. Furthermore, age and pre-existing cardiovascular disease (CVD) were inversely associated and HDL cholesterol concentrations positively associated with long-term DHEAS concentrations respectively. Analyses of short-term changes revealed age was inversely related to DHEAS, but positively related to FSH and LH concentrations. Our community-based study identified modifiable correlates of decreasing TT and DHEAS concentrations in elderly men, suggesting that maintenance of a low CVD risk factor burden may mitigate the age-related decline of these hormones over the late adulthood.

Circulating testosterone and SHBG concentrations are heritable in women: the Framingham Heart Study.

CONTEXT: Many factors influence the concentration of circulating testosterone and its primary binding protein, SHBG. However, little is known about the genetic contribution to their circulating concentrations in women, and their heritability in women is not well established. OBJECTIVE: Our objective was to estimate the heritability of circulating total testosterone (TT), free testosterone (FT), and SHBG in women in families from the Framingham Heart Study. METHODS: Women in the Framingham Heart Study who were not pregnant, had not undergone bilateral oophorectomy, and were not using exogenous hormones were eligible for this investigation. TT was measured using liquid chromatography tandem mass spectrometry and SHBG using an immunofluorometric assay (Delfia-Wallac), and FT was calculated. Heritability estimates were calculated using variance-components methods in Sequential Oligogenic Linkage Analysis Routines (SOLAR) and were adjusted for age, age(2), body mass index (BMI), BMI(2), diabetes, smoking, and menopausal status. Bivariate analyses were done to assess genetic correlation between TT, FT, and SHBG. RESULTS: A total of 2685 women were studied including 868 sister pairs and 688 mother-daughter pairs. Multivariable adjusted heritability estimates were 0.26 ± 0.05 for FT, 0.26 ± 0.05 for TT, and 0.56 ± 0.05 for SHBG (P < 1.0 × 10(-7) for all). TT was genetically correlated with SHBG [genetic correlation coefficient (ρG) = 0.31 ± 0.10] and FT (ρG = 0.54 ± 0.09), whereas SHBG was inversely correlated with FT (ρG = -0.60 ± 0.08). CONCLUSION: Circulating TT, FT, and SHBG concentrations in women are significantly heritable, underscoring the importance of further work to identify the specific genes that contribute significantly to variation in sex steroid concentrations in women. The strong shared genetic component among pairs of TT, FT, and SHBG concentrations suggests potential pleiotropic effects for some of the underlying genes.

Ankle brachial index combined with Framingham Risk Score to predict cardiovascular events and mortality: a meta-analysis.

CONTEXT: Prediction models to identify healthy individuals at high risk of cardiovascular disease have limited accuracy. A low ankle brachial index (ABI) is an indicator of atherosclerosis and has the potential to improve prediction. OBJECTIVE: To determine if the ABI provides information on the risk of cardiovascular events and mortality independently of the Framingham risk score (FRS) and can improve risk prediction. DATA SOURCES: Relevant studies were identified. A search of MEDLINE (1950 to February 2008) and EMBASE (1980 to February 2008) was conducted using common text words for the term ankle brachial index combined with text words and Medical Subject Headings to capture prospective cohort designs. Review of reference lists and conference proceedings, and correspondence with experts was conducted to identify additional published and unpublished studies. STUDY SELECTION: Studies were included if participants were derived from a general population, ABI was measured at baseline, and individuals were followed up to detect total and cardiovascular mortality. DATA EXTRACTION: Prespecified data on individuals in each selected study were extracted into a combined data set and an individual participant data meta-analysis was conducted on individuals who had no previous history of coronary heart disease. RESULTS: Sixteen population cohort studies fulfilling the inclusion criteria were included. During 480,325 person-years of follow-up of 24,955 men and 23,339 women, the risk of death by ABI had a reverse J-shaped distribution with a normal (low risk) ABI of 1.11 to 1.40. The 10-year cardiovascular mortality in men with a low ABI (< or = 0.90) was 18.7% (95% confidence interval [CI], 13.3%-24.1%) and with normal ABI (1.11-1.40) was 4.4% (95% CI, 3.2%-5.7%) (hazard ratio [HR], 4.2; 95% CI, 3.3-5.4). Corresponding mortalities in women were 12.6% (95% CI, 6.2%-19.0%) and 4.1% (95% CI, 2.2%-6.1%) (HR, 3.5; 95% CI, 2.4-5.1). The HRs remained elevated after adjusting for FRS (2.9 [95% CI, 2.3-3.7] for men vs 3.0 [95% CI, 2.0-4.4] for women). A low ABI (< or = 0.90) was associated with approximately twice the 10-year total mortality, cardiovascular mortality, and major coronary event rate compared with the overall rate in each FRS category. Inclusion of the ABI in cardiovascular risk stratification using the FRS would result in reclassification of the risk category and modification of treatment recommendations in approximately 19% of men and 36% of women. CONCLUSION: Measurement of the ABI may improve the accuracy of cardiovascular risk prediction beyond the FRS.

Angina pectoris is a stronger indicator of diffuse vascular atherosclerosis than intermittent claudication: Framingham study.

OBJECTIVE: To compare implications of Angina Pectoris (AP) and Intermittent Claudication (IC) as indicators of clinical atherosclerosis in other vascular territories. STUDY DESIGN AND SETTING: Prospective cohort study of cardiovascular disease (CVD) in 5,209 men and women of Framingham, MA, aged 28-62 years at enrollment in 1948-1951, who received biennial examinations during the first 36 years of follow-up. Comparative 10-year incidence of subsequent atherosclerotic CVD in participants with IC and AP relative to a reference sample free of CVD was determined. RESULTS: On follow-up, 95 CVD events occurred in 186 participants with IC and 206 of 413 with AP. After age, sex, and risk-factor adjustment, the proportion acquiring other CVD was 34.0% for IC and 43.4% for AP. Relative to the reference sample, those with IC had a 2.73-fold higher age and sex-adjusted 10-year hazard of CVD (95% CI 2.21, 3.38) and for AP was 3.17 (95% CI 2.73, 3.69). CVD hazard ratios remained more elevated for AP and statistically significant after standard risk factor adjustment. Risk factors accounted for more of the excess CVD risk associated with IC (34.8%) than AP (9.5%). CONCLUSION: AP is as useful as IC as a hallmark of diffuse atherosclerotic CVD and an indication for comprehensive preventive measures.

Cross-sectional relations of serum aldosterone and urine sodium excretion to urinary albumin excretion in a community-based sample.

Experimental models suggest that increased aldosterone and sodium intake are associated with renovascular damage and resultant proteinuria. We hypothesized that serum aldosterone and urinary sodium would be associated with urinary albumin excretion, an indicator of kidney damage. We evaluated 2700 participants (53% women, mean age 58 years) from the Framingham Offspring Study who attended a routine examination between 1995 and 1998, who were free of heart failure and renal failure, and underwent testing for serum aldosterone, spot urinary sodium, and urinary albumin excretion (urine albumin/creatinine ratio, UACR), the latter two indexed to urinary creatinine. Stepwise multivariable linear regression was used to evaluate the relations between UACR with urinary sodium index and serum aldosterone. In multivariable regression, log urinary sodium index was associated positively with log-UACR (P<0.0001). UACR levels in the fourth and fifth quintiles of urinary sodium index were 24% (95% confidence interval (CI) 3-49%), and twofold higher (95% CI 72-150%), respectively, relative to the lowest quintile (P-value for trend across quintiles <0.001). In multivariable models, log-transformed aldosterone was not related to log-UACR. The top quintile of serum aldosterone levels was associated with a 21% higher (95% 1-44%) UACR levels relative to the lowest quintile. Urinary albumin excretion was strongly and positively associated in a continuous fashion with urinary sodium excretion, whereas a weaker nonlinear positive relation with serum aldosterone was noted. Our cross-sectional observations raise the possibility that dietary salt intake may be associated with early renovascular damage.

Family breast cancer history and mammography: Framingham Offspring Study.

The authors examined mammography use according to family cancer history and identified predictors of recent use (

Postmenopausal estrogen use, type of menopause, and lens opacities: the Framingham studies.

BACKGROUND: Previous studies of estrogen replacement therapy and lens opacities have not reported consistent findings. OBJECTIVE: To investigate whether postmenopausal estrogen use is associated with the occurrence of age-related lens opacities (nuclear, cortical, and posterior subcapsular). METHODS: Surviving members of the original cohort of the Framingham Heart Study who also participated in the Framingham Eye Study (1986-1989) were examined for the absence or presence of lens opacities. Data from the Framingham Heart Study, including information on menopausal status (collected biennially from approximately 1948) and use of estrogen replacement therapy (collected biennially from approximately 1960) were used to examine associations between lens opacities and duration of postmenopausal estrogen use, type of menopause, and age at menopause. Five hundred twenty-nine women, aged 66 to 93 years, were included. Multivariable-adjusted odds ratios of specific types of lens opacities were calculated for (1) duration of estrogen use (never and 1-2, 3-9, and >/=10 years), (2) surgical vs natural menopause, and (3) age at menopause. RESULTS: Longer duration of postmenopausal estrogen therapy was inversely associated with the presence of nuclear lens opacities in an adjusted model. Women who had taken estrogen for 10 years or longer had a 60% reduction in risk compared with nonusers (odds ratio, 0.4; 95% confidence interval, 0.2-1.01). Longer duration of estrogen use was associated with fewer posterior subcapsular opacities at a borderline level of significance. No association was noted for cortical opacities. The risk of posterior subcapsular opacities was significantly increased for women who had undergone surgical menopause compared with women with natural menopause (odds ratio, 2.2; 95% confidence interval, 1.1-4.3). No association was noted for lens opacities and age at menopause. CONCLUSION: Data from our study and other studies suggest that a reduction in the risk of lens opacities may be an additional benefit of postmenopausal estrogen use.

Alcohol consumption and risk of intermittent claudication in the Framingham Heart Study.

BACKGROUND: Intermittent claudication (IC) is associated with an increased risk of cardiovascular disease morbidity and mortality. The relation of alcohol consumption to the risk of IC remains controversial. The purpose of this study was to assess the relation of alcohol consumption and type of beverage to the development of IC among participants in the Framingham Heart Study. METHODS AND RESULTS: Alcohol consumption was categorized as 0, 1 to 6, 7 to 12, 13 to 24, and >/=25 g/d. During a mean follow-up of 6.8 years, 414 subjects developed IC. From the lowest to the highest category of alcohol intake, the age-standardized incidence rates of IC were 5.3, 4.1, 4.2, 3.2, and 4.6 cases/1000 person-years for men and 3.4, 2.5, 1.5, 1.9, and 2.5, respectively, for women. A multivariate Cox regression model demonstrated an inverse relation, with the lowest IC risk at levels of 13 to 24 g/d for men and 7 to 12 g/d for women compared with nondrinkers; the hazard ratio (95% CI) was 0.67 (0.42 to 0.99) for men and 0.44 (0.23 to 0.80) for women. This protective effect was seen mostly with wine and beer consumption. CONCLUSIONS: Our data are consistent with a protective effect of moderate alcohol consumption on IC risk, with lowest risk observed in men consuming 13 to 24 g/d (1 to 2 drinks/d) and in women consuming 7 to 12 g/d (0.5 to 1 drink/d).

Elderly cohort study subjects unable to return for follow-up have lower bone mass than those who can return.

Longitudinal studies of osteoporosis in older persons may underestimate bone loss because of a lack of follow-up measurements on subjects too frail to return. The authors addressed this possible bias as part of the population-based Framingham Study; in 1996-1997, they used quantitative ultrasound to assess the bone status of elderly subjects regardless of their ability to return to the clinic. Broadband ultrasound attenuation (BUA) and speed of sound of the calcaneus (heel) were measured in 433 subjects at the Framingham, Massachusetts, clinic and in 167 subjects at their homes or nursing homes. All ultrasound parameters were measured with intramachine coefficients of variation of <6.0%. The mean BUA for those subjects evaluated at the clinic was higher than for those measured at home (9.2% higher for men, p = 0.081; 8.6% higher for women, p = 0.034). After adjustment for age and weight, the differences in BUA were no longer significant. Among the elderly subjects participating in this longitudinal cohort study, those who were unable to return for follow-up were older, weighed less, and had a lower BUA than those who did return, suggesting that longitudinal studies of changes in bone mass with aging may underestimate the true population values.

Temporal trends in event rates after Q-wave myocardial infarction: the Framingham Heart Study.

BACKGROUND: Short-term (<30 day) mortality after Q-wave myocardial infarction (MI) has declined over the decades, but it is unclear if rates of long-term sequelae after Q-wave MI have improved. METHODS AND RESULTS: In 546 Framingham Heart Study subjects (388 men with a mean age of 60 years; 158 women with a mean age of 69 years) with an initial recognized Q-wave MI from 1950 through 1989, we investigated time trends in risk for coronary heart disease (CHD) death (n=199), all-cause mortality (n=287), reinfarction (n=108), and congestive heart failure (CHF; n=121). With 1950 through 1969 as the reference period, hazards ratios (HRs) for these outcomes were determined for the 1970s and 1980s. Trend analyses across the 3 time periods were performed for each outcome. Compared with the 1950 through 1969 reference period, the HRs for CHD death were lower in subsequent decades (1970 through 1979: HR, 0.69; 95% CI, 0.49 to 0.98; 1980 through 1989: HR, 0.48; 95% CI, 0.33 to 0.72). All-cause mortality also declined (1970 through 1979: HR, 0.70; 95% CI, 0.0.52 to 0.94; 1980 through 1989: HR, 0.59; 95% CI, 0.43 to 0.81). There were no significant temporal changes in the risks for recurrent MI or CHF. CONCLUSIONS: Substantial reductions in risk of CHD death and all-cause mortality occurred over these 4 decades, coincident with improvements in post-MI therapies. The absence of a decline in CHF incidence may be due to improved post-MI survival of individuals with depressed left ventricular systolic function who are at high risk for CHF.

Intermittent claudication. A risk profile from The Framingham Heart Study.

BACKGROUND: Intermittent claudication identifies persons at increased risk for death and disability. METHODS AND RESULTS: Using 38-year follow-up data for the original cohort in the Framingham Heart Study, we developed an intermittent claudication risk profile. Intermittent claudication occurred in a total of 381 men and women. Age, sex, serum cholesterol, hypertension, cigarette smoking, diabetes, and coronary heart disease were associated with an increased risk for claudication and were included in the profile. A pooled logistic regression model was used to compute the probability of intermittent claudication for specified levels of risk factors. CONCLUSIONS: The intermittent claudication risk profile allows physicians to identify high-risk individuals during a routine office visit and can be used to educate patients about modifiable risk factors, particularly smoking and blood pressure. Improved compliance with risk factor modification strategies may result in a beneficial impact on survival.