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1.
Artigo em Inglês | MEDLINE | ID: mdl-31722007

RESUMO

BACKGROUND: Extensive work in basic and clinical science suggests that biological mechanisms of aging are causally related to the development of disease and disability in late life. Modulation of the biological mechanisms of aging can extend both life span and health span in animal models, but translation to humans has been slow. METHODS: Summary of workshop proceedings from the 2018-2019 Epidemiology of Aging Workshop hosted by the Intramural Research Program at the National Institute on Aging. RESULTS: Epidemiologic studies play a vital role to progress in this field, particularly in evaluating new risk factors and measures of biologic aging that may influence health span, as well as developing relevant outcome measures that are robust and relevant for older individuals. CONCLUSIONS: Appropriately designed epidemiological studies are needed to identify targets for intervention and to inform study design and sample size estimates for future clinical trials designed to promote health span.

2.
Artigo em Inglês | MEDLINE | ID: mdl-31621207

RESUMO

BACKGROUND: Muscle mass declines with age. However, common assessments used to quantify muscle mass are indirect. The D3 -creatine (D3 Cr) dilution method is a direct assessment of muscle mass; however, longitudinal changes have not been examined in relation to changes in other measures of muscle mass, strength, and performance. METHODS: A convenience sample of 40 men from the Osteoporotic Fractures in Men Study (mean age = 83.3 years, standard deviation = 3.9) underwent repeat assessment of D3 Cr muscle mass, dual-energy X-ray absorptiometry (DXA) lean mass, grip strength, and walking speed at two time points approximately 1.6 years apart (2014-2016). One-sample t-tests and Pearson correlations were used to examine changes in DXA total body lean mass, DXA appendicular lean mass/height2 , DXA appendicular lean mass/weight, D3 Cr muscle mass, D3 Cr muscle mass/weight, grip strength, walking speed, and weight. RESULTS: D3 -creatine muscle mass, D3 Cr muscle mass/weight, grip strength, and walking speed all significantly declined (all P < 0.01). The change in DXA measures of lean mass was moderately correlated with changes in D3 Cr muscle mass. There was no significant correlation between the change in DXA measures of lean mass and change in walking speed (all P > 0.05). The change in D3 Cr muscle mass/weight was moderately correlated with change in walking speed (r = 0.33, P < .05). The change in grip strength was weakly correlated with the change in DXA measures of lean mass and D3 Cr muscle mass (r = 0.19-0.32). CONCLUSIONS: The results of our study provide new insights regarding the decline in muscle strength and D3 Cr muscle mass. The D3 Cr method may be a feasible tool to measure declines in muscle mass over time.

3.
Breast Cancer Res ; 21(1): 118, 2019 10 28.
Artigo em Inglês | MEDLINE | ID: mdl-31660981

RESUMO

BACKGROUND: Given that breast cancer and normal dense fibroglandular tissue have similar radiographic attenuation, we examine whether automated volumetric density measures identify a differential change between breasts in women with cancer and compare to healthy controls. METHODS: Eligible cases (n = 1160) had unilateral invasive breast cancer and bilateral full-field digital mammograms (FFDMs) at two time points: within 2 months and 1-5 years before diagnosis. Controls (n = 2360) were matched to cases on age and date of FFDMs. Dense volume (DV) and volumetric percent density (VPD) for each breast were assessed using Volpara™. Differences in DV and VPD between mammograms (median 3 years apart) were calculated per breast separately for cases and controls and their difference evaluated by using the Wilcoxon signed-rank test. To simulate clinical practice where cancer laterality is unknown, we examined whether the absolute difference between breasts can discriminate cases from controls using area under the ROC curve (AUC) analysis, adjusting for age, BMI, and time. RESULTS: Among cases, the VPD and DV between mammograms of the cancerous breast decreased to a lesser degree (- 0.26% and - 2.10 cm3) than the normal breast (- 0.39% and - 2.74 cm3) for a difference of 0.13% (p value < 0.001) and 0.63 cm3 (p = 0.002), respectively. Among controls, the differences between breasts were nearly identical for VPD (- 0.02 [p = 0.92]) and DV (0.05 [p = 0.77]). The AUC for discriminating cases from controls using absolute difference between breasts was 0.54 (95% CI 0.52, 0.56) for VPD and 0.56 (95% CI, 0.54, 0.58) for DV. CONCLUSION: There is a small relative increase in volumetric density measures over time in the breast with cancer which is not found in the normal breast. However, the magnitude of this difference is small, and this measure alone does not appear to be a good discriminator between women with and without breast cancer.

4.
Nat Commun ; 10(1): 3669, 2019 Aug 14.
Artigo em Inglês | MEDLINE | ID: mdl-31413261

RESUMO

Human longevity is heritable, but genome-wide association (GWA) studies have had limited success. Here, we perform two meta-analyses of GWA studies of a rigorous longevity phenotype definition including 11,262/3484 cases surviving at or beyond the age corresponding to the 90th/99th survival percentile, respectively, and 25,483 controls whose age at death or at last contact was at or below the age corresponding to the 60th survival percentile. Consistent with previous reports, rs429358 (apolipoprotein E (ApoE) ε4) is associated with lower odds of surviving to the 90th and 99th percentile age, while rs7412 (ApoE ε2) shows the opposite. Moreover, rs7676745, located near GPR78, associates with lower odds of surviving to the 90th percentile age. Gene-level association analysis reveals a role for tissue-specific expression of multiple genes in longevity. Finally, genetic correlation of the longevity GWA results with that of several disease-related phenotypes points to a shared genetic architecture between health and longevity.

5.
JAMA Intern Med ; 2019 Aug 19.
Artigo em Inglês | MEDLINE | ID: mdl-31424486

RESUMO

Importance: Previous studies have reported that drug treatments, particularly treatment with bisphosphonates, is associated with reduced overall mortality rates in addition to decreased fracture risk. If so, drug treatments should be recommended for this reason alone, regardless of a patient's risk of fracture. Objective: To assess whether randomized clinical trials demonstrate that treatment with bisphosphonates, particularly zoledronate, is associated with reduced mortality rates. Data Sources: Science Direct, MEDLINE, Embase, and the Cochrane Library were searched for randomized placebo-controlled clinical trials of drug treatments for osteoporosis published after 2009 and published or in press before April 19, 2019. Conference abstracts from annual osteoporosis society meetings were also included in the search. Study Selection: Included studies were clinical trials that (1) were randomized and placebo-controlled; (2) studied drug treatments with proven antifracture efficacy; (3) used agents at the approved dose for treatment of osteoporosis; and (4) had a duration of 1 year or more. Abstracts from the literature searches were reviewed for inclusion and exclusion criteria, and mortality rate data were abstracted from the article by 1 researcher and validated by a second. A total of 2045 records were screened; 38 (1.8%) were included in the meta-analyses. Data Extraction and Synthesis: The Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) checklist was followed for abstracting data and assessing data quality and validity. Data were pooled using random-effects models, and between-study variability was assessed using the I2 index. The risk of bias for each study was assessed, and funnel plots and Egger and Begg statistics were used to evaluate publication bias. Main Outcomes and Measures: Associations of all drug treatments, particularly bisphosphonate and zoledronate treatments, with overall mortality. Results: Of 38 clinical trials that included 101 642 unique participants, 38 were included in the meta-analyses of all drug treatments (45 594 participants randomized to placebo; 56 048 to treatment); 21 clinical trials, of bisphosphonate treatments (20 244 participants randomized to placebo; 22 623 to treatment); and 6 clinical trials, of zoledronate treatments (6944 participants randomized to placebo; 6926 to treatment). No significant association was found between all drug treatments for osteoporosis and overall mortality rate (risk ratio [RR], 0.98; 95% CI, 0.91-1.05; I2 = 0%). Clinical trials of bisphosphonate treatment (RR, 0.95; 95% CI, 0.86-1.04) showed no significant association with overall mortality. Also, clinical trials of zoledronate treatment (RR, 0.88; 95% CI, 0.68-1.13) showed no association with overall mortality rate; however, evidence existed for heterogeneity of the results (I2 = 48.2%). Conclusions and Relevance: Results of this meta-analysis suggest that bisphosphonate treatment may not be associated with reduced overall mortality rates in addition to decreased fracture risk and should only be recommended to reduce fracture risk. Additional trials are needed to clarify whether treatment with zoledronate reduces mortality rates.

6.
J Bone Miner Res ; 34(7): 1284-1296, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-30888730

RESUMO

Hip geometry is an important predictor of fracture. We performed a meta-analysis of GWAS studies in adults to identify genetic variants that are associated with proximal femur geometry phenotypes. We analyzed four phenotypes: (i) femoral neck length; (ii) neck-shaft angle; (iii) femoral neck width, and (iv) femoral neck section modulus, estimated from DXA scans using algorithms of hip structure analysis. In the Discovery stage, 10 cohort studies were included in the fixed-effect meta-analysis, with up to 18,719 men and women ages 16 to 93 years. Association analyses were performed with ∼2.5 million polymorphisms under an additive model adjusted for age, body mass index, and height. Replication analyses of meta-GWAS significant loci (at adjusted genomewide significance [GWS], threshold p ≤ 2.6 × 10-8 ) were performed in seven additional cohorts in silico. We looked up SNPs associated in our analysis, for association with height, bone mineral density (BMD), and fracture. In meta-analysis (combined Discovery and Replication stages), GWS associations were found at 5p15 (IRX1 and ADAMTS16); 5q35 near FGFR4; at 12p11 (in CCDC91); 11q13 (near LRP5 and PPP6R3 (rs7102273)). Several hip geometry signals overlapped with BMD, including LRP5 (chr. 11). Chr. 11 SNP rs7102273 was associated with any-type fracture (p = 7.5 × 10-5 ). We used bone transcriptome data and discovered several significant eQTLs, including rs7102273 and PPP6R3 expression (p = 0.0007), and rs6556301 (intergenic, chr.5 near FGFR4) and PDLIM7 expression (p = 0.005). In conclusion, we found associations between several genes and hip geometry measures that explained 12% to 22% of heritability at different sites. The results provide a defined set of genes related to biological pathways relevant to BMD and etiology of bone fragility. © 2019 American Society for Bone and Mineral Research.

7.
Am J Clin Nutr ; 109(2): 276-287, 2019 02 01.
Artigo em Inglês | MEDLINE | ID: mdl-30721968

RESUMO

Background: Lean body mass (LM) plays an important role in mobility and metabolic function. We previously identified five loci associated with LM adjusted for fat mass in kilograms. Such an adjustment may reduce the power to identify genetic signals having an association with both lean mass and fat mass. Objectives: To determine the impact of different fat mass adjustments on genetic architecture of LM and identify additional LM loci. Methods: We performed genome-wide association analyses for whole-body LM (20 cohorts of European ancestry with n = 38,292) measured using dual-energy X-ray absorptiometry) or bioelectrical impedance analysis, adjusted for sex, age, age2, and height with or without fat mass adjustments (Model 1 no fat adjustment; Model 2 adjustment for fat mass as a percentage of body mass; Model 3 adjustment for fat mass in kilograms). Results: Seven single-nucleotide polymorphisms (SNPs) in separate loci, including one novel LM locus (TNRC6B), were successfully replicated in an additional 47,227 individuals from 29 cohorts. Based on the strengths of the associations in Model 1 vs Model 3, we divided the LM loci into those with an effect on both lean mass and fat mass in the same direction and refer to those as "sumo wrestler" loci (FTO and MC4R). In contrast, loci with an impact specifically on LM were termed "body builder" loci (VCAN and ADAMTSL3). Using existing available genome-wide association study databases, LM increasing alleles of SNPs in sumo wrestler loci were associated with an adverse metabolic profile, whereas LM increasing alleles of SNPs in "body builder" loci were associated with metabolic protection. Conclusions: In conclusion, we identified one novel LM locus (TNRC6B). Our results suggest that a genetically determined increase in lean mass might exert either harmful or protective effects on metabolic traits, depending on its relation to fat mass.


Assuntos
Tecido Adiposo/metabolismo , Composição Corporal/genética , Compartimentos de Líquidos Corporais/metabolismo , Músculo Esquelético/metabolismo , Fenótipo , Polimorfismo de Nucleotídeo Único , Proteínas ADAMTS/genética , Absorciometria de Fóton , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Dioxigenase FTO Dependente de alfa-Cetoglutarato/genética , Impedância Elétrica , Grupo com Ancestrais do Continente Europeu/genética , Proteínas da Matriz Extracelular/genética , Feminino , Estudo de Associação Genômica Ampla , Humanos , Masculino , Pessoa de Meia-Idade , Proteínas de Ligação a RNA/genética , Receptor Tipo 4 de Melanocortina/genética , Versicanas/genética , Adulto Jovem
8.
Exp Gerontol ; 2018 Nov 30.
Artigo em Inglês | MEDLINE | ID: mdl-30508565

RESUMO

BACKGROUND: We provide the first examination of mitochondrial DNA (mtDNA) variants and pulmonary function in older persons. METHODS: Cross-sectional associations between mtDNA variants and pulmonary function were evaluated as a combined p-values meta-analysis, using data from two independent cohorts of older persons. The latter included white and black participants, aged ≥70 years, from the Lifestyle Interventions and Independence for Elders study (LIFE) (N = 1247) and the Health, Aging and Body Composition study (Health ABC) (N = 731), respectively. Pulmonary function included the forced expiratory volume in one-second as a Z-score (FEV1z) and the maximal inspiratory pressure (MIP) in cm of water. RESULTS: In black participants, significant associations were found between mtDNA variants and MIP: m.7146A > G, COI (p = 3E-5); m.7389 T > C, COI (p = 2E-4); m.15301G > A, CYB (p = 9E-5); m.16265A > G, HV1 (p = 9E-5); meta-analytical p-values <0.0002. Importantly, these mtDNA variants were unique to black participants and were not present in white participants. Moreover, in black participants, aggregate genetic effects on MIP were observed across mutations in oxidative phosphorylation complex IV (p = 0.004), complex V (p = 0.0007), and hypervariable (p = 0.003) regions. The individual and aggregate variant results were significant after adjustment for multiple comparisons. Otherwise, no significant associations were detected for MIP in whites or for FEV1z in whites or blacks. CONCLUSIONS: We have shown that mtDNA variants of African origin are cross-sectionally associated with MIP, a measure of respiratory muscle strength. Thus, our results establish the rationale for longitudinal studies to evaluate whether mtDNA variants of African origin identify those at risk of subsequently developing a respiratory muscle impairment (lower MIP values).

9.
Geroscience ; 2018 Oct 18.
Artigo em Inglês | MEDLINE | ID: mdl-30338417

RESUMO

Declines in walking speed are associated with a variety of poor health outcomes including disability, comorbidity, and mortality. While genetic factors are putative contributors to variability in walking, few genetic loci have been identified for this trait. We examined the role of mitochondrial genomic variation on walking speed by sequencing the entire mitochondrial DNA (mtDNA). Data were meta-analyzed from 1758 Lifestyle Interventions and Independence for Elders (LIFE) Study and replication data from 730 Health, Aging, and Body Composition (HABC) Study participants with baseline walking speed information. Participants were 69+ years old of diverse racial backgrounds (African, European, and other race/ethnic groups) and had a wide range of mean walking speeds [4-6 m (0.78-1.09 m/s) and 400 m (0.83-1.24 m/s)]. Meta-analysis across studies and racial groups showed that m.12705C>T, ND5 variant was significantly associated (p < 0.0001) with walking speed at both short and long distances. Replication and meta-analysis also identified statistically significant walking speed associations (p < 0.0001) between the m.5460.G>A, ND2 and m.309C>CT, HV2 variants at short and long distances, respectively. All results remained statistically significant after multiple comparisons adjustment for 499 mtDNA variants. The m.12705C>T variant can be traced to the beginnings of human global migration and that cells carrying this variant display altered tRNA expression. Significant pooled effects related to stopping during the long-distance walk test were observed across OXPHOS complexes I (p = 0.0017) and III (p = 0.0048). These results suggest that mtDNA-encoded variants are associated with differences in walking speed among older adults, potentially identifying those at risk of developing mobility impairments.

10.
J Bone Miner Res ; 2018 Oct 15.
Artigo em Inglês | MEDLINE | ID: mdl-30320955

RESUMO

We aimed to report the first genomewide association study (GWAS) meta-analysis of dual-energy X-ray absorptiometry (DXA)-derived hip shape, which is thought to be related to the risk of both hip osteoarthritis and hip fracture. Ten hip shape modes (HSMs) were derived by statistical shape modeling using SHAPE software, from hip DXA scans in the Avon Longitudinal Study of Parents and Children (ALSPAC; adult females), TwinsUK (mixed sex), Framingham Osteoporosis Study (FOS; mixed), Osteoporotic Fractures in Men study (MrOS), and Study of Osteoporotic Fractures (SOF; females) (total N = 15,934). Associations were adjusted for age, sex, and ancestry. Five genomewide significant (p < 5 × 10-9 , adjusted for 10 independent outcomes) single-nucleotide polymorphisms (SNPs) were associated with HSM1, and three SNPs with HSM2. One SNP, in high linkage disequilibrium with rs2158915 associated with HSM1, was associated with HSM5 at genomewide significance. In a look-up of previous GWASs, three of the identified SNPs were associated with hip osteoarthritis, one with hip fracture, and five with height. Seven SNPs were within 200 kb of genes involved in endochondral bone formation, namely SOX9, PTHrP, RUNX1, NKX3-2, FGFR4, DICER1, and HHIP. The SNP adjacent to DICER1 also showed osteoblast cis-regulatory activity of GSC, in which mutations have previously been reported to cause hip dysplasia. For three of the lead SNPs, SNPs in high LD (r2 > 0.5) were identified, which intersected with open chromatin sites as detected by ATAC-seq performed on embryonic mouse proximal femora. In conclusion, we identified eight SNPs independently associated with hip shape, most of which were associated with height and/or mapped close to endochondral bone formation genes, consistent with a contribution of processes involved in limb growth to hip shape and pathological sequelae. These findings raise the possibility that genetic studies of hip shape might help in understanding potential pathways involved in hip osteoarthritis and hip fracture. © 2018 The Authors. Journal of Bone and Mineral Research Published by Wiley Periodicals, Inc.

11.
Sci Rep ; 8(1): 11887, 2018 Aug 08.
Artigo em Inglês | MEDLINE | ID: mdl-30089816

RESUMO

Mitochondria contain many copies of a circular DNA molecule (mtDNA), which has been observed as a mixture of normal and mutated states known as heteroplasmy. Elevated heteroplasmy at a single mtDNA site, m.3243A > G, leads to neurologic, sensory, movement, metabolic, and cardiopulmonary impairments. We measured leukocyte mtDNA m.3243A > G heteroplasmy in 789 elderly men and women from the bi-racial, population-based Health, Aging, and Body Composition Study to identify associations with age-related functioning and mortality. Mutation burden for the m.3243A > G ranged from 0-19% and elevated heteroplasmy was associated with reduced strength, cognitive, metabolic, and cardiovascular functioning. Risk of all-cause, dementia and stroke mortality was significantly elevated for participants in the highest tertiles of m.3243A > G heteroplasmy. These results indicate that the accumulation of a rare genetic disease mutation, m.3243A > G, manifests as several aging outcomes and that some diseases of aging may be attributed to the accumulation of mtDNA damage.

12.
J Am Geriatr Soc ; 66(10): 1972-1979, 2018 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-30151825

RESUMO

OBJECTIVES: To determine the association between weight trajectory, health status, and mortality in older women. DESIGN: Cohort study. SETTING: Study of Osteoporotic Fractures. PARTICIPANTS: Older community-dwelling women (age: baseline (1986-88), mean 68, range 65-81; Year 20 (2006-08), mean 88, range 83-102 (N = 1,323)). MEASUREMENTS: Body weight measured repeatedly over 20 years (mean 8 times). Logistic and Cox proportional hazard models were used to evaluate whether 20-year weight trajectory measures were associated with hip fracture, falls, physical performance, and mortality. RESULTS: In models adjusted for age, clinic, calcium use, Year 20 weight, walking speed, comorbidity score, smoking, self-reported health, and walking for exercise, women with moderate weight loss (>9.0 kg) over 20 years had a 74% greater risk of death (hazard ratio (HR) = 1.74, 95% confidence interval (CI) = 1.37-2.20) in the 5 years after the Year 20 visit than those with no weight loss and more than twice the risk of hip fracture (HR = 2.56, 95% CI = 1.39-4.70). They were 3.6 times (odds ratio (OR) = 3.60, 95% CI = 1.86-6.95) as likely to have poor physical function at the Year 20 visit as women with no weight loss but no greater risk of 2 or more falls in the 1.5 years after the Year 20 visit. Weight variability and abrupt weight decline were not associated with adverse health oucomes (falls, fractures, mortality), but those in the highest quartile of variability were 2.3 times (OR = 2.26, 95% CI = 1.34-3.80) as likely to have poor physical function scores. CONCLUSION: In women surviving past 80 years of age, moderate weight loss over 20 years was associated with greater risk of hip fracture, poor physical function, and mortality but not of falls. Future work should separate voluntary from involuntary weight loss.

13.
Int J Geriatr Psychiatry ; 33(10): 1319-1326, 2018 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-29984425

RESUMO

OBJECTIVES: Mitochondrial DNA (mtDNA) heteroplasmy is a mixture of normal and mutated mtDNA molecules in a cell. High levels of heteroplasmy at several mtDNA sites in complex I lead to inherited neurological neurologic diseases and brain magnetic resonance imaging (MRI) abnormalities. Here, we test the hypothesis that mtDNA heteroplasmy at these complex I sites is associated with depressive symptoms in the elderly. METHODS: We examined platelet mtDNA heteroplasmy for associations with depressive symptoms among 137 participants over age 70 from the community-based Health, Aging and Body Composition Study. Depressive symptoms were assessed using the 10-point version of the Center for Epidemiologic Studies Depression Scale (CES-D 10). Complete mtDNA sequencing was performed and heteroplasmy derived for 5 mtDNA sites associated with neurologic mitochondrial diseases and tested for associations with depressive symptoms. RESULTS: Of 5 candidate complex I mtDNA mutations examined for effects on depressive symptoms, increased heteroplasmy at m.13514A>G, ND5, was significantly associated with higher CES-D score (P = .01). A statistically significant interaction between m.13514A > G heteroplasmy and sex was detected (P = .04); in sex-stratified analyses, the impact of m.13514A>G heteroplasmy was stronger in male (P = .003) than in female (P = .98) participants. Men in highest tertile of mtDNA heteroplasmy exhibited significantly higher (P = .0001) mean ± SE CES-D 10 scores, 5.37 ± 0.58, when compared with those in the middle, 2.13 ± 0.52, and lowest tertiles, 2.47 ± 0.58. No associations between the 4 other candidate sites and depressive symptoms were observed. CONCLUSIONS: Increased mtDNA heteroplasmy at m.13514A>G is associated with depressive symptoms in older men. Heteroplasmy may represent a novel biological risk factor for depression.

14.
Artigo em Inglês | MEDLINE | ID: mdl-29897420

RESUMO

Background: Direct assessment of skeletal muscle mass in older adults is clinically challenging. Relationships between lean mass and late-life outcomes have been inconsistent. The D3-creatine dilution method provides a direct assessment of muscle mass. Methods: Muscle mass was assessed by D3-creatine (D3Cr) dilution in 1,382 men (mean age, 84.2 yrs). Participants completed the Short Physical Performance Battery (SPPB); usual walking speed (6 meters); and DXA lean mass. Men self-reported mobility limitations (difficulty walking 2-3 blocks or climbing 10 steps); recurrent falls (2+); and serious injurious falls in the subsequent year. Across quartiles of D3Cr muscle mass/body mass, multivariate linear models calculated means for SPPB and gait speed; multivariate logistic models calculated odds ratios for incident mobility limitations or falls. Results: Compared to men in the highest quartile, those in the lowest quartile of D3Cr muscle mass/body mass had slower gait speed (Q1: 1.04 vs Q4: 1.17 m/s); lower SPPB (Q1: 8.4 vs Q4: 10.4 points); greater likelihood of incident serious injurious falls (OR Q1 vs Q4: 2.49, 95% CI: 1.37, 4.54); prevalent mobility limitation (OR Q1 vs Q4,: 6.1, 95%CI: 3.7, 10.3) and incident mobility limitation (OR Q1 vs Q4: 2.15 95% CI: 1.42, 3.26); p for trend <.001 for all. Results for incident recurrent falls were in the similar direction (p=0.156). DXA lean mass had weaker associations with the outcomes. Conclusions: Unlike DXA lean mass, low D3Cr muscle mass/body mass is strongly related to physical performance, mobility and incident injurious falls in older me.

15.
Ann Intern Med ; 168(11): 757-765, 2018 Jun 05.
Artigo em Inglês | MEDLINE | ID: mdl-29710124

RESUMO

Background: In 30 states, women who have had screening mammography are informed of their breast density on the basis of Breast Imaging Reporting and Data System (BI-RADS) density categories estimated subjectively by radiologists. Variation in these clinical categories across and within radiologists has led to discussion about whether automated BI-RADS density should be reported instead. Objective: To determine whether breast cancer risk and detection are similar for automated and clinical BI-RADS density measures. Design: Case-control. Setting: San Francisco Mammography Registry and Mayo Clinic. Participants: 1609 women with screen-detected cancer, 351 women with interval invasive cancer, and 4409 matched control participants. Measurements: Automated and clinical BI-RADS density assessed on digital mammography at 2 time points from September 2006 to October 2014, interval and screen-detected breast cancer risk, and mammography sensitivity. Results: Of women whose breast density was categorized by automated BI-RADS more than 6 months to 5 years before diagnosis, those with extremely dense breasts had a 5.65-fold higher interval cancer risk (95% CI, 3.33 to 9.60) and a 1.43-fold higher screen-detected risk (CI, 1.14 to 1.79) than those with scattered fibroglandular densities. Associations of interval and screen-detected cancer with clinical BI-RADS density were similar to those with automated BI-RADS density, regardless of whether density was measured more than 6 months to less than 2 years or 2 to 5 years before diagnosis. Automated and clinical BI-RADS density measures had similar discriminatory accuracy, which was higher for interval than screen-detected cancer (c-statistics: 0.70 vs. 0.62 [P < 0.001] and 0.72 vs. 0.62 [P < 0.001], respectively). Mammography sensitivity was similar for automated and clinical BI-RADS categories: fatty, 93% versus 92%; scattered fibroglandular densities, 90% versus 90%; heterogeneously dense, 82% versus 78%; and extremely dense, 63% versus 64%, respectively. Limitation: Neither automated nor clinical BI-RADS density was assessed on tomosynthesis, an emerging breast screening method. Conclusion: Automated and clinical BI-RADS density similarly predict interval and screen-detected cancer risk, suggesting that either measure may be used to inform women of their breast density. Primary Funding Source: National Cancer Institute.

16.
Am J Kidney Dis ; 72(2): 205-213, 2018 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-29602632

RESUMO

RATIONALE & OBJECTIVE: Novel urinary biomarkers have enabled earlier detection of kidney tubular damage, but their prognostic value for adverse cardiovascular outcomes is uncertain. We hypothesized that tubular damage, measured by urine α1-microglobulin (A1M), amino-terminal propeptide of type III procollagen (PIIINP), and neutrophil gelatinase-associated lipocalin (NGAL), would be associated with higher risks for cardiovascular events and mortality among elders. STUDY DESIGN: Case-cohort study. SETTING & PARTICIPANTS: This study included a randomly selected subcohort (n=502), cardiovascular disease (CVD) cases (n=245), and heart failure cases (n=220) from the Health, Aging, and Body Composition (Health ABC) Study. PREDICTORS: Baseline urine A1M, PIIINP, and NGAL concentrations. OUTCOMES: Incident CVD, heart failure, and all-cause mortality. ANALYTICAL APPROACH: Cox proportional hazards models were used to evaluate biomarker associations with each outcome. RESULTS: At baseline, mean age was 74 years and estimated glomerular filtration rate was 73mL/min/1.73m2. After adjustment for demographics, estimated glomerular filtration rate, albumin-creatinine ratio, and other cardiovascular risk factors, each doubling in biomarker concentration was associated with the following adjusted HRs for CVD: A1M, 1.51 (95% CI, 1.16-1.96); PIIINP, 1.21 (95% CI, 1.00-1.46); and NGAL, 1.12 (95% CI, 1.05-1.20). There were 248 deaths in the subcohort during a median follow-up of 12.4 years. Adjusted associations of each biomarker (HR per doubling) with all-cause mortality were: A1M, 1.29 (95% CI, 1.10-1.51); PIIINP, 1.05 (95%, 0.94-1.18); and NGAL, 1.07 (95% CI, 1.02-1.12). Biomarker concentrations did not have statistically significant associations with heart failure after multivariable adjustment. LIMITATIONS: Urine biomarkers were measured at a single time point; no validation cohort available. CONCLUSIONS: Kidney tubular damage is an independent risk factor for CVD and death among elders. Future studies should investigate mechanisms by which kidney tubular damage may adversely affect cardiovascular risk.

17.
J Bone Miner Res ; 33(9): 1622-1629, 2018 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-29701911

RESUMO

We proposed the term "dysmobility syndrome" (DS) to identify individuals with impaired musculoskeletal health, a risk factor for falls and fractures. Whether DS is associated with increased risk of incident fracture is unknown. The Osteoporotic Fractures in Men (MrOS) study enrolled 5994 men ages ≥65 years, between March 2000 and April 2002. We used baseline data to determine whether DS increased fracture risk, independent of the Fracture Risk Assessment Tool (FRAX). Men met DS criteria at baseline if they had three or more of the following: appendicular lean mass/height2 <7.26 kg/m2 , total body fat >30%, spine or hip T-score ≤ -2.5, grip strength <30 kg, gait speed <1.0 m/s, and one or more fall within 12 months. We examined whether baseline DS increased the risk of hip and major osteoporotic fractures (MOFs) over a median of 14 years (IQR, 9 to 15 years). Among 5834 men mean age 74 ± 6 years, 471 (8%) had DS and 635 (11%) experienced an MOF, including 274 (5%) hip fractures. Age (per SD increase) conferred an HR of 1.72 (95% CI, 1.59 to 1.86), DS conferred an HR of 3.45 (95% CI, 2.78 to 4.29) and FRAX calculated with BMD (per %) conferred an HR of 1.10 (95% CI, 1.08 to 1.11) for MOF. Prediction of MOF using the FRAX score provided a concordance value of 0.67 ± 0.012 (concordance values are mean ± SE). Concordance increased to 0.69 ± 0.012 by adding DS and to 0.70 ± 0.012 by adding DS and age to the multivariate model. Kaplan-Meier curves indicated that men with both DS and a FRAX risk above the National Osteoporosis Foundation (NOF) treatment thresholds had higher MOF (HR 6.23; 95% CI, 3.10 to 12.54) and hip (HR 7.73; 95% CI, 5.95 to 10.04) fracture risk than men with neither condition. We suggest further studies to determine the optimal criteria for DS, and to test DS as a predictor of falls and fractures, especially in women. © 2018 American Society for Bone and Mineral Research.

18.
Breast Cancer Res Treat ; 170(1): 129-141, 2018 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-29502324

RESUMO

BACKGROUND: Though mammographic density (MD) has been proposed as an intermediate marker of breast cancer risk, few studies have examined whether the associations between breast cancer risk factors and risk are mediated by MD, particularly by tumor characteristics. METHODS: Our study population included 3392 cases (1105 premenopausal) and 8882 (3192 premenopausal) controls from four case-control studies. For established risk factors, we estimated the percent of the total risk factor association with breast cancer that was mediated by percent MD (secondarily, by dense area and non-dense area) for invasive breast cancer as well as for subtypes defined by the estrogen receptor (ER+/ER-), progesterone receptor (PR+/PR-), and HER2 (HER2+/HER2-). Analyses were conducted separately in pre- and postmenopausal women. RESULTS: Positive associations between prior breast biopsy and risk of invasive breast cancer as well as all subtypes were partially mediated by percent MD in pre- and postmenopausal women (percent mediated = 11-27%, p ≤ 0.02). In postmenopausal women, nulliparity and hormone therapy use were positively associated with invasive, ER+ , PR+ , and HER2- breast cancer; percent MD partially mediated these associations (percent mediated ≥ 31%, p ≤ 0.02). Further, among postmenopausal women, percent MD partially mediated the positive association between later age at first birth and invasive as well as ER+ breast cancer (percent mediated = 16%, p ≤ 0.05). CONCLUSION: Percent MD partially mediated the associations between breast biopsy, nulliparity, age at first birth, and hormone therapy with risk of breast cancer, particularly among postmenopausal women, suggesting that these risk factors at least partially influence breast cancer risk through changes in breast tissue composition.

19.
Ann Neurol ; 83(4): 730-738, 2018 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-29518257

RESUMO

OBJECTIVE: Several cross-sectional studies have reported an association between visual contrast sensitivity (a functional measure of low contrast vision) and poor cognitive performance or dementia, but no studies have investigated this association prospectively in a population-based cohort with final adjudication of mild cognitive impairment (MCI)/dementia. METHODS: In a prospective, community-based study of aging women (Study of Osteoporotic Fractures), we analyzed whether visual contrast sensitivity was associated with increased risk of MCI or dementia and/or worse performance on various cognitive tests assessed 10 years later. Contrast sensitivity was assessed at baseline in each eye using a VISTECH VCTS 6500 wall chart. MCI/dementia was adjudicated by an expert panel. Multivariate logistic and linear regression models were analyzed. RESULTS: Of 1,352 white (88.2%) and African American (11.8%) women with a mean age of 77.7 years (standard deviation = 3.3), 536 (39.6%) went on to develop MCI/dementia over 10 years. MCI/dementia risk was more than doubled (odds ratio = 2.16, 95% confidence interval = 1.58-2.96) in women with the lowest quartile of contrast sensitivity compared to the highest (p < 0.0001 for the linear trend). Reduced baseline contrast sensitivity was also associated with lower performance on several cognitive measures assessed 10 years later. INTERPRETATION: Among older women, reduced contrast sensitivity is associated with a greater risk of MCI/dementia. These findings suggest that visual system neurodegeneration or dysfunction may parallel or precede dementia-related cortical or subcortical degeneration, and that contrast sensitivity testing may be useful in identifying aging adults at high risk for dementia. Ann Neurol 2018;83:730-738.

20.
Arch Osteoporos ; 13(1): 33, 2018 Mar 21.
Artigo em Inglês | MEDLINE | ID: mdl-29564735

RESUMO

Studies examining real-world effectiveness of osteoporosis therapies are beset by limitations due to confounding by indication. By evaluating longitudinal changes in fracture incidence, we demonstrated that osteoporosis therapies are effective in reducing fracture risk in real-world practice settings. INTRODUCTION: Osteoporosis therapies have been shown to reduce incidence of vertebral and non-vertebral fractures in placebo-controlled randomized clinical trials. However, information on the real-world effectiveness of these therapies is limited. METHODS: We examined fracture risk reduction in older, post-menopausal women treated with osteoporosis therapies. Using Medicare claims, we identified 1,278,296 women age ≥ 65 years treated with zoledronic acid, oral bisphosphonates, denosumab, teriparatide, or raloxifene. Fracture incidence rates before and after treatment initiation were described to understand patients' fracture risk profile, and fracture reduction effectiveness of each therapy was evaluated as a longitudinal change in incidence rates. RESULTS: Fracture incidence rates increased during the period leading up to treatment initiation and were highest in the 3-month period most proximal to treatment initiation. Fracture incidence rates following treatment initiation were significantly lower than before treatment initiation. Compared with the 12-month pre-index period, there were reductions in clinical vertebral fractures for denosumab (45%; 95% confidence interval [CI] 39-51%), zoledronic acid (50%; 95% CI 47-52%), oral bisphosphonates (24%; 95% CI 22-26%), and teriparatide (72%; 95% CI 69-75%) during the subsequent 12 months. Relative to the first 3 months after initiation, clinical vertebral fractures were reduced for denosumab (51%; 95% CI 42-59%), zoledronic acid (25%; 95% CI 17-32%), oral bisphosphonates (23%; 95% CI 20-26%), and teriparatide (64%; 95% CI 58-69%) during the subsequent 12 months. CONCLUSION: In summary, reductions in fracture incidence over time were observed in cohorts of patients treated with osteoporosis therapies.

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