The relationship between 11 different polygenic longevity scores, parental lifespan, and disease diagnosis in the UK Biobank.

Large-scale genome-wide association studies (GWAS) strongly suggest that most traits and diseases have a polygenic component. This observation has motivated the development of disease-specific "polygenic scores (PGS)" that are weighted sums of the effects of disease-associated variants identified from GWAS that correlate with an individual's likelihood of expressing a specific phenotype. Although most GWAS have been pursued on disease traits, leading to the creation of refined "Polygenic Risk Scores" (PRS) that quantify risk to diseases, many GWAS have also been pursued on extreme human longevity, general fitness, health span, and other health-positive traits. These GWAS have discovered many genetic variants seemingly protective from disease and are often different from disease-associated variants (i.e., they are not just alternative alleles at disease-associated loci) and suggest that many health-positive traits also have a polygenic basis. This observation has led to an interest in "polygenic longevity scores (PLS)" that quantify the "risk" or genetic predisposition of an individual towards health. We derived 11 different PLS from 4 different available GWAS on lifespan and then investigated the properties of these PLS using data from the UK Biobank (UKB). Tests of association between the PLS and population structure, parental lifespan, and several cancerous and non-cancerous diseases, including death from COVID-19, were performed. Based on the results of our analyses, we argue that PLS are made up of variants not only robustly associated with parental lifespan, but that also contribute to the genetic architecture of disease susceptibility, morbidity, and mortality.

Mitochondrial genetic variation and risk of chronic kidney disease and acute kidney injury in UK Biobank participants.

Experimental models suggest an important role for mitochondrial dysfunction in the pathogenesis of chronic kidney disease (CKD) and acute kidney injury (AKI), but little is known regarding the impact of common mitochondrial genetic variation on kidney health. We sought to evaluate associations of inherited mitochondrial DNA (mtDNA) variation with risk of CKD and AKI in a large population-based cohort. We categorized UK Biobank participants who self-identified as white into eight distinct mtDNA haplotypes, which were previously identified based on their associations with phenotypes associated with mitochondrial DNA copy number, a measure of mitochondrial function. We used linear and logistic regression models to evaluate associations of these mtDNA haplotypes with estimated glomerular filtration rate by serum creatinine and cystatin C (eGFRCr-CysC, N = 362,802), prevalent (N = 416 cases) and incident (N = 405 cases) end-stage kidney disease (ESKD), AKI defined by diagnostic codes (N = 14,170 cases), and urine albumin/creatinine ratio (ACR, N = 114,662). The mean age was 57 ± 8 years and the mean eGFR was 90 ± 14 ml/min/1.73 m2. MtDNA haplotype was significantly associated with eGFR (p = 2.8E-12), but not with prevalent ESKD (p = 5.9E-2), incident ESKD (p = 0.93), AKI (p = 0.26), or urine ACR (p = 0.54). The association of mtDNA haplotype with eGFR remained significant after adjustment for diabetes mellitus and hypertension (p = 1.2E-10). When compared to the reference haplotype, mtDNA haplotypes I (ß = 0.402, standard error (SE) = 0.111; p = 2.7E-4), IV (ß = 0.430, SE = 0.073; p = 4.2E-9), and V (ß = 0.233, SE = 0.050; p = 2.7E-6) were each associated with higher eGFR. Among self-identified white UK Biobank participants, mtDNA haplotype was associated with eGFR, but not with ESKD, AKI or albuminuria.

Effect of baseline oestradiol serum concentration on the efficacy of anastrozole for preventing breast cancer in postmenopausal women at high risk: a case-control study of the IBIS-II prevention trial.

BACKGROUND: An increased risk of breast cancer is associated with high serum concentrations of oestradiol and testosterone in postmenopausal women, but little is known about how these hormones affect response to endocrine therapy for breast cancer prevention or treatment. We aimed to assess the effects of serum oestradiol and testosterone concentrations on the efficacy of the aromatase inhibitor anastrozole for the prevention of breast cancer in postmenopausal women at high risk. METHODS: In this case-control study we used data from the IBIS-II prevention trial, a randomised, controlled, double-blind trial in postmenopausal women aged 40-70 years at high risk of breast cancer, conducted in 153 breast cancer treatment centres across 18 countries. In the trial, women were randomly assigned (1:1) to receive anastrozole (1 mg/day, orally) or placebo daily for 5 years. In this pre-planned case-control study, the primary analysis was the effect of the baseline oestradiol to sex hormone binding globulin (SHBG) ratio (oestradiol-SHBG ratio) on the development of all breast cancers, including ductal carcinoma in situ (the primary endpoint in the trial). Cases were participants in whom breast cancer was reported after trial entry and until the cutoff on Oct 22, 2019, and who had valid blood samples and no use of hormone replacement therapy within 3 months of trial entry or during the trial. For each case, two controls without breast cancer were selected at random, matched on treatment group, age (within 2 years), and follow-up time (at least that of the matching case). For each treatment group, we applied a multinominal logistic regression likelihood-ratio trend test to assess what change in the proportion of cases was associated with a one-quartile change in hormone ratio. Controls were used only to determine quartile cutoffs. Profile likelihood 95% CIs were used to indicate the precision of estimates. A secondary analysis also investigated the effect of the baseline testosterone-SHBG ratio on breast cancer development. We also assessed relative benefit of anastrozole versus placebo (calculated as 1 - the ratio of breast cancer cases in the anastrozole group to cases in the placebo group). The trial was registered with ISRCTN (number ISRCTN31488319) and completed recruitment on Jan 31, 2012, but long-term follow-up is ongoing. FINDINGS: 3864 women were recruited into the trial between Feb 2, 2003, and Jan 31, 2012, and randomly assigned to receive anastrozole (n=1920) or placebo (n=1944). Median follow-up time was 131 months (IQR 106-156), during which 85 (4·4%) cases of breast cancer in the anastrozole group and 165 (8·5%) in the placebo group were identified. No data on gender, race, or ethnicity were collected. After exclusions, the case-control study included 212 participants from the anastrozole group (72 cases, 140 controls) and 416 from the placebo group (142 cases, 274 controls). A trend of increasing breast cancer risk with increasing oestradiol-SHBG ratio was found in the placebo group (trend per quartile 1·25 [95% CI 1·08 to 1·45], p=0·0033), but not in the anastrozole group (1·06 [0·86 to 1·30], p=0·60). A weaker effect was seen for the testosterone-SHBG ratio in the placebo group (trend 1·21 [1·05 to 1·41], p=0·011), but again not in the anastrozole group (trend 1·18 [0·96 to 1·46], p=0·11). A relative benefit of anastrozole was seen in quartile 2 (0·55 [95% CI 0·13 to 0·78]), quartile 3 (0·54 [0·22 to 0·74], and quartile 4 (0·56 [0·23 to 0·76]) of oestradiol-SHBG ratio, but not in quartile 1 (0·18 [-0·60 to 0·59]). INTERPRETATION: These results suggest that serum hormones should be measured more routinely and integrated into risk management decisions. Measuring serum hormone concentrations is inexpensive and might help clinicians differentiate which women will benefit most from an aromatase inhibitor. FUNDING: Cancer Research UK, National Health and Medical Research Council (Australia), Breast Cancer Research Foundation, and DaCosta Fund.

The relationship between visual function and physical performance in the Study of Muscle, Mobility and Aging (SOMMA).

PURPOSE: The relationship of types of visual function to different aspects of physical function, especially strength and coordination, has been understudied, but delineation of these relationships could suggest potentially modifiable targets prior to the onset of disability. METHODS: Cross-sectional analysis of visual function (self-reported eyesight and eye disease, visual acuity, contrast sensitivity) and physical function tests in 877 older adults (mean age 76.36±5.01 years, 59.2% women, and 13.3% Black race). Separate linear regression models were constructed for short physical performance battery (SPPB), expanded SPPB (eSPPB), their components (gait speed, chair stand, balance, narrow walk), stair climb, four-square step, leg extension peak power and strength, and grip strength. RESULTS: In adjusted models, worse acuity, worse contrast sensitivity, and self-reported poor vision were significantly associated with worse performance on the eSPPB and four-square step test. Worse contrast sensitivity, but not acuity, was significantly associated with shorter balance times, slower chair stand pace, longer stair climb time, and worse SPPB score. Associations of worse acuity and contrast sensitivity with weaker leg extension power, leg strength, and grip strength were attenuated by covariate adjustment. Self-reported macular degeneration, but not cataract or glaucoma, was associated with worse performance on SPPB, eSPPB, balance, stair climb, and four-square step tests in adjusted models. Worse contrast sensitivity and macular degeneration remained associated with worse SPPB and balance after controlling for visual acuity and self-reported eyesight. CONCLUSIONS: Poor contrast sensitivity was more strongly associated with worse physical performance than acuity, especially for complex tasks that dynamically challenge coordination and balance. Future studies should examine if older adults with contrast sensitivity impairment would benefit from targeted intervention to decrease their risk of disability.

Establishing the Link Between Lean Mass and Grip Strength Cut Points With Mobility Disability and Other Health Outcomes: Proceedings of the Sarcopenia Definition and Outcomes Consortium Conference.

BACKGROUND: Lack of consensus on how to diagnose sarcopenia has limited the ability to diagnose this condition and hindered drug development. The Sarcopenia Definitions and Outcomes Consortium (SDOC) was formed to develop evidence-based diagnostic cut points for lean mass and/or muscle strength that identify people at increased risk of mobility disability. We describe here the proceedings of a meeting of SDOC and other experts to discuss strategic considerations in the development of evidence-based sarcopenia definition. METHODS: Presentations and panel discussions reviewed the usefulness of sarcopenia as a biomarker, the analytical approach used by SDOC to establish cut points, and preliminary findings, and provided strategic direction to develop an evidence-based definition of sarcopenia. RESULTS: The SDOC assembled data from eight epidemiological cohorts consisting of 18,831 participants, clinical populations from 10 randomized trials and observational studies, and 2 nationally representative cohorts. In preliminary assessments, grip strength or grip strength divided by body mass index was identified as discriminators of risk for mobility disability (walking speed <0.8 m/s), whereas dual-energy X-ray absorptiometry-derived lean mass measures were not good discriminators of mobility disability. Candidate definitions based on grip strength variables were associated with increased risk of mortality, falls, mobility disability, and instrumental activities of daily living disability. The prevalence of low grip strength increased with age. The attendees recommended the establishment of an International Expert Panel to review a series of position statements on sarcopenia definition that are informed by the findings of the SDOC analyses and synthesis of literature. CONCLUSIONS: International consensus on an evidence-based definition of sarcopenia is needed. Grip strength-absolute or adjusted for body mass index-is an important discriminator of mobility disability and other endpoints. Additional research is needed to develop a predictive risk model that takes into account sarcopenia components as well as age, sex, race, and comorbidities.

Mean nocturnal respiratory rate predicts cardiovascular and all-cause mortality in community-dwelling older men and women.

Respiratory frequency (f R) predicts in-hospital and short-term mortality in patients with a variety of pathophysiological conditions, but its predictive value for long-term cardiovascular and all-cause mortality in the general population is unknown. Here, we investigated the relationship between mean nocturnal f R and mortality in community-dwelling older men and women.We measured mean nocturnal f R during sleep from overnight polysomnography in 2686 men participating in the Osteoporotic Fractures in Men Study (MrOS) Sleep study and 406 women participating in the Study of Osteoporotic Fractures (SOF) to investigate the relationship between mean nocturnal f R and long-term cardiovascular and all-cause mortality.166 (6.1%) men in the MrOS cohort (8.9±2.6 years' follow-up) and 46 (11.2%) women in the SOF cohort (6.4±1.6 years' follow-up) died from cardiovascular disease. All-cause mortality was 51.2% and 26.1% during 13.7±3.7 and 6.4±1.6 years' follow-up in the MrOS Sleep study and the SOF cohorts, respectively. Multivariable Cox regression analysis adjusted for significant covariates demonstrated that f R dichotomised at 16 breaths·min-1 was independently associated with cardiovascular mortality (MrOS: hazard ratio (HR) 1.57, 95% CI 1.14-2.15; p=0.005; SOF: HR 2.58, 95% CI 1.41-4.76; p=0.002) and all-cause mortality (MrOS: HR 1.18, 95% CI 1.04-1.32; p=0.007; SOF: HR 1.50, 95% CI 1.02-2.20; p=0.04).In community-dwelling older men and women, polysomnography-derived mean nocturnal f R ≥16 breaths·min-1 is an independent predictor of long-term cardiovascular and all-cause mortality. Whether nocturnal mean f R can be used as a risk marker warrants further prospective studies.

D3 -Creatine dilution and the importance of accuracy in the assessment of skeletal muscle mass.

Sarcopenia has been described as the age-associated decrease in skeletal muscle mass. However, virtually every study of sarcopenia has measured lean body mass (LBM) or fat free mass (FFM) rather than muscle mass, specifically. In a number of published sarcopenia studies, LBM or FFM is referred to as muscle mass, leading to an incorrect assumption that measuring LBM or FFM is an accurate measure of muscle mass. As a result, the data on the effects of changes in LBM or FFM in older populations on outcomes such as functional capacity, disability, and risk of injurious falls have been inconsistent resulting in the conclusion that muscle mass is only weakly related to these outcomes. We review and describe the assumptions for the most commonly used measurements of body composition. Dual-energy X-ray absorptiometry (DXA) has become an increasingly common tool for the assessment of LBM or FFM and appendicular lean mass as a surrogate, but inaccurate, measurement of muscle mass. Other previously used methods (total body water, bioelectric impedance, and imaging) also have significant limitations. D3 -Creatine (D3 -Cr) dilution provides a direct and accurate measurement of creatine pool size and skeletal muscle mass. In a recent study in older men (MrOS cohort), D3 -Cr muscle mass was associated with functional capacity and risk of injurious falls and disability, while assessments of LBM or appendicular lean mass by DXA were only weakly or not associated with these outcomes. Inaccurate measurements of muscle mass by DXA and other methods have led to inconsistent results and potentially erroneous conclusions about the importance of skeletal muscle mass in health and disease. The assessment of skeletal muscle mass using the D3 -Cr dilution method in prospective cohort studies may reveal sarcopenia as a powerful risk factor for late life disability and chronic disease.

Glycated Peptide Levels Are Associated With Cognitive Decline Among Nondiabetic Older Women.

BACKGROUND: The association between diabetes and dementia may be explained in part by elevated levels of glycated peptides; we sought to determine whether serum-glycated peptides predicted cognitive decline in nondiabetic older adults. METHODS: We prospectively studied 525 community-dwelling nondiabetic women, mean age of 82 years, and analyzed baseline glycated peptides (serum level of fructosamine and glycated albumin). Cognitive outcomes included 5-year decline on the short Mini-Mental State Examination (sMMSE), Trails B, and performance on a battery of five other cognitive tests at the follow-up visit. Generalized linear models were adjusted for education, age, race, physical activity, body mass index, and vascular disease. RESULTS: Women with higher level of fructosamine (upper two tertiles) had greater 5-year decline in Trails B performance compared with women in the lowest tertile (adjusted mean change = 67 vs 50 seconds, p = .046), but change in sMMSE was not different between groups. Higher fructosamine was also associated with worse cognitive function 5 years later: adjusted mean score for the California Verbal Learning Test-II Short Form was 22.7 versus 23.9 (p = .010) and for Category Fluency was 10.1 versus 11.1 (p = .003). Higher glycated albumin was also associated with worse performance on Category Fluency (10.1 vs 11.1, p = .003) but not on any other test. CONCLUSIONS: Among older nondiabetic women, higher concentrations of glycated peptides may be associated with greater cognitive decline, especially in measures of executive function. These associations may present new opportunities for targeted prevention and therapeutic strategies in cognitive aging.

High Serum Serotonin Predicts Increased Risk for Hip Fracture and Nonvertebral Osteoporotic Fractures: The MrOS Sweden Study.

Because several studies have implicated serotonin as a regulator of bone mass, we here explore its potential association on fracture risk and falls, as on bone mineral density (BMD) and muscle strength, in humans. Serum levels of serotonin were analyzed in 950 men (aged 69 to 81 years), participating in the Gothenburg part of the population-based study MrOS Sweden. Men taking selective serotonin reuptake inhibitors (SSRIs) had a mean value of 31.2 µg/L compared with 159.4 µg/L in those not taking SSRIs. SSRI users were excluded from further analysis. During 10-year follow-up, 224 men exhibited fractures, including 97 nonvertebral osteoporotic fractures (57 hip fractures), and 86 vertebral fractures. Serotonin was associated with hip fracture in linear analysis (hazard ratio [HR] = 1.27, 95% confidence interval [CI] 1.03-1.58) and to all fractures in a nonlinear manner, when quintiles of serotonin was included in quadratic terms (HR = 1.12, 95% CI 1.04-1.21). Men in serotonin quintile 5 had, in multivariable analysis, a HR of 2.30 (95% CI 1.31-4.02) for hip fracture and 1.82 (95% CI 1.17-2.85) for nonvertebral fractures compared with men in quintiles 1 to 4. Men in quintile 1 had, in multivariable analysis, a HR of 1.76 (95% CI 1.03-2.99) for nonvertebral fractures compared with men in quintiles 2 to 4. No association was found with vertebral fractures. Individuals in serotonin quintile 1 had higher prevalence of falls compared with quintiles 2 to 5 (odds ratio = 1.90, 95% CI 1.26-2.87). Serotonin was positively associated with hand-grip strength (r = 0.08, p = 0.02) and inversely with hip BMD (r = -0.10, p = 0.003). To assess the association between SSRIs and falls and fractures, the total MrOS Sweden cohort was examined (n = 3014). SSRI users (n = 90) had increased prevalence of falls (16% versus 33%, p = 0.0001) and increased rate of incident fractures (28.0 versus 44.7 per 1000 person-years, p = 0.018). We present novel data showing that high levels of serotonin predict an increased risk for hip fracture and nonvertebral osteoporotic fractures. © 2018 American Society for Bone and Mineral Research.

Frailty Phenotype and Healthcare Costs and Utilization in Older Women.

OBJECTIVES: To determine the association of the frailty phenotype with subsequent healthcare costs and utilization. DESIGN: Prospective cohort study (Study of Osteoporotic Fractures (SOF)). SETTING: Four U.S. sites. PARTICIPANTS: Community-dwelling women (mean age 80.2) participating in SOF Year 10 (Y10) examination linked with their Medicare claims data (N=2,150). MEASUREMENTS: At Y10, frailty phenotype defined using criteria similar to those used in the Cardiovascular Health Study frailty phenotype and categorized as robust, intermediate stage, or frail. Participant multimorbidity burden ascertained using claims data. Functional limitations assessed by asking about difficulty performing instrumental activities of daily living. Total direct healthcare costs and utilization ascertained during 12 months after Y10. RESULTS: Mean total annualized cost±standard deviation (2014 dollars) was $3,781±6,920 for robust women, $6,632±12,452 for intermediate stage women, and $10,755 ± 16,589 for frail women. After adjustment for age, site, multimorbidity burden, and cognition, frail women had greater mean total (cost ratio (CR)=1.91, 95% confidence interval (CI)=1.59-2.31) and outpatient (CR=1.55, 95% CI=1.36-1.78) costs than robust women and greater odds of hospitalization (odds ratio (OR)=2.05, 95% CI=1.47-2.87) and a skilled nursing facility stay (OR=3.85, 95% CI=1.88-7.88). There were smaller but significant effects of the intermediate stage category on these outcomes. Individual frailty components (shrinking, poor energy, slowness, low physical activity) were also each associated with higher total costs. Functional limitations partially mediated the association between the frailty phenotype and total costs (CR further adjusted for self-reported limitations=1.32, 95% CI=1.07-1.63 for frail vs robust; CR=1.35, 95% CI=1.18-1.55 for intermediate stage vs robust women). CONCLUSION: Intermediate stage and frail older community-dwelling women had higher subsequent total healthcare costs and utilization after accounting for multimorbidity and functional limitations. Frailty phenotype assessment may improve identification of older adults likely to require costly, extensive care.

Daily Patterns of Accelerometer Activity Predict Changes in Sleep, Cognition, and Mortality in Older Men.

Background: There is growing interest in the area of "wearable tech" and its relationship to health. A common element of many of these devices is a triaxial accelerometer that can yield continuous information on gross motor activity levels; how such data might predict changes in health is less clear. Methods: We examined accelerometry data from 2,976 older men who were part of the Osteoporotic Fractures in Men (MrOS) study. Using a shape-naive technique, functional principal component analysis, we examined the patterns of motor activity over the course of 4-7 days and determined whether these patterns were associated with changes in polysomnographic-determined sleep and cognitive function (Trail Making Test-Part B [Trails B], Modified Mini-Mental State Examination [3MS]), as well as mortality over 6.5-8 years of follow-up. Results: In comparing baseline to 6.5 years later, multivariate modeling indicated that low daytime activity at baseline was associated with worsening of sleep efficiency (p < .05), more wake after sleep onset (p < .05), and a decrease in cognition (Trails B; p < .001), as well as a 1.6-fold higher rate of all-cause mortality (hazard ratio = 1.64 [1.34-2.00]). Earlier wake and bed times were associated with a decrease in cognition (3MS; p < .05). Having a late afternoon peak in activity was associated with a 1.4-fold higher rate of all-cause mortality (hazard ratio = 1.46 [1.21-1.77]). Those having a longer duration of their daytime activity with a bimodal activity pattern also had over a 1.4-fold higher rate of cardiovascular-related mortality (hazard ratio = 1.42 [1.02-1.98]). Conclusions: Patterns of daily activity may be useful as predictive biomarkers for changes in clinically relevant outcomes, including mortality and changes in sleep and cognition in older men.

Determinants of Change in Objectively Assessed Sleep Duration Among Older Men.

We examined potential risk factors for changes in objectively assessed sleep duration within a large sample of community-dwelling older men. Participants (n = 1,055; mean baseline age = 74.6 (standard deviation (SD), 4.7) years) had repeated ActiGraph assessments (ActiGraph LLC, Pensacola, Florida) taken at the baseline (2003-2005) and follow-up (2009-2012) waves of the Outcomes of Sleep Disorders in Older Men Study (an ancillary study to the Osteoporotic Fractures in Men (MrOS) Study conducted in 6 US communities). Among men with a baseline nighttime sleep duration of 5-8 hours, we assessed the odds of becoming a short-duration (<5 hours) or long-duration (>8 hours) sleeper at follow-up. The odds of becoming a short-duration sleeper were higher among men with peripheral vascular disease (adjusted odds ratio (aOR) = 6.54, 95% confidence interval (CI): 2.30, 18.55) and ≥1 impairment in Instrumental Activities of Daily Living (IADL) (aOR = 2.57, 95% CI: 0.97, 6.78). The odds of becoming a long-duration sleeper were higher among those with greater baseline age (per SD increment, aOR = 1.49, 95% CI: 1.12, 2.00), depression symptoms (aOR = 3.13, 95% CI: 1.05, 9.36), and worse global cognitive performance (per SD increment of Modified Mini-Mental State Examination score, aOR = 0.74, 95% CI: 0.58, 0.94). Peripheral vascular disease and IADL impairment, but not chronological age, may be involved in the etiology of short sleep duration in older men. The risk factors for long-duration sleep suggest that deteriorating brain health predicts elongated sleep duration in older men.

Olfaction and risk of dementia in a biracial cohort of older adults.

OBJECTIVE: Prior studies indicate that olfactory function may be an early marker for cognitive impairment, but the body of evidence has been largely restricted to white populations. METHODS: We studied 2,428 community-dwelling black and white older adults (baseline age 70-79 years) without dementia enrolled in the Health, Aging, and Body Composition (Health ABC) study. Olfaction was measured as odor identification (OI) with the 12-item Cross Cultural Smell Identification Test in year 3. We defined incident dementia over 12 years on the basis of hospitalization records, prescription for dementia medication, or 1.5-SD decline in race-stratified global cognition score. We assessed dementia risk associated with OI score (by tertile) using Cox proportional hazards models. All analyses were stratified by race. RESULTS: Poorer OI in older adults without dementia was associated with increased risk of dementia. After adjustment for demographics, medical comorbidities, and lifestyle characteristics, white participants in the poor or moderate OI tertile had greater risk of dementia (adjusted hazard ratio [HR] 3.34, 95% confidence interval [CI] 2.45-4.54; and HR 1.84, 95% CI 1.33-2.54, respectively) compared to those in the good tertile of function. Among blacks, worse OI was associated with an increased risk of dementia, but the magnitude of the effect was weaker (p for interaction = 0.04) for the poor OI tertile (adjusted HR 2.03, 95% CI 1.44-2.84) and for the moderate tertile (adjusted HR 1.42, 95% CI 0.97-2.10). There was no interaction between OI and APOE ε4 and risk of dementia. CONCLUSIONS: While the magnitude of the association was stronger in whites, we found that poor OI was associated with increased risk of dementia among both black and white older adults.

Urinary Incontinence in Older Women: The Role of Body Composition and Muscle Strength: From the Health, Aging, and Body Composition Study.

OBJECTIVES: To evaluate prospective relationships between body composition and muscle strength with predominantly stress urinary incontinence (SUI) and urgency urinary incontinence (UUI) in older women. DESIGN: Prospective community-dwelling observational cohort study (Health, Aging, and Body Composition study). PARTICIPANTS: Women initially aged 70 to 79 recruited from Pittsburgh, Pennsylvania, and Memphis, Tennessee (N = 1,475). MEASUREMENTS: Urinary incontinence was assessed using structured questionnaires. Body mass index (BMI), grip strength, quadriceps torque, and walking speed were assessed using physical examination and performance testing. Appendicular lean body mass (ALM) and whole-body fat mass were measured using dual-energy X-ray absorptiometry. RESULTS: At baseline, 212 (14%) women reported at least monthly predominantly SUI and 233 (16%) at least monthly predominantly UUI. At 3 years, of 1,137 women, 164 (14%) had new or persistent SUI, and 320 (28%) had new or persistent UUI. Women had greater odds of new or persistent SUI if they demonstrated a 5% or greater decrease in grip strength, (adjusted odds ratio (AOR) = 1.60, P = .047) and lower odds of new or persistent SUI if they demonstrated a 5% or greater decrease in BMI (AOR = 0.46, P = .01), a 5% or greater increase in ALM corrected for BMI (AOR = 0.17, P = .004), or a 5% or greater decrease in fat mass (AOR = 0.53, P = .01). Only a 5% or greater increase in walking speed was associated with new or persistent UUI over 3 years (AOR = 1.54, P = .04). CONCLUSION: In women aged 70 and older, changes in body composition and grip strength were associated with changes in SUI frequency over time. In contrast, changes in these factors did not influence UUI. Findings suggest that optimization of body composition and muscle strength is more likely to modify risk of SUI than of UUI in older women.

Long-term Cognitive Trajectories and Mortality in Older Women.

BACKGROUND: Few studies have examined whether change in cognition is linked to mortality. This study examined the relationship between cognitive trajectories in older age and risk of death. METHODS: We studied community-dwelling, nondemented women aged 65+ (mean age = 71) enrolled in a prospective study of aging and followed up to 25 years. A modified Mini-Mental State Examination (mMMSE) and Trail Making Task Part B (TMTB) were administered at multiple visits during follow-up. We examined the association between cognitive trajectories (analyzed by quintiles) from baseline to age 80 (n = 7,477 for mMMSE and n = 6,503 for TMTB) and all-cause mortality after age 80 using Cox regression models, both unadjusted and adjusted for education, physical activity, alcohol, depression score, current smoking and history of hypertension and diabetes. Cause of death was determined from death certificates, classified as cardiovascular, cancer and other. RESULTS: Women with greater rate of decline were older, less educated, less physically active, had higher depression score and were more likely to have a history of hypertension and diabetes (all p < .01). Participants with the greatest decline (quintile 1) had an increased risk of death (mMMSE hazard ratio [HR] = 1.28; TMTB HR = 1.43] and those with the least decline (quintile 5) had a decreased risk of death (mMMSE HR = 0.73; TMTB HR = 0.61) compared with intermediate decliners (quintiles 2-4). Cognitive trajectories were associated with cardiovascular mortality and other causes of death, but not cancer deaths. CONCLUSIONS: Our study suggests that greater decline in general cognition or executive function is associated with higher rates of mortality in oldest-old women.

Hip Fractures Risk in Older Men and Women Associated With DXA-Derived Measures of Thigh Subcutaneous Fat Thickness, Cross-Sectional Muscle Area, and Muscle Density.

Mid-thigh cross-sectional muscle area (CSA), muscle attenuation, and greater trochanter soft tissue thickness have been shown to be independent risk factors of hip fracture. Our aim was to determine whether muscle and adipose tissue measures derived from dual-energy X-ray absorptiometry (DXA) scans would have a similar risk association as those measured using other imaging methods. Using a case-cohort study design, we identified 169 incident hip fracture cases over an average of 13.5 years among participants from the Health ABC Study, a prospective study of 3075 individuals initially aged 70 to 79 years. We modeled the thigh 3D geometry and compared DXA and computed tomography (CT) measures. DXA-derived thigh CSA, muscle attenuation, and subcutaneous fat thickness were found to be highly correlated to their CT counterparts (Pearson's r = 0.82, 0.45, and 0.91, respectively; p < 0.05). The fracture risk of men and women were calculated separately. We found that decreased subcutaneous fat, CT thigh muscle attenuation, and appendicular lean mass by height squared (ALM/Ht(2)) were associated with fracture risk in men; hazard ratios (HR) = 1.44 (1.02, 2.02), 1.40 (1.05, 1.85), and 0.58 (0.36, 0.91), respectively, after adjusting for age, race, clinical site, body mass index (BMI), chronic disease, hip bone mineral density (BMD), self-reported health, alcohol use, smoking status, education, physical activity, and cognitive function. In a similar model for women, only decreases in subcutaneous fat and DXA CSA were associated with hip fracture risk; HR = 1.39 (1.07, 1.82) and 0.78 (0.62, 0.97), respectively. Men with a high ALM/Ht(2) and low subcutaneous fat thickness had greater than 8 times higher risk for hip fracture compared with those with low ALM/Ht(2) and high subcutaneous fat. In women, ALM/Ht(2) did not improve the model when subcutaneous fat was included. We conclude that the DXA-derived subcutaneous fat thickness is a strong marker for hip fracture risk in both men and women, especially in men with high ALM/Ht(2).

Study of Tomography Of Nephrolithiasis Evaluation (STONE): methodology, approach and rationale.

BACKGROUND: Urolithiasis (kidney stones) is a common reason for Emergency Department (ED) visits, accounting for nearly 1% of all visits in the United States. Computed tomography (CT) has become the most common imaging test for these patients but there are few comparative effectiveness data to support its use in comparison to ultrasound. This paper describes the rationale and methods of STONE (Study of Tomography Of Nephrolithiasis Evaluation), a pragmatic randomized comparative effectiveness trial comparing different imaging strategies for patients with suspected urolithiasis. METHODS: STONE is a multi-center, non-blinded pragmatic randomized comparative effectiveness trial of patients between ages 18 and 75 with suspected nephrolithiasis seen in an ED setting. Patients were randomized to one of three initial imaging examinations: point-of-care ultrasound, ultrasound performed by a radiologist or CT. Participants then received diagnosis and treatment per usual care. The primary aim is to compare the rate of severe SAEs (Serious Adverse Events) between the three arms. In addition, a broad range of secondary outcomes was assessed at baseline and regularly for six months post-baseline using phone, email and mail questionnaires. RESULTS: Excluding 17 patients who withdrew after randomization, a total of 2759 patients were randomized and completed a baseline questionnaire (n=908, 893 and 958 in the point-of-care ultrasound, radiology ultrasound and radiology CT arms, respectively). Follow-up is complete, and full or partial outcomes were assessed on over 90% of participants. CONCLUSIONS: The detailed methodology of STONE will provide a roadmap for comparative effectiveness studies of diagnostic imaging conducted in an ED setting.