03487nas a2200505 4500008004100000022001400041245012900055210006900184260001300253300001100266490000700277520205800284653000902342653002202351653001502373653002302388653001902411653001102430653001102441653001702452653004602469653001902515653001802534653001402552653000902566653004502575653001702620100001902637700001802656700001802674700002102692700001702713700001702730700002102747700002202768700001702790700001702807700002002824700001702844700002502861700001902886700002002905700002002925856003602945 2014 eng d a1758-535X00aSimple biologically informed inflammatory index of two serum cytokines predicts 10 year all-cause mortality in older adults.0 aSimple biologically informed inflammatory index of two serum cyt c2014 Feb a165-730 v693 a

BACKGROUND: Individual measurements of inflammation have been utilized to assess adverse outcomes risk in older adults with varying degrees of success. This study was designed to identify biologically informed, aggregate measures of inflammation for optimal risk assessment and to inform further biological study of inflammatory pathways.

METHODS: In total, 15 nuclear factor-kappa B-mediated pathway markers of inflammation were first measured in baseline serum samples of 1,155 older participants in the InCHIANTI population. Of these, C-reactive protein, interleukin-1-receptor antagonist, interleukin-6, interleukin-18, and soluble tumor necrosis factor-α receptor-1 were independent predictors of 5-year mortality. These five inflammatory markers were measured in baseline serum samples of 5,600 Cardiovascular Health Study participants. A weighted summary score, the first principal component summary score, and an inflammation index score were developed from these five log-transformed inflammatory markers, and their prediction of 10-year all-cause mortality was evaluated in Cardiovascular Health Study and then validated in InCHIANTI.

RESULTS: The inflammation index score that included interleukin-6 and soluble tumor necrosis factor-α receptor-1 was the best predictor of 10-year all-cause mortality in Cardiovascular Health Study, after adjusting for age, sex, education, race, smoking, and body mass index (hazards ratio = 1.62; 95% CI: 1.54, 1.70) compared with all other single and combined measures. The inflammation index score was also the best predictor of mortality in the InCHIANTI validation study (hazards ratio 1.33; 95% CI: 1.17-1.52). Stratification by sex and CVD status further strengthened the association of inflammation index score with mortality.

CONCLUSION: A simple additive index of serum interleukin-6 and soluble tumor necrosis factor-α receptor-1 best captures the effect of chronic inflammation on mortality in older adults among the 15 biomarkers measured.

10aAged10aAged, 80 and over10aBiomarkers10aC-Reactive Protein10aCohort Studies10aFemale10aHumans10aInflammation10aInterleukin 1 Receptor Antagonist Protein10aInterleukin-1810aInterleukin-610aLongevity10aMale10aReceptors, Tumor Necrosis Factor, Type I10aRisk Factors1 aVaradhan, Ravi1 aYao, Wenliang1 aMatteini, Amy1 aBeamer, Brock, A1 aXue, Qian-Li1 aYang, Huanle1 aManwani, Bhavish1 aReiner, Alexander1 aJenny, Nancy1 aParekh, Neel1 aFallin, Daniele1 aNewman, Anne1 aBandeen-Roche, Karen1 aTracy, Russell1 aFerrucci, Luigi1 aWalston, Jeremy uhttps://chs-nhlbi.org/node/660802598nas a2200205 4500008004100000022001400041245017200055210006900227260001600296520186400312100002502176700002502201700002202226700001702248700002702265700002102292700002302313700002002336856003602356 2017 eng d a1545-721400aLate-Life Depressive Symptoms as Partial Mediators in the Associations between Subclinical Cardiovascular Disease with Onset of Mild Cognitive Impairment and Dementia.0 aLateLife Depressive Symptoms as Partial Mediators in the Associa c2017 Nov 203 a

OBJECTIVE: To study whether depression contributes to the association between subclinical cardiovascular disease (CVD) and dementia, and identify the contribution's magnitude.

METHODS: Among participants from the Cardiovascular Health Study Cognition Study who did not have baseline CVD-related events (N = 2,450), causal mediation methodology was implemented to examine whether late-life depressive symptoms, defined as 10-item Center for Epidemiologic Studies-Depression (mCES-D) Scale scores ≥8 from 2 to 3 years after baseline, partially mediated the association of baseline subclinical CVD (CAC, carotid intimal medial thickness, stenosis, and ankle brachial index) with mild cognitive impairment (MCI)/dementia onset occurring between 5 and 10 years from baseline. The total effect was decomposed into direct and indirect effects (via late-life depressive symptoms), obtained from an accelerated failure time model with weights derived from multivariable logistic regression of late-life depressive symptoms on subclinical CVD. Analyses were adjusted by baseline covariates: age, race, sex, poverty status, marital status, body mass index, smoking status, ApoE4 status, and mCES-D.

RESULTS: Participants contributed 20,994 person-years of follow-up with a median follow-up time of 9.4 years. Subclinical CVD was associated with 12% faster time to MCI/dementia (time ratio [TR]: 0.88; 95% CI: 0.83, 0.93). The total effect of subclinical CVD on MCI/dementia onset was decomposed into a direct effect (TR: 0.95, 95% CI: 0.92, 0.98) and indirect effect (TR: 0.92, 95% CI: 0.88, 0.97); 64.5% of the total effect was mediated by late-life depressive symptoms.

CONCLUSIONS: These data suggest late-life depressive symptoms partially mediate the association of subclinical CVD with MCI/dementia onset.

1 aArmstrong, Nicole, M1 aCarlson, Michelle, C1 aSchrack, Jennifer1 aXue, Qian-Li1 aCarnethon, Mercedes, R1 aRosano, Caterina1 aChaves, Paulo, H M1 aGross, Alden, L uhttps://chs-nhlbi.org/node/754401869nas a2200205 4500008004100000022001400041245014500055210006900200260001600269300002000285520116300305100002501468700002501493700001701518700002201535700002701557700002301584700002001607856003601627 2017 eng d a1552-688700aRole of Late-Life Depression in the Association of Subclinical Cardiovascular Disease With All-Cause Mortality: Cardiovascular Health Study.0 aRole of LateLife Depression in the Association of Subclinical Ca c2017 Nov 01 a8982643177449213 a

OBJECTIVES: To evaluate whether late-life depression mediates the association of subclinical cardiovascular disease (CVD) with all-cause mortality.

METHOD: Using data from 3,473 Cardiovascular Health Study participants, the Cox proportional hazards model was used to examine the direct and indirect (via late-life depression) effects of the association between baseline subclinical CVD and all-cause mortality with weights derived from multivariable logistic regression of late-life depression on subclinical CVD.

RESULTS: Subclinical CVD led to a higher risk of all-cause mortality (hazard ratio [HR] = 1.51, 95% confidence interval, [CI] = [1.42, 1.94]). Total effect of subclinical CVD on all-cause mortality was decomposed into direct (HR = 1.41, 95% CI = [1.37, 1.58]) and indirect (HR = 1.07, 95% CI = [1.01, 1.23]) effects; 16.3% of the total effect of subclinical CVD on all-cause mortality was mediated by late-life depression.

DISCUSSION: Late-life depression accounts for little, if any, of the association between subclinical CVD, a risk factor of all-cause mortality, and all-cause mortality.

1 aArmstrong, Nicole, M1 aCarlson, Michelle, C1 aXue, Qian-Li1 aSchrack, Jennifer1 aCarnethon, Mercedes, R1 aChaves, Paulo, H M1 aGross, Alden, L uhttps://chs-nhlbi.org/node/754502432nas a2200181 4500008004100000022001400041245013300055210006900188260001600257520183000273100001602103700001602119700001702135700002002152700001902172700002302191856003602214 2018 eng d a1758-535X00aAssociation of Frailty with Recovery from Disability among Community-Dwelling Older Adults: Results from Two Large U.S. Cohorts.0 aAssociation of Frailty with Recovery from Disability among Commu c2018 Apr 103 a

Background: Disability in activities of daily living (ADLs) is a dynamic process and transitions among different disability states are common. However, little is known about factors affecting recovery from disability. We examined the association between frailty and recovery from disability among non-disabled community-dwelling elders.

Methods: We studied 1023 adults from the Cardiovascular Health Study (CHS) and 685 adults from the Health and Retirement Study (HRS), who were ≥65 years and had incident disability, defined as having difficulty in ≥1 ADL (dressing, eating, toileting, bathing, transferring, walking across a room). Disability recovery was defined as having no difficulty in any ADLs. Frailty was assessed by slowness, weakness, exhaustion, inactivity, and shrinking. Persons were classified as "non-frail" (0 criteria), "prefrail" (1-2 criteria), or "frail" (3-5 criteria).

Results: In total, 539 (52.7%) CHS participants recovered from disability within one year. Almost two-thirds of non-frail persons recovered, while less than two-fifths of the frail recovered. In the HRS, 234 (34.2%) participants recovered from disability within two years. Approximately half of the non-frail recovered, while less than one-fifth of the frail recovered. After adjustment, prefrail and frail CHS participants were 16% and 36% less likely to recover than the non-frail, respectively. In the HRS, frail persons had a 41% lower likelihood of recovery than the non-frail.

Conclusions: Frailty is an independent predictor of poor recovery from disability among non-disabled older adults. These findings validate frailty as a marker of decreased resilience and may offer opportunities for individualized interventions and geriatric care based on frailty assessment.

1 aWu, Chenkai1 aKim, Dae, H1 aXue, Qian-Li1 aLee, David, S H1 aVaradhan, Ravi1 aOdden, Michelle, C uhttps://chs-nhlbi.org/node/767402020nas a2200181 4500008004100000022001400041245012900055210006900184260001600253520142300269100001601692700001801708700001701726700001601743700002001759700002301779856003601802 2018 eng d a1476-625600aDevelopment, Construct Validity, and Predictive Validity of a Continuous Frailty Scale: Results from Two Large U.S. Cohorts.0 aDevelopment Construct Validity and Predictive Validity of a Cont c2018 Apr 243 a

Frailty is an age-related clinical syndrome of decreased resilience to stressors. Among numerous assessments of frailty, the frailty phenotype (FP) scale, proposed by Fried and colleagues has been the most widely used one. We aimed to develop a continuous frailty scale that may overcome limitations facing the categorical FP scale and to evaluate its construct validity, predictive validity, and measurement properties. Data were from the Cardiovascular Health Study (N = 4243) and Health and Retirement Study (N = 7600). Frailty was conceptualized as a continuous construct, measured by five measures used in FP scale: gait speed, grip strength, exhaustion, physical activity, and weight loss. We used confirmatory factor analysis to investigate the relationship between five indicators and the latent frailty construct. We examined the association of the continuous frailty scale with mortality and disability. The unidimensional model fit the data satisfactorily; similar factor structure was observed across two cohorts. Gait speed and weight loss were the strongest and weakest indicators, respectively; grip strength, exhaustion, and physical activity had similar strength in measuring frailty. In each cohort, the continuous frailty scale was strongly associated with mortality and disability and persisted to be associated with outcomes among robust and prefrail persons classified by the FP scale.

1 aWu, Chenkai1 aGeldhof, John1 aXue, Qian-Li1 aKim, Dae, H1 aNewman, Anne, B1 aOdden, Michelle, C uhttps://chs-nhlbi.org/node/766202154nas a2200181 4500008004100000022001400041245007600055210006900131260001600200520159700216100001701813700001501830700002301845700002301868700002001891700002501911856003601936 2019 eng d a1758-535X00aDiscrepancy in Frailty Identification: Move beyond Predictive Validity.0 aDiscrepancy in Frailty Identification Move beyond Predictive Val c2019 Feb 213 a

BACKGROUND: To evaluate the discordance in frailty classification between the frailty index (FI) and the physical frailty phenotype (PFP) and identify factors discriminating those with discordant frailty classification from each other and from those for whom the assessments agree.

METHODS: A prospective observational study of older adults aged 65 and older selected from Medicare eligibility lists in four US communities (n=5,362). The PFP was measured by the Cardiovascular Health Study PFP. Subjects meeting ≥3 of the 5 criteria were deemed frail. The FI was calculated as the proportion of deficits in an a priori selected set of 48 measures and subjects were classified as frail if FI>0.35.

RESULTS: The prevalence of frailty was 7.0% by the PFP and 8.3% by the FI. Of the 730 deemed frail by either instrument, only 12% were in agreement; whereas 39% were classified as frail by PFP but not FI; and 48% were classified as frail by FI but not PFP. Participants aged 65-72 or greater disease burden were mostly likely to be characterized as being FI-frail but not PFP-frail. The associations of frailty with age and mortality was stronger when frailty was measured by the PFP rather than the FI.

CONCLUSIONS: Despite comparable frailty prevalence between the PFP and the FI, there was substantial discordance in individual-level classification, with highest agreement existing only in the most vulnerable subset. These findings suggest that there are clinically important contexts in which PFP and FI cannot be used interchangeably.

1 aXue, Qian-Li1 aTian, Jing1 aWalston, Jeremy, D1 aChaves, Paulo, H M1 aNewman, Anne, B1 aBandeen-Roche, Karen uhttps://chs-nhlbi.org/node/798203264nas a2200409 4500008004100000022001400041245010500055210006900160260001300229300001400242490000700256520207500263100002202338700001702360700002102377700001702398700002102415700002102436700002402457700002402481700001702505700002302522700001902545700002702564700002202591700002302613700001902636700001802655700002102673700001902694700002002713700001902733700001502752700002902767700002202796856003602818 2020 eng d a1532-541500aPutative Cut-Points in Sarcopenia Components and Incident Adverse Health Outcomes: An SDOC Analysis.0 aPutative CutPoints in Sarcopenia Components and Incident Adverse c2020 Jul a1429-14370 v683 a

OBJECTIVES: Analyses performed by the Sarcopenia Definitions and Outcomes Consortium (SDOC) identified cut-points in several metrics of grip strength for consideration in a definition of sarcopenia. We describe the associations between the SDOC-identified metrics of low grip strength (absolute or standardized to body size/composition); low dual-energy x-ray absorptiometry (DXA) lean mass as previously defined in the literature (appendicular lean mass [ALM]/ht ); and slowness (walking speed <.8 m/s) with subsequent adverse outcomes (falls, hip fractures, mobility limitation, and mortality).

DESIGN: Individual-level, sex-stratified pooled analysis. We calculated odds ratios (ORs) or hazard ratios (HRs) for incident falls, mobility limitation, hip fractures, and mortality. Follow-up time ranged from 1 year for falls to 8.8 ± 2.3 years for mortality.

SETTING: Eight prospective observational cohort studies.

PARTICIPANTS: A total of 13,421 community-dwelling men and 4,828 community-dwelling women. MEASUREMENTS Grip strength by hand dynamometry, gait speed, and lean mass by DXA.

RESULTS: Low grip strength (absolute or standardized to body size/composition) was associated with incident outcomes, usually independently of slowness, in both men and women. ORs and HRs generally ranged from 1.2 to 3.0 for those below vs above the cut-point. DXA lean mass was not consistently associated with these outcomes. When considered together, those who had both muscle weakness by absolute grip strength (<35.5 kg in men and <20 kg in women) and slowness were consistently more likely to have a fall, hip fracture, mobility limitation, or die than those without either slowness or muscle weakness.

CONCLUSION: Older men and women with both muscle weakness and slowness have a higher likelihood of adverse health outcomes. These results support the inclusion of grip strength and walking speed as components in a summary definition of sarcopenia. J Am Geriatr Soc 68:1429-1437, 2020.

1 aCawthon, Peggy, M1 aManini, Todd1 aPatel, Sheena, M1 aNewman, Anne1 aTravison, Thomas1 aKiel, Douglas, P1 aSantanasto, Adam, J1 aEnsrud, Kristine, E1 aXue, Qian-Li1 aShardell, Michelle1 aDuchowny, Kate1 aErlandson, Kristine, M1 aPencina, Karol, M1 aFielding, Roger, A1 aMagaziner, Jay1 aKwok, Timothy1 aKarlsson, Magnus1 aOhlsson, Claes1 aMellström, Dan1 aHirani, Vasant1 aRibom, Eva1 aCorrea-de-Araujo, Rosaly1 aBhasin, Shalender uhttps://chs-nhlbi.org/node/837703425nas a2200577 4500008004100000022001400041245020400055210006900259260001500328300001400343490000700357520172900364653000902093653001102102653000902113653001102122653002302133653000902156653002402165653001502189653001202204653001802216100002202234700002102256700002802277700002002305700002102325700002102346700002402367700001602391700002402407700002002431700002202451700001802473700001902491700002002510700002402530700002002554700001902574700002102593700001702614700002302631700002202654700002202676700002302698700001902721700002902740700002202769700002002791856003602811 2021 eng d a1758-535X00aWhat Cut-Point in Gait Speed Best Discriminates Community-Dwelling Older Adults With Mobility Complaints From Those Without? A Pooled Analysis From the Sarcopenia Definitions and Outcomes Consortium.0 aWhat CutPoint in Gait Speed Best Discriminates CommunityDwelling c2021 09 13 ae321-e3270 v763 a

BACKGROUND: Cut-points to define slow walking speed have largely been derived from expert opinion.

METHODS: Study participants (13 589 men and 5043 women aged ≥65years) had walking speed (m/s) measured over 4-6 m (mean ± SD: 1.20 ± 0.27 m/s in men and 0.94 ± 0.24 m/s in women.) Mobility limitation was defined as any self-reported difficulty with walking approximately 1/4 mile (prevalence: 12.6% men, 26.4% women). Sex-stratified classification and regression tree (CART) models with 10-fold cross-validation identified walking speed cut-points that optimally discriminated those who reported mobility limitation from those who did not.

RESULTS: Among 5043 women, CART analysis identified 2 cut-points, classifying 4144 (82.2%) with walking speed ≥0.75 m/s, which we labeled as "fast"; 478 (9.5%) as "intermediate" (walking speed ≥0.62 m/s but <0.75 m/s); and 421 (8.3%) as "slow" (walking speed <0.62 m/s). Among 13 589 men, CART analysis identified 3 cut-points, classifying 10 001 (73.6%) with walking speed ≥1.00 m/s ("very fast"); 2901 (21.3%) as "fast" (walking speed ≥0.74 m/s but <1.00 m/s); 497 (3.7%) as "intermediate" (walking speed ≥0.57 m/s but <0.74 m/s); and 190 (1.4%) as "slow" (walking speed <0.57 m/s). Prevalence of self-reported mobility limitation was lowest in the "fast" or "very fast" (11% for men and 19% for women) and highest in the "slow" (60.5% in men and 71.0% in women). Rounding the 2 slower cut-points to 0.60 m/s and 0.75 m/s reclassified very few participants.

CONCLUSIONS: Cut-points in walking speed of approximately 0.60 m/s and 0.75 m/s discriminate those with self-reported mobility limitation from those without.

10aAged10aFemale10aGait10aHumans10aIndependent Living10aMale10aMobility Limitation10aSarcopenia10aWalking10aWalking Speed1 aCawthon, Peggy, M1 aPatel, Sheena, M1 aKritchevsky, Stephen, B1 aNewman, Anne, B1 aSantanasto, Adam1 aKiel, Douglas, P1 aTravison, Thomas, G1 aLane, Nancy1 aCummings, Steven, R1 aOrwoll, Eric, S1 aDuchowny, Kate, A1 aKwok, Timothy1 aHirani, Vasant1 aSchousboe, John1 aKarlsson, Magnus, K1 aMellström, Dan1 aOhlsson, Claes1 aLjunggren, Osten1 aXue, Qian-Li1 aShardell, Michelle1 aJordan, Joanne, M1 aPencina, Karol, M1 aFielding, Roger, A1 aMagaziner, Jay1 aCorrea-de-Araujo, Rosaly1 aBhasin, Shalender1 aManini, Todd, M uhttps://chs-nhlbi.org/node/898903463nas a2200289 4500008004100000022001400041245015900055210006900214260001600283300000800299490000700307520261600314653002302930653001102953653001202964653001802976653001102994653000903005653001403014653001603028100002503044700001503069700001603084700002003100700001703120856003603137 2023 eng d a1471-231800aSubstitution of self-reported measures for objectively assessed grip strength and slow walk in the Physical Frailty Phenotype: ramifications for validity.0 aSubstitution of selfreported measures for objectively assessed g c2023 Jul 22 a4510 v233 a

BACKGROUND: Frailty assessment promises to identify older adults at risk for adverse consequences following stressors and target interventions to improve health outcomes. The Physical Frailty Phenotype (PFP) is a widely-studied, well validated assessment but incorporates performance-based slow walk and grip strength criteria that challenge its use in some clinical settings. Variants replacing performance-based elements with self-reported proxies have been proposed. Our study evaluated whether commonly available disability self-reports could be substituted for the performance-based criteria in the PFP while still identifying as "frail" the same subpopulations of individuals.

METHODS: Parallel analyses were conducted in 3393 female and 2495 male Cardiovascular Health Study, Round 2 participants assessed in 1989-90. Candidate self-reported proxies for the phenotype's "slowness" and "weakness" criteria were evaluated for comparable prevalence and agreement by mode of measurement. For best-performing candidates: Frailty status (3 + positive criteria out of 5) was compared for prevalence and agreement between the PFP and mostly self-reported versions. Personal characteristics were compared between those adjudicated as frail by (a) only a self-reported version; (b) only the PFP; (c) both, using bivariable analyses and multinomial logistic regression.

RESULTS: Self-reported difficulty walking ½ mile was selected as a proxy for the phenotype's slowness criterion. Two self-reported weakness proxies were examined: difficulty transferring from a bed or chair or gripping with hands, and difficulty as just defined or in lifting a 10-pound bag. Prevalences matched to within 4% between self-reported and performance-based criteria in the whole sample, but in all cases the self-reported prevalence for women exceeded that for men by 11% or more. Cross-modal agreement was moderate, with by-criterion and frailty-wide Kappa statistics of 0.55-0.60 in all cases. Frail subgroups (a), (b), (c) were independently discriminated (p < 0.05) by race, BMI, and depression in women; by age in men; and by self-reported health for both.

CONCLUSIONS: Commonly used self-reported disability items cannot be assumed to stand in for performance-based criteria in the PFP. We found subpopulations identified as frail by resultant phenotypes versus the original phenotype to systematically differ. Work to develop self-reported proxies that more closely replicate their objective phenotypic counterparts than standard disability self-reports is needed.

10aAdvance Directives10aFemale10aFrailty10aHand Strength10aHumans10aMale10aPhenotype10aSelf Report1 aBandeen-Roche, Karen1 aTian, Jing1 aButa, Brian1 aWalston, Jeremy1 aXue, Qian-Li uhttps://chs-nhlbi.org/node/9445