Independent Association of Plasma Hydroxysphingomyelins With Physical Function in the Atherosclerosis Risk in Communities (ARIC) Study.

Background: Plasma metabolites such as phosphatidylcholines and sphingomyelins (SMs) are associated with an age-related cognitive decline. However, their relations to age-related physical function decline remain largely unknown. Methods: We examined the cross-sectional relations of 12 plasma metabolites (including four phosphatidylcholines and four SMs) with physical function in 383 older adults in the At herosclerosis Risk in Communities Study at the fifth exam (2011-2013, mean age [standard deviation (SD)]: 78.0 [5.5], 54.4% women, 28.3% African Americans). Physical function was assessed using grip strength, Short Physical Performance Battery, and 4-m walking speed. Individual metabolites were log-transformed and standardized. Multivariable linear regression was performed to account for demographics, APOE genotype, cardiovascular risk factors, comorbidities, use of antihypertensive and lipid-lowering medications, depressive symptoms, and cognition. Results: Lower concentrations of asymmetric dimethylarginine and higher concentrations of SM (OH) C22:1, SM (OH) C22:2, and SM (OH) C24:1 were associated with physical function measures. In particular, SM (OH) C22:1 and SM (OH) C24:1 were associated with all three measures of physical function: ß-coefficients (95% confidence interval) with grip strength were 0.89 kg (0.00, 1.78) and 0.86 kg (0.10, 1.61) per 1 SD higher concentration, respectively; with Short Physical Performance Battery score, were 0.61 (0.34, 0.88) and 0.41 (0.19, 0.63) per 1 SD difference, respectively; with 4-m walking speed were 0.035 m/s (0.013, 0.056) and 0.035 m/s (0.028, 0.047), respectively. Conclusions: Plasma SM (OH)s may be independently associated with physical function in older adults.

Genome-wide studies of verbal declarative memory in nondemented older people: the Cohorts for Heart and Aging Research in Genomic Epidemiology consortium.

BACKGROUND: Memory performance in older persons can reflect genetic influences on cognitive function and dementing processes. We aimed to identify genetic contributions to verbal declarative memory in a community setting. METHODS: We conducted genome-wide association studies for paragraph or word list delayed recall in 19 cohorts from the Cohorts for Heart and Aging Research in Genomic Epidemiology consortium, comprising 29,076 dementia- and stroke-free individuals of European descent, aged ≥45 years. Replication of suggestive associations (p < 5 × 10(-6)) was sought in 10,617 participants of European descent, 3811 African-Americans, and 1561 young adults. RESULTS: rs4420638, near APOE, was associated with poorer delayed recall performance in discovery (p = 5.57 × 10(-10)) and replication cohorts (p = 5.65 × 10(-8)). This association was stronger for paragraph than word list delayed recall and in the oldest persons. Two associations with specific tests, in subsets of the total sample, reached genome-wide significance in combined analyses of discovery and replication (rs11074779 [HS3ST4], p = 3.11 × 10(-8), and rs6813517 [SPOCK3], p = 2.58 × 10(-8)) near genes involved in immune response. A genetic score combining 58 independent suggestive memory risk variants was associated with increasing Alzheimer disease pathology in 725 autopsy samples. Association of memory risk loci with gene expression in 138 human hippocampus samples showed cis-associations with WDR48 and CLDN5, both related to ubiquitin metabolism. CONCLUSIONS: This largest study to date exploring the genetics of memory function in ~40,000 older individuals revealed genome-wide associations and suggested an involvement of immune and ubiquitin pathways.

Predictivity of survival according to different equations for estimating renal function in community-dwelling elderly subjects.

BACKGROUND: Detection of subjects with early chronic kidney disease (CKD) is important because some will progress up to stage 5 CKD, and most are at high risk of cardiovascular morbidity and mortality. While validity and precision of estimated glomerular filtration rate (eGFR) equations in tracking true GFR have been repeatedly investigated, their prognostic performance for mortality has not been hitherto compared. This is especially relevant in an elderly population in whom the risk of death is far more common than progression. METHODS: We analysed data of participants in the InCHIANTI study, a community-based cohort study of older adults. Twenty-four-hour creatinine clearance (Ccr), Cockcroft-Gault (C-G) and Modification of Diet in Renal Disease (MDRD)-derived equations (six and four input variables) were calculated at enrolment (1998-2000), and all-cause mortality and cardiovascular mortality were prospectively ascertained by Cox regression over a 6-year follow-up. RESULTS: Of the 1270 participants, 942 (mean age 75 years) had complete data for this study. The mean renal function ranged from 77 ml/min/1.73 m(2) by Ccr to 64 ml/min/1.73 m(2) by C-G. Comparisons among equations using K/DOQI staging highlight relevant mismatches, with a prevalence of CKD ranging from 22% (MDRD-4) to 40% (C-G). Reduced renal function was a strong independent predictor of death. In a Cox model--adjusted for demographics, physical activity, comorbidities, proteinuria and inflammatory parameters-participants with Ccr 60-90 ml/min/1.73 m(2) and Ccr <60 ml/min/1.73 m(2) were, respectively, 1.70 (95% CI: 1.02-2.83) and 1.91 (95% CI: 1.11-3.29) times more likely to die over the follow-up compared to those with Ccr >90 ml/min/1.73 m(2). For the C-G, the group with values <60 ml/min/1.73 m(2) had a significant higher all-cause mortality compared to those with values >90 ml/min/1.73 m(2) (HR 2.59, 95% CI: 1.13-5.91). The classification based on the MDRD formulae did not provide any significant prognostic information. The adjusted risk of all-cause mortality followed a similar pattern when Ccr and estimating equations were introduced as continuous variables or dichotomized as higher or lower than 60 ml/min. C-G was the best prognostic indicator of cardiovascular mortality. Possibly, Ccr and C-G are better prognostic indicators than MDRD-derived equations because they incorporate a stronger effect of age. CONCLUSIONS: In a South-European elderly population, the prevalence of CKD is high and varies widely according to the method adopted to estimate GFR. Researchers and clinicians who want to capture the prognostic information on mortality related to kidney function should use the Ccr or C-G formula and not MDRD equations. These results highlight the importance of strategies for early detection and clinical management of CKD in elderly subjects.

White blood cell count and mortality in the Baltimore Longitudinal Study of Aging.

OBJECTIVES: We investigated the secular trend in white blood cell (WBC) count and the relationship between WBC count and mortality between 1958 and 2002. BACKGROUND: The WBC count is a clinical marker of inflammation and a strong predictor of mortality. Limited data exist on the WBC count secular trend and the relationship between WBC and mortality. METHODS: One thousand eighty-three women and 1,720 men were evaluated longitudinally in the Baltimore Longitudinal Study of Aging. Blood samples and medical information were collected at the study entry and every 2 years during follow-up visits. The WBC count and all-cause, cardiovascular, and cancer mortality were assessed. RESULTS: A downward trend in WBC count was observed from 1958 to 2002. The secular downward trend was independent of age, gender, race, smoking, body mass index, and physical activity. The WBC count was nonlinearly associated with all-cause mortality and almost linearly associated with cardiovascular mortality. Participants with baseline WBC <3,500 cells/mm3 and WBC >6,000 cells/mm3 had higher mortality than those with 3,500 to 6,000 WBC/mm3. Within each WBC group, age-adjusted mortality rates declined in successive cohorts from the 1960s to the 1990s. Participants who died had higher WBC than those who survived, and the difference was statistically significant within 5 years before death. CONCLUSIONS: Our study provides evidence for a secular downward trend in WBC count over the period from 1958 to 2002. Higher WBC counts are associated with higher mortality in successive cohorts. We found no evidence that the decline of age-specific mortality rates that occurred from 1960 to 2000 was attributable to a secular downward trend in WBC.