@article {640, title = {Associations of subclinical cardiovascular disease with frailty.}, journal = {J Gerontol A Biol Sci Med Sci}, volume = {56}, year = {2001}, month = {2001 Mar}, pages = {M158-66}, abstract = {

BACKGROUND: Frail health in old age has been conceptualized as a loss of physiologic reserve associated with loss of lean mass, neuroendocrine dysregulation, and immune dysfunction. Little work has been done to define frailty and describe the underlying pathophysiology.

METHODS: Frailty status was defined in participants of the Cardiovascular Health Study (CHS), a cohort of 5,201 community-dwelling older adults, based on the presence of three out of five clinical criteria. The five criteria included self-reported weight loss, low grip strength, low energy, slow gait speed, and low physical activity. We examined the spectrum of clinical and subclinical cardiovascular disease in those who were frail (3/5 criteria) or of intermediate frailty status (1 or 2/5 criteria), compared to those who were not frail (0/5). We hypothesized that the severity of frailty would be related to a higher prevalence of reported cardiovascular disease (CVD), as well as to a greater extent of CVD, measured by noninvasive testing.

RESULTS: Of 4,735 eligible participants, 2,289 (48\%) were not frail, 299 (6\%) were frail, and 2.147 (45\%) were of intermediate frailty status. Those who were frail were older (77.2 yrs) compared to those who were not frail (71.5 yrs) or intermediate (73.4 yrs) (p < .001). Frailty status was associated with clinical CVD and most strongly with congestive heart failure (odds ratio [OR] = 7.51 (95\% confidence interval [CI] = 4.66-12.12). In those without a history of a CVD event (n = 1.259), frailty was associated with many noninvasive measures of CVD. Those with carotid stenosis >75\% (adjusted OR = 3.41), ankle-arm index <0.8 (adjusted OR = 3.17) or 0.8-0.9 (adjusted OR = 2.01), major electrocardiography (ECG) abnormalities (adjusted OR = 1.58), greater left ventricular (LV) mass by echocardiography (adjusted OR = 1.16), and higher degree of infarct-like lesions in the brain (adjusted OR = 1.71), were more likely to be frail compared to those who were not frail. The overall associations of each of these noninvasive measures of CVD with frailty level were significant (all p < .05).

CONCLUSIONS: Cardiovascular disease was associated with an increased likelihood of frail health. In those with no history of CVD, the extent of underlying cardiovascular disease measured by carotid ultrasound and ankle-arm index, LV hypertrophy by ECG and echocardiography, was related to frailty. Infarct-like lesions in the brain on magnet resonance imaging were related to frailty as well.

}, keywords = {Aged, Ankle, Arm, Black or African American, Blood Pressure, Brain, Cardiovascular Diseases, Carotid Artery Diseases, Cerebral Infarction, Cerebrovascular Disorders, Cohort Studies, Echocardiography, Electrocardiography, Frail Elderly, Health Status, Heart Failure, Humans, Magnetic Resonance Imaging, United States, Vascular Diseases}, issn = {1079-5006}, doi = {10.1093/gerona/56.3.m158}, author = {Newman, A B and Gottdiener, J S and McBurnie, M A and Hirsch, C H and Kop, W J and Tracy, R and Walston, J D and Fried, L P} } @article {1335, title = {The association of genetic variants in interleukin-1 genes with cognition: findings from the cardiovascular health study.}, journal = {Exp Gerontol}, volume = {46}, year = {2011}, month = {2011 Dec}, pages = {1010-9}, abstract = {

The inflammatory cytokine interleukin-1 (IL1) potentially plays a role in cognitive deterioration through pathology due to a dementing disorder or due to an aging process. Study of genetic variants in the IL1 genes has been mostly limited to diseases such as Alzheimer{\textquoteright}s, however, there may be benefit to studying a continuous measure of cognition. Using data from the Cardiovascular Health Study, we evaluate genetic variation in the genes encoding inflammatory agonists IL1A and IL1B, and the antagonist IL1RN, with repeated measures of global cognition (3MS) and processing speed (DSST), using mixed effects models. We found statistically significant minor allele SNP associations with baseline performance on the 3MS in the IL1RN gene for Caucasians (rs17042917: beta=0.47, 95\%CI=0.09, 0.85, p=0.016; rs4251961: beta=-0.36, 95\%CI=-0.13,-0.60, p=0.0027; rs931471: beta=0.39, 95\%CI=0.13, 0.65, p=0.0032), and the IL1B gene for African Americans (rs1143627: beta=1.6, 95\%CI=0.48, 2.8; p=0.006 and rs1143634: beta=2.09, 95\%CI=0.39, 3.8; p=0.016). Associations appear to be weaker in a subgroup with higher education level. Upon removing those diagnosed with dementia, effect sizes and statistical significance attenuated. These results provide supporting evidence that genetic variants in IL1 genes may be involved in inflammatory-related lowered cognition, that higher education may modify genetic predisposition, and that these associations may be driven by a dementia process.

}, keywords = {African Americans, Aged, Aged, 80 and over, Cognition, Cognition Disorders, Dementia, Educational Status, European Continental Ancestry Group, Female, Genetic Predisposition to Disease, Genetic Variation, Genotype, Humans, Interleukin 1 Receptor Antagonist Protein, Interleukin-1alpha, Interleukin-1beta, Linkage Disequilibrium, Longitudinal Studies, Male, Polymorphism, Single Nucleotide, Prospective Studies, Risk Factors, United States}, issn = {1873-6815}, doi = {10.1016/j.exger.2011.09.005}, author = {Benke, K S and Carlson, M C and Doan, B Q and Walston, J D and Xue, Q L and Reiner, A P and Fried, L P and Arking, D E and Chakravarti, A and Fallin, M D} } @article {6133, title = {Novel gene variants predict serum levels of the cytokines IL-18 and IL-1ra in older adults.}, journal = {Cytokine}, volume = {65}, year = {2014}, month = {2014 Jan}, pages = {10-6}, abstract = {

Activation of inflammatory pathways measured by serum inflammatory markers such as interleukin-18 (IL-18) and interleukin-1 receptor antagonist (IL-1ra) is strongly associated with the progression of chronic disease states in older adults. Given that these serum cytokine levels are in part a heritable trait, genetic variation may predict increased serum levels. Using the Cardiovascular Health Study and InCHIANTI cohorts, a genome-wide association study was performed to identify genetic variants that influence IL-18 and IL-1ra serum levels among older adults. Multiple linear regression models characterized the association between each SNP and log-transformed cytokine values. Tests for multiple independent signals within statistically significant loci were performed using haplotype analysis and regression models conditional on lead SNP in each region. Multiple SNPs were associated with these cytokines with genome-wide significance, including SNPs in the IL-18-BCO gene region of chromosome 2 for IL-18 (top SNP rs2250417, P=1.9{\texttimes}10(-32)) and in the IL-1 gene family region of chromosome 2 for IL-1ra (rs6743376, P=2.3{\texttimes}10(-26)). Haplotype tests and conditional linear regression models showed evidence of multiple independent signals in these regions. Serum IL-18 levels were also associated with a region on chromosome 2 containing the NLRC4 gene (rs12989936, P=2.7{\texttimes}10(-19)). These data characterize multiple robust genetic signals that influence IL-18 and IL-1ra cytokine production. In particular, the signal for serum IL-18 located on chromosome two is novel and potentially important in inflammasome triggered chronic activation of inflammation in older adults. Replication in independent cohorts is an important next step, as well as molecular studies to better understand the role of NLRC4.

}, keywords = {Aged, Aged, 80 and over, Calcium-Binding Proteins, CARD Signaling Adaptor Proteins, Chromosomes, Human, Pair 2, Female, Genetic Variation, Genome-Wide Association Study, Genotype, Haplotypes, Humans, Inflammation, Interleukin 1 Receptor Antagonist Protein, Interleukin-18, Male, Polymorphism, Single Nucleotide}, issn = {1096-0023}, doi = {10.1016/j.cyto.2013.10.002}, author = {Matteini, A M and Li, J and Lange, E M and Tanaka, T and Lange, L A and Tracy, R P and Wang, Y and Biggs, M L and Arking, D E and Fallin, M D and Chakravarti, A and Psaty, B M and Bandinelli, S and Ferrucci, L and Reiner, A P and Walston, J D} }