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1.  Lipoprotein-associated phospholipase A2 and Risk of Dementia in the Cardiovascular Health Study 
Atherosclerosis  2014;235(2):384-391.
To evaluate associations between Lipoprotein-associated phospholipase A2 (Lp-PLA2) mass and activity with risk of dementia and its subtypes.
Analysis were completed on 3,320 participants of the Cardiovascular Health Study (CHS), a population-based longitudinal study of community-dwelling adults age ≥ 65 years followed for an average of 5.4 years. Baseline serum Lp-PLA2 mass was measured using a sandwich enzyme immunoassay and Lp-PLA2 activity utilized a tritiated-platelet activating factor activity assay. Cox proportional hazards regression assessed the relative risk of incident dementia with higher baseline Lp-PLA2 adjusting for demographics, cardiovascular disease (CVD) and risk factors, inflammation markers and apolipoprotein E (APOE) genotype.
Each standard deviation higher Lp-PLA2 mass and activity were related to increased risk of dementia (fully adjusted HR:1.11 per SD, 95% CI:1.00-1.24 for mass; HR:1.12 per SD, 95% CI:1.00-1.26 for activity). Persons in the highest quartile of Lp-PLA2 mass were 50% more likely to develop dementia than those in the lowest quartile in adjusted models (HR: 1.49; 95% CI: 1.08-2.06). Among dementia subtypes, the risk of AD was increased two-fold in the highest compared to lowest quartile of Lp-PLA2 mass (adjusted HR:1.98, 95% CI:1.22-3.21). Results were attenuated in models of mixed dementia and VaD. Lp-PLA2 activity also doubled the risk of mixed dementia in the highest compared to lowest quartile (HR:2.21, 95% CI:1.12-4.373).
These data support Lp-PLA2 as a risk factor for dementia independent of CVD and its risk factors. Further study is required to clarify the role of Lp-PLA2-related mechanisms in dementia subtypes.
PMCID: PMC4096578  PMID: 24929287
Lp-PLA2; dementia; Alzheimer’s disease; cardiovascular risk factors
2.  Participation in Older Adult Physical Activity Programs and Risk for Falls Requiring Medical Care, Washington State, 2005–2011 
Physical activity is known to prevent falls; however, use of widely available exercise programs for older adults, including EnhanceFitness and Silver Sneakers, has not been examined in relation to effects on falls among program participants. We aimed to determine whether participation in EnhanceFitness or Silver Sneakers is associated with a reduced risk of falls resulting in medical care.
A retrospective cohort study examined a demographically representative sample from a Washington State integrated health system. Health plan members aged 65 or older, including 2,095 EnhanceFitness users, 13,576 Silver Sneakers users, and 55,127 nonusers from 2005 through 2011, were classified as consistent users (used a program ≥2 times in all years they were enrolled in the health plan during the study period); intermittent users (used a program ≥2 times in 1 or more years enrolled but not all years), or nonusers of EnhanceFitness or Silver Sneakers. The main outcome was measured as time-to-first-fall requiring inpatient or out-of-hospital medical treatment based on the International Classification of Diseases, 9th Revision, Clinical Modification, Sixth Edition and E-codes.
In fully adjusted Cox proportional hazards models, consistent (hazard ratio [HR], 0.74; 95% confidence interval [CI], 0.63–0.88) and intermittent (HR, 0.87; 95% CI, 0.8–0.94) EnhanceFitness participation were both associated with a reduced risk of falls resulting in medical care. Intermittent Silver Sneakers participation showed a reduced risk (HR, 0.93; 95% CI, 0.90–0.97).
Participation in widely available community-based exercise programs geared toward older adults (but not specific to fall prevention) reduced the risk of medical falls. Structured programs that include balance and strength exercise, as EnhanceFitness does, may be effective in reducing fall risk.
PMCID: PMC4467255  PMID: 26068411
3.  Genome-wide Studies of Verbal Declarative Memory in Nondemented Older People: The Cohorts for Heart and Aging Research in Genomic Epidemiology Consortium 
Debette, Stéphanie | Ibrahim Verbaas, Carla A. | Bressler, Jan | Schuur, Maaike | Smith, Albert | Bis, Joshua C. | Davies, Gail | Wolf, Christiane | Gudnason, Vilmundur | Chibnik, Lori B. | Yang, Qiong | deStefano, Anita L. | de Quervain, Dominique J.F. | Srikanth, Velandai | Lahti, Jari | Grabe, Hans J. | Smith, Jennifer A. | Priebe, Lutz | Yu, Lei | Karbalai, Nazanin | Hayward, Caroline | Wilson, James F. | Campbell, Harry | Petrovic, Katja | Fornage, Myriam | Chauhan, Ganesh | Yeo, Robin | Boxall, Ruth | Becker, James | Stegle, Oliver | Mather, Karen A. | Chouraki, Vincent | Sun, Qi | Rose, Lynda M. | Resnick, Susan | Oldmeadow, Christopher | Kirin, Mirna | Wright, Alan F. | Jonsdottir, Maria K. | Au, Rhoda | Becker, Albert | Amin, Najaf | Nalls, Mike A. | Turner, Stephen T. | Kardia, Sharon L.R. | Oostra, Ben | Windham, Gwen | Coker, Laura H. | Zhao, Wei | Knopman, David S. | Heiss, Gerardo | Griswold, Michael E. | Gottesman, Rebecca F. | Vitart, Veronique | Hastie, Nicholas D. | Zgaga, Lina | Rudan, Igor | Polasek, Ozren | Holliday, Elizabeth G. | Schofield, Peter | Choi, Seung Hoan | Tanaka, Toshiko | An, Yang | Perry, Rodney T. | Kennedy, Richard E. | Sale, Michèle M. | Wang, Jing | Wadley, Virginia G. | Liewald, David C. | Ridker, Paul M. | Gow, Alan J. | Pattie, Alison | Starr, John M. | Porteous, David | Liu, Xuan | Thomson, Russell | Armstrong, Nicola J. | Eiriksdottir, Gudny | Assareh, Arezoo A. | Kochan, Nicole A. | Widen, Elisabeth | Palotie, Aarno | Hsieh, Yi-Chen | Eriksson, Johan G. | Vogler, Christian | van Swieten, John C. | Shulman, Joshua M. | Beiser, Alexa | Rotter, Jerome | Schmidt, Carsten O. | Hoffmann, Wolfgang | Nöthen, Markus M. | Ferrucci, Luigi | Attia, John | Uitterlinden, Andre G. | Amouyel, Philippe | Dartigues, Jean-François | Amieva, Hélène | Räikkönen, Katri | Garcia, Melissa | Wolf, Philip A. | Hofman, Albert | Longstreth, W.T. | Psaty, Bruce M. | Boerwinkle, Eric | DeJager, Philip L. | Sachdev, Perminder S. | Schmidt, Reinhold | Breteler, Monique M.B. | Teumer, Alexander | Lopez, Oscar L. | Cichon, Sven | Chasman, Daniel I. | Grodstein, Francine | Müller-Myhsok, Bertram | Tzourio, Christophe | Papassotiropoulos, Andreas | Bennett, David A. | Ikram, Arfan M. | Deary, Ian J. | van Duijn, Cornelia M. | Launer, Lenore | Fitzpatrick, Annette L. | Seshadri, Sudha | Mosley, Thomas H.
Biological psychiatry  2014;77(8):749-763.
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.
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.
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.
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.
PMCID: PMC4513651  PMID: 25648963
Alzheimer disease; Dementia; Epidemiology; Genetics; Population-based; Verbal declarative memory
4.  Fibrosis-Related Biomarkers and Large and Small Vessel Disease: The Cardiovascular Health Study 
Atherosclerosis  2015;239(2):539-546.
Fibrosis has been implicated in a number of pathological, organ-based conditions of the liver, kidney, heart, and lungs. The objective of this study was to determine whether biomarkers of fibrosis are associated with vascular disease in the large and/or small vessels.
We evaluated the associations of two circulating biomarkers of fibrosis, transforming growth factor-β (TGF-β) and procollagen type III N-terminal propeptide (PIIINP), with incident peripheral artery disease (PAD) and subclinical macrovascular (carotid intima-media thickness, flow-mediated vasodilation, ankle-brachial index, retinal vein diameter), and microvascular (retinal artery diameter and retinopathy) disease among older adults in the Cardiovascular Health Study. We measured TGF-β and PIIINP from samples collected in 1996 and ascertained clinical PAD through 2011. Measurements of large and small vessels were collected between 1996–1998.
After adjustment for sociodemographic, clinical, and biochemical risk factors, TGF-β was associated with incident PAD (hazard ratio [HR]=1.36 per doubling of TGF-β, 95% confidence interval [CI]= 1.04, 1.78) and retinal venular diameter (1.63 µm per doubling of TGF-β, CI=0.23, 3.02). PIIINP was not associated with incident PAD, but was associated with carotid intima-media thickness (0.102 mm per doubling of PIIINP, CI=0.029, 0.174) and impaired brachial artery reactivity (−0.20 % change per doubling of PIIINP, CI=−0.39, −0.02). Neither TGF-β nor PIIINP were associated with retinal arteriolar diameter or retinopathy.
Serum concentrations of fibrosis-related biomarkers were associated with several measures of large vessel disease, including incident PAD, but not with small vessel disease. Fibrosis may contribute to large vessel atherosclerosis in older adults.
PMCID: PMC4517825  PMID: 25725316
fibrosis; peripheral artery disease; atherosclerosis
5.  Symptoms and Risk Factors for Stroke in a Community-Based Observational Sample in Viet Nam 
Viet Nam is experiencing a health transition from infectious to chronic disease. Data on cardiovascular diseases, including strokes, are limited.
Data were randomly collected from six communities in Da Nang, Viet Nam, on participant demographics, medical history, blood pressure, anthropometrics and health behavior using World Health Organization (WHO) guidelines. Stroke symptoms were collected by self-report with the standardized Questionnaire for Verifying Stroke Free Status. Multivariate logistic regression was used to identify factors associated with the presence of stroke symptoms.
1,621 adults were examined with a mean age of 52.0 years (± 12.5 years), of which 56.1% were women. 27.3% of the participants were found to have hypertension, 26.2% used tobacco, and 16.1% were overweight. More than two-thirds of the participants with hypertension were unaware of their condition. Almost one fourth of the participants were identified by the questionnaire as previously experiencing at least one stroke symptom. Age, rural residence, and education were associated with the presence of stroke symptoms. Models adjusted for demographics found hypertension, high cholesterol, reported severe chest pain, former smoking, and being overweight to be associated with a higher prevalence of stroke symptoms.
The high frequency of stroke symptoms in Da Nang calls for further evaluation and interventions to reduce hypertension and other risk factors for chronic disease.
PMCID: PMC3607634  PMID: 23538875
stroke; symptoms; Viet Nam; community-based; risk factors
6.  Mid- and Late-Life Obesity: Risk of Dementia in the Cardiovascular Health Cognition Study 
Archives of neurology  2009;66(3):336-342.
To evaluate associations between mid- and late-life obesity and risk of dementia.
Prospective cohort followed 5.4 years from 1992/4 through 1999.
Community-dwelling sample in four US sites recruited from Medicare eligibility files.
2,798 adults without dementia, mean age 74.7 years, 59.1% women, participating in the Cardiovascular Health Cognition Study completing a magnetic resonance image, measured for height and weight at baseline (late-life) and self-reporting weight at age 50 (mid-life). Body mass index (BMI) was calculated at both times.
Main Outcome Measures
Dementia, Alzheimer’s disease (AD) and vascular dementia (VaD) classified by a multidisciplinary committee using standardized criteria.
Classification resulted in 480 persons with incident dementia, 245 with AD (no VaD) and 213 with VaD (with or without AD). In evaluations of mid-life obesity, an increased risk of dementia was found for obese (BMI >30) compared to normal (BMI 20-25) persons adjusted for demographics (HR: 1.39, 95% CI: 1.03-1.87) and for caradiovascularl risk factors (HR: 1.36, 95% CI: 0.94-1.95). The risk estimates reversed in assessments of late-life BMI. Underweight persons (BMI < 20) had an increased risk of dementia (HR: 1.62, 95% CI: 1.02-2.64) while being overweight (BMI 25-30) was not associated (HR: 0.92, 95% CI: 0.72-1.18) and being obese reduced the risk of dementia (HR: 0.63, 95% CI: 0.44-0.91) compared to those with normal BMI.
These results help explain the “obesity paradox” as differences in dementia risk over time are consistent with physical changes in the trajectory toward disability.
PMCID: PMC3513375  PMID: 19273752
7.  Telomere Length and the Risk of Atrial Fibrillation: Insights into the Role of Biological versus Chronological Aging 
Advanced age is the most important risk factor for atrial fibrillation (AF), however the mechanism remains unknown. Telomeres, regions of DNA that shorten with cell division, are considered reliable markers of biological aging. We sought to examine the association between leukocyte telomere length (LTL) and incident AF in a large population-based cohort using direct LTL measurements and genetic data. To further explore our findings, we compared atrial cell telomere length (ATL) and LTL in cardiac surgery patients.
Methods and Results
Mean LTL and the TERT rs2736100 single nucleotide polymorphism (SNP) were assessed as predictors of incident AF in the Cardiovascular Health Study (CHS). Among the surgical patients, within subject comparison of ATL versus LTL was assessed. Among 1639 CHS participants, we observed no relationship between mean LTL and incident AF prior to and after adjustment for potential confounders (adjusted hazard ratio [HR] 1.09; 95% CI: 0.92–1.29, p=0.299); chronologic age remained strongly associated with AF in the same model. No association was observed between the TERT rs2736100 SNP and incident AF (adjusted HR: 0.95; 95% CI: 0.88–1.04, p=0.265). In 35 cardiac surgery patients (26 with AF), ATL was longer than LTL (1.19 ± 0.20 versus 1.02 ± 0.25 [T/S ratio], p< 0.001), a finding that remained consistent within the AF subgroup.
Our study revealed no evidence of an association between LTL and incident AF and no evidence of relative atrial cell telomere shortening in AF. Chronological aging independent of biological markers of aging is the primary risk factor for AF.
PMCID: PMC4294941  PMID: 25381796
atrial fibrillation; aging; genetics; telomere genetics
8.  Leukocyte Telomere Length and Mortality in the Cardiovascular Health Study 
Leukocyte telomere length (LTL) is related to diseases of aging, but studies of mortality have been inconsistent.
We evaluated LTL in relation to total mortality and specific cause of death in 1,136 participants of the Cardiovascular Health Study who provided blood samples in 1992–1993 and survived through 1997–1998. LTL was measured by Southern blots of the terminal restriction fragments. Cause of death was classified by a committee of physicians reviewing death certificates, medical records, and informant interviews.
A total of 468 (41.2%) deaths occurred over 6.1 years of follow-up in participants with mean age of 73.9 years (SD 4.7), 65.4% female, and 14.8% African American. Although increased age and male gender were associated with shorter LTLs, African Americans had significantly longer LTLs independent of age and sex (p < .001). Adjusted for age, sex, and race, persons with the shortest quartile of LTL were 60% more likely to die during follow-up than those within the longest quartile (hazard ratio: 1.61, 95% confidence interval: 1.22–2.12, p = .001). The association remained after adjustment for cardiovascular disease risk factors. Evaluations of cause of death found LTL to be related to deaths due to an infectious disease etiology (hazard ratio: 2.80, 95% confidence interval: 1.32–5.94, p = .007), whereas a borderline association was found for cardiac deaths (hazard ratio: 1.82, 95% confidence interval: 0.95–3.49, p = .07) in adjusted models. Risk estimates for deaths due to cancer, dementia, and ischemic stroke were not significant.
These data weakly corroborate prior findings of associations between LTL and mortality in the elderly.
PMCID: PMC3055278  PMID: 21289018
Telomere; Mortality; Cause of death; Cardiovascular disease; Heart failure
9.  Ginkgo biloba and risk of cancer: Secondary Analysis of the Ginkgo Evaluation of Memory (GEM) Study 
Evidence from in vitro and in vivo studies suggests that Ginkgo biloba has cancer chemopreventive properties, but epidemiological evidence is sparse. We analyzed cancer as a secondary endpoint in the Ginkgo Evaluation of Memory (GEM) Study, the largest randomized, double-blind, placebo-controlled clinical trial of Ginkgo supplementation to date.
A total of 3,069 GEM participants 75+ years of age were randomized to twice-daily doses of either 120mg Ginkgo extract (EGb 761) or placebo and followed for a median 6.1 years. We identified hospitalizations for invasive cancer by reviewing hospital admission and discharge records for all reported hospitalizations over follow-up. Using an intention-to-treat approach, we compared the risk of cancer hospitalization between participants assigned to treatment and those assigned to placebo.
During the intervention, there were 148 cancer hospitalizations in the placebo group and 162 in the EGb 761 group (Hazard ratio [HR], 1.09; 95% confidence interval [CI], 0.87–1.36; p=0.46). Among the site-specific cancers analyzed, we observed an increased risk of breast (HR, 2.15; 95% CI, 0.97–4.80; p=0.06) and colorectal (HR, 1.62; 95% CI, 0.92–2.87; p=0.10) cancer, and a reduced risk of prostate cancer (HR, 0.71; 95% CI, 0.43–1.17; p=0.18).
Overall, these results do not support the hypothesis that regular use of Ginkgo biloba reduces the risk of cancer.
PMCID: PMC2917376  PMID: 20582906
Ginkgo biloba; randomized controlled trial; breast cancer; prostate cancer; complimentary and alternative medicine
10.  Longitudinal Association of Dementia and Depression 
Depression is an important precursor to dementia, but less is known about the role dementia plays in altering the course of depression. We examined whether depression prevalence, incidence, and severity are higher in those with dementia versus those with mild cognitive impairment (MCI), or normal cognition.
Prospective cohort study using the longitudinal Uniform Data Set of the National Alzheimer's Coordinating Center (2005–2013).
34 Alzheimer Disease research centers.
27,776 subjects with dementia, MCI, or normal cognition.
Depression status was determined by a clinical diagnosis of depression within the prior 2 years and by a Geriatric Depression Scale-Short Form score >5.
Rates of depression were significantly higher in subjects with MCI and dementia compared with those with normal cognition at index visit. Controlling for demographics and common chronic conditions, logistic regression analysis revealed elevated depression in those with MCI (OR: 2.40 [95% CI: 2.25, 2.56]) or dementia (OR: 2.64 [95% CI: 2.43, 2.86]) relative to those with normal cognition. In the subjects without depression at the index visit (N = 18,842), those with MCI and dementia had higher probabilities of depression diagnosis 2 years post index visit than those with normal cognition: MCI = 21.7%, dementia 24.7%, normal cognition = 10.5%.
MCI and dementia were associated with significantly higher rates of depression in concurrent as well as prospective analyses. These findings suggest that efforts to effectively engage and treat older adults with dementia will need also to address co-occurring depression.
PMCID: PMC4369182  PMID: 25441056
Dementia; Alzheimer disease; depression
11.  Perceptions of Cardiovascular Health in Underserved Communities 
Preventing Chronic Disease  2010;7(2):A30.
Cardiovascular disease is the leading cause of deaths and illnesses in US adults, and the prevalence is disproportionately high in underserved populations. In this study, we assessed respondents' understanding of context-specific differences in knowledge and perceptions of disease, risk, and prevention in 6 underserved communities, with the longer-term goal of developing appropriate interventions.
Thirty-nine small-group sessions and 14 interviews yielded data from 318 adults. Each site's researchers coded, analyzed, and extracted key themes from local data. Investigators from all sites synthesized results and identified common themes and differences.
Themes clustered in 3 areas (barriers to cardiovascular health, constraints related to multiple roles, and suggestions for effective communications and programs). Barriers spanned individual, social and cultural, and environmental levels; women in particular cited multiple roles (eg, competing demands, lack of self-care). Programmatic suggestions included the following: personal, interactive, social context; information in language that people use; activities built around cultural values and interests; and community orientation. In addition, respondents preferred health-related information from trusted groups (eg, AARP), health care providers (but with noticeable differences of opinion), family and friends, and printed materials.
Interventions to decrease barriers to cardiovascular health are needed; these strategies should include family and community context, small groups, interactive methods, culturally sensitive materials, and trusted information sources. New-immigrant communities need culturally and linguistically tailored education before receiving more substantive interventions.
PMCID: PMC2831784  PMID: 20158958
12.  Epinephrine Dosing Period and Survival after In-Hospital Cardiac Arrest 
Resuscitation  2013;85(3):350-358.
Expert guidelines for treatment of cardiac arrest recommend administration of epinephrine every three to five minutes. However, different dosing periods of epinephrine have not been systematically assessed.
We evaluated the association between epinephrine dosing frequency and survival to hospital discharge in adults with an in-hospital cardiac arrest (IHCA).
Using data from 2000–2009 in the Get With the Guidelines(GWTG)-Resuscitation IHCA registry (formerly the National Registry of Cardiopulmonary Resuscitation [NRCPR]), we examined the association between epinephrine dosing period and survival to hospital discharge. Epinephrine dosing period was defined as the time between the first epinephrine dose and the resuscitation endpoint, divided by the total number of epinephrine doses received subsequent to the first epinephrine dose. Generalized estimating equations were used to construct multivariable logistic regression models, adjusted for patient and arrest characteristics.
Included were 20,909 eligible IHCA events from 505 GWTG-Resuscitation participating hospitals. Compared to an epinephrine dosing period of 4 to <5 minutes per dose, survival to hospital discharge was significantly higher in patients with an epinephrine dosing period of 6 to <10 minutes per dose: for 6 to <7 min/dose, adjusted odds ratio [OR], 1.41 (95% CI: 1.12, 1.78); for 7 to <8 min/dose, adjusted OR, 1.30 (95%CI: 1.02, 1.65); for 8 to <9 min/dose, adjusted OR, 1.79 (95%CI: 1.38, 2.32); for 9 to <10 min/dose, adjusted OR, 2.17 (95%CI: 1.62, 2.92). This pattern was consistent for both shockable and non-shockable cardiac arrest rhythms. Moreover, for the majority (87%) of cardiac arrests due to non-shockable rhythms, an epinephrine dosing period of 1 to <3 minutes/dose was associated with lower rates of survival.
In this large, observational, national registry of in-hospital cardiac arrest, we found that epinephrine dosing at a less frequent dosing period than recommended by consensus guidelines was associated with improved survival of in-hospital cardiac arrest. Our findings suggest that clinical trials may be needed to determine the role and dose frequency of epinephrine in the treatment of in-hospital cardiac arrest.
PMCID: PMC4544685  PMID: 24252225
13.  Fibrosis-Related Biomarkers and Incident Cardiovascular Disease in Older Adults: The Cardiovascular Health Study 
Fibrotic changes in the heart and arteries have been implicated in a diverse range of cardiovascular diseases (CVD), but whether circulating biomarkers that reflect fibrosis are associated with CVD is unknown.
Methods and Results
We determined the associations of two biomarkers of fibrosis, transforming growth factor- β (TGF-β) and procollagen type III N-terminal propeptide (PIIINP), with incident heart failure, myocardial infarction (MI), and stroke among community-living older adults in the Cardiovascular Health Study. We measured circulating TGF-β (n=1,371) and PIIINP (n=2,568) from plasma samples collected in 1996 and ascertained events through 2010. Given TGF-β’s pleiotropic effects on inflammation and fibrogenesis, we investigated potential effect modification by C-reactive protein (CRP) in secondary analyses. After adjustment for sociodemographic, clinical, and biochemical risk factors, PIIINP was associated with total CVD (hazard ratio [HR] per standard deviation [SD]=1.07, 95% confidence interval [CI]: 1.01-1.14) and heart failure (HR per SD=1.08, CI: 1.01-1.16), but not MI or stroke. TGF-β was not associated with any CVD outcomes in the full cohort, but was associated with total CVD (HR per SD=1.16, CI: 1.02-1.31), heart failure (HR per SD=1.16, CI: 1.01-1.34), and stroke (HR per SD=1.20, CI: 1.01-1.42) among individuals with CRP above the median, 2.3 mg/L (P-interaction < 0.05).
Our findings provide large-scale, prospective evidence that circulating biomarkers of fibrosis, measured in community-living individuals late in life, are associated with CVD. Further research on whether TGF-β has a stronger fibrogenic effect in the setting of inflammation is warranted.
PMCID: PMC4140969  PMID: 24963008
collagen; cardiovascular disease; heart failure; epidemiology
14.  Kidney Function and Cognitive Health in Older Adults: The Cardiovascular Health Study 
American Journal of Epidemiology  2014;180(1):68-75.
Recent evidence has demonstrated the importance of kidney function in healthy aging. We examined the association between kidney function and change in cognitive function in 3,907 participants in the Cardiovascular Health Study who were recruited from 4 US communities and studied from 1992 to 1999. Kidney function was measured by cystatin C–based estimated glomerular filtration rate (eGFRcys). Cognitive function was assessed using the Modified Mini-Mental State Examination and the Digit Symbol Substitution Test, which were administered up to 7 times during annual visits. There was an association between eGFRcys and change in cognitive function after adjustment for confounders; persons with an eGFRcys of less than 60 mL/minute/1.73 m2 had a 0.64 (95% confidence interval: 0.51, 0.77) points/year faster decline in Modified Mini-Mental State Examination score and a 0.42 (95% confidence interval: 0.28, 0.56) points/year faster decline in Digit Symbol Substitution Test score compared with persons with an eGFRcys of 90 or more mL/minute/1.73 m2. Additional adjustment for intermediate cardiovascular events modestly affected these associations. Participants with an eGFRcys of less than 60 mL/minute/1.73 m2 had fewer cognitive impairment–free life-years on average compared with those with eGFRcys of 90 or more mL/minute/1.73 m2, independent of confounders and mediating cardiovascular events (mean difference = −0.44, 95% confidence interval: −0.62, −0.26). Older adults with lower kidney function are at higher risk of worsening cognitive function.
PMCID: PMC4070934  PMID: 24844846
aging; chronic kidney disease; cognitive function; congestive heart failure; myocardial infarction; prospective study; stroke; successful aging
15.  Neighborhood Characteristics and Leukocyte Telomere Length: The Multi-Ethnic Study of Atherosclerosis 
Health & place  2014;28:167-172.
Telomeres are the protective caps at the ends of eukaryotic chromosomes. Telomeres get shorter each time a cell divides, and critically shortened telomeres trigger cellular senescence. Thus, telomere length is hypothesized to be a biological marker of aging. The purpose of this study was to examine the association between neighborhood characteristics and leukocyte telomere length. Using data from a subsample (n=978) of the Multi-Ethnic Study of Atherosclerosis, a population-based study of women and men aged 45–84, we found that neighborhood social environment (but not neighborhood socioeconomic disadvantage) was associated with telomere length. Respondents who lived in neighborhoods characterized by lower aesthetic quality, safety, and social cohesion had shorter telomeres than those who lived in neighborhoods with a more salutary social environment, even after adjusting for individual-level socioeconomic status and biomedical and lifestyle factors related to telomere length. Telomere length may be one biological mechanism by which neighborhood characteristics influence an individual’s risk of disease and death.
PMCID: PMC4096814  PMID: 24859373
neighborhood socioeconomic disadvantage; neighborhood social environment; telomere length; cell aging
16.  A Test of Biological and Behavioral Explanations for Gender Differences in Telomere Length: The Multi-Ethnic Study of Atherosclerosis 
Biodemography and social biology  2014;60(2):156-173.
The purpose of this study was to examine biological and behavioral explanations for gender differences in leukocyte telomere length (LTL), a biomarker of cell aging that has been hypothesized to contribute to women’s greater longevity. Data are from a subsample (n = 851) of the Multi-Ethnic Study of Atherosclerosis, a population-based study of women and men aged 45 to 84. Mediation models were used to examine study hypotheses. We found that women had longer LTL than men, but the gender difference was smaller at older ages. Gender differences in smoking and processed meat consumption partially mediated gender differences in telomere length, whereas gender differences in estradiol, total testosterone, oxidative stress, and body mass index did not. Neither behavioral nor biological factors explained why the gender difference in LTL was smaller at older ages. Longitudinal studies are needed to assess gender differences in the rate of change in LTL over time; to identify the biological, behavioral, and psychosocial factors that contribute to these differences throughout the life course; and to determine whether gender differences in LTL explain the gender gap in longevity.
PMCID: PMC4460606  PMID: 25343364
17.  Fibrosis-Related Biomarkers and Risk of Total and Cause-Specific Mortality 
American Journal of Epidemiology  2014;179(11):1331-1339.
Fibrosis has been implicated in diverse diseases of the liver, kidney, lungs, and heart, but its importance as a risk factor for mortality remains unconfirmed. We determined the prospective associations of 2 complementary biomarkers of fibrosis, transforming growth factor-β (TGF-β) and procollagen type III N-terminal propeptide (PIIINP), with total and cause-specific mortality risks among community-living older adults in the Cardiovascular Health Study (1996–2010). We measured circulating TGF-β and PIIINP levels in plasma samples collected in 1996 and ascertained the number of deaths through 2010. Both TGF-β and PIIINP were associated with elevated risks of total and pulmonary mortality after adjustment for sociodemographic, clinical, and biochemical risk factors. For total mortality, the hazard ratios per doubling of TGF-β and PIIINP were 1.09 (95% confidence interval (CI): 1.01, 1.17; P = 0.02) and 1.14 (CI: 1.03, 1.27; P = 0.01), respectively. The corresponding hazard ratios for pulmonary mortality were 1.27 (CI: 1.01, 1.60; P = 0.04) for TGF-β and 1.52 (CI: 1.11, 2.10; P = 0.01) for PIIINP. Associations of TGF-β and PIIINP with total and pulmonary mortality were strongest among individuals with higher C-reactive protein concentrations (P for interaction < 0.05). Our findings provide some of the first large-scale prospective evidence that circulating biomarkers of fibrosis measured late in life are associated with death.
PMCID: PMC4036218  PMID: 24771724
biomarkers; fibrosis; inflammation; mortality
Critical care medicine  2014;42(5):1037-1046.
Severe infections, often requiring intensive care unit (ICU) admission, have been associated with persistent cognitive dysfunction. Less severe infections are more common and whether they are associated with an increased risk of dementia is unclear. We determined the association of pneumonia hospitalization with risk of dementia in well-functioning older adults.
Secondary analysis of a randomized multicenter trial to determine the effect of Gingko biloba on incident dementia.
Setting and Subjects
Community volunteers (n=3069) with a median follow-up of 6.1 years.
Measurement and Main Results
We identified pneumonia hospitalizations using ICD-9CM codes and validated them in a subset. Less than 3% of pneumonia cases necessitated ICU admission, mechanical ventilation or vasopressor support. Dementia was adjudicated based on neuropsychological evaluation, neurological exam, and magnetic resonance imaging. Two hundred twenty one participants (7.2%) incurred at least one hospitalization with pneumonia (mean time to pneumonia=3.5 years). Of these, 38 (17%) developed dementia after pneumonia with half of these cases occurring 2 years after the pneumonia hospitalization. Hospitalization with pneumonia was associated with increased risk of time to dementia diagnosis (unadjusted hazard ratio [HR] = 2.3, CI: 1.6–3.2, p<0.0001). The association remained significant when adjusted for age, sex, race, study site, education, and baseline Mini-Mental Status Exam (HR=1.9, CI 1.4–2.8, p<.0001). Results were unchanged when additionally adjusted for smoking, hypertension, diabetes, heart disease, and pre-infection functional status. Results were similar using propensity analysis where participants with pneumonia were matched to those without pneumonia based on age, probability of developing pneumonia, and similar trajectories of cognitive and physical function prior to pneumonia (adjusted incidence rates: 91.7 vs. 65 cases per 1,000 person-years, adjusted incidence rate ratio=1.6, CI:1.06–2.7, p=0.03). Sensitivity analyses showed that the higher risk also occurred among those hospitalized with other infections.
Hospitalization with pneumonia is associated with increased risk of dementia.
PMCID: PMC4071960  PMID: 24368344
pneumonia; dementia; older adults
19.  Estimating Pesticide Exposure from Dietary Intake and Organic Food Choices: The Multi-Ethnic Study of Atherosclerosis (MESA) 
Environmental Health Perspectives  2015;123(5):475-483.
Organophosphate pesticide (OP) exposure to the U.S. population is dominated by dietary intake. The magnitude of exposure from diet depends partly on personal decisions such as which foods to eat and whether to choose organic food. Most studies of OP exposure rely on urinary biomarkers, which are limited by short half-lives and often lack specificity to parent compounds. A reliable means of estimating long-term dietary exposure to individual OPs is needed to assess the potential relationship with adverse health effects.
We assessed long-term dietary exposure to 14 OPs among 4,466 participants in the Multi-Ethnic Study of Atherosclerosis, and examined the influence of organic produce consumption on this exposure.
Individual-level exposure was estimated by combining information on typical intake of specific food items with average OP residue levels on those items. In an analysis restricted to a subset of participants who reported rarely or never eating organic produce (“conventional consumers”), we assessed urinary dialkylphosphate (DAP) levels across tertiles of estimated exposure (n = 480). In a second analysis, we compared DAP levels across subgroups with differing self-reported organic produce consumption habits (n = 240).
Among conventional consumers, increasing tertile of estimated dietary OP exposure was associated with higher DAP concentrations (p < 0.05). DAP concentrations were also significantly lower in groups reporting more frequent consumption of organic produce (p < 0.02).
Long-term dietary exposure to OPs was estimated from dietary intake data, and estimates were consistent with DAP measurements. More frequent consumption of organic produce was associated with lower DAPs.
Curl CL, Beresford SA, Fenske RA, Fitzpatrick AL, Lu C, Nettleton JA, Kaufman JD. 2015. Estimating pesticide exposure from dietary intake and organic food choices: the Multi-Ethnic Study of Atherosclerosis (MESA). Environ Health Perspect 123:475–483;
PMCID: PMC4421765  PMID: 25650532
20.  Associations between γ-glutamyltransferase (GGT) and Biomarkers of Atherosclerosis: The Multi-Ethnic Study of Atherosclerosis (MESA) 
Atherosclerosis  2014;233(2):387-393.
To evaluate associations between total serum γ-glutamyltransferase activity (GGT) and biomarkers of arteriosclerosis in the Multi-Ethnic Study of Atherosclerosis (MESA), including 6,783 participants from four ethnic subgroups, i.e., White, Chinese, Black and Hispanic.
Associations between fasting total serum GGT activity and oxidized low-density lipoproteins (oxLDL), interleukin-6 (IL-6), C-reactive protein (CRP), and soluble intercellular adhesion molecule-1 (sICAM-1) were assessed. Following evaluation of linear trends between GGT and biomarkers of interest, multivariable linear regression models were serially adjusted for age, gender, site, ethnicity (M1); M1+lifestyle variables (M2); M2+traditional cardiovascular risk factors plus medications (M3); and M3+metabolic status (M4). Interactions were evaluated between GGT and age and ethnicity in all models.
Linear trends were positive and significant between GGT and oxLDL, IL-6, CRP and sICAM-1 in crude models, and trends remained significant in all ethnic subgroups for CRP (p<0.0001) and sICAM-1 (p<0.001), and for IL-6 except in the Chinese. Trends between GGT and oxLDL were significant in the entire cohort and the White subgroup (p<0.0001), but not in other ethnic subgroups. Multivariable models demonstrated continuous strong, positive associations between GGT and CRP, IL-6 and sICAM-1. Associations between GGT and oxLDL were attenuated upon adjustment for LDL-C and other traditional risk factors. All models were attenuated with adjustment for metabolic status. No age interactions were evident.
Our findings support the hypothesis that total serum GGT activity represents the impact of metabolic disease on vascular injury and atherosclerosis.
PMCID: PMC4000064  PMID: 24530768
GGT; oxidative stress; oxidized LDL; sICAM; CRP; endothelial dysfunction
21.  DCAF4, a novel gene associated with leucocyte telomere length 
Journal of Medical Genetics  2015;52(3):157-162.
Leucocyte telomere length (LTL), which is fashioned by multiple genes, has been linked to a host of human diseases, including sporadic melanoma. A number of genes associated with LTL have already been identified through genome-wide association studies. The main aim of this study was to establish whether DCAF4 (DDB1 and CUL4-associated factor 4) is associated with LTL. In addition, using ingenuity pathway analysis (IPA), we examined whether LTL-associated genes in the general population might partially explain the inherently longer LTL in patients with sporadic melanoma, the risk for which is increased with ultraviolet radiation (UVR).
Genome-wide association (GWA) meta-analysis and de novo genotyping of 20 022 individuals revealed a novel association (p=6.4×10−10) between LTL and rs2535913, which lies within DCAF4. Notably, eQTL analysis showed that rs2535913 is associated with decline in DCAF4 expressions in both lymphoblastoid cells and sun-exposed skin (p=4.1×10−3 and 2×10−3, respectively). Moreover, IPA revealed that LTL-associated genes, derived from GWA meta-analysis (N=9190), are over-represented among genes engaged in melanoma pathways. Meeting increasingly stringent p value thresholds (p<0.05, <0.01, <0.005, <0.001) in the LTL-GWA meta-analysis, these genes were jointly over-represented for melanoma at p values ranging from 1.97×10−169 to 3.42×10−24.
We uncovered a new locus associated with LTL in the general population. We also provided preliminary findings that suggest a link of LTL through genetic mechanisms with UVR and melanoma in the general population.
PMCID: PMC4345921  PMID: 25624462
Complex traits; Telomere; cancer: skin; melanoma
22.  Leukocyte telomere length and age at menopause 
Epidemiology (Cambridge, Mass.)  2014;25(1):139-146.
Telomere length is a marker of cellular aging that varies by the individual, is inherited, and is highly correlated across somatic cell types within persons. Inter-individual telomere length variability may partly explain differences in reproductive aging rates. We examined whether leukocyte telomere length was associated with menopausal age.
We evaluated the relationship between leukocyte telomere length and age at natural menopause in 486 white women aged 65 years or older. We fit linear regression models adjusted for age, income, education, body mass index, physical activity, smoking, and alcohol intake. We repeated the analysis in women with surgical menopause. We also performed sensitivity analyses excluding women (1) with unilateral oophorectomy, (2) who were nulliparous, or (3) reporting menopausal age <40 years, among other exclusions.
For every one kilobase (kb) increase in leukocyte telomere length, average age at natural menopause increased by 10.2 months (95% confidence interval= 1.3 to 19.0). There was no association in 179 women reporting surgical menopause. In all but one sensitivity analysis, the association between leukocyte telomere length and age at menopause became stronger. However, when excluding women with menopausal age <40 years, the association decreased to 7.5 months (−0.4 to 15.5).
Women with the longest leukocyte telomere length underwent menopause three years later than those with the shortest leukocyte telomere length. If artifactual, an association would likely also have been observed in women with surgical menopause. If these results are replicated, leukocyte telomere length may prove to be a useful predictor of age at menopause.
PMCID: PMC3926311  PMID: 24213145
23.  Caregiver perceptions of child nutritional status in Magallanes, Chile 
We aimed to identify risk factors for childhood overweight and obesity and the accuracy of caregivers’ perceptions of their child’s nutritional status in the Magallanes region, Patagonia, Chile.
Heights and weights of children attending day care centers and elementary schools were collected and caregivers completed questionnaires regarding their child’s health and behavior. The child’s nutritional status was diagnosed using the 2006 WHO Child Growth Standards (for children under age 6) and the CDC 2000 Growth Charts (for children age 6 and older). Logistic regression was used to evaluate factors related to childhood overweight/obesity and weight underestimation by caregivers of overweight or obese children.
Of the 795 children included in the study, 247 (31.1%) were overweight and 223 (28.1%) were obese. Risk factors for overweight/obesity included younger age and being perceived to eat more than normal by the caregiver. Caregivers were less likely to underestimate their child’s weight if the child was older or if the caregiver believed the child ate more than a normal amount.
There is a high prevalence of overweight and obesity among children in Magallanes and the majority of caregivers underestimate the extent of the problem in their children.
PMCID: PMC3929963  PMID: 24548582
Nutrition; Overweight; Children; Chile
24.  Antihypertensive drugs decrease risk of Alzheimer disease 
Neurology  2013;81(10):896-903.
The aim of this study was to determine whether use of diuretics, angiotensin-1 receptor blockers (ARB), angiotensin-converting enzyme inhibitors (ACE-I), calcium channel blockers (CCB), or β-blockers (BB) was associated with a reduced risk of Alzheimer disease (AD) dementia in participants with normal cognition or mild cognitive impairment (MCI).
Secondary longitudinal data analysis of the Ginkgo Evaluation of Memory Study in older adults at least 75 years of age with normal cognition (n = 1,928) or MCI (n = 320) over a median 6.1-year period using Cox proportional hazard models after adjusting for confounders.
Diuretic use was reported by 15.6%, ARB 6.1%, ACE-I 15.1%, CCB 14.8%, and BB 20.5%. Of the 2,248 participants, 290 (13%) developed AD dementia. Hazard ratio for incident AD dementia among participants with normal cognition was 0.51 in diuretic (95% confidence interval [CI] 0.31–0.82), 0.31 in ARB (95% CI 0.14–0.68), 0.50 in ACE-I (95% CI 0.29–0.83), 0.62 in CCB (95% CI 0.35–1.09), and 0.58 in BB (95% CI 0.36–0.93) users and was not significantly altered when mean systolic blood pressure was above 140 mm Hg. In participants with MCI, only diuretic use was associated with decreased risk (hazard ratio = 0.38, 95% CI 0.20–0.73).
Diuretic, ARB, and ACE-I use was, in addition to and/or independently of mean systolic blood pressure, associated with reduced risk of AD dementia in participants with normal cognition, while only diuretic use was associated with reduced risk in participants with MCI.
PMCID: PMC3885216  PMID: 23911756
25.  Associations between total serum GGT activity and metabolic risk: MESA 
Biomarkers in medicine  2013;7(5):709-721.
To evaluate associations between total serum GGT activity, metabolic risk factors and prevalent metabolic disease in MESA.
Patients & methods
Continuous associations between GGT and fasting blood glucose (FBG), fasting insulin, HbA1c and Homeostasis Model Assessment Index of Insulin Resistance (HOMA–IR) were evaluated in the entire MESA cohort and in metabolic disease subgroups using linear regression models incrementally adjusted for age, gender, site, race, lifestyle, traditional risk factors and medications. Cross-sectional odds of prevalent impaired FBG, metabolic syndrome and Type 2 diabetes were calculated for GGT quintiles in the entire cohort and in subgroups defined by age (< or ≥65 years) and ethnicity.
In multivariable models, significant associations were present between GGT activity and FBG, fasting insulin, HbA1c and HOMA–IR, with the interaction between GGT and BMI affecting the association between GGT and HOMA–IR as well as the association between BMI and HOMA–IR (p < 0.0001). Adjusted odds ratios (95% CIs) of prevalent impaired FBG, metabolic syndrome and Type 2 diabetes for quintile 5 versus 1 in the entire cohort were 2.4 (1.7–3.5), 3.3 (2.5–4.5) and 2.8 (1.8–4.4), respectively (p < 0.0001). GGT associations weakened with age. The significance of linear trends for increased prevalent metabolic disease by increasing GGT quintile varied by ethnicity.
GGT is strongly associated with both cardiovascular and metabolic risk factors, including prevalent metabolic disease, in the MESA cohort.
PMCID: PMC4106917  PMID: 24044563
γ-glutamyltransferase; GGT; glutathione; metabolic syndrome; oxidative stress; Type 2 diabetes

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