Associations of osteoprotegerin with coronary artery calcification among women with systemic lupus erythematosus and healthy controls.

Objective We tested the hypothesis that higher circulating levels of osteoprotegerin (OPG) are related to higher levels of coronary artery calcification (CAC) among women with systemic lupus erythematosus (SLE) compared with healthy controls (HCs). Methods Among 611 women in two age- and race-matched SLE case-control studies, OPG was assayed in stored blood samples (HEARTS: plasma, n cases/controls = 122/124, and SOLVABLE: serum, n cases/controls = 185/180) and CAC was measured by electron beam computed tomography. Results In both studies, SLE patients had higher OPG and CAC levels than HCs. Higher OPG was associated with high CAC (>100 vs.100) among SLE, and with any CAC (>0 vs. 0) among HCs. Multivariable-adjusted OR (95% CI) for OPG tertile 3 vs. 1 was 3.58 (1.19, 10.76), p trend = 0.01 for SLE, and 2.28 (1.06, 4.89), p trend = 0.04 for HCs. Associations were attenuated when age-adjusted, but remained significant for HC women aged ≥ 40 and SLE women aged ≥ 50. ROC analyses identified 4.60 pmol/l as the optimal OPG cutpoint for predicting high CAC (>100) among SLE patients with sensitivity = 0.74 and specificity = 0.61, overall, but 0.92 and 0.52, respectively, for SLE patients aged ≥ 50. Conclusion Our cross-sectional results suggest that higher OPG levels are related to higher CAC levels among women with SLE vs. healthy controls.

Trans-ethnic analysis of metabochip data identifies two new loci associated with BMI.

OBJECTIVE: Body mass index (BMI) is commonly used to assess obesity, which is associated with numerous diseases and negative health outcomes. BMI has been shown to be a heritable, polygenic trait, with close to 100 loci previously identified and replicated in multiple populations. We aim to replicate known BMI loci and identify novel associations in a trans-ethnic study population. SUBJECTS: Using eligible participants from the Population Architecture using Genomics and Epidemiology consortium, we conducted a trans-ethnic meta-analysis of 102 514 African Americans, Hispanics, Asian/Native Hawaiian, Native Americans and European Americans. Participants were genotyped on over 200 000 SNPs on the Illumina Metabochip custom array, or imputed into the 1000 Genomes Project (Phase I). Linear regression of the natural log of BMI, adjusting for age, sex, study site (if applicable), and ancestry principal components, was conducted for each race/ethnicity within each study cohort. Race/ethnicity-specific, and combined meta-analyses used fixed-effects models. RESULTS: We replicated 15 of 21 BMI loci included on the Metabochip, and identified two novel BMI loci at 1q41 (rs2820436) and 2q31.1 (rs10930502) at the Metabochip-wide significance threshold (P<2.5 × 10-7). Bioinformatic functional investigation of SNPs at these loci suggests a possible impact on pathways that regulate metabolism and adipose tissue. CONCLUSION: Conducting studies in genetically diverse populations continues to be a valuable strategy for replicating known loci and uncovering novel BMI associations.

Generalization and fine mapping of European ancestry-based central adiposity variants in African ancestry populations.

BACKGROUND/OBJECTIVES: Central adiposity measures such as waist circumference (WC) and waist-to-hip ratio (WHR) are associated with cardiometabolic disorders independently of body mass index (BMI) and are gaining clinically utility. Several studies report genetic variants associated with central adiposity, but most utilize only European ancestry populations. Understanding whether the genetic associations discovered among mainly European descendants are shared with African ancestry populations will help elucidate the biological underpinnings of abdominal fat deposition. SUBJECTS/METHODS: To identify the underlying functional genetic determinants of body fat distribution, we conducted an array-wide association meta-analysis among persons of African ancestry across seven studies/consortia participating in the Population Architecture using Genomics and Epidemiology (PAGE) consortium. We used the Metabochip array, designed for fine-mapping cardiovascular-associated loci, to explore novel array-wide associations with WC and WHR among 15 945 African descendants using all and sex-stratified groups. We further interrogated 17 known WHR regions for African ancestry-specific variants. RESULTS: Of the 17 WHR loci, eight single-nucleotide polymorphisms (SNPs) located in four loci were replicated in the sex-combined or sex-stratified meta-analyses. Two of these eight independently associated with WHR after conditioning on the known variant in European descendants (rs12096179 in TBX15-WARS2 and rs2059092 in ADAMTS9). In the fine-mapping assessment, the putative functional region was reduced across all four loci but to varying degrees (average 40% drop in number of putative SNPs and 20% drop in genomic region). Similar to previous studies, the significant SNPs in the female-stratified analysis were stronger than the significant SNPs from the sex-combined analysis. No novel associations were detected in the array-wide analyses. CONCLUSIONS: Of 17 previously identified loci, four loci replicated in the African ancestry populations of this study. Utilizing different linkage disequilibrium patterns observed between European and African ancestries, we narrowed the suggestive region containing causative variants for all four loci.

The Associations of C-Reactive Protein with Serum Levels of Polyunsaturated Fatty Acids and Trans Fatty Acids Among Middle-Aged Men from Three Populations.

BACKGROUND: C-reactive protein (CRP) and many fatty acids (FAs) have been linked to cardiovascular disease. Associations of serum CRP with FAs in different populations have not been established. METHODS: Participants were 926 men aged 40-49 (2002-2006) from a population-based sample; 310 Whites from Pennsylvania, U.S., 313 Japanese from Shiga, Japan, and 303 Japanese Americans from Hawaii, U.S. Serum CRP (mg/L) was measured using immunosorbent assay while serum FAs (%) were measured using capillary-gas-liquid chromatography. RESULTS: Whites had CRP (mg/L) levels higher than Japanese with Japanese Americans in-between (age-adjusted geometric mean "GM" 0.96, 0.38, 0.66, respectively). Whites had also higher levels of total n-6 FAs (%) and trans fatty acids (TFAs) but lower levels of marine-derived n-3 FAs compared to Japanese (41.78 vs. 35.05, 1.04 vs. 0.58, and 3.85 vs. 9.29, respectively). Japanese Americans had FAs levels in-between the other two populations. Whites had significant inverse trends between CRP and tertiles of total n-6 FAs (GM 1.20, 0.91 and 0.80; p=0.002) and marine-derived n-3 FAs (GM 1.22, 1.00 and 0.72; p<0.001) but a significant positive trend with TFAs (GM 0.80, 0.95 and 1.15; p=0.007). Japanese had a significant inverse trend between CRP and only total n-6 FAs (GM 0.50, 0.35 and 0.31; p<0.001). Japanese Americans had CRP associations with n-3 FAs, n-6 FAs, and TFAs similar to but weaker than Whites. CONCLUSIONS: With the exception of consistent inverse association of CRP with total n-6 FAs, there are considerable variations across the three populations in the associations of CRP with different FAs.

Ectopic cardiovascular fat in middle-aged men: effects of race/ethnicity, overall and central adiposity. The ERA JUMP study.

BACKGROUND/OBJECTIVES: Higher volumes of ectopic cardiovascular fat (ECF) are associated with greater risk of coronary heart disease (CHD). Identifying factors that are associated with ECF volumes may lead to new preventive efforts to reduce risk of CHD. Significant racial/ethnic differences exist for overall and central adiposity measures, which are known to be associated with ECF volumes. Whether racial/ethnic differences also exist for ECF volumes and their associations with these adiposity measures remain unclear. SUBJECTS/METHODS: Body mass index (BMI), computerized tomography-measured ECF volumes (epicardial, pericardial and their summation) and visceral adipose tissue (VAT) were examined in a community-based sample of 1199 middle-aged men (24.2% Caucasians, 7.0% African-Americans, 23.6% Japanese-Americans, 22.0% Japanese, 23.2% Koreans). RESULTS: Significant racial/ethnic differences existed in ECF volumes and their relationships with BMI and VAT. ECF volumes were the highest among Japanese-Americans and the lowest among African-Americans. The associations of BMI and VAT with ECF differed by racial/ethnic groups. Compared with Caucasians, for each 1-unit increase in BMI, African-Americans had lower, whereas Koreans had higher increases in ECF volumes (P-values<0.05 for both). Meanwhile, compared with Caucasians, for each 1-unit increase in log-transformed VAT, African-Americans, Japanese-Americans and Japanese had similar increases, whereas Koreans had a lower increase in ECF volumes (P-value<0.05). CONCLUSIONS: Racial/ethnic groups differed in their propensity to accumulate ECF at increasing level of overall and central adiposity. Future studies should evaluate whether reducing central adiposity or overall weight will decrease ECF volumes more in certain racial/ethnic groups. Evaluating these questions might help in designing race-specific prevention strategy of CHD risk associated with higher ECF.

Association between diabetes, diabetes treatment and risk of developing endometrial cancer.

BACKGROUND: A growing body of evidence suggests that diabetes is a risk factor for endometrial cancer incidence. However, most of these studies used case-control study designs and did not adjust for obesity, an established risk factor for endometrial cancer. In addition, few epidemiological studies have examined the association between diabetes treatment and endometrial cancer risk. The objective of this study was to assess the relationships among diabetes, diabetes treatment and endometrial cancer risk in postmenopausal women participating in the Women's Health Initiative (WHI). METHODS: A total of 88 107 postmenopausal women aged 50-79 years who were free of cancer and had no hysterectomy at baseline were followed until date of endometrial cancer diagnosis, death, hysterectomy or loss to follow-up, whichever came first. Endometrial cancers were confirmed by central medical record and pathology report review. Multivariate Cox proportional hazards regression models were used to estimate hazard ratios (HRs) (95% confidence interval (CI)) for diagnosis of diabetes and metformin treatment as risk factors for endometrial cancer. RESULTS: Over a mean of 11 years of follow-up, 1241 endometrial cancers developed. In the primary analysis that focused on prevalent diabetes at enrolment, compared with women without diabetes, women with self-reported diabetes, and the subset of women with treated diabetes, had significantly higher risk of endometrial cancer without adjusting for BMI (HR=1.44, 95% CI: 1.13-1.85 for diabetes, HR=1.57, 95% CI: 1.19-2.07 for treated diabetes). However after adjusting for BMI, the associations between diabetes, diabetes treatment, diabetes duration and the risk of endometrial cancer became non-significant. Elevated risk was noted when considering combining diabetes diagnosed at baseline and during follow-up as time-dependent exposure (HR=1.31, 95% CI: 1.08-1.59) even after adjusting for BMI. No significant association was observed between metformin use and endometrial cancer risk. CONCLUSIONS: Our results suggest that the relationship observed in previous research between diabetes and endometrial cancer incidence may be largely confounded by body weight, although some modest independent elevated risk remains.

Physical activity, inflammation, and volume of the aging brain.

Physical activity influences inflammation, and both affect brain structure and Alzheimer's disease (AD) risk. We hypothesized that older adults with greater reported physical activity intensity and lower serum levels of the inflammatory marker tumor necrosis factor α (TNFα) would have larger regional brain volumes on subsequent magnetic resonance imaging (MRI) scans. In 43 cognitively intact older adults (79.3±4.8 years) and 39 patients with AD (81.9±5.1 years at the time of MRI) participating in the Cardiovascular Health Study, we examined year-1 reported physical activity intensity, year-5 blood serum TNFα measures, and year-9 volumetric brain MRI scans. We examined how prior physical activity intensity and TNFα related to subsequent total and regional brain volumes. Physical activity intensity was measured using the modified Minnesota Leisure Time Physical Activities questionnaire at year 1 of the study, when all subjects included here were cognitively intact. Stability of measures was established for exercise intensity over 9 years and TNFα over 3 years in a subset of subjects who had these measurements at multiple time points. When considered together, more intense physical activity intensity and lower serum TNFα were both associated with greater total brain volume on follow-up MRI scans. TNFα, but not physical activity, was associated with regional volumes of the inferior parietal lobule, a region previously associated with inflammation in AD patients. Physical activity and TNFα may independently influence brain structure in older adults.

Particle numbers of lipoprotein subclasses and arterial stiffness among middle-aged men from the ERA JUMP study.

We examined the association between serum lipoprotein subclasses and the three measures of arterial stiffness, that is, (i) carotid-femoral pulse wave velocity (cfPWV), which is a gold standard measure of central arterial stiffness, (ii) brachial-ankle PWV (baPWV), which is emerging as a combined measure of central and peripheral arterial stiffness and (iii) femoral-ankle PWV (faPWV), which is a measure of peripheral arterial stiffness. Among a population-based sample of 701 apparently healthy Caucasian, Japanese American and Korean men aged 40-49 years, concentrations of lipoprotein particles were assessed by nuclear magnetic resonance (NMR) spectroscopy, and the PWV was assessed with an automated waveform analyzer (VP2000, Omron, Japan). Multiple linear regressions were performed to analyse the association between each NMR lipoprotein subclasses and PWV measures, after adjusting for cardiovascular risk factors and other confounders. A cutoff of P<0.01 was used for determining significance. All PWV measures had significant correlations with total and small low-density lipoprotein particle number (LDL-P) (all P<0.0001) but not LDL cholesterol (LDL-C) (all P>0.1), independent of race and age. In multivariate regression analysis, no NMR lipoprotein subclass was significantly associated with cfPWV (all P>0.01). However, most NMR lipoprotein subclasses had significant associations with both baPWV and faPWV (P<0.01). In this study of healthy middle-aged men, as compared with cfPWV, both baPWV and faPWV had stronger associations with particle numbers of lipoprotein subclasses. Our results may suggest that both baPWV and faPWV are related to arterial stiffness and atherosclerosis, whereas cfPWV may represent arterial stiffness alone.

Generalization of adiposity genetic loci to US Hispanic women.

BACKGROUND: Obesity is a public health concern. Yet the identification of adiposity-related genetic variants among United States (US) Hispanics, which is the largest US minority group, remains largely unknown. OBJECTIVE: To interrogate an a priori list of 47 (32 overall body mass and 15 central adiposity) index single-nucleotide polymorphisms (SNPs) previously studied in individuals of European descent among 3494 US Hispanic women in the Women's Health Initiative SNP Health Association Resource (WHI SHARe). DESIGN: Cross-sectional analysis of measured body mass index (BMI), waist circumference (WC) and waist-to-hip ratio (WHR) were inverse normally transformed after adjusting for age, smoking, center and global ancestry. WC and WHR models were also adjusted for BMI. Genotyping was performed using the Affymetrix 6.0 array. In the absence of an a priori selected SNP, a proxy was selected (r(2)0.8 in CEU). RESULTS: Six BMI loci (TMEM18, NUDT3/HMGA1, FAIM2, FTO, MC4R and KCTD15) and two WC/WHR loci (VEGFA and ITPR2-SSPN) were nominally significant (P<0.05) at the index or proxy SNP in the corresponding BMI and WC/WHR models. To account for distinct linkage disequilibrium patterns in Hispanics and further assess generalization of genetic effects at each locus, we interrogated the evidence for association at the 47 surrounding loci within 1 Mb region of the index or proxy SNP. Three additional BMI loci (FANCL, TFAP2B and ETV5) and five WC/WHR loci (DNM3-PIGC, GRB14, ADAMTS9, LY86 and MSRA) displayed Bonferroni-corrected significant associations with BMI and WC/WHR. Conditional analyses of each index SNP (or its proxy) and the most significant SNP within the 1 Mb region supported the possible presence of index-independent signals at each of these eight loci as well as at KCTD15. CONCLUSION: This study provides evidence for the generalization of nine BMI and seven central adiposity loci in Hispanic women. This study expands the current knowledge of common adiposity-related genetic loci to Hispanic women.

Skeletal muscle adiposity is associated with serum lipid and lipoprotein levels in Afro-Caribbean men.

OBJECTIVE: When compared with other ethnic groups, African ancestry individuals have lower triglycerides and higher High-density lipoprotein cholesterol (HDL-C) levels, although the mechanisms for these differences remain unclear. A comprehensive array of factors potentially related to fasting serum lipid and lipoprotein levels in African ancestry men was evaluated. DESIGN AND METHODS: Men (1,821) underwent dual-energy X-ray absorptiometry measures of total body fat and quantitative computed tomography assessments of calf skeletal muscle adiposity [subcutaneous and intermuscular adipose tissue (AT), and muscle density as a measure of intra-muscular AT]. RESULTS: Multivariable linear regression analysis identified age (-), total body fat (+), subcutaneous AT (-), fasting glucose (+), fasting insulin (+), diastolic blood pressure (+), and non-African ancestry (+) as independent correlates of triglycerides (all P < 0.05). Total body fat (+), intra-muscular AT (-), and diastolic blood pressure (+) were independent correlates of Low-density lipoprotein cholesterol (LDL-C) (all P < 0.001). Age (+), waist circumference (-), fasting insulin (-), physical activity (+), and alcohol intake (+) were independent correlates of HDL-C (all P < 0.05). CONCLUSIONS: A novel relationship between skeletal muscle adiposity and serum lipid and lipoprotein levels in African ancestry men, independent of total and central adiposity was illuminated. In African ancestry populations, genetic factors are likely a significant determinant of triglycerides levels.

Significant inverse association of marine n-3 fatty acids with plasma fibrinogen levels in Japanese in Japan but not in whites or Japanese Americans.

BACKGROUND/OBJECTIVES: Numerous studies reported beneficial effects of marine n-3 fatty acids (n-3 FAs) on cardiovascular disease (CVD) and its risk factors. However, the association of marine n-3 FAs with plasma fibrinogen, a risk factor for CVD, remains uncertain. SUBJECTS/METHODS: In a population-based, cross-sectional study of 795 men aged 40-49 without CVD (262 whites in Allegheny County, Pennsylvania, USA, 302 Japanese in Kusatsu, Japan and 229 Japanese Americans in Honolulu, Hawaii, USA), we examined the association of marine n-3 FAs with plasma fibrinogen. Serum FAs were measured by capillary gas-liquid chromatography. Marine n-3 FAs were defined as the sum of docosahexaenoic, eicosapentaenoic and docosapentaenoic acids. Plasma fibrinogen was measured by an automated clot-rate assay. Multiple linear regression analyses were performed to assess the association. RESULTS: White, Japanese and Japanese-American men had mean marine n-3 FAs levels of 3.47%, 8.78% and 4.46%, respectively. Japanese men had a significant inverse association of marine n-3 FAs with fibrinogen (standardized regression coefficient of -0.11, P=0.049), after adjusting for age, body-mass index and current smoking. The significant inverse association remained after further adjusting for diabetes, C-reactive protein, triglycerides and other variables. White or Japanese-American men did not show a significant association. CONCLUSIONS: We observed the significant inverse association of marine n-3 FAs with fibrinogen in Japanese, but not in whites or Japanese Americans. The observation suggests that marine n-3 FAs at very high levels, as seen in the Japanese, may decrease plasma fibrinogen levels.

Plasma F2-isoprostane level and cognitive function over eight years in non-demented older adults: Findings from the Health ABC Study.

F2-isoprostanes (F2-IsoP) are reportedly increased in dementia patients, and are considered a reliable biomarker of oxidation. However, few studies have examined the predictive value of peripheral F2-IsoP levels in non-demented older adults. This study assesses the association between plasma F2-IsoP and change in cognitive function in non-demented elderly over eight years. Plasma F2-IsoP was measured by gas chromatography-mass spectrometry in a biracial cohort of 726 elderly men and women. Digit Symbol Substitution test and the Modified Mini-Mental State Exam were administered over time. No association was found between F2-IsoP tertile and baseline or change (slope) in cognitive function over eight years. Plasma F2-IsoP is not a valuable biomarker in predicting cognitive change over years in non-demented older adults.

Physical activity predicts gray matter volume in late adulthood: the Cardiovascular Health Study.

OBJECTIVES: Physical activity (PA) has been hypothesized to spare gray matter volume in late adulthood, but longitudinal data testing an association has been lacking. Here we tested whether PA would be associated with greater gray matter volume after a 9-year follow-up, a threshold could be identified for the amount of walking necessary to spare gray matter volume, and greater gray matter volume associated with PA would be associated with a reduced risk for cognitive impairment 13 years after the PA evaluation. METHODS: In 299 adults (mean age 78 years) from the Cardiovascular Health Cognition Study, we examined the association between gray matter volume, PA, and cognitive impairment. Physical activity was quantified as the number of blocks walked over 1 week. High-resolution brain scans were acquired 9 years after the PA assessment on cognitively normal adults. White matter hyperintensities, ventricular grade, and other health variables at baseline were used as covariates. Clinical adjudication for cognitive impairment occurred 13 years after baseline. RESULTS: Walking amounts ranged from 0 to 300 blocks (mean 56.3; SD 69.7). Greater PA predicted greater volumes of frontal, occipital, entorhinal, and hippocampal regions 9 years later. Walking 72 blocks was necessary to detect increased gray matter volume but walking more than 72 blocks did not spare additional volume. Greater gray matter volume with PA reduced the risk for cognitive impairment 2-fold. CONCLUSION: Greater amounts of walking are associated with greater gray matter volume, which is in turn associated with a reduced risk of cognitive impairment.

Association analysis of 33 lipoprotein candidate genes in multi-generational families of African ancestry.

African ancestry individuals have a more favorable lipoprotein profile than Caucasians, although the mechanisms for these differences remain unclear. We measured fasting serum lipoproteins and genotyped 768 tagging or potentially functional single nucleotide polymorphisms (SNPs) across 33 candidate gene regions in 401 Afro-Caribbeans older than 18 years belonging to 7 multi-generational pedigrees (mean family size 51, range 21-113, 3,426 relative pairs). All lipoproteins were significantly heritable (P<0.05). Gender-specific analysis showed that heritability for triglycerides was much higher (P<0.01) in women than in men (women, 0.62+/-0.18, P<0.01; men, 0.13+/-0.17, P>0.10), but the heritability for LDL cholesterol (LDL-C) was higher (P<0.05) in men than in women (men, 0.79+/-0.21, P<0.01; women, 0.39+/-0.12, P<0.01). The top 14 SNPs that passed the false discovery rate threshold in the families were then tested for replication in an independent population-based sample of 1,750 Afro-Caribbean men aged 40+ years. Our results revealed significant associations for three SNPs in two genes (rs5929 and rs6511720 in LDLR and rs7517090 in PCSK9) and LDL-C in both the family study and in the replication study. Our findings suggest that LDLR and PCSK9 variants may contribute to a variation in LDL-C among African ancestry individuals. Future sequencing and functional studies of these loci may advance our understanding of genetic factors contributing to LDL-C in African ancestry populations.

Cancer linked to Alzheimer disease but not vascular dementia.

OBJECTIVE: To investigate whether cancer is associated with Alzheimer disease (AD) and vascular dementia (VaD). METHODS: Cox proportional hazards models were used to test associations between prevalent dementia and risk of future cancer hospitalization, and associations between prevalent cancer and risk of subsequent dementia. Participants in the Cardiovascular Health Study-Cognition Substudy, a prospective cohort study, aged 65 years or older (n = 3,020) were followed a mean of 5.4 years for dementia and 8.3 years for cancer. RESULTS: The presence of any AD (pure AD + mixed AD/VaD; hazard ratio [HR] = 0.41, 95% confidence interval [CI] = 0.20-0.84) and pure AD (HR = 0.31, 95% CI = 0.12-0.86) was associated with a reduced risk of future cancer hospitalization, adjusted for demographic factors, smoking, obesity, and physical activity. No significant associations were found between dementia at baseline and rate of cancer hospitalizations for participants with diagnoses of VaD. Prevalent cancer was associated with reduced risk of any AD (HR = 0.72; 95% CI = 0.52-0.997) and pure AD (HR = 0.57; 95% CI = 0.36-0.90) among white subjects after adjustment for demographics, number of APOE epsilon4 alleles, hypertension, diabetes, and coronary heart disease; the opposite association was found among minorities, but the sample size was too small to provide stable estimates. No significant association was found between cancer and subsequent development of VaD. CONCLUSIONS: In white older adults, prevalent Alzheimer disease (AD) was longitudinally associated with a reduced risk of cancer, and a history of cancer was associated with a reduced risk of AD. Together with other work showing associations between cancer and Parkinson disease, these findings suggest the possibility that cancer is linked to neurodegeneration.

Age, Alzheimer disease, and brain structure.

BACKGROUND: Lack of clear understanding remains on the overlapping atrophy patterns of aging and early Alzheimer disease (AD) pathology in gray matter (GM) of the brain in vivo. OBJECTIVE: To evaluate the independent and overlapping patterns of GM atrophy in normal aging and AD. METHODS: A total of 169 cognitively normal subjects and 33 persons with probable AD enrolled in the longitudinal Cardiovascular Health Study-Cognition Study underwent 3-dimensional volumetric MRI scans. Controls remained cognitively normal for at least 5 years after their MRI scans and the probable AD subjects were relatively early in their clinical course with an average modified Mini-Mental State Examination score of 76/100. The scans were analyzed using voxel-based morphometry adjusting for total intracranial volume, gender, education, and race. RESULTS: With older age, GM volume was lower in the sensorimotor and heteromodal association areas in frontal, temporal, occipital, and parietal lobes, as well as in the cerebellum (false discovery rate p = 0.05). Additional atrophy was observed in the posterior hippocampus, thalamus, and middle cingulate gyrus. By contrast, atrophy was seen in subjects with AD in the anterior hippocampal/parahippocampal regions and the precuneus. Normal aging and AD overlapped in the hippocampal body and the entorhinal cortex. CONCLUSION: Brain atrophy with aging was observed in supratentorial and infratentorial areas, as well in primary motor, sensory, and heteromodal association regions. Age and Alzheimer disease exert independent gray matter atrophy patterns but these effects overlapped substantially in the hippocampus and entorhinal cortex.

Predicting risk of dementia in older adults: The late-life dementia risk index.

OBJECTIVE: To develop a late-life dementia risk index that can accurately stratify older adults into those with a low, moderate, or high risk of developing dementia within 6 years. METHODS: Subjects were 3,375 participants in the Cardiovascular Health Cognition Study without evidence of dementia at baseline. We used logistic regression to identify those factors most predictive of developing incident dementia within 6 years and developed a point system based on the logistic regression coefficients. RESULTS: Subjects had a mean age of 76 years at baseline; 59% were women and 15% were African American. Fourteen percent (n = 480) developed dementia within 6 years. The final late-life dementia risk index included older age (1-2 points), poor cognitive test performance (2-4 points), body mass index <18.5 (2 points), > or =1 apolipoprotein E epsilon4 alleles (1 point), cerebral MRI findings of white matter disease (1 point) or ventricular enlargement (1 point), internal carotid artery thickening on ultrasound (1 point), history of bypass surgery (1 point), slow physical performance (1 point), and lack of alcohol consumption (1 point) (c statistic, 0.81; 95% confidence interval, 0.79-0.83). Four percent of subjects with low scores developed dementia over 6 years compared with 23% of subjects with moderate scores and 56% of subjects with high scores. CONCLUSIONS: The late-life dementia risk index accurately stratified older adults into those with low, moderate, and high risk of developing dementia. This tool could be used in clinical or research settings to target prevention and intervention strategies toward high-risk individuals.

Postmenopausal hormone therapy and subclinical cerebrovascular disease: the WHIMS-MRI Study.

OBJECTIVE: The Women's Health Initiative Memory Study (WHIMS) hormone therapy (HT) trials reported that conjugated equine estrogen (CEE) with or without medroxyprogesterone acetate (MPA) increases risk for all-cause dementia and global cognitive decline. WHIMS MRI measured subclinical cerebrovascular disease as a possible mechanism to explain cognitive decline reported in WHIMS. METHODS: We contacted 2,345 women at 14 WHIMS sites; scans were completed on 1,424 (61%) and 1,403 were accepted for analysis. The primary outcome measure was total ischemic lesion volume on brain MRI. Mean duration of on-trial HT or placebo was 4 (CEE+MPA) or 5.6 years (CEE-Alone) and scans were conducted an average of 3 (CEE+MPA) or 1.4 years (CEE-Alone) post-trial termination. Cross-sectional analysis of MRI lesions was conducted; general linear models were fitted to assess treatment group differences using analysis of covariance. A (two-tailed) critical value of alpha = 0.05 was used. RESULTS: In women evenly matched within trials at baseline, increased lesion volumes were significantly related to age, smoking, history of cardiovascular disease, hypertension, lower post-trial global cognition scores, and increased incident cases of on- or post-trial mild cognitive impairment or probable dementia. Mean ischemic lesion volumes were slightly larger for the CEE+MPA group vs placebo, except for the basal ganglia, but the differences were not significant. Women assigned to CEE-Alone had similar mean ischemic lesion volumes compared to placebo. CONCLUSIONS: Conjugated equine estrogen-based hormone therapy was not associated with a significant increase in ischemic brain lesion volume relative to placebo. This finding was consistent within each trial and in pooled analyses across trials.

Fish consumption and risk of subclinical brain abnormalities on MRI in older adults.

OBJECTIVE: To investigate the association between fish consumption and subclinical brain abnormalities. METHODS: In the population-based Cardiovascular Health Study, 3,660 participants age > or =65 underwent an MRI scan in 1992-1994. Five years later, 2,313 were scanned. Neuroradiologists assessed MRI scans in a standardized and blinded manner. Food frequency questionnaires were used to assess dietary intakes. Participants with known cerebrovascular disease were excluded from the analyses. RESULTS: After adjustment for multiple risk factors, the risk of having one or more prevalent subclinical infarcts was lower among those consuming tuna/other fish > or =3 times/week, compared to <1/month (relative risk 0.74, 95% CI = 0.54-1.01, p = 0.06, p trend = 0.03). Tuna/other fish consumption was also associated with trends toward lower incidence of subclinical infarcts. Additionally, tuna/other fish intake was associated with better white matter grade, but not with sulcal and ventricular grades, markers of brain atrophy. No significant associations were found between fried fish consumption and any subclinical brain abnormalities. CONCLUSIONS: Among older adults, modest consumption of tuna/other fish, but not fried fish, was associated with lower prevalence of subclinical infarcts and white matter abnormalities on MRI examinations. Our results add to prior evidence that suggest that dietary intake of fish with higher eicosapentaenoic acid and docosahexaenoic acid content, and not fried fish intake, may have clinically important health benefits.

PROC, PROCR and PROS1 polymorphisms, plasma anticoagulant phenotypes, and risk of cardiovascular disease and mortality in older adults: the Cardiovascular Health Study.

BACKGROUND AND OBJECTIVES: Genes encoding protein C anticoagulant pathways are candidates for atherothrombotic and other aging-related disorders. METHODS: Using a tagSNP approach, and data from the Cardiovascular Health Study (CHS), we assessed associations of common polymorphisms of PROC, PROS1 and PROCR with: (i) plasma protein C, soluble protein C endothelial receptor (sEPCR) and protein S levels measured in a subsample of 336 participants at study entry; and (ii) risk of incident clinical outcomes [coronary heart disease (CHD), stroke, and mortality] in 4547 participants during follow-up. Secondarily, we explored associations between plasma protein C, protein S and sEPCR levels and other candidate genes involved in thrombosis, inflammation, and aging. RESULTS: The PROCR Ser219Gly polymorphism (rs867186) was strongly associated with higher sEPCR levels, explaining 75% of the phenotypic variation. The PROCR Ser219Gly variant was also associated with higher levels of circulating protein C antigen. An IL10 polymorphism was associated with higher free protein S levels. The minor alleles of PROC rs2069901 and PROS1 rs4857343 were weakly associated with lower protein C and free protein S levels, respectively. There was no association between PROCR Ser219Gly and risk of CHD, stroke, or mortality. The minor allele of another common PROCR tagSNP, rs2069948, was associated with lymphoid PROCR mRNA expression and with increased risk of incident stroke and all-cause mortality, and decreased healthy survival during follow-up. CONCLUSIONS: A common PROCR variant may be associated with decreased healthy survival in older adults. Additional studies are warranted to establish the role of PROCR variants in ischemic and aging-related disorders.