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1.  Personality Assessment in a Diverse Urban Sample 
Psychological assessment  2013;25(3):1007-1012.
The present research examined the data quality and replicability of the Revised NEO Personality Inventory (NEO-PI-R) factor structure in a sample that varied in ethnicity, socioeconomic status, and literacy. Participants (N=546), drawn from the Healthy Aging in Neighborhoods of Diversity across the Life Span study, were African American (58%) and White (42%) urban dwellers living above (49%) and below (51%) 125% of the federal poverty line. The NEO-PI-R, administered via telephone, was evaluated for data quality (percent valid, acquiescence, internal consistency), congruence with the normative factor structure, and readability. All indices of data quality and factor congruence were excellent in the full sample. Literacy was the most consistent predictor of data quality. A slightly worse structure was found for the Openness to Experience and Extraversion factors among lower SES African American and White participants. The overall index of factor congruence, however, supports replication of the normative structure well beyond chance levels even among those with lower literacy. Despite the challenges of low literacy, the present findings indicate that personality traits can be assessed reliably in socioeconomically diverse populations that include those living in poverty.
PMCID: PMC3790259  PMID: 23815114
Personality assessment; psychometrics; literacy; Openness to Experience; Socioeconomic status
2.  Association of Adiposity Status and Changes in Early to Mid-Adulthood With Incidence of Alzheimer’s Disease 
American journal of epidemiology  2008;168(10):1179-1189.
Adiposity status and change are potential risk factors for Alzheimer’s disease (AD). The authors used data on 2,322 participants in the Baltimore Longitudinal Study of Aging to analyze the relation between AD incidence and adiposity in Cox proportional hazards models, with adjustment for sociodemographic factors and smoking status. Body mass index (BMI; weight (kg)/height (m)2) and waist circumference at specific ages were predicted by empirical Bayes estimators from mixed-effects regression models. After a median of 23.4 years of follow-up between 1958 and 2006, 187 participants developed AD. Among men, being underweight (BMI ≤ 18.5) at age 30, 40, or 45 years increased the likelihood of AD (hazard ratio (HR) = 5.76, 95% confidence interval (CI): 2.07, 16.00); among women, being obese (BMI ≥ 30) at age 30, 40, or 45 years and jointly centrally obese (waist circumference ≥ 80th percentile) at age 30, 35, or 50 years increased AD risk (HR = 6.57, 95% CI: 1.96, 22.02). Women who lost weight (BMI change <10th percentile) between ages 30 and 45 years were also at increased risk (HR = 2.02, 95% CI: 1.06, 3.85). Weight gain among men (BMI change >90th percentile) between ages 30 and 50 years increased AD risk (HR = 3.70, 95% CI: 1.43, 9.56). Future studies should identify age- and gender-specific optimal weights and weight-loss strategies for preventing AD and investigate potential mechanisms.
PMCID: PMC2582058  PMID: 18835864
adiposity; aging; Alzheimer disease; body mass index
3.  Effect of Food Insecurity on Chronic Kidney Disease in Lower Income Americans 
American journal of nephrology  2014;39(1):27-35.
The relation of food insecurity (inability to acquire nutritionally adequate and safe foods) and chronic kidney disease (CKD) is unknown. We examined whether food insecurity is associated with prevalent CKD among lower income individuals in both the general U.S. adult population and an urban population.
We conducted cross-sectional analyses of lower income participants of the National Health and Nutrition Examination Survey (NHANES) 2003–2008 (n=9,126); and the Healthy Aging in Neighborhoods of Diversity across the Life Span (HANDLS) study (n=1,239). Food insecurity was defined based on questionnaires and CKD was defined by reduced estimated glomerular filtration rate or albuminuria; adjustment was performed with multivariable logistic regression.
In NHANES, the age-adjusted prevalence of CKD was 20.3%, 17.6% and 15.7% for the high, marginal and no food insecurity groups, respectively. Analyses adjusting for sociodemographics and smoking status revealed high food insecurity to be associated with greater odds of CKD only among participants with either diabetes [odds ratio (OR) 1.67, 95% confidence interval (CI) 1.14–2.45 comparing high to no food insecurity group] or hypertension (OR 1.37, 95% CI 1.03–1.82). In HANDLS, the age-adjusted CKD prevalence was 5.9% and 4.6% for those with and without food insecurity, respectively (P=0.33). Food insecurity was associated with a trend towards greater odds of CKD (OR 1.46, 95% CI 0.98–2.18) with no evidence of effect modification across diabetes, hypertension or obesity subgroups.
Food insecurity may contribute to disparities in kidney disease, especially among persons with diabetes or hypertension, and is worthy of further study.
PMCID: PMC3952065  PMID: 24434743
renal; socioeconomic status; disparity; nutrition
4.  Nonlinear Longitudinal Trajectories of Cholesterol and Neuropsychological Function 
Neuropsychology  2013;28(1):106-112.
Prior literature has identified inconsistent longitudinal associations between total cholesterol and cognitive decline. Here we examined prospective nonlinear relations of coincident trajectories of total cholesterol and cognitive function among persons free of stroke, dementia, and other neurological disease.
Up to 1,601 participants from the Baltimore Longitudinal Study of Aging (aged 19 to 93, 51% male, 75% white) underwent fasting cholesterol measurement and neuropsychological assessment on up to 12 occasions (M = 3.2, SD = 2.1) over up to 19 years (M = 6.4, SD = 5.3) of follow-up. Mixed-effects regression analyses were adjusted for age, sex, race, education, systolic blood pressure, body mass index, cardiovascular disease, lipid-lowering medication use, smoking, alcohol use, and depressive symptoms.
Analyses revealed significant longitudinal associations between quadratic total cholesterol and performance on measures of global mental status, verbal learning, executive function, and language (all p’s < .05). In general, higher total cholesterol was associated with poorer middle-aged or “young-old” (60-69 years) cognitive performance, but better “old-old” (80-89 years) cognitive performance. Linear models also revealed an association between lower total cholesterol and accelerated decline in visual memory performance.
Overall, results indicate nonlinear longitudinal relations of total cholesterol to cognitive decline. Whereas higher cholesterol levels were associated with cognitive decline in the middle-aged or young-old, lower cholesterol levels were related to cognitive decline among old-old participants.
PMCID: PMC3932026  PMID: 24188111
cholesterol; neuropsychology; cognitive decline; longitudinal
5.  Sex and Age Differences in the Relation of Depressive Symptoms With Blood Pressure 
American Journal of Hypertension  2013;26(12):1413-1420.
Longitudinal associations between depressive symptoms and blood pressure have been inconsistent. Most studies have examined incident hypertension as an outcome, and few have examined effect modification.
This study examined moderating influences of sex and age on coincident trajectories of depressive symptoms and blood pressure among 2,087 participants from the Baltimore Longitudinal Study of Aging (aged 19–97 years; 53% men; 74% white). Participants underwent clinical blood pressure measurement and completed the Center for Epidemiological Studies–Depression (CES-D) scale on up to 14 occasions (mean = 3.8; SD = 2.6) over up to 29 years (mean = 7.8; SD = 6.4). CES-D was log-transformed (CES-D(log)) for analyses.
Mixed-effects regression revealed that prospective relations of CES-D(log) to diastolic blood pressure differed by age in women (b = 0.095; P = 0.001) but not men; greater CES-D(log) attenuated the expected age-related decline in diastolic blood pressure. Across all testing sessions, greater CES-D(log) was associated significantly with higher average systolic blood pressure for women (b = 2.238; P = 0.006) but not men. Age-stratified analyses showed that greater CES-D(log) was associated significantly with higher average systolic (b = 3.348; P = 0.02) and diastolic (b = 1.730; P < 0.03) blood pressure for older adults (≥58.8 years at first visit). In the younger age cohort, sex moderated the relation of CES-D(log) to systolic blood pressure (b = −3.563; P = 0.007); greater CES-D(log) in women, but lesser CES-D(log) in men, was associated with higher systolic blood pressure.
Results demonstrate sex and age differences in the relation between depressive symptoms and blood pressure. Findings suggest the potential importance of preventing, detecting, and lowering depressive symptoms to prevent hypertension among women and older adults.
PMCID: PMC3816627  PMID: 23959543
age factors; blood pressure; depressive symptoms; hypertension; longitudinal studies; older adults; repeated measures; sex factors; women.
6.  Diet quality inversely associated with C-reactive protein levels in urban, low-income African American and White adults 
Journal of the Academy of Nutrition and Dietetics  2013;113(12):10.1016/j.jand.2013.07.004.
C-Reactive Protein (CRP), an inflammatory biomarker, is influenced by many factors including socioeconomic position, genetics and diet. The inverse association between diet and CRP is biologically feasible because micronutrients with antioxidative properties may enable the body to manage the balance between production and accumulation of reactive species that cause oxidative stress.
To determine the quality of the diet consumed by urban, low-income African American and White adults aged 30 to 64 years, and association of diet quality with CRP.
Data from a cross-sectional study were used to evaluate diet quality assessed by mean adequacy ratio (MAR). Two 24-hour recalls were collected by trained interviewers using the USDA automated multiple pass method.
The sample consisted of Healthy Aging in Neighborhoods of Diversity across the Life Span baseline study participants, 2004–2009, who completed both recalls (n=2017).
Main outcome measures
MAR equaled the average of the ratio of intakes to RDA for 15 vitamins and minerals. CRP levels were assessed by the nephelometric method utilizing latex particles coated with CRP monoclonal antibodies.
Statistical analysis performed
Linear ordinary least square regression and generalized linear models were performed to determine the association of MAR (independent variable) with CRP (dependent variable) while adjusting for potential confounders.
MAR scores ranged from 74.3 to 82.2. Intakes of magnesium and Vitamins A, C, and E were the most inadequate compared to Estimated Average Requirements. CRP levels were significantly associated with MAR, DXA-measured body fat, and hypertension. A 10% increase in MAR was associated to a 4% decrease in CRP.
The MAR was independently and significantly inversely associated with CRP, suggesting diet is associated with the regulation of inflammation. Interventions to assist people make better food choices may not only improve diet quality but also their health, possibly reducing risk for cardiovascular disease.
PMCID: PMC3833870  PMID: 24035460
7.  Personality Traits and Chronic Disease: Implications for Adult Personality Development 
Personality traits have been associated with chronic disease. Less is known about the longitudinal relation between personality and disease and whether chronic disease is associated with changes in personality.
Participants from the Baltimore Longitudinal Study of Aging (N = 2,008) completed the Revised NEO Personality Inventory and a standard medical interview at regularly scheduled visits; the Charlson Comorbidity Index, a weighted sum of 19 serious diseases, was derived from this interview. Using data from 6,685 visits, we tested whether personality increased risk of disease and whether disease was associated with personality change.
Measured concurrently, neuroticism and conscientiousness were associated with greater disease burden. The impulsiveness facet of neuroticism was the strongest predictor of developing disease across the follow-up period: For every standard deviation increase in impulsiveness, there was a 26% increased risk of developing disease and a 36% increased risk of getting more ill. Personality traits changed only modestly with disease: As participants developed chronic illnesses, they became more conservative (decreased openness).
This research indicates that personality traits confer risk for disease, in part, through health-risk behaviors. These traits, however, were relatively resistant to the effect of serious disease.
PMCID: PMC3805287  PMID: 23685925
Disease burden; Illness; Openness; Personality change; Personality traits.
8.  Sodium Intake of Special Populations in the Healthy Aging in Neighborhoods of Diversity Across the Life Span (HANDLS) Study 
Preventive medicine  2013;57(4):334-338.
The sodium intake of participants of the Healthy Aging in Neighborhoods of Diversity across the Life Span study who were in three of the special population groups identified by the Dietary Guidelines for Americans, 2010 (those with hypertension, African Americans, and those ≥51 years) was analyzed to determine if they met sodium recommendations.
The sample included 2152 African American and White subjects, aged 30-64 years. Major dietary sources of sodium for each group were determined from two 24-hour dietary recalls, and dietary intakes were compared with sodium recommendations. Dietary potassium was also evaluated.
The intakes of the groups studied exceeded 1500 mg sodium while their potassium intakes were lower than the Adequate Intake of 4700 mg. The major contributors of sodium included “cold cuts, sausage, and franks,” “protein foods”, and yeast breads.
Excessive sodium intake characterized the diet of an urban, socioeconomically diverse population who are hypertensive or at risk for having hypertension. These findings have implications for health professionals and the food industry.
PMCID: PMC3775971  PMID: 23769900
nutrition/diet; hypertension; health promotion; public health; prevention; lifestyle modification/health behavior
9.  Serum Nutritional Biomarkers and Their Associations with Sleep among US Adults in Recent National Surveys 
PLoS ONE  2014;9(8):e103490.
The associations between nutritional biomarkers and measures of sleep quantity and quality remain unclear.
Cross-sectional data from the National Health and Nutrition Examination Surveys (NHANES) 2005–2006 were used. We selected 2,459 adults aged 20–85, with complete data on key variables. Five sleep measures were constructed as primary outcomes: (A) Sleep duration; (B) Sleep disorder; (C) Three factors obtained from factor analysis of 15 items and labeled as “Poor sleep-related daytime dysfunction” (Factor 1), “Sleepiness” (Factor 2) and “Sleep disturbance” (Factor 3). Main exposures were serum concentrations of key nutrients, namely retinol, retinyl esters, carotenoids (α-carotene, β-carotene, β-cryptoxanthin, lutein+zeaxanthin, lycopene), folate, vitamin B-12, total homocysteine (tHcy), vitamin C, 25-hydroxyvitamin D (25(OH)D) and vitamin E. Main analyses consisted of multiple linear, logistic and multinomial logit models.
Among key findings, independent inverse associations were found between serum vitamin B-12 and sleep duration, 25(OH)D and sleepiness (as well as insomnia), and between folate and sleep disturbance. Serum total carotenoids concentration was linked to higher odds of short sleep duration (i.e. 5–6 h per night) compared to normal sleep duration (7–8 h per night).
A few of the selected serum nutritional biomarkers were associated with sleep quantity and quality. Longitudinal studies are needed to ascertain temporality and assess putative causal relationships.
PMCID: PMC4138077  PMID: 25137304
10.  Meta-Analysis of Genome-Wide Association Studies in African Americans Provides Insights into the Genetic Architecture of Type 2 Diabetes 
Ng, Maggie C. Y. | Shriner, Daniel | Chen, Brian H. | Li, Jiang | Chen, Wei-Min | Guo, Xiuqing | Liu, Jiankang | Bielinski, Suzette J. | Yanek, Lisa R. | Nalls, Michael A. | Comeau, Mary E. | Rasmussen-Torvik, Laura J. | Jensen, Richard A. | Evans, Daniel S. | Sun, Yan V. | An, Ping | Patel, Sanjay R. | Lu, Yingchang | Long, Jirong | Armstrong, Loren L. | Wagenknecht, Lynne | Yang, Lingyao | Snively, Beverly M. | Palmer, Nicholette D. | Mudgal, Poorva | Langefeld, Carl D. | Keene, Keith L. | Freedman, Barry I. | Mychaleckyj, Josyf C. | Nayak, Uma | Raffel, Leslie J. | Goodarzi, Mark O. | Chen, Y-D Ida | Taylor, Herman A. | Correa, Adolfo | Sims, Mario | Couper, David | Pankow, James S. | Boerwinkle, Eric | Adeyemo, Adebowale | Doumatey, Ayo | Chen, Guanjie | Mathias, Rasika A. | Vaidya, Dhananjay | Singleton, Andrew B. | Zonderman, Alan B. | Igo, Robert P. | Sedor, John R. | Kabagambe, Edmond K. | Siscovick, David S. | McKnight, Barbara | Rice, Kenneth | Liu, Yongmei | Hsueh, Wen-Chi | Zhao, Wei | Bielak, Lawrence F. | Kraja, Aldi | Province, Michael A. | Bottinger, Erwin P. | Gottesman, Omri | Cai, Qiuyin | Zheng, Wei | Blot, William J. | Lowe, William L. | Pacheco, Jennifer A. | Crawford, Dana C. | Grundberg, Elin | Rich, Stephen S. | Hayes, M. Geoffrey | Shu, Xiao-Ou | Loos, Ruth J. F. | Borecki, Ingrid B. | Peyser, Patricia A. | Cummings, Steven R. | Psaty, Bruce M. | Fornage, Myriam | Iyengar, Sudha K. | Evans, Michele K. | Becker, Diane M. | Kao, W. H. Linda | Wilson, James G. | Rotter, Jerome I. | Sale, Michèle M. | Liu, Simin | Rotimi, Charles N. | Bowden, Donald W.
PLoS Genetics  2014;10(8):e1004517.
Type 2 diabetes (T2D) is more prevalent in African Americans than in Europeans. However, little is known about the genetic risk in African Americans despite the recent identification of more than 70 T2D loci primarily by genome-wide association studies (GWAS) in individuals of European ancestry. In order to investigate the genetic architecture of T2D in African Americans, the MEta-analysis of type 2 DIabetes in African Americans (MEDIA) Consortium examined 17 GWAS on T2D comprising 8,284 cases and 15,543 controls in African Americans in stage 1 analysis. Single nucleotide polymorphisms (SNPs) association analysis was conducted in each study under the additive model after adjustment for age, sex, study site, and principal components. Meta-analysis of approximately 2.6 million genotyped and imputed SNPs in all studies was conducted using an inverse variance-weighted fixed effect model. Replications were performed to follow up 21 loci in up to 6,061 cases and 5,483 controls in African Americans, and 8,130 cases and 38,987 controls of European ancestry. We identified three known loci (TCF7L2, HMGA2 and KCNQ1) and two novel loci (HLA-B and INS-IGF2) at genome-wide significance (4.15×10−94
Author Summary
Despite the higher prevalence of type 2 diabetes (T2D) in African Americans than in Europeans, recent genome-wide association studies (GWAS) were examined primarily in individuals of European ancestry. In this study, we performed meta-analysis of 17 GWAS in 8,284 cases and 15,543 controls to explore the genetic architecture of T2D in African Americans. Following replication in additional 6,061 cases and 5,483 controls in African Americans, and 8,130 cases and 38,987 controls of European ancestry, we identified two novel and three previous reported T2D loci reaching genome-wide significance. We also examined 158 loci previously reported to be associated with T2D or regulating glucose homeostasis. While 56% of these loci were shared between African Americans and the other populations, the strongest associations in African Americans are often found in nearby single nucleotide polymorphisms (SNPs) instead of the original SNPs reported in other populations due to differential genetic architecture across populations. Our results highlight the importance of performing genetic studies in non-European populations to fine map the causal genetic variants.
PMCID: PMC4125087  PMID: 25102180
Drug and alcohol dependence  2012;131(3):247-251.
Illicit substances increase risk of morbidity and mortality and have significant consequences for society. Personality traits are associated with drug use; we test whether these associations vary by socioeconomic status.
Participants (N=412) from the Healthy Aging in Neighborhoods of Diversity across the Life Span (HANDLS) study completed the Revised NEO Personality Inventory and self-reported use of opiates and cocaine. 50% of participants were living below 125% of the federal poverty line. Mean-level personality differences across never, former, and current opiate/cocaine users were compared. Logistic regressions compared never versus current users and interactions between personality traits and poverty status tested whether these associations varied by socioeconomic status.
High Neuroticism and low Agreeableness increased risk of drug use. The association between low Conscientiousness and drug use was moderated by poverty, such that low Conscientiousness was a stronger risk factor for illicit substance use among those with relatively higher SES: For every standard deviation decrease in Conscientiousness, there was a greater than 2-fold increase in risk of illicit substance use (OR=2.15, 95% CI=1.45–3.17). Conscientiousness was unrelated to drug use among participants living below 125% of the federal poverty line.
Under favorable economic conditions, the tendency to be organized, disciplined, and deliberate is protective against drug use. These tendencies, however, matter less when financial resources are scarce. In contrast, those prone to emotional distress and antagonism are at greater risk for current drug use, regardless of their economic situation.
PMCID: PMC3610771  PMID: 23265091
personality traits; conscientiousness; substance use; poverty; cocaine; heroin
Biological psychiatry  2013;75(1):10.1016/j.biopsych.2013.02.024.
The ability to control impulses varies greatly, and difficulty with impulse control can have severe consequences; in the extreme, it is the defining feature of many psychiatric disorders. Evidence from disparate lines of research suggests that uric acid is elevated in psychiatric disorders characterized by high impulsivity, such as ADHD and bipolar disorder. The present research tests the hypothesis that impulsivity is associated with higher uric acid in humans and mice.
Using two longitudinal, non-clinical community samples (total N=6883), we test whether there is an association between uric acid and normal variation in trait impulsivity measured with the Revised NEO Personality Inventory. We also examined the effect of uric acid on behavior by comparing wild-type mice (WT), which naturally have low levels of uric acid, to mice genetically modified (UOX) to accumulate high levels of uric acid.
In both human samples, the emotional aspects of trait impulsivity, specifically Impulsiveness and Excitement-Seeking, were associated with higher levels of uric acid concurrently and when uric acid was measured 3–5 years later. Consistent with the human data, the UOX mice displayed significantly more exploratory and novelty-seeking behavior than the WT mice.
Higher uric acid was associated with impulsivity in both humans and mice. The identification of biological markers of impulsivity may lead to a better understanding of the physiological mechanisms involved in impulsivity, and may suggest potential targets for therapeutic intervention.
PMCID: PMC3859133  PMID: 23582268
Impulsivity; Personality traits; Uric Acid; Mouse Model; Excitement-Seeking; Impulse Control
BMC Public Health  2014;14:643.
Cognitive impairment, including dementia, is a major health concern with the increasing aging population. Preventive measures to delay cognitive decline are of utmost importance. Alzheimer’s disease (AD) is the most frequent cause of dementia, increasing in prevalence from <1% below the age of 60 years to >40% above 85 years of age.
We systematically reviewed selected modifiable factors such as education, smoking, alcohol, physical activity, caffeine, antioxidants, homocysteine (Hcy), n-3 fatty acids that were studied in relation to various cognitive health outcomes, including incident AD. We searched MEDLINE for published literature (January 1990 through October 2012), including cross-sectional and cohort studies (sample sizes > 300). Analyses compared study finding consistency across factors, study designs and study-level characteristics. Selecting studies of incident AD, our meta-analysis estimated pooled risk ratios (RR), population attributable risk percent (PAR%) and assessed publication bias.
In total, 247 studies were retrieved for systematic review. Consistency analysis for each risk factor suggested positive findings ranging from ~38.9% for caffeine to ~89% for physical activity. Education also had a significantly higher propensity for “a positive finding” compared to caffeine, smoking and antioxidant-related studies. Meta-analysis of 31 studies with incident AD yielded pooled RR for low education (RR = 1.99; 95% CI: 1.30-3.04), high Hcy (RR = 1.93; 95% CI: 1.50-2.49), and current/ever smoking status (RR = 1.37; 95% CI: 1.23-1.52) while indicating protective effects of higher physical activity and n-3 fatty acids. Estimated PAR% were particularly high for physical activity (PAR% = 31.9; 95% CI: 22.7-41.2) and smoking (PAR%=31.09%; 95% CI: 17.9-44.3). Overall, no significant publication bias was found.
Higher Hcy levels, lower educational attainment, and decreased physical activity were particularly strong predictors of incident AD. Further studies are needed to support other potential modifiable protective factors, such as caffeine.
PMCID: PMC4099157  PMID: 24962204
Cognition; Dementia; Alzheimer’s disease; Risk factor; Nutrition; Meta-analysis
Ethnicity & disease  2010;20(3):267-275.
Examine the influences of race, socioeconomic status, sex, and age on barriers to participation in a study of cross-sectional differences and longitudinal changes in health-related outcomes.
We designed a multidisciplinary, community-based, prospective longitudinal epidemiologic study among socioeconomically diverse African Americans and whites. The study protocol facilitated our ability to recruit 3722 participants from Baltimore, MD with mean age 47.7 (range 30–64) years, % males/female, 2200 African Americans (59%) and 1522 whites (41%); 41% reported household incomes below the 125% poverty delimiter.
There were no significant age differences associated with sex or race. Participants below the 125% poverty delimiter were slightly younger than those above the delimiter. Age, race, and sex, but not poverty status, were associated with the likelihood of an examination. Older participants, women, and whites were more likely to complete their examinations. Among those who completed their examinations, there were no age differences associated with sex and poverty status, but African Americans were negligibly younger than whites.
Although some literature suggests that minorities and low-income people are less willing to participate in clinical research, these baseline data suggest that African Americans individuals and individuals from households with incomes below 125% of the poverty level are at least as willing to participate in observational clinical studies as whites and higher income individuals of similar age and sex.
PMCID: PMC3040595  PMID: 20828101
Healthcare disparities; socioeconomic status; Population groups; Epidemiologic research design; Health surveys; Longitudinal studies
Older adults with intact cognition before death and substantial Alzheimer disease (AD) lesions at autopsy have been termed “asymptomatic AD subjects” (ASYMAD). We previously reported hypertrophy of neuronal cell bodies, nuclei, and nucleoli in the CA1 of the hippocampus (CA1), anterior cingulate gyrus, posterior cingulate gyrus, and primary visual cortex of ASYMAD versus age-matched Control and mild cognitive impairment (MCI) subjects. However, it was unclear whether the neuronal hypertrophy could be attributed to differences in the severity of AD pathology. Here, we performed quantitative analyses of the severity of β-amyloid (Aβ) and phosphorylated tau (tau) loads in the brains of ASYMAD, Control, MCI, and AD subjects (n = 15 per group) from the Baltimore Longitudinal Study of Aging. Tissue sections from CA1, anterior cingulate gyrus, posterior cingulate gyrus, and primary visual cortex were immunostained for Aβ and tau; the respective loads were assessed using unbiased stereology by measuring the fractional areas of immunoreactivity for each protein in each region. The ASYMAD and MCI groups did not differ in Aβ and tau loads. These data confirm that ASYMAD and MCI subjects have comparable loads of insoluble Aβ and tau in regions vulnerable to AD pathology despite divergent cognitive outcomes. These findings imply that cognitive impairment in AD may be caused or modulated by factors other than insoluble forms of Aβ and tau.
PMCID: PMC4062187  PMID: 24607960
Alzheimer disease; Immunoreactivity; Neuronal hypertrophy; Preserved cognition; Soluble β-amyloid; Tau
Human Molecular Genetics  2013;22(12):2529-2538.
Laboratory red blood cell (RBC) measurements are clinically important, heritable and differ among ethnic groups. To identify genetic variants that contribute to RBC phenotypes in African Americans (AAs), we conducted a genome-wide association study in up to ∼16 500 AAs. The alpha-globin locus on chromosome 16pter [lead SNP rs13335629 in ITFG3 gene; P < 1E−13 for hemoglobin (Hgb), RBC count, mean corpuscular volume (MCV), MCH and MCHC] and the G6PD locus on Xq28 [lead SNP rs1050828; P < 1E − 13 for Hgb, hematocrit (Hct), MCV, RBC count and red cell distribution width (RDW)] were each associated with multiple RBC traits. At the alpha-globin region, both the common African 3.7 kb deletion and common single nucleotide polymorphisms (SNPs) appear to contribute independently to RBC phenotypes among AAs. In the 2p21 region, we identified a novel variant of PRKCE distinctly associated with Hct in AAs. In a genome-wide admixture mapping scan, local European ancestry at the 6p22 region containing HFE and LRRC16A was associated with higher Hgb. LRRC16A has been previously associated with the platelet count and mean platelet volume in AAs, but not with Hgb. Finally, we extended to AAs the findings of association of erythrocyte traits with several loci previously reported in Europeans and/or Asians, including CD164 and HBS1L-MYB. In summary, this large-scale genome-wide analysis in AAs has extended the importance of several RBC-associated genetic loci to AAs and identified allelic heterogeneity and pleiotropy at several previously known genetic loci associated with blood cell traits in AAs.
PMCID: PMC3658166  PMID: 23446634
Psychosomatic medicine  2013;75(5):486-496.
Helicobacter pylori (H. pylori) seropositivity is a potential risk for poor cognition among US adults.
Cross-sectional data from the National Health and Nutrition Examination Survey III, phase 1 (1988–91) were used. Measures included age-group specific neuropsychological test batteries and two measures of H. pylori seropositivity (IgG and IgG-CagA) (20–59yo:n=2,090–2,248; 60–90yo:n=2,123–2,388). We explored sex- and race-specific associations.
On the basis of multiple OLS and zero-inflated Poisson regression models, we detected a poorer performance among those 60–90yo with H. pylori IgG+ vs. IgG− on a verbal memory test (story recall, correct items), overall (β=−0.04±0.01, p=0.010). NH blacks and women (20–59yo) performed worse on the serial digits learning errors (SDL-TE) when H. pylori IgG+(vs. IgG−), another verbal memory test (β=+0.94±0.40, p=0.029 and β=+1.19±0.44, p=0.012, respectively); (p<0.10 for interaction by sex and race). More trials to completion on this test (SDL-TTC) were also required among H. pylori IgG+ overall (20–59yo, β=+0.30±0.13, p=0.033). Other race-specific associations without significant interaction by race that were detected in the same direction of worse performance with seropositivity included H. pylori IgG+ in NH blacks with the symbol digits substitution test-number of errors (SDS-E) (20–59yo, p=0.038) and with the incorrect items on the orientation test (ORIENT-INC) (60–90yo, p=0.038). H. pylori IgG CagA+ was associated with poorer Word Recall test performance(WR-CORR) among Mexican Americans(60–90yo, p=0.048), WR-TRIALS among NH whites(60–90yo, p=0.047) and ORIENT-INC among NH blacks(60–90yo, p=0.025).
H. pylori seropositivity markers were associated with poor cognition among US adults. Longitudinal research is needed to extrapolote those findings to cognitive decline, incident dementia and Alzheimer’s Disease.
PMCID: PMC3679320  PMID: 23697465
Helicobacter pylori; seropositivity; cognitive function; adults; aging
Mutation research  2012;736(0):93-103.
It is well accepted that oxidative DNA repair capacity, oxidative damage to DNA and oxidative stress play central roles in aging and disease development. However, the correlation between oxidative damage to DNA, markers of oxidant stress and DNA repair capacity is unclear. In addition, there is no universally accepted panel of markers to assess oxidative stress in humans. Our interest is oxidative damage to DNA and its correlation with DNA repair capacity and other markers of oxidative stress. We present preliminary data from a small comet study that attempts to correlate single strand break (SSB) level with single strand break repair capacity (SSB-RC) and markers of oxidant stress and inflammation. In this limited study of four very small age-matched 24-individual groups of male and female whites and African-Americans aged 30–64 years, we found that females have higher single strand break (SSB) levels than males (p=0.013). There was a significant negative correlation between SSB-RC and SSB level (p=0.041). There was a positive correlation between SSBs in African American males with both heme degradation products (p=0.008) and high-sensitivity C-reactive protein (hs-CRP) (p=0.022). We found a significant interaction between hs-CRP and sex in their effect on residual DNA damage (p=0.002). Red blood cell reduced glutathione concentration was positively correlated with the levels of oxidized bases detected by endonuclease III (p=0.047), heme degradation products (p=0.015) and hs-CRP (p=0.020). However, plasma carbonyl levels showed no significant correlation with other markers. The data from the literature and from our very limited study suggest a complex relationship between measures of oxidative stress and frequently used clinical parameters believed to reflect inflammation or oxidative stress.
PMCID: PMC4037702  PMID: 22273780
oxidative stress; aging; DNA oxidative lesions; DNA repair; comet assay; red blood cell glutathione (RBC GSH); fluorescent heme degradation products; high-sensitivity C-reactive protein (hs-CRP)
The New England journal of medicine  2013;369(21):1991-2000.
Low levels of total 25-hydroxyvitamin D are common among black Americans. Vitamin D–binding protein has not been considered in the assessment of vitamin D deficiency.
In the Healthy Aging in Neighborhoods of Diversity across the Life Span cohort of blacks and whites (2085 participants), we measured levels of total 25-hydroxyvitamin D, vitamin D–binding protein, and parathyroid hormone as well as bone mineral density (BMD). We genotyped study participants for two common polymorphisms in the vitamin D–binding protein gene (rs7041 and rs4588). We estimated levels of bioavailable 25-hydroxyvitamin D in homozygous participants.
Mean (±SE) levels of both total 25-hydroxyvitamin D and vitamin D–binding protein were lower in blacks than in whites (total 25-hydroxyvitamin D, 15.6±0.2 ng per milliliter vs. 25.8±0.4 ng per milliliter, P<0.001; vitamin D–binding protein, 168±3 μg per milliliter vs. 337±5 μg per milliliter, P<0.001). Genetic polymorphisms independently appeared to explain 79.4% and 9.9% of the variation in levels of vitamin D–binding protein and total 25-hydroxyvitamin D, respectively. BMD was higher in blacks than in whites (1.05±0.01 g per square centimeter vs. 0.94±0.01 g per square centimeter, P<0.001). Levels of parathyroid hormone increased with decreasing levels of total or bioavailable 25-hydroxyvitamin D (P<0.001 for both relationships), yet within each quintile of parathyroid hormone concentration, blacks had significantly lower levels of total 25-hydroxyvitamin D than whites. Among homozygous participants, blacks and whites had similar levels of bioavailable 25-hydroxy vitamin D overall (2.9±0.1 ng per milliliter and 3.1±0.1 ng per milliliter, respectively; P = 0.71) and within quintiles of parathyroid hormone concentration.
Community-dwelling black Americans, as compared with whites, had low levels of total 25-hydroxyvitamin D and vitamin D–binding protein, resulting in similar concentrations of estimated bioavailable 25-hydroxyvitamin D. Racial differences in the prevalence of common genetic polymorphisms provide a likely explanation for this observation. (Funded by the National Institute on Aging and others.)
PMCID: PMC4030388  PMID: 24256378
The British journal of nutrition  2012;109(9):10.1017/S0007114512003467.
We examined the relationship of elevated depressive symptoms with antioxidant status. Cross-sectional data from the National Health and Nutrition Examination Surveys 2005–06 on US adults aged 20–85 years were analyzed. Depressive symptoms were measured using the Patient Health Questionnaire with a score cutpoint of 10 to define “elevated depressive symptoms”. Serum antioxidant status was measured by serum levels of carotenoids, retinol (free and retinyl esters), vitamin C and vitamin E. The main analyses consisted of multiple logistic and zero-inflated poisson regression models, taking into account sampling design complexity. The final sample consisted of 1,798 US adults with complete data. Higher total carotenoid serum level was associated with lower likelihood of elevated depressive symptoms with a reduction in the odds by 37% overall with each SD increase in exposure, and by 34% among women (p<0.05). A dose-response relationship was observed when serum total carotenoids were expressed as quartiles [Q4 (1.62–10.1 μmol/L) vs. Q1(0.06–0.86 μmol/L): OR=0.41; 95% CI: 0.23–0.76, P<0.001; p-value for trend=0.035], though no significant associations were found with other antioxidant levels. Among carotenoids, β-carotene (men and women combined) and lutein+zeaxanthins (women only, after control for dietary lutein+zeaxanthin intake and supplement use) had an independent inverse association with elevated depressive symptoms among US adults. None of the other serum antioxidants had a significant association with depressive symptoms, independently of total carotenoids and other covariates. In conclusion, total carotenoids (mainly β-carotene and lutein+zeaxanthins) in serum were associated with reduced levels of depressive symptoms among community-dwelling US adults.
PMCID: PMC3810278  PMID: 22935166
Depressive symptoms; antioxidants; carotenoids; adults
American Journal of Epidemiology  2008;168(10):1179-1189.
Adiposity status and change are potential risk factors for Alzheimer's disease (AD). The authors used data on 2,322 participants in the Baltimore Longitudinal Study of Aging to analyze the relation between AD incidence and adiposity in Cox proportional hazards models, with adjustment for sociodemographic factors and smoking status. Body mass index (BMI; weight (kg)/height (m)2) and waist circumference at specific ages were predicted by empirical Bayes estimators from mixed-effects regression models. After a median of 23.4 years of follow-up between 1958 and 2006, 187 participants developed AD. Among men, being underweight (BMI ≤18.5) at age 30, 40, or 45 years increased the likelihood of AD (hazard ratio (HR) = 5.76, 95% confidence interval (CI): 2.07, 16.00); among women, being obese (BMI ≥30) at age 30, 40, or 45 years and jointly centrally obese (waist circumference ≥80th percentile) at age 30, 35, or 50 years increased AD risk (HR = 6.57, 95% CI: 1.96, 22.02). Women who lost weight (BMI change <10th percentile) between ages 30 and 45 years were also at increased risk (HR = 2.02, 95% CI: 1.06, 3.85). Weight gain among men (BMI change >90th percentile) between ages 30 and 50 years increased AD risk (HR = 3.70, 95% CI: 1.43, 9.56). Future studies should identify age- and gender-specific optimal weights and weight-loss strategies for preventing AD and investigate potential mechanisms.
PMCID: PMC2582058  PMID: 18835864
adiposity; aging; Alzheimer disease; body mass index
Neurobiology of aging  2012;34(4):1045-1050.
Alzheimer's disease (AD) neuropathology is found at autopsy in about 30% of cognitively normal older individuals. We examine whether personality traits are associated with such resilience to clinical dementia in individuals with AD neuropathology. Broad factors and specific facets of personality were assessed up to 28 years (M=11, SD=7) before onset of dementia and up to 30 years (M=15, SD=7) before death in a cohort (N=111) evaluated for AD neuropathology at autopsy. Individuals with higher baseline scores on vulnerability to stress, anxiety, and depression (neuroticism: OR=2.0, 95%CI=1.2-3.5), or lower scores on order and competence (conscientiousness: OR=0.4, 95%CI=0.2-0.9) were less likely to remain asymptomatic in the presence of AD neuropathology. Neuroticism (r=0.26), low agreeableness (r=-0.34), and some facets were also significantly associated with advanced stages of neurofibrillary tangles, but the associations between personality traits and risk of clinical dementia were mostly unchanged by controlling for Braak and CERAD scores. In sum, a resilient personality profile is associated with lower risk or delay of clinical dementia even in persons with AD neuropathology.
PMCID: PMC3541457  PMID: 23040035
Alzheimer's disease; dementia; asymptomatic; personality; neuroticism; depression; conscientiousness; prospective cohort study; autopsy; neurofibrillary tangles; Aβ neuritic plaques; neuropathology
Apolipoprotein E ε4 (ApoE4 carrier) status, sex and cognitive impairment may interact to affect all-cause and cause-specific mortality risk.
To confirm associations of ApoE4 carrier status, sex and time-dependent cognitive status with mortality risk, and investigate these associations' joint effects in a cohort of community-dwelling US adults.
Design & Setting
Data from the Baltimore Longitudinal Study of Aging were used.
Of n=3,047 (First-visit Age:17–98y, 60.1% men), we selected a sample with complete genetic data and with ≥1 visit at age≥50y (n=1,461).
Time-to-death from all, cardiovascular or non-cardiovascular causes.
Survival probability was lower for ApoE4 carriers, particularly at oldest ages. Cox proportional hazards model for all-cause mortality yielded a hazard ratio (HR) for ApoE4 carrier vs. non-carriers of 1.31,95%CI:1.02–1.68. This association was also found for cardiovascular mortality. Time-dependent all-cause dementia (HR=1.73, 95%CI:1.33–2.26) and mild cognitive impairment (HR=1.95,95%CI:1.42–2.67) increased all-cause mortality risk, associations also detected for non-cardiovascular mortality. When individuals were free of cognitive impairment, a dose-response relationship with ε4 alleles was found for all-cause mortality (HR=1.40,95%CI:0.94–2.07 for 1 ε4, and HR=2.61; 95%CI:1.12–6.07 for 2 ε4). After Alzheimer's Disease-type (AD) dementia onset, carrying only 1 ε4 allele increased all-cause mortality risk by ~77% compared to non-carriers. ApoE4 carrier status increased all-cause mortality risk in men and interacted with time-dependent AD to increase the risk of this outcome (RERI=2.15; 95% CI:1.22–3.07).
We found that ApoE4 carrier status increased all-cause and cardiovascular mortality risks, while interacting with sex and time-dependent AD status to affect all-cause mortality.
PMCID: PMC3628727  PMID: 23581910
Apolipoprotein E genotype; dementia; mild cognitive impairment; mortality; cardiovascular disease
Hek, Karin | Demirkan, Ayse | Lahti, Jari | Terracciano, Antonio | Teumer, Alexander | Cornelis, Marilyn C. | Amin, Najaf | Bakshis, Erin | Baumert, Jens | Ding, Jingzhong | Liu, Yongmei | Marciante, Kristin | Meirelles, Osorio | Nalls, Michael A. | Sun, Yan V. | Vogelzangs, Nicole | Yu, Lei | Bandinelli, Stefania | Benjamin, Emelia J. | Bennett, David A. | Boomsma, Dorret | Cannas, Alessandra | Coker, Laura H. | de Geus, Eco | De Jager, Philip L. | Diez-Roux, Ana V. | Purcell, Shaun | Hu, Frank B. | Rimma, Eric B. | Hunter, David J. | Jensen, Majken K. | Curhan, Gary | Rice, Kenneth | Penman, Alan D. | Rotter, Jerome I. | Sotoodehnia, Nona | Emeny, Rebecca | Eriksson, Johan G. | Evans, Denis A. | Ferrucci, Luigi | Fornage, Myriam | Gudnason, Vilmundur | Hofman, Albert | Illig, Thomas | Kardia, Sharon | Kelly-Hayes, Margaret | Koenen, Karestan | Kraft, Peter | Kuningas, Maris | Massaro, Joseph M. | Melzer, David | Mulas, Antonella | Mulder, Cornelis L. | Murray, Anna | Oostra, Ben A. | Palotie, Aarno | Penninx, Brenda | Petersmann, Astrid | Pilling, Luke C. | Psaty, Bruce | Rawal, Rajesh | Reiman, Eric M. | Schulz, Andrea | Shulman, Joshua M. | Singleton, Andrew B. | Smith, Albert V. | Sutin, Angelina R. | Uitterlinden, André G. | Völzke, Henry | Widen, Elisabeth | Yaffe, Kristine | Zonderman, Alan B. | Cucca, Francesco | Harris, Tamara | Ladwig, Karl-Heinz | Llewellyn, David J. | Räikkönen, Katri | Tanaka, Toshiko | van Duijn, Cornelia M. | Grabe, Hans J. | Launer, Lenore J. | Lunetta, Kathryn L. | Mosley, Thomas H. | Newman, Anne B. | Tiemeier, Henning | Murabito, Joanne
Biological psychiatry  2013;73(7):10.1016/j.biopsych.2012.09.033.
Depression is a heritable trait that exists on a continuum of varying severity and duration. Yet, the search for genetic variants associated with depression has had few successes. We exploit the entire continuum of depression to find common variants for depressive symptoms.
In this genome-wide association study, we combined the results of 17 population-based studies assessing depressive symptoms with the Center for Epidemiological Studies Depression Scale. Replication of the independent top hits (p < 1 × 10−5) was performed in five studies assessing depressive symptoms with other instruments. In addition, we performed a combined meta-analysis of all 22 discovery and replication studies.
The discovery sample comprised 34,549 individuals (mean age of 66.5) and no loci reached genome-wide significance (lowest p = 1.05 × 10−7). Seven independent single nucleotide polymorphisms were considered for replication. In the replication set (n = 16,709), we found suggestive association of one single nucleotide polymorphism with depressive symptoms (rs161645, 5q21, p = 9.19 × 10−3). This 5q21 region reached genome-wide significance (p = 4.78 × 10−8) in the overall meta-analysis combining discovery and replication studies (n = 51,258).
The results suggest that only a large sample comprising more than 50,000 subjects may be sufficiently powered to detect genes for depressive symptoms.
PMCID: PMC3845085  PMID: 23290196
Center for Epidemiologic Studies Depression Scale; CHARGE consortium; depression; depressive symptoms; genetics; genome-wide association study; meta-analysis
Biological psychiatry  2012;73(5):399-405.
We examined the effect of the novel Alzheimer's disease (AD) risk variant rs11136000 single nucleotide polymorphism (SNP) in the clusterin gene (CLU) on longitudinal changes in resting state regional cerebral blood flow (rCBF) during normal aging and investigated its influence on cognitive decline in pre-symptomatic stages of disease progression.
Subjects were participants in the Baltimore Longitudinal Study of Aging. A subset of 88 cognitively normal older individuals had longitudinal 15O-water PET measurements of rCBF at baseline and up to 8 annual follow-up visits. We also analyzed trajectories of cognitive decline among CLU risk carriers and non-carriers both in individuals who remained cognitively normal (N=599) as well as in those who subsequently converted to mild cognitive impairment (MCI) or AD (N=95).
Cognitively normal carriers of the CLU risk allele show significant and dose-dependent longitudinal increases in resting state rCBF in brain regions intrinsic to memory processes. There were no differences in trajectories of memory performance between CLU risk carriers and non-carriers who remained cognitively normal. However, in cognitively normal individuals who eventually convert to MCI or AD, CLU risk carriers show faster rates of decline in memory performance relative to non-carriers in the pre-symptomatic stages of disease progression.
The AD risk variant CLU influences longitudinal changes in brain function in asymptomatic individuals and is associated with faster cognitive decline in pre-symptomatic stages of disease progression. These results suggest mechanisms underlying the role of CLU in AD and may be important in monitoring disease progression in at-risk elderly.
PMCID: PMC3488132  PMID: 22795969
Clusterin; single nucleotide polymorphism; Alzheimer's disease; 15O-water PET; cerebral blood flow; memory

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