The effect of missing data and imputation on the detection of bias in cognitive testing using differential item functioning methods.

BACKGROUND: Item response theory (IRT) methods for addressing differential item functioning (DIF) can detect group differences in responses to individual items (e.g., bias). IRT and DIF-detection methods have been used increasingly often to identify bias in cognitive test performance by characteristics (DIF grouping variables) such as hearing impairment, race, and educational attainment. Previous analyses have not considered the effect of missing data on inferences, although levels of missing cognitive data can be substantial in epidemiologic studies. METHODS: We used data from Visit 6 (2016-2017) of the Atherosclerosis Risk in Communities Neurocognitive Study (N = 3,580) to explicate the effect of artificially imposed missing data patterns and imputation on DIF detection. RESULTS: When missing data was imposed among individuals in a specific DIF group but was unrelated to cognitive test performance, there was no systematic error. However, when missing data was related to cognitive test performance and DIF group membership, there was systematic error in DIF detection. Given this missing data pattern, the median DIF detection error associated with 10%, 30%, and 50% missingness was -0.03, -0.08, and -0.14 standard deviation (SD) units without imputation, but this decreased to -0.02, -0.04, and -0.08 SD units with multiple imputation. CONCLUSIONS: Incorrect inferences in DIF testing have downstream consequences for the use of cognitive tests in research. It is therefore crucial to consider the effect and reasons behind missing data when evaluating bias in cognitive testing.

Assessing Bias in Cognitive Testing for Older Adults with Sensory Impairment: An Analysis of Differential Item Functioning in the Baltimore Longitudinal Study on Aging (BLSA) and the Atherosclerosis Risk in Communities Neurocognitive Study (ARIC-NCS).

OBJECTIVES: Vision and hearing impairments affect 55% of people aged 60+ years and are associated with lower cognitive test performance; however, tests rely on vision, hearing, or both. We hypothesized that scores on tests that depend on vision or hearing are different among those with vision or hearing impairments, respectively, controlling for underlying cognition. METHODS: Leveraging cross-sectional data from the Baltimore Longitudinal Study of Aging (BLSA) and the Atherosclerosis Risk in Communities Neurocognitive Study (ARIC-NCS), we used item response theory to test for differential item functioning (DIF) by vision impairment (better eye presenting visual acuity worse than 20/40) and hearing impairment (better ear .5-4 kHz pure-tone average > 25 decibels). RESULTS: We identified DIF by vision impairment for tests whose administrations do not rely on vision [e.g., Delayed Word Recall both in ARIC-NCS: .50 logit difference between impaired and unimpaired (p = .04) and in BLSA: .62 logits (p = .02)] and DIF by hearing impairment for tests whose administrations do not rely on hearing [Digit Symbol Substitution test in BLSA: 1.25 logits (p = .001) and Incidental Learning test in ARIC-NCS: .35 logits (p = .001)]. However, no individuals had differences between unadjusted and DIF-adjusted measures of greater than the standard error of measurement. CONCLUSIONS: DIF by sensory impairment in cognitive tests was independent of administration characteristics, which could indicate that elevated cognitive load among persons with sensory impairment plays a larger role in test performance than previously acknowledged. While these results were unexpected, neither of these samples are nationally representative and each has unique selection factors; thus, replication is critical.

Metabolomics and cognition in African American adults in midlife: the atherosclerosis risk in communities study.

Clinical studies have shown alterations in metabolic profiles when patients with mild cognitive impairment and Alzheimer's disease dementia were compared to cognitively normal subjects. Associations between 204 serum metabolites measured at baseline (1987-1989) and cognitive change were investigated in 1035 middle-aged community-dwelling African American participants in the biracial Atherosclerosis Risk in Communities (ARIC) Study. Cognition was evaluated using the Delayed Word Recall Test (DWRT; verbal memory), the Digit Symbol Substitution Test (DSST; processing speed) and the Word Fluency Test (WFT; verbal fluency) at visits 2 (1990-1992) and 4 (1996-1998). In addition, Cox regression was used to analyze the metabolites as predictors of incident hospitalized dementia between baseline and 2011. There were 141 cases among 1534 participants over a median 17.1-year follow-up period. After adjustment for established risk factors, one standard deviation increase in N-acetyl-1-methylhistidine was significantly associated with greater 6-year change in DWRT scores (ß=-0.66 words; P=3.65 × 10-4). Two metabolites (one unnamed and a long-chain omega-6 polyunsaturated fatty acid found in vegetable oils (docosapentaenoate (DPA, 22:5 n-6)) were significantly associated with less decline on the DSST (DPA: ß=1.25 digit-symbol pairs, P=9.47 × 10-5). Two unnamed compounds and three sex steroid hormones were associated with an increased risk of dementia (all P<3.9 × 10-4). The association of 4-androstene-3beta, 17beta-diol disulfate 1 with dementia was replicated in European Americans. These results demonstrate that screening the metabolome in midlife can detect biologically plausible biomarkers that may improve risk stratification for cognitive impairment at older ages.

Somatic, positive and negative domains of the Center for Epidemiological Studies Depression (CES-D) scale: a meta-analysis of genome-wide association studies.

BACKGROUND: Major depressive disorder (MDD) is moderately heritable, however genome-wide association studies (GWAS) for MDD, as well as for related continuous outcomes, have not shown consistent results. Attempts to elucidate the genetic basis of MDD may be hindered by heterogeneity in diagnosis. The Center for Epidemiological Studies Depression (CES-D) scale provides a widely used tool for measuring depressive symptoms clustered in four different domains which can be combined together into a total score but also can be analysed as separate symptom domains. METHOD: We performed a meta-analysis of GWAS of the CES-D symptom clusters. We recruited 12 cohorts with the 20- or 10-item CES-D scale (32 528 persons). RESULTS: One single nucleotide polymorphism (SNP), rs713224, located near the brain-expressed melatonin receptor (MTNR1A) gene, was associated with the somatic complaints domain of depression symptoms, with borderline genome-wide significance (p discovery = 3.82 × 10-8). The SNP was analysed in an additional five cohorts comprising the replication sample (6813 persons). However, the association was not consistent among the replication sample (p discovery+replication = 1.10 × 10-6) with evidence of heterogeneity. CONCLUSIONS: Despite the effort to harmonize the phenotypes across cohorts and participants, our study is still underpowered to detect consistent association for depression, even by means of symptom classification. On the contrary, the SNP-based heritability and co-heritability estimation results suggest that a very minor part of the variation could be captured by GWAS, explaining the reason of sparse findings.

Vitamin D, vitamin D binding protein gene polymorphisms, race and risk of incident stroke: the Atherosclerosis Risk in Communities (ARIC) study.

BACKGROUND AND PURPOSE: Low vitamin D levels, measured by serum 25-hydroxyvitamin D [25(OH)D], are associated with increased stroke risk. Less is known about whether this association differs by race or D binding protein (DBP) single nucleotide polymorphism (SNP) status. Our objective was to characterize the associations of and interactions between 25(OH)D levels and DBP SNPs with incident stroke. It was hypothesized that associations of low 25(OH)D with stroke risk would be stronger amongst persons with genotypes associated with higher DBP levels. METHODS: 25(OH)D was measured by mass spectroscopy in 12 158 participants in the Atherosclerosis Risk in Communities (ARIC) study (baseline 1990-1992, mean age 57 years, 57% female, 23% black) and they were followed through 2011 for adjudicated stroke events. Two DBP SNPs (rs7041, rs4588) were genotyped. Cox models were adjusted for demographic/behavioral/socioeconomic factors. RESULTS: During a median of 20 years follow-up, 804 incident strokes occurred. The lowest quintile of 25(OH)D (<17.2 ng/ml) was associated with higher stroke risk [hazard ratio (HR) 1.34 (1.06-1.71) versus highest quintile]; this association was similar by race (P interaction 0.60). There was weak evidence of increased risk of stroke amongst those with 25(OH)D < 17.2 ng/ml and either rs7041 TG/GG [HR = 1.29 (1.00-1.67)] versus TT genotype [HR = 1.19 (0.94-1.52)] (P interaction 0.28) or rs4588 CA/AA [HR = 1.37 (1.07-1.74)] versus CC genotype [HR = 1.14 (0.91-1.41)] (P interaction 0.11). CONCLUSIONS: Low 25(OH)D is a risk factor for stroke. Persons with low 25(OH)D who are genetically predisposed to high DBP (rs7041 G, rs4588 A alleles), who therefore have lower predicted bioavailable 25(OH)D, may be at greater risk for stroke, although our results were not conclusive and should be interpreted as hypothesis generating.

Vitamin D and cognitive function and dementia risk in a biracial cohort: the ARIC Brain MRI Study.

BACKGROUND AND PURPOSE: Some recent studies in older, largely white populations suggest that vitamin D, measured by 25-hydroxyvitamin D [25(OH)D], is important for cognition, but such results may be affected by reverse causation. Measuring 25(OH)D in late middle age before poor cognition affects behavior may provide clearer results. METHODS: This was a prospective cohort analysis of 1652 participants (52% white, 48% black) in the Atherosclerosis Risk in Communities (ARIC) Brain MRI Study. 25(OH)D was measured from serum collected in 1993-1995. Cognition was measured by the delayed word recall test (DWRT), the digit symbol substitution test (DSST) and the word fluency test (WFT). Dementia hospitalization was defined by ICD-9 codes. Adjusted linear, logistic and Cox proportional hazards models were used. RESULTS: Mean age of participants was 62 years and 60% were female. Mean 25(OH)D was higher in whites than blacks (25.5 vs. 17.3 ng/ml, P < 0.001). Lower 25(OH)D was not associated with lower baseline scores or with greater DWRT, DSST or WFT decline over a median of 3 or 10 years of follow-up (P > 0.05). Over a median of 16.6 years, there were 145 incident hospitalized dementia cases. Although not statistically significant, lower levels of 25(OH)D were suggestive of an association with increased dementia risk [hazard ratio for lowest versus highest race-specific tertile: whites 1.32 (95% confidence interval 0.69, 2.55); blacks 1.53 (95% confidence interval 0.84, 2.79)]. CONCLUSIONS: In contrast to prior studies performed in older white populations, our study of late middle age white and black participants did not find significant associations between lower levels of 25(OH)D with lower cognitive test scores at baseline, change in scores over time or dementia risk.

Cognitive decline and oral health in middle-aged adults in the ARIC study.

Even before dementia becomes apparent, cognitive decline may contribute to deterioration in oral health. This cohort study of middle-aged adults evaluated associations of six-year change in cognitive function with oral health behaviors and conditions in the Atherosclerosis Risk in Communities (ARIC) study. Cognitive function was measured at study visits in 1990-1992 and 1996-1998 with three tests: (a) Delayed Word Recall (DWR), (b) Digit Symbol Substitution (DSS), and (c) Word Fluency (WF). Cognitive decline scores were computed as 'studentized' residuals of 1996-1998 scores regressed against 1990-1992 scores. In 1996-1998, 10,050 participants answered dental screening questions, and 5,878 of 8,782 dentate participants received a comprehensive oral examination. Multiple regression models used cognitive change to predict oral health behaviors and conditions with adjustment for covariates. In the fully adjusted models, greater decline in all three measures of cognitive function was associated with increased odds of complete tooth loss. Greater decline in DSS and WF scores was associated with infrequent toothbrushing. Decline in WF scores was also associated with higher plaque levels. In these middle-aged adults, six-year cognitive decline was modestly associated with less frequent toothbrushing, plaque deposit, and greater odds of edentulism, but not with other oral behaviors or diseases.

Do systolic BP and pulse pressure relate to ventricular enlargement?

BACKGROUND AND PURPOSE: To evaluate the association between systolic, diastolic and pulse pressure, and increase in ventricular size (VS). Observations in laboratory animals suggest intraventricular pulse pressure (systolic-diastolic) may play a role in ventricular enlargement. METHODS: Initial magnetic resonance (MR) scans and vascular risk factors evaluation were performed in 1812 Atherosclerosis Risk in Communities participants in 1994-1995. In 2004-2006, 1130 participants underwent repeat MR. VS was rated using a validated nine-point scale. Multiple logistic regression analysis assessed association between blood pressure measures and pulse pressure, and the change between the MR scans of VS controlling for age, sex and race. RESULTS: At baseline 1112 participants (385 black women, 200 black men, 304 white women and 223 white men) had a mean age of 61.7 ± 4.3 years. In adjusted models pulse pressure at baseline was associated with an increase in VS [odds ratio (OR) 1.19, 95% confidence interval (CI) 1.01-1.40], as was systolic pressure (OR 1.28, 95% CI 1.03-1.58). CONCLUSIONS: Systolic pressure and pulse pressure are associated with future development of increased VS. The findings are consistent with the animal literature that increased pulse pressure predisposes to risk of future increased VS. High pulse pressure might play a role in the pathogenesis of normal pressure hydrocephalus.

Risk factors for lacune subtypes in the Atherosclerosis Risk in Communities (ARIC) Study.

OBJECTIVE: Lacunar infarctions are mainly due to 2 microvascular pathologies: lipohyalinosis and microatheroma. Little is known about risk factor differences for these subtypes. We hypothesized that diabetes and glycated hemoglobin (HbA(1)c) would be related preferentially to the lipohyalinotic subtype. METHODS: We performed a cross-section analysis of the brain MRI data from 1,827 participants in the Atherosclerosis Risk in Communities study. We divided subcortical lesions ≤ 20 mm in diameter into those ≤ 7 mm (of probable lipohyalinotic etiology) and 8-20 mm (probably due to microatheroma) and used Poisson regression to investigate associations with the number of each type of lesion. Unlike previous studies, we also fitted a model involving lesions <3 mm. RESULTS: Age (prevalence ratio [PR] 1.11 per year; 95% confidence interval [CI] 1.08-1.14), black ethnicity (vs white, PR 1.66; 95% CI 1.27-2.16), hypertension (PR 2.12; 95% CI 1.61-2.79), diabetes (PR 1.42; 95% CI 1.08-1.87), and ever-smoking (PR 1.34; 95% CI 1.04-1.74) were significantly associated with lesions ≤ 7 mm. Findings were similar for lesions <3 mm. HbA(1)c, substituted for diabetes, was also associated with smaller lesions. Significantly associated with 8-20 mm lesions were age (PR 1.14; 95% CI 1.09-1.20), hypertension (PR 1.79; 95% CI 1.14-2.83), ever-smoking (PR 2.66; 95% CI 1.63-4.34), and low-density lipoprotein (LDL) cholesterol (PR 1.27 per SD; 95% CI 1.06-1.52). When we analyzed only participants with lesions, history of smoking (PR 1.99; 95% CI 1.23-3.20) and LDL (PR 1.33 per SD; 95% CI 1.08-1.65) were associated with lesions 8-20 mm. CONCLUSIONS: Smaller lacunes (even those <3 mm) were associated with diabetes and HbA(1)c, and larger lacunes associated with LDL cholesterol, differences which support long-held theories relating to their underlying pathology. The findings may contribute to broader understanding of cerebral microvascular disease.

Vascular risk factors and longitudinal changes on brain MRI: the ARIC study.

OBJECTIVE: To evaluate associations between vascular risk factors and changes in burden of infarcts, ventricular size (VS), sulcal widening (SW), and white matter hyperintensities (WMH) in an initially middle-aged, biracial cohort from the Atherosclerosis Risk in Communities (ARIC) study. METHODS: Initial brain magnetic resonance (MR) scans and evaluations for vascular risk factors were performed in 1,812 ARIC participants in 1994-1995. In 2004-2006, 1,130 ARIC participants underwent repeat MR scans. MR scans were rated using a validated 9-point scale for VS, SW, and WMH. Infarcts were recorded. Multiple logistic regression analysis was used to assess associations between vascular risk factors and change between MR scans of one or more grades in VS, SW, WMH, or appearance of new infarcts, controlling for age, sex, and race. RESULTS: At baseline, the 1,112 participants with usable scans (385 black women, 200 black men, 304 white women, 223 white men) had a mean age of 61.7 ± 4.3 years. In adjusted models, diabetes at baseline was associated with incident infarcts (odds ratio [OR] 1.95, 95% confidence interval [CI] 1.29-2.95) and worsening SW (OR 2.10, 95% CI 1.36-3.24). Hypertension at baseline was associated with incident infarcts (OR 1.73, 95% CI 1.23-2.42). In subjects with the highest tertile of fasting blood sugar and systolic blood pressure at baseline, the risk of incident infarcts was 3.68 times higher (95% CI 1.89-7.19) than those in the lowest tertile for both. CONCLUSION: Both atrophic and ischemic imaging changes were driven by altered glycemic and blood pressure control beginning in midlife.

Association of lung function with cognitive decline and dementia: the Atherosclerosis Risk in Communities (ARIC) Study.

BACKGROUND: Previous studies reported a higher risk of cognitive decline and dementia amongst individuals with impaired lung function. However, many did not adjust for important confounders or did not include women and non-whites. METHODS: We studied 10,975 men and women aged 47-70 years (23% African-Americans) enrolled in the Atherosclerosis Risk in Communities Study. Pulmonary function tests and a cognitive assessment, including the Delayed Word Recall, the Digit Symbol Substitution, and the World Fluency Tests, were carried out in 1990-1992. Repeated cognitive assessments were performed in 1996-1998 for the entire cohort, and in 1993-1995, and 2004-2006 in 904 eligible individuals. Dementia hospitalization was ascertained through 2005. RESULTS: In analysis adjusted for lifestyles, APOE genotype, and cardiovascular risk factors, impaired lung function was associated with worse cognitive function at baseline. No association was found between lung function and cognitive decline over time. Impaired lung function at baseline was associated with higher risk of dementia hospitalization during follow-up, particularly amongst younger individuals. The hazard ratios (95% confidence intervals) of dementia hospitalization were 1.6 (0.9, 2.8) and 2.1 (1.2, 3.7) comparing the lowest with the highest quartile of forced expiratory volume in 1 s and forced vital capacity, respectively. Presence of a restrictive ventilatory pattern, but not of an obstructive pattern, was associated with reduced cognitive scores and higher dementia risk. CONCLUSION: Reduced lung function was associated with worse performance in cognitive assessments and with an increased risk of dementia hospitalization. Future research should determine whether maintaining optimal pulmonary health might prevent cognitive impairment and dementia.

Plasma C-terminal pro-endothelin-1 is associated with left ventricular mass index and aortic root diameter in African-American adults with hypertension.

Endothelin-1 (ET-1), a circulating vasoactive peptide with potent vasoconstricting and mitogenic properties, may contribute to target-organ damage in hypertension. We investigated whether plasma levels of C-terminal pro-endothelin-1 (CT-pro-ET-1) are associated with left ventricular (LV) mass and aortic root diameter in African-American adults with hypertension. Plasma CT-pro-ET-1 was measured by an immunoluminometric assay in 1041 African Americans (65±9 years, 72% women) with hypertension. LV mass and aortic root diameter were measured according to the American Society of Echocardiography guidelines, and LV mass was indexed by height to the power 2.7 (LVMi). Multivariable regression analyses were used to assess whether plasma CT-pro-ET-1 was associated with LVMi and aortic root diameter, independent of potential confounding variables. Plasma CT-pro-ET-1 was modestly correlated with LVMi (r=0.21, P<0.0001) and aortic root diameter (r=0.09, P=0.004). In separate multivariable regression models that adjusted for age, sex, body mass index, total and high-density lipoprotein cholesterol, smoking history, diabetes, history of myocardial infarction or stroke, and blood pressure-lowering medication and statin use, log CT-pro-ET-1 was significantly associated with greater LVMi (P=0.001) and larger aortic root diameter (P=0.006). CT-pro-ET-1 is independently associated with LVMi and aortic root diameter and may be a marker of target-organ damage in African-Americans adults with hypertension.

Retinal microvascular abnormalities and cognitive decline: the ARIC 14-year follow-up study.

BACKGROUND: Because retinal and cerebral arterioles share similar pathologic processes, retinal microvascular changes are expected to be markers of cerebral small vessel disease (SVD). To better understand the role of SVD in cognitive function, we investigated the relationship between retinal microvascular abnormalities and longitudinal changes in cognitive function in a community-based study. METHODS: A total of 803 participants underwent 4 cognitive assessments between 1990-1992 and 2004-2006, using the Word Fluency (WF) test, Digit Symbol Substitution (DSS), and Delayed Word Recall as well as retinal photography in 1993-1995. Covariate adjusted random effects linear models for repeated measures were used to determine the associations of cognitive change with specific retinal vascular abnormalities. RESULTS: Individuals with retinopathy showed declines in executive function and psychomotor speed, with 1) an average decline in WF of -1.64 words per decade (95% confidence interval [CI] -3.3, -0.02) compared to no decline in those without retinopathy +0.06 (95% CI -0.6, 0.8) and 2) a higher frequency of rapid decliners on the DSS test. CONCLUSION: Signs of retinal vascular changes, as markers of the cerebral microvasculature, are associated with declines in executive function and psychomotor speed, adding to the growing evidence for the role of microvascular disease in cognitive decline in the elderly.

Risk of dementia hospitalisation associated with cardiovascular risk factors in midlife and older age: the Atherosclerosis Risk in Communities (ARIC) study.

BACKGROUND: Cardiovascular risk factors are associated with a higher risk of developing dementia. Studies in older populations, however, have often failed to show this relationship. We assessed the association between cardiovascular risk factors measured in midlife and risk of being hospitalised with dementia and determined whether this association was modified by age and ethnicity. METHODS: We studied 11 151 participants in the population-based Atherosclerosis Risk in Communities cohort, aged 46-70 (23% African-Americans) in 1990-2, when participants underwent a physical exam and cognitive testing. Hospitalisations with dementia were ascertained through December 2004. RESULTS: During follow-up, 203 cases of hospitalisation with dementia were identified. Smoking (hazard ratio (HR), 95% CI 1.7, 1.2 to 2.5), hypertension (HR, 95% CI 1.6, 1.2 to 2.2) and diabetes (HR, 95% CI 2.2, 1.6 to 3.0) were strongly associated with dementia, in Caucasians and African-Americans. These associations were stronger when risk factors were measured at a younger age than at an older age. In analyses including updated information on risk factors during follow-up, the HR of dementia in hypertensive versus non-hypertensive participants was 1.8 at age <55 years compared with 1.0 at age 70+ years. Parallel results were observed for diabetes (HR 3.4 in <55, 2.0 in >or=70), smoking (4.8 in <55, 0.5 in >or=70) and hypercholesterolaemia (HR 1.7 in <55, 0.9 in >or=70) CONCLUSION: In this prospective study, smoking, hypertension and diabetes were strongly associated with subsequent risk of hospitalisation with dementia, particularly in middle-aged individuals. Our results emphasise the importance of early lifestyle modification and risk factor treatment to prevent dementia.

Haemostatic markers are associated with measures of vascular disease in adults with hypertension.

Haemostatic markers have been implicated in the development and progression of vascular disease. We investigated the associations of several haemostatic markers (fibrinogen, D-dimer, FV, FVII, FVIII, von Willebrand factor (vWF) and antithrombin III) with two quantitative measures of vascular disease in adults with hypertension. Participants included 1051 African Americans (65+/-9 years, 72% women) and 894 non-Hispanic whites (61+/-9 years, 55% women) belonging to hypertensive sibships. Phenotypes of vascular disease included the ankle-brachial index (ABI), a measure of peripheral arterial disease, and urinary albumin/creatinine ratio (UACR), a surrogate of glomerular endothelial function. Generalized estimating equations were used to assess whether plasma levels of haemostatic markers were associated with measures of arteriosclerosis, after adjustment for conventional risk factors and medication (statin, aspirin and oestrogen) use. Higher fibrinogen and D-dimer were significantly associated with lower ABI in African Americans (P<0.001 and 0.004 respectively) and in non-Hispanic whites (P<0.001 and 0.010 respectively). Higher fibrinogen (P<0.001), D-dimer (P=0.003), FVIII (P<0.001) and vWF (P<0.001) were significantly associated with higher UACR in African Americans, whereas, in non-Hispanic whites, higher fibrinogen (P=0.020) and FVII (P=0.006) were significantly associated with higher UACR. Our findings indicate that in adults with essential hypertension, several markers in the haemostatic pathway are independently associated with ABI and UACR, two measures of vascular disease..

African-American ethnicity is associated with higher plasma levels of D-dimer in adults with hypertension.

BACKGROUND: African Americans with hypertension have higher cardiovascular morbidity and mortality than hypertensives from other ethnic groups. Plasma D-dimer, a fragment generated from fibrin during lysis of mature clot in vivo, is a predictor of adverse cardiovascular events. OBJECTIVE: We investigated whether plasma levels of D-dimer differ between African American (AA) and non-Hispanic white (NHW) adults with hypertension. METHODS: Participants included 933 AA (65 +/- 9 years, 72% women) and 821 NHW (61 +/- 9 years, 56% women) from the community. D-dimer was measured using an immunoturbidimetric assay. Multivariable regression analyses, stratified by gender, were performed to assess whether AA ethnicity was associated with D-dimer levels after adjustment for age, body mass index (BMI), total and high-density lipoprotein (HDL) cholesterol, systolic blood pressure, diabetes, history of smoking, medication (statin and aspirin) use, lifestyle variables (physical activity, alcohol intake, and education), estimated glomerular filtration rate (eGFR), and a marker of inflammation, C-reactive protein (CRP). RESULTS: D-dimer levels were higher in AA men and women than in their NHW counterparts (mean +/- SD; men 256 +/- 199 vs. 190 +/- 183 ng mL(-1), P < 0.001; women, 290 +/- 233 vs. 225 +/- 195 ng mL(-1), P < 0.001). In both sexes, after adjustment for age, conventional risk factors, medication use, and lifestyle variables, AA ethnicity remained associated with higher D-dimer levels (P = 0.002 in men, P = 0.006 in women). These associations remained significant after additional adjustment for eGFR and plasma CRP (P = 0.003 in men, P < 0.0001 in women). CONCLUSIONS: Among adults with hypertension, AA ethnicity was independently associated with higher plasma levels of D-dimer.

Genomic regions that influence plasma levels of inflammatory markers in hypertensive sibships.

We carried out univariate and bivariate linkage analyses to identify genomic regions that may influence plasma levels of C-reactive protein (CRP) and fibrinogen and exert pleiotropic effects on both traits. Subjects included African American (AA, n=1310, mean age 62.7+/-9.4 years) and non-Hispanic white (NHW, n=796, mean age 58.4+/-9.8 years) belonging to hypertensive sibships. Plasma CRP was measured by an immunoturbidimetric assay and fibrinogen by the Clauss method. Genotyping was performed at 366 microsatellite marker loci spaced approximately 10 cM apart across the 22 autosomes. Estimation of heritability and linkage analyses was carried out using a variance components approach. Significant heritability was noted for CRP (0.38 in AA and 0.37 in NHW subjects) and fibrinogen (0.44 in AA and 0.28 in NHW subjects). Significant genetic correlation between CRP and fibrinogen was present in both AA (0.39) and NHW (0.40) subjects. In univariate linkage analysis, the maximum logarithm of odds (LOD) score for CRP was on chromosome 10q22 in NHW (LOD=1.69, 106.75 cM, P=0.0026) and for fibrinogen on chromosome 2 in AA (LOD=2.14, 55.5 cM, P=0.0009) subjects. Bivariate linkage analysis demonstrated suggestive evidence of linkage (defined as LOD score >or= 2.87) for both traits on chromosome 12 (LOD=3.44, 152.16 cM, P=0.0003) in AA and on chromosome 21 (LOD=3.03, 13.05 cM, P=0.0008) in NHW subjects. Plasma CRP and fibrinogen levels are heritable and genetically correlated. Linkage analyses identified several chromosomal regions that may harbour genes influencing CRP and fibrinogen levels and exert pleiotropic effects on both traits.

Cerebral MRI findings and cognitive functioning: the Atherosclerosis Risk in Communities study.

OBJECTIVE: To examine the association between prevalent cerebral abnormalities identified on MRI and cognitive functioning in a predominantly middle-aged, population-based study cohort. METHODS: Cerebral MRI was performed on 1,538 individuals (aged 55 to 72) from the Atherosclerosis Risk in Communities (ARIC) cohort, with no history of stroke or TIA, at study sites in Forsyth County, NC, and Jackson, MS. White matter hyperintensities (WMHs), ventricular size, and sulcal size were graded by trained neuroradiologists on a semiquantitative, 10-point scale. Cognitive functioning was assessed using the Delayed Word Recall Test (DWRT), Digit Symbol Substitution Test (DSST), and Word Fluency Test (WFT). RESULTS: High ventricular grade was independently associated with significantly lower scores on the DWRT and DSST and greater risk (odds ratio [OR] 2.32, 95% confidence interval [CI] 1.51 to 3.56) of impaired scores (i.e., < or =10th percentile) on the DWRT. High sulcal grade was associated with a modest decrement in scores on the DWRT. The presence of coexisting high grade WMHs and silent infarcts was independently associated with lower scores on all cognitive tests and greater risk of impaired functioning on the DSST (OR 2.91, 95% CI: 1.23 to 6.89) and WFT (OR 2.28, 95% CI 1.03 to 5.08). The presence of two or more high-grade abnormalities was associated with increased risk of impaired functioning on all cognitive tests (DWRT: OR 2.23, 95% CI 1.40 to 3.55; DSST: OR 2.06, 95% CI 1.13 to 3.76; WFT: OR 2.07, 95% CI 1.23 to 3.49) independent of multiple covariates and silent infarcts. CONCLUSION: Common changes in brain morphology are associated with diminished cognitive functioning in middle-aged and young-elderly individuals.

APOE genotype and cognitive decline in a middle-aged cohort.

BACKGROUND: Most longitudinal studies of nondemented persons have reported greater cognitive decline among APOE epsilon4 carriers vs noncarriers. However, most studies involved elderly samples (aged 65+) and were not large enough to examine the three APOE alleles separately. METHODS: Change in cognitive function was examined over a 6-year period using three neuropsychological tests among four APOE genotype groups (epsilon2/2 + epsilon2/3, epsilon3/3 (referent), epsilon4/2 + epsilon4/3, epsilon4/4). The population-based sample included 1,693 African Americans and 6,202 Caucasians initially ages 47 to 68. RESULTS: There was increasingly greater cognitive decline from the epsilon2 group to the epsilon4/4 group in Caucasians for two of the three tests. The combination of APOE epsilon4 with hypercholesterolemia or diabetes showed the greatest cognitive decline. Among African Americans, only the test measuring psychomotor speed showed associations with APOE genotype. CONCLUSIONS: APOE epsilon4 is associated with greater cognitive decline in middle-aged Caucasian individuals, with a reduced decline among epsilon2 carriers. This suggests that the processes by which APOE genotype mediates dementia risk are operative well in advance of overt dementia.

Retinal microvascular changes and MRI signs of cerebral atrophy in healthy, middle-aged people.

OBJECTIVE: To examine the relation of retinal microvascular abnormalities and MRI signs of cerebral atrophy in healthy middle-aged people. METHODS: A population-based, cross-sectional study involved 1,684 persons aged 51 to 72 years who had cerebral MRI and retinal photography in 1993 to 1995. Sulcal and ventricular size were quantified from the MRI scans and coded as grades 0 to 9, with sulcal widening (SW) and ventricular enlargement (VE) defined as grades 3 or higher. The presence or absence of retinopathy, microaneurysms, hemorrhages, and other characteristics were defined from retinal photographs using a standardized protocol. Generalized arteriolar narrowing was defined from a computer-assisted measurement of arteriolar diameters from digitized photographs. RESULTS: Persons with retinopathy had higher sulcal (p = 0.001) and ventricular (p = 0.03) grades than persons without retinopathy. After adjusting for age, gender, race, mean arterial blood pressure, diabetes, cigarette smoking, common carotid artery intima-media thickness, and other vascular risk factors, retinopathy was significantly associated with SW (odds ratio [OR], 1.9; 95% CI, 1.2, 3.0) and VE (OR, 1.5; 95% CI, 1.0, 2.3). These associations persisted even in people without diabetes or hypertension (OR 1.9, 95% CI, 0.8, 4.4 for SW; OR 2.7, 95% CI, 1.2, 6.5 for VE). Other retinal arteriolar characteristics (arteriovenous nicking, focal and generalized arteriolar narrowing) were not related to sulcal or ventricular grade. CONCLUSIONS: In healthy, middle-aged people, retinopathy is independently associated with sulcal and ventricular enlargement on MRI. This finding is compatible with the hypothesis that microvascular characteristics may influence the development of cerebral atrophic changes.