Ellen S. O'Meara

Cognitive Impairment and Decline Are Associated with Carotid Artery Disease in Patients without Clinically Evident Cerebrovascular Disease

Context While stroke is a known cause of cognitive impairment, the relationship between carotid artery stenosis and cognitive function in people without a history of stroke is unclear. Contribution In this study of 4006 right-handed individuals 65 years of age and older, left-sided carotid artery stenosis of at least 75% was associated with cognitive impairment at baseline and cognitive decline over 5 years. This association persisted after right-sided carotid stenosis and cardiovascular risk factors were taken into account, which means that left-sided stenosis is more than simply an indicator of cardiovascular disease. Cautions This observational study does not constitute evidence that treatment of left-sided stenosis would benefit cognition. The Editors Cognitive impairment is common in elderly persons, with a prevalence of 25% in those 65 years of age or older and 65% in those 85 years of age or older (1). It is associated with disability, institutionalization, and early death (2, 3). Cerebral infarction contributes to cognitive impairment in approximately 50% of cases (3), sometimes in conjunction with Alzheimer disease (4). Imaging studies of the brain may reveal infarction in patients without history of stroke or transient ischemic attack (5), and these silent infarctions have been associated with cognitive impairment (5, 6). Furthermore, brain hypoperfusion may result in ischemic injury without evidence of infarction (7). Thus, silent cerebral infarction and brain hypoperfusion may be important causes of cognitive impairment. Markers of atherosclerotic disease of the internal carotid artery and common carotid artery have been associated with brain injury. High-grade stenosis of the internal carotid artery accounts for 20% to 30% of ischemic strokes (8). Stenosis of the internal carotid artery and intimamedia thickness of the internal and common carotid arteries are associated with silent cerebral infarction and symptomatic infarctions that are ipsilateral or contralateral to the side of maximal disease (9-11). Some studies have suggested that stenosis of the internal carotid artery may be a risk factor for cognitive impairment even in persons without a history of stroke, but other studies have not demonstrated such an association (12). Small samples, variable definitions of internal carotid artery stenosis, and case selection may have contributed to these inconsistent results. Carotid artery disease is also associated with underlying vascular disease and its risk factors. Hypertension, diabetes mellitus, cigarette smoking, and dyslipidemia are associated with an increased risk for carotid artery disease (13, 14), but these same risk factors may also cause ischemic injury to the brain independent of carotid disease (15). Furthermore, several risk factors for vascular disease are associated with cognitive impairment (16-25). This may be because carotid artery disease causes cognitive impairment, or because it is a marker for underlying risk factors and vascular disease that are themselves the cause. Epidemiologic studies have not distinguished between these possibilities (12). The distinction is important because a direct intervention, such as endarterectomy, may prevent cognitive decline if a measure of carotid artery disease is associated with a cause of decline, whereas if the disease measure is a marker for underlying risk factors, treatment of the risk factors might be more appropriate. The effect of medical or surgical management of left carotid artery disease on cognitive function has not been specifically evaluated. The Modified Mini-Mental State Examination (26, 27) primarily measures cognitive function in the dominant cerebral hemisphere (28), which is the left hemisphere in more than 98% of right-handed persons (29). Results of the Modified Mini-Mental State Examination and the similar, more familiar Mini-Mental State Examination are often normal in right-handed patients with right hemispheric strokes or mass lesions (28, 30, 31). If carotid artery disease is a cause of cognitive impairment as measured by the Modified Mini-Mental State Examination, impairment should be associated with left-sided disease but not right-sided disease. Because both arteries should be affected equally by systemic vascular risk factors, a causal association should persist after adjustment for right-sided disease and for vascular risk factors. Alternatively, if measures of carotid artery disease are markers for underlying risk factors for vascular disease, measures of both left and right carotid disease should be similarly associated with cognitive impairment. We hypothesized that high-grade stenosis of the left, but not the right, internal carotid artery is a cause of cognitive impairment as measured by the Modified Mini-Mental State Examination in right-handed persons and that an association would persist after adjustment for contralateral stenosis and risk factors for vascular disease. We also hypothesized that intimamedia thickness of both the left and right common carotid artery would be associated with cognitive impairment because we assumed that intimamedia thickness was a marker for underlying vascular disease and its risk factors rather than a direct cause of cerebral ischemia and cognitive impairment. Methods Sample The Cardiovascular Health Study is an observational, prospective study of men and women 65 years of age or older drawn from 4 U.S. communities: Sacramento County, California; Allegheny County, Pennsylvania; Washington County, Maryland; and Forsyth County, North Carolina. Participants were enrolled by random sampling of Medicare eligibility lists. The Cardiovascular Health Study enrolled 5201 participants in 1989 to 1990 and an additional 687 African-American participants in 1992 to 1993. Annual clinic examinations were conducted during follow-up. Details of recruitment into (32) and design of (33) the Cardiovascular Health Study are reported elsewhere. The study was approved by the institutional review board at each site, and all participants gave informed consent. We restricted our analysis to right-handed participants. Participants were classified as right-handed if they reported using their right hand to brush their teeth and throw a ball and were observed to write with their right hand. We excluded participants with a history of stroke, transient ischemic attack, or carotid endarterectomy as of the 19921993 examination, on the basis of self-report at study entry and surveillance during follow-up (34, 35). Data Collection The baseline examination included standard questionnaires about medical and personal history and an array of physical and laboratory evaluations (33). Testing for the apolipoprotein E 4 (ApoE 4) genotype was done in participants who consented to genetic research. Ultrasonography of the carotid arteries was performed at the 19921993 examination. Measurements were standardized among field centers and were interpreted centrally by readers who were blinded to clinical information (13, 36). The left and right common and internal carotid arteries were imaged longitudinally by using high-resolution B-mode ultrasonography. The intimamedia thickness of the common carotid artery was defined as the mean of the maximum intimamedia thicknesses of the near and far walls. Pulsed-wave Doppler frequency spectra were used to measure the peak systolic flow velocity in each internal carotid artery. Stenosis of the internal carotid artery lumen of 50% to 74% was defined as peak flow velocity of 1.5 to 2.5 m/s, and stenosis of 75% to 99% as peak velocity of 2.5 m/s or greater. No flow indicated 100% stenosis. Stenosis of 0%, 1% to 24%, or 25% to 49% was estimated visually from imaging data. Inter-reader agreement in measures of carotid disease was assessed by comparing ratings from different reviewers for more than 4800 ultrasonograms. Agreement in measurement of internal carotid artery stenosis was high ( = 0.68 for a cut-point of 75% stenosis), as was measurement of common carotid artery intimamedia thickness (Spearman rank correlation coefficient = 0.72). Cognitive function was measured annually by using the Modified Mini-Mental State Examination. Higher scores indicate greater cognitive function. Cognitive impairment was defined as a score of less than 80 of 100 points (37). The Digit Symbol Substitution Test (number of correct answers in 90 seconds) was used as a secondary measure of cognitive function (38). This test measures function in both cerebral hemispheres but is thought to be more dramatically affected by left-sided injuries. Impairment was defined as a score of less than 19; this cut-point was chosen at 1.5 SDs below the mean score. Cranial magnetic resonance imaging was performed at the 19921994 examinations. Infarct on magnetic resonance imaging was defined as an area with abnormal signal intensity in a vascular distribution, without mass effect (39). Outcome Measures We examined the association between asymptomatic carotid artery disease and cognitive impairment in a cross-sectional analysis based on data from the 19921993 examination and in a longitudinal analysis of cognitive decline during 5 years of follow-up. Carotid artery measures of primary interest were the degree of internal carotid artery stenosis and quartiles of intimamedia thickness of the common carotid artery. Results are shown for participants with 75% or greater (high-grade) stenosis compared with those with no stenosis and participants in the fourth compared with the first quartile of intimamedia thickness. Statistical Analysis Characteristics were compared between carotid artery groups by using the chi-square test or the t-test. Cognitive scores were compared between carotid groups using the Wilcoxon rank-sum test. The average rate of cognitive decline was calculated for each participant by using linear regression, based on the slope of the line fitting all cognitive measures from baseline and follow-up. Thus

Risk Factors for Breast Cancer for Women Aged 40 to 49 Years: A Systematic Review and Meta-analysis

BACKGROUND Identifying risk factors for breast cancer specific to women in their 40s could inform screening decisions. PURPOSE To determine what factors increase risk for breast cancer in women aged 40 to 49 years and the magnitude of risk for each factor. DATA SOURCES MEDLINE (January 1996 to the second week of November 2011), Cochrane Central Register of Controlled Trials and Cochrane Database of Systematic Reviews (fourth quarter of 2011), Scopus, reference lists of published studies, and the Breast Cancer Surveillance Consortium. STUDY SELECTION English-language studies and systematic reviews of risk factors for breast cancer in women aged 40 to 49 years. Additional inclusion criteria were applied for each risk factor. DATA EXTRACTION Data on participants, study design, analysis, follow-up, and outcomes were abstracted. Study quality was rated by using established criteria, and only studies rated as good or fair were included. Results were summarized by using meta-analysis when sufficient studies were available or from the best evidence based on study quality, size, and applicability when meta-analysis was not possible. Data from the Breast Cancer Surveillance Consortium were analyzed with proportional hazards models by using partly conditional Cox regression. Reference groups for comparisons were set at U.S. population means. DATA SYNTHESIS Sixty-six studies provided data for estimates. Extremely dense breasts on mammography or first-degree relatives with breast cancer were associated with at least a 2-fold increase in risk for breast cancer. Prior breast biopsy, second-degree relatives with breast cancer, or heterogeneously dense breasts were associated with a 1.5- to 2.0-fold increased risk; current use of oral contraceptives, nulliparity, and age 30 years or older at first birth were associated with a 1.0- to 1.5-fold increased risk. LIMITATIONS Studies varied by measures, reference groups, and adjustment for confounders, which could bias combined estimates. Effects of multiple risk factors were not considered. CONCLUSION Extremely dense breasts and first-degree relatives with breast cancer were each associated with at least a 2-fold increase in risk for breast cancer in women aged 40 to 49 years. Identification of these risk factors may be useful for personalized mammography screening. PRIMARY FUNDING SOURCE National Cancer Institute.

Ginkgo biloba for preventing cognitive decline in older adults: a randomized trial.

CONTEXT The herbal product Ginkgo biloba is taken frequently with the intention of improving cognitive health in aging. However, evidence from adequately powered clinical trials is lacking regarding its effect on long-term cognitive functioning. OBJECTIVE To determine whether G. biloba slows the rates of global or domain-specific cognitive decline in older adults. DESIGN, SETTING, AND PARTICIPANTS The Ginkgo Evaluation of Memory (GEM) study, a randomized, double-blind, placebo-controlled clinical trial of 3069 community-dwelling participants aged 72 to 96 years, conducted in 6 academic medical centers in the United States between 2000 and 2008, with a median follow-up of 6.1 years. INTERVENTION Twice-daily dose of 120-mg extract of G. biloba (n = 1545) or identical-appearing placebo (n = 1524). MAIN OUTCOME MEASURES Rates of change over time in the Modified Mini-Mental State Examination (3MSE), in the cognitive subscale of the Alzheimer Disease Assessment Scale (ADAS-Cog), and in neuropsychological domains of memory, attention, visual-spatial construction, language, and executive functions, based on sums of z scores of individual tests. RESULTS Annual rates of decline in z scores did not differ between G. biloba and placebo groups in any domains, including memory (0.043; 95% confidence interval [CI], 0.034-0.051 vs 0.041; 95% CI, 0.032-0.050), attention (0.043; 95% CI, 0.037-0.050 vs 0.048; 95% CI, 0.041-0.054), visuospatial abilities (0.107; 95% CI, 0.097-0.117 vs 0.118; 95% CI, 0.108-0.128), language (0.045; 95% CI, 0.037-0.054 vs 0.041; 95% CI, 0.033-0.048), and executive functions (0.092; 95% CI, 0.086-0.099 vs 0.089; 95% CI, 0.082-0.096). For the 3MSE and ADAS-Cog, rates of change varied by baseline cognitive status (mild cognitive impairment), but there were no differences in rates of change between treatment groups (for 3MSE, P = .71; for ADAS-Cog, P = .97). There was no significant effect modification of treatment on rate of decline by age, sex, race, education, APOE*E4 allele, or baseline mild cognitive impairment (P > .05). CONCLUSION Compared with placebo, the use of G. biloba, 120 mg twice daily, did not result in less cognitive decline in older adults with normal cognition or with mild cognitive impairment. TRIAL REGISTRATION clinicaltrials.gov Identifier: NCT00010803.

Association of Gene Variants With Incident Myocardial Infarction in the Cardiovascular Health Study

Objective—We asked whether single nucleotide polymorphisms (SNPs) that had been nominally associated with cardiovascular disease in antecedent studies were also associated with cardiovascular disease in a population-based prospective study of 4522 individuals aged 65 or older. Methods and Results—Based on antecedent studies, we prespecified a risk allele and an inheritance model for each of 74 SNPs. We then tested the association of these SNPs with myocardial infarction (MI) in the Cardiovascular Health Study (CHS). The prespecified risk alleles of 8 SNPs were nominally associated (1-sided P<0.05) with increased risk of MI in White CHS participants. The false discovery rate for these 8 was 0.43, suggesting that about 4 of these 8 are likely to be true positives. The 4 of these 8 SNPs that had the strongest evidence for association with cardiovascular disease before testing in CHS (association in 3 antecedent studies) were in KIF6 (CHS HR=1.29; 90%CI 1.1 to 1.52), VAMP8 (HR=1.2; 90%CI 1.02 to 1.41), TAS2R50 (HR=1.13; 90%CI 1 to 1.27), and LPA (HR=1.62; 90%CI 1.09 to 2.42). Conclusions—Although most of the SNPs investigated were not associated with MI in CHS, evidence from this investigation combined with previous studies suggests that 4 of these SNPs are likely associated with MI.

Genetic ancestry in lung-function predictions

BACKGROUND Self-identified race or ethnic group is used to determine normal reference standards in the prediction of pulmonary function. We conducted a study to determine whether the genetically determined percentage of African ancestry is associated with lung function and whether its use could improve predictions of lung function among persons who identified themselves as African American. METHODS We assessed the ancestry of 777 participants self-identified as African American in the Coronary Artery Risk Development in Young Adults (CARDIA) study and evaluated the relation between pulmonary function and ancestry by means of linear regression. We performed similar analyses of data for two independent cohorts of subjects identifying themselves as African American: 813 participants in the Health, Aging, and Body Composition (HABC) study and 579 participants in the Cardiovascular Health Study (CHS). We compared the fit of two types of models to lung-function measurements: models based on the covariates used in standard prediction equations and models incorporating ancestry. We also evaluated the effect of the ancestry-based models on the classification of disease severity in two asthma-study populations. RESULTS African ancestry was inversely related to forced expiratory volume in 1 second (FEV(1)) and forced vital capacity in the CARDIA cohort. These relations were also seen in the HABC and CHS cohorts. In predicting lung function, the ancestry-based model fit the data better than standard models. Ancestry-based models resulted in the reclassification of asthma severity (based on the percentage of the predicted FEV(1)) in 4 to 5% of participants. CONCLUSIONS Current predictive equations, which rely on self-identified race alone, may misestimate lung function among subjects who identify themselves as African American. Incorporating ancestry into normative equations may improve lung-function estimates and more accurately categorize disease severity. (Funded by the National Institutes of Health and others.)

Biomarkers of Inflammation and MRI-Defined Small Vessel Disease of the Brain The Cardiovascular Health Study

Background and Purpose— To clarify the role of inflammation in the pathogenesis of small vessel disease of the brain, we investigated the association between common variation in the C-reactive protein (CRP) and interleukin (IL)-6 genes, plasma CRP and IL6 levels, and presence of MRI-defined white matter lesions (WML) and brain infarcts (BI) in elderly participants of the Cardiovascular Health Study. Methods— Tag single nucleotide polymorphisms (SNPs) in the CRP and IL6 genes were selected from the SeattleSNPs database. In cross-sectional analyses, logistic regression models adjusting for known cardiovascular disease risk factors were constructed to assess the associations of plasma CRP and IL6 levels and common CRP and IL6 gene haplotypes with presence of WML or BI in Blacks (n=532) and Whites (n=2905). Results— Plasma IL6 and CRP levels were associated with presence of WML and BI in both races. In Whites, common haplotypes of the IL6 gene were significantly associated with WML and BI. The common haplotype tagged by the −174G/C promoter polymorphism was associated with an increased risk of WML (OR=1.14; 95% CI: [1.02; 1.28]). The common haplotype tagged by the −572G/C promoter polymorphism was associated with an increased risk of BI (OR=1.57; 95% CI: [1.15; 2.14]). Significant associations were lacking for WML or BI with IL6 gene variation in Blacks, or with CRP gene variation in either race. Conclusions— This study provides evidence of a genetic basis underlying the relationship between plasma biomarkers of inflammation and small vessel disease of the brain. Further studies to elucidate the specific role of IL6 in disease pathogenesis are warranted.

Subclinical atherosclerosis and the risk of future venous thrombosis in the Cardiovascular Health Study

Summary.  Background: Recent reports have suggested an association of atherosclerosis with risk of venous thrombosis. Objective: To confirm whether subclinical atherosclerosis is a risk factor for venous thrombosis (VT) among men and women age 65 and older. Methods: Participants of the Cardiovascular Health Study (n = 4108) without baseline clinical cardiovascular disease, anticoagulant use or previous VT were followed for a median of 11.7 years after non‐invasive assessment of subclinical atherosclerosis using carotid ultrasound (intima‐media thickness and presence of plaques), ankle‐brachial blood pressure index and electrocardiogram. Each event was classified as idiopathic or secondary. We used Cox proportional hazards regression to estimate the relative risk of overall and idiopathic VT for individuals with and without baseline subclinical atherosclerosis. Results: There were 133 first time VT events. No subclinical atherosclerosis measures were associated with increased risk of overall or idiopathic VT. The adjusted relative risks of overall and idiopathic VT for presence of any type of subclinical disease were 0.60 (95% confidence interval 0.39–0.91) and 0.32 (0.18–0.59), respectively. Most of this association was explained by an inverse association of high‐risk carotid plaques (prevalent in 54% of those at risk) with VT. Conclusion: Non‐invasively measured subclinical atherosclerosis was not associated with increased risk of overall or idiopathic VT in this observational study. Carotid plaques and arterial events during follow up were inversely associated, a finding that requires further study.

Coagulation factors IX through XIII and the risk of future venous thrombosis: the Longitudinal Investigation of Thromboembolism Etiology.

Higher levels of procoagulant factors and factor XII deficiency may be risk factors for first venous thromboembolism (VTE). We studied associations of coagulation factors IX through XIII with risk of future VTE in 2 general population samples. Using a nested case-control study combining the 21 860 participants of the Atherosclerosis Risk in Communities study and the Cardiovascular Health Study, we determined antigenic levels of these coagulation factors in primarily pre-event blood samples from 462 participants who subsequently developed VTE and 1047 participants who remained free of VTE. Only elevated levels of factors IX and XI were associated with increased risk of VTE after adjustment for age, sex, race, and study. For factor IX, the odds ratio (OR) was 1.4 (95% confidence interval [CI], 1.0-2.0) comparing the top to bottom quintile. The OR for factor XI was higher: 2.0 (95% CI, 1.4-2.9). With further adjustment for body mass index and diabetes, only elevated factor XI remained associated with VTE risk: OR 1.8 (95% CI, 1.3-2.7). Associations were similar by study and whether the thrombosis was idiopathic or secondary. Factor XII deficiency was not related to VTE risk. Among these procoagulant factors, only elevated factor XI was a risk factor for VTE.

Cross-Sectional and Longitudinal Associations of Neighborhood Cohesion and Stressors with Depressive Symptoms in the Multiethnic Study of Atherosclerosis

PURPOSE This study examined associations of neighborhood social cohesion, violence, and aesthetic quality with depressive symptoms among 2,619 healthy adults aged 45-84 years enrolled in the Multiethnic Study of Atherosclerosis. METHODS Neighborhood characteristics were estimated by surveying a separate sample of area residents. Measures of aesthetic environment, social cohesion, and violence were combined into a summary score with increasing scores indicating more favorable environments. Depressive symptoms were measured using the Center for Epidemiologic Studies-Depression (CES-D) scale. Marginal maximum likelihood estimation was used to assess associations of neighborhood characteristics with CES-D score at baseline and with the odds of developing incident depression (CES-D score >/=16 or use of antidepressants) over a 4-5 year follow-up among persons with CES-D less than 16 at baseline. Models were adjusted for age, income, education, and race/ethnicity. RESULTS Lower levels of social cohesion and aesthetic quality and higher levels of violence were associated with higher mean CES-D scores in men and women (P for trend <0.01, adjusted mean difference in CES-D per 1 SD increase in summary score -1.01 [95% confidence interval = -1.85, -0.17] and -1.08 [95% confidence interval = -1.88, -0.28] in men and women, respectively). Associations of neighborhood characteristics with incident depression were in the expected direction for women but confidence intervals were wide (odds ratio of incident depression = 0.89 [0.63, 1.26]). No association was seen for men (odds ratio = 0.96 [0.74, 1.25]). CONCLUSION Neighborhood social cohesion, aesthetic quality, and violence are associated with the presence of depressive symptoms in residents.

Weight, mortality, years of healthy life, and active life expectancy in older adults

OBJECTIVES: To determine whether weight categories predict subsequent mortality and morbidity in older adults.