Coronary heart disease (CHD) is the major cause of death in the United States. Coronary artery calcification (CAC) scores are independent predictors of CHD. African Americans (AA) have higher rates of CHD but are less well-studied in genomic studies. We assembled the largest AA data resource currently available with measured CAC to identify associated genetic variants.
We analyzed log transformed CAC quantity (ln(CAC + 1)), for association with ~2.5 million single nucleotide polymorphisms (SNPs) and performed an inverse-variance weighted meta-analysis on results for 5,823 AA from 8 studies. Heritability was calculated using family studies. The most significant SNPs among AAs were evaluated in European Ancestry (EA) CAC data; conversely, the significance of published SNPs for CAC/CHD in EA was queried within our AA meta-analysis.
Heritability of CAC was lower in AA (~30%) than previously reported for EA (~50%). No SNP reached genome wide significance (p < 5E-08). Of 67 SNPs with p < 1E-05 in AA there was no evidence of association in EA CAC data. Four SNPs in regions previously implicated in CAC/CHD (at 9p21 and PHACTR1) in EA reached nominal significance for CAC in AA, with concordant direction. Among AA, rs16905644 (p = 4.08E-05) had the strongest association in the 9p21 region.
While we observed substantial heritability for CAC in AA, we failed to identify loci for CAC at genome-wide significant levels despite having adequate power to detect alleles with moderate to large effects. Although suggestive signals in AA were apparent at 9p21 and additional CAC and CAD EA loci, overall the data suggest that even larger samples and an ethnic specific focus will be required for GWAS discoveries for CAC in AA populations.
Atherosclerosis; Coronary artery calcium; Genetics; Meta-analysis; African-American
This report provides practical recommendations for the design and execution of Multi-Center functional Magnetic Resonance Imaging (MC-fMRI) studies based on the collective experience of the Function Biomedical Informatics Research Network (FBIRN). The paper was inspired by many requests from the fMRI community to FBIRN group members for advice on how to conduct MC-fMRI studies. The introduction briefly discusses the advantages and complexities of MC-fMRI studies. Prerequisites for MC-fMRI studies are addressed before delving into the practical aspects of carefully and efficiently setting up a MC-fMRI study. Practical multi-site aspects include: (1) establishing and verifying scan parameters including scanner types and magnetic fields, (2) establishing and monitoring of a scanner quality program, (3) developing task paradigms and scan session documentation, (4) establishing clinical and scanner training to ensure consistency over time, (5) developing means for uploading, storing, and monitoring of imaging and other data, (6) the use of a traveling fMRI expert and (7) collectively analyzing imaging data and disseminating results. We conclude that when MC-fMRI studies are organized well with careful attention to unification of hardware, software and procedural aspects, the process can be a highly effective means for accessing a desired participant demographics while accelerating scientific discovery.
Functional magnetic resonance imaging; fMRI; multi-center; multi-site; FIRST Biomedica Informatics Research Network; FBIRN
The cholesteryl ester transport protein (CETP) plays a key role in high-density lipoprotein (HDL) metabolism. Genetic variants that alter CETP activity and concentration may cause significant alterations in HDL-cholesterol (HDL-C) concentration; however, controversies remain about whether these genetic variants are associated with atherosclerosis. We genotyped the CETP R451Q, A373P, -629C/A, Taq1B, and -2505C/A polymorphisms in a cohort of Caucasian, Chinese, African-American, and Hispanic individuals within the Multi-Ethnic Study of Atherosclerosis. Genotypes were examined in relationship to HDL-C, CETP activity, CETP concentration, and three measures of subclinical cardiovascular disease (CVD): coronary artery calcium (CAC) measured by fast CT scanning, and carotid intimal-medial thickness (IMT) and carotid artery plaque, measured by ultrasonography. Carriers of the 451Q and 373P alleles have significantly higher CETP concentration (22.4% and 19.5%, respectively; p<0.001) and activity (13.1% and 9.4%, respectively; p<0.01) and lower HDL-C (5.6% and 6.0%, respectively; p<0.05). The minor alleles of the R451Q and A373P polymorphisms are associated with the presence of CAC, even after adjusting for CVD risk factors and HDL-C (p=0.006 and p=0.01, respectively). The R451Q polymorphism is also associated with presence of carotid artery plaque (p=0.036). Neither polymorphism is associated with common or internal carotid IMT. We confirmed that the -629A, Taq1B B2, and -2505A alleles are significantly associated with lower CETP concentration (20.8%, 25.0%, and 23.7%, respectively; p<0.001) and activity (14.8%, 19.8%, and 18.4%, respectively; p<0.001) and higher HDL-C concentration (9.7%, 11.5%, and 10.4%, respectively; p<0.01). However, we did not find any associations between these non-coding polymorphisms and subclinical CVD.
CETP; CVD; HDL; MESA
Adolescence is associated with a dramatic increase in risky and impulsive behaviors that have been attributed to developmental differences in neural processing of rewards. In the present study, we sought to identify age differences in anticipation of absolute and relative rewards. To do so, we modified a commonly used monetary incentive delay (MID) task in order to examine brain activity to relative anticipated reward value (neural sensitivity to the value of a reward as a function of other available rewards). This design also made it possible to examine developmental differences in brain activation to absolute anticipated reward magnitude (the degree to which neural activity increases with increasing reward magnitude). While undergoing fMRI, 18 adolescents and 18 adult participants were presented with cues associated with different reward magnitudes. After the cue, participants responded to a target to win money on that trial. Presentation of cues was blocked such that two reward cues associated with $.20, $1.00, or $5.00 were in play on a given block. Thus, the relative value of the $1.00 reward varied depending on whether it was paired with a smaller or larger reward. Reflecting age differences in neural responses to relative anticipated reward (i.e., reference dependent processing), adults, but not adolescents, demonstrated greater activity to a $1 reward when it was the larger of the two available rewards. Adults also demonstrated a more linear increase in ventral striatal activity as a function of increasing absolute reward magnitude compared to adolescents. Additionally, reduced ventral striatal sensitivity to absolute anticipated reward (i.e., the difference in activity to medium versus small rewards) correlated with higher levels of trait Impulsivity. Thus, ventral striatal activity in anticipation of absolute and relative rewards develops with age. Absolute reward processing is also linked to individual differences in Impulsivity.
Marijuana (MJ) acutely acts on cannabinoid receptors that are found in numerous brain regions, including those involved in reward processing and decision-making. However, it remains unclear how long-term, chronic MJ use alters reward-based decision-making. In the present study, using [15O]water PET imaging, we measured brain activity in chronic MJ users, who underwent monitored abstinence from MJ for approximately 24 h before imaging, and control participants, while they took part in the Iowa Gambling Task (IGT), a monetary decision making task that strongly relies on the ventromedial prefrontal cortex (vmPFC). During PET imaging, participants took part in the standard and a variant version of the IGT as well as a control task. Chronic MJ users performed equally well on the standard IGT, but significantly worse than controls on the variant IGT. Chronic MJ users and control subjects showed increased regional cerebral blood flow (rCBF) in the vmPFC on both versions of the IGT compared to the control task. In the two-group comparison, chronic MJ users showed significantly greater rCBF than controls in the vmPFC on the standard IGT and greater activity in the cerebellum on both versions of the IGT. Furthermore, duration of use, but not age of first use, was associated with greater activity in the vmPFC. Thus, chronic MJ users tend to strongly recruit neural circuitry involved in decision-making and reward processing (vmPFC), and probabilistic learning (cerebellum) when performing the IGT.
marijuana; decision-making; ventromedial prefrontal cortex; chronic use; cerebellum; PET; addiction & substance abuse; cannabinoids; cognition; decision-making; imaging; clinical or preclinical; PET; prefrontal cortex
Carotid artery intima-media thickness (IMT) is a marker of cardiovascular disease associated with incident stroke. We study whether IMT rate-of-change is associated with stroke.
Materials and Methods
We studied 5028 participants of the Multi-Ethnic Study of Atherosclerosis (MESA) composed of whites, Chinese, Hispanic and African-Americans free of cardiovascular disease. In this MESA IMT progression study, IMT rate-of-change (mm/year) was the difference in right common carotid artery (CCA) far-wall IMT (mm) divided by the interval between two ultrasound examinations (median interval of 32 months). CCA IMT was measured in a region free of plaque. Cardiovascular risk factors and baseline IMT were determined when IMT rate-of-change was measured. Multivariable Cox proportional hazards models generated Hazard risk Ratios (HR) with cardiovascular risk factors, ethnicity and education level/income as predictors.
There were 42 first time strokes seen during a mean follow-up of 3.22 years (median 3.0 years). Average age was 64.2 years, with 48% males. In multivariable models, age (HR: 1.05 per year), systolic blood pressure (HR 1.02 per mmHg), lower HDL cholesterol levels (HR: 0.96 per mg/dL) and IMT rate-of-change (HR 1.23 per 0.05 mm/year; 95% C.L. 1.02, 1.48) were significantly associated with incident stroke. The upper quartile of IMT rate-of-change had an HR of 2.18 (95% C.L.: 1.07, 4.46) compared to the lower three quartiles combined.
Common carotid artery IMT progression is associated with incident stroke in this cohort free of prevalent cardiovascular disease and atrial fibrillation at baseline.
Ultrasonography; Risk Factors; Carotid Arteries; Carotid Intima Media Thickness; stroke
Common carotid artery inter-adventitial diameter (IAD) and intima-media thickness (IMT) are measurable by ultrasound. IAD may be associated with left ventricular mass (LV mass) while IMT is a marker of subclinical atherosclerosis. It is not clear if IAD is associated with LV mass after accounting for IMT and traditional cardiovascular risk factors.
IAD and IMT were measured on participants of the Multi-Ethnic Study of Atherosclerosis (MESA) IMT progression study. A total of 5641 of the originally enrolled 6814 MESA participants were studied. LV mass was measured by magnetic resonance imaging. Multivariable linear regression was used with IAD as the outcome and adjustment for risk factors, as well as IMT and LV mass.
Traditional cardiovascular risk factors, height, weight and ethnicity were significantly associated with IAD. After adjustment for risk factors, a one mm difference in IMT was associated with a 1.802 mm (95% CI: 1.553, 2.051) higher mean IAD. A one gm difference in LV mass was associated with a 0.006 mm (95% CI: 0.005, 0.007) higher mean IAD. LV mass was independently associated with IAD after adjusting for cardiovascular risk factors and IMT. These associations were slightly different for men and women.
Inter-adventitial diameters are associated with left ventricular mass after adjusting for cardiovascular risk factors and IMT. IAD might serve as a surrogate for left ventricular mass and have predictive value for cardiovascular outcomes.
carotid arteries; ultrasonics; hypertrophy; magnetic resonance imaging; remodeling; risk factors; left ventricle
The JUPITER trial demonstrated that some patients with LDL-C <130 mg/dL and hsCRP ≥2 mg/L benefit from rosuvastatin, although absolute event rates were low. We sought to determine whether coronary artery calcium (CAC) may further risk stratify a JUPITER-eligible population, and to compare hsCRP vs. CAC for risk prediction in otherwise JUPITER-eligible participants.
A total of 950 MESA participants met all JUPITER entry criteria. We compared CHD and CVD event rates and multivariable-adjusted hazard ratios after stratifying by both presence and burden of CAC (0, 1–100, >100). We also calculated 5-year number needed to treat (NNT5) by applying the benefit observed in JUPITER to the observed event rates within each CAC strata.
Median follow-up was 5.8 years. Approximately 47% of the MESA JUPITER population had CAC=0, and CHD event rates in this group were <1 per 1000 person-years. Over 2/3 of all CHD events occurred in the 25% of participants with CAC >100 (20.2 per 1000 person-years). For CHD, the predicted NNT5 for CAC 0, 1–100, and >100 was 549, 94, and 24 respectively. For CVD, the NNT5 was 124, 54, and 19. Amongst otherwise JUPITER-eligible patients, presence of CAC was associated with 4.3-fold increased CHD (95% CI 2.0 – 9.3) and 2.6-fold increased CVD (95% CI 1.5–4.5), while hsCRP was not associated with either CHD or CVD after multivariable adjustment.
Within MESA, approximately half of JUPITER-eligible participants had CAC=0 and experienced an extremely low 6-year event rate. Nearly all events occurred in patients with CAC. CAC appears to further risk stratify JUPITER-eligible patients and may be used to target a subgroup of patients expected to derive the most, and the least, absolute benefit from statin treatment. Focusing treatment on the subset of individuals with measurable atherosclerosis may represent a more appropriate allocation of resources.
hsCRP; CAC; and Clinical Events
Common carotid artery intima-media thickness (IMT), a measure of subclinical cardiovascular disease, changes during the cardiac cycle. The magnitude of this effect and its implications have not been well studied.
Methods and Results
Far-wall IMT measurements of the right common carotid artery were measured at end diastole and peak systole in 5633 individuals from the Multi-Ethnic Study of Atherosclerosis (MESA). Multivariable regression models were generated with end-diastolic IMT, peak-systolic IMT, and change in IMT during the cardiac cycle as dependent variables and traditional cardiovascular risk factors as independent variables. The average age of our population was 61.9 (45 to 84) years. Average change in carotid IMT during the cardiac cycle was 0.041 mm (95% confidence interval: 0.039 to 0.042 mm), with a mean IMT of 0.68 mm. End-diastolic IMT and peak-systolic IMT were similarly associated with risk factors. In a fully adjusted model, change in carotid IMT during the cardiac cycle was associated with ethnicity and pulse pressure (P=0.001) and not age, sex, or other risk factors. Chinese and Hispanics had less of a change in IMT than did non-Hispanic whites. With peak-systolic IMT reference values used as normative data, 31.3% more individuals were classified as being in the upper quartile of IMT and at high risk for cardiovascular disease than would be expected when IMT is measured at end diastole.
Measurable differences in IMT are seen during the cardiac cycle. This affects the interpretation of IMT measurements used for cardiovascular risk assessment, given published normative data with IMT measured at peak systole.
Clinical Trial Registration
URL: www.ClinicalTrials.gov. Unique identifier: NCT00063440. (J Am Heart Assoc. 2012;1:e001420 doi: 10.1161/JAHA.112.001420.)
atherosclerosis; blood pressure; carotid arteries; diastole; epidemiology; risk factors; systole; ultrasonics
Carotid intima-media thickness (IMT) is a marker of cardiovascular disease derived from ultrasound images of the carotid artery. In most outcome studies, human readers identify and trace the key IMT interfaces. We evaluate an alternate approach using automated edge detection.
We study a subset of 5640 participants with an average age 61.7 years (48% men) of the Multi-Ethnic Study of Atherosclerosis composed of whites, Chinese, Hispanic and African-Americans that are part of the MESA IMT progression study. Manual tracing IMT (mt_IMT) and edge-detected IMT (ed_IMT) measurements of the far wall of the common carotid artery (CCA) served as outcome variables for multivariable linear regression models using Framingham cardiovascular risk factors and ethnicity as independent predictors.
Measurements of mt_IMT was obtainable in 99.9% (5633/5640) and of ed_IMT in 98.9% (5579/5640) of individuals. Average ed_IMT was 0.19 mm larger than mt_IMT. Inter-reader systematic differences (bias) in IMT measurements were apparent for mt_IMT but not ed_IMT. Based on complete data on 5538 individuals, associations of IMT with risk factors were stronger (p < 0.0001) for mt_IMT (model r2: 19.5%) than ed_IMT (model r2: 18.5%).
We conclude that this edge-detection process generates IMT values equivalent to manually traced ones since it preserves key associations with cardiovascular risk factors. It also decreases inter-reader bias, potentially making it applicable for use in cardiovascular risk assessment.
Ultrasonography; Risk Factors; Carotid Arteries; Carotid Intima Media Thickness
High-sensitivity C-reactive protein (hsCRP) levels are closely associated with abdominal obesity, metabolic syndrome, and atherosclerotic cardiovascular disease. The JUPITER trial has encouraged using hsCRP ≥2 mg/L to guide statin therapy; however the association of hsCRP to atherosclerosis, independent of obesity, remains unknown.
Methods and Results
We studied 6,760 participants from the Multi-Ethnic Study of Atherosclerosis (MESA). Participants were stratified into 4 groups: non-obese/low hsCRP, non-obese/high hsCRP, obese/low hsCRP, and obese/high hsCRP. Using multivariable logistic and robust linear regression, we described the association with subclinical atherosclerosis, using coronary artery calcium (CAC) and carotid intima-media thickness (cIMT). Mean BMI was 28.3 ± 5.5 kg/m2, and median hsCRP was 1.9 mg/L (0.84 – 4.26). High hsCRP, in the absence of obesity, was not associated with CAC and was mildly associated with cIMT. Obesity was strongly associated with CAC and cIMT independent of hsCRP. When obesity and high hsCRP were both present, there was no evidence of multiplicative interaction. Similar associations were seen among 2,083 JUPITER-eligible individuals.
High hsCRP, as defined by JUPITER, was not associated with CAC and was mildly associated with cIMT in the absence of obesity. In contrast, obesity was associated with both measures of subclinical atherosclerosis independent of hsCRP status.
obesity; hsCRP; high sensitivity C-reactive protein; subclinical atherosclerosis; coronary artery calcium; carotid intima-media thickness
Persons with diabetic retinopathy (DR) have an increased risk of clinical cardiovascular events. Our study aimed to determine whether DR is associated with a range of measures of subclinical cardiovascular disease (CVD) in persons without clinical CVD.
Population-based, cross-sectional epidemiologic study
Nine hundred and twenty seven persons with diabetes without clinical CVD in the Multi-Ethnic Study of Atherosclerosis.
DR was ascertained from retinal photographs according to modification of the Airlie House Classification system. Vision threatening DR (VTDR) was defined as severe non-proliferative DR, proliferative DR or clinically significant macular edema. Subclinical CVD measures were assessed and defined as follows: high coronary artery calcium (CAC) score, defined as CAC score≥400; low ankle-brachial index (ABI), defined as ABI<0.9; high ABI, defined as ABI≥1.4; high carotid intima-media thickness (IMT), defined as highest 25% of IMT; and carotid stenosis, defined as >25% stenosis or presence of carotid plaque.
MAIN OUTCOME MEASURES
Associations between DR and subclinical CVD measures.
The prevalence of DR and VTDR in this sample was 30.0% and 7.2%, respectively. VTDR was associated with a high CAC score (odds ratio [OR] 2.33, 95% condifence interval [CI] 1.15–4.73), low ABI (OR 2.54; 95%CI, 1.08–5.99) and high ABI (OR 12.6, 95% CI, 1.14, 140.6), after adjusting for risk factors including hemoglobin A1c level and duration of diabetes. The association between VTDR and high CAC score remained significant after further adjustment for hypoglycemic, anti-hypertensive and cholesterol-lowering medications. DR was not significantly associated with measures of carotid artery disease.
In persons with diabetes without a history of clinical CVD, the presence of advanced stage of DR is associated with subclinical coronary artery disease. These findings emphasize the need to be careful about the use of anti-vascular endothelial growth factor for the treatment of DR.
The role of atherosclerosis in the acute coronary syndromes (ACS) that occur in patients with rheumatoid arthritis (RA) has not been quantified in detail. We determined the extent to which ACS are associated with carotid atherosclerosis in RA.
We prospectively ascertained ACS, defined as myocardial infarction, unstable angina, cardiac arrest or death due to ischemic heart disease in an RA cohort. We measured carotid atherosclerosis using high-resolution ultrasound. We used Cox proportional hazards models to estimate the association between ACS and atherosclerosis, adjusting for demographics, CV risk factors, and RA manifestations.
We performed carotid ultrasound on 636 patients, whom we followed 3,402 person-years. During this time, 84 patients experienced 121 new or recurrent ACS, a rate of 3.5 ACS per 100 patient-years (95% CI 3.0, 4.3). Among the 599 patients without prior history of ACS, 66 incident ACS occurred over 3,085 person-years, an incidence of 2.1 ACS per 100 person-years (95% CI 1.7, 2.7). The incidence of new ACS per 100 patient-years among patients without plaque was 1.1 (0.6, 1.7); with unilateral plaque 2.5 (1.7, 3.8); and with bilateral plaque 4.3 (2.9, 6.3). Covariates associated with incident ACS independent of atherosclerosis included male sex, diabetes mellitus, and a cumulative glucocorticoid dose of ≥ 20 grams. In addition, hypertension and the number of swollen joints were associated with new or recurrent ACS.
Atherosclerosis is strongly associated with ACS in RA. Patients with carotid plaque, multiple CV risk factors, particularly diabetes or hypertension, many swollen joints, high cumulative dose of glucocorticoids or who are men, are at high risk of ACS.
Rheumatoid Arthritis; Cardiovascular Risk Factors; Atherosclerosis; Systemic Inflammation; Carotid Intima-media Thickness
This study investigated the long-term effects of intensive diabetic treatment on the progression of atherosclerosis, measured as common carotid artery intima-media thickness (IMT).
RESEARCH DESIGN AND METHODS
A total of 1,116 participants (52% men) in the Epidemiology of Diabetes Interventions and Complications (EDIC) trial, a long-term follow-up of the Diabetes Control and Complications Trial (DCCT), had carotid IMT measurements at EDIC years 1, 6, and 12. Mean age was 46 years, with diabetes duration of 24.5 years at EDIC year 12. Differences in IMT progression between DCCT intensive and conventional treatment groups were examined, controlling for clinical characteristics, IMT reader, and imaging device.
Common carotid IMT progression from EDIC years 1 to 6 was 0.019 mm less in intensive than in conventional (P < 0.0001), and from years 1 to 12 was 0.014 mm less (P = 0.048); but change from years 6 to 12 was similar (intensive − conventional = 0.005 mm, P = 0.379). Mean A1C levels during DCCT and DCCT/EDIC were strongly associated with progression of IMT, explaining most of the differences in IMT progression between DCCT treatment groups. Albuminuria, older age, male sex, smoking, and higher systolic blood pressure were significant predictors of IMT progression.
Intensive treatment slowed IMT progression for 6 years after the end of DCCT but did not affect IMT progression thereafter (6–12 years). A beneficial effect of prior intensive treatment was still evident 13 years after DCCT ended. These differences were attenuated but not negated after adjusting for blood pressure. These results support the early initiation and continued maintenance of intensive diabetes management in type 1 diabetes to retard atherosclerosis.
Previous research has demonstrated an increase in carotid intima–media thickness (cIMT) in HIV-infected individuals compared to controls. However, the reason for this increased level of subclinical vascular disease is unknown.
To identify HIV-related risk factors for increased cIMT.
We evaluated the relationship between HIV-related characteristics (including markers of HIV disease severity and use of antiretroviral therapy) and cIMT measurements in the internal/bulb and common carotid regions among 538 HIV-infected participants from the Study of Fat Redistribution and Metabolic Change in HIV Infection (FRAM). We used Bayesian model averaging to estimate the posterior probability of candidate HIV and non-HIV-related risk factors being true predictors of increased cIMT. Variables with a posterior probability of more than 50% were used to develop a selected regression model for each of the anatomic regions.
For common cIMT, the Bayesian model selection process identified age, African-American race, and systolic and diastolic blood pressure with probability more than 95%, HDL cholesterol with probability 85% and Hispanic ethnicity with probability 51%. Among the HIV-related factors included in the analysis, only tenofovir use was selected (51% probability). In the selected model, duration of tenofovir use was associated with lower common cIMT (−0.0094 mm/year of use; 95% confidence interval: −0.0177 to −0.0010). For internal cIMT, no HIV-related risk factors were above the 50% posterior probability threshold.
We observed an inverse association between duration of tenofovir use and common carotid cIMT. Whether this association is causal or due to confounding by indication needs further investigation.
atherosclerosis; carotid intima–media thickness; HIV; tenofovir
Background and Purpose
We propose to study possible differences in the associations between risk factors for cardiovascular disease (myocardial infarction and stroke) and Carotid Intima-Media thickness (IMT) measurements made at three different levels of the carotid bifurcation. Methods: Cross-sectional study of a cohort of Whites and African Americans of both genders with mean age 45 years. Traditional cardiovascular risk factors were determined in cohort members. Carotid IMT was measured from high-resolution B-mode ultrasound images at three levels: the common carotid artery (CCA), the carotid artery bulb (Bulb) and the internal carotid artery (ICA). Associations with risk factors were evaluated by multivariate linear regression analyses.
Of 3258 who underwent carotid IMT measurements, CCA, Bulb, and ICA IMT were measured at all three separate levels in 3023 (92.7%). A large proportion of the variability of CCA IMT was explained by cardiovascular risk factors (26.8%) but less so for the Bulb (11.2%) and ICA (8.0%). Carotid IMT was consistently associated with age, LDL-cholesterol, smoking and hypertension in all segments. Associations with fasting glucose and diastolic blood pressure were stronger for CCA than for the other segments. Hypertension, diabetes and current smoking had qualitatively stronger associations with Bulb IMT, and LDL cholesterol with ICA IMT. Conclusion: In our cohort of relatively young white and African-American men and women, a greater proportion of the variability in common carotid IMT can be explained by traditional cardiovascular risk factors than for the carotid artery bulb and internal carotid arteries.
Carotid Intimal Medial Thickness; Risk Factors; Carotid Ultrasound
Despite the knowledge that many drugs affect men and women differently, few studies exploring the effects of marijuana use on cognition have included women. Findings from both animal and human studies suggest marijuana may have more marked effects in women. This study examined sex differences in the acute effects of marijuana on cognition in 70 (n= 35 male, 35 female) occasional users of marijuana. Tasks were chosen to tap a wide variety of cognitive domains affected by sex and/or marijuana including attention, cognitive flexibility, time estimation, and visuospatial processing. As expected, acute marijuana use impaired performance on selective and divided attention, time estimation, and cognitive flexibility. While there did not appear to be sex differences in marijuana's effects on cognition, women requested to discontinue the smoking session more often than men likely leading to an underestimation of differences. Further study of psychological differences in marijuana's effects on men and women following both acute and residual effects of marijuana is warranted.
acute effects; marijuana; cannabis; cognition; sex; gender
Relatively little is known about genetic determinants of cognitive dysfunction in schizophrenia. Recent studies suggest that a BDNF prodomain SNP, resulting in valine to methionine substitution, is associated with impaired declarative memory in healthy volunteers and in schizophrenia patients. These studies indicate that BDNFMet variant may mediate hippocampal cognitive functions by modulating intracellular trafficking and activity-dependent BDNF release. How this functional SNP affects other neurocognitive measures have not been examined. Its role in determining cognitive deficits in schizophrenia has not been systematically studied either.
To characterize the neurocognitive and brain morphometric phenotypic correlates of BDNF val66met polymorphism, and test the specificity of BDNFMet variant on cognitive dysfunction in schizophrenia.
Design, Setting and Participants
A comprehensive battery of standardized neuropsychological tests was administered to 144 healthy volunteers and 293 schizophrenia-spectrum disorder patients at a tertiary-care university hospital. Approximately two-thirds of the sample also underwent high-resolution MRI brain scans.
Main Outcome Measures
Genotype effects (Met-allele-carriers versus Val homozygotes) on five cognitive domain z-scores and MRI gray matter (GM) brain volume measures (Talairach-atlas based cerebral lobes and optimized voxel-based morphometry (VBM)) were examined using general linear models.
On verbal memory, there was a significant genotype effect but no genotype-by-diagnosis effects. In both patients and healthy volunteers, Met-allele-carriers had poorer verbal memory performance than their Val/Val counterparts. On visuospatial abilities, there were significant genotype and genotype-by-diagnosis effects. Met allele-associated visuospatial impairment was specific to patients, but not healthy volunteers. There were significant genotype effects on GM volumes within brain regions known to subserve these two cognitive domains, with Met-allele-carriers having smaller temporal and occipital lobar GM. Optimized VBM further suggests that parietal heteromodal cortical GM deficits may underlie visuospatial impairment in Met-allele-carrier patients.
We replicated the association between BDNFMet variant and poor medial temporal lobe-related memory performance. The consonance of our cognitive and brain morphology findings further suggests that BDNFMet variant may have a specific role in conferring visuospatial dysfunction in schizophrenia.
Mean maximum carotid intima-media thickness (CIMT) is associated with both coronary artery disease and cerebral thromboembolism. Thoracic aortic calcification (TAC) detected by computed tomography (CT) is also highly associated with vascular disease and cardiovascular risk. No previous study has examined the relationship between CIMT and TAC in a large patient cohort. We performed a cross-sectional study to determine whether, at baseline, there is a relationship between CIMT and CT-determined TAC score.
In the Multi-Ethnic Study of Atherosclerosis, the study cohort included a population based sample of four ethnic groups (Chinese, White, Hispanic and African-American) of 6814 women and men ages 45-84 years. After exclusion of 198 persons due to incomplete information, we compared results of 6616 participants with both CIMT and TAC. TAC was measured from the lower edge of the pulmonary artery bifurcation to the cardiac apex. CIMT at the common carotid artery site was represented as the mean maximal CIMT of the right and left near and far walls, respectively. Multivariable relative risk regression analysis was used to evaluate relationships between TAC and CIMT.
The prevalence of TAC was 28% (n=1846) and the mean maximum (±SD) CIMT was 0.87±0.19 mm. A higher prevalence of TAC was noted across increasing CIMT quartiles (1st: 12%, 2nd: 21%, 3rd: 30%, 4th: 49%, P<0.0001). One standard deviation increase in CIMT was associated with a 16% higher likelihood for presence of TAC after adjusting for demographics and cardiovascular disease (CVD) risk factors (95% CI: 1.12-1.26). In addition, individuals with CIMT in the highest quartile, as compared to those with CIMT in the first quartile, had a 76% higher likelihood for presence of TAC (prevalence ratio [PR]: 1.76, 95% CI: 1.37-2.26). In race-ethnic stratified analyses, similar associations were seen in all groups. Among those with TAC>0, a higher CIMT was significantly associated with continuous TAC scores (log transformed) in the overall population as well as among all ethnic-racial groups.
Our study demonstrates that TAC is associated with increasing severity of carotid atherosclerotic burden as measured by CIMT. The combined utility of these two noninvasive measures of subclinical atherosclerosis for CVD risk assessment needs to be determined in future studies.
Atherosclerosis; carotid IMT; aortic calcification; ethnic; cardiac CT
In the United States, one in six teenagers has driven under the influence of marijuana. Driving under the influence of marijuana and alcohol is equally prevalent, despite the fact that marijuana use is less common than alcohol use. Much of the research examining the effects of marijuana on driving performance was conducted in the 1970s and led to equivocal findings. During that time, few studies included women and driving simulators were rudimentary. Further, the potency of marijuana commonly used recreationally has increased. This study examined sex differences in the acute effects of marijuana on driving performance using a realistic, validated driving simulator. Eighty-five subjects (n = 50 males, 35 females) participated in this between-subjects, double-blind, placebo controlled study. In addition to an uneventful, baseline segment of driving, participants were challenged with collision avoidance and distracted driving scenarios. Under the influence of marijuana, participants decreased their speed and failed to show expected practice effects during a distracted drive. No differences were found during the baseline driving segment or collision avoidance scenarios. No differences attributable to sex were observed. This study enhances the current literature by identifying distracted driving and the integration of prior experience as particularly problematic under the influence of marijuana.
acute effects; cannabis; cognition; driving; marijuana
We hypothesized that individuals with low 10-year but high lifetime cardiovascular disease (CVD) risk would have a greater burden of subclinical atherosclerosis than those with low 10-year but low lifetime risk.
Methods and Results
We included 2988 individuals age ≤50 at exam year 15 from the Coronary Artery Risk Development in Young Adults (CARDIA) study and 1076 individuals age ≤50 at study entry from the Multi-Ethnic Study of Atherosclerosis (MESA). The 10-year risk and lifetime risk for CVD were estimated for each participant, permitting stratification into three groups: low 10-year (<10%)/low lifetime (<39%) risk, low 10-year (<10%)/high lifetime risk (≥39%), and high 10-year risk (≥10%) or diagnosed diabetes. Baseline levels and change in levels of subclinical atherosclerosis (coronary artery calcium [CAC] or carotid intima-media thickness [IMT]) were compared across risk strata. Among participants with low 10-year risk (91% of all participants) in CARDIA, those with a high lifetime risk compared to low lifetime risk had significantly greater common (0.83 vs 0.80 mm in men; 0.79 vs 0.75 mm in women) and internal (0.85 vs 0.80 mm; 0.80 vs 0.76 mm) carotid IMT, higher CAC prevalence (16.6 vs 9.8%; 7.1 vs 2.3%), and significantly greater incidence of CAC progression (22.3 vs 15.4%; 8.7 vs 5.3%). Similar results were observed in MESA.
Individuals with low 10-year but high lifetime risk have a greater subclinical disease burden and greater incidence of atherosclerotic progression compared to individuals with low 10-year and low lifetime risk, even at younger ages.
epidemiology; risk estimation; prevention
The structure of ruthenium-based olefin metathesis catalyst 3 and model π-complex 5 in solution and in the solid state are reported. The N-tolyl ligands, due to their lower symmetry than the traditional N-mesityl substituents, complicate this analysis, but ultimately provide explanation for the enhanced reactivity of 3 relative to standard catalyst 2. The tilt of the N-tolyl ring provides additional space near the ruthenium center, which is consistent with the enhanced reactivity of 3 towards sterically demanding substrates. Due to this tilt, the more sterically accessible face bears the two methyl substituents of the N-aryl rings. These experimental studies are supported by computational studies of these complexes by DFT. The experimental data provides a means to validate the accuracy of the B3LYP and M06 functionals. B3LYP provides geometries that match X-ray crystal structural data more closely, though it leads to slightly less (∼0.5 kcal mol−1) accuracy than M06 most likely because it underestimates attractive non-covalent interactions.
Introduction: Auditory hallucinations or voices are experienced by 75% of people diagnosed with schizophrenia. We presumed that auditory cortex of schizophrenia patients who experience hallucinations is tonically “tuned” to internal auditory channels, at the cost of processing external sounds, both speech and nonspeech. Accordingly, we predicted that patients who hallucinate would show less auditory cortical activation to external acoustic stimuli than patients who did not. Methods: At 9 Functional Imaging Biomedical Informatics Research Network (FBIRN) sites, whole-brain images from 106 patients and 111 healthy comparison subjects were collected while subjects performed an auditory target detection task. Data were processed with the FBIRN processing stream. A region of interest analysis extracted activation values from primary (BA41) and secondary auditory cortex (BA42), auditory association cortex (BA22), and middle temporal gyrus (BA21). Patients were sorted into hallucinators (n = 66) and nonhallucinators (n = 40) based on symptom ratings done during the previous week. Results: Hallucinators had less activation to probe tones in left primary auditory cortex (BA41) than nonhallucinators. This effect was not seen on the right. Discussion: Although “voices” are the anticipated sensory experience, it appears that even primary auditory cortex is “turned on” and “tuned in” to process internal acoustic information at the cost of processing external sounds. Although this study was not designed to probe cortical competition for auditory resources, we were able to take advantage of the data and find significant effects, perhaps because of the power afforded by such a large sample.
schizophrenia; auditory hallucinations; fMRI; auditory cortex
Correlations of cognitive functioning with brain activation during a sternberg item recognition paradigm (SIRP) were investigated in patients with schizophrenia and in healthy controls studied at 8 sites. To measure memory scanning times, 4 response time models were fit to SIRP data. The best fitting model assumed exhaustive serial memory scanning followed by self-terminating memory search and involved one intercept parameter to represent SIRP processes not contributing directly to memory scanning. Patients displayed significantly longer response times with increasing memory load and differed on the memory scanning, memory search, and intercept parameters of the best fitting probability model. Groups differed in the correlation between the memory scanning parameter and linear brain response to increasing memory load within left inferior and left middle frontal gyrus, bilateral caudate, and right precuneus. The pattern of findings in these regions indicated that high scanning capacity was associated with high neural capacity among healthy subjects but that scanning speed was uncoupled from brain response to increasing memory load among schizophrenia patients. Group differences in correlation of the best fitting model's scanning parameter with a quadratic trend in brain response to increasing memory load suggested inefficient or disordered patterns of neural inhibition among individuals with schizophrenia, especially in the left perirhinal and entorhinal cortices. The results show at both cognitive and neural levels that disordered memory scanning contributes to deficient SIRP performance among schizophrenia patients.
schizophrenia; item recognition; functional magnetic resonance imaging; stochastic models
Twenty-seven schizophrenia spectrum patients and 25 healthy controls performed a probabilistic version of the serial reaction time task (SRT) that included sequence trials embedded within random trials. Patients showed diminished, yet measurable, sequence learning. Postexperimental analyses revealed that a group of patients performed above chance when generating short spans of the sequence. This high-generation group showed SRT learning that was similar in magnitude to that of controls. Their learning was evident from the very 1st block; however, unlike controls, learning did not develop further with continued testing. A subset of 12 patients and 11 controls performed the SRT in conjunction with positron emission tomography. High-generation performance, which corresponded to SRT learning in patients, correlated to activity in the premotor cortex and parahippocampus. These areas have been associated with stimulus-driven visuospatial processing. Taken together, these results suggest that a subset of patients who showed moderate success on the SRT used an explicit stimulus-driven strategy to process the sequential stimuli. This adaptive strategy facilitated sequence learning but may have interfered with conventional implicit learning of the overall stimulus pattern.
implicit sequence learning; schizophrenia; positron emission tomography (PET); serial reaction time task (SRT); visuomotor