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1.  Interleukin 6 Plasma Concentration Associates with Cognitive Decline: The Northern Manhattan Study 
Neuroepidemiology  2013;40(4):253-259.
Background
Interleukin 6 (IL-6) is an inflammatory cytokine that has been associated with vascular disease and cognitive impairment, but few studies have examined these relationships in population-based studies that include Hispanic white and black people who often have a greater prevalence of vascular risk factors and are at elevated risk of dementia. We examined relative elevations of plasma IL-6 concentrations in relation to cognitive decline in a stroke-free race/ethnically diverse community-based sample from Northern Manhattan.
Methods
We used mixed effects models to measure the effect of IL-6 on change in performance on the Telephone Interview for Cognitive Status (TICS-m) measured annually in our cohort, adjusting for sociodemographic and vascular risk factors.
Results
There were 1224 participants with IL-6 levels (median 1.5 pg/mL, interquartile range (IQR) 0.83 – 2.57 pg/mL) and TICS-m data available (mean=31.6 points, SD 6.5). The mean age was 71 (SD 9.3; 64% women, 59% Hispanic, 19% Black, 19% White) with 3,406 person- and a median 3.0 years of follow-up (IQR 1.1 – 4.0). Participants with IL-6 levels above the median showed greater cognitive decline on the TICS-m compared to those with levels below the median, adjusting for sociodemographic and vascular factors (β= −0.17 points per year, p=0.02). Decline on the TICS-m among participants with IL-6 above the median differed by age (P for interaction <0.001). There was no interaction by race-ethnicity, vascular risk factors, C-reactive protein (CRP), APOE4 allele status, or the metabolic syndrome among non-diabetics.
Conclusions
Interleukin 6 associated with cognitive decline among older participants in this race/ethnically diverse sample independent of other vascular risk factors and CRP.
doi:10.1159/000343276
PMCID: PMC3725587  PMID: 23364322
cognitive decline; cohort studies; Interleukin-6; inflammation
2.  Trajectory of functional decline before and after ischemic stroke: The Northern Manhattan Study 
Background
Previous research in our cohort showed a delayed decline in functional status after first ischemic stroke. We compared the long-term trajectory of functional status before and after ischemic stroke.
Methods
The Northern Manhattan Study contains a prospective, population-based study of stroke-free individuals >40 years of age, followed for a median 11 years. The Barthel index (BI), a commonly used measure of activities of daily living, was assessed annually. Generalized estimating equations were used to assess functional decline over time before and beginning 6 months after stroke. Follow-up was censored at the time of recurrent stroke.
Results
Among 3298 participants, 210 had an ischemic stroke during follow-up and had post-stroke BI assessed. Mean age (+standard deviation) was 77+9 years, 38% were male, 52% were Hispanic, 37% had diabetes, and 31% had coronary artery disease. There was no difference in rate of functional decline over time before and after stroke (p=0.51), with a decline of 0.96 BI points per year before stroke (p<.0001) and 1.24 after stroke (p=0.001). However, when stratified by insurance status, among those with Medicaid or no insurance, in a fully adjusted model, there was a difference in slope before and after stroke (p=0.04), with a decline of 0.58 BI points per year before stroke (p=0.02) and 1.94 after stroke (p=0.001).
Conclusions
In this large, prospective, population-based study with long-term follow-up, there was a significantly steeper decline in functional status after ischemic stroke compared to before stroke among those with Medicaid or no insurance, after adjusting for confounders.
doi:10.1161/STROKEAHA.112.658922
PMCID: PMC3404224  PMID: 22649168
Epidemiology; Disability; Rehabilitation
3.  Coronary Death and Myocardial Infarction among Hispanics in the Northern Manhattan Study: Exploring the Hispanic Paradox 
Annals of epidemiology  2012;22(5):303-309.
PURPOSE
Prior studies have reported that Hispanics have lower cardiovascular disease (CVD) mortality despite a higher burden of risk factors. We examined whether Hispanic ethnicity was associated with a lower risk of nonfatal myocardial infarction (MI) coronary death (CD) and vascular death.
METHODS
A total of 2671 participants in the Northern Manhattan Study without clinical CVD were prospectively evaluated. Cox models were used to calculate hazard ratios (HR) and 95% confidence intervals (CI) for the association of race–ethnicity with nonfatal MI, CD, and vascular death after adjusting for demographic and CVD risk factors.
RESULTS
Mean age was 68.8 (10.4) years; 52.8% were Hispanic (88% Caribbean-Hispanic). Hispanics were more likely to have hypertension (73.1% vs. 62.2%, p < .001) and diabetes (22.0% vs. 13.3%, p < .001), and less likely to perform any physical activity (50.1% vs. 69.2%, p < .001) compared to non-Hispanic whites (NHW). During a mean 10 years of follow-up there were 154 nonfatal MIs, 186 CD, and 386 vascular deaths. In fully adjusted models, Hispanics had a lower risk of CD (adjusted HR = 0.36, 95% CI: 0.21–0.60), and vascular death (adjusted HR = 0.62, 95% CI: 0.43–0.89), but not nonfatal MI (adjusted HR = 0.95, 95% CI: 0.56–1.60) when compared to NHW.
CONCLUSIONS
We found a “Hispanic paradox” for coronary and vascular deaths, but not nonfatal MI.
doi:10.1016/j.annepidem.2012.02.014
PMCID: PMC3657757  PMID: 22424967
Hispanic; Paradox; Mortality; Cardiovascular Disease
4.  The Metabolic Syndrome and Cognitive Performance: The Northern Manhattan Study 
Neuroepidemiology  2011;37(3-4):153-159.
Background
The metabolic syndrome (MetS) is a risk factor for diabetes, stroke, myocardial infarction, and increased mortality, and has been associated with cognition in some populations. We hypothesized that MetS would be associated with lower Mini-Mental State Examination (MMSE) scores in a multi-ethnic population, and that MetS is a better predictor of cognition than its individual components or diabetes.
Methods
We conducted a cross-sectional analysis among 3,150 stroke-free participants. MetS was defined by the modified National Cholesterol Education Program guidelines-Adult Treatment Panel III (NCEP-ATPIII) criteria. Linear regression and polytomous logistic regression estimated the association between MMSE score and MetS, its individual components, diabetes, and inflammatory biomarkers.
Results
MetS was inversely associated with MMSE score (unadjusted β = −0.67; 95% CI −0.92, −0.41). Adjusting for potential confounders, MetS was associated with lower MMSE score (adjusted β = −0.24; 95% CI −0.47, −0.01), but its individual components and diabetes were not. Those with MetS were more likely to have an MMSE score of <18 than a score of ≥24 (adjusted OR = 1.94; 95% CI 1.26, 3.01). There was an interaction between MetS and race-ethnicity, such that MetS was associated with lower MMSE score among non-Hispanic whites and Hispanics but not non-Hispanic blacks.
Conclusions
MetS was associated with lower cognition in a multi-ethnic population. Further studies of the effect of MetS on cognition are warranted, and should account for demographic differences.
doi:10.1159/000332208
PMCID: PMC3214939  PMID: 22005335
Cognitive performance; Cognitive impairment; Vascular dementia; Vascular cognitive impairment; Cerebrovascular disorders; Metabolic syndrome
5.  The inclusion of stroke in risk stratification for primary prevention of vascular events: the Northern Manhattan Study 
Background and Purpose
The Framingham coronary heart disease (CHD) risk score (FRS) estimates 10-year risk of myocardial infarction (MI) and CHD death. Since preventive approaches to CHD and stroke are similar, a composite outcome may be more appropriate. We compared 10-year risk of 1) MI or CHD death, and 2) stroke, MI, or CHD death, among individuals free of vascular disease.
Methods
The Northern Manhattan Study contains a prospective, population-based study of stroke- and CHD-free individuals ≥40 years of age, followed for a median of 10 years for vascular events. FRS was calculated for each individual, and for each category of predicted risk, Kaplan-Meier observed 10-year cumulative probabilities were calculated for 1) MI or CHD death and 2) stroke, MI, or CHD death. The cumulative probability of (1) was subtracted from (2), and 95% confidence intervals (CI) for the difference were obtained with 1000 bootstrap samples. Using stratified analyses by race-ethnicity, we compared risk differences between race-ethnic groups.
Results
Among 2613 participants (53% Hispanic, 25% non-Hispanic black and 20% non-Hispanic white), observed 10-year risk of MI or CHD death was 14.20%. With stroke in the outcome, observed risk was 21.98% (absolute risk difference 7.78%, 95% CI 5.86-9.75%). The absolute risk difference among blacks was significantly larger than among whites (p=0.01).
Conclusions
In this multi-ethnic urban population, adding stroke to the risk stratification outcome cluster resulted in a 55% relative increase in estimated risk, and crossing of the absolute risk threshold (>20% over 10 years) considered for preventive treatments such as statins.
doi:10.1161/STROKEAHA.111.616912
PMCID: PMC3183175  PMID: 21852611
Epidemiology; Stroke Management; Risk Factors
6.  Association of serum soluble Receptor for Advanced Glycation End-products with subclinical cerebrovascular disease: the Northern Manhattan Study (NOMAS) 
Atherosclerosis  2011;216(1):192-198.
Objective
Serum levels of the soluble Receptor for Advanced Glycation End-products (sRAGE) have been associated with risk of cardiovascular disease. We hypothesized that sRAGE levels are associated with subclinical cerebrovascular disease in an ethnically diverse population.
Methods
Clinically stroke-free participants in the multi-ethnic Northern Manhattan Study (NOMAS) underwent brain MRI to quantify subclinical brain infarcts (SBI) and white matter hyperintensity volume (WMHV) (n=1102). Serum levels of sRAGE were measured by ELISA. Logistic and multiple linear regression were employed to estimate associations of sRAGE with SBI and WMHV, after adjusting for demographics and vascular risk factors.
Results
Median sRAGE levels were significantly lower in Hispanics (891.9 pg/ml; n=708) and non-Hispanic blacks (757.4 pg/ml; n=197) than in non-Hispanic whites (1120.5 pg/ml; n=170), and these differences remained after adjusting for other risk factors. Interactions were observed by race-ethnicity between sRAGE levels and MRI measurements, including for SBI in Hispanics (p=0.04) and WMHV among blacks (p=0.03). In Hispanics, increasing sRAGE levels were associated with a lower odds of SBI, with those in the upper sRAGE quartile displaying a 50% lower odds of SBI after adjusting for sociodemographic and vascular risk factors (p=0.05). Among blacks, those in the upper quartile of sRAGE had a similarly reduced increased risk of SBI (p=0.06) and greater WMHV (p=0.04).
Conclusion
Compared to whites, Hispanics and blacks have significantly lower sRAGE levels, and these levels were associated with more subclinical brain disease. Taken together, these findings suggest sRAGE levels may be significantly influence by ethnicity. Further studies of sRAGE and stroke risk, particularly in minorities, are warranted.
doi:10.1016/j.atherosclerosis.2011.01.024
PMCID: PMC3089661  PMID: 21316677
RAGE (receptor for advanced glycation end products); biological marker; Hispanics; white matter hyperintensities; subclinical infarct; MRI
7.  Race-ethnic differences in the relationship between lipid profile components and risk of myocardial infarction: the Northern Manhattan Study 
American heart journal  2011;161(5):886-892.
Objective
To explore race-ethnic differences in the relationship between plasma lipid components and risk of incident myocardial infarction (MI).
Design/Methods
As part of the Northern Manhattan Study, 2738 community residents without cardiovascular disease were prospectively evaluated. Baseline fasting blood samples were collected and lipid panel components were analyzed as continuous and categorical variables. Cox proportional hazard models were used to calculate hazard ratios (HR) and 95% confidence intervals (CI) for incident MI after adjusting for demographic and cardiovascular risk factors.
Results
The mean age was 68.8±10.4 years; 36.7% men, 19.9% non-Hispanic white, 24.9% non-Hispanic black, and 52.8% Hispanic (over 80% from the Caribbean). Hispanics had lower mean HDL-C, and higher TG/HDL-C. During a mean 8.9 years of follow-up there were 163 incident MIs. In the whole cohort all lipid profile components were associated with risk of MI in the expected directions. However, HDL-C (adjusted HR per 10 mg/dl increase 0.93, 95%CI 0.76–1.12) and TG/HDL-C>2 (adjusted HR 0.89, 95%CI 0.51–1.55) were not predictive of MI among Hispanics, but were predictive among non-Hispanic blacks and whites. TG/HDL-C per unit increase was associated with an 8% higher risk of MI among Hispanics (adjusted HR 1.08, 95%CI 1.04–1.12).
Conclusions
In Hispanics, low HDL-C and TG/HDL-C>2 were not associated with MI risk. Our data suggests that a different TG/HDL ratio cutoff may be needed among Hispanics to predict MI risk.
doi:10.1016/j.ahj.2011.01.018
PMCID: PMC3095911  PMID: 21570518
8.  Early Depressed mood after stroke predicts long-term disability: the Northern Manhattan Stroke Study (NOMASS) 
Introduction
Depression is highly prevalent after stroke, and may influence recovery. We aimed to determine whether depressed mood acutely after stroke predicts subsequent disability and mortality.
Methods
As part of the Northern Manhattan Stroke Study, a population-based incident stroke case follow-up study performed in a multiethnic urban population, participants were asked about depressed mood within 7–10 days after stroke. Participants were followed every 6 months the first 2 years, and yearly thereafter for 5 years, for death and disability measured by the Barthel Index (BI). We fitted polytomous logistic regression models using canonical link to examine the association between depressed mood after stroke and disability, comparing moderate (BI 60–95) and severe (BI < 60) disability to no disability (BI ≥ 95). Cox-proportional hazards models were created to examine the association between depressed mood and mortality.
Results
A question about depressed mood within 7–10 days after stroke was asked in 340 of 655 ischemic stroke patients enrolled, and 139 reported that they felt depressed. In multivariate analyses controlling for socio-demographic factors, stroke severity, and medical conditions, depressed mood was associated with a greater odds of severe disability compared to no disability at one (OR 2.91, 95% CI 1.07–7.91) and two years (OR 3.72, 95% CI 1.29–10.71) after stroke. Depressed mood was not associated with all cause mortality or vascular death.
Conclusion
Depressed mood after stroke is associated with disability but not mortality after stroke. Early screening and intervention for mood disorders after stroke may improve outcomes and requires further research.
doi:10.1161/STROKEAHA.110.583997
PMCID: PMC2932858  PMID: 20671256
9.  Lipid Profile Components and Risk of Ischemic Stroke 
Archives of neurology  2009;66(11):1400-1406.
Objective
To explore the relationship between lipid profile components and incident ischemic stroke in a stroke-free prospective cohort.
Design
Population-based prospective cohort study.
Setting
Northern Manhattan, New York.
Patients
Stroke-free community residents.
Intervention
As part of the Northern Manhattan Study, baseline fasting blood samples were collected on stroke-free community residents followed up for a mean of 7.5 years.
Main Outcome Measures
Cox proportional hazard models were used to calculate hazard ratios and 95% confidence intervals for lipid profile components and ischemic stroke after adjusting for demographic and risk factors. In secondary analyses, we used repeated lipid measures over 5 years from a 10% sample of the population to calculate the change per year of each of the lipid parameters and to impute time-dependent lipid parameters for the full cohort.
Results
After excluding those with a history of myocardial infarction, 2940 participants were available for analysis. Baseline high-density lipoprotein cholesterol, triglyceride, and total cholesterol levels were not associated with risk of ischemic stroke. Low-density lipoprotein cholesterol (LDL-C) and non–high-density lipoprotein cholesterol levels were associated with a paradoxical reduction in risk of stroke. There was an interaction with use of cholesterol-lowering medication on follow-up, such that LDL-C level was only associated with a reduction in stroke risk among those taking medications. An LDL-C level greater than 130 mg/dL as a time-dependent covariate showed an increased risk of ischemic stroke (adjusted hazard ratio, 3.81; 95% confidence interval, 1.53–9.51).
Conclusions
Baseline lipid panel components were not associated with an increased stroke risk in this cohort. Treatment with cholesterol-lowering medications and changes in LDL-C level over time may have attenuated the risk in this population, and lipid measurements at several points may be a better marker of stroke risk.
doi:10.1001/archneurol.2009.210
PMCID: PMC2830863  PMID: 19901173
10.  Infectious Burden and Carotid Plaque Thickness: The Northern Manhattan Study 
Background
The overall burden of prior infections may contribute to atherosclerosis and stroke risk. We hypothesized that serological evidence of common infections would be associated with carotid plaque thickness in a multi-ethnic cohort.
Methods
Antibody titers to five common infectious microorganisms (i.e. Chlamydia pneumoniae, Helicobacter pylori, cytomegalovirus, and herpesvirus 1 and 2) were measured among stroke-free community participants, and a weighted index of infectious burden (IB) was calculated based on Cox models previously derived from for the association of each infection with stroke risk. High-resolution carotid duplex Doppler studies were used to assess maximum carotid plaque thickness (MCPT). Weighted least squares regression was used to measure the association between IB and MCPT after adjusting for other risk factors.
Results
Serological results for all five infectious organisms were available in 861 participants with MCPT measurements available (mean age 67.2+/−9.6 yrs). Each individual infection was associated with stroke risk after adjusting for other risk factors. The IB index (n=861) had a mean of 1.00 ± standard deviation 0.35, median 1.08. Plaque was present in 52% of participants (mean 0.90+/−1.04 mm). IB was associated with MCPT (adjusted increase in MCPT 0.09 mm, 95% confidence interval 0.03–0.15 mm, per standard deviation increase of IB).
Conclusion
A quantitative weighted index of infectious burden, derived from the magnitude of association of individual infections with stroke, was associated with carotid plaque thickness in this multi-ethnic cohort. These results lend support to the notion that past or chronic exposure to common infections, perhaps by exacerbating inflammation, contributes to atherosclerosis. Future studies are needed to confirm this hypothesis and to define optimal measures of infectious burden as a vascular risk factor.
doi:10.1161/STROKEAHA.109.571299
PMCID: PMC2830875  PMID: 20075350
11.  Long-term functional recovery after first ischemic stroke: The Northern Manhattan Study 
Background and Purpose
Several factors predict functional status after stroke, but most studies have included hospitalized patients with limited follow-up. We hypothesized that ischemic stroke patients experience functional decline over 5 years independent of recurrent stroke and other risk factors.
Methods
In the population-based Northern Manhattan Study, incident ischemic stroke patients ≥40 years were prospectively followed using the Barthel index (BI) at 6 months and annually to 5 years. Baseline stroke severity was categorized as mild (NIH Stroke Scale <6), moderate (6–13), and severe (≥14). Follow-up was censored at death, recurrent stroke, or myocardial infarction. Generalized Estimating Equations provided odds ratios (OR) and 95% confidence intervals (95%CI) for predictors of favorable (BI≥95) versus unfavorable (BI<95) functional status, after adjusting for demographic and medical risk factors.
Results
Of 525 patients, mean age was 68.6±12.4 years, 45.5% were male, 54.7% Hispanic, 54.7% had Medicaid/no insurance, and 35.1% had moderate stroke. The proportion with BI≥95 declined over time (OR 0.91, 95% CI 0.84–0.99). Changes in BI by insurance status were confirmed by a significant interaction term (β for interaction=−0.167, p=0.034); those with Medicaid/no insurance declined (OR 0.84, p=0.003), whereas those with Medicare/private insurance did not (OR 0.99, p=0.92).
Conclusions
The proportion of patients with functional independence after stroke declines annually for up to 5 years, and these effects are greatest for those with Medicaid or no health insurance. This decline is independent of age, stroke severity, and other predictors of functional decline, and occurs even among those without recurrent stroke or myocardial infarction.
doi:10.1161/STROKEAHA.109.549576
PMCID: PMC2830874  PMID: 19556535
disability; stroke; recovery
12.  Infectious burden and cognitive function 
Neurology  2013;80(13):1209-1215.
Objective:
We hypothesized that infectious burden (IB), a composite serologic measure of exposure to common pathogens (i.e., Chlamydia pneumoniae, Helicobacter pylori, cytomegalovirus, and herpes simplex virus 1 and 2) associated with vascular risk in the prospective Northern Manhattan Study (NOMAS), would also be associated with cognition.
Methods:
Cognition was assessed using the Mini-Mental State Examination (MMSE) at enrollment and the modified Telephone Interview for Cognitive Status (TICS-m) at annual follow-up visits. Adjusted linear and logistic regressions were used to measure the association between IB index and MMSE. Generalized estimating equation models were used to evaluate associations with TICS-m and its change over time.
Results:
Serologies and cognitive assessments were available in 1,625 participants of the NOMAS cohort. In unadjusted analyses, higher IB index was associated with worse cognition (change per standard deviation [SD] of IB for MMSE was −0.77, p < 0.0001, and for first measurements of TICS-m was −1.89, p < 0.0001). These effects were attenuated after adjusting for risk factors (for MMSE adjusted change per SD of IB = −0.17, p = 0.06, for TICS-m adjusted change per SD IB = −0.68, p < 0.0001). IB was associated with MMSE ≤24 (compared to MMSE >24, adjusted odds ratio 1.26 per SD of IB, 95% confidence interval 1.06–1.51). IB was not associated with cognitive decline over time. The results were similar when IB was limited to viral serologies only.
Conclusion:
A measure of IB associated with stroke risk and atherosclerosis was independently associated with cognitive performance in this multiethnic cohort. Past infections may contribute to cognitive impairment.
doi:10.1212/WNL.0b013e3182896e79
PMCID: PMC3691781  PMID: 23530151

Results 1-12 (12)