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1.  The Neuroprotection with Statin Therapy for Acute Recovery Trial (NeuSTART): an adaptive design phase I dose-escalation study of high-dose lovastatin in acute ischemic stroke 
There is growing experimental and clinical evidence that by reducing downstream products of the mevalonate pathway other than cholesterol, HMG-CoA reductase inhibitors (‘statins’) have beneficial effects on endothelial function, coronary and cerebral blood flow, inflammation, and hemostasis. Statins have been shown in rodent models of acute ischemic stroke to reduce neuronal injury and infarct size in a dose-dependent fashion. The objective of this early phase trial will be to determine the maximal-tolerated dose of lovastatin for short-term acute stroke therapy. In this multicenter phase 1B dose-escalation and dose-finding study, 33 patients with acute ischemic stroke will be administered lovastatin in increasing doses from one to 10 mg/kg daily for 3 days beginning within 24 hours after symptom onset. The primary safety outcomewill be occurrence of myotoxicity or hepatotoxicity, defined by clinical and laboratory criteria, and the study is designed to determine the highest dose of lovastatin that can be administered with <10% risk of myotoxicity or hepatotoxicity. The statistical design of the study utilizes an adaptive design, the Continual Reassessment Method, which is novel to stroke trials, to find the optimal dosage. The dose–toxicity model is calibrated such that the method will eventually select a dose that causes 7–13% dose-limiting toxicity (within 3% of target). A sample size of 33 will ensure that estimates of any binary variables will have a 95% confidence interval of width ≤0·34, and enable us to detect any unexpected toxicity that occurs at 5% rate (in a non-dose-dependent fashion) with probability 0·82. The probability of choosing a dose for further trials with 25% or higher likelihood of toxicity is no more than 23%. The presently described trial represents a new approach for treatment of acute ischemic stroke, as well as a novel way of conducting a phase I trial, evaluating safety and determining an optimal dose of a potential neuroprotectant drug.
PMCID: PMC4130457  PMID: 18705902
stroke; neuroprotection; statins; clinical trial
2.  Transesophageal Echocardiography in Cryptogenic Stroke and PFO: The Analysis of Putative High Risk Features from the Risk of Paradoxical Embolism (RoPE) Database 
Patent foramen ovale (PFO) is associated with cryptogenic stroke (CS), though the pathogenicity of a discovered PFO in the setting of CS is typically unclear. Transesophageal echocardiography (TEE) features such as PFO size, an associated hypermobile septum, and presence of a right-to-left shunt at rest have all been proposed as markers of risk. The association of these TEE features with other markers of pathogenicity has not been examined.
Methods and Results
We used a recently derived score based on clinical and neuroimaging features to stratify patients with PFO and CS by the probability that their stroke is PFO-attributable. We examined whether high risk TEE features are seen more frequently in patients more likely to have had a PFO-attributable stroke (n = 637) compared to those less likely to have a PFO attributable stroke (n = 657). Large physiologic shunt size was not more frequently seen among those with probable PFO-attributable strokes (OR=0.92; p = 0.53). Neither the presence of a hypermobile septum nor a right-to-left shunt at rest were detected more often in those with a probable PFO-attributable stroke (OR=0.80; p = 0.45 and OR=1.15; 0.11 respectively).
We found no evidence that the proposed TEE risk markers of large PFO size, hypermobile septum, and presence of right-to-left shunt at rest are associated with clinical features suggesting that a CS is PFO-attributable. Additional tools to describe PFOs may be useful in helping to determine whether an observed PFO is incidental or pathogenically related to CS.
PMCID: PMC3934652  PMID: 24214884
cerebrovascular disease/stroke; echocardiography; cardiovascular imaging; risk factor; congenital heart disease
3.  Serum IgG Antibody Levels to Periodontal Microbiota Are Associated with Incident Alzheimer Disease 
PLoS ONE  2014;9(12):e114959.
Periodontitis and Alzheimer disease (AD) are associated with systemic inflammation. This research studied serum IgG to periodontal microbiota as possible predictors of incident AD.
Using a case-cohort study design, 219 subjects (110 incident AD cases and 109 controls without incident cognitive impairment at last follow-up), matched on race-ethnicity, were drawn from the Washington Heights-Inwood Columbia Aging Project (WHICAP), a cohort of longitudinally followed northern Manhattan residents aged >65 years. Mean follow-up was five years (SD 2.6). In baseline sera, serum IgG levels were determined for bacteria known to be positively or negatively associated with periodontitis (Porphyromonas gingivalis, Tannerella forsythia, Actinobacillus actinomycetemcomitans Y4, Treponema denticola, Campylobacter rectus, Eubacterium nodatum, and Actinomyces naeslundii genospecies-2). In all analyses, we used antibody threshold levels shown to correlate with presence of moderate-severe periodontitis.
Mean age was 72 years (SD 6.9) for controls, and 79 years (SD 4.6) for cases (p<0.001). Non-Hispanic Whites comprised 26%, non-Hispanic Blacks 27%, and Hispanics 48% of the sample. In a model adjusting for baseline age, sex, education, diabetes mellitus, hypertension, smoking, prior history of stroke, and apolipoprotein E genotype, high anti-A. naeslundii titer (>640 ng/ml, present in 10% of subjects) was associated with increased risk of AD (HR = 2.0, 95%CI: 1.1–3.8). This association was stronger after adjusting for other significant titers (HR = 3.1, 95%CI: 1.5–6.4). In this model, high anti-E. nodatum IgG (>1755 ng/ml; 19% of subjects) was associated with lower risk of AD (HR = 0.5, 95%CI: 0.2–0.9).
Serum IgG levels to common periodontal microbiota are associated with risk for developing incident AD.
PMCID: PMC4270775  PMID: 25522313
4.  The Ethnic/Racial Variations of Intracerebral Hemorrhage (ERICH) Study Protocol 
Stroke; a journal of cerebral circulation  2013;44(10):10.1161/STROKEAHA.113.002332.
Background and Purpose
Epidemiologic studies of intracerebral hemorrhage (ICH) have consistently demonstrated variation in incidence, location, age at presentation, and outcomes among non-Hispanic white, black, and Hispanic populations. We report here the design and methods for this large, prospective, multi-center case-control study of ICH.
The ERICH study is a multi-center, prospective case-control study of ICH. Cases are identified by hot-pursuit and enrolled using standard phenotype and risk factor information and include neuroimaging and blood sample collection. Controls are centrally identified by random digit dialing to match cases by age (+/−5 years), race, ethnicity, gender and metropolitan region.
As of March 22, 2013, 1,655 cases of ICH had been recruited into the study which is 101.5% of the target for that date and 851 controls had been recruited which is 67.2% of the target for that date (1,267 controls) for a total of 2,506 subjects which is 86.5% of the target for that date (2,897 subjects). Of the 1,655 cases enrolled, 1,640 cases had the case interview entered into the database of which 628 (38%) were non-Hispanic black, 458 (28%) were non-Hispanic white and 554 (34%) were Hispanic. Of the 1,197 cases with imaging submitted, 876 (73.2%) had a 24 hour follow-up CT available In addition to CT imaging, 607 cases have had MRI evaluation.
The ERICH study is a large, case-control study of ICH with particular emphasis on recruitment of minority populations for the identification of genetic and epidemiologic risk factors for ICH and outcomes after ICH.
PMCID: PMC3873723  PMID: 24021679
Stroke; Intracerebral Hemorrhage; Risk Factors; Hypertension; Minorities; Genetics; Genomics
5.  Stroke: do statins improve outcomes after acute ischemic stroke? 
Nature reviews. Neurology  2011;7(7):364-365.
PMCID: PMC3616135  PMID: 21670760
6.  Stroke Location and Association With Fatal Cardiac Outcomes 
Background and Purpose
Cardiac mortality after stroke is common, and small studies have suggested an association of short-term cardiac mortality with insular location of cerebral infarction. Few population-based studies with long-term follow-up have evaluated the effect of stroke location on the long-term risk of cardiac death or myocardial infarction (MI) after first ischemic stroke. We sought to determine the association between stroke location and cardiac death or MI in a multiethnic community-based cohort.
The Northern Manhattan Study is a population-based study designed to determine stroke incidence, risk factors, and prognosis in a multiethnic urban population. First ischemic stroke patients age 40 or older were prospectively followed up for cardiac death defined as fatal MI, fatal congestive heart failure, or sudden death/arrhythmia and for nonfatal MI. Primary brain anatomic site was determined by consensus of research neurologists. Hazard ratios (HRs) and 95% CIs were calculated by Cox proportional-hazards models and adjusted for vascular risk factors (age, sex, history of coronary disease, hypertension, diabetes, cholesterol, and smoking), stroke severity, infarct size, and stroke etiology.
The study population consisted of 655 patients whose mean age was 69.7 ± 12.7 years; 44.6% were men and 51.3% were Hispanic. During a median follow-up of 4.0 years, 44 patients (6.7%) had fatal cardiac events. Of these, fatal MI occurred in 38.6%, fatal congestive heart failure in 18.2%, and sudden death in 43.2%. In multivariate models, clinical diagnosis of left parietal lobe infarction was associated with cardiac death (adjusted HR = 4.45; 95% CI, 1.83 to 10.83) and cardiac death or MI (adjusted HR = 3.30; 95% CI, 1.45 to 7.51). When analysis of anatomic location was restricted to neuroimaging (computed tomography, magnetic resonance imaging, or both [n = 447]), left parietal lobe infarction was associated with cardiac death (adjusted HR = 3.37; 95% CI, 1.26 to 8.97), and both left (adjusted HR = 3.49; 95% CI, 1.38 to 8.80) and right (adjusted HR = 3.13; 95% CI, 1.04 to 9.45) parietal lobe infarctions were associated with cardiac death or MI. We did not find an association between frontal, temporal, or insular stroke and fatal cardiac events, although the number of purely insular strokes was small.
Parietal lobe infarction is an independent predictor of long-term cardiac death or MI in this population. Further studies are needed to confirm whether parietal lobe infarction is an independent predictor of cardiac events and death. Surveillance for cardiac disease and implementation of cardioprotective therapies may reduce cardiac mortality in patients with parietal stroke.
PMCID: PMC4112463  PMID: 18635863
acute stroke; cardiac arrhythmia; epidemiology; sudden death
7.  The Risk of Paradoxical Embolism (RoPE) Study: Initial description of the completed database 
Detecting a benefit from closure of patent foramen ovale (PFO) in patients with cryptogenic stroke (CS) is hampered by low rates of stroke recurrence and uncertainty about the causal role of PFO in the index event. A method to predict PFO-attributable recurrence risk is needed. However, individual databases generally have too few stroke recurrences to support risk modeling. Prior studies of this population have been limited by low statistical power for examining factors related to recurrence.
To develop a database to support modeling of PFO-attributable recurrence risk by combining extant data sets.
We identified investigators with extant databases including subjects with CS investigated for PFO; determined the availability and characteristics of data in each database; collaboratively specified the variables to be included in the Risk of Paradoxical Embolism (RoPE) database; harmonized the variables across databases, and collected new primary data when necessary and feasible.
The RoPE database has individual clinical, radiologic, and echocardiographic data from 12 component databases including subjects with CS both with (n=1925) and without (n=1749) PFO. In the PFO subjects, a total of 381 outcomes (stroke, TIA, death) occurred (median follow-up = 2.2yrs). While there were substantial variations in data collection between studies, there was sufficient overlap to define a common set of variables suitable for risk modeling.
While individual studies are inadequate for modeling PFO-attributable recurrence risk, collaboration between investigators has yielded a database with sufficient power to identify those patients at highest risk for a PFO-related stroke recurrence who may have the greatest potential benefit from PFO closure.
PMCID: PMC4060865  PMID: 22883936
cryptogenic stroke; patent foramen ovale; secondary stroke prevention; risk modeling; endovascular closure; individual patient metaanalysis
8.  Review of Lipid and Lipoprotein(a) Abnormalities in Childhood Arterial Ischemic Stroke 
National organizations recommend cholesterol screening in children to prevent vascular disease in adulthood. There are currently no recommendations for cholesterol and lipoprotein (a) testing in children who experience an arterial ischemic stroke. While dyslipidemia and elevated lipoprotein (a) are associated with ischemic stroke in adults, the role of atherosclerotic risk factors in childhood arterial ischemic stroke is not known. A review of the literature was performed from 1966- 4/2012 to evaluate the association between childhood arterial ischemic stroke and dyslipidemia or elevated lipoprotein (a). Of 239 citations, there were 16 original observational studies in children (with or without neonates,) with imaging-confirmed arterial ischemic stroke and data on cholesterol or lipoprotein (a) values. Three pairs of studies reported overlapping subjects, and 2 were eliminated. Among 14 studies, there was data on cholesterol in 7 and lipoprotein (a) in 10. After stroke, testing was performed at > 3 months in 9 studies, at ≤3 months in 4 studies and not specified in one study. There were 5 case-control studies: 4 compared elevated lipoprotein (a) and one compared abnormal cholesterol in children with arterial ischemic stroke to controls. A consistent positive association between elevated lipoprotein (a) and stroke was found [Mantel-Haenszel OR 4.24 (2.94–6.11)]. There was no association in one study on total cholesterol, and a positive association in one study on triglycerides. The literature suggests that elevated lipoprotein (a) may be more likely in children with arterial ischemic stroke than in control children. The absence of confirmatory study on dyslipidemia should be addressed with future research.
PMCID: PMC3869879  PMID: 24148253
childhood stroke; cholesterol; lipid; lipoprotein(a); risk factor; atherosclerosis; review
9.  Physical activity and cognition in the Northern Manhattan Study 
Neuroepidemiology  2013;42(2):100-106.
To test the hypothesis that leisure time PA is associated with cognitive status.
We assessed cognition using the Mini-Mental Status Examination (MMSE) at enrollment, and using the modified Telephone Interview for Cognitive Status (TICS-m) administered annually since 2001 in the Northern Manhattan Study. Baseline measures of leisure-time PA were collected via in-person questionnaires. Total PA was categorized in three groups based on the metabolic equivalent (MET) score, a composite of total reported intensity and time. We used linear regression models to examine the association of PA with MMSE, and generalized estimating equations for change in TICS-m over time.
There were 3298 stroke-free participants with MMSE data (mean MMSE 26.0±3.8) and 2279 with TICS-m scores available. Compared to no PA, those with the upper quartile ofMET-score had greater baseline MMSE scores (adjusted β=0.4,p=0.01) but no association with change in TICS-m over time. There were interactions (p<0.05) between PA and both insurance and education; compared to no PA those in the upper quartile of MET-score had a greater MMSE score only among those with Medicaid/no insurance (adjusted β =0.83,p=0.0005) and those who did not complete high school (adjusted β=0.68, p=0.001).
Increased levels of physical activity were associated with better baseline MMSE, particularly among those with socioeconomic disadvantages, but not with cognitive decline.
PMCID: PMC3942085  PMID: 24335048
physical activity; cognition; dementia
10.  Tumour necrosis factor receptor 1 and mortality in a multi-ethnic cohort: the Northern Manhattan Study 
Age and Ageing  2013;42(3):385-390.
Objective: to study the association between soluble tumour necrosis factor receptor 1 (sTNFR1) levels and mortality in the population-based Northern Manhattan Study (NOMAS).
Methods: NOMAS is a multi-ethnic, community-based cohort study with mean 8.4 years of follow-up. sTNFR1 was measured using ELISA. Cox proportional hazards models were used to calculate hazard ratios and 95% confidence intervals (HR, 95% CI) for the association of sTNFR1 with risk of all-cause mortality after adjusting for relevant confounders.
Results: sTNFR1 measurements were available in 1,862 participants (mean age 69.2 ± 10.2 years) with 512 all-cause deaths. Median sTNFR1 was 2.28 ng/ml. Those with sTNFR1 levels in the highest quartile (Q4), compared with those with sTNFR1 in the lowest quartile (Q1), were at an increased risk of all-cause mortality (adjusted HR: 1.8, 95% CI: 1.4–2.4) and non-vascular mortality (adjusted HR: 2.5, 95% CI: 1.5–3.6), but not vascular mortality (adjusted HR: 1.3, 95% CI: 0.9–1.9). There were interactions between sTNFR1 quartiles and medical insurance-status [likelihood ratio test (LRT) with 3 degrees of freedom, Pinteraction = 0.02] and alcohol consumption (LRT with 3 degrees of freedom, Pinteraction < 0.01) for all-cause mortality. In participants with no insurance or Medicaid, those with sTNFR1 in the top quartile had nearly a threefold increased risk of total mortality than the lowest quartile (adjusted HR: 2.9, 95% CI: 1.9–4.4).
Conclusion: in this multi-ethnic cohort, sTNFR1 was associated with all-cause and non-vascular mortality, particularly among those of a lower socioeconomic status.
PMCID: PMC3693433  PMID: 23321203
inflammation; insurance status; mortality risk; alcohol use; older people
11.  Stochastic approximation with virtual observations for dose-finding on discrete levels 
Biometrika  2009;97(1):109-121.
Phase I clinical studies are experiments in which a new drug is administered to humans to determine the maximum dose that causes toxicity with a target probability. Phase I dose-finding is often formulated as a quantile estimation problem. For studies with a biological endpoint, it is common to define toxicity by dichotomizing the continuous biomarker expression. In this article, we propose a novel variant of the Robbins–Monro stochastic approximation that utilizes the continuous measurements for quantile estimation. The Robbins–Monro method has seldom seen clinical applications, because it does not perform well for quantile estimation with binary data and it works with a continuum of doses that are generally not available in practice. To address these issues, we formulate the dose-finding problem as root-finding for the mean of a continuous variable, for which the stochastic approximation procedure is efficient. To accommodate the use of discrete doses, we introduce the idea of virtual observation that is defined on a continuous dosage range. Our proposed method inherits the convergence properties of the stochastic approximation algorithm and its computational simplicity. Simulations based on real trial data show that our proposed method improves accuracy compared with the continual re-assessment method and produces results robust to model misspecification.
PMCID: PMC3412600  PMID: 23049118
Continual re-assessment method; Dichotomized data; Discrete barrier; Heteroscedasticity; Robust estimation; Semiparametric mean-variance relationship
12.  Infectious Burden and Risk of Stroke: The Northern Manhattan Study 
Archives of neurology  2009;67(1):33-38.
Common infections may be associated with stroke risk, though no single infection is likely a major independent predictor.
To determine the association between a composite measure of serologies to common infections (Chlamydia pneumoniae, Helicobacter pylori, cytomegalovirus, Herpes Simplex Virus 1 and 2) and stroke risk in a prospective cohort study.
Prospective cohort followed longitudinally for median 8 years.
Randomly selected stroke-free participants from a multiethnic urban community.
Northern Manhattan Study (NOMAS).
Main Outcome measure
Incident stroke and other vascular events.
All five infectious serologies were available from baseline samples in 1625 participants (mean age 68.5 ± 10.1 years; 64.9% women). Cox proportional hazards models were used to estimate associations of each positive serology with stroke. Individual parameter estimates were then combined into a weighted index of infectious burden (IB) and used to calculate hazard ratios and confidence intervals (HR, 95% CI) for association with risk of stroke and other outcomes, adjusted for risk factors. Each individual infection was positively though not significantly associated with stroke risk after adjusting for other risk factors. The IB index was associated with an increased risk of all strokes (adjusted HR per standard deviation 1.39, 95% CI 1.02–1.90) after adjusting for demographics and risk factors. Results were similar after excluding those with coronary disease (adjusted HR 1.50, 95% CI 1.05–2.13) and adjusting for inflammatory biomarkers.
A quantitative weighted index of infectious burden was associated with risk of first stroke in this cohort. Future studies are needed to confirm these findings and to further define optimal measures of IB as a stroke risk factor.
PMCID: PMC2830860  PMID: 19901154
13.  Association of the Northern Manhattan Study Global Vascular Risk Score and Successful Aging 
To examine the association between successful aging without subsequent cognitive decline (SA-ND) and the Northern Manhattan Study (NOMAS) global vascular risk score (GVRS), which is predictive of stroke, MI, and vascular death.
Prospective cohort study.
A stroke-free sample of Hispanic, black, and white participants living in the same community enrolled in an MRI substudy of NOMAS, a population-based prospective cohort study.
A cognitive screen was administered at baseline and at enrollment in the MRI substudy (n=1,290).
SA-ND was based on disease, disability, and cognitive function. The GVRS includes age, sex, race-ethnicity, waist circumference, alcohol intake, smoking, physical activity, blood pressure, antihypertensive medication use, fasting blood sugar, lipid levels, and peripheral vascular disease.
Data at baseline and follow-up were available for 1,162 participants (mean age 70 ± 9 years; 61% women; 13% white, 16% black, 69% Hispanic; mean GVRS 8.6 ± 0.9). Logistic regression, adjusted for education, socioeconomic status, and follow-up time, showed that the odds of SA-ND were 38% greater for each additional one-point decrease on the GVRS (OR=1.38, 95% C.I. 1.17-1.61; p<0.0001). We also observed an inverse dose-response for quartiles of GVRS with SA-ND. Greater diastolic blood pressure among those on antihypertensive medication, and a history of claudication or peripheral arterial disease, were inversely associated with SA-ND in our fully adjusted model (p<0.005).
Potentially modifiable vascular risk factors were independently associated with SA-ND in a multi-ethnic community-based sample. Improvements in global vascular risk scores could help promote healthy longevity in the aging population.
PMCID: PMC3628415  PMID: 23527874
Successful Aging; Cognitive Aging; Global Vascular Risk; Vascular Risk Factors
14.  Lipid Profile Components and Risk of Ischemic Stroke 
Archives of neurology  2009;66(11):1400-1406.
To explore the relationship between lipid profile components and incident ischemic stroke in a stroke-free prospective cohort.
Population-based prospective cohort study.
Northern Manhattan, New York.
Stroke-free community residents.
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.
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).
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.
PMCID: PMC2830863  PMID: 19901173
15.  High-Sensitivity C-Reactive Protein and Lipoprotein-Associated Phospholipase A2 Stability Before and After Stroke and Myocardial Infarction 
High-sensitivity C-reactive protein (hsCRP) and lipoprotein-associated phospholipase A2 (Lp-PLA2) are hypothesized to be biomarkers of systemic inflammation and risk of myocardial infarction (MI) and stroke. Little is known, however, about the stability of these markers over time, and in particular, about the effects of acute vascular events on these marker levels.
Serum samples were collected at 4 annual intervals in 52 stroke-free participants from the Northern Manhattan Study (NOMAS), and assayed for hsCRP and Lp-PLA2 mass and activitylevels using standard techniques. Log transformation of levels was performed as needed to stabilize the variance. Stability of marker levels over time was assessed using random effects models unadjusted and adjusted for demographics and other risk factors. In addition, samples from 37 initially stroke-free participants with stroke (n=17) or MI (n=20) were available for measurement before and after the vascular event (median 5 days, range 2–40 days). Levels before and after events were compared using non-parametric tests.
HsCRP and Lp-PLA2 activity levels were stable over time, while Lp-PLA2 mass levels decreased on average 5% per year (p=0.0015). Using accepted thresholds to define risk categories of Lp-PLA2 mass, there was no significant change over time. HsCRP increased after stroke (from median 2.2 mg/L pre-stroke to 6.5 mg/L post-stroke; p=0.0067) and MI (from median 2.5 mg/L pre-MI to 13.5 mg/L post-MI; p<0.0001). Lp-PLA2 mass and activity levels both decreased significantly after stroke and MI (for Lp-PLA2 mass, from median 210.0 ng/mL to 169.4 ng/mL post-stroke, p=0.0348, and from median 233.0 ng/mL to 153.9 post-MI, p<0.0001).
Lp-PLA2 mass levels decrease modestly, while hsCRP and Lp-PLA2 activity appear stable over time. Acutely after stroke and MI, hsCRP increases, while Lp-PLA2 mass and activity levels decrease. These changes imply that measurements made soon after stroke and MI are not reflective of pre-stroke levels, and may be less reliable for long-term risk stratification.
PMCID: PMC2761676  PMID: 19644070
C-reactive protein; Biomarker; Inflammation; Ischemic-Stroke; Myocardial Infarction
16.  Infectious Burden and Carotid Plaque Thickness: The Northern Manhattan Study 
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.
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.
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).
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.
PMCID: PMC2830875  PMID: 20075350
17.  Soluble Tumor Necrosis Factor Receptor 1 Level Is Associated With Left Ventricular Hypertrophy: The Northern Manhattan Study 
American journal of hypertension  2009;22(7):763-769.
Although inflammatory markers may be associated with risk of cardiovascular events, few data are available regarding these markers and their association with left ventricular hypertrophy (LVH). We sought to evaluate whether inflammatory markers were independently associated with LVH in a multiethnic population in northern Manhattan.
A population-based cross-sectional study was conducted in 660 participants without stroke, who had undergone both transthoracic echocardiography and testing for soluble tumor necrosis factor receptor (sTNFR) 1, interleukin (IL)-6, and high-sensitivity C-reactive protein (hsCRP). LV mass was calculated according to an established formula. LVH was defined as LV mass greater than the 90th percentile of the participants.
The mean age was 67.4 ± 8.8 years, 35.5% were men, 61.7% were Hispanic, 19.7% were black, and 18.6% were white. In univariate analyses, hsCRP, IL-6 and sTNFR1 were significantly associated with LV mass. Multiple linear regression analyses demonstrated that sTNFR1 (P = 0.0008) was associated with LV mass after adjusting for demographic and medical risk factors, but hsCRP and IL-6 were not. When all markers were included in the same model, sTNFR1 remained significant, but hsCRP and IL-6 did not. Compared with the lowest quartile of sTNFR1, those in the highest quartile were more likely to have LVH (Odds ratio = 1.84, 95% Confidence interval, 0.97 to 3.64, P = 0.06).
Soluble TNFR1, but not hsCRP nor IL-6, is independently associated with increased LV mass. Chronic subclinical inflammation including the TNFR1-associated system may contribute to LVH.
PMCID: PMC2848526  PMID: 19390513
echocardiography; epidemiology; left ventricular hypertrophy; inflammation
18.  Neuroimaging Findings in Cryptogenic Stroke Patients with and without PFO 
Patent foramen ovale (PFO) and cryptogenic stroke (CS) are commonly associated but some PFOs are incidental. Specific radiological findings associated with PFO may be more likely to indicate a PFO-related etiology. We examined whether specific radiological findings are associated with PFO among subjects with CS and known PFO status.
We analyzed the Risk of Paradoxical Embolism (RoPE) database of subjects with CS and known PFO status, for associations between PFO and: 1) index stroke seen on imaging, 2) index stroke size, 3) index stroke location, 4) multiple index strokes, and 5) prior stroke on baseline imaging. We also compared imaging with purported “high risk” echocardiographic features.
Subjects (n=2680) were significantly more likely to have a PFO if their index stroke was large (OR 1.36, p=0.0025), seen on index imaging (OR 1.53, p=0.003), and superficially located (OR 1.54, p<0.0001). A prior stroke on baseline imaging was associated with not having a PFO (OR 0.66, p<0.0001). Finding multiple index strokes was unrelated to PFO status (OR 1.21, p=0.161). No echocardiographic variables were related to PFO status.
This is the largest study to report the radiological characteristics of patients with CS and known PFO status. Strokes that were large, radiologically apparent, superficially located, or unassociated with prior radiological infarcts were more likely to be PFO associated than were unapparent, smaller, or deep strokes, and those accompanied by chronic infarcts. There was no association between PFO and multiple acute strokes nor between specific echocardiographic PFO features with neuroimaging findings.
PMCID: PMC3595100  PMID: 23339957
Patent Foramen Ovale; Cryptogenic Stroke; Imaging
19.  Lipoprotein-associated phospholipase A2 activity and risk of recurrent stroke 
Mass levels of lipoprotein-associated phospholipase A2 (Lp-PLA2), a leukocyte-derived enzyme involved in metabolism of low-density lipoprotein to pro-inflammatory mediators, are associated with prognosis after stroke. Lp-PLA2 mass correlates only moderately with levels of Lp-PLA2 activity. The relationship of Lp-PLA2 activity to risk of stroke recurrence is unknown. We hypothesized that Lp-PLA2 activity levels would predict risk of recurrence.
In the population-based Northern Manhattan Study (NOMAS), first ischemic stroke patients ≥40 years were followed for recurrent stroke. Levels of Lp-PLA2 activity were measured in 467 patients, and categorized by quartile. Cox proportional hazard models were used to calculate hazard ratios and 95% confidence intervals (HR, 95% CI) for risk of recurrent stroke associated with marker quartiles after adjusting for demographics, vascular risk factors, and high sensitivity C-reactive protein (hsCRP).
Mean age was 68.9 ± 12.7 years; 54.6% were women, 53.3% Hispanic, 27.2% black, and 17.8% white. Median follow-up was 4.0 years, and there were 80 recurrent strokes. Compared to the lowest quartile of Lp-PLA2 activity, those in the highest had an increased risk of recurrent stroke (adjusted HR 2.54, 95% CI 1.01-6.39).
Stroke patients with Lp-PLA2 activity levels in the highest quartile, compared to those in the lowest quartile, had an increased risk of recurrence after first ischemic stroke. Further studies are warranted to determine whether this biomarker has clinical utility in determining high-risk populations of stroke survivors, and whether anti-inflammatory strategies that reduce levels of activity of Lp-PLA2 reduce risk of stroke recurrence.
PMCID: PMC2846303  PMID: 19018137
20.  A quantitative perspective to the study of brain arterial remodeling of donors with and without HIV in the Brain Arterial Remodeling Study (BARS) 
Mechanisms underlying brain arterial remodeling are uncertain. We tested the hypothesis that arterial size and location are important determinants of arterial characteristics. We collected large and penetrating brain arteries from cadavers with and without HIV. Morphometric characterization was obtained from digital images using color-based thresholding. The association of arterial size and location with lumen diameter, media and adventitia area, media proportion, a wall thickness, wall-to-lumen ratio and stenosis was obtained with multilevel mixed models and a P value ≤ 0.05 was considered significant. We included 336 brains, in which 2279 large arteries and 1488 penetrating arteries were identified. We found that arterial size was significantly associated with all arterial characteristics studied of large and penetrating arteries with exception of arterial stenosis in large arteries. After adjusting for size, an independent association was found between lumen diameters, media and adventitia thickness with artery locations. Arterial stenosis was also associated with artery location in both large and penetrating arteries. In summary, significant effects of size and/or location were found in arterial characteristics typically used to define arterial remodeling. Brain arterial remodeling characteristics differ across arterial sizes and location, and these differences should be controlled for in future studies of brain arterial remodeling.
PMCID: PMC3928551  PMID: 24600402
brain arteries; arterial remodeling; media thickness; stenosis; HIV; cardiovascular disease
21.  Interleukin 6 Plasma Concentration Associates with Cognitive Decline: The Northern Manhattan Study 
Neuroepidemiology  2013;40(4):253-259.
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.
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.
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.
Interleukin 6 associated with cognitive decline among older participants in this race/ethnically diverse sample independent of other vascular risk factors and CRP.
PMCID: PMC3725587  PMID: 23364322
cognitive decline; cohort studies; Interleukin-6; inflammation
22.  Lipoprotein-Associated Phospholipase A2 Is Associated with Atherosclerotic Stroke Risk: The Northern Manhattan Study 
PLoS ONE  2014;9(1):e83393.
Lipoprotein-associated phospholipase A2 (LpPLA2) levels are associated with stroke, though whether this extends to all populations and stroke subtypes is unknown.
Serum samples from stroke-free community participants in the Northern Manhattan Study were assayed for LpPLA2 mass and activity. Participants were followed annually for stroke. Cox-proportional-hazard models were fitted to estimate hazard-ratios and 95% confidence intervals (HR, 95% CI) for the association of LpPLA2 levels with ischemic stroke (IS), after adjusting for demographic and medical risk factors.
Serum samples were available in 1946 participants, of whom 151 (7.8%) experienced a first IS during median follow-up 11 years. Mean age was 69 (SD 10), 35.6% were men, 20% non-Hispanic Whites, 22% non-Hispanic Blacks, and 55% Hispanics. LpPLA2 mass and activity levels were not associated with overall IS risk.
LpPLA2 mass but not activity levels were associated with strokes due to large artery atherosclerosis (LAA; adjusted HR per SD 1.55, 95% CI 1.17–2.04). There was a dose-response relationship with LAA (compared to first quartile, 2nd quartile HR = 1.43, 95% CI 0.23–8.64; 3rd quartile HR = 4.47, 95% CI 0.93–21.54; 4th quartile HR = 5.07, 95% CI 1.07–24.06). The associations between LpPLA2-mass and LAA-stroke risk differed by race-ethnicity (p = 0.01); LpPLA2-mass was associated with increased risk of LAA among non-Hispanic Whites (adjusted HR per SD 1.44, 95% CI 0.98–2.11), but not other race-ethnic groups.
LpPLA2-mass levels were associated with risk of atherosclerotic stroke among non-Hispanic White participants, but not in other race-ethnic groups in the cohort. Further study is needed to confirm these race-ethnic differences and the reasons for them.
PMCID: PMC3886969  PMID: 24416164
23.  Hospitalization for infection and risk of acute ischemic stroke: The Cardiovascular Health Study 
Background and Purpose
Little is known about acute precipitants of ischemic stroke, although evidence suggests infections contribute to risk. We hypothesized that acute hospitalization for infection is associated with short-term risk of stroke.
The case-crossover design was used to compare hospitalization for infection during case periods (90, 30, or 14 days prior to incident ischemic stroke) and control periods (equivalent time periods exactly 1 or 2 years prior to stroke) in the Cardiovascular Health Study, a population-based cohort of 5888 elderly participants from 4 US sites. Odds ratios and 95% confidence intervals (OR, 95% CI) were calculated using conditional logistic regression. Confirmatory analyses assessed hazard ratios (HR) of stroke from Cox regression models with hospitalization for infection as a time-varying exposure.
During a median follow-up of 12.2 years, 669 incident ischemic strokes were observed in participants without baseline history of stroke. Hospitalization for infection was more likely during case than control time periods; for 90 days prior to stroke, OR=3.4 (95% CI 1.8–6.5). The point estimates of risks were higher when examining shorter intervals: for 30 days, OR= 7.3 (95% CI 1.9–40.9), and 14 days, OR=8.0 (95% CI 1.7–77.3). In survival analyses, risk of stroke was associated with hospitalization for infection in the preceding 90 days, adjusted HR=2.4 (95% CI 1.6–3.4).
Hospitalization for infection is associated with a short-term increased risk of stroke, with higher risks observed for shorter intervals preceding stroke.
PMCID: PMC3125478  PMID: 21546476
Epidemiology; Cerebral Infarction; Infectious Diseases
24.  Risk of a Thrombotic Event after the 6-Week Postpartum Period 
The New England journal of medicine  2014;370(14):1307-1315.
The postpartum state is associated with a substantially increased risk of thrombosis. It is uncertain to what extent this heightened risk persists beyond the conventionally defined 6-week postpartum period.
Using claims data on all discharges from nonfederal emergency departments and acute care hospitals in California, we identified women who were hospitalized for labor and delivery between January 1, 2005, and June 30, 2010. We used validated diagnosis codes to identify a composite primary outcome of ischemic stroke, acute myocardial infarction, or venous thromboembolism. We then used conditional logistic regression to assess each patient's likelihood of a first thrombotic event during sequential 6-week periods after delivery, as compared with the corresponding 6-week period 1 year later.
Among the 1,687,930 women with a first recorded delivery, 1015 had a thrombotic event (248 cases of stroke, 47 cases of myocardial infarction, and 720 cases of venous thromboembolism) in the period of 1 year plus up to 24 weeks after delivery. The risk of primary thrombotic events was markedly higher within 6 weeks after delivery than in the same period 1 year later, with 411 events versus 38 events, for an absolute risk difference of 22.1 events (95% confidence interval [CI], 19.6 to 24.6) per 100,000 deliveries and an odds ratio of 10.8 (95% CI, 7.8 to 15.1). There was also a modest but significant increase in risk during the period of 7 to 12 weeks after delivery as compared with the same period 1 year later, with 95 versus 44 events, for an absolute risk difference of 3.0 events (95% CI, 1.6 to 4.5) per 100,000 deliveries and an odds ratio of 2.2 (95% CI, 1.5 to 3.1). Risks of thrombotic events were not significantly increased beyond the first 12 weeks after delivery.
Among patients in our study, an elevated risk of thrombosis persisted until at least 12 weeks after delivery. However, the absolute increase in risk beyond 6 weeks after delivery was low. (Funded by the National Institute of Neurological Disorders and Stroke.)
PMCID: PMC4035479  PMID: 24524551
25.  Princeton Proceedings: Inflammatory Mechanisms of Stroke 
Stroke; a journal of cerebral circulation  2010;41(10 Suppl):S3-S8.
Basic and clinical research provide evidence that inflammatory mechanisms play a central role in the pathogenesis and progression of atherosclerosis, plaque rupture, thrombosis, and stroke. Inflammatory biomarkers such as high-sensitivity C-reactive protein (hsCRP) have been identified as predictors of first stroke and prognosis after stroke. The value of hsCRP and other markers may depend on the characteristics of the study population; their utility may be less among populations with high vascular risk. A recent randomized clinical trial suggests that the use of rosuvastatin therapy in otherwise healthy patients with hsCRP > 2 mg/dl can reduce the risk of a first stroke by 50%. The prognostic role of hsCRP among patients after a stroke, however, is less clear, and other biomarkers, including lipoprotein-associated phospholipase A2, may provide complementary information about risk of stroke recurrence. Infections, moreover, may contribute to inflammation and stroke risk. While no single infectious organism is likely to be identified as the direct cause of atherosclerosis, summary measures of multiple chronic infectious exposures, or “infectious burden,” have been associated with risk of stroke and atherosclerosis affecting carotid arteries. Acute infections have also been found to serve as stroke triggers in epidemiological studies. Recommendations to vaccinate patients with cardiovascular disease against influenza represent the first specific anti-infective strategy to be employed in vascular prophylaxis. Further studies are needed to determine the role of treatment of inflammation and infection in stroke prevention.
PMCID: PMC2963080  PMID: 20876499
atherosclerosis; inflammation; infection; infectious burden; statins; stroke; cerebral thrombosis; risk factors

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