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Executive function is a cognitive domain with sizable heritability representing higher-order cognitive abilities. Genome-wide association studies (GWAS) of executive function are sparse, particularly in populations underrepresented in medical research. We performed a GWAS on a composite measure of executive function that included measures of mental flexibility and reasoning using data from the Northern Manhattan Study, a racially and ethnically diverse cohort (N = 1077, 69% Hispanic, 17% non-Hispanic Black and 14% non-Hispanic White). Four SNPs located in the long intergenic non-protein coding RNA 1362 gene, LINC01362, on chromosome 1p31.1, were significantly associated with the composite measure of executive function in this cohort (top SNP rs2788328, ß = 0.22, p = 3.1 × 10 -10 ). The associated SNPs have been shown to influence expression of the tubulin tyrosine ligase like 7 gene, TTLL7 and the protein kinase CAMP-activated catalytic subunit beta gene, PRKACB, in several regions of the brain involved in executive function. Together, these findings present new insight into the genetic underpinnings of executive function in an understudied population., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Introduction: Non-traumatic Cervical Artery Dissection (CeAD) is a leading cause of ischemic stroke in the young. Influenza-like illnesses (ILI) trigger ischemic strokes. We hypothesized that influenza and ILI are associated with CeAD., Methods: In a case-crossover study within the New York State (NYS) Department of Health Statewide Planning and Research Cooperative System (2006-2014), we used ICD-9 codes to exclude major trauma and to define CeAD, influenza, and the Centers for Disease Control defined ILI. We estimated the association of ILI and influenza with CeAD by comparing their prevalence in intervals immediately prior (0-30,0-90,0-180, and 0-365 days) to CeAD (case period) to their prevalence exactly one and two years earlier (control periods). Conditional logistic regression models generated odds ratios and 95% confidence intervals (OR, 95% CI). Models were adjusted for NYS estimates of influenza prevalence rates., Results: Our sample included 3,610 cases of CeAD (mean age 52±16 years, 54.7% male, 6.2% Hispanic, 9.9% Black, 68.7% White). During case periods, 7.3% had one or more ILI. ILI was more likely within 90 days of CeAD compared to the same time interval one and two years before (0-15 days: adjusted OR 1.88, 95%CI 1.20-2.94; 0-30 days: adjusted OR 1.74, 95%CI 1.22-2.46; 0-90 days: adjusted OR 1.35, 95%CI 1.00-1.81). Influenza trended with CeAD (adjusted OR 1.86, 95%CI 0.37-9.24), but these results were not statistically significant, due to limited instances of confirmed influenza., Conclusions: ILI may increase risk of CeAD for 15 days, and possibly up to three months., Competing Interests: Declaration of Competing Interest The authors have no conflicts of interest to declare., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Background/objectives: Inflammatory biomarkers have been associated with stroke and mortality, but inflammation may also have detrimental effects beyond acute events. We hypothesized that serum concentrations of interleukin-6 (IL6) and lipoprotein-associated phospholipase A2 (LpPLA2) were inversely associated with long-term functional decline independently of vascular risk factors, stroke and myocardial infarction (MI) occurring during follow-up., Design: Prospective population based cohort study., Setting: The Northern Manhattan Study., Participants (including the Sample Size): Race/ethnically diverse stroke-free individuals in northern Manhattan aged ≥40 years (n = 3298)., Intervention: None., Measurements: Annual functional assessments with the Barthel index (BI), for a median of 13 years. BI was analyzed as a continuous variable (range 0-100). Baseline demographics, risk factors, and laboratory studies were collected, including IL6 (n = 1679), LpPLA2 mass (n = 1912) and activity (n = 1937). Separate mixed models estimated standardized associations between each biomarker and baseline functional status and change over time, adjusting for demographics, vascular risk factors, social variables, cognition, and depression measured at baseline, and stroke and MI occurring during follow-up., Results: Mean age was 69 (SD 10) years, 35% were male, 53% Hispanic, 74% hypertensive, and 16-24% diabetic. LogIL6 was associated with decline in BI over time (-0.13 points per year, 95% CI -0.24, -0.02) and marginally with baseline BI (-0.20, 95% CI -0.40, 0.01). LpPLA2 activity levels were associated with baseline BI (-0.36, 95% CI -0.68, -0.04) but not change over time, and LpPLA2 mass levels were not associated with either., Conclusion: In this large population-based study, higher serum inflammatory biomarker levels were associated with disability, even when adjusting for baseline covariates and stroke and MI occurring during follow-up., Competing Interests: Dr. Sacco receives grant support from the NIH, AHA, and Boehringer Ingelheim. Dr. Elkind receives compensation for providing consultative services for Biotelemetry/Cardionet, BMSPfizer Partnership, Boehringer-Ingelheim, and Sanofi-Regeneron; serves as an expert witness for Merck/Organon (Nuvaring and stroke), BMS-Sanofi Partnership (Plavix and stroke), and Hi-Tech (DMAA and stroke); serves on the National, Founders Affiliate, and New York City chapter boards of the American Heart Association/American Stroke Association; and receives royalties from UpToDate for chapters related to cryptogenic stroke. There are no patents, products in development or marketed products associated with this research to declare. This does not alter our adherence to PLOS ONE policies on sharing data and materials.

Objectives: To test associations between subclinical brain infarcts (SBIs) and functional decline independently of intervening clinical vascular events and other vascular risk factors., Design: Longitudinal follow-up for a mean 7.3 years. Generalized estimating equation models were used to test associations between SBIs, number of perivascular spaces (PVSs), baseline Barthel Index (BI), and change in BI, adjusting for sociodemographic, vascular, and cognitive risk factors and for stroke and myocardial infarction occurring during follow-up., Setting: Population-based prospective cohort study., Participants: Stroke-free individuals from the racially and ethnically diverse Northern Manhattan Study (N=1,290)., Measurements: Annual functional assessments using the BI (range 0-100)., Results: Mean age was 70.6 ± 9.0, 40% of participants were male, 66% were Hispanic, 193 (16%) had SBIs, and 508 (42%) had large PVSs. SBIs were not associated with baseline BI. In a fully adjusted model, there was a change in BI of -0.85 points per year (95% confidence interval (CI)=-1.01 to -0.69); those with SBI had an additional change in BI 0f -0.88 points (95% CI=-1.43 to -0.32). There were no associations between PVS and baseline BI or change in BI., Conclusion: In a large population-based study, we found a strong and independent association between "subclinical" markers of cerebrovascular injury and important clinical, person-centered functional trajectories. Future research could clarify the evolution of such subclinical markers over time and test strategies to prevent their progression and minimize related disability. J Am Geriatr Soc 66:2144-2150, 2018., (© 2018, Copyright the Authors Journal compilation © 2018, The American Geriatrics Society.)

Background and Purpose: Cognition and education influence functional trajectories, but whether associations differ with subclinical brain infarcts (SBI) or white matter hyperintensity volume (WMHV) is unknown. We hypothesized that SBI and WMHV moderated relationships between cognitive performance and education and functional trajectories., Methods: A total of 1290 stroke-free individuals underwent brain magnetic resonance imaging and were followed for 7.3 years (mean) with annual functional assessments with the Barthel index (range, 0-100). Magnetic resonance imaging measurements included pathology-informed SBI (PI-SBI) and WMHV (% total cranial volume). Generalized estimating equation models tested associations between magnetic resonance imaging variables and baseline Barthel index and change in Barthel index, adjusting for demographic, vascular, cognitive, and social risk factors, and stroke and myocardial infarction during follow-up. We tested interactions among education level, baseline cognitive performance (Mini-Mental State score), and functional trajectories and ran models stratified by levels of magnetic resonance imaging variables., Results: Mean age was 70.6 (SD, 9.0) years; 19% had PI-SBI, and mean WMHV was 0.68%. Education did not modify associations between cognition and functional trajectories. PI-SBI modified associations between cognition and functional trajectories ( P =0.04) with a significant protective effect of better cognition on functional decline seen only in those without PI-SBI. There was no significant interaction for WMHV ( P =0.8). PI-SBI, and greater WMHV, were associated with 2- to 3-fold steeper functional decline, holding cognition constant., Conclusions: PI-SBI moderated the association between cognition and functional trajectories, with 3-fold greater decline among those with PI-SBI (compared with no PI-SBI) and normal baseline cognition. This highlights the strong and independent association between subclinical markers and patient-centered trajectories over time., (© 2018 American Heart Association, Inc.)

Background: Artificially (diet) and sugar-sweetened (regular) soda consumption have been associated with an increased risk of diabetes, but the literature on diet soda is inconsistent and the mechanisms unclear., Objective: We examined the relation between diet soda and regular soda consumption with the risk of incident diabetes in a longitudinal multiethnic population-based cohort., Methods: The study population included 2019 participants (mean ± SD age:  69 ± 10 y; 64% women; 23% white, 22% black, 53% Hispanic) in the Northern Manhattan Study who were free of diabetes and stroke at baseline. Soda consumption was assessed by a food-frequency questionnaire at baseline and examined continuously and categorically (<1/mo: sugar-sweetened = 908, diet = 1615; 1/mo-6/wk: sugar-sweetened = 830, diet = 298; daily: sugar-sweetened = 281, diet = 106). Weibull regression models were used to estimate the associations between soda consumption and incident diabetes, adjusting for demographics and vascular risk factors including body mass index (BMI) and calorie consumption., Results: During a mean ± SD follow-up of 11 ± 5 y, 368 participants developed diabetes. Sugar-sweetened soda was positively associated with incident diabetes (per soda per day HR = 1.15, 95% CI:  1.02, 1.31). The observed association between diet soda and elevated risk of diabetes was largely explained by BMI at the time of diet assessment, though the association remained strong and independent of BMI among those who were overweight or obese (daily compared to <1/mo: HR = 1.63, 95% CI:  1.04, 2.55)., Conclusions: This study supports the importance of sugar-sweetened beverage consumption in the diabetes epidemic. However, the results support previous studies suggesting that switching to artificially sweetened diet beverages may not lower the risk of diabetes, as diet soda consumption cannot be ruled out as an independent diabetes risk factor.

Introduction: White matter hyperintensity volume (WMHV) and subclinical brain infarcts (SBI) are associated with impaired mobility, but less is known about the association of WMHV in specific brain regions. We hypothesized that anterior WMHV would be associated with lower scores on the Short Physical Performance Battery (SPPB), a well-validated mobility scale., Methods: The SPPB was measured a median of 5 years after enrollment into the Northern Manhattan MRI sub study. Volumetric distributions for WMHV in 14 brain regions as a proportion of total cranial volume were determined. Multi-variable linear regression was performed to examine the association of SBI and regional log-WMHV with the SPPB score., Results: Among 668 participants with SPPB measurements (mean 74 ± 9 years, 37% male and 70% Hispanic), the mean SPPB score was 8.2 ± 2.9. Total (beta = -0.3 per SD, p = 0.001), anterior periventricular (beta = -0.4 per SD, p = 0.001), parietal (beta = -0.2 per SD, p = 0.02) and frontal (beta = -0.3 per SD, p = 0.002) WMHVs were associated with SPPB; other WMHV and SBI were not associated with the SPPB., Conclusions: WMHV, especially in the anterior -cerebral regions, is associated with a lower SPPB. Prevention of subclinical cerebrovascular disease is a potential target to prevent physical decline in the elderly., (© 2018 S. Karger AG, Basel.)

Purpose: Cardiovascular disease is a major contributor to morbidity and mortality, and prevention relies on accurate identification of those at risk. Studies of the association between quality of life (QOL) and mortality and vascular events incompletely accounted for depression, cognitive status, social support, and functional status, all of which have an impact on vascular outcomes. We hypothesized that baseline QOL is independently associated with long-term mortality in a large, multi-ethnic urban cohort., Methods: In the prospective, population-based Northern Manhattan Study, Spitzer QOL index (SQI, range 0-10, with ten signifying the highest QOL) was assessed at baseline. Participants were followed over a median 11 years for stroke, myocardial infarction (MI), and vascular and non-vascular death. Multivariable Cox proportional hazards regression estimated hazard ratio and 95% confidence interval (HR, 95% CI) for each outcome, with SQI as the main predictor, dichotomized at 10, adjusting for baseline demographics, vascular risk factors, history of cancer, social support, cognitive status, depression, and functional status., Results: Among 3298 participants, mean age was 69.7 + 10.3 years; 1795 (54.5%) had SQI of 10. In fully adjusted models, SQI of 10 (compared to SQI <10) was associated with reduced risk of all-cause mortality (HR 0.80, 95% CI 0.72-0.90), vascular death (0.81, 0.69-0.97), non-vascular death (0.78, 0.67-0.91), and stroke or MI or death (0.82, 0.74-0.91). In fully adjusted competing risk models, there was no association with stroke (0.93, 0.74-1.17), MI (0.98, 0.75-1.28), and stroke or MI (1.03, 0.86-1.24). Results were consistent when SQI was analyzed continuously., Conclusion: In this large population-based cohort, highest QOL was inversely associated with long-term mortality, vascular and non-vascular, independently of baseline primary vascular risk factors, social support, cognition, depression, and functional status. QOL was not associated with non-fatal vascular events.

We hypothesized that tumor necrosis factor receptor 1 (TNFR1) levels are associated with long-term trajectories of functional status independently of vascular risk factors and the occurrence of stroke and myocardial infarction (MI) during follow-up. In the Northern Manhattan Study, stroke-free persons aged ≥40 years in northern Manhattan (New York, New York) had annual assessments with the Barthel index (BI) for a median of 13 years (1993-2015). Assessment of baseline demographic factors, risk factors, and laboratory studies included measurement of TNFR1 (n = 1,863). Generalized estimating equations models were used to estimate standardized associations between TNFR1 and 1) baseline functional status and 2) change in function over time, adjusting for demographic factors, vascular risk factors, social variables, cognition, and depression, as well as stroke and MI occurrence during follow-up. The mean age of participants was 70 (standard deviation (SD), 10) years; 66% were women, and 55% were Hispanic. The mean TNFR1 level was 2.57 mg/L. TNFR1 was associated with baseline BI (-0.93 BI points per SD increment in TNFR1; 95% confidence interval: -1.59, -0.26) and change over time (-0.36 BI points per year per SD increment in TNFR1; 95% confidence interval: -0.69, -0.03). In this large population-based study, higher TNFR1 levels were associated with greater baseline disability and disability over time, even with adjustment for baseline covariates and stroke and MI occurrence during follow-up., (© The Author 2017. Published by Oxford University Press on behalf of the Johns Hopkins Bloomberg School of Public Health. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Background: Previous studies of exercise have focused on measuring physical activity in totality using summary statistics such as metabolic equivalent score for total intensity or total energy count., Objective: We aimed to examine the multidimensionality of leisure-time physical activity (LTPA) and to identify the specific LTPA components that were associated with cardiovascular mortality in the elderly., Design and Participants: The Northern Manhattan Study (NOMAS) is a multiethnic prospective cohort of elderly stroke-free individuals consisting of a total of 3298 participants recruited between 1993 and 2001, with a median follow-up of 17 years., Main Measures: Physical activity questionnaire data were available in 3293 NOMAS participants, who were categorized into subgroups with similar exercise patterns by model-based cluster analysis. Three subgroup-defining LTPA features were identified and were considered as primary exposures in Cox proportional hazard models: frequency of activity, number of activity types (variety), and energy-to-duration ratio (EDR). We considered cardiovascular mortality and non-cardiovascular mortality as outcomes in Cox cause-specific proportional hazard models, and all-cause mortality as outcome in Cox models., Key Results: A high activity frequency was associated with reduced cardiovascular mortality (hazard ratio, HR = 0.93, P = 0.03), but demonstrated no effect on non-cardiovascular death. A high EDR was associated with increased risk of cardiovascular death (HR = 1.30, P = 0.01). A high number of activity types was beneficial in reducing all-cause mortality (HR = 0.87, P = 0.01)., Conclusions: Exercise frequency was protective against cardiovascular mortality, and a high variety of activity was protective against all-cause mortality. The performance of frequent and varied non-intense exercise in an elderly population such as ours is achievable and can reduce the risk of death., Competing Interests: The authors declare that they have no conflict of interest. Funding/Support This study was supported by the National Institutes of Health grants R01 HL111195 (Cheung/Elkind), NS K23073104 (Willey), and R01 NS029993 (Sacco/Elkind). Role of the Funder/Sponsor The funding source had no role in the design and conduct of the study with regard to the collection, management, analysis, or interpretation of the data; preparation, review, or approval of the manuscript; or the decision to submit the manuscript for publication.

Background The fastest growing segment of the population is those age ≥80 who have the highest stroke incidence. Risk factor management is complicated by polypharmacy-related adverse events. Aims To characterize the impact of physical inactivity for stroke by age in a multi-ethnic prospective cohort study (NOMAS, n = 3298). Methods Leisure time physical activity was assessed by a validated questionnaire and our primary exposure was physical inactivity (PI). Participants were followed annually for incident stroke. We fit Cox-proportional hazard models to calculate hazard ratios and 95% confidence intervals (HR 95% CI) for the association of PI and other risk factors with risk of stroke including two-way interaction terms between the primary exposures and age (<80 vs. ≥80). Results The mean age was 69 ± 10.3 years and 562 (17%) were ≥80 at enrolment. PI was common in the cohort (40.8%). Over a median of 14 years, we found 391 strokes. We found a significant interaction of age ≥80 on the risk of stroke with PI ( p = 0.03). In stratified models, PI versus any activity (adjusted HR 1.60, 95%CI 1.05-2.42) was associated with an increased risk of stroke among those ≥80. Conclusion Physical inactivity is a treatable risk factor for stroke among those older than age 80. Improving activity may reduce the risk of stroke in this segment of the population.

Background: High-sensitivity C-reactive protein (CRP) has been associated with cardiovascular events and mortality, but the association of CRP with functional status is not well defined. We hypothesised that serum levels of high-sensitivity CRP are associated with long-term trajectories of functional status independently of vascular risk factors and stroke and myocardial infarction (MI) occurring during follow-up., Design: Prospective, population-based., Setting: Northern Manhattan Study., Participants: Stroke-free participants aged ≥40 years., Measurements: Annual assessments of disability with the Barthel index (BI) for a median of 13 years. BI was analysed as a continuous variable (range 0–100). Baseline demographics, risk factors and laboratory studies were collected, including CRP (n = 2,240). Separate generalised estimating equation models estimated standardised associations between CRP and (i) baseline functional status and (ii) change in function over time, adjusting for demographics, vascular risk factors, social variables, cognition, and depression measured at baseline, and stroke and MI occurring during follow-up., Results: Mean age was 69 (SD 10) years, 36% were male, 55% Hispanic, 75% hypertensive and 21% diabetic; 337 MIs and 369 first strokes occurred during follow-up. Mean CRP level was 5.24 mg/l (SD 8.86). logCRP was associated with baseline BI (−0.34 BI points per unit logCRP, 95% confidence interval −0.62, −0.06) but not with change over time., Conclusions: In this large population-based study, higher serum CRP levels were associated with higher baseline disability, even when adjusting for baseline covariates and stroke and MI occurring during follow-up. Systemic inflammation may contribute to disability independently of clinical vascular events.

Introduction: Gait speed is associated with multiple adverse outcomes of aging. We hypothesized that physical inactivity would be prospectively inversely associated with gait speed independently of white matter hyperintensity volume and silent brain infarcts on MRI., Methods: Participants in the Northern Manhattan Study MRI sub-study had physical activity assessed when they were enrolled into the study. A mean of 5 years after the MRI, participants had gait speed measured via a timed 5-meter walk test. Physical inactivity was defined as reporting no leisure-time physical activity. Multi-variable logistic and quantile regression was performed to examine the associations between physical inactivity and future gait speed adjusted for confounders., Results: Among 711 participants with MRI and gait speed measures (62% women, 71% Hispanic, mean age 74.1 ± 8.4), the mean gait speed was 1.02 ± 0.26 m/s. Physical inactivity was associated with a greater odds of gait speed in the lowest quartile (<0.85 m/s, adjusted OR 1.90, 95% CI 1.17-3.08), and in quantile regression with 0.06 m/s slower gait speed at the lowest 20 percentile (p = 0.005)., Conclusions: Physical inactivity is associated with slower gait speed independently of osteoarthritis, grip strength, and subclinical ischemic brain injury. Modifying sedentary behavior poses a target for interventions aimed at reducing decline in mobility., (© 2017 S. Karger AG, Basel.)

Background and Purpose: Chronic infections and neuroendocrine dysfunction may be risk factors for ischemic stroke (IS). We hypothesized that selected blood biomarkers of infection (procalcitonin [PCT]), hypothalamic-pituitary-axis function (copeptin), and hemodynamic dysfunction (midregional proatrial natriuretic peptide [MRproANP]) are associated with incident IS risk in the multiethnic, urban Northern Manhattan Study (NOMAS) cohort., Methods: A nested case-control study was performed among initially stroke-free participants. Cases were defined as first IS (n=172). We randomly selected controls among those who did not develop an event (n=344). We calculated Cox proportional hazards models with inverse probability weighting to estimate the association of blood biomarkers with risk of stroke after adjusting for demographic, behavioral, and medical risk factors., Results: Those with PCT and MRproANP, but not copeptin, in the top quartile, compared with the lowest quartile, were associated with IS (for PCT adjusted hazard ratio [HR], 1.9; 95% confidence interval [CI], 1.0-3.8 and for MRproANP adjusted HR, 3.5; 95% CI, 1.6-7.5). The associations of PCT and MRproANP differed by stroke etiology; PCT levels in the top quartile were particularly associated with small vessel stroke (adjusted HR, 5.1; 95% CI, 1.4-18.7) and MRproANP levels with cardioembolic stroke (adjusted HR, 16.3; 95% CI, 3.7-70.9)., Conclusions: Higher levels of PCT, a marker of infection, and MRproANP, a marker for hemodynamic stress, were independently associated with IS risk. PCT was specifically associated with small vessel and MRproANP with cardioembolic stroke risk. Further study is needed to validate these biomarkers and determine their significance in stroke risk prediction and prevention., (© 2016 American Heart Association, Inc.)

Purpose: To identify risk factors (RF) for diabetes within a multiethnic cohort and to examine whether race-ethnicity modified their effects., Methods: Participants in the Northern Manhattan Study without diabetes at baseline were studied from 1993 to 2014 (n=2430). Weibull regression models with interval censoring data were fit to calculate hazard ratios and 95% confidence intervals for incident diabetes. We tested for interactions between RF and race-ethnicity., Results: During a mean follow-up period of 11years, there were 449 diagnoses of diabetes. Being non-Hispanic black (HR 1.69 95% CI 1.11-2.59) or Hispanic (HR 2.25 95% CI 1.48-3.40) versus non-Hispanic white, and body mass index (BMI; HR 1.34 per SD 95% CI 1.21-1.49) were associated with greater risk of diabetes; high-density lipoprotein cholesterol (HR 0.75 95% CI 0.66-0.86) was protective. There were interactions by race-ethnicity. In stratified models, the effects of BMI, current smoking, and C-reactive protein (CRP) on risk of diabetes differed by race-ethnicity (p for interaction <0.05). The effects were greater among non-Hispanic whites than non-Hispanic blacks and Hispanics., Conclusions: Although Hispanics and non-Hispanic blacks had a greater risk of diabetes than whites, there were variations by race-ethnicity in the association of BMI, smoking, and CRP with risk of diabetes. Unique approaches should be considered to reduce diabetes as traditional RF may not be as influential in minority populations., (Copyright © 2015 Elsevier Inc. All rights reserved.)

Background and Purpose: Electrocardiographic left atrial abnormality has been associated with stroke independently of atrial fibrillation (AF), suggesting that atrial thromboembolism may occur in the absence of AF. If true, we would expect an association with cryptogenic or cardioembolic stroke rather than noncardioembolic stroke., Methods: We conducted a case-cohort analysis in the Northern Manhattan Study, a prospective cohort study of stroke risk factors. P-wave terminal force in lead V1 was manually measured from baseline ECGs of participants in sinus rhythm who subsequently had ischemic stroke (n=241) and a randomly selected subcohort without stroke (n=798). Weighted Cox proportional hazard models were used to examine the association between P-wave terminal force in lead V1 and stroke etiologic subtypes while adjusting for baseline demographic characteristics, history of AF, heart failure, diabetes mellitus, hypertension, tobacco use, and lipid levels., Results: Mean P-wave terminal force in lead V1 was 4452 (±3368) μV*ms among stroke cases and 3934 (±2541) μV*ms in the subcohort. P-wave terminal force in lead V1 was associated with ischemic stroke (adjusted hazard ratio per SD, 1.20; 95% confidence interval, 1.03-1.39) and the composite of cryptogenic or cardioembolic stroke (adjusted hazard ratio per SD, 1.31; 95% confidence interval, 1.08-1.58). There was no definite association with noncardioembolic stroke subtypes (adjusted hazard ratio per SD, 1.14; 95% confidence interval, 0.92-1.40). Results were similar after excluding participants with a history of AF at baseline or new AF during follow-up., Conclusions: ECG-defined left atrial abnormality was associated with incident cryptogenic or cardioembolic stroke independently of the presence of AF, suggesting atrial thromboembolism may occur without recognized AF., (© 2015 American Heart Association, Inc.)

Background and Purpose: Although left atrial enlargement (LAE) increases incident stroke risk, the association with recurrent stroke is less clear. Our aim was to determine the association of LAE with recurrent stroke most likely related to embolism (cryptogenic and cardioembolic) and all ischemic stroke recurrences., Methods: We followed 655 first ischemic stroke patients in the Northern Manhattan Stroke Study for ≤5 years. LA size from 2D echocardiography was categorized as normal LAE (52.7%), mild LAE (31.6%), and moderate-severe LAE (15.7%). We used Cox proportional hazard models to calculate the hazard ratios and 95% confidence intervals for the association of LA size and LAE with recurrent cryptogenic/cardioembolic and total recurrent ischemic stroke., Results: LA size was available in 529 (81%) patients. Mean age at enrollment was 69±13 years; 45.8% were male, 54.0% Hispanic, and 18.5% had atrial fibrillation. Over a median of 4 years, there were 65 recurrent ischemic strokes (29 were cardioembolic or cryptogenic). In multivariable models adjusted for confounders, including atrial fibrillation and heart failure, moderate-severe LAE compared with normal LA size was associated with greater risk of recurrent cardioembolic/cryptogenic stroke (adjusted hazard ratio 2.83, 95% confidence interval 1.03-7.81), but not total ischemic stroke (adjusted hazard ratio 1.06, 95% confidence interval, 0.48-2.30). Mild LAE was not associated with recurrent stroke., Conclusion: Moderate to severe LAE was an independent marker of recurrent cardioembolic or cryptogenic stroke in a multiethnic cohort of ischemic stroke patients. Further research is needed to determine whether anticoagulant use may reduce risk of recurrence in ischemic stroke patients with moderate to severe LAE., (© 2015 American Heart Association, Inc.)

Background and Objectives: Various dietary strategies have been investigated to slow kidney function decline. However, it is unknown whether a Mediterranean diet, which has been associated with improved cardiovascular risk, is associated with change in kidney function., Design, Setting, Participants, & Measurements: This study used the Northern Manhattan Study, a prospective, multiethnic, observational cohort of participants who were stroke free at baseline. Data were collected between 1993 and 2008. Serum creatinine measurements were taken a mean 6.9 years apart. A baseline dietary questionnaire was extrapolated into a previously used 9-point scoring system (MeDi). The primary outcome was incident eGFR<60 ml/min per 1.73 m(2)using the Modification of Diet in Renal Disease formula. A secondary outcome was the upper quartile of annualized eGFR decline (≥ 2.5 ml/min per 1.73 m(2) per year). Conditional logistic regression models adjusted for demographics and baseline vascular risk factors., Results: Mean baseline age was 64 years, with 59% women and 65% Hispanics (N=900); mean baseline eGFR was 83.1 ml/min per 1.73 m(2). Incident eGFR<60 ml/min per 1.73 m(2) developed in 14% . In adjusted models, every 1-point increase in the MeDi score, indicating increasing adherence to a Mediterranean diet, was associated with decreased odds of incident eGFR<60 ml/min per 1.73 m(2) (odds ratio, 0.83; 95% confidence interval, 0.71 to 0.96) and decreased odds of being in the upper quartile of eGFR decline (odds ratio, 0.88; 95% confidence interval, 0.79 to 0.98)., Conclusions: A Mediterranean diet was associated with a reduced incidence of eGFR<60 ml/min per 1.73 m(2) and upper quartile of eGFR decline in a multiethnic cohort., (Copyright © 2014 by the American Society of Nephrology.)

Background and Purpose: Interleukin-6 (IL-6) is a proinflammatory cytokine with known autoregulatory feedback mechanisms. We hypothesized that elevated high-sensitivity C-reactive protein (hsCRP) relative to IL-6 confers an increased risk of ischemic stroke (IS), and low hsCRP relative to IL-6 a decreased risk, for individuals in the prospective, multiethnic, population-based Northern Manhattan Study (NOMAS)., Methods: Serum hsCRP and IL-6 were measured in NOMAS participants at baseline. We created a trichotomized predictor based on the dominant biomarker in terms of quartiles: hsCRP-dominant, IL-6-dominant, and codominant groups. Cox proportional hazards models were used to calculate hazard ratios and 95% confidence intervals for the association between inflammatory biomarker group status and risk of incident IS., Results: Of 3298 participants, both hsCRP and IL-6 were available in 1656 participants (mean follow-up, 7.8 years; 113 incident IS). The hsCRP-dominant group had increased risk of IS (adjusted hazard ratio, 2.62; 95% confidence interval, 1.56-4.41) and the IL-6-dominant group had decreased risk (adjusted hazard ratio, 0.38; 95% confidence interval, 0.18-0.82) when compared with the referent group, after adjusting for potential confounders. Model fit was improved using the inflammation-dominant construct, over either biomarker alone., Conclusions: In this multiethnic cohort, when hsCRP-quartile was higher than IL-6 quartile, IS risk was increased, and conversely when IL-6 quartiles were elevated relative to hsCRP, IS risk was decreased. Construct validity requires confirmation in other cohorts.

Background: Lipoprotein-associated phospholipase A2 (LpPLA2) levels are associated with stroke, though whether this extends to all populations and stroke subtypes is unknown., Methods: 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., Results: 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., Conclusion: 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.

Background: Subclinical cerebrovascular disease has been associated with multiple adverse events related to aging, including stroke and dementia. The modifiable risk factors for subclinical cerebrovascular disease beyond hypertension have not been well characterized. Our objective was to examine the association between baseline, and changes over time, in lipid profile components and subclinical cerebrovascular disease on magnetic resonance imaging (MRI)., Methods: Fasting plasma lipids were collected on participants in the Northern Manhattan Study, a prospective cohort study examining risk factors for cardiovascular disease in a multiethnic elderly urban-dwelling population. A subsample of the cohort underwent brain MRI between 2003 and 2008 (a median of 6.2 years, range = 0-14, after enrollment), when repeat fasting lipids were obtained. We used lipid profile components at the time of initial enrollment (n = 1,256 with lipids available) as categorical variables, as well as change in clinical categories over the two measures (n = 1,029). The main outcome measures were (1) total white matter hyperintensity volume (WMHV) using linear regression and (2) silent brain infarcts (SBI) using logistic regression., Results: None of the plasma lipid profile components at the time of enrollment were associated with WMHV. The association between baseline lipids and WMHV was, however, modified by apolipoprotein E (apoE) status (χ(2) with 2 degrees of freedom, p = 0.03), such that among apoE4 carriers those with total cholesterol (TC) ≥200 mg/dl had a trend towards smaller WMHV than those with TC <200 mg/dl (difference in log​WMHV -0.19, p = 0.07), while there was no difference among apoE3 carriers. When examining the association between WMHV and change in lipid profile components we noted an association with change in high-density lipoprotein cholesterol (HDL-C, >50 mg/dl for women, >40 mg/dl for men) and TC. A transition from low-risk HDL-C (>50 mg/dl for women, >40 mg/dl for men) at baseline to high-risk HDL-C at the time of MRI (vs. starting and remaining low risk) was associated with greater WMHV (difference in logWMHV 0.34, p value 0.03). We noted a similar association with transitioning to a TC ≥200 mg/dl at the time of MRI (difference in logWMHV 0.25, p value 0.006). There were no associations with baseline or change in lipid profile components with SBI., Conclusions: The association of plasma lipid profile components with greater WMHV may depend on apoE genotype and worsening HDL and TC risk levels over time., (© 2014 S. Karger AG, Basel.)

Background and Purpose: 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 age ≥40 years, followed for a median of 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 stroke and beginning 6 months after stroke. Follow-up was censored at the time of recurrent stroke., Results: Among 3298 participants, 210 participants had an ischemic stroke during follow-up and had poststroke BI assessed. Mean age (±SD) was 77±9 years, 38% were men, 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<0.0001) and 1.24 BI points 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 BI points 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 with before stroke among those with Medicaid or no insurance, after adjusting for confounders.

Background and Purpose: Diabetes increases stroke risk, but whether diabetes status immediately before stroke improves prediction and whether duration is important are less clear. We hypothesized that diabetes duration independently predicts ischemic stroke., Methods: Among 3298 stroke-free participants in the Northern Manhattan Study, baseline diabetes and age at diagnosis were determined. Incident diabetes was assessed annually (median, 9 years). Cox proportional hazard models were used to estimate hazard ratios (HR) and 95% CI for incident ischemic stroke using baseline diabetes, diabetes as a time-dependent covariate, and duration of diabetes as a time-varying covariate; models were adjusted for demographic and cardiovascular risk factors., Results: Mean age was 69 ± 10 years (52% Hispanic, 21% white, and 24% black); 22% had diabetes at baseline and 10% had development of diabetes. There were 244 ischemic strokes, and both baseline diabetes (HR, 2.5; 95% CI, 1.9-3.3) and diabetes considered as a time-dependent covariate (HR, 2.4; 95% CI, 1.8-3.2) were similarly associated with stroke risk. Duration of diabetes was associated with ischemic stroke (adjusted HR, 1.03 per year with diabetes; 95% CI, 1.02-1.04). Compared to nondiabetic participants, those with diabetes for 0 to 5 years (adjusted HR, 1.7; 95% CI, 1.1-2.7), 5 to 10 years (adjusted HR, 1.8; 95% CI, 1.1-3.0), and ≥ 10 years (adjusted HR, 3.2; 95% CI, 2.4-4.5) were at increased risk., Conclusions: Duration of diabetes is independently associated with ischemic stroke risk adjusting for risk factors. The risk increases 3% each year, and triples with diabetes ≥ 10 years.

Objective: To determine the association between a composite measure of serological test results for common infections (Chlamydia pneumoniae, Helicobacter pylori, cytomegalovirus, and herpes simplex virus 1 and 2) and stroke risk in a prospective cohort study., Design: Prospective cohort followed up longitudinally for median 8 years., Setting: Northern Manhattan Study. Patients Randomly selected stroke-free participants from a multiethnic urban community. Main Outcome Measure Incident stroke and other vascular events., Results: All 5 infectious serological results were available from baseline samples in 1625 participants (mean [SD] age, 68.4 [10.1] years; 64.9% women). Cox proportional hazards models were used to estimate associations of each positive serological test result with stroke. Individual parameter estimates were then combined into a weighted index of infectious burden and used to calculate hazard ratios and confidence intervals 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 infectious burden index was associated with an increased risk of all strokes (adjusted hazard ratio per standard deviation, 1.39; 95% confidence interval, 1.02-1.90) after adjusting for demographics and risk factors. Results were similar after excluding those with coronary disease (adjusted hazard ratio, 1.50; 95% confidence interval, 1.05-2.13) and adjusting for inflammatory biomarkers., Conclusions: 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 infectious burden as a stroke risk factor.

Cognitive impairment and chronic kidney disease (CKD) will become increasingly prevalent in the aging US population. Although evidence exists that CKD is a risk factor for cognitive decline, longitudinal studies are limited and largely have excluded ethnically diverse populations. The Northern Manhattan Study includes a population-based, prospective, stroke-free cohort. We assessed global cognitive function annually using the modified Telephone Interview for Cognitive Status (TICS-m) and estimated kidney function using Cockcroft-Gault creatinine clearance (CCl), Modification of Diet in Renal Disease estimated GFR (eGFR), and serum creatinine (sCr). We examined the association between CKD and change in TICS-m scores over time, adjusting for sociodemographic and vascular risk factors. Of 2172 subjects (mean age 71.5 yr, mean follow-up 2.9 yr), 59% were Hispanic, 20% were black, and 63% were women. Participants with a CCl <60 ml/min and those with a CCl between 60 and 90 ml/min performed significantly worse on the TICS-m over time than those with a CCl >90 ml/min, adjusting for potential confounders. Our results were similar when we used eGFR or sCr to estimate kidney function. In conclusion, decreased kidney function associates with greater cognitive decline, even in those with mild CKD. Kidney disease may represent a novel mechanism leading to cognitive impairment and a target for early intervention.

Background and Purpose: 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., Methods: 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 activity levels 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 to 40 days). Levels before and after events were compared using nonparametric tests., Results: HsCRP and Lp-PLA2 activity levels were stable over time, whereas 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 prestroke to 6.5 mg/L poststroke; 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 poststroke, P=0.0348, and from median 233.0 ng/mL to 153.9 post-MI, P<0.0001)., Conclusion: Lp-PLA2 mass levels decrease modestly, whereas hsCRP and Lp-PLA2 activity appear stable over time. Acutely after stroke and MI, hsCRP increases whereas Lp-PLA2 mass and activity levels decrease. These changes imply that measurements made soon after stroke and MI are not reflective of prestroke levels and may be less reliable for long-term risk stratification.