Plasma Amyloid and in vivo Brain Amyloid in Late Middle-Aged Hispanics

BACKGROUND: Determining amyloid positivity is possible with cerebrospinal fluid and brain imaging of amyloid, but these methods are invasive and expensive. OBJECTIVE: To relate plasma amyloid-β (Aβ), measured using Single-molecule array (Simoatrademark) assays, to in vivo brain Aβ, measured using positron emission tomography (PET), examine the accuracy of plasma Aβ to predict brain Aβ positivity, and the relation of APOE ɛ4 with plasma Aβ. METHODS: We performed a cross-sectional analysis in a cohort of 345 late middle-aged Hispanic men and women (age 64 years, 72% women). Our primary plasma variable was Aβ 42/Aβ 40 ratio measured with Simoa. Brain Aβ burden was measured as global SUVR with 18F-Florbetaben PET examined continuously and categorically. RESULTS: Plasma Aβ 42/Aβ 40 ratio was inversely associated with global Aβ SUVR (β= -0.13, 95% Confidence Interval (CI): -0.23, -0.03; p = 0.013) and Aβ positivity (Odds Ratio: 0.59, 95% CI: 0.38, 0.91; p = 0.016), independent of demographics and APOE ɛ4. ROC curves (AUC = 0.73, 95% CI: 0.64, 0.82; p <  0.0001) showed that the optimal threshold for plasma Aβ 42/Aβ 40 ratio in relation to brain Aβ positivity was 0.060 with a sensitivity of 82.4% and specificity of 62.8% . APOE ɛ4 carriers had lower Aβ 42/Aβ 40 ratio and a higher Aβ positivity determined with the Aβ 42/Aβ 40 ratio threshold of 0.060. CONCLUSION: Plasma Aβ 42/Aβ 40 ratio assayed using Simoa is weakly correlated with in vivo brain amyloid and has limited accuracy in screening for amyloid positivity and for studying risk factors of brain amyloid burden when in vivo imaging is not feasible

Abstract 91: Small Perivascular Spaces as Vascular Risk Factors

Introduction: Small perivascular spaces (SPVS) are gaining momentum as imaging biomarkers of cerebrovascular health. Hypothesis: SPVS confer vascular risks and the coexistence of SPVS with lacunar infarcts (LI) heightens these risks. Methods: Stroke-free participants in the population-based Northern Manhattan Study were followed for incident stroke (ischemic and hemorrhagic), MI, all death, vascular death, and any vascular event. Lesions with diameter of 3 mm or less and absence of FLAIR rim were classified as SPVS on a semi-quantitative scale (range 0 to 28). We defined “high SPVS burden” as the upper quintile and compared the rate of vascular events in this group to individuals in the lower 4 quintiles combined. LI were defined as lesions greater than 3 mm with associated FLAIR rim, round shape, and typical location. Cox models were used to calculate risks of outcomes after adjusting for confounders. Results: This analysis includes 1208 NOMAS participants (40% male, 65% Hispanic; mean age 71 ± 9 years at time of MRI) followed a mean of 6 ± 2 years. SPVS were present in 91% of the sample (median SPVS scale score 5). Compared to participants with a lesser burden of SPVS, participants with a high SPVS burden had a higher incidence rate per 1000 person-years of death (48 vs 34), vascular death (20 vs 11), ischemic stroke (12 vs 7) and any vascular event (37 vs 24). After adjusting for demographics and vascular risk factors, participants with a high burden of SPVS had a higher risk of death (HR 1.35, 1.00-1.78), vascular death (HR 1.55, 0.96-2.51), any stroke (HR 1.53, 0.91-2.57), MI (HR 1.29, 0.69-2.41), and any vascular event (HR 1.50, 1.07-2.11). The presence of lacunar infarcts was an effect modifier such that those with LI and a high SPVS burden had a greater risk of vascular death (B=0.63, P=0.03), any stroke (B=0.72, P=0.03) and any vascular event (B=0.54, P=0.02) compared to those without LI. Conclusions: In this multi-ethnic, population-based study, participants with a high burden of SPVS had increased incidence rates of vascular events. Furthermore, the joint presence of SPVS and LI heighten the risk of vascular death, any stroke and any vascular event. The presence of SPVS may help select subjects for randomized trials to assess intervention strategies

Abstract P318: Dietary Sodium to Potassium Ratio and Risk of Stroke in a Multi-ethnic Urban Dwelling Population: The Northern Manhattan Study

Background: There is growing evidence that an increase in dietary sodium increases morbidity and mortality from cardiovascular disease (CVD) at least in part via an increase in blood pressure (BP). Several researchers have identified an association of higher dietary potassium, seen with increased intake of fruits and vegetables, with lower BP. Moreover, there may be a potential interaction of sodium and potassium on CVD health, such that the relative levels of these variables may be more important than their absolute levels. The goal of this study was to determine the association of dietary sodium to potassium ratio (Na:K) with the risk of stroke and CVD in a multi-ethnic urban dwelling population. Methods: Stroke-free participants from the Northern Manhattan Study, a population-based cohort study of stroke incidence, were followed prospectively to assess incident stroke, myocardial infarction and vascular death. Baseline food-frequency questionnaires were analyzed for Sodium and Potassium intake based on self-reported food consumption using DIETSYS software (Block Dietary Data System: Dietsys+ analysis software, version 59, 1999). We examined the association of Na:K with incident stroke (ischemic and overall) as well as combined vascular events (CVE)(stroke, myocardial infarction and vascular death) using Cox-proportional Hazards models adjusting for age, sex, race/ethnicity, total daily calories, adherence to a Mediterranean-style diet, smoking, physical activity, BMI, diabetes, hypertension, and hypercholesterolemia. Results: 2570 participants had dietary data, (mean age 69 ± 10 years, 64% women, 21% white, 53% Hispanic, 24% black); the mean of the Na:K ratio intake was 1.22 with a standard deviation of 0.43. Over a mean follow-up time of 11.9 years (SD=5.4), 274 participants developed stroke (N=232 ischemic) and 745 had a vascular event overall. In adjusted models the Na:K intake ratio was associated with an increased risk for ischemic Stroke (HR=1.5, 95% CI: 1.2-2.0), all stroke (HR=1.5, 95% CI: 1.2-1.9) and CVE (HR=1.2, 95% CI: 1.0-1.4). These results were unchanged in models adjusting for sociodemographic variables only. Conclusions: Our findings suggest that Na:K intake may be an important predictor of the risk of ischemic stroke and overall CVE

Dietary Sodium to Potassium Ratio and Risk of Stroke in a Multiethnic Urban Population

There is growing evidence that increased dietary sodium (Na) intake increases the risk of vascular diseases, including stroke, at least in part via an increase in blood pressure. Higher dietary potassium (K), seen with increased intake of fruits and vegetables, is associated with lower blood pressure. The goal of this study was to determine the association of a dietary Na:K with risk of stroke in a multiethnic urban population. Stroke-free participants from the Northern Manhattan Study, a population-based cohort study of stroke incidence, were followed-up for incident stroke. Baseline food frequency questionnaires were analyzed for Na and K intake. We estimated the hazard ratios and 95% confidence intervals for the association of Na:K with incident total stroke using multivariable Cox proportional hazards models. Among 2570 participants with dietary data (mean age, 69±10 years; 64% women; 21% white; 55% Hispanic; 24% black), the mean Na:K ratio was 1.22±0.43. Over a mean follow-up of 12 years, there were 274 strokes. In adjusted models, a higher Na:K ratio was associated with increased risk for stroke (hazard ratio, 1.6; 95% confidence interval, 1.2-2.1) and specifically ischemic stroke (hazard ratio, 1.6; 95% confidence interval, 1.2-2.1). Na:K intake is an independent predictor of stroke risk. Further studies are required to understand the joint effect of Na and K intake on risk of cardiovascular disease

Abstract T P151: Fibroblast Growth Factor 23 and Carotid Plaque: the Northern Manhattan Study (NOMAS)

Introduction: Fibroblast growth factor 23 (FGF23), a hormone that regulates phosphate homeostasis, has recently been linked with mortality, cardiovascular events, and stroke. While limited evidence suggests that FGF23 is associated with arterial calcification in chronic kidney disease (CKD), data on the association between FGF23 and carotid plaque are lacking, especially in population-based studies. This study aimed to determine if relative elevations of FGF23 are associated with presence and area of carotid plaque in a race/ethnically diverse community-based sample. Methods: There were 1,512 stroke-free NOMAS participants with FGF23 levels and 2D carotid ultrasound data available (mean age, 68±9; 61% women; 62% Hispanic, 18% black, 18% white, 2% other). We evaluated the association of FGF23, continuously and by quintiles, with presence of carotid plaque using logistic regression models and with plaque area (cubic root transformed) using linear regression models, adjusting for age, sex, race/ethnicity, estimated glomerular filtration rate (eGFR), body mass index, smoking, alcohol use, blood pressure, fasting glucose, lipids, and hypertension, diabetes, and dyslipidemia medication use. Results: Participants with FGF23 levels in the top quintile had greater odds of having carotid plaque (OR=1.5 95% CI=1.0-2.2, p=0.04) and larger plaque area (beta=0.3, 95% CI=0.1-0.5, p=0.006) than those in the lowest quintile, adjusting for eGFR and demographic factors, although the association was attenuated after adjusting for vascular risk factors. Linear regression models also showed that log transformed FGF23 was associated with greater plaque area adjusting for eGFR and sociodemographic factors (beta=0.2, 95% CI=0.03-0.3, p=0.02), and this remained marginally significant after adjusting for vascular risk factors (beta=0.1, 95% CI=0.0-0.3, p=0.05). Conclusions: These data suggest that FGF23 is associated with the likelihood and burden of carotid atherosclerosis in a stroke-free community based sample. Our finding that the association between FGF23 and carotid plaque measures was weaker after adjusting for vascular risk factors suggests possible mediation and requires further study

Abstract P172: Attributable risks of hypertension and diabetes for stroke, myocardial infarction and vascular death in the Northern Manhattan Study

Objective: To determine the attributable risks (AR) for vascular events (VE: stroke, myocardial infarction, and vascular death) due to hypertension and diabetes by race/ethnicity, sex and age. Background: Understanding the distribution of risk factors and their contribution to disease incidence is critical for effective allocation of resources for disease prevention. There is little data on the relative contribution of vascular risk factors among multiethnic elderly populations. Methods: The Northern Manhattan Study is a population-based prospective cohort study of incidence, risk factors, and outcomes in a multiethnic urban population. Multi-variable Cox models adjusted for socio-demographic and vascular risk factors were used to calculate hazard ratios, AR and 95% confidence intervals (95%CI) for (1) all stroke and (2) VE. Results: The cohort (n=3,298) had mean age 69.2+/-10 years with 63% women, 52% Hispanic, 73% hypertensive and 21% diabetics. There were 347 strokes and 835 VE during a median follow-up of 12 years. The AR due to hypertension was 30% (95%CI 13-48%) for stroke and 24% (95%CI 13-35%) for VE; AR due to diabetes was 19% (95%CI 12-27%) for stroke and 13% (95%CI 8-17%) for VE.The AR for stroke from hypertension differed by age and race-ethnicity (table), while for diabetes it only differed by age. For VE, the AR of hypertension and diabetes did not differ by age, sex, or race-ethnicity. Conclusions: On a population level diabetes and hypertension have important effects on the risk of VE across all socio-demographic groups. For stroke, these effects are more notable at age< 80. Our results may in part be driven by competing risks for other VE outcomes with stroke, or a differential impact of risk factors on stroke in younger individuals

Abstract W MP68: Brain Arterial Diameters and Risk of Vascular Events

Objective: Inward and outward remodeling of cerebral vessels may represent alternate pathological vascular phenotypes. Our aim was to test whether extremes of brain arterial diameters increase risk of death and vascular events. Methods: Cerebral large artery diameters were measured in 1,034 stroke-free participants from Northern Manhattan. Arteries from the Circle of Willis (8) and posterior circulation (5) were measured in regions free of stenosis, adjusted for head size, standardized, and added to create a global measure of diameters in each person. Participants were categorized into the top 5% of the diameter distribution (“outward remodelers”) and bottom 5% (“inward remodelers”), as well as an intermediate referent category (90% of population). We used logistic regression to calculate associations with risk factors and Cox models to calculate risks of outcomes after adjusting for demographic and vascular risk factors. Results: Mean follow-up was 5 ± 2 years. Inward remodelers were more likely to be men (OR 3.3, 95%CI 1.8-6.1) and less likely to be hypertensive (OR 0.5, 95%CI 0.3-0.9) or Hispanic (OR 0.3, 95%CI 0.2-0.6), while outward remodelers were more likely to be women (OR 14.6, 95%CI 3.5-60.5) and Hispanic (OR 8.7, 95%CI 1.2-65.0) compared to participants with less extreme diameters. Inward remodelers had a higher risk of death (HR 1.8, 95%CI 1.1-3.0), vascular death (HR 2.8, 95%CI 1.4-5.7), myocardial infarction (HR 2.5, 95%CI 1.0-6.4) and ischemic stroke (HR 3.4, 95%CI 1.0-10.2). Outward remodelers were not at increased risk of death or vascular events. Compared to those with less extreme diameters, risk of cardioembolic stroke was higher among inward remodelers (11.3 vs. 1.4%, HR 13.9, 95%CI 4.4-44.0) while strokes due to large or small artery disease were more frequent in outward remodelers (3.8 vs 1.8 %, HR 3.4, 95%CI 0.7-16.3). Conclusions: Individuals with the smallest brain arterial diameters are at greater risk of death, myocardial infarction, and ischemic stroke, while those with the largest brain arterial diameters were not. Cerebral arterial phenotypes might identify people at greater risk of cardiac disease and stroke, and direct targeting of primary preventive measures at likely stroke subtypes

Abstract MP73: Leisure Time Physical Activity and Cognitive Decline in the Northern Manhattan Study

Background: Leisure time physical activity (LTPA) has been associated with a lower risk of dementia, but whether the effects are specific to particular cognitive abilities or improvement in functional status remains unclear. We examined LTPA in relation to domain-specific neurocognitive (NC) performance and change over time in a diverse community sample. Methods: Data on LTPA was collected during enrollment (1993-2001) into the Northern Manhattan Study (NOMAS), a prospective cohort study of risk factors for stroke and cognitive decline, using a validated in-person questionnaire, and two waves of NC assessments were done on a subcohort of participants undergoing brain MRI an mean of six and 12 years later (NC1: 2003-2008; NC2: 2008-2014). Baseline LTPA was defined in two manners: (1) maximum intensity of all activities performed categorized as moderate-heavy, light, and none; (2) total summarized as a continuous variable with the metabolic equivalent (MET) score, a composite of total reported intensity and time. Factor analysis-derived construct-relevant cognitive domains, including memory (MEM), executive function (EXEC), processing speed (PS), and language ability (LA), were computed by averaging z-transformed NC test scores. We used multivariable linear regression to examine LTPA in relation to baseline domain-specific NC performance, and change in performance over time, adjusting for socio-demographics, vascular risk factors, and MRI markers of cerebrovascular injury (white matter hyperintensity volume and total cerebral volume, both adjusted for total intracranial volume, and silent brain infarcts). Results: There were 1236 participants (mean age=64 years, 61% women, 67% Latino, 18% black, 15% white) with LTPA and NC data, and 879 with a second NC assessment. Moderate-to-heavy activity was associated with higher baseline LA (p <0.05) and PS (p <0.05), and with a protective effect on change of MEM (p <0.05) and PS (p <0.05); these effects were not attenuated after adjustment for MRI variables. Total MET-score was not associated with baseline NC domain performance. However, participants with greater MET-scores had significantly less decline in processing speed adjusting for age and education. Inclusion of vascular risk factors and MRI markers each attenuated these associations though they remained statistically significant. Conclusions: Leisure time physical activity is independently protective against a decline in processing speed and memory, and was partly mediated by MRI markers. Leisure-time physical activity may protect against dementia through preventing cerebrovascular correlates of brain injury

Abstract 247: Association of Soluble RAGE Levels with Carotid Atherosclerosis: The Northern Manhattan Study (NOMAS)

Introduction The Receptor for Advanced Glycation End-products (RAGE) is a multi-ligand receptor that propagates vascular cell dysfunction leading to proinflammatory disease states. RAGE is produced as a membrane bound and soluble isoform (soluble RAGE (sRAGE)), with the soluble isoform demonstrated to act as a RAGE decoy preventing cellular activation and atherosclerosis. Recent cohort studies have suggested that serum levels of sRAGE are associated with the risk of CVD and therefore may be a novel biomarker for cardiovascular disease states. Hypothesis We hypothesized that sRAGE levels are associated with subclinical atherosclerosis in an ethnically diverse population. Methods We included 1,102 stroke-free participants from the multi-ethnic Northern Manhattan Study (NOMAS) who underwent high-resolution carotid B-mode ultrasound to measure carotid plaque phenotypes (density, thickness, and area) and carotid intima-media thickness (IMT). Plaque density was characterized by Gray Scale Median (GSM). Serum sRAGE was measured by ELISA and log-transformed to stabilize variance. Multiple linear and logistic regressions were employed to estimate sRAGE associations with IMT and plaque measures. Results The mean age at time of ultrasound was 70.7±8.6yrs; 65% were Hispanic, 19% black, and 16% white. The majority of subjects had carotid plaque present (54%) with the median GSM 38(0-190). Mean plaque thickness (IQR) was 1.30(0-3.99)mm and mean area (IQR) 2.43(0-96.75)mm2. Mean IMT was 0.93±0.09mm. High sRAGE levels were associated with more echolucent plaques (OR 1.2, 95% CI 1.03-1.42), especially among Hispanics (OR 1.26, 95% CI 1.04-1.54). These relationships remained after adjusting for sociodemographic and vascular risk factors. No association was seen between sRAGE levels and carotid IMT, plaque thickness or area. Conclusion In the present study, higher sRAGE levels were associated with echolucent (lower density) plaque, especially among Hispanic subjects. Our data suggest sRAGE levels may be associated with atherosclerotic plaque morphology and its vulnerability, especially among minority groups. These findings further support RAGE as a novel target for anti-atherosclerosis interventions