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Introduction: Rural versus urban living is a social determinant of cognitive health. We estimated the association of rural versus urban residence in the USA with incident cognitive impairment (ICI) and assessed effect heterogeneity by sociodemographic, behavioral, and clinical factors., Methods: The Reasons for Geographic and Racial Differences in Stroke Study (REGARDS) is a population-based prospective observational cohort of 30,239 adults, 57% female, 36% Black, aged 45+ years, sampled from 48 contiguous states in the USA in 2003-2007. We analyzed 20,878 participants who at baseline were cognitively intact with no history of stroke and had ICI assessed on average 9.4 years later. We classified participants' home addresses at baseline as urban (population ≥50,000), large rural (10,000-49,999), or small rural (≤9,999) by Rural-Urban Commuting Area codes. We defined ICI as ≥1.5 SD below the mean on at least 2 of the following tests: word list learning, word list delayed recall, and animal naming., Results: Participants' home addresses were 79.8% urban, 11.7% large rural, and 8.5% small rural. ICI occurred in 1,658 participants (7.9%). Small rural residents had higher odds of ICI than urban residents, adjusted for age, sex, race, region, and education (OR = 1.34 [95% CI: 1.10, 1.64]), and after further adjustment for income, health behaviors, and clinical characteristics (OR = 1.24 [95% CI: 1.02, 1.53]). Former smoking versus never, nondrinking versus light alcohol drinking, no exercise versus ≥4 times/week, CES-D depressive symptom score of 2 versus 0, and fair versus excellent self-rated health had stronger associations with ICI in small rural areas than in urban areas. For example, in urban areas, lack of exercise was not associated with ICI (OR = 0.90 [95% CI: 0.77, 1.06]); however, lack of exercise combined with small rural residence was associated with 1.45 times the odds of ICI compared with ≥4 bouts of exercise/week in urban areas (95% CI: 1.03, 2.03). Overall, large rural residence was not associated with ICI; however, black race, hypertension, and depressive symptoms had somewhat weaker associations with ICI, and heavy alcohol drinking a stronger association with ICI, in large rural areas than in urban areas., Conclusion: Small rural residence was associated with ICI among USA adults. Further research to better understand why rural residents are at higher risk for developing ICI and mechanisms to ameliorate that risk will support efforts to advance rural public health., (© 2023 S. Karger AG, Basel.)

Objectives: Describe novel methods for ascertaining verbal fluency in a large national sample of adults, examine demographic factors influencing performance, and compare scores to studies using in-person assessment., Methods/design: Participants were from the Reasons for Geographic and Racial Differences in Stroke (REGARDS) study, a national, population-based, longitudinal study of stroke in adults aged 45 years and older. Letter and semantic fluency were gathered, using Letter "F" and Animal Naming, via a telephone-based assessment with computer-assisted scoring of digital recordings., Results: Initial letter and semantic fluency scores were obtained on 18 505 and 18 072 participants, respectively. For both fluency tests, scores were normally distributed. Younger age and more years of education were associated with better performances (p < 0.0001). The mean and standard deviation for matched subgroups, based on age, gender, and education, were quite comparable with scores reported out of samples using an in-person administration format. Telephone-based assessment also allowed for a level of quality control not available via in-person measurement., Conclusions: Telephone-based assessment of verbal fluency and computer-assisted scoring programs designed for this study facilitated large-scale data acquisition, storage, and scoring of protocols. The resulting scores have similar characteristics to those obtained by traditional methods. These findings extend validation of cognitive assessment methods, using survey research staff and computer-assisted technology for test administration., (© 2018 John Wiley & Sons, Ltd.)

Selection due to survival or attrition might bias estimates of racial disparities in health, but few studies quantify the likely magnitude of such bias. In a large national cohort with moderate loss to follow-up, we contrasted racial differences in 2 stroke risk factors, incident hypertension and incident left ventricular hypertrophy, estimated by complete-case analyses, inverse probability of attrition weighting, and the survivor average causal effect. We used data on 12,497 black and 17,660 white participants enrolled in the United States (2003-2007) and collected incident risk factor data approximately 10 years after baseline. At follow-up, 21.0% of white participants and 23.0% of black participants had died; additionally 22.0% of white participants and 28.4% of black participants had withdrawn. Individual probabilities of completing the follow-up visit were estimated using baseline demographic and health characteristics. Adjusted risk ratio estimates of racial disparities from complete-case analyses in both incident hypertension (1.11, 95% confidence interval: 1.02, 1.21) and incident left ventricular hypertrophy (1.02, 95% confidence interval: 0.84, 1.24) were virtually identical to estimates from inverse probability of attrition weighting and survivor average causal effect. Despite racial differences in mortality and attrition, we found little evidence of selection bias in the estimation of racial differences for these incident risk factors., (© The Author(s) 2018. 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 and Purpose: Poststroke cognitive decline causes disability. Risk factors for poststroke cognitive decline independent of survivors' prestroke cognitive trajectories are uncertain., Methods: Among 22 875 participants aged ≥45 years without baseline cognitive impairment from the REGARDS cohort (Reasons for Geographic and Racial Differences in Stroke), enrolled from 2003 to 2007 and followed through September 2015, we measured the effect of incident stroke (n=694) on changes in cognitive functions and cognitive impairment (Six-Item Screener score <5) and tested whether patient factors modified the effect. Median follow-up was 8.2 years., Results: Incident stroke was associated with acute declines in global cognition, new learning, verbal memory, and executive function. Acute declines in global cognition after stroke were greater in survivors who were black ( P =0.04), men ( P =0.04), and had cardioembolic ( P =0.001) or large artery stroke ( P =0.001). Acute declines in executive function after stroke were greater in survivors who had

Background: Despite concerns about adverse neurocognitive events raised by prior trials, pharmacological PCSK9 (proprotein convertase subtilisin/kexin type-9) inhibition was not associated with neurocognitive effects in a recent phase 3 randomized trial. PCSK9 loss-of-function (LOF) variants that result in lifelong exposure to lower levels of low-density lipoprotein cholesterol can provide information on the potential long-term effects of lower low-density lipoprotein cholesterol on neurocognitive impairment and decline., Methods: We investigated the association between PCSK9 LOF variants and neurocognitive impairment and decline among black REGARDS study (Reasons for Geographic and Racial Differences in Stroke) participants with (n=241) and without (n=10 454) C697X or Y142X LOF variants. Neurocognitive tests included the Consortium to Establish a Registry for Alzheimer's Disease (CERAD) battery (Word List Learning, World List Delayed Recall, Semantic Animal Fluency) and Six-Item Screener (SIS) assessments, administered longitudinally during follow-up. Neurocognitive impairment was defined as a score ≥1.5 SD below age, sex, and education-based stratum-specific means on 2 or 3 CERAD assessments or, separately, a score <5 on any SIS assessment at baseline or during follow-up. Neurocognitive decline was assessed using standardized continuous scores on individual neurocognitive tests., Results: The mean sample age was 64 years (SD, 9), 62% were women, and the prevalence of neurocognitive impairment at any assessment was 6.3% by CERAD and 15.4% by SIS definitions. Adjusted odds ratios for neurocognitive impairment for participants with versus without PCSK9 LOF variants were 1.11 (95% confidence interval [CI], 0.58-2.13) using the CERAD battery and 0.89 (95% CI, 0.61-1.30) using the SIS assessment. Standardized average differences in individual neurocognitive assessment scores over the 5.6-year (range, 0.1-9.1) study period ranged between 0.07 (95% CI, -0.06 to 0.20) and -0.07 (95% CI, -0.18 to 0.05) among participants with versus without PCSK9 LOF variants. Patterns of neurocognitive decline were similar between participants with and without PCSK9 LOF variants (all P >0.10). Odds ratios for neurocognitive impairment per 20 mg/dL low-density lipoprotein cholesterol decrements were 1.02 (95% CI, 0.96-1.08) and 0.99 (95% CI, 0.95-1.02) for the CERAD and SIS definitions of impairment, respectively., Conclusions: These results suggest that lifelong exposure to low PCSK9 levels and cumulative exposure to lower levels of low-density lipoprotein cholesterol are not associated with neurocognitive effects in blacks., (© 2017 The Authors.)

Rationale Trials conducted decades ago demonstrated that carotid endarterectomy by skilled surgeons reduced stroke risk in asymptomatic patients. Developments in carotid stenting and improvements in medical prevention of stroke caused by atherothrombotic disease challenge understanding of the benefits of revascularization. Aim Carotid Revascularization and Medical Management for Asymptomatic Carotid Stenosis Trial (CREST-2) will test whether carotid endarterectomy or carotid stenting plus contemporary intensive medical therapy is superior to intensive medical therapy alone in the primary prevention of stroke in patients with high-grade asymptomatic carotid stenosis. Methods and design CREST-2 is two multicenter randomized trials of revascularization plus intensive medical therapy versus intensive medical therapy alone. One trial randomizes patients to carotid endarterectomy plus intensive medical therapy versus intensive medical therapy alone; the other, to carotid stenting plus intensive medical therapy versus intensive medical therapy alone. The risk factor targets of centrally directed intensive medical therapy are LDL cholesterol <70 mg/dl and systolic blood pressure <140 mmHg. Study outcomes The primary outcome is the composite of stroke and death within 44 days following randomization and stroke ipsilateral to the target vessel thereafter, up to four years. Change in cognition and differences in major and minor stroke are secondary outcomes. Sample size Enrollment of 1240 patients in each trial provides 85% power to detect a treatment difference if the event rate in the intensive medical therapy alone arm is 4.8% higher or 2.8% lower than an anticipated 3.6% rate in the revascularization arm. Discussion Management of asymptomatic carotid stenosis requires contemporary randomized trials to address whether carotid endarterectomy or carotid stenting plus intensive medical therapy is superior in preventing stroke beyond intensive medical therapy alone. Whether carotid endarterectomy or carotid stenting has favorable effects on cognition will also be tested. Trial registration United States National Institutes of Health Clinicaltrials.gov NCT02089217.

Background and Purpose: At age 45 years, blacks have a stroke mortality ≈3× greater than their white counterparts, with a declining disparity at older ages. We assess whether this black-white disparity in stroke mortality is attributable to a black-white disparity in stroke incidence versus a disparity in case fatality., Methods: We first assess if black-white differences in stroke mortality within 29 681 participants in the Reasons for Geographic and Racial Differences in Stroke (REGARDS) cohort reflect national black-white differences in stroke mortality and then assess the degree to which black-white differences in stroke incidence or 30-day case fatality after stroke contribute to the disparities in stroke mortality., Results: The pattern of stroke mortality within the study mirrors the national pattern, with the black-to-white hazard ratio of ≈4.0 at age 45 years decreasing to ≈1.0 at age 85 years. The pattern of black-to-white disparities in stroke incidence shows a similar pattern but no evidence of a corresponding disparity in stroke case fatality., Conclusions: These findings show that the black-white differences in stroke mortality are largely driven by differences in stroke incidence, with case fatality playing at most a minor role. Therefore, to reduce the black-white disparity in stroke mortality, interventions need to focus on prevention of stroke in blacks., (© 2016 American Heart Association, Inc.)

Self-reported stroke symptoms may represent unrecognized cerebrovascular events leading to poorer cognitive and mental health. We examined relationships between stroke symptoms, cognitive impairment, and depressive symptoms in a high-risk sample: 247 adults aged ≥65 with diabetes. Stroke symptoms were assessed using the Questionnaire for Verifying Stroke-free Status, cognitive impairment was measured with the modified Telephone Interview for Cognitive Status, and depressive symptoms were measured using the 15-item Geriatric Depression Scale. In 206 participants without history of stroke/transient ischemic attack, 27.7% reported stroke symptoms, with sudden loss of comprehension most frequently reported (11.7%). Having >1 versus 0 stroke symptoms was associated with greater odds of cognitive impairment (odds ratio = 3.04, 95% confidence interval 1.15-8.05) and more depressive symptoms (b= 2.60,P< .001) while controlling for age, race, gender, education, diabetes duration, diabetes severity, and cardiovascular comorbidities. Better recognition and treatment of cerebrovascular problems in older adults with diabetes may lead to improved cognition and mental health., (© The Author(s) 2016.)

Background: Black individuals are at greater risk of stroke and vitamin D deficiency than white individuals. Epidemiologic studies have shown that low 25-hydroxyvitamin D concentrations are associated with increased risk of stroke, but these studies had limited representation of black individuals., Methods: We examined the association of 25-hydroxyvitamin D with incident stroke in the Reasons for Geographic and Racial Differences in Stroke (REGARDS) study, a cohort of black and white adults ≥45 years of age. Using a case-cohort study design, plasma 25-hydroxyvitamin D was measured in 610 participants who developed incident stroke (cases) and in 937 stroke-free individuals from a stratified cohort random sample of REGARDS participants (comparison cohort)., Results: In multivariable models adjusted for socio-demographic factors, co-morbidities and laboratory values including parathyroid hormone, lower 25-hydroxyvitamin D concentrations were associated with higher risk of stroke (25-hydroxyvitamin D >30 ng/mL reference; 25-hydroxyvitamin D concentrations 20-30 ng/mL, hazard ratio 1.33, 95% confidence interval (95% CI) 0.89,1.96; 25-hydroxyvitamin D <20 ng/mL, hazard ratio 1.85, 95% CI 1.17, 2.93). There were no statistically significant differences in the association of lower 25-hydroxyvitamin D with higher risk of stroke in black vs. white participants in fully adjusted models (hazard ratio comparing lowest vs. highest 25-hydroxyvitamin D category 2.62, 95% CI 1.18, 5.83 in blacks vs. 1.64, 95% CI 0.83, 3.24 in whites, P(interaction) = 0.82). The associations were qualitatively unchanged when restricted to ischemic or hemorrhagic stroke subtypes or when using race-specific cut-offs for 25-hydroxyvitamin D categories., Conclusions: Vitamin D deficiency is a risk factor for incident stroke and the strength of this association does not appear to differ by race., (© 2016 World Stroke Organization.)

Importance: Cognitive decline is a major cause of disability in stroke survivors. The magnitude of survivors' cognitive changes after stroke is uncertain., Objective: To measure changes in cognitive function among survivors of incident stroke, controlling for their prestroke cognitive trajectories., Design, Setting, and Participants: Prospective study of 23,572 participants 45 years or older without baseline cognitive impairment from the Reasons for Geographic and Racial Differences in Stroke (REGARDS) cohort, residing in the continental United States, enrolled 2003-2007 and followed up through March 31, 2013. Over a median follow-up of 6.1 years (interquartile range, 5.0-7.1 years), 515 participants survived expert-adjudicated incident stroke and 23,057 remained stroke free., Exposure: Time-dependent incident stroke., Main Outcomes and Measures: The primary outcome was change in global cognition (Six-Item Screener [SIS], range, 0-6). Secondary outcomes were change in new learning (Consortium to Establish a Registry for Alzheimer Disease Word-List Learning; range, 0-30), verbal memory (Word-List Delayed Recall; range, 0-10), and executive function (Animal Fluency Test; range, ≥0), and cognitive impairment (SIS score <5 [impaired] vs ≥5 [unimpaired]). For all tests, higher scores indicate better performance., Results: Stroke was associated with acute decline in global cognition (0.10 points [95% CI, 0.04 to 0.17]), new learning (1.80 points [95% CI, 0.73 to 2.86]), and verbal memory (0.60 points [95% CI, 0.13 to 1.07]). Participants with stroke, compared with those without stroke, demonstrated faster declines in global cognition (0.06 points per year faster [95% CI, 0.03 to 0.08]) and executive function (0.63 points per year faster [95% CI, 0.12 to 1.15]), but not in new learning and verbal memory, compared with prestroke slopes. Among survivors, the difference in risk of cognitive impairment acutely after stroke, compared with immediately before stroke, was not statistically significant (odds ratio, 1.32 [95% CI, 0.95 to 1.83]; P = .10); however, there was a significantly faster poststroke rate of incident cognitive impairment compared with the prestroke rate (odds ratio, 1.23 per year [95% CI, 1.10 to 1.38]; P < .001). For a 70-year-old black woman with average values for all covariates at baseline, stroke at year 3 was associated with greater incident cognitive impairment: absolute difference of 4.0% (95% CI, -1.2% to 9.2%) at year 3 and 12.4% (95% CI, 7.7% to 17.1%) at year 6., Conclusions and Relevance: Incident stroke was associated with an acute decline in cognitive function and also accelerated and persistent cognitive decline over 6 years.

Background and Purpose: There are limited data on the potential association of adherence to Mediterranean diet (MeD) with incident stroke. We sought to assess the longitudinal association between greater adherence to MeD and risk of incident stroke., Methods: We prospectively evaluated a population-based cohort of 30 239 individuals enrolled in REasons for Geographic and Racial Differences in Stroke (REGARDS) study, after excluding participants with stroke history, missing demographic data or food frequency questionnaires, and unavailable follow-up information. Adherence to MeD was categorized using MeD score. Incident stroke was adjudicated by expert panel review of medical records during a mean follow-up period of 6.5 years., Results: Incident stroke was identified in 565 participants (2.8%; 497 and 68 cases of ischemic stroke [IS] and hemorrhagic stroke, respectively) of 20 197 individuals fulfilling the inclusion criteria. High adherence to MeD (MeD score, 5-9) was associated with lower risk of incident IS in unadjusted analyses (hazard ratio, 0.83; 95% confidence interval, 0.70-1.00; P=0.046). The former association retained its significance (hazard ratio, 0.79; 95% confidence interval, 0.65-0.96; P=0.016) after adjustment for demographics, vascular risk factors, blood pressure levels, and antihypertensive medications. When MeD was evaluated as a continuous variable, a 1-point increase in MeD score was independently associated with a 5% reduction in the risk of incident IS (95% confidence interval, 0-11%). We documented no association of adherence to MeD with incident hemorrhagic stroke. There was no interaction of race (P=0.37) on the association of adherence to MeD with incident IS., Conclusions: High adherence to MeD seems to be associated with a lower risk of incident IS independent of potential confounders. Adherence to MeD is not related to the risk of incident hemorrhagic stroke., (© 2015 American Heart Association, Inc.)

Background and Purpose: Fibroblast growth factor 23 (FGF23) is a hormone that regulates phosphorus and vitamin D metabolism. Elevated FGF23 concentrations are associated with excess risk of cardiovascular disease. Associations of FGF23 with stroke outcomes are less clear., Methods: Using a case-cohort study design, we examined the association of baseline plasma FGF23 concentrations with incident stroke in the Reasons for Geographic and Racial Differences in Stroke (REGARDS) study, a cohort of black and white adults aged ≥45 years. FGF23 was measured in 615 participants who developed incident stroke (cases) and in 936 participants randomly selected from the REGARDS cohort (comparison subcohort)., Results: In multivariable-adjusted models, higher calcium and phosphorus concentrations, lower estimated glomerular filtration rate and higher urine albumin excretion were independently associated with higher FGF23. There was no statistically significant association of FGF23 with risk of all-cause stroke in Cox models adjusted for demographic factors and established stroke risk factors (hazard ratio comparing fourth with first quartile 1.19; 95% confidence interval, 0.78-1.82). In prespecified models stratified by stroke subtypes, there was a graded association of FGF23 with risk of cardioembolic stroke in fully adjusted models (quartile 1, reference; quartile 2 hazard ratio, 1.48; 95% confidence interval, 0.63-3.47; quartile 3 hazard ratio, 1.99; 95% confidence interval, 0.89-4.44; quartile 4 hazard ratio, 2.52; 95% confidence interval, 1.08-5.91). There were no statistically significant associations of FGF23 with other ischemic stroke subtypes or with hemorrhagic strokes., Conclusions: Higher FGF23 concentrations were associated with higher risk of cardioembolic but not with other stroke subtypes in community-dwelling adults. Additional studies should delineate reasons for these findings., (© 2015 American Heart Association, Inc.)

Objective: To identify approximately 500 cases of incident cognitive impairment (ICI) in a large, national sample adapting an existing cognitive test-based case definition and to examine relationships of vascular risk factors with ICI., Method: Participants were from the REGARDS study, a national sample of 30,239 African-American and White Americans. Participants included in this analysis had normal cognitive screening and no history of stroke at baseline, and at least one follow-up cognitive assessment with a three-test battery (TTB). Regression-based norms were applied to TTB scores to identify cases of ICI. Logistic regression was used to model associations with baseline vascular risk factors., Results: We identified 495 participants with ICI of 17,630 eligible participants. In multivariable modeling, income (OR 1.83 CI 1.27,2.62), stroke belt residence (OR 1.45 CI 1.18,1.78), history of transient ischemic attack (OR 1.90 CI 1.29,2.81), coronary artery disease(OR 1.32 CI 1.02,1.70), diabetes (OR 1.48 CI 1.17,1.87), obesity (OR 1.40 CI 1.05,1.86), and incident stroke (OR 2.73 CI 1.52,4.90) were associated with ICI., Conclusions: We adapted a previously validated cognitive test-based case definition to identify cases of ICI. Many previously identified risk factors were associated with ICI, supporting the criterion-related validity of our definition.

In 2006, the National Institute of Neurological Disorders and Stroke-Canadian Stroke Network (NINDS-CSN) Vascular Cognitive Impairment Harmonization Standards recommended a 5-Minute Protocol as a brief screening instrument for vascular cognitive impairment (VCI). We report demographically adjusted norms for the 5-Minute Protocol and its relation to other measures of cognitive function and cerebrovascular risk factors. We performed a cross-sectional analysis of 7199 stroke-free adults in the REasons for Geographic And Racial Differences in Stroke (REGARDS) study on the NINDS-CSN 5-Minute Protocol score. Total scores on the 5-Minute Protocol were inversely correlated with age and positively correlated with years of education, and performance on the Six-Item Screener, Word List Learning, and Animal Fluency (all p-values <.001). Higher cerebrovascular risk on the Framingham Stroke Risk Profile (FSRP) was associated with lower total 5-Minute Protocol scores (p <.001). The 5-Minute Protocol also differentiated between participants with and without confirmed stroke and with and without stroke symptom histories (p <.001). The NINDS-CSN 5-Minute Protocol is a brief, easily administered screening measure that is sensitive to cerebrovascular risk and offers a valid method of screening for cognitive impairment in populations at risk for VCI.

Studies of the effect of air pollution on cognitive health are often limited to populations living near cities that have air monitoring stations. Little is known about whether the estimates from such studies can be generalized to the U.S. population, or whether the relationship differs between urban and rural areas. To address these questions, we used a satellite-derived estimate of fine particulate matter (PM2.5) concentration to determine whether PM2.5 was associated with incident cognitive impairment in a geographically diverse, biracial US cohort of men and women (n = 20,150). A 1-year mean baseline PM2.5 concentration was estimated for each participant, and cognitive status at the most recent follow-up was assessed over the telephone using the Six-Item Screener (SIS) in a subsample that was cognitively intact at baseline. Logistic regression was used to determine whether PM2.5 was related to the odds of incident cognitive impairment. A 10 µg/m(3) increase in PM2.5 concentration was not reliably associated with an increased odds of incident impairment, after adjusting for temperature, season, incident stroke, and length of follow-up [OR (95% CI): 1.26 (0.97, 1.64)]. The odds ratio was attenuated towards 1 after adding demographic covariates, behavioral factors, and known comorbidities of cognitive impairment. A 10 µg/m(3) increase in PM2.5 concentration was slightly associated with incident impairment in urban areas (1.40 [1.06-1.85]), but this relationship was also attenuated after including additional covariates in the model. Evidence is lacking that the effect of PM2.5 on incident cognitive impairment is robust in a heterogeneous US cohort, even in urban areas.

Objective: The present study characterizes the relationship between report of stroke symptoms (SS) or TIA and incident cognitive impairment in the large biracial cohort of the Reasons for Geographic and Racial Differences in Stroke (REGARDS) Study., Methods: The REGARDS Study is a population-based, biracial, longitudinal cohort study that has enrolled 30,239 participants from the United States. Exclusion of those with baseline cognitive impairment, stroke before enrollment, or incomplete data resulted in a sample size of 23,830. Participants reported SS/TIA on the Questionnaire for Verifying Stroke-free Status at baseline and every 6 months during follow-up. Incident cognitive impairment was detected using the Six-item Screener, which was administered annually., Results: Logistic regression found significant association between report of SS/TIA and subsequent incident cognitive impairment. Among white participants, the odds ratio for incident cognitive impairment was 2.08 (95% confidence interval: 1.81, 2.39) for those reporting at least one SS/TIA compared with those reporting no SS/TIA. Among black participants, the odds ratio was 1.66 (95% confidence interval: 1.45, 1.89) using the same modeling. The magnitude of impact was largest among those with fewer traditional stroke risk factors, particularly among white participants., Conclusions: Report of SS/TIA showed a strong association with incident cognitive impairment and supports the use of the Questionnaire for Verifying Stroke-free Status as a quick, low-cost instrument to screen for people at increased risk of cognitive decline.

Background: Heart failure (HF) is associated with an overall stroke rate that is too low to justify anticoagulation in all patients. This study was conducted to determine if vascular risk factors can identify a subgroup of individuals with heart failure with a stroke rate high enough to warrant anticoagulation., Methods: The REGARDS study is a population-based cohort of US adults aged ≥45 years. Participants are contacted every 6 months by telephone for self- or proxy-reported stroke and medical records are retrieved and adjudicated by physicians. Participants were characterized into 3 groups: HF without atrial fibrillation (AF), AF with or without HF, and neither HF nor AF. Cardiovascular risk factors at baseline were compared between participants with and without incident stroke in HF and AF. Stroke incidence was assessed in risk factor subgroups in HF participants., Results: Of the 30,239 participants, those with missing/anomalous data were excluded. Of the remaining 28,832, 1360 (5%) had HF without AF, 2528 (9%) had AF, and 24,944 (86%) had neither. Previous stroke/transient ischemic attack (TIA; P = .0004), diabetes mellitus (DM; P = .03), and higher systolic blood pressure (P = .046) were associated with increased stroke risk in participants with HF without AF. In participants with HF without AF, stroke incidence was highest in those with previous stroke/TIA and DM (2.4 [1.1, 4.0] per 100 person-years)., Conclusions: The combination of previous stroke/TIA and DM increases the incidence of stroke in participants with HF without AF. No analyzed subgroup had a stroke rate high enough to make it likely that the benefits of warfarin would outweigh the risks., (Copyright © 2013 National Stroke Association. Published by Elsevier Inc. All rights reserved.)

Objectives: To evaluate the association between six nondisease-specific problems (problems that cross multiple domains of health) and mortality in middle-aged and older adults., Design: Prospective, observational cohort., Setting: U.S. population sample., Participants: Participants included 23,669 black and white U.S. adults aged 45 and older enrolled in the REasons for Geographic and Racial Differences in Stroke (REGARDS) study., Measurements: Nondisease-specific problems included cognitive impairment, depressive symptoms, exhaustion, falls, impaired mobility, and polypharmacy. Age-stratified (<65, 65-74, ≥ 75) hazard ratios for all-cause mortality were calculated for each problem individually and according to number of problems., Results: One or more nondisease-specific problems occurred in 40% of participants younger than 65, 45% of those aged 65 to 74, and 55% of those aged 75 and older. Compared with participants with none of these problems, the multivariable adjusted hazard ratio for all-cause mortality associated with each additional nondisease-specific problem was 1.34 (95% confidence interval (CI) = 1.23-1.46) for participants younger than 65, 1.24 (95% CI = 1.15-1.35) for those aged 65 to 74, and 1.30 (95% CI = 1.21-1.39) for those aged 75 and older., Conclusion: Nondisease-specific problems were associated with mortality across a wide age spectrum. Future studies should explore whether treating these problems will improve survival and identify innovative healthcare models to address multiple nondisease-specific problems simultaneously., (© 2013, Copyright the Authors Journal compilation © 2013, The American Geriatrics Society.)

Objective: To assess whether there are differences in the strength of association with incident stroke for specific periods of life in the Stroke Belt (SB)., Methods: The risk of stroke was studied in 24,544 black and white stroke-free participants, aged 45+, in the Reasons for Geographic and Racial Differences in Stroke study, a national population-based cohort enrolled 2003-2007. Incident stroke was defined as first occurrence of stroke over an average 5.8 years of follow-up. Residential histories (city/state) were obtained by questionnaire. SB exposure was quantified by combinations of SB birthplace and current residence and proportion of years in SB during discrete age categories (0-12, 13-18, 19-30, 31-45, last 20 years) and entire life. Proportional hazards models were used to establish association of incident stroke with indices of exposure to SB, adjusted for demographic, socioeconomic (SES), and stroke risk factors., Results: In the demographic and SES models, risk of stroke was significantly associated with proportion of life in the SB and with all other exposure periods except birth, ages 31-45, and current residence. The strongest association was for the proportion of the entire life in SB. After adjustment for risk factors, the risk of stroke remained significantly associated only with proportion of residence in SB in adolescence (hazard ratio 1.17, 95% confidence interval 1.00-1.37)., Conclusions: Childhood emerged as the most important period of vulnerability to SB residence as a predictor of future stroke. Improvement in childhood health circumstances should be considered as part of long-term health improvement strategies in the SB.

Objective: Stroke is a leading cause of long-term disability in the United States. Family caregivers are susceptible to negative outcomes as a result of their caregiving role. A stress process model was utilized to identify characteristics of stroke caregivers who are at risk for poor physical and mental health-related quality of life (QOL)., Research Method: Individuals who experienced an incident stroke event within the previous year were identified from a larger epidemiologic study of stroke incidence. These stroke survivors were enrolled in the Caring for Adults Recovering from the Effects of Stroke (CARES) study along with their primary family caregivers (N = 146 dyads). Caregivers completed a baseline telephone interview that assessed physical and mental health-related QOL, problems their family members were experiencing, appraisals of those problems, and caregiver resources., Results: Objective stressors, appraisals, and caregiver resources were related to caregiver physical and mental health-related QOL, ps <.05. Objective stressors were found to have a stronger association with caregiver mental health than physical health. Hierarchical regression models showed the relative importance of each category of predictors. In the final models, older age and receiving more support were associated with worse physical health-related QOL whereas African American race and fewer stroke survivor problems were associated with better mental health., Conclusions: The correlates of health-related QOL identified in this national sample of caregivers can help identify stroke caregivers who are at risk for poor adjustment to the caregiving role and aid in identifying areas that can potentially be intervened upon for these caregivers.

Objective: Examine whether long- and short-term sunlight radiation is related to stroke incidence., Methods: Fifteen-year residential histories merged with satellite, ground monitor, and model reanalysis data were used to determine sunlight radiation (insolation) and temperature exposure for a cohort of 16,606 stroke and coronary artery disease-free black and white participants aged ≥45 years from the 48 contiguous United States. Fifteen-, 10-, 5-, 2-, and 1-year exposures were used to predict stroke incidence during follow-up in Cox proportional hazard models. Potential confounders and mediators were included during model building., Results: Shorter exposure periods exhibited similar, but slightly stronger relationships than longer exposure periods. After adjustment for other covariates, the previous year's monthly average insolation exposure below the median gave a hazard ratio (HR) of 1.61 (95% confidence interval [CI], 1.15-2.26), and the previous year's highest compared to the second highest quartile of monthly average maximum temperature exposure gave an HR of 1.92 (95%, 1.27-2.92)., Interpretation: These results indicate a relationship between lower levels of sunlight radiation and higher stroke incidence. The biological pathway of this relationship is not clear. Future research will show whether this finding stands, the pathway for this relationship, and whether it is due to short- or long-term exposures., (Copyright © 2012 American Neurological Association.)

Background and Purpose: Studies suggest that family caregiver well-being (ie, depressive symptoms and life satisfaction) may affect stroke survivor depressive symptoms. We used mediation analysis to assess whether caregiver well-being might be a factor explaining stroke survivor depressive symptoms, after controlling for demographic factors and stroke survivor impairments and problems., Methods: Caregiver/stroke participant dyads (N = 146) completed measures of stroke survivor impairments and problems and depressive symptoms and caregiver depressive symptoms and life satisfaction. Mediation analysis was used to examine whether caregiver well-being mediated the relationship between stroke survivor impairments and problems and stroke survivor depressive symptoms., Results: As expected, more stroke survivor problems and impairments were associated with higher levels of stroke survivor depressive symptoms (P < .0001). After controlling for demographic factors, we found that this relationship was partially mediated by caregiver life satisfaction (29.29%) and caregiver depressive symptoms (32.95%). Although these measures combined to account for 40.50% of the relationship between survivor problems and impairments and depressive symptoms, the direct effect remained significant., Conclusions: Findings indicate that stroke survivor impairments and problems may affect family caregivers and stroke survivors and a high level of caregiver distress may result in poorer outcomes for stroke survivors. Results highlight the likely importance of intervening with both stroke survivors and family caregivers to optimize recovery after stroke.

Objective: The purpose of this cross-sectional study was to determine the prevalence and potential significance of stroke symptoms among end-stage renal disease (ESRD) patients without a prior diagnosis of stroke or TIA., Methods: We enrolled 148 participants with ESRD from 5 clinics. Stroke symptoms and functional status, basic and instrumental activities of daily living (ADL, IADL), were ascertained by validated questionnaires. Cognitive function was assessed with a neurocognitive battery. Cognitive impairment was defined as a score 2 SDs below norms for age and education in 2 domains. IADL impairment was defined as needing assistance in at least 1 of 7 IADLs., Results: Among the 126 participants without a prior stroke or TIA, 46 (36.5%) had experienced one or more stroke symptoms. After adjustment for age, sex, race, education, language, diabetes, and cardiovascular disease, participants with stroke symptoms had lower scores on tests of attention, psychomotor speed, and executive function, and more pronounced dependence in IADLs and ADLs (p ≤ 0.01 for all). After adjustment for age, sex, race, education, language, diabetes, and cardiovascular disease, participants with stroke symptoms had a higher likelihood of cognitive impairment (odds ratio [OR] 2.47, 95% confidence interval [CI] 1.03-5.92) and IADL impairment (OR 3.86, 95% CI 1.60-9.28)., Conclusions: Stroke symptoms are common among patients with ESRD and strongly associated with impairments in cognition and functional status. These findings suggest that clinically significant stroke events may go undiagnosed in this high-risk population.

Objective: To determine whether incidence of impaired cognitive screening status is higher in the southern Stroke Belt region of the United States than in the remaining United States., Methods: A national cohort of adults age ≥45 years was recruited by the Reasons for Geographic and Racial Differences in Stroke (REGARDS) study from 2003 to 2007. Participants' global cognitive status was assessed annually by telephone with the Six-Item Screener (SIS) and every 2 years with fluency and recall tasks. Participants who reported no stroke history and who were cognitively intact at enrollment (SIS >4 of 6) were included (N = 23,913, including 56% women; 38% African Americans and 62% European Americans; 56% Stroke Belt residents and 44% from the remaining contiguous United States and the District of Columbia). Regional differences in incident cognitive impairment (SIS score ≤4) were adjusted for age, sex, race, education, and time between first and last assessments., Results: A total of 1,937 participants (8.1%) declined to an SIS score ≤4 at their most recent assessment, over a mean of 4.1 (±1.6) years. Residents of the Stroke Belt had greater adjusted odds of incident cognitive impairment than non-Belt residents (odds ratio, 1.18; 95% confidence interval, 1.07-1.30). All demographic factors and time independently predicted impairment., Interpretation: Regional disparities in cognitive decline mirror regional disparities in stroke mortality, suggesting shared risk factors for these adverse outcomes. Efforts to promote cerebrovascular and cognitive health should be directed to the Stroke Belt., (Copyright © 2011 American Neurological Association.)

Background and Purpose: Previous research has reported worse outcomes after stroke for women and for African Americans, but few prospective population-based studies have systematically examined demographic differences on long-term stroke outcomes. Race and gender differences in 1-year stroke outcomes were examined using an epidemiologically derived sample of first-time stroke survivors from the national REasons for Geographic and Racial Differences in Stroke (REGARDS) study., Methods: Participants of REGARDS who reported a first-time stroke event during regular surveillance calls were interviewed by telephone and then completed an in-home evaluation approximately 1 year after the verified first-time stroke event (N=112). A primary family caregiver was also enrolled and interviewed for each stroke survivor. Measures from the in-home evaluation included previously validated stroke outcomes assessments of neurological deficits, functional impairments, and patient-reported effects of stroke in multiple domains. Results- African American stroke survivors were less likely to be living with their primary family caregivers than white participants. Analyses that controlled for age, education, and whether the stroke survivors lived with their primary family caregivers indicated that African Americans and women showed significantly greater deficits on multiple 1-year outcome measures compared to whites and men, respectively., Conclusions: Among community-dwelling stroke survivors with family caregivers, women and African Americans are at heightened risk for poor long-term outcomes 1 year after first-time stroke events. Rehabilitation services and public health policies aimed at enhancing stroke recovery rates should address these disparities in poststroke outcomes.

Background and Purpose: The prevalence of stroke is increased in individuals with heart failure (HF). The stroke mechanism in HF may be cardiogenic embolism or cerebral hypoperfusion. Stroke risk increases with decreasing ejection fraction and low cardiac output is associated with hypotension and poor survival. We examine the relationship among blood pressure level, history of stroke/transient ischemic attack (TIA), and HF., Methods: We compared the prevalence of self-reported history of stroke or TIA in the REasons for Geographic And Racial Differences in Stroke (REGARDS) participants with HF (as defined by current digoxin use) and without HF. We excluded participants with atrial fibrillation or missing data. We examined the relationship between HF and history of stroke/TIA within tertiles of systolic blood pressure (SBP) adjusting for patient demographic and health characteristics., Results: Prevalent stroke/TIA were reported by 66 (26.3%) of 251 participants with and 1805 (8.5%) of 21 202 participants without HF (P<0.0001). Within each tertile of SBP, the unadjusted OR (95% CI) for prior stroke/TIA among those with HF compared with those without HF (the reference group) was, 4.0 (2.8 to 5.8) for SBP <119.5 mm Hg, 2.7 (1.8 to 3.9) for SBP >or=119.5 but <131.5 mm Hg, and 2.3 (1.6 to 3.2) for SBP >or=131.5 mm Hg. After adjustment, the relationship between prior stroke/TIA and HF remained significant only within the lowest tertile of SBP (<119.5 mm Hg; 3.0; 1.5 to 6.1)., Conclusions: The odds of prevalent self-reported stroke/TIA are increased in participants with HF and most markedly increased in participants with low SBP. Longitudinal data are needed to determine whether this reflects stroke/TIA secondary to thromboembolism from poor cardiac function or secondary to cerebral hypoperfusion.

Background and Purpose: Vascular disorders that increase risk for stroke may be accompanied by decrements in cognitive functioning and by stroke symptoms in the absence of diagnosed stroke or transient ischemic attack. This study evaluates relationships among cognitive status, stroke symptom reports, and cardiovascular and behavioral factors., Methods: REasons for Geographic and Racial Differences in Stroke (REGARDS), a prospective population study of stroke incidence, assesses stroke risk with telephone interviews and in-home physicals. Excluding subjects with a history of stroke or transient ischemic attack, this analysis includes 14,566 black and white men and women > or =45 years of age. Incremental logistic models examine baseline relationships among cognitive status (Six-item Screener scores), stroke symptom reports, demographics, health behaviors, cardiovascular indices, and depressive symptoms., Results: A history of stroke symptoms was related to impaired cognitive status after adjusting for age, gender, race, and education but not after adjusting for poor health behaviors, vascular risk factors, and depressive symptoms. Odds of experiencing a stroke symptom increased 35% with each of five modifiable factors (hypertension, diabetes, smoking, lack of exercise, depressive symptoms), and odds of cognitive impairment increased an additional 12% with each modifiable factor. Lifelong abstinence from alcohol, lack of exercise, and depressive symptoms were independently related to impaired cognitive status., Conclusions: The increased likelihood of cognitive impairment among subjects reporting stroke symptoms in the absence of a diagnosed stroke or transient ischemic attack suggests that such symptoms are not benign and may warrant clinical evaluation that includes a cognitive assessment. Future studies that include brain imaging may clarify the etiology of these symptoms.

This study examined the relationship between cognitive change and instrumental activities of daily living (IADL) in a large, national, population-based sample. Cognitive change was assessed via verbal fluency, word list learning (WLL), and word list delayed recall (WLD). Incident cognitive impairment was defined by change in Six-Item Screener (SIS) status over a period of 10 years. Impaired IADL was defined as self-reported difficulty or needing assistance performing any IADL at Year 10. A one-word decrease in WLL over a 10-year span increased the odds of impaired IADL by 16% (95% CI 1.08-1.24) and incident cognitive impairment increased the odds of impaired IADL by 59% (95% CI 1.36-1.85) when adjusting for demographic factors, health-related behaviors, vascular risk factors and disease, and depressive symptoms. Cognitive change most strongly predicted impairment in managing finances (OR 2.47, 95% CI 2.04-3.00) and driving (OR 2.06, 95% CI 1.73-2.44). [ABSTRACT FROM AUTHOR]

Although the association between high blood pressure (BP), particularly in midlife, and late-life dementia is known, less is known about variations by race and sex. In a prospective national study of 22 164 blacks and whites ≥45 years without baseline cognitive impairment or stroke from the REGARDS cohort study (Reasons for Geographic and Racial Differences in Stroke), enrolled 2003 to 2007 and followed through September 2015, we measured changes in cognition associated with baseline systolic and diastolic BP (SBP and DBP), as well as pulse pressure (PP) and mean arterial pressure, and we tested whether age, race, and sex modified the effects. Outcomes were global cognition (Six-Item Screener; primary outcome), new learning (Word List Learning), verbal memory (Word List Delayed Recall), and executive function (Animal Fluency Test). Median follow-up was 8.1 years. Significantly faster declines in global cognition were associated with higher SBP, lower DBP, and higher PP with increasing age ( P<0.001 for age×SBP×follow-up-time, age×DBP×follow-up-time, and age×PP×follow-up-time interaction). Declines in global cognition were not associated with mean arterial pressure after adjusting for PP. Blacks, compared with whites, had faster declines in global cognition associated with SBP ( P=0.02) and mean arterial pressure ( P=0.04). Men, compared with women, had faster declines in new learning associated with SBP ( P=0.04). BP was not associated with decline of verbal memory and executive function, after controlling for the effect of age on cognitive trajectories. Significantly faster declines in global cognition over 8 years were associated with higher SBP, lower DBP, and higher PP with increasing age. SBP-related cognitive declines were greater in blacks and men. [ABSTRACT FROM AUTHOR]

Purpose: Emerging evidence suggests physical activity (PA) is associated with cognitive function. To overcome limitations of self-report PA measures, this study investigated the association of accelerometer-measured PA with incident cognitive impairment and longitudinal cognition among older adults. Methods: Participants were recruited from the cohort study Reasons for Geographic and Racial Differences in Stroke in the United States. Accelerometers provided PA measures, including the percentage of total accelerometer wearing time spent in moderate-to-vigorous-intensity PA (MVPA%), light-intensity PA, and sedentary time for four to seven consecutive days at baseline. Cognitive impairment was defined by the Six-Item Screener. Letter fluency, animal fluency, word list learning, and Montreal Cognitive Assessment (orientation and recall) were conducted to assess executive function and memory. Results: Participants (N = 6452, 69.7 ± 8.5 yr, 55.3% women, 30.5% Black) with usable accelerometer and cognition measures spent extremely limited time in MVPA (1.5% ± 1.9% of accelerometer wearing time). During an average of 3 yr of follow-up, 346 cases of incident cognitive impairment were observed. After adjustments, participants in higher MVPA% quartiles had a lower risk of cognitive impairment (i.e., quartile 2: odds ratio = 0.64,95% confidence interval = 0.48-0.84) and better maintenance in executive function (≥0.03 z-score units) and memory (≥0.12 z-score units) compared with quartile 1 (P < 0.05). Stratified analyses showed the same association among White adults, but higher MVPA% was associated with better maintenance of only memory among Black adults. No significance was found for light-intensity PA or sedentary time. Conclusion: There was a dose-response relationship between MVPA% and cognitive function in older adults, with higher levels associated with a 36% or lower risk of cognitive impairment and better maintenance of memory and executive function over time, particularly in White adults. [ABSTRACT FROM AUTHOR]

Vitamin D protects against cognitive decline in animals but evidence in humans has been inconsistent. Fibroblast growth factor 23 (FGF23) is a hormone that inhibits vitamin D activation yet few studies examined whether FGF23 is associated with cognitive impairment. The objective of this study was to examine associations of 25(OH)D and FGF23 with incident cognitive impairment in the Reasons for Geographic and Racial Differences in Stroke (REGARDS) study, a cohort of black and white adults ≥45 years old. FGF23 and 25(OH)D were measured in 474 incident impairment cases and 561 controls. In multivariable-adjusted models, there were no significant associations of FGF23 with incident cognitive impairment. In analyses using clinically-relevant categories of 25(OH)D (< 20 ng/ml, 20–29.9 ng/ml, ≥30 ng/ml), there was no statistically significant association of lower 25(OH)D concentrations with odds of incident cognitive impairment in models adjusted for demographic, clinical, and laboratory variables and season of blood draw (tertile 1 [≥30 ng/ml] reference; tertile 2 [20–29.9 ng/ml], odds ratio [OR] 0.96, 95%CI 0.67, 1.38; tertile 3 [<20 ng/ml] OR 1.26, 95%CI 0.83, 1.91). When 25(OH)D was modeled as race-specific tertiles, there were no significant associations of 25(OH)D with incident cognitive impairment in whites, whereas lower 25(OH)D was associated with higher odds in blacks (tertile 1 [>23 ng/ml] reference; tertile 2 [15–23 ng/ml], OR 2.96, 95%CI 1.48,5.94; tertile 3 [<15 ng/ml] OR 2.40, 95%CI 1.07,5.40) in the fully adjusted model. In this cohort of older adults, lower race-specific tertiles of 25(OH)D were associated with higher incidence of cognitive impairment in black individuals but not white individuals. These data suggest that treating low 25(OH)D may be a novel strategy for addressing racial disparities in neurocognitive outcomes. [ABSTRACT FROM AUTHOR]

Abstract: Background: Heart failure (HF) and cognitive impairment are both common in older adults. However, the association between the two has not been well studied. Methods and Results: We explored the relationship between very probable HF, determined by self-reported symptoms, and cognitive impairment, defined as four or fewer correct on the Six-item Screener, in 14,089 participants of the Reasons for Geographic and Racial Differences in Stroke cohort. We determined the effect of adding demographic, socioeconomic status (SES), health behavior, and comorbidity covariates. In the univariate model, participants with very probable HF were 1.51 (95% confidence interval: 1.15–1.96) times more likely to have cognitive impairment than those without HF. As covariates were added to the model, the relationship between HF and cognitive impairment was attenuated and lost statistical significance after adjustment for depression. Demographic variables, Stroke Belt location (1.28 [1.11–1.48]), SES factors, prior stroke (1.43 [1.18–1.73]), and depression (1.66 [1.38–2.01]) remained significant in the multivariable model. Higher hemoglobin was associated (0.95 [0.9–1.00]) with modestly reduced odds of cognitive impairment. Conclusions: The relationship between cognitive impairment and HF can be accounted for by multiple demographic and SES factors, and by comorbidities, some of which are modifiable. Persons with HF and cognitive impairment should be screened for anemia and depression. [Copyright &y& Elsevier]