Trends in Stroke Incidence Rates in Older US Adults: An Update from the Atherosclerosis Risk in Communities (ARIC) Cohort Study

Importance: Determining whether the previously reported decreased stroke incidence rates from 1987 to 2011 among US adults 65 years and older in the Atherosclerosis Risk in Communities (ARIC) study continued to decrease subsequently can help guide policy and planning efforts. Objective: To evaluate whether stroke incidence declines among older adults in the ARIC study continued after 2011. Design, Setting, and Participants: ARIC is a community-based prospective cohort study including 15792 individuals aged 45 to 64 years at baseline (1987-1989), selected by probability sampling from residents of Forsyth County, North Carolina; Jackson, Mississippi (black individuals only); the northwestern suburbs of Minneapolis, Minneapolis; and Washington County, Maryland (ie, center). The present study included ARIC participants free of stroke at baseline, followed up through December 31, 2017. Data were collected through personal interviews and physical examinations during study visits, annual/semiannual telephone interviews, and active surveillance of discharges from local hospitals. Stroke events were adjudicated by study-physicians reviewers. Analysis began September 2018. Main Outcomes and Measures: The main outcome was stroke incidence rates, which were computed with 95% CIs stratifying the analysis by age and calendar time. Trends in adjusted incidence rates were assessed using Poisson regression incidence rate ratios. Models included calendar time, age, sex, race/center, and time-varying risk factors (hypertension, diabetes, coronary heart disease, cholesterol-lowering medication use, and smoking). Results: Of 14357 ARIC participants with 326654 person-years of follow-up, the mean (SD) age at baseline was 54.1 (5.8) years and 7955 (55.4%) were women. From 1987 to 2017, a total of 1340 incident strokes occurred among ARIC participants, and among them, 1028 (76.7%) occurred in participants 65 years and older. Crude incidence rates of stroke for participants 65 years and older decreased progressively from 1987 to 2017. Incidence rates, adjusted for age, sex, race/center, and time-varying risk factors, decreased by 32% (95% CI, 23%-40%) per 10 years in participants 65 years and older. Findings were consistent across decades, sex, and race. Conclusions and Relevance: Validated total stroke incidence rates in adults 65 years and older decreased over the last 30 years in the ARIC cohort. The decrease in rates previously reported for 1987 to 2011 extends for the subsequent 6 years in men and women as well as in white and black individuals

Association between white matter hyperintensities, cortical volumes, and late-onset epilepsy

ObjectiveTo identify the association between brain vascular changes and cortical volumes on MRI and late-onset epilepsy.MethodsIn 1993-1995, 1,920 participants (median age 62.7, 59.9% female) in the community-based Atherosclerosis Risk in Communities (ARIC) Study underwent MRI, and white matter hyperintensities were measured. In addition, in 2011-2013, 1,964 ARIC participants (median age 72.4, 61.1% female) underwent MRI, and cortical volumes and white matter hyperintensities were measured. We identified cases of late-onset epilepsy (starting at age 60 or later) from ARIC hospitalization records and Medicare claims data. Using the 1993-1995 MRI, we evaluated the association between white matter hyperintensities and subsequent epilepsy using survival analysis. We used the 2011-2013 MRI to conduct cross-sectional logistic regression to examine the association of cortical volumes and white matter hyperintensities with late-onset epilepsy. All models were adjusted for demographics, hypertension, diabetes, smoking, and APOE ϵ4 allele status.ResultsNinety-seven ARIC participants developed epilepsy after having an MRI in 1993-1995 (incidence 3.34 per 1,000 person-years). The degree of white matter hyperintensities measured at ages 49-72 years was associated with the risk of late-onset epilepsy (hazard ratio 1.27 per age-adjusted SD, 95% confidence interval [CI] 1.06-1.54). Lower cortical volume scores were associated cross-sectionally with higher odds of late-onset epilepsy (odds ratio 1.87, 95% CI 1.16-3.02) per age-adjusted SD.ConclusionsThis study demonstrates associations between earlier-life white matter hyperintensities on MRI and later-life incident epilepsy, and between cortical volumes measured later in life and late-onset epilepsy. These findings may help illuminate the causes of late-onset epilepsy

Association of Head Injury with Late-Onset Epilepsy: Results from the Atherosclerosis Risk in Communities Cohort

Background and Objectives Late-onset epilepsy (LOE; i.e., epilepsy starting in later adulthood) affects a significant number of individuals. Head injury is also a risk factor for acquired epilepsy, but the degree to which prior head injury may contribute to LOE is less well understood. Our objective was to determine the association between head injury and subsequent development of LOE. Methods Included were 8,872 participants enrolled in the Atherosclerosis Risk in Communities (ARIC) study with continuous Centers for Medicare Services fee-for-service (FFS) coverage (55.1% women, 21.6% Black). We identified head injuries through 2018 from linked Medicare fee for service claims for inpatient/emergency department care, active surveillance of hospitalizations, and participant self-report. LOE cases through 2018 were identified from linked Medicare FFS claims. We used Cox proportional hazards models to evaluate associations of head injury with LOE, adjusting for demographic, cardiovascular, and lifestyle factors. Results The adjusted hazard ratio (HR) for developing LOE after a history of head injury was 1.88 (95% confidence interval [CI] 1.44-2.43). There was evidence for dose-response associations with greater risk for LOE with increasing number of prior head injuries (HR 1.37, 95% CI 1.01-1.88 for 1 prior head injury and HR 3.55, 95% CI 2.51-5.02 for 2+ prior head injuries, compared to no head injuries) and with more severe head injury (HR 2.53, 95% CI 1.83-3.49 for mild injury and HR 4.90, 95% CI 3.15-7.64 for moderate/severe injury, compared to no head injuries). Associations with LOE were significant for head injuries sustained at older age (age ≥67 years: HR 4.01, 95% CI 2.91-5.54), but not for head injuries sustained at younger age (age < 67 years: HR 0.98, 95% CI 0.68-1.41). Discussion Head injury was associated with increased risk of developing LOE, particularly when head injuries were sustained at an older age, and there was evidence for higher risk for LOE after a greater number of prior head injuries and after more severe head injuries. Classification of Evidence This study provides Class I evidence that an increased risk of late-onset epilepsy is associated with head injury and that this risk increases further with multiple and more severe head injuries

Association between Midlife Risk Factors and Late-Onset Epilepsy: Results from the Atherosclerosis Risk in Communities Study

Importance: The incidence of epilepsy is higher in older age than at any other period of life. Stroke, dementia, and hypertension are associated with late-onset epilepsy; however, the role of other vascular and lifestyle factors remains unclear. Objective: To identify midlife vascular and lifestyle risk factors for late-onset epilepsy. Design, Setting, and Participants: The Atherosclerosis Risk in Communities (ARIC) study is a prospective cohort study of 15792 participants followed up since 1987 to 1989 with in-person visits, telephone calls, and surveillance of hospitalizations (10974 invited without completing enrollment). The ARIC is a multicenter study with participants selected from 4 US communities. This study included 10420 black or white participants from ARIC with at least 2 years of Medicare fee-for-service coverage and without missing baseline data. Data were analyzed betweeen April 2017 and May 2018. Exposures: Demographic, vascular, lifestyle, and other possible epilepsy risk factors measured at baseline (age 45-64 years) were evaluated in multivariable survival models including demographics, vascular risk factors, and lifestyle risk factors. Main Outcomes and Measures: Time to development of late-onset epilepsy (2 or more International Classification of Diseases, Ninth Revision codes for epilepsy or seizures starting at 60 years or older in any claim [hospitalization or outpatient Medicare through 2013]), with first code for seizures after at least 2 years without code for seizures. Results: Of the 10420 total participants (5878 women [56.4%] and 2794 black participants [26.8%]; median age 55 years at first visit), 596 participants developed late-onset epilepsy (3.33 per 1000 person-years). The incidence was higher in black than in white participants (4.71; 95% CI, 4.12-5.40 vs 2.88; 95% CI, 2.60-3.18 per 1000 person-years). In multivariable analysis, baseline hypertension (hazard ratio [HR], 1.30; 95% CI, 1.09-1.55), diabetes (HR, 1.45; 95% CI, 1.17-1.80), smoking (HR, 1.09; 95% CI, 1.01-1.17), apolipoprotein E ϵ4 genotype (1 allele HR, 1.22; 95% CI, 1.02-1.45; 2 alleles HR, 1.95; 95% CI, 1.35-2.81), and incident stroke (HR, 3.38; 95% CI, 2.78-4.10) and dementia (HR, 2.56; 95% CI, 2.11-3.12) were associated with an increased risk of late-onset epilepsy, while higher levels of physical activity (HR, 0.90; 95% CI, 0.83-0.98) and moderate alcohol intake (HR, 0.72; 95% CI, 0.57-0.90) were associated with a lower risk. Results were similar after censoring individuals with stroke or dementia. Conclusions and Relevance: Potentially modifiable risk factors in midlife and the APOE ϵ4 genotype were positively associated with risk of developing late-onset epilepsy. Although stroke and dementia were both associated with late-onset epilepsy, vascular and lifestyle risk factors were significant even in the absence of stroke or dementia

Association of Ischemic Stroke Incidence, Severity, and Recurrence with Dementia in the Atherosclerosis Risk in Communities Cohort Study

Importance: Ischemic stroke is associated with increased risk of dementia, but the association of stroke severity and recurrence with risk of impaired cognition is not well known. Objective: To examine the risk of dementia after incident ischemic stroke and assess how it differed by stroke severity and recurrence. Design, Setting, and Participants: The Atherosclerosis Risk in Communities (ARIC) study is an ongoing prospective cohort of 15792 community-dwelling individuals from 4 US states (Mississippi, Maryland, Minnesota, and North Carolina). Among them, 15379 participants free of stroke and dementia at baseline (1987 to 1989) were monitored through 2019. Data were analyzed from April to October 2021. Associations between dementia and time-varying ischemic stroke incidence, frequency, and severity were studied across an average of 4.4 visits over a median follow-up of 25.5 years with Cox proportional hazards models adjusted for sociodemographic characteristics, apolipoprotein E, and vascular risk factors. Exposures: Incident and recurrent ischemic strokes were classified by expert review of hospital records, with severity defined by the National Institutes of Health Stroke Scale (NIHSS; minor, ≤5; mild, 6-10; moderate, 11-15; and severe, ≥16). Main Outcomes and Measures: Dementia cases adjudicated through expert review of in-person evaluations, informant interviews, telephone assessments, hospitalization codes, and death certificates. In participants with stroke, dementia events in the first year after stroke were not counted. Results: At baseline, the mean (SD) age of participants was 54.1 (5.8) years, and 8485 of 15379 participants (55.2%) were women. A total of 4110 participants (26.7%) were Black and 11269 (73.3%) were White. A total of 1378 ischemic strokes (1155 incident) and 2860 dementia cases were diagnosed 1 year or more after incident stroke in participants with stroke, or at any point after baseline in participants without stroke, were identified through December 31, 2019. NIHSS scores were available for 1184 of 1378 ischemic strokes (85.9%). Risk of dementia increased with both the number and severity of strokes. Compared with no stroke, risk of dementia by adjusted hazard ratio was 1.76 (95% CI, 1.49-2.00) for 1 minor to mild stroke, 3.47 (95% CI, 2.23-5.40) for 1 moderate to severe stroke, 3.48 (95% CI, 2.54-4.76) for 2 or more minor to mild strokes, and 6.68 (95% CI, 3.77-11.83) for 2 or more moderate to severe strokes. Conclusions and Relevance: In this study, risk of dementia significantly increased after ischemic stroke, independent of vascular risk factors. Results suggest a dose-response association of stroke severity and recurrence with risk of dementia

Proinflammatory cytokine secretion is suppressed by TMEM16A or CFTR channel activity in human cystic fibrosis bronchial epithelia

Cystic fibrosis (CF) is caused by the functional expression defect of the CF transmembrane conductance regulator (CFTR) chloride channel at the apical plasma membrane. Impaired bacterial clearance and hyperactive innate immune response are hallmarks of th

Embedding the Stable Failures Model of CSP in PVS

We present an embedding of the stable failures model of CSP in the PVS theorem prover. Our work, extending a previous embedding of the traces model of CSP in [6], provides a platform for the formal verification not only of safety specifications, but also of liveness specifications of concurrent systems in theorem provers. Such a platform is particularly good at analyzing infinite-state systems with an arbitrary number of components. We demonstrate the power of this embedding by using it to construct formal proofs that the asymmetric dining philosophers problem with an arbitrary number of philosophers is deterministic and deadlock-free, and that an industrial-scale example, a 'virtual network' [21], with any number of dimensions, is deadlock-free. We have established some generic proof tactics for verification of properties of networks with many components. In addition, our technique of integrating FDR and PVS in our demonstration allows for handling of systems that would be difficult or impossible to analyze using either tool on its own. © Springer-Verlag Berlin Heidelberg 2005

Supplementary Material for: Timing of cognitive test score decline prior to incident dementia diagnosis in Blacks and Whites: The Atherosclerosis Risk in Communities Neurocognitive Study (ARIC-NCS)

Introduction: Commonly occurring dementias include those of Alzheimer’s, vascular, and mixtures of these and other pathologies. They are believed to evolve over many years, but that time interval has been difficult to establish. Our objective is to determine how many years in advance of a dementia diagnosis cognitive scores begin to change. Methods: 14,086 dementia-free ARIC participants underwent a cognitive exam at baseline visit 2 (1990-1992, mean age 57±5.72), and in 11,244 at visit 4 (1996-1998), 5,640 at visit 5 (2011-2013), and 3,574 at visit 6 (2016-2017) with surveillance for dementias of all causes combined. Within 5-year intervals after each visit, we compared performance on the Delayed Word Recall Test (DWRT), the Digit Symbol Substitution Test (DSST), the Word Fluency Test (WFT), and the combined mean of three cognitive tests at baseline in participants who were diagnosed with dementia within each interval versus those who survived the interval without a dementia diagnosis. Z-scores were adjusted for demographics and education in separate regression models for each visit. We plotted adjusted z-score means by time interval following each visit. Results: During follow-up 3,334, 2,821, 1,218, and 329 dementia cases were ascertained after visits 2, 4, 5, and 6 respectively. Adjusted DWRT z-scores were significantly lower 20-25 years before dementia than those who did not experience dementia within 25 years. DSST z-scores were significantly lower at 25-30 years and 3-test combination z-scores were significantly lower as early as 30-31 years before onset. The difference between dementia and non-dementia group in the visit 2 3-test combination z-score was -0.20 at 30-31 years prior to dementia diagnosis. As expected, differences between the dementia and non-dementia groups increased closer to the time of dementia occurrence, up to their widest point at 0-5 years prior to dementia diagnosis. The difference between dementia and non-dementia groups in the visit 2 3-test combination z-score was -0.90. WFT z-score differences were smaller than for the DSST or DWRT and began later. Patterns were similar in Black and White participants. Conclusion: DWRT, DSST and combined 3-test z-scores were significantly lower more than 20 years prior to diagnosis in the dementia group versus the non-dementia group. Findings contribute to our knowledge of the long prodromal period in Blacks and Whites

Supplementary Material for: Cognition and Incident Dementia Hospitalization: Results from the Atherosclerosis Risk in Communities Study

<b><i>Background/Aims:</i></b> Cognitive decline is a defining feature of dementia. We sought to determine if a single baseline cognitive test score or change in test score over time is more strongly associated with risk of dementia hospitalization. We also sought to compare short- and long-term dementia risk. <b><i>Methods:</i></b> Prospective cohort study of 9,399 individuals from the Atherosclerosis Risk in Communities Study (median 10 years of follow-up). Cognition was assessed at two time points (6 years apart) using three tests: Delayed Word Recall Test (DWRT), Digit Symbol Substitution Test (DSST), and Word Fluency Test. Dementia hospitalizations were determined using ICD-9 codes. <b><i>Results:</i></b> Baseline cognitive test scores were associated with both short-term and long-term risk of dementia. The association of 6-year change in cognitive test score with dementia risk was stronger than that of individual test scores at a single visit [change from highest to lowest tertile, DWRT: hazard ratio = 6.45 (95% confidence interval = 1.80–23.08); DSST: hazard ratio = 10.94 (95% confidence interval = 3.07–38.97)]. <b><i>Conclusions:</i></b> In this community-based population, 6-year changes in cognitive scores were more strongly associated with risk of incident dementia hospitalization than baseline scores, although single DWRT and DSST scores were predictive. Our findings support the contention that cognitive changes may precede clinical dementia by a decade or more

Supplementary Material for: Occupation, Retirement Age, and 20-Year Cognitive Decline: The Atherosclerosis Risk in Communities Neurocognitive Study

Introduction: We examined the association of both midlife occupation and age at retirement with cognitive decline in the Atherosclerosis Risk in Communities (ARIC) biracial community-based cohort. Methods: Current or most recent occupation at ARIC baseline (1987-89; ages 45-64y) was categorized based on 1980 US census major occupation groups and tertiles of the Nam-Powers-Boyd occupational status score (n=14,090). Retirement status via annual follow-up questionnaires administered ascertained in 1999-2007 was classified as occurring before or after age 70 (n=7,503). Generalized estimating equation models were used to examine associations of occupation and age at retirement with trajectories of global cognitive factor scores, assessed from visit 2 (1990-92) to visit 5 (2011–2013). Models were a priori stratified by race and sex and adjusted for demographics and comorbidities. Results: Low occupational status and blue-collar occupations were associated with low baseline cognitive scores in all race-sex strata. Low occupational status and homemaker status were associated with faster decline in White women but slower decline in Black women compared to high occupational status. Retirement before age 70 was associated with slower cognitive decline in White men and women and in Black men. Results did not change substantially after accounting for attrition. Conclusion: Low occupational status was associated with cognitive decline in women but not in men. Earlier retirement was associated with a slower cognitive decline in White participants and in Black men. Further research should explore reasons for the observed associations and race-sex differences