Premorbid physical activity and prognosis after incident myocardial infarction: the Atherosclerosis Risk in Communities Study.

BACKGROUND: High to moderate levels of physical activity (PA) are associated with low risk of incident cardiovascular disease. However, it is unclear whether the benefits of PA in midlife extend to cardiovascular health following myocardial infarction (MI) in later life. METHODS: Among 1,111 ARIC participants with incident MI during ARIC follow-up (mean age 73 [SD 9] years at MI, 54% men, 21% Black), PA on average 11.9 (SD 6.9) years prior to incident MI (premorbid PA) was evaluated as the average score of PA between visit 1 (1987-89) and visit 3 (1993-95) using a modified Baecke questionnaire. Total and domain-specific PA (sport, non-sport leisure, and work PA) was analyzed for associations with composite and individual outcomes of mortality, recurrent MI, and stroke after index MI using multivariable Cox models. RESULTS: During a median follow-up of 4.6 (IQI 1.0-10.5) years after incident MI, 823 participants (74%) developed a composite outcome. The 10-year cumulative incidence of the composite outcome was lower in the highest, as compared to the lowest tertile of premorbid total PA (56% vs. 70%, respectively). This association remained statistically significant even after adjusting for potential confounders (adjusted hazard ratio [aHR] 0.80 [0.67-0.96] for the highest vs. lowest tertile). For individual outcomes, high premorbid total PA was associated with a low risk of recurrent MI (corresponding aHR 0.64 [0.44, 0.93]). When domain-specific PA was analyzed, similar results were seen for sport and work PA. The association was strongest in the first year following MI (e.g., aHR of composite outcome 0.66 [95% CI 0.47, 0.91] for the highest vs. lowest tertile of total PA). CONCLUSIONS: Premorbid PA was associated positively with post-MI cardiovascular health. Our results demonstrate the additional prognostic advantages of PA beyond reducing the risk of incident MI.

Social relationships, amyloid burden, and dementia: The ARIC-PET study.

INTRODUCTION: This study aimed to assess whether social relationships in mid-life reduce the risk of dementia related to amyloid burden. METHODS: Participants in the Atherosclerosis Risk in Communities (ARIC) study were assessed for social support and isolation (visit 2; 1990-1992). A composite measure, "social relationships," was generated. Brain amyloid was evaluated with florbetapir positron emission tomography (PET); (visit 5; 2012-2014). Incident dementia cases were identified following visit 5 through 2019 using ongoing surveillance. Relative contributions of mid-life social relationships and elevated brain amyloid to incident dementia were evaluated with Cox regression models. RESULTS: Among 310 participants without dementia, strong mid-life social relationships were associated independently with lower dementia risk. Elevated late-life brain amyloid was associated with greater dementia risk. DISCUSSION: Although mid-life social relationships did not moderate the relationship between amyloid burden and dementia, these findings affirm the importance of strong social relationships as a potentially protective factor against dementia.

Self-Rated Health in Middle Age and Risk of Hospitalizations and Death: Recurrent Event Analysis of the ARIC Study.

BACKGROUND: Self-rated health is a simple measure that may identify individuals who are at a higher risk for hospitalization or death. OBJECTIVE: To quantify the association between a single measure of self-rated health and future risk of recurrent hospitalizations or death. PARTICIPANTS: Atherosclerosis Risk in Communities (ARIC) study, a community-based prospective cohort study of middle-aged men and women with follow-up beginning from 1987 to 1989. MAIN MEASURES: We quantified the associations between initial self-rated health with risk of recurrent hospitalizations and of death using a recurrent events survival model that allowed for dependency between the rates of hospitalization and hazards of death, adjusted for demographic and clinical factors. KEY RESULTS: Of the 14,937 ARIC cohort individuals with available self-rated health and covariate information, 34% of individuals reported "excellent" health, 47% "good," 16% "fair," and 3% "poor" at study baseline. After a median follow-up of 27.7 years, 1955 (39%), 3569 (51%), 1626 (67%), and 402 (83%) individuals with "excellent," "good," "fair," and "poor" health, respectively, had died. After adjusting for demographic factors and medical history, a less favorable self-rated health status was associated with increased rates of hospitalization and death. As compared to those reporting "excellent" health, adults with "good," "fair," and "poor" health had 1.22 (1.07 to 1.40), 2.01 (1.63 to 2.47), and 3.13 (2.39 to 4.09) times the rate of hospitalizations, respectively. The hazards of death also increased with worsening categories of self-rated health, with "good," "fair," and "poor" health individuals experiencing 1.30 (1.12 to 1.51), 2.15 (1.71 to 2.69), and 3.40 (2.54 to 4.56) times the hazard of death compared to "excellent," respectively. CONCLUSIONS: Even after adjusting for demographic and clinical factors, having a less favorable response on a single measure of self-rated health taken in middle age is a potent marker of future hospitalizations and death.

Maintenance of Normal Blood Pressure From Middle to Older Age: Results From the Atherosclerosis Risk in Communities Study.

BACKGROUND: It is unknown whether maintaining normal blood pressure (BP) from middle to older age is associated with improved health outcomes. METHODS: We estimated the proportion of Atherosclerosis Risk in Communities study participants who maintained normal BP from 1987 to 1989 (visit 1) through 1996 to 1998 and 2011 to 2013 (over 4 and 5 visits, respectively). Normal BP was defined as systolic BP <120 mm Hg and diastolic BP <80 mm Hg, without antihypertensive medication. We estimated the risk of cardiovascular disease, dementia, and poor physical functioning after visit 5. In exploratory analyses, we examined participant characteristics associated with maintaining normal BP. RESULTS: Among 2699 participants with normal BP at baseline (mean age 51.3 years), 47.1% and 15.0% maintained normal BP through visits 4 and 5, respectively. The hazard ratios comparing participants who maintained normal BP through visit 4 but not visit 5 and through visit 5 versus those who did not maintain normal BP through visit 4 were 0.80 (95% CI, 0.63-1.03) and 0.60 (95% CI, 0.42-0.86), respectively, for cardiovascular disease, and 0.85 (95% CI, 0.71-1.01) and 0.69 (95% CI, 0.54-0.90), respectively, for poor physical functioning. Maintaining normal BP through visit 5 was more common among participants with normal body mass index versus obesity at visit 1, those with normal body mass index at visits 1 and 5, and those with overweight at visit 1 and overweight or normal body mass index at visit 5, compared with those with obesity at visits 1 and 5. CONCLUSIONS: Maintaining normal BP was associated with a lower risk of cardiovascular disease and poor physical functioning.

Association of Continuity of Care With Health Care Utilization and Expenditures Among Patients Discharged Home After Stroke or Transient Ischemic Attack.

OBJECTIVES: To examine the association of prestroke continuity of care (COC) with postdischarge health care utilization and expenditures. STUDY POPULATION: The study population included 2233 patients with a diagnosis of stroke or a transient ischemic attack hospitalized in one of 41 hospitals in North Carolina between March 2016 and July 2019 and discharged directly home from acute care. METHODS: COC was assessed from linked Centers for Medicare and Medicaid Services Medicare claims using the Modified, Modified Continuity Index. Logistic regressions and 2-part models were used to examine the association of prestroke primary care COC with postdischarge health care utilization and expenditures. RESULTS: Relative to patients in the first (lowest) COC quartile, patients in the second and third COC quartiles were more likely [21% (95% CI: 8.5%, 33.5%) and 33% (95% CI: 20.5%, 46.1%), respectively] to have an ambulatory care visit within 14 days. Patients in the highest COC quartile were more likely to visit a primary care provider but less likely to see a stroke specialist. Highest as compared with lowest primary care COC quartile was associated with $45 lower (95% CI: $14, $76) average expenditure for ambulatory care visits within 30 days postdischarge. Patients in the highest, as compared with the lowest, primary care COC quartile were 36% less likely (95% CI: 8%, 64%) to be readmitted within 30 days postdischarge and spent $340 less (95% CI: $2, $678) on unplanned readmissions. CONCLUSIONS: These findings underscore the importance of primary care COC received before stroke hospitalization to postdischarge care and expenditures.

Posttraumatic Epilepsy and Dementia Risk.

Importance: Although both head injury and epilepsy are associated with long-term dementia risk, posttraumatic epilepsy (PTE) has only been evaluated in association with short-term cognitive outcomes. Objective: To investigate associations of PTE with dementia risk. Design, Setting, and Participants: The Atherosclerosis Risk in Communities (ARIC) study initially enrolled participants from 1987 to 1989 and this prospective cohort study uses data through December 31, 2019, with a median follow-up of 25 years. Data were analyzed between March 14, 2023, and January 2, 2024. The study took place in 4 US communities in Minnesota, Maryland, North Carolina, and Mississippi. Of 15 792 ARIC study participants initially enrolled, 2061 were ineligible and 1173 were excluded for missing data, resulting in 12 558 included participants. Exposures: Head injury was defined by self-report and International Classification of Diseases (ICD) diagnostic codes. Seizure/epilepsy was defined using ICD codes. PTE was defined as a diagnosis of seizure/epilepsy occurring more than 7 days after head injury. Head injury, seizure/epilepsy, and PTE were analyzed as time-varying exposures. Main Outcomes and Measures: Dementia was defined using cognitive assessments, informant interviews, and ICD and death certificate codes. Adjusted Cox and Fine and Gray proportional hazards models were used to estimate dementia risk. Results: Participants had a mean (SD) age of 54.3 (5.8) years at baseline, 57.7% were female, 28.2% were of self-reported Black race, 14.4% were ultimately categorized as having head injury, 5.1% as having seizure/epilepsy, and 1.2% as having PTE. Over a median follow-up of 25 (25th to 75th percentile, 17-30) years, 19.9% developed dementia. In fully adjusted models, compared with no head injury and no seizure/epilepsy, PTE was associated with 4.56 (95% CI, 4.49-5.95) times the risk of dementia, while seizure/epilepsy was associated with 2.61 (95% CI, 2.21-3.07) times the risk and head injury with 1.63 (95% CI, 1.47-1.80) times the risk. The risk of dementia associated with PTE was significantly higher than the risk associated with head injury alone and with nontraumatic seizure/epilepsy alone. Results were slightly attenuated in models accounting for the competing risks of mortality and stroke, but patterns of association remained similar. In secondary analyses, the increased dementia risk associated with PTE occurring after first vs second head injury and after mild vs moderate/severe injury was similar. Conclusions and Relevance: In this community-based cohort, there was an increased risk of dementia associated with PTE that was significantly higher than the risk associated with head injury or seizure/epilepsy alone. These findings provide evidence that PTE is associated with long-term outcomes and supports both the prevention of head injuries via public health measures and further research into the underlying mechanisms and the risk factors for the development of PTE, so that efforts can also be focused on the prevention of PTE after a head injury.

Associations Between Mid-Life Psychosocial Measures and Estimated Late Life Amyloid Burden: The Atherosclerosis Risk in Communities (ARIC)-PET Study.

Background: Psychosocial factors are modifiable risk factors for Alzheimer's disease (AD). One mechanism linking psychosocial factors to AD risk may be through biological measures of brain amyloid; however, this association has not been widely studied. Objective: To determine if mid-life measures of social support and social isolation in the Atherosclerosis Risk in Communities (ARIC) Study cohort are associated with late life brain amyloid burden, measured using florbetapir positron emission tomography (PET). Methods: Measures of social support and social isolation were assessed in ARIC participants (visit 2: 1990-1992). Brain amyloid was evaluated with florbetapir PET standardized uptake value ratios (SUVRs; visit 5: 2012-2014). Results: Among 316 participants without dementia, participants with intermediate (odds ratio (OR), 0.47; 95% CI, 0.25-0.88), or low social support (OR, 0.43; 95% CI, 0.22-0.83) in mid-life were less likely to have elevated amyloid SUVRs, relative to participants with high social support. Participants with moderate risk for social isolation in mid-life (OR, 0.32; 95% CI, 0.14-0.74) were less likely to have elevated amyloid burden than participants at low risk for social isolation. These associations were not significantly modified by sex or race. Conclusions: Lower social support and moderate risk of social isolation in mid-life were associated with lower odds of elevated amyloid SUVR in late life, compared to participants with greater mid-life psychosocial measures. Future longitudinal studies evaluating mid-life psychosocial factors, in relation to brain amyloid as well as other health outcomes, will strengthen our understanding of the role of these factors throughout the lifetime.

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.

Stroke Subtype and Risk of Subsequent Hospitalization: The Atherosclerosis Risk in Communities Study

BACKGROUND AND OBJECTIVES: Risk of readmission after stroke differs by stroke (sub)type and etiology, with higher risks reported for hemorrhagic stroke and cardioembolic stroke. We examined the risk and cause of first readmission by stroke subtype over the years post incident stroke. METHODS: Atherosclerosis Risk in Communities (ARIC) study participants (n = 1,412) with first-ever stroke were followed up for all-cause readmission after incident stroke. Risk of first readmission was examined by stroke subtypes (cardioembolic, thrombotic/lacunar, and hemorrhagic [intracerebral and subarachnoid]) using Cox and Fine-Gray proportional hazards models, adjusting for sociodemographic and cardiometabolic risk factors. RESULTS: Among 1,412 participants (mean [SD] age 72.4 [9.3] years, 52.1% women, 35.3% Black), 1,143 hospitalizations occurred over 41,849 person-months. Overall, 81% of participants were hospitalized over a maximum of 26.6 years of follow-up (83% of participants with thrombotic/lacunar stroke, 77% of participants with cardioembolic stroke, and 78% of participants with hemorrhagic stroke). Primary cardiovascular and cerebrovascular diagnoses were reported for half of readmissions. Over the entire follow-up period, compared with cardioembolic stroke, readmission risk was lower for thrombotic/lacunar stroke (hazard ratio [HR] 0.82, 95% CI 0.71-0.95) and hemorrhagic stroke (HR 0.74, 95% CI 0.58-0.93) in adjusted Cox proportional hazards models. By contrast, there was no statistically significant difference among subtypes when adjusting for atrial fibrillation and competing risk of death. Compared with cardioembolic stroke, thrombotic/lacunar stroke was associated with lower readmission risk within 1 month (HR 0.66, 95% CI 0.46-0.93) and during 1 month-1 year (HR 0.78, 95% CI 0.62-0.97), and hemorrhagic stroke was associated with lower risk during 1 month-1 year (HR 0.60, 95% CI 0.41-0.87). There was no significant difference between subtypes in readmission risk during later periods. DISCUSSION: Over 26 years of follow-up, 81% of stroke participants experienced a readmission. Cardiovascular and cerebrovascular diagnoses at readmission were most common across stroke subtypes. Though cardioembolic stroke has previously been reported to confer higher risk of readmission, in this study, the readmission risk was not statistically significantly different between stroke subtypes or over different periods when accounting for the competing risk of death.

Olfaction and Mobility in Older Adults.

Importance: Decreased mobility is a hallmark of aging. Olfactory dysfunction is common in older adults and may be associated with declines in mobility. Objective: To determine whether poor olfaction was associated with faster declines in mobility in older adults. Design, Setting, and Participants: This cohort study included 2500 participants from the Health, Aging, and Body Composition Study. Participants completed the Brief Smell Identification Test during the year 3 clinical visit (1999-2000) and were followed for up to 7 years. A data analysis was conducted between January and July 2023. Exposures: Olfaction was defined as good (test score, 11-12), moderate (9-10), hyposmia (7-8), or anosmia (0-6). Main Outcomes and Measures: Mobility was measured using the 20-m usual and fast walking tests in clinical visit years 3 to 6, 8, and 10 and the 400-m fast walking test in years 4, 6, 8, and 10. Results: The primary analyses included 2500 participants (1292 women [51.7%]; 1208 men [48.3%]; 960 Black [38.4%] and 1540 White [61.6%] individuals; mean [SD] age, 75.6 [2.8] years). Multivariate-adjusted analyses showed that poor olfaction was associated with slower walking speed at baseline and a faster decline over time. Taking the 20-m usual walking test as an example, compared with participants with good olfaction, the speed at baseline was 0.027 (95% CI, 0-0.053) m/s slower for those with hyposmia and 0.034 (95% CI, 0.005-0.062) m/s slower for those with anosmia. Longitudinally, the annual decline was 0.004 (95% CI, 0.002-0.007) m/s/year faster for those with hyposmia and 0.01 (95% CI, 0.007-0.013) m/s/year faster for those with anosmia. Similar results were obtained for the 20-m and 400-m fast walking tests. Further, compared with participants with good olfaction, the odds of being unable to do the 400-m test were 2.02 (95% CI, 1.17-3.48) times higher for those with anosmia at the year 8 visit and 2.73 (95% CI, 1.40-5.35) times higher at year 10. Multiple sensitivity and subgroup analyses supported the robustness and generalizability of the findings. Conclusion and Relevance: The results of this cohort study suggest that poor olfaction is associated with a faster decline in mobility in older adults. Future studies should investigate underlying mechanisms and potential health implications.

Moving towards the detection of frailty with biomarkers: A population health study.

Aging adults experience increased health vulnerability and compromised abilities to cope with stressors, which are the clinical manifestations of frailty. Frailty is complex, and efforts to identify biomarkers to detect frailty and pre-frailty in the clinical setting are rarely reproduced across cohorts. We developed a predictive model incorporating biological and clinical frailty measures to identify robust biomarkers across data sets. Data were from two large cohorts of older adults: "Invecchiare in Chianti (Aging in Chianti, InCHIANTI Study") (n = 1453) from two small towns in Tuscany, Italy, and replicated in the Atherosclerosis Risk in Communities Study (ARIC) (n = 6508) from four U.S. communities. A complex systems approach to biomarker selection with a tree-boosting machine learning (ML) technique for supervised learning analysis was used to examine biomarker population differences across both datasets. Our approach compared predictors with robust, pre-frail, and frail participants and examined the ability to detect frailty status by race. Unique biomarker features identified in the InCHIANTI study allowed us to predict frailty with a model accuracy of 0.72 (95% confidence interval (CI) 0.66-0.80). Replication models in ARIC maintained a model accuracy of 0.64 (95% CI 0.66-0.72). Frail and pre-frail Black participant models maintained a lower model accuracy. The predictive panel of biomarkers identified in this study may improve the ability to detect frailty as a complex aging syndrome in the clinical setting. We propose several concrete next steps to keep research moving toward detecting frailty with biomarker-based detection methods.

Central arterial stiffening and intracranial atherosclerosis: the atherosclerosis risk in communities neurocognitive study (ARIC-NCS): Aortic stiffness & intracranial atherosclerosis.

OBJECTIVES: Previous studies suggest an association between central arterial stiffness (CAS) and intracranial atherosclerotic disease (ICAD) among Asian participants with stroke or hypertension; this association has not been evaluated in United States populations. We assessed the cross-sectional association of CAS with ICAD presence and burden in late-life, and differences in association by age, sex, and race. MATERIALS AND METHODS: We conducted a cross-sectional analysis of 1,285 Atherosclerosis Risk in Communities Study participants [mean age 75 (standard deviation: 5) years, 38 % male, 20  % Black] at Visit 5 (2011-2013). CAS was measured as carotid-femoral pulse wave velocity (cfPWV) using the Omron VP-1000 Plus. ICAD was assessed using high-resolution vessel wall MRI and MR angiography. We evaluated associations of a 1 standard deviation (SD) cfPWV (3.02 m/s) and high vs. non-high cfPWV (≥ 13.57 m/s vs. < 13.57 m/s) with presence of plaques (yes/no) and plaque number (0, 1-2, and >2) using multivariable logistic and ordinal logistic regression models adjusted for covariates. RESULTS: Each one SD greater cfPWV was associated with higher odds of plaque presence (odds ratio (OR)=1.32, 95 % confidence interval (CI): 1.22, 1.43), and an incrementally higher odds of number of plaques (OR 1-2 vs. 0 plaques = 1.21, 95 % CI: 1.10, 1.33; OR >2 vs. 0 plaques = 1.51, 95 % CI: 1.33,1.71). Results suggested differences by race, with greater magnitude associations among Black participants. CONCLUSIONS: CAS was positively associated with ICAD presence and burden; cfPWV may be a useful subclinical vascular measure for identification of individuals who are at high risk for cerebrovascular disease.

Association between structural brain MRI abnormalities and epilepsy in older adults.

OBJECTIVE: To determine the association between brain MRI abnormalities and incident epilepsy in older adults. METHODS: Men and women (ages 45-64 years) from the Atherosclerosis Risk in Communities study were followed up from 1987 to 2018 with brain MRI performed between 2011 and 2013. We identified cases of incident late-onset epilepsy (LOE) with onset of seizures occurring after the acquisition of brain MRI. We evaluated the relative pattern of cortical thickness, subcortical volume, and white matter integrity among participants with incident LOE after MRI in comparison with participants without seizures. We examined the association between MRI abnormalities and incident LOE using Cox proportional hazards regression. Models were adjusted for demographics, hypertension, diabetes, smoking, stroke, and dementia status. RESULTS: Among 1251 participants with brain MRI data, 27 (2.2%) developed LOE after MRI over a median of 6.4 years (25-75 percentile 5.8-6.9) of follow-up. Participants with incident LOE after MRI had higher levels of cortical thinning and white matter microstructural abnormalities before seizure onset compared to those without seizures. In longitudinal analyses, greater number of abnormalities was associated with incident LOE after controlling for demographic factors, risk factors for cardiovascular disease, stroke, and dementia (gray matter: hazard ratio [HR]: 2.3, 95% confidence interval [CI]: 1.0-4.9; white matter diffusivity: HR: 3.0, 95% CI: 1.2-7.3). INTERPRETATION: This study demonstrates considerable gray and white matter pathology among individuals with LOE, which is present prior to the onset of seizures and provides important insights into the role of neurodegeneration, both of gray and white matter, and the risk of LOE.

Olfactory impairment and the risk of major adverse cardiovascular outcomes in older adults.

Background: Olfactory impairment is common in older adults and may be associated with adverse cardiovascular health; however, empirical evidence is sparse. Objective: To examine olfaction and the risk of coronary heart disease (CHD), stroke, and congestive heart failure (CHF). Methods: This study included 2,537 older adults (aged 75.6±2.8 years) from the Health ABC Study with olfaction assessed by the 12-item Brief Smell Identification Test in 1999-2000, defined as poor (score ≤8), moderate (9-10), or good (11-12). The outcomes were incident CHD, stroke, and CHF. Results: During up to 12-year follow-up, 353 incident CHD, 258 stroke, and 477 CHF events were identified. Olfaction was associated with incident CHF, but not with CHD or stroke. After adjusting for demographics, the cause-specific hazard ratio (HR) of CHF was 1.35 (95% confidence interval (CI): 1.08, 1.70) for moderate and 1.39 (95%CI: 1.09, 1.76) for poor olfaction. With additional adjustment for lifestyle, chronic diseases, and biomarkers of CHF, the HR was modestly attenuated to 1.32 (95%CI: 1.05, 1.66) for moderate and 1.28 (95%CI: 1.01, 1.64) for poor olfaction. These associations were robust in pre-planned subgroup analyses by age, sex, race, and prevalent CHD/stroke. However, the associations appeared to be evident among participants who reported very-good-to-excellent health (HR=1.47 (95%CI: 1.02, 2.13) for moderate and 1.76, (95%CI: 1.20, 2.57) for poor olfaction). In contrast, null association with CHF was found among those with fair-to-poor self-reported health. Conclusions: In community-dwelling older adults, a single olfaction test was associated with a long-term risk for incident CHF, particularly among those reporting very-good-to-excellent health.

Cognitive phenotypes in late-onset epilepsy: results from the atherosclerosis risk in communities study.

Introduction: Cognitive phenotyping is a widely used approach to characterize the heterogeneity of deficits in patients with a range of neurological disorders but has only recently been applied to patients with epilepsy. In this study, we identify cognitive phenotypes in older adults with late-onset epilepsy (LOE) and examine their demographic, clinical, and vascular profiles. Further, we examine whether specific phenotypes pose an increased risk for progressive cognitive decline. Methods: Participants were part of the Atherosclerosis Risk in Communities Study (ARIC), a prospective longitudinal community-based cohort study of 15,792 individuals initially enrolled in 1987-1989. LOE was identified from linked Centers for Medicare and Medicaid Services claims data. Ninety-one participants with LOE completed comprehensive testing either prior to or after seizure onset as part of a larger cohort in the ARIC Neurocognitive Study in either 2011-2013 or 2016-2017 (follow-up mean = 4.9 years). Cognitive phenotypes in individuals with LOE were derived by calculating test-level impairments for each participant (i.e., ≤1 SD below cognitively normal participants on measures of language, memory, and executive function/processing speed); and then assigning participants to phenotypes if they were impaired on at least two tests within a domain. The total number of impaired domains was used to determine the cognitive phenotypes (i.e., Minimal/No Impairment, Single Domain, or Multidomain). Results: At our baseline (Visit 5), 36.3% met criteria for Minimal/No Impairment, 35% for Single Domain Impairment (with executive functioning/ processing speed impaired in 53.6%), and 28.7% for Multidomain Impairment. The Minimal/No Impairment group had higher education and occupational complexity. There were no differences in clinical or vascular risk factors across phenotypes. Of those participants with longitudinal data (Visit 6; n = 24), 62.5% declined (i.e., progressed to a more impaired phenotype) and 37.5% remained stable. Those who remained stable were more highly educated compared to those that declined. Discussion: Our results demonstrate the presence of identifiable cognitive phenotypes in older adults with LOE. These results also highlight the high prevalence of cognitive impairments across domains, with deficits in executive function/processing speed the most common isolated impairment. We also demonstrate that higher education was associated with a Minimal/No Impairment phenotype and lower risk for cognitive decline over time.

Sleep apnea, hypoxia, and late-onset epilepsy: the Atherosclerosis Risk in Communities study.

STUDY OBJECTIVE: Sleep apnea is associated with unexplained epilepsy in older adults in small studies. We sought to determine the relationship between sleep apnea and additional sleep characteristics and late-onset epilepsy, adjusting for comorbidities, using data from the large, prospective Atherosclerosis Risk in Communities (ARIC) Study cohort. METHODS: We used Medicare claims to identify cases of late-onset epilepsy (LOE) in ARIC participants. We used polysomnography data from 1309 ARIC participants who also participated in the Sleep Heart Health Study in 1995-1998, and demographic and comorbidity data from ARIC. Later risk of LOE was evaluated using survival analysis with a competing risk of death. We also used survival analysis in 2672 ARIC participants to identify the association between self-reported obstructive sleep apnea (2011-2013), and the risk of subsequent LOE. RESULTS: Late-midlife oxygen desaturation to less than 80% during sleep was associated with subsequent development of LOE, adjusted subhazard ratio 3.28 (1.18-9.08), but the apnea-hypopnea index was not related. Participant report of diagnosis of sleep apnea in 2011-2013 was also associated with subsequent LOE, adjusted subhazard ratio 2.59 (1.24-5.39). CONCLUSIONS: Sleep apnea and oxygen saturation nadir during sleep are associated with LOE, independently of hypertension and other comorbidities. These potentially modifiable risk factors could have large clinical implications for LOE.

Association of Childhood and Midlife Neighborhood Socioeconomic Position With Cognitive Decline.

Importance: Early-life socioeconomic adversity may be associated with poor cognitive health over the life course. Objective: To examine the association of childhood and midlife neighborhood socioeconomic position (nSEP) with cognitive decline. Design, Setting, and Participants: This cohort study included 5711 men and women enrolled in the community-based Atherosclerosis Risk in Communities (ARIC) Study with repeated cognitive data measured over a median 27.0 years (IQR, 26.0-27.9 years) (1990-2019). Statistical analysis was performed from December 2022 through March 2023. Exposure: Residence addresses for ARIC Study cohort participants were obtained at midlife (1990-1993) and as recalled addresses at 10 years of age (childhood). A composite nSEP z score was created as a sum of z scores for US Census-based measures of median household income; median value of owner-occupied housing units; percentage of households receiving interest, dividend, or net rental income; percentage of adults with a high school degree; percentage of adults with a college degree; and percentage of adults in professional, managerial, or executive occupations. Childhood nSEP and midlife nSEP were modeled as continuous measures and discretized into tertiles. Main Outcomes and Measures: A factor score for global cognition was derived from a battery of cognitive tests administered at 5 in-person visits from baseline to 2019. The rate of cognitive decline from 50 to 90 years of age was calculated by fitting mixed-effects linear regression models with age as the time scale and adjusted for race, sex, birth decade, educational level, and presence of the apolipoprotein E ε4 allele. Results: Among 5711 ARIC Study participants (mean [SD] baseline age, 55.1 [4.7] years; 3372 women [59.0%]; and 1313 Black participants [23.0%]), the median rate of cognitive decline was -0.33 SDs (IQR, -0.49 to -0.20 SDs) per decade. In adjusted analyses, each 1-SD-higher childhood nSEP score was associated with a slower (ß, -9.2%; 95% CI, -12.1% to -6.4%) rate of cognitive decline relative to the sample median. A comparable association was observed when comparing the highest tertile with the lowest tertile of childhood nSEP (ß, -17.7%; 95% CI, -24.1% to -11.3%). Midlife nSEP was not associated with the rate of cognitive decline. Conclusions and Relevance: In this cohort study of contextual factors associated with cognitive decline, childhood nSEP was inversely associated with trajectories of cognitive function throughout adulthood.

Association of Plasma Aß42/Aß40 Ratio and Late-Onset Epilepsy: Results From the Atherosclerosis Risk in Communities Study.

BACKGROUND AND OBJECTIVES: The objective of this study was to determine the relationship between plasma ß-amyloid (Aß), specifically the ratio of 2 Aß peptides (the Aß42/Aß40 ratio, which correlates with increased accumulation of Aß in the CNS), and late-onset epilepsy (LOE). METHODS: We used Medicare fee-for-service claims codes from 1991 to 2018 to identify cases of LOE among 1,424 Black and White men and women enrolled in the Atherosclerosis Risk in Communities (ARIC) study cohort. The Aß42/Aß40 ratio was calculated from plasma samples collected from ARIC participants in 1993-1995 (age 50-71 years) and 2011-2013 (age 67-90 years). We used survival analysis accounting for the competing risk of death to determine the relationship between late-life plasma Aß42/Aß40, and its change from midlife to late life, and the subsequent development of epilepsy. We adjusted for demographics, the apolipoprotein e4 genotype, and comorbidities, including stroke, dementia, and head injury. A low plasma ratio of 2 Aß peptides, the Aß42/Aß40 ratio, correlates with low CSF Aß42/Aß40 and with increased accumulation of Aß in the CNS. RESULTS: Decrease in plasma Aß42/Aß40 ratio from midlife to late life, but not an isolated measurement of Aß42/Aß40, was associated with development of epilepsy in later life. For every 50% reduction in Aß42/Aß40, there was a 2-fold increase in risk of epilepsy (adjusted subhazard ratio 2.30, 95% CI 1.27-4.17). DISCUSSION: A reduction in plasma Aß42/Aß40 is associated with an increased risk of subsequent epilepsy. Our observations provide a further validation of the link between Aß, hyperexcitable states, and LOE.