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Accumulating evidence supports a link between sleep disorders, disturbed sleep, and adverse brain health, ranging from stroke to subclinical cerebrovascular disease to cognitive outcomes, including the development of Alzheimer disease and Alzheimer disease–related dementias. Sleep disorders such as sleep-disordered breathing (eg, obstructive sleep apnea), and other sleep disturbances, as well, some of which are also considered sleep disorders (eg, insomnia, sleep fragmentation, circadian rhythm disorders, and extreme sleep duration), have been associated with adverse brain health. Understanding the causal role of sleep disorders and disturbances in the development of adverse brain health is complicated by the common development of sleep disorders among individuals with neurodegenerative disease. In addition to the role of sleep disorders in stroke and cerebrovascular injury, mechanistic hypotheses linking sleep with brain health and biomarker data (blood-based, cerebrospinal fluid-based, and imaging) suggest direct links to Alzheimer disease–specific pathology. These potential mechanisms and the increasing understanding of the “glymphatic system,” and the recognition of the importance of sleep in poststroke recovery, as well, support a biological basis for the indirect (through the worsening of vascular disease) and direct (through specific effects on neuropathology) connections between sleep disorders and brain health. Given promising evidence for the benefits of treatment and prevention, sleep disorders and disturbances represent potential targets for early treatment that may improve brain health more broadly. In this scientific statement, we discuss the evidence supporting an association between sleep disorders and disturbances and poor brain health ranging from stroke to dementia and opportunities for prevention and early treatment.

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Few randomized controlled trials have evaluated the effectiveness of continuous positive airway pressure (CPAP) in reducing recurrent vascular events and mortality in poststroke obstructive sleep apnea (OSA). To date, results have been mixed, most studies were underpowered and definitive conclusions are not available. Using lessons learned from prior negative trials in stroke, we reappraise prior randomized controlled trials that examined the use of CPAP in treating poststroke OSA and propose the following considerations: (1) Intervention-based changes, such as ensuring that patients are using CPAP for at least 4 hours per night (eg, through use of improvements in CPAP technology that make it easier for patients to use), as well as considering alternative treatment strategies for poststroke OSA; (2) Population-based changes (ie, including stroke patients with severe and symptomatic OSA and CPAP noncompliers); and (3) Changes to timing of intervention and follow-up (ie, early initiation of CPAP therapy within the first 48 hours of stroke and long-term follow-up calculated in accordance with sample size to ensure adequate power). Given the burden of vascular morbidity and mortality in stroke patients with OSA, there is a strong need to learn from past negative trials and explore innovative stroke prevention strategies to improve stroke-free survival.

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Supplemental Digital Content is available in the text.

Introduction:Despite their high risk of mortality, recurrent stroke, and dementia, stroke survivors underutilize ACP. In a non-prespecified subgroup analysis of a randomized trial to increase ACP, we compared the efficacy of the PREPARE for Your Care (PREPARE) plus an easy-to-read advance directive (AD) to an AD alone among stroke survivors.Methods:PREPARE is an interactive digital program with easy-to-read, state-specific ADs, and video stories. Stroke survivors in the PREPARE trial were identified using the International Classification of Diseasescodes. The primary outcome was new ACP documentation in the electronic medical record after 12 months; secondary outcome was self-reported ACP completion of: (1) signing official papers naming a surrogate decision maker; (2) discussion of patients’ wishes with surrogates; (3) discussion of patients’ wishes with medical providers; and (4) an AD, scored 0-4. We calculated the change from baseline to 12-month follow-up. Mixed-effects regression models were used, adjusted for health literacy (adequate or limited), baseline ACP documentation, and clustering by physician.Results:Of 986 PREPARE trial participants, 91 (9.2%) were stroke survivors and 72 had complete data. The mean age was 64 years (SD, 6.8 years), 47% were women, 74% identified as a minority race/ethnicity, 40% were Spanish-speaking, 49% had limited health literacy, and 41% had ACP before enrollment. There was a trend toward greater ACP documentation in the PREPARE-arm (table). The PREPARE-arm had significantly greater increase in completed ACP elements than the AD-only arm.Discussion:The PREPARE program shows promise to engage ethnically diverse stroke survivors in ACP and should be studied further. Addition of stroke-specific content and engagement of acute stroke survivors in adaptations may increase the impact of the program.

Background:Post-stroke fatigue (PSF) is a common and often disabling symptom, the etiology of which is poorly understood. Sleep-disordered breathing (SDB) is also highly prevalent among stroke survivors. We explored the relationship between SDB and PSF over time in a bi-ethnic cohort.Methods:Ischemic stroke (IS) patients within the Brain Attack Surveillance in Corpus Christi (BASIC) project were identified through active and passive surveillance, and were offered home SDB screening with a well-validated cardiopulmonary sleep apnea testing device, the ApneaLink Plus. The primary exposure was the respiratory event index (REI). The primary outcome was PSF as measured by the SF-36 vitality scale (lower scores reflect greater fatigue). SDB and PSF were measured at baseline, 3, 6, and 12 months post-stroke. A linear regression model, using GEE to account for repeated measures, was used to examine the associations between REI and PSF at each time point adjusting for sociodemographics, stroke severity, depressive symptoms, pre-stroke fatigue, and comorbidities.Results:SDB screening and at least one PSF assessment were completed by 462 IS patients, who were 44% female, 61% Mexican American (MA), 26% non-Hispanic white, 7% Black, and 5% other race/ethnicity. Median NIHSS was 2 (IQR: 1-4). Multivariable regression model results are presented in the Table. Higher REI at 3 months was associated with greater PSF at 3 months (β= -1.87, 95%CI -3.47, -0.27), but there was no association between REI and PSF at 6 or 12 months. Across timepoints, female sex, depressive symptoms at time of assessment, pre-stroke medication for depression, higher levels of pre-stroke fatigue, and vascular risk factor burden were associated with greater PSF, whereas MA ethnicity was associated with less PSF.Conclusions:Higher REI was associated with greater PSF in the early post-stroke period, but no association was observed at 6 months and beyond. MA ethnicity seems to be protective against PSF.

Introduction:Neighborhood socioeconomic status is associated with stroke recovery and mortality. Researchers suggest increased recreation, civic, and social sites (referred to as sites) may support physical, social, and cognitive activity resulting in more favorable outcomes.Hypothesis:Stroke survivors in neighborhoods with lower versus higher number of sites will have a higher rate of mortality and stroke recurrence; these associations will be modified by stroke severity, ethnicity, and sex.Methods:We included non-Hispanic white and Mexican American first-ever stroke survivors enrolled in the Brain Attack Surveillance in Corpus Christi project (2009-19), a population-based cohort in Nueces County, Texas. From a national database, we linked sites per square mile by census tract. We censored at second stroke (stroke recurrence model), death, or 1/1/2020, whichever occurred first. We fit cox regression models using a shared frailty model, adjusting for individual, interpersonal, and neighborhood factors. We considered interactions with stroke severity, sex, and ethnicity. We applied inverse probability weighting and multiple imputation to account for missing data.Results:There were 1,688 survivors; 408 deaths, 189 stroke recurrences, over median follow-up of 1372 days. Median age was 64 years, 74% with mild stroke, 54% male and 60% Mexican American. There was no association between site density and mortality (HR comparing 75thto 25thpercentile=1.01, 95% CI=0.83-1.23) or stroke recurrence (HR=0.98, 95% CI=0.74-1.30). Stroke severity, sex, and ethnicity did not modify the effect of site density on post-stroke mortality (p=0.33, p=0.17, p=0.58, respectively) or stroke recurrence (p=0.43, p=0.91, p=0.99, respectively).Conclusions:We did not observe associations between neighborhood density of sites and post-stroke recurrence or mortality. Future research is needed to determine if other neighborhood features may support secondary stroke prevention or post-stroke survival.

Introduction:Sleep apnea, a very common condition among post-stroke patients, is associated with worse functional, cognitive, and neurological outcomes after stroke. Little is known about the association between change of sleep apnea and changes in outcome over time.Methods:Associated with the Brain Attack Surveillance in Corpus Christi (BASIC) project, ischemic stroke patients (2016-2019) were offered sleep apnea testing with a portable respiratory monitor (ApneaLink Plus) shortly after stroke and at 3, 6, and 12 months post-stroke. Sleep apnea was quantified using the respiratory event index (REI), the number of apneas plus hypopneas per recording hour. At 3, 6, and 12-months post-stroke, functional outcome was assessed using activities of daily living (ADL)/instrumental activities of daily living (IADL) score (1-4, lower better); cognitive outcome was assessed using the Modified Mini-Mental State Examination (3MS) (0-100, higher better); neurological outcome was assessed using the NIHSS (0-42, lower better). Multivariate mixed models were fitted under a Bayesian approach to obtain random slopes in REI over time and the three outcomes (1-unit change in outcome per month), adjusted for age, sex, ethnicity, pre-stroke function and cognitive status, education, marital status, stroke history, tpa use, recurrent stroke, and depression. Linear regression models assessed the association between random slope of REI and random slopes of the three outcomes.Results:Of the 482 Mexican American or non-Hispanic white participants with at least one REI measurement, in fully adjusted models, improvement in sleep apnea was significantly associated with improvement in NIHSS (0.0094 (95% CI: 0.0070, 0.0118)) but not with changes in ADL/IADL or 3MS.Conclusions:Improvement in sleep apnea paralleled improvement in neurological status over the first year after stroke.

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Our objective was to identify factors that contribute to or modify the sex difference in poststroke functional outcome.

Mexican Americans (MAs) were previously found to have lower mortality after ischemic stroke than non-Hispanic whites. We studied mortality trends in a population-based design.

Our objective was to compare neurological, functional, and cognitive stroke outcomes in Mexican Americans (MAs) and non-Hispanic whites using data from a population-based study.

Limitations in essential daily activities are common among older adults after stroke, but little is known about restrictions in their ability to participate in valued social activities. We sought to broaden our understanding of disability after stroke by characterizing poststroke participation restrictions and investigating the extent to which they are accounted for by differences in physical and cognitive capacity, aphasiadysarthria, depressive, and anxiety symptoms.

In a previous study, 0.3 and 0.45 mgkg of intravenous recombinant tissue plasminogen activator (rt-PA) were safe when combined with eptifibatide 75 mcgkg bolus and a 2-hour infusion (0.75 mcgkg per minute). The Combined Approach to Lysis Utilizing Eptifibatide and rt-PA in Acute Ischemic Stroke–Enhanced Regimen (CLEAR-ER) trial sought to determine the safety of a higher-dose regimen and to establish evidence for a phase III trial.

Previous studies suggest that genetic variation plays a substantial role in occurrence and evolution of intracerebral hemorrhage (ICH). Genetic contribution to disease can be determined by calculating heritability using family-based data, but such an approach is impractical for ICH because of lack of large pedigree-based studies. However, a novel analytic tool based on genome-wide data allows heritability estimation from unrelated subjects. We sought to apply this method to provide heritability estimates for ICH risk, severity, and outcome.

Previous studies demonstrated association between mitochondrial DNA variants and ischemic stroke (IS). We investigated whether variants within a larger set of oxidative phosphorylation (OXPHOS) genes encoded by both autosomal and mitochondrial DNA were associated with risk of IS and, based on our results, extended our investigation to intracerebral hemorrhage (ICH).

Intracerebral hemorrhage (ICH) is the acute manifestation of a progressive disease of the cerebral small vessels. The severity of this disease seems to influence not only risk of ICH but also the size of the hematoma. As the burden of high blood pressure–related alleles is associated with both hypertension-related end-organ damage and risk of ICH, we sought to determine whether this burden influences ICH baseline hematoma volume.

Genetic variation influences risk of intracerebral hemorrhage (ICH). Hypertension (HTN) is a potent risk factor for ICH and several common genetic variants (single nucleotide polymorphisms SNPs) associated with blood pressure levels have been identified. We sought to determine whether the cumulative burden of blood pressure-related SNPs is associated with risk of ICH and pre-ICH diagnosis of HTN.

Stroke has fallen from the second to the fourth leading cause of death in the United States without large declines in stroke incidence or case fatality. We explored whether this decline may be attributable to changes in mortality attribution methodology.

Acute stroke treatments are underutilized primarily because of delayed hospital arrival. Using a community-based participatory research approach, we explored stroke self-efficacy, knowledge, and perceptions of stroke among a predominately African American population in Flint, Michigan.

Intravenous alteplase (rtPA) remains the only approved treatment for acute ischemic stroke, but its use remains limited. In a previous pilot dose-escalation study, intravenous tenecteplase showed promise as a potentially safer alternative. Therefore, a Phase IIB clinical trial was begun to (1) choose a best dose of tenecteplase to carry forward; and (2) to provide evidence for either promise or futility of further testing of tenecteplase versus rtPA. If promise was established, then the trial would continue as a Phase III efficacy trial comparing the selected tenecteplase dose to standard rtPA.

The purpose of this study was to evaluate stroke patient–proxy agreement with respect to social determinants of health, including depression, optimism, and spirituality, and to explore approaches to minimize proxy-introduced bias.

In a recent meta-analysis, women with stroke had 30% lower odds of receiving tissue plasminogen activator than did men, and some studies have reported greater in-hospital delays in women with stroke. Causes of these disparities are unclear but could result from a different symptom presentation in women. Our objective was to prospectively investigate gender differences in acute stroke symptoms.

Women have increased lifetime stroke risk and more disabling strokes compared with men. Insights into the association between menopause and stroke could lead to new prevention strategies for women. The objective of this study was to examine the association of age at natural menopause with ischemic stroke risk in the Framingham Heart Study.

Sleep apnea is very common after stroke and is associated with poor outcome. Supine sleep is known to exacerbate apneas in the general sleep apnea population. We therefore investigated the pattern of sleep positions in the acute stroke period.

Underutilization of acute stroke therapy is driven by delay to hospital arrival. We present the primary results of a pilot, randomized, controlled trial to encourage calling 911 for witnessed stroke among middle school children and their parents.

Dizziness, vertigo, and imbalance are common presenting symptoms in the emergency department. Stroke is a leading concern even when these symptoms occur in isolation. The objective of the present study was to determine the “real-world” proportion of stroke among patients presenting to the emergency department with these dizziness symptoms (DS).

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Introduction:Sleep-disordered breathing (SDB) is common after stroke and is associated with poor functional and cognitive outcomes, and recurrent stroke. Despite increasing prevalence of SDB in the general population, no data are available about trends in post-stroke SDB. We therefore sought to assess changes in post-stroke SDB prevalence over a 10-year period.Methods:Within the Brain Attack Surveillance In Corpus Christi (BASIC) project, a population-based stroke surveillance study in south Texas, participants with acute ischemic stroke were offered assessment of SDB with the ApneaLink Plus device. Medical record abstraction and baseline interviews were conducted and included the Berlin questionnaire to assess SDB status in reference to the prestroke state. SDB testing was performed shortly after stroke presentation (median 12 days (IQR: (6, 21)). Respiratory event index (REI) was calculated as the sum of apneas and hypopneas per hour of overnight recording. SDB was defined as an REI ≥10. SDB assessment procedures remained unchanged throughout (2010-2020). Logistic (SDB) and linear (REI) regression were used to test associations with time (parameterized as years since 2010) adjusted for demographics, and stroke and SDB risk factors including BMI and pre-stroke SDB status.Results:Among the 1,197 participants, median age was 65, 53% were male, and 65% were Mexican American. SDB prevalence was 61% in 2010-2011 and 75% in 2018-2019. Median REI was 19 in 2010-2011 and 23 in 2018-2019. A linear association was identified between time and SDB (REI≥10), with an odds ratio of 1.123 (95% CI: 1.062, 1.187) per year, after adjustment. Similarly, a linear association was identified between time and REI, with an average increase of 0.504 (95% CI: 0.148, 0.860) per year, after adjustment. Based on models with interaction terms added, no differences in time trends were found by sex or ethnicity.Conclusions:Post-stroke SDB prevalence in this population-based sample has increased over the last 10 years. These data highlight the importance of post-stroke SDB and the pressing need to determine whether its treatment improves outcomes.

Sleep apnea is a modifiable independent stroke risk factor and is associated with poor stroke outcomes. Mexican Americans have a higher incidence of stroke than non-Hispanic whites. In a biethnic community, we sought to determine the frequency of screening, testing, and treatment of sleep apnea among stroke survivors and to compare self-perceived risk of sleep apnea with actual risk.

We performed a pilot project to assess the need for and feasibility of a church-based stroke risk reduction intervention in a predominantly Mexican American community.

Local television news commonly reports on health. This study aimed to characterize local TV news stroke reporting in America.