Sleep and Perivascular Spaces.

PURPOSE OF REVIEW: The glymphatic system is hypothesized to act as the brain's filtration system to remove toxic solutes that accumulate throughout the day. Perivascular spaces (PVSs) play a fundamental role in the ability of the glymphatic system to function, and sleep influences the effectiveness of this system. This article reviews the complexity of the interplay between sleep, the glymphatic system, and PVS. RECENT FINDINGS: New imaging techniques have illuminated the structure of PVS and their associations with differing disease states. Research has shown that sleep may play a key role in the function of PVS and the influence of adenosine, astrocyte, and aquaporin-4 channel in the function of the glymphatic system. Emerging data suggest that differing pathological states such as neuroinflammatory conditions, neurodegenerative diseases, and cognitive dysfunction may be associated with underlying glymphatic system dysfunction, and sleep disorders could be a potential intervention target.

Lack of Association between Periodic Limb Movements during Sleep and Neuroimaging Signatures of Cerebral Small Vessel Disease in Stroke-Free Community-Dwelling Older Adults. The Atahualpa Project.

BACKGROUND: Evidence of the relationship between periodic limb movements during sleep (PLMS) and cerebral small vessel disease (cSVD) is limited and inconsistent. Here, we aimed to assess the independent association between PLMS and the different neuroimaging signatures of cSVD. METHODS: Atahualpa residents aged more than or equal to 60 years enrolled in the Atahualpa Project undergoing polysomnography and MRI with time intervals less than or equal to 6 months were included. MRI readings focused on white matter hyperintensities (WMH) of presumed vascular origin, deep cerebral microbleeds (CMB), silent lacunar infarcts (LI), and more than 10 enlarged basal ganglia-perivascular spaces (BG-PVS). Data from single-night polysomnograms were interpreted according to recommendations of the American Academy of Sleep Medicine. Associations between the PLMS index and neuroimaging signatures of cSVD (as dependent variables) were assessed by means of logistic regression models, adjusted for relevant confounders. RESULTS: A total of 146 individuals (mean age: 71.4 ± 7.5 years; 64% women) were included. A PLMS index more than or equal to 15 per hour were noted in 48 (33%) participants. Moderate-to-severe WMH were present in 33 individuals (23%), deep CMB in 9 (6%), silent LI in 16 (11%), and more than 10 BG-PVS in 44 (30%). In univariate analyses, silent LI (P = .035) and the presence of more than 10 enlarged BG-PVS (P = .034) were significantly higher among participants with a PLMS index more than or equal to 15 per hour. However, fully-adjusted multivariate models showed no significant association between PLMS index more than or equal to 15 per hour and any of the neuroimaging signatures of cSVD. CONCLUSIONS: This study shows no independent association between the PLMS index and neuroimaging signatures of cSVD in stroke-free community-dwelling older adults.

Effect of Heart Rate Variability on the Association Between the Apnea-Hypopnea Index and Cerebral Small Vessel Disease.

Background and Purpose- The apnea-hypopnea index (AHI) is associated with cerebral small vessel disease (cSVD), but pathogenesis of this association is elusive. We aimed to assess the effect of nighttime heart rate variability (HRV)-as a proxy of sympathetic upregulation-on the aforementioned association. Methods- Atahualpa residents aged ≥60 years undergoing brain magnetic resonance imaging, polysomnography, and 24-hour Holter monitoring (N=176) were included. The presence of moderate-to-severe white matter hyperintensities, deep cerebral microbleeds, lacunar infarcts, and >10 enlarged basal ganglia perivascular spaces were added for estimating the cSVD score. Interaction models were fitted to assess the effect modification of nighttime HRV in the association between the AHI and the cSVD score, and mediation analysis was utilized to assess the proportion of total effect by nighttime HRV on this association. Results- Generalized linear models showed a significant association between the AHI and the cSVD score (P=0.025), as well as a significant inverse association between nighttime HRV and the cSVD score (P=0.002), but no association between daytime HRV and the cSVD score (P=0.097). Interaction models showed a significant interaction of nighttime HRV on the association between AHI and the cSVD score (P=0.001), and mediation analysis found that the percent of total effect between AHI and cSVD score mediated by HRV was 30.8%. Predictive marginal means of the cSVD score were highly significant when the 10th percentile of nighttime HRV was compared across categories of 10th and 90th percentiles of the AHI (cSVD score margins, 0.61 [95% CI, 0.37-0.86] versus 1.67 [95% CI, 1.26-2.09]). Contour plots showed the effect of nighttime (but not daytime) HRV on the association between AHI and the cSVD score. Conclusions- This study shows an important effect of nighttime HRV on the association between the AHI and the cSVD score and provides further support for the role of sympathetic overactivity on this association.

No association between the abdominal aorta diameter and cervicocephalic atherosclerosis-Potential non-atherosclerotic origins of abdominal aorta aneurysms?

The atherosclerotic origin of abdominal aorta (AA) aneurysms is controversial. Using the Atahualpa Project Cohort, we aimed to assess the relationship between the AA diameter and two surrogates of cervicocephalic atherosclerosis, including the carotid intima-media thickness (cIMT) and the presence of carotid siphon calcifications (CSC). Atahualpa residents aged ≥60 years undergoing ultrasound examinations of the abdominal aorta and the carotid arteries (to calculate the AA diameter and the cIMT), and head CT (to assess CSC severity) were included. Associations between AA diameter and cIMT and CSC severity were assessed by generalized linear models, after adjusting for relevant confounders. Of 256 participants, 64 (25%) had an increased cIMT and 85 (33%) had high calcium content in the carotid siphons. In univariate analysis, being male (p < 0.001) and having total cholesterol blood levels <240 mg/dL (p = 0.022) were associated with a higher AA diameter. Also in univariate analysis, the mean AA diameter was higher in individuals with an increased cIMT (p = 0.021), but such association disappeared in adjusted models. The AA diameter was not associated with high calcium content in the carotid siphons in either univariate or multivariate analyses. This population study shows no association between the AA diameter and cervicocephalic atherosclerosis in community-dwelling older adults, suggesting a non-atherosclerotic origin of AA aneurysms.

Cardiovascular Consequences of Obstructive Sleep Apnea.

PURPOSE OF REVIEW: To review the clinical evidence for a relationship between obstructive sleep apnea and hypertension, arrhythmias, coronary artery disease, and congestive heart failure. RECENT FINDINGS: Current data show that obstructive sleep apnea is a risk for cardiovascular disease. Studies have linked untreated moderate to severe obstructive sleep apnea to hypertension, cardiac arrhythmias, coronary artery disease, and congestive heart failure. However, uncertainty regarding benefits of treatment of obstructive sleep apnea to reduce the risk of cardiovascular disease still exists. The issue of poor compliance has been an on-going limitation of CPAP trials. Evidence shows obstructive sleep apnea is a risk factor for cardiovascular disease but trials have yet to clarify if cardiovascular disease morbidity and mortality decreases with treatment of the apnea. Future treatment trials are needed to address the question of whether treatment decreases cardiovascular risk in patients with obstructive sleep apnea.

The relationship between the neck circumference and the carotid intima-media thickness in Amerindians. Potential links to health risks?

The carotid intima media thickness (cIMT) is a predictor of cardiovascular events. The neck circumference (NC) has been investigated as a risk factor for increased cIMT with contradictory results. This study assessed the relationship between NC and cIMT in Atahualpa residents aged ≥40 years who had sonographic examination of carotid arteries (n = 590). We also discussed on potential pathogenetic mechanisms underlying this association. Participants belonged to the Native Ecuadorian (Amerindians) ethnic group. Non-parametric regression models were used to assess the aforementioned relationship, after adjusting for relevant confounders. The mean age of participants was 60.9 ± 12.7 years (58% women). The mean value of the cIMT was 0.85 ± 0.19 mm. The mean NC was 35.8 ± 34 cm. The NC was normally distributed, but the cIMT was not. Mean values of NC and cIMT were significantly greater in men than in women. Non-parametric models showed significant differences in median cIMT values according to quartiles of NC. Predictive cIMT margins increased by quartiles of NC, significantly among individuals in the 1st quartile as compared to the 3rd quartile. In this population of Amerindians, smaller NC is associated with lower values of cIMT. The pattern of this association is different in men than in women. Sex-related differences in cervical fat tissue distribution probably accounted for such differences.

Distribution of Cervicocephalic Atherosclerotic Lesions and Their Correlation with Cardiovascular Risk Factors in a Population of Amerindians. The Atahualpa Project.

BACKGROUND: No information is available on the distribution of cervicocephalic atherosclerosis in Amerindians. We aimed to assess the distribution of these lesions and their correlation with cardiovascular risk factors in Amerindians living in rural Ecuador. METHODS: Atahualpa residents aged ≥40years underwent head CT for assessment of carotid siphon calcifications (CSC) and sonographic examination for measurement of the carotid intima media thickness (cIMT). CSC were used as a surrogate of intracranial atherosclerosis and the cIMT as a surrogate of extracranial atherosclerosis. Linear regression and multinomial logistic regression models were fitted to assess the association between cIMT and CSC, and to evaluate differences in risk factors across individuals with atherosclerosis involving both arterial beds when compared with those with extra- or intracranial atherosclerosis alone, or no atherosclerosis. RESULTS: Of 590 participants, 145 had high calcium content in the carotid siphons and 87 had a cIMT >1mm (25% versus 15%, P < .001). Thirty-eight (7%) individuals had atherosclerosis at both vascular beds, 107 (18%) had intracranial atherosclerosis, and 49 (8%) had extracranial atherosclerosis alone. The cIMT and CSC were independently associated (P = .008). When compared with participants without atherosclerosis, those with atherosclerosis at both vascular beds were older, more often male, hypertensive and diabetic. Subjects with intracranial atherosclerosis alone were older, and those with extracranial atherosclerosis alone reported less physical activity than those without atherosclerosis. CONCLUSION: Intracranial atherosclerosis is more common than extracranial atherosclerosis in Amerindians. Traditional risk factors only explain a minority of cases of cervicocephalic atherosclerosis in this population.

Oily fish consumption is inversely correlated with cerebral microbleeds in community-dwelling older adults: results from the Atahualpa Project.

BACKGROUND: Oily fish is a major dietary source of omega-3 polyunsaturated fatty acids (ω-3 PUFAs). These nutrients improve endothelial dysfunction, reduce ß-amyloid induced damage of neurovascular units, and might prevent the occurrence of cerebral microbleeds. However, this relationship has not been investigated so far. AIM: To evaluate the association between oily fish intake and cerebral microbleeds in a population of frequent fish consumers living in coastal Ecuador. METHODS: Cerebral microbleeds were identified by gradient-echo MRI and oily fish consumption was calculated in community-dwellers aged ≥60 years enrolled in the Atahualpa Project. The association between cerebral microbleeds and fish servings was examined in regression models adjusted for relevant confounders. A predictive model was constructed using quintiles of fish servings to take into account the non-linearity in the relationship. RESULTS: Out of 311 eligible individuals, 293 (94 %) were enrolled. Cerebral microbleeds were recognized in 37 (13 %) individuals. Mean fish consumption was 8.8 ± 5.4 servings per week (ω-3 PUFAs estimates: 10.2 ± 7.1 g). Multivariate analysis showed an inverse relationship between cerebral microbleeds and fish consumption (p < 0.001). Predictive margins of CMB were higher for individuals in the lowest (≤4.3) than for those in the highest (≥13.1) quintile of fish servings (17.4 vs 2.3 %, p < 0.001). CONCLUSIONS: This study shows a lower cerebral microbleed presence among older adults eating large amounts of oily fish (13 servings per week, equivalent to about 15 g of ω-3 PUFAs). These high requirements can be more readily accomplished in other populations by taking fish oil preparations. Longitudinal studies are warranted to assess whether these interventions reduce incident cerebral microbleeds in high-risk individuals.

Temporal bone thickness and texture are major determinants of the high rate of insonation failures of transcranial Doppler in Amerindians (the Atahualpa Project).

PURPOSE: To assess the role of temporal bone characteristics in transcranial Doppler (TCD) insonation failures in Amerindians living in rural Ecuador. METHODS: We evaluated thickness and texture of temporal bones in community-dwelling Amerindians ≥65 years old undergoing TCD. Using receiver operator characteristics curve analysis and generalized estimating equations, we investigated factors associated with insonation failures. RESULTS: Of 65 participants (mean age 74.7 ± 6.7 years, 60% women), 32 (49%) had uni- or bilateral insonation failure through temporal windows. Considering temporal bones independently, 57 of 130 (44%) had poor insonation. Mean thickness was higher (4.7 ± 1.2 versus 2.7 ± 0.9, p < 0.0001), and texture more often heterogeneous (93% versus 22%, p < 0.0001) in bones with poor acoustic windows. Thickness, better predicting poor insonation, was ≥3.6 mm if used alone, and ≥2.7 mm if used together with heterogeneous texture. For every millimeter of increase in thickness, subjects were 2.9 times more likely to have insonation failures. Per se, heterogeneous texture increased by 3.2 times the odds for poor insonation. In all models, being woman increased the odds for poor insonation by six to nine times. CONCLUSIONS: Temporal bone thickness and texture are independent predictors of TCD insonation failure in Amerindians.

Willis-Ekbom disease is not associated with poor cardiovascular health in adults.

BACKGROUND: Willis-Ekbom disease (WED), also called restless legs syndrome (RLS), is a neurologic sensorimotor disease that may be associated with cardiovascular disease. Given high morbidity and mortality rates of cardiovascular disease worldwide, we assessed the relation between WED/RLS and cardiovascular health risks in a native South American population. We prospectively analyzed data from The Atahualpa Project of Ecuadorian adults aged 40 years and older. Physicians interviewed consented persons on the health behavior and health factors of the American Heart Association (AHA) for ideal cardiovascular health in adults and underwent fasting laboratory blood collection and blood pressure evaluation. Certified neurologists conducted face-to-face interviews using the International Restless Legs Syndrome Study Group (IRLSSG) field instrument. Persons testing positive for WED/RLS and age-and sex-matched controls underwent confirmatory physical examinations conducted by a neurologist and a sleep specialist to whom IRLSSG designation was blinded. FINDINGS: Of 665 persons, 94 (14 %) tested positive in IRLSSG; 40 (6 %) had a diagnosis of WED/RLS after neurologic examination and interview. Patients with WED/RLS were younger (53.5 vs 59.9 years, P = .001), without significant differences in sex ratios. Among AHA risk factors, only obesity was significantly more prevalent among patients with WED/RLS (42.5 % vs 23.5 %, P = .01). However, after adjustment for confounders, body mass index was not significantly associated with WED/RLS. CONCLUSIONS: In adult Amerindians, although obesity and body mass index were associated with WED/RLS on univariate analyses, the association was not present after adjustment for confounders. No other significant associations were found between WED/RLS and AHA cardiovascular metrics.

Population-based study of facial morphology and excessive daytime somnolence.

Studies in patients seeking attention for nasal obstruction or pharyngeal disorders suggest that craniofacial abnormalities correlate with obstructive sleep apnea, but there is little information on the relevance of this association in the population at large. We aimed to determine whether characteristics of facial morphology correlate with excessive daytime somnolence (EDS) in a population-based, door-to-door survey. Residents of a village in rural Ecuador were screened with the Epworth sleepiness scale to assess EDS and underwent physical examination with attention to nasal septum deflection, mandibular retrognathia and presence of Friedman's palate position type IV. From 665 participants aged ≥40 years, 155 had EDS, 98 had nasal septum deflection, 47 had mandibular retrognathia and 528 had a Friedman's palate position type IV. In a logistic regression model adjusted for age, sex, body mass index, and nightly sleep hours, persons with nasal septum deflection were twice as likely to have EDS (p=0.009). The other two variables were not associated with EDS. Identification of nasal septum deflection may be a cost-effective method of detecting persons at risk for obstructive sleep apnea in remote areas where sophisticated technology is not readily available.

Cerebrovascular correlates of sleep disorders-rational and protocol of a door-to-door survey in rural Coastal Ecuador.

BACKGROUND: Little is known on the role of sleep disorders in the increased prevalence of cerebrovascular diseases in the developing world. AIMS: The aim of this study is to assess the prevalence of major sleep disorders in a rural South American population and to determine whether these conditions are associated with stroke, ischemic heart disease, or with a poor cardiovascular health (CVH). DESIGN: Three-phase, population-based, door-to-door survey in Atahualpa. During phase I, all residents aged 40 years or older will be screened with validated Spanish versions of 5 questionnaires to evaluate major sleep disorders. In phase II, neurologists will examine persons suspected of having a sleep disorder and a random sample of negative individuals to assess the prevalence of these conditions and to validate the accuracy of questionnaires. In phase III, patients with a confirmed sleep disorder will undergo nocturnal polysomnography for achieving a more specific diagnosis. The occurrence of sleep disorders will be correlated with the CVH of the population and with the presence of stroke and ischemic heart disease. DISCUSSION: This epidemiologic study may prove cost-effective in improving sleep conditions of people living in rural areas of developing countries and may be used as a model for the evaluation of sleep disorders and their cerebrovascular correlates in these populations.

Association between sleep quality and cardiovascular health: a door-to-door survey in rural Ecuador.

OBJECTIVES: Cardiovascular correlates of sleep disorders have not been well investigated in underserved populations. The aim of this door-to-door survey was to evaluate the association between sleep quality and cardiovascular health status in persons aged ≥40 years living in a village that is representative of rural Ecuador. METHODS: All stroke-free Atahualpa residents aged ≥40 years were screened with a validated Spanish version of the Pittsburgh Sleep Quality Index and the seven cardiovascular health (CVH) metrics proposed by the American Heart Association to assess the CVH status. RESULTS: A total of 635 persons (mean age 59 ± 13 years; 58 % women) were identified. A poor sleep quality was present in 27 % of the subjects (95 % CI 24-31 %) and a poor cardiovascular health in 69 % (95 % CI 63-71 %). In a multivariate logistic regression model, a poor sleep quality was associated with some CVH metrics in the poor range, including smoking status (p = 0.026), physical activity (p = 0.01) and blood glucose levels (p = 0.036). CONCLUSIONS: A poor sleep quality may be linked to individual cardiovascular risk factors in this underserved Latin American population. This finding provides useful insights for the implementation of regional prevention priorities.

Poor sleep quality increases mortality risk: A population-based longitudinal prospective study in community-dwelling middle-aged and older adults.

OBJECTIVES: To assess the association between sleep quality and all-cause mortality in community-dwelling adults living in rural Ecuador. METHODS: Individuals aged ≥40years enrolled in the prospective population-based Three Villages Study cohort were included. Sleep quality was assessed by means of the Pittsburgh Sleep Quality Index. Study participants were evaluated at baseline and at every annual door-to-door survey until they remained enrolled in the study. Mixed models Poisson regression for repeated Pittsburgh Sleep Quality Index determinations and multivariate Cox-proportional hazards models were fitted to estimate mortality risk according to sleep quality. RESULTS: Analysis included 1494 individuals (mean age: 56.6 ± 12.5years; 56% women) followed for a median of 6.3 ± 3.3years. At baseline, 978 (65%) individuals had good sleep quality and 516 (35%) had poor sleep quality. The effects of Pittsburgh Sleep Quality Index scores changing over time on mortality was confounded by the impact of the SARS-CoV-2 pandemic on both. One hundred ninety-five individuals (13%) died during the follow-up, resulting in a crude mortality rate of 1.58 per 100 person years (95% C.I.: 1.27-1.88) for individuals with good sleep quality, and 3.18 (95% C.I.: 2.53-3.82) for those with poor sleep quality at baseline. A multivariate Cox-proportional hazards model showed that individuals with poor sleep quality at baseline were 1.38 times (95% C.I.: 1.02-1.85) more likely to die compared to those with good sleep quality; in this model, increased age, poor physical activity, and high fasting glucose remained significant. CONCLUSIONS: Poor sleep quality is associated with increased mortality risk among middle-aged and older adults.

Choroid plexus calcifications are not associated with putative markers of glymphatic dysfunction: A population study in middle-aged and older adults.

BACKGROUND AND PURPOSE: Recent studies have suggested an association between dysfunction of the choroid plexus and the glymphatic system. However, information is inconclusive. Following a population-based study design, we aimed to assess the association between choroid plexus calcifications (CPCs)-as a surrogate of choroid plexus dysfunction-and severity and progression of putative markers of glymphatic dysfunction, including white matter hyperintensities (WMH) of presumed vascular origin and abnormally enlarged basal ganglia perivascular spaces (BG-PVS). METHODS: This study recruited community-dwellers aged ≥40 years living in neighboring Ecuadorian villages. Participants who had baseline head CTs and brain MRIs were included in cross-sectional analyses and those who additional had follow-up MRIs (after a mean of 6.4 ± 1.5 years) were included in longitudinal analyses. Logistic and Poisson regression models, adjusted for demographics and cardiovascular risk factors, were fitted to assess associations between CPCs and WMH and enlarged BG-PVS severity and progression. RESULTS: A total of 590 individuals were included in the cross-sectional component of the study, and 215 in the longitudinal component. At baseline, 25% of participants had moderate-to-severe WMH and 27% had abnormally enlarged BG-PVS. At follow-up, 36% and 20% of participants had WMH and enlarged BG-PVS progression, respectively. Logistic regression models showed no significant differences between CPCs volumes stratified in quartiles and severity of WMH and enlarged BG-PVS. Poisson regression models showed no association between the exposure and WMH and enlarged BG-PVS progression. Baseline age remained significant in these models. CONCLUSIONS: Choroid plexus calcifications are not associated with putative markers of glymphatic system dysfunction.

Impact on health outcomes associated with changing the clock 1 hour during fall and spring transitions in the Southern Hemisphere.

STUDY OBJECTIVES: Changing the clocks seasonally is potentially harmful because it interferes with normal daytime activities. Studies aimed at quantifying this association are scant. The objective of this study was to determine the effects of 1 year's worth of changing the clocks (fall and spring transitions) on healthy young men located in the Southern Hemisphere in South America. METHODS: We performed an observational prospective study. Thirty healthy male university students were evaluated from 2 weeks before to 2 weeks after both the fall and spring transitions. We administered an overall sleep questionnaire, assessed quality of life, recorded 7-day wrist actigraphy, and had participants perform a psychomotor vigilance task. We defined the 1-hour clock change as the primary exposure and the change in psychomotor vigilance task lapses of 500 milliseconds or more in response time as our primary outcome. Changes were evaluated by the Wilcoxon rank test (significance: P < .05). RESULTS: After the fall transition, we found a significant worsening in psychomotor vigilance task performance (median [interquartile range], 9.9 [6.0-14.3] lapses of ≥ 500 milliseconds in response time at baseline vs 16.8 [8.2-28.0] after transition; P < .002). Additionally, we found a median loss of about 1 hour of total sleep time and time in bed after the fall transition. Furthermore, participants presented with insomnia. Performance on the psychomotor vigilance task was also affected after the spring transition (16.7 [10-23] vs 23 [12.2-32.2]; P < .001). CONCLUSIONS: A decrease in performance in neurocognitive tests was found after both time transitions. The transition led to insomnia and a significant worsening of sleep variables. CITATION: Labarca G, Henriquez-Beltrán M, Sanhueza R, et al. Impact on health outcomes associated with changing the clock 1 hour during fall and spring transitions in the Southern Hemisphere. J Clin Sleep Med. 2024;20(6):887-893.

Clinical Neurobiology of Sleep and Wakefulness.

OBJECTIVE: This article focuses on novel neuronal mechanisms of sleep and wakefulness and relates basic science developments with potential translational implications in circadian neurobiology, pharmacology, behavioral factors, and the recently integrated potential pathways of sleep-related motor inhibition. LATEST DEVELOPMENTS: During the past decade, remarkable advances in the molecular biology of sleep and wakefulness have taken place, opening a promising path for the understanding of clinical sleep disorders. Newly gained insights include the role of astrocytes in sleep brain homeostasis through the glymphatic system, the promotion of memory consolidation during states of reduced cholinergic activity during slow wave sleep, and the differential functions of melatonin receptors involving regulation of both circadian rhythm and sleep initiation. Ongoing investigations exploring sleep and circadian rhythm disruptions are beginning to unlock pathophysiologic aspects of neurologic, psychiatric, and medical disorders. ESSENTIAL POINTS: An understanding of sleep and circadian neurobiology provides coherent and biologically credible approaches to treatments, including the identification of potential targets for neuromodulation.

Out of the Laboratory and into the Home: Home Testing for Sleep Apnea and Other Sleep Disorders.

SUMMARY: Home sleep testing has emerged over the past decade and become an intriguing option for patients and providers because it can be conducted in the home environment. However, appropriate application of this technology is key to ensure accurate and validated results to provide appropriate patient care. In this review, we will cover the current guidelines for the use of home sleep apnea tests, the types of testing available, and future directions of home testing.