Faculty Bibliography

STUDY OBJECTIVES/OBJECTIVE:Sleep apnea is associated with hypertension, and treatment may improve outcomes. We examine national burden of sleep apnea, rates of sleep apnea treatment, and whether racial/ethnic disparities exist among patients with hypertension. METHODS:Data from the National Ambulatory Medical Care Survey/National Hospital Ambulatory Medical Care Survey (NAMCS/NHAMCS), 2005-2012, were analyzed (N = 417,950). We identified hypertension patient visits where sleep apnea diagnosis or complaint was recorded. Primary outcome measures were sleep study, medication, or behavioral therapy (diet, weight loss, or exercise counseling). We used multivariate logistic regression to examine treatment by demographic/clinical factors. RESULTS:Among patients with hypertension, sleep apnea was identified in 11.2-per-1,000 visits. Overall, patients with hypertension and a sleep disorder were referred for sleep study in 14.4% of visits, prescribed sleep medication in 11.2% of visits, and offered behavioral therapy in 34.8% of visits. Adjusted analyses show behavioral therapy more likely to be provided to obese patients than normal/overweight (OR = 4.96, 95%CI[2.93-8.38]), but less likely to be provided to smokers than nonsmokers (OR = 0.54, 95%CI[0.32-0.93]). Non-Hispanic blacks were less likely to receive medications than non-Hispanic whites (OR = 0.19, 95% CI[0.06-0.65]). CONCLUSIONS:In the U.S., sleep apnea were observed in a small proportion of hypertension visits, a population at high-risk for the disorder. One explanation for the low prevalence of sleep apnea observed in this patient population at high risk for the disorder is under-diagnosis of sleep related breathing disorders. Behavioral therapy was underutilized, and non-Hispanic Blacks were less likely to receive medications than non-Hispanic Whites.

Introduction: Increasing evidence suggests sleep can influence the risk for development of Alzheimer disease (AD), but the precise features of sleep architecture influencing this risk and the role of obstructive sleep apnea (OSA) in contributing to this risk remain only partially characterized. Current models of AD suggest that pathological changes, including the accumulation of proteins beta-amyloid (Ab) and tau, can occur years to even decades before clinical symptoms of memory impairment become evident. In this study, we examined the impact of OSA severity on longitudinal changes in Ab measured both in cerebrospinal fluid (CSF) and with brain PET imaging with Pittsburgh compound B (PiB). In subsets of individuals without significant OSA, we examined the impact of features of sleep architecture such as slow wave activity (SWA) and spindles on concentrations CSF Ab and tau at cross-section. Materials and Methods: 208 cognitively normal elderly subjects (68 +/- 7 years, CDR score = 0) received medical, neurological, and psychiatric evaluations, home polysomnography (PSG) for OSA severity, structural magnetic resonance imaging (MRI) scans, a lumbar puncture (LP) and/or PiB PET scans. A subset of 109 subjects completed a second LP 2.4 +/- 0.9 years after the first LP, and a subset of 34 subjects completed a second brain PiB PET scan 2.5 +/- 0.4 years after the first. A subset of 50 subjects without significant OSA (AHI4% < 15/hour) completed in-laboratory nocturnal PSG for measurements of sleep architecture. SWA was calculated using the average power density in the 0.5-4.0 Hz range at the F4- lead during full night EEG recordings. Spindles were isolated and quantified using DETOKS in which the EEG from the C3-lead was decomposed into oscillatory and non-oscillatory components. Oscillatory components were further scored for sleep spindles using threshold values in the frequency band of 11-16 Hz and time duration of 0.5 to 3 seconds. Results: OSA increased amyloid burden over the years, as a significant association was found between longitudinal decreases in CSF Ab42 and increasing OSA severity indices AHI-all (F1,88 = 4.26, p< .05) and AHI4% (F1,87 = 4.36, p< .05). This was corroborated by a trend toward longitudinal increases in brain PiB PET uptake positively associating with increasing OSA severity by AHI-all (F1,28 = 2.96, p=.09). At cross-section, in those subjects without significant OSA, low frontal SWA was significantly associated with high concentrations of CSF Ab42 and low sleep spindle counts and density were significantly associated with high levels of total and phosphorylated tau in the CSF

BACKGROUND: Automated single-channel spindle detectors, for human sleep EEG, are blind to the presence of spindles in other recorded channels unlike visual annotation by a human expert. NEW METHOD: We propose a multichannel spindle detection method that aims to detect global and local spindle activity in human sleep EEG. Using a non-linear signal model, which assumes the input EEG to be the sum of a transient and an oscillatory component, we propose a multichannel transient separation algorithm. Consecutive overlapping blocks of the multichannel oscillatory component are assumed to be low-rank whereas the transient component is assumed to be piecewise constant with a zero baseline. The estimated oscillatory component is used in conjunction with a bandpass filter and the Teager operator for detecting sleep spindles. RESULTS AND COMPARISON WITH OTHER METHODS: The proposed method is applied to two publicly available databases and compared with 7 existing single-channel automated detectors. F1 scores for the proposed spindle detection method averaged 0.66 (0.02) and 0.62 (0.06) for the two databases, respectively. For an overnight 6 channel EEG signal, the proposed algorithm takes about 4min to detect sleep spindles simultaneously across all channels with a single setting of corresponding algorithmic parameters. CONCLUSIONS: The proposed method attempts to mimic and utilize, for better spindle detection, a particular human expert behavior where the decision to mark a spindle event may be subconsciously influenced by the presence of a spindle in EEG channels other than the central channel visible on a digital screen.

This report summarizes the proceedings of the American Thoracic Society Workshop on the Noninvasive Identification of Inspiratory Flow Limitation in Sleep Studies held on May 16, 2015, in Denver, Colorado. The goal of the workshop was to discuss methods for standardizing the scoring of flow limitation from nasal cannula pressure tracings. The workshop began with presentations on the physiology underlying flow limitation, existing methods of scoring flow limitation, the effects of signal acquisition and filtering on flow shapes, and a review of the literature examining the adverse outcomes related to flow limitation. After these presentations, the results from online scoring exercises, which were crowdsourced to workshop participants in advance of the workshop, were reviewed and discussed. Break-out sessions were then held to discuss potential algorithms for scoring flow limitation. Based on these discussions, subsequent online scoring exercises, and webinars after the workshop, a consensus-based set of recommendations for a scoring algorithm for flow limitation was developed. Key conclusions from the workshop were: (1) a standardized and automated approach to scoring flow limitation is needed to provide a metric of nonepisodic elevated upper airway resistance, which can then be related to clinical outcomes in large cohorts and patient groups; (2) at this time, the most feasible method for standardization is by proposing a consensus-based framework, which includes scoring rules, developed by experts (3) hardware and software settings of acquisition devices, including filter settings, affect the shape of the flow curve, and should be clearly specified; and (4) a priority for future research is the generation of an open-source, expert-derived training set to encourage and support validation of automated flow limitation scoring algorithms.

OBJECTIVE: Sleep disordered breathing (SDB) has not been well studied in urban adolescents with asthma in community settings. Nor has the association of SDB symptoms and asthma severity been studied. We characterized self-reported symptoms suggesting SDB and investigated the association of SDB symptoms, probable asthma, and asthma severity. METHODS: 9,565 adolescents from 21 inner-city high schools were screened for an asthma intervention study. Students reported on symptoms suggesting SDB using questions from the 2007 NHANES, if they were ever diagnosed with asthma, and on asthma symptoms. Using generalized linear mixed models with logit link with school as a random intercept and adjusting for age, gender, and race/ethnicity, we examined associations of SDB symptoms, and demographic characteristics, probable asthma, and asthma severity. RESULTS: 12% reported SDB symptoms. Older and bi-racial participants (compared to Caucasian) had higher odds of symptoms suggesting SDB (p<.001). Compared to those without probable asthma, adolescents with probable asthma had 2.63 greater odds of reporting SDB symptoms (p<.001). Among those with probable asthma, the odds of reporting SDB symptoms increased with asthma severity. When exploring daytime severity and severity due to night wakening separately, results were similar. All results remained significant when controlling for age, gender, and ethnicity. CONCLUSIONS: In a large urban community cohort of predominately ethnic minority adolescents, self-reported SDB symptoms were associated with probable asthma and increased asthma severity. This study highlights the importance of SDB as a modifiable co-morbidity of asthma.

Sleep duration varies widely across individuals and appears to be trait-like. Differences in the stability of underlying sleep processes may underlie this phenomenon. To investigate underlying mechanisms, we examined the relationship between sleep duration and sleep continuity in baseline polysomnography (PSG) recordings from three independently collected datasets: 1) 134 healthy controls (ages 37 +/- 13 years) from the Sao Paulo Epidemiologic Sleep Study, who spent one night in a sleep laboratory, 2) 21 obstructive sleep apnea (OSA) patients who were treated with continuous positive airway pressure for at least 2 months (45 +/- 12 years, respiratory disturbance index <15), who spent one night in a sleep laboratory with previous experience of multiple PSG studies, and 3) 62 healthy controls (28 +/- 6 years) who, as part of larger experiments, spent 2 consecutive nights in a sleep laboratory. For each dataset, we used total sleep time (TST) to separate subjects into those with shorter sleep (S-TST) and those with longer sleep (L-TST). In all three datasets, survival curves of continuous sleep segments showed greater sleep continuity in L-TST than in S-TST. Correlation analyses with TST as a continuous variable corroborated the results; and the results also held true after controlling for age. There were no significant differences in baseline waking performance and sleepiness between S-TST and L-TST. In conclusion, in both healthy controls and treated OSA patients, sleep continuity was positively correlated with sleep duration. These findings suggest that S-TST may differ from L-TST in processes underlying sleep continuity, shedding new light on mechanisms underlying individual differences in sleep duration.

Introduction: Slow wave sleep (SWS) is thought to benefit spatial memory consolidation. This study investigates whether disrupting SWS via sleep-stage specific OSA affects spatial memory consolidation and how sleep fragmentation and intermittent hypoxia differentially impact this effect. Methods: We recruited 5 subjects with severe OSA who are well treated and compliant with CPAP. Individual subjects spent 3 different nights in the lab and performed timed trials before and after sleep on unique but equally difficult 3D spatial mazes. The 3 conditions included: 1) consolidated sleep with treated OSA 2) CPAP withdrawn exclusively in SWS (SWS-OSA) and 3) CPAP withdrawn exclusively in SWS with simultaneous addition of supplemental oxygen (SWS-OSA+O2). Results: CPAP withdrawal in SWS both decreased %SWS (21% +/- 11% during consolidated sleep vs. 13% +/- 7% with SWS-OSA), and fragmented remaining SWS (SWS apnea hypopnea index with 3% oxygen desaturation or arousal (AHI3A) = 0.5/hour +/- 1 during consolidated sleep vs. 36/hour +/- 12 with SWS-OSA). During SWSOSA+ O2, SWS was also reduced (11% +/ 8%) and respiratory events continued (AHI3A 31/hour +/- 20), however indices of oxygen desaturation were minimized (%time below 90% in SWS = 4.3% +/- 1.7% during SWS-OSA vs 0.5% +/- 0.9% during SWS-OSA+O2; average oxygen saturation during respiratory event = 88.7% +/- 3.3% during SWS-OSA vs. 94% +/- 1.4% during SWS-OSA+O2). During consolidated sleep, median completion time improved from 180 sec pre-sleep (range 86 to 248 sec) to 111 sec post-sleep (range 87 to 412 sec) (38%). During SWS-OSA median completion time improved from 138 sec pre-sleep (range 116 to 272 sec) to 133 sec post-sleep (range 73 to 453 sec) (4%) and during SWS-OSA+O2 median completion time improved from 172 sec pre-sleep (range 61 to 339 sec) to 161 sec postsleep (range 51 to 306 sec) (6%). Conclusion: CPAP withdrawal during SWS in subjects with severe OSA reduces and fragments SWS. The addition of supplemental oxygen during CPAP withdrawal minimizes the associated intermittent hypoxia. Early evidence suggests a greater benefit of consolidated sleep on overnight change in spatial navigation performance than sleep with SWS disruption either with or without intermittent hypoxia

Introduction: Sleep may play a role in AD pathogenesis, but the timing, role, and extent to which sleep disturbances in late-life are associated with increasing burden of AD neuropathology remains unclear. Sleep spindles have been implicated in sleep quality. Wakefulness is mediated by an arousal system beginning in the brainstem and continuing on to the diencephalon and innervating the thalamus, the region where sleep spindle oscillations are generated. In AD pathology, hyperphosphorylated tau (P-Tau) protein accumulates in the brainstem, from where it spreads to the entorhinal cortices, hippocampi and other brain regions. These tau aggregates may interfere with the sleep-wake cycle resulting in down-regulation of sleep spindles and associated sleep disruption. Increased CSF P-tau and T-tau levels are likely related to the formation of neurofibrillary tangles in the brainstem and limbic system (Braak stages I-IV). Methods: 49 cognitively normal (CDR=0) elderly (66.95 +/- 7.76 years) subjects completed a structural MRI, lumbar puncture (LP) and nocturnal polysomnography (NPSG) within 4.65 +/- 6.81 months of the LP. From the NPSG, spindle frequency and density were analyzed for stages NREM1, NREM2 and NREM3, using an automated optimization algorithm which decomposes the EEG as a sum of transient and oscillatory components. This was used to detect the spindles and a Fourier analysis was performed to evaluate the spindle frequency in Hz. Results: Spindle frequency and density in NREM2 sleep were inversely associated with CSF P-tau (r= -0.355, p<0.05; r=-0.476, p<0.05) and CSF T-tau (r=-0.405, p<.05; r=-0.542, p<.05) using partial correlation controlling for age and ApoE4 allele. There were no associations between spindle frequency or density and CSF P-tau or CSF T-tau in stages NREM1, NREM3. Conclusion: The association of spindle frequency and density in NREM2 to CSF P-tau and CSF T-tau in cognitively normal elderly suggest either that tau pathology may produce an early downstream effect on sleep spindles, or that changes in sleep spindles can identify a process relating to tau pathology. Whether the association of tau to spindles is a non-specific effect of tau on increasing sleep fragmentation in general remains an area of active investigation

STUDY OBJECTIVES: In familial dysautonomia (FD) patients, sleep-disordered breathing (SDB) might contribute to their high risk of sleep-related sudden death. Prevalence of central versus obstructive sleep apneas is controversial but may be therapeutically relevant. We, therefore, assessed sleep structure and SDB in FD-patients with no history of SDB. METHODS: 11 mildly affected FD-patients (28 +/- 11 years) without clinically overt SDB and 13 controls (28 +/- 10 years) underwent polysomnographic recording during one night. We assessed sleep stages, obstructive and central apneas (>/= 90% air flow reduction) and hypopneas (> 30% decrease in airflow with >/= 4% oxygen-desaturation), and determined obstructive (oAI) and central (cAI) apnea indices and the hypopnea index (HI) as count of respective apneas/hypopneas divided by sleep time. We obtained the apnea-hypopnea index (AHI4%) from the total of apneas and hypopneas divided by sleep time. We determined differences between FD-patients and controls using the U-test and within-group differences between oAIs, cAIs, and HIs using the Friedman test and Wilcoxon test. RESULTS: Sleep structure was similar in FD-patients and controls. AHI4% and HI were significantly higher in patients than controls. In patients, HIs were higher than oAIs and oAIs were higher than cAIs. In controls, there was no difference between HIs, oAIs, and cAIs. Only patients had apneas and hypopneas during slow wave sleep. CONCLUSIONS: In our FD-patients, obstructive apneas were more common than central apneas. These findings may be related to FD-specific pathophysiology. The potential ramifications of SDB in FD-patients suggest the utility of polysomnography to unveil SDB and initiate treatment. COMMENTARY: A commentary on this article appears in this issue on page 1583.