Indu Ayappa

Sleep-disordered breathing advances cognitive decline in the elderly

Objective: To examine whether the presence of sleep-disordered breathing (SDB) is associated with an earlier age at mild cognitive impairment (MCI) or Alzheimer disease (AD)-dementia onset in participants from the Alzheimers Disease Neuroimaging Initiative (ADNI) cohort. We also examined whether continuous positive airway pressure (CPAP) use is associated with delayed onset of cognitive decline. Methods: From the ADNI cohort, 3 subsets with progressively stringent criteria were created in a step-wise manner. Age at MCI or AD-dementia onset was the main outcome variable. Analyses were performed separately for each subset in untreated SDB+ vs SDB− and untreated SDB+ vs CPAP+ groups. Chi-square and t tests were performed to examine between-group differences. Survival analyses were performed using the Kaplan–Meier method, compared by the log-rank test, and assessed by multivariate Cox regression adjusting for potential confounders. Results: SDB+ patients had a younger age at MCI onset in all subsets (MC1: 72.63 vs 83.67; MC2: 72.15 vs 83.45; MC3: 77.40 vs 89.89; p < 0.01). SDB+ patients had a younger age at AD-dementia onset only in our most conservative subset (AC3: 83.46 vs 88.13; p < 0.05). In a combined outcome analysis, SDB+ patients had a younger age at onset to MCI or AD-dementia in all subsets. In subsets 1 and 2, CPAP use delayed the age at MCI onset (CMC1: 72.63 vs 82.10; CMC2: 72.11 vs 82.10; p < 0.01). Conclusions: Consistent with our hypothesis, the presence of SDB was associated with an earlier age at cognitive decline. Our findings in CPAP+ participants suggest that CPAP treatment of SDB may delay progression of cognitive impairment.

GREATER RISK OF ALZHEIMER’S DISEASE IN OLDER ADULTS WITH INSOMNIA

ACKNOWLEDGMENTS Conflict of Interest: This work was supported by the Fundamental Research Grant Scheme, Ministry of Higher Education, Malaysia. Dr. Noran N. Hairi’s work on this study was supported by the Public Service Department of Malaysia. The authors would like to express their appreciation to Dr. Siti Halimah Shaikh and all healthcare providers of Masjid Tanah Health Clinic, Ministry of Health, Malaysia, for their contributions to this research. Author Contributions: NNH: study concept, chief investigator, designing research protocol, data analysis, interpretation of data, and writing manuscript. AB, IM: conceptualization of research and data collection. RGC, VN, AB: critically editing of the manuscript. All authors read and approved the final manuscript. Sponsor’s Role: None.

The interaction between sleep-disordered breathing and apolipoprotein E genotype on cerebrospinal fluid biomarkers for Alzheimer's disease in cognitively normal elderly individuals

Previous studies have suggested a link between sleep disordered breathing (SDB) and dementia risk. In the present study, we analyzed the relationship between SDB severity, cerebrospinal fluid (CSF) Alzheimers disease-biomarkers, and the ApoE alleles. A total of 95 cognitively normal elderly participants were analyzed for SDB severity, CSF measures of phosphorylated-tau (p-tau), total-tau (t-tau), and amyloid beta 42 (Aβ-42), as well as ApoE allele status. In ApoE3+ subjects, significant differences were found between sleep groups for p-tau (F[df2] = 4.3, p = 0.017), and t-tau (F[df2] = 3.3, p = 0.043). Additionally, among ApoE3+ subjects, the apnea and/or hypopnea with 4% O2-desaturation index was positively correlated with p-tau (r = 0.30, p = 0.023), t-tau (r = 0.31, p = 0.021), and Aβ-42 (r = 0.31, p = 0.021). In ApoE2+ subjects, the apnea and/or hypopnea with 4% O2-desaturation index was correlated with lower levels of CSF Aβ-42 (r = -0.71, p = 0.004), similarly to ApoE4+ subjects where there was also a trend toward lower CSF Aβ-42 levels. Our observations suggest that there is an association between SDB and CSF Alzheimers disease-biomarkers in cognitively normal elderly individuals. Existing therapies for SDB such as continuous positive airway pressure could delay the onset to mild cognitive impairment or dementia in normal elderly individuals.

Comparison of the maintenance of wakefulness test (MWT) to a modified behavioral test (OSLER) in the evaluation of daytime sleepiness

The objectives were to evaluate the correlation between sleep onset as defined by the Oxford sleep resistance (OSLER) test and by simultaneous electroencephalography (EEG) and to determine the correlation between sleep latencies measured by the OSLER test and maintenance of wakefulness test (MWT) performed on the same day. This was a prospective, cross‐sectional study carried out in a tertiary‐care university‐based sleep laboratory. Participants were 11 consecutive subjects presenting to the sleep center with clinical indications for nocturnal polysomnography and MWT. The interventions included MWT and OSLER test. Mean sleep latencies for the OSLER and MWT in each subject were closely correlated (ICC = 0.94, [Intra‐class correlation]P < 0.05). Sleep latency by OSLER and simultaneous measurement of EEG also had excellent agreement (ICC = 0.91) with a bias of −0.97 min. The OSLER test is a practical and reliable tool for evaluating daytime sleepiness when compared with the MWT. No obvious systematic adaptation was seen during sequential OSLER test performance. Given its portability and minimal technical requirements, the OSLER test may be useful for large‐scale applications in the evaluation of daytime wakefulness and vigilance.

Changes in lung volume and upper airway using MRI during application of nasal expiratory positive airway pressure in patients with sleep-disordered breathing

Nasal expiratory positive airway pressure (nEPAP) delivered with a disposable device (Provent, Ventus Medical) has been shown to improve sleep-disordered breathing (SDB) in some subjects. Possible mechanisms of action are 1) increased functional residual capacity (FRC), producing tracheal traction and reducing upper airway (UA) collapsibility, and 2) passive dilatation of the airway by the expiratory pressure, carrying over into inspiration. Using MRI, we estimated change in FRC and ventilation, as well as UA cross-sectional area (CSA), in awake patients breathing on and off the nEPAP device. Ten patients with SDB underwent nocturnal polysomnography and MRI with and without nEPAP. Simultaneous images of the lung and UA were obtained at 6 images/s. Image sequences were obtained during mouth and nose breathing with and without the nEPAP device. The nEPAP device produced an end-expiratory pressure of 4-17 cmH(2)O. End-tidal Pco(2) rose from 39.7 ± 5.3 to 47.1 ± 6.0 Torr (P < 0.01). Lung volume changes were estimated from sagittal MRI of the right lung. Changes in UA CSA were calculated from transverse MRI at the level of the pharynx above the epiglottis. FRC determined by MRI was well correlated to FRC determined by N(2) washout (r = 0.76, P = 0.03). nEPAP resulted in a consistent increase in FRC (46 ± 29%, P < 0.001) and decrease in ventilation (50 ± 15%, P < 0.001), with no change in respiratory frequency. UA CSA at end expiration showed a trend to increase. During wakefulness, nEPAP caused significant hyperinflation, consistent with an increase in tracheal traction and a decrease in UA collapsibility. Direct imaging effects on the UA were less consistent, but there was a trend to dilatation. Finally, we showed significant hypoventilation and rise in Pco(2) during use of the nEPAP device during wakefulness and sleep. Thus, at least three mechanisms of action have the potential to contribute to the therapeutic effect of nEPAP on SDB.

Response to CPAP withdrawal in patients with mild versus severe obstructive sleep apnea/hypopnea syndrome.

BACKGROUND Patients with obstructive sleep apnea/hypopnea syndrome (OSAHS), even those generally compliant with CPAP therapy, often intermittently discontinue CPAP. STUDY OBJECTIVE Examine the impact of CPAP withdrawal on sleep, sleep disordered breathing (SDB), and daytime function in subjects with varying severity of OSAHS. PATIENTS AND INTERVENTIONS Forty-two subjects (26M/16 F) with OSAHS (AHI4% = 45.2 ± 35.5/h pretreatment) on CPAP for 4 months were evaluated on the second night of CPAP withdrawal. Sleep architecture, SDB indices, and subjective/objective daytime function were assessed pretreatment, on CPAP therapy, and after CPAP withdrawal. Comparisons were made between pretreatment and CPAP withdrawal for the entire group, and for subgroups of mild/moderate (AHI4% < 30/h, n = 22) and severe (AHI4% > 30/h, n = 20) SDB. RESULTS Overall, and for mild/moderate subjects, SDB indices returned to pretreatment values on CPAP withdrawal but with fewer apneas and more hypopneas/RERAs. For severe SDB, the event frequency (AI, AHI4%, and RDI) was lower and O2 desaturation was improved on CPAP withdrawal. Across SDB severity, sleep architecture showed lower %REM (15.6% vs 12.9%, P = 0.009) on the CPAP withdrawal compared to pretreatment. Stanford Sleepiness Score, MSLT, and PVT measures were not significantly different between pretreatment and CPAP withdrawal. CONCLUSIONS Over a wide range of SDB severity CPAP withdrawal results in recurrence of SDB, albeit with less severe O2 desaturation. Subjective/objective daytime function returned to pretreatment levels. Sleep architecture changes on CPAP withdrawal (acute SDB) may reflect reduced sleep pressure compared to pretreatment chronic SDB. Our data suggest detrimental effects of even brief withdrawal of CPAP in subjects with both mild and severe OSAHS. CITATION Young LR; Taxin ZH; Norman RG; Walsleben JA; Rapoport DM; Ayappa I. Response to CPAP withdrawal in patients with mild versus severe obstructive sleep apnea/hypopnea syndrome. SLEEP 2013;36(3):405-412.

Scoring accuracy of automated sleep staging from a bipolar electroocular recording compared to manual scoring by multiple raters

OBJECTIVES Electroencephalography (EEG) assessment in research and clinical studies is limited by the patient burden of multiple electrodes and the time needed to manually score records. The objective of our study was to investigate the accuracy of an automated sleep-staging algorithm which is based on a single bipolar EEG signal. METHODS Three raters each manually scored the polysomnographic (PSG) records from 44 patients referred for sleep evaluation. Twenty-one PSG records were scored by Rechtschaffen and Kales (R&K) criteria (group 1) and 23 PSGs were scored by American Academy of Sleep Medicine (AASM) 2007 criteria (group 2). Majority agreement was present in 98.4% of epochs and was used for comparison to automated scoring from a single EEG lead derived from the left and right electrooculogram. RESULTS The κ coefficients for interrater manual scoring ranged from 0.46 to 0.89. The κ coefficient for the auto algorithm vs manual scoring by rater ranged from 0.42 to 0.63 and was 0.61 (group 1, κ=0.61 and group 2, κ=0.62) for majority agreement for all studies. The mean positive percent agreement across subjects and stages was 72.6%, approximately 80% for stages wake (78.3%), stage 2 sleep (N2) (80.9%), and stage 3 sleep (N3) (78.1%); the percentage slightly decreased to 73.2% for rapid eye movement (REM) sleep and dropped to 31.9% for stage 1 sleep (N1). Differences in agreement were observed based on raters, obstructive sleep apnea (OSA) severity, medications, and signal quality. CONCLUSIONS Our study demonstrated that automated scoring of sleep obtained from a single-channel of forehead EEG results in agreement to majority manual scoring are similar to results obtained from studies of manual interrater agreement. The benefit in assessing auto-staging accuracy with consensus agreement across multiple raters is most apparent in patients with OSA; additionally, assessing auto-staging accuracy limited disagreements in patients on medications and in those with compromised signal quality.

Apnea-Induced Rapid Eye Movement Sleep Disruption Impairs Human Spatial Navigational Memory

Hippocampal electrophysiology and behavioral evidence support a role for sleep in spatial navigational memory, but the role of particular sleep stages is less clear. Although rodent models suggest the importance of rapid eye movement (REM) sleep in spatial navigational memory, a similar role for REM sleep has never been examined in humans. We recruited subjects with severe obstructive sleep apnea (OSA) who were well treated and adherent with continuous positive airway pressure (CPAP). Restricting CPAP withdrawal to REM through real-time monitoring of the polysomnogram provides a novel way of addressing the role of REM sleep in spatial navigational memory with a physiologically relevant stimulus. Individuals spent two different nights in the laboratory, during which subjects performed timed trials before and after sleep on one of two unique 3D spatial mazes. One night of sleep was normally consolidated with use of therapeutic CPAP throughout, whereas on the other night, CPAP was reduced only in REM sleep, allowing REM OSA to recur. REM disruption via this method caused REM sleep reduction and significantly fragmented any remaining REM sleep without affecting total sleep time, sleep efficiency, or slow-wave sleep. We observed improvements in maze performance after a night of normal sleep that were significantly attenuated after a night of REM disruption without changes in psychomotor vigilance. Furthermore, the improvement in maze completion time significantly positively correlated with the mean REM run duration across both sleep conditions. In conclusion, we demonstrate a novel role for REM sleep in human memory formation and highlight a significant cognitive consequence of OSA.

Interaction between sleep-disordered breathing and apolipoprotein E genotype on cerebrospinal fluid biomarkers for Alzheimer's disease in cognitively normal elderly individuals.

Previous studies have suggested a link between sleep disordered breathing (SDB) and dementia risk. In the present study, we analyzed the relationship between SDB severity, cerebrospinal fluid (CSF) Alzheimers disease-biomarkers, and the ApoE alleles. A total of 95 cognitively normal elderly participants were analyzed for SDB severity, CSF measures of phosphorylated-tau (p-tau), total-tau (t-tau), and amyloid beta 42 (Aβ-42), as well as ApoE allele status. In ApoE3+ subjects, significant differences were found between sleep groups for p-tau (F[df2] = 4.3, p = 0.017), and t-tau (F[df2] = 3.3, p = 0.043). Additionally, among ApoE3+ subjects, the apnea and/or hypopnea with 4% O2-desaturation index was positively correlated with p-tau (r = 0.30, p = 0.023), t-tau (r = 0.31, p = 0.021), and Aβ-42 (r = 0.31, p = 0.021). In ApoE2+ subjects, the apnea and/or hypopnea with 4% O2-desaturation index was correlated with lower levels of CSF Aβ-42 (r = -0.71, p = 0.004), similarly to ApoE4+ subjects where there was also a trend toward lower CSF Aβ-42 levels. Our observations suggest that there is an association between SDB and CSF Alzheimers disease-biomarkers in cognitively normal elderly individuals. Existing therapies for SDB such as continuous positive airway pressure could delay the onset to mild cognitive impairment or dementia in normal elderly individuals.

Potential Mechanism for Transition Between Acute Hypercapnia During Sleep to Chronic Hypercapnia During Wakefulness in Obstructive Sleep Apnea

This paper presents a series of experiments, both in patients and computer models, investigating the transition from acute to chronic hypercapnia in OSA. The data demonstrate that acute hypercapnia during periodic breathing occurs due to either reduction in magnitude of inter-event ventilation and/or reduction in inter-event ventilatory duration relative to duration of the preceding event. The transition between acute hypercapnia during sleep and chronic sustained hypercapnia during wakefulness may be determined by an interaction between respiratory control and renal handling of HCO3-.