Clinical features of sleep apnea syndrome and cognitive impairment in multiple sclerosis.

BACKGROUND: Complications of obstructive sleep apnea (OSA) have been reported in patients with multiple sclerosis (MS). Patients with sleep apnea syndrome (SAS) due to OSA also show cognitive decline, with similar clinical characteristics to that manifested in MS. SAS due to OSA is a treatable condition, and the associated cognitive decline is expected to improve. This study investigates clinical features of SAS in people living with MS and contribute to improve cognitive dysfunction of MS. METHODS: A case-control study was conducted. Cognitive functions were evaluated by the Symbol Digit Modalities Test (SDMT) and the Paced Auditory Serial Addition Test 2 (PASAT-2) and 3 (PASAT-3). The Respiratory Event Index (REI) was measured using Out of Center Sleep Testing (OCST). We defined subjects with REI ≥ 5 as OSA and divided participants into two groups with or without SAS due to OSA. Cognitive and respiratory characteristics were statistically compared between patients with MS and healthy controls. RESULTS: We enrolled 67 people living with MS and 31 age- and sex-matched controls. OCST detected OSA in people living with MS and controls, and the prevalence rates were 28.4 % and 25.8 %, respectively. REI values (5.2 ± 7.9 vs 3.9 ± 5.2, p = 0.509) and number of participants with REI ≥ 5 (19 vs 8, p = 0.793) were similar between the MS and control group. The SDMT, PASAT-2, and PASAT-3 scores were significantly lower in the MS group than the control group (p < 0.001, p = 0.001, and p < 0.001, respectively). The interaction effect of MS and SAS on cognitive function was not significant in the SDMT (p = 0.078), but in the PASAT-2 (p = 0.043) and PASAT-3 (p = 0.020). CONCLUSION: This study revealed the prevalence rates of SAS in Japanese people living with MS and the usefulness of OCST for detection of SAS. This study also revealed that concomitant SAS can facilitate cognitive decline in people living with MS. These findings suggest that an appropriate intervention for OSA can be beneficial for people living with MS with cognitive decline.

Therapeutic effect of laparoscopic sleeve gastrectomy on obstructive sleep apnea and relationship of type 2 diabetes in Japanese patients with severe obesity.

AIMS/INTRODUCTION: Obstructive sleep apnea (OSA) is among the most important obesity-related diseases, and offers the potential for accelerated the early onset and progression of type 2 diabetes. The aim of the present study was to clarify the therapeutic effect of laparoscopic sleeve gastrectomy on OSA in severely obese Japanese patients, and to find correlations between OSA improvements and ß-cell function (BCF). MATERIALS AND METHODS: Between September 2013 and December 2019, 61 patients who underwent laparoscopic sleeve gastrectomy were enrolled. The apnea-hypopnea index (AHI) was used to diagnose OSA. The tongue area, uvula area and other parameters were measured using cone-beam computed tomography. Regarding BCF parameters, the homeostasis model assessment of ß-cell function, insulinogenic, Matsuda and disposition indexes were used to evaluate the improvement in BCF. Improvement of OSA was defined as AHI <15. RESULTS: The improvement rate of OSA was 51.8% (29/56). The change in AHI was significantly correlated with the excess weight loss percentage (ρ = 0.501), changes in tongue area (ρ = 0.350) and uvula area (ρ = 0.341). Multivariate analysis showed that preoperative AHI and postoperative hemoglobin A1c were independent prognostic factors of OSA non-improvement. The homeostasis model assessment of ß-cell function (P < 0.001), the insulinogenic index (P < 0.001) and the disposition index (P = 0.019) of patients with AHI of <15 were significantly higher than those in patients with AHI of ≥15. CONCLUSIONS: Laparoscopic sleeve gastrectomy is a promising procedure for severely obese patients with OSA. BCF recovery was found to be significantly higher in patients with OSA improvement.

False-positive cases in multiple sleep latency test by accumulated sleep debt.

PURPOSE: Multiple sleep latency test (MSLT) is performed as objective assessment of sleepiness, on the following day after polysomnography (PSG). In most clinics, patients are required to stay for 2 days. However, if patients have chronic sleep debt before the examination, even if they get adequate nocturnal sleep during the initial PSG, their sleep debt would not be fully resolved, affecting MSLT results. This may lead to improper administration of psycho-stimulant medication. To clarify the sleep debt for the patients who showed short sleep latencies, we compared the mean sleep latencies of MSLTs. METHODS: Twelve hypersomnolent males, who underwent MSLTs (1st MSLT with 1 night and 2nd MSLT with more than 3 nights), were enrolled. We selected these cases based on the longer total sleep time on PSG night compared to the mean total sleep time on pre-examination sleep logs and shortened sleep latencies on PSG. To evaluate the effect of the sleep debt for the patients who showed short sleep latencies, we extended their hospitalization or re-hospitalized them. RESULTS: The mean sleep latency of 1st MSLT was 5.8 minutes and that of 2nd was 13.9 minutes (P < .001). Among these 12 cases, 5 cases altered from short to normal sleep latencies at the 2nd MSLT. These 5 cases were prevented from over-diagnoses by the extension of evaluations. CONCLUSIONS: The sleep debt may produce false-positive results when patients are examined by standard PSG and MSLT. Accumulation of sleep debt will cause shortened sleep latencies in the following nights. Patients should be advised to extend their hospitalization before PSG and MSLT to reduce the chronic sleep debt for accurate diagnosis of hypersomnia.

Potential patient screening for late-onset Pompe disease in suspected sleep apnea: a rationale and study design for a Prospective Multicenter Observational Cohort Study in Japan (PSSAP-J Study).

BACKGROUND: Pompe disease is an autosomal recessive disorder caused by deficiency of the acid α-glucosidase (GAA) enzyme. GAA deficiency induces progressive glycogen accumulation which leads to weakness of the respiratory muscle including the diaphragm. Pompe disease is one of the few myopathies, for which an established therapy is available. Thus, earlier detection of potential late-onset Pompe disease (LOPD) and earlier intervention would have a significant clinical impact. PURPOSE: Our hypothesis is that sleep problems including sleep disordered breathing (SDB) and clinical symptoms may indicate an early stage of LOPD since decreased respiratory muscle activity generally first presents during sleep. Thus, the aims of this prospective, multicenter observational cohort study in Japan (PSSAP-J) are to demonstrate a higher prevalence of LOPD in a sleep lab-based population (primary outcome), and to identify predictive factors for LOPD from findings in diagnostic polysomnography (PSG) and clinical symptoms (secondary outcomes). METHODS: The study design is a prospective multicenter observational cohort study. Consecutive patients who present to sleep labs due to suspected SDB for an overnight PSG will be enrolled. All patients will be measured for creatine kinase, GAA activity, and if necessary, genetic analysis of GAA. Furthermore, chest X-ray, pulmonary function test, and arterial blood gas analysis will be collected. Then, prevalence and specific findings of LOPD will be assessed. RESULT: Congenital myopathy shows a shift from slow-deep to rapid-shallow breathing during transition from wakefulness to sleep accompanying a symptom of waking with gasping (actual further results are pending). DISCUSSION: The distribution in respiratory physiology between during wakefulness and sleep specific to LOPD may provide insights into early-stage detection. CLINICAL TRIAL REGISTRATION NUMBER: UMIN000039191, UMIN Clinical Trials Registry ( http://www.umin.ac.jp/ctr ).

Decrease of Plasma Soluble (Pro)renin Receptor by Bariatric Surgery in Patients with Obstructive Sleep Apnea and Morbid Obesity.

BACKGROUND: Plasma concentrations of soluble (pro)renin receptor [s(P)RR], which are elevated in patients with obstructive sleep apnea (OSA), have not been studied in morbid obesity. The aim of this study is to clarify effects of bariatric surgery on plasma s(P)RR concentrations and identify associated factors for their changes in OSA patients with morbid obesity. METHODS: Twenty-three patients with OSA complicated by morbid obesity (10 men and 13 women; body mass index, 40.7 ± 6.16 kg/m2) without chronic kidney disease were followed up after bariatric surgery. Overnight polysomnography (PSG) was performed before surgery, and 4 and 24 weeks after surgery. Plasma s(P)RR concentrations were measured each morning after PSG. RESULTS: Preoperative plasma s(P)RR concentrations showed significant positive correlations with serum creatinine (P < 0.05), arousal index (P < 0.01), apnea-hypopnea index (AHI) (P < 0.05), apnea index (P < 0.005), and desaturation index (P < 0.05), and a significant inverse correlation with an estimated glomerular filtration rate (P < 0.05). With the improvement of these PSG parameters, plasma s(P)RR concentrations significantly decreased from 15.3 ± 3.6 to 12.5 ± 2.7 ng/mL 4 weeks after surgery, which further decreased to 11.4 ± 2.4 ng/mL 24 weeks after surgery. The association observed before surgery between plasma s(P)RR concentrations and the PSG parameters was not seen after surgery. CONCLUSIONS: Bariatric surgery in patients with OSA complicated by morbid obesity decreased plasma s(P)RR concentrations. The most associated factors for their changes were arousal index, AHI, apnea index, and desaturation index.

Prevalence of sleep-disordered breathing in Japanese medical students based on type-3 out-of-center sleep test.

BACKGROUND: Sleep-disordered breathing (SDB), especially obstructive sleep apnea disorder (OSA), is thought to mainly affect men over the age of 40. Following findings that Asian people are more likely to experience severe OSA, regardless of obesity, we investigated the prevalence of SDB and OSA in a larger sample and in more younger age groups than those described in previous reports. METHODS: Between 2011 and 2016, 487 medical students (358 males, mean age 24.8 ± 1.9 years; 129 females: mean age 23.8 ± 1.6 years) underwent an out-of-center sleep test using a type-3 portable monitor. The results were analyzed visually. RESULTS: The mean ± standard deviation of the respiratory event index (REI: events/hour of monitoring) was 5.4 ± 6.7 (6.7 ± 7.5 in male participants, 2.6 ± 2.1 in female participants). There were 170 participants (36.6%) with an REI≥5, including 158 male participants (46.9%) and 12 female participants (9.1%). SDB or undefined OSA with low REI (15 > REI≥5) was observed in 141 participants (30.4%), defined OSA with moderate REI (30 > REI≥15) in 19 participants (4.1%), and defined OSA with high REI (REI≥30) in 10 participants (2.2%). Among the male students, 129 had low REI (38.3%), 19 had moderate REI (5.6%), and 10 had high REI (3.0%). All female participants with OSA events (9.4%) had a low REI. CONCLUSIONS: The prevalence of OSA in Japanese young adults, especially males under 30 years old, is similar or even higher than that in older age groups described previously. Thus, an aggressive sleep study for SDB might be necessary for the younger generation in the Asian population.

Soluble (Pro)renin Receptor and Obstructive Sleep Apnea Syndrome: Oxidative Stress in Brain?

(Pro)renin receptor ((P)RR) is a multi-functional molecule that is related to both the renin-angiotensin system (RAS) and vacuolar H⁺-ATPase (v-ATPase), an ATP-dependent multi-subunit proton pump. Soluble (P)RR (s(P)RR), which consists of the extracellular domain of (P)RR, is present in blood and urine. Elevated plasma s(P)RR concentrations are reported in patients with chronic kidney disease and pregnant women with hypertension or diabetes mellitus. In addition, we have shown that plasma s(P)RR concentrations are elevated in patients with obstructive sleep apnea syndrome (OSAS). Interestingly, the levels are elevated in parallel with the severity of OSAS, but are not related to the presence of hypertension or the status of the circulating RAS in OSAS. It is known that v-ATPase activity protects cells from endogenous oxidative stress, and loss of v-ATPase activity results in chronic oxidative stress. We hypothesize that hypoxia and subsequent oxidative stress, perhaps in the brain, may be one of the factors that elevate plasma s(P)RR levels in OSAS.

Elevated Plasma Levels of Soluble (Pro)Renin Receptor in Patients with Obstructive Sleep Apnea Syndrome in Parallel with the Disease Severity.

(Pro)renin receptor ((P)RR), a receptor for renin and prorenin, is implicated in the pathophysiology of diabetes mellitus, hypertension and their complications. Soluble (P)RR (s(P)RR) is composed of extracellular domain of (P)RR and thus exists in blood. We have reported that plasma concentrations of s(P)RR were elevated in male patients with obstructive sleep apnea syndrome (OSAS). The aim of the present study was to clarify the difference in plasma s(P)RR concentrations between male and female OSAS patients. Plasma s(P)RR concentrations were studied in 289 subjects (206 males and 83 females) consisting of 259 OSAS patients and 30 non-OSAS control subjects. The 259 OSAS patients were classified into mild (5 ≤ apnea hypopnea index (AHI) < 15 events/h), moderate (15 ≤ AHI < 30), and severe OSAS (AHI ≥ 30). Plasma s(P)RR levels were significantly elevated in all three OSAS groups compared to non-OSAS control subjects (AHI < 5) in the entire cohort and male subjects, whereas in female subjects, the significant elevation was found only in severe OSAS. Plasma s(P)RR levels were significantly correlated with AHI in both sexes, with a higher r value found in male subjects (male r = 0.413, p < 0.0001; female r = 0.263, p < 0.05). Importantly, when OSAS patients (26 males and 15 females) with AHI ≥ 20 underwent continuous positive airway pressure treatment, plasma s(P)RR levels were significantly decreased. In conclusion, plasma s(P)RR levels are elevated in both male and female OSAS patients in parallel with the disease severity.

Elevated plasma levels of soluble (pro)renin receptor in patients with obstructive sleep apnea syndrome: association with polysomnographic parameters.

(Pro)renin receptor ((P)RR) is a specific receptor for both renin and its precursor prorenin. (P)RR was shown to be involved in pathophysiology of cardiovascular and renal diseases. Soluble (pro)renin receptor (s(P)RR), which is generated by furin from full length (P)RR, is present in blood. The aim of the present study is to clarify the association of plasma s(P)RR levels and the severity of OSAS. Plasma levels of s(P)RR were measured by ELISA in 58 male patients diagnosed as OSAS based on polysomnography, and 14 age-matched male control subjects. Blood samples were obtained at 6:00 a.m. just after overnight polysomnography. Plasma s(P)RR levels were significantly higher in patients with OSAS (9.0±2.0 ng/mL, mean ± SD) than in control subjects (7.4±1.5 ng/mL) (P=0.0026). Plasma s(P)RR levels showed a significant negative correlation with % stage rapid eye movement (REM) sleep (r=-0.377, p<0.005), and significant positive correlations with % stage 1 (r=0.374, p<0.005), arousal index (r=0.341, p<0.01), apnea hypopnea index (AHI) (r=0.352, p<0.01) and desaturation index (r=0.302, p<0. 05). In 12 OSAS patients with AHI ≥20, plasma levels of s(P)RR were studied after 3-month treatment with nasal continuous positive airway pressure (nCPAP). Plasma s(P)RR levels were significantly decreased after the nCPAP treatment (p=0.0016). The present study has shown for the first time elevated plasma s(P)RR levels in patients with OSAS. Plasma s(P)RR levels were associated with the severity of OSAS. Soluble (P)RR may serve as a plasma marker reflecting the severity of OSAS.

Effects of CPAP treatment interruption due to disasters: patients with sleep-disordered breathing in the Great East Japan Earthquake and tsunami area.

INTRODUCTION: The 2011 Great East Japan Earthquake caused major disruptions in the provision of health care, including that for patients with sleep-disordered breathing (SDB) using a nasal continuous positive airway pressure (nCPAP) device. This study investigated the ability of SDB patients to continue using the nCPAP device in the weeks immediately following the earthquake, whether inability to use the nCPAP device led to symptom relapse, and measures that should be taken to prevent disruptions in nCPAP therapy during future disasters. Hypothesis If nCPAP devices cannot be used during disasters, SDB patients' health will be affected negatively. METHODS: Within 14 days of the disaster, 1,047 SDB patients completed a questionnaire that collected data regarding ability to use, duration of inability to use, and reasons for inability to use the nCPAP device; symptom relapse while unable to use the nCPAP device; ability to use the nCPAP device use at evacuation sites; and recommendations for improvement of the nCPAP device. RESULTS: Of the 1,047 patients, 966 (92.3%) had been unable to use the nCPAP device in the days immediately following the earthquake. The most common reason for inability to use the nCPAP device was power failure, followed by anxiety about sleeping at night due to fear of aftershocks, involvement in disaster-relief activities, loss of the nasal CPAP device, and fear of being unable to wake up in case of an emergency. Among the 966 patients, 242 (25.1%) had experienced relapse of symptoms, the most common of which was excessive daytime sleepiness (EDS), followed by insomnia, headache, irritability, and chest pain. CONCLUSION: Developing strategies for the continuation of nCPAP therapy during disasters is important for providing healthy sleeping environments for SDB patients in emergency situations.

Essential roles of angiotensin II in vascular endothelial growth factor expression in sleep apnea syndrome.

BACKGROUND: Hypoxia-induced endothelial cell dysfunction has been implicated in increased cardiovascular disease associated with obstructive sleep apnea syndrome (OSAS). OSAS mediates hypertension by stimulating angiotensin II (Ang II) production. Hypoxia and Ang II are the major stimuli of vascular endothelial growth factor (VEGF), which is a potent angiogenic cytokine and also contributes to the atherogenic process itself. METHODS AND RESULTS: We observed serum Ang II and VEGF levels and peripheral blood mononuclear cell (PBMC) and neutrophil VEGF expression. Compared to controls, subjects with OSAS had significantly increased levels of serum Ang II and VEGF and VEGF mRNA expression in their leukocytes. To examine whether Ang II stimulates VEGF expression in OSAS, we treated PBMCs obtained from control subjects with Ang II and with an Ang II receptor type 1 (AT(1)) blocker, olmesartan. We observed an increased expression of VEGF in the Ang II-stimulated PBMCs and decreased in VEGF mRNA and protein expression in the PBMCs treated with olmesartan. CONCLUSIONS: These findings suggest that the Ang II-AT(1) receptors pathway potentially are involved in OSAS and VEGF-induced vascularity and that endothelial dysfunction might be linked to this change in Ang II activity within leukocytes of OSAS patients.

Low plasma orexin-A levels were improved by continuous positive airway pressure treatment in patients with severe obstructive sleep apnea-hypopnea syndrome.

INTRODUCTION: We have previously shown that plasma levels of orexin-A, a neuropeptide with an arousal-stimulating action, were decreased in parallel with the severity of the disease in patients with obstructive sleep apnea-hypopnea syndrome (OSAHS). OBJECTIVE: To clarify the effects of nasal continuous positive airway pressure (nCPAP) treatment on plasma orexin-A levels in patients with this syndrome. METHOD: Sleep tests and blood sample collections were conducted at the sleep-related respiratory disorders clinic and the sleep laboratory of the Iwate Medical University Hospital. We studied 27 patients with OSAHS (apnea-hypopnea index [AHI], >/= 20 by polysomnography) who were treated with nCPAP for 3 to 6 months. These patients were divided into the following two groups according to the arousal index (AI): group A (n = 11), >/= 60; group B (n = 16), < 60. Plasma samples were obtained before and after the nCPAP treatment for 3 to 6 months. Plasma immunoreactive (IR)-orexin-A concentrations were measured by radioimmunoassay after the extraction using cartridges. RESULTS: Plasma IR-orexin-A concentrations were inversely correlated with the AI (r = -0.807; p < 0.0001) and AHI (r = -0.661; p < 0.0001) in 27 patients before the nCPAP treatment. Mean (+/- SEM) plasma IR-orexin-A concentrations were significantly lower in group A (1.0 +/- 0.3 pmol/L) than in group B (4.6 +/- 0.4 pmol/L). Mean plasma IR-orexin-A concentrations were significantly increased after the nCPAP treatment in group A (to 3.4 +/- 1.2 pmol/L; p = 0.0069), whereas they were not significantly changed in group B. The increases in plasma IR-orexin-A concentrations after the nCPAP treatment were in parallel with the improvements in AI and Epworth sleepiness scale (a marker of severity of daytime excessive sleepiness) score in group A. CONCLUSIONS: The low plasma orexin-A levels were increased by the nCPAP treatment in patients with severe OSAHS, suggesting that orexin-A is a plasma marker that reflects the severity of OSAHS and the response to treatment.

Clinical significance of daytime plasma orexin-A-like immunoreactivity concentrations in patients with obstructive sleep apnea hypopnea syndrome.

BACKGROUND: Polysomnography (PSG) tests are very complicated and time consuming, despite their clinical benefits in the diagnosis of patients with obstructive sleep apnea hypopnea syndrome (OSAHS). A plasma marker would be desirable to select patients suspected of OSAHS for further PSG studies. We have recently reported that orexin-A concentrations in plasma collected immediately after waking early in the morning were significantly lower in patients with OSAHS than in controls. OBJECTIVES: We conducted the present study to assess the clinical usefulness of the measurement of orexin-A concentrations in plasma obtained in the daytime as a diagnostic predictor to screen patients with OSAHS. METHODS: Blood samples were collected in the daytime from 19 male patients with suspected sleep-disordered breathing. Plasma orexin-A concentrations were measured by radioimmunoassay before performing PSG. RESULTS: PSG was conducted in all 19 subjects. PSG showed that 14 subjects had OSAHS and 5 subjects did not. Plasma orexin-A concentrations were significantly lower in patients with OSAHS (4.9 +/- 0.8 pmol/l, mean +/- SE, n = 14) than in control subjects (12.3 +/- 1.9 pmol/l, n = 5) (p = 0.0004). CONCLUSIONS: These findings suggest that the orexin-A concentration in plasma obtained even in the daytime may be a useful plasma marker for screening OSAHS.

Plasma orexin-A-like immunoreactivity in patients with sleep apnea hypopnea syndrome.

Orexin-A (hypocretin-1), a neuropeptide produced in hypothalamus, stimulates arousal. We studied plasma concentrations of orexin-A-like immunoreactivity (orexin-A-LI) in 156 patients with sleep apnea hypopnea syndrome (SAHS) and 22 control subjects. Plasma orexin-A-LI levels were significantly decreased in 156 patients with SAHS (4.4+/-0.15 pmol/l, mean+/-S.E.) as compared with controls (5.3+/-0.45 pmol/l). The levels were decreased in parallel with the severity of sleep-related respiratory disturbance and magnitude of sleep fragmentation. These findings raise the possibility that a low plasma level of orexin-A-LI may be a marker to show the severity of the disease in patients with SAHS.