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Background: Cognitive impairment is common in patients with obstructive sleep apnea (OSA). Previous studies indicated that intermittent hypoxia, sleep fragmentation, and depressive symptoms were associated with cognitive impairment in OSA patients. Objective: The study aimed to investigate whether sleep characteristics and depressive symptoms affected cognitive abilities mediated by Alzheimer's disease (AD) biomarkers and complement proteins in OSA patients without dementia. Methods: A total of 317 subjects without dementia who had undergone polysomnography, cognitive and neuropsychological evaluations, were recruited. Neuronal-derived exosomes (NDEs) levels for amyloid-β (Aβ), total tau (T-tau), and tau phosphorylated 62 at threonine 181 (P-T181-tau) and astrocyte-derived exosomes (ADEs) levels for complement proteins were measured. Mediation analysis were performed to explore the mediation effects of AD biomarkers (Aβ42, T-tau, P-T181-tau) and complement proteins (C3b and C5b-9) on cognition. Results: The findings revealed that the association between sleep fragmentation and cognition was mediated by Aβ42 (the percentage varied from 18.25% to 30.6%), P-T181-tau (the percentage varied from 24.36% to 32.3%), and C5b-9 (the percentage varied from 30.88% to 60.7%). The influence of depressive symptoms on cognition was only mediated via C3b (the percentage varied from 24.1% to 36.6%). Conclusions: In OSA patients without dementia, Aβ42 and P-T181-tau levels in NDEs, and C5b-9 levels in ADEs mediated the impact of sleep fragmentation on cognitive impairment, and C3b levels in ADEs mediated the impact of depressive symptoms on cognitive impairment. [ABSTRACT FROM AUTHOR]

Background: Increasing evidence has supported a link between obstructive sleep apnea (OSA) and cognition, and blood-brain barrier (BBB) dysfunction which can be reflected by paroxysmal slow wave events (PSWEs) may be a potential mechanism. The purpose of our study was to investigate the correlation between the PSWEs and cognitive impairment in patients with OSA, with a focus on the possible mechanism. Methods: In total, 339 subjects with subjective snoring complaints from the Sleep Medicine Center underwent magnetic resonance imaging and whole-night polysomnography. OSA was defined as apnea-hypopnea index (AHI) ≥ 5 events/h. MCI was defined as the MoCA < 26 and met the criteria: (1) subjective cognitive impairment; (2) objective impairment in one or more cognitive domains; (3) slightly impaired complex instrumental daily abilities, but independent daily living abilities; and (4) no dementia. The PSWEs calculated by self-developed Python scripts were defined for EEG recordings as a median power frequency of < 6 Hz for more than five consecutive seconds. Serum cyclophilin A (CyPA) and matrix metalloproteinase-9 (MMP-9) levels and amyloid-β 42 levels in neuron-derived exosomes were determined. The participants who received continuous positive airway pressure (CPAP) were followed up and their PSWEs were recalculated after 1 year of treatment. Results: A total of 339 participants were divided into the OSA+MCI group (n = 157), OSA-MCI group (n = 118), and controls (normal cognitive state without OSA) (n = 64). The total PSWEs and the occurrence per minute of PSWEs at stage REM in the OSA+MCI group were higher than those in the OSA-MCI and control groups. The duration ratio of PSWEs at stage REM in the OSA+MCI group significantly increased. The total PSWEs and PSWEs at the F4-M1, O1-M2, and O2-M1 channels in stage REM were independently associated with cognitive impairment in OSA patients. There were positive correlations between the PSWEs and serum CyPA and MMP-9 levels in patients with OSA. The mediation analysis showed that the relationship between mean SaO2 and percentage of sleep time spent with oxygen saturation <90% with MoCA scores was mediated by the total PSWEs (proportion of mediation 77.89% and 82.89%). The PSWEs were negatively correlated with global cognitive performance and cognitive subdomains. After 1 year of CPAP treatment, the total PSWEs, PSWEs in stage REM, and serum CyPA and MMP-9 levels decreased significantly, and MoCA scores were improved compared with baseline. Conclusions: The PSWEs were implicated in cognitive impairment in patients with OSA, and the mechanisms of cognitive impairment due to hypoxia in OSA patients could be BBB dysfunction. The PSWEs can be used as a marker of cognitive impairment in patients with OSA. Trial registration: This trial is registered on the Chinese Clinical Trial Registry, number ChiCTR1900021544. The trial was registered on February 27, 2019. [ABSTRACT FROM AUTHOR]

Objectives: To investigate the relationship between serum cyclophilin A (CyPA) and matrix metalloproteinase-9 (MMP-9) levels and mild cognitive impairment (MCI) in patients with obstructive sleep apnea (OSA).Methods: Study subjects underwent whole-night in-laboratory polysomnography (PSG), and all participants were scored using a neuropsychological scale and peripheral blood samples were collected the next morning. The presence and severity of OSA were assessed with the apnea hypopnea index (AHI), and OSA was defined as AHI ≥5 events/hour. MCI was defined as the MoCA ≤25, and met the revised Mayo Clinic criteria. Serum CyPA and MMP-9 levels were measured with enzyme-linked immunosorbent assays (ELISAs). A univariate analysis and a logistic model were used to assess risk factors for MCI in patients with OSA. A correlation analysis was performed to estimate whether a linear relationship existed between serum CyPA and MMP-9 levels and the severity of cerebral small vessel disease (CSVD) and white matter hyperintensities (WMHs). A linear regression analysis was used to clarify the relationship between serum CyPA and MMP-9 levels and the degree of cognitive impairment in patients with OSA.Results: The 186 patients who met the criteria for inclusion and exclusion comprised 71 patients with OSA presenting with MCI (OSA + MCI), 73 patients with OSA without MCI (OSA-MCI), and 42 controls. Patients with OSA + MCI presented higher serum CyPA and MMP-9 levels than patients in the OSA-MCI (11.56 ± 4.52 ng/ml vs 9.95 ± 3.63 ng/ml, p = 0.020; 597.71 ± 204.41 ng/ml vs 523.05 ± 205.47 ng/ml, p = 0.030) and control groups (11.56 ± 4.52 ng/ml vs 8.80 ± 3.71 ng/m, p = 0.001; 597.71 ± 204.41 ng/ml vs 490.39 ± 155.07 ng/ml, p = 0.002). The logistic regression analysis revealed that both CyPA (OR: 1.111, 95% CIs: 1.012-1.219, p = 0.027) and MMP-9 levels (OR: 1.003, 95% CIs: 1.000-1.004, p = 0.011) contributed significantly to MCI in patients with OSA. In the OSA + MCI group, positive correlations were observed between serum CyPA and MMP-9 levels with Scheltens scores (r = 0.437, p = 0.000; r = 0.613, p = 0.000, respectively) and total CSVD burden scores (r = 0.318, p = 0.003; r = 0.487, p = 0.000, respectively). Serum CyPA and MMP-9 levels were linearly negatively correlated with mean oxygen saturation during sleep (mean SaO2) (r = -0.595, p = 0.000; r = -0.570, p = 0.000). There was linear correlation between mean SaO2 and MoCA scores by Pearson's correlation coefficient (r = 0.403, p = 0.000). The linear regression analysis revealed negative correlations between serum CyPA and MMP-9 levels and the Montreal Cognitive Assessment (MoCA) scores (r = -0.528, p = 0.000; r = -0.459, p = 0.000, respectively), and serum CyPA levels were negatively correlated with score of cognitive subdomainss, including visuo-executive function, attention and delayed recall. However, serum MMP-9 levels were negatively correlated with score of cognitive subdomains, including visuo-executive function and delayed recall.Conclusions: Increased serum levels of CyPA and MMP-9 are associated with MCI in OSA patients and directly related to the severity of CSVD and WMHs. The results suggest that damage to the blood-brain barrier (BBB) may be involved in the early stages of cognitive impairment in patients with OSA. [ABSTRACT FROM AUTHOR]

The purpose of our study was to investigate the correlation between neural-derived plasma exosomal amyloid-β (Aβ)42, total tau (T-tau) and tau phosphorylated at threonine 181 (P-T181-tau) protein levels and cognitive impairment in patients with obstructive sleep apnea (OSA). There were 122 subjects without dementia included in the study: 27 patients with OSA and mild cognitive impairment (MCI), 52 OSA patients without MCI, and 43 subjects diagnosed with simple snoring but not MCI as the control group. Neuronal-derived exosomal proteins were measured by ELISA kits for Aβ42, T-tau and P-T181-tau. The cognitive function was evaluated by a Chinese version of the Montreal Cognitive Assessment (MoCA) questionnaire, and a normal cognitive score was ≥26. The exosomal Aβ42, T-tau and P-T181-tau levels in the OSA with MCI group were higher than those in the OSA group. The Aβ42, T-tau, and P-T181-tau levels in the plasma neuronal-derived exosomes were associated with an increased risk of cognitive impairment in OSA patients after additional adjustment for age, gender, education, vascular risk factors, apnea–hypopnea index (AHI) or oxygen reduction index (ODI). Furthermore, there were also significant associations between Aβ42, T-tau, and P-T181-tau in neural-derived plasma exosomes and Epworth Sleepiness Scale, AHI, and ODI in OSA patients. After 1 year of continuous positive airway pressure (CPAP) intervention, the neuronal-derived exosome levels of Aβ42, T-tau, and P-T181-tau were significantly lower than those at baseline (P = 0.001, P = 0.012, and P = 0.034). These findings indicate that peripheral blood levels of neuronal-derived exosomal Aβ and tau proteins were increased in OSA patients with cognitive impairment. CPAP interventions could possibly improve cognitive function and be associated with decreased levels of exosomal Aβ and tau proteins. • Exosomal Aβ and tau proteins were increased in OSA and OSA with MCI patients. • Exosomal Aβ and tau proteins levels were correlated with ESS and MOCA scores in OSA patients. • CPAP interventions could be decreases the exosomal Aβ and tau levels in OSA patients. [ABSTRACT FROM AUTHOR]

• Plasma NDEs EAAT2 level in obstructive sleep apnea patients were higher than heathy controls. • Plasma NDEs EAAT2 level is independently related to mild cognitive impairment in obstructive sleep apnea without dementia. • One year after CPAP treatment, plasma NDEs EAAT2 level was significantly lower compared with baseline. Increasing evidence supports a link between obstructive sleep apnea (OSA) and cognition, and the mechanism is complex and still not well understood. We analyzed the relationship between the glutamate transporters and cognitive impairment in OSA. For this study 317 subjects without dementia, including 64 healthy controls (HCs), 140 OSA patients with mild cognitive impairment (MCI) and 113 OSA patients without cognitive impairment were assessed. All participants who completed polysomnography, cognition and white matter hyperintensity (WMH) volume were used. Plasma neuron-derived exosomes (NDEs) excitatory amino acid transporter 2 (EAAT2) and vesicular glutamate transporter 1 (VGLUT1) proteins were measured by ELISA kits. After 1 year of continuous positive airway pressure (CPAP) treatment, we analyzed plasma NDEs EAAT2 level and cognition changes. Plasma NDEs EAAT2 level was significantly higher in OSA patients than in HCs. Higher plasma NDEs EAAT2 level were significantly associated with cognitive impairment than normal cognition in OSA patients. Plasma NDEs EAAT2 level was inversely associated with the total Montreal Cognitive Assessment (MoCA) scores, visuo-executive function, naming, attention, language, abstraction, delayed recall and orientation. One year after CPAP treatment, plasma NDEs EAAT2 level (P = 0.019) was significantly lower, while MoCA scores (P = 0.013) were significantly increased compared with baseline. Upregulation of neuronal glutamate transporters at baseline may reflect a self-compensatory mechanism to prevent further neuronal damage, while plasma NDEs EAAT2 level was decreased after one year of CPAP therapy, which may be due to the loss of astrocytes and neurons. [ABSTRACT FROM AUTHOR]

• C8G levels in obstructive sleep apnea patients were higher than the controls. • C8G is independently related to mild cognitive impairment in obstructive sleep apnea. • C8G is linked with all cognitive subdomains in obstructive sleep apnea. • C8G is linearly positively correlated with white matter hyperintensity volumes. The complement system plays a crucial role in cognitive impairment in obstructive sleep apnea (OSA). The present study aimed to investigate the connections between complement component 8 gamma (C8G) levels in astrocyte-derived exosomes (ADEs) and cognitive impairment in OSA patients without dementia. This cross-sectional cohort study recruited 274 participants without dementia, including 124 OSA patients with mild cognitive impairment (MCI), 100 OSA patients without MCI, and 50 healthy control subjects. Enrolled participants underwent polysomnography (PSG) evaluation, neuropsychological scale assessment, magnetic resonance imaging scanning, and collection of peripheral blood samples for quantification of complement proteins in ADEs. The findings showed higher C8G concentrations in ADEs from OSA patients with MCI than in the controls and OSA without MCI group. Logistic regression analysis suggested that C8G levels in ADEs were independently associated with MCI in OSA patients. Multivariable linear regression analysis demonstrated that C8G levels in ADEs were significantly correlated with global cognitive scores and all cognitive subdomain scores after adjusting for demographic factors (age, sex, education), vascular risk factors (Body mass index, history of hypertension, diabetes, dyslipidemia), depressive symptoms measures, and apnea-hypopnea index (AHI) values. The levels of C8G were linearly positively related to the white matter hyperintensity (WMH) volumes in Pearson's correlation analysis. Our research confirmed that C8G levels are significantly associated with cognitive impairment in OSA patients, which paves the way for novel therapeutic targets for neurocognitive dysfunction progression in OSA patients in the future. [ABSTRACT FROM AUTHOR]