Abstract
Obstructive sleep apnea (OSA) is a severe sleep disorder associated with intermittent hypoxia and sleep fragmentation. Cognitive impairment is a signifi- cant and common OSA complication often described in such patients. The most commonly utilized methods in clinical OSA treatment are oral appliances and continuous positive airway pressure (CPAP). However, the current therapeutic methods for improving cognitive function could not achieve the expected efficacy in same patients. Therefore, further understanding the molecular mechanism behind cognitive dysfunction in OSA disease will provide new treatment methods and targets. This review briefly summarized the clinical manifestations of cognitive impairment in OSA disease. Moreover, the pathophysiological molecular mechanism of OSA was outlined. Our study concluded that both SF and IH could induce cognitive impairment by multiple signaling pathways, such as oxidative stress activation, inflammation, and apoptosis. However, there is a lack of effective drug therapy for cognitive impairment in OSA. Finally, the therapeutic potential of some novel compounds and herbal medicine was evaluated on attenuating cognitive impairment based on certain preclinical studies.
1. Introduction
Obstructive sleep apnea (OSA) is a common sleep disorder characterized by intermittent hypoxia (IH) and sleep fragmentation (SF) due to upper airway collapse during sleep (Hoyos et al., 2017). Clinical studies indicate that OSA has a high incidence rate, with an estimated prevalence of 7% among adult men and 2–5% among adult women (Lumeng and Chervin, 2008). OSA patients have many symptoms related cognitive impairment, including spatial learning and memory impairment, executive function decline, and behavioral changes (Patel and Chong, 2021).
The most commonly used methods in the clinical treatment of OSA are oral appliances, surgery, and continuous positive airway pressure (CPAP) (Li et al., 2019; Toraldo et al., 2019). However, these methods have their shortcomings. First, surgical treatment must be strictly applied, as it needs to consider other factors, including apnea-hypopnea index (AHI), age, and mental state (). Second, although oral appliances and CPAP are commonly used practices for OSA therapy, it is ineffective in some patients. Some patients refuse to use them due to uncomfortable feelings (). Finally, cognitive impairment or cognitive dysfunction could not be fully recovered in OSA patients through current therapy methods (). For example, one clinical trial described that most of scores neuropsychological tests for did not significantly improve after CPAP treatment in OSA patients (). It is consistent with other RCTs demonstrating that CPAP treatment did not depict overall beneficial cognitive effects (Hui et al., 2000; Lim et al., 2007). Therefore, an in-depth understanding of the molecular mechanism of cognitive dysfunction in OSA disease will provide new treatment methods and targets. This article reviews the progress mechanism of cognitive dysfunction in OSA patients and summarizes some novel compounds and herbal medicine for treating cognitive impairment due to OSA.
2. Disease definition
Overnight polysomnography (PSG) is the standard diagnostic test for obstructive sleep apnea (St Louis, 2010). During PSG, electroencephalogram, electrooculogram, electromyogram, oronasal airflow, and oxyhemoglobin saturation can identify sleep stages, airflow, respiratory effort, body position, limb movements, ECG, and oxygen saturation. Whether the pharyngeal collapse is completely blocked or not, it is called sleep-related apnea and hypopnea, respectively (Jordan et al., 2014). An apnea is the complete cessation of airflow for at least 10 s. Hypopnea is defined as airflow reduction. “Obstructive” means breathing is frequently interrupted by upper airway obstruction, and more than 90% of airflow is reduced. AHI measures the number of apneas and hypopneas per hour of sleep to assess the severity of OSA disease. Based on the guidelines of the American Academy of Sleep Medicine (AASM), AHI < 5 indicates no disease, 5 ≤ AHI < 15 depicts a mild disease, 15 ≤ AHI < 30 represents a moderate disease, and AHI ≥ 30 characterizes a severe disease form (Muraja-Murro et al., 2014).
3. Symptoms of cognitive impairment in OSA
Obstructive sleep apnea is commonly associated with cognitive impairments, such as attention, verbal and visual episodic memory, and executive function (Sateia, 2003; ). A meta-analysis revealed that vigilance, motor coordination, and executive functions were significantly impaired in OSA adults, whereas intelligence, verbal, and visual perceptual abilities were unaffected (). Some studies have characterized attention (; ; Vanek et al., 2020), episodic memory, working memory, and executive functions (Olaithe and Bucks, 2013) as the most affected cognitive domains in OSA.
3.1. Attention
Attention refers to the psychological abilities of people to focus on relevant stimuli. Attention processing involves multiple aspects, such as reaction time, selective attention, and divided attention (). These processes are associated with midline frontal areas and dorsolateral prefrontal cortices (Muller-Oehring and Schulte, 2014). Several studies have indicated that OSA subjects have attention impairment in all aspects (; ; Vanek et al., 2020). For instance, OSA patients have more lapses and longer reaction times in tasks demanding sustained attention (Mazza et al., 2005; ; Karimi et al., 2015) while significantly less reaction time after CPAP treatment (). Furthermore, according to the Test of Attentional Performance (TAP), OSA patients manifest deficits in divided and selective attention processes (; ).
3.2. Executive function
Executive function is an individually controlled and conscious effort to escort the operation of various cognitive processes. These include different cognitive abilities, such as concept formation, decision-making, mental flexibility, and problem-solving. A meta-analysis reported that executive functions across multiple tasks were impaired among OSA patients (Olaithe and Bucks, 2013).
Concept formation is a high cognitive function often operationalized as transferring the matching rule to new stimuli in a matching-to-sample task (Sukova et al., 2013). Concept formation is clinically assessed using the Wechsler Adult Intelligence Scale-Revised (WAIS-R) with these subtests: information, digit span, similarities, picture completion, block design, and digit symbol. WAIS-R demonstrated that OSA subjects had poorer scores than controls on block design, digit symbol, and picture completion (Saunamaki et al., 2009a,b, 2010). However, CPAP treatment did not significantly improve neuropsychological assessment (Saunamaki et al., 2009b,2010).
Decision-making is reaching decisions assessed with the Iowa Gambling Task (IGT), in which participants select cards from one of four decks. IGT characterized that scores were significantly lower in patients than in controls (). Furthermore, a higher rate of road traffic accidents was observed in OSA patients, impairing decision-making (Udholm et al., 2022). Moreover, OSA patients are inattentive, showing reduced reaction times on choice reaction tests () and decreased brain activation during an attention task involving decision-making leading to mistakes while driving ().
Mental flexibility is an essential executive function underlying the ability to adapt to changing situations and respond to new information. Several investigations demonstrated a significant reduction of mental flexibility in OSA subjects (Verstraeten and Cluydts, 2004; Olaithe and Bucks, 2013). Meanwhile, the speed of mental flexibility was also enhanced after CPAP treatment ().
Problem-solving is evaluating and selecting a sequence of actions to achieve a goal clinically assessed by tower test with more steps for OSA patients to solve problems (Naegele et al., 1995). Additionally, a deficit of executive functions in other aspects was observed in OSA patients, including easy impulsivity, reduced processing speed, and elevated perseverance.
3.3. Working memory
Working memory is the cognitive system temporarily maintaining and storing information, a short-term memory. Working memory impairment is always observed in OSA (; Lau et al., 2015). Although the underlying mechanism is not fully classified, it could be related to the damage of frontoparietal connectivity since complete working memory tasks recruited a frontoparietal network of brain areas (Owen et al., 2005). A neuroimaging study revealed that the functional connectivity of the frontoparietal network showed abnormality in OSA patients (Liu et al., 2022).
3.4. Episodic memory
Episodic memory is remembering verbal or visual information in a space-time long-term memory. Multiple tasks could assess the ability of episodic memory, such as immediate recall, total recall for multiple steps or learning, delayed recall, free recall, and auditory task. OSA patients suffered impairment in free recall, delayed free recall, and transformed auditory span (Naegele et al., 2006). Moreover, based on the visuospatial episodic memory tasks results, there was a deficit in immediate and delayed recalls (Wallace and Bucks, 2013). Although CPAP improved the immediate and delayed memory performances, it could not ameliorate all the episodic memory components (; ).
As discussed above, multiple cognitive ability was affected in OSA patients. However, OSA prevalence varied between 11 and 71% with cognitive impairment which was affected by OSA diagnostic methods. For example, the prevalence rates of cognitive impairment in OSA were 11, 27, 59, and 71%, respectively detected by self-report, home sleep apnea testing, Berlin questionnaire and polysomnography (Mubashir et al., 2019). Furthermore, the prevalence of cognitive impairment in OSA is related with other factors, such as severity of OSA, age and gender. Patients POSSESSING moderate to severe OSA had more severe sleep disturbances and a lower score on delayed recall test than the mild OSA group (). Moreover, age is a significant risk factor for cognitive decline. Therefore, middle-aged OSA individuals are more likely to suffer cognitive impairment than younger ones with the similar severity of OSA (; Mathieu et al., 2008). Although several previous studies have assessed the gender-specific relationship between OSA and cognitive impairment, the conclusion need more consistency. One study described that female OSA patients had a higher risk of possessing poor prospective memory (Qiu et al., 2022). Meanwhile, OSA in women significantly reduced cortical and subcortical white matter than in men (Macey et al., 2012). However, another study indicated OSA men displayed had decreased power of extensive frequency range (sigma, beta and gamma) during sleep than in women, which plays a critical role in cognition formation (Munoz-Torres et al., 2020).
4. Pathophysiology of cognitive impairment in OSA
The causal mechanism of cognitive impairment remains debatable, and the existing literature has been primarily descriptive rather than based on well-defined theories. SF and intermittent blood gas abnormalities have been the most immediate physiological disturbances. They are associated with the exaggerated enhancement in upper airway resistance with sleep onset in OSA patients (Lin et al., 2019). Therefore, SF and IH are the two independent factors affecting cognitive function in OSA patients (Sforza and Roche, 2012).
4.1. Sleep fragmentation
Sleep fragmentation refers to sleep architecture disruption in OSA disease with poor sleep efficiency in OSA patients. This included a smaller proportion of sleep period time and reduced slow-wave sleep (SWS) (Walter et al., 2011). SF in OSA patients results in significant cognitive impairments, such as decreased mental flexibility, sustained attention, and spatial memory (Stepanski, 2002; ). However, the underlying mechanisms remain poorly understood. The primary theory is that SF elicits oxidative stress and cellular damage (Shamsuzzaman et al., 2003). Since increased antioxidant activity promotes brain protection against free radicals during sleep, and wakefulness, reactive oxygen species (ROS) and other oxidative stress markers could be accumulated in the brain tissue (Mamelak, 2022). A study reported spatial learning deficits in mice exposed to SF by significantly activating oxidative stress. This could be associated with NADPH oxidase activity since mice without NADPH oxidase had normal learning after SF exposure (Nair et al., 2011b). NADPH oxidase is a vital source of generating intracellular ROS. SF could induce oxidative stress by activating NADPH oxidase to impair cognition and learning ability. The activity of nitric oxide synthase (iNOS), which regulate electron flow to enhance ROS production, was also increased in the SF model (Pandey and Kar, 2018). Then, oxidative stress results in cognitive impairment by inhibiting some neurotrophic factors expression and antioxidant genes, including BDNF and Nrf-2 (Zhang et al., 2013; Lee et al., 2022). Some synapse proteins, such as growth-associated protein 43 (GAP-43), post-synaptic density-95 (PSD-95), synapsin 1 (SYN-1), and synaptophysin (SYP), were also inhibited by SF-induced oxidative stress ().
Sleep fragmentation could also trigger an inflammatory response (Mishra et al., 2022). SF induced the expression of pro-inflammatory cytokines, such as IL-1 and TNF-α (). On the other hand, long-term SF could cause vascular endothelial dysfunction by enhancing the recruitment of inflammatory cells and IL-6 expression (). In the SF model, multiple signaling pathways were responsible for pro-inflammatory cytokines expression, such as Toll-like receptor 4 (TLR4)/myeloid differentiation primary response protein 88 (MyD88) pathway (Xu et al., 2021b), TNF-α/NF-κB pathway (Zhang et al., 2022) and p38 MAPK pathway (). One report indicated that SF could activate some microglial expression, vital in the inflammatory response (Kaneshwaran et al., 2019). Additionally, SF induced a selective increase in pro-inflammatory M1 macrophages by enhancing the NADPH oxidase 2 (NOX2) activity (Zhang et al., 2014).
Furthermore, SF significantly reduced rapid eye movement (REM) sleep in the SF rodent model, which is associated with impairing spatial learning and the losing the NMDA receptors (Tartar et al., 2006). Therefore, the loss of the NMDA receptor could be another underlying mechanism of inducing cognitive impairment in the SF model. SF could also disrupt neurotransmitter release, such as adenosine, monoamine, and dopamine (Ramesh et al., 1999; Proenca et al., 2014). Adenosine receptor antagonists could attenuate the decline in memory-induced sleep deprivation by increasing BDNF expression in the hippocampus region (). Activating the dopaminergic D2 receptor helped counteract memory impairment in the sleep deprivation model (Proenca et al., 2014; Figure 1).
FIGURE 1
4.2. Intermittent hypoxia
Intermittent hypoxia (IH) is also a substantial variable associated with cognitive deficits (). However, IH and SF simultaneously occur in OSA, dissecting the influences of these two factors on cognitive functions, which is challenging in human subjects. An IH animal model was developed to assess the neurobehavioral effects of IH in the absence of SF, which many researchers widely accepted (; Row et al., 2002). Multiple mechanisms, including oxidative stress, inflammation, apoptosis, and reduction of neurotrophic factor, have been proposed to induce neurocognitive deficits due to IH (Figure 2).
FIGURE 2
4.2.1. Oxidative stress
Previous studies have demonstrated increased oxidative stress in OSA, including MDA and protein carbonyl upregulation (Xu et al., 2015), excessive lipid peroxidation production (Maniaci et al., 2021) and decline of reduced glutathione (). Therefore, inhibiting oxidative stress is a potential therapeutic target. Under IH conditions, ROS production, as indicated by oxidative stress, is elevated due to the reduced activity of oxidoreductases in mitochondrial respiration (Xu et al., 2020). Then, elevated ROS could affect some important gene expression, such as heme oxygenase-1 (HO-1), hypoxia-inducible factor-1α (HIF-1α), and NF-κB, which also aggravate oxidative stress (Lavie, 2012). For example, stabilizing HIF-1α by IH promotes ROS synthesis in mitochondria to induce apoptosis. The inhibition of HIF-1α can reduce neuronal apoptosis (). In addition, Beta-secretase 1 (BACE1), as a primary agonist to generate amyloid β (Aβ), is activated by HIF-1α. Therefore, OSA patients were highly associated with Alzheimer’s (). Finally, increased HIF-1α production disrupts long-term potentiation (LTP) of the hippocampus and impaired spatial memory function by downregulating the N-methyl d-aspartate receptor (NMDAR) (). Thus, HIF-1α could be a potential target for future OSA therapy.
Other than altering the expression of some genes, oxidative stress could cause mitochondrial dysfunction since ROS is primarily generated in mitochondria. In IH conditions, enhanced ROS production inhibits the electron transport chain activity in mitochondria and damages mitochondrial function (Prabhakar, 2011). However, suppressing ROS production rescued the mitochondrial morphology and function in the brain (Xu et al., 2015). A previous study observed a significant correlation between OSA severity and a significant decrease in mitochondrial DNA (mtDNA) copy number in OSA patients associated with oxidative stress (Kim et al., 2014). This finding is consistent with another study that revealed that mitochondrial bioenergetics are impaired in the frontal brain regions in OSA patients (Vakulin et al., 2022).
Furthermore, ER is another region partially producing ROS. Approximately 25% of ROS are derived from the ER and are required for oxidative protein folding (). Furthermore, an oxidative environment favors protein folding, particularly the formation of disulfide bonds between two cysteine residues in proteins through thiol oxidation. Therefore, increased ROS production may lead to ER homeostasis loss and accumulation of misfolded proteins. This process is called ER stress (Mello et al., 2016). Moreover, additional synthesis of misfolded or unfolded proteins could deplete glutathione (GSH) due to ER stress (Tu and Weissman, 2002). After GSH is utilized, the oxidizing environment facilitates the reoxidation of protein thiols by interacting with protein disulfide isomerase (PDI) and endoplasmic reticulum oxidoreduction (ERO-1) (). These steps lead to repetitive cycles of disulfide bond breakage and formation, with each process generating additional ROS as a byproduct (Higa and Chevet, 2012). This evidence strongly implies that ER stress and ROS could reciprocally activate each other under chronic IH conditions. Increased oxidative and ER stress levels were confirmed by our previous works, contributing to the impairment of learning and memory by inducing neuronal apoptosis (Xu et al., 2015, 2021a). Thus, decreasing oxidative stress could attenuate cognitive deficits induced by hypoxia.
4.2.2. Inflammation
A large number of inflammatory cytokines, such as interleukin (IL)-1, IL-6, IL-8, tumor necrosis factor-α (TNF-α), nuclear factor kappa B (NF-κB), etc., are activated in OSA patients (Liu et al., 2020). Although many factors could be implicated in the activation and progression of inflammation in OSA patients, a close relationship exists between inflammation and chronic IH ().
Hypoxia-inducible factor-1α, induced under IH condition, could increase NO synthesis by activating iNOS gene expression. NO is critical in initiating and regulating the inflammatory process (). Then, excessive NO generation induced by IH could enhance neuronal apoptosis in the hippocampal CA1 region by generating lipid peroxidation (Yuan et al., 2015b). Moreover, the pro-inflammatory transcription factor NF-κB was enhanced in neutrophils and monocytes of OSA patients (Htoo et al., 2006). Meanwhile, IH treatment increased NF-kB expression in hippocampal neurons of rodent OSA model (; Zhang C. Q. et al., 2021). However, the underlying mechanism was not elusive, with two significant explanations. One is that ROS could directly elevate NF-κB expression by activating the phosphorylation of IκBα and releasing p50 and RelA, binding to the DNA-binding domains of NF-κB and activating NF-κB transcription (Hayden and Ghosh, 2008). Another reason is that the dysregulation of leptin levels in OSA patients could increase the production of TNF-α, stimulating NF-κB activity ().
How could these inflammatory cytokines aggravate cognitive deficits in chronic IH? There were two major theories to classify the inflammation mechanism leading to cognitive impairment under the IH condition. One is activating microglia-mediated neuroinflammation. Microglia, as inflammatory cells in the CNS, were also activated, leading to in neurocognitive and behavioral deficits caused by the IH of the animal model. IH exposure could significantly increase the density and morphological features of microglia, secreting cytokines such as IL-1β, IL-6, TNF-α, adhesion molecules, and other signaling mediators (Kiernan et al., 2016). These high cytokine levels produced by microglia can aggravate neuronal axon and synaptic damage, impairing the integrity of white matter across multiple brain regions (Hong et al., 2016). BDNF levels, crucial in neural plasticity, were decreased under IH conditions (Xie et al., 2010). Although pro-BDNF was partially released by microglia, pro-BDNF cannot change into BDNF during the persistent inflammatory phase to impair spatial memory performance (Mohammadi et al., 2020). Increasing BDNF expression can improve synaptic plasticity and decrease apoptosis caused by IH (Yin et al., 2015).
The mRNA levels of toll-like receptors-4 (TLR-4) were significantly upregulated by IH (Smith et al., 2013). Meanwhile, the monocytes from OSA patients significantly increased TLR-4 surface expression (). Therefore, TLR4 is an essential factor in IH-induced inflammation, produced by glial cells, and promotes inflammatory disorders. Glial cells are another significant category of cells activated by the IH condition (Liu et al., 2020). Then, the NF-κB signaling pathway can be activated by TLR4, enhancing the release of TNF-α and IL-1β. Moreover, TLR4 could bind with myeloid differentiation protein (MyD88) to induce cell apoptosis (Xue et al., 2017). Meanwhile, suppressing TLR4 expression could attenuate IH-induced neuronal apoptosis ().
The nucleotide-binding domain-like receptor protein 3 (NLRP3) is a necessary inflammation interacting with procaspase-1 and apoptosis-associated speck-like protein (ASC) within the NLRP3 inflammation complex. Then, it leads to the release of caspase-1 and IL-1β (He et al., 2016). A recent study indicated that the NLRP3 inflammasome expression was increased in the brain tissue after IH treatment (She et al., 2022). Meanwhile, NLRP3 deletion elicited neuroprotection against IH treatment eliminating damaged mitochondria and reducing oxidative stress levels (Wu et al., 2021). Finally, inhibiting the NLRP3 inflammasome could suppress neuroinflammation and enhance cognitive function which was impaired by IH (Zhang et al., 2023). Therefore, NLRP3 inflammasome may be a potential target to ameliorate cognitive impairment.
4.2.3. Apoptosis
Many factors involved apoptosis under IH conditions, including oxidative stress, ER stress, and inflammation response (; ; Xu et al., 2015, 2021a). However, there were also other signaling pathways involved in IH-induced apoptosis. For instance, cyclic AMP response element-binding protein (CREB) activity decreased in the hippocampal CA1 after IH exposure with increased cleaved caspases-3-positive cells. Meanwhile, enhanced phosphorylation of CREB could attenuate IH-induced neurocognitive impairments by suppressing neuronal apoptosis (Wang et al., 2015). Moreover, IH-induced autophagy attenuates apoptosis by activating AMP-activated protein kinase (AMPK) and enhancing the expression levels of Bax and cleaved caspase 3. Furthermore, 3-methyladenine, as an autophagy inhibitor, could suppress these alterations (Guo et al., 2021). More factors and signaling pathways would be associated with IH-induced apoptosis with further research.
5. Current drug therapies for neurocognitive dysfunction in OSA patients
Presently, some drugs are adjunctive therapy for treating OSA disease, achieving good efficacy in improving cognitive impairment (Table 1).
TABLE 1
| Name | Operation mode | Research design | Diagnosis | Treatment method | Treatment duration | Outcome | References | |
| Treatment group (n) | Control group (n) | |||||||
| Modafinil | Oral administration | Randomized controlled trial | Polysomnography | Modafinil (200 mg/day) (77) | Placebo (80) | 4 weeks | Improved performance on a test of behavioral alertness and reduced functional impairments | |
| Oral administration | Randomized controlled trial | Polysomnography | Modafinil (400 mg/day) (77) | Placebo (80) | 4 weeks | Normalized daytime sleepiness, reduce the incidence of headache, nervousness | Pack et al., 2001 | |
| Oral administration | Open-label trial | Polysomnography | Modafinil (200-400 mg/day) (58) | Placebo (67) | 12 weeks | Reduced daytime sleepiness | Schwartz et al., 2003 | |
| Oral administration | Randomized controlled trial | Polysomnography | Modafinil (100 mg/day) (9) | Placebo (11) | 4 weeks | Reduced daytime sleepiness | ||
| Oral administration | Randomized controlled trial | Polysomnography | Modafinil (200 mg/day) (62) | Placebo (52) | 4 weeks | Reduced daytime sleepiness | Inoue et al., 2013 | |
| Oral administration | Randomized controlled trial | Polysomnography | Modafinil (400 mg/day) (30) | Placebo (30) | 7 weeks | A significant improvement in alertness | Kingshott et al., 2001 | |
| Armodafinil | Oral administration | Randomized controlled trial | Polysomnography | Armodafinil (150 mg/day) (129) | Placebo (130) | 12 weeks | Improved alertness, overall clinical condition, and long-term memory | Hirshkowitz et al., 2007 |
| Oral administration | Randomized controlled trial | Polysomnography | Armodafinil (150 mg/day) (35) | Placebo (34) | 6 weeks | Improved driving safety performance and sleep quality | Kay and Feldman, 2013 | |
| Oral administration | Randomized controlled trial | Polysomnography | Armodafinil (150 mg/day) (133), Armodafinil (250 mg/day) (131), | Placebo (130) | 12 weeks | Improved sleep latency | Roth et al., 2006 | |
| Oral administration | Randomized controlled trial | Polysomnography | Armodafinil (200 mg/day) (20) | Placebo (19) | 2 weeks | Reduced sleepiness, improved the performance on standardized memory and attention | Greve et al., 2014 | |
| Atomoxetine and Oxybutynin | Oral administration | Randomized controlled trial | Polysomnography | Atomoxetine (80 mg/day) and Oxybutynin (5 mg/day) (10) | Placebo (10) | 1 days | Reduced the number of obstructive events, improved the overnight oxygen desaturation and enhanced the genioglossus muscle activity | Taranto-Montemurro et al., 2017b |
| Oral administration | Randomized controlled trial | Polysomnography | Atomoxetine (80 mg/day) and Oxybutynin (5 mg/day) (7) | Placebo (7) | 7 days | Improved the measures of upper airway collapsibility, increased breathing stability, and slightly reduced the arousal threshold | Taranto-Montemurro et al., 2020 | |
| Fluticasone | Nasal spray | Randomized controlled trial | Polysomnography | Fluticasone (55 μg) (40) | Placebo (40) | 90 days | Decreased rhinorrhea and congestion symptoms | Segsarnviriya et al., 2021 |
| Fluticasone and montelukast | Nasal spray (Fluticasone) and Oral (montelukast) | Randomized controlled trial | Polysomnography | Fluticasone (55 μg) (13) | Placebo (13) | 12 weeks | Increased sleep time and percent of REM sleep | Smith et al., 2019 |
| Budesonide | Nasal spray | Randomized controlled trial | Polysomnography | Budesonide (64 μg) (18) | Placebo (25) | 6 weeks | Improves sleep latency, slow-wave sleep, and REM sleep | Kheirandish-Gozal and Gozal, 2008 |
| Tiagabine | Oral administration | Randomized controlled trial | Polysomnography | Tiagabine (12 mg) (7) | Placebo (7) | 3 days | Increased slow-wave sleep | Taranto-Montemurro et al., 2017 |
| γ-hydroxybutyrate | Oral administration | Self-controlled trial | Polysomnography | γ-hydroxybutyrate (12 mg) (8) | Placebo (8) | 3 days | Increase in slow-wave sleep and non-REM sleep time | Series et al., 1992 |
Summary of the drug medicine treated for OSA in clinical trials.
5.1. Modafinil
Modafinil is a novel wake-promoting agent that improves wakefulness in various clinical models. The American Academy of Sleep Medicine has recommended modafinil as a ‘golden standard’ treatment for this patient population (Littner et al., 2001). Modafinil is used as an adjunct therapy in OSA disease. A randomized, double-blind, placebo-controlled trial indicated that modafinil improved performance on behavioral alertness tests and reduced functional impairments in OSA patients assessed using the psychomotor vigilance task (PVT) and the Functional Outcomes of Sleep Questionnaire (). Meanwhile, modafinil also reduces the incidence of adverse events, including headaches, nervousness (Pack et al., 2001), and daytime sleepiness (Schwartz et al., 2003; ; Inoue et al., 2013). Although modafinil did not affect sleepiness measured by the Epworth Sleepiness Scale or the Multiple Sleep Latency Test, a significant improvement in alertness was observed on the Maintenance of Wakefulness Test (Kingshott et al., 2001).
5.2. Armodafinil
Armodafinil is the (R)-enantiomer of the wake-promoting compound modafinil, approved for treating excessive sleepiness, OSA, and shift work disorder (Nishino and Okuro, 2008). In this 12-week, randomized, double-blind study, armodafinil significantly enhanced episodic secondary memory, patient-estimated wakefulness, and decreased fatigue with fewer adverse events (Hirshkowitz et al., 2007). Furthermore, armodafinil enhanced simulated driving safety performance in OSA patients awaiting CPA therapy (Kay and Feldman, 2013). Although the underlying mechanism is elusive, one study indicated that it could be related to increased sleep latency (Roth et al., 2006). However, no significant differences were observed in armodafinil treatment for 2 weeks compared with the placebo group according to the 2-back working memory task. Meanwhile, the neuroimaging study also indicated that armodafinil could not improve functional magnetic resonance imaging (fMRI)-measured functional brain activation (Greve et al., 2014). Another clinical trial also described that 6 months of armodafinil treatment could not improve driving task performance but affected weight loss (). Therefore, armodafinil did not improve all the cognitive ability aspects.
5.3. Anti-inflammatory drugs
Inflammation is essential in cognitive impairment, with some anti-inflammatory drugs used in clinical trials. Though AHI and rhinorrhea symptoms in OSA patients significantly decreased after treatment with intranasal fluticasone propionate, a common corticosteroid, cognitive function was not assessed (Kiely et al., 2004; Segsarnviriya et al., 2021). Montelukast, a leukotriene receptor antagonist, also affects reducing AHI (). Although fluticasone and montelukast did not decrease AHI in one study, total sleep time and percent of rapid eye movement (REM) sleep were significantly elevated (Smith et al., 2019). Additionally, intranasal budesonide, another effective anti-inflammatory drug, enhances sleep latency, SWS, and REM sleep among children (Kheirandish-Gozal and Gozal, 2008). However, these clinical trials did not reveal the effect of anti-inflammatory drugs on cognitive function, which needs further investigation.
5.4. Atomoxetine
Atomoxetine is a selective norepinephrine reuptake inhibitor reducing hypoglossal motoneuron excitability by blocking G-coupled inwardly rectifying the potassium channels (Taranto-Montemurro et al., 2017a). Oxybutynin is an antimuscarinic with mixed effects on suppressing exceeding nicotinic excitation (Liu et al., 2005). One study demonstrated that a combination of atomoxetine with oxybutynin could decrease the number of obstructive events, enhance the overnight oxygen desaturation, elevate the genioglossus muscle activity, and reduce AHI (Taranto-Montemurro et al., 2019, 2020). However, the effect of atomoxetine and oxybutynin on reducing cognitive function is still unknown.
5.5. Tiagabine
Tiagabine is a γ-aminobutyric acid (GABA) reuptake receptor inhibitor increasing GABA concentration at the synaptic level of the central nervous system. Tiagabine enhanced slow-wave activity (SWA) (Taranto-Montemurro et al., 2017b) with a crucial cognitive role (Wilckens et al., 2018). On the other hand, γ-hydroxybutyrate derived from GABA also increases SWS and REM sleep time (Series et al., 1992).
5.6. Desipramine
Desipramine is a common tricyclic antidepressant reducing the sleep-related loss of genioglossus activity and improving pharyngeal collapsibility (Taranto-Montemurro et al., 2016a). A placebo-controlled, double-blind, randomized trial described that desipramine could mitigate the sleep-related loss of muscle activity and AHI (Taranto-Montemurro et al., 2016b). There is direct evidence to enhance the protective effect on rescuing the cognition ability of OSA patients. However, some literature depicts that desipramine improves working memory (; Wang et al., 2016). The impact of desipramine on improving cognition ability in OSA requires further investigation. Furthermore, other neurological drugs, such as physostigmine and mirtazapine, could reduce the AHI in diabetes patients. However, these studies did not investigate whether these drugs could improve cognitive function (Hedner et al., 2003; ).
6. The therapeutic mechanisms of other agents to attenuate cognitive impairment due to OSA
A few drugs were used to ameliorate cognitive deficits induced by OSA. However, experimental studies on OSA animal models indicate that chemical substances and natural products from Chinese herbs improve cognitive impairment (Table 2). Based on the action and molecular target mechanisms, these compounds are divided into: anti-oxidative properties, anti- inflammatory effects and anti-apoptosis effects.
TABLE 2
| Property | Drug name | Type of study | Treatment method | Treatment duration | Outcomes | Targets or pathways | References | |
| Experiment group | Control group | |||||||
| Anti-oxidation | EPO | Intermittent hypoxia in mice (a cyclical pattern of 5.7% and 21% oxygen every 90 s) | EPO (5000 IU/kg/day, i.p., n = 24) | PBS i.p. injection (n = 24) | 12 h/day for 14 days | Improved spatial learning and attenuated oxidative stress | Elevated levels of NADPH oxidase expression | |
| Intermittent hypoxia in rat (a cyclical pattern of 5.7% and 21% oxygen every 90 s) | EPO (500, 1000 IU/kg/day, i.p., n = 10) | PBS i.p. injection (n = 10) | 12 h/day for 6 weeks | Improved spatial learning and attenuated oxidative stress | Increased glutathione levels and glutathione peroxidase activity | |||
| Edaravone | Intermittent hypoxia in rat (a cyclical pattern of 6% and 21% oxygen every 120 s) | Edaravone (5 mg/kg/day, i.p., n = 20) | Saline injection (n = 20) | 8 h/day for 4 weeks | Attenuated IH-induced cognitive impairment | Upregulated the expression of SOD and p-CREB | Ling et al., 2020 | |
| Hu A | Intermittent hypoxia in mice (5% and 21% oxygen 20 times/h) | Hu A (0.1 mg/kg/day, i.p., n = 10) | Empty liposomes (n = 10) | 8 h/day for 3 weeks | Improved cognitive impairment and resisted oxidative stress | Activated the PKAα/Erk/CREB/BDNF signaling pathway | Yang et al., 2023 | |
| GH | Intermittent hypoxia in rat (a cyclical pattern of 10% and 21% oxygen every 90 s) | GH (50 μg/kg/day, s.c., n = 8) | Vehicle injection (n = 8) | 12 h/day for 2 weeks | Attenuated IH-induced cognitive deficits | Increased the expression of IGF-1, EPO and VEGF | Li et al., 2011 | |
| JI-34 | Intermittent hypoxia in mice (a cyclical pattern of 5.7% and 21% oxygen every 90 s) | JI-34 (50 mg/kg/day, s.c., n = 12) | 0.1% DMSO in 10% aqueous propylene glycol solution (n = 12) | 12 h/day for 3 weeks | Improved neurocognitive deficits, anxiety, and depression | Increased the expression of HIF-1α and EPO | Nair et al., 2013 | |
| SFN | Intermittent hypoxia in mice (a cyclical pattern of 10% and 21% oxygen every 90 s) | SFN (0.5 mg/kg/day, i.p., n = 10) | Saline injection (n = 10) | 7 h/day for 4 weeks | Decreased memory errors and apoptosis | Downregulated cleaved PARP, cleaved caspase 3, and upregulated Bcl-2 and Nrf2 | Li et al., 2022 | |
| Anti- inflammation | Sesamol | Intermittent hypoxia in rat (a cyclical pattern of 10% and 21% oxygen every 120 s) | Sesamol (20 mg/kg/day, i.p., n = 15) | Saline injection (n = 15) | 8 h/day for 2, 4, 6,8 weeks | Improved spatial learning assessed by Morris water maze | Reduced the levels of TNF-α and IL-1β | Zhang P. et al., 2021 |
| Anti-apoptosis | TUDCA | Intermittent hypoxia in mice (10% and 21% oxygen every 90 s) | TUDCA (100 mg/kg/day, i.p., n = 15) | PBS injection (n = 15) | 8 h/day for 2, 4 weeks | Improved spatial learning and reduced apoptosis | Inhibited endoplasmic reticulum stress | Xu et al., 2015 |
| Apocynin | Intermittent hypoxia in rat (a cyclical pattern of 10% and 21% oxygen every 90 s) | Apocynin (3 mg/kg/day, i.g., n = 10) | Saline injection (n = 10) | 10 h/day for 4 weeks | Improved spatial learning and reduced apoptosis | Inhibiting NADPH oxidase | Hui-guo et al., 2010 | |
| Hu A | Intermittent hypoxia in mice (9% and 21% oxygen 20 times/h) | Hu A (0.1 mg/kg/day, i.p., n = 10) | Empty liposomes (n = 10) | 8 h/day for 3 weeks | Improved cognitive impairment and reduced apoptosis | Increased Bcl-2 and inhibited caspase-3 cleavage | ||
| PCA | Intermittent hypoxia in rat (6% and 21% oxygen every 120 s) | PCA (15 mg/kg/day, i.p., n = 15) | Saline (n = 15) | 8 h/day for 3 weeks | Enhanced learning and memory ability | Increased the expression of Bcl-2, BDNF and pro-BDNF | Yin et al., 2015 | |
| SMD | Intermittent hypoxia in mice (9% and 21% oxygen every 90 s) | SMD (5.265 g/kg/day, i.g., n = 12) | Saline (n = 12) | 8 h/day for 35 days | Enhanced learning and memory ability | Increased the expression of PSD-95 and BDNF | Zhao et al., 2021 | |
| NBP | Intermittent hypoxia in rat (9% and 21% oxygen every 90 s) | NBP (80 mg/kg/day, i.g., n = 12) | Vegetable oil (n = 12) | 8 h/day for 2 weeks | Enhanced learning and memory ability | Activated SIRT1/PGC-1a signaling pathway | Min et al., 2014 | |
The mechanisms by which some chemical substances and herbs medicine treat cognitive impairment in OSA animal model.
APOE, apolipoprotein E; DAPT, N-[N-(3,5-difluorophenacetyl)-Lalany]-S-phenylglycine t-butyl ester; DSS, dextran sodium sulfate; EPO, erythropoietin; GH, growth hormone; i.g.: intragastrically; i.p.: intraperitoneally; NBP, Dl-3n-Butylphthalide; PCA, Protocatechuic acid; p-CREB, phosphorylated-cAMP response element-binding; s.c.: subcutaneously; SFN, Sulforaphane; SMD, Shashen-Maidong Decoction; SOD, superoxide dismutase; TUDCA, Tauroursodeoxycholic acid.
6.1. Anti-oxidative property
Erythropoietin (EPO), a prototypic cytokine and hypoxia-sensitive gene, has been implicated in improving cognitive ability through multiple signaling pathways (Sanchez et al., 2009; ). For instance, mice treated with exogenously administered erythropoietin (EPO) had protection from IH-induced spatial learning deficits caused by attenuating oxidative stress responses and suppressing NADPH oxidase expression (). Another study indicated that this beneficial effect elevated glutathione levels and glutathione peroxidase activity ().
Edaravone is another potent free radical scavenger used to treat acute attacks of cerebral infarction and improve neurological symptoms with cognitive impairment. Edaravone attenuated IH-induced cognitive impairment and elevated the number of mitochondria by upregulating the expression of SOD and phosphorylated-cAMP response element-binding (p-CREB) (Ling et al., 2020).
One study revealed Huperzine A (Hu A) elevated T-SOD and GSH-Px abilities and reduced MDA content to resist oxidative stress damage with PKAα/Erk/CREB/BDNF signaling pathway (Yang et al., 2023).
Growth hormone (GH) modulates memory and cognitive functions and is impaired in OSA (). GH could attenuate IH-induced cognitive deficits by elevating the expression of IGF-1, EPO, and VEGF (Li et al., 2011). GH secretion is controlled by growth hormone-releasing hormone (GHRH) (Schussler et al., 2006). JI-34 is an agonist of GHRH, attenuating IH- induced neurocognitive deficits. The underlying mechanism is associated with increased expression of HIF-1α and EPO (Nair et al., 2013).
Sulforaphane (SFN) is extracted from cruciferous vegetables of the Brassica genus, exerting neuroprotective effects by activating autophagy or transcription factor Nrf2 (Uddin et al., 2020). SFN treatment ameliorated neurocognitive dysfunction within IH mice by downregulated cleaved PARP, cleaved caspase 3, and upregulated Bcl-2 and Nrf2 (Li et al., 2022).
6.2. Anti-inflammatory effects
Sesamol can alleviate cognitive impairments in chronic IH-exposed rats. This beneficial effect could reduce hippocampal TNF-α and IL-1β levels (Zhang P. et al., 2021).
6.3. Anti-apoptosis effects
Based on our previous research, Tauroursodeoxycholic acid (TUDCA) can decrease neuronal apoptosis and enhance hippocampal synaptic plasticity by inhibiting endoplasmic reticulum stress activation (Xu et al., 2015).
Some natural products extracted from herbal medicine are also beneficial. Apocynin is a plant drug derived from Picrorhiza kurroa. Apocynin attenuated IH-induced spatial learning deficits and oxidative stress by inhibiting NADPH oxidase subunit p47phox mRNA and ameliorating cell apoptosis (Hui-guo et al., 2010; Yuan et al., 2015a).
Hu A is isolated from the Chinese herb Huperzia serrata and could cross the blood-brain barrier (BBB). Hu A could improve cognitive impairment and neuronal damage induced by IH by increasing the Bcl-2/Bax ratio and inhibiting caspase-3 cleavage ().
Protocatechuic acid (PCA) is abundant in edible fruits and vegetables and is naturally present in various herbal medicine, including Hibiscus sabdariffa and Salvia miltiorrhiza. PCA could enhance learning and memory ability and alleviate oxidative stress and apoptosis in IH-treated rats by improving the expression of Bcl-2, BDNF, and pro-BDNF and reducing cleaved caspase-3 and IL-1β (Yin et al., 2015).
Shashen-Maidong Decoction (SMD) is an herbal formula with eight Chinese medicines [Ophiopogon japonicus (Thunb.) Ker Gawl. (9 g); Glehnia littoralis (A.Gray) F.Schmidt ex Miq. (9 g); Lablab purpureus (L.) Sweet (4.5 g); Morus indica L. (4.5 g); Polygonatum odoratum (Mill.) Druce (6 g); Trichosanthes kirilowii Maxim (4.5 g); Glycyrrhiza uralensis Fisch. Ex DC. (3 g)]. SMD treatment in a previous study improved performance assessed using the Morris Water Maze and Y-Maze test in mice exposed to IH by enhancing ERK/CREB phosphorylation and elevating PSD-95 and BDNF expression (Zhao et al., 2021).
Finally, Dl-3n-Butylphthalide (NBP) is extracted from Apium graveolens L with a broad spectrum of neuroprotective properties. One study described that NBP could inhibit apoptosis and promote IH-induced autophagy by activating the SIRT1/PGC-1a signaling pathway (Min et al., 2014).
7. Discussion
Cognitive impairment is a common symptom of OSA, irrespective of age (Vardanian and Ravdin, 2022). Neuroimaging studies depicted cerebral cortex morphology in multiple affected regions (Kizilgoz et al., 2013), with clinical impairment across various cognition aspects. Since the cognitive impairment mechanism in OSA is complex, SF and IH are significant factors activating multiple downstream signaling pathways while causing cognitive impairment (Figures 1, 2). Some signaling pathways and proteins were targeted by SF and IH, such as excessive NADPH oxidase activity (Nair et al., 2011a,b), inducing the expression of pro-inflammatory cytokines (; Liu et al., 2020) and activating the TNF-α/NF-κB pathway (; Zhang et al., 2022). These processes do not function alone and are affected by each other. For example, HIF-1α an oxidative stress marker, could activate inflammation response by inducing NO expression (). Initially, oxidative stress is induced by impaired antioxidant capacity. Then, some pro-inflammation cytokines are generated, accelerating oxidative stress injury and triggering neuronal apoptosis.
Although some traditional methods, including oral appliances, surgery, and CPAP, have improved certain aspects of cognitive functioning, they do not fully alleviate cognitive complaints (Vardanian and Ravdin, 2022). Therefore, drug therapy could enhance treatment outcomes and be used with other therapy methods. Some drugs have beneficial effects on improving sleep quality (Taranto-Montemurro et al., 2016b,2017b). However, more large clinical trials are required to validate these findings. Meanwhile, some chemical substances and herbal medicine could improve cognitive ability in animal studies, while could become a complementary method based on successful clinical trials.
8. Conclusion and perspectives
Multiple cognitive aspects are affected in OSA, which current therapy cannot improve. This review summarized the randomized controlled trials of drugs for treating OSA-related cognitive impairment. Although these drugs could improve cognition, the studies have several limitations.
First, the sample size is very small for clinical studies. There is a lack of large-scale, multicenter, randomized controlled trials on drugs treating OSA-induced cognitive impairment. Second, a wide variation occurs in the characteristics of referred patients, such as age, disease history, and disease severity. Third, the drug treatment duration is short, and the prolonged effect has yet to be investigated. Fourth, there is a lack of preclinical studies examining the possible drug targets.
Future research should be directed toward these aspects to overcome these limitations. First, some large-scale, multicenter, and controlled trials are required to determine the efficacy of these drugs. Second, standardization of the clinical drug use process should be established in treating OSA-induced cognitive impairment. Lastly, additional studies should be performed in clinical trials for some novel chemical substances and herbal medicine.
Statements
Author contributions
DH and JC wrote the manuscript. XD and LX conceptualized the research work. LX revised the manuscript. All authors read and approved the final manuscript.
Funding
This work was supported by the National Natural Science Foundation of China (No: 81601972), the Zhejiang Provincial Natural Science Foundation of China under Grant (No: LQ21H090006), the Zhejiang Province Traditional Chinese Medicine Science and Technology Projection under Grant (No: 2021ZQ071) and the Zhejiang Special Health Funding Program of Hangzhou Medical College (No: YS2022002).
Conflict of interest
The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
Publisher’s note
All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.
References
1
AbeH.SembaH.TakedaN. (2017). The roles of hypoxia signaling in the pathogenesis of cardiovascular diseases.J. Atheroscler. Thromb.24884–894. 10.5551/jat.RV17009
2
AkinnusiM.JaoudeP.KufelT.El-SolhA. A. (2013). Toll-like receptor activity in patients with obstructive sleep apnea.Sleep Breath171009–1016. 10.1007/s11325-012-0791-2
3
AlchanatisM.DeligiorgisN.ZiasN.AmfilochiouA.GotsisE.KarakatsaniA.et al (2004). Frontal brain lobe impairment in obstructive sleep apnoea: A proton MR spectroscopy study.Eur. Respir. J.24980–986. 10.1183/09031936.04.00127603
4
AlchanatisM.ZiasN.DeligiorgisN.LiappasI.ChroneouA.SoldatosC.et al (2008). Comparison of cognitive performance among different age groups in patients with obstructive sleep apnea.Sleep Breath1217–24. 10.1007/s11325-007-0133-y
5
AlkanU.NachalonY.WeissP.RitterA.FeinmesserR.GilatH.et al (2021). Effects of surgery for obstructive sleep apnea on cognitive function and driving performance.Sleep Breath251593–1600. 10.1007/s11325-020-02285-w
6
AlmendrosI.FarreR.PlanasA. M.TorresM.BonsignoreM. R.NavajasD.et al (2011). Tissue oxygenation in brain, muscle, and fat in a rat model of sleep apnea: Differential effect of obstructive apneas and intermittent hypoxia.Sleep341127–1133. 10.5665/SLEEP.1176
7
AloiaM. S.ArnedtJ. T.DavisJ. D.RiggsR. L.ByrdD. (2004). Neuropsychological sequelae of obstructive sleep apnea-hypopnea syndrome: A critical review.J. Int. Neuropsychol. Soc.10772–785. 10.1017/S1355617704105134
8
Al-QahtaniJ. M.Abdel-WahabB. A.Abd El-AzizS. M. (2014). Long-term moderate dose exogenous erythropoietin treatment protects from intermittent hypoxia-induced spatial learning deficits and hippocampal oxidative stress in young rats.Neurochem. Res.39161–171. 10.1007/s11064-013-1201-2
9
AnJ. R.ZhaoY. S.LuoL. F.GuanP.TanM.JiE. S. (2020). Huperzine A, reduces brain iron overload and alleviates cognitive deficit in mice exposed to chronic intermittent hypoxia.Life Sci.250:117573. 10.1016/j.lfs.2020.117573
10
AndradeA. G.BubuO. M.VargaA. W.OsorioR. S. (2018). The relationship between obstructive sleep apnea and Alzheimer’s disease.J. Alzheimers Dis.64S255–S270. 10.3233/JAD-179936
11
AngelelliP.MacchitellaL.ToraldoD. M.AbbateE.MarinelliC. V.AriglianiM.et al (2020). The neuropsychological profile of attention deficits of patients with obstructive sleep apnea: An update on the daytime attentional impairment.Brain Sci.10:325. 10.3390/brainsci10060325
12
Arias-CavieresA.KhuuM. A.NwakuduC. U.BarnardJ. E.DalginG.GarciaA. J.III (2020). A HIF1a-dependent pro-oxidant state disrupts synaptic plasticity and impairs spatial memory in response to intermittent hypoxia.eNeuro7ENEURO.24–ENEURO.20. 10.1523/ENEURO.0024-20.2020
13
AyalonL.Ancoli-IsraelS.AkaA. A.McKennaB. S.DrummondS. P. (2009). Relationship between obstructive sleep apnea severity and brain activation during a sustained attention task.Sleep32373–381. 10.1093/sleep/32.3.373
14
BardwellW. A.Ancoli-IsraelS.BerryC. C.DimsdaleJ. E. (2001). Neuropsychological effects of one-week continuous positive airway pressure treatment in patients with obstructive sleep apnea: A placebo-controlled study.Psychosom. Med.63579–584. 10.1097/00006842-200107000-00010
15
BeebeD. W.GroeszL.WellsC.NicholsA.McGeeK. (2003). The neuropsychological effects of obstructive sleep apnea: A meta-analysis of norm-referenced and case-controlled data.Sleep26298–307. 10.1093/sleep/26.3.298
16
BergerS.PolotskyV. Y. (2018). Leptin and leptin resistance in the pathogenesis of obstructive sleep apnea: A possible link to oxidative stress and cardiovascular complications.Oxid. Med. Cell Longev.2018:5137947. 10.1155/2018/5137947
17
BertrandS. J.ZhangZ.PatelR.O’FerrellC.PunjabiN. M.KudchadkarS. R.et al (2020). Transient neonatal sleep fragmentation results in long-term neuroinflammation and cognitive impairment in a rabbit model.Exp. Neurol.327:113212. 10.1016/j.expneurol.2020.113212
18
BhandaryB.MarahattaA.KimH. R.ChaeH. J. (2012). An involvement of oxidative stress in endoplasmic reticulum stress and its associated diseases.Int. J. Mol. Sci.14434–456. 10.3390/ijms14010434
19
BittencourtL. R.LucchesiL. M.RuedaA. D.GarbuioS. A.PalombiniL. O.GuilleminaultC.et al (2008). Placebo and modafinil effect on sleepiness in obstructive sleep apnea.Prog. Neuropsychopharmacol. Biol. Psychiatry32552–559. 10.1016/j.pnpbp.2007.10.016
20
BubuO. M.AndradeA. G.Umasabor-BubuO. Q.HoganM. M.TurnerA. D.de LeonM. J.et al (2020). Obstructive sleep apnea, cognition and Alzheimer’s disease: A systematic review integrating three decades of multidisciplinary research.Sleep Med. Rev.50:101250. 10.1016/j.smrv.2019.101250
21
BucksR. S.OlaitheM.EastwoodP. (2013). Neurocognitive function in obstructive sleep apnoea: A meta-review.Respirology1861–70. 10.1111/j.1440-1843.2012.02255.x
22
CaiS.LiZ.WangJ.WangQ.ChenR. (2023). Excessive daytime sleepiness in young and middle-aged Chinese adults with obstructive sleep apnea: Implications for cognitive dysfunction.Sleep Breath10.1007/s11325-023-02854-9[Epub ahead of print].
23
CarleyD. W.OlopadeC.RuigtG. S.RadulovackiM. (2007). Efficacy of mirtazapine in obstructive sleep apnea syndrome.Sleep3035–41. 10.1093/sleep/30.1.35
24
CarlucciA.CerianaP.ManciniM.CirioS.PierucciP.D’Artavilla LupoN.et al (2015). Efficacy of bilevel-auto treatment in patients with obstructive sleep apnea not responsive to or intolerant of continuous positive airway pressure ventilation.J. Clin. Sleep Med.11981–985. 10.5664/jcsm.5008
25
CarrerasA.ZhangS. X.PerisE.QiaoZ.Gileles-HillelA.LiR. C.et al (2014). Chronic sleep fragmentation induces endothelial dysfunction and structural vascular changes in mice.Sleep371817–1824. 10.5665/sleep.4178
26
ChapmanJ. L.CayananE. A.HoyosC. M.SerinelY.ComasM.YeeB. J.et al (2018). Does armodafinil improve driving task performance and weight loss in sleep apnea? A randomized trial.Am. J. Respir. Crit Care Med.198941–950. 10.1164/rccm.201712-2439OC
27
ChauhanG.RayK.SahuS.RoyK.JainV.WadhwaM.et al (2016). Adenosine A1 receptor antagonist mitigates deleterious effects of sleep deprivation on adult neurogenesis and spatial reference memory in rats.Neuroscience337107–116. 10.1016/j.neuroscience.2016.09.007
28
ClintonS. M.SucharskiI. L.FinlayJ. M. (2006). Desipramine attenuates working memory impairments induced by partial loss of catecholamines in the rat medial prefrontal cortex.Psychopharmacology183404–412. 10.1007/s00213-005-0221-2
29
CosentinoF. I.BoscoP.DragoV.PrestianniG.LanuzzaB.IeroI.et al (2008). The APOE epsilon4 allele increases the risk of impaired spatial working memory in obstructive sleep apnea.Sleep Med.9831–839. 10.1016/j.sleep.2007.10.015
30
CuiL.XueR.ZhangX.ChenS.WanY.WuW. (2019). Sleep deprivation inhibits proliferation of adult hippocampal neural progenitor cells by a mechanism involving IL-17 and p38 MAPK.Brain Res.171481–87. 10.1016/j.brainres.2019.01.024
31
da RosaD. P.ForgiariniL. F.SilvaM. B.FioriC. Z.AndradeC. F.MartinezD.et al (2015). Antioxidants inhibit the inflammatory and apoptotic processes in an intermittent hypoxia model of sleep apnea.Inflamm. Res.6421–29. 10.1007/s00011-014-0778-5
32
DalmasesM.Sole-PadullesC.TorresM.EmbidC.NunezM. D.Martinez-GarciaM. A.et al (2015). Effect of CPAP on cognition, brain function, and structure among elderly patients with OSA: A randomized pilot study.Chest1481214–1223. 10.1378/chest.15-0171
33
DauratA.RicarrereM.TibergeM. (2013). Decision making is affected in obstructive sleep apnoea syndrome.J. Neuropsychol.7139–144. 10.1111/j.1748-6653.2012.02039.x
34
DayyatE. A.ZhangS. X.WangY.ChengZ. J.GozalD. (2012). Exogenous erythropoietin administration attenuates intermittent hypoxia-induced cognitive deficits in a murine model of sleep apnea.BMC Neurosci.13:77. 10.1186/1471-2202-13-77
35
DengY.YuanX.GuoX. L.ZhuD.PanY. Y.LiuH. G. (2015). Efficacy of atorvastatin on hippocampal neuronal damage caused by chronic intermittent hypoxia: Involving TLR4 and its downstream signaling pathway.Respir. Physiol. Neurobiol.21857–63. 10.1016/j.resp.2015.07.006
36
DewanN. A.NietoF. J.SomersV. K. (2015). Intermittent hypoxemia and OSA: Implications for comorbidities.Chest147266–274. 10.1378/chest.14-0500
37
DingesD. F.WeaverT. E. (2003). Effects of modafinil on sustained attention performance and quality of life in OSA patients with residual sleepiness while being treated with nCPAP.Sleep Med.4393–402. 10.1016/s1389-9457(03)00108-4
38
DjonlagicI.GuoM.MatteisP.CarusonaA.StickgoldR.MalhotraA. (2014). Untreated sleep-disordered breathing: Links to aging-related decline in sleep-dependent memory consolidation.PLoS One9:e85918. 10.1371/journal.pone.0085918
39
DjonlagicI.GuoM.MatteisP.CarusonaA.StickgoldR.MalhotraA. (2015). First night of CPAP: Impact on memory consolidation attention and subjective experience.Sleep Med.16697–702. 10.1016/j.sleep.2015.01.017
40
EpsteinL. J.KristoD.StrolloP. J.Jr.FriedmanN.MalhotraA.PatilS. P.et al (2009). Clinical guideline for the evaluation, management and long-term care of obstructive sleep apnea in adults.J. Clin. Sleep Med.5263–276.
41
FarajdokhtF.VatandoustS. M.HosseiniL.FekriK.Rahigh AghsanS.MajdiA.et al (2021). Sericin protects against acute sleep deprivation-induced memory impairment via enhancement of hippocampal synaptic protein levels and inhibition of oxidative stress and neuroinflammation in mice.Brain Res. Bull.174203–211. 10.1016/j.brainresbull.2021.06.013
42
FeiW.JiaoW.FengX.ChenX.WangY. (2021). Intermittent hypoxia mimicking obstructive sleep apnea aggravates early brain injury following ICH via neuroinflammation and apoptosis.Mol. Med. Rep.24:12464. 10.3892/mmr.2021.12464
43
GagnonK.BarilA. A.GagnonJ. F.FortinM.DecaryA.LafondC.et al (2014). Cognitive impairment in obstructive sleep apnea.Pathol. Biol.62233–240. 10.1016/j.patbio.2014.05.015
44
GelirE.BasaranC.BayrakS.YagciogluS.BudakM. T.FiratH.et al (2014). Electrophysiological assessment of the effects of obstructive sleep apnea on cognition.PLoS One9:e90647. 10.1371/journal.pone.0090647
45
GeorgeC. F. (2004). Sleep. 5: Driving and automobile crashes in patients with obstructive sleep apnoea/hypopnoea syndrome.Thorax59804–807. 10.1136/thx.2003.007187
46
GianottiL.PivettiS.LanfrancoF.TassoneF.NavoneF.VittoriE.et al (2002). Concomitant impairment of growth hormone secretion and peripheral sensitivity in obese patients with obstructive sleep apnea syndrome.J. Clin. Endocrinol. Metab.875052–5057. 10.1210/jc.2001-011441
47
GoldbartA. D.Greenberg-DotanS.TalA. (2012). Montelukast for children with obstructive sleep apnea: A double-blind, placebo-controlled study.Pediatrics130e575–e580. 10.1542/peds.2012-0310
48
GorlachA.BertramK.HudecovaS.KrizanovaO. (2015). Calcium and ROS: A mutual interplay.Redox Biol.6260–271. 10.1016/j.redox.2015.08.010
49
GozalD.DanielJ. M.DohanichG. P. (2001). Behavioral and anatomical correlates of chronic episodic hypoxia during sleep in the rat.J. Neurosci.212442–2450.
50
GreveD. N.DuntleyS. P.Larson-PriorL.KrystalA. D.DiazM. T.DrummondS. P.et al (2014). Effect of armodafinil on cortical activity and working memory in patients with residual excessive sleepiness associated with CPAP-Treated OSA: A multicenter fMRI study.J. Clin. Sleep Med.10143–153. 10.5664/jcsm.3440
51
GuoH.DingH.YanY.ChenQ.ZhangJ.ChenB.et al (2021). Intermittent hypoxia-induced autophagy via AMPK/mTOR signaling pathway attenuates endothelial apoptosis and dysfunction in vitro.Sleep Breath251859–1865. 10.1007/s11325-021-02297-0
52
HaydenM. S.GhoshS. (2008). Shared principles in NF-kappaB signaling.Cell132344–362. 10.1016/j.cell.2008.01.020
53
HeY.HaraH.NunezG. (2016). Mechanism and regulation of NLRP3 inflammasome activation.Trends Biochem. Sci.411012–1021. 10.1016/j.tibs.2016.09.002
54
HednerJ.KraicziH.PekerY.MurphyP. (2003). Reduction of sleep-disordered breathing after physostigmine.Am. J. Respir. Crit. Care Med.1681246–1251. 10.1164/rccm.200211-1344OC
55
HigaA.ChevetE. (2012). Redox signaling loops in the unfolded protein response.Cell Signal241548–1555. 10.1016/j.cellsig.2012.03.011
56
HirshkowitzM.BlackJ. E.WesnesK.NieblerG.AroraS.RothT. (2007). Adjunct armodafinil improves wakefulness and memory in obstructive sleep apnea/hypopnea syndrome.Respir. Med.101616–627. 10.1016/j.rmed.2006.06.007
57
HongS.Beja-GlasserV. F.NfonoyimB. M.FrouinA.LiS.RamakrishnanS.et al (2016). Complement and microglia mediate early synapse loss in Alzheimer mouse models.Science352712–716. 10.1126/science.aad8373
58
HoyosC. M.DragerL. F.PatelS. R. (2017). OSA and cardiometabolic risk: What’s the bottom line?Respirology22420–429. 10.1111/resp.12984
59
HtooA. K.GreenbergH.TongiaS.ChenG.HendersonT.WilsonD.et al (2006). Activation of nuclear factor kappaB in obstructive sleep apnea: A pathway leading to systemic inflammation.Sleep Breath1043–50. 10.1007/s11325-005-0046-6
60
HuiD. S.ChanJ. K.ChoyD. K.KoF. W.LiT. S.LeungR. C.et al (2000). Effects of augmented continuous positive airway pressure education and support on compliance and outcome in a Chinese population.Chest1171410–1416. 10.1378/chest.117.5.1410
61
Hui-guoL.KuiL.Yan-ningZ.Yong-jianX. (2010). Apocynin attenuate spatial learning deficits and oxidative responses to intermittent hypoxia.Sleep Med.11205–212. 10.1016/j.sleep.2009.05.015
62
InoueY.TakasakiY.YamashiroY. (2013). Efficacy and safety of adjunctive modafinil treatment on residual excessive daytime sleepiness among nasal continuous positive airway pressure-treated japanese patients with obstructive sleep apnea syndrome: A double-blind placebo-controlled study.J. Clin. Sleep Med.9751–757. 10.5664/jcsm.2912
63
JordanA. S.McSharryD. G.MalhotraA. (2014). Adult obstructive sleep apnoea.Lancet383736–747. 10.1016/S0140-6736(13)60734-5
64
KaneshwaranK.OlahM.TasakiS.YuL.BradshawE. M.SchneiderJ. A.et al (2019). Sleep fragmentation, microglial aging, and cognitive impairment in adults with and without Alzheimer’s dementia.Sci. Adv.5eaax7331. 10.1126/sciadv.aax7331
65
KarimiM.HednerJ.ZouD.EskandariD.LundquistA. C.GroteL. (2015). Attention deficits detected in cognitive tests differentiate between sleep apnea patients with or without a motor vehicle accident.Sleep Med.16528–533. 10.1016/j.sleep.2014.11.015
66
KayG. G.FeldmanN. (2013). Effects of armodafinil on simulated driving and self-report measures in obstructive sleep apnea patients prior to treatment with continuous positive airway pressure.J. Clin. Sleep Med.9445–454. 10.5664/jcsm.2662
67
Kheirandish-GozalL.GozalD. (2008). Intranasal budesonide treatment for children with mild obstructive sleep apnea syndrome.Pediatrics122e149–e155. 10.1542/peds.2007-3398
68
KielyJ. L.NolanP.McNicholasW. T. (2004). Intranasal corticosteroid therapy for obstructive sleep apnoea in patients with co-existing rhinitis.Thorax5950–55.
69
KiernanE. A.SmithS. M.MitchellG. S.WattersJ. J. (2016). Mechanisms of microglial activation in models of inflammation and hypoxia: Implications for chronic intermittent hypoxia.J. Physiol.5941563–1577. 10.1113/JP271502
70
KimY. S.KwakJ. W.LeeK. E.ChoH. S.LimS. J.KimK. S.et al (2014). Can mitochondrial dysfunction be a predictive factor for oxidative stress in patients with obstructive sleep apnea?Antioxid. Redox Signal211285–1288. 10.1089/ars.2014.5955
71
KingshottR. N.VennelleM.ColemanE. L.EnglemanH. M.MackayT. W.DouglasN. J. (2001). Randomized, double-blind, placebo-controlled crossover trial of modafinil in the treatment of residual excessive daytime sleepiness in the sleep apnea/hypopnea syndrome.Am. J. Respir. Crit Care Med.163918–923. 10.1164/ajrccm.163.4.2005036
72
KizilgozV.AydinH.TatarI. G.HekimogluB.ArdicS.FiratH.et al (2013). Proton magnetic resonance spectroscopy of periventricular white matter and hippocampus in obstructive sleep apnea patients.Pol. J. Radiol.787–14. 10.12659/PJR.889923
73
LauE. Y.ChoiE. W.LaiE. S.LauK. N.AuC. T.YungW. H.et al (2015). Working memory impairment and its associated sleep-related respiratory parameters in children with obstructive sleep apnea.Sleep Med.161109–1115. 10.1016/j.sleep.2015.04.025
74
LavieL. (2012). Oxidative stress inflammation and endothelial dysfunction in obstructive sleep apnea.Front. Biosci.4:1391–1403. 10.2741/469
75
LeeJ. M.LeeJ. H.SongM. K.KimY. J. (2022). NXP032 ameliorates aging-induced oxidative stress and cognitive impairment in mice through activation of Nrf2 signaling.Antioxidants11:10130. 10.3390/antiox11010130
76
LiR. C.GuoS. Z.RaccurtM.MoudilouE.MorelG.BrittianK. R.et al (2011). Exogenous growth hormone attenuates cognitive deficits induced by intermittent hypoxia in rats.Neuroscience196237–250. 10.1016/j.neuroscience.2011.08.029
77
LiX.YingH.ZhangZ.YangZ.YouC.CaiX.et al (2022). Sulforaphane attenuates chronic intermittent hypoxia-induced brain damage in mice via augmenting Nrf2 nuclear translocation and autophagy.Front. Cell Neurosci.16:827527. 10.3389/fncel.2022.827527
78
LiY.YeJ.HanD.ZhaoD.CaoX.OrrJ.et al (2019). The effect of upper airway surgery on loop gain in obstructive sleep apnea.J. Clin. Sleep Med.15907–913. 10.5664/jcsm.7848
79
LimW.BardwellW. A.LoredoJ. S.KimE. J.Ancoli-IsraelS.MorganE. E.et al (2007). Neuropsychological effects of 2-week continuous positive airway pressure treatment and supplemental oxygen in patients with obstructive sleep apnea: A randomized placebo-controlled study.J. Clin. Sleep Med.3380–386.
80
LinH.WangC.ZhangH.XiongH.LiZ.HuangX.et al (2019). Threshold of the upper airway cross-section for hypopnea onset during sleep and its identification under waking condition.Respir. Res.20:280. 10.1186/s12931-019-1250-4
81
LingJ.YuQ.LiY.YuanX.WangX.LiuW.et al (2020). Edaravone improves intermittent hypoxia-induced cognitive impairment and hippocampal damage in rats.Biol. Pharm Bull.431196–1201. 10.1248/bpb.b20-00085
82
LittnerM.JohnsonS. F.McCallW. V.AndersonW. M.DavilaD.HartseS. K.et al (2001). Practice parameters for the treatment of narcolepsy: An update for 2000.Sleep24451–466.
83
LiuX.ChenL.DuanW.LiH.KongL.ShuY.et al (2022). Abnormal functional connectivity of hippocampal subdivisions in obstructive sleep apnea: A resting-state functional magnetic resonance imaging study.Front. Neurosci.16:850940. 10.3389/fnins.2022.850940
84
LiuX.MaY.OuyangR.ZengZ.ZhanZ.LuH.et al (2020). The relationship between inflammation and neurocognitive dysfunction in obstructive sleep apnea syndrome.J. Neuroinflammation17:229. 10.1186/s12974-020-01905-2
85
LiuX.SoodS.LiuH.HornerR. L. (2005). Opposing muscarinic and nicotinic modulation of hypoglossal motor output to genioglossus muscle in rats in vivo.J. Physiol.565965–980. 10.1113/jphysiol.2005.084657
86
LumengJ. C.ChervinR. D. (2008). Epidemiology of pediatric obstructive sleep apnea.Proc. Am. Thorac. Soc.5242–252. 10.1513/pats.200708-135MG
87
MaceyP. M.KumarR.Yan-GoF. L.WooM. A.HarperR. M. (2012). Sex differences in white matter alterations accompanying obstructive sleep apnea.Sleep351603–1613. 10.5665/sleep.2228
88
MamelakM. (2022). Sleep, narcolepsy, and sodium oxybate.Curr. Neuropharmacol.20272–291. 10.2174/1570159X19666210407151227
89
ManiaciA.IannellaG.CocuzzaS.ViciniC.MagliuloG.FerlitoS.et al (2021). Oxidative stress and inflammation biomarker expression in obstructive sleep apnea patients.J. Clin. Med.10:277. 10.3390/jcm10020277
90
MathieuA.MazzaS.DecaryA.Massicotte-MarquezJ.PetitD.GosselinN.et al (2008). Effects of obstructive sleep apnea on cognitive function: A comparison between younger and older OSAS patients.Sleep Med.9112–120. 10.1016/j.sleep.2007.03.014
91
MazzaS.PepinJ. L.NaegeleB.PlanteJ.DeschauxC.LevyP. (2005). Most obstructive sleep apnoea patients exhibit vigilance and attention deficits on an extended battery of tests.Eur. Respir. J.2575–80. 10.1183/09031936.04.00011204
92
MelloT.ZanieriF.CeniE.GalliA. (2016). Oxidative stress in the healthy and wounded hepatocyte: A cellular organelles perspective.Oxid. Med. Cell Longev.2016:8327410. 10.1155/2016/8327410
93
MinJ. J.HuoX. L.XiangL. Y.QinY. Q.ChaiK. Q.WuB.et al (2014). Protective effect of Dl-3n-butylphthalide on learning and memory impairment induced by chronic intermittent hypoxia-hypercapnia exposure.Sci. Rep.4:5555. 10.1038/srep05555
94
MishraI.PullumK. B.EadsK. N.StrunjasA. R.AshleyN. T. (2022). Peripheral sympathectomy alters neuroinflammatory and microglial responses to sleep fragmentation in female mice.Neuroscience505111–124. 10.1016/j.neuroscience.2022.09.022
95
MohammadiM.ManahejiH.MaghsoudiN.DanyaliS.BaniasadiM.ZaringhalamJ. (2020). Microglia dependent BDNF and proBDNF can impair spatial memory performance during persistent inflammatory pain.Behav. Brain Res.390:112683. 10.1016/j.bbr.2020.112683
96
MubashirT.AbrahamyanL.NiaziA.PiyasenaD.ArifA. A.WongJ.et al (2019). The prevalence of obstructive sleep apnea in mild cognitive impairment: A systematic review.BMC Neurol.19:195. 10.1186/s12883-019-1422-3
97
Muller-OehringE. M.SchulteT. (2014). Cognition, emotion, and attention.Handb. Clin. Neurol.125341–354. 10.1016/B978-0-444-62619-6.00020-3
98
Munoz-TorresZ.Jimenez-CorreaU.Montes-RodriguezC. J. (2020). Sex differences in brain oscillatory activity during sleep and wakefulness in obstructive sleep apnea.J. Sleep Res.29e12977. 10.1111/jsr.12977
99
Muraja-MurroA.KulkasA.HiltunenM.KupariS.HukkanenT.TiihonenP.et al (2014). Adjustment of apnea-hypopnea index with severity of obstruction events enhances detection of sleep apnea patients with the highest risk of severe health consequences.Sleep Breath18641–647. 10.1007/s11325-013-0927-z
100
NaegeleB.LaunoisS. H.MazzaS.FeuersteinC.PepinJ. L.LevyP. (2006). Which memory processes are affected in patients with obstructive sleep apnea? An evaluation of 3 types of memory.Sleep29533–544. 10.1093/sleep/29.4.533
101
NaegeleB.ThouvardV.PepinJ. L.LevyP.BonnetC.PerretJ. E.et al (1995). Deficits of cognitive executive functions in patients with sleep apnea syndrome.Sleep1843–52.
102
NairD.DayyatE. A.ZhangS. X.WangY.GozalD. (2011a). Intermittent hypoxia-induced cognitive deficits are mediated by NADPH oxidase activity in a murine model of sleep apnea.PLoS One6:e19847. 10.1371/journal.pone.0019847
103
NairD.ZhangS. X.RameshV.HakimF.KaushalN.WangY.et al (2011b). Sleep fragmentation induces cognitive deficits via nicotinamide adenine dinucleotide phosphate oxidase-dependent pathways in mouse.Am. J. Respir. Crit. Care Med.1841305–1312. 10.1164/rccm.201107-1173OC
104
NairD.RameshV.LiR. C.SchallyA. V.GozalD. (2013). Growth hormone releasing hormone (GHRH) signaling modulates intermittent hypoxia-induced oxidative stress and cognitive deficits in mouse.J Neurochem127531–540. 10.1111/jnc.12360
105
NishinoS.OkuroM. (2008). Armodafinil for excessive daytime sleepiness.Drugs Today44395–414. 10.1358/dot.2008.44.6.1195861
106
OlaitheM.BucksR. S. (2013). Executive dysfunction in OSA before and after treatment: A meta-analysis.Sleep361297–1305. 10.5665/sleep.2950
107
OwenA. M.McMillanK. M.LairdA. R.BullmoreE. (2005). N-back working memory paradigm: A meta-analysis of normative functional neuroimaging studies.Hum. Brain Mapp.2546–59. 10.1002/hbm.20131
108
PackA. I.BlackJ. E.SchwartzJ. R.MathesonJ. K. (2001). Modafinil as adjunct therapy for daytime sleepiness in obstructive sleep apnea.Am. J. Respir. Crit. Care Med.1641675–1681. 10.1164/ajrccm.164.9.2103032
109
PandeyA.KarS. K. (2018). Rapid eye movement sleep deprivation of rat generates ROS in the hepatocytes and makes them more susceptible to oxidative stress.Sleep Sci.11245–253. 10.5935/1984-0063.20180039
110
PatelA.ChongD. J. (2021). Obstructive sleep apnea: Cognitive outcomes.Clin. Geriatr. Med.37457–467. 10.1016/j.cger.2021.04.007
111
PrabhakarN. R. (2011). Sensory plasticity of the carotid body: Role of reactive oxygen species and physiological significance.Respir. Physiol. Neurobiol.178375–380. 10.1016/j.resp.2011.05.012
112
ProencaM. B.DombrowskiP. A.Da CunhaC.FischerL.FerrazA. C.LimaM. M. (2014). Dopaminergic D2 receptor is a key player in the substantia nigra pars compacta neuronal activation mediated by REM sleep deprivation.Neuropharmacology76118–126. 10.1016/j.neuropharm.2013.08.024
113
QiuK.MaoM.HuY.YiX.ZhengY.YingZ.et al (2022). Gender-specific association between obstructive sleep apnea and cognitive impairment among adults.Sleep Med.98158–166. 10.1016/j.sleep.2022.07.004
114
RameshV.LakshmanaM. K.RaoS.RajuT. R.KumarV. M. (1999). Alterations in monoamine neurotransmitters and dendritic spine densities at the medial preoptic area after sleep deprivation.Sleep Res. Online249–55.
115
RothT.WhiteD.Schmidt-NowaraW.WesnesK. A.NieblerG.AroraS.et al (2006). Effects of armodafinil in the treatment of residual excessive sleepiness associated with obstructive sleep apnea/hypopnea syndrome: A 12-week, multicenter, double-blind, randomized, placebo-controlled study in nCPAP-adherent adults.Clin. Ther.28689–706. 10.1016/j.clinthera.2006.05.013
116
RowB. W.KheirandishL.NevilleJ. J.GozalD. (2002). Impaired spatial learning and hyperactivity in developing rats exposed to intermittent hypoxia.Pediatr. Res.52449–453. 10.1203/00006450-200209000-00024
117
SanchezP. E.FaresR. P.RissoJ. J.BonnetC.BouvardS.Le-CavorsinM.et al (2009). Optimal neuroprotection by erythropoietin requires elevated expression of its receptor in neurons.Proc. Natl. Acad. Sci. U. S. A.1069848–9853. 10.1073/pnas.0901840106
118
SateiaM. J. (2003). Neuropsychological impairment and quality of life in obstructive sleep apnea.Clin. Chest Med.24249–259. 10.1016/s0272-5231(03)00014-5
119
SaunamakiT.HimanenS. L.PoloO.JehkonenM. (2009a). Executive dysfunction in patients with obstructive sleep apnea syndrome.Eur. Neurol.62237–242. 10.1159/000232156
120
SaunamakiT.JehkonenM.HuupponenE.PoloO.HimanenS. L. (2009b). Visual dysfunction and computational sleep depth changes in obstructive sleep apnea syndrome.Clin. EEG Neurosci.40162–167. 10.1177/155005940904000308
121
SaunamakiT.HimanenS. L.PoloO.JehkonenM. (2010). Executive dysfunction and learning effect after continuous positive airway pressure treatment in patients with obstructive sleep apnea syndrome.Eur. Neurol.63215–220. 10.1159/000278301
122
SchusslerP.YassouridisA.UhrM.KlugeM.WeikelJ.HolsboerF.et al (2006). Growth hormone-releasing hormone and corticotropin-releasing hormone enhance non-rapid-eye-movement sleep after sleep deprivation.Am. J. Physiol. Endocrinol. Metab.291E549–E556. 10.1152/ajpendo.00641.2005
123
SchwartzJ. R.HirshkowitzM.ErmanM. K.Schmidt-NowaraW. (2003). Modafinil as adjunct therapy for daytime sleepiness in obstructive sleep apnea: A 12-week, open-label study.Chest1242192–2199. 10.1378/chest.124.6.2192
124
SegsarnviriyaC.ChumthongR.MahakitP. (2021). Effects of intranasal steroids on continuous positive airway pressure compliance among patients with obstructive sleep apnea.Sleep Breath251293–1299. 10.1007/s11325-020-02236-5
125
SeriesF.SeriesI.CormierY. (1992). Effects of enhancing slow-wave sleep by gamma-hydroxybutyrate on obstructive sleep apnea.Am. Rev. Respir. Dis.1451378–1383. 10.1164/ajrccm/145.6.1378
126
SforzaE.RocheF. (2012). Sleep apnea syndrome and cognition.Front. Neurol.3:87. 10.3389/fneur.2012.00087
127
ShamsuzzamanA. S.GershB. J.SomersV. K. (2003). Obstructive sleep apnea: Implications for cardiac and vascular disease.JAMA2901906–1914. 10.1001/jama.290.14.1906
128
SheN.ShiY.FengY.MaL.YuanY.ZhangY.et al (2022). NLRP3 inflammasome regulates astrocyte transformation in brain injury induced by chronic intermittent hypoxia.BMC Neurosci.23:70. 10.1186/s12868-022-00756-2
129
SmithD. F.SarberK. M.SpicelandC. P.IshmanS. L.AugelliD. M.RomakerA. M. (2019). Effects of medical therapy on mild obstructive sleep apnea in adult patients.J. Clin. Sleep Med.15979–983. 10.5664/jcsm.7876
130
SmithS. M.FriedleS. A.WattersJ. J. (2013). Chronic intermittent hypoxia exerts CNS region-specific effects on rat microglial inflammatory and TLR4 gene expression.PLoS One8:e81584. 10.1371/journal.pone.0081584
131
St LouisE. K. (2010). Diagnosing and treating co-morbid sleep apnea in neurological disorders. Part II.Pract. Neurol.926–31.
132
StepanskiE. J. (2002). The effect of sleep fragmentation on daytime function.Sleep25268–276. 10.1093/sleep/25.3.268
133
SukovaK.UchytilovaM.LindovaJ. (2013). Abstract concept formation in African grey parrots (Psittacus erithacus) on the basis of a low number of cues.Behav. Processes9636–41. 10.1016/j.beproc.2013.02.008
134
Taranto-MontemurroL.EdwardsB. A.SandsS. A.MarquesM.EckertD. J.WhiteD. P.et al (2016a). Desipramine increases genioglossus activity and reduces upper airway collapsibility during Non-REM sleep in healthy subjects.Am. J. Respir. Crit. Care Med.194878–885. 10.1164/rccm.201511-2172OC
135
Taranto-MontemurroL.SandsS. A.EdwardsB. A.AzarbarzinA.MarquesM.de MeloC.et al (2016b). Desipramine improves upper airway collapsibility and reduces OSA severity in patients with minimal muscle compensation.Eur. Respir. J.481340–1350. 10.1183/13993003.00823-2016
136
Taranto-MontemurroL.MessineoL.AzarbarzinA.VenaD.HessL. B.CalianeseN. A.et al (2020). Effects of the combination of atomoxetine and oxybutynin on OSA endotypic traits.Chest1571626–1636. 10.1016/j.chest.2020.01.012
137
Taranto-MontemurroL.MessineoL.SandsS. A.AzarbarzinA.MarquesM.EdwardsB. A.et al (2019). The combination of atomoxetine and oxybutynin greatly reduces obstructive sleep apnea severity. A randomized, placebo-controlled, double-blind crossover trial.Am. J. Respir. Crit. Care Med.1991267–1276. 10.1164/rccm.201808-1493OC
138
Taranto-MontemurroL.SandsS. A.AzarbarzinA.MarquesM.de MeloC. M.EdwardsB. A.et al (2017a). Effect of 4-aminopyridine on genioglossus muscle activity during sleep in healthy adults.Ann Am. Thorac. Soc.141177–1183. 10.1513/AnnalsATS.201701-006OC
139
Taranto-MontemurroL.SandsS. A.EdwardsB. A.AzarbarzinA.MarquesM.de MeloC.et al (2017b). Effects of tiagabine on slow wave sleep and arousal threshold in patients with obstructive sleep apnea.Sleep40zsw047. 10.1093/sleep/zsw047
140
TartarJ. L.WardC. P.McKennaJ. T.ThakkarM.ArrigoniE.McCarleyR. W.et al (2006). Hippocampal synaptic plasticity and spatial learning are impaired in a rat model of sleep fragmentation.Eur. J. Neurosci.232739–2748. 10.1111/j.1460-9568.2006.04808.x
141
ToraldoD. M.Di MicheleL.RalliM.AriglianiM.PassaliG. C.De BenedettoM.et al (2019). Obstructive sleep apnea syndrome in the pediatric age: The role of the pneumologist.Eur. Rev. Med. Pharmacol. Sci.115–18. 10.26355/eurrev_201903_17342
142
TuB. P.WeissmanJ. S. (2002). The FAD- and O2-dependent reaction cycle of Ero1-mediated oxidative protein folding in the endoplasmic reticulum.Mol. Cell10983–994. 10.1016/s1097-2765(02)00696-2
143
UddinM. S.MamunA. A.JakariaM.ThangapandiyanS.AhmadJ.RahmanM. A.et al (2020). Emerging promise of sulforaphane-mediated Nrf2 signaling cascade against neurological disorders.Sci. Total Environ.707:135624. 10.1016/j.scitotenv.2019.135624
144
UdholmN.RexC. E.FuglsangM.Lundbye-ChristensenS.BilleJ.UdholmS. (2022). Obstructive sleep apnea and road traffic accidents: A Danish nationwide cohort study.Sleep Med.9664–69. 10.1016/j.sleep.2022.04.003
145
VakulinA.GreenM. A.D’RozarioA. L.StevensD.OpenshawH.BartlettD.et al (2022). Brain mitochondrial dysfunction and driving simulator performance in untreated obstructive sleep apnea.J. Sleep Res.31e13482. 10.1111/jsr.13482
146
VanekJ.PraskoJ.GenzorS.OciskovaM.KantorK.HolubovaM.et al (2020). Obstructive sleep apnea, depression and cognitive impairment.Sleep Med.7250–58. 10.1016/j.sleep.2020.03.017
147
VardanianM.RavdinL. (2022). Cognitive Complaints and Comorbidities in Obstructive Sleep Apnea.Sleep Med. Clin.17647–656. 10.1016/j.jsmc.2022.07.009
148
VerstraetenE.CluydtsR. (2004). Executive control of attention in sleep apnea patients: Theoretical concepts and methodological considerations.Sleep Med. Rev.8257–267. 10.1016/j.smrv.2004.01.001
149
WallaceA.BucksR. S. (2013). Memory and obstructive sleep apnea: A meta-analysis.Sleep36203–220. 10.5665/sleep.2374
150
WalterL. M.NixonG. M.DaveyM. J.O’DriscollD. M.TrinderJ.HorneR. S. (2011). Sleep disturbance in pre-school children with obstructive sleep apnoea syndrome.Sleep Med.12880–886. 10.1016/j.sleep.2011.07.007
151
WangD. D.LiJ.YuL. P.WuM. N.SunL. N.QiJ. S. (2016). Desipramine improves depression-like behavior and working memory by up-regulating p-CREB in Alzheimer’s disease associated mice.J. Integr. Neurosci.15247–260. 10.1142/S021963521650014X
152
WangJ.MingH.ChenR.JuJ. M.PengW. D.ZhangG. X.et al (2015). CIH-induced neurocognitive impairments are associated with hippocampal Ca2+ overload, apoptosis, and dephosphorylation of ERK1/2 and CREB that are mediated by overactivation of NMDARs.Brain Res.162564–72. 10.1016/j.brainres.2015.08.012
153
WilckensK. A.FerrarelliF.WalkerM. P.BuysseD. J. (2018). Slow-wave activity enhancement to improve cognition.Trends Neurosci.41470–482. 10.1016/j.tins.2018.03.003
154
WuX.GongL.XieL.GuW.WangX.LiuZ.et al (2021). NLRP3 deficiency protects against intermittent hypoxia-induced neuroinflammation and mitochondrial ROS by promoting the PINK1-parkin pathway of mitophagy in a murine model of sleep apnea.Front. Immunol.12:628168. 10.3389/fimmu.2021.628168
155
XieH.LeungK. L.ChenL.ChanY. S.NgP. C.FokT. F.et al (2010). Brain-derived neurotrophic factor rescues and prevents chronic intermittent hypoxia-induced impairment of hippocampal long-term synaptic plasticity.Neurobiol. Dis.40155–162. 10.1016/j.nbd.2010.05.020
156
XuL.BiY.XuY.WuY.DuX.MouY.et al (2021a). Suppression of CHOP reduces neuronal apoptosis and rescues cognitive impairment induced by intermittent hypoxia by inhibiting bax and bak activation.Neural Plast.2021:4090441. 10.1155/2021/4090441
157
XuY. P.TaoY. N.WuY. P.ZhangJ.JiaoW.WangY. H.et al (2021b). Sleep deprivation aggravates brain injury after experimental subarachnoid hemorrhage via TLR4-MyD88 pathway.Aging133101–3111. 10.18632/aging.202503
158
XuL.YangY.ChenJ. (2020). The role of reactive oxygen species in cognitive impairment associated with sleep apnea.Exp. Ther. Med.20:4. 10.3892/etm.2020.9132
159
XuL. H.XieH.ShiZ. H.DuL. D.WingY. K.LiA. M.et al (2015). Critical role of endoplasmic reticulum stress in chronic intermittent hypoxia-induced deficits in synaptic plasticity and long-term memory.Antioxid. Redox. Signal23695–710. 10.1089/ars.2014.6122
160
XueX.QiuY.YangH. L. (2017). Immunoregulatory role of MicroRNA-21 in macrophages in response to bacillus calmette-guerin infection involves modulation of the TLR4/MyD88 signaling pathway.Cell Physiol. Biochem.4291–102. 10.1159/000477118
161
YangX. Y.GengL.LiR.SongJ. X.JiaC. L.AnJ. R.et al (2023). Huperzine A-liposomes efficiently improve neural injury in the hippocampus of mice with chronic intermittent hypoxia.Int. J. Nanomed.18843–859. 10.2147/IJN.S393346
162
YinX.ZhangX.LvC.LiC.YuY.WangX.et al (2015). Protocatechuic acid ameliorates neurocognitive functions impairment induced by chronic intermittent hypoxia.Sci. Rep.5:14507. 10.1038/srep14507
163
YuanL.WuJ.LiuJ.LiG.LiangD. (2015a). Intermittent hypoxia-induced parvalbumin-immunoreactive interneurons loss and neurobehavioral impairment is mediated by NADPH-oxidase-2.Neurochem. Res.401232–1242. 10.1007/s11064-015-1586-1
164
YuanX.GuoX.DengY.ZhuD.ShangJ.LiuH. (2015b). Chronic intermittent hypoxia-induced neuronal apoptosis in the hippocampus is attenuated by telmisartan through suppression of iNOS/NO and inhibition of lipid peroxidation and inflammatory responses.Brain Res.159648–57. 10.1016/j.brainres.2014.11.035
165
ZhangC. Q.YiS.ChenB. B.CuiP. P.WangY.LiY. Z. (2021). mTOR/NF-kappaB signaling pathway protects hippocampal neurons from injury induced by intermittent hypoxia in rats.Int J Neurosci131994–1003. 10.1080/00207454.2020.1766460
166
ZhangD. D.LiH. J.ZhangH. R.YeX. C. (2022). Poria cocos water-soluble polysaccharide modulates anxiety-like behavior induced by sleep deprivation by regulating the gut dysbiosis, metabolic disorders and TNF-alpha/NF-kappaB signaling pathway.Food Funct.136648–6664. 10.1039/d2fo00811d
167
ZhangL.ZhangH. Q.LiangX. Y.ZhangH. F.ZhangT.LiuF. E. (2013). Melatonin ameliorates cognitive impairment induced by sleep deprivation in rats: Role of oxidative stress. BDNF and CaMKII.Behav. Brain Res.25672–81. 10.1016/j.bbr.2013.07.051
168
ZhangP.WangY.WangH.CaoJ. (2021). Sesamol alleviates chronic intermittent hypoxia-induced cognitive deficits via inhibiting oxidative stress and inflammation in rats.Neuroreport32105–111. 10.1097/WNR.0000000000001564
169
ZhangS. X.KhalyfaA.WangY.CarrerasA.HakimF.NeelB. A.et al (2014). Sleep fragmentation promotes NADPH oxidase 2-mediated adipose tissue inflammation leading to insulin resistance in mice.Int. J. Obes.38619–624. 10.1038/ijo.2013.139
170
ZhangY.MiaoY.XiongX.TanJ.HanZ.ChenF.et al (2023). Microglial exosomes alleviate intermittent hypoxia-induced cognitive deficits by suppressing NLRP3 inflammasome.Biol. Direct.18:29. 10.1186/s13062-023-00387-5
171
ZhaoY.YangS.GuoQ.GuoY.ZhengY.JiE. (2021). Shashen-maidong decoction improved chronic intermittent hypoxia-induced cognitive impairment through regulating glutamatergic signaling pathway.J. Ethnopharmacol.274:114040. 10.1016/j.jep.2021.114040
Summary
Keywords
obstructive sleep apnea, intermittent hypoxia, sleep fragmentation, cognitive impairment, drug therapy
Citation
He D, Chen J, Du X and Xu L (2023) Summary of drug therapy to treat cognitive impairment-induced obstructive sleep apnea. Front. Cell. Neurosci. 17:1222626. doi: 10.3389/fncel.2023.1222626
Received
15 May 2023
Accepted
01 August 2023
Published
04 September 2023
Volume
17 - 2023
Edited by
Robert Warren Gould, Wake Forest University, United States
Reviewed by
Anne Briançon-Marjollet, Université Grenoble Alpes, France; Shiyong Li, Huazhong University of Science and Technology, China
Updates
Copyright
© 2023 He, Chen, Du and Xu.
This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
*Correspondence: Xiaoxue Du, dxiaoxue@zju.edu.cnLinhao Xu, xulinhaoluck@163.com
†These authors have contributed equally to this work
Disclaimer
All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article or claim that may be made by its manufacturer is not guaranteed or endorsed by the publisher.