The Complex Relationship between Neuromodulators, Circadian Rhythms, and Insomnia in Patients with Obstructive Sleep Apnea.

Obstructive sleep apnea (OSA) has been linked to disruptions in circadian rhythm and neurotrophin (NFT) signaling. This study explored the link between neuromodulators, chronotype, and insomnia in OSA. The participants (n = 166) underwent polysomnography (PSG) before being categorized into either the control or the OSA group. The following questionnaires were completed: Insomnia Severity Index (ISI), Epworth Sleepiness Scale, Chronotype Questionnaire (morningness-eveningness (ME), and subjective amplitude (AM). Blood samples were collected post-PSG for protein level assessment using ELISA kits for brain-derived neurotrophic factor (BDNF), proBDNF, glial-cell-line-derived neurotrophic factor, NFT3, and NFT4. Gene expression was analyzed utilizing qRT-PCR. No significant differences were found in neuromodulator levels between OSA patients and controls. The controls with insomnia exhibited elevated neuromodulator gene expression (p < 0.05). In the non-insomnia individuals, BDNF and NTF3 expression was increased in the OSA group compared to controls (p = 0.007 for both); there were no significant differences between the insomnia groups. The ISI scores positively correlated with all gene expressions in both groups, except for NTF4 in OSA (R = 0.127, p = 0.172). AM and ME were predicting factors for the ISI score and clinically significant insomnia (p < 0.05 for both groups). Compromised compensatory mechanisms in OSA may exacerbate insomnia. The correlation between chronotype and NFT expression highlights the role of circadian misalignments in sleep disruptions.

The effect of sleep and its restriction on selected inflammatory parameters.

Insufficient sleep duration may lead to a series of immune dysfunctions. One of the factors influencing this effect could be physical activity (PA). The study aimed to assess the impact of deprivation of sleep (DS) on selected inflammatory parameters. Seventy-seven participants completed the protocol consisting of polysomnography (PSG) conducted in a sleep laboratory and DS, monitored with an actigraph. PA was assessed with actigraphy, which categorized participants as active or inactive. White blood cells (WBC) values negatively correlated with sleep efficiency based on sleep diaries and PSG parameters (total sleep time, sleep efficiency, and REM duration), but regression analysis showed that WBC depends only on the sleep diary parameter. Granulocytes (GRA) positively correlated with REM latency, and negatively with sleep efficiency. After DS, all participants exhibited an elevated GRA count. The number of WBC and GRA increased also in the active group; inactive participants showed no changes in inflammatory parameters. The overall number of WBC depends primarily on the quality of sleep over a period of several days. Under the influence of sleep deprivation, the number of GRA increases, but the number of leukocytes depends on the level of physical activity during DS.

Interactions between neurotrophins, mood, and physical activity under the conditions of sleep deprivation.

Sleep deprivation (DS) is the forced elimination of sleep. While brain-derived neurotrophic factor (BDNF) has been extensively studied in the context of in mood changes following DS, the role of other neurotrophins remains elusive. This study explores the impact of DS on BDNF, glial cell line-derived neurotrophic factor (GDNF), neurotrophin-3 (NT3), and neurotrophin-4 (NT4) at mRNA and protein level, considering their potential links to mood disturbances. The study involved 81 participants subjected to polysomnography (PSG) and DS. Blood samples, mood assessments, and actigraphy data were collected twice, after PSG and DS. NT mRNA expression and serum protein concentrations of BDNF, GDNF, NT3, and NT4 were measured. Participants were divided into Responders and Non-Responders based on mood improvement after DS. DS reduced BDNF mRNA expression in all participants, with no change in serum BDNF protein. GDNF protein decreased in Non-Responders, while Responders exhibited reduced GDNF mRNA. NT3 protein increased in both groups, while NT3 mRNA decreased in Respondents. NT4 protein rose universally post-DS, but NT4 mRNA remained unchanged. Physical activity (PA) negatively correlated with mRNA expression of BDNF, GDNF, and NT3 post-DS. The study's short DS duration and exclusion of immature NT forms limit comprehensive insights. GDNF, together with NT3, might play an important role in mood response to DS. PA during DS seems to impair the mRNA expression of NTs in leukocytes. Future studies on the subject of sleep deprivation might consider investigating the relationship between BDNF and NT4 in the context of their apparent redundancy.

The Relationship between Sleep Parameters Measured by Polysomnography and Selected Neurotrophic Factors.

BACKGROUND: The molecular underpinnings of insufficient sleep remain underexplored, with disruptions in the neurotrophic signaling pathway emerging as a potential explanation. Neurotrophins (NTs), including brain-derived neurotrophic factor (BDNF), neurotrophin-3 (NT3), neurotrophin 4 (NT4), and glial-cell-line-derived growth factor (GDNF), play crucial roles in nerve cell growth and repair. However, their associations with sleep patterns are poorly understood. This study aimed to investigate the relationship between the chosen neurotrophins and objective sleep parameters. METHODS: The study involved 81 participants subjected to polysomnography (PSG). Blood samples were collected after PSG. The mRNA expression and serum protein concentrations of BDNF, GDNF, NT3, and NT4 were measured using real-time quantitative reverse-transcription PCR (qRT-PCR) or enzyme-linked immunosorbent assay (ELISA) methods, respectively. RESULTS: BDNF and NT3 proteins were negatively correlated with NREM events, while NT4 protein positively correlated with REM events. Electroencephalography power analysis revealed BDNF protein's negative correlation with delta waves during rapid eye movement and non-rapid eye movement sleep. CONCLUSION: The study highlights associations between neurotrophins and sleep, emphasizing BDNF's role in regulating NREM and REM sleep. The EEG power analysis implicated BDNF in delta wave modulation, shedding light on potential neurotrophic mechanisms underlying sleep effects on cognitive and mood processes.

Evaluation of the Continuous Positive Airway Pressure Effect on Neurotrophins' Gene Expression and Protein Levels.

Neurotrophins (NT) might be associated with the pathophysiology of obstructive sleep apnea (OSA) due to concurrent intermittent hypoxia and sleep fragmentation. Such a relationship could have implications for the health and overall well-being of patients; however, the literature on this subject is sparse. This study investigated the alterations in the serum protein concentration and the mRNA expression of the brain-derived neurotrophic factor (BDNF), glial cell line-derived neurotrophic factor (GDNF), neurotrophin-3 (NTF3), and neurotrophin-4 (NTF4) proteins following a single night of continuous positive airway pressure (CPAP) therapy. This study group consisted of 30 patients with OSA. Venous blood was collected twice after a diagnostic polysomnography (PSG) and PSG with CPAP treatment. Gene expression was assessed with a quantitative real-time polymerase chain reaction. An enzyme-linked immunosorbent assay was used to determine the protein concentrations. After CPAP treatment, BDNF, proBDNF, GDNF, and NTF4 protein levels decreased (p = 0.002, p = 0.003, p = 0.047, and p = 0.009, respectively), while NTF3 increased (p = 0.001). Sleep latency was correlated with ΔPSG + CPAP/PSG gene expression for BDNF (R = 0.387, p = 0.038), NTF3 (R = 0.440, p = 0.019), and NTF4 (R = 0.424, p = 0.025). OSA severity parameters were not associated with protein levels or gene expressions. CPAP therapy could have an impact on the posttranscriptional stages of NT synthesis. The expression of different NTs appears to be connected with sleep architecture but not with OSA severity.

Investigating the Role of BDNF in Insomnia: Current Insights.

Insomnia is a common disorder defined as frequent and persistent difficulty initiating, maintaining, or going back to sleep. A hallmark symptom of this condition is a sense of nonrestorative sleep. It is frequently associated with other psychiatric disorders, such as depression, as well as somatic ones, including immunomediated diseases. BDNF is a neurotrophin primarily responsible for synaptic plasticity and proper functioning of neurons. Due to its role in the central nervous system, it might be connected to insomnia of multiple levels, from predisposing traits (neuroticism, genetic/epigenetic factors, etc.) through its influence on different modes of neurotransmission (histaminergic and GABAergic in particular), maintenance of circadian rhythm, and sleep architecture, and changes occurring in the course of mood disturbances, substance abuse, or dementia. Extensive and interdisciplinary evaluation of the role of BDNF could aid in charting new areas for research and further elucidate the molecular background of sleep disorder. In this review, we summarize knowledge on the role of BDNF in insomnia with a focus on currently relevant studies and discuss their implications for future projects.

Correlations between the symptoms of insomnia, depression, sleep quality, antitumor necrosis factor therapy, and disrupted circadian clock gene expression in inflammatory bowel disease.

INTRODUCTION: Inflammatory bowel disease (IBD) might be accompanied by emotional disturbances. Circadian rhythm genes, such as brain and muscle ARNT­Like 1 (BMAL1), circadian locomotor output cycles kaput (CLOCK), neuronal PAS domain protein 2 (NPAS2), or nuclear receptor subfamily 1 group D member 1 (NR1D1) are related to inflammation and psychiatric symptoms that might modulate their expression. OBJECTIVES: The study aimed to compare the expression of the BMAL1, CLOCK, NPAS2, NR1D1 mRNA in IBD patients and healthy controls (HCs). We evaluated the association between the gene expression and the disease severity, antitumor necrosis factor (TNF) therapy, sleep quality, insomnia, and depression. PATIENTS AND METHODS: A total of 81 IBD patients and 44 HCs were recruited and classified according to the disease activity and IBD type (ulcerative colitis [UC] or Crohn disease [CD]). The participants filled out questionnaires assessing their sleep quality, daytime sleepiness, insomnia, and depression. Venous blood samples were collected, and the IBD patients on the anti­TNF therapy had their blood drawn before and after 14 weeks of the treatment. RESULTS: In comparison with HCs, the IBD group had decreased expression of all studied genes apart from the BMAL1 gene. UC individuals with exacerbation had decreased expression of the CLOCK and the NPAS2 genes, as compared with the remission group. UC severity negatively correlated with the CLOCK, NPAS2, and NR1D1 mRNA levels. The IBD participants with depression symptoms had a decreased expression of the CLOCK and the NR1D1 genes, as compared with those without mood disturbances. Poor sleep quality was associated with a decreased expression of the NR1D1 gene. Biologic treatment decreased the expression of the BMAL1 gene. CONCLUSIONS: Disruption of the clock gene expression might constitute a molecular background of sleep disorders and depression in IBD and might contribute to UC exacerbation.

Relation between Selected Sleep Parameters, Depression, Anti-Tumor Necrosis Factor Therapy, and the Brain-Derived Neurotrophic Factor Pathway in Inflammatory Bowel Disease.

Inflammatory bowel disease (IBD) patients often have sleep and mood disorders. Brain-derived neurotrophic factor (BDNF) and proBDNF were shown to modulate interactions between the central nervous system and the gastrointestinal tract, possibly contributing to psychological issues. Anti-tumor necrosis factor (TNF) therapy in IBD can alter BDNF expression and further affect the brain-gut axis. Eighty IBD patients and 44 healthy controls (HCs) were enrolled and divided into subsets based on disease activity and condition (ulcerative colitis (UC)/Crohn's disease (CD)). Questionnaires evaluating sleep parameters and depression as well as venous blood were collected. The IBD group had a lower expression of BDNF mRNA, but higher proBDNF and BDNF protein concentration than HCs. The UC group had a higher BDNF protein concentration than the CD. BDNF protein was positively correlated to sleep efficiency in the IBD group. Depression severity was associated positively with BDNF mRNA and negatively with BDNF protein in the remission group. Anti-TNF therapy enhanced BDNF mRNA expression. The BDNF pathway might be disturbed in IBD, linking it to sleep disorders and depression. Systemic inflammation could be the main cause of this disruption. BDNF mRNA is a more reliable parameter than protein due to numerous post-translational modifications.

Neurotrophins in the Neuropathophysiology, Course, and Complications of Obstructive Sleep Apnea-A Narrative Review.

Obstructive sleep apnea (OSA) is a disorder characterized by chronic intermittent hypoxia and sleep fragmentation due to recurring airway collapse during sleep. It is highly prevalent in modern societies, and due to its pleiotropic influence on the organism and numerous sequelae, it burdens patients and physicians. Neurotrophins (NTs), proteins that modulate the functioning and development of the central nervous system, such as brain-derived neurotrophic factor (BDNF), have been associated with OSA, primarily due to their probable involvement in offsetting the decline in cognitive functions which accompanies OSA. However, NTs influence multiple aspects of biological functioning, such as immunity. Thus, extensive evaluation of their role in OSA might enlighten the mechanism behind some of its elusive features, such as the increased risk of developing an immune-mediated disease or the association of OSA with cardiovascular diseases. In this review, we examine the interactions between NTs and OSA and discuss their contribution to OSA pathophysiology, complications, as well as comorbidities.

Evaluation of cognitive and psychomotor faculties in relation to mood-related symptoms under the conditions of sleep deprivation.

Introduction: Deprivation of sleep (DS) has been associated with changes in mood and cognitive function, rapidly but transiently improving the severity of depression symptoms. However, it remains unclear whether there are differences in performance between DS responders and non-responders. The relationship between DS, mood, cognitive, and psychomotor function is also poorly understood. Methods: Participants (n = 77) underwent a baseline assessment of sleep under the control of polysomnography (PSG). Later they were subjected to DS with actigraphy monitoring. Evaluation of mood as well as completing a battery of tests assessing cognitive functions and eye-hand coordination was conducted four times, pre/post PSG and DS. Participants were further divided into respondents (RE, n = 48) and non-respondents (NR, n = 29) depending on alleviation of depression symptoms severity following DS. Results: All participants exhibited increased response speed to visual triggers after DS compared to baseline (p = 0.024). Psychomotor vigilance test (PVT) results remained intact in the RE, whereas it was increased in the NR (p = 0.008). Exposure time in the eye-hand coordination test improved in both groups, but total error duration was reduced only in RE individuals (p < 0.001, p = 0.009 for RE and NR, respectively). All subjects were more proficient at trail-making test (p ≤ 0.001 for Part 1 and 2 in all, NR, RE). Stroop test also improved regardless of mood changes after DS (p = 0.007, p = 0.008 for Part 1 and 2, respectively); cognitive interference remained at a similar level within groups (p = 0.059, p = 0.057 for NR and RE, respectively). A positive correlation was observed between the difference in PSG morning/DS morning depression severity and vigilance (R = 0.37, p = 0.001, R = 0.33, p = 0.005, for error duration eye-hand coordination test and PVT total average score, respectively). Conclusion: RE tend to maintain or improve cognitive function after DS, oppositely to NR. Vigilance in particular might be tightly associated with changes in depression symptoms after DS. Future studies should examine the biological basis behind the response to sleep loss.

BDNF and proBDNF Serum Protein Levels in Obstructive Sleep Apnea Patients and Their Involvement in Insomnia and Depression Symptoms.

Introduction: Obstructive sleep apnea (OSA) is a disorder that, apart from somatic sequelae, increases the risk of developing psychiatric conditions. Brain-derived neurotrophic factor (BDNF) signaling pathway is involved in the pathophysiology of depression and insomnia. Therefore, the study aimed to investigate differences in concentrations of BDNF and proBDNF in patients with OSA and healthy individuals, to evaluate diurnal changes of these proteins, and to assess the correlations with psychiatric symptoms. Methods: Sixty individuals following polysomnography (PSG) were divided into two groups based on the apnea-hypopnea index (AHI): OSA patients (AHI ≥ 30; n = 30) and control group (AHI < 5; n = 30). Participants filled out questionnaires: Beck Depression Inventory (BDI), Athens Insomnia Scale (AIS), and Pittsburgh Sleep Quality Index (PSQI). Peripheral blood was collected before and after PSG. Protein concentrations were measured using ELISA. OSA group was divided into subgroups: AIS (−)/AIS (+) (AIS > 5), PSQI (−)/PSQI (+) (PSQI > 5), and BDI (−)/BDI (+) (BDI > 19). Results: No differences in BDNF and proBDNF protein levels were observed between OSA and the control groups. However, BDNF and proBDNF evening protein concentrations were higher in the AIS (+) and PSQI (+) groups (p < 0.001 for all). The BDI (+) group was characterized by lower morning levels of both proteins (p = 0.047 and p = 0.003, respectively). Conclusions: BDNF signaling pathway might be involved in the pathophysiology of depression and insomnia in patients with OSA. BDNF and proBDNF protein levels might be useful in defining OSA phenotypes.

The Role of Brain-Derived Neurotrophic Factor in Immune-Related Diseases: A Narrative Review.

Brain-derived neurotrophic factor (BDNF) is a neurotrophin regulating synaptic plasticity, neuronal excitability, and nociception. It seems to be one of the key molecules in interactions between the central nervous system and immune-related diseases, i.e., diseases with an inflammatory background of unknown etiology, such as inflammatory bowel diseases or rheumatoid arthritis. Studies show that BDNF levels might change in the tissues and serum of patients during the course of these conditions, e.g., affecting cell survival and modulating pain severity and signaling pathways involving different neurotransmitters. Immune-related conditions often feature psychiatric comorbidities, such as sleep disorders (e.g., insomnia) and symptoms of depression/anxiety; BDNF may be related as well to them as it seems to exert an influence on sleep structure; studies also show that patients with psychiatric disorders have decreased BDNF levels, which increase after treatment. BDNF also has a vital role in nociception, particularly in chronic pain, hyperalgesia, and allodynia, participating in the formation of central hypersensitization. In this review, we summarize the current knowledge on BDNF's function in immune-related diseases, sleep, and pain. We also discuss how BDNF is affected by treatment and what consequences these changes might have beyond the nervous system.

Potential Role of Sleep Deficiency in Inducing Immune Dysfunction.

Sleep deficiency and insomnia deteriorate the quality of patients' lives, yet the exact influence of these factors on the immune system has only begun to gain interest in recent years. Growing evidence shows that insomnia is a risk factor for numerous diseases, including common infections and autoimmune diseases. Levels of inflammatory markers also seem to be abnormal in sleep deficient individuals, which may lead to low-grade inflammation. The interpretation of studies is difficult due to the equivocal term "sleep disturbances," as well as due to the various criteria used in studies. This narrative review aims to summarize the available knowledge regarding the bidirectional influence of the immune system and sleep disturbances.

Adolescent Congenital Central Hypoventilation Syndrome: An Easily Overlooked Diagnosis.

Congenital central hypoventilation syndrome (CCHS), also known as Ondine's curse, is a rare, potentially fatal genetic disease, manifesting as a lack of respiratory drive. Most diagnoses are made in pediatric patients, however late-onset cases have been rarely reported. Due to the milder symptoms at presentation that might easily go overlooked, these late-onset cases can result in serious health consequences later in life. Here, we present a case report of late-onset CCHS in an adolescent female patient. In this review we summarize the current knowledge about symptoms, as well as clinical management of CCHS, and describe in detail the molecular mechanism responsible for this disorder.

Obstructive Sleep Apnea as an Acceleration Trigger of Cellular Senescence Processes through Telomere Shortening.

Obstructive sleep apnea (OSA) is chronic disorder which is characterized by recurrent pauses of breathing during sleep which leads to hypoxia and its two main pathological sequelae: oxidative stress and chronic inflammation. Both are also associated with cellular senescence. As OSA patients present with higher prevalence of age-related disorders, such as atrial hypertension or diabetes mellitus type 2, a relationship between OSA and accelerated aging is observable. Furthermore, it has been established that these OSA are associated with telomere shortening. This process in OSA is likely caused by increased oxidative DNA damage due to increased reactive oxygen species levels, DNA repair disruptions, hypoxia, chronic inflammation, and circadian clock disturbances. The aim of the review is to summarize study outcomes on changes in leukocyte telomere length (LTL) in OSA patients and describe possible molecular mechanisms which connect cellular senescence and the pathophysiology of OSA. The majority of OSA patients are characterized by LTL attrition due to oxidative stress, hypoxia and inflammation, which make a kind of positive feedback loop, and circadian clock disturbance.

Nocturnal Oxygen Saturation Parameters as Independent Risk Factors for Type 2 Diabetes Mellitus among Obstructive Sleep Apnea Patients.

Obstructive sleep apnea (OSA) is a recognized independent risk factor for metabolic disorders, type 2 diabetes mellites (DM2) in particular. Therefore, the study aimed to assess the influence of nocturnal oxygen saturation parameters on the onset of DM2 among OSA patients. The study consisted of 549 participants, who underwent polysomnography examination. Based on apnea hypopnea index (AHI), 465 patients were diagnosed with OSA. One hundred and seven individuals had comorbid DM2. Cox regression models were used to assess the effect of oxygen saturation parameters on the onset of DM2. Classification and regression trees (CART) analysis was used to assess the onset of the DM2 in the study group in context of oxygen saturation variables. One-way Cox regression showed higher risk of earlier DM2 for increased values of BMI, AHI, decreased basal O2 and O2 nadir value, while lowered mean O2 desaturation has not shown statistical significance. In the CART analysis, the following cut-off points 92.2%, 81.7%, 87.1% were determined for basal O2, O2 nadir and mean O2 desaturation, respectively, with the first two parameters being statistically significant. Therefore, basal O2 is independent from AHI, BMI and age is a risk factor of DM2 among OSA patients.

Sleep Problems in Chronic Inflammatory Diseases: Prevalence, Treatment, and New Perspectives: A Narrative Review.

Epidemiological studies have shown that individuals with sleep problems are at a greater risk of developing immune and chronic inflammatory diseases. As sleep disorders and low sleep quality in the general population are frequent ailments, it seems important to recognize them as serious public health problems. The exact relation between immunity and sleep remains elusive; however, it might be suspected that it is shaped by others stress and alterations of the circadian rhythm (commonly caused by for example shift work). As studies show, drugs used in the therapy of chronic inflammatory diseases, such as steroids or monoclonal antibodies, also influence sleep in more complex ways than those resulting from attenuation of the disease symptoms. Interestingly, the relation between sleep and immunity appears to be bidirectional; that is, sleep may influence the course of immune diseases, such as inflammatory bowel disease. Thus, proper diagnosis and treatment of sleep disorders are vital to the patient's immune status and, in effect, health. This review examines the epidemiology of sleep disorders and immune diseases, the associations between them, and their current treatment and novel perspectives in therapy.