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Purpose Obesity is the most important risk factor for obstructive sleep apnea (OSA); however, the exact underlying mechanisms are still not fully understood. The aim of this study was to examine the morphology of upper airways in overweight habitual snorers and in mild OSA patients. Furthermore, the associations between weight loss, parapharyngeal fat pad area and OSA were assessed in a 1-year randomised, controlled follow-up study originally conducted to determine the effects of lifestyle changes with weight reduction as a treatment of OSA. Methods Thirty-six overweight adult patients with mild OSA [apnea–hypopnea index (AHI) 5–15 events/h] and 24 weight-matched habitual snorers (AHI < 5 events/h) were included in the study. All patients underwent nocturnal cardiorespiratory recordings and multislice computed tomography (CT) of parapharyngeal fat pad area, the smallest diameter and area in naso-, oro- and hypopharynx, the smallest diameter and area of the whole pharyngeal airway, the distance from the hyoid bone to the mandibular plane and to cervical tangent as well as the distance between mandibular symphysis and cervical spine. In addition, OSA patients were further randomised to receive either an active 1-year lifestyle intervention with an early weight loss programme or routine lifestyle counselling. After 1 year, the cardiorespiratory recordings and CT scans were repeated. Results The pharyngeal fat pad area was significantly larger, and the distance from the hyoid bone to cervical spine was longer in patients with OSA than in habitual snorers ( p  = 0.002 and p  = 0.018, respectively). The multiple regression analysis showed that besides a large pharyngeal fat pad area and a long distance from the cervical spine to hyoid bone, also a short distance from the mandibular symphysis to cervical tangent increased a risk to OSA. During the 1-year follow-up in OSA patients, the pharyngeal fat pad area and AHI decreased significantly in the intervention group ( p  = 0.003 and p  < 0.001, respectively). Conclusions In the early stages of OSA, the pharyngeal fat pad seems to play an important role in the development of disease in overweight patients. Furthermore, weight reduction by lifestyle intervention-based programme reduces both central obesity and pharyngeal fat pads, resulting in an improvement of OSA.

Rationale: Obesity is a major risk factor towards the development of obstructive sleep apnea, while significant weight loss (both conservatively managed and surgically assisted) has a variable effect upon its severity. Differences in the effect of weight loss on obstructive sleep apnea may be due to underlying craniofacial characteristics. Objectives: To determine whether craniofacial characteristics can predict OSA treatment response to significant weight loss. Methods: We analyzed craniofacial measurements from lateral cephalograms performed at baseline on 57 patients enrolled in a previously reported 2-year randomized clinical weight loss trial (laparoscopic adjustable gastric band surgery versus conservatively [dietician and very low calorie diet] treated). Group mean weight loss was ∼ 13% (mean weight loss 131 to 114 kg), with corresponding reduction in mean apnea-hypopnea index (AHI) from 61 to 41 events/h. Computer assisted lateral cephalogram analysis was undertaken by three trained staff blinded to treatment. We analyzed lateral cephalogram and demographic data at baseline (cross-sectional) and change over two years (interventional) in 54 patients. Measurements and Main Results: Baseline cross-sectional analysis indicated no cephalometric measurement correlated significantly with baseline AHI when corrected for neck circumference. The percentage change in AHI over 2 years correlated with a shorter menton-gonion distance (i.e., mandibular body length). The % change in AHI correlated with the % weight change (R 2 = 0.25, p < 0.001) and mandibular body length (R 2 = 0.19, p = 0.002). The % change in AHI correlated with combined weight change and mandibular body length (combined R 2 = 0.31, p < 0.001). Conclusions: Weight loss as a therapeutic option for severe OSA with severe obesity may be predicted by shorter mandibular body length as measured by lateral cephalometry. Citation: Naughton MT, Monteith BD, Manton DJ, Dever P, Schachter LM, O’Brien PE, Dixon JB. Shorter mandibular length is associated with a greater fall in AHI with weight loss. J Clin Sleep Med 2015;11(4):451–456.

To investigate the impact of obstructive sleep apnea (OSA) on endothelial repair capacity and apoptosis in the absence of potentially confounding factors including obesity. Sixteen patients with a body mass index <30 and newly diagnosed OSA and 16 controls were studied. Circulating levels of endothelial progenitor cells, a marker of endothelial repair capacity, and endothelial microparticles, a marker of endothelial apoptosis, were quantified before and after four-week therapy with continuous positive airway pressure (CPAP). Endothelial cell apoptotic rate was also quantified in freshly harvested venous endothelial cells. Vascular reactivity was measured by flow-mediated dilation. Before treatment, endothelial microparticle levels were greater and endothelial progenitor cell levels were lower in patients with OSA than in controls (P < 0.001 for both). Levels of endothelial microparticles and progenitors cells were inversely related (r = -0.67, P < 0.001). Endothelial progenitor cell levels increased after effective treatment (P = 0.036). In the absence of any co-morbid conditions including obesity, OSA alone impairs endothelial repair capacity and promotes endothelial apoptosis. These early endothelial alterations may underlie accelerated atherosclerosis and increased cardiovascular risk in OSA.

Abstract Rationale The pathophysiologic causes of obstructive sleep apnea (OSA) likely vary among patients but have not been well characterized. Objectives To define carefully the proportion of key anatomic and nonanatomic contributions in a relatively large cohort of patients with OSA and control subjects to identify pathophysiologic targets for future novel therapies for OSA. Methods Seventy-five men and women with and without OSA aged 20–65 years were studied on three separate nights. Initially, the apnea-hypopnea index was determined by polysomnography followed by determination of anatomic (passive critical closing pressure of the upper airway [Pcrit]) and nonanatomic (genioglossus muscle responsiveness, arousal threshold, and respiratory control stability; loop gain) contributions to OSA. Measurements and Main Results Pathophysiologic traits varied substantially among participants. A total of 36% of patients with OSA had minimal genioglossus muscle responsiveness during sleep, 37% had a low arousal threshold, and 36% had high loop gain. A total of 28% had multiple nonanatomic features. Although overall the upper airway was more collapsible in patients with OSA (Pcrit, 0.3 [−1.5 to 1.9] vs. −6.2 [−12.4 to −3.6] cm H2O; P <0.01), 19% had a relatively noncollapsible upper airway similar to many of the control subjects (Pcrit, −2 to −5 cm H2O). In these patients, loop gain was almost twice as high as patients with a Pcrit greater than −2 cm H2O (−5.9 [−8.8 to −4.5] vs. −3.2 [−4.8 to −2.4] dimensionless; P = 0.01). A three-point scale for weighting the relative contribution of the traits is proposed. It suggests that nonanatomic features play an important role in 56% of patients with OSA. Conclusions This study confirms that OSA is a heterogeneous disorder. Although Pcrit-anatomy is an important determinant, abnormalities in nonanatomic traits are also present in most patients with OSA.

Abstract We performed respiratory-gated magnetic resonance imaging to evaluate airway dynamics during tidal breathing in 10 children with obstructive sleep apnea syndrome (OSAS; age, 4.3 ± 2.3 years) and 10 matched control subjects (age, 5.0 ± 2.0 years). We hypothesized that respiratory cycle fluctuations in upper airway cross-sectional area would be larger in children with OSAS. Methods: Studies were performed under sedation. Respiratory gating was performed automatically at 10, 30, 50, 70, and 90% of inspiratory and expiratory volume. Airway cross-sectional area was measured at four ascending oropharyngeal levels at each increment of the respiratory cycle. Results: We noted the following in subjects with OSAS compared with control subjects: (1) a smaller upper airway cross-sectional area, particularly during inspiration; (2) airway narrowing occurred during inspiration without evidence of complete airway collapse; (3) airway dilatation occurred during expiration, particularly early in the phase; and (4) magnitude of cross-sectional areas fluctuations during tidal breathing noted in OSAS at levels 1 through 4 were 317, 422, 785, and 922%, compared with 19, 15 17, and 24% in control subjects (p < 0.001, p < 0.005, p < 0.001, and p < 0.001, respectively). Conclusions: Fluctuations in airway area during tidal breathing are significantly greater in subjects with OSAS compared with control subjects. Resistive pressure loading is a probable explanation, although increased airway compliance may be a contributing factor.

Autoimmunity might be associated with or implicated in sleep and neurodegenerative disorders. We aimed to describe the features of a novel neurological syndrome associated with prominent sleep dysfunction and antibodies to a neuronal antigen. In this observational study, we used clinical and video polysomnography to identify a novel sleep disorder in three patients referred to the Sleep Unit of Hospital Clinic, University of Barcelona, Spain, for abnormal sleep behaviours and obstructive sleep apnoea. These patients had antibodies against a neuronal surface antigen, which were also present in five additional patients referred to our laboratory for antibody studies. These five patients had been assessed with polysomnography, which was done in our sleep unit in one patient and the recording reviewed in a second patient. Two patients underwent post-mortem brain examination. Immunoprecipitation and mass spectrometry were used to characterise the antigen and develop an assay for antibody testing. Serum or CSF from 298 patients with neurodegenerative, sleep, or autoimmune disorders served as control samples. All eight patients (five women; median age at disease onset 59 years [range 52–76]) had abnormal sleep movements and behaviours and obstructive sleep apnoea, as confirmed by polysomnography. Six patients had chronic progression with a median duration from symptom onset to death or last visit of 5 years (range 2–12); in four the sleep disorder was the initial and most prominent feature, and in two it was preceded by gait instability followed by dysarthria, dysphagia, ataxia, or chorea. Two patients had a rapid progression with disequilibrium, dysarthria, dysphagia, and central hypoventilation, and died 2 months and 6 months, respectively, after symptom onset. In five of five patients, video polysomnography showed features of obstructive sleep apnoea, stridor, and abnormal sleep architecture (undifferentiated non-rapid-eye-movement [non-REM] sleep or poorly structured stage N2, simple movements and finalistic behaviours, normalisation of non-REM sleep by the end of the night, and, in the four patients with REM sleep recorded, REM sleep behaviour disorder). Four of four patients had HLA-DRB1*1001 and HLA-DQB1*0501 alleles. All patients had antibodies (mainly IgG4) against IgLON5, a neuronal cell adhesion molecule. Only one of the 298 controls, who had progressive supranuclear palsy, had IgLON5 antibodies. Neuropathology showed neuronal loss and extensive deposits of hyperphosphorylated tau mainly involving the tegmentum of the brainstem and hypothalamus in the two patients studied. IgLON5 antibodies identify a unique non-REM and REM parasomnia with sleep breathing dysfunction and pathological features suggesting a tauopathy. Fondo de Investigaciones Sanitarias, Centros de Investigación Biomédica en Red de enfermedades neurodegenerativas (CIBERNED) and Respiratorias (CIBERES), Ministerio de Economía y Competitividad, Fundació la Marató TV3, and the National Institutes of Health.

Abstract Rationale Obstructive sleep apnea (OSA) is commonly associated with neurocognitive impairments that have not been consistently related to specific brain structure abnormalities. Knowledge of the brain structures involved in OSA and the corresponding functional implications could provide clues to the pathogenesis of cognitive impairment and its reversibility in this disorder. Objectives To investigate the cognitive deficits and the corresponding brain morphology changes in OSA, and the modifications after treatment, using combined neuropsychologic testing and voxel-based morphometry. Methods A total of 17 patients treatment-naive to sleep apnea and 15 age-matched healthy control subjects underwent a sleep study, cognitive tests, and magnetic resonance imaging. After 3 months of treatment, cognitive and imaging data were collected to assess therapy efficacy. Measurements and Main Results Neuropsychologic results in pretreatment OSA showed impairments in most cognitive areas, and in mood and sleepiness. These impairments were associated with focal reductions of gray-matter volume in the left hippocampus (entorhinal cortex), left posterior parietal cortex, and right superior frontal gyrus. After treatment, we observed significant improvements involving memory, attention, and executive-functioning that paralleled gray-matter volume increases in hippocampal and frontal structures. Conclusions The cognitive and structural deficits in OSA may be secondary to sleep deprivation and repetitive nocturnal intermittent hypoxemia. These negative effects may be recovered by consistent and thorough treatment. Our findings highlight the importance of early diagnosis and successful treatment of this disorder.

Obstructive sleep apnea (OSA) is a highly prevalent worldwide public health problem that is characterized by repetitive upper airway collapse leading to intermittent hypoxia, pronounced negative intrathoracic pressures, and recurrent arousals resulting in sleep fragmentation. Obesity is a major risk factor of OSA and both of these two closely intertwined conditions result in increased sympathetic activity, oxidative stress, and chronic low-grade inflammation, which ultimately contribute, among other morbidities, to metabolic dysfunction, as reflected by visceral white adipose tissue (VWAT) insulin resistance (IR). Circulating extracellular vesicles (EVs), including exosomes, are released by most cell types and their cargos vary greatly and reflect underlying changes in cellular homeostasis. Thus, exosomes can provide insights into how cells and systems cope with physiological perturbations by virtue of the identity and abundance of miRNAs, mRNAs, proteins, and lipids that are packaged in the EVs cargo, and are secreted from the cells into bodily fluids under normal as well as diseased states. Accordingly, exosomes represent a novel pathway via which a cohort of biomolecules can travel long distances and result in the modulation of gene expression in selected and targeted recipient cells. For example, exosomes secreted from macrophages play a critical role in innate immunity and also initiate the adaptive immune response within specific metabolic tissues such as VWAT. Under normal conditions, phagocyte-derived exosomes represent a large portion of circulating EVs in blood, and carry a protective signature against IR that is altered when secreting cells are exposed to altered physiological conditions such as those elicited by OSA, leading to emergence of IR within VWAT compartment. Consequently, increased understanding of exosome biogenesis and biology should lead to development of new diagnostic biomarker assays and personalized therapeutic approaches. Here, the evidence on the major biological functions of macrophages and exosomes as pathophysiological effectors of OSA-induced metabolic dysfunction is discussed.

Obstructive sleep apnea syndrome (OSAS) is characterized by intermittent hypoxia (IH) during sleep due to recurrent upper airway obstruction. The derived oxidative stress (OS) leads to complications that do not only concern the sleep-wake rhythm but also systemic dysfunctions. The aim of this narrative literature review is to investigate molecular alterations, diagnostic markers, and potential medical therapies for OSAS. We analyzed the literature and synthesized the evidence collected. IH increases oxygen free radicals (ROS) and reduces antioxidant capacities. OS and metabolic alterations lead OSAS patients to undergo endothelial dysfunction, osteoporosis, systemic inflammation, increased cardiovascular risk, pulmonary remodeling, and neurological alterations. We treated molecular alterations known to date as useful for understanding the pathogenetic mechanisms and for their potential application as diagnostic markers. The most promising pharmacological therapies are those based on N-acetylcysteine (NAC), Vitamin C, Leptin, Dronabinol, or Atomoxetine + Oxybutynin, but all require further experimentation. CPAP remains the approved therapy capable of reversing most of the known molecular alterations; future drugs may be useful in treating the remaining dysfunctions.

Background Obstructive sleep apnea (OSA) is linked to brain alterations, but the specific regions affected and the causal associations between these changes remain unclear. Methods We studied 20 pairs of age-, sex-, BMI-, and education- matched OSA patients and healthy controls using multimodal magnetic resonance imaging (MRI) from August 2019 to February 2020. Additionally, large-scale Mendelian randomization analyses were performed using genome-wide association study (GWAS) data on OSA and 3935 brain imaging-derived phenotypes (IDPs), assessed in up to 33,224 individuals between December 2023 and March 2024, to explore potential genetic causality between OSA and alterations in whole brain structure and function. Results In the cohort study, OSA patients exhibited significantly lower fractional amplitude of low-frequency fluctuation and regional homogeneity in the right posterior cerebellar lobe and bilateral superior and middle frontal gyrus, while showing higher levels in the left occipital lobe and left posterior central gyrus. Decreased fractional anisotropy (FA) but increased apparent diffusion coefficient (ADC) was shown in the bilateral superior longitudinal fasciculus. According to the results of Affiliation file 2: table s6, it is the ADC value of right superior longitudinal fasciculus was shown a positive correlation with the lowest oxygen saturation. In the Mendelian randomization analyses, the area of left inferior temporal sulcus (OR: 0.89; 95% CI: 0.82–0.96), rfMRI connectivity ICA100 edge 893 (OR: 0.88; 95% CI: 0.82–0.96), ICA100 edge 951 (OR: 0.89; 95% CI: 0.82–0.97), and ICA100 edge 1213 (OR: 0.89; 95% CI: 0.82–0.96) were significantly decreased in OSA. Conversely, mean thickness of G-front-inf-Triangul in right hemisphere (OR: 1.14; 95% CI: 1.05–1.23), mean orientation dispersion index in right tapetum (OR: 1.13; 95% CI: 1.04–1.23), and rfMRI connectivity ICA100 edge 258 (OR: 1.13; 95% CI: 1.04–1.22) showed opposite results. Conclusions Nerve fiber damage and imbalances in neuronal activity across multiple brain regions caused by hypoxia, particularly the frontal lobe, underlie the structural and the functional connectivity impairments in OSA.