Unraveling the Molecular Mechanisms of OSA-Related Cardiovascular Event Recurrence: A Post Hoc Analysis From the ISAACC Study.

RATIONALE: Although obstructive sleep apnea (OSA) is a prevalent condition among patients with acute coronary syndrome (ACS), the impact of OSA on cardiovascular event (CVE) recurrence is not homogeneous. We previously defined a specific phenotype of first-ACS patients without previous cardiovascular disease who are at increased risk of OSA-related CVE recurrence. However, the pathobiological mechanisms whereby OSA leads to adverse cardiovascular outcomes in this singular ACS phenotype remain to be investigated. OBJECTIVE: To characterize the molecular pathways that relate OSA with CVE recurrence. METHODS: This post hoc analysis of the ISAACC study (NCT01335087) included subjects without previous cardiovascular disease who were hospitalized for a first ACS and developed a recurrent CVE during the follow-up. Patients underwent respiratory polygraphy and fasting blood extraction during hospitalization. Two study groups were established on the basis of the apnea-hypopnea index (AHI): untreated severe OSA (AHI≥30events/h) and non-OSA (AHI<15events/h) groups. Proteomic profiling analysis included 276 cardiovascular and inflammatory-related plasma proteins via Olink® technology. RESULTS: Proteomics was performed in 58 patients (77.6% male, median [p25;p75] age 58.0 [51.2;65.8] years, and median BMI 28.6 [25.8;31.2]kg/m2). Thirty patients had severe OSA, and 28 subjects were considered non-OSA controls. A total of 24 plasma proteins were differentially expressed between the groups. Among these proteins, 18 were significantly associated with OSA severity parameters derived from respiratory polygraphy. Further bioinformatic analyses of OSA-related proteins revealed their involvement in several molecular pathways, mostly related to immune function, cell signaling, and inflammatory processes. CONCLUSION: A specific proteomic profile related to OSA presence and severity was identified in the plasma of ACS patients who developed recurrent CVEs. This analysis suggests the activation of key OSA-mediated molecular pathways with potential implications for cardiovascular prognosis.

The Effect of Obstructive Sleep Apnea on Subclinical Target Organ Damage in Patients With Resistant Hypertension.

INTRODUCTION: Among all patients with hypertension, those with resistant hypertension (RH) have the highest rates of subclinical organ damage (SOD). The prevalence of obstructive sleep apnea (OSA) is high in RH patients, and it could contribute to SOD. We aimed to investigate how OSA and its treatment are related to SOD in a large cohort of RH patients. METHODS: This is an ancillary analysis to the SARAH study, a multicentre observational cohort aiming to evaluate the impact of OSA on RH. Individuals with RH who were undergoing a sleep study and have information on at least one of the SOD variables (vascular, cardiac or renal damage) were selected. Patients were followed-up for three years. RESULTS: In total, 503 subjects were included. The participants were predominantly male, obese, and the median (IQR) apnea-hypopnea index (AHI) was 15.5 (7.90-31.5)events/h. No differences in the presence of vascular or cardiac damage were observed between OSA and non-OSA patients. A lower estimated glomerular filtration rate (eGFR) was observed in participants with OSA than in those without OSA, with an adjusted effect of -8.69mL/min/1.73m2 (-13.59, -3.79; p value<0.001). Kidney damage was also greater in subjects with OSA, with an adjusted OR (95% CI) of 1.77 (1.09, 2.87; p value=0.02). The eGFR showed a linear dose-response relationship with OSA severity. Among patients treated with CPAP, lower eGFR values were observed in noncompliant subjects. CONCLUSIONS: OSA could contribute to worsening renal function in patients with RH. No compliance with CPAP was associated with lower values of eGFR.

Predictors and markers of the cardiovascular impact of obstructive sleep apnoea.

PURPOSE OF REVIEW: Obstructive sleep apnoea (OSA) is the most common form of sleep-disordered breathing and has been linked to cardiovascular health. However, some of the findings supporting this are controversial. These discrepancies might be a result of heterogeneity among OSA patients, and thus, additional information would be required to better stratify OSA patients according to cardiovascular risk. In this review, we aim to discuss the potential of biomarkers to fulfil this role. RECENT FINDINGS: Randomized controlled trials have been unable to confirm whether OSA treatment with continuous positive airway pressure (CPAP) has a positive effect on cardiovascular outcomes. Emerging physiology-based metrics of OSA seem to be more suitable for identifying patients at higher risk of cardiovascular disease and predicting the effects of CPAP outcomes on cardiovascular health. Similarly, blood-based molecular markers have gained attention in this context over the last few years. SUMMARY: Accurate cardiovascular risk stratification and appropriate treatment allocation for OSA patients remain challenging. However, significant efforts are being made to develop novel tools to address these important issues.

Predicting Alzheimer's disease CSF core biomarkers: a multimodal Machine Learning approach.

Introduction: Alzheimer's disease (AD) is a progressive neurodegenerative disorder. Current core cerebrospinal fluid (CSF) AD biomarkers, widely employed for diagnosis, require a lumbar puncture to be performed, making them impractical as screening tools. Considering the role of sleep disturbances in AD, recent research suggests quantitative sleep electroencephalography features as potential non-invasive biomarkers of AD pathology. However, quantitative analysis of comprehensive polysomnography (PSG) signals remains relatively understudied. PSG is a non-invasive test enabling qualitative and quantitative analysis of a wide range of parameters, offering additional insights alongside other biomarkers. Machine Learning (ML) gained interest for its ability to discern intricate patterns within complex datasets, offering promise in AD neuropathology detection. Therefore, this study aims to evaluate the effectiveness of a multimodal ML approach in predicting core AD CSF biomarkers. Methods: Mild-moderate AD patients were prospectively recruited for PSG, followed by testing of CSF and blood samples for biomarkers. PSG signals underwent preprocessing to extract non-linear, time domain and frequency domain statistics quantitative features. Multiple ML algorithms were trained using four subsets of input features: clinical variables (CLINVAR), conventional PSG parameters (SLEEPVAR), quantitative PSG signal features (PSGVAR) and a combination of all subsets (ALL). Cross-validation techniques were employed to evaluate model performance and ensure generalizability. Regression models were developed to determine the most effective variable combinations for explaining variance in the biomarkers. Results: On 49 subjects, Gradient Boosting Regressors achieved the best results in estimating biomarkers levels, using different loss functions for each biomarker: least absolute deviation (LAD) for the Aß42, least squares (LS) for p-tau and Huber for t-tau. The ALL subset demonstrated the lowest training errors for all three biomarkers, albeit with varying test performance. Specifically, the SLEEPVAR subset yielded the best test performance in predicting Aß42, while the ALL subset most accurately predicted p-tau and t-tau due to the lowest test errors. Conclusions: Multimodal ML can help predict the outcome of CSF biomarkers in early AD by utilizing non-invasive and economically feasible variables. The integration of computational models into medical practice offers a promising tool for the screening of patients at risk of AD, potentially guiding clinical decisions.

The Hypoxic Burden, Clinical Implication of a New Biomarker in the Cardiovascular Management of Sleep Apnea Patients: A Systematic Review.

Background: Obstructive sleep apnea (OSA) is a highly prevalent sleep-disordered breathing. It is associated with adverse co-morbidities, being the most scientific evidence of cardiovascular (CV) disease. Currently, OSA is measured through the apnea-hypopnea index (AHI), the total number of respiratory events per hour of sleep. However, different studies have questioned its utility in OSA management, highlighting the need to search for new parameters that better reflect the heterogeneity of the disease. Hypoxic burden (HB) has emerged as a novel biomarker that informs about the frequency, duration and depth of the desaturation related to the respiratory events. We conducted a systematic review in order to find publications about the heterogeneity of OSA measured by HB and its associations with future disease. Methods: Systematic review was conducted using PubMed and Web of Science. The terms "sleep apne" and "hypoxic burden" were used to look for publications from the date of inception to August 15, 2023. Inclusion criteria: articles in English published in peer-reviewed journals. Exclusion criteria: (1) not available publications; (2) duplicated articles; (3) letters, editorials, and congress communications; (4) articles not including information about HB as a specific biomarker of OSA. Results: 33 studies were included. The results were classified in 2 main sections: (1) HB implication in the CV sphere: HB showed to be a better predictor of CV risk in OSA patients than traditional measures such as AHI with possible clinical management implication in OSA. (2) HB response to OSA treatment: pharmacological and nonpharmacological treatments have demonstrated to be effective in improving hypoxia measured through the HB. Conclusions: HB could be a better and more effective parameter than traditional measurements in terms of diagnosis, risk prediction and therapeutic decisions in patients with OSA. This measure could be incorporated in sleep units and could play a role in OSA management, driving the clinic to a more personalized medicine.

Long-term effect of obstructive sleep apnoea management on blood pressure in patients with resistant hypertension: the SARAH study.

BACKGROUND: There is a close relationship between obstructive sleep apnoea (OSA) and resistant hypertension (RH). However, studies assessing the long-term effect of diagnosing and treating OSA on blood pressure (BP) control in these patients are lacking. METHODS: To address this gap, we recruited 478 RH patients from hypertension units and followed them prospectively after they were screened for OSA through a sleep study. By performing 24-h ambulatory BP monitoring (ABPM) annually, the effect of OSA management was assessed. RESULTS: The patients had a median (interquartile range (IQR)) age of 64.0 (57.2-69.0) years, 67% were males and most were nonsleepy, with a median (IQR) apnoea-hypopnoea index (AHI) of 15.8 (7.9-30.7) events·h-1. The median (IQR) follow-up time was 3.01 (2.93-3.12) years. At baseline, severe OSA was associated with uncontrolled BP, nocturnal hypertension and a nondipper circadian BP pattern. Moreover, these patients had higher BP values during follow-up than did patients in the other groups. However, among patients with moderate and severe OSA, the management of sleep disordered breathing, including the implementation of continuous positive airway pressure treatment, was associated with a reduction in 24-h ABPM parameters, especially night-time BP values, at the 1-year follow-up. These benefits were attenuated over time and only subjects with severe OSA maintained an ABPM night-time reduction at 3 years. Furthermore, clinical variables such as uncontrolled BP, sex and age showed a predictive value for the BP response at 1 year of follow-up. CONCLUSION: A favourable long-term decrease in BP was detected by diagnosing and treating OSA in a cohort of RH patients from hypertension units, but over time this decrease was only partially maintained in severe OSA patients.

Effect of CPAP Treatment on Cardiovascular Outcomes.

INTRODUCTION: Randomized controlled trials (RCT) have not demonstrated a role for continuous positive airway pressure (CPAP) on the secondary prevention of major cardiovascular events in obstructive sleep apnea (OSA) patients. However, participants in RCTs are substantially different from real-world patients. Therefore, we aimed to assess the effect of CPAP treatment on major cardiovascular events in real-world OSA patients. METHODS: Population-based longitudinal observational study including all OSA patients with an active CPAP prescription at the beginning of 2011 in Catalonia, Spain, that terminated CPAP treatment during 2011 and did not have CPAP prescriptions between 2012-2015; and propensity-score-matched OSA patients that continued CPAP treatment until the end of 2015 or death. Adjusted hazard ratios were used to assess the association between CPAP treatment and overall and cardiovascular mortality, cardiovascular hospitalizations, or major adverse cardiovascular events (MACEs). RESULTS: 3638 CPAP terminators and 10,914 propensity-score-matched continuators were included (median age 67 [57-77] years, 71.4% male). During a median follow-up of 47.9 months CPAP continuators showed a lower risk of cardiovascular death than terminators (hazard ratio [HR]: 0.61; 95% confidence interval [CI]: 0.50-0.75) after adjusting by age, sex and key comorbidities. Similar results were found for cardiovascular hospitalizations (HR: 0.87; 95% CI: 0.76-0.99) and MACEs (HR: 0.84; 95% CI: 0.75-0.95). CONCLUSION: CPAP treatment continuation could be associated with a significantly lower risk of major cardiovascular events in real-world OSA patients. This result highlights the importance of including real-world patients in studies on OSA.

ERS International Congress 2023: highlights from the Sleep Disordered Breathing Assembly.

The topic of sleep-related breathing disorders is always evolving, and during the European Respiratory Society (ERS) International Congress 2023 in Milan, Italy, the latest research and clinical topics in respiratory medicine were presented. The most interesting issues included new diagnostic tools, such as cardiovascular parameters and artificial intelligence, pathophysiological traits of sleep disordered breathing from routine polysomnography or polygraphy signals, and new biomarkers and the diagnostic approach in patients with excessive daytime sleepiness. This article summarises the most relevant studies and topics presented at the ERS International Congress 2023. Each section has been written by early career members of ERS Assembly 4.

Obstructive sleep apnea and cardiovascular risk. / Apnea obstructiva del sueño y riesgo cardiovascular.

Patients with obstructive sleep apnea (OSA) experience repetitive episodes of upper airway obstruction due to recurrent collapse during sleep. This leads to intermittent hypoxia episodes, which, through complex pathophysiological mechanisms, trigger sympathetic overactivation, endothelial dysfunction, hypercoagulation, and metabolic dysregulation. Consequently, other cardiovascular risk factors such as hypertension, metabolic syndrome, and diabetes are induced. Furthermore, this enhances target organ damage, affecting the heart, arteries, and kidneys, leading to an increased risk of cardiovascular morbidity and mortality. Among the various treatments for OSA, Continuous Positive Airway Pressure (CPAP) has been extensively studied. To date, this treatment has shown mild benefits in reducing blood pressure, particularly noticeable in patients with resistant hypertension. Furthermore, CPAP treatment appears to reduce cardiovascular events, both in primary and secondary prevention, though this benefit is limited to individuals with good compliance (CPAP use ≥4h/night). Future research perspectives in OSA seem to focus on identifying patients in whom the condition significantly influences cardiovascular risk, thus determining those who would benefit the most from treatment in the reduction of cardiovascular risk.

Heterogeneous Effects of Continuous Positive Airway Pressure in Non-Sleepy Obstructive Sleep Apnea on Cardiovascular Disease Outcomes: Post Hoc Machine Learning Analysis of the ISAACC Trial (ECSACT Study).

Rationale: Randomized controlled trials of continuous positive airway pressure (CPAP) therapy for cardiovascular disease (CVD) prevention among patients with obstructive sleep apnea (OSA) have been largely neutral. However, given that OSA is a heterogeneous disease, there may be unidentified subgroups demonstrating differential treatment effects. Objectives: We sought to apply a novel data-drive approach to identify nonsleepy OSA subgroups with heterogeneous effects of CPAP on CVD outcomes within the Impact of Sleep Apnea Syndrome in the Evolution of Acute Coronary Syndrome (ISAACC) study. Methods: Participants were randomly partitioned into two datasets. One for training (70%) our machine-learning model and a second (30%) for validation of significant findings. Model-based recursive partitioning was applied to identify subgroups with heterogeneous treatment effects. Survival analysis was conducted to compare treatment (CPAP vs. usual care [UC]) outcomes within subgroups. Results: A total of 1,224 nonsleepy OSA participants were included. Of 55 features entered into our model, only two appeared in the final model (i.e., average OSA event duration and hypercholesterolemia). Among participants at or below the model-derived average event duration threshold (19.5 s), CPAP was protective for a composite of CVD events (training hazard ratio [HR], 0.46; P = 0.002). For those with longer event duration (>19.5 s), an additional split occurred by hypercholesterolemia status. Among participants with longer event duration and hypercholesterolemia, CPAP resulted in more CVD events compared with UC (training HR, 2.24; P = 0.011). The point estimate for this harmful signal was also replicated in the testing dataset (HR, 1.83; P = 0.118). Conclusions: We discovered subgroups of nonsleepy OSA participants within the ISAACC study with heterogeneous effects of CPAP. Among the training dataset, those with longer OSA event duration and hypercholesterolemia had nearly 2.5 times more CVD events with CPAP compared with UC, whereas those with shorter OSA event duration had roughly half the rate of CVD events if randomized to CPAP.

Metabolipidomic Analysis in Patients with Obstructive Sleep Apnea Discloses a Circulating Metabotype of Non-Dipping Blood Pressure.

A non-dipping blood pressure (BP) pattern, which is frequently present in patients with obstructive sleep apnea (OSA), confers high cardiovascular risk. The mechanisms connecting these two conditions remain unclear. In the present study we performed a comprehensive analysis of the blood metabolipidome that aims to provide new insights into the molecular link between OSA and the dysregulation of circadian BP rhythmicity. This was an observational prospective longitudinal study involving adults with suspected OSA who were subjected to full polysomnography (PSG). Patients with an apnea-hypopnea index ≥ 5 events/h were included. Fasting plasma samples were obtained the morning after PSG. Based on the dipping ratio (DR; ratio of night/day BP values) measured via 24 h ambulatory BP monitoring, two groups were established: dippers (DR ≤ 0.9) and non-dippers (DR > 0.9). Treatment recommendations for OSA followed the clinical guidelines. Untargeted metabolomic and lipidomic analyses were performed in plasma samples via liquid chromatography-tandem mass spectrometry. Non-dipper patients represented 53.7% of the cohort (88/164 patients). A set of 31 metabolic species and 13 lipidic species were differentially detected between OSA patients who present a physiologic nocturnal BP decrease and those with abnormal BP dipping. Among the 44 differentially abundant plasma compounds, 25 were putatively identified, notably glycerophospholipids, glycolipids, sterols, and fatty acid derivates. Multivariate analysis defined a specific metabotype of non-dipping BP, which showed a significant dose-response relationship with PSG parameters of OSA severity, and with BP dipping changes after 6 months of OSA treatment with continuous positive airway pressure (CPAP). Bioinformatic analyses revealed that the identified metabolipidomic profile was found to be implicated in multiple systemic biological pathways, with potential physiopathologic implications for the circadian control of BP among individuals with OSA.

Sleep and Breathing Conference highlights 2023: a summary by ERS Assembly 4.

This paper presents some of the highlights of the Sleep and Breathing Conference 2023 https://bit.ly/46MxJml.

Adherence to CPAP Treatment and the Risk of Recurrent Cardiovascular Events: A Meta-Analysis.

Importance: The effect of continuous positive airway pressure (CPAP) on secondary cardiovascular disease prevention is highly debated. Objective: To assess the effect of CPAP treatment for obstructive sleep apnea (OSA) on the risk of adverse cardiovascular events in randomized clinical trials. Data Sources: PubMed (MEDLINE), EMBASE, Current Controlled Trials: metaRegister of Controlled Trials, ISRCTN Registry, European Union clinical trials database, CENTRAL (Cochrane Central Register of Controlled Trials), and ClinicalTrials.gov databases were systematically searched through June 22, 2023. Study Selection: For qualitative and individual participant data (IPD) meta-analysis, randomized clinical trials addressing the therapeutic effect of CPAP on cardiovascular outcomes and mortality in adults with cardiovascular disease and OSA were included. Data Extraction and Synthesis: Two reviewers independently screened records, evaluated potentially eligible primary studies in full text, extracted data, and cross-checked errors. IPD were requested from authors of the selected studies (SAVE [NCT00738179], ISAACC [NCT01335087], and RICCADSA [NCT00519597]). Main Outcomes and Measures: One-stage and 2-stage IPD meta-analyses were completed to estimate the effect of CPAP treatment on risk of recurrent major adverse cardiac and cerebrovascular events (MACCEs) using mixed-effect Cox regression models. Additionally, an on-treatment analysis with marginal structural Cox models using inverse probability of treatment weighting was fitted to assess the effect of good adherence to CPAP (≥4 hours per day). Results: A total of 4186 individual participants were evaluated (82.1% men; mean [SD] body mass index, 28.9 [4.5]; mean [SD] age, 61.2 [8.7] years; mean [SD] apnea-hypopnea index, 31.2 [17] events per hour; 71% with hypertension; 50.1% receiving CPAP [mean {SD} adherence, 3.1 {2.4} hours per day]; 49.9% not receiving CPAP [usual care], mean [SD] follow-up, 3.25 [1.8] years). The main outcome was defined as the first MACCE, which was similar for the CPAP and no CPAP groups (hazard ratio, 1.01 [95% CI, 0.87-1.17]). However, an on-treatment analysis by marginal structural model revealed a reduced risk of MACCEs associated with good adherence to CPAP (hazard ratio, 0.69 [95% CI, 0.52-0.92]). Conclusions and Relevance: Adherence to CPAP was associated with a reduced MACCE recurrence risk, suggesting that treatment adherence is a key factor in secondary cardiovascular prevention in patients with OSA.

Aquatic therapy improves self-reported sleep quality in fibromyalgia patients: a systematic review and meta-analysis.

BACKGROUND: This systematic review and meta-analysis aimed to evaluate the effectiveness of aquatic therapy on pain, sleep quality, psychological symptoms, quality of life, and health status in people diagnosed with fibromyalgia. METHODS: We searched PubMed, CINAHL, The Cochrane Library, PEDro and Scopus databases. Articles were eligible if they were randomised controlled trials (RCTs) analysing the effects of aquatic therapy in adult people diagnosed with fibromyalgia, and published by October of 2022 in English or Spanish. The Cochrane Risk of Bias tool was employed to conduct the methodological quality assessment of the encompassed studies, and the overall quality of evidence for each comparison was determined using the GRADE approach. RESULTS: Of 375 articles found, 22 met the inclusion criteria. Forest plot analysis of Pittsburgh sleep quality index at short- and mid-term follow-up showed a trend in favour of aquatic therapy, although not statistically significant, with weighted mean difference (WMD) = -1.71 (95% CI: -4.17 to -0.75, p = 0.17). Heterogeneity was substantial (χ2 = 8.74, df = 5 (p < 0.000001; I2 = 95%). Relating the pain outcome by fibromyalgia impact questionnaire (FIQ) short term showed a trend in favour of the aquatic therapy group with WMD = -5.04 (95% CI: - 9.26 to - 0.82, p =  = 0.02) with heterogeneity χ2 = 11.07, df = 4 (p = 0.03; I2 = 64%). Great heterogeneity was found between trials in medium term. CONCLUSION: This systematic review and meta-analysis demonstrated the effectiveness of aquatic therapy as an adjunct treatment to usual care in people suffering from fibromyalgia. Aquatic therapeutic exercise improves the symptomats of sleep quality, pain, and quality of life of adults with fibromyalgia. Further research on long-term outcomes may contribute to the currently available evidence.

Hypoxic burden to guide CPAP treatment allocation in patients with obstructive sleep apnoea: a post hoc study of the ISAACC trial.

BACKGROUND: Hypoxic burden (HB) has emerged as a strong predictor of cardiovascular risk in obstructive sleep apnoea (OSA). We aimed to assess the potential of HB to predict the cardiovascular benefit of treating OSA with continuous positive airway pressure (CPAP). METHODS: This was a post hoc analysis of the ISAACC trial (ClinicalTrials.gov: NCT01335087) including non-sleepy patients with acute coronary syndrome (ACS) diagnosed with OSA (apnoea-hypopnoea index ≥15 events·h-1) by respiratory polygraphy. Patients were randomised to CPAP or usual care and followed for a minimum of 1 year. HB was calculated as the total area under all automatically identified desaturations divided by total sleep time. Patients were categorised as having high or low baseline HB according to the median value (73.1%min·h-1). Multivariable Cox regression models were used to assess whether the effect of CPAP on the incidence of cardiovascular outcomes was dependent on the baseline HB level. RESULTS: The population (362 patients assigned to CPAP and 365 patients assigned to usual care) was middle-aged (mean age 59.7 years), overweight/obese and mostly male (84.5%). A significant interaction was found between the treatment arm and the HB categories. In the high HB group, CPAP treatment was associated with a significant reduction in the incidence of cardiovascular events (HR 0.57, 95% CI 0.34-0.96). In the low HB group, CPAP-treated patients exhibited a trend toward a higher risk of cardiovascular outcomes than those receiving usual care (HR 1.33, 95% CI 0.79-2.25). The differential effect of the treatment depending on the baseline HB level followed a dose-response relationship. CONCLUSION: In non-sleepy ACS patients with OSA, high HB levels were associated with a long-term protective effect of CPAP on cardiovascular prognosis.

Cerebrospinal fluid lipidomic fingerprint of obstructive sleep apnoea in Alzheimer's disease.

BACKGROUND: Obstructive sleep apnoea (OSA) has a high prevalence in patients with Alzheimer's disease (AD). Both conditions have been shown to be associated with lipid dysregulation. However, the relationship between OSA severity and alterations in lipid metabolism in the brains of patients with AD has yet to be fully elucidated. In this context, we examined the cerebrospinal fluid (CSF) lipidome of patients with suspected OSA to identify potential diagnostic biomarkers and to provide insights into the pathophysiological mechanisms underlying the effect of OSA on AD. METHODS: The study included 91 consecutive AD patients who underwent overnight polysomnography (PSG) to diagnose severe OSA (apnoea-hypopnea index ≥ 30/h). The next morning, CSF samples were collected and analysed by liquid chromatography coupled to mass spectrometry in an LC-ESI-QTOF-MS/MS platform. RESULTS: The CSF levels of 11 lipid species were significantly different between AD patients with (N = 38) and without (N = 58) severe OSA. Five lipids (including oxidized triglyceride OxTG(57:2) and four unknown lipids) were significantly correlated with specific PSG measures of OSA severity related to sleep fragmentation and hypoxemia. Our analyses revealed a 4-lipid signature (including oxidized ceramide OxCer(40:6) and three unknown lipids) that provided an accuracy of 0.80 (95% CI: 0.71-0.89) in the detection of severe OSA. These lipids increased the discriminative power of the STOP-Bang questionnaire in terms of the area under the curve (AUC) from 0.61 (0.50-0.74) to 0.85 (0.71-0.93). CONCLUSIONS: Our results reveal a CSF lipidomic fingerprint that allows the identification of AD patients with severe OSA. Our findings suggest that an increase in central nervous system lipoxidation may be the principal mechanism underlying the association between OSA and AD.

Breathing cessation events that compose the apnea-hypopnea index are distinctively associated with the adverse outcomes in Alzheimer's disease.

BACKGROUND: Previous studies challenge the impact of obstructive sleep apnea (OSA) once patients are diagnosed with Alzheimer's disease (AD). Nevertheless, OSA recognizably disrupts sleep, and relevant associations between sleep, AD pathological markers, and cognition have been demonstrated. We aimed to further explore this, evaluating the associations between each breathing cessation event that compose the apnea-hypopnea index (AHI) and the sleep structure to finally investigate whether this was related to increased levels of AD markers and higher cognitive decline. METHODS: Observational, prospective study, including consecutive patients diagnosed with mild-moderate AD. The participants were submitted to overnight polysomnography followed by a cerebrospinal fluid collection for AD pathological markers levels determination. Neuropsychological assessment was performed at baseline and after 12 months of follow-up. RESULTS: The cohort was composed of 116 patients (55.2% females) with a median [p25;p75] age of 76.0 [72.0;80.0] years and an AHI of 25.9 [15.1;48.5], which was mainly defined by the presence of hypopneas and obstructive apneas. These were distinctively associated with the sleep structure, with obstructive apneas being related to arousals and sleep lightening and hypopneas being related to an increased number of arousals only. Despite having a lower frequency, mixed and central apneas also presented associations with the sleep structure, particularly increasing the time spent in the lighter sleep stages. In relation to AD pathological markers, obstructive and mixed apneas were related to an augment in neurofilament light levels while hypopneas were associated with a higher phosphorylated-tau/amyloid-beta protein ratio. Hypopneas were the most important event for an increased cognitive decline at the 12-month follow-up. CONCLUSIONS: Our findings highlight the importance of a patient-centered approach, with a comprehensive and detailed analysis of the AHI to effectively predict the different outcomes and tailor the appropriate therapeutic strategies.