Study On The Risk Factors And Mechanism Of OSA In Narcolepsy

BackgroundNarcolepsy is a chronic sleep disorder associated with rapid eye movement sleep,which is mainly characterized by excessive daytime sleepiness.It can be divided into type 1(narcolepsy type 1,NT1)and type 2(narcolepsy type 2,NT2).In addition to the four common clinical symptoms,in recent years,some scholars have proposed that disrupted nighttime sleep(DNS)is the fifth main symptom.Among them,obstructive sleep apnea(OS A)is a common type of DNS.Because narcolepsy and OS A have similar clinical symptoms and high comorbidity rate,which may lead to more serious adverse outcomes and prognosis,it is urgent to pay attention to the comorbidity and possible mechanisms.Some previous clinical studies have found that obesity is a risk factor for OSA in both the general population and narcolepsy patients.However,there are still some limitations in the study of narcolepsy patients.For example,the study population is more a mixed population of NT1 and NT2,and the severity of OSA and obesity is not defined strictly according to the standards of different age groups.At present,there is no research report on the association among the level of cerebrospinal fluid Orexin-A and obesity,OSA and metabolic disorders in China.And whether there may be alterations of epigenetic mechanisms is unclear.Therefore,in view of the limitations of previous studies,our study will explore the association between obesity and the risk of OSA in narcolepsy from the clinical and mechanistic perspectives.Purpose1.Based on the 8-year cross-sectional data of a single center,the patients were grouped according to OSA and obesity severity criteria,and the comorbidity of OSA and obesity in patients with narcolepsy of different disease types and ages was compared and analyzed.2.The association between obesity(severity and BMI)and OSA(presence or absence and AHI)was analyzed according to different types(NT1 and NT2)and different ages(children and adolescents group and adults group)in order to explore the association and consistency between obesity and OSA in different types and ages.3.Explore the association among the level of cerebrospinal fluid Orexin-A,obesity and OSA in different ages NT1 patients,especially between the level of cerebrospinal fluid Orexin-A and metabolic disorders.4.Based on the epigenetic mechanism of DNA methylation,we prospectively explore the possible mechanism of comorbid OSA in narcolepsy.MethodSection 1Patients with excessive daytime sleepiness(EDS)in the sleep center of the Department of Neurology,the Second Affiliated Hospital of Air Force Military Medical University from January 2015 to January 2023 were retrospectively enrolled ed and divided into NT1 group,NT2 group and OSA group.We collected the demographic information,nighttime sleep and daytime symptoms,disease history,subjective questionnaires,polysomnography(PSG),multiple sleep latency test(MSLT)and other data.According to the 2022 version of the Expert Consensus on Obesity Prevention and Treatment in China,the obesity degree was graded.According to the Chinese guideline for the diagnosis and treatment of children obstructive sleep apnea in children(2020),the OSA grade of children and adolescents was graded.According to the International Classification of Sleep Disorders-3rd Edition(ICSD-3),adult OSA grading was performed.Section 2Patients with narcolepsy diagnosed according to ICSD-3 diagnostic criteria and without medication or other treatment who were treated in the sleep center of the Department of Neurology,Tangdu Hospital,Air Force Military Medical University from January 2015 to January 2023 were retrospectively included.According to different disease types(NT1 and NT2)and different ages(children,adolescents and adult groups),the association between obesity(severity and BMI)and OSA(presence or absence and AHI)was analyzed by multivariate logistic regression and linear regression.Section 3The third part included NT1 patients diagnosed according to ICSD-3 diagnostic criteria who were treated in the sleep center of the Department of Neurology,Tangdu Hospital,Air Force Military Medical University from May 2020 to January 2023.The data collected included demographic information,nighttime sleep and daytime symptoms,disease history,objective sleep monitoring,cerebrospinal fluid orexin-A level,blood routine,fasting blood glucose and blood lipids(total cholesterol,triglycerides,highdensity lipoprotein cholesterol,low-density lipoprotein cholesterol)and other data.The correlation analysis was used to explore the correlation between the decline of cerebrospinal fluid orexin-A level and obesity,OSA and metabolic disorders.Section 4We prospectively included NT1 patients who were treated in the sleep center of the Department of Neurology,Tangdu Hospital,Air Force Military Medical University from January 2022 to January 2023.The healthy control group was guaranteed to be of the similar age and same gender.The correlation analysis of DNA methylation was carried out to explore the epigenetic mechanism of DNA methylation,OSA and metabolic disorders in NT1.ResultsSection 1Through the comparative analysis of the clinical symptoms,objective sleep structure and anthropometric indicators of NT1,NT2 and OS A groups,it was found that:(1)the proportion of patients with EDS as the main complaint was higher than that of OSA.At the same time,the comorbid OSA in the narcolepsy group was as high as 42.4%,and the comorbid OSA in NT1 group was 37.9%and that in NT2 group was 54.3%,suggesting the similarity and high comorbidity of the symptoms of the two sleep disorders,which may increase the difficulty of disease differential diagnosis.(2)The proportion of cardiovascular disease in OSA group was significantly higher than that in narcolepsy group,and the proportion of hypertension and heart diseases in NT1 group was higher than that in NT2 group.The proportion of diabetes and hyperthyroidism in OSA group was higher than that in narcolepsy group,and the proportion of both NT1 group was higher than that in NT2 group,suggesting that narcolepsy also has adverse effects on cardiovascular and endocrine metabolic systems,and NT1 may have more significant effects than NT2.(3)The proportion of overweight in narcolepsy was 31.7%,and the proportion of obesity was 38.2%,suggesting a high comorbidity of narcolepsy and obesity.This study also found that the proportion of obesity in the adult group was significantly higher than that in the children and adolescent group(41.8%vs.26.8%),suggesting that the distribution of obesity in different subtypes of people is different,which may lead to different outcomes.(4)PSG results showed that both narcolepsy group and OSA group had nocturnal sleep disturbances,and OSA group was worse than narcolepsy group in total sleep time,sleep latency and sleep maintenance;MSLT results suggested that compared with OSA group,narcolepsy group had more obvious tendency of excessive daytime sleepiness.In addition,when analyzing the proportion of different stages before REM sleep periods in MSLT,it was found that the proportion of N1-SOREMP in narcolepsy was the highest,followed by W-SOREMP,and the proportion was significantly higher than that in OSA group,which may suggest that the characteristics of the sleep stage before REM sleep in MSLT may be helpful for the differential diagnosis of the disease in the future.Section 2This part of the study explored the association between obesity and OSA in different types of narcolepsy at different ages.The results showed that:(1)in the overall narcolepsy population,male gender and obesity were related to OSA(all P<0.05).Further analysis according to the disease type revealed that male gender and obesity in adult NT1 were related to OSA(all P<0.05),and as BMI increased by 5 units,AHI increased by 1 unit(P=0.041),It is suggested that obesity is a risk factor for comorbid OSA in adult NT1.(2)This part of the study did not find the association between obesity and OSA in children with narcolepsy,suggesting that there may be differences in the clinical phenotype of the disease between children and adolescents and adults.(3)Obesity is associated with OSA in adult NT1,but not in NT2,which may be due to the difference in the mechanism between NT1 and NT2.Section 3The results of this part found that in adult NT1,the decreased CSF orexin-A levels were negatively correlated with BMI,blood glucose,triglycerides,cholesterol and lowdensity lipoprotein levels(all P<0.05),suggesting that the decreased CSF orexin-A levels have an impact on obesity and glucose and lipid metabolism.Section 4This part based on the DNA methylation study of NT1 and normal control group found that:(1)The screened differentially methylated sites can better distinguish the two groups,especially the top 20 differentially methylated sites(including 10 hypermethylated sites and 10 hypomethylated sites).(2)The distribution on the genome is mainly concentrated in the intergenic,rather than CpG islands,and the CPG region where the differential site is located is mainly in the open sea region.It is presumed that methylation of the open region may lead to transcriptional abnormalities.(3)Go enrichment analysis revealed that the functions of differentially methylated genes were mainly concentrated in fatty acid oxidative metabolism,monocarboxylic acid metabolism,neuropeptide secretion,antigen processing and presentation process and ribosome composition.(4)KEGG enrichment analysis found that the differentiated genes were mainly involved in the immune process and ribosomal protein translation process,and the specific genes were HLA-DRB1、PRG2、RPL17 and RPL17-C18orf32.Conclusion1.Narcolepsy and OS A have a high comorbidity rate,and their clinical symptoms are similar,suggesting that they may lead to more serious adverse disease outcomes and prognosis,which should be paid attention to clinically.2.In adult NT1,obesity is related to OSA,and with the increase of BMI,AHI will also increase,suggesting that obesity is a risk factor for comorbid OS A in adult NT1.3.In adult NT1,the decrease of cerebrospinal fluid orexin-A level was negatively correlated with BMI,blood glucose,triglycerides,cholesterol and low-density lipoprotein levels,suggesting that the decrease of cerebrospinal fluid orexin-A level has an impact on obesity and glucose and lipid metabolism.4.The functions of differentially methylated genes in NT1 are mainly enriched in fatty acid oxidative metabolism,monocarboxylic acid metabolism,neuropeptide secretion,antigen processing and presentation process,and ribosome composition.At the same time,it is presumed that HLA-DRB1 gene may be related to narcolepsy and OSA.