【作者】 岳伟华；

【导师】 郝伟； 刘破资；

【作者基本信息】 中南大学 ， 精神病学与精神卫生学， 2003， 博士

【摘要】 理论假设： 睡眠呼吸暂停综合征是一种常见的睡眠疾病，一般人群中的发病率为2％～4％，老年人中发病率为20％～40％。其发病率随着年龄和肥胖程度的增加而增加，且男性发病率是女性的2～4倍。近年来，SAS因其心血管和神经认知功能方面的后果引起了医学界的重视。由于SAS患者反复出现夜间憋醒和血氧饱和度下降，故睡眠质量受到严重影响。但由于缺乏统一的临床评估工具，SAS患者的白天功能，包括心理状况、认知功能等，所得研究结论纷纭不一。文献报道，NO、5-HT和CA在睡眠和呼吸的调节过程中起重要作用，且一些能够改变NO、5-HT和CA水平的药物，对SAS有一定的治疗作用，故推测此几种物质参与了SAS的发生和相关功能损害的神经生化机制。此外，流行病学研究表明，SAS是一种有明显家族聚集性的疾病，但迄今为止，有关该病的遗传方式和遗传易感位点的研究尚无为大家所接受的结论。考虑到5-HT系统参与睡眠呼吸的调节，以及5-羟色胺转运体(5-HTT)能影响神经递质5-HT的回吸收和体液中的有效浓度，是多种有效治疗SAS的SSRI类药物的作用靶点，我们选择5-HTT基因的两个重要的功能性位点——启动子区缺失／插入多态性(LPR)和第2内含子可变数目串联重复区多态性(VNTR)，作为研究的切入点，进行关联分析，以了解SAS的遗传特性。 目的： 了解SAS患者的夜间睡眠模式、临床特征(包括白天困倦程度、心理和神经认知功能)，初步探讨夜间各睡眠变量对患者白天功能的影响情况；进一步探讨SAS发病及相关功能损害可能的神经生化学机制；初步探讨SAS的遗传易感因素。博士学位论文 中文摘要 方法： 采用病例对照研究方法，对78例 SAS患者和 30例正常对照者进行整夜多导睡眠仪监测，勾画出SAS患者独特的夜间睡眠特征，初步探讨不同肥胖程度和低氧血症的SAS患者的睡眠差异；另一方面，应用相关临床评定量表或工具对45例SAS患者和30例正常对照者白天精力、心理状态、认知功能等进行评定，了解SAS患者的白天功能状况：在此基础上，通过血浆＊0、5KT和多种＊A水平检测，探讨SAS及其相关功能损害的可能神经生化学机制；采用聚合酶链式反应技术，检测45例SAS患者和55例正常对照组的5．羟色胺转运体基因启动子区LRP和第2内含于VNTR多态性，分别对所得基因型和等位基因的频率进行相关统计学分析；应用相关分析统计方法，对上述各变量进行关联分析，了解其间的内在关联，推测SAS发生和相关功能损害可能的分子生物学机制；并对不同基因型SAS患者的临床特征和生化机制的异质性进行初步探讨。 结果： 1．与正常对照组相比，SAS患者存在明显的睡眠结构紊乱，表现为：①深睡眠（Ill、IV期NREM睡眠）比例减少、浅睡眠u、11期NREM睡眠）相对增加，REM期睡眠减少，觉醒增加，睡眠潜伏期缩短等。②不同严重程度夜间低氧血症的SAS患者之间，TST、SE、N’REM睡眠时间、觉醒比例、AHI、夜间最快心率差异有显著性p刀刀5人 并以血氧饱和度下降最低值的S＊S组指标异常最为显著。③不同BMI组的SAS患者的睡眠效率、N’REM睡眠I期比例和REM周期、低通气指数、夜间平均SaO乔呼吸暂停时期最快心率存在统计学差异①刃．05人 并以超肥胖组SAS患者睡眠、呼吸、血氧饱和度、迷走神经功能受损最为严重。 2．SAS患者临床特征突出：①常见临床症状为：睡眠打鼾、睡眠不解困乏、夜间易醒、憋醒等；②SAS组白天困倦量表ESS总分高于正常对照组，差异有显著性①＜0．01＼③SAS患者SCL刁0总因博士学位论文 中文摘要子分以及躯体化、强迫、敌意、抑郁、焦虑和附加因子分高于对照组①＜O．05）；相关分析表明，S＊S患者的心理症状与夜间总睡眠时间、NREM睡眠1期比例、睡眠潜伏期呈显著负相关，与觉醒比例、N’REM睡眠立期比例、白天困倦量表总分呈显著正相关（OO．2，P＜0．05），与呼吸紊乱变量 AH、in SaO邢无显著相关r＜0．2）。 3．SAS患者神经认知功能较正常对照组差：①SAS患者总记忆商数及即刻、短时记忆因子得分低于正常对照组，差异有显著性 仔＜o．0门；②与正常对照组相比，＊＊S患者在数字符号、填图西因子方面得分较低，差异有显著性冲幻05人而在木块图、图形排列、拼图、总操作智商方面，两组无显著性差异（P＞0刀5人③SAS患者在中等难度划销测验项目上得分低于正常对照组，差异有统计学意义 0功“），在难度较小和难度较大的项目上得分两组间无显著差异 （P＞0．05）。 4．SAS患者的血浆NOI－HT和5－HI批水平均低于正常对照组 0d．05），相反，8＊S组血浆NE水平则高于正常对照组oJ05人 5．相关分析结果表明：①浅睡眠比例与血浆5KT水平正相关，与血浆NO水平负相关；觉醒次数和比例与血浆5－HT水平正相关，与NE水平负相关；深睡眠比例与血浆NO、NE水平正相关；睡眠潜伏期与血浆NO水平负相关，与血浆NE水平正相关；Alll与血浆NO水平负相关，MinsaOZ与血浆NO、5－HT水平正相关（rro．2?更多还原

【Abstract】 Background:Sleep apnea syndrome (SAS) is a common sleep disorder, prevalent in approximately 2% to 4% of adult people. Its frequency increases with increased age and body mass index (BMI), and the incidence rate for men is about two to nine times than in women. The patients with SAS suffer from fragmented sleep and decreased arterial oxygen saturations, but it is still unclear whether SAS is a cause of mental changes and psychiatric abnormalities in some of these patients. Previous reports have linked SAS with cardiovascular morbidity, depression, anxiety and cognitive deficits. The severity and mechanisms of these impairments are yet uncertain. Previous studies demonstrated several lines of pharmacological, neurobehavioral and therapeutic evidence implicated nitric oxide (NO), serotonin (5-HT) and catecholamines (CA) in the pathogenesis of regulation of sleep and respiration. Moreover, SAS has been shown to aggregate significantly within families. Although there have been many researches had paid attention to the genotypic markers for this condition, no certain genetic vulnerabilities for SAS have been found. The serotonin transporter (5-HTT) reuptakes serotonin into the pre-synaptic neuron. Most antidepressants block the action of 5-HTT and can also treat the major depression or sleep disorders. Two common polymorphisms have been described in the 5-HTT gene: a deletion/ insertion of 44bp in the promoter region approximately 1kb upstream of the transcription site (5-HTTLPR) and a Variable-Number-Tandem-Repeat (VNTR) region containing 9, 10 or 12 copies of a 17bp repeat element located in intron 2 (5-HTTVNTR). Therefore, we evaluated the roles of the 5-HTTLPR and VNTR in SAS and impaired sleep or daytimefunctions of this condition. Study objectives:To evaluate the association between SAS and sleep disturbant patterns, psychological abnormalities or cognitive impairment. Another purpose of this study was to evaluate the possible roles of nitric oxide, serotonin and catecholamines in the pathogenesis of sleep apnea. The third objective was to identify polymorphisms of the serotonin transporter gene and to find out whether there was correlation between any such polymorphisms and the occurrence of sleep apnea. Methods:The study comprised 78 patients diagnosed as SAS who refered to the sleep laboratories and then underwent a whole-night polysomno-graphic examination. The study population was stratified into subgroups based on MinSaO2 and BMI. Of 78 patients with SAS, 45 subjects completed psychological and cognitive examination. Thirty healthy controls underwent the same examination. In 45 patients and 30 healthy controls, NO, 5-HT and CA levels were measured in peripheral venous blood samples by chemiluminescence and high-performance liquid chro-matography (HPLC), respectively. The frequencies of the different forms of the genotypes and alleles of 5-HTT gene was analysed in 45 patients with SAS and 55 healthy controls. Results:1. Compared with healthy controls, SAS patients suffered more from disturbed or fragmented sleep, (i). In addition to intermittent nocturnal hypoxemia and apneic attacks, stages of sleep were also disturbed, such as decreased SWS% and REM%, increased S1% or S2% and brief arousal frequency from sleep, etc. And the latency of sleep in SAS group was significantly shorter than that in control group (P<0.05).(ii). The sleep disturbance within the group of severe nocturnal hypoxemia (Min SaO2<60%) was significantly more prominent than in both mild and moderate hypoxemic groups (P<0.05). (iii). The sleep structure, respiration and heart rate were most disturbed in the group of severe fat patients (BMI>30.01kg/m2) than in the two other groups in SAS patients (P<0.05).2. Compared with, healthy controls, SAS patients suffered from striking clinical features, including impaired daytime functions, (i). The common clinical complaints were snoring, unrefreshing sleep, daytime sleepiness, choking episodes, etc. (ii). The total scores of ESS in SAS group were significantly hig更多还原