OSAS患者尿中AD7c-NTP和血清SAA水平的研究及MMSE对治疗效果的评价

发布时间：2018-06-30 20:09

本文选题：睡眠呼吸暂停 + 阻塞性　；参考：《山东大学》2011年硕士论文

【摘要】：背景：阻塞性睡眠呼吸暂停综合征(obstructive sleep apnea syndrome, OSAS)能导致患者出现认知障碍,据研究,患者出现认知障碍的发生机制主要和慢性、反复性、可逆性的夜间低氧与睡眠结构紊乱有关。缺氧敏感区脑组织的病理生理改变可能就是OSAS患者产生认知障碍的病理基础。有关研究表明,OSAS患者的认知障碍表现为全面的认知功能缺损,并且可能与老年痴呆症(senile dementia, SD)有一定的相关性。随着科技的发展,神经影像技术等检查方法的进步和应用,增加了对OSAS患者认知功能的评估手段,但仍然不够完善,仍有待建立一套特异性高、可操作性强的临床评价体系。阿尔茨海默病相关神经丝蛋白(Alzheimer-associated neuronalthread protein, AD7c-NTP)是神经丝蛋白家族中的一个成员,它在神经元中表达,并定位于生发神经细胞的轴突,在早期或中度SD患者的皮层神经元、脑组织抽提物、脑脊液中都有升高,并且其含量与痴呆的严重程度成正比。国外有关研究发现,检测SD患者尿样中AD7c-NTP能达到与检测脑脊液中其含量同样的效果。尿中AD7c-NTP的检测作为一种无创性的检查更容易被患者接受,也更易于在临床上推广。血清淀粉样蛋白A (serum amyloid A protein, SAA)是人体主要急性时相蛋白之一,受炎性细胞因子的正性调节,这些炎性细胞因子包括白细胞介素-1(IL-1)和白细胞介素-6(IL-6)等。SAA主要由肝脏合成,并且以高密度脂蛋白(HDL)颗粒中载脂蛋白的一种主要成分分泌。SAA可以在SD患者的大脑中积聚,此现象可能与慢性大脑炎症有关,并且可能导致神经元的损耗和白质的损伤。OSAS患者血清中SAA浓度的持续升高有助于解释OSAS患者心血管疾病及痴呆发病率增加的原因。简易精神状态量表(Mini-Mentalstat Examination, MMSE)可做简单的智力状态检查,评价所采取干预措施的疗效,MMSE是认知检查中最常用的一个量表,它可以评价受试者的方位定向、计算力、短时记忆、语言复述、视觉空间认知、结构模仿以及执行能力。MMSE包括：①方位定向力：时间定向力(5分)和地点定向力(5分)；②短时记忆力：即刻记忆力(3分)；延迟回忆力(3分)；③语言能力：命名(2分)、复述(1分)、书写(1分)；④视空间认知能力(1分)；⑤执行能力(4分)；⑥计算力(5分)。MMSE共计30分。方法：依据2009年中华耳鼻咽喉--头颈外科杂志编辑委员会,中华医学会耳鼻咽喉--头颈外科学分会咽喉学组,关于阻塞性睡眠呼吸暂停综合征的诊断依据,选择2009年5月至2010年10月在山东大学第二医院诊断为OSAS的门诊或住院的患者,根据多导睡眠监测(polysomnography, PSG)中的呼吸暂停低通气指数(apnea-hypopnea index, AHI)的结果,将52例仅患OSAS的患者分为轻度OSAS组(n=11),中度OSAS组(n=12)和重度OSAS组(n=29)。另选18例在门诊查体的年龄及体重指数(body mass index, BMI)与实验组相匹配的健康者作为对照组。以AD7c-NTP及SAA酶联免疫吸附法(enzyme-linked immunosorbent assays, ELISA)测定和比较各组间晨尿AD7c-NTP及上午6：00时的血清SAA浓度。此外,将OSAS患者的AD7c-NTP, SAA水平分别与AHI和最低血氧饱和度(the lowest arterial oxygen saturation, LSaO2)作相关性分析。正常组、实验组及实验组应用MMSE评价实验组与正常对照组的认知功能差别以及实验组经3个月的持续正压通气治疗(continuous positive airways pressure, CPAP)前后的认知功能差别。所有数据均经SPSS 17.0 for windows软件进行统计学处理,包括方差齐性检验、t检验,以及相关性分析等。结果：各组间年龄、体重指数无显著差异,但多导睡眠监测指标AHI, LSaO2组间差异非常显著(P0.01),并随OSAS患者程度的加重而增高。正常对照组AD7c-NTP、SAA浓度分别是(1.56±0.67) ng/ml、(6.22±2.63μg/ml),与此相比,实验组AD7c-NTP在轻度组无明显升高、但SAA浓度在轻度组就明显升高,AD7c-NTP为1.63±0.87 n g/ml (P=0.4)、SAA为11.13±3.41μg/ml (P 0.05);中度OSAS组AD7c-NTP为2.06±0.64 n g/ml (P0.05), SAA为18.37±1.17μg/ml (P0.01);重度OSAS组AD7c-NTP为2.20±0. 83 n g/ml (P0.005), SAA为23.76±2.94μg/ml (P 0.01)。OSAS各组间AD7c-NTP、SAA浓度亦有显著差异。OSAS各组患者尿液AD7c-NTP含量与其AHI呈显著正相关,其相关系数r为0.48(P0.05)；与夜间LSaO,呈显著负相关,其相关系数r为-0.56(P0.05)。相关性分析还显示OSAS患者SAA浓度与AHI呈显著正相关,相关系数r为0.90(P0.001),与LSaO,之间呈显著负相关,相关系数r为-0.85(P0.001)。实验组与正常对照组之间及实验组经CPAP治疗前后的定向力(时间定向力和地点定向力)、记忆力(即刻记忆力、延迟回忆力)、语言能力(命名、复述、书写；视空间能力)、执行能力、计算力均无明显统计学差异(P0.05)。结论：OSAS患者尿液AD7c-NTP及血清SAA浓度较正常对照组显著增高,且与OSAS的严重程度相关。AD7c-NTP及SAA浓度的升高可能与OSAS患者罹患老年痴呆症的高危状态有关。实验组与正常对照组相比较及实验组经3个月的CPAP治疗前后智能精神状态无明显统计学差异,分析可能与患病和(或)治疗时间过短以及MMSE作为认知功能减退的随访工具亦不够敏感所致。
[Abstract]:Background: obstructive sleep apnea syndrome (OSAS) can cause cognitive impairment in patients. According to the study, the pathogenesis of cognitive impairment is mainly and chronic, the recurrent, reversible nocturnal hypoxia is related to the disorder of sleep structure. The pathophysiological changes in the brain tissue in the hypoxic sensitive area may be altered. This is the pathological basis of cognitive impairment in patients with OSAS. Studies have shown that cognitive impairment in OSAS patients is characterized by comprehensive cognitive impairment and may be associated with Alzheimer's disease (senile dementia, SD). With the development of science and technology, the progress and application of the methods of neuroimaging techniques, such as neuroimaging techniques, have increased the incidence of OSAS. Alzheimer-associated neuronalthread protein (AD7c-NTP), a member of the neurofilament family, is a member of the neurofilament family, which is located in the neuron and is located in the neuron. The axons of the germinal nerve cells were increased in the cortical neurons, brain tissue extracts and cerebrospinal fluid in the early and moderate SD patients, and their content was proportional to the severity of the dementia. Foreign related studies abroad found that the same effect of AD7c-NTP in the urine samples of patients with SD was detected. Urine AD7c-NTP was detected in the urine. As a noninvasive test, it is easier to be accepted by the patient and is more likely to be popularized in clinical. Serum amyloid A (serum amyloid A protein, SAA) is one of the major acute phase proteins in the human body, and is regulated by the positive regulation of inflammatory cytokines, including interleukin -1 (IL-1) and interleukin -6 (IL-6). .SAA, which is mainly synthesized by the liver and secreted by a major component of the apolipoprotein (HDL) particles in the high density lipoprotein (HDL) particles, can accumulate in the brain of the patients with SD, which may be associated with chronic inflammation of the brain and may lead to the loss of neurons and the damage of white matter to the sustained increase in the concentration of SAA in the serum of.OSAS patients. The reasons for the increase in the incidence of cardiovascular disease and dementia in OSAS patients are explained. Simple mental state scale (Mini-Mentalstat Examination, MMSE) can be used for a simple mental state examination to evaluate the effectiveness of the intervention measures. MMSE is the most commonly used scale in cognitive examination. It can evaluate the orientation, calculation, and short time of the subjects. Memory, language rehearsal, visual spatial cognition, structural imitation, and executive ability.MMSE include: (1) orientation force (5 points) and location orientation (5); second time memory: immediate memory (3); delayed memory (3); language power: naming (2), rehearsal (1), 1); (4) visual spatial cognition Ability (1 points); execution ability (4 points); calculation power (5 points).MMSE total 30 points.
Methods: according to the 2009 Chinese Otorhinolaryngology, the editorial board of the Journal of head and neck surgery, the pharyngology group of the Chinese Medical Association of Otolaryngology, head and neck surgery branch, on the diagnosis of obstructive sleep apnea syndrome, selected outpatients or hospitalized patients who were diagnosed as OSAS in Second Hospital of Shandong University from May 2009 to October 2010. According to the results of the apnea hypopnea index (apnea-hypopnea index, AHI) in polysomnography (PSG), 52 patients with OSAS were divided into mild OSAS group (n=11), moderate OSAS group (n=12) and severe OSAS group (n=29). The age and body mass index of 18 cases in the outpatient examination were selected as the experimental group. The matched healthy subjects were used as the control group. The serum SAA concentration was measured and compared between the morning urine AD7c-NTP and the serum SAA at 6:00 a.m. by AD7c-NTP and SAA enzyme linked immunosorbent assay (enzyme-linked immunosorbent assays, ELISA). The AD7c-NTP, SAA level of the OSAS patients were respectively compared with AHI and minimum oxygen saturation. Uration, LSaO2) for correlation analysis. The cognitive function differences between the normal group, the experimental group and the experimental group were used to evaluate the cognitive function of the experimental group and the normal control group and the experimental group after 3 months of continuous positive pressure ventilation (continuous positive airways pressure, CPAP). All the data were carried out by the SPSS 17 for Windows software. Statistical analysis including homogeneity test, t test and correlation analysis were conducted.
Results: there was no significant difference in age and body mass index among all groups, but the polysomnography index AHI, LSaO2 group was very significant (P0.01), and increased with the severity of OSAS. The concentration of AD7c-NTP and SAA in the normal control group was (1.56 + 0.67) ng/ml, respectively, (6.22 + 2.63 mu g/ml). Compared with this, the experimental group had no obvious rise in the mild group. But the concentration of SAA was significantly higher in the mild group, AD7c-NTP was 1.63 + 0.87 n g/ml (P=0.4), SAA was 11.13 + 3.41 mu g/ml (P 0.05), and AD7c-NTP in the moderate OSAS group was 2.06 + 0.64 n g/ml, and 18.37 + 1.17 micron. The concentrations of c-NTP and SAA were also significantly different in the urine AD7c-NTP content in.OSAS groups, and the correlation coefficient was 0.48 (P0.05), and the correlation coefficient was negatively correlated with night LSaO, and the correlation coefficient r was -0.56 (P0.05). The correlation analysis also showed that the concentration of the OSAS patients was positively correlated with the LSaO, and the correlation coefficient was 0.90. There was a significant negative correlation between O, and the correlation coefficient r was -0.85 (P0.001). In the experimental group and between the normal control group and the experimental group, the directional force (time orientation and location orientation), memory (immediate memory, delayed recall), language ability (naming, rehearsal, writing; visual space), execution ability and computational power were not obvious between the experimental group and the normal control group and the experimental group before and after the treatment of CPAP. Statistical difference (P0.05).
Conclusion: the concentration of urine AD7c-NTP and serum SAA in OSAS patients was significantly higher than that in the normal control group, and the increase of.AD7c-NTP and SAA concentration associated with the severity of OSAS may be related to the high risk state of Alzheimer's disease in OSAS patients. The experimental group compared with the normal control group and the experimental group after 3 months of CPAP therapy in the mental state. There was no statistically significant difference between the two groups. The analysis may be due to the short duration of treatment and / or the lack of sensitivity of MMSE as a follow-up tool for cognitive decline.
【学位授予单位】：山东大学
【学位级别】：硕士
【学位授予年份】：2011
【分类号】：R766.7

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