睡眠片段化对AD疾病进展和病理改变的影响及机制研究
发布时间：2018-08-16 14:08
【摘要】：第一部分Alzheimer病患者睡眠片段化与Alzheimer病的交互作用目的明确Alzheimer病患者睡眠片段化与Alzheimer病的交互作用。首先观察Alzheimer病患者睡眠片段化的发生情况,了解睡眠片段化对Alzheimer病患者远期预后的影响。探讨AD患者与正常老年人相比,睡眠片段化的发生率是否更高,反之,睡眠片段化是否造成AD患者更为不良的远期预后,并讨论睡眠片段化对AD患者配偶照顾者的照料情绪产生何种影响。方法研究一:共43例未用药物的AD患者(AD组)和22名健康老年人(对照组)进行连续两个整晚的多导睡眠仪(PSG)监测,该监测用于评估睡眠片段化状态。日间嗜睡度用Epworth嗜睡量表(ESS)进行评估。研究二:共156例接受小剂量胆碱酯酶抑制剂治疗的AD患者纳入研究,其中患有睡眠片段化的为实验组(AD+SD组),共93例,入组标准为其照顾者报告患者每晚有两次以上的明显觉醒;未患有睡眠障碍(AD-SD)的为对照组,共63例。患者状况由PSG、系列睡眠和认知量表(包括MMSE、ADL、NPI、ESS)来评估。评估时间为入组时间和5年后,期间共死亡14例。所有AD+SD组患者(包括服药组和未服药组)的配偶照顾者都通过一系列量表来评估(包括PSQI、ESS、HAMA、HAMD和自编治疗态度问卷)其照料状况。结果研究一显示,73%的AD患者存在睡眠障碍,53.5%的AD患者存在日间嗜睡。两组间在总睡眠时间、睡眠效率、觉醒次数、入睡后觉醒时间上存在显著差异。有日间嗜睡(ESS分数10分)和无日间嗜睡(ESS分数10分)AD患者的总睡眠时间都显著低于对照组(p0.01),有日间嗜睡组的总睡眠时间显著低于无日间嗜睡组(p0.05)。有日间嗜睡(ESS分数10分)和无日间嗜睡(ESS分数10分)AD患者的睡眠效率都显著低于对照组(p0.01)。有日间嗜睡(ESS分数10分)和无日间嗜睡(ESS分数10分)AD患者的觉醒次数都显著高于对照组(p0.01)。有日间嗜睡(ESS分数10分)和无日间嗜睡(ESS分数10分)AD患者的入睡后觉醒时间都显著高于对照组(p0.01)。同对照组相比,无日间嗜睡(ESS分数10分)AD患者的慢波睡眠(SWS)潜伏期所占比例明显减少(p0.05)。以上结果说明AD患者会出现明显的睡眠片段化现象。研究二显示,存在睡眠片段化的AD组(AD+SD组)的一系列睡眠参数基线值,包括觉醒次数(P0.01)、ESS分数(P0.01)、PSG指标[卧床时间(P0.05)、睡眠时间(P0.01)、睡眠效率(P0.05)、REM潜伏期(P0.01)、S3期比率(P0.01)、REM期比率(P0.01)]比AD-SD组的结果更差,该结果验证了入组标准(AD患者存在睡眠片段化现象)。5年后,AD+SD组的MMSE(P0.01)和ADL(P0.01)的分数显著低于AD-SD组;AD+SD组内有更多的患者住在养老院(P0.05),其饮食问题(P0.05)、精神病性症状(P0.01)出现更多,这一结果显示由于睡眠片段化的存在导致AD患者预后更差。AD+SD患者中服药组配偶照顾者的ESS(P0.01)、PSQI(P0.01)、HAMA(P0.05)、HAMD(P0.01)的分数显著优于未服药组,AD+SD组配偶照顾者对患者剩余存活时间(P0.01)和当患者存在躯体疾病时愿意积极抢救的比例(P0.01)也显著低于AD-SD组,说明AD患者睡眠片段化会显著影响其照顾者的照料情绪,对AD患者存在不利影响。结论AD患者更易出现睡眠片段化,睡眠片段化也会导致AD患者更加不良的远期预后,并影响到AD患者照顾者的照料情绪。临床上AD患者的睡眠片段化与Alzheimer病之间存在交互作用,具体机制有待进一步研究。第二部分睡眠片段化对AD模型大鼠脑病理改变的影响及机制研究目的根据上文可知,临床AD患者的睡眠片段化与Alzheimer病之间存在交互作用,其具体机制未明。本部分研究首先利用AD模型大鼠,观察AD模型大鼠是否出现睡眠片段化。其次,为了加速睡眠片段化对AD病理改变的病理进程,本研究使用了睡眠干扰(sleep interruption,SI)对AD模型大鼠进行睡眠片段化处理,观察海马脑组织间液β淀粉样蛋白(ISF Aβ)浓度,并观察下丘脑orexin浓度变化。最后,在睡眠片段化后AD模型大鼠进行侧脑室注射orexin及其受体拮抗剂Almorexant,观察海马ISF Aβ浓度变化和觉醒时间变化,明确orexin是否在睡眠片段化加速AD病理改变中是否起到中介作用。方法选用雄性成年Sprague-Dawley大鼠,麻醉后同时安放脑电记录电极和微透析引导管及基座。研究一中,第一部分是将大鼠分为模型组和假手术组,模型组经1周恢复期后在双侧海马注射Aβ25-35制作AD模型,假手术组同样位置注射生理盐水。两组于造模后第21天至第26天(d21-d26)进行Morris水迷宫行为学检测。两组在d30,d31连续两天收集脑电数据。研究一的第二部分是在大鼠AD造模验证后,d27收集一天的海马脑ISF Aβ和下丘脑orexin数据作为基线,d28进行分组,一组进行睡眠干扰(SI),目的是加速进行睡眠片段化,该组为SI组,共7天。该法将大鼠放置在一自动运行的皮带上,速度为0.02m/s,皮带停止与运动时间比为90s:30s。另一组为运动对照组(EC),保证两组大鼠运动量相同。恢复3天后,分别收集d38,d39两天的海马和下丘脑处脑组织间液,检测海马ISF Aβ和下丘脑orexin水平。研究二中,大鼠在前期的手术、AD造模、片段睡眠剥夺、恢复期之后,一组大鼠于d39分两组分别进行orexin和vehicle侧脑室注射,于d38,d39收集2天的脑组织间液,测ISF Aβ,同时记录睡眠脑电指标。另一组大鼠于d39分两组分别进行orexin拮抗剂Almorexant和vehicle侧脑室注射,于d38,d39,d40收集3天的脑组织间液,测ISF Aβ,同时记录睡眠脑电指标。睡眠脑电指标采用Sleep Sign软件自动分析后人工修正,脑ISF中的Aβ浓度和orexin浓度均由ELISA法测定。结果研究一的结果显示,夜间期和日间期AD模型组大鼠的总觉醒时间明显高于假手术对照组(P0.01),说明AD模型大鼠会随着病情进展出现睡眠片段化现象。与运动对照组(EC)相比,睡眠片段化组(SI)的ISF Aβ浓度显著升高(P0.01),说明睡眠片段化可加速AD模型大鼠脑的病理改变。SI组的orexin浓度(与ISF Aβ相比)呈同时相的显著升高(P0.01),说明睡眠片段化使orexin与ISF Aβ呈同时相、同趋势的变化。研究二的结果显示,在睡眠片段化处理后的AD模型大鼠中,orexin注射后AD模型大鼠的ISF Aβ浓度显著升高(P0.01),觉醒时间显著延长(P0.01);orexin受体拮抗剂Almorexant注射后AD模型大鼠的ISF Aβ浓度降低(P0.05),觉醒时间显著缩短(P0.01);两组Vehicle的注射对大鼠脑ISFAβ的影响都不显著(p0.05)。以上结果说明睡眠片段化可以通过orexin通路来进一步调节ISFAβ浓度。结论AD模型大鼠存在睡眠片段化现象,睡眠片段化也会加速AD模型大鼠脑的病理改变,其机制可能是睡眠片段化通过Orexin通路进一步影响AD模型大鼠的ISFAβ水平。以上结果表明,睡眠片段化与AD存在交互作用,orexin在此过程中可能起到一定作用。
[Abstract]:The first part is the interaction between sleep fragmentation and Alzheimer's disease in Alzheimer's disease. The purpose is to clarify the interaction between sleep fragmentation and Alzheimer's disease in Alzheimer's disease. Whether the incidence of sleep fragmentation is higher in the elderly than in the elderly, on the contrary, whether sleep fragmentation leads to worse long-term prognosis in AD patients, and how sleep fragmentation affects the care mood of spouse caregivers in AD patients. Methods Study 1: A total of 43 AD patients (AD group) and 22 healthy elderly people (control group) Two consecutive nights of polysomnography (PSG) monitoring were performed to assess sleep fragmentation. Daytime somnolence was assessed with the Epworth Sleepiness Scale (ESS). Study 2: 156 AD patients treated with low-dose cholinesterase inhibitors were enrolled in the study, including 93 patients with sleep fragmentation (AD + SD group). Patients were assessed by PSG, a series of sleep and cognition scales (including MMSE, ADL, NPI, ESS). The assessment time was enrollment time and five years later, a total of 14 deaths were recorded. All patients in the AD + SD group (including taking medication) died. Spouse caregivers in both groups were assessed by a series of questionnaires (including PSQI, ESS, HAMA, HAMD and the self-designed Therapeutic Attitude Questionnaire). Results Study 1 showed that 73% of AD patients had sleep disorders and 53.5% of AD patients had daytime sleepiness. The total sleep time of AD patients with daytime somnolence (ESS score 10 points) and without daytime somnolence (ESS score 10 points) was significantly lower than that of the control group (p0.01). The total sleep time of AD patients with daytime somnolence (ESS score 10 points) and without daytime somnolence (ESS score 10 points) was significantly lower than that of the control group (p0.05). The sleep efficiency of AD patients with daytime somnolence (ESS score 10 points) and without daytime somnolence (ESS score 10 points) was significantly higher than that of the control group (p0.01). The awakening time of AD patients with daytime somnolence (ESS score 10 points) and daytime somnolence (ESS score 10 points) was significantly longer than that of the control group (p0.01). Compared with the control group, the proportion of slow wave sleep (SWS) latency in AD patients without daytime somnolence (ESS score 10 points) was significantly reduced (p0.05). The above results suggest that AD patients have obvious sleep fragmentation. Study 2 showed that there was a series of baseline values of sleep parameters, including the number of wakefulness (P 0.01) in the sleep fragmentation AD group (AD + SD group). ESS score (P 0.01), PSG index (bedridden time (P 0.05), sleep time (P 0.01), sleep efficiency (P 0.05), REM latency (P 0.01), S3 ratio (P 0.01), REM ratio (P 0.01)] were worse than those of AD-SD group. The results validated the inclusion criteria (sleep fragmentation in AD patients). Five years later, the scores of MMSE (P 0.01) and AD+SD group (P 0.01) were significantly higher than those of AD-SD group. In AD + SD group, there were more patients living in nursing homes (P 0.05), more dietary problems (P 0.05), more psychotic symptoms (P 0.01), which showed that the prognosis of AD patients was worse because of sleep fragmentation. ESS (P 0.01), PSQI (P 0.01), HAMA (P 0.05), HAMD (P 0.01) scores of spouse caregivers in AD + SD group were worse than those in AD-SD group. The number of spouse caregivers in AD+SD group was significantly higher than that in non-AD group. The remaining survival time (P 0.01) and the proportion of active rescue when the patients had somatic diseases (P 0.01) in AD+SD group were also significantly lower than that in AD-SD group, indicating that sleep fragmentation of AD patients significantly affected the caregivers'care mood and had adverse effects on AD patients. Sleep fragmentation and sleep fragmentation can also lead to worse long-term prognosis in AD patients and affect the care mood of caregivers of AD patients.There is an interaction between sleep fragmentation and Alzheimer's disease in AD patients clinically.The specific mechanism needs further study.Part II Sleep fragmentation on the brain pathological changes of AD model rats. The effect and mechanism of sleep fragmentation in AD patients is unclear. In this part, we first used AD model rats to observe whether sleep fragmentation occurred in AD model rats. Secondly, in order to accelerate the pathological process of sleep fragmentation on AD pathological changes. In this study, sleep interruption (SI) was used to segment sleep in AD model rats to observe the concentration of amyloid beta protein (ISF-A-beta) in hippocampal interstitial fluid (HIS) and the change of orexin concentration in hypothalamus. Methods Male adult Sprague-Dawley rats were anesthetized with electroencephalographic recording electrode and microdialysis guide tube and base. The first part of the study was to divide the rats into models. The AD model was made by injecting A-beta 25-35 into the bilateral hippocampus in the model group and normal saline in the sham-operation group at the same position after one week of recovery. Morris water maze behavioral tests were performed in both groups from day 21 to day 26 (d21-d26). After the AD model was validated, the rats were divided into two groups according to the baseline data of hippocampal ISF A beta and hypothalamus orexin on day 27. One group was treated with sleep disturbance (SI) to accelerate sleep fragmentation. The rats were placed on a self-operated belt at a speed of 0.02m/s and the rate of belt stopping versus exercise time. The other group was the exercise control group (EC). After 3 days of recovery, the hippocampal and hypothalamic interstitial fluid was collected and the levels of ISF-A beta and orexin in the hippocampus and hypothalamus were measured. In study 2, the rats in the early stage of surgery, AD modeling, fragment sleep deprivation, recovery stage, one group of rats in the d3. The rats in the other group were injected into the lateral ventricles of orexin antagonist Almorexant and vehicle respectively at d39, D39 and D38 respectively, and the intracerebral interstitial fluid was collected for 2 days, ISF A beta was measured, and sleep EEG was recorded. Sleep EEG parameters were automatically analyzed by Sleep Sign software and then manually revised. The concentrations of A beta and orexin in brain ISF were determined by ELISA. Results The results of study 1 showed that the total awakening time of AD model rats in nighttime and daytime was significantly longer than that of sham operation control group (P 0.01), indicating that AD model rats would develop with disease. Compared with exercise control group (EC), the concentration of ISF-A-beta in sleep fragmentation group (SI) was significantly higher (P 0.01), indicating that sleep fragmentation could accelerate the pathological changes of brain in AD model rats. The results of study 2 showed that the concentration of ISF-A-beta increased significantly (P 0.01) and the awakening time prolonged significantly (P 0.01) in AD model rats after orexin injection, while the concentration of ISF-A-beta decreased (P 0.05) after orexin receptor antagonist Almorexant injection. These results suggest that sleep fragmentation can further regulate the concentration of ISFA beta through orexin pathway. Conclusion Sleep fragmentation exists in AD model rats, and sleep fragmentation can also accelerate the pathological changes of AD model rats brain, and its mechanism. These results suggest that sleep fragmentation interacts with AD and orexin may play a role in this process.
【学位授予单位】：第二军医大学
【学位级别】：博士
【学位授予年份】：2015
【分类号】：R749.16
本文编号：2186214
[Abstract]:The first part is the interaction between sleep fragmentation and Alzheimer's disease in Alzheimer's disease. The purpose is to clarify the interaction between sleep fragmentation and Alzheimer's disease in Alzheimer's disease. Whether the incidence of sleep fragmentation is higher in the elderly than in the elderly, on the contrary, whether sleep fragmentation leads to worse long-term prognosis in AD patients, and how sleep fragmentation affects the care mood of spouse caregivers in AD patients. Methods Study 1: A total of 43 AD patients (AD group) and 22 healthy elderly people (control group) Two consecutive nights of polysomnography (PSG) monitoring were performed to assess sleep fragmentation. Daytime somnolence was assessed with the Epworth Sleepiness Scale (ESS). Study 2: 156 AD patients treated with low-dose cholinesterase inhibitors were enrolled in the study, including 93 patients with sleep fragmentation (AD + SD group). Patients were assessed by PSG, a series of sleep and cognition scales (including MMSE, ADL, NPI, ESS). The assessment time was enrollment time and five years later, a total of 14 deaths were recorded. All patients in the AD + SD group (including taking medication) died. Spouse caregivers in both groups were assessed by a series of questionnaires (including PSQI, ESS, HAMA, HAMD and the self-designed Therapeutic Attitude Questionnaire). Results Study 1 showed that 73% of AD patients had sleep disorders and 53.5% of AD patients had daytime sleepiness. The total sleep time of AD patients with daytime somnolence (ESS score 10 points) and without daytime somnolence (ESS score 10 points) was significantly lower than that of the control group (p0.01). The total sleep time of AD patients with daytime somnolence (ESS score 10 points) and without daytime somnolence (ESS score 10 points) was significantly lower than that of the control group (p0.05). The sleep efficiency of AD patients with daytime somnolence (ESS score 10 points) and without daytime somnolence (ESS score 10 points) was significantly higher than that of the control group (p0.01). The awakening time of AD patients with daytime somnolence (ESS score 10 points) and daytime somnolence (ESS score 10 points) was significantly longer than that of the control group (p0.01). Compared with the control group, the proportion of slow wave sleep (SWS) latency in AD patients without daytime somnolence (ESS score 10 points) was significantly reduced (p0.05). The above results suggest that AD patients have obvious sleep fragmentation. Study 2 showed that there was a series of baseline values of sleep parameters, including the number of wakefulness (P 0.01) in the sleep fragmentation AD group (AD + SD group). ESS score (P 0.01), PSG index (bedridden time (P 0.05), sleep time (P 0.01), sleep efficiency (P 0.05), REM latency (P 0.01), S3 ratio (P 0.01), REM ratio (P 0.01)] were worse than those of AD-SD group. The results validated the inclusion criteria (sleep fragmentation in AD patients). Five years later, the scores of MMSE (P 0.01) and AD+SD group (P 0.01) were significantly higher than those of AD-SD group. In AD + SD group, there were more patients living in nursing homes (P 0.05), more dietary problems (P 0.05), more psychotic symptoms (P 0.01), which showed that the prognosis of AD patients was worse because of sleep fragmentation. ESS (P 0.01), PSQI (P 0.01), HAMA (P 0.05), HAMD (P 0.01) scores of spouse caregivers in AD + SD group were worse than those in AD-SD group. The number of spouse caregivers in AD+SD group was significantly higher than that in non-AD group. The remaining survival time (P 0.01) and the proportion of active rescue when the patients had somatic diseases (P 0.01) in AD+SD group were also significantly lower than that in AD-SD group, indicating that sleep fragmentation of AD patients significantly affected the caregivers'care mood and had adverse effects on AD patients. Sleep fragmentation and sleep fragmentation can also lead to worse long-term prognosis in AD patients and affect the care mood of caregivers of AD patients.There is an interaction between sleep fragmentation and Alzheimer's disease in AD patients clinically.The specific mechanism needs further study.Part II Sleep fragmentation on the brain pathological changes of AD model rats. The effect and mechanism of sleep fragmentation in AD patients is unclear. In this part, we first used AD model rats to observe whether sleep fragmentation occurred in AD model rats. Secondly, in order to accelerate the pathological process of sleep fragmentation on AD pathological changes. In this study, sleep interruption (SI) was used to segment sleep in AD model rats to observe the concentration of amyloid beta protein (ISF-A-beta) in hippocampal interstitial fluid (HIS) and the change of orexin concentration in hypothalamus. Methods Male adult Sprague-Dawley rats were anesthetized with electroencephalographic recording electrode and microdialysis guide tube and base. The first part of the study was to divide the rats into models. The AD model was made by injecting A-beta 25-35 into the bilateral hippocampus in the model group and normal saline in the sham-operation group at the same position after one week of recovery. Morris water maze behavioral tests were performed in both groups from day 21 to day 26 (d21-d26). After the AD model was validated, the rats were divided into two groups according to the baseline data of hippocampal ISF A beta and hypothalamus orexin on day 27. One group was treated with sleep disturbance (SI) to accelerate sleep fragmentation. The rats were placed on a self-operated belt at a speed of 0.02m/s and the rate of belt stopping versus exercise time. The other group was the exercise control group (EC). After 3 days of recovery, the hippocampal and hypothalamic interstitial fluid was collected and the levels of ISF-A beta and orexin in the hippocampus and hypothalamus were measured. In study 2, the rats in the early stage of surgery, AD modeling, fragment sleep deprivation, recovery stage, one group of rats in the d3. The rats in the other group were injected into the lateral ventricles of orexin antagonist Almorexant and vehicle respectively at d39, D39 and D38 respectively, and the intracerebral interstitial fluid was collected for 2 days, ISF A beta was measured, and sleep EEG was recorded. Sleep EEG parameters were automatically analyzed by Sleep Sign software and then manually revised. The concentrations of A beta and orexin in brain ISF were determined by ELISA. Results The results of study 1 showed that the total awakening time of AD model rats in nighttime and daytime was significantly longer than that of sham operation control group (P 0.01), indicating that AD model rats would develop with disease. Compared with exercise control group (EC), the concentration of ISF-A-beta in sleep fragmentation group (SI) was significantly higher (P 0.01), indicating that sleep fragmentation could accelerate the pathological changes of brain in AD model rats. The results of study 2 showed that the concentration of ISF-A-beta increased significantly (P 0.01) and the awakening time prolonged significantly (P 0.01) in AD model rats after orexin injection, while the concentration of ISF-A-beta decreased (P 0.05) after orexin receptor antagonist Almorexant injection. These results suggest that sleep fragmentation can further regulate the concentration of ISFA beta through orexin pathway. Conclusion Sleep fragmentation exists in AD model rats, and sleep fragmentation can also accelerate the pathological changes of AD model rats brain, and its mechanism. These results suggest that sleep fragmentation interacts with AD and orexin may play a role in this process.
【学位授予单位】：第二军医大学
【学位级别】：博士
【学位授予年份】：2015
【分类号】：R749.16
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