睡眠片段化對AD疾病進展和病理改變的影響及機制研究
發(fā)布時間：2018-08-16 14:08
【摘要】：第一部分Alzheimer病患者睡眠片段化與Alzheimer病的交互作用目的明確Alzheimer病患者睡眠片段化與Alzheimer病的交互作用。首先觀察Alzheimer病患者睡眠片段化的發(fā)生情況,了解睡眠片段化對Alzheimer病患者遠期預后的影響。探討AD患者與正常老年人相比,睡眠片段化的發(fā)生率是否更高,反之,睡眠片段化是否造成AD患者更為不良的遠期預后,并討論睡眠片段化對AD患者配偶照顧者的照料情緒產(chǎn)生何種影響。方法研究一:共43例未用藥物的AD患者(AD組)和22名健康老年人(對照組)進行連續(xù)兩個整晚的多導睡眠儀(PSG)監(jiān)測,該監(jiān)測用于評估睡眠片段化狀態(tài)。日間嗜睡度用Epworth嗜睡量表(ESS)進行評估。研究二:共156例接受小劑量膽堿酯酶抑制劑治療的AD患者納入研究,其中患有睡眠片段化的為實驗組(AD+SD組),共93例,入組標準為其照顧者報告患者每晚有兩次以上的明顯覺醒;未患有睡眠障礙(AD-SD)的為對照組,共63例�；颊郀顩r由PSG、系列睡眠和認知量表(包括MMSE、ADL、NPI、ESS)來評估。評估時間為入組時間和5年后,期間共死亡14例。所有AD+SD組患者(包括服藥組和未服藥組)的配偶照顧者都通過一系列量表來評估(包括PSQI、ESS、HAMA、HAMD和自編治療態(tài)度問卷)其照料狀況。結(jié)果研究一顯示,73%的AD患者存在睡眠障礙,53.5%的AD患者存在日間嗜睡。兩組間在總睡眠時間、睡眠效率、覺醒次數(shù)、入睡后覺醒時間上存在顯著差異。有日間嗜睡(ESS分數(shù)10分)和無日間嗜睡(ESS分數(shù)10分)AD患者的總睡眠時間都顯著低于對照組(p0.01),有日間嗜睡組的總睡眠時間顯著低于無日間嗜睡組(p0.05)。有日間嗜睡(ESS分數(shù)10分)和無日間嗜睡(ESS分數(shù)10分)AD患者的睡眠效率都顯著低于對照組(p0.01)。有日間嗜睡(ESS分數(shù)10分)和無日間嗜睡(ESS分數(shù)10分)AD患者的覺醒次數(shù)都顯著高于對照組(p0.01)。有日間嗜睡(ESS分數(shù)10分)和無日間嗜睡(ESS分數(shù)10分)AD患者的入睡后覺醒時間都顯著高于對照組(p0.01)。同對照組相比,無日間嗜睡(ESS分數(shù)10分)AD患者的慢波睡眠(SWS)潛伏期所占比例明顯減少(p0.05)。以上結(jié)果說明AD患者會出現(xiàn)明顯的睡眠片段化現(xiàn)象。研究二顯示,存在睡眠片段化的AD組(AD+SD組)的一系列睡眠參數(shù)基線值,包括覺醒次數(shù)(P0.01)、ESS分數(shù)(P0.01)、PSG指標[臥床時間(P0.05)、睡眠時間(P0.01)、睡眠效率(P0.05)、REM潛伏期(P0.01)、S3期比率(P0.01)、REM期比率(P0.01)]比AD-SD組的結(jié)果更差,該結(jié)果驗證了入組標準(AD患者存在睡眠片段化現(xiàn)象)。5年后,AD+SD組的MMSE(P0.01)和ADL(P0.01)的分數(shù)顯著低于AD-SD組;AD+SD組內(nèi)有更多的患者住在養(yǎng)老院(P0.05),其飲食問題(P0.05)、精神病性癥狀(P0.01)出現(xiàn)更多,這一結(jié)果顯示由于睡眠片段化的存在導致AD患者預后更差。AD+SD患者中服藥組配偶照顧者的ESS(P0.01)、PSQI(P0.01)、HAMA(P0.05)、HAMD(P0.01)的分數(shù)顯著優(yōu)于未服藥組,AD+SD組配偶照顧者對患者剩余存活時間(P0.01)和當患者存在軀體疾病時愿意積極搶救的比例(P0.01)也顯著低于AD-SD組,說明AD患者睡眠片段化會顯著影響其照顧者的照料情緒,對AD患者存在不利影響。結(jié)論AD患者更易出現(xiàn)睡眠片段化,睡眠片段化也會導致AD患者更加不良的遠期預后,并影響到AD患者照顧者的照料情緒。臨床上AD患者的睡眠片段化與Alzheimer病之間存在交互作用,具體機制有待進一步研究。第二部分睡眠片段化對AD模型大鼠腦病理改變的影響及機制研究目的根據(jù)上文可知,臨床AD患者的睡眠片段化與Alzheimer病之間存在交互作用,其具體機制未明。本部分研究首先利用AD模型大鼠,觀察AD模型大鼠是否出現(xiàn)睡眠片段化。其次,為了加速睡眠片段化對AD病理改變的病理進程,本研究使用了睡眠干擾(sleep interruption,SI)對AD模型大鼠進行睡眠片段化處理,觀察海馬腦組織間液β淀粉樣蛋白(ISF Aβ)濃度,并觀察下丘腦orexin濃度變化。最后,在睡眠片段化后AD模型大鼠進行側(cè)腦室注射orexin及其受體拮抗劑Almorexant,觀察海馬ISF Aβ濃度變化和覺醒時間變化,明確orexin是否在睡眠片段化加速AD病理改變中是否起到中介作用。方法選用雄性成年Sprague-Dawley大鼠,麻醉后同時安放腦電記錄電極和微透析引導管及基座。研究一中,第一部分是將大鼠分為模型組和假手術(shù)組,模型組經(jīng)1周恢復期后在雙側(cè)海馬注射Aβ25-35制作AD模型,假手術(shù)組同樣位置注射生理鹽水。兩組于造模后第21天至第26天(d21-d26)進行Morris水迷宮行為學檢測。兩組在d30,d31連續(xù)兩天收集腦電數(shù)據(jù)。研究一的第二部分是在大鼠AD造模驗證后,d27收集一天的海馬腦ISF Aβ和下丘腦orexin數(shù)據(jù)作為基線,d28進行分組,一組進行睡眠干擾(SI),目的是加速進行睡眠片段化,該組為SI組,共7天。該法將大鼠放置在一自動運行的皮帶上,速度為0.02m/s,皮帶停止與運動時間比為90s:30s。另一組為運動對照組(EC),保證兩組大鼠運動量相同�；謴�3天后,分別收集d38,d39兩天的海馬和下丘腦處腦組織間液,檢測海馬ISF Aβ和下丘腦orexin水平。研究二中,大鼠在前期的手術(shù)、AD造模、片段睡眠剝奪、恢復期之后,一組大鼠于d39分兩組分別進行orexin和vehicle側(cè)腦室注射,于d38,d39收集2天的腦組織間液,測ISF Aβ,同時記錄睡眠腦電指標。另一組大鼠于d39分兩組分別進行orexin拮抗劑Almorexant和vehicle側(cè)腦室注射,于d38,d39,d40收集3天的腦組織間液,測ISF Aβ,同時記錄睡眠腦電指標。睡眠腦電指標采用Sleep Sign軟件自動分析后人工修正,腦ISF中的Aβ濃度和orexin濃度均由ELISA法測定。結(jié)果研究一的結(jié)果顯示,夜間期和日間期AD模型組大鼠的總覺醒時間明顯高于假手術(shù)對照組(P0.01),說明AD模型大鼠會隨著病情進展出現(xiàn)睡眠片段化現(xiàn)象。與運動對照組(EC)相比,睡眠片段化組(SI)的ISF Aβ濃度顯著升高(P0.01),說明睡眠片段化可加速AD模型大鼠腦的病理改變。SI組的orexin濃度(與ISF Aβ相比)呈同時相的顯著升高(P0.01),說明睡眠片段化使orexin與ISF Aβ呈同時相、同趨勢的變化。研究二的結(jié)果顯示,在睡眠片段化處理后的AD模型大鼠中,orexin注射后AD模型大鼠的ISF Aβ濃度顯著升高(P0.01),覺醒時間顯著延長(P0.01);orexin受體拮抗劑Almorexant注射后AD模型大鼠的ISF Aβ濃度降低(P0.05),覺醒時間顯著縮短(P0.01);兩組Vehicle的注射對大鼠腦ISFAβ的影響都不顯著(p0.05)。以上結(jié)果說明睡眠片段化可以通過orexin通路來進一步調(diào)節(jié)ISFAβ濃度。結(jié)論AD模型大鼠存在睡眠片段化現(xiàn)象,睡眠片段化也會加速AD模型大鼠腦的病理改變,其機制可能是睡眠片段化通過Orexin通路進一步影響AD模型大鼠的ISFAβ水平。以上結(jié)果表明,睡眠片段化與AD存在交互作用,orexin在此過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.
【學位授予單位】：第二軍醫(yī)大學
【學位級別】：博士
【學位授予年份】：2015
【分類號】：R749.16
本文編號：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.
【學位授予單位】：第二軍醫(yī)大學
【學位級別】：博士
【學位授予年份】：2015
【分類號】：R749.16
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