睡眠障碍与阿尔茨海默病

作者:肖卫忠[1] 张娜[1] 
单位:北京大学第三医院[1]

   阿尔茨海默病(Alzheimer’s Disease, AD)是发生于老年和老年前期的中枢神经系统退行性病变,是老年期痴呆最常见的类型,以进行性认知功能障碍和行为损害为特征,约25-60%的AD患者存在睡眠障碍和昼夜节律改变[1-4] ,最常见的包括夜间失眠,睡眠片段化,日间过度嗜睡[5-6] ,“落日征”也较常见[7] ,表现为傍晚出现更为显著的行为紊乱,如激越、异常运动(踱步)、思维语言紊乱、情感异常(焦虑、惊恐、易怒)和知觉障碍(幻听、幻视)等。睡眠障碍和昼夜节律异常随着病情进展和认知功能损害而逐渐加重[8] 。睡眠改变见于AD临床前期,早于认知功能障碍出现。AD患者多导睡眠监测显示慢波睡眠和快速(Rapid Eye Movement , REM)眼动睡眠减少,REM潜伏期延长,非快速眼动睡眠期N1和N2延长,睡眠片断增多,导致睡眠时间总体缩短[9] 。究其原因是多因素所致,调节睡眠觉醒周期的神经通路变性,如视交叉上核、松果体区褪黑素级其受体的改变、授时因子的变化,躯体/精神合并症都会导致AD患者出现睡眠障碍。目前一些临床和实验室证据表明,睡眠障碍与阿尔茨海默病相互影响,除性别、年龄、生活习惯改变外,它也可能是阿尔茨海默病的危险因素之一。
   睡眠对维持和巩固记忆至关重要,特定睡眠时相可增强特定记忆功能。NREM或慢波睡眠可强化陈述性记忆(如有关重大事件的记忆),而REM睡眠有助于非陈述性记忆(如技能/习惯,程序性记忆)[10]。睡眠质量下降和睡眠剥夺影响突触可塑性和记忆[11-13] 。多项横断面研究显示,每晚睡眠时间<5小时[14]和>11小时[15]与认知障碍有关。一项前瞻性研究采用体动记录仪记录睡眠,结果显示睡眠片段化也可增加AD风险[16] 。另一项前瞻性研究显示睡眠障碍性呼吸进展为轻度认知功能障碍或痴呆的OR值是1.85[17] ,与频繁氧饱和度下降(>15/小时)有关。
   β淀粉样蛋白(Aβ)沉积导致一系列级联反应,在AD发病中起到关键作用。动物实验以及人体研究均显示[18,19] ,可溶性Aβ随睡眠-觉醒周期波动,这一现象提示睡眠障碍可增加AD风险。两种转基因小鼠淀粉样变模型(APPSWE和APPSWE/PS1DE9模型)研究也显示睡眠剥夺可增加Aβ浓度,而慢性睡眠剥夺可加速Aβ沉积为淀粉样斑块,相反,利用褪黑素受体拮抗剂改善睡眠可减少Aβ沉积。与动物模型相比,人类脑脊液中Aβ也呈现类似的日间节律,而存在淀粉样斑块的AD患者(匹兹堡复合物B-PET成像)脑脊液可溶性Aβ尤其是Aβ42缺少日间波动。无论是动物试验[20-22]还是人体研究[23] ,一旦淀粉样斑块形成,睡眠觉醒和昼夜节律随之破坏。睡眠障碍导致淀粉样沉积,而淀粉样斑块通过影响睡眠脑区进一步加重睡眠障碍,从而导致恶性循环。随着病情进展,AD患者白天活动日益减少,日照量减低,以及针对激越症状的药物都会加重其睡眠障碍,进一步导致认知功能下降,进而加速AD病理生理过程。
   AD可导致睡眠障碍,而睡眠障碍使AD恶化,有关其相互作用机制有以下几种推[24] :第一、NERM睡眠期慢波活动引起神经元活动下降,可减少细胞外Aβ沉积以及淀粉样斑块形成。动物试验证明细胞外Aβ 水平与神经元放电以及觉醒紧密相关。第二,睡眠相关的脑干神经通路功能障碍,导致大脑网络“默认模式”区域化连接中断,而这一模式是AD患者的选择性易损脑区。第三,Aβ清除与乳酸(源于星形胶质细胞)以及载脂蛋白E(ApoE)的神经代谢偶联有关。第四,动物实验发现新的Aβ清除途径,即神经胶质-淋巴或者血管周围间隙;睡眠/麻醉状态的小鼠组织间隙的外源性Aβ清除率远高于觉醒状态。第五,虽研究甚少,但这一机制涉及AD、睡眠和免疫系统的相互作用。睡眠可调节免疫系统功能,而细胞因子或其他免疫调节剂可影响睡眠;胶质细胞,尤其是小胶质细胞功能障碍常见于老年人和AD患者。
   睡眠障碍和阿尔茨海默病关系密切,改善睡眠质量可能成为预防和治疗阿尔茨海默病的重要手段,对其机制的研究有可能为AD提供新的治疗靶点。

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