孫文靜， 賀　斌， 尹　又

第二軍醫(yī)大學(xué)長征醫(yī)院神經(jīng)內(nèi)科，上?！?00003

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·綜述·

阿爾茲海默病睡眠障礙的機制與治療進展

孫文靜， 賀斌， 尹又*

第二軍醫(yī)大學(xué)長征醫(yī)院神經(jīng)內(nèi)科，上海200003

阿爾茲海默病(Alzheimer's disease, AD)是一種與年齡高度相關(guān)的、以進行性認知功能障礙和記憶力損害為主的中樞神經(jīng)系統(tǒng)變性疾病，又稱為老年性癡呆。調(diào)查顯示，40%以上的AD患者合并不同程度的睡眠問題(睡眠結(jié)構(gòu)改變、晝夜節(jié)律紊亂或睡眠呼吸障礙)，可導(dǎo)致患者認知與行為能力加速惡化、神經(jīng)-內(nèi)分泌系統(tǒng)功能失調(diào)、情緒易怒和低落，甚至導(dǎo)致死亡。由于目前AD的一線治療藥物療效欠佳，且近10余年幾乎所有的AD新藥研發(fā)無明顯陽性結(jié)果，故如何有效改善AD伴隨癥狀亦成為臨床延緩AD進展的治療重點之一。近5年針對睡眠與AD的關(guān)系及相關(guān)藥物、非藥物治療等研究日益受到重視。本文就目前對于AD患者睡眠障礙的發(fā)病機制、治療現(xiàn)狀作一綜述。

睡眠障礙；阿爾茲海默??；機制；治療

阿爾茲海默病(Alzheime's disease，AD)是最常見的癡呆類型。40%～80%的AD患者伴有不同程度的睡眠障礙，輕度AD即出現(xiàn)睡眠時間及結(jié)構(gòu)紊亂[1]。目前，AD相關(guān)睡眠障礙的診斷主要依據(jù)Yesavage等[2]制定的標準。AD相關(guān)睡眠障礙中，尤以睡眠-覺醒節(jié)律紊亂、日落綜合征等給患者及其家屬的生活帶來的身心及經(jīng)濟負擔更為沉重[3]。

1　AD藥物研發(fā)進展

近10余年針對不同靶點的AD藥物的研發(fā)均進展緩慢，且療效評估中未涉及AD睡眠障礙的改善報道(表1)[4-6]。

2　AD睡眠障礙的可能發(fā)病機制

AD睡眠障礙的可能發(fā)病機制包括生物節(jié)律中樞的紊亂、松果體區(qū)褪黑素(melatonine，MT)及其受體的改變、授時因子(zeitgeber)的變化以及基因因素等，其中睡眠/覺醒節(jié)律紊亂是其核心假說[7]。

表1　近10年AD睡眠障礙新藥研發(fā)報告(1期、2期)

2.1生物節(jié)律中樞紊亂作為生物節(jié)律的起始點，AD患者的視交叉上核神經(jīng)元數(shù)目明顯減少，并出現(xiàn)神經(jīng)纖維纏結(jié)和β淀粉樣蛋白沉積。

2.2褪黑素及其受體改變褪黑素由松果體分泌后通過其受體MT1(占主要部分)和MT2調(diào)控晝夜節(jié)律。AD患者腦脊液中褪黑素水平僅占同齡健康人的1/5，MT1的表達也明顯降低，晚期神經(jīng)元的數(shù)量明顯減少。

2.3授時因子變化光照是最強的授時因子，而AD患者常不愿外出，且伴有視網(wǎng)膜和視神經(jīng)病變、視野缺損等[8]，導(dǎo)致光照作用減弱。2.4基因因素基因可能決定AD個體睡眠障礙的嚴重程度。轉(zhuǎn)基因鼠睡眠調(diào)節(jié)紊亂較野生型鼠更早，進一步證實AD患者睡眠障礙與基因密切相關(guān)[5]。

3　AD睡眠障礙的藥物治療

目前，目前約有10余項較大規(guī)模的AD睡眠障礙相關(guān)臨床藥物研究，涉及膽堿酯酶抑制劑、褪黑素、抗精神病藥及非藥物療法等，其中涉及681例患者的6項隨機對照試驗(RCT)研究中僅有一半陽性結(jié)果(表2)。

表2　AD睡眠障礙的大規(guī)模臨床研究

3.1改善認知癥狀的藥物

3.1.1膽堿酯酶抑制劑基底前腦作為膽堿能傳導(dǎo)通路的發(fā)源地，可能存在膽堿能/腺苷/睡眠-覺醒的控通路。兩項對加蘭他敏的臨床試驗研究均為陰性結(jié)果[9-10]。Cooke等[11]對分別服用加蘭他敏、重酒石酸卡巴拉汀和多奈哌齊的AD患者的睡眠結(jié)構(gòu)進行觀察，發(fā)現(xiàn)AD患者快速動眼睡眠時間均增加，而非快速動眼時間1期減少，2期增加；多奈哌齊組比加蘭他敏組1期睡眠減少，較安慰劑組2期睡眠增加，表明多奈哌齊對患者睡眠有一定益處。 Mizuno等[12]也證實，5 mg多奈哌齊能增加患者的快速動眼睡眠時間百分比，提高睡眠效率，減少睡眠片段化。

3.1.2NMDA受體激動劑美金剛胺是第1個被證實對AD(尤其是中、重度AD)患者有顯著療效的藥物。美金剛胺可以阻止過量谷氨酸等的傳遞而達到保護神經(jīng)元的作用。García-Alberca等[13]研究表明，AD患者使用美金剛后睡眠紊亂量表(神經(jīng)精神、神經(jīng)心理及功能狀態(tài))評分均下降。

3.2褪黑素及其受體激動劑

3.2.1褪黑素AD睡眠障礙的主要因素是褪黑素合成和分泌減少，導(dǎo)致正常生物節(jié)律紊亂。一項包含14例參與者的回顧性研究[14]發(fā)現(xiàn)，每日口服9 mg褪黑素能明顯改善睡眠質(zhì)量。但另一項對比研究[15]中，AD睡眠障礙每日口服6 mg褪黑素7周后，睡眠參數(shù)無變化，分別服用2.5 mg、5 mg和10 mg褪黑素8周后亦睡眠無顯著改善[16]。

3.2.2褪黑素受體激動劑AD患者體內(nèi)不僅褪黑素水平下降[22]，其受體表達也明顯下降，導(dǎo)致患者生理節(jié)律紊亂加重。瑞美替昂是已經(jīng)被美國食品和藥品管理局(FDA)認證的治療失眠的藥物。瑞美替昂對MT1及MT2均有激動作用，但目前對其療效的觀察時間未超過35 d[23]。

3.3抗精神失常藥

4　非藥物治療

4.1光照光照主要通過視網(wǎng)膜下丘腦束引起視交叉上核神經(jīng)細胞膜去極化，增強神經(jīng)元發(fā)放率，并阻止年齡相關(guān)的精氨酸加壓素(AVP)表達，從而改善老年人的睡眠、神經(jīng)內(nèi)分泌、體溫及睡眠-覺醒節(jié)律。AD患者上述正常節(jié)律常較健康老年人破壞更為嚴重，對光照治療反應(yīng)良好。McCurry等[20]證實，AD睡眠障礙患者可以進行光照等治療。

4.2其他方法研究[21]顯示，增加體育鍛煉不僅對老年人的睡眠-覺醒節(jié)律有明顯的改善作用，而且可以提高老年人的身心健康及生活熱情，但此研究沒有進行睡眠相關(guān)參數(shù)的評估。此外，踱步似乎能改善AD患者睡眠-覺醒周期的同步化[29]。通過經(jīng)皮電刺激激活A(yù)D患者背部胸1～胸5脊髓神經(jīng)元也可以改善睡眠節(jié)律[30]。有研究[31]初步表明，針灸可以通過增加夜間褪黑素的分泌而減少失眠及焦慮。也有研究[32]通過直接干預(yù)體溫(如熱水澡)來提高老年人的睡眠質(zhì)量。

AD患者睡眠障礙的發(fā)生率高、危害大，盡管不斷對其病因、發(fā)病機制進行探索，但仍未找到較好的治療方法。目前常用的藥物各有利弊，應(yīng)針對AD睡眠障礙表現(xiàn)的差異選擇藥物。膽堿酯酶抑制劑中的多奈哌齊在改善認知功能的同時有助于調(diào)節(jié)睡眠，有望成為該類AD患者的基礎(chǔ)治療藥物；褪黑素可提高患者的睡眠及認知能力，但治療周期較長；患者對小劑量(40 mg)齊拉西酮的耐受性良好，且照料者的負擔較輕，但類帕金森表現(xiàn)等不良反應(yīng)常見；小劑量非典型抗精神病藥對伴有行為障礙或夜間睡眠-覺醒紊亂的AD患者更優(yōu)；曲唑酮是目前最受肯定的AD睡眠障礙輔助藥物，其能改善AD患者的睡眠質(zhì)量和睡眠結(jié)構(gòu)，且無認知損傷等不良反應(yīng)?？傊珹D睡眠障礙的治療正逐漸受到關(guān)注，其作為AD輔助治療的意義日益凸顯，但治療方案尚缺乏大樣本、前瞻性以及對照研究的支持。

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[本文編輯]廖曉瑜，姬靜芳

Mechanism and treatment of sleep disorders in Alzheimer’s disease

SUN Wen-jing, HE Bin, YIN You*

Department of Neurology, Changzheng Hospital, Second Military Medical University, Shanghai 200003, China

Alzheimer's disease (AD) is a neurodegenerative disease highly correlated with age and characterized by progressive impairment in memory and cognition, also known as senile dementia. Survey shows more than 40% of AD patients with varying degrees of sleep problems (sleep structure changes, circadian rhythm disorder, sleep apnea and so on), which can lead to accelerated cognitive and behavioral deterioration, the nerve-endocrine system dysfunction, emotional irritability and depression, and even death. Due to the poor efficacy of first-line treatment drugs, and no significant positive results were achieved in AD drug development over the past ten years, how to effectively improve the associated symptoms of AD has become one of the therapeutic targets for delaying the progression of AD. In the past 5 years, research on the relationship between sleep and AD, related drugs and non-drug therapy has attracted increasing attention. In this paper, a review of the pathogenesis and clinical treatment of sleep disorders in patients with AD will be presented.

sleep disorders; Alzheimer's disease; pathogenesis; treatment

2016-01-28[接受日期]2016-07-25

國家自然科學(xué)基金(30900473，81371459，81171252), 國家科技部重大專項(2011ZXJ09202-015)，國家科技支撐計劃項目(2015BAI13B01)，上海市科學(xué)技術(shù)委員會重點項目(11411950203),上海市自然科學(xué)基金(15ZR1414600). Supported by National Natural Science Foundation of China(30900473，81371459，81171252), National Ministry of Science and Technology Major Project(2011ZXJ09202-015), National Key Technology Research and Development Program of Ministry of Science and Technology of China (2015BAI13B01), Medical Key Project of Shanghai Municipal Science and Technology Commission(11411950203)and Natural Science Foundation of Shanghai(15ZR1414600).

孫文靜，碩士生. E-mail：sunwj1121@163.com

Corresponding author). Tel: 021-64041990, E-mail：yinyou179@163.com

10.12025/j.issn.1008-6358.2016.20160098

R 749.1+6

A