快速眼動睡眠期行為障礙與神經(jīng)變性病發(fā)病機(jī)制研究進(jìn)展

姜海洋 黃金莎 王濤

·專題綜述·

快速眼動睡眠期行為障礙與神經(jīng)變性病發(fā)病機(jī)制研究進(jìn)展

姜海洋 黃金莎 王濤

快速眼動睡眠期行為障礙系指快速眼動睡眠期肌肉失弛緩，并出現(xiàn)夢境（通常是暴力夢境）相關(guān)肢體運(yùn)動（夢境演繹行為）。其人群發(fā)病率為0.38%～2.01%，在神經(jīng)變性病尤其是α?突觸核蛋白病患者中的發(fā)病率明顯增加?？焖傺蹌铀咂谛袨檎系K可早于α?突觸核蛋白病數(shù)十年出現(xiàn)，因此可以作為預(yù)測神經(jīng)變性病的早期標(biāo)記。本文擬就近年來關(guān)于快速眼動睡眠期行為障礙發(fā)病機(jī)制及其與神經(jīng)變性病之間的關(guān)系進(jìn)行簡要綜述。

REM睡眠行為障礙； 神經(jīng)變性疾?。?綜述

快速眼動睡眠期行為障礙（RBD）系指快速眼動睡眠期（REM）肌肉失弛緩，伴惡夢和夢境相關(guān)激烈言語或肢體復(fù)雜不自主運(yùn)動。根據(jù)病因可以分為兩種類型，一種是特發(fā)性快速眼動睡眠期行為障礙，不存在其他明確的神經(jīng)系統(tǒng)疾?。灰环N是繼發(fā)性快速眼動睡眠期行為障礙，也稱癥狀性快速眼動睡眠期行為障礙，系快速眼動睡眠期行為障礙合并其他神經(jīng)系統(tǒng)疾病如發(fā)作性睡病、神經(jīng)變性病等。近年來，隨著前瞻性臨床研究結(jié)果的公布，特發(fā)性快速眼動睡眠期行為障礙被認(rèn)為是神經(jīng)變性病尤其是α?突觸核蛋白病的早期臨床標(biāo)記［1?5］。2010 年，Claassen等［6］發(fā)現(xiàn)，快速眼動睡眠期行為障礙較帕金森?。≒D）、路易體癡呆（DLB）或多系統(tǒng)萎縮（MSA）的首發(fā)癥狀早數(shù)十年。近年來，越來越多的研究關(guān)注快速眼動睡眠期行為障礙發(fā)病機(jī)制及其與神經(jīng)變性病之間的關(guān)系，本文擬就此方面研究進(jìn)展進(jìn)行簡要綜述。

一、快速眼動睡眠期行為障礙的臨床特點

快速眼動睡眠期行為障礙根據(jù)發(fā)病年齡可以分為早發(fā)型（50歲前發(fā)?。┖屯戆l(fā)型（50歲及以后發(fā)病），二者在社會人口學(xué)資料、疾病表現(xiàn)形式等方面存在明顯差異。早發(fā)型快速眼動睡眠期行為障礙患者中女性、特發(fā)性快速眼動睡眠期行為障礙、使用抗抑郁藥、合并發(fā)作性睡病和自身免疫性疾病比例均較高［7?12］。此外，早發(fā)型患者較晚發(fā)型的睡眠障礙方式緩和，可能與早發(fā)型患者中女性、合并發(fā)作性睡病比例較高有關(guān)［7］。晚發(fā)型快速眼動睡眠期行為障礙患者合并神經(jīng)變性病比例較高，且睡眠障礙通常早于α?突觸核蛋白病如帕金森病、路易體癡呆和多系統(tǒng)萎縮 15 年出現(xiàn)［1?5］。研究顯示，嗅覺和色覺基線水平下降的快速眼動睡眠期行為障礙患者更易進(jìn)展為α?突觸核蛋白?。?3?17］。

二、快速眼動睡眠期行為障礙的診斷

快速眼動睡眠期行為障礙患者均存在反復(fù)發(fā)作的夜間夢境演繹行為（DEBs），但具有上述行為的并非均是快速眼動睡眠期行為障礙［18］。嚴(yán)重睡眠呼吸暫停（OSA）、創(chuàng)傷后應(yīng)激障礙（PTSD）、夜間額葉癲、非快速眼動睡眠期（NREM）異態(tài)睡眠（如夢游、夜驚）等也可能出現(xiàn)生動夢境和夢境演繹行為。使用或戒斷酒精或某些藥物也可能發(fā)生夢境演繹行為。因此，為區(qū)分上述情況，需要詳細(xì)的病史資料和多導(dǎo)睡眠圖（PSG）監(jiān)測。肌肉失遲緩系指快速眼動睡眠期持續(xù)性或間斷性頦下肌群或肢體肌電張力增高［19］。根據(jù)2014年美國睡眠醫(yī)學(xué)會（AASM）標(biāo)準(zhǔn)［7］，診斷確定的（definite）快速眼動睡眠期行為障礙應(yīng)同時滿足以下條件：（1）睡眠中反復(fù)出現(xiàn)的發(fā)聲和（或）復(fù)雜行為表現(xiàn)，單夜視頻多導(dǎo)睡眠圖監(jiān)測到反復(fù)出現(xiàn)的發(fā)聲和（或）動作。（2）多導(dǎo)睡眠圖監(jiān)測到的上述行為發(fā)生于快速眼動睡眠期。（3）多導(dǎo)睡眠圖監(jiān)測到的肌肉失遲緩符合美國睡眠醫(yī)學(xué)會制定的睡眠相關(guān)事件評分手冊標(biāo)準(zhǔn)。（4）上述異常不能用其他睡眠障礙、精神病、藥物因素或物質(zhì)濫用等解釋。快速眼動睡眠期行為障礙患者覺醒后警醒程度、動作協(xié)調(diào)性和定向力均正常。發(fā)生以下情況時，臨床醫(yī)師可以基于臨床判斷暫時診斷為快速眼動睡眠期行為障礙：多導(dǎo)睡眠圖監(jiān)測到快速眼動睡眠期異常行為，但肌肉失遲緩未達(dá)到美國睡眠醫(yī)學(xué)會制定的睡眠相關(guān)事件評分手冊標(biāo)準(zhǔn)，或者臨床存在典型快速眼動睡眠期行為障礙病史，但多導(dǎo)睡眠圖監(jiān)測未達(dá)到快速眼動睡眠期行為障礙的診斷標(biāo)準(zhǔn)。對于沒有條件進(jìn)行視頻多導(dǎo)睡眠圖監(jiān)測的患者亦是如此。此外，某些藥物如三環(huán)類抗抑郁藥和選擇性5?羥色胺再攝取抑制劑（SSRI）可以誘發(fā)快速眼動睡眠期行為障礙，此時可以診斷為快速眼動睡眠期行為障礙，但應(yīng)密切隨訪。國內(nèi)某些睡眠中心進(jìn)行連續(xù)兩夜視頻多導(dǎo)睡眠圖監(jiān)測以排除環(huán)境因素的干擾，然而，2015年H?gl和 Stefani［20］更新的診斷標(biāo)準(zhǔn)提出，單夜視頻多導(dǎo)睡眠圖監(jiān)測到快速眼動睡眠期睡眠即可明確診斷。此項更新的診斷標(biāo)準(zhǔn)的提出是根據(jù)Innsbruck Barcelona睡眠工作組（SINBAR）的研究，增加指淺屈肌肌電圖以更好地補(bǔ)充頦肌和雙側(cè)脛骨前肌肌電圖，并認(rèn)為常規(guī)脛骨前肌肌電圖并不具有特異性，這是由于老年患者易合并周圍神經(jīng)病和神經(jīng)根損害，導(dǎo)致快速眼動睡眠期肌肉異常活動，從而造成混淆。更新的診斷標(biāo)準(zhǔn)還借用 Sixel?D?ring等［21］的快速眼動睡眠期行為障礙嚴(yán)重程度分級：0分，僅有肌肉失遲緩而無快速眼動睡眠期異常行為；1分，有肢體遠(yuǎn)端小幅度動作；2分，有肢體近端肌肉活動；3分，有軀干運(yùn)動；其中，監(jiān)測到快速眼動睡眠期發(fā)聲評1分，未監(jiān)測到評0分。因此，對于未予治療的帕金森病患者，如果視頻多導(dǎo)睡眠圖監(jiān)測無法達(dá)到快速眼動睡眠期行為障礙的診斷標(biāo)準(zhǔn)，但有快速眼動睡眠期異常行為，則可以作為神經(jīng)變性病的早期標(biāo)記［22］。此外，更新的診斷標(biāo)準(zhǔn)系指將不符合原有的時相性和緊張性肌張力增高定義為“任意形式的肌張力增高”，并進(jìn)行定量分析，從而提出的診斷標(biāo)準(zhǔn)［20］。

三、快速眼動睡眠期行為障礙的發(fā)病機(jī)制

維持快速眼動睡眠期肌肉弛緩的兩種功能相反神經(jīng)元分別稱為“REM?on”神經(jīng)元和“REM?off”神經(jīng)元，共同組成“開?關(guān)”模型，負(fù)責(zé)調(diào)控非快速眼動睡眠期與快速眼動睡眠期的轉(zhuǎn)換［23?24］?？焖傺蹌铀咂谛袨檎系K動物（貓）模型顯示，“REM?on”神經(jīng)元位于藍(lán)斑（LC）腹側(cè)，向上投射引起腦電活動和意識改變，向下投射抑制肌張力和快速眼動睡眠期自主神經(jīng)功能［25］。Jeannerod 等［26］于 1965 年通過特異性毀損貓藍(lán)斑核α周圍區(qū)域（相當(dāng)于人藍(lán)斑下核）成功制備快速眼動睡眠期肌肉失弛緩動物模型，表現(xiàn)為貓在睡眠情況下出現(xiàn)類似捕食、盯梢、打斗和舔舐行為。研究顯示，藍(lán)斑核α周圍區(qū)域經(jīng)乙酰膽堿激活后投射谷氨酸能神經(jīng)元至髓內(nèi)大細(xì)胞核，后者經(jīng)突觸后膜釋放谷氨酸以阻斷脊髓下運(yùn)動神經(jīng)元［27］，導(dǎo)致肌張力缺失。大鼠背側(cè)下核（SLD）相當(dāng)于貓藍(lán)斑核α周圍區(qū)域［28］。2017 年，Valencia Garcia 等［29］采用小發(fā)夾RNA（shRNA）技術(shù)使大鼠背側(cè)下核表達(dá)囊泡谷氨酸轉(zhuǎn)運(yùn)體2（vGluT2）的谷氨酸能神經(jīng)元失活，并于1個月后行睡眠監(jiān)測，結(jié)果顯示，大鼠快速眼動睡眠期比例僅較基線下降30%，但呈現(xiàn)出快速眼動睡眠期肌肉失弛緩，證實背側(cè)下核谷氨酸能神經(jīng)元下行投射至髓內(nèi)腹側(cè)核甘氨酸能和（或）γ?氨基丁酸（GABA）能運(yùn)動前神經(jīng)元致快速眼動睡眠期肌肉失弛緩，但并無神經(jīng)元上行投射至丘腦板內(nèi)核，提示背側(cè)下核并不參與快速眼動睡眠期的發(fā)生，但對快速眼動睡眠期肌肉失弛緩的維持具有至關(guān)重要的作用。該動物模型首次定量研究快速眼動睡眠期肌張力變化和異常行為，但仍有缺陷：背側(cè)下核膽堿能和γ?氨基丁酸能神經(jīng)元進(jìn)行性損害也可以引起快速眼動睡眠期肌電圖改變和異常行為，該動物模型完全抑制背側(cè)下核谷氨酸能神經(jīng)元，而不包含“REM?on”和“REM?off”神經(jīng)元。此外，快速眼動睡眠期行為障礙患者間斷性出現(xiàn)肌肉失遲緩，如何與該動物模型相聯(lián)系尚待進(jìn)一步研究。關(guān)于“REM?off”神經(jīng)元的研究相對明確，該神經(jīng)元位于中腦導(dǎo)水管周圍灰質(zhì)腹外側(cè)核（vlPAG）和腦橋外側(cè)被蓋（LPT），這兩個區(qū)域神經(jīng)元失活可以導(dǎo)致異相睡眠增加［23，30］。

然而，目前對調(diào)節(jié)快速眼動睡眠期特異性神經(jīng)核團(tuán)和確切神經(jīng)網(wǎng)絡(luò)的認(rèn)識尚不明確。腦干損傷如腦血管病、炎癥和腫瘤可以導(dǎo)致快速眼動睡眠期行為障礙，提示腦干尤其是中腦和腦橋被蓋與快速眼動睡眠期行為障礙密切相關(guān)［31?32］。Garcia?Lorenzo等［33］對帕金森病合并快速眼動睡眠期行為障礙患者進(jìn)行神經(jīng)色素敏感成像（neuromelanin?sensitive imaging）研究，結(jié)果顯示，其藍(lán)斑/藍(lán)斑下區(qū)域信號強(qiáng)度較帕金森病不合并快速眼動睡眠期行為障礙患者降低，提示藍(lán)斑/藍(lán)斑下復(fù)合體變性可能導(dǎo)致快速眼動睡眠期行為障礙。晚近一項神經(jīng)影像學(xué)研究顯示，快速眼動睡眠期行為障礙患者雙側(cè)殼核體積較性別和年齡相匹配的正常對照者縮小，可以作為快速眼動睡眠期行為障礙的一項神經(jīng)結(jié)構(gòu)標(biāo)記［34］。

激活5?羥色胺能系統(tǒng)的藥物如氟西汀、文拉法辛和帕羅西汀，以及阻斷乙酰膽堿能傳遞的藥物如三環(huán)類抗抑郁藥氯丙咪嗪均可誘發(fā)快速眼動睡眠期行為障礙和肌肉失遲緩［35］，可能是由于此類藥物阻止正常睡眠相關(guān)肌張力降低（5?羥色胺再攝取抑制劑）或肌張力缺失（抗膽堿能藥物）。為明確抗抑郁藥相關(guān)快速眼動睡眠期行為障礙究竟是藥物不良反應(yīng)，還是神經(jīng)變性病早期獨立危險因素，Postuma等［36］的研究顯示，盡管抗抑郁藥相關(guān)快速眼動睡眠期行為障礙較“純粹的”特發(fā)性快速眼動睡眠期行為障礙進(jìn)展為神經(jīng)變性病的風(fēng)險低，但抗抑郁藥相關(guān)快速眼動睡眠期行為障礙是潛在的神經(jīng)變性病早期標(biāo)記。

四、快速眼動睡眠期行為障礙與神經(jīng)變性病的潛在分子學(xué)機(jī)制

Hypocretin（Hcrt）/Orexin 僅由下丘腦背側(cè)和外側(cè)神經(jīng)元分泌［37］，對維持機(jī)體生理功能如攝食、血壓、體溫、神經(jīng)內(nèi)分泌和睡眠?覺醒周期發(fā)揮重要作用［38?41］。Orexin基因敲除小鼠［42］、Hcrt/Orexin 能神經(jīng)元缺失的轉(zhuǎn)基因小鼠［43］以及Orexin受體2（OX2R）基因無義突變的小鼠和狗［44?45］均呈現(xiàn)睡眠周期片段化，其中前兩者還出現(xiàn)快速眼動睡眠期猝倒發(fā)作［42?43］，而后者僅受輕微影響［44］。Mieda 等［46］研究顯示，Hcrt/Orexin能神經(jīng)元缺失的轉(zhuǎn)基因小鼠腦組織異位表達(dá)編碼Hcrt/Orexin前體蛋白的基因，可以避免快速眼動睡眠期猝倒發(fā)作和其他異常；予中樞性Hcrt?1/Orexin?1可以迅速抑制猝倒發(fā)作并增加3小時覺醒時間。分泌Hcrt/Orexin的神經(jīng)元可以投射至多個神經(jīng)系統(tǒng)，其中下丘腦以外投射密度最集中的區(qū)域是藍(lán)斑核［38，47］。Bourgin 等［48］報道，于藍(lán)斑核局部注射Hcrt?1/Orexin?1可以劑量依賴性抑制快速眼動睡眠期，減少非快速眼動睡眠期3期（也稱慢波睡眠）時間，增加覺醒時間，并且可以通過抗體中和以阻斷上述效應(yīng)。Gerashchenko等［49］認(rèn)為，大鼠腦脊液Hcrt/Orexin水平下降與快速眼動睡眠期時間增加有關(guān)。上述研究均提示Hcrt/Orexin是調(diào)節(jié)快速眼動睡眠期的重要因子，其表達(dá)異?？梢詫?dǎo)致異?？焖傺蹌铀咂凇?010年，Knudsen等［50］研究顯示，腦脊液Hcrt?1/Orexin?1表達(dá)下調(diào)是發(fā)作性睡病患者發(fā)生快速眼動睡眠期行為障礙的獨立危險因素，提示合并快速眼動睡眠期行為障礙的神經(jīng)變性病患者可能存在Hcrt/Orexin能神經(jīng)元數(shù)目減少或分泌下降。研究顯示，帕金森病患者腦脊液Hcrt?1/Orexin?1 水平在正常范圍內(nèi)［51?56］；亦有研究顯示，帕金森病患者腦脊液Hcrt?1/Orexin?1水平低于正常對照者［57?58］；晚近有 2 項研究顯示，帕金森病患者下丘腦 Hcrt/Orexin 能神經(jīng)元缺失（50%）［59?60］。Thannickal等［61］認(rèn)為，造成上述結(jié)果差異的原因可能是腦脊液Hcrt/Orexin水平并不與Hcrt/Orexin能神經(jīng)元數(shù)目成正比，殘留的Hcrt/Orexin能神經(jīng)元可能通過Hcrt/Orexin代償性分泌增加在一定時間內(nèi)維持腦脊液Hcrt/Orexin處于正常水平，因此，早期帕金森病患者腦脊液Hcrt/Orexin水平可能無明顯變化。關(guān)于多系統(tǒng)萎縮患者Hcrt/Orexin能神經(jīng)元是否受累的研究結(jié)論不盡一致，Benarroch等［62］的免疫組織化學(xué)染色顯示，多系統(tǒng)萎縮患者Hcrt/Orexin能神經(jīng)元數(shù)目較正常對照者減少；Abdo等［63］則認(rèn)為，多系統(tǒng)萎縮患者腦脊液Hcrt?1/Orexin?1處于正常水平，且與年齡匹配的正常對照者差異無統(tǒng)計學(xué)意義。關(guān)于路易體癡呆的研究顯示，新皮質(zhì)區(qū)Hcrt/Orexin水平下降與α?突觸核蛋白（α?Syn）水平和嗜睡有關(guān)，提示Hcrt/Orexin表達(dá)變化與路易體癡呆患者睡眠障礙有關(guān)［64］。此外，有研究顯示，路易體癡呆患者下丘腦外側(cè)Hcrt/Orexin能神經(jīng)元和藍(lán)斑核Hcrt/Orexin軸突末端數(shù)目減少，且下丘腦外側(cè)Hcrt/Orexin能神經(jīng)元數(shù)目與神經(jīng)原纖維纏結(jié)（NFTs）程度呈明顯負(fù)相關(guān)［65］。關(guān)于阿爾茨海默?。ˋD）患者、路易體癡呆患者與非癡呆對照者的研究顯示，路易體癡呆患者腦脊液Hcrt/Orexin水平低于阿爾茨海默病患者和非癡呆對照者［66］。Friedman 等［67］研究顯示，盡管阿爾茨海默病患者腦脊液Hcrt?1/Orexin?1水平在正常范圍內(nèi)，但水平較低者出現(xiàn)日間覺醒片段化增加，提示Hcrt?1/Orexin?1可能參與睡眠?覺醒周期的調(diào)節(jié)。關(guān)于亨廷頓病（HD）患者Hcrt/Orexin能神經(jīng)元的研究，既往已有文獻(xiàn)報道，亨廷頓病轉(zhuǎn)基因小鼠R6/2和亨廷頓病患者下丘腦外側(cè)Hcrt/Orexin能神經(jīng)元明顯萎縮和缺失［68］。Gabery等［69］也于2010年得出相似結(jié)論。然而迄今為止，Hcrt/Orexin如何參與快速眼動睡眠期的調(diào)節(jié)，從而影響神經(jīng)變性病的發(fā)生與發(fā)展尚無明確定論，尚待更多研究。

綜上所述，大鼠背側(cè)下核神經(jīng)核團(tuán)對維持快速眼動睡眠期肌肉弛緩至關(guān)重要，背側(cè)下核谷氨酸能神經(jīng)元下行投射至髓內(nèi)腹側(cè)核甘氨酸能和（或）γ?氨基丁酸能運(yùn)動前神經(jīng)元導(dǎo)致快速眼動睡眠期肌肉失弛緩，但并不參與快速眼動睡眠期的發(fā)生。腦脊液Hcrt/Orexin水平下降與1型發(fā)作性睡病的發(fā)病密切相關(guān)，提示Hcrt/Orexin參與快速眼動睡眠期的調(diào)節(jié)。然而，背側(cè)下核膽堿能和γ?氨基丁酸能神經(jīng)元如何參與快速眼動睡眠期肌肉失遲緩的調(diào)節(jié)以及Hcrt/Orexin如何參與快速眼動睡眠期的調(diào)節(jié)尚待進(jìn)一步研究。

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Research progresson thepathogenesisofrapid eyemovementsleep behavior disorder and neurodegenerative diseases

JIANG Hai?yang1,HUANG Jin?sha2,WANG Tao2
1Department of Neurology,Nanjing Drum Tower Hospital,the Affiliated Hospital of Nanjing Medical University,Nanjing 210008,Jiangsu,China
2Department of Neurology,Wuhan Union Hospital,Tongji Medical College,Huazhong University of Science and Technology,Wuhan 430022,Hubei,China
Corresponding author:WANG Tao(Email:wangtaowh@hust.edu.cn)

Rapid eye movement sleep behavior disorder(RBD)is a sleep disorder characterized by the disappearance of muscle relaxation and enacting one's dreams during rapid eye movement(REM),with most of the dreams being violent or aggressive.Prevalence of RBD,based on population,is 0.38%-2.01%,but it becomes much higher in patients with neurodegenerative diseases,especially α ?synucleinopathies.RBD may herald the emergence of α ?synucleinopathies by decades,thus it may be used as an effective early marker of neurodegenerative diseases.In this review,we summarized the progress on the pathogenesis of RBD and its relationship with neurodegenerative diseases.

REM sleep behavior disorder; Neurodegenerative diseases; Review

10.3969/j.issn.1672?6731.2017.10.003

國家自然科學(xué)基金資助項目（項目編號：31171211）；國家自然科學(xué)基金資助項目（項目編號：81471305）；國家自然科學(xué)基金資助項目（項目編號：81671260）

210008南京大學(xué)醫(yī)學(xué)院附屬鼓樓醫(yī)院神經(jīng)內(nèi)科（姜海洋）；430022武漢，華中科技大學(xué)同濟(jì)醫(yī)學(xué)院附屬協(xié)和醫(yī)院神經(jīng)內(nèi)科（黃金莎，王濤）

王濤（Email：wangtaowh@hust.edu.cn）

This study was supported by the National Natural Science Foundation of China(No.31171211,81471305,81671260).

2017?08?03）