快速眼動睡眠期行為障礙與神經變性病發病機制研究進展

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變性病發病機制研究進展

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，并出現夢境（通常是暴力夢境）相關肢體運動（夢境演繹行為）。其人群發病率為0.38%～2.01%，在神經變性病尤其是α?突觸核蛋白病患者中的發病率明顯增加?？焖傺蹌铀咂谛袨檎系K可早于α?突觸核蛋白病數十年出現，因此可以作為預測神經變性病的早期標記。本文擬就近年來關于快速眼動睡眠期行為障礙發病機制及其與神經變性病之間的關系進行簡要綜述。

REM睡眠行為障礙； 神經變性疾?。?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，伴惡夢和夢境相關激烈言語或肢體復雜不自主運動。根據病因可以分為兩種類型，一種是特發性快速眼動睡眠期行為障礙，不存在其他明確的神經系統疾?。灰环N是繼發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系統疾病如發作性睡病、神經變性病等。近年來，隨著前瞻性臨床研究結果的公布，特發性快速眼動睡眠期行為障礙被認為是神經變性病尤其是α?突觸核蛋白病的早期臨床標記［1?5］。2010 年，Claassen等［6］發現，快速眼動睡眠期行為障礙較帕金森病（PD）、路易體癡呆（DLB）或多系統萎縮（MSA）的首發癥狀早數十年。近年來，越來越多的研究關注快速眼動睡眠期行為障礙發病機制及其與神經變性病之間的關系，本文擬就此方面研究進展進行簡要綜述。

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發病年齡可以分為早發型（50歲前發病）和晚發型（50歲及以后發病），二者在社會人口學資料、疾病表現形式等方面存在明顯差異。早發型快速眼動睡眠期行為障礙患者中女性、特發性快速眼動睡眠期行為障礙、使用抗抑郁藥、合并發作性睡病和自身免疫性疾病比例均較高［7?12］。此外，早發型患者較晚發型的睡眠障礙方式緩和，可能與早發型患者中女性、合并發作性睡病比例較高有關［7］。晚發型快速眼動睡眠期行為障礙患者合并神經變性病比例較高，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萎縮 15 年出現［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發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］。嚴重睡眠呼吸暫停（OSA）、創傷后應激障礙（PTSD）、夜間額葉癲、非快速眼動睡眠期（NREM）異態睡眠（如夢游、夜驚）等也可能出現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生夢境演繹行為。因此，為區分上述情況，需要詳細的病史資料和多導睡眠圖（PSG）監測。肌肉失遲緩系指快速眼動睡眠期持續性或間斷性頦下肌群或肢體肌電張力增高［19］。根據2014年美國睡眠醫學會（AASM）標準［7］，診斷確定的（definite）快速眼動睡眠期行為障礙應同時滿足以下條件：（1）睡眠中反復出現的發聲和（或）復雜行為表現，單夜視頻多導睡眠圖監測到反復出現的發聲和（或）動作。（2）多導睡眠圖監測到的上述行為發生于快速眼動睡眠期。（3）多導睡眠圖監測到的肌肉失遲緩符合美國睡眠醫學會制定的睡眠相關事件評分手冊標準。（4）上述異常不能用其他睡眠障礙、精神病、藥物因素或物質濫用等解釋。快速眼動睡眠期行為障礙患者覺醒后警醒程度、動作協調性和定向力均正常。發生以下情況時，臨床醫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：多導睡眠圖監測到快速眼動睡眠期異常行為，但肌肉失遲緩未達到美國睡眠醫學會制定的睡眠相關事件評分手冊標準，或者臨床存在典型快速眼動睡眠期行為障礙病史，但多導睡眠圖監測未達到快速眼動睡眠期行為障礙的診斷標準。對于沒有條件進行視頻多導睡眠圖監測的患者亦是如此。此外，某些藥物如三環類抗抑郁藥和選擇性5?羥色胺再攝取抑制劑（SSRI）可以誘發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，但應密切隨訪。國內某些睡眠中心進行連續兩夜視頻多導睡眠圖監測以排除環境因素的干擾，然而，2015年H?gl和 Stefani［20］更新的診斷標準提出，單夜視頻多導睡眠圖監測到快速眼動睡眠期睡眠即可明確診斷。此項更新的診斷標準的提出是根據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充頦肌和雙側脛骨前肌肌電圖，并認為常規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病和神經根損害，導致快速眼動睡眠期肌肉異常活動，從而造成混淆。更新的診斷標準還借用 Sixel?D?ring等［21］的快速眼動睡眠期行為障礙嚴重程度分級：0分，僅有肌肉失遲緩而無快速眼動睡眠期異常行為；1分，有肢體遠端小幅度動作；2分，有肢體近端肌肉活動；3分，有軀干運動；其中，監測到快速眼動睡眠期發聲評1分，未監測到評0分。因此，對于未予治療的帕金森病患者，如果視頻多導睡眠圖監測無法達到快速眼動睡眠期行為障礙的診斷標準，但有快速眼動睡眠期異常行為，則可以作為神經變性病的早期標記［22］。此外，更新的診斷標準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”，并進行定量分析，從而提出的診斷標準［20］。

三、快速眼動睡眠期行為障礙的發病機制

維持快速眼動睡眠期肌肉弛緩的兩種功能相反神經元分別稱為“REM?on”神經元和“REM?off”神經元，共同組成“開?關”模型，負責調控非快速眼動睡眠期與快速眼動睡眠期的轉換［23?24］?？焖傺蹌铀咂谛袨檎系K動物（貓）模型顯示，“REM?on”神經元位于藍斑（LC）腹側，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功能［25］。Jeannerod 等［26］于 1965 年通過特異性毀損貓藍斑核α周圍區域（相當于人藍斑下核）成功制備快速眼動睡眠期肌肉失弛緩動物模型，表現為貓在睡眠情況下出現類似捕食、盯梢、打斗和舔舐行為。研究顯示，藍斑核α周圍區域經乙酰膽堿激活后投射谷氨酸能神經元至髓內大細胞核，后者經突觸后膜釋放谷氨酸以阻斷脊髓下運動神經元［27］，導致肌張力缺失。大鼠背側下核（SLD）相當于貓藍斑核α周圍區域［28］。2017 年，Valencia Garcia 等［29］采用小發夾RNA（shRNA）技術使大鼠背側下核表達囊泡谷氨酸轉運體2（vGluT2）的谷氨酸能神經元失活，并于1個月后行睡眠監測，結果顯示，大鼠快速眼動睡眠期比例僅較基線下降30%，但呈現出快速眼動睡眠期肌肉失弛緩，證實背側下核谷氨酸能神經元下行投射至髓內腹側核甘氨酸能和（或）γ?氨基丁酸（GABA）能運動前神經元致快速眼動睡眠期肌肉失弛緩，但并無神經元上行投射至丘腦板內核，提示背側下核并不參與快速眼動睡眠期的發生，但對快速眼動睡眠期肌肉失弛緩的維持具有至關重要的作用。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：背側下核膽堿能和γ?氨基丁酸能神經元進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下核谷氨酸能神經元，而不包含“REM?on”和“REM?off”神經元。此外，快速眼動睡眠期行為障礙患者間斷性出現肌肉失遲緩，如何與該動物模型相聯系尚待進一步研究。關于“REM?off”神經元的研究相對明確，該神經元位于中腦導水管周圍灰質腹外側核（vlPAG）和腦橋外側被蓋（LPT），這兩個區域神經元失活可以導致異相睡眠增加［23，30］。

然而，目前對調節快速眼動睡眠期特異性神經核團和確切神經網絡的認識尚不明確。腦干損傷如腦血管病、炎癥和腫瘤可以導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［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行神經色素敏感成像（neuromelanin?sensitive imaging）研究，結果顯示，其藍斑/藍斑下區域信號強度較帕金森病不合并快速眼動睡眠期行為障礙患者降低，提示藍斑/藍斑下復合體變性可能導致快速眼動睡眠期行為障礙。晚近一項神經影像學研究顯示，快速眼動睡眠期行為障礙患者雙側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結構標記［34］。

激活5?羥色胺能系統的藥物如氟西汀、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類抗抑郁藥氯丙咪嗪均可誘發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快速眼動睡眠期行為障礙究竟是藥物不良反應，還是神經變性病早期獨立危險因素，Postuma等［36］的研究顯示，盡管抗抑郁藥相關快速眼動睡眠期行為障礙較“純粹的”特發性快速眼動睡眠期行為障礙進展為神經變性病的風險低，但抗抑郁藥相關快速眼動睡眠期行為障礙是潛在的神經變性病早期標記。

四、快速眼動睡眠期行為障礙與神經變性病的潛在分子學機制

Hypocretin（Hcrt）/Orexin 僅由下丘腦背側和外側神經元分泌［37］，對維持機體生理功能如攝食、血壓、體溫、神經內分泌和睡眠?覺醒周期發揮重要作用［38?41］。Orexin基因敲除小鼠［42］、Hcrt/Orexin 能神經元缺失的轉基因小鼠［43］以及Orexin受體2（OX2R）基因無義突變的小鼠和狗［44?45］均呈現睡眠周期片段化，其中前兩者還出現快速眼動睡眠期猝倒發作［42?43］，而后者僅受輕微影響［44］。Mieda 等［46］研究顯示，Hcrt/Orexin能神經元缺失的轉基因小鼠腦組織異位表達編碼Hcrt/Orexin前體蛋白的基因，可以避免快速眼動睡眠期猝倒發作和其他異常；予中樞性Hcrt?1/Orexin?1可以迅速抑制猝倒發作并增加3小時覺醒時間。分泌Hcrt/Orexin的神經元可以投射至多個神經系統，其中下丘腦以外投射密度最集中的區域是藍斑核［38，47］。Bourgin 等［48］報道，于藍斑核局部注射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。Gerashchenko等［49］認為，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。上述研究均提示Hcrt/Orexin是調節快速眼動睡眠期的重要因子，其表達異?？梢詫е庐惓？焖傺蹌铀咂?。2010年，Knudsen等［50］研究顯示，腦脊液Hcrt?1/Orexin?1表達下調是發作性睡病患者發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變性病患者可能存在Hcrt/Orexin能神經元數目減少或分泌下降。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［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 能神經元缺失（50%）［59?60］。Thannickal等［61］認為，造成上述結果差異的原因可能是腦脊液Hcrt/Orexin水平并不與Hcrt/Orexin能神經元數目成正比，殘留的Hcrt/Orexin能神經元可能通過Hcrt/Orexin代償性分泌增加在一定時間內維持腦脊液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。關于多系統萎縮患者Hcrt/Orexin能神經元是否受累的研究結論不盡一致，Benarroch等［62］的免疫組織化學染色顯示，多系統萎縮患者Hcrt/Orexin能神經元數目較正常對照者減少；Abdo等［63］則認為，多系統萎縮患者腦脊液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計學意義。關于路易體癡呆的研究顯示，新皮質區Hcrt/Orexin水平下降與α?突觸核蛋白（α?Syn）水平和嗜睡有關，提示Hcrt/Orexin表達變化與路易體癡呆患者睡眠障礙有關［64］。此外，有研究顯示，路易體癡呆患者下丘腦外側Hcrt/Orexin能神經元和藍斑核Hcrt/Orexin軸突末端數目減少，且下丘腦外側Hcrt/Orexin能神經元數目與神經原纖維纏結（NFTs）程度呈明顯負相關［65］。關于阿爾茨海默?。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，但水平較低者出現日間覺醒片段化增加，提示Hcrt?1/Orexin?1可能參與睡眠?覺醒周期的調節。關于亨廷頓?。℉D）患者Hcrt/Orexin能神經元的研究，既往已有文獻報道，亨廷頓病轉基因小鼠R6/2和亨廷頓病患者下丘腦外側Hcrt/Orexin能神經元明顯萎縮和缺失［68］。Gabery等［69］也于2010年得出相似結論。然而迄今為止，Hcrt/Orexin如何參與快速眼動睡眠期的調節，從而影響神經變性病的發生與發展尚無明確定論，尚待更多研究。

綜上所述，大鼠背側下核神經核團對維持快速眼動睡眠期肌肉弛緩至關重要，背側下核谷氨酸能神經元下行投射至髓內腹側核甘氨酸能和（或）γ?氨基丁酸能運動前神經元導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生。腦脊液Hcrt/Orexin水平下降與1型發作性睡病的發病密切相關，提示Hcrt/Orexin參與快速眼動睡眠期的調節。然而，背側下核膽堿能和γ?氨基丁酸能神經元如何參與快速眼動睡眠期肌肉失遲緩的調節以及Hcrt/Orexin如何參與快速眼動睡眠期的調節尚待進一步研究。

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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

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

210008南京大學醫學院附屬鼓樓醫院神經內科（姜海洋）；430022武漢，華中科技大學同濟醫學院附屬協和醫院神經內科（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）