朱 琳，劉 軍

上海交通大學(xué)醫(yī)學(xué)院附屬瑞金醫(yī)院神經(jīng)內(nèi)科，上海200025

多系統(tǒng)萎縮（multiple system atrophy，MSA）是以自主神經(jīng)、錐體外系、錐體束等多系統(tǒng)受累為主要病理特征，且對左旋多巴治療反應(yīng)不佳的一種帕金森綜合征。目前，MSA 的診斷共識將其分為“確診”“很可能”和“可能”3 個(gè)等級。確診MSA 需依據(jù)病理診斷[1]。MSA 可根據(jù)臨床癥狀分為以帕金森綜合征為主要表現(xiàn)的MSA-P 型和以小腦性共濟(jì)失調(diào)為主要表現(xiàn)的MSA-C 型[1]。少突膠質(zhì)細(xì)胞中的一個(gè)類型——嗜銀性膠質(zhì)細(xì)胞，其細(xì)胞質(zhì)包涵體（glial cytoplasmic inclusion，GCI）是MSA 的病理特征[2]。因此MSA 的神經(jīng)病理確診標(biāo)準(zhǔn)為與大量廣泛分布的GCI 密切相關(guān)的黑質(zhì)-紋狀體或橄欖-腦橋-小腦退行性病變[3]。目前MSA 無有效治療方法，臨床上主要對癥治療，改善患者生活質(zhì)量。

MSA 臨床癥狀異質(zhì)性大，與其他α-突觸核蛋白相關(guān)疾病及tau 蛋白相關(guān)疾病常有類似臨床特征，且缺乏特異度高的生物標(biāo)志物?；颊呱按_診難度大，多依據(jù)臨床表現(xiàn)進(jìn)行診斷。一項(xiàng)研究[4]顯示，臨床診斷為MSA 的134 例 患者中，尸檢結(jié)果確診者僅占62%。因此，高敏感度和特異度的生物標(biāo)志物對MSA 的診斷、預(yù)后以及臨床試驗(yàn)中的療效評估都極為重要。本文總結(jié)近年來MSA 生物標(biāo)志物的研究進(jìn)展。

1 體液生物標(biāo)志物

MSA 體液標(biāo)志物包括血清和腦脊液中的α-突觸核蛋白、DJ-1、tau 蛋白、兒茶酚胺及其代謝產(chǎn)物、細(xì)胞因子、miRNA 等；但研究結(jié)果并不完全一致，對MSA 的臨床診斷意義也并不明確[5]。

1.1 蛋白質(zhì)

對于MSA 患者腦脊液中總α-突觸核蛋白含量是否降低，各研究結(jié)論不一致。僅有1 項(xiàng)研究[6]顯示，MSA 患者與帕金森病（Parkinson's disease，PD）患者腦脊液中總α-突觸核蛋白含量存在差異；因此，將腦脊液中總α-突觸核蛋白含量作為2 種疾病鑒別診斷依據(jù)尚不充分。MSA患者腦脊液及血清中神經(jīng)絲蛋白輕鏈（neurofilament light chain，NF-L）較健康者及PD 患者均有明顯升高[7]，腦脊液中神經(jīng)絲蛋白重鏈（neurofilament heavy chain，NF-H）較健康者及PD 患者也有顯著升高[6]，有一定的臨床應(yīng)用價(jià)值。

另外，需要指出的是體液單個(gè)生物標(biāo)志物的特異度及敏感度均較低，2 種及以上的標(biāo)志物相結(jié)合可提高疾病診斷和鑒別診斷的特異度或敏感度。如將腦脊液中DJ-1 和總tau 蛋白相結(jié)合，鑒別MSA 和PD 的敏感度（82%）和特異度（81%）均較高[8]，但還需要大樣本量的臨床驗(yàn)證。

1.2 RNA

miRNA 是由20 ～25 個(gè)核苷酸組成的單鏈非編碼RNA，參與調(diào)節(jié)許多生理過程[9]。多種生物樣本中miRNA 都較穩(wěn)定，如血清、血漿、唾液和腦脊液等。因此，近年有許多關(guān)于診斷MSA 及鑒別PD 和MSA 的生物標(biāo)志物的研究聚焦于體液標(biāo)本中的miRNA，證明了組間表達(dá)的差異，且顯示了一些miRNA 在中樞神經(jīng)系統(tǒng)中高表達(dá)，參與了細(xì)胞凋亡的調(diào)節(jié)、基因轉(zhuǎn)錄后的修飾、神經(jīng)炎癥過程等[10]。

一項(xiàng)研究[11]顯示，與健康對照相比，MSA 患者血漿中miR-30c-5p 表達(dá)明顯上調(diào)，且其表達(dá)水平與病程長短相關(guān)，用于MSA 患者和健康對照的鑒別準(zhǔn)確度較高（敏感度為80%，特異度為90%），用于鑒別MSA 與PD 的敏感度為82%，特異度則較低（54%）。該研究團(tuán)隊(duì)還發(fā)現(xiàn)：與健康對照相比，MSA 患者血漿中miR-24、miR-148b、miR-223*、miR-324-3p 表 達(dá) 上 調(diào)，miR-339-5p 表 達(dá) 下降；與PD 患者相比，MSA 患者血漿中miR-148b 表達(dá)上調(diào)[12]。除血漿中miRNA 表達(dá)變化外，2017 年一項(xiàng)研究[13]報(bào)道，腦脊液中miR-34a、miR-34b 和miR-34c 在MSA患者與健康對照間有差異，在MSA 患者中表達(dá)偏低。有些miRNA 還可能與MSA 不同類型相關(guān)。miR-24 和miR-148b 與MSA 中小腦共濟(jì)失調(diào)癥狀具有相關(guān)性，提示這些miRNA 參與MSA 的小腦退行性變[13]。

單個(gè)miRNA 用于鑒別PD 與MSA 或診斷MSA 時(shí)，敏感度及特異度均不高，聯(lián)合多種miRNA 可能提高診斷的準(zhǔn)確性。腦脊液中miR-133b 和miR-148b 聯(lián)合應(yīng)用，可較好地區(qū)分PD 和MSA[13]。研究[14]表明：腦脊液中3 種miRNA 聯(lián)合檢測可有效區(qū)分α-突觸核蛋白相關(guān)疾病與健康對照；其中miR-7-5p、miR-34c-3p 和miR-let-7b-5p 可區(qū)分MSA 與健康對照，miR-9-3p 和miR-106b-5p 聯(lián)合檢測可鑒別MSA 與PD。

體液中miRNA 應(yīng)用于MSA 的診斷有一定前景，但目前仍有許多局限性：尚無統(tǒng)一的內(nèi)源性對照miRNA 用于標(biāo)準(zhǔn)量化miRNA；腦脊液miRNA 含量較低，不同樣本處理方法可造成miRNA 定量差異較大；既往研究樣本數(shù)量有限，從而影響結(jié)論的可靠性。因此，還需大樣本隊(duì)列研究探索miRNA 在MSA 診斷和鑒別診斷中的應(yīng)用。

2 神經(jīng)影像學(xué)標(biāo)志物

2.1 磁共振成像

MSA 結(jié)構(gòu)磁共振成像（magnetic resonance imaging，MRI）中灰質(zhì)的萎縮不僅常用于鑒別MSA 和其他神經(jīng)退行性病變，如原發(fā)性PD、路易體癡呆（dementia with Lewy bodies，DLB）、進(jìn)行性核上性麻痹（progressive superanuclear palsy，PSP）、皮質(zhì)基底節(jié)變性等，還可用于鑒別MSA 中P 型及C 型。十字面包征和殼核裂隙征都是經(jīng)典MSA 征象。十字面包征即T2 加權(quán)相中腦橋可見高信號十字交叉，該征提示腦橋及腦橋小腦束退行性病變，但皮質(zhì)脊髓束正常；殼核裂隙征指T2 加權(quán)相中殼核外緣可見高信號。兩者診斷MSA 的特異度較高，但敏感度偏低[15]。此外，MSA-P 中還可見殼核的萎縮和低信號，MSA-C 中可見腦干、小腦萎縮及小腦中腳（middle cerebellar peduncle，MCP）的高信號[16]。多數(shù)MSA 患者在疾病不同階段都可見上述多個(gè)征象[17]，將多個(gè)征象相結(jié)合用于鑒別MSA 和PD 的敏感度及特異度明顯升高[18]。

具體量化上述結(jié)構(gòu)變化也可以有效提高診斷的準(zhǔn)確度，如測量MCP 寬度以量化MCP 萎縮程度，當(dāng)矢狀位MCP 寬度＜8 mm 可鑒別MSA 和原發(fā)性PD，敏感度及特異度均可達(dá)到100%[19]。有研究采用了更加準(zhǔn)確測量橫斷面灰質(zhì)萎縮的方法，包括人工或半自動感興趣區(qū)域（region of interest，ROI）體積分析及基于體素的形態(tài)學(xué)全腦分析（voxel-based morphometry，VBM）[20]。以上定量方法可準(zhǔn)確反映MSA 患者幕上、幕下部分腦區(qū)的萎縮程度[21-22]；但鑒別早期MSA-P 和原發(fā)性PD（病程＜3 年）時(shí)，VBM 準(zhǔn)確程度不佳[23]。另外，萎縮率是評價(jià)疾病進(jìn)程的重要指標(biāo)[24]。目前，2 項(xiàng)縱向研究分析MSA 患者全腦萎縮率（whole-brain atrophy rate，WBAR）[25-26]，發(fā)現(xiàn)早期MSA 患者比原發(fā)性PD 患者WBAR 更高，該指標(biāo)可應(yīng)用于監(jiān)測疾病進(jìn)展程度，較臨床評分更為客觀，但需要更大樣本和更長隨訪時(shí)間驗(yàn)證。

除了常規(guī)的MRI 序列，某些MRI 特殊序列對MSA診斷和鑒別也有重要意義，如彌散加權(quán)成像（diffusion weighted imaging，DWI）中，MSA 患者殼核信號較PD患者增加[27-28]。一項(xiàng)縱向研究[29]顯示，殼核、腦橋、小腦白質(zhì)DWI 信號變化與MSA 病程、疾病嚴(yán)重程度相關(guān)。由于MSA 殼核、紋狀體、黑質(zhì)中鐵沉積增加，磁敏感加權(quán)成像（susceptibility weighted imaging，SWI） 可顯示其與原發(fā)性PD、PSP 相比，MSA-P 在殼核和蒼白球有更多的鐵沉積[30-31]。以磁化傳遞成像（magnetization transfer imaging，MTI）計(jì)算特定ROI 的磁化傳遞率（magnetization transfer ratio，MTR），結(jié)果表明MSA 患者蒼白球、殼核、黑質(zhì)的MTR 較原發(fā)性PD 患者降低[32]。另外，磁敏感定量成像技術(shù)（quantitative susceptibility mapping，QSM）等也可應(yīng)用于MSA 的診斷[33-37]；但由于樣本量小，結(jié)論并不一致。

2.2 MRI 功能成像

近年來將功能MRI 應(yīng)用于鑒別α-突觸核蛋白相關(guān)疾病成為新的發(fā)展方向。多項(xiàng)研究[38-39]利用彌散張量成像（diffusion tensor imaging，DTI）評估MSA 患者白質(zhì)傳導(dǎo)束變化，結(jié)果發(fā)現(xiàn)與原發(fā)性PD 患者相比，MSA 患者小腦、蒼白球部分各向異性（fractional anisotropy，F(xiàn)A）減小，平均擴(kuò)散率（mean diffusion，MD）增大。有研究[40]顯示MSA 中主要受影響的神經(jīng)網(wǎng)絡(luò)為默認(rèn)模式網(wǎng)絡(luò)及感覺運(yùn)動網(wǎng)絡(luò)。功能影像也可應(yīng)用于MSA 經(jīng)顱磁刺激治療后的療效評價(jià)，功能網(wǎng)絡(luò)中的變化可能與患者的運(yùn)動癥狀改善有一定相關(guān)性[41]。

2.3 分子核素顯像

正電子發(fā)射型計(jì)算機(jī)斷層顯像（positron emission tomography，PET）可反映腦區(qū)某些物質(zhì)代謝過程，也可用于MSA 診斷和鑒別[42]。如18F-FDG-PET 顯示MSA患者殼核、腦干、小腦的葡萄糖代謝降低；18F-多巴及11C-DTBZ（dihydrotetrabenazine） 作 配 體 的PET 則顯示MSA 患者尾狀核、殼核等區(qū)域的多巴胺攝取減少；11C-PMP-PET 可見MSA-P 皮層和皮層下乙酰膽堿酯酶活性降低；11C-PK11195-PET 可見MSA 中背外側(cè)前額葉皮質(zhì)、尾狀核、殼核、蒼白球等處小膠質(zhì)細(xì)胞活化。但上述只是現(xiàn)象的觀察，還需要更多的縱向研究結(jié)果驗(yàn)證。Tau-PET 雖可用于鑒別tau 蛋白相關(guān)的PD 綜合征和MSA，但有嚴(yán)重細(xì)胞質(zhì)內(nèi)包涵體病變的MSA 患者可呈現(xiàn)假陽性。有關(guān)于18F- AV-1451 PET[43]和11C-PBB3 PET 的研究[44]顯示，MSA 患者后殼核、皮層及皮層下有tau 蛋白明顯沉積，致使鑒別診斷效能下降。

目前，國際運(yùn)動障礙協(xié)會PD 診斷指南中已將間碘芐胍 （metaiodobenzylguanidine，MIBG） 心肌顯像用于鑒別PD 和其他綜合征[45-47]。PD 與MSA 心肌MIBG 攝取有顯著差異[46,48-49]。與PD 相比，部分MSA 患者心肌MIBG攝取輕度降低，與健康對照差異并不顯著；但該變化與MSA 病程和嚴(yán)重程度并無明確相關(guān)性[50-52]，其對MSA 確診作用有限，只可用于與PD 的鑒別。

綜上所述，除一些直觀的MRI 特殊征象外，MSA 患者腦部結(jié)構(gòu)改變的具體量化及反映腦部生物化學(xué)指標(biāo)代謝改變的分子顯像將是未來的發(fā)展趨勢。

3 組織活檢的病理標(biāo)志物

α-突觸核蛋白相關(guān)疾病的病理特征為α-突觸核蛋白在神經(jīng)元、神經(jīng)膠質(zhì)細(xì)胞的異常聚集；原發(fā)性PD、DLB以神經(jīng)元累及為主，而MSA 以神經(jīng)膠質(zhì)細(xì)胞受累為主[53]。越來越多的證據(jù)表明α-突觸核蛋白相關(guān)疾病中，多種外周組織中也存在α-突觸核蛋白的異常聚集，包括皮膚、唾液腺、交感神經(jīng)節(jié)、迷走神經(jīng)、胃腸道和心臟等[54-55]。因此，外周組織活檢有助于該類疾病的診斷和鑒別。

3.1 外周神經(jīng)及神經(jīng)節(jié)活檢

早期即有研究[56-59]顯示，MSA 患者的腓腸神經(jīng)、心臟交感神經(jīng)均有退行性病變，提示MSA 作為α-突觸核蛋白相關(guān)疾病，同時(shí)累及中樞及外周神經(jīng)系統(tǒng)。一項(xiàng)研究檢測皮膚活檢組織中的磷酸化α-突觸核蛋白（phosphorylated a-synuclein，p-αSN）， 結(jié) 果 發(fā) 現(xiàn)12 例MSA 患者中，8 例（67%）患者皮膚神經(jīng)中p-αSN 陽性，與tau 蛋白相關(guān)疾病和正常組的鑒別特異度為100%。與PD 患者p-αSN 主要沉積于自主神經(jīng)纖維不同，MSA 患者p-αSN 主要沉積于無髓鞘軀體感覺纖維[60]。但另2 項(xiàng)分別納入10 例和13 例MSA 患者的研究[61-62]結(jié)果則顯示：皮神經(jīng)中p-αSN 沉積均為陰性。上述研究結(jié)果不完全一致的原因可能與皮膚活檢部位、活檢組織處理方式和檢測方法差異等有關(guān)。

MSA 患者外周交感神經(jīng)節(jié)的病理改變可能與其自主神經(jīng)功能障礙有關(guān)[58-59]；但多數(shù)研究樣本量小，研究結(jié)論不完全一致，陰性結(jié)果居多。如對8 例MSA 患者腦及外周神經(jīng)節(jié)進(jìn)行p-αSN 的免疫組織化學(xué)染色，其中僅2 例患者的交感神經(jīng)節(jié)中發(fā)現(xiàn)神經(jīng)元胞質(zhì)包涵體（neuronal cytoplasmic inclusion，NCI）[63]。另一項(xiàng)研究則顯示42.3%的MSA 患者交感神經(jīng)節(jié)中，神經(jīng)元細(xì)胞質(zhì)和突觸的α-突觸核蛋白免疫組織化學(xué)檢測陽性，施萬細(xì)胞中未見α-突觸核蛋白沉積，且α-突觸核蛋白陽性與MSA 病程有一定關(guān)聯(lián)[64]。一項(xiàng)日本研究[65]則報(bào)道，MSA 患者存在外周神經(jīng)系統(tǒng)的施萬細(xì)胞胞質(zhì)p-αSN 聚集，但僅在33.3%的交感神經(jīng)節(jié)中找到施萬細(xì)胞胞質(zhì)陽性的包涵體（Schwann cell cytoplasmic inclusion，SCCI）。

近年來，隨著PD 患者異常α-突觸核蛋白沉積起源于腸道假說的提出，有研究[56-66]證明大部分PD 患者腸道神經(jīng)系統(tǒng)中都存在α-突觸核蛋白沉積的病理改變，且可在腦黑質(zhì)區(qū)出現(xiàn)病理改變前。但2016 年一項(xiàng)研究[67]發(fā)現(xiàn)，PD、MSA 患者及健康對照者均出現(xiàn)胃腸黏膜α-突觸核蛋白免疫染色陽性，且組間無明顯差異。

3.2 下頜下腺活檢

多項(xiàng)研究[68-70]顯示，對下頜下腺細(xì)針活檢組織進(jìn)行α-突觸核蛋白免疫組織化學(xué)染色，PD 患者陽性率較高，與健康對照存在顯著差異。另有2 項(xiàng)研究分別納入 2 例MSA 患者，則檢測結(jié)果均為陰性[71-72]。由于MSA 患者行下頜下腺組織α-突觸核蛋白免疫組織化學(xué)染色的研究較少，樣本量極有限，結(jié)果還需進(jìn)一步驗(yàn)證。

4 總結(jié)

關(guān)于MSA 生物標(biāo)志物的研究眾多，但可應(yīng)用于臨床診斷的陽性結(jié)果有限，體液中的蛋白質(zhì)、miRNA 及分子影像等方向值得進(jìn)一步探索。許多研究中MSA 患者均為臨床診斷，診斷準(zhǔn)確度差異較大，患者有很大的異質(zhì)性，從而影響了研究結(jié)果的質(zhì)量。許多生物標(biāo)志物的采樣、樣本處理方法、數(shù)據(jù)處理等無統(tǒng)一標(biāo)準(zhǔn)，且多數(shù)研究的樣本量較小，可能為各研究間結(jié)論不完全一致的原因。未來需要更多大樣本的臨床研究驗(yàn)證現(xiàn)有生物標(biāo)志物的特異度、敏感度，發(fā)現(xiàn)更多疾病早期生物標(biāo)志物，并聯(lián)合檢測多項(xiàng)生物標(biāo)志物以提高疾病診斷和鑒別診斷的準(zhǔn) 確度。

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