多系統(tǒng)萎縮生物標志物的研究進展

朱 琳，劉 軍

上海交通大學醫(yī)學院附屬瑞金醫(yī)院神經(jīng)內科，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 型和以小腦性共濟失調為主要表現(xiàn)的MSA-C 型[1]。少突膠質細胞中的一個類型——嗜銀性膠質細胞，其細胞質包涵體（glial cytoplasmic inclusion，GCI）是MSA 的病理特征[2]。因此MSA 的神經(jīng)病理確診標準為與大量廣泛分布的GCI 密切相關的黑質-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，改善患者生活質量。

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

1 體液生物標志物

MSA 體液標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、細胞因子、miRNA 等；但研究結果并不完全一致，對MSA 的臨床診斷意義也并不明確[5]。

1.1 蛋白質

對于MSA 患者腦脊液中總α-突觸核蛋白含量是否降低，各研究結論不一致。僅有1 項研究[6]顯示，MSA 患者與帕金森?。≒arkinson'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]，有一定的臨床應用價值。

另外，需要指出的是體液單個生物標志物的特異度及敏感度均較低，2 種及以上的標志物相結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證。

1.2 RNA

miRNA 是由20 ～25 個核苷酸組成的單鏈非編碼RNA，參與調節(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，近年有許多關于診斷MSA 及鑒別PD 和MSA 的生物標志物的研究聚焦于體液標本中的miRNA，證明了組間表達的差異，且顯示了一些miRNA 在中樞神經(jīng)系統(tǒng)中高表達，參與了細胞凋亡的調節(jié)、基因轉錄后的修飾、神經(jīng)炎癥過程等[10]。

一項研究[11]顯示，與健康對照相比，MSA 患者血漿中miR-30c-5p 表達明顯上調，且其表達水平與病程長短相關，用于MSA 患者和健康對照的鑒別準確度較高（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%）。該研究團隊還發(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 上 調，miR-339-5p 表 達 下降；與PD 患者相比，MSA 患者血漿中miR-148b 表達上調[12]。除血漿中miRNA 表達變化外，2017 年一項研究[13]報道，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 患者中表達偏低。有些miRNA 還可能與MSA 不同類型相關。miR-24 和miR-148b 與MSA 中小腦共濟失調癥狀具有相關性，提示這些miRNA 參與MSA 的小腦退行性變[13]。

單個miRNA 用于鑒別PD 與MSA 或診斷MSA 時，敏感度及特異度均不高，聯(lián)合多種miRNA 可能提高診斷的準確性。腦脊液中miR-133b 和miR-148b 聯(lián)合應用，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)一的內源性對照miRNA 用于標準量化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，從而影響結論的可靠性。因此，還需大樣本隊列研究探索miRNA 在MSA 診斷和鑒別診斷中的應用。

2 神經(jīng)影像學標志物

2.1 磁共振成像

MSA 結構磁共振成像（magnetic resonance imaging，MRI）中灰質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）、進行性核上性麻痹（progressive superanuclear palsy，PSP）、皮質基底節(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，但皮質脊髓束正常；殼核裂隙征指T2 加權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征象[17]，將多個征象相結合用于鑒別MSA 和PD 的敏感度及特異度明顯升高[18]。

具體量化上述結構變化也可以有效提高診斷的準確度，如測量MCP 寬度以量化MCP 萎縮程度，當矢狀位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到100%[19]。有研究采用了更加準確測量橫斷面灰質萎縮的方法，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)學全腦分析（voxel-based morphometry，VBM）[20]。以上定量方法可準確反映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，VBM 準確程度不佳[23]。另外，萎縮率是評價疾病進程的重要指標[24]。目前，2 項縱向研究分析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，該指標可應用于監(jiān)測疾病進展程度，較臨床評分更為客觀，但需要更大樣本和更長隨訪時間驗證。

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，如彌散加權成像（diffusion weighted imaging，DWI）中，MSA 患者殼核信號較PD患者增加[27-28]。一項縱向研究[29]顯示，殼核、腦橋、小腦白質DWI 信號變化與MSA 病程、疾病嚴重程度相關。由于MSA 殼核、紋狀體、黑質中鐵沉積增加，磁敏感加權成像（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）計算特定ROI 的磁化傳遞率（magnetization transfer ratio，MTR），結果表明MSA 患者蒼白球、殼核、黑質的MTR 較原發(fā)性PD 患者降低[32]。另外，磁敏感定量成像技術（quantitative susceptibility mapping，QSM）等也可應用于MSA 的診斷[33-37]；但由于樣本量小，結論并不一致。

2.2 MRI 功能成像

近年來將功能MRI 應用于鑒別α-突觸核蛋白相關疾病成為新的發(fā)展方向。多項研究[38-39]利用彌散張量成像（diffusion tensor imaging，DTI）評估MSA 患者白質傳導束變化，結果發(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)絡為默認模式網(wǎng)絡及感覺運動網(wǎng)絡。功能影像也可應用于MSA 經(jīng)顱磁刺激治療后的療效評價，功能網(wǎng)絡中的變化可能與患者的運動癥狀改善有一定相關性[41]。

2.3 分子核素顯像

正電子發(fā)射型計算機斷層顯像（positron emission tomography，PET）可反映腦區(qū)某些物質代謝過程，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 中背外側前額葉皮質、尾狀核、殼核、蒼白球等處小膠質細胞活化。但上述只是現(xiàn)象的觀察，還需要更多的縱向研究結果驗證。Tau-PET 雖可用于鑒別tau 蛋白相關的PD 綜合征和MSA，但有嚴重細胞質內包涵體病變的MSA 患者可呈現(xiàn)假陽性。有關于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 病程和嚴重程度并無明確相關性[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 患者腦部結構改變的具體量化及反映腦部生物化學指標代謝改變的分子顯像將是未來的發(fā)展趨勢。

3 組織活檢的病理標志物

α-突觸核蛋白相關疾病的病理特征為α-突觸核蛋白在神經(jīng)元、神經(jīng)膠質細胞的異常聚集；原發(fā)性PD、DLB以神經(jīng)元累及為主，而MSA 以神經(jīng)膠質細胞受累為主[53]。越來越多的證據(jù)表明α-突觸核蛋白相關疾病中，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-突觸核蛋白相關疾病，同時累及中樞及外周神經(jīng)系統(tǒng)。一項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 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 項分別納入10 例和13 例MSA 患者的研究[61-62]結果則顯示：皮神經(jīng)中p-αSN 沉積均為陰性。上述研究結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。

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[58-59]；但多數(shù)研究樣本量小，研究結論不完全一致，陰性結果居多。如對8 例MSA 患者腦及外周神經(jīng)節(jié)進行p-αSN 的免疫組織化學染色，其中僅2 例患者的交感神經(jīng)節(jié)中發(fā)現(xiàn)神經(jīng)元胞質包涵體（neuronal cytoplasmic inclusion，NCI）[63]。另一項研究則顯示42.3%的MSA 患者交感神經(jīng)節(jié)中，神經(jīng)元細胞質和突觸的α-突觸核蛋白免疫組織化學檢測陽性，施萬細胞中未見α-突觸核蛋白沉積，且α-突觸核蛋白陽性與MSA 病程有一定關聯(lián)[64]。一項日本研究[65]則報道，MSA 患者存在外周神經(jīng)系統(tǒng)的施萬細胞胞質p-αSN 聚集，但僅在33.3%的交感神經(jīng)節(jié)中找到施萬細胞胞質陽性的包涵體（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，且可在腦黑質區(qū)出現(xiàn)病理改變前。但2016 年一項研究[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

多項研究[68-70]顯示，對下頜下腺細針活檢組織進行α-突觸核蛋白免疫組織化學染色，PD 患者陽性率較高，與健康對照存在顯著差異。另有2 項研究分別納入 2 例MSA 患者，則檢測結果均為陰性[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染色的研究較少，樣本量極有限，結果還需進一步驗證。

4 總結

關于MSA 生物標志物的研究眾多，但可應用于臨床診斷的陽性結果有限，體液中的蛋白質、miRNA 及分子影像等方向值得進一步探索。許多研究中MSA 患者均為臨床診斷，診斷準確度差異較大，患者有很大的異質性，從而影響了研究結果的質量。許多生物標志物的采樣、樣本處理方法、數(shù)據(jù)處理等無統(tǒng)一標準，且多數(shù)研究的樣本量較小，可能為各研究間結論不完全一致的原因。未來需要更多大樣本的臨床研究驗證現(xiàn)有生物標志物的特異度、敏感度，發(fā)現(xiàn)更多疾病早期生物標志物，并聯(lián)合檢測多項生物標志物以提高疾病診斷和鑒別診斷的準 確度。

參·考·文·獻

[1] Gilman S, Wenning GK, Low PA, et al. Second consensus statement on the diagnosis of multiple system atrophy[J]. Neurology, 2008, 71(9): 670-676.

[2] Papp MI, Kahn JE, Lantos PL. Glial cytoplasmic inclusions in the CNS of patients with multiple system atrophy (striatonigral degeneration, olivopontocerebellar atrophy and Shy-Drager syndrome)[J]. J Neurol Sci, 1989, 94(1-3): 79-100.

[3] Wenning GK, Ben Shlomo Y, Magalhaes M, et al. Clinical features and natural history of multiple system atrophy. An analysis of 100 cases[J]. Brain, 1994, 117 ( Pt 4): 835-845.

[4] Koga S, Aoki N, Uitti RJ, et al. When DLB, PD, and PSP masquerade as MSA: an autopsy study of 134 patients[J]. Neurology, 2015, 85(5): 404-412.

[5] Laurens B, Constantinescu R, Freeman R, et al. Fluid biomarkers in multiple system atrophy: a review of the MSA Biomarker Initiative[J]. Neurobiol Dis, 2015, 80: 29-41.

[6] Chen D, Wei XB, Zou J, et al. Contra-directional expression of serum homocysteine and uric acid as important biomarkers of multiple system atrophy severity: a cross-sectional study[J]. Front Cell Neurosci, 2015, 9: 247.

[7] Hansson O, Janelidze S, Hall S, et al. Blood-based NfL: a biomarker for differential diagnosis of parkinsonian disorder[J]. Neurology, 2017, 88(10): 930-937.

[8] Herbert MK, Eeftens JM, Aerts MB, et al. CSF levels of DJ-1 and tau distinguish MSA patients from PD patients and controls[J]. Parkinsonism Relat Disord, 2014, 20(1): 112-115.

[9] Marz M, Ferracin M, Klein C. MicroRNAs as biomarker of Parkinson disease? Small but mighty[J]. Neurology, 2015, 84(7): 636-638.

[10] Kim T, Valera E, Desplats P. Alterations in striatal microRNA-mRNA networks contribute to neuroinflammation in multiple system atrophy[J]. Mol Neurobiol, 2019, 56(10): 7003-7021.

[11] Vallelunga A, Iannitti T, Dati G, et al. Serum miR-30c-5p is a potential biomarker for multiple system atrophy[J]. Mol Biol Rep, 2019, 46(2): 1661-1666.

[12] Vallelunga A, Ragusa M, Di Mauro S, et al. Identification of circulating microRNAs for the differential diagnosis of Parkinson's disease and Multiple System Atrophy[J]. Front Cell Neurosci, 2014, 8: 156.

[13] Marques TM, Kuiperij HB, Bruinsma IB, et al. MicroRNAs in cerebrospinal fluid as potential biomarkers for Parkinson's disease and multiple system atrophy[J]. Mol Neurobiol, 2017, 54(10): 7736-7745.

[14] Starhof C, Hejl AM, Heegaard NHH, et al. The biomarker potential of cell-free microRNA from cerebrospinal fluid in Parkinsonian Syndromes[J]. Mov Disord, 2019, 34(2): 246-254.

[15] Lee EA, Cho HI, Kim SS, et al. Comparison of magnetic resonance imaging in subtypes of multiple system atrophy[J]. Parkinsonism Relat Disord, 2004, 10(6): 363-368.

[16] Burk K, Buhring U, Schulz JB, et al. Clinical and magnetic resonance imaging characteristics of sporadic cerebellar ataxia[J]. Arch Neurol, 2005, 62(6): 981-985.

[17] Horimoto Y, Aiba I, Yasuda T, et al. Longitudinal MRI study of multiple system atrophy: when do the findings appear, and what is the course?[J]. J Neurol, 2002, 249(7): 847-854.

[18] Wang N, Yang HG, Li CB, et al. Using 'swallow-tail' sign and putaminal hypointensity as biomarkers to distinguish multiple system atrophy from idiopathic Parkinson's disease: a susceptibility-weighted imaging study[J]. Eur Radiol, 2017, 27(8): 3174-3180.

[19] Quattrone A, Nicoletti G, Messina D, et al. MR imaging index for differentiation of progressive supranuclear palsy from Parkinson disease and the Parkinson variant of multiple system atrophy[J]. Radiology, 2008, 246(1): 214-221.

[20] Ridgway GR, Henley SM, Rohrer JD, et al. Ten simple rules for reporting voxel-based morphometry studies[J]. Neuroimage, 2008, 40(4): 1429-1435.

[21] Ghaemi M, Hilker R, Rudolf J, et al. Differentiating multiple system atrophy from Parkinson's disease: contribution of striatal and midbrain MRI volumetry and multi-tracer PET imaging[J]. J Neurol Neurosurg Psychiatry, 2002, 73(5): 517-523.

[22] Brenneis C, Seppi K, Schocke MF, et al. Voxel-based morphometry detects cortical atrophy in the Parkinson variant of multiple system atrophy[J]. Mov Disord, 2003, 18(10): 1132-1138.

[23] Shao N, Yang J, Shang HF. Voxelwise meta-analysis of gray matter anomalies in Parkinson variant of multiple system atrophy and Parkinson's disease using anatomic likelihood estimation[J]. Neurosci Lett, 2015, 587: 79-86.

[24] Cash DM, Rohrer JD, Ryan NS, et al. Imaging endpoints for clinical trials in Alzheimer's disease[J]. Alzheimers Res Ther, 2014, 6(9): 87.

[25] Paviour DC, Price SL, Jahanshahi M, et al. Longitudinal MRI in progressive supranuclear palsy and multiple system atrophy: rates and regions of atrophy[J]. Brain, 2006, 129(Pt 4): 1040-1049.

[26] Guevara C, Bulatova K, Barker GJ, et al. Whole-brain atrophy rate in idiopathic Parkinson's disease, multiple system atrophy, and progressive supranuclear palsy[J]. Parkinsons Dis, 2016, 2016: 1-7.

[27] Barbagallo G, Sierra-Pena M, Nemmi F, et al. Multimodal MRI assessment of nigro-striatal pathway in multiple system atrophy and Parkinson disease[J]. Mov Disord, 2016, 31(3): 325-334.

[28] Pellecchia MT, Barone P, Mollica C, et al. Diffusion-weighted imaging in multiple system atrophy: a comparison between clinical subtypes[J]. Mov Disord, 2009, 24(5): 689-696.

[29] Pellecchia MT, Barone P, Vicidomini C, et al. Progression of striatal and extrastriatal degeneration in multiple system atrophy: a longitudinal diffusionweighted MR study[J]. Mov Disord, 2011, 26(7): 1303-1309.

[30] Dexter DT, Jenner P, Schapira AH, et al. Alterations in levels of iron, ferritin, and other trace metals in neurodegenerative diseases affecting the basal ganglia. The Royal Kings and Queens Parkinson's Disease Research Group[J]. Ann Neurol, 1992, 32(Suppl): S94-S100.

[31] Yoon RG, Kim SJ, Kim HS, et al. The utility of susceptibility-weighted imaging for differentiating Parkinsonism-predominant multiple system atrophy from Parkinson's disease: correlation with 18F-flurodeoxyglucose positron-emission tomography[J]. Neurosci Lett, 2015, 584: 296-301.

[32] Eckert T, Sailer M, Kaufmann J, et al. Differentiation of idiopathic Parkinson's disease, multiple system atrophy, progressive supranuclear palsy, and healthy controls using magnetization transfer imaging[J]. Neuroimage, 2004, 21(1): 229-235.

[33] Specht K, Minnerop M, Muller-Hubenthal J, et al. Voxel-based analysis of multiple-system atrophy of cerebellar type: complementary results by combining voxel-based morphometry and voxel-based relaxometry[J]. Neuroimage, 2005, 25(1): 287-293.

[34] Lewis MM, Du GW, Baccon J, et al. Susceptibility MRI captures nigral pathology in patients with parkinsonian syndromes[J]. Mov Disord, 2018, 33(9): 1432-1439.

[35] Adler CH, Beach TG, Hentz JG, et al. Low clinical diagnostic accuracy of earlyvsadvanced Parkinson disease: clinicopathologic study[J]. Neurology, 2014, 83(5): 406-412.

[36] Sjostrom H, Granberg T, Westman E, et al. Quantitative susceptibility mapping differentiates between parkinsonian disorders[J]. Parkinsonism Relat Disord, 2017, 44: 51-57.

[37] Tsuda M, Asano S, Kato Y, et al. Differential diagnosis of multiple system atrophy with predominant Parkinsonism and Parkinson's disease using neural networks[J]. J Neurol Sci, 2019, 401: 19-26.

[38] Tsukamoto K, Matsusue E, Kanasaki Y, et al. Significance of apparent diffusion coefficient measurement for the differential diagnosis of multiple system atrophy, progressive supranuclear palsy, and Parkinson's disease: evaluation by 3.0-T MR imaging[J]. Neuroradiology, 2012, 54(9): 947-955.

[39] Nair SR, Tan LK, Mohd Ramli N, et al. A decision tree for differentiating multiple system atrophy from Parkinson's disease using 3-T MR imaging[J]. Eur Radiol, 2013, 23(6): 1459-1466.

[40] You H, Wang J, Wang H, et al. Altered regional homogeneity in motor cortices in patients with multiple system atrophy[J]. Neurosci Lett, 2011, 502(1): 18-23.

[41] Chou YH, You H, Wang H, et al. Effect of repetitive transcranial magnetic stimulation on fMRI resting-state connectivity in multiple system atrophy[J]. Brain Connect, 2015, 5(7): 451-459.

[42] Niccolini F, Politis M. A systematic review of lessons learned from PET molecular imaging research in atypical Parkinsonism[J]. Eur J Nucl Med Mol Imaging, 2016, 43(12): 2244-2254.

[43] Cho H, Choi JY, Lee SH, et al.18F-AV-1451 binds to putamen in multiple system atrophy[J]. Mov Disord, 2017, 32(1): 171-173.

[44] Perez-Soriano A, Arena JE, Dinelle K, et al. PBB3 imaging in Parkinsonian disorders: Evidence for binding to tau and other proteins[J]. Mov Disord, 2017, 32(7): 1016-1024.

[45] Braune S, Reinhardt M, Schnitzer R, et al. Cardiac uptake of123I-MIBG separates Parkinson's disease from multiple system atrophy[J]. Neurology, 1999, 53(5): 1020-1025.

[46] Treglia G, Stefanelli A, Cason E, et al. Diagnostic performance of iodine-123-metaiodobenzylguanidine scintigraphy in differential diagnosis between Parkinson's disease and multiple-system atrophy: a systematic review and a meta-analysis[J]. Clin Neurol Neurosurg, 2011, 113(10): 823-829.

[47] Orimo S, Suzuki M, Inaba A, et al.123I-MIBG myocardial scintigraphy for differentiating Parkinson's disease from other neurodegenerative Parkinsonism: a systematic review and meta-analysis[J]. Parkinsonism Relat Disord, 2012, 18(5): 494-500.

[48] King AE, Mintz J, Royall DR. Meta-analysis of123I-MIBG cardiac scintigraphy for the diagnosis of Lewy body-related disorders[J]. Mov Disord, 2011, 26(7): 1218-1224.

[49] Yang TF, Wang L, Li Y, et al.131I-MIBG myocardial scintigraphy for differentiation of Parkinson's disease from multiple system atrophy or essential tremor in Chinese population[J]. J Neurol Sci, 2017, 373: 48-51.

[50] Rascol O, Schelosky L.123I-metaiodobenzylguanidine scintigraphy in Parkinson's disease and related disorders[J]. Mov Disord, 2009, 24(Suppl 2): S732-S741.

[51] Nagayama H, Ueda M, Yamazaki M, et al. Abnormal cardiac123I-metaiodobenzylguanidine uptake in multiple system atrophy[J]. Mov Disord, 2010, 25(11): 1744-1747.

[52] Soboll L, Leppert D, Dillmann U, et al. MIBG scintigraphy of the major salivary glands in multiple system atrophy[J]. Parkinsonism Relat Disord, 2018, 53: 112-114.

[53] Jellinger KA. Neuropathological spectrum of synucleinopathies[J]. Mov Disord, 2003, 18(Suppl 6): S2-S12.

[54] Beach TG, Adler CH, Sue LI, et al. Multi-organ distribution of phosphorylated α-synuclein histopathology in subjects with Lewy body disorders[J]. Acta Neuropathol, 2010, 119(6): 689-702.

[55] Schneider SA, Boettner M, Alexoudi A, et al. Can we use peripheral tissue biopsies to diagnose Parkinson's disease? A review of the literature[J]. Eur J Neurol, 2016, 23(2): 247-261.

[56] Orimo S, Amino T, Itoh Y, et al. Cardiac sympathetic denervation precedes neuronal loss in the sympathetic Ganglia in Lewy body disease[J]. Acta Neuropathol, 2005, 109(6): 583-588.

[57] Orimo S, Kanazawa T, Nakamura A, et al. Degeneration of cardiac sympathetic nerve can occur in multiple system atrophy[J]. Acta Neuropathol, 2007, 113(1): 81-86.

[58] Kanda T, Tsukagoshi H, Oda M, et al. Changes of unmyelinated nerve fibers in sural nerve in amyotrophic lateral sclerosis, Parkinson's disease and multiple system atrophy[J]. Acta Neuropathol, 1996, 91(2): 145-154.

[59] Orimo S, Uchihara T, Nakamura A, et al. Axonal alpha-synuclein aggregates herald centripetal degeneration of cardiac sympathetic nerve in Parkinson's disease[J]. Brain, 2008, 131(Pt 3): 642-650.

[60] Doppler K, Weis J, Karl K, et al. Distinctive distribution of phospho-αsynuclein in dermal nerves in multiple system atrophy[J]. Mov Disord, 2015, 30(12): 1688-1692.

[61] Zange L, Noack C, Hahn K, et al. Phosphorylated α-synuclein in skin nerve fibres differentiates Parkinson's disease from multiple system atrophy[J]. Brain, 2015, 138(Pt 8): 2310-2321.

[62] Haga R, Sugimoto K, Nishijima H, et al. Clinical utility of skin biopsy in differentiating between Parkinson's disease and multiple system atrophy[J]. Parkinsons Dis, 2015, 2015: 167038.

[63] Nishie M, Mori F, Fujiwara H, et al. Accumulation of phosphorylated alphasynuclein in the brain and peripheral Ganglia of patients with multiple system atrophy[J]. Acta Neuropathol, 2004, 107(4): 292-298.

[64] Sone M, Yoshida M, Hashizume Y, et al. α-synuclein-immunoreactive structure formation is enhanced in sympathetic ganglia of patients with multiple system atrophy[J]. Acta Neuropathol, 2005, 110(1): 19-26.

[65] Nakamura K, Mori F, Kon T, et al. Filamentous aggregations of phosphorylated α-synuclein in Schwann cells (Schwann cell cytoplasmic inclusions) in multiple system atrophy[J]. Acta Neuropathol Commun, 2015, 3: 29.

[66] Lebouvier T, Chaumette T, Paillusson S, et al. The second brain and Parkinson's disease[J]. Eur J Neurosci, 2009, 30(5): 735-741.

[67] Chung SJ, Kim J, Lee HJ, et al. α-synuclein in gastric and colonic mucosa in Parkinson's disease: limited role as a biomarker[J]. Mov Disord, 2016, 31(2): 241-249.

[68] Vilas D, Iranzo A, Tolosa E, et al. Assessment of α-synuclein in submandibular glands of patients with idiopathic rapid-eye-movement sleep behaviour disorder: a case-control study[J]. Lancet Neurol, 2016, 15(7): 708-718.

[69] Adler CH, Dugger BN, Hentz JG, et al. Peripheral synucleinopathy in early Parkinson's disease: submandibular gland needle biopsy findings[J]. Mov Disord, 2017, 32(5): 722-723.

[70] Shin J, Park SH, Shin C, et al. Submandibular gland is a suitable site for alpha synuclein pathology in Parkinson disease[J]. Parkinsonism Relat Disord, 2019, 58: 35-39.

[71] Beach TG, Adler CH, Serrano G, et al. Prevalence of submandibular gland synucleinopathy in Parkinson's disease, dementia with Lewy bodies and other Lewy body disorders[J]. J Parkinsons Dis, 2016, 6(1): 153-163.

[72] Del Tredici K, Hawkes CH, Ghebremedhin E, et al. Lewy pathology in the submandibular gland of individuals with incidental Lewy body disease and sporadic Parkinson's disease[J]. Acta Neuropathol, 2010, 119(6): 703-713.