劉長彬，李建軍，楊德剛，楊明亮，杜良杰，李軍，高峰，蒙倩茹，董學(xué)超

彌散張量成像在脊髓損傷臨床和基礎(chǔ)研究中的應(yīng)用

劉長彬，李建軍，楊德剛，楊明亮，杜良杰，李軍，高峰，蒙倩茹，董學(xué)超

[摘要]彌散張量成像(DTI)技術(shù)可以檢測(cè)脊髓白質(zhì)中水分子的彌散情況、脊髓纖維束的完整性及損傷后的病理變化。臨床上，DTI對(duì)急性和慢性脊髓損傷病變都比較敏感，多用于脊髓型頸椎病、多發(fā)性硬化癥、脊髓損傷后繼發(fā)性腦損害、脊髓神經(jīng)根損害等?；A(chǔ)研究，DTI可定量分析損傷脊髓的微觀結(jié)構(gòu)變化、病理變化，并可為行為學(xué)評(píng)估提供有力的輔助診斷依據(jù)，主要?jiǎng)游镉惺?、猴、牛、貓、豬、犬等。

[關(guān)鍵詞]脊髓損傷；彌散張量成像；臨床；動(dòng)物模型；綜述

[本文著錄格式]劉長彬，李建軍，楊德剛，等.彌散張量成像在脊髓損傷臨床和基礎(chǔ)研究中的應(yīng)用[J].中國康復(fù)理論與實(shí)踐, 2015, 21(9): 1031-1036.

CITEDAS: Liu CB, Li JJ, Yang DG, et al.Application of diffusion tensor imaging in clinical and basic studies of spinal cord injury (review) [J]. Zhongguo Kangfu Lilun Yu Shijian, 2015, 21(9): 1031-1036.

近年來，彌散張量成像(diffusion tensor imaging, DTI)是目前功能磁共振成像(fMRI)研究的熱點(diǎn)之一。傳統(tǒng)MRI可用來檢查中樞神經(jīng)系統(tǒng)的基本結(jié)構(gòu)，并可進(jìn)一步顯示病理改變，如出血、水腫以及物理損傷，但對(duì)白質(zhì)纖維束完整性分析的特異性和敏感性都較低[1]。研究表明，DTI對(duì)脫髓鞘和軸突退化都具有較高敏感性，雖然目前研究尚有爭(zhēng)議，但結(jié)合相關(guān)指標(biāo)可以提高脊髓疾病的診斷[1]。

DTI是一種研究白質(zhì)纖維束的非侵入性技術(shù)，同時(shí)也是對(duì)MRI的補(bǔ)充[2-4]。DTI的原理是測(cè)定水分子的各向異性和彌散張量。各組織中水分子彌散的方向和強(qiáng)度不同。彌散的方向性用彌散各向異性(fractional anisotropy, FA)表示，F(xiàn)A對(duì)纖維束的數(shù)量敏感，被廣泛用于檢測(cè)纖維束的完整性，范圍是0～1(完全各向同性到完全各向異性)，數(shù)值越大代表水分子彌散的方向性越強(qiáng)[5]。表觀彌散系數(shù)(apparent diffusion coefficient, ADC)與平均彌散率(mean diffusivity, MD)代表彌散的強(qiáng)度。在三維空間中，彌散的主軸方向稱為軸向彌散(axial diffusivity, AD)，與軸向彌散垂直的方向稱為徑向彌散(radial diffusivity, RD)[6]。

1　臨床應(yīng)用

1.1脊髓型頸椎病

脊髓型頸椎病(cervical spondylotic myelopathy, CSM)是由于頸椎椎骨間連接結(jié)構(gòu)退變，如椎間盤突出、椎體后緣骨質(zhì)增生、鉤椎關(guān)節(jié)增生、后縱韌帶骨化、黃韌帶肥厚或鈣化等，導(dǎo)致脊髓受壓或脊髓缺血，繼而出現(xiàn)脊髓的功能障礙。在脊髓受壓最嚴(yán)重的節(jié)段，F(xiàn)A下降，RD上升[7]，且FA的下降與臨床癥狀的嚴(yán)重性呈線性關(guān)系[8]。DTI可以觀察到MRI幾乎檢測(cè)不到的脊髓異常信號(hào)。Cui等通過纖維示蹤技術(shù)(diffusion tensortractography, DTT)研究損傷脊髓的背側(cè)與兩側(cè)，測(cè)量FA和MD等相關(guān)指標(biāo)，結(jié)果顯示背側(cè)與兩側(cè)的FA下降，而在腹側(cè)FA下降并不明顯；MD上升[9]。表明經(jīng)過長期壓迫后，脊髓背面與側(cè)面纖維束的結(jié)構(gòu)完整性下降，而腹側(cè)無明顯變化[10-11]。Banaszek等評(píng)估頸脊髓疾病不同節(jié)段的髓內(nèi)退化情況，結(jié)果平均FA下降，平均ADC上升，其中平均FA是脊髓組織病變最敏感的指標(biāo)，且平均FA與前后椎管的直徑呈現(xiàn)明顯正相關(guān)[12]。

許多研究者對(duì)類似實(shí)驗(yàn)組和對(duì)照組間FA與ADC的變化進(jìn)行報(bào)道[10,13-15]。更有研究稱，此類結(jié)果可能是由損傷細(xì)胞外的水腫造成。有研究者將DTI用于多節(jié)段脊髓型頸椎病中，并提出了“方向熵”的概念?！胺较蜢亍弊鳛镈TI的一個(gè)參數(shù)，可以反映主方向彌散的分布和多節(jié)段損傷脊髓的受壓情況，但其效果仍有待考查[16]。

DTI可以顯示傳統(tǒng)MRI無法顯示的信號(hào)，為我們了解脊髓型頸椎病的微觀結(jié)構(gòu)和病理變化提供了重要信息，對(duì)制定治療方案也有指導(dǎo)價(jià)值。

1.2多發(fā)性硬化癥

多發(fā)性硬化癥(multiple sclerosis, MS)是一種中樞神經(jīng)系統(tǒng)的慢性炎性、神經(jīng)變性疾病，是造成青年人非創(chuàng)傷性殘疾最常見的原因[17]。DTI研究表明，在MS患者中，損傷脊髓的FA明顯下降[18]。之前研究也表明，在MS患者頸脊髓中，F(xiàn)A下降，MD上升[19-20]。Raz等應(yīng)用彌散峰值成像(diffusional kurtosis imaging, DKI)觀察損傷脊髓的灰質(zhì)變化情況，指出灰質(zhì)的損傷可能在殘疾病程中起重要作用，導(dǎo)致疾病不可逆轉(zhuǎn)[21]，這也與之前應(yīng)用磁化轉(zhuǎn)移研究的結(jié)果一致[22-23]。Naismith等指出，F(xiàn)A和RD與臨床評(píng)估有明顯相關(guān)性[24]，特別是RD在遠(yuǎn)端脊髓損傷的研究中更是一項(xiàng)可靠的指標(biāo)[25-26]。Naismith等研究表明，在脊髓退化性疾病中，DTI的相關(guān)參數(shù)(FA、MD、AD、RD)都與相應(yīng)臨床評(píng)估相關(guān)[24]。多項(xiàng)臨床評(píng)估顯示，正常或輕度損傷的MS患者，DTI可以觀察到明顯的病理改變。由此可見，DTI對(duì)于評(píng)估MS病情具有重要的臨床意義。

1.3脊髓損傷后繼發(fā)性腦損害

脊髓損傷后，大腦相應(yīng)區(qū)域會(huì)發(fā)生明顯的變化。Koskinen等通過DTI分析脊髓損傷后大腦白質(zhì)纖維束的狀態(tài)，在半卵圓中心的后區(qū)發(fā)現(xiàn)實(shí)驗(yàn)組與對(duì)照組間的顯著性差異。患者這一區(qū)域FA較正常人低，完全性脊髓損傷患者降低更加明顯；脊髓損傷神經(jīng)學(xué)分類國際標(biāo)準(zhǔn)(ASIA)感覺運(yùn)動(dòng)評(píng)分與FA正相關(guān)，與ADC負(fù)相關(guān)[27]。

在脊髓損傷的超急性期，因腫脹引起的神經(jīng)病理變化可以加劇原始損傷部位和周圍部位的神經(jīng)元損害，這種沿著脊髓白質(zhì)順行和逆行的退化會(huì)進(jìn)一步導(dǎo)致神經(jīng)元凋亡和髓鞘脫失。通過DTI可以觀察到這樣的退化延伸到顱內(nèi)，甚至到達(dá)大腦的相關(guān)區(qū)域。此外，感覺運(yùn)動(dòng)皮層的灰質(zhì)體積在脊髓損傷后減小[28-29]。有關(guān)研究指出，神經(jīng)組織中，纖維束方向、軸突直徑和密度，以及髓鞘都會(huì)對(duì)DTI的參數(shù)產(chǎn)生相應(yīng)影響[30-31]。

目前對(duì)人類脊髓損傷后大腦變化的報(bào)道相對(duì)較少。Yamamoto等通過組織學(xué)方法觀察到脊椎上區(qū)域的脊髓損傷逆行退化到達(dá)腦橋的高度[32]；Guleria等通過DTI研究發(fā)現(xiàn)，脊髓損傷后，沿著皮質(zhì)脊髓束發(fā)生髓質(zhì)、腦橋、中腦及內(nèi)囊后腳部位的逆行退化[33]；Freund等研究指出，脊髓損傷后內(nèi)囊后腳區(qū)FA下降，大腦腳水平FA無明顯差異，彌散方向發(fā)現(xiàn)軸突的退化和髓鞘脫失等變化[34]。Wrigley等通過DTT，觀察到皮質(zhì)脊髓束的變化[28]。

在脊髓損傷患者中，DTI可以發(fā)現(xiàn)大腦白質(zhì)纖維束的變化，且DTI相關(guān)參數(shù)與臨床損傷的嚴(yán)重程度相關(guān)。

1.4脊髓神經(jīng)根損害

最近，研究人員通過DTT成功檢測(cè)到健康人和腰椎間盤突出癥患者的腰叢神經(jīng)和骶叢神經(jīng)[35-39]，研究結(jié)果表明，受壓神經(jīng)根FA下降而彌散率增加，這可能反映腰椎間盤突出癥患者受壓神經(jīng)微觀結(jié)構(gòu)的變化。Chen等研究表明，受壓神經(jīng)根FA明顯降低[40]，與之前報(bào)道的關(guān)于周圍神經(jīng)受壓迫的研究一致，如腰神經(jīng)、正中神經(jīng)、三叉神經(jīng)壓迫[41-43]。ASIA評(píng)分與MD、AD、RD相關(guān)，與FA無關(guān)，表明受壓迫神經(jīng)根的軸突脫髓鞘、軸突腫脹或水腫和炎癥造成相應(yīng)的臨床癥狀，而與軸突密度的改變無關(guān)[40]。

除了髓鞘脫失和沃勒變性及缺血造成的髓鞘損害，軸突密度的下降以及軸突的炎癥和水腫都可能導(dǎo)致細(xì)胞外水含量增加，進(jìn)而導(dǎo)致RD增大[44]。盡管AD和RD是非特異性指標(biāo)，但與其他指標(biāo)結(jié)合，可以提供更多關(guān)于神經(jīng)纖維微觀結(jié)構(gòu)的細(xì)節(jié)變化。ASIA有助于精確評(píng)估受壓神經(jīng)根的節(jié)段，聯(lián)合使用DTI技術(shù)可以在腰椎間盤突出癥患者的早期階段對(duì)受壓神經(jīng)根微觀結(jié)構(gòu)的變化進(jìn)行檢測(cè)和評(píng)估。DTI對(duì)評(píng)估椎間盤突出癥患者的受壓神經(jīng)根是可行的。

此外，Petersen等聯(lián)合使用DTI與電生理研究頸脊髓損傷患者，指出DTI彌散特性與電生理檢測(cè)相關(guān)[45]。感覺誘發(fā)電位和運(yùn)動(dòng)誘發(fā)電位可以客觀評(píng)估脊髓傳導(dǎo)通路的功能狀態(tài)。脊髓損傷后DTI參數(shù)的變化可以定量反映脊髓纖維束的結(jié)構(gòu)變化，也可以反映感覺誘發(fā)電位和運(yùn)動(dòng)誘發(fā)電位的變化。研究發(fā)現(xiàn)，脛神經(jīng)的感覺誘發(fā)電位振幅與頸脊髓損傷背側(cè)束FA相關(guān)，而與ADC無關(guān)。理論上，運(yùn)動(dòng)誘發(fā)電位振幅反映中樞運(yùn)動(dòng)神經(jīng)元的數(shù)量，但這種關(guān)系仍然比較模糊。脊髓損傷后DTI與電生理的相關(guān)性研究有待進(jìn)一步開展。

在正常人的脊髓，F(xiàn)A的變化范圍是0.545～0.601；而在脊髓損傷患者中，殘余纖維束區(qū)域的FA是(0.220±0.121)，未損傷的脊髓區(qū)域是(0.535±0.101)[46]。據(jù)報(bào)道，計(jì)算FA比影像學(xué)在檢測(cè)脊髓纖維束完整性方面更加敏感[47-49]。因此，DTI在評(píng)估損傷脊髓殘余纖維束方面具有重要價(jià)值。

DTI技術(shù)還被應(yīng)用于腦腫瘤[50-52]、神經(jīng)膠質(zhì)瘤、脊髓腫瘤、癲癇癥、彌漫性軸索損傷、顱腦損傷[53- 55]、老年癡呆癥[56-58]、缺血性腦卒中[59]等臨床疾病的研究中。

2　基礎(chǔ)研究

2.1鼠

DTI在動(dòng)物模型中的應(yīng)用，研究最多的是大鼠模型。對(duì)多種類型(脊髓半切、脊髓橫斷、脊髓挫傷、脊髓切除)的大鼠模型進(jìn)行DTI檢查和BBB評(píng)分，結(jié)果顯示，所有脊髓損傷模型的FA下降，ADC上升，BBB評(píng)分與FA呈現(xiàn)明顯正相關(guān)，與ADC呈現(xiàn)明顯負(fù)相關(guān)，脊髓橫斷損傷是最理想的脊髓損傷模型[60]。大鼠損傷后24 h可能是評(píng)估損傷程度的最佳時(shí)機(jī)[61]。電針刺激后，脊髓損傷大鼠FA好于對(duì)照組，且電針介入的時(shí)間越早，治療效果越好[62]。

然而對(duì)FA或ADC作為脊髓損傷的生物學(xué)指標(biāo)還存在一些爭(zhēng)議。Shanmuganathan等認(rèn)為ADC值比FA值更敏感[63]，而Mondragon-Lozano等則建議用FA取代ADC[64]。有研究表明BBB評(píng)分與ADC和FA有相關(guān)性，因此用行為學(xué)評(píng)分來驗(yàn)證損傷的DTI結(jié)果是可行的[60]。Kelley等指出，DTI可作為脊髓損傷后運(yùn)動(dòng)功能恢復(fù)的指標(biāo)[65]。Jirjis等通過DTI研究大鼠脊髓損傷對(duì)腦的影響，結(jié)果表明在大腦內(nèi)囊區(qū)域和腦干錐體位置的MD與運(yùn)動(dòng)功能相關(guān)，不同損傷程度的大鼠皮質(zhì)脊髓束的FA 和MD明顯不同[66]。實(shí)際上，脊髓損傷后大腦相關(guān)區(qū)域DTI的變化已經(jīng)在大鼠和人身上得到驗(yàn)證，相關(guān)區(qū)域包括丘腦、皮質(zhì)脊髓束、初級(jí)軀體感覺皮層、放射冠、內(nèi)囊等[67-69]。通過進(jìn)一步組織學(xué)分析，我們能對(duì)脊髓損傷后大腦相關(guān)區(qū)域的DTI參數(shù)變化以及病理生理機(jī)制有更深刻的理解。

2.2猴

Wang等聯(lián)合應(yīng)用多項(xiàng)MRI技術(shù)研究猴脊髓損傷的病理變化，包括DTI、磁化轉(zhuǎn)移技術(shù)、化學(xué)交換飽和轉(zhuǎn)移技術(shù)，通過異常低磁化轉(zhuǎn)移率、高ADC和低FA的特點(diǎn)證明，損傷脊髓區(qū)域形成囊腫，里面充滿液體、半固體物質(zhì)[70]，或是由血液、礦物質(zhì)、壞死組織甚至腦脊液組成的混合物[71]。多種影像學(xué)技術(shù)的使用可以定量、定性地觀察脊髓損傷后組織的病理變化，各項(xiàng)技術(shù)相互補(bǔ)充，如DTI的ADC和FA提供了細(xì)胞的密度、微觀結(jié)構(gòu)、白質(zhì)纖維束密度的相關(guān)信息[72-73]，這種方式比傳統(tǒng)的MRI更具有特異性。

2.3牛

Rajasekaran等通過DTI研究牛犢體外新鮮脊髓損傷的程度，應(yīng)用指標(biāo)包括FA、ADC、相對(duì)各向異性、容積比、特征向量。結(jié)果顯示，在輕度壓迫的脊髓區(qū)域，F(xiàn)A和相對(duì)各向異性明顯下降；隨著受壓迫程度的增加，F(xiàn)A、相對(duì)各向異性、容積比也會(huì)相應(yīng)變化，而ADC和特征向量卻無明顯的變化[74]。表明FA、相對(duì)各向異性、容積比在評(píng)估脊髓壓迫傷嚴(yán)重程度方面更加敏感。

2.4貓

研究貓脊髓損傷的文獻(xiàn)報(bào)道較少，之前有通過DTI對(duì)貓脊髓損傷特性的研究[75]。Ellingson等采用SNAILS-DTI技術(shù)研究貓的脊髓損傷情況，獲得了高質(zhì)量、高分辨率、低偽影的脊髓損傷圖像，體素分辨率達(dá)546μm×546μm×3.0 mm[76]。與之前研究類似，脊髓損傷組織的FA比正常脊髓組織低。表明SNAILS-DTI技術(shù)可以得到比傳統(tǒng)DTI技術(shù)更高質(zhì)量的圖像，且可以用于定量對(duì)比實(shí)驗(yàn)的研究中。

2.5豬

Feng等通過DTI研究患有腦脊髓炎的豬脊髓損傷模型，檢測(cè)急性期軸突損傷情況。結(jié)果顯示急性期AD下降，而RD無變化[77]，提示急性軸索損傷可不伴有髓鞘脫失。這一結(jié)果與之前研究一致，急性軸索損傷獨(dú)立于脫髓鞘之外，它的病理機(jī)制可能與髓鞘脫失不同[78]。

2.6犬

犬腰椎間盤突出癥是一種自發(fā)的疾病過程，可導(dǎo)致脊髓壓迫，其發(fā)病時(shí)間、組織學(xué)特點(diǎn)、嚴(yán)重性以及治療方案與人類具有相似性[79-80]。有研究測(cè)定13只不同品種犬的DTI，評(píng)估脊髓纖維束的完整性，證明DTI適合形像觀察犬的脊髓，這種三維重建技術(shù)可以定量描述軸突束和神經(jīng)根，F(xiàn)A和ADC在評(píng)估犬損傷脊髓的纖維束完整性方面提供了客觀依據(jù)[81]。有研究人員通過DTT分析正常犬大腦白質(zhì)的傳導(dǎo)通路，以三維立體形式顯示纖維束的解剖結(jié)構(gòu)、幾何構(gòu)型和空間特性，通過FA和ADC定量評(píng)估纖維束的傳導(dǎo)特性。認(rèn)為DTT是一種研究犬大腦白質(zhì)的非侵入性可行技術(shù)，通過DTT可以觀察到大腦白質(zhì)的微觀結(jié)構(gòu)以及發(fā)病后纖維束的解剖病理變化等。Wu等也指出，DTI可以研究犬的髓鞘形成障礙及出生后大腦發(fā)育成熟情況[82]。

3　小結(jié)

雖然DTI已經(jīng)廣泛應(yīng)用于臨床和多種動(dòng)物模型，但仍存在較多不足。DTI臨床研究樣本量較少，樣本間年齡差異較大，感興趣區(qū)的人為選擇使研究的可信度、可重復(fù)性降低[83]；目前普遍存在較小的空間分辨率，脊髓的生理特性對(duì)選擇最佳的成像方法也是一種挑戰(zhàn)[84-85]。

對(duì)動(dòng)物模型而言，脊髓解剖結(jié)構(gòu)相對(duì)較小，反映脊髓組織的FA及圖像分辨率受限制；低信噪比和空間分辨率是兩個(gè)主要的影響因素，脊髓背側(cè)的血液循環(huán)、呼吸及腦脊液也對(duì)成像質(zhì)量產(chǎn)生影響，造成偽影，唯一的解決方案就是采取循環(huán)補(bǔ)償機(jī)制，這以增加回波時(shí)間為代價(jià)，同時(shí)較長的成像時(shí)間也限制DTI數(shù)據(jù)的獲取[86-87]。此外還需要研究標(biāo)準(zhǔn)化的軟件來加工獲得的彌散數(shù)據(jù)。

DTI已廣泛應(yīng)用于脊髓和大腦相關(guān)疾病的研究中，它是一項(xiàng)非侵入性成像技術(shù)，可以觀察白質(zhì)纖維束的生理病理和微觀結(jié)構(gòu)變化，彌補(bǔ)傳統(tǒng)MRI的不足，對(duì)疾病診斷、功能預(yù)后和手術(shù)方案具有指導(dǎo)價(jià)值。我們應(yīng)該通過盡量增加樣本量、提高信噪比、減少成像偽影、縮短掃描時(shí)間、標(biāo)準(zhǔn)化成像流程來不斷提高成像技術(shù)和科研的嚴(yán)謹(jǐn)性，進(jìn)一步將DTI技術(shù)普及到臨床影像檢查中。

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·綜述·

作者單位：1.首都醫(yī)科大學(xué)康復(fù)醫(yī)學(xué)院，北京市100068；2.中國康復(fù)研究中心北京博愛醫(yī)院，北京市100068。作者簡(jiǎn)介：劉長彬(1990-)，男，漢族，山東德州市人，碩士研究生，主要研究方向：脊柱脊髓損傷的康復(fù)與治療。通訊作者：李建軍(1962-)，男，漢族，教授，主要研究方向：脊柱脊髓損傷的康復(fù)與治療。E-mail: crrc100@163.com。

Application of Diffusion Tensor Imaging in Clinical and Basic Studies of Spinal Cord Injury (review)

LIU Chang- bin, LI Jian- jun, YANG De- gang, YANG Ming- liang, DU Liang- jie, LI Jun, GAO Feng, MENG Qian-ru, DONG Xue-chao
1. Capital Medical University School of Rehabilitation Medicine, Beijing 100068, China; 2. Beijing Bo'ai Hospital, China Rehabilitation Research Center, Beijing 100068, China

Abstract:Diffusion tensor imaging (DTI), which responds with the diffusion of water molecules in spinal cord white matter, may be used to detect the integrity of the spinal cord fiber bundles and the pathological changes after injury. It is sensitive in acute and chronic spinal cord injury, such as cervical spondylotic myelopathy, multiple sclerosis, brain damage secondary spinal cord injury, spinal nerve root damage, and so on. In basic studies, DTI can reveal the microstructure and pathological changes of the injured spinal, and be correlated with behavioral assessment, which involved mice, monkeys, calves, cats, swines, dogs, and so on.

Key words:spinal cord injury; diffusion tensor imaging; clinic; animals model; review

(收稿日期：2015-08-14修回日期：2015-08-25)

基金項(xiàng)目：1.國家自然科學(xué)基金項(xiàng)目(No.81272164)；2.中央級(jí)公益性科研院所基本科研業(yè)務(wù)費(fèi)專項(xiàng)資金項(xiàng)目(No.2015CZ-6)。

DOI:10.3969/j.issn.1006-9771.2015.09.010

[中圖分類號(hào)]R651.2

[文獻(xiàn)標(biāo)識(shí)碼]A

[文章編號(hào)]1006-9771(2015)09-1031-06