弥散张量成像在脊髓损伤临床和基础研究中的应用

刘长彬，李建军，杨德刚，杨明亮，杜良杰，李军，高峰，蒙倩茹，董学超

弥散张量成像在脊髓损伤临床和基础研究中的应用

刘长彬，李建军，杨德刚，杨明亮，杜良杰，李军，高峰，蒙倩茹，董学超

[摘要]弥散张量成像(DTI)技术可以检测脊髓白质中水分子的弥散情况、脊髓纤维束的完整性及损伤后的病理变化。临床上，DTI对急性和慢性脊髓损伤病变都比较敏感，多用于脊髓型颈椎病、多发性硬化症、脊髓损伤后继发性脑损害、脊髓神经根损害等。基础研究，DTI可定量分析损伤脊髓的微观结构变化、病理变化，并可为行为学评估提供有力的辅助诊断依据，主要动物有鼠、猴、牛、猫、猪、犬等。

[关键词]脊髓损伤；弥散张量成像；临床；动物模型；综述

[本文著录格式]刘长彬，李建军，杨德刚，等.弥散张量成像在脊髓损伤临床和基础研究中的应用[J].中国康复理论与实践, 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.

近年来，弥散张量成像(diffusion tensor imaging, DTI)是目前功能磁共振成像(fMRI)研究的热点之一。传统MRI可用来检查中枢神经系统的基本结构，并可进一步显示病理改变，如出血、水肿以及物理损伤，但对白质纤维束完整性分析的特异性和敏感性都较低[1]。研究表明，DTI对脱髓鞘和轴突退化都具有较高敏感性，虽然目前研究尚有争议，但结合相关指标可以提高脊髓疾病的诊断[1]。

DTI是一种研究白质纤维束的非侵入性技术，同时也是对MRI的补充[2-4]。DTI的原理是测定水分子的各向异性和弥散张量。各组织中水分子弥散的方向和强度不同。弥散的方向性用弥散各向异性(fractional anisotropy, FA)表示，FA对纤维束的数量敏感，被广泛用于检测纤维束的完整性，范围是0～1(完全各向同性到完全各向异性)，数值越大代表水分子弥散的方向性越强[5]。表观弥散系数(apparent diffusion coefficient, ADC)与平均弥散率(mean diffusivity, MD)代表弥散的强度。在三维空间中，弥散的主轴方向称为轴向弥散(axial diffusivity, AD)，与轴向弥散垂直的方向称为径向弥散(radial diffusivity, RD)[6]。

1　临床应用

1.1脊髓型颈椎病

脊髓型颈椎病(cervical spondylotic myelopathy, CSM)是由于颈椎椎骨间连接结构退变，如椎间盘突出、椎体后缘骨质增生、钩椎关节增生、后纵韧带骨化、黄韧带肥厚或钙化等，导致脊髓受压或脊髓缺血，继而出现脊髓的功能障碍。在脊髓受压最严重的节段，FA下降，RD上升[7]，且FA的下降与临床症状的严重性呈线性关系[8]。DTI可以观察到MRI几乎检测不到的脊髓异常信号。Cui等通过纤维示踪技术(diffusion tensortractography, DTT)研究损伤脊髓的背侧与两侧，测量FA和MD等相关指标，结果显示背侧与两侧的FA下降，而在腹侧FA下降并不明显；MD上升[9]。表明经过长期压迫后，脊髓背面与侧面纤维束的结构完整性下降，而腹侧无明显变化[10-11]。Banaszek等评估颈脊髓疾病不同节段的髓内退化情况，结果平均FA下降，平均ADC上升，其中平均FA是脊髓组织病变最敏感的指标，且平均FA与前后椎管的直径呈现明显正相关[12]。

许多研究者对类似实验组和对照组间FA与ADC的变化进行报道[10,13-15]。更有研究称，此类结果可能是由损伤细胞外的水肿造成。有研究者将DTI用于多节段脊髓型颈椎病中，并提出了“方向熵”的概念。“方向熵”作为DTI的一个参数，可以反映主方向弥散的分布和多节段损伤脊髓的受压情况，但其效果仍有待考查[16]。

DTI可以显示传统MRI无法显示的信号，为我们了解脊髓型颈椎病的微观结构和病理变化提供了重要信息，对制定治疗方案也有指导价值。

1.2多发性硬化症

多发性硬化症(multiple sclerosis, MS)是一种中枢神经系统的慢性炎性、神经变性疾病，是造成青年人非创伤性残疾最常见的原因[17]。DTI研究表明，在MS患者中，损伤脊髓的FA明显下降[18]。之前研究也表明，在MS患者颈脊髓中，FA下降，MD上升[19-20]。Raz等应用弥散峰值成像(diffusional kurtosis imaging, DKI)观察损伤脊髓的灰质变化情况，指出灰质的损伤可能在残疾病程中起重要作用，导致疾病不可逆转[21]，这也与之前应用磁化转移研究的结果一致[22-23]。Naismith等指出，FA和RD与临床评估有明显相关性[24]，特别是RD在远端脊髓损伤的研究中更是一项可靠的指标[25-26]。Naismith等研究表明，在脊髓退化性疾病中，DTI的相关参数(FA、MD、AD、RD)都与相应临床评估相关[24]。多项临床评估显示，正常或轻度损伤的MS患者，DTI可以观察到明显的病理改变。由此可见，DTI对于评估MS病情具有重要的临床意义。

1.3脊髓损伤后继发性脑损害

脊髓损伤后，大脑相应区域会发生明显的变化。Koskinen等通过DTI分析脊髓损伤后大脑白质纤维束的状态，在半卵圆中心的后区发现实验组与对照组间的显著性差异。患者这一区域FA较正常人低，完全性脊髓损伤患者降低更加明显；脊髓损伤神经学分类国际标准(ASIA)感觉运动评分与FA正相关，与ADC负相关[27]。

在脊髓损伤的超急性期，因肿胀引起的神经病理变化可以加剧原始损伤部位和周围部位的神经元损害，这种沿着脊髓白质顺行和逆行的退化会进一步导致神经元凋亡和髓鞘脱失。通过DTI可以观察到这样的退化延伸到颅内，甚至到达大脑的相关区域。此外，感觉运动皮层的灰质体积在脊髓损伤后减小[28-29]。有关研究指出，神经组织中，纤维束方向、轴突直径和密度，以及髓鞘都会对DTI的参数产生相应影响[30-31]。

目前对人类脊髓损伤后大脑变化的报道相对较少。Yamamoto等通过组织学方法观察到脊椎上区域的脊髓损伤逆行退化到达脑桥的高度[32]；Guleria等通过DTI研究发现，脊髓损伤后，沿着皮质脊髓束发生髓质、脑桥、中脑及内囊后脚部位的逆行退化[33]；Freund等研究指出，脊髓损伤后内囊后脚区FA下降，大脑脚水平FA无明显差异，弥散方向发现轴突的退化和髓鞘脱失等变化[34]。Wrigley等通过DTT，观察到皮质脊髓束的变化[28]。

在脊髓损伤患者中，DTI可以发现大脑白质纤维束的变化，且DTI相关参数与临床损伤的严重程度相关。

1.4脊髓神经根损害

最近，研究人员通过DTT成功检测到健康人和腰椎间盘突出症患者的腰丛神经和骶丛神经[35-39]，研究结果表明，受压神经根FA下降而弥散率增加，这可能反映腰椎间盘突出症患者受压神经微观结构的变化。Chen等研究表明，受压神经根FA明显降低[40]，与之前报道的关于周围神经受压迫的研究一致，如腰神经、正中神经、三叉神经压迫[41-43]。ASIA评分与MD、AD、RD相关，与FA无关，表明受压迫神经根的轴突脱髓鞘、轴突肿胀或水肿和炎症造成相应的临床症状，而与轴突密度的改变无关[40]。

除了髓鞘脱失和沃勒变性及缺血造成的髓鞘损害，轴突密度的下降以及轴突的炎症和水肿都可能导致细胞外水含量增加，进而导致RD增大[44]。尽管AD和RD是非特异性指标，但与其他指标结合，可以提供更多关于神经纤维微观结构的细节变化。ASIA有助于精确评估受压神经根的节段，联合使用DTI技术可以在腰椎间盘突出症患者的早期阶段对受压神经根微观结构的变化进行检测和评估。DTI对评估椎间盘突出症患者的受压神经根是可行的。

此外，Petersen等联合使用DTI与电生理研究颈脊髓损伤患者，指出DTI弥散特性与电生理检测相关[45]。感觉诱发电位和运动诱发电位可以客观评估脊髓传导通路的功能状态。脊髓损伤后DTI参数的变化可以定量反映脊髓纤维束的结构变化，也可以反映感觉诱发电位和运动诱发电位的变化。研究发现，胫神经的感觉诱发电位振幅与颈脊髓损伤背侧束FA相关，而与ADC无关。理论上，运动诱发电位振幅反映中枢运动神经元的数量，但这种关系仍然比较模糊。脊髓损伤后DTI与电生理的相关性研究有待进一步开展。

在正常人的脊髓，FA的变化范围是0.545～0.601；而在脊髓损伤患者中，残余纤维束区域的FA是(0.220±0.121)，未损伤的脊髓区域是(0.535±0.101)[46]。据报道，计算FA比影像学在检测脊髓纤维束完整性方面更加敏感[47-49]。因此，DTI在评估损伤脊髓残余纤维束方面具有重要价值。

DTI技术还被应用于脑肿瘤[50-52]、神经胶质瘤、脊髓肿瘤、癫痫症、弥漫性轴索损伤、颅脑损伤[53- 55]、老年痴呆症[56-58]、缺血性脑卒中[59]等临床疾病的研究中。

2　基础研究

2.1鼠

DTI在动物模型中的应用，研究最多的是大鼠模型。对多种类型(脊髓半切、脊髓横断、脊髓挫伤、脊髓切除)的大鼠模型进行DTI检查和BBB评分，结果显示，所有脊髓损伤模型的FA下降，ADC上升，BBB评分与FA呈现明显正相关，与ADC呈现明显负相关，脊髓横断损伤是最理想的脊髓损伤模型[60]。大鼠损伤后24 h可能是评估损伤程度的最佳时机[61]。电针刺激后，脊髓损伤大鼠FA好于对照组，且电针介入的时间越早，治疗效果越好[62]。

然而对FA或ADC作为脊髓损伤的生物学指标还存在一些争议。Shanmuganathan等认为ADC值比FA值更敏感[63]，而Mondragon-Lozano等则建议用FA取代ADC[64]。有研究表明BBB评分与ADC和FA有相关性，因此用行为学评分来验证损伤的DTI结果是可行的[60]。Kelley等指出，DTI可作为脊髓损伤后运动功能恢复的指标[65]。Jirjis等通过DTI研究大鼠脊髓损伤对脑的影响，结果表明在大脑内囊区域和脑干锥体位置的MD与运动功能相关，不同损伤程度的大鼠皮质脊髓束的FA 和MD明显不同[66]。实际上，脊髓损伤后大脑相关区域DTI的变化已经在大鼠和人身上得到验证，相关区域包括丘脑、皮质脊髓束、初级躯体感觉皮层、放射冠、内囊等[67-69]。通过进一步组织学分析，我们能对脊髓损伤后大脑相关区域的DTI参数变化以及病理生理机制有更深刻的理解。

2.2猴

Wang等联合应用多项MRI技术研究猴脊髓损伤的病理变化，包括DTI、磁化转移技术、化学交换饱和转移技术，通过异常低磁化转移率、高ADC和低FA的特点证明，损伤脊髓区域形成囊肿，里面充满液体、半固体物质[70]，或是由血液、矿物质、坏死组织甚至脑脊液组成的混合物[71]。多种影像学技术的使用可以定量、定性地观察脊髓损伤后组织的病理变化，各项技术相互补充，如DTI的ADC和FA提供了细胞的密度、微观结构、白质纤维束密度的相关信息[72-73]，这种方式比传统的MRI更具有特异性。

2.3牛

Rajasekaran等通过DTI研究牛犊体外新鲜脊髓损伤的程度，应用指标包括FA、ADC、相对各向异性、容积比、特征向量。结果显示，在轻度压迫的脊髓区域，FA和相对各向异性明显下降；随着受压迫程度的增加，FA、相对各向异性、容积比也会相应变化，而ADC和特征向量却无明显的变化[74]。表明FA、相对各向异性、容积比在评估脊髓压迫伤严重程度方面更加敏感。

2.4猫

研究猫脊髓损伤的文献报道较少，之前有通过DTI对猫脊髓损伤特性的研究[75]。Ellingson等采用SNAILS-DTI技术研究猫的脊髓损伤情况，获得了高质量、高分辨率、低伪影的脊髓损伤图像，体素分辨率达546µm×546µm×3.0 mm[76]。与之前研究类似，脊髓损伤组织的FA比正常脊髓组织低。表明SNAILS-DTI技术可以得到比传统DTI技术更高质量的图像，且可以用于定量对比实验的研究中。

2.5猪

Feng等通过DTI研究患有脑脊髓炎的猪脊髓损伤模型，检测急性期轴突损伤情况。结果显示急性期AD下降，而RD无变化[77]，提示急性轴索损伤可不伴有髓鞘脱失。这一结果与之前研究一致，急性轴索损伤独立于脱髓鞘之外，它的病理机制可能与髓鞘脱失不同[78]。

2.6犬

犬腰椎间盘突出症是一种自发的疾病过程，可导致脊髓压迫，其发病时间、组织学特点、严重性以及治疗方案与人类具有相似性[79-80]。有研究测定13只不同品种犬的DTI，评估脊髓纤维束的完整性，证明DTI适合形像观察犬的脊髓，这种三维重建技术可以定量描述轴突束和神经根，FA和ADC在评估犬损伤脊髓的纤维束完整性方面提供了客观依据[81]。有研究人员通过DTT分析正常犬大脑白质的传导通路，以三维立体形式显示纤维束的解剖结构、几何构型和空间特性，通过FA和ADC定量评估纤维束的传导特性。认为DTT是一种研究犬大脑白质的非侵入性可行技术，通过DTT可以观察到大脑白质的微观结构以及发病后纤维束的解剖病理变化等。Wu等也指出，DTI可以研究犬的髓鞘形成障碍及出生后大脑发育成熟情况[82]。

3　小结

虽然DTI已经广泛应用于临床和多种动物模型，但仍存在较多不足。DTI临床研究样本量较少，样本间年龄差异较大，感兴趣区的人为选择使研究的可信度、可重复性降低[83]；目前普遍存在较小的空间分辨率，脊髓的生理特性对选择最佳的成像方法也是一种挑战[84-85]。

对动物模型而言，脊髓解剖结构相对较小，反映脊髓组织的FA及图像分辨率受限制；低信噪比和空间分辨率是两个主要的影响因素，脊髓背侧的血液循环、呼吸及脑脊液也对成像质量产生影响，造成伪影，唯一的解决方案就是采取循环补偿机制，这以增加回波时间为代价，同时较长的成像时间也限制DTI数据的获取[86-87]。此外还需要研究标准化的软件来加工获得的弥散数据。

DTI已广泛应用于脊髓和大脑相关疾病的研究中，它是一项非侵入性成像技术，可以观察白质纤维束的生理病理和微观结构变化，弥补传统MRI的不足，对疾病诊断、功能预后和手术方案具有指导价值。我们应该通过尽量增加样本量、提高信噪比、减少成像伪影、缩短扫描时间、标准化成像流程来不断提高成像技术和科研的严谨性，进一步将DTI技术普及到临床影像检查中。

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·综述·

作者单位：1.首都医科大学康复医学院，北京市100068；2.中国康复研究中心北京博爱医院，北京市100068。作者简介：刘长彬(1990-)，男，汉族，山东德州市人，硕士研究生，主要研究方向：脊柱脊髓损伤的康复与治疗。通讯作者：李建军(1962-)，男，汉族，教授，主要研究方向：脊柱脊髓损伤的康复与治疗。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)

基金项目：1.国家自然科学基金项目(No.81272164)；2.中央级公益性科研院所基本科研业务费专项资金项目(No.2015CZ-6)。

DOI:10.3969/j.issn.1006-9771.2015.09.010

[中图分类号]R651.2

[文献标识码]A

[文章编号]1006-9771(2015)09-1031-06