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原发性开角型青光眼患者脑磁共振成像研究进展
杨冰冰 曲晓霞 王倩 李婷 鲜军舫

Cite this article as: Yang BB, Qu XX, Wang Q, et al. Research progress of brain magnetic resonance imaging in patients with primary open-angle glaucoma[J]. Chin J Magn Reson Imaging, 2022, 13(11): 37-41.本文引用格式:杨冰冰, 曲晓霞, 王倩, 等. 原发性开角型青光眼患者脑磁共振成像研究进展[J]. 磁共振成像, 2022, 13(11): 37-41. DOI:10.12015/issn.1674-8034.2022.11.007.


[摘要] 青光眼是全球首位不可逆致盲性眼病,最常见类型为原发性开角型青光眼(primary open-angle glaucoma, POAG),由于发病机制不清,因此治疗效果不佳。近年来,包含多模态MRI在内的神经影像学研究表明:POAG是一种神经退行性病变,视觉传导通路及视路以外脑区的结构、功能、血流灌注及代谢等都发生了广泛改变,且与POAG患者病情严重程度相关。未来更加需要多中心大样本量前瞻性队列研究,采用机器学习、深度学习方法将多模态MRI数据融合,进一步研究中枢神经系统改变之间的相互关系及其与视网膜改变和视觉障碍的相关性,为早期诊断和治疗提供更加明确的依据。本文系统综述了POAG患者脑MRI研究进展和价值,同时提出存在的问题与未来研究思路,旨在为该领域研究提供参考。
[Abstract] Glaucoma is the most frequent cause of irreversible blindness worldwide. As the most prevalent type of glaucoma, primary open-angle glaucoma (POAG) is facing challenges in pathogenesis, diagnosis, and management. In recent years, neuroimaging studies including multimodal MRI have shown that POAG is considered as a neurodegenerative disease. Alterations of brain structure, function, blood perfusion, and metabolism involving visual pathway and other brain regions were shown, which were correlated with the severity of the disease in POAG patients. In the future, multi-center prospective cohort studies with large sample sizes will be more needed, and multi-modal MRI data will be analyzed with machine learning and deep learning methods to investigate the relationship between changes in the central nervous system and their correlation with retinal changes and visual disorders, to provide a more explicit basis for early diagnosis and treatment. Therefore, MRI findings of the brain in patients with POAG and the potential role in the pathogenesis and diagnosis of POAG, as well as probable solutions to the unsolved problems, were systematically reviewed, aiming to provide a reference for the researchers in this field.
[关键词] 原发性开角型青光眼;脑;磁共振成像;多模态;进展
[Keywords] primary open-angle glaucoma;brain;magnetic resonance imaging;multimodality;advance

杨冰冰    曲晓霞    王倩    李婷    鲜军舫 *  

首都医科大学附属北京同仁医院放射科,北京 100730

鲜军舫,E-mail:cjr.xianjunfang@vip.163.com

作者利益冲突声明:全体作者均声明无利益冲突。


基金项目: 国家自然科学基金 81571649,81701666,81871340,81901719,82071906 北京市医院管理中心“登峰”计划专项 DFL20190203 北京市医院管理局临床医学发展专项 ZYLX201704
收稿日期:2022-08-08
接受日期:2022-11-10
中图分类号:R445.2  R775.2 
文献标识码:A
DOI: 10.12015/issn.1674-8034.2022.11.007
本文引用格式:杨冰冰, 曲晓霞, 王倩, 等. 原发性开角型青光眼患者脑磁共振成像研究进展[J]. 磁共振成像, 2022, 13(11): 37-41. DOI:10.12015/issn.1674-8034.2022.11.007

       青光眼是全球首位不可逆致盲性眼病,严重影响患者的生活质量,全球患者已超过七千万,预计到2040年时患者数将增至1.12亿,已成为全球重大公共卫生问题[1, 2, 3]。原发性开角型青光眼(primary open-angle glaucoma, POAG)是最常见的青光眼类型[2],其发病隐匿、漏诊率高,确诊时往往已是中晚期,且缺乏有效干预治疗手段,致盲率高[1],因此弄清其发病机制对早期诊断与制订干预策略至关重要。最早提出的“眼内压升高”假说受到了广泛认可,降眼压是目前最常用的治疗方法,但并不能有效控制病情发展,视野损害仍在进展[4, 5, 6]。此外,50%以上的POAG患者眼压不高[7],用“眼内压升高”假说无法解释这些现象。因此,有学者提出“跨筛板压力差假说”[8],眼内压不高的患者颅内压减低,而且动物实验结果显示筛板后视神经退行性改变[9],MRI显示视神经蛛网膜下腔增宽[8],该学说可很好地解释眼内压不高的青光眼患者的发病机制,但其不能完全解释后视路及其他脑区的广泛脑改变情况。近年来,包含多模态MRI在内的神经影像学研究表明:POAG是一种表现为视路内外脑区广泛结构、功能、血流灌注及代谢异常[10, 11, 12, 13]的神经退行性病变[14],其脑改变与典型的神经退行性病如阿尔茨海默病和帕金森病等具有相似性[14, 15, 16],且神经保护治疗对延缓青光眼进展有效[17, 18, 19],这些结果提示神经退行性变可能是POAG的重要发病机制。多模态MRI能很好地显示POAG患者脑的形态、功能、血流灌注和代谢等方面的改变[20],为研究POAG发病机制提供了重要的方法,研究结果有望为POAG早期诊断和治疗提供新的思路[21]。本文系统性综述了POAG患者脑多模态MRI研究进展和价值以及存在的问题与未来研究思路,为该领域研究提供参考。

1 POAG患者脑结构研究进展及存在的问题与未来研究思路

1.1 基于体积和皮层厚度分析的脑形态学研究进展及前景

       基于高分辨率三维T1WI序列的脑形态学研究结果显示,POAG患者脑结构体积或厚度存在广泛异常,视觉通路结构出现萎缩性改变,包括视神经[22]、视交叉[23]、视束[22]、外侧膝状体(lateral geniculate nucleus, LGN)[23, 24]和视辐射[22]。视皮层同样可存在萎缩改变,有研究表明其灰质体积减小、厚度变薄[11,25, 26];也有研究发现这种形态学改变与病程相关,早期POAG患者的视皮层厚度显著减低,但晚期患者视皮层厚度却显著高于健康对照组和早期患者,提示晚期POAG患者的视皮层可能存在代偿性增厚[23];此外,还有研究持相反观点,认为早中期POAG患者高级视皮层灰质体积增大,其机制尚不清楚[27]。除视皮层以外,海马[11]、额叶[25]和颞叶[28]等脑区灰质体积也有减小。相关性分析结果进一步表明:POAG患者视觉通路内外的脑体积和厚度等形态学异常改变与视野指标或视网膜神经纤维层厚度(retinal nerve fiber layer, RNFL)等指标显著相关[11,22, 23,25]

       值得注意的是,上述研究报告的结果并不完全一致,主要原因可能有:一是样本量较小,且大多数研究的病例选择为非随机性和回顾性;二是发病机制复杂,全身性与心理性因素以及衰老、治疗等混杂因素可能对结果产生影响;三是以往形态学研究主要采用组间对比分析方法,缺乏对患者个体脑区的深入研究。针对这些问题,期待今后开展多中心大样本量前瞻性研究,提高重复性和可靠性;研究指标中纳入一些可能对脑结构产生影响的因素,并采用个体化脑区精确定位方法进行研究,提高结果的准确性。

1.2 基于扩散MRI的脑微结构研究进展及前景

       基于扩散MRI的脑微结构研究方法包括扩散张量成像(diffusion tensor imaging, DTI)、扩散峰度成像(diffusion kurtosis imaging, DKI)以及基于高级扩散模型的扩散成像方法,研究发现POAG患者多个脑区的白质、灰质微结构存在异常改变。DTI研究方法假设扩散过程符合高斯分布并将其简化为椭球形张量,从而计算出微结构中的各向异性分数(fractional anisotropy, FA)等参数,可评估POAG患者视路内外白质纤维束的完整性。DTI研究结果显示,POAG患者的视神经[29, 30]、视交叉[31]、视辐射[30, 31, 32, 33]等视路结构的FA值显著减低,且与视野平均缺损、RNFL和杯盘比之间具有显著相关性[32,34],提示POAG患者视路结构可能存在髓鞘损伤。除视觉通路以外,胼胝体、顶叶、额叶等认知相关脑区的白质也有明显损害[11,25]。与DTI相比,DKI参数具有更高的特异性,该技术表征组织中细胞膜等微观结构中的水分子扩散位移偏离高斯分布的程度,研究结果表明POAG患者的视神经、LGN、视辐射和视皮层等视路结构的FA和平均扩散峰度(mean kurtosis, MK)值显著减低,平均扩散系数(mean diffusivity, MD)值显著增加,且MK比FA和MD更敏感[35]。除视路以外,POAG患者脑内微结构损伤也可发生在认知、运动、面部识别和定向功能相关的脑区[36]。多模态研究通过联合DKI与静息态功能磁共振成像(functional magnetic resonance imaging, fMRI)方法,发现POAG患者双侧视皮层显著减低的MK、径向峰度、轴向峰度值与效应连接显著相关,提示患者视皮层微结构损伤与信息流异常改变间可能存在一致性[37]。另外,基于高级扩散模型的POAG脑结构网络研究结果发现,视皮层和中央旁回的局部效率与聚类系数增高,全脑结构网络发生了重组,在一定程度上支持了POAG的神经退行性变假说[38]。总的来说,POAG患者的视路内外多个脑区微结构发生损伤,并与疾病严重程度显著相关,DKI参数有望成为判断早期青光眼脑白质与灰质损害的生物标记物。

       现阶段,POAG扩散MRI研究面临以下挑战:一是由于缺乏理想的POAG动物模型,患者与动物模型的扩散MRI结果无法互相验证[39],需要建立理想的青光眼实验动物模型后进行深入研究,弄清POAG患者脑微结构扩散MRI参数改变与病理及分子改变之间的关系,进一步明确扩散MRI参数的意义,为POAG发病机制提供更多信息,发掘早期青光眼脑白质与灰质微结构损害生物标记物;二是扩散MRI的扫描参数及后处理模型有待进一步优化和规范化,从而提高参数的准确性、重复性和可靠性[40]

2 POAG患者脑功能研究进展及存在的问题与未来研究思路

       基于血氧水平依赖(Blood oxygenation level dependent, BOLD)的fMRI研究结果表明POAG患者脑功能存在广泛异常,从以下三个方面进行阐述。

2.1 任务态脑功能研究进展及前景

       基于视觉刺激任务的fMRI研究结果发现POAG患者的初级视皮层、高级视皮层及其他相关皮层结构与皮下核团的功能存在异常改变。视皮层功能损害与视功能减退密切相关,表明视觉剥夺可对脑功能产生影响,因此,基于fMRI的视功能重建提供了检测视功能缺损的另外一种客观方法,可作为标准自动视野计(standard automated perimetry, SAP)方法的补充,对于无法进行SAP的患者,则能检测视功能情况[41, 42, 43]。POAG患者初级视皮层在受到视觉刺激后激活强度减低[44, 45, 46, 47],与相应脑区皮层体积或厚度减小具有一致性[25],这些变化可能是由于视网膜神经节细胞损害导致通过视觉传导通路传入的刺激与信息减少[15]。然而,POAG患者的高级视皮层功能激活改变意见不一,有研究发现该区域功能激活减低[48]与该皮质区域体积减小一致[49],可能提示这些脑区发生了跨突触神经退行性变;也有研究观察到高级视觉区域的功能激活增加,同时伴有视觉相关区域的皮质体积增加[27],推测是由于初级视觉区域受损,导致其对其他视觉相关区域的抑制作用减低。除视皮层以外,POAG患者的额叶、顶叶、颞叶皮层等区域的激活也减低,且与病变严重程度相关[27];早期POAG患者的皮层下结构的功能也发生了改变,LGN研究表明巨细胞层以及上丘表层对短暂性非彩色刺激的反应比持续性彩色刺激的反应程度增大,并且LGN巨细胞层的反应程度与青光眼行为缺陷程度显著相关,提示早期POAG患者的皮层下结构可出现“大细胞”选择性功能损害[46]。总之,在视觉刺激任务下,POAG患者的视皮层和视皮层以外的脑区及部分皮层下结构的激活范围和程度出现异常改变,且与疾病严重程度相关。

       然而目前研究仍然存在以下问题:视觉刺激任务设计(刺激的类型、频率、大小、亮度和颜色以及任务的复杂程度等因素设置)不完全相同,设备的场强和采集序列以及试验前对受试者的训练方法和效果等也可能不完全一致,以上因素都可能会对结果产生影响,甚至导致相互矛盾的试验结果。因此,未来研究应针对这些因素将试验流程规范化,以提高结果的可靠性、重复性和准确性。

2.2 静息态脑功能研究进展及前景

       基于静息态fMRI脑功能研究结果发现,POAG患者的视皮层及其他相关脑区功能存在广泛异常改变。其中,低频振幅研究结果发现POAG患者的视觉、感觉、运动及认知脑区局部自发脑活动波动幅度异常,且与青光眼严重程度相关[50, 51]。此外,自发脑活动局部一致性(regional homogeneity, ReHo)研究结果表明POAG患者的视觉、感觉和认知相关脑区的自发脑活动局部同步性异常,且左侧楔前叶ReHo值与视野缺损严重程度显著相关[52]。基于静息态fMRI的功能连接研究观察到POAG患者的视觉相关脑区[12,53, 54]以及工作记忆和认知[12,55]相关脑区之间的功能连接减低,初级视皮层与高级视皮层之间的功能连接也有减低[53,56]。为进一步探索功能连接改变的因果关系,采用格兰杰分析研究结果显示正常眼压青光眼患者的视皮层自下而上的信息流减少,而自上而下的信息处理明显增强,且视皮层信息流改变与微结构损伤相关[37]。此外,体素镜像同伦连接(voxel-mirrored homotopic connectivity, VMHC)研究结果表明POAG患者的视皮层半球间VMHC值减低,且脑改变与视网膜神经纤维层损害呈显著正相关,提示POAG半球之间的视觉信息交换和传递功能受损[57]。综上所述,POAG患者的局部自发脑活动的波动、一致性和功能连接存在广泛改变,且与疾病严重程度相关。

       然而,由于静息态fMRI研究结果受到患者、设备、采集参数和后处理方法等方面的影响,有待于今后严格设计试验方案并制订和严格落实全过程质量控制。此外,目前研究仅限于静态指标,今后需要进一步关注自发脑活动的动态变化特征,为POAG脑改变机制提供更多信息。

2.3 脑网络研究进展及前景

       基于BOLD-fMRI数据的图论研究结果表明POAG患者的脑网络全局指标未见显著异常,但脑网络的局部指标发生改变,舌回等脑区是网络中的关键节点,其介数中心度和特征向量中心度改变均与视野损害显著相关[58, 59]。后续研究在图论方法基础上引入网络“破坏指数”概念(“破坏指数”是衡量脑网络中特定属性重塑程度的高敏感性、高特异性参数),结果显示POAG患者脑网络全局与局部拓扑属性的“破坏指数”均存在异常,且与视野缺损和RNFL显著相关,一些关键节点(如左侧角回与左侧小脑)在对照组脑网络中存在,但POAG患者脑网络中未显示,可能与青光眼患者面部识别困难与运动障碍发生机制有关[60]。此外,选择特定脑区能进一步深入挖掘局部网络属性改变,将视觉网络(visual network, VN)与默认网络(default mode network, DMN)作为感兴趣区,基于静息态fMRI数据和独立成分分析方法的脑网络分析结果显示,POAG患者VN-VN和VN-DMN功能连接减低,且与视野损害显著相关[54]。基于数据驱动方法无需先验假设划分视皮层的图论研究结果也观察到POAG患者视皮层网络发生了重组改变[61]。综上所述,POAG患者脑网络改变不只局限于视皮层,面部识别和精细运动协调相关脑区的脑网络也发生明显改变。

       研究结果可能与研究脑区的范围、网络节点选取方法和网络边的构建方法以及上文提到的静息态fMRI结果的影响因素等有关,今后仍需扩大样本量并将研究方法进行规范化,提高其可靠性和重复性,进一步明确脑网络重组改变情况及其与POAG严重程度和病程、治疗干预之间的关系。

3 POAG患者脑血流灌注研究进展及前景

       动脉自旋标记(arterial spin label, ASL)图像低灌注区与正电子发射断层扫描低代谢区相吻合[62],说明脑血流灌注与代谢密切相关,因此ASL指标有望表征脑代谢情况,加之无辐射且无需注射对比剂(或显像剂)的优势,脑ASL研究具有一定优势和发展前景。POAG患者脑ASL研究结果显示早中期患者初级与高级视皮层的脑血流(cerebral blood flow, CBF)灌注减低,且血流灌注异常改变与RNFL和杯盘比等显著相关,提示早中期POAG患者的脑改变可能与视皮层脑血流灌注异常有关,脑灌注改变可有助于POAG早期诊断[63]。晚期POAG患者视皮层血流灌注显著减低,且CBF减低区域与灰质体积减小区基本一致,与对照组和早中期POAG患者相比,在给予视觉刺激后,晚期POAG患者的CBF增长幅度明显减小,提示POAG患者的视皮层萎缩和脑血流灌注异常密切相关,且这些异常与疾病严重程度显著相关[64]。多模态研究通过静息态fMRI与ASL联合分析发现POAG患者的脑神经-血管单元复合体发生改变,视皮层、突显网络、默认网络和背侧注意网络的CBF与功能连接强度的比值发生改变,提示视皮层和高级认知皮层的神经血管耦合功能障碍,且与青光眼分期和视野损害密切相关[12]。综上所述,POAG患者视觉通路及其他相关脑区血流异常灌注及脑神经-血管单元复合体耦合发生广泛改变,为POAG患者脑改变发生机制提供了更多信息,脑血流灌注参数有望成为青光眼患者脑改变的潜在生物标记物。

       目前研究中存在问题包括:以往研究多为单延迟ASL扫描,获得的信息较局限,后处理软件来自于不同公司或研究者自己编程获得,参数的准确性、可靠性和重复性有待于提高。今后可从以下两个方面努力:(1)采集和后处理规范化;(2)采用多个标记后延迟以及多延迟ASL序列,采集的信息更全面客观[65]

4 POAG患者视觉通路代谢研究进展及前景

       磁共振波谱(magnetic resonance spectroscopy, MRS)是一种无创性成像技术,可用于检测、识别和量化脑组织中的化合物或代谢物,主要包括正乙酰基天冬氨酸(NAA)、胆碱(Cho)、肌酸(Cr)、肌醇(Ins)和谷氨酰胺-谷氨酸(Glx)等。POAG患者LGN中NAA和Cho值降低,视皮层的NAA值与杯盘比呈负相关[66],提示视觉通路和视皮层存在神经组织损伤和变性等改变。此外,早期POAG患者初级视皮层的平均Glx/Cr比值显著增加,而平均Ins/Cr比值显著降低[13],但这些改变与青光眼严重程度并没有显著相关,原因可能有二:一是神经元标志物NAA的大幅降低常发生在细胞变性急性期,而青光眼一般进展缓慢,代谢物浓度改变不明显;二是受影响范围可能较小,无法进行准确测量[67]。MRS可准确描述每种代谢物的功能及其在光谱中的峰值位置,有望挖掘更多能够帮助诊断、监测和评估POAG的代谢分子标志物,并在此基础上开发新的靶向治疗策略[68]

       由于目前MRS空间分辨率和敏感度不足、影响因素较多,且LGN等视觉传导通路的结构较为细微,因此,研究发现的阳性结果较少,随着MRS技术显著提升,未来可能实现准确评估POAG患者视觉传导通路相关代谢物及其生物意义。

5 总结和展望

       POAG患者脑MRI研究揭示了患者视觉传导通路及其他脑区的结构、功能、血流灌注、代谢和脑网络等均发生了广泛变化,并与疾病严重程度和临床检查指标密切相关,在一定程度上验证了“POAG是一种广泛累及视觉传导通路和相关脑区的神经退行性变”假说,为POAG发生机制探索、潜在生物标志物挖掘和干预策略制订方面提供了更多客观依据和新思路。但由于主客观因素的限制和技术本身的局限性,结果的准确性、可靠性和重复性有待于进一步验证和提高。未来更需要开展多中心大样本量前瞻性队列研究,获得高质量的数据,采用影像组学和机器学习、深度学习方法将多模态MRI数据融合,进一步研究中枢神经系统改变之间的相互关系及其与视网膜改变和视觉障碍的相关性,全面解释发病因素及在发病机制中的作用,为早期诊断和治疗提供更明确的重要依据,延缓青光眼进展。

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