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光学相干断层扫描血管成像在神经退行性疾病中的应用进展

Advances in the application of optical coherence tomography angiography in neurodegenerative disorders

来源期刊: 眼科学报 | 2021年10月 第36卷 第10期 804-809 发布时间: 收稿时间:2023/7/28 15:13:03 阅读量:2909
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光学相干断层扫描血管造影术神经退行性疾病阿尔茨海默病帕金森病多发性硬化症
optical coherence tomography angiography neurodegenerative disorders Alzheimer’s disease Parkinson’s disease multiple sclerosis
DOI:
10.3978/j.issn.1000-4432.2021.07.26
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视网膜微循环与脑小血管具有相似的特征。视网膜被认为是可检测到的“窗口”,以检测在神经退行性疾病中发生的微血管损伤。光学相干断层扫描血管造影(optical coherence tomography angiography,OCTA)是一种非侵入性成像方式,可提供视网膜、脉络膜和视神经中血流的深度分辨
图像。现总结有关OCTA在与眼科相关的阿尔茨海默病、帕金森病、多发性硬化症及视神经退行性疾病等神经系统疾病中的应用,并讨论其可否作为早期诊断和监测神经退行性疾病的重要工具。
Retinal microcirculation shares similar features with cerebral small blood vessels. Thus, the retina may be considered as an accessible ‘window’ to detect the microvascular damage occurred during the development and progression of neurodegenerative disorders. Optical coherence tomography angiography (OCTA) is a non-invasive imaging modality providing in-depth and high-resolved images of blood flow in the retina, choroid,and optic nerve. In this review, we summarize the current advances in the application of OCT-A in neurological diseases associated with ophthalmology such as Alzheimer’s disease, Parkinson’s disease, multiple sclerosis and optic nerve degenerative diseases. Future directions for evaluating whether OCTA can be used as an important tool to early diagnose and monitor the neurodegenerative disorders are also discussed.

神经退行性疾病是全球残疾的主要原因,它是由神经元和/或其髓鞘丧失所致,随着时间的推移而恶化,出现功能障碍。视网膜和视神经被认为是中枢神经系统的一部分。在胚胎发生过程中,它们起源于发育中的大脑,特别是胚胎间脑[1]。解剖学上,视网膜包含神经胶质细胞以及由细胞体、树突和轴突组成的相互连接的神经元,类似于大脑皮质的细胞结构。在微血管系统方面,血视网膜屏障中紧密的内皮细胞连接的存在类似于血脑屏障的存在。虽然视网膜循环类似于大脑的,它缺乏自主控制[2]。鉴于这两个组织之间的解剖学和生理学同源性,这表明中枢神经系统疾病可能与独特的视网膜变化有关。老化主要是在脑血管解剖和功能的变化,这可能损害神经元功能和提高神经变性的风险[3]。神经病学家通常使用检测和定义神经退行性综合征的诊断方法,如脑脊液常规检验(cerebrospinal fluid,CSF),正电子发射断层扫描(positron emission tomography , PET) 和磁共振成像(magnetic resonance imaging,MRI),但是它们具有侵入性或需要高昂的费用[4]。视网膜可以代表一个易于访问的“窗口”,以评估脑神经元和微血管损伤。作为一种最新的非侵入性视网膜成像技术,光学相干断层扫描血管造影(optical coherence tomography angiography,OCTA)可使视网膜的血管可视化,提供有关脉络膜和视网膜微循环的深度分辨信息。这篇综述旨在讨论OCTA作为一种非侵入性工具在研究神经退行性疾病中发生的视神经改变方面的应用。

1 OCTA 技术

OCTA是一种迅速兴起的成像技术,能够无创地产生眼睛的血管造影图像。OCTA的工作方式是收集同一位置的多个横截面扫描(B扫描),然后检测运动对比度、振幅、强度或相位的差异。使用方法取决于特定的设备。由于与运动的物体相反,静止的物体不会在信号中产生任何变化,并且视网膜和脉络膜是静止的组织,因此,值的差异被认为来自其中唯一的运动粒子,即血液。红细胞由于其双凹结构而反射光。可视化血管结构无需注入染料。重要的是要知道,与眼底荧光素造影(fluorescein fundus angiography,FFA)不同,OTCA创建的图像只是计算机数学计算的结果。这在计算各种参数时很有用,包括血流[5]、血管密度、血管化和黄斑中心凹无血管区(foveal avascular zone,FAZ)的大小[6]、灌注大小[7]、分形分析甚至是复杂度测量[8]。然后通过在同一位置进行多个横截面扫描(B扫描)以创建3D图像,而且还可以计算出血管结构的数据,例如直径、长度或分支数[9]。OTCA为测量视网膜血管内的结构和流量提供了一种客观的定量无创技术。

2 OCTA 在与眼部相关的中枢神经退行性疾病中的应用

2.1 阿尔茨海默病

阿尔茨海默病(Alzheimer’s disease,AD)被认为是最常见的痴呆类型。AD的常见眼科症状和体征是视野改变和视力下降[10]。其病理特征为分别由淀粉样蛋白的积累和tau蛋白的过度磷酸化。据估计,视网膜微血管的改变,例如微动脉瘤、软或硬的渗出、视网膜出血、黄斑水肿、视网膜内微血管异常、新生血管及玻璃体出血与认知能力下降有关[11]。此外,其他视网膜改变,例如黄斑视网膜神经纤维层(retinal nerve fiber layer,RNFL)厚度的改变与AD型痴呆的早期改变有关[12]。尽管其他研究[12]表明神经节细胞层(ganglion cell layer,GCL)减少,但RNFL和内部丛状神经节层的变化[13]与淀粉样蛋白的积累有关,而 GCL 则 没有[14]。最近的一项研究评估了OCTA在A D中 的发现。Bulut等[15]描述了通过OCTA测得的FAZ增大,视网膜血管密度和脉络膜厚度降低。该研究将这些变化归因于血管内皮生长因子(vascular endothelial growth factor,VEGF)与淀粉样蛋白的积累引起的血管生成减少。研究比较双胞胎发现:与健康胎儿相比,患有AD的双胞胎的FAZ较大,脉络膜更薄[16]。同样,在Jiang等[17]的一项研究中,与对照组相比,AD患者的浅表毛细血管丛(superficial capillary plexus,SCP)和深层毛细血管丛(deep capillary plexus,DCP)密度均降低,而轻度认知障碍患者仅在DCP和鼻上象限中的密度降低。因此,由于来自视网膜中央动脉的血液首先供给SCP,然后供给DCP,SCP密度降低可导致通过视网膜外层的血流减少,这可能导致神经节细胞轴突持续丢失。

2.2 帕金森病

帕金森病(Parkinson’s disease,PD)是老年人中第二常见的神经退行性疾病[18]。该病主要是由纤维状α-突触核蛋白(即路易体)在细胞内沉积,导致黑质和其他皮质下核中多巴胺能神经元的逐渐丧失[19]。最常见的临床特征是不同的运动改变,例如运动迟缓、静息性震颤或僵硬及认知功能不可逆转的恶化。此外,也有报道视觉症状,例如视力改变,对比敏感度降低和色觉恶化[20]。使用OCTA可以显示出不同的视网膜结构变化,在OCTA观察PD患者研究[21]中发现视网膜内层和视网膜神经纤维层显著变薄,这表明这些参数可以被认为是有助于诊断脑损伤。除神经变性外,血管损伤已被确定为PD发生和发展的可能关键因素。最近,已经有研究[22]使用OCTA评估PD患者的视网膜微血管状态。早期P D患者在OCTA单独评估的所有象限和整个环形区[定义为中央凹(不包括FAZ)直径为2.5 mm的区域]显示SCP灌注血管密度降低[23]。鉴于先前关于PD动物模型的研究报道了纤维状α-突触核蛋白在动脉壁的蓄积,作者认为除了神经变性外,血管损伤也是导致PD患者SCP的灌注密度降低的重要因素。此外,在PD患者中,视网膜神经节细胞-内丛状层(ganglion cell and inner plexiform layer,GCIPL)的厚度与SCP的整个环形区域呈正相关,这也支持了微血管损伤可能促进神经退行性变的假说[22]。Shi等[23]还使用OCTA分析研究了毛细血管的复杂度,结果显示SCP和DCP的复杂度均降低。此外,SCP的复杂度与神经节细胞和内部丛状层的厚度呈负相关,而DCP的复杂度与疾病的持续时间呈负相关。该研究表明:对视网膜毛细血管的复杂度分析能够检测出PD患者血管改变的细微变化,并且它显示出与视网膜结构更紧密的关系[23]。这些发现表明,OCTA可能代表P D研究的一条新途径,并且将来可能会作为早期发现有价值的检测方式。

2.3 多发性硬化症

多发性硬化症(multiple sclerosis,MS)是一种慢性脱髓鞘炎性疾病。尸检显示,99%的患者在视神经内有脱髓鞘迹象[24]。视神经炎是25%的患者的主要表现,在疾病发展过程中可能发生在50%的患者中[25]。在利用OCTA对MS患者进行研究发现:对视神经炎患者的整个视神经头(optic nerve head,ONH)内测得的血流量相比降低了12.5%,无视神经炎的患者的血流指数也低于对照组。此外,有21%的具有良好视力的M S患者出现血流异 常[26]。M S患者尤其是视神经炎病史的患者,OCTA可以检测出ONH灌注的减少。尽管将OCTA与其他OCT参数结合使用可提高视神经炎眼中MS的诊断准确性,但血流指数与神经节细胞复合体(ganglion cell complex,GCC)和RNFL之间无显相关性[25]。一项相对较大的OCTA研究[27]表明:与健康对照组相比,中央凹周围区SCP和DCP血管密度的降低与相应视网膜层厚度的降低有关。此外,脉络膜毛细血管密度的增加与过去2 4个月内的炎症有关。
研究[26]表明OCTA在对MS患者测量中发现视网膜神经节细胞的减少和RNFL的厚度降低,这导致较低的代谢活性和血管丛的稀疏化。Wang等[26]在MS脑中观察到自我调节机制或内皮细胞的改变,各组中央凹的变化可能是由于黄斑RNFL的缺乏以及黄斑的血流是由脉络膜提供,并且自动调节的范围比视网膜血管所提供的区域要大得多。然而,他们没有区分视网膜血管丛,而是测量了整个视网膜的血流指数。Lanzillo等[28]对稳定M S患者进行了在1年的随访纵向评估,报告中心凹旁血管密度显著增加。由于所有患者都在接受稳定的疾病改良治疗,并且近期没有出现任何疾病复发,作者推测随着时间的推移,血管密度的增加可能是治疗的结果。此外,中心凹旁血管密度与扩展残疾状态量表(expanded disability status scale,EDSS)呈负相关,EDSS是评估MS致残最常用的评分之一[28]。根据这些结果,Murphy等[29]表明浅表血管丛的血管密度(superficial vascular density,SVD)与EDSS和多发性硬化症功能综合评分呈负相关。这些结果强调了视网膜血管密度作为监测多发性硬化进展的一种新的生物标志物的作用。总之,OCTA揭示MS患者视网膜血管化的损伤,并在检测早期微血管改变方面显示出有前景的作用,同时也作为监测疾病进展的潜在新型生物标志物。

3 视神经退行性疾病

视盘的检眼镜检查可能不足以区分各种视神经病变,因为它们的大多数特征在于视盘水肿或视神经萎缩。 OCTA 已被提议作为一种有用的非侵入性工具,可以更好地可视化视神经乳头血管[30]。Ghasemi Falavarjani等[30]通过OCTA扫描在不同的视神经病变中评估了视盘脉管系统,这些视神经病变分别是非动脉性前部缺血性视神经病变(non-arteritic anterior ischemic optic neuropathy,NAION),Leber遗传性视神经病变,常染色体显性视神经萎缩,自身免疫性视神经炎和特发性颅内高压。所有类型的视神经病变均与视神经乳头周围血管血流减少有关,在视神经萎缩的眼睛中更为明显。尚不清楚是否由于视盘微脉管系统的损伤,或者纤维数量较少而引起的新陈代谢降低,还是两种机制的结合导致了乳头周围血管血流量的减少。临床上对大动脉前部缺血性视神经病变(arteritic anterior ischemic optic neuropathy,A-AION)和NAION之间的鉴别诊断具有重要的意义,因为前者可能导致严重的双侧视力丧失,而大剂量皮质类固醇治疗可以预防[31]。OCTA研究结果,在保留脉络膜毛细血管灌注的情况下,径向毛细血管周围的灌注不足[32]。另一方面,两项利用OCTA评估A-AION患者血管变化的研究报告了脉络膜毛细血管灌注不足[33]。脉络膜灌注不足被认为是A-AION的显着特征,即睫状体后动脉的炎症和闭塞发生在其分为视旁支和脉络膜支的附近[34]。因此,OCTA可能在区分A-AION和NAION中起作用。
Leber遗传性视神经病变是一种线粒体神经退行性疾病,会影响视网膜神经节细胞及其视神经轴突,其特征是在成年时期双侧亚急性中心视力丧失[35]。该疾病与包括毛细血管扩张性微血管病和小血管曲折的周围乳头状血管的异常有关[36]。一项前瞻性研究报告说,在Leber遗传性视神经病变的亚急性期,视神经颞区的血管血流量减少,而在慢性期,慢性期所有的血管血流减少[37]。Borrelli等[38]研究表明患有Leber遗传性视神经病变的眼睛出现SCP和DCP改变,这些改变主要局限于与乳头黄斑束相对应的鼻侧和下凹旁区。此外,视力丧失与SCP流量受损有关,但与OCTA可检测到的结构损害无关。在常染色体显性视神经萎缩中也证实了黄斑和乳头周围区域的微血管损伤,这是最常见的遗传性视神经病变[39]。Cennamo等[40]评估了3种先天性视神经异常的形态和血管变化,即牵牛花视盘综合征、先天性视盘缺损和先天性视盘小凹。在有牵牛花视盘综合征的患者中,OCTA显示出致密的乳头周围微血管网,在先天性视盘缺损和先天性视盘小凹中都没有。这些特征可能有助于了解这3种先天性疾病的发病机制。

4 结语

OCTA可以对视网膜中的微血管进行无创评估,这代表了中枢神经系统最容易接近的部分。大量证据表明,眼部神经退行性疾病和中枢神经系统疾病(例如A D,P D和MS)的特征是视网膜微血管受损。然而毛细血管丛密度降低是非特异性的,在许多其他疾病如糖尿病视网膜病变[41]及手术后[42]可以观察到。这些血管变化的病理机制仍需充分阐明,需要进一步研究来确定微血管损伤与神经元损害之间的偶然关系。此外,研究仅评估了黄斑周围和乳头状区域,不可能只根据OCTA检测血流的检查结果来进行诊断。血流量的计算可能会更好地了解病理学并促进许多神经疾病的诊断。由于神经退行性疾病往往是在广泛的神经元损伤已经发生时才被诊断出来,因此人们花费了大量的精力来寻找有用的生物标志物,用于早期诊断和监测神经退行性疾病的程度。OCTA可以有助于诊断神经退行性疾病的一种快速、便宜且非侵入性的检测方式。尽管OCTA在临床前阶段的临床应用需要进一步确认,但通过将其整合到多模式成像方法中,可能会提高其敏感性和特异性。未来的研究应探索OCTA与其他检查方式(CSF、MRI和PET)相结合的诊断和预后价值。

利益冲突

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1、徐俊.光学相干断层扫描仪检查视网膜疾病中应用护理配合的效果[J].名医,2022(23):120-122.Xu J. Effect of nursing cooperation in the examination of retinal diseases by optical coherence tomography[J]. Renowned Dr, 2022(23): 120-122.
1、国家自然科学基金(81660158);江西省重点研发项目(20181BBG70004);江西省卫计委科技计划面上 项目(20175116)。
This work was supported by the National Natural Science Foundation (81660158), Key Research Foundation of Jiangxi Province (20181BBG70004), and Health Development Planning Commission Science Foundation of Jiangxi Province (20175116), China.()
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