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综述
阿尔茨海默病磁共振脑灌注成像研究进展
李栋学 刘本琴 张家仁 黄清 刘家骥 江林

Cite this article as: LI D X, LIU B Q, ZHANG J R, et al. Research progress of magnetic resonance cerebral perfusion imaging in Alzheimer's disease[J]. Chin J Magn Reson Imaging, 2023, 14(7): 129-133.本文引用格式:李栋学, 刘本琴, 张家仁, 等. 阿尔茨海默病磁共振脑灌注成像研究进展[J]. 磁共振成像, 2023, 14(7): 129-133. DOI:10.12015/issn.1674-8034.2023.07.023.


[摘要] 目前阿尔茨海默病(Alzheimer's disease, AD)被认为是包括主观认知下降(subjective cognitive decline, SCD)、轻度认知障碍(mild cognitive impairment, MCI)及AD源性痴呆的连续性AD谱系(AD spectrum, ADS)疾病。研究证实血管损伤、血脑屏障破坏参与了ADS疾病发病、发展过程,MR灌注成像通过定量分析脑血流变化能较好地显示这些病理改变,部分异常灌注脑区的影像指标可作为其早期诊断的生物标志物。本文对现阶段MR灌注成像技术特点及其在AD谱系疾病的应用研究作了总结分析,以期为后续相关的MR灌注成像研究提供一些参考,同时提出融合多模态MRI可提供更多反映疾病生物学改变的影像信息,为ADS疾病早期无创诊断提供影像学客观依据。
[Abstract] Alzheimer's disease (AD) is currently considered to be a continuous AD spectrum (ADS) disease that includes subjective cognitive decline (SCD), mild cognitive impairment (MCI), and AD-derived dementia. Studies have confirmed that vascular injury and destruction of blood-brain barrier are involved in the onset and development of AD spectrum (ADS) disease. MR perfusion imaging can better display these pathological changes through quantitative analysis of cerebral blood flow changes, and image indicators of some abnormal perfusion brain areas can be used as biomarkers for early diagnosis. This paper summarizes and analyzes the characteristics of MR perfusion imaging technology at the present stage and its application research in ADS diseases, in order to provide some references for MR perfusion imaging in subsequent relevant studies. Meanwhile, it is proposed that fusion multimodal MRI can provide more imaging information reflecting the biological changes of the disease, and provide an objective imaging basis for the early non-invasive diagnosis of ADS diseases.
[关键词] 阿尔茨海默病;灌注成像;磁共振成像;研究进展
[Keywords] Alzheimer's disease;perfusion imaging;magnetic resonance imaging;research progress

李栋学    刘本琴    张家仁    黄清    刘家骥    江林 *  

遵义医科大学第三附属医院/遵义市第一人民医院放射科,遵义 563000

通信作者:江林,E-mail:jlinzmc@163.com

作者贡献声明:江林设计本研究方案,对稿件重要内容进行了修改;李栋学起草和撰写稿件,分析文献及研究进展;刘本琴、张家仁、黄清、刘家骥等主要负责检索既往研究文献,分析或解释文献,对稿件重要内容进行了修改;江林获得了国家自然科学基金的资助,李栋学获得了遵义市科技计划项目的基金资助;全体作者都同意发表最后的修改稿,同意对本研究的所有方面负责,确保本研究的准确性和诚信。


基金项目: 国家自然科学基金 82160328 遵义市科技计划项目 遵市科合HZ字(2021)267号
收稿日期:2023-03-18
接受日期:2023-06-25
中图分类号:R445.2  R749.16 
文献标识码:A
DOI: 10.12015/issn.1674-8034.2023.07.023
本文引用格式:李栋学, 刘本琴, 张家仁, 等. 阿尔茨海默病磁共振脑灌注成像研究进展[J]. 磁共振成像, 2023, 14(7): 129-133. DOI:10.12015/issn.1674-8034.2023.07.023.

0 前言

       阿尔茨海默病(Alzheimer's disease, AD)俗称老年性痴呆,主要表现为认知能力下降和记忆力减退,是继心脑血管疾病和恶性肿瘤之后的老年人致死、致残的第三大类疾病。AD发病率逐年增高,据《2021年世界阿尔茨海默病报告》估计,2030年全球AD患者将达到7800万,其中我国将占到2075万。但AD早期诊断困难使得绝大部分患病人群被确诊时多为中晚期,此时大量神经元已发生不可逆性坏死,从而错失治疗良机。因此,突破AD早期诊断瓶颈、早防早治,是延缓或阻断病程进展的关键一环。脑血流灌注异常是AD发病及进展的高危因素之一,MR脑灌注成像有助于发现疾病血流动力学改变且无辐射损伤,对发现灌注异常脑区、动态监测灌注变化及个体化治疗具有重要意义。研究发现血流灌注异常、血脑屏障破坏是AD发生、发展一项重要的影响因素[1, 2, 3],MR无创脑灌注成像定量测量脑区灌注可为进一步探究AD病理生理机制提供重要客观依据、为AD早期诊断提供影像学参考。既往有关于AD的血液灌注研究进展报道,但缺乏连续性病程的逐一归纳及对比分析。因此,本文基于MR脑灌注成像技术,综述AD连续性病程即主观认知下降(subjective cognitive decline, SCD)、轻度认知障碍(mild cognitive impairment, MCI)及AD源性痴呆的脑灌注研究进展。以期为探索AD发病机制提供影像学依据、为后续此类研究提供有关参考。

1 脑灌注成像概述

       灌注的定义是氧、葡萄糖、氨基酸等营养物质通过毛细血管网输送给组织细胞,将二氧化碳等代谢产物运输走。毛细血管网和脑组织细胞间存在由软脑膜、脉络丛的脑毛细血管壁和包在壁外的胶质膜共同组成的血脑屏障,其能够阻止大多数物质由血液进入脑组织,而水分子则可通过被动扩散方式经过,这是脑灌注成像的生物学基础。1948年,从第一个用氧化亚氮测量全脑灌注的方法到20世纪80年代正电子发射计算机断层显像(positron emission tomography, PET)在人脑第一个横断面成像的发展,脑灌注成像有了巨大的改进。后续CT灌注成像(CT perfusion imaging, CTP)、T1加权动态增强(dynamic contrast-enhanced, DCE)及T2*加权磁敏感动态增强(dynamic susceptibility contrast, DSC)MRI、动脉自旋标记(arterial spin labeling, ASL)、体素内不相干运动(intravoxel incoherent motion, IVIM)等成功应用于脑灌注研究,为脑缺血性疾病、脑血管狭窄疾病、脑胶质瘤、癫痫等多种颅内疾病提供了重要的血流动力学信息。

       根据成像设备类型,脑灌注成像可分为CT、PET和MRI三种成像方式。其中PET和单光子发射计算机断层成像术(single-photon emission computed tomography, SPECT)是临床运用较早、较深入的检测手段,但两者均受限于放射性辐射安全和检查成本压力;CTP临床应用的限制主要是射线辐射和对比剂不良反应问题;MR脑灌注成像具有无创伤、无辐射并且可定量测定,现已经被广泛应用。根据是否需要借助外源性对比剂,MR脑灌注成像又分为对比和非对比灌注成像。DCE-MRI、DSC-MRI等是典型的外源性对比灌注成像技术,ASL、IVIM等则是非对比灌注成像技术。下文将简述不同MR灌注成像原理及方式,以AD不同病程作为研究对象,综述其在相关领域的研究进展。

2 AD脑灌注异常基础

       AD是一种连续变化的谱系疾病,包括SCD、MCI和AD导致的痴呆[4]。神经纤维缠结和Aβ蛋白沉积是广为认可的AD经典病理改变,其发病机制涉及炎症、线粒体功能异常、氧化应激、葡萄糖代谢异常等多种学说[5, 6, 7, 8]。研究发现血管损伤、血流灌注减低导致微循环障碍,使得Aβ和tau蛋白清除减少引起神经元变性,在AD发病机制和进展中起重要作用[1,3];血管危险因素和氧化应激炎症共同效应,损伤了神经血管单元(血管内皮因子、胶质细胞和相邻神经元),耗尽了血管储备,破坏了血脑屏障,降低了大脑的修复潜力,从而导致了AD的发生[9]。微血管的减少和血脑屏障的破坏是导致血脑屏障受损脑区血流灌注减少的主要原因[10]。血流灌注的减低一方面可以降低认知障碍阈值,另一方面则加快了痴呆的进展,因此可能是AD发病的一大诱因。有研究指出[11],预防和干预血管危险因素,改善脑血流量(cerebral blood flow, CBF)调节能力可以延缓AD的病程进展。因此,检测脑血流改变可为AD谱系(AD spectrum, ADS)疾病早期诊断、疗效评估提供重要信息,本文将对MR脑灌注成像在AD研究取得的进展进行总结分析。

3 ADS MR灌注成像进展

3.1 DSC和DCE

       DSC和DCE均为钆对比剂MR灌注成像,两者权重序列不同。DSC主要基于T2*权重为主的序列成像,也叫T2*灌注或MR灌注加权成像(perfusion weighted imaging, PWI),PWI的称谓更为常用。其主要原理是血管内钆对比剂可以缩短周围组织T2*引起信号减低,通过时间-信号强度曲线变化,半定量测量脑组织灌注参数,获取局部CBF、脑血容量(cerebral blood volume, CBV)、平均通过时间(mean transit time, MTT)以及达峰时间(time to peak, TTP),从而反映脑组织血流动力学信息。有研究[12]应用PWI对比分析了30名AD患者、23名MCI患者和15名正常对照的脑血容量参数,发现AD、MCI后扣带回灌注参数具有显著差异性,PWI结合认知评估量表能显著提高MCI转化的准确性,且基于PWI参数区分AD、MCI和正常对照组的准确性均较高。另有研究[13]比较了PWI参数与PET代谢率在AD、MCI患者的相关性,发现低灌注和葡萄糖低代谢的模式相似,说明PWI评估灌注能力接近PET水平。尽管多项研究[14, 15]指出PWI参数评估AD谱系疾病脑灌注具有准确性和可行性,大血管灌注与AD的tau沉积在皮质水平明显相关,但微血管区域灌注变化与tau的沉积并不完全一致[16],这给临床改善AD脑血管微循环治疗方面带来挑战,同时也为PWI精准检出AD微血管脑区灌注异常提出更高技术要求。

       DCE则是基于T1权重序列成像,主要有动态增强和渗透性分析两种应用。DCE动态增强临床应用非常广泛,通过分析对比剂引起的时间-信号曲线,判别肝脏、垂体、乳腺等病变的强化方式和程度,从而为疾病诊断提供血液灌注依据。本文讲的为后一种,即DCE渗透性分析,其主要反映微循环情况,得到全定量参数如体积传递常数(volume transfer constant, Ktrans)反映对比剂从血管到血管外细胞外间隙速率,血浆容量分数(fractional plasma volume, Vp)反映对比剂在血管内的容积分数等。最近发表在《Radiology》的一项研究[17]采用DCE渗透性分析评估脉络丛微循环与认知能力的关系,发现脉络丛通透性的改变与疾病严重程度相关,提示脉络丛通透性可能是AD认知损害的潜在成像标志物。同样,一项基于AD的动物模型研究[18]指出,DCE能较好地评估脑脊液循环改变,发现脑脊液循环受阻可能跟星形胶质细胞增生和淀粉样蛋白正常淋巴通路受阻有关,提示评估脑液循环功能有望成为AD早期诊断、SCD人群筛查的影像标志物和ADS治疗靶点。现阶段研究表明,DCE-MRI评估血脑屏障通透性改变参与了ADS的早期过程[19, 20, 21],但同时存在一些挑战,早期检测血脑屏障微漏可能需要在DCE-MRI采集与处理以及替代性技术方面进行额外创新[22],以此进一步了解血脑屏障复杂交换的必要性,以期为ADS疾病提供更多影像学信息。

3.2 ASL

       ASL是一种利用血液中水分子作为内源性示踪剂的MRI灌注技术,将标记像与控制像剪影得到血流灌注图,从而反映某一时刻组织器官的血流分布,可定量测定CBF[23]。ASL灌注技术于1992年首次提出并在老鼠身上实验成功,标志着无需外源对比剂的脑灌注成像的实现,并于1994年将其成功应用于人体,标志着人脑血流灌注定量测量的实现[24]。ASL定量CBF技术较为成熟、其详细成像原理不再赘述。基于伪连续式动脉自旋标记(pseudo-continuous ASL, pC-ASL)技术的3D-ASL成像具备高信噪比和高标记效率并克服了连续式及脉冲式ASL的磁敏感和运动伪影问题,被认为是目前最好的ASL脑灌注方法。3D-ASL无需外源性对比剂、无创伤、无辐射以及可重复操作等优势,在评估AD脑组织血流灌注方面具有重要前景。

       ASL定量CBF具有较高的准确性。有研究发现3D-ASL对AD的诊断结果与SPECT近似[25, 26]。应用3D-ASL技术对AD、MCI和正常对照组的多项对比研究[27, 28]发现,AD、MCI患者的CBF值较正常人减低,如海马、双侧颞叶和左侧枕叶,差异性脑区不尽相同,绝大多数表现为明显的灌注减低改变。这些低灌注改变其实质是血管床减少、神经-血管单元失调的必然结果。但有研究发现,AD患者有结构萎缩的脑区,ASL未检出灌注减低,部分甚至呈高灌注,提示可能与脑灌注代偿作用有关[29]。这与DING等[30]、LI等[31]、HAYS等[32]研究发现AD患者右颞下回、MCI患者双额叶和右颞下回以及SCD患者丘脑、壳核存在CBF增高现象相仿。这些现象提示AD神经血管失调后脑灌注由血流量减少到灌注代偿,再到失代偿最后呈低灌注的发展模式,脑区CBF增高是侧支血管代偿的结果。

       ASL联合临床信息可提供更多的生物学信息。现阶段研究发现,ASL定量CBF值不仅能评估AD脑功能异常改变,还可判断病情严重程度[33];ASL测量的CBF值有望成为诊断AD的指标之一[31,34, 35, 36];ASL结合神经精神量可提高鉴别AD和MCI的准确性[37]。另有研究使用ASL技术对比分析SCD和健康对照,发现SCD组除额叶皮层CBF减低外,部分脑区CBF增高与言语记忆评分减低呈明显负相关,这表明ASL检测疾病早期灌注异常具有可行性且SCD患者可能存在神经血管失调,CBF改变可能是其风险评估指标[32]。另外,有研究使用ASL灌注图对支持向量机(support vector machines, SVM)分类器进行训练,在分类和预测诊断AD以及MCI到AD的转换具有良好的准确性[38],提示基于ASL成像的影像组学、深度学习技术在疾病鉴别诊断、转换预测方面具有重要价值。总之,ASL定量测量CBF评估脑灌注改变前景可观,对进一步理解AD病理生理机制和识别ADS人群具有重要意义。

3.3 IVIM

       IVIM即多b值MR扩散加权成像,该技术于1986年被首次提出。水分子的运动包含血管内和间质内,b值为扩散敏感因子,扩散越快所需的b值越小,扩散越慢所需的b值越大。由于血管内水分子的扩散速度远大于间质内的水分子,所以低b值显示灌注信息,高b值显示间质内水分子的扩散特征。IVIM定量参数主要有真实扩散系数D值、灌注相关扩散系数D*值和灌注分数f值。D值为真正意义上的扩散系数,比扩散加权成像的表观扩散系数更能反映间质内真实的水分子扩散;D*值取决于微循环密度;f值代表灌注分数,取决于微循环所占比例。因此,IVIM利用高低b值、双指数模型分别去表征水分子的扩散和灌注,不仅可定量测量水分子扩散情况,还可评估组织微循环灌注情况。

       基于IVIM技术对比分析13例AD患者、12例MCI患者和24例健康对照的灌注参数组间差异性以及与认知评分的相关性纵向研究[39, 40]发现,海马和杏仁核组间存在显著差异,左侧海马可能对未来认知变化具有预测价值,提示IVIM指标可能是AD相关变化的早期生物标志物。多项研究表明,IVIM可用于ADS与正常对照的鉴别诊断[40, 41],IVIM灌注参数与PWI半定量结果具有高度一致性[42]。IVIM检出AD谱系疾病异常脑区具有准确性和可行性,但结果不尽相同,差异性脑区有海马和杏仁核[39,43],也有楔前叶和小脑[41],可能跟多数研究为小样本量有关。另外,IVIM参数分类AD和正常对照组的潜力跟基于机器学习的分析结果相仿,其中楔前叶、海马和顶叶的IVIM-D和IVIM-f在分类算法中具有显著特征[41]。当然,IVIM的另一优势是同时评估灌注和扩散,因灌注影响作用,常规扩散加权成像的表观扩散系数会高估组织扩散率,所以IVIM-D值更能反映组织扩散情况。研究发现MCI和AD患者的IVIM-f减低[44]、IVIM-D增高[45],前者跟低灌注率有关,后者跟神经变性蛋白沉积有关。现阶段研究表明,基于IVIM指标评估ADS疾病的灌注和扩散变化前景可观,但相关研究相对较少且未检索到在SCD的应用研究,后续研究有待加大样本量并覆盖ADS疾病谱,有望为AD早期诊断提供影像依据。

3.4 化学交换饱和转移技术

       化学交换饱和转移(chemical exchange saturation transfer, CEST)技术并非严格意义上的MR灌注成像,因其直接检测物质为自由水信号,而自由水运动间接反映灌注或扩散信息,所以本文将其纳入灌注成像范畴进行综述。CEST基于磁化转移技术及化学交换理论基础,对特定物质施加饱和脉冲进行充分的预饱和,再通过化学交换影响自由水的信号强度,从而通过检测水的信号强度变化间接反映该物质的体内分布信息。目前临床研究中最为常用的CEST技术为酰胺质子转移(amide proton transfer, APT),其基于多肽的酰胺基质子与水的氢质子化学交换比较快。AD经典病理改变为脑内异常蛋白沉积,因此基于APT成像检测这些蛋白沉积可能为诊断ADS提供帮助。多项研究[46, 47, 48]发现,与正常对照比较,APT值存在组间差异性,异常脑区与AD病理蛋白沉积及免疫组化结果一致,提示APT成像可作为AD的诊断标志物。但APT成像仍存在诊断敏感性及特异性不足等缺点[49],有待后续技术进一步解决。此外,CEST成像还可检测脑内氨基酸、葡萄糖、肌酸等物质的分布,如有研究发现AD组大脑皮层的甘氨酸浓度异常[50]、海马区葡萄糖代谢升高[51]。总之,CEST作为一种新兴MRI技术,今后有望在多模态、大样本、多中心神经退行性疾病研究中发挥重要作用。

4 总结与展望

       本文基于AD病程中血管损伤及血脑屏障破坏的生物学基础,对现阶段MR灌注成像在AD谱系疾病的应用研究作了总结分析,主要从MR灌注成像各技术特点、优缺点及各自在ADS疾病的研究进展两方面展开。总的来说,MR灌注成像在ADS疾病的早期诊断、异常检测等方面具有重要作用,但存在单一成像技术定量分析欠精准、揭示疾病病理生理特点欠客观的问题,后续有望通过队列研究融合多种MR定量技术多模态成像提供更多反映疾病生物学改变的影像信息,为ADS疾病早期无创诊断提供影像学客观依据[52]。此外,临床前疾病阶段被认为是干预的最佳时机,迫切需要确定可靠和灵敏的临床进展预测指标[53],以便在出现临床痴呆症状之前评估早期AD的个体风险,制订和应用治疗策略,MR功能成像无疑具有广阔前景。

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