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综述
认知障碍的海马多模态MRI研究进展
何万利 黄刚 赵莲萍

Cite this article as: He WL, Huang G, Zhao LP. The hippocampus multimodal MRI progress of cognitive impairment[J]. Chin J Magn Reson Imaging, 2018, 12(4): 111-114.本文引用格式:何万利, 黄刚, 赵莲萍. 认知障碍的海马多模态MRI研究进展[J]. 磁共振成像, 2021, 12(4): 111-114. DOI:10.12015/issn.1674-8034.2021.04.028.


[摘要] 认知障碍是一种未达到痴呆程度的疾病,不仅影响患者的日常生活能力,严重者可能发展为痴呆。海马是承载机体认知功能的重要脑区,近年来,MRI技术被广泛地应用于认知障碍患者海马的研究,因此,笔者就认知障碍的海马MRI神经影像的研究现状进行综述,以了解其最新进展。大量研究一致认为海马是认知功能损害的主要受累脑区,尤其海马CA1区,其功能和结构改变可能是认知功能损害的重要神经影像学标志物,相比于结构变化,功能改变对检测认知障碍可能更敏感。
[Abstract] Cognitive impairment is a disease that has not reached the level of dementia. It not only affects the patient's ability of daily living, but may develop into dementia in severe cases. The hippocampus is an important brain area for cognitive function. In recent years, MRI technology has been widely used in the study of the hippocampus of patients with cognitive impairment. Therefore, this article reviews the research status of hippocampal MRI neuroimaging of cognitive impairment to understand it's latest development. A large number of studies have agreed that the hippocampus is the main brain area affected by cognitive impairment, especially the hippocampal CA1 area. Its functional and structural changes may be important neuroimaging markers for cognitive impairment. Compared with structural changes, functional changes may be more sensitive to the detection of cognitive impairment.
[关键词] 认知障碍;海马;磁共振成像;结构磁共振成像;功能磁共振成像
[Keywords] cognitive impairment;hippocampus;magnetic resonance imaging;structural magnetic resonance imaging;functional magnetic resonance imaging

何万利 1   黄刚 2   赵莲萍 2*  

1 甘肃中医药大学第一临床医学院,兰州 730000

2 甘肃省人民医院放射科,兰州 730000

赵莲萍,E-mail:lianping_zhao007@163.com

全体作者均声明无利益冲突。


基金项目: 国家自然科学基金 81860306,81901724 甘肃省自然科学基金 20JR5RA156
收稿日期:2021-01-21
接受日期:2021-02-02
DOI: 10.12015/issn.1674-8034.2021.04.028
本文引用格式:何万利, 黄刚, 赵莲萍. 认知障碍的海马多模态MRI研究进展[J]. 磁共振成像, 2021, 12(4): 111-114. DOI:10.12015/issn.1674-8034.2021.04.028.

       认知是指人脑接受外界信息,经过加工处理,转换成内在的心理活动,从而获得知识或应用知识的过程。它包括记忆、语言、视空间、执行、计算和理解判断等方面。认知障碍是指上述几项认知功能中的一项或多项受损,表现为记忆障碍、失语、失用、失认、视空间障碍、执行功能障碍及计算力障碍。海马是承载机体认知功能的重要脑区,与机体学习能力、记忆力、情感调节密切相关[1]。近年来,随着MRI新技术的飞速发展,学者们利用该技术就认知障碍对海马结构和功能进行了大量研究。因此,本文就认知障碍的海马MRI神经影像的研究现状进行综述,以了解其最新研究进展。

1 海马解剖

       海马也称海马角(cornu ammonis,CA),位于侧脑室下角及内侧壁上,因形状与海马相似而得名。自胼胝体压部向前到侧脑室下角,其前端膨大,称海马脚,上有隆起为海马趾,后端狭细,由海马裂深陷卷曲而成,此裂的下壁形成海马回。海马表面被室管膜覆盖,下方有一束有髓鞘纤维称海马槽,其纤维沿海马背内侧缘集中,形成白色纵行扁带称海马伞。海马根据细胞形态和皮质区发育不同分为CA1、CA2、CA3和CA4 4个扇形亚区,不同亚区在认知中有不同功能,其中CA1在记忆过程起关键作用,CA2参与空间信息存储和编码,CA3联系刺激-匹配模式与先前经验[2]。海马属异生皮质,为三层结构,从外至内为分子层、锥体细胞层和多行层。

2 认知障碍的海马MRI研究

2.1 基于结构MRI的认知障碍海马研究

       结构MR影像技术主要包括:基于体素的形态学分析(voxel-based morphometry,VBM)、FreeSurfer自动分割技术、扩散张量成像(diffusion tensor imaging,DTI)、扩散峰度成像(diffusion kurtosis imaging,DKI)等。

       VBM分析是指在体素水平上评估局部灰、白质体积和密度的变化,反映脑结构的形态学差异。大量基于VBM的研究发现,海马灰质萎缩与阿尔茨海默病(Alzheimer's disease,AD)[3]、帕金森病[4]、精神分裂症[5]及抑郁[5, 6]的认知障碍有关。Schmidt-Wilcke等[7]通过VBM技术发现轻度认知障碍(mild cognitive impairment,MCI)患者左侧海马灰、白质密度减低,且灰度密度减低与延迟自由回忆相关。基于VBM的荟萃分析亦证实,MCI患者左侧海马和海马旁回灰质萎缩[8]。糖尿病患者伴发认知障碍已引起广泛关注,一项采用VBM技术的动物研究发现,糖尿病模型小鼠伴认知损害组的海马灰、白质体积萎缩[9]。McIntosh等[10]采用FreeSurfer自动分割技术发现老年人的海马灰质厚度有减小趋势,亦有学者利用此技术发现认知障碍患者海马CA1区体积萎缩[11, 12],认为海马亚区体积萎缩有助于认知功能损害的检测[12]。可见,认知障碍患者存在海马灰质及白质的萎缩,尤其是CA1区萎缩可能是认知功能损害的神经影像学生物标记。随着自动分割技术的应用,关于海马及海马亚区的形态学研究将广泛引起学者们的注意。

       DTI可无创地分析脑白质纤维束结构完整性,基本原理是水分子在扩散过程中受到限制,在各个方向扩散程度是不同的,即具有各向异性,其常用的指标有各向异性分数、平均扩散率及ADC等。Hong等[13]发现AD和MCI的海马各向异性分数降低,平均扩散率升高,且与认知显著相关。遗忘性认知障碍患者早期可有白质微观结构的改变[14],大量研究表明,与海马体积萎缩相比,海马各向异性分数降低和平均扩散率升高检测认知障碍更敏感[12,15, 16]。所以有学者认为,白质微观结构改变检测认知障碍优于宏观体积萎缩。然而,有研究认为相比于各向异性分数和平均扩散率,海马体积萎缩是认知障碍更好的影像预测指标[17],如Mak等[18]发现AD及MCI患者海马体积萎缩,平均扩散率升高,各向异性分数降低,但是海马体积萎缩和记忆相关性更为明显。总之,海马白质微观结构的改变与认知功能受损密切相关,但其检测认知障碍的敏感性是否优于海马体积萎缩还有待研究,因此,需大样本量及同质的纵向研究来进一步探讨。

       DKI是基于DTI的新兴衍生技术,描绘脑组织内水分子非高斯扩散状态,不仅可评价白质的微观结构完整性,还可对灰质及交叉白质纤维微观结构进行定量评价,其参数指标包括平均峰度、轴向峰度、径向峰度等。Wang等[19]利用此技术发现,AD患者海马平均峰度降低并与认知损害呈正相关。研究指出,MCI和AD患者早期已经发生白质与灰质的改变,DKI能够早期敏感地检测出这些异常改变[20]。Yuan等[21]研究发现,早期AD患者海马平均峰度及径向峰度降低,相比于各向异性分数及平均扩散率,平均峰度能够反映水分子真实扩散模式,其可能是检测认知障碍更敏感的影像标记。在技术上,DKI补充了DTI技术的不足,可更客观、敏感地反映脑组织微观结构的改变。然而,DKI技术结合形态学改变共同探讨认知障碍的神经病理学机制的研究较少,因此,今后研究中应当充分发挥DKI技术的优势,更系统地对认知障碍海马结构进行研究。

2.2 基于功能MRI的认知障碍海马研究

       功能MR影像技术主要包括静息态功能磁共振成像(rest-state functional magnetic resonance imaging,rs-fMRI)任务态功能磁共振成像、磁共振波谱(magnetic resonance spectroscopy,MRS)、动脉自旋标记(arterial spin labeling,ASL)成像、磁化传递(magnetization transfer,MT)成像、酰胺质子转移(amide proton transfer,APT)成像技术等。

       rs-fMRI是指受试者在安静状态下无特定任务的情况下进行的磁共振扫描,反映了大脑在静息状态下的自发脑功能活动,不少学者采用该技术以不同的分析方法就认知障碍对海马进行了研究。

       局部一致性(regional homogeneity,ReHo)通过分析某一体素与周围体素的时间一致性,从而反映脑区神经元活动的同步性。Wang等[22]发现MCI患者海马ReHo降低,认为海马功能损害是认知障碍的重要标志。一项荟萃分析报道,遗忘性MCI患者存在默认网络、执行控制网络、视觉网络及感觉运动网络的ReHo异常,ReHo有升高也有降低,可能是功能损害与代偿共存的表现,且认为海马ReHo升高有助于补偿MCI患者的记忆障碍[23]。同样,Ni等[24]亦发现,与健康对照组相比,MCI患者双侧海马ReHo升高,其可能是局部脑区功能代偿的一种表现。大部分研究认为认知障碍患者存在海马神经元活动异常,这可能参与了认知障碍脑损害的神经病理学机制。神经元活动降低可能是海马脑区存在损害,损害发生早期周围的神经元活动可代偿性升高,然而后期失代偿,神经元活动可能会普遍降低,以往的研究鲜有将认知障碍分期,所以之后的研究中要考虑分期因素。

       低频震荡幅度(amplitude of low frequency fluctuation,ALFF)是从能量角度评价各个体素神经元自发活动水平的一种rs-fMR技术。不少学者利用此技术对认知障碍进行研究,有人发现海马ALFF值降低[25],亦有报道海马ALFF值升高[26],研究结果尚不一致。于是研究者利用荟萃分析进一步分析MCI患者脑区ALFF值的变化,发现海马ALFF值升高,认为海马神经元活性增加与认知障碍患者中海马萎缩后的代偿机制有关[27]。神经元自发活动水平的降低与升高可能与认知障碍的分期有关,认知障碍早期神经元自发活动水平降低合并代偿性升高,而认知障碍晚期神经元自发活动降低。研究发现,2型糖尿病(type 2 diabetes mellitus,T2DM)伴认知损害患者海马的ALFF值与认知密切相关,这可能有助于阐明T2DM与认知障碍之间的联系[28]

       功能连接(functional connectivity,FC)分析方法主要有独立成分、基于图论的脑网络、基于体素格兰杰因果、基于种子点的功能连接及基于体素镜像同伦连接分析等。Wang等[29]、De Vogelaere等[30]使用独立成分分析方法发现认知障碍患者海马激活减弱且与情景记忆和痴呆程度显著相关,然而,有学者发现MCI及AD患者海马激活增强且与延迟回忆呈负相关,认为其与海马和默认网络间的FC减弱有关,可能是功能受损代偿表现[31]。Gilligan等[32]使用图论的脑网络分析方法发现MCI患者海马与默认网络节点间的功能连接降低,基于图论的海马脑网络分析亦发现,伴有认知障碍的精神分裂症患者海马网络模块性降低并与记忆功能呈正相关[33]。T2DM常伴认知功能障碍,基于图论的脑网络分析发现,T2DM患者海马节点效率降低并与认知相关,这可能参与了T2DM脑损害的神经病理学机制[34]。学者使用格兰杰因果分析方法研究认知障碍患者海马与全脑的定向FC,发现海马与默认网络、执行控制网络、突显网络及辅助运动区间FC异常,且与认知损害相关[35]。同样,学者以海马为种子点的FC研究发现MCI患者海马与默认网络FC改变且与认知相关[36]。此外,Li等[2]发现MCI患者的右侧海马CA1区和右侧颞中回间FC降低且与情景记忆能力下降相关,这种连通性受损可能是MCI中记忆功能障碍的重要神经影像学标记。基于镜像同伦连接分析发现,脑卒中伴基底节损害患者海马功能协同性降低且与认知损害相关[37]。可见,不少学者使用功能连接分析研究认知障碍的海马改变,这可能与海马(尤其海马CA1区)FC检测认知损害优于海马体积萎缩[38]有关。目前,功能连接分析亦是静息态功能磁共振最常用的分析方法,为探讨认知障碍的神经病理学机制提供一定的影像学依据。

       任务态功能磁共振研究是依据认知障碍的特点,给予受试者特定任务,进而判断认知功能损害患者在执行此任务时相关脑区和脑网络的变化。目前,认知障碍患者的任务态研究多以记忆任务为主,记忆过程可分为编码、储存和提取,任务态研究主要针对编码和提取过程,研究表明海马在记忆的系统组织中起关键作用[39]。编码任务中认知障碍患者海马的功能活性下降[40],且编码任务时海马活性的改变与记忆提取相关[41],然而,有研究报道MCI患者海马功能活性增加,这可能与早期认知功能损害代偿有关[42],也可能与β淀粉样蛋白沉积有关[43]。研究表明,MCI患者的海马激活程度越高,认知损害的程度越重[44]。然而,近几年鲜有学者利用任务态功能磁共振对认知障碍的海马功能进行研究,可能与任务态功能磁共振相对复杂的设计及要求被试要有较高的配合度有关。

       MRS是一种无创地分析活体组织代谢和生化改变的成像技术,能在组织发生形态学改变之前从生化代谢角度评价脑损害。N-乙酰天门冬氨酸可作为认知损害的可靠代谢指标[45],研究一致认为,MCI患者海马的N-乙酰天门冬氨酸降低[46, 47, 48],是早期诊断和定量评估认知功能受损的有效影像学方法。MRS可以预测认知能力下降和向痴呆的转化,尤其是合并糖尿病的MCI患者[49]。学者对T2DM伴视网膜病变患者的海马进行MRS研究,发现N-乙酰天门冬氨酸显著减低且与认知功能呈正相关[50],这可能是T2DM患者脑糖原代谢受损的结果,也可能与视网膜病变有关。由于MRS技术检测的是生物代谢物,所以其可能对认知障碍的脑损害的探测优于脑组织形态学的改变,为早发现、早诊断认知障碍提供一定的影像学依据。

       ASL是利用血液中标记的水分子作为内源性示踪剂来定量反映脑血流灌注情况。学者利用此技术发现,认知障碍患者海马脑血流量降低[51],这可能与β淀粉样蛋白沉积有关[52],可为认知障碍早期诊断提供有价值的影像学依据。研究报道,T2DM患者海马脑血流量亦减低并且其与记忆力、执行功能呈正相关,灌注不足可能参与T2DM认知损害的神经病理学机制[53]。然而近期有研究表明,认知障碍患者海马脑血流量升高[54],可能是神经血管失调的结果,这也是认知损害的一种表现。近年来,越来越多的学者采用ASL技术从血流灌注的角度评价认知障碍脑损害,因为其不用注射人工对比剂就可了解脑血流情况,为阐明认知障碍的神经病理学机制提供一定的影像学依据。

       MT通过磁化转移使得组织信号强度不同程度降低,从而改变组织器官对比度,产生新的图像对比。学者利用此技术发现,与健康对照相比,MCI与AD患者海马磁化转移率降低,且AD降低更明显[55],磁化转移可能是检测认知障碍的敏感影像指标。APT由磁化传递技术衍生而来,通过测定酰胺质子的化学交换饱和转移特性,来间接测定细胞游离蛋白和多肽类物质的含量。王蕊等[56]使用APT技术测量双侧海马的酰胺质子不对称磁化转移率,发现健康对照、MCI及AD磁化转移率依次升高,且与认知呈负相关,这可能与认知障碍患者海马的游离蛋白和多肽的异常增加有关。MT与APT可通过蛋白质浓度来评估认知障碍脑损害,为探讨认知障碍神经病理学机制提供新思路。

       综上所述,不少学者利用磁共振新技术从功能和结构角度对认知障碍的海马改变进行了大量研究,一致认为海马是认知功能损害的主要受累脑区,尤其是海马CA1区,其功能和结构改变可能是认知功能损害的重要神经影像学标志物。结构磁共振成像技术中,相比于DTI,DKI能够更客观地反映微观结构改变,DTI检测海马微观结构的改变是否优于海马形态改变有待进一步探讨。功能磁共振可从神经元活性、生化代谢、血流量及磁化转移等多角度评价海马功能,相比于结构变化,功能改变对检测认知障碍可能更敏感。海马的每个亚区都有其特定功能,而关于海马亚区研究相对较少,因此,今后的研究中应发挥多模态MRI的优势,探讨海马各亚区结构及功能改变,从而为更进一步探明认知障碍神经病理机制提供依据。

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