轻度认知损害的神经影像学研究进展
2014-03-06李伯英综述张增强审校
李伯英(综述),张增强(审校)
(1.庆阳市西峰区人民医院神经内科,甘肃 庆阳 745000; 2.解放军总医院海南分院保健科,海南 三亚 572013)
随着人类预期寿命的延长和社会人口的老龄化,越来越多的老年人面临罹患痴呆疾病的危险。轻度认知损害(mild cognitive impairment,MCI)是介于正常老年人和痴呆之间的一种认知功能受损状态。MCI患者的认知能力低于同龄阶段的正常老人但未到达痴呆的标准,许多MCI是临床前期的阿尔茨海默病(Alzheimer′s disease,AD)或AD的极早期阶段,每年有10%~15%的MCI患者发展成痴呆。目前MCI仍缺乏统一诊断标准,其诊断主要依据病史和神经心理学检查。随着影像学以及计算机辅助技术、基于体素的统计分析、功能成像等技术的发展,使得神经影像在MCI诊断中的作用越来越重要。
1 结构磁共振成像
AD极早阶段的病理变化存在于内嗅皮质和海马,因此大部分对于MCI脑容积的研究集中于此区域。Krasuski等[1]发现,MCI有类似AD的内侧颞叶结构(包括海马旁回、内嗅皮质、杏仁核和海马)萎缩,Wolf等[2]的研究也显示MCI患者双侧海马较对照组缩小,且海马萎缩程度与认知损害程度呈正相关。定量结构磁共振成像(structural magnetic resonance imaging,sMRI)研究提示,轻度AD患者的内侧颞叶、扣带回峡部和眶额区萎缩,有类似表现的MCI患者发展成AD的比例远高于无萎缩的患者[3]。Rossi等[4]根据sMRI表现将MCI患者按照有无内侧颞叶萎缩和白质高信号进行分组,随访发现存在内侧颞叶萎缩更易于进展为AD,白质高信号则没有。基于体素形态计量法研究发现,根据海马萎缩程度能够预测MCI是否向AD转化;MCI和AD患者与健康老人的海马萎缩方式不同,MCI和AD的萎缩出现在CA1亚区,健康老人随年龄增长出现海马下托萎缩[5];遗忘型MCI患者的海马萎缩与其他类型MCI及正常人有差别,但是与AD并无显著差异[6]。以上研究显示,内侧颞叶萎缩可能是MCI的特异表现并预示进展为AD的可能。Kumar等[7]持不同观点,认为目前众多研究都是基于就诊患者群体,病例选择会有抽样偏倚,他们随机抽查社区居民,筛查出224例被试者进行纵向研究,利用磁共振扫描脑室脑比率、测定皮质萎缩、海马和杏仁核体积、脑白质高信号,发现这些指标不能作为预测MCI的特征,而抑郁及教育程度低却有预测作用,得出这一结论可能与该研究被试者年龄偏年轻有关(60~64岁)。
2 正电子发射断层扫描
2.118F-氟脱氧葡萄糖正电子发射断层扫描18F-氟脱氧葡萄糖(18F-fluoro deoxyglucose,FDG)正电子发射断层扫描(positron emission tomography,PET)是利用18F标记的FDG的生化特性与组织利用的葡萄糖相似,能够在分子水平定量测定脑组织代谢改变。Chételat等[8]对17例MCI患者进行为期18个月的随访发现,转变成AD的10例MCI患者均有颞、顶叶皮质18F-FDG吸收下降;对21例遗忘型MCI患者进行研究发现,记忆编码过程与经海马标准化部分容积效应校正的脑葡萄糖利用率有关,提取过程与扣带回后部这种校正的脑葡萄糖利用率有关,表明MCI患者存在记忆编码和提取的神经基础部分性分离。另一项纵向研究观察了20例MCI患者,1年后有8例发展为AD;与健康对照组比较,进展型MCI患者在静息状态下,海马、额下回、颞叶中部、顶下小叶和后扣带回的葡萄糖代谢减低,而在稳定型MCI患者中只观察到很少区域有代谢减低;进展型与稳定型MCI比较,代谢降低的区域为楔前叶和后扣带回[9]。以上研究结果提示,18F-FDG PET有助于将MCI患者分为不同的亚型,并预示将来进展为AD的可能性。将心理学任务结合PET试验,Nishi等[10]发现MCI患者的右内侧颞叶、前额叶、左侧顶下小叶和两侧扣带回后部的低代谢与延迟记忆受损有关,右前额叶的低代谢则与执行功能降低有关;而Walhovd等[11]发现,MCI患者海马代谢能够预测情景记忆再认知测试成绩。
2.218F-FDG PET探测的是葡萄糖代谢变化,不能反映AD的特征性改变——β淀粉样蛋白(amyloid beta,Aβ)沉积。11C-6-匹茨堡化合物B(Pittsburgh compound B,PIB)可与脑内Aβ特异性结合,从而进行定性、定量分析。Klunk等[12]最早将11C-PIB作为示踪剂用于AD患者PET显像,发现在AD患者额叶、顶叶、颞叶和枕叶等Aβ易于沉积的区域与11C-PIB结合越多。在一部分MCI患者的额叶、颞叶及后扣带回也发现PIB摄取增高,这种增高预示MCI转化为AD的概率增大[13-14]。但有人认为,11C-PIB PET诊断MCI的特异性不如AD[15]。Aβ沉积与认知之间的关系存在争议,Chételat等[16]发现Aβ沉积尤其是在颞叶与情景记忆损害相关;而Jack等[17-18]认为,MCI患者脑内Aβ沉积的增加不能预示认知功能下降,也不能预示MCI向AD进展加快。11C-PIB PET观察到的MCI患者Aβ沉积可能是AD病程中较早的代谢异常,与神经变性的下游表现如神经元破坏、皮质萎缩及痴呆症状等有何联系仍有待研究。研究MCI患者Aβ负荷与脑萎缩的关系发现,楔前叶Aβ增加与内侧颞叶萎缩速率呈正相关[19],这增加了将11C-PIB PET用于AD早期预测的信心。
3 单光子发射计算机断层显像
单光子发射计算机断层显像(single photon emission computed tomography,SPECT)可通过观测局部脑血流(regional cerebral blood flow,rCBF)来判断该区域脑功能状况,以前研究发现AD患者认知功能的改变与脑血流的改变有密切关系[20]。以小脑为参照,AD及MCI患者扣带回后部rCBF比率显著下降;AD患者额叶、颞叶和顶叶的rCBF比率下降,但MCI则无此改变。据此认为,MCI后扣带回低灌注是其向AD发展的一个高危信号;采用脑脊液tau蛋白水平与扣带回后部rCBF的比值作为MCI向AD转化的预测指标时,其灵敏度、特异度分别为88.5%和90.0%[21-22]。Huang等[23-24]通过2年的随访研究发现,以稳定型MCI为基线,进展型MCI的rCBF在顶叶降低,在前额叶增加,其情景记忆与视空间功能受损比稳定型MCI严重,提示结合SPECT和神经心理学测试可以预测MCI患者的转归。Høgh等[25]和Staffen等[26]发现,MCI患者颞叶灌注显著减低。Hirao等[27]对76例遗忘型MCI患者进行3年的随访,其中52例进展型MCI两侧海马旁回、楔前叶后扣带回皮质及两侧顶叶、右侧颞叶中部rCBF显著下降,而24例稳定型MCI只表现为后扣带回和右侧尾状核的rCBF降低;进展型与稳定型MCI比较,前者表现为两侧颞-顶叶和楔前叶的rCBF降低,Logistics回归模型显示顶下小叶、角回和楔前叶的灌注减低有重要的预测价值。其他一些研究表明扣带回、海马或顶叶等区域灌注对MCI进展有预测作用。Caroli等[28]观察到遗忘型MCI海马旁回和下颞叶的低灌注预示着向AD的转变;Johnson等[29]也发现进展型MCI的前扣带回尾侧和后扣带回灌注显著降低,而前扣带回嘴侧灌注增加。在另一个纵向研究中,Habert等[30]发现进展型MCI右顶叶和海马的灌注显著降低。
4 功能磁共振成像
4.1任务功能磁共振成像 任务功能磁共振成像(functional magnetic resonance imaging,fMRI)显示,MCI患者与正常人比较,在某些感兴趣区表现出激活增高或者降低,表明MCI患者在这些脑区的适应性发生改变。Bokde等[31]发现,正常人面孔和空间识别任务分别激活背侧和腹侧通路,而MCI则无这种差别,且与正常人相比MCI患者视觉通路和左额叶激活代偿性增强。进行情景记忆编码时,正常对照组左腹外侧前额叶皮质的激活强度与再认知正确率呈正相关,而遗忘型MCI患者在这一区域的激活减低,说明遗忘型MCI患者的情景记忆受损与左腹外侧前额叶的功能障碍有关[32]。Jauhiainen等[33]将词语-图画配对线索回忆任务fMRI与结构MRI进行比较,发现fMRI在鉴别MCI、AD患者及正常人的准确率低于基于结构MRI的内嗅皮质容积测量,这可能与分析方法有关,因其只以海马为感兴趣区考察激活强度。
4.2静息态fMRI 静息状态下,血氧水平依赖性信号中的自发低频(<0.1 Hz)震荡可被用于监测大脑自发活动。Bai等[34]用局部一致性的分析方法发现,MCI患者的后扣带回局部一致性减低,而作为代偿,顶下小叶、梭状回和壳核等脑区激活增高。Han等[35]也发现,静息状态下MCI患者后扣带回、内侧前额叶、海马和基底核等区域低频振荡波幅(amplitude of low-frequency fluctuations,ALFF)显著降低,而在枕叶和颞叶的某些区域ALFF增高。Xi等[36]的研究结果显示,MCI患者内侧颞叶、外侧颞叶和内侧前额叶的ALFF降低,而在颞-顶交界区和顶下小叶出现代偿性增高,这一点与Zhang等[37]的结果一致。同样采用ALFF方法,Wang等[38]观察到后扣带回的自发活动从正常对照到MCI,再到AD被试者呈下降趋势。而Jin等[39]发现,MCI患者在外侧前额叶、内侧颞叶、颞中回、后扣带回和角回等区域的自发活动降低,中扣带回、内侧前额叶、顶下皮质增高。总之,MCI患者自发活动异常的脑区主要存在于由后扣带回、内侧前额叶、内侧颞叶和顶下小叶等构成的默认网络系统。
5 小结与展望
综合以上各种成像技术,MCI的主要影像学表现有:结构MRI观察到内嗅皮质、海马和颞叶的萎缩;PET和SPECT检测到额叶、颞叶、顶叶、扣带回后部、楔前叶和海马等部位的脑灌注减低或代谢异常;fMRI显示人脑默认网络、前额叶的激活异常。部分研究者借助影像学致力于MCI的分型、转归及AD的预测研究,但由于目前MCI的概念仍处于发展中,缺乏操作性强的统一标准,使得各研究结果无法在研究对象一致的基础上形成统一的结论。但是,随着影像学资料的积累,影像学与神经心理学、生物学标志物研究的配合,以及大规模人群长期随访研究,一定会推动对MCI发病机制、发展过程的认识,为预后和早期干预提供科学可靠的依据。
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