主观认知减退影像学研究进展

2018-01-20赵志莲齐志刚李坤成

中国医学影像技术 2018年3期

樊响，赵志莲，齐志刚，李坤成*

(1.首都医科大学宣武医院放射科，北京 100053；2.磁共振成像脑信息学北京市重点实验室，北京 100053)

阿尔茨海默病(Alzheimer disease, AD)是以进行性认知功能障碍和记忆力损害为特征的神经系统变性疾病。随着诊断阶段前移，主观认知减退(subjective cognitive decline, SCD)的概念被引入。2014年，SCD概念启动组(Subjective Cognitive Decline Initiative, SCD-I)成立，Jessen等[1]提出SCD概念框架：SCD是患者主诉有记忆障碍而无相应客观临床表现的阶段，可检测到相关生物标志物证据，但尚未达到轻度认知障碍(mild cognitive impairment, MCI)程度。SCD是最终进展为AD的高危群体，但AD并非是引起主观认知损害的唯一原因，某些精神疾病或正常老化等均可导致认知损害。AD患者尚未出现认知障碍临床表现时，生物学标记即可出现异常。生物学标记主要分为体液标志物和影像学生物标志物，其中影像学生物标志物近年发展迅速，可检测β-淀粉样蛋白(amyloid β-protein, Aβ)沉积，评估神经退行性改变，故可用来预测SCD是否进展为AD。本文对SCD的影像学研究进展进行综述。

1 MRI

1.1 结构MRI(structural MRI, SMRI) SMRI可观察皮质萎缩情况。AD患者皮层萎缩具有一定分布特点和发展规律，而SCD患者皮质萎缩特点与AD具有相似性。SCD患者海马、内嗅皮层、后扣带回及内颞叶等可较正常老年人更早出现萎缩[2]，以颞叶为著[3]，但是否具有诊断及预测意义尚存争议。Cantero等[4]发现SCD患者海马CA1区、CA2区及齿状回区的分子层体积较小，且血浆Aβ42水平较高；但海马特定区域体积与血浆Aβ42是否可作为组合标志物还需进一步观察。既往研究[5]认为神经变性晚期杏仁核体积减小，但Schultz等[6]发现SCD患者皮层萎缩也可发生于杏仁核，且皮层萎缩患者神经心理检查分数更易减低。Zanchi等[7]发现右侧杏仁核(及双层海马)体积减小可早于认知下降。

1.2 fMRI

1.2.1 静息态fMRI 静息态BOLD自发性低频振荡信号可反映神经自发活动[8]。静息态脑功能网络研究[9]发现，默认网络(default mode network, DMN)是一组脑区，在执行认知任务时表现为负激活，静息时存在同步低频振荡，与Aβ沉积区域高度重叠。DMN不同脑区活动在AD病程中变化各异，前侧及腹侧先增强后下降，而后侧较早出现下降[10]。近年来，fMRI已广泛被应用于AD研究中，但相对较少用于SCD。Wang等[11]发现SCD患者右侧海马功能连接下降，程度轻于MCI患者。Edelman等[12]发现认知正常老年人执行海马记忆任务时，内颞叶激活与Aβ沉积相关，提出AD临床前期中内颞叶激活可能是神经变性的早期生物学标记。

1.2.2 任务态fMRI SCD患者脑激活在工作记忆时与正常人无明显差异，而进行情景记忆再认时其右侧海马活性减低，同时右背外侧前额叶皮质活性增强[13]。在编码任务时，SCD患者与正常人均有左侧前额叶皮质及小脑激活，且完成任务的表现无明显差异，但SCD患者左侧前额叶皮质激活强度与任务表现有关，提示可能存在代偿机制[14]。在注意分散任务时，SCD患者左侧内颞叶、双侧丘脑、后扣带回和尾状核激活增强[15]。在跨时决定任务时，SCD患者可出现延时折扣，即更倾向于选择即刻奖赏；而正常人倾向选择未来更多奖赏，可能与额叶前极皮层、右侧岛叶皮质和扣带回前部皮质激活有关[16]。上述研究表明，SCD患者执行不同认知任务时脑区激活表现各异。

1.3 扩散成像

1.3.1 DTI DTI由DWI发展而来，可三维显示神经纤维束改变及走行方向；测量指标包括各向异性分数(fractional anisotropy, FA)、平均扩散率(mean diffusivity, MD)、轴向扩散系数和径向扩散系数。研究[17]表明，AD和MCI患者多个部位白质纤维束受损，包括胼胝体、扣带回、海马旁纤维束、颞叶、顶叶及额叶等脑区纤维束；而SCD患者内嗅皮层、内颞叶、海马旁纤维及后扣带回白质纤维束易受损害[18]，且进展为MCI的SCD患者胼胝体、内颞叶、内嗅皮层、楔前叶及缘上回等部位的纤维束更易受累。SCD在DTI测量指标上主要表现为FA下降、径向扩散系数及MD升高。Doan等[19]发现SCD患者穹窿、钩状束、胼胝体和主要感觉运动通路中存在双向改变，提示白质微观结构在AD进展全程中存在连续性改变。正常老年人也常出现脑白质高信号(white matter hyperintensities, WMHs)，致进展为MCI及AD的风险增加。有学者[20]采用DTI与脑脊液(cerebrospinal fluid, CSF)观察具有WMHs的SCD及MCI患者，发现以DTI测量的指标差异均无统计学意义，而CSF中Aβ42(+)患者DA、DR和MD值较Aβ42(-)患者更高。还有学者[21]提出SCD患者脑白质网络结构全局及局部效率均明显下降，且主要集中于双侧眶额区及左侧丘脑等脑区。DTI发生改变的部位无法与皮层萎缩部位相对应，提示白质纤维束损害的病理生理基础可能与皮层萎缩不同。此外，有学者[22]提出DTI比CSF更能预测认知功能减退，提示DTI可能发展为独立预测AD风险的标志物[23]。

1.3.2 扩散峰度成像(diffusion kurtosis imaging, DKI) DKI是基于DTI技术的延伸，DTI理论前提为水分子扩散呈正态分布，而DKI可量化非正态分布水分子扩散，以描绘组织微观结构。DKI主要参数包括平均峰度(mean kurtosis, MK)、径向峰度(radial kurtosis, RK)及峰度各向异性(kurtosis anisotrop, KA)。有学者[24]发现AD、MCI及正常对照组胼胝体压部及放射冠MK明显不同；还有学者[25]发现，与正常对照组相比，AD患者胼胝体膝部、扣带束，颞叶及额叶体素数量在MK上高于FA及MD，提示MK较FA和MD更敏感。Gong等[26]发现早期MCI患者深部灰质有大量异常MK区域，提示MK可作为补充指标，用于检测深部灰质微观结构变化。

1.4 动脉自旋标记(arterial spin labeling, ASL) ASL可无创测量脑血流，无需注射对比剂即可获得血流绝对值，可重复性较好。采用3D ASL测量的脑血流量值有助于检测AD前驱期功能变化，可作为提示AD严重程度的标志[27]。Collij等[28]发现，ASL灌注图基于多元模式分析的方法鉴别SCD与AD的准确率较高，但鉴别SCD与MCI的准确率较低。对于ASL诊断SCD的价值尚需进一步观察。

2 PET

18F-FDG PET可通过测定脑葡萄糖代谢率而反映脑功能变化。目前对于SCD患者18F-FDG PET代谢变化尚无定论。Scheef等[29]发现SCD患者右侧楔前叶表现为低代谢，同时右侧内颞叶为高代谢。Ewers等[30]提出内颞叶和顶叶低代谢可较准确地预测正常老年人是否进展为AD。还有学者[29,31]发现，SCD患者纵向记忆力下降与右侧楔前叶葡萄糖代谢减低在基线水平相关。Jeong等[32]发现SCD患者左侧颞上回、右侧扣带回、左侧海马旁回、右侧舌回及右侧角回早期代谢易下降，执行功能变化与右侧扣带回后部代谢率呈正相关。

11C-匹茨堡化合物(11C-PIB)PET可用于显示Aβ沉积。认知功能正常的记忆门诊患者Aβ沉积高于正常健康对照组[33]。与18F-FDG PET与临床症状相关不同，11C-PIB可于临床症状出现前达到平台期，沉积量与临床症状严重程度不一定相关。SCD患者Aβ沉积与特定区域皮质萎缩相关，而正常人无此相关性[34]。Dore等[3]提出Aβ沉积并非正常过程，伴Aβ沉积的老年人海马及颞叶皮层萎缩较不伴Aβ沉积的老年人更快。有学者[35]发现，伴有Aβ沉积的受试者主诉常有认知功能下降。此外，半量淀粉样蛋白PET比CSF标志物更能指导AD分级及预后判断，其标准化摄取率(standardised uptake value ratio, SUVr)可作为确定认知程度的独立因素[36]。既往研究通常认为Aβ沉积是导致AD的重要原因[37]，而Kumar等[38-39]提出Aβ是一种对脑细胞具有保护作用的抗菌肽，为Aβ的研究提出了新方向。

Tau PET与CSF标志物检查的一致性较高[40]，且Tau PET可监测AD病理进展程度[41]。有学者[42]发现正常老年人无论是否伴有有Aβ沉积，其颞叶均易出现Tau聚集。目前关于Tau PET与SCD相关性的研究较少见，SCD患者脑内Tau聚集是否较正常老人更多还有待进一步证实。

3 展望

SCD亚临床特征于个体水平较难发现[43]。SCD自身表现具有异质性，国内外研究的入组标准及诊断也具有异质性，可能导致研究结果差异及偏倚。统一入组标准和诊断标准，建立大样本多中心研究和数据库十分必要。近年来，AD神经影像学计划已取得许多重要突破，可推动未来AD大样本多中心研究。此外，中国人群的脑成像与西方脑图谱存在差异，国内AD影像学研究采用中国人3D结构脑图谱(Chinese2020)[44]，可获得更准确的结果。随着大数据时代来临，多元模式分析(multivariate pattern analysis， MVPA)用途广泛，其中，支持向量机是AD研究中较常用的MVPA方法，且多项研究[45-46]表明支持向量机诊断及鉴别AD的准确率较高。Peter等[2]提出多元模式识别可敏感、有效鉴别SCD；Collij等[28]基于多元模式分析表明ASL灌注图可用于鉴别SCD与AD。另有研究[47]认为老年患者主观认知下降与抑郁症状相关，而与客观认知无关，故对于SCD的研究须排除抑郁因素的干扰，并通过随访加以证实。

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本刊可以直接使用的英文缩略语(一)

计算机体层摄影术(computed tomography, CT)

多层螺旋CT(multiple-slice CT, MSCT)

高分辨率CT(high resolution CT, HRCT)

容积CT(volumetric computed tomography, VCT)

CT血管造影(computed tomographic angiography, CTA)

CT静脉造影(CT venography, CTV)

磁共振成像(magnetic resonance imaging, MRI)

功能磁共振成像(functional magnetic resonance imaging, fMRI)

扩散(弥散)加权成像(diffusion weighted imaging, DWI)

磁敏感加权成像(susceptibility-weighted imaging, SWI)

扩散(弥散)张量成像(diffusion tensor imaging, DTI)