血管性和老年性认知损害患者基于Stroop任务的fMRI研究
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摘要
目的
应用基于Stroop任务的功能磁共振(blood oxygen level dependency-functional magnetic resonance imaging, Bold-fMRI)技术探讨血管性认知损害(vascular cognitive impairment, VCI)和老年性认知损害患者注意相关脑区功能变化特点,主要目的包括:
1.探讨皮质下缺血性血管性认知损害(subcortical ischemic vascular cognitive impairment, SIVCI)患者注意相关脑区功能变化特点,评价皮质下小血管病变对注意认知环路的影响,促进对血管性认知损害病理机制的认识;
2.定量分析皮质下缺血性血管性认知损害非痴呆(subcortical ischemic vascular cognitive impairment no dementia,SIVCIND)和皮质下缺血性血管性痴呆(subcortical ischemic vascular dementia,SIVD)患者脑功能图谱特点,探索fMRI在SIVCI诊断中的价值,期望为早期诊断提出客观评价指标;
3.分析阿尔茨海默病(Alzheimer disease, AD)、轻度认知功能损害(mild cognitive impairment, MCI)患者脑功能图谱特点,评价老年性认知损害不同阶段功能区变化特点;并与皮质下缺血性血管性认知损害进行比较,探索两种不同认知损害脑功能区变化机制的不同,以及fMRI在两种不同认知损害鉴别诊断中的意义和指标,促进血管性认知损害诊断水平的提高。
对象和方法
本研究分为两部分,共纳入研究对象51例。
1.对10例SIVCIND患者和10例SIVD患者,运用蒙特利尔认知测评量表(Montreal Cognitive Assessment,MoCA,Beijing Version)和简易精神状态检查量表(mini-mental state examination, MMSE)检测总体认知功能,与10例年龄、性别及教育程度匹配的健康对照者比较,探讨VCI患者认知功能损害特点;采用计算机辅助的Stroop测验,红、绿、蓝色字刺激,字体颜色和字义相冲突并随机呈现,要求受试者判断色字的颜色,分析其错误率、漏报率和反应时间,探讨VCI患者行为学反应特点;采用SIEMENS Magnetom Sonata 1.5 T超导型全身磁共振成像系统和fMRI技术采集脑功能图像数据。FMRI采用单因素单水平组块(block)设计,组块由激活状态(activation state)与控制状态(control state)交替组成。采用快速自旋回波(turbo spin echo, TSE)序列采集横断位20层T1WI结构图像(TE=13 msec, TR=500 msec, field of view=40×40 cm, 256×192 data matrix),EPI(echoplanar imaging)序列采集血氧依赖性功能成像数据(64 x 64 matrix, 220 x 220mm field of view, echo time (TE) 40 ms, volume repetition time (TR)3000 ms, flip angle 90°)。采用MPRAGE序列作失状位薄层扫描采集三维解剖图像。数据的处理和分析采用AFNI(analysis of functional neuroimages)软件。首先进行头动和层面间的校正,以除外受试者轻微头动造成的影响。然后采用半高宽3mm进行三维空间平滑。采用相关分析法,对功能图像的时间进程进行区域内的相关分析,选定刺激任务的时间曲线设定成理想的参考波形(3个方波),将每一像素的时间强度曲线与参考波形进行对照分析,计算每一个体素与理想曲线的相关系数,作为脑组织BOLD信号和目标任务的相关强度,凡相关系数大于或等于设定阈值的像素作为显著活动,得到时间-信号强度动态曲线图和脑功能激活图像。将脑功能激活图像及三维立体解剖图像转入Talairach坐标系,获得标准化后的脑结构和功能图像。统计分析SIVCIND、SIVD患者和正常对照组脑激活功能区的部位、范围和体积的差异,评价SIVCI不同阶段脑功能区变化特点并探索早期诊断的敏感指标。
2.对年龄、性别和教育程度相匹配的11例AD和10例MCI患者进行汉语Stroop任务操作和脑功能成像,实验参数和方法与前完全相同。分析测定AD和MCI行为学测验错误率、漏报率、反应时间,评价老年性认知损害与皮质下血管性认知损害行为学反应的异同;分析AD、MCI脑激活功能区的部位、范围和体积改变情况,评价老年性认知损害不同阶段功能区变化特点;并与血管性认知损害进行比较,探索两种不同认知损害脑功能区变化机制的不同,以及fMRI在两种不同认知损害鉴别诊断中的意义和指标,促进认知损害诊断水平的提高。
结果
1.皮质下缺血性血管性认知损害患者总体认知功能评价SIVD组MOCA各分项评分与年龄、性别和教育程度匹配正常对照组比较发现,执行、注意、延迟回忆、抽象、定向等认知功能水平降低(P<0.05),命名能力等认知功能水平无明显改变(P>0.05)。SIVCIND组与正常对照组比较,执行、注意、语言和延迟回忆等认知功能水平降低(P<0.05),抽象、定向、命名能力等认知功能水平无明显降低(P>0.05)。
2.皮质下缺血性血管性认知损害患者行为学测验
SIVD组与年龄、性别和教育程度匹配正常对照组比较发现,Stroop操作反应时延长(P<0.05),漏报率增加(P<0.05),错误率增高(P<0.05)。SIVCIND组患者与正常对照组比较,反应时延长(P<0.05),漏报率增加(P<0.05),错误率无明显改变(P>0.05)。
3.皮质下缺血性血管性认知损害患者功能区损害情况
SIVCI患者主要激活双侧前扣带回、背外侧前额叶(额上回、额中回),腹内侧前额叶(额下回、岛叶)、后顶叶(顶下小叶)、中央前回、基底节区及枕叶视觉区。SIVCIND组脑激活部位计数与对照组无显著差异(χ2检验或Fisher精确检验,P>0.05);SIVD组在右侧基底节区激活计数少于对照组(χ2检验或Fisher精确检验,P<0.05)。脑功能区激活体积定量分析发现,SIVCIND组双侧背外侧前额叶(dosolateral prefrontal cortex, DLPFC),腹内侧前额叶(ventralateral prefrontal cortex, VLPFC)和右侧后顶叶激活体积显著大于对照组(两独立样本Mann-Whitney U检验,P<0.05),左侧后顶叶与对照组无显著差异(两独立样本Mann-Whitney U检验,P>0.05);SIVD组在双侧DLPFC、VLPFC、后顶叶激活体积显著小于对照组(两独立样本Mann-Whitney U检验,P<0.05)。
4.侧性化及相关性分析
SIVCIND组大脑激活部位计数及功能区激活体积无明显左右侧差异(χ2检验或Fisher精确检验,P>0.05;两独立样本Mann-Whitney U检验,P>0.05);SIVD组脑激活部位计数无明显左右侧差异(χ2检验或Fisher精确检验,P>0.05),左侧后顶叶激活体积显著大于右侧(两独立样本Mann-Whitney U检验,P<0.05),提示SIVD脑功能区存在侧性化。经pearson correlation\Spearman等级相关分析,SIVCI组双侧DLPFC、VLPFC和后顶叶激活体积与MoCA总分、视空间与执行、注意分项得分明显相关(P<0.05)。双侧DLPFC和左侧VLPFC激活体积与语言分项评分明显相关(P<0.05);双侧DLPFC、双侧后顶叶激活体积与延迟回忆分项评分明显相关(P<0.05);右侧DLPFC、左侧VLPFC和右侧后顶叶激活体积与定向分项评分明显相关(P<0.05)。
5.老年性认知损害患者行为学反应
MCI组患者与年龄、性别、教育程度相匹配的对照组比较,反应时延长(P>0.05),漏报率增加(P<0.05);AD组患者与对照组比较,反应时延长(P<0.05),漏报率增加(P<0.05),错误率增高(P<0.05)。SIVCIND和MCI组相比组错误率(P>0.05)、漏报率(P>0.05)、反应时(P>0.05)相比均无显著差异。SIVD和AD相比错误率(P>0.05)、漏报率(P>0.05)、反应时(P>0.05)均无显著差异。
6.老年性认知损害患者脑功能区损害情况
MCI和AD患者主要激活双侧前扣带回、背外侧前额叶(额上回、额中回),腹内侧前额叶(额下回、岛叶),后顶叶(顶下小叶)、中央前回、基底节区及枕叶视觉区。MCI组脑激活部位计数与对照组无显著差异(χ2检验或Fisher精确检验,P>0.05),AD组在右侧基底节区计数少于对照组(χ2检验或Fisher精确检验,P<0.01)。脑功能区激活体积定量分析发现,MCI组在双侧DLPFC、双侧后顶叶激活体积明显大于对照组(两独立样本Mann-Whitney U检验,P<0.05),双侧VLPFC与对照组无显著差异(两独立样本Mann-Whitney U检验,P>0.05);AD组双侧DLPFC、VLPFC激活体积明显小于对照组(两独立样本Mann-Whitney U检验,P<0.01),双侧后顶叶与对照组无显著差异(两独立样本Mann-Whitney U检验,P>0.05)。侧性化分析表明,MCI、AD组双侧脑功能区激活部位计数无显著性差异(χ2检验或Fisher精确检验,P>0.05);MCI组左侧后顶叶激活体积显著大于右侧(两独立样本Mann-Whitney U检验,P<0.05);双侧DLPFC、VLPFC激活体积无显著差异(两独立样本Mann-Whitney U检验,P>0.05);AD组左侧VLPFC激活体积显著大于右侧(两独立样本Mann-Whitney U检验,P<0.05),双侧DLPFC、后顶叶激活体积无显著差异(两独立样本Mann-Whitney U检验,P>0.05)。
7.两种不同认知损害的fMRI比较
在大脑激活定位方面, MCI与SIVCIND组相比无显著差异(χ2检验或Fisher精确检验,P>0.05),AD与SIVD组相比无显著差异(χ2检验或Fisher精确检验,P>0.05);脑功能区激活体积定量分析方面,MCI与SIVCIND组相比无显著差异(两独立样本Mann-Whitney U检验,P>0.05),AD组双侧后顶叶激活体积大于SIVD组,有显著差异(两独立样本Mann-Whitney U检验,P<0.05),双侧DLPFC、VLPFC激活体积与SIVD组无显著性差异(两独立样本Mann-Whitney U检验,P>0.05)。提示fMRI对MCI与SIVCIND的鉴别无明显意义,但对AD与SIVD的鉴别有较大价值,主要鉴别指标为双侧后顶叶的激活体积和范围。
结论
1.总体认知功能评价研究发现皮质下缺血性血管性认知损害早期患者(SIVCIND)以执行、注意、语言、延迟回忆等认知损害较突出,而晚期患者(SIVD)主要表现执行、注意、语言、延迟回忆、抽象和定向等认知水平降低。
2.计算机辅助Stroop操作研究发现,皮质下缺血性血管性认知损害早期患者(SIVCIND)和老年性认知损害早期患者(MCI)以漏报率增高、反应时延长为主要表现,而皮质下缺血性血管性认知损害晚期患者(SIVD)和阿尔茨海默病患者以漏报率增高、反应时延长、错误率增高为表现。但老年性认知损害和血管性认知损害配对患者的错误率、漏报率、反应时均无显著差异,提示它们不是鉴别两种不同认知损害的指标。
3.注意和执行功能的脑功能区主要包括双侧前扣带回、DLPFC、VLPFC、后顶叶和基底节区。皮质下缺血性血管性认知损害早期(SIVCIND)脑功能区改变主要以双侧DLPFC、VLPFC代偿增加为主;晚期(SIVD)主要以右侧基底节区、双侧DLPFC、VLPFC、后顶叶全方位功能损害为主。SIVCI不同阶段具有不同的fMRI表现,fMRI对SIVCI的早期诊断具有较大的意义。
4. SIVCIND大脑注意和执行功能区不存在侧性化;SIVD存在侧性化,右侧损害比左侧更加严重。SIVCI患者双侧DLPFC、VLPFC和后顶叶功能区激活体积与MoCA总分、视空间与执行、注意分项得分显著相关。提示Stroop任务操作中脑功能区的激活体积可较好的反映SIVCI患者的认知功能,功能磁共振是一种评价和反映SIVCI认知功能的良好的方法。
5.老年性认知损害早期(MCI)脑功能区改变主要以双侧DLPFC、后顶叶代偿为主;晚期(AD)以右侧基底节区、双侧DLPFC、VLPFC功能损害为主。MCI和AD大脑均存在侧性化,MCI左侧半球代偿明显,AD右侧半球损害明显。
6.MCI和SIVCIND脑功能区fMRI表现无显著差异, fMRI不能对两者进行鉴别。AD和SIVD具有不同的脑功能损害特征及fMRI表现,fMRI可以对其进行鉴别诊断,后顶叶的激活体积是两者的鉴别指标。
Purpose
In this study, used Bold-fMRI(blood oxygen level dependency - function magnetic resonance imaging) technology we observed and analyzed the cortex activation evoked by Stroop task in patients with SIVCI(subcortical ischemic vascular cognitive impairments), in order to inspect the influence on attention nerve circuit loop by ischemic impairment from small subcortical vessel lesion to enhance the understanding for the pathomechanism of subcortical ischemic vascular impairment and to find new indexes to reflect attention impairment in earlier period of vascular cognitive impairment. We studied the relationship and differences between brain activations of vascular, senile cognitive impairment patients and normal controls, in order to investigate the different pathomechanism between vascular and senile cognitive impairments and to appreciate the value of fMRI in the differential diagnosis of different cognitive impairments for improving their diagnostic quality.
Methods
The study was divided into two parts:
1. The subjects included 10 patients with SIVCIND (subcortical ischemic vascular cognitive impairment no dementia), 10 patients with SIVD (subcortical ischemic vascular dementia) and 10 age, sex, and education-matched normal controls. The general cognitive functions of the subjects were assessed by Montreal cognitive assessment (MoCA) Beijing Version and mini-mental state examination (MMSE). Subjects performed the incongruent Stroop color-word task. In the test subjects were presented with a list of words“red”,“green”, and“blue”, however, the ink color of the words was discordant with the presented word. The control task was a solid white cross centered on the black background. The response time, incorrect response rate and no response rate were analyzed. All the patients and healthy volunteers underwent fMRI used the mode of stimulus-rest-stimulus when performing Stroop test. All images were taken with a Siemens Sonuta 1.5 Tesla MR scanner. Twenty T1-weighted axial slices (TE=13 msec, TR=500 msec, field of view=40×40 cm, 256×192 data matrix) were obtained parallel to the anterior–post commissure, which was identified with the aid of a sagittal localizer anatomical image. The functional image data were acquired with an echo-planar imaging sequence(64 x 64 matrix, 22 x 22cm field of view, echo time (TE) 40 ms, volume repetition time (TR)3000 ms, flip angle 90°). High-resolution structural imaging of the whole brain was performed with 3D gradient-echo, T1-weighted sequence, with the following parameters: 256x 256 matrix, inversion time (TI) 50.5 s, TE 56.3 ms, TR 511.7ms, flip angle 11°. Image processing and analyses were performed online with“T-test”and offline with Analysis of Functional Neuro Images (AFNI) software. The fMRI data were slice time-corrected. Echo planar images were coregistered to the image that minimized image translation and rotation relative to all other images. Corrected images were spatially filtered by using a Gaussian filter with a full width half maximum of 3 mm. The block design time-series was convolved to account for the ideal hemodynamic response function. For each voxel, a correlation coefficient was calculated, indicating the strength of relationship between the subjects’BOLD signal and the target reference function. The time-signal intensity curves and the functional images were obtained. After the functional and anatomical images for each participant were transformed into the Talairach and Tournoux coordinate system, the activation locations and areas of the SIVCIND, SIVD patients and normal control subjects were measured and analyzed.
2. The subjects included 10 patients with mild cognitive impairment and 11 patients with Alzheimer's disease, who were age, sex, and education-matched with the subcortical ischemic vascular cognitive impairment no dementia and subcortical ischemic vascular dementia. The Stroop task performance and fMRI examination were the same as part 1. The response time, incorrect response rate and no response rate were analyzed. The activation areas and locations evoked by Stroop task were measured and analyzed. The relationship and differences between SIVCI, MCI and AD were analyzed.
Results
1. Subcortical ischemic vascular dementia patients had obvious cognitive disorder in visualspatial and executive function, attention, delayed memory, abstract, verbalization and orientation (P<0.05), and no cognitive disorder in naming compared with normal controls (P>0.05). Subcortical ischemic vascular cognitive impairment no dementia patients had obvious cognitive disorder in visualspatial and executive function, verbalization, attention and delayed memory (P<0.05), and no cognitive disorder in abstract, orientation and naming compared with normal controls (P>0.05).
2. On Stroop color-word task SIVD patients showed higher incorrect response rate (P<0.05), higher omission rate (P<0.05) and longer reaction time (P<0.05) than those of normal control subjects. SIVCIND patients showed higher omission rate (P<0.05) and longer reaction time (P<0.05) than those of normal control subjects.
3. For SIVCI groups bilateral anterior cingulate, DLPFC(dosolateral prefrontal cortex), VLPFC(ventralateral prefrontal cortex), inferior parietal lobe, occipital lobe and basal ganglia were activated. There was no difference of activation locations between SIVCIND and normal control subjects (P>0.05). The right basal ganglias for SIVD were less activated than those of normal controls (P<0.05). Compared to controls, SIVCIND patients showed distinctly increased prefrontal cortex activation, including bilateral DLPFC, VLPFC and right inferior parietal lobe (P<0.05), no difference in left inferior parietal lobe (P>0.05). SIVD patients exhibited decreased fMRI responses in bilateral DLPFC, VLPFC and inferior parietal lobe (P<0.05).
4. There was no cortex activation difference between two hemispheres of normal control and SIVCIND subjects (P>0.05). However, for SIVD patients the activation areas of right inferior parietal lobe was less than that of the left (P<0.05). Pearson correlation\Spearman rank correlation analysis revealed that for SIVCI patients there were significant correlations between cortex activation areas of bilateral DLPFC, VLPFC, inferior parietal lobe and MoCA scores of total, attention, and visualspatial(P<0.05). There were significant correlations between cortex activation areas of bilateral DLPFC, left VLPFC and MoCA scores of language (P<0.05). There were significant correlations between cortex activation areas of bilateral DLPFC, inferior parietal lobe and MoCA scores of delay memory (P<0.05). There were significant correlations between cortex activation areas of right DLPFC, left VLPFC, right inferior parietal lobe and MoCA scores of orientation (P<0.05).
5. On Stroop color-word task AD patients showed higher incorrect response rate (P<0.05), higher omission response rate (P<0.05) and longer reaction time (P<0.05) than those of normal control subjects. The MCI patients showed higher omission rate (P<0.05) and longer reaction time (P<0.05) than those of normal control subjects. However, there was no difference of incorrect response rate, omission rate and reaction time between MCI and SIVCIND, AD and SIVD patients (P>0.05).
6. For AD and MCI groups bilateral anterior cingulate, DLPFC, VLPFC, inferior parietal lobe, occipital lobe and basal ganglia were activated. There was no difference of activation locations between MCI and normal control subjects (P>0.05). The right basal ganglias for AD were less activated than those of normal controls (P<0.01). Compared to controls, MCI patients showed distinctly increased cortex activation, including bilateral DLPFC and inferior parietal lobe (P<0.05), no difference in bilateral VLPFC (P>0.05). AD patients exhibited decreased fMRI responses in the regions of bilateral DLPFC and VLPFC (P<0.01), no difference in bilateral inferior parietal lobe (P>0.05). The activation areas of the two hemispheres for MCI and AD patients were not symmetrical. For MCI patients the activation areas of right inferior parietal lobe was less than that of the left (P<0.05). And for AD patients the activation areas of right VLPFC were less than that of the left (P<0.05).
7. There was no difference of cortex activation locations evoked by Stroop task between MCI and SIVCIND, AD and SIVD patients (P>0.05). There was no difference of activation areas between MCI and SIVCIND patients (P>0.05). However, the activation areas of bilateral inferior parietal lobe for SIVD patients were less than that of the AD patients (P<0.05). So fMRI can not discriminate MCI and SIVCIND but can discriminate AD and SIVD by the activation areas of bilateral inferior parietal lobe.
Conclusion
1. SIVCI patients have obvious disorders in general assessment of cognitive function. Executive function, verbalization, attention and delayed memory are predominant in cognitive impairment of SIVCIND patients. SIVD patients have obvious cognitive impairment in executive function, attention, verbalization, delayed memory, abstract and orientation, but no cognitive disorder in naming.
2. The results of computer-assisted Stroop test reveal that SIVCIND and MCI patients show higher omission rate and longer reaction time than those of normal control subjects. AD and SIVD patients show higher omission rate, incorrect response rate and longer reaction time than those of normal control subjects. However, the omission rate, incorrect response rate and reaction time can not discriminate SIVCIND and MCI, SIVD and AD.
3. Our results suggest that for Stroop task the cortex activation areas include bilateral anterior cingulate, DLPFC, VLPFC, inferior parietal lobe, occipital lobe and basal ganglia. There is a bilateral DLPFC, VLPFC compensation in SIVCIND, and right basal ganglia, bilateral DLPFC, VLPFC and inferior parietal lobe dysfunction in SIVD, which suggests different neurophysiological characteristics between SIVCIND and SIVD. SIVCIND and SIVD have different fMRI characteristics and fMRI is a usefull tool in the examination and appreciation of the earlier period of vascular cognitive impairment.
4. There was no cortex activation difference between two hemispheres of normal control and SIVCIND subjects. For SIVD patients the damage is not symmetrical and the left is the dominant hemisphere. There are significant correlations between cortex activation areas of bilateral DLPFC, VLPFC, inferior parietal lobe and MoCA scores of total, attention and visualspatial for SIVCI patients. The cortex activation of SIVCI during Stroop task performance in fMRI can reflect the cogniton of them well.
5. There is a right basal ganglia, bilateral DLPFC and VLPFC cortex dysfunction in AD, and bilateral DLPFC and inferior parietal lobe compensation in MCI, which suggests different neurophysiological characteristics between AD and MCI. For MCI and AD the damage and compensation of the two hemispheres is not symmetrical and the left is the dominant hemisphere.
6. There is no difference of cortex activation between MCI and SIVCIND patients. FMRI can not discriminate them. However, fMRI can discriminate AD and SIVD by the activation areas of bilateral inferior parietal lobe. The fMRI examination may have some potential value in the discrimination and assessment of different type of dementia.
应用基于Stroop任务的功能磁共振(blood oxygen level dependency-functional magnetic resonance imaging, Bold-fMRI)技术探讨血管性认知损害(vascular cognitive impairment, VCI)和老年性认知损害患者注意相关脑区功能变化特点,主要目的包括:
1.探讨皮质下缺血性血管性认知损害(subcortical ischemic vascular cognitive impairment, SIVCI)患者注意相关脑区功能变化特点,评价皮质下小血管病变对注意认知环路的影响,促进对血管性认知损害病理机制的认识;
2.定量分析皮质下缺血性血管性认知损害非痴呆(subcortical ischemic vascular cognitive impairment no dementia,SIVCIND)和皮质下缺血性血管性痴呆(subcortical ischemic vascular dementia,SIVD)患者脑功能图谱特点,探索fMRI在SIVCI诊断中的价值,期望为早期诊断提出客观评价指标;
3.分析阿尔茨海默病(Alzheimer disease, AD)、轻度认知功能损害(mild cognitive impairment, MCI)患者脑功能图谱特点,评价老年性认知损害不同阶段功能区变化特点;并与皮质下缺血性血管性认知损害进行比较,探索两种不同认知损害脑功能区变化机制的不同,以及fMRI在两种不同认知损害鉴别诊断中的意义和指标,促进血管性认知损害诊断水平的提高。
对象和方法
本研究分为两部分,共纳入研究对象51例。
1.对10例SIVCIND患者和10例SIVD患者,运用蒙特利尔认知测评量表(Montreal Cognitive Assessment,MoCA,Beijing Version)和简易精神状态检查量表(mini-mental state examination, MMSE)检测总体认知功能,与10例年龄、性别及教育程度匹配的健康对照者比较,探讨VCI患者认知功能损害特点;采用计算机辅助的Stroop测验,红、绿、蓝色字刺激,字体颜色和字义相冲突并随机呈现,要求受试者判断色字的颜色,分析其错误率、漏报率和反应时间,探讨VCI患者行为学反应特点;采用SIEMENS Magnetom Sonata 1.5 T超导型全身磁共振成像系统和fMRI技术采集脑功能图像数据。FMRI采用单因素单水平组块(block)设计,组块由激活状态(activation state)与控制状态(control state)交替组成。采用快速自旋回波(turbo spin echo, TSE)序列采集横断位20层T1WI结构图像(TE=13 msec, TR=500 msec, field of view=40×40 cm, 256×192 data matrix),EPI(echoplanar imaging)序列采集血氧依赖性功能成像数据(64 x 64 matrix, 220 x 220mm field of view, echo time (TE) 40 ms, volume repetition time (TR)3000 ms, flip angle 90°)。采用MPRAGE序列作失状位薄层扫描采集三维解剖图像。数据的处理和分析采用AFNI(analysis of functional neuroimages)软件。首先进行头动和层面间的校正,以除外受试者轻微头动造成的影响。然后采用半高宽3mm进行三维空间平滑。采用相关分析法,对功能图像的时间进程进行区域内的相关分析,选定刺激任务的时间曲线设定成理想的参考波形(3个方波),将每一像素的时间强度曲线与参考波形进行对照分析,计算每一个体素与理想曲线的相关系数,作为脑组织BOLD信号和目标任务的相关强度,凡相关系数大于或等于设定阈值的像素作为显著活动,得到时间-信号强度动态曲线图和脑功能激活图像。将脑功能激活图像及三维立体解剖图像转入Talairach坐标系,获得标准化后的脑结构和功能图像。统计分析SIVCIND、SIVD患者和正常对照组脑激活功能区的部位、范围和体积的差异,评价SIVCI不同阶段脑功能区变化特点并探索早期诊断的敏感指标。
2.对年龄、性别和教育程度相匹配的11例AD和10例MCI患者进行汉语Stroop任务操作和脑功能成像,实验参数和方法与前完全相同。分析测定AD和MCI行为学测验错误率、漏报率、反应时间,评价老年性认知损害与皮质下血管性认知损害行为学反应的异同;分析AD、MCI脑激活功能区的部位、范围和体积改变情况,评价老年性认知损害不同阶段功能区变化特点;并与血管性认知损害进行比较,探索两种不同认知损害脑功能区变化机制的不同,以及fMRI在两种不同认知损害鉴别诊断中的意义和指标,促进认知损害诊断水平的提高。
结果
1.皮质下缺血性血管性认知损害患者总体认知功能评价SIVD组MOCA各分项评分与年龄、性别和教育程度匹配正常对照组比较发现,执行、注意、延迟回忆、抽象、定向等认知功能水平降低(P<0.05),命名能力等认知功能水平无明显改变(P>0.05)。SIVCIND组与正常对照组比较,执行、注意、语言和延迟回忆等认知功能水平降低(P<0.05),抽象、定向、命名能力等认知功能水平无明显降低(P>0.05)。
2.皮质下缺血性血管性认知损害患者行为学测验
SIVD组与年龄、性别和教育程度匹配正常对照组比较发现,Stroop操作反应时延长(P<0.05),漏报率增加(P<0.05),错误率增高(P<0.05)。SIVCIND组患者与正常对照组比较,反应时延长(P<0.05),漏报率增加(P<0.05),错误率无明显改变(P>0.05)。
3.皮质下缺血性血管性认知损害患者功能区损害情况
SIVCI患者主要激活双侧前扣带回、背外侧前额叶(额上回、额中回),腹内侧前额叶(额下回、岛叶)、后顶叶(顶下小叶)、中央前回、基底节区及枕叶视觉区。SIVCIND组脑激活部位计数与对照组无显著差异(χ2检验或Fisher精确检验,P>0.05);SIVD组在右侧基底节区激活计数少于对照组(χ2检验或Fisher精确检验,P<0.05)。脑功能区激活体积定量分析发现,SIVCIND组双侧背外侧前额叶(dosolateral prefrontal cortex, DLPFC),腹内侧前额叶(ventralateral prefrontal cortex, VLPFC)和右侧后顶叶激活体积显著大于对照组(两独立样本Mann-Whitney U检验,P<0.05),左侧后顶叶与对照组无显著差异(两独立样本Mann-Whitney U检验,P>0.05);SIVD组在双侧DLPFC、VLPFC、后顶叶激活体积显著小于对照组(两独立样本Mann-Whitney U检验,P<0.05)。
4.侧性化及相关性分析
SIVCIND组大脑激活部位计数及功能区激活体积无明显左右侧差异(χ2检验或Fisher精确检验,P>0.05;两独立样本Mann-Whitney U检验,P>0.05);SIVD组脑激活部位计数无明显左右侧差异(χ2检验或Fisher精确检验,P>0.05),左侧后顶叶激活体积显著大于右侧(两独立样本Mann-Whitney U检验,P<0.05),提示SIVD脑功能区存在侧性化。经pearson correlation\Spearman等级相关分析,SIVCI组双侧DLPFC、VLPFC和后顶叶激活体积与MoCA总分、视空间与执行、注意分项得分明显相关(P<0.05)。双侧DLPFC和左侧VLPFC激活体积与语言分项评分明显相关(P<0.05);双侧DLPFC、双侧后顶叶激活体积与延迟回忆分项评分明显相关(P<0.05);右侧DLPFC、左侧VLPFC和右侧后顶叶激活体积与定向分项评分明显相关(P<0.05)。
5.老年性认知损害患者行为学反应
MCI组患者与年龄、性别、教育程度相匹配的对照组比较,反应时延长(P>0.05),漏报率增加(P<0.05);AD组患者与对照组比较,反应时延长(P<0.05),漏报率增加(P<0.05),错误率增高(P<0.05)。SIVCIND和MCI组相比组错误率(P>0.05)、漏报率(P>0.05)、反应时(P>0.05)相比均无显著差异。SIVD和AD相比错误率(P>0.05)、漏报率(P>0.05)、反应时(P>0.05)均无显著差异。
6.老年性认知损害患者脑功能区损害情况
MCI和AD患者主要激活双侧前扣带回、背外侧前额叶(额上回、额中回),腹内侧前额叶(额下回、岛叶),后顶叶(顶下小叶)、中央前回、基底节区及枕叶视觉区。MCI组脑激活部位计数与对照组无显著差异(χ2检验或Fisher精确检验,P>0.05),AD组在右侧基底节区计数少于对照组(χ2检验或Fisher精确检验,P<0.01)。脑功能区激活体积定量分析发现,MCI组在双侧DLPFC、双侧后顶叶激活体积明显大于对照组(两独立样本Mann-Whitney U检验,P<0.05),双侧VLPFC与对照组无显著差异(两独立样本Mann-Whitney U检验,P>0.05);AD组双侧DLPFC、VLPFC激活体积明显小于对照组(两独立样本Mann-Whitney U检验,P<0.01),双侧后顶叶与对照组无显著差异(两独立样本Mann-Whitney U检验,P>0.05)。侧性化分析表明,MCI、AD组双侧脑功能区激活部位计数无显著性差异(χ2检验或Fisher精确检验,P>0.05);MCI组左侧后顶叶激活体积显著大于右侧(两独立样本Mann-Whitney U检验,P<0.05);双侧DLPFC、VLPFC激活体积无显著差异(两独立样本Mann-Whitney U检验,P>0.05);AD组左侧VLPFC激活体积显著大于右侧(两独立样本Mann-Whitney U检验,P<0.05),双侧DLPFC、后顶叶激活体积无显著差异(两独立样本Mann-Whitney U检验,P>0.05)。
7.两种不同认知损害的fMRI比较
在大脑激活定位方面, MCI与SIVCIND组相比无显著差异(χ2检验或Fisher精确检验,P>0.05),AD与SIVD组相比无显著差异(χ2检验或Fisher精确检验,P>0.05);脑功能区激活体积定量分析方面,MCI与SIVCIND组相比无显著差异(两独立样本Mann-Whitney U检验,P>0.05),AD组双侧后顶叶激活体积大于SIVD组,有显著差异(两独立样本Mann-Whitney U检验,P<0.05),双侧DLPFC、VLPFC激活体积与SIVD组无显著性差异(两独立样本Mann-Whitney U检验,P>0.05)。提示fMRI对MCI与SIVCIND的鉴别无明显意义,但对AD与SIVD的鉴别有较大价值,主要鉴别指标为双侧后顶叶的激活体积和范围。
结论
1.总体认知功能评价研究发现皮质下缺血性血管性认知损害早期患者(SIVCIND)以执行、注意、语言、延迟回忆等认知损害较突出,而晚期患者(SIVD)主要表现执行、注意、语言、延迟回忆、抽象和定向等认知水平降低。
2.计算机辅助Stroop操作研究发现,皮质下缺血性血管性认知损害早期患者(SIVCIND)和老年性认知损害早期患者(MCI)以漏报率增高、反应时延长为主要表现,而皮质下缺血性血管性认知损害晚期患者(SIVD)和阿尔茨海默病患者以漏报率增高、反应时延长、错误率增高为表现。但老年性认知损害和血管性认知损害配对患者的错误率、漏报率、反应时均无显著差异,提示它们不是鉴别两种不同认知损害的指标。
3.注意和执行功能的脑功能区主要包括双侧前扣带回、DLPFC、VLPFC、后顶叶和基底节区。皮质下缺血性血管性认知损害早期(SIVCIND)脑功能区改变主要以双侧DLPFC、VLPFC代偿增加为主;晚期(SIVD)主要以右侧基底节区、双侧DLPFC、VLPFC、后顶叶全方位功能损害为主。SIVCI不同阶段具有不同的fMRI表现,fMRI对SIVCI的早期诊断具有较大的意义。
4. SIVCIND大脑注意和执行功能区不存在侧性化;SIVD存在侧性化,右侧损害比左侧更加严重。SIVCI患者双侧DLPFC、VLPFC和后顶叶功能区激活体积与MoCA总分、视空间与执行、注意分项得分显著相关。提示Stroop任务操作中脑功能区的激活体积可较好的反映SIVCI患者的认知功能,功能磁共振是一种评价和反映SIVCI认知功能的良好的方法。
5.老年性认知损害早期(MCI)脑功能区改变主要以双侧DLPFC、后顶叶代偿为主;晚期(AD)以右侧基底节区、双侧DLPFC、VLPFC功能损害为主。MCI和AD大脑均存在侧性化,MCI左侧半球代偿明显,AD右侧半球损害明显。
6.MCI和SIVCIND脑功能区fMRI表现无显著差异, fMRI不能对两者进行鉴别。AD和SIVD具有不同的脑功能损害特征及fMRI表现,fMRI可以对其进行鉴别诊断,后顶叶的激活体积是两者的鉴别指标。
Purpose
In this study, used Bold-fMRI(blood oxygen level dependency - function magnetic resonance imaging) technology we observed and analyzed the cortex activation evoked by Stroop task in patients with SIVCI(subcortical ischemic vascular cognitive impairments), in order to inspect the influence on attention nerve circuit loop by ischemic impairment from small subcortical vessel lesion to enhance the understanding for the pathomechanism of subcortical ischemic vascular impairment and to find new indexes to reflect attention impairment in earlier period of vascular cognitive impairment. We studied the relationship and differences between brain activations of vascular, senile cognitive impairment patients and normal controls, in order to investigate the different pathomechanism between vascular and senile cognitive impairments and to appreciate the value of fMRI in the differential diagnosis of different cognitive impairments for improving their diagnostic quality.
Methods
The study was divided into two parts:
1. The subjects included 10 patients with SIVCIND (subcortical ischemic vascular cognitive impairment no dementia), 10 patients with SIVD (subcortical ischemic vascular dementia) and 10 age, sex, and education-matched normal controls. The general cognitive functions of the subjects were assessed by Montreal cognitive assessment (MoCA) Beijing Version and mini-mental state examination (MMSE). Subjects performed the incongruent Stroop color-word task. In the test subjects were presented with a list of words“red”,“green”, and“blue”, however, the ink color of the words was discordant with the presented word. The control task was a solid white cross centered on the black background. The response time, incorrect response rate and no response rate were analyzed. All the patients and healthy volunteers underwent fMRI used the mode of stimulus-rest-stimulus when performing Stroop test. All images were taken with a Siemens Sonuta 1.5 Tesla MR scanner. Twenty T1-weighted axial slices (TE=13 msec, TR=500 msec, field of view=40×40 cm, 256×192 data matrix) were obtained parallel to the anterior–post commissure, which was identified with the aid of a sagittal localizer anatomical image. The functional image data were acquired with an echo-planar imaging sequence(64 x 64 matrix, 22 x 22cm field of view, echo time (TE) 40 ms, volume repetition time (TR)3000 ms, flip angle 90°). High-resolution structural imaging of the whole brain was performed with 3D gradient-echo, T1-weighted sequence, with the following parameters: 256x 256 matrix, inversion time (TI) 50.5 s, TE 56.3 ms, TR 511.7ms, flip angle 11°. Image processing and analyses were performed online with“T-test”and offline with Analysis of Functional Neuro Images (AFNI) software. The fMRI data were slice time-corrected. Echo planar images were coregistered to the image that minimized image translation and rotation relative to all other images. Corrected images were spatially filtered by using a Gaussian filter with a full width half maximum of 3 mm. The block design time-series was convolved to account for the ideal hemodynamic response function. For each voxel, a correlation coefficient was calculated, indicating the strength of relationship between the subjects’BOLD signal and the target reference function. The time-signal intensity curves and the functional images were obtained. After the functional and anatomical images for each participant were transformed into the Talairach and Tournoux coordinate system, the activation locations and areas of the SIVCIND, SIVD patients and normal control subjects were measured and analyzed.
2. The subjects included 10 patients with mild cognitive impairment and 11 patients with Alzheimer's disease, who were age, sex, and education-matched with the subcortical ischemic vascular cognitive impairment no dementia and subcortical ischemic vascular dementia. The Stroop task performance and fMRI examination were the same as part 1. The response time, incorrect response rate and no response rate were analyzed. The activation areas and locations evoked by Stroop task were measured and analyzed. The relationship and differences between SIVCI, MCI and AD were analyzed.
Results
1. Subcortical ischemic vascular dementia patients had obvious cognitive disorder in visualspatial and executive function, attention, delayed memory, abstract, verbalization and orientation (P<0.05), and no cognitive disorder in naming compared with normal controls (P>0.05). Subcortical ischemic vascular cognitive impairment no dementia patients had obvious cognitive disorder in visualspatial and executive function, verbalization, attention and delayed memory (P<0.05), and no cognitive disorder in abstract, orientation and naming compared with normal controls (P>0.05).
2. On Stroop color-word task SIVD patients showed higher incorrect response rate (P<0.05), higher omission rate (P<0.05) and longer reaction time (P<0.05) than those of normal control subjects. SIVCIND patients showed higher omission rate (P<0.05) and longer reaction time (P<0.05) than those of normal control subjects.
3. For SIVCI groups bilateral anterior cingulate, DLPFC(dosolateral prefrontal cortex), VLPFC(ventralateral prefrontal cortex), inferior parietal lobe, occipital lobe and basal ganglia were activated. There was no difference of activation locations between SIVCIND and normal control subjects (P>0.05). The right basal ganglias for SIVD were less activated than those of normal controls (P<0.05). Compared to controls, SIVCIND patients showed distinctly increased prefrontal cortex activation, including bilateral DLPFC, VLPFC and right inferior parietal lobe (P<0.05), no difference in left inferior parietal lobe (P>0.05). SIVD patients exhibited decreased fMRI responses in bilateral DLPFC, VLPFC and inferior parietal lobe (P<0.05).
4. There was no cortex activation difference between two hemispheres of normal control and SIVCIND subjects (P>0.05). However, for SIVD patients the activation areas of right inferior parietal lobe was less than that of the left (P<0.05). Pearson correlation\Spearman rank correlation analysis revealed that for SIVCI patients there were significant correlations between cortex activation areas of bilateral DLPFC, VLPFC, inferior parietal lobe and MoCA scores of total, attention, and visualspatial(P<0.05). There were significant correlations between cortex activation areas of bilateral DLPFC, left VLPFC and MoCA scores of language (P<0.05). There were significant correlations between cortex activation areas of bilateral DLPFC, inferior parietal lobe and MoCA scores of delay memory (P<0.05). There were significant correlations between cortex activation areas of right DLPFC, left VLPFC, right inferior parietal lobe and MoCA scores of orientation (P<0.05).
5. On Stroop color-word task AD patients showed higher incorrect response rate (P<0.05), higher omission response rate (P<0.05) and longer reaction time (P<0.05) than those of normal control subjects. The MCI patients showed higher omission rate (P<0.05) and longer reaction time (P<0.05) than those of normal control subjects. However, there was no difference of incorrect response rate, omission rate and reaction time between MCI and SIVCIND, AD and SIVD patients (P>0.05).
6. For AD and MCI groups bilateral anterior cingulate, DLPFC, VLPFC, inferior parietal lobe, occipital lobe and basal ganglia were activated. There was no difference of activation locations between MCI and normal control subjects (P>0.05). The right basal ganglias for AD were less activated than those of normal controls (P<0.01). Compared to controls, MCI patients showed distinctly increased cortex activation, including bilateral DLPFC and inferior parietal lobe (P<0.05), no difference in bilateral VLPFC (P>0.05). AD patients exhibited decreased fMRI responses in the regions of bilateral DLPFC and VLPFC (P<0.01), no difference in bilateral inferior parietal lobe (P>0.05). The activation areas of the two hemispheres for MCI and AD patients were not symmetrical. For MCI patients the activation areas of right inferior parietal lobe was less than that of the left (P<0.05). And for AD patients the activation areas of right VLPFC were less than that of the left (P<0.05).
7. There was no difference of cortex activation locations evoked by Stroop task between MCI and SIVCIND, AD and SIVD patients (P>0.05). There was no difference of activation areas between MCI and SIVCIND patients (P>0.05). However, the activation areas of bilateral inferior parietal lobe for SIVD patients were less than that of the AD patients (P<0.05). So fMRI can not discriminate MCI and SIVCIND but can discriminate AD and SIVD by the activation areas of bilateral inferior parietal lobe.
Conclusion
1. SIVCI patients have obvious disorders in general assessment of cognitive function. Executive function, verbalization, attention and delayed memory are predominant in cognitive impairment of SIVCIND patients. SIVD patients have obvious cognitive impairment in executive function, attention, verbalization, delayed memory, abstract and orientation, but no cognitive disorder in naming.
2. The results of computer-assisted Stroop test reveal that SIVCIND and MCI patients show higher omission rate and longer reaction time than those of normal control subjects. AD and SIVD patients show higher omission rate, incorrect response rate and longer reaction time than those of normal control subjects. However, the omission rate, incorrect response rate and reaction time can not discriminate SIVCIND and MCI, SIVD and AD.
3. Our results suggest that for Stroop task the cortex activation areas include bilateral anterior cingulate, DLPFC, VLPFC, inferior parietal lobe, occipital lobe and basal ganglia. There is a bilateral DLPFC, VLPFC compensation in SIVCIND, and right basal ganglia, bilateral DLPFC, VLPFC and inferior parietal lobe dysfunction in SIVD, which suggests different neurophysiological characteristics between SIVCIND and SIVD. SIVCIND and SIVD have different fMRI characteristics and fMRI is a usefull tool in the examination and appreciation of the earlier period of vascular cognitive impairment.
4. There was no cortex activation difference between two hemispheres of normal control and SIVCIND subjects. For SIVD patients the damage is not symmetrical and the left is the dominant hemisphere. There are significant correlations between cortex activation areas of bilateral DLPFC, VLPFC, inferior parietal lobe and MoCA scores of total, attention and visualspatial for SIVCI patients. The cortex activation of SIVCI during Stroop task performance in fMRI can reflect the cogniton of them well.
5. There is a right basal ganglia, bilateral DLPFC and VLPFC cortex dysfunction in AD, and bilateral DLPFC and inferior parietal lobe compensation in MCI, which suggests different neurophysiological characteristics between AD and MCI. For MCI and AD the damage and compensation of the two hemispheres is not symmetrical and the left is the dominant hemisphere.
6. There is no difference of cortex activation between MCI and SIVCIND patients. FMRI can not discriminate them. However, fMRI can discriminate AD and SIVD by the activation areas of bilateral inferior parietal lobe. The fMRI examination may have some potential value in the discrimination and assessment of different type of dementia.
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