Alzheimer病和MCI病人扣带束DTI及相关脑区静息态fMRI研究
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摘要
目的：研究AD(Alzheimer's disease, AD)、MCI(mild cognitive impairment,MCI)病人Papez环路中海马-扣带束-扣带回通路的DTI与静息态功能连接异常改变,并分析其与临床认知功能之间的关系,为早期诊断MCI、AD提供参考指标；探讨DTI多参数组合在脑白质微观结构研究中的价值及功能连接水平与其连接通路微观结构改变的内在联系,为DTI参数选择及联合DTI和fMRI研究相关疾病提供参考。
方法：采用3.0T磁共振扫描仪对15例AD、11例MCI病人及15例NC(normal cognition,NC)进行横断位T1WI、T2WI、FLAIR、T1-MPRAGE、DTI和BOLD-EPI序列扫描。在syngo B17后处理工作站上结合DTI张量图和高分辨率解剖像同步测量双侧扣带束海马旁回部(PH-C)、后部(PC-C)和前部(AC-C)的FA、DA和DR值,对双侧同部位各项参数值在组内进行独立样本t检验和组间LSD和Dunnett's T3法检验。应用Matlab 7.1、SPM5、DPARSF_V2.0和rest_V1.4软件包进行数据预处理(层间时间点校正、头动校正、空间标准化、平滑)、线性校正及带通滤波(带宽：0.01～0.08HZ)得到全脑低频信号图；提取后扣带回种子点平均时间序列(0,-53,26,r=4mm)并去除协变量(全脑平均信号、脑白质、脑积液、6个头动参数),与全脑其余体素进行Pearson相关分析得到全脑功能连接图,经Fisher Z转换为Z图；将各组Z图进行组内单样本t检验和组间独立样本t检验,得到各组大脑静息态默认网络图及组间功能连接差异图；在AAL模板中提取双侧海马mask,导入组间功能连接差异图,经过AlphaSim校正后得到双侧海马与后扣带回功能连接差异图；提取双侧海马功能连接差异部位平均时间序列,与MMSE评分进行相关分析,与相关部位扣带束DTI各参数值进行线性回归分析。
结果：1.组内比较：各组双侧同部位DTI各项参数值差异均无统计学意义；NC组默认网络主要包括双侧腹内侧前额叶皮层、前扣带回、视觉皮层、海马、中下颞叶皮层、下顶叶、后扣带回及楔前叶,MCI、AD组主要默认网络脑区与NC组相似；2.组间比较：(1)MCI组与NC组：双侧PH-C部DA值减低,右侧PH-C部DR值减低,左侧PH C部FA减低；右侧海马前部与后扣带回功能连接减弱；(2)AD组与NC组：双侧PH-C部、双侧PC_C部DA值减小、DR值增加及FA值减低；双侧海马前部活动减弱,双侧海马尾部活动增强；(3)AD组与MCI组：双侧PH_C部、双侧PC_C部DA值减小、DR值增加及FA值减低；3.相关性分析：双侧扣带束PH-C部和PC_C部DA值与MMSE评分呈显著正相关(0.609/0.512；0.599/0.521)；双侧扣带束PH_C部DR值与MMSE评分呈显著负相关(-0.453/-0.428)；左侧扣带束PH-C部和双侧PC_C部FA值与MMSE呈显著正相关(0.627,0.64I/0.533)(p<0.01)；双侧海马与后扣带回功能连接分数与MMSE评分呈显著相关(r=0.513,0.522)(p<0.01)；5.线性回归分析：右侧扣带束PH-C部DA值、PC_C部DR值对右侧海马与后扣带回功能连接贡献有统计学意义,其回归方程为R_FC=0.047+0.556*R_PH_C_DA-1.160*R_PC_C_DR (R=0.671, R2=0.450);左侧扣带束PH_C部DA值与DR值对左侧海马与后扣带回功能连接贡献有统计学意义,其归回方程L_FC=0.379+1.098*L_PH_C_DA-1.105*L_PH_C_DR (R=0.562, R2=0.315)。
结论：1. Papez环路中海马-扣带束-扣带回通路在MCI向AD进展发病机制中的DTI和fMRI研究中具有重要意义,为临床早期诊断MCI、AD提供参考指标；2.扣带束不是唯一连接海马与后扣带回的纤维束,还存在其它纤维束直接或间接连接海马与后扣带回；3. DA、DR参数组合较FA参数更好的反映脑白质微观结构改变；4.静息态默认网络节点间功能连接强度与DTI反映的其连接通路微观结构损害密切相关；5.DA、海马与后扣带回功能连接分数能为临床评估病人认知功能提供参考。
Purpose:To reseach the diffusion and functional connectivity abnormality of hippocampus-cingulum-cingulate cortex pathway in Papez circuit in MCI and AD patients, and study its relationship with clinical cognitive function for the early diagnosis of MCI and AD. To evaluate the value of DTI parameters pack in wihte matter micro-structure detection and study the inner connection between the functional connectivity strength and micro-stucture change of its connectionroute as the references in selecting DTI parameters and joint research of DTI and fMRI in related disease.
Material and method:15 cases of AD,11 cases of MCI patients and 15 cases of normal cognition controls underwent routine T1WI, T2WI, FLAIR, T1_MPRAGE, DTI, EPI_BOLD scans using German Siemens Magnetom Trio Tim MR 3.0T MR scanner. Fractional Anisotropy(FA), Axial Diffusivity(DA) and Radical Diffusivity(DR) values of bilateral para_hippocampal regions of cingulum(PH_C), posterior dorsal curve of cinglum(PC_C) and anterior dorsal curve of cingulum(AC_C) were simultaneously measured in combination of tensor and T1_MPRAGE images on post processing workstation Syngo B17. Independent sample t-test, one_way analysis of variance(ANOVAs) with LSD and Dunnett's T3 were taken to compare the within_group and inter_group differences. The data was preprocessed through software Matlab 7.1, DPARSF_V2.0, SPM5, VBM and Rest_V1.4, which included slice timing, realign, normalize, smooth, detrend and bandpass filter(pass band0.01-0.08Hz). A mean time series for ROI was computed for reference time course, which was extracted out at a spherical region of interest (ROI)(radius=4mm) centered at a given coordinate(0,-53,26) within PCC. Cross correlation analysis was then carried out between the mean signal change in the PCC and the time series of every voxel of whole brain. Functional connectivity z_maps in rest were obtained after a Fisher's z transformamation, and at the same time the six head motion parameters, mean global signal, white matter and cerebrospinal fluid signals were removed as covariates. Next, the resting state default network maps within_group and functional connectivity abnormality maps inter_group were carried out though one_simple t_texts and two_sample t_texts. Then, functional connectivity maps between bilateral hippocampal and PCC were attained after input the bilateral hippocapal masks and AlphaSim correction. Finally, the correlation analysis and linear regression analysis were performed between the time series of abnormal regions and MMSE scores and correlated DTI parameter values of cingulum.
Results:1.within_group analysis:no significant differences of bilateral cingulum in every patameter; MCI, AD groups and NC groups showed similar pattern of default networks, which included ventral MPFC, anterior cingulated cortex, visual cortex, hippocampus, cuneus/precuneus, PCC, middle and inferior temporal cortex 2.inter_group analysis:(1) MCI patients had significantly lower bilateral PH_C DA values, right PH_C DR value, and left PH_C FA value than controls; MCI patients showed decreased functional connectivity between right hippocapal and PCC compared with NC; (2) AD patients had significantly lower bilateral PH_C and PC_C DA values, bilateral PH_C and PC_C FA values, and higher bilateral PH_C and PC_C DR values than controls; AD patients showed decreased functional connectivity between bilateral hippocapal and PCC compared with NC;(3) AD patients had significantly lower bilateral PH_C and PC_C DA values, bilateral PH_C and PC_C FA values, and higher bilateral PH_C and PC_C DR values than MCI patients; 3.correlation analysis:(1)bilateral PH_C and PC_C DA values were positively correlated with MMSE scores(r=0.609/0.512,0.599/0.521, p<0.05); (2) bilateral PH_C DR values were negatively correlated with MMSE scores (r=-0.453/-0.428,p<0.05); (3) left PH_C and bilateral PC_C FA values were positively correlated with MMSE scores(r=0.627,0.641/0.533,p<0.05); functional connectivity between bilateral hippocapal and PCC was significantly correlated with MMSE scores(r=0.513,0.522,p<0.01).5.linear regression analysis:right PH_C DA values, PC_C DR values were contributed to functional connectivity of right hippocampus and PCC, and equation of linear regression was R_FC=0.047+0.556*R_PH_C_DA-1.160*R_PC_C_DR(R=0.671, R2=0.450); left PH_C DA values, PH_C DR values were contributed to functional connectivity of left hippocampus and PCC, and equation of linear regression was L FC=0.379+1.098*L PH C DA-1.105*L PH C DR (R=0.562, R2=0.315)
Conclusion:1. the DTI and fMRI research of hippocampus-cingulum-cingulate cortex pathway in Papez circuit reflected the significance for MCI progressed to AD, and provided indexes in early diagnosis of MCI and AD.2.the cingulum is not the sole fiber connecting the hippocampus and PCC.3.DR and DA parameters pack is better than FA detecting the white matter microstructure alterations of MCI and AD patients.4.functinal connection strength within the DMN in resting state is significantly correlated with the micro-structure damage of its connectionroute.5. DA values of the damaged cingulum and functional connectivity which are significantly correlated with MMSE scores can be sensitive indicators evaluating the cognitive function of patients.
方法：采用3.0T磁共振扫描仪对15例AD、11例MCI病人及15例NC(normal cognition,NC)进行横断位T1WI、T2WI、FLAIR、T1-MPRAGE、DTI和BOLD-EPI序列扫描。在syngo B17后处理工作站上结合DTI张量图和高分辨率解剖像同步测量双侧扣带束海马旁回部(PH-C)、后部(PC-C)和前部(AC-C)的FA、DA和DR值,对双侧同部位各项参数值在组内进行独立样本t检验和组间LSD和Dunnett's T3法检验。应用Matlab 7.1、SPM5、DPARSF_V2.0和rest_V1.4软件包进行数据预处理(层间时间点校正、头动校正、空间标准化、平滑)、线性校正及带通滤波(带宽：0.01～0.08HZ)得到全脑低频信号图；提取后扣带回种子点平均时间序列(0,-53,26,r=4mm)并去除协变量(全脑平均信号、脑白质、脑积液、6个头动参数),与全脑其余体素进行Pearson相关分析得到全脑功能连接图,经Fisher Z转换为Z图；将各组Z图进行组内单样本t检验和组间独立样本t检验,得到各组大脑静息态默认网络图及组间功能连接差异图；在AAL模板中提取双侧海马mask,导入组间功能连接差异图,经过AlphaSim校正后得到双侧海马与后扣带回功能连接差异图；提取双侧海马功能连接差异部位平均时间序列,与MMSE评分进行相关分析,与相关部位扣带束DTI各参数值进行线性回归分析。
结果：1.组内比较：各组双侧同部位DTI各项参数值差异均无统计学意义；NC组默认网络主要包括双侧腹内侧前额叶皮层、前扣带回、视觉皮层、海马、中下颞叶皮层、下顶叶、后扣带回及楔前叶,MCI、AD组主要默认网络脑区与NC组相似；2.组间比较：(1)MCI组与NC组：双侧PH-C部DA值减低,右侧PH-C部DR值减低,左侧PH C部FA减低；右侧海马前部与后扣带回功能连接减弱；(2)AD组与NC组：双侧PH-C部、双侧PC_C部DA值减小、DR值增加及FA值减低；双侧海马前部活动减弱,双侧海马尾部活动增强；(3)AD组与MCI组：双侧PH_C部、双侧PC_C部DA值减小、DR值增加及FA值减低；3.相关性分析：双侧扣带束PH-C部和PC_C部DA值与MMSE评分呈显著正相关(0.609/0.512；0.599/0.521)；双侧扣带束PH_C部DR值与MMSE评分呈显著负相关(-0.453/-0.428)；左侧扣带束PH-C部和双侧PC_C部FA值与MMSE呈显著正相关(0.627,0.64I/0.533)(p<0.01)；双侧海马与后扣带回功能连接分数与MMSE评分呈显著相关(r=0.513,0.522)(p<0.01)；5.线性回归分析：右侧扣带束PH-C部DA值、PC_C部DR值对右侧海马与后扣带回功能连接贡献有统计学意义,其回归方程为R_FC=0.047+0.556*R_PH_C_DA-1.160*R_PC_C_DR (R=0.671, R2=0.450);左侧扣带束PH_C部DA值与DR值对左侧海马与后扣带回功能连接贡献有统计学意义,其归回方程L_FC=0.379+1.098*L_PH_C_DA-1.105*L_PH_C_DR (R=0.562, R2=0.315)。
结论：1. Papez环路中海马-扣带束-扣带回通路在MCI向AD进展发病机制中的DTI和fMRI研究中具有重要意义,为临床早期诊断MCI、AD提供参考指标；2.扣带束不是唯一连接海马与后扣带回的纤维束,还存在其它纤维束直接或间接连接海马与后扣带回；3. DA、DR参数组合较FA参数更好的反映脑白质微观结构改变；4.静息态默认网络节点间功能连接强度与DTI反映的其连接通路微观结构损害密切相关；5.DA、海马与后扣带回功能连接分数能为临床评估病人认知功能提供参考。
Purpose:To reseach the diffusion and functional connectivity abnormality of hippocampus-cingulum-cingulate cortex pathway in Papez circuit in MCI and AD patients, and study its relationship with clinical cognitive function for the early diagnosis of MCI and AD. To evaluate the value of DTI parameters pack in wihte matter micro-structure detection and study the inner connection between the functional connectivity strength and micro-stucture change of its connectionroute as the references in selecting DTI parameters and joint research of DTI and fMRI in related disease.
Material and method:15 cases of AD,11 cases of MCI patients and 15 cases of normal cognition controls underwent routine T1WI, T2WI, FLAIR, T1_MPRAGE, DTI, EPI_BOLD scans using German Siemens Magnetom Trio Tim MR 3.0T MR scanner. Fractional Anisotropy(FA), Axial Diffusivity(DA) and Radical Diffusivity(DR) values of bilateral para_hippocampal regions of cingulum(PH_C), posterior dorsal curve of cinglum(PC_C) and anterior dorsal curve of cingulum(AC_C) were simultaneously measured in combination of tensor and T1_MPRAGE images on post processing workstation Syngo B17. Independent sample t-test, one_way analysis of variance(ANOVAs) with LSD and Dunnett's T3 were taken to compare the within_group and inter_group differences. The data was preprocessed through software Matlab 7.1, DPARSF_V2.0, SPM5, VBM and Rest_V1.4, which included slice timing, realign, normalize, smooth, detrend and bandpass filter(pass band0.01-0.08Hz). A mean time series for ROI was computed for reference time course, which was extracted out at a spherical region of interest (ROI)(radius=4mm) centered at a given coordinate(0,-53,26) within PCC. Cross correlation analysis was then carried out between the mean signal change in the PCC and the time series of every voxel of whole brain. Functional connectivity z_maps in rest were obtained after a Fisher's z transformamation, and at the same time the six head motion parameters, mean global signal, white matter and cerebrospinal fluid signals were removed as covariates. Next, the resting state default network maps within_group and functional connectivity abnormality maps inter_group were carried out though one_simple t_texts and two_sample t_texts. Then, functional connectivity maps between bilateral hippocampal and PCC were attained after input the bilateral hippocapal masks and AlphaSim correction. Finally, the correlation analysis and linear regression analysis were performed between the time series of abnormal regions and MMSE scores and correlated DTI parameter values of cingulum.
Results:1.within_group analysis:no significant differences of bilateral cingulum in every patameter; MCI, AD groups and NC groups showed similar pattern of default networks, which included ventral MPFC, anterior cingulated cortex, visual cortex, hippocampus, cuneus/precuneus, PCC, middle and inferior temporal cortex 2.inter_group analysis:(1) MCI patients had significantly lower bilateral PH_C DA values, right PH_C DR value, and left PH_C FA value than controls; MCI patients showed decreased functional connectivity between right hippocapal and PCC compared with NC; (2) AD patients had significantly lower bilateral PH_C and PC_C DA values, bilateral PH_C and PC_C FA values, and higher bilateral PH_C and PC_C DR values than controls; AD patients showed decreased functional connectivity between bilateral hippocapal and PCC compared with NC;(3) AD patients had significantly lower bilateral PH_C and PC_C DA values, bilateral PH_C and PC_C FA values, and higher bilateral PH_C and PC_C DR values than MCI patients; 3.correlation analysis:(1)bilateral PH_C and PC_C DA values were positively correlated with MMSE scores(r=0.609/0.512,0.599/0.521, p<0.05); (2) bilateral PH_C DR values were negatively correlated with MMSE scores (r=-0.453/-0.428,p<0.05); (3) left PH_C and bilateral PC_C FA values were positively correlated with MMSE scores(r=0.627,0.641/0.533,p<0.05); functional connectivity between bilateral hippocapal and PCC was significantly correlated with MMSE scores(r=0.513,0.522,p<0.01).5.linear regression analysis:right PH_C DA values, PC_C DR values were contributed to functional connectivity of right hippocampus and PCC, and equation of linear regression was R_FC=0.047+0.556*R_PH_C_DA-1.160*R_PC_C_DR(R=0.671, R2=0.450); left PH_C DA values, PH_C DR values were contributed to functional connectivity of left hippocampus and PCC, and equation of linear regression was L FC=0.379+1.098*L PH C DA-1.105*L PH C DR (R=0.562, R2=0.315)
Conclusion:1. the DTI and fMRI research of hippocampus-cingulum-cingulate cortex pathway in Papez circuit reflected the significance for MCI progressed to AD, and provided indexes in early diagnosis of MCI and AD.2.the cingulum is not the sole fiber connecting the hippocampus and PCC.3.DR and DA parameters pack is better than FA detecting the white matter microstructure alterations of MCI and AD patients.4.functinal connection strength within the DMN in resting state is significantly correlated with the micro-structure damage of its connectionroute.5. DA values of the damaged cingulum and functional connectivity which are significantly correlated with MMSE scores can be sensitive indicators evaluating the cognitive function of patients.
引文
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