【作者】 陈聪；

【导师】 冯逢；

【作者基本信息】 北京协和医学院 ， 影像医学与核医学， 2014， 博士

【摘要】 第一节视神经脊髓炎患者脑体积变化的研究目的：本研究应用基于体素的形态测量学方法(VBM)尝试(1)比较视神经脊髓炎(NMO)患者与健康对照者(HC)的脑灰、白质体积,探讨NMO患者脑灰、白质体积的变化。(2)分析灰、白质体积与临床指标的相关性。材料与方法：入组24例NMO患者及24例性别、年龄匹配的健康对照者,数据采集使用3T MR成像系统,扫描序列包括T2WI、FLAIR和全脑三维结构像,应用基于统计参数图(SPM)8软件的VBM8Toolbox工具箱分析NMO组及对照组的数据。两组之间全脑体积的比较使用两独立样本t检验,P<0.05时为差异具有统计学意义。使用SPM8的两独立样本t检验比较两组之间局部脑灰、白质体积变化情况,阈值选择参考既往文献,P<0.005时被认为有显著统计学意义,簇阈值设为30个相邻体素。利用Rest相关分析对NMO患者体积异常脑区与患者的临床病程、复发次数及EDSS评分进行相关性分析,P<0.05时为差异具有统计学意义。结果：NMO和HC组的全脑体积没有显著差异(P>0.05)。在基于体素水平,与对照组相比,NMO组小脑、中央前回、中央后回、舌回、颞中回、颞下回、枕叶、楔叶、楔前叶、边缘叶、梭状回、距状裂周围皮层、尾状核、丘脑、视束、Brodmann3、4、6、17、18及19区的多个区域灰质体积减小(P<0.005,非校正)。NMO患者双侧小脑、中脑、边缘叶、顶叶、视束、海马、海马旁回及楔前叶的多个区域白质体积减小(P<0.005,非校正)。NMO患者灰质体积减小脑区的体积与病程呈负相关的区域有小脑、左侧颞叶、右侧丘脑、右侧颞上回、双侧顶叶、中央后回(P<0.05)。NMO患者右侧小脑、左侧颞叶的灰质体积与EDSS评分呈负相关(P<0.05)。NMO患者双侧小脑、双侧颞下回、双侧颞中回、左侧颞极、梭状回、右侧颞上回、右侧中央后回、右侧顶叶、双侧丘脑、左侧顶叶、左侧中央后回、右侧顶上小叶、右侧楔前叶的灰质体积与复发次数呈负相关(P<0.05)。NMO患者白质体积减小脑区的体积与EDSS评分呈负相关的区域有左侧小脑、双侧海马及海马旁回(P<0.05)。NMO患者双侧小脑的白质体积与复发次数呈负相关(P<0.05)。结论：NMO患者较健康对照出现多个脑区灰、白质萎缩,多个脑区的灰白质体积减小与临床指标显著相关,提示VBM技术可以灵敏的反应脑体积的变化,并可监测疾病严重程度和病程。第二节视神经脊髓炎患者脑部基于体素的扩散张量成像研究目的：对视神经脊髓炎患者和健康对照的弥散张量成像(DTI)数据进行基于体素的分析,利用多个弥散参数分析NMO患者全脑弥散的改变,并探讨NMO患者弥散指标改变和临床指标的相关性。材料与方法：入组16例NMO患者及16例性别、年龄匹配的健康对照者,分别行全脑结构成像及弥散张量成像,之后对其多个弥散指标,包括各向异性分数(FA)、平均弥散率(MD)、轴向弥散值(AD/λ1)和径向弥散值(RD/λ23)进行基于体素的分析。使用SPM8的两独立样本t检验比较两组之间各弥散指标变化情况,阈值选择参考既往文献,P<0.005时被认为有显著统计学意义,簇阈值设为30个相邻体素。利用Pearson相关分析评价弥散异常与患者临床指标的相关性。结果：与对照组相比,NMO组FA值显著减低的区域包括双侧额叶、枕叶、颞叶、丘脑、中脑、视束、小脑(P<0.005,非校正)；λ1值升高的区域分布于双侧小脑、枕叶、额叶、顶叶、丘脑、中脑、海马旁回、扣带回、胼胝体、基底节、尾状核、岛叶、边缘叶(P<0.005,非校正)；λ2值升高的区域分布于双侧小脑、枕叶、颞叶、额叶、顶叶、丘脑、中脑、海马旁回、扣带回、胼胝体、双侧基底节、尾状核、边缘叶、岛叶(P<0.005,非校正)。λ3值升高的区域分布于小脑、颞叶、额叶、丘脑、苍白球、中脑、扣带回、边缘叶、肼胝体(P<0.005,非校正)。NMO患者MD值升高的区域分布于小脑、枕叶、额叶、丘脑、扣带回、胼胝体、基底节、右侧尾状核、边缘叶(P<0.005,非校正)。NMO患者的各向扩散指标改变和患者的临床各项指标无明显相关关系(P>0.05)。结论：NMO患者脑组织存在弥散异常,DTI的AD、RD和MD三个指标可以可靠的反应NMO患者的弥散异常改变,尤其以AD和MD更为敏感。NMO患者皮质损害以轴索损伤为主,而白质纤维损伤则是轴索损伤和髓鞘损伤并存。基于体素的分析方法有助于客观展示全脑受累情况。第一节视神经脊髓炎患者脑体积变化的超高场磁共振成像研究目的：本研究尝试(1)利用超高场(7T)MR成像系统采集NMO患者和健康对照的数据,(2)应用基于体素的形态测量学方法比较视神经脊髓炎患者(NMO)患者与健康对照者的脑灰、白质体积,分析灰、白质体积与临床指标的相关性,(3)探索7T MRI在NMO脑改变研究中的作用。材料与方法：入组12例NMO患者及12例性别、年龄匹配的健康对照者,数据采集使用7T MR成像系统,扫描序列包括T2WI、FLAIR和全脑三维结构像,应用基于统计参数图(SPM)8软件的VBM8Toolbox工具箱分析NMO组及对照组的数据。两组之间全脑体积的比较使用两独立样本t检验,P<0.05为差异具有统计学意义。使用SPM8的两独立样本t检验比较两组之间局部脑灰、白质体积变化情况,阈值选择参考既往文献,P<0.005时被认为有显著统计学意义,簇阂值设为30个相邻体素。利用Rest相关分析对NMO患者体积异常脑区与患者的临床病程、复发次数及EDSS评分进行相关性分析。结果：NMO和HC组的全脑体积没有显著差异(P>0.05)。在基于体素水平,与对照组相比,NMO组颞叶、额叶、中央前回、中央后回、Brodmann area6、9、22、顶叶、梭状回、海马旁回及小脑的多个区域灰质体积减小(P<0.005,非校正)。NMO组双侧壳核、枕叶、海马旁回、边缘叶、舌回、Brodmann area6、17、18、19、40、缘上回、杏仁核、中央后回、楔前叶、顶叶、额叶及小脑的多个区域白质体积减小(P<0.005,非校正)。NMO患者灰质体积减小脑区的体积与病程及复发次数呈负相关的区域有左侧中央前回、左侧中央后回、Brodmann area6(P<0.05)NMO患者白质体积减小脑区的体积与EDSS评分呈负相关的区域有右侧缘上回(P<0.05)。结论：NMO患者存在弥漫性脑组织损伤,VBM技术可以敏感的反应脑组织隐匿性的结构改变。同时场强的提高能够更敏感的发现脑结构微小的改变,提供更为准确的研究结果。第二节视神经脊髓炎患者脑部皮层厚度变化的超高场磁共振成像研究目的：本研究利用高场(3T)和超高场(7T)MR成像系统采集NMO患者和健康对照的数据,应用皮层厚度测量分析NMO患者与健康对照者的皮层厚度差异,探索NMO患者皮层损伤的模式,并分析NMO皮层厚度改变与临床指标的相关性。比较3T和7T MRI在脑皮层厚度研究中的价值。材料与方法：入组24例NMO患者及24例性别、年龄匹配的健康对照者,使用3T MR成像系统采集被试图像；入组12例NMO患者及12例性别、年龄匹配的健康志愿者,使用7TMR成像系统采集被试图像。所有被试均扫描以下序列,包括T2WI、FLAIR和全脑三维结构像。应用FreeSurfer软件分别分析3T和7T数据,测量NMO患者和健康对照的皮层厚度,然后利用配对t检验从全脑和体素水平分析两组间的皮层厚度差异,P<0.01时被认为有显著统计学差异。对全脑皮层厚度与患者的临床病程、复发次数及EDSS评分进行一元线性回归分析。结果：3T研究结果显示,NMO病例组和对照组间全脑皮层厚度无显著统计学差异,在脑区水平皮层厚度也无显著性统计学差异,但NMO组较正常组在局部脑区皮层厚度有变薄的趋势。7T研究结果显示,NMO病例组和对照组间全脑皮层厚度无显著统计学差异(P>0.05),但在脑区水平,NMO患者左侧梭状回(Brodmann area37)、舌回(Brodmann area17、18、19)、左侧颞下回(Brodmann area20)、左侧额上回及额中回(Brodmann area6、8、9)的皮层显著变薄((P<0.01,非校正))。皮层厚度与患者的临床指标未见明显相关。结论：NMO患者的视觉、运动及认知相关脑区皮层厚度变薄,进一步证实了NMO患者皮层损伤的存在。皮层厚度测量可以敏感的反应皮层局部微小的损伤,与3MR成像设备相比,7T MRI在NMO皮层厚度分析研究中具有重要价值。目的：本研究尝试利用超高场(7T)MR成像系统采集NMO患者和健康对照的静息态功能磁共振数据,分别应用时间域的振幅(Amplitude in the time domain,AM)和局部一致性(egional homogeneity, ReHo)两个指标观察NMO患者的脑基线活动。材料与方法：入组12例NMO患者及12例性别、年龄匹配的健康对照者,利用超高场(7T)MR成像系统采集NMO患者和健康对照的静息态功能磁共振数据。分别比较两组间AM和ReHo的差异,观察NMO患者的脑基线活动强度和局部一致性的变化。结果：和对照组相比较,NMO组AM值显著增高的区域有左侧额中回、额下回、中央前回、Brodmann area6、左侧岛盖部额下回、Brodmann area44。NMO组未见到有AM值明显减低的区域。NMO组ReHo值有显著降低的区域有右侧颞中回、右侧颞下回和右侧梭状回。NMO组ReHo值显著增高的区域有右侧前额叶内侧面、右侧额中回、右侧三角部额下回、左侧岛盖部额下回、左侧中央前回、中央后回及Brodmann area6。结论：NMO患者静息态脑功能的改变与视觉、感觉运动、认知和语言相关,与形态学研究结果相互印证,提示NMO患者神经元活动异常,为NMO患者相应的临床表现提供了功能基础。更多还原

【Abstract】 1. A Voxel-based Morphometry Study of Brain Tissue Volume Changes in Neuromyelitis Optica Patients Using High filed (3T) MRI ScannerPurpose:To explore the brain tissue volume (BTV) changes in neuromyelitis optica (NMO) patients with voxel-based morphometry (VBM) method using high filed (3.0T) MRI Scanner. To investigate the correlations between brain tissue volume changes with clinical variables.Materials and Methods:24NMO patients and24gender and age matched healthy controls were scanned at3T MR system with T2WI, FLAIR and sagittal three-dimensional (3D) volumetric T1-weighted fast spoiled gradient echo (FSPGR) sequences. Raw data was processed and analyzed using VBM8toolbox of statistical parametric mapping (SPM)8software. Comparison of focal grey matter volume (GMV) and white matter volume (WMV) between the two groups was analyzed by independent two samples t-test, and statistical maps were thresholded with uncorrected P value,0.005with a minimum cluster size of30voxels according to previous published study. For the patient group, correlation analyses were performed between brain tissue volume loss and clinical variables, including disease duration, relapse and EDSS score.Results:For global mean GMV and WMV, there is no significant difference between the two groups (P>0.05). At vertex-wise level, compared with the controls, the GMV decrease was observed in NMO patients in several regions of cerebellum, precentral gyrus, postcentral gyrus, lingual gyrus, middle temporal gyrus, inferior temporal gyrus, occipital lobe, cuneus, precuneus, limbic lobe, fusiform gyrus, calcarine, caudate, thalamus, optic tract and Brodmann area3,4,6,17,8,19(P<0.005, uncorrected). The focal WMV decrease was observed in NMO patients in cerebellum, midbrain, limbic lobe, parietal lobe, optic tract, hippocampus, parahippocampal gyrus and precuneus (P<0.005, uncorrected). The disease duration negatively correlated with GMV in bilateral cerebellum, left temporal lobe, right thalamus, right superior temporal gyrus, bilateral parietal lobe and postcentral gyrus (P<0.05). The EDSS score negatively correlated with GMV in right cerebellum and left temporal lobe (P<0.05). The relapse negatively correlated with GMV in bilateral cerebellum, bilateral inferior temporal gyrus, bilateral middle temporal gyrus, left temporal pole, fusiform gyrus, right superior temporal gyrus, right postcentral gyrus, right parietal lobe, bilateral thalamus, left parietal lobe, left postcentral gyrus, right superior parietal lobule and right precuneus (P<0.05). The EDSS score negatively correlated with WMV in left cerebellum, bilateral hippocampus and parahippocampal gyrus (P<0.05). The WMV in bilateral cerebellum negatively correlated with relapse (P<0.05).Conclusions:Regional atrophy of grey matter and white matter was found in NMO patients. Brain tissue volume in several brain areas correlated with clinical variables significantly. VBM can reveal brain volume changes sensitively and could be an imaging biomarker to monitor clinical severity and disease progression. 2. A Voxel-based Analysis of Diffusion Tensor Imaging in Neuromyelitis Optica PatientsPurpose: To explore the whole brain diffusion changes in neuromyelitis optica (NMO) patients using voxel-based analysis of diffusion tensor imaging (DTI) by multiple diffusion indices. To investigate the correlations between diffusion indices changes with clinical variables.Materials and Methods:Whole brain structural images and diffusion weighted images (DTI) were acquired in16NMO patients and16gender and age matched healthy controls. Fractional anisotropy (FA), mean diffusivity (MD), axial diffusivity (AD/λ1) and radial diffusivity (RD/λ23) of NMO patients were compared with the controls by voxel-based analysis of DTI data using independent two samples t-test, and statistical maps were thresholded with uncorrected P value,0.005with a minimum cluster size of30voxels according to previous published study. For the patient group, correlation analyses were performed between diffusion indices changes and clinical variables by Pearson correlation analysis.Results:Compared with the controls, NMO patients showed significant FA decrease in bilateral frontal lobe, occipital lobe, temporal lobe, thalamus, midbrain, optic tract and cerebellum (P<0.005, uncorrected). λ1increase in NMO patients could be seen in bilateral cerebellum, occipital lobe, frontal lobe, parietal lobe, thalamus, midbrain, parahippocampal gyrus, cingulate cortex, corpus callosum, basal ganglia, caudate nucleus, insula and limbic lobe (P<0.005, uncorrected). λ2increase in NMO patients could be seen in bilateral cerebellum, occipital lobe, temporal lobe, frontal lobe, parietal lobe, thalamus, midbrain, parahippocampal gyrus, cingulate cortex, corpus callosum, basal ganglia, caudate nucleus, limbic lobe and insula (P<0.005, uncorrected). X3increase in NMO patients could be seen in cerebellum, temporal lobe, frontal lobe, thalamus, globus pallidus, midbrain, cingulate cortex, limbic lobe and corpus callosum (P<0.005, uncorrected). MD increase in NMO patients could be seen in cerebellum, occipital lobe, frontal lobe, thalamus, cingulate cortex, corpus callosum, basal ganglia, right caudate nucleus and limbic lobe (P<0.005, uncorrected). No significant correlation was found between diffusion indices changes with clinical variables (P>0.05).Conclusions: DTI could reveal the significant diffusion abnormalities in NMO by diffusion indices of AD, RD and MD sensitively, especially AD and MD. This study revealed that the cortical damage in NMO is mainly characterized by axonal injury while the white matter damage is characterized by both axonal injury and demyelination. 1. A Voxel-based Morphometry Study of Brain Tissue Volume Changes in Neuromyelitis Optica Patients Using Ultra-high filed (7T) MRI SystemPurpose:To explore the brain issue volume (BTV) changes in neuromyelitis optica (NMO) patients with voxel-based morphometry (VBM) method using ultra-high filed (7T) MRI Scanner. To investigate the correlations between brain tissue volume changes with clinical variables. To identify the usefulness of7T MRI in brain structural research.Materials and Methods:12NMO patients and12gender and age matched healthy controls were scanned at7T MR system with T2WI, FLAIR and sagittal three-dimensional (3D) volumetric T1-weighted magnetization-prepared rapid acquisition gradient echo (MPRAGE) sequences. Raw data was processed and analyzed using VBM8toolbox of statistical parametric mapping (SPM)8software. Comparison of focal grey matter volume (GMV) and white matter volume (WMV) between the two groups was analyzed by independent two samples t-test, and statistical maps were thresholded with uncorrected P value,0.005with a minimum cluster size of30voxels according to previous published study. For the patient group, correlation analyses were performed between brain tissue volume loss and clinical variables, including disease duration, relapse and EDSS score.Results:For global mean GMV and WMV, there is no significant difference between the two groups (P>0.05). At vertex-wise level, compared with the controls, the GMV decrease was observed in NMO patients in several regions of temporal lobe, frontal lobe, precentral gyrus, postcentral gyrus, Brodmann area6,9,22, parietal lobe, fusiform gyrus, parahippocampal gyrus and cerebellum (P<0.005, uncorrected). The focal WMV decrease was observed in NMO patients in bilateral putamen nucleus, occipital lobe, parahippocampal gyrus, limbic lobe, lingual gyrus, Brodmann area6,7,17,18,19,40, supramarginal gyrus, amygdaloid nucleus, postcentral gyrus, precuneus, parietal lobe, frontal lobe and cerebellum (P<0.005, uncorrected). Both disease duration and relapse negatively correlated with GMV in left precentral gyrus, left postcentral gyrus and Brodmann area6(P<0.05). The EDSS score negatively correlated with WMV in right supramarginal gyrus (P<0.05).Conclusions:Diffuse atrophy of grey matter and white matter was found in NMO patients. VBM can reveal subtle brain volume changes. Higher field strength MRI scanner could detective the subtle brain damage more sensitively. 2. Focal Cortical Thinning in Neuromyelitis Optica Using Ultra-high Field (7T) MRI ScannerPurpose:The present study is aimed to prospectively evaluate cortical thickness changes of patients with neuromyelitis optica (NMO) without visible lesions in the grey matter using high Field (3T) and ultra-high field (7T) MRI scanner. To investigate the correlations between cortical thickness changes with clinical variables. To identify the usefulness of7T MRI in cortical thickness study.Materials and Methods:24NMO patients without visible lesions in the grey matter and24gender and age matched healthy controls were scanned at3T MR system with sagittal three-dimensional (3D) volumetric T1-weighted fast spoiled gradient echo (FSPGR) sequences.12patients with NMO without visible lesions in the grey matter on conventional MRI and12sex-and age-matched healthy control subjects were scanned at7T whole-body human MR system with sagittal three-dimensional (3D) volumetric T1-weighted magnetization-prepared rapid acquisition gradient echo (3D-MPRAGE) sequence. Cortical thickness measurement was performed by FreeSurfer software5.0. Comparison of cortical thickness between the two groups was analyzed by paired t-test, and the significance of the P-value was set at0.01because of the number of statistical tests. For the patient group, correlation analyses were performed between brain cortical thickness changes and clinical variables, including disease duration, relapse and EDSS score.Results:There is no significant difference of both global and focal cortical thickness between the two groups by analyzing3T data. As for7T data, no significant difference of global cortical thickness was found between the two groups (P>0.05). However, as compared with the controls, NMO patients showed focal cortical thinning in left middle frontal gyrus (MFGL), left fusiform gyrus (FG.L), left lingual gyrus and left inferior temporal gyrus (P<0.01,uncorrected). No significant correlation was found between cortical thickness changes with clinical variables (P>0.05).Conclusion: Significant cortical thinning was identified in NMO patients, involving visual, motor and cognition system, suggesting the presence of occult tissue damage in normal-appearance grey matter in NMO patients. This study also suggests that ultra-high field imaging may be useful for characterizing subtle lesions of the grey matter in NMO. Purpose:To prospectively evaluate how brain baseline activity changes in NMO patients using amplitude in the time domain (AM) and regional homogeneity (ReHo) as indices with ultra-high field (7T) MRI system.Materials and Methods:12NMO patients and12gender and age matched healthy controls were scanned at7T MR system to collect resting-sate fMRI data. Raw data was preprocessed using statistical parametric mapping (SPM)8software. AM and ReHo were compared between the two groups to investigate the brain baseline activity changes in NMO patients.Results: Our results showed that NMO patients had significantly increased AM in left middle frontal gyrus (MFGL), inferior frontal gyrus (IFGL), precentral gyrus (PreCG.L), Brodmann area6, Brodmann area45and Brodmann area44. NMO patients showed no regions with decreased AM. Comparing the NMO group with the healthy controls, we found ReHo decreased in right middle temporal gyrus (MTG/.R), right inferior temporal gyrus (ITG.R), right fusiform gyrus (FuGR); and increased in right medial prefrontal cortex (MPFC.R/Brodmann area9、10), right middle frontal gyrus (MFG.R), bilateral inferior frontal gyrus (IFG), Brodmann area44, Brodmann area45, left precentral gyrus (PreCG.L), postcentral gyrus (PosCG.L) and Brodmann area6.Conclusions: The abnormal baseline brain activity shown by resting-state fMRI in NMO is relevant to visual, motor and cognition systems that is consistent with the structural research results. These results demonstrate that neural activity in the resting state changes in patients with NMO.更多还原