【作者】 张静；

【导师】 张云亭；

【作者基本信息】 天津医科大学 ， 影像医学与核医学， 2009， 博士

【摘要】 一、磁敏感加权序列测量帕金森病脑铁含量的研究目的应用磁敏感加权序列(susceptibility weighted imaging，SWI)相位图全面测量帕金森病(Parkinson’s disease，PD)患者中脑及基底节脑铁含量。对象和方法应用SWI序列对42名PD患者和37例健康受试行全脑扫描，后处理得到校正相位图。在校正相位图上勾画并测量中脑及基底节各核团相位值，包括黑质致密带(substantia nigra compacta，SNc)、黑质网状带(substantia mgrareticulata，SNr)、红核(red nucleus，RN)、丘脑底核(subthalamic nucleus，STN)、黑质苍白球束(fasicula nigrale，FN)、壳核(putamen，PUT)、苍白球(globus pallidus，GP)、尾状核(caudate nucleus，CN)、丘脑(thalamus，THA)，并按照解剖分区或PD铁病理沉积的特点将不同脑区又细分为多个亚区。分析37例健康受试不同脑区相位值与铁含量参考值之间的相关性；比较PD和与之年龄、性别匹配的23例正常对照(normal controls，NC)两组间不同脑区相位值有无显著性差异；比较病情程度和病程长短不同的两组间各脑区相位值之间有无显著性差异。结果①健康受试各脑区相位值与铁含量参考值之间存在高度的负相关(r~2=-0．839，p=0．037)。②PD组SNc内、SNc外相位值小于NC组，两组间存在显著差异；其余脑区均未见显著性差异；病重侧SNc相位值小于病轻侧。③PD进展期组病重侧SNc内、SNc外相位值小于PD早期组，两组间存在显著性差异。④各脑区相位值在病程长短两组间未见显著性差异。结论①PD脑铁含量的异常增加只特异的局限在SNc，而其他基底节核团均未见显著增加。从影像学的角度说明：铁与PD选择性的造成SNc多巴胺能神经元的凋亡密切相关，这种特定的分布方式有助于与其他疾病鉴别。②PD患者SNc两侧铁含量不一致，病重侧高于病轻侧，且病重侧铁含量与病程长短无明显关系，但随病情的加重而增加。这不仅支持过量铁是PD的发病机制，同时也提示铁的定量测量可成为判断病情进展的一个重要指标。③正常STN就具有较高的铁含量，SWI相位图可清晰显示，利用这一特点可进行立体定向术前定位，以提高手术疗效。④SWI序列相位图像，具有极佳的解剖分辨率，是目前活体测量脑铁含量的最佳方法，在PD及其它神经变性疾病的研究中具有重要意义。二、帕金森病全脑结构基于体素的MRI形态学分析目的采用基于体素的形态学分析(voxel based morphometry，VBM)方法，揭示PD患者全脑灰质结构的改变，探寻与轻度认知障碍有关的脑结构变化。对象和方法应用T1WI三维脑容积扫描序列(Brain Volume，BRAVO)对35名PD患者和20名NC进行扫描，获得全脑结构图像。根据认知损害的情况将PD患者进一步分为：14例无轻度认知障碍(none mild cognitive impairment，nMCI)组和21例轻度认知障碍(mild cognitive impairment，MCI)组。采用以SPM5为基础的VBM方法进行数据处理得到全脑灰质图。结果①相比NC，PD患者出现广泛脑区灰质密度的减低，范围累及双侧颞叶、额叶、顶叶、枕叶，边缘系统的右侧海马、海马旁回，右侧小脑后叶及左侧CN。②相比NC，PD-nMCI组灰质密度减少的脑区主要集中在右侧颞叶，包括颞中回、下回及右侧海马、右侧前扣带回皮质(anterior cingulate cortex，ACC)。③相比PD-nMCI组，PD-MCI组右侧楔叶、楔前叶、双侧中央前回、右侧眶额回(orbit frontal cortex，OFC)、双侧颞中回、左侧梭状回灰质密度明显减少。结论①PD患者出现全脑广泛区域灰质结构密度的减低，包括双侧额、颞、顶、枕叶、右侧边缘系统等。②PD-nMCI患者灰质密度的减低主要局限在右侧颞叶和边缘系统的右侧海马和ACC；随认知障碍的出现，范围逐渐扩大。③双侧顶、枕叶联合脑区灰质密度的减低与PD患者的轻度认知障碍关系密切。④VBM技术可以在活体状态客观地评价脑内结构的早期变化，是研究脑内形态学改变的首选方法。三、帕金森病静息态下纹状体功能连接的fMRI研究目的应用功能连接(functional connectivity MRI，Fc-MRI)技术研究PD患者静息态下脑功能变化。对象和方法对35例PD患者和17例NC在静息状态下行fMRI成像，采用SPM5统计软件进行数据处理。以双侧纹状体(striatum，STR)为种子点，获得每个受试的STR功能连接图，比较PD和NC两组间功能连接的差异。结果①PD患者与双侧STR正连接减弱的区域主要位于右侧前额叶背外侧部(dors-olateral prefrontal cortex，DLPFC)和双侧后扣带回皮质(posteriorcingulate cortex，PCC)，此外，左顶叶后部皮层(左侧楔前叶、顶下小叶、左侧缘上回)显示与L-STR正连接减弱。②海马、海马旁回以及岛叶等边缘系统与双侧STR正连接增强。结论PD患者脑内神经网络出现广泛的改变，额、顶叶是患者认知功能损伤的主要神经位点，而海马、海马旁回及岛叶等边缘系统可能发挥着重要的代偿机制。四、帕金森病静息态fMRI的局部一致性分析目的应用局部一致性(regional homogeneity，ReHo)技术研究PD患者静息态下脑功能变化，分析随疾病进展，脑内ReHo变化的规律。对象和方法对象及检查方法同第三部分。按病情将PD进一步分为：早期组，15例(Hoehn & Yahr评分≤1．5)和进展期组，20例(Hoehn & Yahr评分＞1．5)。采用SPM5统计软件进行数据处理。通过计算全脑每个体素的肯德尔协和系数(Kendall’s coefficient concordance，KCC)，得到每个受试的全脑ReHo图，比较PD和NC两组间ReHo的差异，比较早期和进展期两组间ReHo的差异。结果①相比NC，PD组ReHo降低的区域主要集中在运动皮层，包括：初级运动皮层M1、前运动皮质(premotor cortex，PMC)、辅助运动区(supplementarymotor area，SMA)、ACC，以及左侧DLPFC、右侧小脑后叶及右侧颞上回。②在PD早期就存在运动皮层以外脑区的受损，包括双侧岛叶后部、DLPFC、顶叶角回、缘上回、左侧楔前叶及右侧颞上回、小脑后叶，显示ReHo减低。③随疾病进展，ReHo减低的异常脑区逐渐增多。右侧小脑后叶(小脑蚓)、双侧OFC、直回、左侧颞中、下回ReHo显著减低；而双侧枕中回、岛叶前部、扣带回、颢上回，右侧颞中回、丘脑ReHo显著增加；运动皮层未见显著变化。结论①PD患者ReHo降低的区域主要集中在运动皮层及左侧DLPFC。②在疾病早期就存在运动回路以外脑区的受损，包括双侧岛叶后部、DLPFC、顶叶及右侧颞上回、小脑后叶。而OFC的损伤出现相对较晚。③在静息状态下，运动皮层局部神经元活动减低，随着疾病进展，运动皮层的改变未见显著变化，提示运动皮层的损伤在疾病的一定阶段达到平衡状态，而认知功能的下降是临床运动症状的进一步恶化的重要原因。更多还原

【Abstract】 PartⅠMeasurement of brain iron in patients with Parkinson’s disease usingsusceptibility weighted imagingObjective To comprehensively measure iron content in nucleus of midbrain andbasal ganglia in patients with Parkinson’s disease (PD) on phase images ofsusceptibility weighted imaging (SWI) sequence.Materials and Methods 42 PD patients and 37 healthy subjects were examinedby using SWI sequence.Corrected phase images were obtained after postprocessed.Nucleus of midbrain and basal ganglia were drawn by hand and the phase values weremeasured on corrected phase images.The regions evaluated included substantia nigracompacta (SNc),substantia nigra reticulate (SNr),red nucleus (RN),subthalamicnucleus(STN),fasicula nigrale (FN),putamen (PUT),globus pallidus (GP),caudatenucleus (CN) and thalamus(THA).According to the anatomical and pathologicalfeatures,corresponding brain regions were subdivided into several subregionsfurthermore.The correlation between phase values of 37 healthy subjects in our studyand values of regional brain iron concentration in published in literatures wereanalyzed.Phase values were compared between PD patients and 23 age,sex-matchednormal controls (NC).Phase values were also compared between two groups withdifferent severity and duration of disease..Results①Phase values of healthy subjects were negatively correlated withpublished values of regional brain iron concentration (r~2=-0.839,p=0.037).②Phasevalues of SNc-internal and SNc-external in PD were significantly lower than that inthe NC,but other brain regions no.Phase values of the more affected SNc were lowerthan that of the less affected side.③A significantly difference in phase values wasobserved in the more affected SNc-internal and SNc-external between early stage andadvanced PD groups,but not in other brain regions.Phase values of the more affectedSNc-internal and SNc-external in early stage group were significantly lower than that in advanced group.④No difference in phase values was observed in any brainregions between two groups with different duration of disease.Conclusion①Specific increasement of iron content of PD was observed onlyin SNc,but not in other brain regions.This suggests excessive iron accumulation isclosely related to the apoptosis of dopaminergic neurons in SNc and the specificdistribution pattern can afford useful information to differeate from other diseases.②Iron content was significantly difference on bilateral SNcs and the more affectedSNc were higher than that of the less affected side.Iron content of the more affectedSNc increased with evolution of PD patient’s pathogenetic condition,but not withdisease duration.These suggest excessive iron accumulation is likely to be a primarypathogenesis and iron measurement can be an important biomarker to evaluate theseverity of disease.③SWI can be used to improve the visibility of the STN forprecise surgical targeting because of higher iron content in normal STN.④Thephase images acquired by SWI sequence have superb anatomic resolution.It is theoptimal modality to measure brain iron content in vivo and has important significancein the study of PD and other neural degeneration diseases.PartⅡA whole-brain analysis in patients with Parkinson’s disease usingVoxel-based MRI morphometryObjective To analyze the structural changes of whole brain gray matter in PDusing voxel-based morphometry (VBM).Furthermore,to disclosure bain structuralchanges closely related to mild cognitive impairment.Materials and Methods 35 PD patients and 20 NC were examined by usingTlWI three-dimensional Brain Volume (BRAVO)sequence.We further classified PDpatients into 2 groups according to the extent of cognitive impairment:14 cases ofnone mild cognitive impairment (nMCI) and 21 cases of mild cognitive impairment(MCI).The data were analyzed by using VBM based on SPM5 to generate gray matter density map.Results①Compared to NC,PD patients showed extensived_decreased graymatter density in widespread brain region involving bilateral temporal,frontal,parietal,occipital lobes,right hippocampus,right parahippocampus gyrus,rightcerebellar hemisphere and left CN.②Compared to NC,decreased gray matter densityin PD-nMCI was observed in right temporal lobe,including middle temporal gyrus,inferior temporal gyrus,and right hippocampus and ACC.③Compared to PD-nMCI,decreased gray matter density in PD-MCI was observed in right cuneus,precuneus,bilateral precentral gyrus,right orbit frontal cortex (OFC),bilateral midtemporalgyrus and left fusiform gyrus.Conclusion①Gray matter atrophy in widespread brain region can exist in PDpatients,involving bilateral temporal,frontal,parietal,occipital lobes,righthippocampus,parahippocamus gyrus etc.②Decreased gray density in PD-nMCI wasmainly located in right temporal lobe and right hippocampus and ACC.Withoccurrence of mild cognitive impairment,abnormal brain regions were graduallyextended.③Gray matter atrophy in bilateral parietal,occipital lobe association cortex,right OFC,and bilateral middle temporal gyrus are related to the mild cognitiveimpairment.④VBM can evaluate the early structural changes of full-brain in vivoand is the first choice to the study of brain morphology.PARTⅢResting-state functional connectivity of striaturn in PDObjective To demonstrate brain functional changes of PD in resting state usingfunctional connectivity MRI (Fc-MRI).Materials and Methods 35 PD patients and 17 NC accepted fMRI scan duringresting state.The fMRI data were processed with statistical parametric mapping 5(SPM5).Bilateral striatum (STR) areas were defined as the seed voxels.Wholebrain map of functional connectivity for every subject was acquired.The difference offunctional connectivity between PD patients and NC was compared. Results①Compared to NC,PD patients showed decreased positive functionalconnectivity in right dorsolateral prefrontal cortex (DLPFC) and bilateral posteriorcingulate cortex (PCC) related to bilateral STR.In addition,left parietal posteriorcortex (including precuneus,inferior parietal lobule,supramarginal gyrus) showeddecreased positive functional connectivity with L-STR.②Regions of limbic systemincluding hippocamp,parahippocamp,insular lobes showed increased positivefunctional connectivity with the bilateral STR.Conclusion Extensive changes happened in the neural network in PD patientsduring resting state.Frontal and parietal cortex may be the main substrate of cognitiveimpairment,but limbic system including hippocamp,parahippocamp,insular lobesplay an important compensative role in PD.PARTⅣThe analysis of regional homogeneity in resting-state in PDObjective To demonstrate brain functional changes of PD in resting state usingregional homogeneity (ReHo).Materials and Methods 35 PD patients and 17 NC accepted fMRI scan duringresting state.According to the severity,PD subjects were further classified into twogroups:early stage group,15 cases (Hohen&Yahr score≤1.5) and advanced stagegroup,20 cases (Hohen&Yahr score＞1.5).The fMRI data were processed withstatistical parametric mapping5 (SPMS).ReHo map for each subject was acquired bycalculating each voxel’s Kendall’s coefficient concordance (KCC) in whole brain.The difference of ReHo between PD patients and NC was compared.The differenceof ReHo in both groups was compared and analyzed.Results①Compared to NC,the PD patients showed decreased ReHo in motorcortex,including primary motor areas (M1),premotor cortex(PMC),supplementarymotor area (SMA),anterior cingulate cortex (ACC),and left DLPFC,right posteriorlobe of cerebellum and right superior temporal gyrus.②In early stage of PD,decreased ReHo was located in bilateral posterior insula,DLPFC,parietal lobe and right superior temporal gyrus,right posterior lobe of cerebellum,besides motor cortex.③With disease evolution,regions of decreased ReHo gradually increased andinvolved right posterior lobe of cerebellum,bilateral OFC,rectus gyri and leftmiddle-inferior temporal gyrus.At the same time,increased ReHo was located inbilateral mid-occipital gyri,anterior insula,cingulated gyri,superior temporal gyri,and right middle temporal gyrus,right thalamus.No changes were observed inbilateral motor cortex.Conclusion①Regions of decreased ReHo was located mainly in motor cortexand left DLPFC.②In early stage of PD,bilateral posterior insula,DLPFC,parietallobe and right superior temporal gyms,fight posterior lobe of cerebellum besidesmotor cortex was impaired.OFC impaired occurred in advanced stage.③In restingstate,motor cortex showed regional neuron activity decreased and no markedvariation with disease progression.Decreased cognitive impairment may be the maincause of motor control deterioration.更多还原