磁敏感加权成像对脑微出血检测价值的实验研究
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摘要
[背景和目的]近年来,随着磁共振(magnetic resonance,MR)技术的不断进步,新的MR序列不断涌现,Haacke博士等在T_2*梯度回波的基础上开发出了一种新型磁共振对比成像技术——磁敏感加权成像(susceptibilityweighted-imaging,SWI),该序列是在三个方向上均有流动补偿和长回波时间的全新梯度回波序列,具有高分辨,三维和高信噪比的特点,同时充分使用相位信息并将幅值图和相位图融合,进一步增强了局部对比。由于其对组织之间磁化率不同造成的磁场不均匀尤为敏感,可以准确显示血液产物和小静脉结构。使得常规MR序列无法准确显示的微小出血得以显示,同时,它的出现将脑微出血的研究带入了一个新境界,成为研究的热点之一。脑微出血(cerebral microbleeds,CMBs)是在1994年MRI的梯度回波序列(gradient-echo sequence,GRE)临床运用后首次描述的。其定义为T2*加权梯度回波序列检出的均匀一致的圆形信号减低区,直径2～5mm,曾被称为点状出血(intracerebral patechialhemorrhage,IPH)。脑微出血病灶小,周围无水肿,多不引起临床症状,往往被人们忽视。大量研究表明微出血是微血管病变的重要标志,可在健康老年人、缺血性脑血管疾病、脑内出血、脑血管淀粉样变性(cerebral amyloid angiopathy,CAA)、常染色体显性遗传性皮层下缺血性脑动脉病(cerebral autosomaldominant arteriopathy with subcortical infarcts and leukoencephalopathy,CADASIL)和脑白质病等中出现,可预测再发性脑出血及抗凝后脑出血等并发症,具有重要的临床意义。
本实验研究的目的是通过动物实验比较脑出血在MR常规序列与SWI检出率的差异,探讨其对微出血检出的敏感性;通过与组织学血肿体积的比较,计算出SWI对出血病变的放大率。
[材料和方法]
1、实验动物和分组
随机选择清洁级雄性SD大鼠54只,体重210～240g。由郑州大学动物实验中心提供。随机分为对照组和实验组,对照组:9只,行开颅、钻孔、进针但不注血,实验组:45只,行开颅、钻孔、进针及注血。以上动物于手术结束后0.5h、3h、12h、24h、48h、72h、1w、2w、4w分别进行MRI检查,并取各时段病理标本。
2、脑内血肿模型制作:
将大鼠固定于立体定位仪,取前囟前0.4mm,向右旁开3mm处,使用颅骨钻钻一大小约1mm直径的小孔,进针6mm。取自体股静脉血20ul注入(2分钟内),留针10分钟后拔出,封闭骨孔,缝合,行MR扫描。
3、MR扫描技术参数及观察指标
使用德国西门子公司Trio Tim3.0T超导磁共振,Loop 4线圈,实验组和对照组在造模后0.5h、3h、12h、24h、48h、72h、1w、2w、4w行T_1WI、T_2WI、T_2*WI、SWI扫描,T_1WI采用快速自旋回波(TSE)序列:TE12ms,TR430ms,矩阵256×256,FOV 70×70mm,层厚2mm,层间距0.2mm,层数20;T_2WI采用快速自旋回波(TSE)序列:TE98ms,TR5990ms,矩阵256×256,FOV 70×70mm,层厚2mm,层间距0.2mm,层数20;GRE序列:TE20ms,TR500ms,矩阵256×256,FOV 70×70mm,层厚2mm,层间距0.2mm,层数20,翻转角20度;SWI序列:TE20ms,TR29ms,矩阵256×256,FOV 70×70mm,层厚0.6mm,层间距0.12mm,层数20,翻转角15度。图像传入SyngoVE27工作站测量各序列血肿体积值,SWI序列血肿体积的测量在MNIP图上进行。血肿体积=各层血肿面积×(层厚+层间距)×1/2;SWI放大率=SWI所测得体积/大体标本所测得体积。
4、神经行为测试
大鼠处死前参照Zea Longa等的方法进行神经功能缺损评分,以测试脑微出血模型建立后大鼠是否存在神经功能损伤。
5、病理检查
各时段MRI扫描并完成神经行为测试后,将大鼠处死,取脑,以穿刺针道为中心,以层厚2mm均匀冠状面切开鼠脑,脱水、石蜡包埋后行普鲁士蓝染色,测量血肿体积及观察出现异常MR信号区域的组织学改变。
6、统计学分析
数据使用SPSS11.0统计软件包进行统计学处理,两组计量资料比较用t检验,多组计量资料比较用方差分析,计数资料使用x~2检验,以以α=0.05作为检验水准。
[结果]
1、45只实验组大鼠T_1WI和T_2WI共检出血肿39处,检出率为86.7%;SWI序列全部检出,检出率100%;
2、T_2WI共检出血肿39处,平均体积为0.830±0.416(×10~(-3)mm~3);SWI序列共检出血肿45处,血肿平均体积1.271±0.530(×10~(-3)mm~3);大体标本血肿平均体积0.967±0.764(×10~(-3)mm~3);
3、各时间点SWI序列(MNIP图)、T_2WI与大体标本血肿体积进行比较,大体标本所测得血肿体积与T_2WI所示体积相比无统计学意义(P=0.285＞0.05),大体标本所测得血肿体积与SWI序列(MNIP图)所示体积相比有统计学意义(P=0.017＜0.05),T_2WI与SWI序列(MNIP图)相比,T_2WI对血肿的显示较为准确,而SWI序列(MNIP图)对血肿的显示有放大作用;平均放大率为2.152±1.500;
4、0.5h-4w之间血肿平均体积变化在T_2WI、SWI及大体标本均逐渐减小,SWI放大率在1w时最大,0.5h时最小。
[结论]
1、SWI序列对微出血的检出优于T_WI和T_2WI;
2、T_2WI所检出的血肿体积更接近大体标本,SWI序列(MNIP图)对血肿有放大效应,放大率为2.152±1.500;
3、SWI作为一种新技术辅助常规序列检测脑微出血,具有敏感性高,图像清晰的特点,本研究为进一步运用于临床提供了实验基础和理论基础的依据,并为临床诊治脑微出血提供了重要的指导意义。
Background and Purpose:Recently,accompany with the development of the MR device,Susceptibility-weighted imaging(SWI) is an new imaging technique that was developed by Haacke et al.in 2004 based on T_2~*-gradient echo sequence,which is a high-spatial-resolution 3D gradient-echo MR imaging technique with long echo time and flow compensation applied in 3 directions,so the character of it is high resolution,3D,high signal-noise-ratio,and the magnitude image is multiplited several times by the phase mask imaging in this technique,which is generated by filtering the phase imaging,it become very sensitive to the nonhomogenuous of magnetic field generated by the different magnetic susceptibilitys,so SWI has dramatically improved the visualization not only hemorrhage and ferrugination,but also of venous structures, permitting smaller bleeding lesions to be depicted.The cerebral microbleeds get to the new level because of it and become one of the hots.Cerebral microbleeds as called as intracerebral patechial hemorrhage were first described after the clinical use of GRE in 1994 and are usually defined as rounded foci of＜5mm in size.We often ignore them because the person has them is not present syndrome,and no edema induced by microbleeds.Many study indicates cerebral microbleeds are the macker of the microvascular diseases,which have documented in healthy populations,patients with ischemic cerebrovascular disease,cerebral hemorrhage,intracerebral amyloid angiopathy,cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy,leukoencephalopathy and so on.Cerebral microbleeds have important clinical application because they can predict the recurrent of intracerebrl hemorrhage and hemorrhage after anticoagulant therapy.
The research is to(1) compare with routine sequence of MR and SWI,to assess the susceptibility of SWI in cerebral microbleeds(2) compared by histopathological hematoma volume,figure out the amplification ratio of SWI.
Materials and methods:
1.Experiment materials:This study used 54 male Sprague-Dawley rats weighting from 210-240g,provided by experimental animal center of Zhengzhou university. Divided into control group(n=9) and experimental group(n=45).The rats of control group underwent intracranial needle insertion but without blood injection,the rats of control group underwent intracranial needle insertion anf blood injection.At 0.5h、3h、12h、24h、48h、72h、1w、2w、4w after operation,all the rats were scaned by MRI,And then the rats were sacrificed,the brain tissue were moved from skull for histopathology.
2.Production of cerebral microbleed:The rat was placed in a stereotactic frame,and a cranial drill was introduced through a burr hole(1mm) into the right striatum(3mm lateral to midline,0.4mm anterior to bregma,6mm below the surface of the skull. Each rat received a 20μL injection of fresh blood(over 2 min).The blood used for injection was taken from a femoral vein.The injection cannula was slowly withdrawn 10 min after injection,and the burr hole was sealed with bone wax,the wound was sutured,and the animal was immediately transferred to the magnet.Control group was underwent intracranial needle insertion but without blood injection.
3.MR scan:ALL rats underwent the T_1WI、T_2WI、T_2~*WI and SWI with SIEMENS Trio Tim 3.0T MR scanner.Choose the Loop 4 coil.The T_1WI(TSE):12ms TE,430ms TR,256×256 matrix,70×70mm FOV,2mm slicethickness,0.2mm slicethickness insertion,20 sclices;T_2WI(TSE):98ms TE,5990ms TR,256×256 matrix,70×70mm FOV,2mm slicethickness,0.2mm slicethickness insertion,20 sclices;T_2~*WI(GRE): 20ms TE 500ms,TR 256×256 matrix,70×70mm FOV 2mm slicethickness 0.2mm slicethickness insertion 20,sclices 20,Flip angle;SWI:20ms TE,29ms TR,256×256 matrix,70×70mm FOV,0.6mm slicethickness,0.12mm slicethickness insertion,20 sclices,15 Flip angle.ALL process were on the Syno VE27 workshop to calculate the volumes of microblees on T2WI and SWI.The volume was equal to half of sclicethickness and insertion.
4.Test of neurological behavior:according to Zea Longa neurological deficit score to assessed whether have the damaged degree of neurological function after produce cerebral microbleed model or not.
5.Histopathology
After scan and test of neurological behavior,rats were sacrificed,the brain tissues were quickly moved from the skull,and 2mm thick sections were cut in the coronal plane through the needle,Brain slices were dehydrated and embedded in the paraffin wax and stained with Prussian blue.
6.Statistical analysis
Statistical analysis was performed with SPSS 11.0 software;statistical methods were t-test and analysis of variance.
Result
1.In 45 experimental rats,39 microbleeds are apperence on T_1WI and T_2WI which detection ratio is 86.7%;all of microbleeds are apperence on SWI which detection ratio is 100%;
2.39 microbleeds are found on T_2WI,the average volume of the lesions is 0.830±0.416 (×10~(-3)mm~3);45 microbleeds are found on SWI,the average volume of the lesions is 1.271±0.530(×10~(-3)mm~3);the average volume of the lesions in histopathology is 0.967±0.764(×10~(-3)mm~3)
3.Compared with SWI(MNIP mapping),T_2WI and histopathology,There were not statistically differences between volumes in T_2WI and histopathology(P=0.285＞0.05) but were tatistically differences between volumes in histopathology and SWI(MNIP mapping).The T_2WI and histological volumes were in close numerical agreement.By contrast,the SWI lesion volume overestimated the histological volume by 2.152±1.500;
4.Volume of the lesions is decreased from 0.5h to 4w on T_2WI,SWI and histology,but amplification ratio of SWI is the largest in 1w and the smallest in 0.5h
Conclusions
1.According to experiment,SWI is prior to the routine sequence to find out microbleeds
2.According to the volumes computed from SWI(MNIP mapping),T_2WI and histopathology,we find the T_2WI and histological volumes were in close numerical agreement.By contrast,the SWI lesion volume overestimated the histological volume by 2.152±1.500.
3.SWI could be served as an effective method for diagnosing cerebral microbleeds.
本实验研究的目的是通过动物实验比较脑出血在MR常规序列与SWI检出率的差异,探讨其对微出血检出的敏感性;通过与组织学血肿体积的比较,计算出SWI对出血病变的放大率。
[材料和方法]
1、实验动物和分组
随机选择清洁级雄性SD大鼠54只,体重210～240g。由郑州大学动物实验中心提供。随机分为对照组和实验组,对照组:9只,行开颅、钻孔、进针但不注血,实验组:45只,行开颅、钻孔、进针及注血。以上动物于手术结束后0.5h、3h、12h、24h、48h、72h、1w、2w、4w分别进行MRI检查,并取各时段病理标本。
2、脑内血肿模型制作:
将大鼠固定于立体定位仪,取前囟前0.4mm,向右旁开3mm处,使用颅骨钻钻一大小约1mm直径的小孔,进针6mm。取自体股静脉血20ul注入(2分钟内),留针10分钟后拔出,封闭骨孔,缝合,行MR扫描。
3、MR扫描技术参数及观察指标
使用德国西门子公司Trio Tim3.0T超导磁共振,Loop 4线圈,实验组和对照组在造模后0.5h、3h、12h、24h、48h、72h、1w、2w、4w行T_1WI、T_2WI、T_2*WI、SWI扫描,T_1WI采用快速自旋回波(TSE)序列:TE12ms,TR430ms,矩阵256×256,FOV 70×70mm,层厚2mm,层间距0.2mm,层数20;T_2WI采用快速自旋回波(TSE)序列:TE98ms,TR5990ms,矩阵256×256,FOV 70×70mm,层厚2mm,层间距0.2mm,层数20;GRE序列:TE20ms,TR500ms,矩阵256×256,FOV 70×70mm,层厚2mm,层间距0.2mm,层数20,翻转角20度;SWI序列:TE20ms,TR29ms,矩阵256×256,FOV 70×70mm,层厚0.6mm,层间距0.12mm,层数20,翻转角15度。图像传入SyngoVE27工作站测量各序列血肿体积值,SWI序列血肿体积的测量在MNIP图上进行。血肿体积=各层血肿面积×(层厚+层间距)×1/2;SWI放大率=SWI所测得体积/大体标本所测得体积。
4、神经行为测试
大鼠处死前参照Zea Longa等的方法进行神经功能缺损评分,以测试脑微出血模型建立后大鼠是否存在神经功能损伤。
5、病理检查
各时段MRI扫描并完成神经行为测试后,将大鼠处死,取脑,以穿刺针道为中心,以层厚2mm均匀冠状面切开鼠脑,脱水、石蜡包埋后行普鲁士蓝染色,测量血肿体积及观察出现异常MR信号区域的组织学改变。
6、统计学分析
数据使用SPSS11.0统计软件包进行统计学处理,两组计量资料比较用t检验,多组计量资料比较用方差分析,计数资料使用x~2检验,以以α=0.05作为检验水准。
[结果]
1、45只实验组大鼠T_1WI和T_2WI共检出血肿39处,检出率为86.7%;SWI序列全部检出,检出率100%;
2、T_2WI共检出血肿39处,平均体积为0.830±0.416(×10~(-3)mm~3);SWI序列共检出血肿45处,血肿平均体积1.271±0.530(×10~(-3)mm~3);大体标本血肿平均体积0.967±0.764(×10~(-3)mm~3);
3、各时间点SWI序列(MNIP图)、T_2WI与大体标本血肿体积进行比较,大体标本所测得血肿体积与T_2WI所示体积相比无统计学意义(P=0.285＞0.05),大体标本所测得血肿体积与SWI序列(MNIP图)所示体积相比有统计学意义(P=0.017＜0.05),T_2WI与SWI序列(MNIP图)相比,T_2WI对血肿的显示较为准确,而SWI序列(MNIP图)对血肿的显示有放大作用;平均放大率为2.152±1.500;
4、0.5h-4w之间血肿平均体积变化在T_2WI、SWI及大体标本均逐渐减小,SWI放大率在1w时最大,0.5h时最小。
[结论]
1、SWI序列对微出血的检出优于T_WI和T_2WI;
2、T_2WI所检出的血肿体积更接近大体标本,SWI序列(MNIP图)对血肿有放大效应,放大率为2.152±1.500;
3、SWI作为一种新技术辅助常规序列检测脑微出血,具有敏感性高,图像清晰的特点,本研究为进一步运用于临床提供了实验基础和理论基础的依据,并为临床诊治脑微出血提供了重要的指导意义。
Background and Purpose:Recently,accompany with the development of the MR device,Susceptibility-weighted imaging(SWI) is an new imaging technique that was developed by Haacke et al.in 2004 based on T_2~*-gradient echo sequence,which is a high-spatial-resolution 3D gradient-echo MR imaging technique with long echo time and flow compensation applied in 3 directions,so the character of it is high resolution,3D,high signal-noise-ratio,and the magnitude image is multiplited several times by the phase mask imaging in this technique,which is generated by filtering the phase imaging,it become very sensitive to the nonhomogenuous of magnetic field generated by the different magnetic susceptibilitys,so SWI has dramatically improved the visualization not only hemorrhage and ferrugination,but also of venous structures, permitting smaller bleeding lesions to be depicted.The cerebral microbleeds get to the new level because of it and become one of the hots.Cerebral microbleeds as called as intracerebral patechial hemorrhage were first described after the clinical use of GRE in 1994 and are usually defined as rounded foci of＜5mm in size.We often ignore them because the person has them is not present syndrome,and no edema induced by microbleeds.Many study indicates cerebral microbleeds are the macker of the microvascular diseases,which have documented in healthy populations,patients with ischemic cerebrovascular disease,cerebral hemorrhage,intracerebral amyloid angiopathy,cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy,leukoencephalopathy and so on.Cerebral microbleeds have important clinical application because they can predict the recurrent of intracerebrl hemorrhage and hemorrhage after anticoagulant therapy.
The research is to(1) compare with routine sequence of MR and SWI,to assess the susceptibility of SWI in cerebral microbleeds(2) compared by histopathological hematoma volume,figure out the amplification ratio of SWI.
Materials and methods:
1.Experiment materials:This study used 54 male Sprague-Dawley rats weighting from 210-240g,provided by experimental animal center of Zhengzhou university. Divided into control group(n=9) and experimental group(n=45).The rats of control group underwent intracranial needle insertion but without blood injection,the rats of control group underwent intracranial needle insertion anf blood injection.At 0.5h、3h、12h、24h、48h、72h、1w、2w、4w after operation,all the rats were scaned by MRI,And then the rats were sacrificed,the brain tissue were moved from skull for histopathology.
2.Production of cerebral microbleed:The rat was placed in a stereotactic frame,and a cranial drill was introduced through a burr hole(1mm) into the right striatum(3mm lateral to midline,0.4mm anterior to bregma,6mm below the surface of the skull. Each rat received a 20μL injection of fresh blood(over 2 min).The blood used for injection was taken from a femoral vein.The injection cannula was slowly withdrawn 10 min after injection,and the burr hole was sealed with bone wax,the wound was sutured,and the animal was immediately transferred to the magnet.Control group was underwent intracranial needle insertion but without blood injection.
3.MR scan:ALL rats underwent the T_1WI、T_2WI、T_2~*WI and SWI with SIEMENS Trio Tim 3.0T MR scanner.Choose the Loop 4 coil.The T_1WI(TSE):12ms TE,430ms TR,256×256 matrix,70×70mm FOV,2mm slicethickness,0.2mm slicethickness insertion,20 sclices;T_2WI(TSE):98ms TE,5990ms TR,256×256 matrix,70×70mm FOV,2mm slicethickness,0.2mm slicethickness insertion,20 sclices;T_2~*WI(GRE): 20ms TE 500ms,TR 256×256 matrix,70×70mm FOV 2mm slicethickness 0.2mm slicethickness insertion 20,sclices 20,Flip angle;SWI:20ms TE,29ms TR,256×256 matrix,70×70mm FOV,0.6mm slicethickness,0.12mm slicethickness insertion,20 sclices,15 Flip angle.ALL process were on the Syno VE27 workshop to calculate the volumes of microblees on T2WI and SWI.The volume was equal to half of sclicethickness and insertion.
4.Test of neurological behavior:according to Zea Longa neurological deficit score to assessed whether have the damaged degree of neurological function after produce cerebral microbleed model or not.
5.Histopathology
After scan and test of neurological behavior,rats were sacrificed,the brain tissues were quickly moved from the skull,and 2mm thick sections were cut in the coronal plane through the needle,Brain slices were dehydrated and embedded in the paraffin wax and stained with Prussian blue.
6.Statistical analysis
Statistical analysis was performed with SPSS 11.0 software;statistical methods were t-test and analysis of variance.
Result
1.In 45 experimental rats,39 microbleeds are apperence on T_1WI and T_2WI which detection ratio is 86.7%;all of microbleeds are apperence on SWI which detection ratio is 100%;
2.39 microbleeds are found on T_2WI,the average volume of the lesions is 0.830±0.416 (×10~(-3)mm~3);45 microbleeds are found on SWI,the average volume of the lesions is 1.271±0.530(×10~(-3)mm~3);the average volume of the lesions in histopathology is 0.967±0.764(×10~(-3)mm~3)
3.Compared with SWI(MNIP mapping),T_2WI and histopathology,There were not statistically differences between volumes in T_2WI and histopathology(P=0.285＞0.05) but were tatistically differences between volumes in histopathology and SWI(MNIP mapping).The T_2WI and histological volumes were in close numerical agreement.By contrast,the SWI lesion volume overestimated the histological volume by 2.152±1.500;
4.Volume of the lesions is decreased from 0.5h to 4w on T_2WI,SWI and histology,but amplification ratio of SWI is the largest in 1w and the smallest in 0.5h
Conclusions
1.According to experiment,SWI is prior to the routine sequence to find out microbleeds
2.According to the volumes computed from SWI(MNIP mapping),T_2WI and histopathology,we find the T_2WI and histological volumes were in close numerical agreement.By contrast,the SWI lesion volume overestimated the histological volume by 2.152±1.500.
3.SWI could be served as an effective method for diagnosing cerebral microbleeds.
引文
1.Fazekas F,Kleinert R,Roob C,Kleinert G,Kapeller P,Schmidt R,Hartung HP.Histopathologic analysis of foci of signal loss on gradient-echo T2~*-weighted MR images in patients with spontaneous intracerebral hemorrhage:evidence of microangiopathy-related microbleeds.AJNR AM J Neuroradiol.1999;20(4):637-642.
2.Offenbacher H,Fazekas F,Schmidt R,Koch M,Fazekas G,Kapeller P.MR of cerebral abnormalities concomitant with primary intracerebral hematomas.AJNR Am J Neuroradiol.1996;17:573-578.
3.Scharf J,Brauherr E,Forsting M,Sartor K.Significance of haemorrhagic lacunes on MRI in patients with hypertensive cerebrovascular disease and intracerebral haemorrhage.Neuroradiology.1994;36(7):504-508.
4.Anand Viswanathan,Huguer Chabriat,et al.Cerebral microhemorrhage.Stroke,2006;37:550-555
5.Salka S.Staekenborg,Esther L.G.E.Koedam,Wouter J.P.Henneman,Progression of mild cognitive impairment to dementia contribution of cerebrovascular disease compared with medial temporal lobe atrophy.Stroke.2009;40:1269-1274.
6.杨正汉,冯逢,王霄英等,《磁共振成像技术指南》,2007,1,324-326.
7.邓世山,王松,张本斯等,自体血与胶原酶注入大鼠尾状核建立脑出血模型的比较研究【J】.四川解剖学报,2003,11(1):8-11.
8.张朋奇,朱贤立,赵甲山,等.一种大鼠脑内出血模型的建立与评价【J】.中国临床神经外科杂志,2005,10(1):33-35.
9.Longa EZ.Weinstein PR.Carlson S et al.Reversible middle cerebral artery occlusion without craniectomy in rats.Stroke 1989:20(1):84-91.
10.Meike W.Vernooi J,M.Arfan Ikram,Piotr A,et al.Cerebral microleeds:accelerated 3D T2~*-weighted GRE MR imaging versus conventional 2D T2~*-weighted GRE MR imaging for detection.Radiology,2008,248(19):272-277.
11. E.Mark Haacke,Muhammad Ayaz,Asadullan Khan,et al.Establishing a baseline phase behavior in magnetic resonance imaging to determine normal vs abnormal iron content in the brain.Journal of magnetic resonance imaging,2007, 26:256-264.
12. Haacke EM,Xu Y,Cheng YC,et al.Susceptibility weighted imaging(SWI). Magn Reson Med,2004,52(3):612-618.
13. Gomori JM,Grossman RI,Yu-Ip C,et al.NMR relaxation times of blood: dependence on field strength:oxidation state,and cell integrity.J Comput Assist Tomogr,1987,ll:684-690.
14. Reichinbach JR,Venkatesan R,Yablonskiy DA,et al.Theory and application of static field inhomegeneity effects in gradient-echo imaging.J Magn Reson Imaging. 1997,7:266-279.
15. Wang Y,Yu Y,Li D,et al.Artery and vein separation using susceptibility -dependent phase in contrast-enhanced MRA.J Magn Reson Imaging, 1999, 10: 118-123.
16. Kwa VI,Franke CL,Verbeeten B Jr,et al.Silent intracerebral microhemorrhages in patients with ischemic stroke.Amesterdam Vascular Medicine Group.Ann Neurol,1998,44(3):372-377.
17. Greenberg SM,O ' Donnel HC,Schaefer PW,et al.MRI detection of new hemorrhage:potential marker of progression in cerebral amyloid angiopathy. Neurology,1999,53(5):1135-1138.
18. Roob G, Lechner A, Schmidt R,et al.Frequency and location of microbleeds in patients with primary intracerebml hemorrhage. Stroke, 2000, 31(11):2665-2669.
19. Kato H, Lzumiyama M, Lzumiyama K, et al.Slienct cerebral microbleeds on T2*-weighted MRI:correlation with stroke subtype,stroke recurrence and leukoaraiosis. Stroke, 2002, 3(6)3: 1536-1540.
20. Nighoghossian N,Hermier M,Adeleine P,et al.Old microbleeds are a potential risk factor for cerebral bleeding after ischemic stroke:a gradient-echo T2*-weighted brain MRI study. Stroke, 2002,33(3):735-742.
21. Hans-Christian Koennecke.Cerebral microbleeds on MRI: prevalence, associations,and potential clinical implications.Neurology,2006,66:165-171.
22. Jeerakathil T, Wolf PA, Beiser A, et al.Cerebral microbleeds prevalence and associations with cardiovascular risk factors in the Framingham study. Stroke, 2004, 35(8):1831-1835.
23. Horita Y, lmaizumi T, Niwa J, e t al. Anaysis of dot-like hemosiderin spots using brain dock system.NoShinkei Geka,2003,31(3):263-267.
24. Kinoshita T,Okudera T,Tamura H,et al.Assessment of lacunar hemorrhage associated with hypertensive stroke by echo-plannar gradient-echo T2*- weighted MRI. Stroke, 2000, 31(7): 1646 -1650.
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26. Lee SH, Park JM, Kwon SJ,et al.Left ventricular hypertrophy is associated with cerebral microbleeds in hypertensive patients. Neurology, 2004, 63:16-21.
27. Greenberg SM, Eng JA, Ning MM,et al.Hemorrhage burden predicts recurrent intracerebral hemorrhage after lobar hemorrhage [J].Stroke, 2004,35:1415-1420.
28. Lee SH, Bae HJ, Kwon SJ et al.Cerebral microbleeds are regionally assiociated with intracerebral hemorrhage [J].Neurology, 2004,62(1):72-76.
29. Kim DE, Bae HJ,Lee SH,et al.Gradient echo magetic resonance imaging in the prediction of hemorrhagic vs ischiemic stroke:a need for the consideration of the extent of lerkoarosis[J].Arch Neurl.2002,59(3):425-429.
30. E.M.Haacke,Z.S.Delproposto,S.Chaturvedi,et al.Imaging cerebral amyloid angiopathy with susceptibility-weighted imaging.AJNR Am J Neuroradiol, 2007, 28:316-317.
31. Greenberg SM, Eng JA, Ning M,et al. Hemorrhage burden prdict recurrent intracerebral hemorrhage after lobar hemorrhage[J]Stroke, 2004,35(6): 415- 420.
32. Choi JC, Kang SY, Kang JH,et al. Intracerebral hemorrhages in CADASIL[J].Neurology, 2006,67(1):2042-2044.
33. Lee SH,Bae HJ,Yoon BW, et al.Low concentration of serum total cholesterol is associated with multi focal signal loss lesions on gradient-echo magnetic resonance imaging.Analysis of risk factors for multi focal signal loss lesions [J]. Stroke,2002,33(12):2845-2849.
34. Salka S. Staekenborg, Esther L.G.E. Koedam, Wouter J.P. Henneman,et al. Progression of mild cognitive impairment to dementia:contribution of cerebrovascular disease compared with medial temporal lobe atrophy.Stroke 2009,40:1269-1274.
35. David J.Werring,Duncan W. Frazer,Lucy J.Coward,et al.Cognitive dys- function in patients with cerebral microbleeds on T2*-weighted gradient-echo MRI,Brain,2004,127:2265-2275.
36. Kidwell CS,Chalela JA,Saver JI,et al.Comparison of MRI and CT for detection of acute intracerebral hemorrhage [J]. JAMA, 2004,292 (15): 1823 - 1830.
37. Hermier M, Nighoghossian N. Contribution of susceptibility-weigted imaging to acute stroke assessment.Stroke, 2004,35:1989 -1994.
38. Luxia Liang, Yukunori Korogi, Takeshi Sugahara,et al. Detection of hyperacute primary intraparenchymal hemorrhage by magnetic resonance imaging[J]. AJNR Am J Neuroradiol.1999,20:1527-1534.
39. Linfante I, Llinas RH, Caplan LR, Warach S. MRI features of intracerebral hemorrhage within 2 hours from symptom onset. Stroke. 1999;30:2263-2267.
40. Wycliffe ND,Choe J,Holshouser B,et al.Reliability in detection of hemorrhage in acute stroke by a new three-dimensional gradient recalled echo susceptibility-weighted imaging techniques compared to computed tomography : a restropective study.J Magn Reson Imaging,2004,20(3): 372-377.
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2.Offenbacher H,Fazekas F,Schmidt R,Koch M,Fazekas G,Kapeller P.MR of cerebral abnormalities concomitant with primary intracerebral hematomas.AJNR Am J Neuroradiol.1996;17:573-578.
3.Scharf J,Brauherr E,Forsting M,Sartor K.Significance of haemorrhagic lacunes on MRI in patients with hypertensive cerebrovascular disease and intracerebral haemorrhage.Neuroradiology.1994;36(7):504-508.
4.Anand Viswanathan,Huguer Chabriat,et al.Cerebral microhemorrhage.Stroke,2006;37:550-555
5.Salka S.Staekenborg,Esther L.G.E.Koedam,Wouter J.P.Henneman,Progression of mild cognitive impairment to dementia contribution of cerebrovascular disease compared with medial temporal lobe atrophy.Stroke.2009;40:1269-1274.
6.杨正汉,冯逢,王霄英等,《磁共振成像技术指南》,2007,1,324-326.
7.邓世山,王松,张本斯等,自体血与胶原酶注入大鼠尾状核建立脑出血模型的比较研究【J】.四川解剖学报,2003,11(1):8-11.
8.张朋奇,朱贤立,赵甲山,等.一种大鼠脑内出血模型的建立与评价【J】.中国临床神经外科杂志,2005,10(1):33-35.
9.Longa EZ.Weinstein PR.Carlson S et al.Reversible middle cerebral artery occlusion without craniectomy in rats.Stroke 1989:20(1):84-91.
10.Meike W.Vernooi J,M.Arfan Ikram,Piotr A,et al.Cerebral microleeds:accelerated 3D T2~*-weighted GRE MR imaging versus conventional 2D T2~*-weighted GRE MR imaging for detection.Radiology,2008,248(19):272-277.
11. E.Mark Haacke,Muhammad Ayaz,Asadullan Khan,et al.Establishing a baseline phase behavior in magnetic resonance imaging to determine normal vs abnormal iron content in the brain.Journal of magnetic resonance imaging,2007, 26:256-264.
12. Haacke EM,Xu Y,Cheng YC,et al.Susceptibility weighted imaging(SWI). Magn Reson Med,2004,52(3):612-618.
13. Gomori JM,Grossman RI,Yu-Ip C,et al.NMR relaxation times of blood: dependence on field strength:oxidation state,and cell integrity.J Comput Assist Tomogr,1987,ll:684-690.
14. Reichinbach JR,Venkatesan R,Yablonskiy DA,et al.Theory and application of static field inhomegeneity effects in gradient-echo imaging.J Magn Reson Imaging. 1997,7:266-279.
15. Wang Y,Yu Y,Li D,et al.Artery and vein separation using susceptibility -dependent phase in contrast-enhanced MRA.J Magn Reson Imaging, 1999, 10: 118-123.
16. Kwa VI,Franke CL,Verbeeten B Jr,et al.Silent intracerebral microhemorrhages in patients with ischemic stroke.Amesterdam Vascular Medicine Group.Ann Neurol,1998,44(3):372-377.
17. Greenberg SM,O ' Donnel HC,Schaefer PW,et al.MRI detection of new hemorrhage:potential marker of progression in cerebral amyloid angiopathy. Neurology,1999,53(5):1135-1138.
18. Roob G, Lechner A, Schmidt R,et al.Frequency and location of microbleeds in patients with primary intracerebml hemorrhage. Stroke, 2000, 31(11):2665-2669.
19. Kato H, Lzumiyama M, Lzumiyama K, et al.Slienct cerebral microbleeds on T2*-weighted MRI:correlation with stroke subtype,stroke recurrence and leukoaraiosis. Stroke, 2002, 3(6)3: 1536-1540.
20. Nighoghossian N,Hermier M,Adeleine P,et al.Old microbleeds are a potential risk factor for cerebral bleeding after ischemic stroke:a gradient-echo T2*-weighted brain MRI study. Stroke, 2002,33(3):735-742.
21. Hans-Christian Koennecke.Cerebral microbleeds on MRI: prevalence, associations,and potential clinical implications.Neurology,2006,66:165-171.
22. Jeerakathil T, Wolf PA, Beiser A, et al.Cerebral microbleeds prevalence and associations with cardiovascular risk factors in the Framingham study. Stroke, 2004, 35(8):1831-1835.
23. Horita Y, lmaizumi T, Niwa J, e t al. Anaysis of dot-like hemosiderin spots using brain dock system.NoShinkei Geka,2003,31(3):263-267.
24. Kinoshita T,Okudera T,Tamura H,et al.Assessment of lacunar hemorrhage associated with hypertensive stroke by echo-plannar gradient-echo T2*- weighted MRI. Stroke, 2000, 31(7): 1646 -1650.
25. Leon H.G Henskens,Robert J.van Oostenbrugge,Abranham A. Kroon,et al.Brain microbleeds are associated with ambulatory blood pressure levels in a hypertensive population.Hypertension,2008,51;62-28.
26. Lee SH, Park JM, Kwon SJ,et al.Left ventricular hypertrophy is associated with cerebral microbleeds in hypertensive patients. Neurology, 2004, 63:16-21.
27. Greenberg SM, Eng JA, Ning MM,et al.Hemorrhage burden predicts recurrent intracerebral hemorrhage after lobar hemorrhage [J].Stroke, 2004,35:1415-1420.
28. Lee SH, Bae HJ, Kwon SJ et al.Cerebral microbleeds are regionally assiociated with intracerebral hemorrhage [J].Neurology, 2004,62(1):72-76.
29. Kim DE, Bae HJ,Lee SH,et al.Gradient echo magetic resonance imaging in the prediction of hemorrhagic vs ischiemic stroke:a need for the consideration of the extent of lerkoarosis[J].Arch Neurl.2002,59(3):425-429.
30. E.M.Haacke,Z.S.Delproposto,S.Chaturvedi,et al.Imaging cerebral amyloid angiopathy with susceptibility-weighted imaging.AJNR Am J Neuroradiol, 2007, 28:316-317.
31. Greenberg SM, Eng JA, Ning M,et al. Hemorrhage burden prdict recurrent intracerebral hemorrhage after lobar hemorrhage[J]Stroke, 2004,35(6): 415- 420.
32. Choi JC, Kang SY, Kang JH,et al. Intracerebral hemorrhages in CADASIL[J].Neurology, 2006,67(1):2042-2044.
33. Lee SH,Bae HJ,Yoon BW, et al.Low concentration of serum total cholesterol is associated with multi focal signal loss lesions on gradient-echo magnetic resonance imaging.Analysis of risk factors for multi focal signal loss lesions [J]. Stroke,2002,33(12):2845-2849.
34. Salka S. Staekenborg, Esther L.G.E. Koedam, Wouter J.P. Henneman,et al. Progression of mild cognitive impairment to dementia:contribution of cerebrovascular disease compared with medial temporal lobe atrophy.Stroke 2009,40:1269-1274.
35. David J.Werring,Duncan W. Frazer,Lucy J.Coward,et al.Cognitive dys- function in patients with cerebral microbleeds on T2*-weighted gradient-echo MRI,Brain,2004,127:2265-2275.
36. Kidwell CS,Chalela JA,Saver JI,et al.Comparison of MRI and CT for detection of acute intracerebral hemorrhage [J]. JAMA, 2004,292 (15): 1823 - 1830.
37. Hermier M, Nighoghossian N. Contribution of susceptibility-weigted imaging to acute stroke assessment.Stroke, 2004,35:1989 -1994.
38. Luxia Liang, Yukunori Korogi, Takeshi Sugahara,et al. Detection of hyperacute primary intraparenchymal hemorrhage by magnetic resonance imaging[J]. AJNR Am J Neuroradiol.1999,20:1527-1534.
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