BOLD及MRS脑温测量对缺血半暗带的价值：实验研究
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摘要
一、BOLD评价猴MCAO及再灌注模型脑缺血半暗带
目的建立猴大脑中动脉闭塞(middle cerebral artery occlusion,MCAO)及再灌注模型。应用血氧合水平依赖(blood oxygenation level dependent,BOLD)成像评价缺血半暗带(ischemic penumbra,IP)特征及演变规律,探讨血流动力学改变对BOLD效应的影响。
对象与方法成年猴6只,应用血管内法制备MCAO及再灌注模型。影像检查包括CT灌注(CTP)、MR灌注(PWI)、弥散成像(DWI)、T2WI、T2像及T2~*像。应用T2像及T2~*像计算R2'像,即BOLD像。测量参数包括局部脑血流量(rCBF)、局部脑血容量(rCBV)、平均通过时间(MTT)、表观弥散系数(ADC)、T2、T2~*及R2'值,计算缺血区与健侧比值,得到相对值。扫描时间为动脉闭塞1-1.5h及再灌注后1h、3h、6h、12h、24h及48h。将低灌注组织定义为在闭塞动脉供血区,再灌注前任何一种PWI参数存在灌注异常的脑区。以缺血组织转归为依据,将低灌注组织划分为三个区域:缺血核心、缺血半暗带及低灌注区。缺血核心定义为动脉闭塞期DWI及再灌注24小时T2WI均为高信号的脑区;半暗带为动脉闭塞期DWI高信号,再灌注24小时T2WI为等信号的脑区;低灌注区为动脉闭塞期DWI及再灌注24小时T2WI均为等信号的低灌注组织。应用多元线性回归分析血流动力学改变对BOLD效应的影响。处死动物后,制作5mm厚横断面大体切片,行TTC染色。
结果(1)6只猴中4只模型成功,TTC染色梗死灶体积与再灌注后24小时T2WI缺血灶体积差别不显著。动脉闭塞期DWI病变体积到再灌注24小时于T2WI明显缩小,平均缩小28%。(2)CTP与PWI所测灌注参数绝对值存在差异,而相对值之间差异不显著。(3)动脉闭塞期,缺血核心、缺血半暗带及低灌注区R2'值存在显著差异,负性BOLD效应以低灌注区最显著,缺血半暗带次之,低灌注区不明显。(4)再灌注期,缺血核心、缺血半暗带及低灌注R2'演变过程不一,以缺血核心变化最显著,由轻度负性BOLD迅速变为正性BOLD。而对于缺血半暗带及低灌注区,负性BOLD效应持续存在,且有增强趋势。(5)rCBF及MTT对缺血区R2'分别具有负性及正性影响。
结论(1)在动脉闭塞期,负性BOLD效应可以区分缺血核心、缺血半暗带及低灌注区,判断缺血组织活性。(2)再灌注期,持续存在的负性BOLD效应提示组织存活;负性BOLD效应消失或转化为正性BOLD效应提示组织坏死。(3)rCBF及MTT为影响缺血区BOLD效应的因素。
二、MRS脑温测量评价猴MCAO及再灌注模型缺血半暗带的可行性研究
目的建立修正的脑温(T)-NAA化学位移方程。应用~1H MRS评价猴MCAO及再灌注模型不同缺血区及对侧脑组织温度演变规律,分析血流动力学及BOLD对脑温变化的影响。
对象与方法制备MR兼容的恒温控制系统,评价系统精度及稳定性。应用~1H MRS对含脑生理液的体模进行检查,得到修正的温度-NAA化学位移方程。应用~1H MRS检测正常猴脑及缺血区温度。应用多元线性回归分析血流动力学及BOLD对脑温变化的影响。
结果(1)制备MR兼容的恒温控制系统控温精度高,可重复性好。建立T-NAA化学位移方程:T=37+100(CS_(NAA)-2.039)。(2)正常猴平均脑温37.16℃,双侧半球间无显著差别。(3)动脉闭塞期,缺血区脑温升高并高于对侧半球脑温。缺血灶内存在温度梯度,缺血半暗带脑温最高,高于缺血核心,而以低灌注区最低。(4)再灌注早期,缺血区脑温均有不同程度下降,以核心区下降最明显;再灌注后期,半暗带及低灌注区脑温逐渐恢复正常,而缺血核心温度反而升高。(5)rCBF对脑温有负性影响,MTT及BOLD对脑温有正性影响。
结论(1)~1H MRS可无创性测量脑温,可显示猴MCAO模型不同缺血区温度梯度。(2)对于猴MCAO模型,rCBF及MTT为影响缺血区脑温的重要因素;BOLD效应有助于对脑温变化的理解。
PartⅠ:The applications of BOLD in brain ischemic penumbra of monkey reversible MCAO model
Objective Cynomologous macaques were used to develop reversible middle cerebral artery occlusion(MCAO)model.To investigate the features and evolution of ischemic penumbra(IP)on blood oxygenation level dependent(BOLD)images and the effects of cerebral hemodynamic changes on BOLD.
Methods Reversible MCAO model were developed in male cynomologous macaques(n=6)by using endovascular techniques.We used the following imaging protocols:CT perfusion,T2WI,DWI,PWI,as well as quantitative T2 map and T2~* map.Animals were scanned with CT and MRI between 1-1.5 hours after occlusion to 1h,3h,6h,12h,24h and 48h hours after reperfusion.Parameters included regional cerebral blood flow(rCBF),regional cerebral blood volume(rCBV),mean transit time(MTT),ADC,T2,T2~* and R2'.Quantitative T2 was linked to quantitative T2~* resulting in BOLD images(R2').The flow-compromised tissue was defined as the abonormal perfusion area on any PWI maps.According to the fate of the ischemic tissue,the flow-compromised tissue could be divided into three distinct areas:ischemic core,ischemic penumbra and regions of oligemia.Ischemic core:the region showed high signal intensity(SI)both on initial DWI and T2WI of hour 24 after reperfusion;ischemic penumbra:the region showed high SI on initial DWI and iso-SI on T2WI of hour 24 after reperfusion;the regions of oligemia:iso-SI both on initial DWI and T2WI of hours 24 after reperfusion.The effects of cerebral hemodynamic changes on BOLD were analyzed using multiple linear regression. Immediately after killing animals,the brains were removed and sliced fresh into axial 5-mm-thick axial slabs and stained with 2,3,5-triphenyltetrazolium chloride(TTC).
Results(1)Reversible MCAO model were demonstrated successful in four cynomologous macaques.T2WI derived lesion volumes in hour 24 after reperfusion were similar to those of infarct measured on TTC.However,T2WI derived lesion volumes were smaller than the volumes of high SI on initial DWI about 28%.(2)The absolute perfusion values derived from CTP and PWI demonstrated definitely different.The discrimination disappeared when the relative ratios were considered. (3)During the MCAO,the SI of ischemic core,ischemic penumbra and regions of oligemia on R2' were different significantly.Strongest negative BOLD appeared within the regions of oligemia,then in ischemic penumbra.No remarkably negative BOLD could be detected within the regions of ischemic core.(4)Afer reperfusion, ischemic penumbra and regions of oligemia on R2' showed different time course.The bold effct changed dramatically from slight negative bold to positive in the region of ischemic core.The negative bold persisted during the reperfusion in the areas of ischemic penumbra and oligemia,and demonstrated a tendency stronger over time.(5)rCBF and MTT showed negative and positive influence on the SI on R2' respectively.
Conculsion(1)During the MCAO,negative BOLD can be used to distinguish the ischemic core from ischemic penumbra and regions of oligemia,and to assess viability of brain tissue.(2)Afer reperfusion,the persistent negative bold sugest the tissue being salvaged while loss of negative blod or positive bold appeared imply tissue being dead.(3)rCBF and MTT are both important factors on BOLD effect.
PartⅡ:Measurement of Brain Temperature with Magnetic Resonance Spectroscopy in brain ischemic penumbra of monkey reversible MCAO model
Objective To establish the modified equation between brain temperature and chemical shift of NAA.To investigate the features and evolution of ischemic penumbra(IP)in brain temperature measured with magnetic resonance spectroscopy and the influence on brain temperature from cerebral hemodynamic changes.
Methods To develope the MRI-compatible thermostatic control system,and assess the precision and stability of the sytem.To establish the modified brain temperature and NAA form through vitro experiment.To measure the brain temperature in flow-compromised tissue in monkey transient MCAO model and normal temperature in the controls.The effects of cerebral hemodynamic changes on brain temperature were analyzed using multiple linear regression.
Results(1)The MRI-compatible thermostatic control system showed high performance in precision and stability.The chemical shift of NAA therefore appeared to vary with temperature,and a modified version of Eq.was given by:T=37+100(CSN_(NAA)-2.039).(2)The normal brain temperature of monkeys was 37.16℃with no different between bilateral hemispheres.(3)After MCAO, temperature in the flow compromised tissue showed higher than those in contralateral hemisphere and normal monkeys.Temperature gradients could be found within the flow compromised region.Highest brain temperature appeared in ischemic penumbra,then the ischemic core and region of oligemia.(4)In the early stage after reperfusion,temperature in the flow compromised tissue decreased in different levels,most significant decrease in ischemic core.In the late stage,after reperfusion,the temperature within region of ischemic penumbra and oligemia recovered to normal while temperature within the ischemic core elevated again.(5) rCBF showed negative influence on brain temperature.
Conculsion(1)~H MRS can be used to measure brain temperature noninvasively and to disclose the the temperature gradient within flow compromised areas.(2) rCBF and MTT are both important factors on brain temperature in monkey reversible MCAO model.Bold is helpful for understanding the changes of brain temperature.
目的建立猴大脑中动脉闭塞(middle cerebral artery occlusion,MCAO)及再灌注模型。应用血氧合水平依赖(blood oxygenation level dependent,BOLD)成像评价缺血半暗带(ischemic penumbra,IP)特征及演变规律,探讨血流动力学改变对BOLD效应的影响。
对象与方法成年猴6只,应用血管内法制备MCAO及再灌注模型。影像检查包括CT灌注(CTP)、MR灌注(PWI)、弥散成像(DWI)、T2WI、T2像及T2~*像。应用T2像及T2~*像计算R2'像,即BOLD像。测量参数包括局部脑血流量(rCBF)、局部脑血容量(rCBV)、平均通过时间(MTT)、表观弥散系数(ADC)、T2、T2~*及R2'值,计算缺血区与健侧比值,得到相对值。扫描时间为动脉闭塞1-1.5h及再灌注后1h、3h、6h、12h、24h及48h。将低灌注组织定义为在闭塞动脉供血区,再灌注前任何一种PWI参数存在灌注异常的脑区。以缺血组织转归为依据,将低灌注组织划分为三个区域:缺血核心、缺血半暗带及低灌注区。缺血核心定义为动脉闭塞期DWI及再灌注24小时T2WI均为高信号的脑区;半暗带为动脉闭塞期DWI高信号,再灌注24小时T2WI为等信号的脑区;低灌注区为动脉闭塞期DWI及再灌注24小时T2WI均为等信号的低灌注组织。应用多元线性回归分析血流动力学改变对BOLD效应的影响。处死动物后,制作5mm厚横断面大体切片,行TTC染色。
结果(1)6只猴中4只模型成功,TTC染色梗死灶体积与再灌注后24小时T2WI缺血灶体积差别不显著。动脉闭塞期DWI病变体积到再灌注24小时于T2WI明显缩小,平均缩小28%。(2)CTP与PWI所测灌注参数绝对值存在差异,而相对值之间差异不显著。(3)动脉闭塞期,缺血核心、缺血半暗带及低灌注区R2'值存在显著差异,负性BOLD效应以低灌注区最显著,缺血半暗带次之,低灌注区不明显。(4)再灌注期,缺血核心、缺血半暗带及低灌注R2'演变过程不一,以缺血核心变化最显著,由轻度负性BOLD迅速变为正性BOLD。而对于缺血半暗带及低灌注区,负性BOLD效应持续存在,且有增强趋势。(5)rCBF及MTT对缺血区R2'分别具有负性及正性影响。
结论(1)在动脉闭塞期,负性BOLD效应可以区分缺血核心、缺血半暗带及低灌注区,判断缺血组织活性。(2)再灌注期,持续存在的负性BOLD效应提示组织存活;负性BOLD效应消失或转化为正性BOLD效应提示组织坏死。(3)rCBF及MTT为影响缺血区BOLD效应的因素。
二、MRS脑温测量评价猴MCAO及再灌注模型缺血半暗带的可行性研究
目的建立修正的脑温(T)-NAA化学位移方程。应用~1H MRS评价猴MCAO及再灌注模型不同缺血区及对侧脑组织温度演变规律,分析血流动力学及BOLD对脑温变化的影响。
对象与方法制备MR兼容的恒温控制系统,评价系统精度及稳定性。应用~1H MRS对含脑生理液的体模进行检查,得到修正的温度-NAA化学位移方程。应用~1H MRS检测正常猴脑及缺血区温度。应用多元线性回归分析血流动力学及BOLD对脑温变化的影响。
结果(1)制备MR兼容的恒温控制系统控温精度高,可重复性好。建立T-NAA化学位移方程:T=37+100(CS_(NAA)-2.039)。(2)正常猴平均脑温37.16℃,双侧半球间无显著差别。(3)动脉闭塞期,缺血区脑温升高并高于对侧半球脑温。缺血灶内存在温度梯度,缺血半暗带脑温最高,高于缺血核心,而以低灌注区最低。(4)再灌注早期,缺血区脑温均有不同程度下降,以核心区下降最明显;再灌注后期,半暗带及低灌注区脑温逐渐恢复正常,而缺血核心温度反而升高。(5)rCBF对脑温有负性影响,MTT及BOLD对脑温有正性影响。
结论(1)~1H MRS可无创性测量脑温,可显示猴MCAO模型不同缺血区温度梯度。(2)对于猴MCAO模型,rCBF及MTT为影响缺血区脑温的重要因素;BOLD效应有助于对脑温变化的理解。
PartⅠ:The applications of BOLD in brain ischemic penumbra of monkey reversible MCAO model
Objective Cynomologous macaques were used to develop reversible middle cerebral artery occlusion(MCAO)model.To investigate the features and evolution of ischemic penumbra(IP)on blood oxygenation level dependent(BOLD)images and the effects of cerebral hemodynamic changes on BOLD.
Methods Reversible MCAO model were developed in male cynomologous macaques(n=6)by using endovascular techniques.We used the following imaging protocols:CT perfusion,T2WI,DWI,PWI,as well as quantitative T2 map and T2~* map.Animals were scanned with CT and MRI between 1-1.5 hours after occlusion to 1h,3h,6h,12h,24h and 48h hours after reperfusion.Parameters included regional cerebral blood flow(rCBF),regional cerebral blood volume(rCBV),mean transit time(MTT),ADC,T2,T2~* and R2'.Quantitative T2 was linked to quantitative T2~* resulting in BOLD images(R2').The flow-compromised tissue was defined as the abonormal perfusion area on any PWI maps.According to the fate of the ischemic tissue,the flow-compromised tissue could be divided into three distinct areas:ischemic core,ischemic penumbra and regions of oligemia.Ischemic core:the region showed high signal intensity(SI)both on initial DWI and T2WI of hour 24 after reperfusion;ischemic penumbra:the region showed high SI on initial DWI and iso-SI on T2WI of hour 24 after reperfusion;the regions of oligemia:iso-SI both on initial DWI and T2WI of hours 24 after reperfusion.The effects of cerebral hemodynamic changes on BOLD were analyzed using multiple linear regression. Immediately after killing animals,the brains were removed and sliced fresh into axial 5-mm-thick axial slabs and stained with 2,3,5-triphenyltetrazolium chloride(TTC).
Results(1)Reversible MCAO model were demonstrated successful in four cynomologous macaques.T2WI derived lesion volumes in hour 24 after reperfusion were similar to those of infarct measured on TTC.However,T2WI derived lesion volumes were smaller than the volumes of high SI on initial DWI about 28%.(2)The absolute perfusion values derived from CTP and PWI demonstrated definitely different.The discrimination disappeared when the relative ratios were considered. (3)During the MCAO,the SI of ischemic core,ischemic penumbra and regions of oligemia on R2' were different significantly.Strongest negative BOLD appeared within the regions of oligemia,then in ischemic penumbra.No remarkably negative BOLD could be detected within the regions of ischemic core.(4)Afer reperfusion, ischemic penumbra and regions of oligemia on R2' showed different time course.The bold effct changed dramatically from slight negative bold to positive in the region of ischemic core.The negative bold persisted during the reperfusion in the areas of ischemic penumbra and oligemia,and demonstrated a tendency stronger over time.(5)rCBF and MTT showed negative and positive influence on the SI on R2' respectively.
Conculsion(1)During the MCAO,negative BOLD can be used to distinguish the ischemic core from ischemic penumbra and regions of oligemia,and to assess viability of brain tissue.(2)Afer reperfusion,the persistent negative bold sugest the tissue being salvaged while loss of negative blod or positive bold appeared imply tissue being dead.(3)rCBF and MTT are both important factors on BOLD effect.
PartⅡ:Measurement of Brain Temperature with Magnetic Resonance Spectroscopy in brain ischemic penumbra of monkey reversible MCAO model
Objective To establish the modified equation between brain temperature and chemical shift of NAA.To investigate the features and evolution of ischemic penumbra(IP)in brain temperature measured with magnetic resonance spectroscopy and the influence on brain temperature from cerebral hemodynamic changes.
Methods To develope the MRI-compatible thermostatic control system,and assess the precision and stability of the sytem.To establish the modified brain temperature and NAA form through vitro experiment.To measure the brain temperature in flow-compromised tissue in monkey transient MCAO model and normal temperature in the controls.The effects of cerebral hemodynamic changes on brain temperature were analyzed using multiple linear regression.
Results(1)The MRI-compatible thermostatic control system showed high performance in precision and stability.The chemical shift of NAA therefore appeared to vary with temperature,and a modified version of Eq.was given by:T=37+100(CSN_(NAA)-2.039).(2)The normal brain temperature of monkeys was 37.16℃with no different between bilateral hemispheres.(3)After MCAO, temperature in the flow compromised tissue showed higher than those in contralateral hemisphere and normal monkeys.Temperature gradients could be found within the flow compromised region.Highest brain temperature appeared in ischemic penumbra,then the ischemic core and region of oligemia.(4)In the early stage after reperfusion,temperature in the flow compromised tissue decreased in different levels,most significant decrease in ischemic core.In the late stage,after reperfusion,the temperature within region of ischemic penumbra and oligemia recovered to normal while temperature within the ischemic core elevated again.(5) rCBF showed negative influence on brain temperature.
Conculsion(1)~H MRS can be used to measure brain temperature noninvasively and to disclose the the temperature gradient within flow compromised areas.(2) rCBF and MTT are both important factors on brain temperature in monkey reversible MCAO model.Bold is helpful for understanding the changes of brain temperature.
引文
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