两血管闭塞联合高Cu~（2+）喂养法致大鼠痴呆模型的MR成像研究
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摘要
目的1.研究双侧颈总动脉结扎联合高喂养法诱导大鼠阿尔茨海默病样行为学和病理学的特征性改变。
2.使用临床型MR活体观察AD模型大鼠不同时期脑的改变,对不同脑区使用T_2 map进行定量分析,同时运用MR序列进行老年斑可视化的可行性研究。
方法随机选择SD大鼠66只,进行双侧颈总动脉结扎术,术中死亡6只,剩余60只。分为两组,2VO+高Cu~(2+)组(30只):饮用水为蒸馏水+Cu~(2+)+5%蔗糖喂养(3月后停止Cu~(2+)喂养,给予蒸馏水),又分为术后3月、6月、9月三组;2VO组(30只):饮用水为蒸馏水+5%蔗糖,也分为术后3月、6月、9月三组;另设正常组24只,采用同样方法分配到各组中,饮用水为蒸馏水+5%蔗糖。分别于术后3月、6月、9月2VO+高Cu~(2+)组、2VO组各组取10只、正常组取8只,进行Morris测试评价行为学改变,然后对大鼠大脑使用T_1WI、T_2WI、T_2*WI、SWI序列进行MR成像研究,使用T_2 map进行大鼠大脑不同脑区的T_2弛豫时间定量分析。最后处死大鼠,进行相关病理学研究(HE染色、银染、Aβ免疫组织化学染色、铁染色、Thioflavine S染色)。三组大鼠不同时间点的平均逃避潜伏时间和T_2磁豫时间比较用两因素测量资料的方差分析。组间比较使用ANOVA方差分析。
结果通过永久性双侧颈总动脉结扎联合高Cu~(2+)法建立了一种新的复合型痴呆模型。Morris水迷宫试验发现术后3、6、9月2VO+Cu~(2+)组、2VO组平均逃避潜伏时间较对照组明显延长(P<0.05或p<0.01),说明与正常组相比出现记忆学习能力缺陷,2VO+Cu~(2+)组与2VO组间比较差异无统计学意义。该模型组病理学研究出现了类似人类AD的神经病理学改变,特别是6月2VO+Cu~(2+)组、9月2VO+Cu~(2+)组及2VO组大鼠出现了类似SPs的结构,皮质和海马区出现Aβ免疫反应阳性细胞。Thioflavine S染色、铁染色、银染都有阳性发现,一些部位出现重叠。6月2VO+Cu~(2+)组、9月2VO+Cu~(2+)组及2VO组皮质和海马区的T_2弛豫时间明显减低,与正常组比较,差异有统计学意义,部分差异显著,2VO+Cu~(2+)组、2VO组海马、颞叶、顶叶皮质的T_2弛豫时间随着年龄的增长,呈下降趋势,差异有统计学意义。而纹状体、丘脑、胼胝体等脑区未见明显差别。使用T_1WI、T_2WI、T_2*WI、SWI序列对模型大鼠进行MR成像,可以发现6月2VO+Cu~(2+)组、9月2VO+Cu~(2+)组及2VO组皮质和海马发现类圆形的低信号区,部分病灶与Aβ免疫组化、Thioflavine S及铁染色阳性发现区域相重叠。对该病灶的显示能力,以T_2*WI最好,T_2WI次之,T_1WI作用不大,SWI虽然对比度好,但是信噪比差,不能排除血管等的影响。
结论两血管闭塞联合高Cu~(2+)喂养法致大鼠痴呆模型是研究AD影像学改变的一种有用的动物模型,它不仅模拟出AD相关的行为学改变,而且亦出现类似人类AD的神经病理学及病理生理学改变。铜的引入,可能通过多种机制加速AD的病理进程。使用MR对这种模型进行影像评价是可行的,该模型大鼠早期海马及皮质的T_2弛豫时间的减低可能提示AD的病理进程,有可能成为AD生物学的标记。同时使用临床型MRI对老年斑的可视化有一定价值,值得进一步探讨。
Objective 1.To study the characteristic behavioral and pathological findings of Alzheimer’s disease induced by 2-vessel occlusion and copper exposure.2. To observed MR findings of brain of the Alzheimer’s disease model rats with clinical 1.5T MR imager in vivo at different stage, T_2 map was used to assess quantitatively the rat brain in different encephalic regions. To investigate the feasibility that plaques can be detected by MRI in this AD rat model in vivo.
Methods Sixty-six SD rats, aged 7~8weeks, were performed by permanent occlusion of bilateral common carotid arteries(2VO). Six rates dead during operation, the surviving 60 rats were divided into two groups randomly. Group 2VO+Cu~(2+) (n=30) and group 2VO. Group 2VO+Cu~(2+)were food with 250ppm copper chloride(CuCl2) in drinking water ( rcontained 5% sucrose ) for 3 months.Control groups included 24 same age rates which were received the same operation but without occlusion of the arteries,The drinking water contained 5% sucrose. At 3th month, 6th month and 9th month after operation, 10 rates selected randomly from each test group and 8 rates from control group were tested by Morris water maze experiment to observe their behavior changes, then performed MR examination using T_1WI、T_2WI、T_2*WI、SWI. T_2 map was used to assess quantitatively T_2 value of the rat brain in different regions. After MR scanning, rates were sacrificed, Whole brains of rates were removed immediately for pathological study (HE staining,thioflavin S staining, immunohistochemistical staining for Aβ,histochemical staining of iron and silver staining ). The SPSS17.0 statistical package (SPSS, Chicago, USA) was used for all calculations.,Mean latent phase and T_2 value of the whole sample at different time-points were evaluated with two-factor measures analysis of variance. Comparison between groups was evaluatated with one-way anova(ANOVA). The results are indicated with mean+standard deviation( x±s) which had a significance level of 0.05.
Results A novel complex rat model of dementia were established by permanent occlusion of bilateral common carotid arteries(2VO) and copper exposure for research of AD. After Morris water maze experiment, mean latent phase of VD+Cu~(2+) group and VO group were longer than that of the sham-operated rats(control group)(p<0.05),but there was no significant difference between 2VO+Cu~(2+)group and 2VO group(p>0.05). The brains of AD rat model appeared pathological changes of Alzheimer’s disease in Group 2VO+CU2+ at the 6th month and the 9th month, group 2VO at the 9th month, which appeared a similar SPs structure, Aβpositive immunoreaction in the cortex and hippocampus .Thioflavin S staining, iron staining and silver staining appeared positive result.some positive appeared in the same brain region. In groups 2VO+Cu~(2+) at the 6th month and the 9th month and groups2VO at 9th month,T_2 value in the cortex and hippocampus of the rat brain descend, there was significant difference compared with control groups. T_2 value had no significant difference in corpus striatum, thalamus and corpus callosum in the rat brain between test group and control group. On MR images with T_1WI、T_2WI、T_2*WI、SWI sequence, some round hypointensity focus can be detected in the cortex and hippocampus of the rat brain in group 2VO+Cu~(2+)at the 6th month and the 9th month, group 2VO at 9th month, Preliminary results indicate that T_2*WI acquisition best accurately reflects plaque,T_2WI inferior to T_2*WI,T_1WI have no effect. SWI have best CNR, but it can not remove the effect of blood vessels.
Conclusion Dementia Rats induced by 2-vessel occlusion and copper exposure is good model for MR imaging. This rat model appeared the behavioral and pathological changes of Alzheimer’s disease. Copper, it can accelerate pathological process of AD. The rat model can be evaluated with MR imaing in vivo.T_2 value descend in the cortex and hippocampus of the rat brain initially, which suggested pathological process of AD.T_2 value may become biological markers of AD. To detect senile plaques with MR imaging in vivo is feasible and deserves further exploration.
2.使用临床型MR活体观察AD模型大鼠不同时期脑的改变,对不同脑区使用T_2 map进行定量分析,同时运用MR序列进行老年斑可视化的可行性研究。
方法随机选择SD大鼠66只,进行双侧颈总动脉结扎术,术中死亡6只,剩余60只。分为两组,2VO+高Cu~(2+)组(30只):饮用水为蒸馏水+Cu~(2+)+5%蔗糖喂养(3月后停止Cu~(2+)喂养,给予蒸馏水),又分为术后3月、6月、9月三组;2VO组(30只):饮用水为蒸馏水+5%蔗糖,也分为术后3月、6月、9月三组;另设正常组24只,采用同样方法分配到各组中,饮用水为蒸馏水+5%蔗糖。分别于术后3月、6月、9月2VO+高Cu~(2+)组、2VO组各组取10只、正常组取8只,进行Morris测试评价行为学改变,然后对大鼠大脑使用T_1WI、T_2WI、T_2*WI、SWI序列进行MR成像研究,使用T_2 map进行大鼠大脑不同脑区的T_2弛豫时间定量分析。最后处死大鼠,进行相关病理学研究(HE染色、银染、Aβ免疫组织化学染色、铁染色、Thioflavine S染色)。三组大鼠不同时间点的平均逃避潜伏时间和T_2磁豫时间比较用两因素测量资料的方差分析。组间比较使用ANOVA方差分析。
结果通过永久性双侧颈总动脉结扎联合高Cu~(2+)法建立了一种新的复合型痴呆模型。Morris水迷宫试验发现术后3、6、9月2VO+Cu~(2+)组、2VO组平均逃避潜伏时间较对照组明显延长(P<0.05或p<0.01),说明与正常组相比出现记忆学习能力缺陷,2VO+Cu~(2+)组与2VO组间比较差异无统计学意义。该模型组病理学研究出现了类似人类AD的神经病理学改变,特别是6月2VO+Cu~(2+)组、9月2VO+Cu~(2+)组及2VO组大鼠出现了类似SPs的结构,皮质和海马区出现Aβ免疫反应阳性细胞。Thioflavine S染色、铁染色、银染都有阳性发现,一些部位出现重叠。6月2VO+Cu~(2+)组、9月2VO+Cu~(2+)组及2VO组皮质和海马区的T_2弛豫时间明显减低,与正常组比较,差异有统计学意义,部分差异显著,2VO+Cu~(2+)组、2VO组海马、颞叶、顶叶皮质的T_2弛豫时间随着年龄的增长,呈下降趋势,差异有统计学意义。而纹状体、丘脑、胼胝体等脑区未见明显差别。使用T_1WI、T_2WI、T_2*WI、SWI序列对模型大鼠进行MR成像,可以发现6月2VO+Cu~(2+)组、9月2VO+Cu~(2+)组及2VO组皮质和海马发现类圆形的低信号区,部分病灶与Aβ免疫组化、Thioflavine S及铁染色阳性发现区域相重叠。对该病灶的显示能力,以T_2*WI最好,T_2WI次之,T_1WI作用不大,SWI虽然对比度好,但是信噪比差,不能排除血管等的影响。
结论两血管闭塞联合高Cu~(2+)喂养法致大鼠痴呆模型是研究AD影像学改变的一种有用的动物模型,它不仅模拟出AD相关的行为学改变,而且亦出现类似人类AD的神经病理学及病理生理学改变。铜的引入,可能通过多种机制加速AD的病理进程。使用MR对这种模型进行影像评价是可行的,该模型大鼠早期海马及皮质的T_2弛豫时间的减低可能提示AD的病理进程,有可能成为AD生物学的标记。同时使用临床型MRI对老年斑的可视化有一定价值,值得进一步探讨。
Objective 1.To study the characteristic behavioral and pathological findings of Alzheimer’s disease induced by 2-vessel occlusion and copper exposure.2. To observed MR findings of brain of the Alzheimer’s disease model rats with clinical 1.5T MR imager in vivo at different stage, T_2 map was used to assess quantitatively the rat brain in different encephalic regions. To investigate the feasibility that plaques can be detected by MRI in this AD rat model in vivo.
Methods Sixty-six SD rats, aged 7~8weeks, were performed by permanent occlusion of bilateral common carotid arteries(2VO). Six rates dead during operation, the surviving 60 rats were divided into two groups randomly. Group 2VO+Cu~(2+) (n=30) and group 2VO. Group 2VO+Cu~(2+)were food with 250ppm copper chloride(CuCl2) in drinking water ( rcontained 5% sucrose ) for 3 months.Control groups included 24 same age rates which were received the same operation but without occlusion of the arteries,The drinking water contained 5% sucrose. At 3th month, 6th month and 9th month after operation, 10 rates selected randomly from each test group and 8 rates from control group were tested by Morris water maze experiment to observe their behavior changes, then performed MR examination using T_1WI、T_2WI、T_2*WI、SWI. T_2 map was used to assess quantitatively T_2 value of the rat brain in different regions. After MR scanning, rates were sacrificed, Whole brains of rates were removed immediately for pathological study (HE staining,thioflavin S staining, immunohistochemistical staining for Aβ,histochemical staining of iron and silver staining ). The SPSS17.0 statistical package (SPSS, Chicago, USA) was used for all calculations.,Mean latent phase and T_2 value of the whole sample at different time-points were evaluated with two-factor measures analysis of variance. Comparison between groups was evaluatated with one-way anova(ANOVA). The results are indicated with mean+standard deviation( x±s) which had a significance level of 0.05.
Results A novel complex rat model of dementia were established by permanent occlusion of bilateral common carotid arteries(2VO) and copper exposure for research of AD. After Morris water maze experiment, mean latent phase of VD+Cu~(2+) group and VO group were longer than that of the sham-operated rats(control group)(p<0.05),but there was no significant difference between 2VO+Cu~(2+)group and 2VO group(p>0.05). The brains of AD rat model appeared pathological changes of Alzheimer’s disease in Group 2VO+CU2+ at the 6th month and the 9th month, group 2VO at the 9th month, which appeared a similar SPs structure, Aβpositive immunoreaction in the cortex and hippocampus .Thioflavin S staining, iron staining and silver staining appeared positive result.some positive appeared in the same brain region. In groups 2VO+Cu~(2+) at the 6th month and the 9th month and groups2VO at 9th month,T_2 value in the cortex and hippocampus of the rat brain descend, there was significant difference compared with control groups. T_2 value had no significant difference in corpus striatum, thalamus and corpus callosum in the rat brain between test group and control group. On MR images with T_1WI、T_2WI、T_2*WI、SWI sequence, some round hypointensity focus can be detected in the cortex and hippocampus of the rat brain in group 2VO+Cu~(2+)at the 6th month and the 9th month, group 2VO at 9th month, Preliminary results indicate that T_2*WI acquisition best accurately reflects plaque,T_2WI inferior to T_2*WI,T_1WI have no effect. SWI have best CNR, but it can not remove the effect of blood vessels.
Conclusion Dementia Rats induced by 2-vessel occlusion and copper exposure is good model for MR imaging. This rat model appeared the behavioral and pathological changes of Alzheimer’s disease. Copper, it can accelerate pathological process of AD. The rat model can be evaluated with MR imaing in vivo.T_2 value descend in the cortex and hippocampus of the rat brain initially, which suggested pathological process of AD.T_2 value may become biological markers of AD. To detect senile plaques with MR imaging in vivo is feasible and deserves further exploration.
引文
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