重复经颅磁刺激对血管性痴呆大鼠学习记忆障碍的影响及其分子机制的研究
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摘要
目的
本课题通过应用重复经颅磁刺激,从行为学、形态学和分子生物学等不同层面综合研究重复经颅磁刺激对血管性痴呆大鼠学习记忆的影响,探讨其作用的分子机制,为血管性痴呆的临床治疗提供有价值的实验依据和方法。
方法
将Wistar大鼠随机分为以下四组:①正常对照组、②痴呆模型组、③重复经颅磁刺激低频治疗组(简称低频刺激组)、④重复经颅磁刺激高频治疗组(简称高频刺激组)。痴呆模型组、低频刺激组和高频刺激组均采用两血管阻断法(2VO)制备血管性痴呆模型。
造模前、造模后和重复经颅磁刺激治疗后均进行Morris水迷宫行为学测试,包括定位航行试验和空间探索试验,计算全时程平均逃避潜伏期和游泳路程,计算在原平台象限的游泳时间和在原平台象限游泳路程占总游泳路程的百分比。低频刺激组大鼠接受频率0.5Hz重复经颅磁刺激(六个疗程,每疗程持续5天),高频刺激组大鼠接受频率5Hz重复经颅磁刺激(六个疗程,每疗程持续5天)。各组大鼠断头取脑,应用免疫组织化学方法检测海马CA1区BDNF、NMDAR1、SYN蛋白表达情况。应用HE染色,光镜观察各组大鼠海马CA1区细胞形态。应用透射电镜观察各组大鼠海马CA1区突触形态、数量等超微结构。
结果
1.Morris水迷宫测试结果
大鼠造模后2天进行水迷宫定位航行试验,痴呆模型组、低频刺激组、高频刺激组大鼠的全时程平均逃避潜伏期和游泳路程比正常对照组延长(p＜0.05),空间探索试验中在原平台象限的游泳时间和在原平台象限的游泳路程占总路程百分比比正常对照组缩短(p＜0.05)。重复经颅磁刺激治疗6个疗程后,低频刺激组和高频刺激组大鼠全时程平均逃避潜伏期和游泳路程比痴呆模型组缩短(p＜0.05),低频刺激组与高频刺激组差异无统计学意义(p＞0.05),空间探索试验中在原平台象限的游泳时间和在原平台象限的游泳路程占总路程百分比比痴呆模型组延长(p＜0.05),低频刺激组与高频刺激组差异无统计学意义(p＞0.05)。
2.免疫组化染色结果:痴呆模型组大鼠BDNF、NMDAR1、SYN蛋白表达量比正常对照组大鼠减低(p＜0.05),低频刺激组和高频刺激组BDNF、NMDAR1、SYN蛋白表达量比痴呆模型组增高(p＜0.05),低频刺激组与高频刺激组差异无统计学意义(p＞0.05)。
3.光镜观察显示,痴呆模型组大鼠海马CA1区神经细胞层次数量明显减少,排列松散,细胞受损严重,大量萎缩,轮廓不清,细胞深染,出现核固缩,细胞器结构不清。低频刺激组和高频刺激组多数细胞排列较整齐,细胞形态较完好,仅见少量核固缩。
4.电镜下观察,痴呆模型组突触数量虽多于正常组,但突触体积明显减小,形态改变,为长形或不规则形;高倍观,突触前区变形,突触小泡减少并聚集,线粒体凝聚,突触后区体积减小,突触前后膜增厚,融合,突触间隙消失,失去其正常形态。低频刺激组和高频刺激组的部分突触结构近于正常,部分突触前后膜略见增厚,但突触间隙可辨认。
结论
1.本研究从行为学、形态学及分子生物学等不同水平,研究了血管性痴呆的特点,通过对血管性痴呆大鼠海马CA1区BDNF、NMDAR1、SYN等几个蛋白的表达情况综合分析,结果表明BDNF、NMDAR、SYN蛋白表达的增加有利于学习记忆功能的恢复。
2.重复经颅磁刺激对血管性痴呆认知功能障碍有恢复治疗作用,主要表现为影响了突触可塑性,其可能的机制为:
(1)rTMS对突触后可塑性的影响:rTMS促进BDNF等神经营养因子的表达,进而可通过增加NMDA受体通道的开放频率,特异性地增强突触后致密物上NMDA亚单位的磷酸化。NMDA受体被激活时,使钙离子通透性增加,进入细胞内。钙离子可进一步激活细胞内钙离子依赖的酶,从而引起一系列生化过程,并且促进了NMDA受体依赖的长时程增强的产生,改变突触的传递效能,促使学习记忆功能的增强。
(2)rTMS对突触前可塑性的影响:rTMS使突触前区内的SYN表达增加,具有促进突触再建和增强,提高突触效能的作用,促进神经损伤修复和功能重塑,对于血管性痴呆大鼠的学习记忆有恢复作用。
3.本研究为血管性痴呆的临床治疗提供了新的线索,为临床应用重复经颅磁刺激治疗血管性痴呆提供了有价值的理论依据,同时为血管性痴呆的药物治疗提供了可能的新的作用靶点。
Objective
Vascular dementia(VaD)is one of main types of senile dementia.While the definite pathogenesis is still not clear.Repetitive transcranial magnetic stimulation (rTMS)plays an important role in the recovery of cerebral ischemia.We investigated the effect of repetitive transcranial magnetic stimulation on the ability of learning and memory and studied its molecular mechanism.This will provide therapy foundation in clinical rTMS application on vascular dementia and help to discover more effective therapy of vascular dementia.
Methods
Two-vessel occlusion(2VO)was employed to make vascular dementia rat models. Morris water-maze test was performed to study the ability of learning and memory in each group of rats.The expression of BDNF,NMDAR1,Synaptophysin(SYN)in hippocampal CA1 region were determined by immunohistochemistry assay.The ultrastucture changes of the synapses were observed with electron microscopy.
1.Animals
36 male Wistar rats weighting 290±20g were randomly divided into control group, vascular dementia group,vascular dementia with low frequency stimulation group and vascular dementia with high frequency stimulation group.
2.Vascular dementia rat model
Two-vessel occlusion(2VO)method was used to make vascular dementia animal model.The rats were performed fasting while could drink 8-12h before operation. Apply abdominal anesthesia with 10%chloral hydrate(0.3ml/100g body weight). Fixed the rats lying on the back,selected median incision on abdomen,and performed blunt dissection to expose double-side common carotid.The artery was occlusion by 4 type line.In the control group,rats were not performed 2VO operation.
3.Repetitive transcranial magnetic stimulation
Low frequency rTMS group rats were given 0.5 Hz rTMS for six weeks.High frequency rTMS group rats were given 5 Hz rTMS for six weeks.
4.Morris water maze test
Before Morris water maze test,a free swimming trail was run in which the platform was removed so that all rats were adapted to temperature and environment of Morris water maze.The rats that had poor ability of swimming were ticked out of test.During the place navigation test,a submerged platform was placed in the Morris water maze and rats were studied to learn the location of the platform that could be used to escape from swimming.The rats were placed in the maze in different starting positions that were equally distributed around the perimeter of the maze.The trail was lasted for 4 days.Record the escape latencies in each group.In the 5~(th)day,a spatial probe test was given which consisted of a 120 seconds free swimming period without the platform.Times of crossing the former site of the removed hidden platform were calculated statistically.
5.Immunohistochemistry assay
The expression of BDNF,NMDAR1,SYN in hippocampal CA1 region were detected with immunohistochemistry assay.
6.Statistical analysis
Use SPSS 13.0 software for statistical disposition.All results were shown by mean±standard deviation.Differences between three groups were evaluated using one-way ANOVA,and differences between two groups were evaluated using Student's t test for statistical analysis.P＜0.05 was considered as the level of significance.
Results
1.Morris water maze test results
There was significant difference among four groups.The escape latencies in VaD group were statistically longer than those in control group significantly(p＜0.05),and the escape latencies in the low frequency rTMS group and in the high frequency rTMS group were shorter than those in VaD group significantly(P＜0.05).The time and distance of crossing the former site of the removed hidden platform in VaD group were less than those in control group(P＜0.05),and the time and distance of crossing the former site of the removed hidden platform in the low frequency rTMS group and in the high frequency rTMS group were longer than those in VaD group significantly (P＜0.05).Low frequency rTMS group had no statistical difference with high frequency rTMS group(P＞0.05).
2.The expression of BDNF,NMDAR1,SYN in hippocampus CA1 region
The average expression of BDNF,NMDAR1,SYN protein in VaD group was lower than that in control group(P＜0.05).The average expression of BDNF, NMDAR1,SYN protein expression in low frequency rTMS group and in the high frequency rTMS group were higher than that in VaD group(P＜0.05).Low frequency rTMS group had no statistical difference with high frequency rTMS group(P＞0.05).
3.The morphology of nerve cell in hippocampus CA1 region
The morphology of nerve cell in hippocampus CA1 reginon in VaD group disordered and damaged obviously compared with control group.The damaged changes of nerve cell morphology not only in low frequency rTMS group but also in high frequency rTMS group improved compared with VaD group.There was no statistical difference with low frequency rTMS group and high frequency rTMS group.
4.The ultra-micro structure changes of the synapses
The structure of synapses in VaD group disordered and damaged obviously compared with control group.The damaged changes of synapses structure not only in low frequency rTMS group but also in high frequency rTMS group improved compared with VaD group.There was no statistical difference with low frequency rTMS group and high frequency rTMS group.
Conclusions
Vascular dementia rats have deficiency in the ability of spatial learning and memory,rTMS can improve the ability of spatial learning and memory in vascular dementia rats.Our research proved that rTMS could increase the expression of BDNF, NMDAR1 and SYN protein,and influence the plasticity of synapses,thus in the end it improve the function of behavior,learning and memory.
本课题通过应用重复经颅磁刺激,从行为学、形态学和分子生物学等不同层面综合研究重复经颅磁刺激对血管性痴呆大鼠学习记忆的影响,探讨其作用的分子机制,为血管性痴呆的临床治疗提供有价值的实验依据和方法。
方法
将Wistar大鼠随机分为以下四组:①正常对照组、②痴呆模型组、③重复经颅磁刺激低频治疗组(简称低频刺激组)、④重复经颅磁刺激高频治疗组(简称高频刺激组)。痴呆模型组、低频刺激组和高频刺激组均采用两血管阻断法(2VO)制备血管性痴呆模型。
造模前、造模后和重复经颅磁刺激治疗后均进行Morris水迷宫行为学测试,包括定位航行试验和空间探索试验,计算全时程平均逃避潜伏期和游泳路程,计算在原平台象限的游泳时间和在原平台象限游泳路程占总游泳路程的百分比。低频刺激组大鼠接受频率0.5Hz重复经颅磁刺激(六个疗程,每疗程持续5天),高频刺激组大鼠接受频率5Hz重复经颅磁刺激(六个疗程,每疗程持续5天)。各组大鼠断头取脑,应用免疫组织化学方法检测海马CA1区BDNF、NMDAR1、SYN蛋白表达情况。应用HE染色,光镜观察各组大鼠海马CA1区细胞形态。应用透射电镜观察各组大鼠海马CA1区突触形态、数量等超微结构。
结果
1.Morris水迷宫测试结果
大鼠造模后2天进行水迷宫定位航行试验,痴呆模型组、低频刺激组、高频刺激组大鼠的全时程平均逃避潜伏期和游泳路程比正常对照组延长(p＜0.05),空间探索试验中在原平台象限的游泳时间和在原平台象限的游泳路程占总路程百分比比正常对照组缩短(p＜0.05)。重复经颅磁刺激治疗6个疗程后,低频刺激组和高频刺激组大鼠全时程平均逃避潜伏期和游泳路程比痴呆模型组缩短(p＜0.05),低频刺激组与高频刺激组差异无统计学意义(p＞0.05),空间探索试验中在原平台象限的游泳时间和在原平台象限的游泳路程占总路程百分比比痴呆模型组延长(p＜0.05),低频刺激组与高频刺激组差异无统计学意义(p＞0.05)。
2.免疫组化染色结果:痴呆模型组大鼠BDNF、NMDAR1、SYN蛋白表达量比正常对照组大鼠减低(p＜0.05),低频刺激组和高频刺激组BDNF、NMDAR1、SYN蛋白表达量比痴呆模型组增高(p＜0.05),低频刺激组与高频刺激组差异无统计学意义(p＞0.05)。
3.光镜观察显示,痴呆模型组大鼠海马CA1区神经细胞层次数量明显减少,排列松散,细胞受损严重,大量萎缩,轮廓不清,细胞深染,出现核固缩,细胞器结构不清。低频刺激组和高频刺激组多数细胞排列较整齐,细胞形态较完好,仅见少量核固缩。
4.电镜下观察,痴呆模型组突触数量虽多于正常组,但突触体积明显减小,形态改变,为长形或不规则形;高倍观,突触前区变形,突触小泡减少并聚集,线粒体凝聚,突触后区体积减小,突触前后膜增厚,融合,突触间隙消失,失去其正常形态。低频刺激组和高频刺激组的部分突触结构近于正常,部分突触前后膜略见增厚,但突触间隙可辨认。
结论
1.本研究从行为学、形态学及分子生物学等不同水平,研究了血管性痴呆的特点,通过对血管性痴呆大鼠海马CA1区BDNF、NMDAR1、SYN等几个蛋白的表达情况综合分析,结果表明BDNF、NMDAR、SYN蛋白表达的增加有利于学习记忆功能的恢复。
2.重复经颅磁刺激对血管性痴呆认知功能障碍有恢复治疗作用,主要表现为影响了突触可塑性,其可能的机制为:
(1)rTMS对突触后可塑性的影响:rTMS促进BDNF等神经营养因子的表达,进而可通过增加NMDA受体通道的开放频率,特异性地增强突触后致密物上NMDA亚单位的磷酸化。NMDA受体被激活时,使钙离子通透性增加,进入细胞内。钙离子可进一步激活细胞内钙离子依赖的酶,从而引起一系列生化过程,并且促进了NMDA受体依赖的长时程增强的产生,改变突触的传递效能,促使学习记忆功能的增强。
(2)rTMS对突触前可塑性的影响:rTMS使突触前区内的SYN表达增加,具有促进突触再建和增强,提高突触效能的作用,促进神经损伤修复和功能重塑,对于血管性痴呆大鼠的学习记忆有恢复作用。
3.本研究为血管性痴呆的临床治疗提供了新的线索,为临床应用重复经颅磁刺激治疗血管性痴呆提供了有价值的理论依据,同时为血管性痴呆的药物治疗提供了可能的新的作用靶点。
Objective
Vascular dementia(VaD)is one of main types of senile dementia.While the definite pathogenesis is still not clear.Repetitive transcranial magnetic stimulation (rTMS)plays an important role in the recovery of cerebral ischemia.We investigated the effect of repetitive transcranial magnetic stimulation on the ability of learning and memory and studied its molecular mechanism.This will provide therapy foundation in clinical rTMS application on vascular dementia and help to discover more effective therapy of vascular dementia.
Methods
Two-vessel occlusion(2VO)was employed to make vascular dementia rat models. Morris water-maze test was performed to study the ability of learning and memory in each group of rats.The expression of BDNF,NMDAR1,Synaptophysin(SYN)in hippocampal CA1 region were determined by immunohistochemistry assay.The ultrastucture changes of the synapses were observed with electron microscopy.
1.Animals
36 male Wistar rats weighting 290±20g were randomly divided into control group, vascular dementia group,vascular dementia with low frequency stimulation group and vascular dementia with high frequency stimulation group.
2.Vascular dementia rat model
Two-vessel occlusion(2VO)method was used to make vascular dementia animal model.The rats were performed fasting while could drink 8-12h before operation. Apply abdominal anesthesia with 10%chloral hydrate(0.3ml/100g body weight). Fixed the rats lying on the back,selected median incision on abdomen,and performed blunt dissection to expose double-side common carotid.The artery was occlusion by 4 type line.In the control group,rats were not performed 2VO operation.
3.Repetitive transcranial magnetic stimulation
Low frequency rTMS group rats were given 0.5 Hz rTMS for six weeks.High frequency rTMS group rats were given 5 Hz rTMS for six weeks.
4.Morris water maze test
Before Morris water maze test,a free swimming trail was run in which the platform was removed so that all rats were adapted to temperature and environment of Morris water maze.The rats that had poor ability of swimming were ticked out of test.During the place navigation test,a submerged platform was placed in the Morris water maze and rats were studied to learn the location of the platform that could be used to escape from swimming.The rats were placed in the maze in different starting positions that were equally distributed around the perimeter of the maze.The trail was lasted for 4 days.Record the escape latencies in each group.In the 5~(th)day,a spatial probe test was given which consisted of a 120 seconds free swimming period without the platform.Times of crossing the former site of the removed hidden platform were calculated statistically.
5.Immunohistochemistry assay
The expression of BDNF,NMDAR1,SYN in hippocampal CA1 region were detected with immunohistochemistry assay.
6.Statistical analysis
Use SPSS 13.0 software for statistical disposition.All results were shown by mean±standard deviation.Differences between three groups were evaluated using one-way ANOVA,and differences between two groups were evaluated using Student's t test for statistical analysis.P＜0.05 was considered as the level of significance.
Results
1.Morris water maze test results
There was significant difference among four groups.The escape latencies in VaD group were statistically longer than those in control group significantly(p＜0.05),and the escape latencies in the low frequency rTMS group and in the high frequency rTMS group were shorter than those in VaD group significantly(P＜0.05).The time and distance of crossing the former site of the removed hidden platform in VaD group were less than those in control group(P＜0.05),and the time and distance of crossing the former site of the removed hidden platform in the low frequency rTMS group and in the high frequency rTMS group were longer than those in VaD group significantly (P＜0.05).Low frequency rTMS group had no statistical difference with high frequency rTMS group(P＞0.05).
2.The expression of BDNF,NMDAR1,SYN in hippocampus CA1 region
The average expression of BDNF,NMDAR1,SYN protein in VaD group was lower than that in control group(P＜0.05).The average expression of BDNF, NMDAR1,SYN protein expression in low frequency rTMS group and in the high frequency rTMS group were higher than that in VaD group(P＜0.05).Low frequency rTMS group had no statistical difference with high frequency rTMS group(P＞0.05).
3.The morphology of nerve cell in hippocampus CA1 region
The morphology of nerve cell in hippocampus CA1 reginon in VaD group disordered and damaged obviously compared with control group.The damaged changes of nerve cell morphology not only in low frequency rTMS group but also in high frequency rTMS group improved compared with VaD group.There was no statistical difference with low frequency rTMS group and high frequency rTMS group.
4.The ultra-micro structure changes of the synapses
The structure of synapses in VaD group disordered and damaged obviously compared with control group.The damaged changes of synapses structure not only in low frequency rTMS group but also in high frequency rTMS group improved compared with VaD group.There was no statistical difference with low frequency rTMS group and high frequency rTMS group.
Conclusions
Vascular dementia rats have deficiency in the ability of spatial learning and memory,rTMS can improve the ability of spatial learning and memory in vascular dementia rats.Our research proved that rTMS could increase the expression of BDNF, NMDAR1 and SYN protein,and influence the plasticity of synapses,thus in the end it improve the function of behavior,learning and memory.
引文
1.Zhang ZX,Zahner GE,Roman GC,et al.Dementia subtypes in China:prevalence in Beijing,Xian,Shanghai and Chengdu.Arch Neurel,2005,62:447-453.
2.Roman GC.Vascular dementia may be the most common form of dementia in the elderly.J Neurol Sci,2002,203-204:7-10.
3.Hentschel F,Kolsch H.The molecular genetics of the risk factors of vascular dementias.Clin Neuroradiol,2007,17:23-29.
4.Inzitari D,Lamassa M,Pantoni L,et al.Therapy of vascular dementia.Arch Gerontol Geriatr suppl,2004:229-234.
5.Pantoni L,del Ser T,Soglian AG,et al.Efficacy and safety of nimodipine in subcortical vascular dementia:a randomized placebo-controlled trial.Stroke,2005,36:619-624.
6.Alvaro PI.Repetitive transcranial magnetic stimulation:Technical principles safety and potential therapeutic applications.EEG and Clin Neurophysiol,1997,103(4):48.
7.Remondes M,Schuman EM.Molecular mechanisms contributing to long-1 asting synaptic plasticity at the temporoammanic-CA1 synapse.Learn Mem,2003,10:247-252.
8.Tang YP,Shimizu E,Dube G,et al.Genetic enhancement of learning and memory in mice.Nature,2004,401:63-69.
9.Jovanovic JN,Czemik AJ,Fienherg AA,et al.Synapsins as mediators of BDNF-enhanced neurotransmitter release.Nat Neurosci,2000,3:323-329.
10.Tomimoto H,Ohtani R,Shibata M,et al.Loss of cholinergic pathways in vascular dementia of the Binswanger type.Dement Geriatr Cogn Disord,2005;19:282-288.
11.贾建平,贾建民,周卫东,等.阿尔茨海默病和血管性痴呆患者脑脊液中乙酰胆碱和胆碱检测及其临床意义.中华神经科杂志,2002,35:168-170.
12.樊敬峰,王伟斌,吕佩源,等.血管性痴呆小鼠海马胆碱乙酰转移酶mRNA 表达特征研究.中华神经医学杂志,2006,5:986-988.
13.Perry E,McKeith I,Ballard C.Butyrylcholinesterase and progression of cognitive deficits in dementia with Lewy bodies.Neurology,2003;60:1852-1853.
14.姚国恩,王景周,陈曼娥.血管性痴呆大鼠认知障碍的NMDAR机制研究.第三军医大学学报,2002,24:1408-1410.
15.Yamada KA.Modulating excitatory synaptic neurotransmission:potential treatment for neurological diseases? Neurobiol Dis,1998,5:67-80.
16.Wada-Isoe K,Wakutani Y,Urakami K,et al.Elevated interleukin-6 levels in cerebrospinal fluid of vascular dementia patients.Acta Neurol Scand,2004,110:124-127.
17.Engelberg H.Pathogenic factors in vascular dementia and Alzheimer's disease.Multiple actions of heparin that probably are beneficial,Dement Geriatr Cogn Disord,2004,18:278-298.
18.Bajetto A,Boxarvia R,Barbero S,et al.Chemokine and their receptors in the central nervous system.Front Neuroendocrinol,2001,22:147-181.
19.Zhu X,Smith MA,Honda K,et al.Vascular oxidative stress in Alzheimer disease.J Neurol Sci.2007 Jun 15;257(1-2):240-246.
20.Ryglewicz D,Rodo M,Kunicki PK,et al.Plasma antioxidant activity and vascular dementia.J Neurol Sci,2002,203-204:195-197.
21.Remondes M,Schuman EM.Molecular mechanisms contributing to long-1 asting synaptic plasticity at the temporoammanic-CA1 synapse.Learn Mem,2003,10:247-252.
22.Kovalenko TM,Osadchenko IO,Smozhanyk KH,et al.Structural organization of CA1 zone in the hippocampus of rats in the experimental brain ischemia.Fiziol ZH,2004,50:86-93.
23.Murphy GG,Glanzman DL.Mediation of classical conditioning in Aplysis California by long-term potention ofsensomotor synapses.Science,1997,278:467-471
24.Jovanovic JN,Czemik AJ,Fienherg AA,et al.Synapsins as mediators of BDNF-enhanced neurotransmitter release.Nat Neurosci,2000,3:323-329.
25.Ahmed T,Frey JU.Plasticity-specific phosphorylation of CaMK Ⅱ,MAP-kinases and CREB during late-LTP in rat hippocampal slices in vitro.Neuropharmacology,2005,49:477-492.
26.冯亚青,王建华,郭雪,等.载脂蛋白E基因多态性及血脂与血管性痴呆的关系.中国神经免疫学和神经病学杂志,2005,12:51-52.
27.Barba R,Martinez-Espinosa S,Rodriguez-Garcia E,et al.Post-stroke dementia:clinical features and vascular factor.Stroke,2000,31:1494-1501.
28.Zurru MC,Casas Parem I,Moya G,et al.Cadasil:a case with molecular diagnosis.Medicina(B Aires),2002,62:48-52.
29.Yoo JH,Choi GD,Kang SS.Pathogenicity ofthermolabile methylenetetrahydrofolate reductase for vascular dementia.Arterioscler Thromb Vase Biol,2000,20:1921-1925.
30.毕胜,潘尚哈,隋丹,等.血浆同型半胱氨酸水平及MTHFR基因多态与血管性痴呆的关系.中风与神经疾病杂志,2006,23:297-299.
31.Pola R,Flex A,Gaetani E,et al.Association between intercellular adhesion molecule-1 E/K gene polymorphism and probable vascular dementia in humans.Neurosci Lett,2002,326:171-174.
32.Magalhaes JP,Sandberg A.Cognitive aging as an extentien of brain development:a model linking learning,brain plasticity told neucode generation.Mech Ageing Dev,2005,7:57-68.
33.张荣伟,王希福,王慕一,等.老年缺血性脑卒中患者的认知功能与胰岛素抵抗的关系.中国临床康复,2005,9:16-17.
34.谭纪萍,王莹,王鲁宁,等.血管性痴呆的危险因素探讨.中华老年心脑血管病杂志,2005,7:118-120.
35.Demaerschalk BM,Wingerchuk DM.Treatment of vascular dementia and vascular cognitive impairment.Neurologist,2007,13:37-41.
36.Inzitari D,Lamassa M,Pantoni L,et al.Therapy of vascular dementia.Arch Gerontol Geriatr suppl,2004:229-234.
37.Pantoni L,del Ser T,Soglian AG,et al.Efficacy and safety of nimodipine in subcortical vascular dementia:a randomized placebo-controlled trial.Stroke,2005,36:619-624.
38.Ang ET,W ong PT,M o chhala S,et al.Neuroprotection associated with rtmning: Is it a result of increased endogenous neurotrophic factors? Neuroscience,2003,118:335-345.
39.Fomai F,Busceti CL,Ferrucci M,et al.Is there a role for uridine and pyrimidine nucleosides in the treatment of Vascular dementia.Functional neurol,2002,17:93-99.
40.Enrique I.,Phillip R.W.,Sara C.Reversible middle cerebral artery occlusion without camiectomy in rats.Stroke,1989,20:84
41.Pulsinelli WA,Brierley JB.A new model of bilateral hemispheric ischemia in the unanesthetized rat.Stroke,1979,10(3):267
42.陈俊抛,田时雨,于薇薇,等.多发性脑梗塞痴呆模型的研究.中华神经精神科杂志,1994,24(6):311
43.YamamotoM,Tamura A,Krino T,et al.Behavioral changes after focal cerebral ischemia by left middle cerebral artery occlusion in rats[J].Brain Res,1988,452(12):323-328
44.Saito H,Togashi H,Yoshioka M,et al.Animal model of vascular dementia with emphasis on stroke-prone spontaneously hypertension rats.Clin.Exp.Pharmacol.Physiol.1995,22:257.
45.Barker AT,lalinous R,Frceston IL.Non-invasive magnetic stimulation of human motor cortex.Lancet,1985,1:1106-7
46.王修信,胡维平,杨永栩等.磁刺激中线圈感应电场的聚焦性研究.北京生物医学工程,2005,24(1):33-35
47.Levy WJ,Amasssian VE,Schmid UD,et al.Mapping of motor cortex gyral sites non-invasively by transcranial magnetic stimulation in normal subjects and patients.Electroencephalogr Clin Neurophysiol.1991;43:51-75,suppl
48.Wassermann EM,Lisanby SH.Therapeutic application of repetitive transcranial magnetic stimulation:A review.Chilinical Neurophysiology,2001,112(8):1367-1377
49.Gorsler A,Baumer T,Weiller C,et al.Interhemispheric effects of high and low frequency rTMS in healthy humans.Clin Neurophysiol,2003,114:1800-1807
50.Pedro C,Miranda,Mark Hallett,Peter J.Basser the electric field induced in the brain by magnetic stimulation:A 3-D finite-element analysis of the effect of tissue heterogeneity and anisotropy.IEEE Transactions on Biomedical Engineering,2003, 50(9):1074-1085
51. Barde, YA, Edgar, D and Thoenen, H. Purification of a new neurotrophic factor from mammalian brain- BDNF is a neurotrophic factor for dopaminergic neurons o f the substantia nigra. Nature, 1982, 350, 230-232
52. Emfors P, Ibanez GF, Ebendal T, et al. Molecular cloning and neurotrophic activities of a protein with structural similarities to nerve growth factor: developmental and topographical expression in the brain. Proc Natl Acad Sci USA, 1990, 87: 5454-5458
53. Kawmoto Y, Nakamura S, Nalcano S, et al. Immunohistochemical location of brain-derived neurotrophic factor in adult rat brain. Neuroscience, 1996, 74: 1209-1226.
54. Brandoli C, Sanna A, De Bernardi MA, et al. Brain-derived neurotrophic factor and basic fibroblast growth factor downregulate NMDA receptor function in cerebellar granule cells. J Neurosci, 1998, 8: 7953-7961.
55. Pappas IS, Parnavelas JG. Neurotrophins and basic fibroblast growth factor induce the differentiation of calbindin-containing neurons in the cerebral cortex. Exp Neural. 1997,144:302
56. Kiprianova I,Freiman TM,Desiderato S,et al.Brain-derived neurotrophic factor prevents neuronal death and glia activation after global ischemia in the rat[J].J Neurosci Res,1999.56(1):21-27.
57. Schabitz WR, Sommer C, Zoder W, et al. Intravenous brain-derived neurotrophic factor reduces infarct size and counterregulates Bax and Bcl-2 expression after temporary focal cerebral ischemia. Stroke, 2000,31:2212-2217
58. Mu JS, Li WP, Yao ZB, et al. Deprivation of endogenous brain derived neurotrophic factors results in impairment of spatial learning and memory in adult rats. Brain Res, 1999, 835(2): 259-265
59. Dragunow M, Hughes P, Mason-Parker SE, et al. TrKB expression in dentale granule cell is associated with a late phase of long-term potentiation. Brain Res Mol, 1997, 46: 274-280
60. Patterson SL, Abel T, Deuel TA, et al. Recombinant BDNF rescues deficits in basal synaptic transmission and hippocampal LTP in BDNF knockout mice. Neuron, 1996,16:1137-1145
61. Kiprianova I, Sandkuhler J, Schwab S, et al. Brain-derived neurotrophic factor improves long-term potentiation and cognitive functions after transient forebrain ischemia in the rat. Exp Neural, 1999, 159: 511-519
62. Gooney M, Lynch Ma. Long-term potentiation in the dentate gyrus of the rat hippocampus is accompanied by brain-derived neurotrophic factor-induced activation of TrkB. JNeurochm, 2001, 77: 1198-1207
63. Muller MB, Toschi N, Kresse AE, et al. Long-term repetitive transcranial magnetic stimulation increases the expression of brain-derived neurotrophic factor and cholecystokinin mRNA, but not neuropeptide tyrosine mRNA in specific areas of rat brain. Neuropsychopharmacology. 2000,23(2): 205-15
64. Doi W,Sato D,Fukuzako H,et al.c-Fos expression in rat brain after repetitive transcranial magnetic stimulation.Neuroreport,2001,12(6):1307-1310.
65. Behe P, Stem P, Wyllie DJ. Determination of NMD AR NR1 subunit copy number in recombinant NMDA receptor. Proc-R-Soc-Lond-B-Biol-Sci. 1995; 262: 205-213
66. Tsien JZ, Huerta PT, Tonegawa S. The essential role of hippocampal CA1 NMDA receptor dependent synaptic plasticity in spatial memory. Cell, 1996, 87(7): 1327-1338
67. Levy HI, Hanscom B, Boden SD. Three- question depression screener used for lumbar disc herniation and spinal stenosis. Spine, 2002,27(11): 1232- 1237
68. Jahn R, Schiebler W, Ovimetc, et al. A 38000-dalton membrane protein (p38) present in synaptic vesicles. Proc Nall Acad USA. 1985, 82:4137-4141
69. Tarsa L , Goda Y. Synaptophysin regulates activity- dependent synapse formation in cultured hippocampal neurons. Proc Natl Acad Sci USA , 2002 , 99(2): 1012-1016
70. Lauri SE, Lamsa K, Pavlov I. Activity blockade increases the number of functional synapses in the hippocampus of newborn rats. Mol Cell Neurosci, 2003, 22(1): 107-117
71. Janz R, Sudhof TC, Hzmmer RE, et al. Essential roles in synaptic plasticity for synaptohysin II and synaptophysin I. Neuron, 1999,24(3): 687
72. Nadeau SE, McCoy KJ, Crucian GP, et al. cerebral blood flow changes in depressed patients after treatment with repetitive transcranial magnetic stimulation: evidence of individual variability. Neuropsychiatry Neuropsychol Behav Neurol,2002,15:159-175
73. Black IB. Trophic regulation of synaptic plasticity. J Neurobiol, 1999,41: 108-118
1 Englund E.Neuropathology of white matter lesions in vascular cognitive impairment.Cerebrovasc Dis,2002,13:Suppl 2:11-115.
2 Whalley LJ.Brain aging and dementia:what makes the difference? Br J Psychiatry,2002,181:369-371.
3 DeLeeuw FE,Richard F,deGroot JC,et al.Interaction between hyperintension,apoE,and cerebral white matter lesion.Stroke,2004,35:1057-1062.
4 Hebert R,Lindsay J,Verreault R,et al.Vascular dementia:incidence and risk factors in the Canadian study of health and aging.Stroke,2000,31:1487-1493.
5 Baum L,Lam LC,Kwok T,et al.Apolipoprotein E epsilon4 allele is associated with vascular dementia.Dement Geriatr Cogn Disord.2006,22:301-305.
6 Davidson Y,Gibbons L,Purandare N,et al.Apolipoprotein E epsilon4 allele frequency in vascular dementia.Dement Geriatr Cogn Disord.2006,22:15-19.
7 Dantoine TF,Debord J,Merle L,et al.Paraoxonase 1 activity:a new vascular marker of dementia? Ann N Y Acad Sci.2002,977:96-101.
8 Ranade K,Kirchgessner TG,Iakoubova OA,et al.Evaluation of the paraoxonases as candidate genes for stroke:Gln192Arg polymorphism in the paraoxonase 1 gene is associated with increased risk of stroke.Stroke,2005,36:2346-2350.
9 Schmidt R,Schmidt H,Fazekas F,et al.MRI cerebral white matter lesions and paraoxonase PON 1 polymorphisms.Arterioscler Thromb Vase Biol,2000,20:1811-1816.
10 Spell C,Kolsch H,Lutjohann D,et al.SREBP-1a polymorphism influences the risk of Alzheimer's disease in carriers of the ApoE4 allele. Dement Geriatr Cogn Disord, 2004, 18:245-249.
11 Kolsch H, Heun R, Kerksiek A, et al. Altered levels of plasma 24S and 27-hydroxycholesterol in demented patients. Neurosci Lett, 2002, 368: 303-308.
12 Panzenboeck U, Balazs Z, Sovic A, et al. ABCA1 and scavenger receptor class B, type I, are modulators of reverse sterol transport at an in vitro blood-brain barrier constituted of porcine brain capillary endothelial cells. J Biol Chem, 2002, 277: 42781-42789.
13 Cheng CY, Hong CJ, Liu HC, et al. Study of the association between Alzheimer's disease and angiotensin-converting enzyme gene polymorphism using DNA from lymphocytes. Eur Neurol, 2002,47: 26- 29.
14 Sharma P. Meta-analysis of the ACE gene in ischaemic stroke. J Neurol Neurosurg Psychiatry, 1998, 64: 227-230.
15 Purandare N, Oude Voshaar RC, Davidson Y, et al. Deletion/insertion polymorphism of the angiotensin-converting enzyme gene and white matter hyperintensities in dementia: A pilot study. J Am Geriatr Soc. 2006, 54: 1395-1400.
16 Wang HK, Fung HC, Hsu WC,et al. Apolipoprotein E, angiotensin-converting enzyme and kallikrein gene polymorphisms and the risk of Alzheimer's disease and vascular dementia. J Neural Transm. 2006,113: 1499-1509.
17 Kolsch H, Jessen F, Freymann N, et al. ACE I/D polymorphism is a risk factor of Alzheimer's disease but not of vascular dementia. Neurosci Lett, 2005, 377: 37-39.
18 Hassan A, Gormley K, O'Sullivan M, et al. Endothelial nitric oxide gene haplotypes and risk of cerebral small vessel disease. Stroke, 2004, 35: 654- 659.
19 Szolnoki Z, Havasi V, Bene J, et al. Endothelial nitric oxide synthase gene interactions and the risk of ischemic stroke. Acta Neurol Scand, 2005, 111: 29- 33.
20 Martiskainen M, Pohjasvaara T, Mikkelsson J, et al. Fibrinogen gene promotor-455 A allele as a risk factor for lacunar stroke. Stroke, 2003, 34: 886-891.
21 Van Oijen M, Wittman JC, Hofman A, et al. Fibrinogen is associated with an increased risk of Alzheimer disease and vascular dementia. Stroke 2005, 36:2637-41.
22 Slowik A, Dziedzic T, Pera J, et al. Coagulation factor XIU Val34Leu polymorphism in patients with small vessel disease or primary intracerebral hemorrhage. Cerebrovasc Dis, 2005, 19: 165-170.
23 Austin H, Chimowitz MI, Hill HA, et al. Cryptogenic stroke in relation to genetic variation in clotting factors and other genetic polymorphisms among young men and women. Stroke, 2002, 33: 2762- 2769.
24 Alluri RV, Mohan V, Komandur S, et al. MTHFR C677T gene mutation as a risk factor for arterial stroke: a hospital based study. Eur J Neurol, 2005,12: 40- 44.
25 Cronin S, Furie KL, Kelly PJ. Dose-related association of MTHFR 677T allele with risk of ischemic stroke. Evidence from a cumulative meta-analysis. Stroke, 2002, 36:1581- 1587.
26 Kohara K, Fujisawa M, Ando F, et al. MTHFR gene polymorphism as a risk factor for silent brain infarcts and white matter lesions in the Japanese general population. The NILS-LSA study. Stroke, 2003, 34: 1130-1135.
27 McIlroy SP, Dynan KB, Lawson JT, et al. Moderately elevated plasma homocysteine, methylenetetrahydrofolate reductase genotype, and risk for stroke, vascular dementia, and Alzheimer disease in Northern Ireland. Stroke, 2002, 33: 2351-2356.
28 Yoo JH, Choi GD, Kang SS. Pathogenicity of thermolabile methylenetetrahydrofolate reductase for vascular dementia. Arterioscler Thromb Vasc Biol. 2000, 20: 1921-1925.
29 Hentschel F, Kolsch H. The molecular genetics of the risk factors of vascular dementias. Clin Neuroradiol, 2007,17: 23- 29.
30 Ashfield-Watt PAL, Knowles RM, Cale SB, et al. A folate enriched diet lowers plasma homocysteine in patients with hyperlipidaemia: a randomized controlled trial. BrJCardiol,2001,8:28-35.
31 Koseoglu E, Karaman Y. Relations between homocysteine, folate and vitamin B12 in vascular dementia and in Alzheimer disease. Clin Biochem. 2007,40: 859-863.
32 Seshadri S, Beiser A, Selhub J, et al. Plasma homocysteine as a risk factor for dementia and Alzheimer's disease. N Engl J Med, 2002,346: 476- 483.
33 Bushnell CD, Goldstein LB. Homocysteine testing in patients with acute ischemic stroke. Neurology, 2002, 59:1541-1546.
34 Kolsch H, Linnebank M, Lutjohann D, et al. Polymorphisms in glutathione S-transferase omega-1 and AD, vascular dementia, and stroke. Neurology, 2004, 63: 2255-2260.
35 Zaremba J, Losy J. sPECAM-1 in serum and CSF of acute ischaemic stroke patients. Acta Neurol Scand, 2002,106: 292- 298.
36 Zuliani G, Guerra G, Ranzini M, et al. High interleukin-6 plasma levels are associated with functional impairment in older patients with vascular dementia. Int J Geriatr Psychiatry. 2007, 22: 305- 311.
37 Wada-Isoe K, Wakutani Y, Urakami K, et al. Elevated interleukin-6 levels in cerebrospinal fluid of vascular dementia patients. Acta Neurol Scand, 2004, 110: 124-127.
38 Pola R, Flex A, Gaetani E, et al. Synergistic effect of-174 G/C polymorphism of the interleukin-6 promotor and 469 E/K polymorphism of the intercellular adhesion molecule-1 gene in Italian patients with history of ischemic stroke. Stroke, 2003, 34: 881-885.
39 Aberle J, Hopfer I, Beil FU, et al. Association of peroxisome proliferators-activated receptor delta +294T/C with mass index and interaction with peroxisome proliferators-activated receptor alpha L162V. Int J Obes, 2006, 3: 108-111.
40 Flavell DM, Jamshidi Y, Hawe E, et al. Peroxisome proliferator-activated receptor alpha gene variants influence progression of coronary atherosclerosis and risk of coronary artery disease. Circulation, 2002,105: 1440-1445.
41 Combs CK, Johnson DE, Karlo JC et al. Inflammatory mechanisms in Alzheimer's disease: inhibition of beta-amyloid-stimulated proinflammatory responses and neurotoxicity by PPARgamma agonists. J Neurosci, 2000,20: 558- 567.
2.Roman GC.Vascular dementia may be the most common form of dementia in the elderly.J Neurol Sci,2002,203-204:7-10.
3.Hentschel F,Kolsch H.The molecular genetics of the risk factors of vascular dementias.Clin Neuroradiol,2007,17:23-29.
4.Inzitari D,Lamassa M,Pantoni L,et al.Therapy of vascular dementia.Arch Gerontol Geriatr suppl,2004:229-234.
5.Pantoni L,del Ser T,Soglian AG,et al.Efficacy and safety of nimodipine in subcortical vascular dementia:a randomized placebo-controlled trial.Stroke,2005,36:619-624.
6.Alvaro PI.Repetitive transcranial magnetic stimulation:Technical principles safety and potential therapeutic applications.EEG and Clin Neurophysiol,1997,103(4):48.
7.Remondes M,Schuman EM.Molecular mechanisms contributing to long-1 asting synaptic plasticity at the temporoammanic-CA1 synapse.Learn Mem,2003,10:247-252.
8.Tang YP,Shimizu E,Dube G,et al.Genetic enhancement of learning and memory in mice.Nature,2004,401:63-69.
9.Jovanovic JN,Czemik AJ,Fienherg AA,et al.Synapsins as mediators of BDNF-enhanced neurotransmitter release.Nat Neurosci,2000,3:323-329.
10.Tomimoto H,Ohtani R,Shibata M,et al.Loss of cholinergic pathways in vascular dementia of the Binswanger type.Dement Geriatr Cogn Disord,2005;19:282-288.
11.贾建平,贾建民,周卫东,等.阿尔茨海默病和血管性痴呆患者脑脊液中乙酰胆碱和胆碱检测及其临床意义.中华神经科杂志,2002,35:168-170.
12.樊敬峰,王伟斌,吕佩源,等.血管性痴呆小鼠海马胆碱乙酰转移酶mRNA 表达特征研究.中华神经医学杂志,2006,5:986-988.
13.Perry E,McKeith I,Ballard C.Butyrylcholinesterase and progression of cognitive deficits in dementia with Lewy bodies.Neurology,2003;60:1852-1853.
14.姚国恩,王景周,陈曼娥.血管性痴呆大鼠认知障碍的NMDAR机制研究.第三军医大学学报,2002,24:1408-1410.
15.Yamada KA.Modulating excitatory synaptic neurotransmission:potential treatment for neurological diseases? Neurobiol Dis,1998,5:67-80.
16.Wada-Isoe K,Wakutani Y,Urakami K,et al.Elevated interleukin-6 levels in cerebrospinal fluid of vascular dementia patients.Acta Neurol Scand,2004,110:124-127.
17.Engelberg H.Pathogenic factors in vascular dementia and Alzheimer's disease.Multiple actions of heparin that probably are beneficial,Dement Geriatr Cogn Disord,2004,18:278-298.
18.Bajetto A,Boxarvia R,Barbero S,et al.Chemokine and their receptors in the central nervous system.Front Neuroendocrinol,2001,22:147-181.
19.Zhu X,Smith MA,Honda K,et al.Vascular oxidative stress in Alzheimer disease.J Neurol Sci.2007 Jun 15;257(1-2):240-246.
20.Ryglewicz D,Rodo M,Kunicki PK,et al.Plasma antioxidant activity and vascular dementia.J Neurol Sci,2002,203-204:195-197.
21.Remondes M,Schuman EM.Molecular mechanisms contributing to long-1 asting synaptic plasticity at the temporoammanic-CA1 synapse.Learn Mem,2003,10:247-252.
22.Kovalenko TM,Osadchenko IO,Smozhanyk KH,et al.Structural organization of CA1 zone in the hippocampus of rats in the experimental brain ischemia.Fiziol ZH,2004,50:86-93.
23.Murphy GG,Glanzman DL.Mediation of classical conditioning in Aplysis California by long-term potention ofsensomotor synapses.Science,1997,278:467-471
24.Jovanovic JN,Czemik AJ,Fienherg AA,et al.Synapsins as mediators of BDNF-enhanced neurotransmitter release.Nat Neurosci,2000,3:323-329.
25.Ahmed T,Frey JU.Plasticity-specific phosphorylation of CaMK Ⅱ,MAP-kinases and CREB during late-LTP in rat hippocampal slices in vitro.Neuropharmacology,2005,49:477-492.
26.冯亚青,王建华,郭雪,等.载脂蛋白E基因多态性及血脂与血管性痴呆的关系.中国神经免疫学和神经病学杂志,2005,12:51-52.
27.Barba R,Martinez-Espinosa S,Rodriguez-Garcia E,et al.Post-stroke dementia:clinical features and vascular factor.Stroke,2000,31:1494-1501.
28.Zurru MC,Casas Parem I,Moya G,et al.Cadasil:a case with molecular diagnosis.Medicina(B Aires),2002,62:48-52.
29.Yoo JH,Choi GD,Kang SS.Pathogenicity ofthermolabile methylenetetrahydrofolate reductase for vascular dementia.Arterioscler Thromb Vase Biol,2000,20:1921-1925.
30.毕胜,潘尚哈,隋丹,等.血浆同型半胱氨酸水平及MTHFR基因多态与血管性痴呆的关系.中风与神经疾病杂志,2006,23:297-299.
31.Pola R,Flex A,Gaetani E,et al.Association between intercellular adhesion molecule-1 E/K gene polymorphism and probable vascular dementia in humans.Neurosci Lett,2002,326:171-174.
32.Magalhaes JP,Sandberg A.Cognitive aging as an extentien of brain development:a model linking learning,brain plasticity told neucode generation.Mech Ageing Dev,2005,7:57-68.
33.张荣伟,王希福,王慕一,等.老年缺血性脑卒中患者的认知功能与胰岛素抵抗的关系.中国临床康复,2005,9:16-17.
34.谭纪萍,王莹,王鲁宁,等.血管性痴呆的危险因素探讨.中华老年心脑血管病杂志,2005,7:118-120.
35.Demaerschalk BM,Wingerchuk DM.Treatment of vascular dementia and vascular cognitive impairment.Neurologist,2007,13:37-41.
36.Inzitari D,Lamassa M,Pantoni L,et al.Therapy of vascular dementia.Arch Gerontol Geriatr suppl,2004:229-234.
37.Pantoni L,del Ser T,Soglian AG,et al.Efficacy and safety of nimodipine in subcortical vascular dementia:a randomized placebo-controlled trial.Stroke,2005,36:619-624.
38.Ang ET,W ong PT,M o chhala S,et al.Neuroprotection associated with rtmning: Is it a result of increased endogenous neurotrophic factors? Neuroscience,2003,118:335-345.
39.Fomai F,Busceti CL,Ferrucci M,et al.Is there a role for uridine and pyrimidine nucleosides in the treatment of Vascular dementia.Functional neurol,2002,17:93-99.
40.Enrique I.,Phillip R.W.,Sara C.Reversible middle cerebral artery occlusion without camiectomy in rats.Stroke,1989,20:84
41.Pulsinelli WA,Brierley JB.A new model of bilateral hemispheric ischemia in the unanesthetized rat.Stroke,1979,10(3):267
42.陈俊抛,田时雨,于薇薇,等.多发性脑梗塞痴呆模型的研究.中华神经精神科杂志,1994,24(6):311
43.YamamotoM,Tamura A,Krino T,et al.Behavioral changes after focal cerebral ischemia by left middle cerebral artery occlusion in rats[J].Brain Res,1988,452(12):323-328
44.Saito H,Togashi H,Yoshioka M,et al.Animal model of vascular dementia with emphasis on stroke-prone spontaneously hypertension rats.Clin.Exp.Pharmacol.Physiol.1995,22:257.
45.Barker AT,lalinous R,Frceston IL.Non-invasive magnetic stimulation of human motor cortex.Lancet,1985,1:1106-7
46.王修信,胡维平,杨永栩等.磁刺激中线圈感应电场的聚焦性研究.北京生物医学工程,2005,24(1):33-35
47.Levy WJ,Amasssian VE,Schmid UD,et al.Mapping of motor cortex gyral sites non-invasively by transcranial magnetic stimulation in normal subjects and patients.Electroencephalogr Clin Neurophysiol.1991;43:51-75,suppl
48.Wassermann EM,Lisanby SH.Therapeutic application of repetitive transcranial magnetic stimulation:A review.Chilinical Neurophysiology,2001,112(8):1367-1377
49.Gorsler A,Baumer T,Weiller C,et al.Interhemispheric effects of high and low frequency rTMS in healthy humans.Clin Neurophysiol,2003,114:1800-1807
50.Pedro C,Miranda,Mark Hallett,Peter J.Basser the electric field induced in the brain by magnetic stimulation:A 3-D finite-element analysis of the effect of tissue heterogeneity and anisotropy.IEEE Transactions on Biomedical Engineering,2003, 50(9):1074-1085
51. Barde, YA, Edgar, D and Thoenen, H. Purification of a new neurotrophic factor from mammalian brain- BDNF is a neurotrophic factor for dopaminergic neurons o f the substantia nigra. Nature, 1982, 350, 230-232
52. Emfors P, Ibanez GF, Ebendal T, et al. Molecular cloning and neurotrophic activities of a protein with structural similarities to nerve growth factor: developmental and topographical expression in the brain. Proc Natl Acad Sci USA, 1990, 87: 5454-5458
53. Kawmoto Y, Nakamura S, Nalcano S, et al. Immunohistochemical location of brain-derived neurotrophic factor in adult rat brain. Neuroscience, 1996, 74: 1209-1226.
54. Brandoli C, Sanna A, De Bernardi MA, et al. Brain-derived neurotrophic factor and basic fibroblast growth factor downregulate NMDA receptor function in cerebellar granule cells. J Neurosci, 1998, 8: 7953-7961.
55. Pappas IS, Parnavelas JG. Neurotrophins and basic fibroblast growth factor induce the differentiation of calbindin-containing neurons in the cerebral cortex. Exp Neural. 1997,144:302
56. Kiprianova I,Freiman TM,Desiderato S,et al.Brain-derived neurotrophic factor prevents neuronal death and glia activation after global ischemia in the rat[J].J Neurosci Res,1999.56(1):21-27.
57. Schabitz WR, Sommer C, Zoder W, et al. Intravenous brain-derived neurotrophic factor reduces infarct size and counterregulates Bax and Bcl-2 expression after temporary focal cerebral ischemia. Stroke, 2000,31:2212-2217
58. Mu JS, Li WP, Yao ZB, et al. Deprivation of endogenous brain derived neurotrophic factors results in impairment of spatial learning and memory in adult rats. Brain Res, 1999, 835(2): 259-265
59. Dragunow M, Hughes P, Mason-Parker SE, et al. TrKB expression in dentale granule cell is associated with a late phase of long-term potentiation. Brain Res Mol, 1997, 46: 274-280
60. Patterson SL, Abel T, Deuel TA, et al. Recombinant BDNF rescues deficits in basal synaptic transmission and hippocampal LTP in BDNF knockout mice. Neuron, 1996,16:1137-1145
61. Kiprianova I, Sandkuhler J, Schwab S, et al. Brain-derived neurotrophic factor improves long-term potentiation and cognitive functions after transient forebrain ischemia in the rat. Exp Neural, 1999, 159: 511-519
62. Gooney M, Lynch Ma. Long-term potentiation in the dentate gyrus of the rat hippocampus is accompanied by brain-derived neurotrophic factor-induced activation of TrkB. JNeurochm, 2001, 77: 1198-1207
63. Muller MB, Toschi N, Kresse AE, et al. Long-term repetitive transcranial magnetic stimulation increases the expression of brain-derived neurotrophic factor and cholecystokinin mRNA, but not neuropeptide tyrosine mRNA in specific areas of rat brain. Neuropsychopharmacology. 2000,23(2): 205-15
64. Doi W,Sato D,Fukuzako H,et al.c-Fos expression in rat brain after repetitive transcranial magnetic stimulation.Neuroreport,2001,12(6):1307-1310.
65. Behe P, Stem P, Wyllie DJ. Determination of NMD AR NR1 subunit copy number in recombinant NMDA receptor. Proc-R-Soc-Lond-B-Biol-Sci. 1995; 262: 205-213
66. Tsien JZ, Huerta PT, Tonegawa S. The essential role of hippocampal CA1 NMDA receptor dependent synaptic plasticity in spatial memory. Cell, 1996, 87(7): 1327-1338
67. Levy HI, Hanscom B, Boden SD. Three- question depression screener used for lumbar disc herniation and spinal stenosis. Spine, 2002,27(11): 1232- 1237
68. Jahn R, Schiebler W, Ovimetc, et al. A 38000-dalton membrane protein (p38) present in synaptic vesicles. Proc Nall Acad USA. 1985, 82:4137-4141
69. Tarsa L , Goda Y. Synaptophysin regulates activity- dependent synapse formation in cultured hippocampal neurons. Proc Natl Acad Sci USA , 2002 , 99(2): 1012-1016
70. Lauri SE, Lamsa K, Pavlov I. Activity blockade increases the number of functional synapses in the hippocampus of newborn rats. Mol Cell Neurosci, 2003, 22(1): 107-117
71. Janz R, Sudhof TC, Hzmmer RE, et al. Essential roles in synaptic plasticity for synaptohysin II and synaptophysin I. Neuron, 1999,24(3): 687
72. Nadeau SE, McCoy KJ, Crucian GP, et al. cerebral blood flow changes in depressed patients after treatment with repetitive transcranial magnetic stimulation: evidence of individual variability. Neuropsychiatry Neuropsychol Behav Neurol,2002,15:159-175
73. Black IB. Trophic regulation of synaptic plasticity. J Neurobiol, 1999,41: 108-118
1 Englund E.Neuropathology of white matter lesions in vascular cognitive impairment.Cerebrovasc Dis,2002,13:Suppl 2:11-115.
2 Whalley LJ.Brain aging and dementia:what makes the difference? Br J Psychiatry,2002,181:369-371.
3 DeLeeuw FE,Richard F,deGroot JC,et al.Interaction between hyperintension,apoE,and cerebral white matter lesion.Stroke,2004,35:1057-1062.
4 Hebert R,Lindsay J,Verreault R,et al.Vascular dementia:incidence and risk factors in the Canadian study of health and aging.Stroke,2000,31:1487-1493.
5 Baum L,Lam LC,Kwok T,et al.Apolipoprotein E epsilon4 allele is associated with vascular dementia.Dement Geriatr Cogn Disord.2006,22:301-305.
6 Davidson Y,Gibbons L,Purandare N,et al.Apolipoprotein E epsilon4 allele frequency in vascular dementia.Dement Geriatr Cogn Disord.2006,22:15-19.
7 Dantoine TF,Debord J,Merle L,et al.Paraoxonase 1 activity:a new vascular marker of dementia? Ann N Y Acad Sci.2002,977:96-101.
8 Ranade K,Kirchgessner TG,Iakoubova OA,et al.Evaluation of the paraoxonases as candidate genes for stroke:Gln192Arg polymorphism in the paraoxonase 1 gene is associated with increased risk of stroke.Stroke,2005,36:2346-2350.
9 Schmidt R,Schmidt H,Fazekas F,et al.MRI cerebral white matter lesions and paraoxonase PON 1 polymorphisms.Arterioscler Thromb Vase Biol,2000,20:1811-1816.
10 Spell C,Kolsch H,Lutjohann D,et al.SREBP-1a polymorphism influences the risk of Alzheimer's disease in carriers of the ApoE4 allele. Dement Geriatr Cogn Disord, 2004, 18:245-249.
11 Kolsch H, Heun R, Kerksiek A, et al. Altered levels of plasma 24S and 27-hydroxycholesterol in demented patients. Neurosci Lett, 2002, 368: 303-308.
12 Panzenboeck U, Balazs Z, Sovic A, et al. ABCA1 and scavenger receptor class B, type I, are modulators of reverse sterol transport at an in vitro blood-brain barrier constituted of porcine brain capillary endothelial cells. J Biol Chem, 2002, 277: 42781-42789.
13 Cheng CY, Hong CJ, Liu HC, et al. Study of the association between Alzheimer's disease and angiotensin-converting enzyme gene polymorphism using DNA from lymphocytes. Eur Neurol, 2002,47: 26- 29.
14 Sharma P. Meta-analysis of the ACE gene in ischaemic stroke. J Neurol Neurosurg Psychiatry, 1998, 64: 227-230.
15 Purandare N, Oude Voshaar RC, Davidson Y, et al. Deletion/insertion polymorphism of the angiotensin-converting enzyme gene and white matter hyperintensities in dementia: A pilot study. J Am Geriatr Soc. 2006, 54: 1395-1400.
16 Wang HK, Fung HC, Hsu WC,et al. Apolipoprotein E, angiotensin-converting enzyme and kallikrein gene polymorphisms and the risk of Alzheimer's disease and vascular dementia. J Neural Transm. 2006,113: 1499-1509.
17 Kolsch H, Jessen F, Freymann N, et al. ACE I/D polymorphism is a risk factor of Alzheimer's disease but not of vascular dementia. Neurosci Lett, 2005, 377: 37-39.
18 Hassan A, Gormley K, O'Sullivan M, et al. Endothelial nitric oxide gene haplotypes and risk of cerebral small vessel disease. Stroke, 2004, 35: 654- 659.
19 Szolnoki Z, Havasi V, Bene J, et al. Endothelial nitric oxide synthase gene interactions and the risk of ischemic stroke. Acta Neurol Scand, 2005, 111: 29- 33.
20 Martiskainen M, Pohjasvaara T, Mikkelsson J, et al. Fibrinogen gene promotor-455 A allele as a risk factor for lacunar stroke. Stroke, 2003, 34: 886-891.
21 Van Oijen M, Wittman JC, Hofman A, et al. Fibrinogen is associated with an increased risk of Alzheimer disease and vascular dementia. Stroke 2005, 36:2637-41.
22 Slowik A, Dziedzic T, Pera J, et al. Coagulation factor XIU Val34Leu polymorphism in patients with small vessel disease or primary intracerebral hemorrhage. Cerebrovasc Dis, 2005, 19: 165-170.
23 Austin H, Chimowitz MI, Hill HA, et al. Cryptogenic stroke in relation to genetic variation in clotting factors and other genetic polymorphisms among young men and women. Stroke, 2002, 33: 2762- 2769.
24 Alluri RV, Mohan V, Komandur S, et al. MTHFR C677T gene mutation as a risk factor for arterial stroke: a hospital based study. Eur J Neurol, 2005,12: 40- 44.
25 Cronin S, Furie KL, Kelly PJ. Dose-related association of MTHFR 677T allele with risk of ischemic stroke. Evidence from a cumulative meta-analysis. Stroke, 2002, 36:1581- 1587.
26 Kohara K, Fujisawa M, Ando F, et al. MTHFR gene polymorphism as a risk factor for silent brain infarcts and white matter lesions in the Japanese general population. The NILS-LSA study. Stroke, 2003, 34: 1130-1135.
27 McIlroy SP, Dynan KB, Lawson JT, et al. Moderately elevated plasma homocysteine, methylenetetrahydrofolate reductase genotype, and risk for stroke, vascular dementia, and Alzheimer disease in Northern Ireland. Stroke, 2002, 33: 2351-2356.
28 Yoo JH, Choi GD, Kang SS. Pathogenicity of thermolabile methylenetetrahydrofolate reductase for vascular dementia. Arterioscler Thromb Vasc Biol. 2000, 20: 1921-1925.
29 Hentschel F, Kolsch H. The molecular genetics of the risk factors of vascular dementias. Clin Neuroradiol, 2007,17: 23- 29.
30 Ashfield-Watt PAL, Knowles RM, Cale SB, et al. A folate enriched diet lowers plasma homocysteine in patients with hyperlipidaemia: a randomized controlled trial. BrJCardiol,2001,8:28-35.
31 Koseoglu E, Karaman Y. Relations between homocysteine, folate and vitamin B12 in vascular dementia and in Alzheimer disease. Clin Biochem. 2007,40: 859-863.
32 Seshadri S, Beiser A, Selhub J, et al. Plasma homocysteine as a risk factor for dementia and Alzheimer's disease. N Engl J Med, 2002,346: 476- 483.
33 Bushnell CD, Goldstein LB. Homocysteine testing in patients with acute ischemic stroke. Neurology, 2002, 59:1541-1546.
34 Kolsch H, Linnebank M, Lutjohann D, et al. Polymorphisms in glutathione S-transferase omega-1 and AD, vascular dementia, and stroke. Neurology, 2004, 63: 2255-2260.
35 Zaremba J, Losy J. sPECAM-1 in serum and CSF of acute ischaemic stroke patients. Acta Neurol Scand, 2002,106: 292- 298.
36 Zuliani G, Guerra G, Ranzini M, et al. High interleukin-6 plasma levels are associated with functional impairment in older patients with vascular dementia. Int J Geriatr Psychiatry. 2007, 22: 305- 311.
37 Wada-Isoe K, Wakutani Y, Urakami K, et al. Elevated interleukin-6 levels in cerebrospinal fluid of vascular dementia patients. Acta Neurol Scand, 2004, 110: 124-127.
38 Pola R, Flex A, Gaetani E, et al. Synergistic effect of-174 G/C polymorphism of the interleukin-6 promotor and 469 E/K polymorphism of the intercellular adhesion molecule-1 gene in Italian patients with history of ischemic stroke. Stroke, 2003, 34: 881-885.
39 Aberle J, Hopfer I, Beil FU, et al. Association of peroxisome proliferators-activated receptor delta +294T/C with mass index and interaction with peroxisome proliferators-activated receptor alpha L162V. Int J Obes, 2006, 3: 108-111.
40 Flavell DM, Jamshidi Y, Hawe E, et al. Peroxisome proliferator-activated receptor alpha gene variants influence progression of coronary atherosclerosis and risk of coronary artery disease. Circulation, 2002,105: 1440-1445.
41 Combs CK, Johnson DE, Karlo JC et al. Inflammatory mechanisms in Alzheimer's disease: inhibition of beta-amyloid-stimulated proinflammatory responses and neurotoxicity by PPARgamma agonists. J Neurosci, 2000,20: 558- 567.
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