正电子成像技术在阿尔茨海默病模型和神经干细胞移植治疗中的实验方法研究
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摘要
[目的]建立阿尔茨海默病(AD)大鼠模型后进行神经干细胞(NSCs)移植治疗,以正常组、模型组、移植组的行为学、组织学改变为标准,探讨~(11)C-PIB和~(18)F-FDG显像在模型验证及监测细胞移植中的应用价值,有望为AD的诊断治疗研究提供在体的、可视化的技术平台。
[方法]建立Aβ(1-40)海马注射的AD大鼠模型,通过行为学及组织学改变验证模型成功后进行~(11)C-PIB PET和~(18)F-FDG micro PET成像,观察图像结果是否与行为学、组织学结果相匹配。对造模成功的大鼠进行细胞移植,比较模型组与移植组行为学、组织学改变,同时进行~(11)C-PIB和~(18)F-FDG显像,观察显像结果是否与行为学、组织学结果相匹配。
[结果]模型组在Morris水迷宫中的潜伏期明显长于正常组(P＜0.01),组织学显示海马CA_1及齿状回出现神经元丢失和Aβ沉积,~(11)C-PIB显像中模型组海马区域PIB放射性摄取明显增高(P＜0.05),~(18)F-FDG显像中模型组海马注射侧的放射性摄取明显低于对侧和正常组的同侧(P＜0.001),显像结果与行为学、组织学结果匹配。细胞移植后移植组潜伏期较模型组减少33.7%～51.5%(P＜0.01),组织学显示Aβ沉积无明显改变,NSCs分化表达ChaT、GFAP、NeuN阳性细胞,并持续6周表达Brdu阳性细胞,~(11)C-PIB显像表明移植组与模型组放射性摄取无显著差异(P＞0.05),显像结果与Aβ沉积相匹配,与行为学、细胞分化结果不匹配。~(18)F-FDG显像表明移植组与模型组海马注射侧的放射性摄取基本一致(P＞0.05),显像结果同样与行为学、细胞分化结果不匹配。
[结论]~(11)C-PIB和~(18)F-FDG显像有助于诊断AD和活体监测AD模型的病理学改变,但目前尚不能为AD干细胞移植的疗效监测提供一安全、动态、在体的可视化工具。
[Purpose]Established rat model of Alzheimer's disease(AD)and grafted neural stem cells(NSCs),choosing the changes of behavior test and histology of normal group,model group and transplantation group as the reference standard, discussing the value of ~(11)C-PIB and ~(18)F-FDG imaging in model verification and cell transplantation monitoring,hoping to providing the visualed technology method in vivo for the research of AD's diagnose and therapy.
[Methods]Established the Aβhippocampus injected rat model,verified by behavior test and histology,then performed ~(11)C-PIB PET and ~(18)F-FDG micro PET imaging and observed whether the result of imaging was matched with behavior test and histology's.Grafted NSCs to the successful rat model,comparing the changes of behavior test and histology between model group and transplantation group,then performing the ~(11)C-PIB and ~(18)F-FDG imaging,observing whether the result of imaging was matched with behavior test and histology's
[Result]The Morris water maze improved that the escaped latent period of model group was longer than that of normal group(P＜0.01),in histology neuron loss and Aβdeposition were found in hippocampus CAl and dentate gyrus of rat model, ~(11)C-PIB imaging showed increased uptake in model rat hippocampus district (P＜0.05),~(18)F-FDG imaging showed that the uptake in hippocampus inject district of model group was lower than that of normal group(P＜0.001),there was also much different uptake between bilateral hippocampus of model group(P＜0.001), these results were matched with behavior test and histology.After cell transplantation,the escaped latent period of transplantation group was shorter than that of model group(P＜0.01),which reduced 33.7%～51.5%,in histology there was no much change in Aβdeposition,NSCs differentiated and expressed ChaT、GFAP、NeuN positive cells,and expressed Brdu positive cells for six weeks, ~(11)C-PIB imaging showed there was no much change in hippocampus district between model group and transplantation group(P＞0.05),which was matched with Aβdeposition,but not matched with results of behavior test and cell differentiation of histology.~(18)F-FDG imaging showed there was no much chang in injected hippocampus of the two groups(P＞0.05),the result was not matched with the behavior test and cell differentiation of histology..
[Conclusion]~(11)C-PIB and ~(18)F-FDG imaging can be the ideal of AD diagnose and monitoring the pathological change of AD model in vivo.But it can not provide a safe,dynamic,in vivo imaging tool for monitoring therapeutic effect of implant stem cell for AD at present.
[方法]建立Aβ(1-40)海马注射的AD大鼠模型,通过行为学及组织学改变验证模型成功后进行~(11)C-PIB PET和~(18)F-FDG micro PET成像,观察图像结果是否与行为学、组织学结果相匹配。对造模成功的大鼠进行细胞移植,比较模型组与移植组行为学、组织学改变,同时进行~(11)C-PIB和~(18)F-FDG显像,观察显像结果是否与行为学、组织学结果相匹配。
[结果]模型组在Morris水迷宫中的潜伏期明显长于正常组(P＜0.01),组织学显示海马CA_1及齿状回出现神经元丢失和Aβ沉积,~(11)C-PIB显像中模型组海马区域PIB放射性摄取明显增高(P＜0.05),~(18)F-FDG显像中模型组海马注射侧的放射性摄取明显低于对侧和正常组的同侧(P＜0.001),显像结果与行为学、组织学结果匹配。细胞移植后移植组潜伏期较模型组减少33.7%～51.5%(P＜0.01),组织学显示Aβ沉积无明显改变,NSCs分化表达ChaT、GFAP、NeuN阳性细胞,并持续6周表达Brdu阳性细胞,~(11)C-PIB显像表明移植组与模型组放射性摄取无显著差异(P＞0.05),显像结果与Aβ沉积相匹配,与行为学、细胞分化结果不匹配。~(18)F-FDG显像表明移植组与模型组海马注射侧的放射性摄取基本一致(P＞0.05),显像结果同样与行为学、细胞分化结果不匹配。
[结论]~(11)C-PIB和~(18)F-FDG显像有助于诊断AD和活体监测AD模型的病理学改变,但目前尚不能为AD干细胞移植的疗效监测提供一安全、动态、在体的可视化工具。
[Purpose]Established rat model of Alzheimer's disease(AD)and grafted neural stem cells(NSCs),choosing the changes of behavior test and histology of normal group,model group and transplantation group as the reference standard, discussing the value of ~(11)C-PIB and ~(18)F-FDG imaging in model verification and cell transplantation monitoring,hoping to providing the visualed technology method in vivo for the research of AD's diagnose and therapy.
[Methods]Established the Aβhippocampus injected rat model,verified by behavior test and histology,then performed ~(11)C-PIB PET and ~(18)F-FDG micro PET imaging and observed whether the result of imaging was matched with behavior test and histology's.Grafted NSCs to the successful rat model,comparing the changes of behavior test and histology between model group and transplantation group,then performing the ~(11)C-PIB and ~(18)F-FDG imaging,observing whether the result of imaging was matched with behavior test and histology's
[Result]The Morris water maze improved that the escaped latent period of model group was longer than that of normal group(P＜0.01),in histology neuron loss and Aβdeposition were found in hippocampus CAl and dentate gyrus of rat model, ~(11)C-PIB imaging showed increased uptake in model rat hippocampus district (P＜0.05),~(18)F-FDG imaging showed that the uptake in hippocampus inject district of model group was lower than that of normal group(P＜0.001),there was also much different uptake between bilateral hippocampus of model group(P＜0.001), these results were matched with behavior test and histology.After cell transplantation,the escaped latent period of transplantation group was shorter than that of model group(P＜0.01),which reduced 33.7%～51.5%,in histology there was no much change in Aβdeposition,NSCs differentiated and expressed ChaT、GFAP、NeuN positive cells,and expressed Brdu positive cells for six weeks, ~(11)C-PIB imaging showed there was no much change in hippocampus district between model group and transplantation group(P＞0.05),which was matched with Aβdeposition,but not matched with results of behavior test and cell differentiation of histology.~(18)F-FDG imaging showed there was no much chang in injected hippocampus of the two groups(P＞0.05),the result was not matched with the behavior test and cell differentiation of histology..
[Conclusion]~(11)C-PIB and ~(18)F-FDG imaging can be the ideal of AD diagnose and monitoring the pathological change of AD model in vivo.But it can not provide a safe,dynamic,in vivo imaging tool for monitoring therapeutic effect of implant stem cell for AD at present.
引文
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[3]Reiman EM,Uecker A,Caselli RJ,et al.Hippocampal volumes in cognitively normal persons at genetic risk for Alzheimer's disease[J].Ann,Neurol 1998,44(2):288-291
[4]Petrella JR,Coleman RE,Doraiswamy PM.Neuroimaging and early diagnosis of Alzheimer's disease:a look to the future.Radiology 2003,226:315-336.
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[6]Agdeppa ED,Kepe V,Liu J,et al.Binding Characteristics of Radiofluorinated 6-dialkylamino-2-naphthylethylidene Derivatives as Positron Emission Tomography Imaging Probes for Beta-amyloid Plaques in Alzheimer's Disease[J].J Neurosci,2001,21:RC189.
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[9]J.J.Miguel-Hidalgo,X.A.Alvarez,R.Cacabelos,et al Neuroprotection by memantine against neurodegeneration induced by β-amyloid(1-40)Brain Research 2002,958:210-221
[10]George P,Charles W The Rat Brain in Stereotaxic Coordinates.Academic Press 1998
[11]Solbach C,Uebele M,Reisch G,et al.Efficient radiosynthesis of carbon-11 labelled uncharged Thioflavin T derivatives using[~(11)C]methyl triflate for β-amyloid imaging in Alzheimer's Disease with PET.Appl Radiat Istope,2005,62:591-595.
[12]张锦明,田嘉禾,王武尚,等.单管法自动化合成~(11)C-碘代甲烷,中华核医学杂志,2004,24:243-244.
[13]Bacskai BJ,Hickey GA,Skoch J,et al.Four-dimensional imaging of brain entry,amyloid-binding and clearance of an amyloid-β ligand in transgenic mice using multiphoton microscopy.Proc Natl Acad Sci USA 2003,100:12462-12467
[14]Klunk WE,EnglerI-I,NordbergA,et al.Imaging brain amyloid in Alzheimer's disease with Pittsburgh Compound-B.Ann Neuro.2004,55:306-319.
[15]Ono M,Wilson A,Nobrega J,et al.11C-labeled stilbene derivatives as A βaggregate specific PET imagingagents for Alzheimer's disease.Nucl Med Biol.2003,30:565-571.
[16]Nitta A.,Itoh A.,Hasegawa,T.et al.13-amyloid protein-induced Alzheimer's disease animal model.Neurosci.Lett.,1994,170 63-66
[17]Dornan W.A.,Kang D.E.,McCampbell A,et al.Bilateral injections of beta A(25-35)+ IBO into the hippocampus disrupts acquisition of spatial learning in the rat,Neuroreport.1993,5:165-168
[18]Winkler J.,Conoer D.J.,Frautschy SA,et al.Lack of long-term effects after β-amyloid protein injections in rat brain,Neurobiol.Aging.1994,15:601-607
[19]Ralph Myers The biological application of small animal PET imaging Nuclear Medicine and Biology.2001,28:585-593
[20]Van Praag H,Kempermann G,Gage FH.Running increases cell proliferation and neurogenesis in the adult mouse dentate gyrus[J].Nature Neurosci.1999,2(3):266-270.
[21]Jin KL,Minami M,Lan JQ,et al.Neurogenesis in dentate sub-granular zone and rostral subventricular zone after focal cerebral is chemia in the rat[J]. PNAS,2001,98(8):4710-4715.
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