帕金森病的实验和临床神经功能影像学研究
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摘要
帕金森病（Parkinson's disease,PD）是一中老年人常见的慢性进行性神经变性疾病，主要临床表现为震颤、运动减少、肌强直和姿势障碍等。近年来，随着社会人口老龄化进程的加快，PD的发病呈逐年增多的趋势，据文献报道，我国55岁以上人口中PD患病率为1%，而由PD所导致的运动残疾，给家庭、社会带来沉重的经济、精神负担。对PD的早期诊断和神经保护干预是目前PD临床工作中的两个主要课题。目前，PD的诊断为临床诊断，即根据临床表现进行，缺乏客观、简便的早期影像学诊断指标。PET和SPECT可以对多巴胺能突触前受体和突触后受体功能进行活体显像。99Tcm-TRODAT-1是近年发明的一种99Tcm标记的多巴胺转运蛋白(dopamine transporter, DAT) SPECT显像剂，11C-Raclopride是常用的多巴胺D2受体PET显像剂，国内尚无成功合成及应用的报道。本文在建立亚临床期和临床期PD模型猴的基础上，分别应用以上两种DAT和D2R显像剂对PD模型猴进行SPECT和PET脑显像，研究亚临床期和临床期PD多巴胺转运蛋白和多巴胺D2受体功能特点，探讨99Tcm-TRODAT-1 SPECT脑显像和11C-Raclopride PET脑显像在PD早期诊断，特别是亚临床期诊断上的价值。本文还将就99Tcm-TRODAT-1 SPECT脑显像在PD患者早期诊断和疾病严重程度评价中的价值进行探讨，并就PD患者纹状体99Tcm-TRODAT-1特异性摄取与帕金森病统一评分量表（unified parkinson's disease rating scale ,UPDRS）运动功能障碍评分间的相关关系进行分析。司来吉兰是目前常用的一种B型单胺氧化酶抑制剂，有研究表明它具有延缓PD病情进展、推迟应用左旋多巴时间，可能具有神经保护作用。本文就司来吉兰的可能神经保护作用进行实验研究，并应用99Tcm-TRODAT-1就司来吉兰预处理对纹状体DAT功能的影响进行评价。本文包括以下主要内容：1.司来吉兰对帕金森病小鼠黑质神经保护作用及其评价；2.亚临床期和临床期帕金森病模型猴
99Tcm-TRODAT-1 多巴胺转运蛋白SPECT脑显像；3.亚临床期和临床期帕金森病模型猴11C-Raclopride多巴胺D2受体PET脑显像；4. 99Tcm-TRODAT-1 多巴胺转运蛋白SPECT脑显像在帕金森病早期诊断和病情监测中的价值；5.帕金森病纹状99Tcm-TRODAT-1
特异性摄取与运动功能障碍评分的关系。
第一部分：司来吉兰对帕金森病小鼠黑质的神经保护作用及其评价
目的：探讨司来吉兰对PD小鼠黑质的神经保护作用。方法：24只雄性C57BL小鼠被随机分成三组，即司来吉兰预处理组、模型组和对照组，每组8只。分别给予司来吉兰+MPTP、MPTP和生理盐水，连续应用7天。司来吉兰在MPTP腹腔注射前30min灌胃给予。观察各组小鼠的行为学变化。7天后处死，每组中取6只行黑质流式细胞学检查，分别测定黑质细胞凋亡率、bcl-2和bax蛋白表达的平均荧光强度（mean fluorescence intensity,MFI）。每组的另外2只小鼠分别进行黑质酪氨酸羟化酶（thyrosine hydroxylase,TH）免疫组化和透射电镜观察。21只雄性C57BL小鼠被随机分成司来吉兰预处理组、模型组和对照组。处理方法同前。7天后尾静脉注射99Tcm-TRODAT-1 37MBq，2h后处死，分离纹状体、小脑并称重，并用γ计数器测量放射性计数，计算纹状体/小脑单位重量的放射性计数比值。结果：模型组小鼠出现PD症状，司来吉兰预处理组和对照组无行为异常。司来吉兰预处理组、模型组和对照组黑质细胞的凋亡率分别为5.17±0.73%、19.96±1.77%和4.68±1.04%和，与对照组比较模型组凋亡率比司来吉兰预处理组和对照组分别增高14.79%（P<0.01）和15.28%（P<0.01），司来吉兰预处理组与对照组的凋亡率无差异（P>0.05）。司来吉兰预处理组、MPTP组和对照组的bcl-2蛋白表达的MFI分别为10.01±1.43、3.67±0.83和6.37±0.90。司来吉兰预处理组、模型组和对照组的bax表达分别为4.40±1.12、13.85±1.99和8.34±0.80。与对照组比较，模型组bax高表达（P<0.01）而bcl-2低表达（P<0.01）；与对照组比较，司来吉兰预处理组bax低表达（P<0.01）而bcl-2高表达(P<0.01)。司来吉兰预处理组、模型组和对照组的小鼠纹状体/小脑放射性计数比值分别为2.59±0.98、1.02±0.61和2.47±1.05。司来吉兰预处理组和对照组小鼠的纹状体/小脑放射性计数比值无差异（P>0.05）。与对照
组和司来吉兰组比较，模型组小鼠纹状体/小脑放射性计数比值明显降低（P<0.01,P<0.01）。结论：1.MPTP处理小鼠黑质细胞发生了凋亡，细胞凋亡参与MPTP处理 PD小鼠的发病；2.MAO-B抑制剂——司来吉兰预处理对小鼠黑质产生神经保护作用，阻断了MPTP所致的细胞凋亡；3.司来吉兰对MPTP处理小鼠黑质的保护作用机制之一是通过上调bcl-2基因和下调bax基因而实现的；4.新型DAT显像剂——99Tcm-TRODAT-1可用于PD的神经保护作用的客观影像学评价。
第二部分：亚临床期和临床期帕金森病模型猴99Tcm-TRODAT-1多巴胺转运蛋白SPECT脑显像
目的：探讨99Tcm-TRODAT-1 多巴胺转运蛋白SPECT脑显像在亚临床期帕金森病诊断中的价值。方法：静脉注射多巴胺转运蛋白显像剂99Tcm-TRODAT-1，进行不同时间点的全身扫描和SPECT脑断层显像，观察99Tcm-TRODAT-1在正常猴体内分布和纹状体DAT功能分析。对M1-M4 4只猴
Parkinson's disease (PD) is a chronic progressive neurodegenerative disorder among middle age and old-age persons. PD's cardinal manifestations are tremor, rigidity, bradykinesia and postural instability et al. The episode rate increased year by year as the course of population aging. According to literature's report, about 1% population above 55 years old were patients with PD in our country. Motor disability caused by PD burden on families and society. There are two topics in clinical practices: how to diagnosis PD early and how to neuroprotect PD. At present, the diagnosis of PD still depends on clinical criteria. Recent studies showed that an unexpectedly high rate of misdiagnosis occurred if the diagnosis was based on only the clinical diagnostic criteria only. In addition, motor disturbances began only after a loss of approximately 70%-80% of striatal dopamine, resulting in a long "latent" stage preceding the development of clinical manifestations. There is no objective technique in early diagnosis of PD. PET and SPECT have enabled noninvasive, in vivo visualization of the progression of striatal neuronal function including dopamine transporter (DAT) and dopamine receptor (DR) in PD. 99Tcm-TRODAT-1 is a novel DAT SPECT agent. 11C-raclopride is a commonly used D2R PET agent. At the basis of success establishment of Hemi-parkinsonism monkeys, we investigated the functions of DAT and D2R in subclinical and clinical PD monkeys using above two agents. To explore the values of 99Tcm-TRODAT-1 SPECT brain imaging and 11C-raclopride PET brain imaging in the early diagnosis of PD, especially in the diagnosis of subclinical PD. In clinical research part, we investigated the clinical values of 99Tcm-TRODAT-1 DAT SPECT imaging in early diagnosis of patients
with PD. We also evaluated the values of 99Tcm-TRODAT-1 DAT SPECT imaging for assessing the degrees about the severity of patients with PD. To investigate the relationship of striatal 99Tcm-TRODAT-1 specific uptake values (SUVs) and motor's severity in patients with PD. Selegiline is a common monoamine oxidase-B inhibitor. According to literatures, selegiline may be having neuroprotective effects in the progression of PD. At the basis of establishment of mice with MPTP-induced parkinsonism, we investigated the selegiline's neuroprotective effects on substantia nigra using flow cytometry (FCM), thyrosine hydroxylase (TH) immunohistochemistry and transmission electorn microscope (TEM). We also investigated selegiline's neuroprotective effects on striatal DAT using 99Tcm-TRODAT-1 agent. The thesis was composed of five parts: Ⅰ. The neuroprotective effects of selegiline on substantia nigra neurons of mice with MPTP-induced parkinsonism. Ⅱ. Study on the values of 99Tcm-TRODAT-1 DAT SPECT in diagnosis of subclinical PD monkey.Ⅲ.Study on the values of 11C-raclopride D2R PET in the diagnosis of subclinical and clinical PD monkey. Ⅳ. Study on values of 99Tcm-TRODAT-1 DAT SPECT in the early diagnosis and assessing the severity of patients with PD.Ⅴ. Relationship of striatal 99Tcm-TRODAT-1 specific uptake and motor's severity in patients with Parkinson's disease.
Part Ⅰ: The neuroprotective effects of selegiline on substantia nigra neurons of mice with MPTP-induced parkinsonism
Objective: To investigate the neuroprotective effects of selegilne on substantia nigna neurons of PD mice. Methods: 24 male C57BL mice were divided into three groups randomly (each had 8 mice). Three groups of C57BL mice treated with selegiline plus MPTP, MPTP and normal saline, respectively, for 7 days before performing FCM, TEM and TH immunohistochemistry in substantia nigra. Mice of selegiline group were fed 10mg/Kg selegiline daily for 7 days, a half an hour prior to 30mg/Kg MPTP treatment. Mice with MPTP-induced parkinsonism were received intraperitoneal injection of 30mg/Kg MPTP once a day for 7 days. Mice of
control group received normal saline intraperitoneally once a day for 7 days. Apoptosis rate, bcl-2 protein expression mean fluorescence intensity (MFI), bax
99Tcm-TRODAT-1 多巴胺转运蛋白SPECT脑显像；3.亚临床期和临床期帕金森病模型猴11C-Raclopride多巴胺D2受体PET脑显像；4. 99Tcm-TRODAT-1 多巴胺转运蛋白SPECT脑显像在帕金森病早期诊断和病情监测中的价值；5.帕金森病纹状99Tcm-TRODAT-1
特异性摄取与运动功能障碍评分的关系。
第一部分：司来吉兰对帕金森病小鼠黑质的神经保护作用及其评价
目的：探讨司来吉兰对PD小鼠黑质的神经保护作用。方法：24只雄性C57BL小鼠被随机分成三组，即司来吉兰预处理组、模型组和对照组，每组8只。分别给予司来吉兰+MPTP、MPTP和生理盐水，连续应用7天。司来吉兰在MPTP腹腔注射前30min灌胃给予。观察各组小鼠的行为学变化。7天后处死，每组中取6只行黑质流式细胞学检查，分别测定黑质细胞凋亡率、bcl-2和bax蛋白表达的平均荧光强度（mean fluorescence intensity,MFI）。每组的另外2只小鼠分别进行黑质酪氨酸羟化酶（thyrosine hydroxylase,TH）免疫组化和透射电镜观察。21只雄性C57BL小鼠被随机分成司来吉兰预处理组、模型组和对照组。处理方法同前。7天后尾静脉注射99Tcm-TRODAT-1 37MBq，2h后处死，分离纹状体、小脑并称重，并用γ计数器测量放射性计数，计算纹状体/小脑单位重量的放射性计数比值。结果：模型组小鼠出现PD症状，司来吉兰预处理组和对照组无行为异常。司来吉兰预处理组、模型组和对照组黑质细胞的凋亡率分别为5.17±0.73%、19.96±1.77%和4.68±1.04%和，与对照组比较模型组凋亡率比司来吉兰预处理组和对照组分别增高14.79%（P<0.01）和15.28%（P<0.01），司来吉兰预处理组与对照组的凋亡率无差异（P>0.05）。司来吉兰预处理组、MPTP组和对照组的bcl-2蛋白表达的MFI分别为10.01±1.43、3.67±0.83和6.37±0.90。司来吉兰预处理组、模型组和对照组的bax表达分别为4.40±1.12、13.85±1.99和8.34±0.80。与对照组比较，模型组bax高表达（P<0.01）而bcl-2低表达（P<0.01）；与对照组比较，司来吉兰预处理组bax低表达（P<0.01）而bcl-2高表达(P<0.01)。司来吉兰预处理组、模型组和对照组的小鼠纹状体/小脑放射性计数比值分别为2.59±0.98、1.02±0.61和2.47±1.05。司来吉兰预处理组和对照组小鼠的纹状体/小脑放射性计数比值无差异（P>0.05）。与对照
组和司来吉兰组比较，模型组小鼠纹状体/小脑放射性计数比值明显降低（P<0.01,P<0.01）。结论：1.MPTP处理小鼠黑质细胞发生了凋亡，细胞凋亡参与MPTP处理 PD小鼠的发病；2.MAO-B抑制剂——司来吉兰预处理对小鼠黑质产生神经保护作用，阻断了MPTP所致的细胞凋亡；3.司来吉兰对MPTP处理小鼠黑质的保护作用机制之一是通过上调bcl-2基因和下调bax基因而实现的；4.新型DAT显像剂——99Tcm-TRODAT-1可用于PD的神经保护作用的客观影像学评价。
第二部分：亚临床期和临床期帕金森病模型猴99Tcm-TRODAT-1多巴胺转运蛋白SPECT脑显像
目的：探讨99Tcm-TRODAT-1 多巴胺转运蛋白SPECT脑显像在亚临床期帕金森病诊断中的价值。方法：静脉注射多巴胺转运蛋白显像剂99Tcm-TRODAT-1，进行不同时间点的全身扫描和SPECT脑断层显像，观察99Tcm-TRODAT-1在正常猴体内分布和纹状体DAT功能分析。对M1-M4 4只猴
Parkinson's disease (PD) is a chronic progressive neurodegenerative disorder among middle age and old-age persons. PD's cardinal manifestations are tremor, rigidity, bradykinesia and postural instability et al. The episode rate increased year by year as the course of population aging. According to literature's report, about 1% population above 55 years old were patients with PD in our country. Motor disability caused by PD burden on families and society. There are two topics in clinical practices: how to diagnosis PD early and how to neuroprotect PD. At present, the diagnosis of PD still depends on clinical criteria. Recent studies showed that an unexpectedly high rate of misdiagnosis occurred if the diagnosis was based on only the clinical diagnostic criteria only. In addition, motor disturbances began only after a loss of approximately 70%-80% of striatal dopamine, resulting in a long "latent" stage preceding the development of clinical manifestations. There is no objective technique in early diagnosis of PD. PET and SPECT have enabled noninvasive, in vivo visualization of the progression of striatal neuronal function including dopamine transporter (DAT) and dopamine receptor (DR) in PD. 99Tcm-TRODAT-1 is a novel DAT SPECT agent. 11C-raclopride is a commonly used D2R PET agent. At the basis of success establishment of Hemi-parkinsonism monkeys, we investigated the functions of DAT and D2R in subclinical and clinical PD monkeys using above two agents. To explore the values of 99Tcm-TRODAT-1 SPECT brain imaging and 11C-raclopride PET brain imaging in the early diagnosis of PD, especially in the diagnosis of subclinical PD. In clinical research part, we investigated the clinical values of 99Tcm-TRODAT-1 DAT SPECT imaging in early diagnosis of patients
with PD. We also evaluated the values of 99Tcm-TRODAT-1 DAT SPECT imaging for assessing the degrees about the severity of patients with PD. To investigate the relationship of striatal 99Tcm-TRODAT-1 specific uptake values (SUVs) and motor's severity in patients with PD. Selegiline is a common monoamine oxidase-B inhibitor. According to literatures, selegiline may be having neuroprotective effects in the progression of PD. At the basis of establishment of mice with MPTP-induced parkinsonism, we investigated the selegiline's neuroprotective effects on substantia nigra using flow cytometry (FCM), thyrosine hydroxylase (TH) immunohistochemistry and transmission electorn microscope (TEM). We also investigated selegiline's neuroprotective effects on striatal DAT using 99Tcm-TRODAT-1 agent. The thesis was composed of five parts: Ⅰ. The neuroprotective effects of selegiline on substantia nigra neurons of mice with MPTP-induced parkinsonism. Ⅱ. Study on the values of 99Tcm-TRODAT-1 DAT SPECT in diagnosis of subclinical PD monkey.Ⅲ.Study on the values of 11C-raclopride D2R PET in the diagnosis of subclinical and clinical PD monkey. Ⅳ. Study on values of 99Tcm-TRODAT-1 DAT SPECT in the early diagnosis and assessing the severity of patients with PD.Ⅴ. Relationship of striatal 99Tcm-TRODAT-1 specific uptake and motor's severity in patients with Parkinson's disease.
Part Ⅰ: The neuroprotective effects of selegiline on substantia nigra neurons of mice with MPTP-induced parkinsonism
Objective: To investigate the neuroprotective effects of selegilne on substantia nigna neurons of PD mice. Methods: 24 male C57BL mice were divided into three groups randomly (each had 8 mice). Three groups of C57BL mice treated with selegiline plus MPTP, MPTP and normal saline, respectively, for 7 days before performing FCM, TEM and TH immunohistochemistry in substantia nigra. Mice of selegiline group were fed 10mg/Kg selegiline daily for 7 days, a half an hour prior to 30mg/Kg MPTP treatment. Mice with MPTP-induced parkinsonism were received intraperitoneal injection of 30mg/Kg MPTP once a day for 7 days. Mice of
control group received normal saline intraperitoneally once a day for 7 days. Apoptosis rate, bcl-2 protein expression mean fluorescence intensity (MFI), bax
引文
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2. 陈生弟,陈先文.帕金森病神经保护治疗研究现状及存在的问题.中华神经科杂志,2000,33(4):197-199
3. DATATOP: a multicenter controlled clinical trial in early Parkinson's disease.Parkinson Study Group. Arch Neurol,1989,46(10):1052-1060
4. LeWitt PA.Deprenyl's effect at slowing progression of parkinsonian disability: the DATATOP study. The Parkinson Study Group.Acta Neurol Scand Suppl,1991,136:79-86
5. Shoulson I . Neuro protective clinical strategies for Parkinson's disease. Ann Neurol,1992,32(suppl 1):S143-S145
6. Olanow CW. Deprenyl in the treatment of Parkinson's disease: clinical effects and speculations on mechanism of action.J Neural Transm Suppl,1996,48:75-84
7. LeWitt PA.Clinical trials of neuroprotection in Parkinson's disease: long-term selegiline and alpha-tocopherol treatment.J Neural Transm Suppl,1994,43:171-181
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