偏侧猴帕金森病模型的脑深部电刺激研究

目的 探讨丘脑底核脑深部电刺激(STN DBS)对纹状体多巴胺代谢的影响.方法 2只偏侧帕金森病(PD)模型猴,在电极植入术前及电刺激后1、3个月分别行单光子放射计算机断层扫描(SPECT)测定脑内多巴胺转运体(DAT)及多巴胺D2受体(D2R)的含量;利用高效液相色谱分析(HPLE-ECD)检测脑脊液中多巴胺及其代谢产物的含量和变化.结果 偏侧PD模型猴在深部脑刺激下症状明显缓解,SPECT显示在有效刺激后纹状体区DAT特异性摄取率增高,D2R特异性摄取率下降.脑脊液中多巴胺及其代谢产物的含量与术前相比无明显差异.结论 STN DBS可有效改善偏侧PD模型猴的症状.SPECT提示有效电刺激STN提高了纹状体区多巴胺代谢活性.     

4000/丘脑底核脑深部电刺激治疗帕金森病的功能显像实验研究

目的：通过PET、SPECT功能显像研究探讨丘脑底核(subthalamic nucleus ,STN) 脑深部电刺激（deep brain stimulation,DBS）对猴偏侧帕金森病（Parkinson’s disease, PD）模型纹状体区代谢的影响。方法：采用单侧颈内动脉注入1-甲基-4-苯基-1,2,3,6四氢吡啶(1-methy-4-phenyl-1,2,3,6-tetrahydropy-rindine, MPTP)建立猴偏侧PD模型,行右侧STN脑深部电极植入术,给予慢性高频电刺激。在刺激前及刺激后1、3个月分别行SPECT、PET功能显像测定。结果：PD模型猴在慢性高频电刺激下对侧肢体僵硬明显缓解,活动增多,步态稳定。SPECT检查显示注药侧纹状体区的多巴胺转运体（DAT）特异摄取率在给予有效刺激后较术前增高,多巴胺D2受体（D2R）的特异摄取率逐渐下降至接近正常侧水平。PET检查提示在电极植入术前右侧基底节区放射性摄取浓度较左侧偏低,给予慢性高频电刺激1个月后复查提示右侧放射性摄取浓度稍高于左侧,但双侧均较低, 3个月时复查右侧放射性摄取浓度明显高于左侧。结论：STN DBS可有效的改善偏侧猴PD模型症状。通过刺激后纹状体区DAT的升高, D2R逐渐下降以及糖代谢的提高提示在给予STN核有效慢性高频电刺激可能提高了纹状体区的代谢活性。     

丘脑底核脑深部电刺激治疗帕金森病的功能显像研究

目的通过单光子放射计算机断层扫描(SPECT)功能显像研究探讨丘脑底核脑深部电刺激(STN DBS)对纹状体多巴胺系统代谢的影响。方法对2只偏侧帕金森病(PD)模型猴及4例临床PD患者在施行单侧STN DBS手术前后给予SPECT检查,测定纹状体区域多巴胺转运体(DAT)及多巴胺D2受体(D2R)含量变化。结果STN DBS电刺激后2只偏侧PD模型猴及3例疗效较好的PD患者纹状体区DAT含量明显增加,2只PD模型猴D2R含量逐渐下降,4例患者D2R检测与术前无统计学意义。结论STN DBS可以明显改善PD症状,SPECT检查显示刺激侧纹状体区DAT含量升高,提示STN DBS可能改善了刺激侧纹状体区多巴胺的代谢,这可能是STN DBS的作用机制之一。     

丘脑底核脑深部电刺激治疗帕金森病临床SPECT随访

目的探讨丘脑底核脑深部电刺激(STN DBS)治疗帕金森病(PD)患者症状的改善及单光子放射计算机断层扫描(SPECT)的影像学变化。方法4例施行单侧STN DBS患者术前和给予电刺激后进行帕金森病综合评分(UPDRS)和SPECT测定。结果STN DBS术后临床症状明显改善,UPDRS运动评分缓解60%。3例改善良好的患者SPECT检查提示纹状体区域多巴胺转运体(DAT)含量较术前提高,另1例疗效欠佳的患者DAT含量降低,所有的患者多巴胺D2受体(D2R)检测与术前无明显差异。结论STN DBS可以明显改善PD患者的临床症状,SPECT检查显示刺激侧纹状体区DAT含量的升高提示STN DBS可能改善了多巴胺的代谢,而这种改善可能是STN DBS缓解PD症状的作用机制之一。     

99Tcm-TRODAT-1 SPECT与131I-epideprideSPECT显像对早期帕金森病人的临床应用价值

目的探讨脑多巴胺转运体（DAT）^99Tc^m-TRODAT-1 SPECT显像与多巴胺D2受体（D2R）^131I-epidepride SPECT显像在早期帕金森病（PD）中的临床应用价值。方法10例正常对照者及46例早期未经替代治疗的PD患者分别接受脑DAT ^99Tc^m-TRODAT-1 SPECT与多巴胺D2R ^131I-epidepride SPECT断层显像，利用感兴趣区技术计算纹状体与枕叶、额叶的放射性比值（ST-OC／OC和ST-FC／FC）。结果PD患者起病肢体对侧脑DAT比值ST-OC／OC和ST-FC／FC比同侧均降低，双侧ST-OC／OC较对照组均降低。PD患者起病肢体对侧脑D2R比值ST-OC／OC和ST-FC／FC比同侧均增高。PD患者起病肢体对侧脑DAT比值ST-OC／OC与患者病程呈负相关，起病肢体对侧脑D2R比值ST-OC／OC与患者年龄及UPDRS运动评分呈负相关。结论人脑DAT ^99Tc^m-TRODAT-1 SPECT显像与D2R ^131I-epidepride SPECT显像均有助于PD的早期诊断及病情监测。     

帕金森病功能显像实验研究

目的　应用99mTc TRODAT 1SPECT显像观察偏侧帕金森病 (PD)猴模型两侧纹状体多巴胺转运体 (DAT)密度的变化。方法　 4只恒河猴 ,编号为M1～ 4,M1为正常者 ,M2～M4为右侧颈总动脉注射神经毒素MPTP的PD模型者。静脉注射99mTc TRODAT 1(3 70～ 5 5 0MBq) ,1～ 2小时后进行SPECT断层扫描 ,选取清晰图像进行处理分析。结果　M1两侧纹状体感兴趣区比值为 1 0 0 ,M2～ 4左右侧纹状体感兴趣区比值为 1 10～ 1 2 2 ,而且右侧纹状体与各脑叶感兴趣区的比值均低于左侧。结论　99mTc TRODAT 1SPECT可以在体评估偏侧PD模型猴纹状体DAT的变化 ,有助于定量研究PD的诊断     

帕金森病多巴胺系统单光子发射计算机断层扫描显像研究进展

帕金森病(PD)的病理和生化研究已明确黑质-纹状体区多巴胺(DA)能神经通路的变性是确定本病的重要依据.PD的病理生理机制涉及到DA神经元突触前和突触后的复杂改变,既存在黑质-纹状体系统DA合成功能的减退,也有突触后DA受体活性和突触前多巴胺转运体(DAT)释放、回收DA功能的改变.临床上常通过以下方法对PD患者取得这些改变的依据:正电子发射计算机断层扫描(PET)和单光子发射计算机断层扫描(SPECT)基底节核素显像(DA代谢、DAT、DA受体等)、局部脑血流、葡萄糖代谢测定及磁共振成像(MRI)、超声测量黑质一纹状体体积、磁共振波谱(MRS)分析.在上述众多方法中纹状体区的PET和SPECT核素DA能系统显像能在PD早期提供诊断帮助,此时仅有病变区域功能障碍而无结构异常.     

脑内植入APA-BCC的偏侧帕金森病样猴的多巴胺D2受体功能影像观察

目的 观察海藻酸钙-多聚赖氨酸-海藻酸钙微囊化牛肾上腺嗜铬细胞(APA-BCC)脑内移植后偏侧帕金森病(PD)样猴行为的改善及纹状体区D2受体的活性。方法 1只MPTP诱发右侧PD样猴接受右侧脑纹状体区APA-BCC植入；观察移植后的行为变化；于移植后48个月时行^11C-raclopride标记多巴胺D2受体活性的PET检查。结果 APA-BCC脑内移植后48个月时，偏侧PD样猴的异常行为仍得到明显纠正；脑PET三维图像显示移植侧纹状体区D2受体活性较对侧明显增高。结论 APA-BCC脑内移植可长时间地纠正偏侧PD样猴的异常行为并升高移植区突触后膜多巴胺D2受体的活性。     

^99mTc-TRODAT-1 SPECT多巴胺转运体显像在诊断早期帕金森病中的意义

目的探讨99mTc-TRODAT-1 SPECT多巴胺转运体(DAT)显像在诊断早期帕金森病(PD)中的意义.方法对62例早期PD、12例晚期PD及10名正常人进行99mTc-TRODAT-1 SPECT 基底节DAT显像,选取纹状体区和小脑为感兴趣区,计算两者的放射性比值,比较3组间该比值的差异,并分析早期PD患者DAT放射性结合率与H&Y分级及UPDRS评分之间的相关性.结果PD患者基底节99m Tc-TRODAT-1摄取率显著降低,早期PD患者病变较重肢体对侧纹状体放射性摄取率较同侧纹状体显著下降.PD患者纹状体区放射性摄取率与PD患者的H&Y分级呈负相关,而与UPDRS Ⅱ、Ⅲ评分无相关性.结论99mTc-TRODAT-1 SPECT基底节 DAT显像可用于临床早期PD的诊断.     

丘脑底核电刺激对猴偏侧帕金森病纹状体神经递质的影响

目的 探讨应用微透析技术在慢性STN—DBS对纹状体细胞外液多巴胺及代谢产物的影响。方法 选择已经成功安装脑深部刺激电极的偏侧PD猕猴模型2只，分别在打开脉冲发生器前、后的不同时间点取样（开机后8h、1周、1个月、2个月）。应用高效液相电化学方法检测开机前后的尾状核和壳核细胞外液的多巴胺（DA）及其代谢产物含量。结果 电极侧壳核和尾状核的DA在开机后8h、1周、1个月、2个月相应地分别较各自开机前的DA含量增高了39％、91％、111％、114％和31％、91％、106％、102％（P〈0．05）。电极侧壳核和尾状核HVA／DA在开机后8h分别较各自开机前增高了186％和91％（P〈0．05），而开机后1周、1个月、2个月HVA／DA较开机前无明显变化（P〉0．05）。电极侧的多巴胺周转率在开机后的各时间点均显著低于非电极侧（P〈0．01）。结论 STN—DBS可有效的改善猴偏侧PD模型的症状，应用微透析取样技术结合高效液相色谱测，定法发现在给予有效电刺激后可增加刺激侧纹状体细胞外液的多巴胺及其代谢产物含量。为STN—DBS治疗帕金森病提供理论依据。     

Markers of dopamine depletion and compensatory response in striatum and cerebrospinal fluid

Summary Though depletion of CSF homovanillic acid (HVA) concentration has often been regarded as a direct indicator of dopamine (DA) deficiency in Parkinson's Disease (PD), CSF HVA is normal in mildly affected patients. To explore why, we measured DA and its metabolites in striatum and CSF in rabbits receiving reserpine for 5 days. Reserpine, which depletes striatal DA by disrupting vesicular storage of the neurotransmitter, results in a compensatory increase of DA turnover. In response to a 96% depletion of striatal DA, its catabolic intermediates 3,4-dihydroxyphenylacetic acid (DOPAC) and 3-methoxytyramine (3-MT) decreased 64% and 92% in striatum, although the endproduct, HVA, was unchanged. In contrast, CSF concentrations of HVA and DOPAC increased significantly, though 3-MT and levodopa (LD) were unaltered. A 5-fold rise in striatal LD concentration after reserpine-induced DA depletion provided evidence for enhanced DA synthesis. As in PD, the compensatory increase of DA synthesis after reserpine administration confounds the ability of CSF HVA to reflect DA depletion.     

Subthalamic nucleus stimulation and lesioning have distinct state‐dependent effects upon striatal dopamine metabolism

The mechanism by which deep brain stimulation (DBS) of the subthalamic nucleus (STN) achieves its effects in Parkinson's disease (PD) is not known. In animal models of PD, stimulation and lesioning of the STN have some effects which are the same, but others which differ, in reversing cellular and behavioral changes induced by dopamine depletion. We compared the effects of short‐term STN stimulation and lesions upon extracellular levels of dopamine and metabolites using in vivo microdialysis of the dorsal striatum of awake, intact and unilateral 6‐hydroxydopamine (6OHDA)‐lesioned rats. STN stimulation in control rats decreased striatal dopamine levels and caused a relative increase in dopamine metabolism, as expressed by HVA/dopamine and DOPAC/dopamine ratios. This suggests an increase in both vesicular dopamine release (metabolized to HVA), and release from the cytoplasmic dopamine pool (metabolized to DOPAC). STN lesions in control rats increased the HVA/dopamine ratio, also suggesting a relative increase in vesicular dopamine release. These results indicate that STN stimulation and lesioning can affect striatal dopamine metabolism in the intact system. In 6OHDA‐lesioned rats at baseline, metabolic ratios were markedly decreased as compared with controls. STN lesions of 6OHDA‐lesioned rats did not affect relative metabolic ratios as compared with baseline levels. In 6‐OHDA‐lesioned rats, STN stimulation decreased extracellular levels of dopamine, and, to a greater extent, metabolites, resulting in a decrease in metabolic ratios. This further decrease in dopamine turnover with STN stimulation would serve to maintain dopamine levels in the dopamine‐depleted striatum, and may account for the therapeutic benefit of DBS in Parkinson's disease. Synapse 63:136–146, 2009. Published 2008 Wiley‐Liss, Inc.     

Experimental research on functional imaging of Parkinson's disease

Objective To analyse the change of density of dopamine transporter (DAT) in striatum of hemiparkinsonian monkeys by SPECT inaging with 99mTc-TRODAT i. Methods four rhesus monkeys were used for this study, and named M1-4. M1 was normal monkey, others were hemiparkinsonian models induced by unilateral infusion of MPTP into the right common carotid artery. Acquisitions were performed 1～2 hours after an injection ot 370 ～550MBq 99mTc-TRODAT-1, exceilent imagings were selected for analysis. Regions of interest(ROls)were drawn over the striata and the cerebral cortexes. Results In healthy monkey (M1), Left striatum/right striatum ratio was 1.00 in the radioactivtity of RO1, but in hemiparkinsonian monkeys, left striatum/right striatum ratios were 1.10～1.22, and right striatum/cerebral cotexes ratios were decreased compared with that of left striatum/corebral cotexes. Conclusion SPECT imaging with 99mTc-TRODAT-1 can be used to in vivoo evaluate the loss of DAT in the striatum of the hemiparkinsonian monkeys, and to adjunctively make a diagnosis for Parkinson's disease, even in the earlier stage.     

Striatal dopamine receptors and transporters in monkeys with neonatal temporal limbic damage

Developmental cortical damage has been implicated in the basic neurobiology of schizophrenia. Adult rhesus monkeys with neonatal temporal limbic damage show a stimulus-dependent disinhibition of subcortical dopamine (DA) release. We measured dopamine D2 receptors and transporters in vivo in rhesus monkeys with neonatal and adult mesial temporal limbic lesions and control monkeys to explore further the effects of this developmental lesion on striatal DA function. All monkeys were studied with [I-123]IBZM SPECT to assess the availability of striatal dopamine D2 receptors and with [I-123]beta-CIT SPECT to measure the availability of dopamine transporters in the striatum. IBZM binding was significantly reduced in monkeys with neonatal limbic lesions. No group difference in beta-CIT binding was found. The reduction in IBZM binding was significantly correlated with subcortical dopamine release after monoaminergic prefrontal stimulation as determined with in vivo microdialysis. Our findings imply specific interactions between age at lesion and the availability of DA transporter and receptors in non-human primates, and suggest that stimulus-dependent DA activity affects the expression of DA receptors.     

Intraventricular microdialysis: a new method for determining monoamine metabolite concentrations in the cerebrospinal fluid of freely moving rats

A new method is described to estimate the cerebrospinal fluid (CSF) concentrations of monoamine metabolites (dihydroxyphenylacetic acid (DOPAC), homovanillic acid (HVA) and 5-hydroxyindoleacetic acid (5-HIAA] in the lateral ventricle of freely moving rats by use of in vivo microdialysis. Both the baseline concentrations of these metabolites and the rate of dopamine (DA) turnover (estimated by the accumulation of total DA metabolites after 200 mg/kg probenecid) were within the range reported when other methods were used to sample CSF. A series of preliminary studies were conducted to demonstrate that this method can be used to repeatedly sample CSF, and to show that the method is sensitive to local changes in dopaminergic activity induced by lesions, drugs or grafts. (1) Unilateral 6-hydroxydopamine (6-OHDA) lesions of the substantia nigra produced a significant decrease in the CSF concentrations of DOPAC and HVA ipsilateral to the lesion, relative to the contralateral side or to concentrations in animals without lesions. (2) When left and right lateral ventricles were sampled simultaneously in animals with a unilateral 6-OHDA lesion, haloperidol induced an increase in DOPAC and HVA concentrations in CSF on both sides of the brain. Interestingly, the haloperidol-induced increase in CSF concentrations of DA metabolites was greater adjacent to the intact striatum of rats with unilateral 6-OHDA lesions than in animals with no lesion. (3) Finally, in animals with adrenal medulla tissue grafted into the lateral ventricle there was an increase in the CSF concentration of DOPAC compared to pregraft values or to those of animals with control grafts.