^99mTc—TRODAT—1 SPECT多巴胺转运蛋白显像诊断帕金森病的临床应用

目的：利用^99mTc-TRODAT-1进行脑多巴胺转运蛋白（DAT）SPECT显像，探讨其对帕金森病（PD）诊断的价值。方法：对25例PD患者，5例健康志愿者行^99mTc-TRODAT-1SPECT DAT显像，并应用ROI技术测定纹状体与小脑部位的放射性比值。结果：单侧PD患者患肢对侧纹状体对^99mTc-TRODAT-1的摄取比同侧纹状体明显下降，双侧PD患者两侧纹状体对^99mTc-TRODAT-1的摄取均明显减少。结论：^99mTc-TRODAT-1SPECT DAT显像对PD的诊断、病情评估具有临床应用价值。     

99mTC-TRODAT-1 SPECT脑显像对帕金森病的早期诊断和应用

目的：探讨^99mTC-TRODAT-1 SPECT多巴胺转运体（DAT）显像对帕金森病（PD）早期诊断的临床价值。方法：13例早期PD患者（PD组）和15例健康者（对照组）行脑DAT^99mTC-TRODAT-1 SPECT显像,利用感兴趣区技术测定纹状体/小脑DAT摄取放射性比值（ST/CB）。结果：PD组患者症状两侧纹状体DAT摄取及症状同侧与对照组比较均显著降低（P〈0.01）。对照组双侧纹状体DAT摄取差异无显著性意义。结论：脑99mTC-TRODAT-1SPECT DAT显像有助于PD早期诊断。     

多巴胺受体激动剂治疗早期帕金森病的临床研究

帕金森病（Parkinson＇s disease,PD）是好发于中老年人群的一种神经变性疾病。临床表现主要为运动减少、震颤和肌强直等。本病的晚期致残率较高,其发病率随年龄的增加而上升,我国每年新增的PD患者近10万人。传统的药物治疗一直以左旋多巴制剂替代治疗为主,而多巴胺（DA）受体激动剂最初应用于左旋多巴的辅助治疗。但近年研究表明DA受体激动剂不但能缓解其临床症状,还具有神经保护作用嘲。本研究观察了32例应用DA受体激动剂单药治疗或左旋多巴／苄丝肼（商品名：美多芭）单药治疗的早期PD患者,初步探索DA受体激动剂治疗早期PD的临床疗效。     

运用单光子发射计算机断层扫描显像研究培补肝肾中药治疗帕金森病的疗效机制

目的：运用99Tc^m-TRODAT-1的单光发射计算机断层扫描(SPECT)显像研究培补肝肾中药治疗帕金森病疗效机制。方法：制备偏侧猴模型，造模前后及服用培补肝肾中药2个月后分别进行脑99Tc^m-TRODAT-1的SPECT检查，观察纹状体对多巴胺转运体(DAT)特异性放射性摄取率的变化，并观察行为学改变。结果：偏侧帕金森病模型猴1-甲基-4-苯基1，2，3，6-四氢吡啶(MPTP)注射侧和对侧纹状体DAT的特异性放射性摄取率均显著低于正常猴，中药治疗2个月后，偏侧帕金森病模型猴的主要症状有所改善，MPTP注射侧和对侧纹状体DAT的特异性放射性摄取率较治疗前明显增加。结论：培补肝肾中药对多巴胺能神经元有一定的保护作用。     

99Tcm-TRODAT-1脑显像在帕金森病诊断与分级中的应用

目的应用^99Tc^m-TRODAT-1对不同UPDRS分级的帕金森病（PD）患者进行多巴胺转运蛋白SPECT脑显像,探讨其在PD诊断与分级中的应用价值.方法对不同分级（Hoehn ＆ YahrⅠ～Ⅳ级,UPDRS评分9～108分）PD患者58例和对照组13例进行^99Tc^m-TRODAT-1 SPECT/CT脑断层融合显像.应用计算机感兴趣区（ROI）技术分别计算双侧纹状体/小脑、尾核/小脑、壳核/小脑的放射性计数比值,比较健康对照组及不同分级PD患者纹状体及其主要区域DAT功能差异,并对发病肢体对侧与同侧DAT功能进行比较,研究纹状体/小脑放射性计数比值与UPDRS评分之间相关性.结果与健康对照组比较,Ⅰ～Ⅳ级PD患者纹状体DAT功能均明显减低,与UPDRS评分呈负相关;Ⅰ级～2.5级PD患者均以发病肢体对侧减低更为明显;Ⅲ、Ⅳ级两组患者间纹状体DAT功能及其同侧、对侧DAT功能无明显差异.Ⅰ级～2.5级PD患者尾核、壳核功能均较健康对照组减低且存在差异,以壳核减低更为明显;Ⅲ、Ⅳ级患者尾核、壳核DAT功能虽都明显减低但二者间无显著性差异.结论 ^99Tc^m-TRODAT-1 SPECT脑显像可用于PD的早期诊断及病程分期,纹状体/小脑放射性计数比值可作为PD诊断及检测病情轻重的半定量分析指标,是H-Y分级与UPDRS评分的有益补充.     

帕金森病早期治疗的理论与实践

帕金森病（Parkinson disease，PD）是一种慢性进行性疾病，最主要的化学病理为黑质神经元死亡，其致密部不能合成多巴胺（dopamine，DA），而致纹状体中乙酰胆碱（acetylcholine，Ach）与DA的功能失去平衡而发病。理想的治疗应该阻止或延缓疾病进展，尽可能控制症状，同时不良反应最小。20世纪60年代引入左旋多巴治疗PD取得显著性症状改善以来，近年已经开发了多种药物用于治疗PD，包括单胺氧化酶（MAO）抑制剂、多巴胺受体激动剂、儿茶酚O-甲基转移酶抑制剂、谷氨酰胺释放抑制剂等。不过，左旋多巴／外周多巴胺脱羧酶抑制剂（L-dopa／PDI）疗法仍是PD的对症治疗的最佳选择，通常可以满意地控制症状长达6年左右或者更长时间，随后症状进行性发展。很多因素可以影响疾病的长期预后，包括选择何种药物、何时用药、剂量和用药次序等。本文我们先讨论帕金森病早期的临床特征，然后根据循证医学的观点有关证据，提出帕金森病早期的治疗镱略。     

多巴胺转运蛋白显像剂18F-FP-CIT脑PET显像评价脑内多巴胺能系统功能

目的本研究应用放射性显像剂18F-FP-CIT进行脑PET显像来评价脑内的DA能系统的功能变化,并从安全性、有效性等方面对本方法进行评价.方法分别对猴、正常人和不同程度的帕金森病患者应用18F-FP-CIT进行脑PET显像,观察其安全性和在不同程度PD患者的图像表现.结果正常猴1 h断层图像上脑内双侧尾状核和壳核出现较高的放射性浓聚;3 h双侧纹状体放射性相对更为浓聚.正常人15 min和30 min脑断层图像上双侧尾状核和壳核出现放射性摄取,同时大脑皮层有一定程度的放射性摄取,2 h图像已非常清晰,仅尾状核和壳核清晰可见.57例PD患者PET图像中,PD患者症状与对侧脑后壳核放射性的降低明显相关.结论 DAT显像可从分子水平评价多巴胺递质系统功能的客观情况,是有很好临床价值的分子影像学手段.     

心力衰竭患者外周淋巴细胞β受体变化及与心室重塑的相关性研究

目的 研究心力衰竭（心衰）患者外周血淋巴细胞β受体的变化及与心室重塑的相关性。方法 采用^3H—dihydroalpnenolol（^3H—DHA）放射性配基结合分析法，测定59例NYHAⅡ-Ⅳ级心衰患者外周血淋巴细胞膜上β受体密度，并以心脏超声仪测定和计算左心室质量指数（LVMI）。结果 心衰患者外周血淋巴细胞β受体密度随心功能分级增高而下降，LVMI随心功能分级增高而增高。冠心病、瓣膜病患者淋巴细胞β受体密度均显著低于高血压患者（P〈0．05）。心衰患者β受体密度与LVMI显著负相关（r=-0．219，P〈0．05），β受体密度的变化出现较早，在心功能Ⅱ级及LVMI正常时已有明显下降。结论 外周血淋巴细胞β受体密度能反映心功能受损和心室重塑的程度；β受体密度下调与心衰病因有关；心衰时β受体系统变化早于左心室心肌结构改变，提示心衰患者β受体系统可能参与左心室重塑的调控。     

运用单光子发射计算机断层扫描显像研究培补肝肾中药治疗帕金森病的疗效机制

目的:运用99Tcm-TRODAT-1的单光发射计算机断层扫描(SPECT)显像研究培补肝肾中药治疗帕金森病疗效机制。方法:制备偏侧猴模型,造模前后及服用培补肝肾中药2个月后分别进行脑99Tcm-TRODAT-1的SPECT检查,观察纹状体对多巴胺转运体(DAT)特异性放射性摄取率的变化,并观察行为学改变。结果:偏侧帕金森病模型猴1-甲基-4-苯基1,2,3,6-四氢吡啶(MPTP)注射侧和对侧纹状体DAT的特异性放射性摄取率均显著低于正常猴,中药治疗2个月后,偏侧帕金森病模型猴的主要症状有所改善,MPTP注射侧和对侧纹状体DAT的特异性放射性摄取率较治疗前明显增加。结论:培补肝肾中药对多巴胺能神经元有一定的保护作用。     

^99mTc-TRODAT-1脑SPECT显像对帕金森病的早期诊断价值

目的：评价脑^99Tc^m-2β[N，N’-双（2-巯乙基）乙撑二胺基]甲基，3β-（4-氯苯基）托烷（^99mTe—TRODAT-1）SPECT多巴胺转运蛋白（dopaminetransporter，DAT）显像对帕金森病（Parkinson’Sdisease，PD）早期诊断的临床应用价值。方法：对21例早期PD患者（Hoehn-Yahr1级12例，2级9例）及15例健康对照者分别进行”“Te-TRODAT-1SPECT脑显像，剂量为740MBq。应用计算机感兴趣区技术及2个数学模型分别计算早期PD患者及健康对照者双侧纹状体体积（V，cm^3）、质量（W，g），代表相应部位的多巴胺转运蛋白功能水平。结果：健康对照组SPECT扫描示DAT核素密度集中于双侧纹状体呈红色，左右基本对称，双侧纹状体貌似“熊猫眼”。早期PD患者双侧纹状体DAT核素分布不均匀，形状各异，其体积和质量均低于健康对照者，差异有显著性（P〈0.01）；早期PD患者症状对侧纹状体体积和质量均显著低于症状同侧（P〈0.01）；Hoehn—Yahr2级PD患者双侧纹状体DAT体积和质量均低于Hoehn—Yahr1级PD患者，差异有显著性（P〈0.05）。结论：DAT数量减少是PD发病的重要环节之-，^99mTc-TRODAT-1脑SPECT显像有勖于PD的早期临床诊断。     

Dopamine transporter (DAT) inhibitors alleviate specific parkinsonian deficits in monkeys: association with DAT occupancy in vivo

Viable dopamine neurons in Parkinson's disease express the dopamine transporter (DAT) and release dopamine (DA). We postulated that potent DAT inhibitors, with low affinity for the serotonin transporter (SERT), may elevate endogenously released extracellular dopamine levels to provide therapeutic benefit. The therapeutic potential of eight DAT inhibitors was investigated in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-treated cynomolgus monkeys (Macaca fascicularis), with efficacy correlated with DAT occupancy as determined by positron emission tomography imaging in striatum. Four potent DAT inhibitors, with relatively high norepinephrine transporter, but low SERT affinities, that occupied the DAT improved activity in parkinsonian monkeys, whereas three high-affinity DAT inhibitors with low DAT occupancy did not. 2beta-Carbomethoxy-3alpha-(3,4-dichlorophenyl)-7beta-hydroxy-8-methyl-8-azabicyclo[3.2.1.]octane (O-1163) occupied the DAT but had short-lived pharmacological effects. The benztropine analog difluoropine increased general activity, improved posture, reduced body freeze, and produced sleep disturbances at high doses. (1R)-2beta-(1-Propanoyl)-3alpha-(4-fluorophenyl)tropane (O-1369) alleviated parkinsonian signs in advanced parkinsonian monkeys, by increasing general activity, improving posture, reducing body freeze, and sedation, but not significantly reducing bradykinesia or increasing locomotor activity. In comparison with the D(2)-D(3) DA receptor agonist quinelorane, O-1369 elicited oral/facial dyskinesias, whereas quinelorane did not improve posture or reduce balance and promoted stereotypy. In conclusion, DAT inhibitors with therapeutic potential combine high DAT affinity in vitro and high DAT occupancy of brain striatum in vivo with enduring day-time effects that do not extend into the nighttime. Advanced parkinsonian monkeys (80% DAT loss) respond more effectively to DAT inhibitors than mild parkinsonian monkeys (46% DAT loss). The therapeutic potential of dopamine transport inhibitors for Parkinson's disease warrants preclinical investigation.     

Treatment of Parkinson's disease and restless legs syndrome with cabergoline,a long-acting dopamine agonist

Dopamine agonists have diverse chemical and physical properties that can directly stimulate the dopamine receptors, unlike levodopa which undergoes presynaptic breakdown to dopamine before dopaminergic effects in Parkinson's disease (PD). Cabergoline, a dopamine agonist effective given once daily, is being used as treatment for PD. In theory, therapy with cabergoline provides striatal intrasynaptic dopamine replacement of PD in a physiological manner because of its long half-life and the resultant sustained rather than pulsatile dopaminergic stimulation. Several placebo-controlled trials using cabergoline as adjunctive therapy in PD have shown that cabergoline significantly reduces 'off' time, improves motor function and reduces levodopa requirement. Cabergoline has also been used as monotherapy in PD and has been shown to be as effective as other dopamine agonists in improving motor function and to be superior to levodopa in reducing dyskinesias over a five-year period. Work from our group and others have also demonstrated the efficacy of cabergoline in PD patients with nocturnal disabilities and those with restless legs syndrome (RLS). More recently we have reported that cabergoline is a well-tolerated dopamine agonist in both young and elderly patients and has an acceptable side-effect profile.     

Myometry revealed medication-induced decrease in resting skeletal muscle stiffness in Parkinson's disease patients

Background

Based on combined analysis of clinical assessment of parkinsonian rigidity (constant resistance force generated during passive movement in a joint), electromyography and/or dynamometry many studies showed objectively that anti-parkinsonian medication decreases the rigidity in Parkinson's disease (PD). Rigidity-related changes in resting muscle stiffness (changed muscle's mechanical property related to its structural changes and changed neural drive) in PD patients have been revealed by myometry, a simple, sensitive, and reliable method for measuring mechanical properties in human soft tissues.However, an application of myometry in estimation of medication effects on the PD rigidity-related muscle stiffness has not been reported yet. Therefore, our study aimed to assess medication-induced changes in resting muscle stiffness in PD patients using myometry.

Methods

We measured resting muscle stiffness by myometry and recorded a surface electromyogram of relaxed biceps brachii, brachioradialis and triceps brachii muscles in ten patients with PD (age: 51–80 years; Hoehn and Yahr stage: 2.5–4) during medication on-phase (when subjects felt best comfort and fitness after medication: Levodopa, Piribedil, Ropinirol) and medication off-phase (12 h after withdrawal of the medication).

Findings

Our patients had significantly lower myometric stiffness and electromyogram amplitude in all tested muscles, and also lower clinical rigidity scores during the medication on-phase compared with the medication off-phase.

Interpretation

Myometry revealed that anti-parkinsonian medication decreases not only rigidity in PD, but also rigidity-related stiffness in resting skeletal muscles in PD patients. These findings show that myometry can enrich neurological practice, by allowing objective and reliable assessment of parkinsonian rigidity treatment effectiveness.     

Migraine patients show an increased density of dopamine D3 and D4 receptors on lymphocytes

Recent studies have revealed peculiar functional and genetic features of dopamine receptors in migraine. As peripheral blood lymphocytes (PBL) may represent a tool for peripheral detection of neuroreceptors, we compared the expression of dopamine D3 (DRD3) and D4 (DRD4) receptors on PBL in migraine patients and in healthy controls using radioligand binding assay techniques in the presence of antidopamine D2-like receptor antibodies. The dopamine D2-like receptor agonist [3H]7-OH-DPAT was used as a radioligand. An increased density of both DRD3 (P=0.0006) and DRD4 (P=0.002) on PBL was observed in migraineurs compared with controls. This up-regulation might reflect central and/or peripheral dopamine receptor hypersensitivity due to hypofunction of the dopaminergic system. These findings support the view that dopamine D2-like receptors are involved in the determination of the so-called migraine trait, which may help to elucidate several clinical features of the disease.     

Mapping of brain function after MPTP-induced neurotoxicity in a primate Parkinson's disease model

Neurophysiological studies of the brain in normal and Parkinson's disease (PD) patients have indicated intricate connections for basal ganglia-induced control of signaling into the motor cortex. To investigate if similar mechanisms are controlling function in the primate brain (Macaca fascicularis) after MPTP-induced neurotoxicity, we conducted PET studies of cerebral blood flow, oxygen and glucose metabolism, dopamine transporter, and D2 receptor function. Our observations after MPTP-induced dopamine terminal degeneration of the caudate and putamen revealed increased blood flow (15%) in the globus pallidus (GP), while blood flow was moderately decreased (15-25%) in the caudate, putamen, and thalamus and 40 % in the primary motor cortex (PMC). Oxygen extraction fraction was moderately increased (10-20%) in other brain areas but the thalamus, where no change was observable. Oxygen metabolism was increased in the GP and SMA (supplementary motor area including premotor cortex, Fig. 3) by a range of 20-40% and decreased in the putamen and caudate and in the PMC. Glucose metabolism was decreased in the caudate, putamen, thalamus, and PMC (range 35-50%) and enhanced in the GP by 15%. No change was observed in the SMA. In the parkinsonian primate, [(11)C]CFT (2beta-carbomethoxy-3beta-(4-fluorophenyltropane) dopamine transporter binding was significantly decreased in the putamen and caudate (range 60-65%). [(11)C]Raclopride binding of dopamine D(2) receptors did not show any significant changes. These experimental results obtained in primate studies of striato-thalamo-cortico circuitry show a similar trend as hypothetized in Parkinson's disease-type degeneration.     

Levodopa is toxic to dopamine neurons in an in vitro but not an in vivo model of oxidative stress

Levodopa is the "gold standard" for the symptomatic treatment of Parkinson's disease (PD). There is a theoretical concern, however, that levodopa might accelerate the rate of nigral degeneration, because it undergoes oxidative metabolism and is toxic to cultured dopaminergic neurons. Most in vivo studies do not show evidence of levodopa toxicity; levodopa is not toxic to normal rodents, nonhuman primates, or humans and is not toxic to dopamine neurons in dopamine-lesioned rodents or nonhuman primates in most studies. However, the potential for levodopa to be toxic in vivo has not been tested under conditions of oxidative stress such as exist in PD. To assess whether levodopa is toxic under these circumstances, we have examined the effects of levodopa on dopamine neurons in mesencephalic cultures and rat pups in which glutathione synthesis has been inhibited by L-buthionine sulfoximine. Levodopa toxicity to cultured dopaminergic neurons was enhanced by glutathione depletion and diminished by antioxidants. In contrast, treatment of neonatal rats with levodopa, administered either alone or in combination with glutathione depletion, did not cause damage to the dopamine neurons of the substantia nigra or changes in striatal levels of dopamine and its metabolites. This study provides further evidence to support the notion that although levodopa can be toxic to dopamine neurons in vitro, it is not likely to be toxic to dopamine neurons in vivo and specifically in conditions such as PD.     

SPECT and PET in Parkinson's disease

In Parkinson's disease(PD) cerebral blood flow and glucose metabolic rate measurements using SPECT and PET have demonstrated functional abnormality in basal ganglia-thalamocortical and its related circuits. [123I] IBF SPECT and [11C] raclopride PET seemed promising tools to assessing D2 receptor status in humans. Studies of D2 status have demonstrated normal or increased receptor density in PD and decreased receptor density in multiple system atrophy. Marked differences of the dopamine transporters located on dopaminergic terminals in the striatum has been demonstrated in healthy controls and PD patients using SPECT. The correlation of SPECT measures of dopamine transporters and motor severity suggests that this may be an useful marker of disease severity in PD.     

Effects of riluzole (2-amino-6-trifluoromethoxy benzothiazole) on striatal neurochemical markers in the rat, with special reference to the dopamine, choline, GABA and glutamate synaptosomal high affinity uptake systems

Riluzole, a new compound with anticonvulsant properties, was found to induce a dose-dependent decrease in the uptake of 3H-dopamine, 3H-GABA and 3H-glutamate into striatal synaptosomes when added to the incubation medium or after in vivo administration, whereas an inhibition of 3H-choline uptake was detected only in the in vitro experiments. Interestingly, riluzole affected 3H-dopamine and 3H-glutamate uptake differentially since 3H-dopamine uptake was found to be more sensitive to the compound. Moreover, riluzole inhibited 3H-dopamine uptake competitively and 3H-glutamate uptake non-competitively, which further suggests that the action of the compound is selective. After in vivo injection, riluzole did not affect the striatal dopamine, DOPAC, serotonin, 5HIAA, glutamate, aspartate or GABA contents. Since this compound was previously reported to induce a decrease in the spontaneous release of glutamate, serotonin, dopamine and possibly acetylcholine, the hypothesis is put forward that riluzole may, at least at high concentrations, have general effects on the striatal nerve terminals affecting both the uptake and release processes. This action may be correlated with the recently identified blocking properties of the compound on the sodium channels, as previously shown for local anaesthetics.