Characterization of the nigroestriatal system in a sample of patients with amyotrophic lateral sclerosis / Caracterização do sistema nigroestriatal em uma amostra de pacientes com esclerose lateral amiotrófica

Abstract Background The coexistence of amyotrophic lateral sclerosis (ALS) with clinical forms of Parkinson disease (PD), although uncommon, is found to a greater degree than one would expect by chance. The pathological mechanisms of ALS and PD are still not fully understood, and the coexistence of these two diseases suggests that they could share mechanisms in common. Objective Here we present a sample of patients with clinically definitive or probable ALS who were evaluated with single-photon emission computed tomography SPECT/TRODAT and compared with non-ALS controls. Methods Patients with clinically definite or probable ALS were assessed with the amyotrophic lateral sclerosis functional rating scale (ALSFRS) to define severity and had their demographic data collected. The TRODAT results of patients with ALS were compared with those of patients with a diagnosis of PD with less than 10 years of duration, and with patients with a diagnosis of others movement disorders not associated with neurodegenerative diseases. Results A total of 75% of patients with ALS had TRODAT results below the levels considered normal; that was also true for 25% of the patients in the control group without neurodegenerative disease, and for 100% of the patients in the PD group. A statistically significant difference was found between patients with ALS and the control group without neurodegenerative disease in the TRODAT values < 0.05. Conclusions Our study fits with the neuropathological and functional evidence that demonstrates the existence of nigrostriatal dysfunction in patients with ALS. Further research to better understand the role of these changes in the pathophysiological process of ALS needs to be performed.

Resumo Antecedentes A coexistência da esclerose lateral amiotrófica (ELA) com formas clínicas da doença de Parkinson (DP), embora incomum, é encontrada em um grau maior do que seria esperado ao acaso. Os mecanismos patológicos da ELA e da DP ainda não são totalmente compreendidos e a coexistência dessas duas doenças sugere que elas podem compartilhar mecanismos em comum. Objetivo Apresentamos uma amostra de pacientes com ELA clinicamente definida ou provável que foram avaliados com tomografia computadorizada por emissão de fóton único (SPECT)/TRODAT e comparados com controles sem ELA. Métodos Pacientes com ELA clinicamente definida ou provável foram avaliados com a escala funcional de esclerose lateral amiotrófica (ALSFRS) para definir a gravidade e foram coletados os seus dados demográficos. Os resultados do TRODAT de pacientes com ELA foram comparados com aqueles de pacientes com diagnóstico de DP com menos de 10 anos de duração e com pacientes com diagnóstico de outros distúrbios do movimento não associados a doenças neurodegenerativas. Resultados Um total de 75% dos pacientes com ELA apresentou resultados de TRODAT abaixo dos níveis considerados normais; 25% no grupo controle sem doença neurodegenerativa e 100% no grupo DP. Uma diferença estatisticamente significativa foi encontrada entre os pacientes com ELA e o grupo controle sem doença neurodegenerativa nos valores de TRODAT p< 0,05. Conclusões Nosso estudo está de acordo com as evidências neuropatológicas e funcionais que demonstram a existência de disfunção nigroestriatal em pacientes com ELA. Mais pesquisas para entender melhor o papel dessas mudanças no processo fisiopatológico da ELA precisam ser realizadas.

Correlations between striatal dopamine transporter distribution, glucose metabolism and clinical symptoms in Parkinson′s disease / 中华核医学与分子影像杂志

Objective@#To investigate the correlations among striatal dopamine transporter (DAT) distribution, glucose metabolism and Parkinson′s disease (PD) clinical symptoms.@*Methods@#Twenty-five clinically confirmed idiopathic PD patients (17 males, 8 females, age: (59.8±9.2) years) who underwent 11C-2-beta-carbomethoxy-3-beta-(4-fluorophenyl)tropane (CFT) and 18F-fluorodeoxyglucose (FDG) PET imaging from January 2015 to December 2016 were reviewed. The detailed clinical scores were systematically collected from all patients. Correlations between DAT distribution, glucose metabolism and clinical symptoms were evaluated at global and voxel levels using Pearson correlation analysis.@*Results@#There were significantly positive correlations between the PD-related pattern (PDRP) value and unified PD rating scale (UPDRS) motor scores, non-motor symptoms scale (NMSS) scores, activity of daily living scale (ADL) scores (r values: 0.580, 0.522, 0.557, all P<0.05). The CFT uptake of ipsilateral caudate nucleus, anterior putamen, and posterior putamen were negatively correlated with UPDRS motor scores (r values: -0.496, -0.492, -0.457, all P<0.05), while those had no significant correlations with NMSS scores (r values: -0.420, -0.402, -0.355, all P>0.05). The CFT uptake of ipsilateral caudate nucleus and anterior putamen were negatively correlated with ADL scores (r values: -0.502, -0.522, both P<0.05). There were no significant correlations between CFT uptake in contralateral striatal, anterior putamen, posterior putamen and PDRP values, UPDRS motor scores, NMSS scores and ADL scores(r values: from -0.466 to -0.129, all P>0.05). The presence of the significant correlations between UPDRS motor scores, ADL scores and the CFT radioactive count were confirmed in left caudate nucleus and left putamen (r values: from -0.90 to -0.47, all P<0.05). The metabolic PET imaging disclosed a set of brain regions correlating with the clinical symptoms. The presence of significant correlations between the metabolic PET imaging and CFT uptake were confirmed in bilateral caudate nucleus (r values: 0.47-0.90, both P<0.01), precentral gyrus and insula (r values: -0.90 to -0.47, all P<0.01).@*Conclusion@#The correlations between DAT distribution, glucose metabolism and PD clinical symptoms are complicated, which promote the understanding in the proper application of dopaminergic and metabolic PET imaging in PD and offer more evidences in PD pathophysiological mechanisms.

Correlations between striatal dopamine transporter distribution, glucose metabolism and clinical symptoms in Parkinson's disease / 中华核医学与分子影像杂志

Objective To investigate the correlations among striatal dopamine transporter (DAT) distribution,glucose metabolism and Parkinson's disease (PD) clinical symptoms.Methods Twenty-five clinically confirmed idiopathic PD patients (17 males,8 females,age:(59.8± 9.2) years) who underwent 11 C-2-beta-carbomethoxy-3-beta-(4-fluorophenyl) tropane (CFT) and 18 F-fluorodeoxyglucose (FDG) PET imaging from January 2015 to December 2016 were reviewed.The detailed clinical scores were systematically collected from all patients.Correlations between DAT distribution,glucose metabolism and clinical symptoms were evaluated at global and voxel levels using Pearson correlation analysis.Results There were significantly positive correlations between the PD-related pattern (PDRP) value and unified PD rating scale (UPDRS) motor scores,non-motor symptoms scale (NMSS) scores,activity of daily living scale (ADL) scores (r values:0.580,0.522,0.557,all P＜0.05).The CFT uptake of ipsilateral caudate nucleus,anterior putamen,and posterior putamen were negatively correlated with UPDRS motor scores (r values:-0.496,-0.492,-0.457,all P＜0.05),while those had no significant correlations with NMSS scores (r values:-0.420,-0.402,-0.355,all P＞0.05).The CFT uptake of ipsilateral caudate nucleus and anterior putamen were negatively correlated with ADL scores (r values:-0.502,-0.522,both P＜0.05).There were no significant correlations between CFT uptake in contralateral striatal,anterior putamen,posterior putamen and PDRP values,UPDRS motor scores,NMSS scores and ADL scores(r values:from-0.466 to-0.129,all P＞0.05).The presence of the significant correlations between UPDRS motor scores,ADL scores and the CFT radioactive count were confirmed in left caudate nucleus and left putamen (r values:from-0.90 to-0.47,all P＜0.05).The metabolic PET imaging disclosed a set of brain regions correlating with the clinical symptoms.The presence of significant correlations between the metabolic PET imaging and CFT uptake were confirmed in bilateral caudate nucleus (r values:0.47-0.90,both P＜0.01),precentral gyrus and insula (r values:-0.90 to-0.47,all P＜0.01).Conclusion The correlations between DAT distribution,glucose metabolism and PD clinical symptoms are complicated,which promote the understanding in the proper application of dopaminergic and metabolic PET imaging in PD and offer more evidences in PD pathophysiological mechanisms.

Effect of rs3910105 in the Synuclein Gene on Dopamine Transporter Availability in Healthy Subjects

PURPOSE: The present study investigated associations between dopamine transporter (DAT) availability and α-synuclein levels in cerebrospinal fluid, as well as synuclein gene (SNCA) transcripts, and the effect of single nucleotide polymorphism of SNCA on DAT availability in healthy subjects. MATERIALS AND METHODS: The study population comprised healthy controls who underwent 123I-FP-CIT single-photon emission computed tomography screening. Five SNCA probes were used to target the boundaries of exon 3 and exon 4 (SNCA-E3E4), transcripts with a long 3′UTR region (SNCA-3UTR-1, SNCA-3UTR-2), transcripts that skip exon 5 (SNCA-E4E6), and the rare short transcript isoforms that comprise exons 1–4 (SNCA-007). RESULTS: In total, 123 healthy subjects (male 75, female 48) were included in this study. DAT availability in the caudate nucleus (p=0.0661) and putamen (p=0.0739) tended to differ according to rs3910105 genotype. In post-hoc analysis, DAT availability in the putamen was lower in subjects of TT genotype than those of CC/CT (p=0.0317). DAT availability in the caudate nucleus also showed a trend similar to that in the putamen (p=0.0597). Subjects of CT genotype with rs3910105 showed negative correlations with DAT availability in the putamen with SNCA-E3E4 (p=0.037, rho=−0.277), and SNCA-E4E6 (p=0.042, rho=−0.270), but not those of CC/TT genotypes. CONCLUSION: This is the first study to investigate the association of rs3910105 in SNCA with DAT availability. rs3910105 had an effect on DAT availability, and the correlation between DAT availability and SNCA transcripts were significant in CT genotypes of rs3910105.

Multiple modalities PET/CT neuroimaging for the diagnosis of Parkinson's disease and multiple system atrophy: statistical parametric mapping analysis / 中华神经科杂志

Objective To investigate the topographic distributions of dopamine transporter (DAT),dopamine D2 receptor and glucose in Parkinson's disease (PD) and multiple system atrophy (MSA) using positron emission tomography/computed tomography (PET/CT) scanning and statistical parametric mapping (SPM) analysis.Methods Seventy subjects (39 PD patients,15 MSA patients and 16 normal controls) who came from People's Liberation Army General Hospital from September 2013 to November 2015 underwent DAT,D2 receptor and glucose brain PET/CT scans using 11 C-methyl-N-2-β-carbomethoxy-3-β-(4-fluorophenyl) tropane (11C-β-CFT),11C-raclopride and 18F-fluorodeoxyglucose (18 F-FDG) as radiotracers,respectively.The uptake patterns were analyzed using SPM software.Results Striatal DAT binding decreased in the putamen in PD patients compared with controls (Z =5.21-5.77,P =0.002-0.016).D2 receptor showed no significant differences.However,glucose uptake decreased in cingulate gyrus(Z =4.51-4.67,P =0.010-0.017).For MSA patients,both DAT and D2 receptor binding decreased in the putamen(Z =2.13-3.42,P =0.000-0.016).Glucose uptake decreased in the bilateral putamen,cerebellum and part of frontal temporal lobes (Z =1.86-3.75,P =0.000-0.032).Conclusion Multiple modalities PET/CT scans using the ligands 11 C-β-CFT,11C-raclopride,and 18F-FDG are valuable in diagnosis of MSA and differential diagnosis of MSA from PD.

Assessment of effects of 7,8-dihydroxyflavone on the striatum in normal cynomolgus monkeys with 99TCm-TRODAT-1 SPECT/CT imaging / 中华核医学与分子影像杂志

Objective To assess the effects of 7,8-dihydroxyflavone (7,8-DHF) on the striatum (ST) in normal cynomolgus monkeys using 99Tcm-TRODAT-1 imaging.Methods A total of six healthy female cynomolgus monkeys were included in this study.Three of them were fed with normal food (control group),and the other three were given oral administration of 7,8-DHF in addition to normal food (experimental group).The SPECT/CT imaging was performed at different time after 99Tcm-TRODAT-1 injection.The ROI of ST was drawn on images of 3 consecutive transverse slices that could be visualized best.The cerebellum (CB) was taken as the background reference area.The radioactivity uptake ratios of ST/CB at 1,3,4 and 5 h were calculated respectively.Paired-t test was used to analyze the data.Results ST radioactive uptake ratios showed continuing increase on the delay images.ST/CB uptake ratios of the control group at 1,3,4 and 5 h were 1.43±0.04,1.82±0.06,2.04±0.12,2.42±0.23,respectively,and those of the experimental group were 1.35±0.08,2.40±0.09,2.74±0.13 and 3.25±0.15 respectively.There was no significant difference between the two groups at 1 h (t =2.57,P＞0.05),while ST/CB uptake ratios of the experimental group at 3,4 and 5 h were significantly higher (t values:2.77,2.87 and 2.92,all P＜0.05).Conclusion 99Tcm-TRODAT-1 SPECT/CT imaging can be used to assess the DAT activation effect by 7,8-DHF on ST of cynomolgus monkeys.

Classic Studies on the Interaction of Cocaine and the Dopamine Transporter

The dopamine transporter is responsible for recycling dopamine after release. Inhibitors of the dopamine transporter, such as cocaine, will stop the reuptake of dopamine and allow it to stay extracellularly, causing prominent changes at the molecular, cellular, and behavioral levels. There is much left to be known about the mechanism and site(s) of binding, as well as the effect that cocaine administration does to dopamine transporter-cocaine binding sites and gene expression which also plays a strong role in cocaine abusers and their behavioral characteristics. Thus, if more light is shed on the dopamine transporter-cocaine interaction, treatments for addiction and even other diseases of the dopaminergic system may not be too far ahead. As today's ongoing research expands on the shoulders of classic research done in the 1990s and 2000s, the foundation of core research done in that time period will be reviewed, which forms the basis of today's work and tomorrow's therapies.

Solution space of pharmacokinetics and its application on mice brain with 18F-FECNT / 中华核医学杂志

Objective To forward the concept of solution space of pharmacokinetics for studying radiophannaceutical distributions in animal models. Methods On the basis of special solutions of differential equations of pharmacokinetics, the solution space was established using the characteristics of linearly independent particular solutions and used to express the pharmacokinetics of pharmaceuticals in vivo. 0. 2 ml (7.4 MBq) 2β-carbomethoxy-3β- (4-corophenyl)-8-(2-18F-fluoroethyl) nortropane (18F-FECNT) was injected through tail vein into normal mice. The mice were sacrificed by decapitation at 5, 15, 30, 60, 120 and 180 min post-injection. Brain tissues were removed and weighed, and radioactivity was counted with the γ-counter. The solution space theory was used to study pharmacokinetics of 18F-FECNT in brain tissues of mice. Results The result showed that all solutions of pharmacokinetics models, based on differential equations, were included in the solution space. The solution of any organ or tissue could be linearly expressed by bases of the solution space. When the dimension number of the solution space was no more than 3, the solution could be directly expressed with coordinate picture. By this rule in our theory, the quantity of 18F-FECNT in brain tissues of mice changed with time, which was accorded with the experiment. The coordinates of striatum, frontal cortex, temporal cortex, occipital cortex, parietal cortex, hippocampus and cerebellum in the solution space were ( 10.13, 1.49), (4.27, 0. 84), (4.48, 0.81 ), (2.89, 0.98), (3.65, 0. 83),(3.55, 0. 98) and (2.03, 1.25 ), respectively. Conclusion The theory of solution space could be used to study pharmacokinetics of 18 F-FECNT in mice brain.

Dopamine transporter SPECT imaging of the peroral addictors of compound codeine phosphate solution / 中华核医学杂志

Objective To study the damage to striatum in patients perorally addicted to compound codeine phosphate solution by using the brain dopamine transporter SPECT imaging. Methods Patients p erorally addicted to compound codeine phosphate solution ( n = 29 ) and addicted to heroin ( n = 27 ), as well as healthy volunteers (n = 31 ) were included in the study. Each of them underwent dopamine transporter (DAT) SPECT imaging with 99Tcm-2β-[N, N'-bis-( 2- mercaptoethyl ) ethylenediamino] methyl, 3β-(4-chlorophenyl)tropane (99Tcm-TRODAT-1). The striatum volume (V, cm3), mass (m, g) and radiactivity ratio (Ra) of striatum to whole brain were calculated using physio-mathematical modeling method.R esults Bilateral striatum of healthy volunteers showed typical "panda eyes" pattern and the distribution of DAT was uniform and symmetrical. Bilateral striatum of patients addicted to compound codeine phosphate showed impaired tracer uptake, similar to those addicted to heroin. The V, m and Ra of bilateral striatum of patients addicted to compound codeine phosphate were (23.68 ±4.94) cm3, (24.87 ±5.19) g and (5.01 ±0. 88 ) %, respectively, which were significantly lower than those of healthy controls: ( 35.39 ± 4.42 ) cm3,(37.16 ±4.64) g and (7.93 ±0.86)% (t = -9.69, -9.69, - 13.01, all P =0.000), but significantly higher than those addicted to heroin: ( 18.87 ± 4.66 ) cm3, ( 19.81 ± 4.90 ) g and (4.26 ± 1.02 ) % ( t =3.74, 3.74, 2.96, P = 0.000, 0.000, 0.005 ). Conclusion Long-term peroral intake of compound codeine phosphate solution may damage the function of cerebral striatum, which is someway similar to though less severe than, the impairment caused by heroin.

Influence of aging on motor function and striatum dopamine transporter of rats / 中华老年医学杂志

Objective To investigate the influence of aging on motor function,binding activity and protein expression level of striatum dopamine transporter(DAT)of rats. Methods Rolling-bar test was performed to assess motor function.Western blot and 131I-FP-β-CIT up-take ratio were used to evaluate DAT protein 1evel and striatum DAT binding activity respectively. Results There were an age-related decline of rolling-bar latency and striatum 131I-FP-β-CIT up-take ratio in rats older than6 months.There was a significant difference between 6-month-old rats and older rats(12-month-old rats,16-month-old rats,20-month-old rats),and rolling-bar latency was correlated with striatum 131I-FP-β-CIT up-take ratio(r=0.656,P＜0.01).There was no change in DAT protein 1evel during aging process. Conclusions The age-related decline of motor function of rats was correlated with the decreasing of striatum DAT binding activity.The synaptic membrane expression of striatum DAT may decrease in aged rats.