Parkinson Disease: Yen TC

Kung HF, Kung MP, Wey SP, Lin KJ, Yen TC. · Department of Radiology, University of Pennsylvania, Philadelphia, PA 19104, USA. · Nucl Med Biol. · Pubmed #17921030 No free full text.

Abstract: In the past 10 years, significant progress has been made in using a technetium-99m dopamine transporter imaging agent, [99mTc]TRODAT, for routine clinical studies. Developing a molecular imaging agent from bench to the bedside is more than a simple scientific venture. Currently, Taiwan is the only place where [99mTc]TRODAT is approved for routine clinical use in the diagnosis of Parkinson's disease. The trials and tribulations of developing [99mTc]TRODAT for routine clinical use in Taiwan provide an interesting case study in how to (critics may say, how not to) develop a molecular imaging agent.

Weng YH, Yen TC, Chen MC, Kao PF, Tzen KY, Chen RS, Wey SP, Ting G, Lu CS. · Movement Disorders Unit, the First Department of Neurology, Chang Gung Memorial Hospital and Medical College, Taipei, Taiwan. · J Nucl Med. · Pubmed #15001678 links to  free full text

Abstract: The imaging of dopamine transporter (DAT) with (99m)Tc-TRODAT-1 ([2-[[2-[[[3-(4-chlorophenyl)-8-methyl-8-azabicyclo[3,2,1]oct-2-yl]methyl](2-mercaptoethyl)amino]ethyl]amino]ethanethiolato(3-)-N2,N2',S2,S2']oxo-[1R-(exo-exo)]-(99m)Tc-technetium) and SPECT has been recently proposed to be a valuable and feasible means of assessment of the integrity of dopamine neurons. The purpose of this study was to further investigate the clinical correlations and the age-specific sensitivity and specificity of this new approach in the diagnosis of patients with idiopathic Parkinson's disease (PD) that manifests in patients >50 y of age. METHODS: SPECT imaging with (99m)Tc-TRODAT-1 was conducted in 78 consecutive PD patients and in 40 age-matched healthy subjects. The images were obtained 4 h after the intravenous injection of the tracer. The ratios of specific striatal binding to nonspecific occipital binding were calculated. S/O represents the ratio for whole striatal binding, whereas P/O and C/O represent the putamen and caudate nucleus, respectively. Statistical analyses of the sensitivity and specificity of these ratios in different age-specific subgroups were performed. The correlations between these ratios and clinical assessments were also analyzed. The age-related declines in the striatal binding in both patients and controls were given particular focus. RESULTS: The S/O, C/O, and P/O ratios decreased significantly both contralaterally and ipsilaterally to the dominant symptomatic side in the PD group (P < 0.0001). The mean reduction of binding was found in the order of putamen (contralateral side, -81%; ipsilateral side, -67%) and caudate nucleus (contralateral side, -46%; ipsilateral side, -40%). The sensitivity and specificity of both P/O and S/O ratios were 100% in discriminating PD patients from healthy subjects in the age-specific groups. The binding ratios correlated negatively with the Unified Parkinson's Rating Scale and Hoehn and Yahr (H-Y) staging. Of particular interest, the binding of the striatum contralateral to the asymptomatic side in H-Y stage I patients also decreased significantly. The age-related decline of these ratios was significant in the control group. CONCLUSION: We have demonstrated that (99m)Tc-TRODAT-1 SPECT has a high sensitivity and specificity for measuring the decrement of DAT in PD patients. In addition to its wide availability, we suggest that this new approach may serve as a diagnostic marker for PD.

Lu CS, Weng YH, Chen MC, Chen RS, Tzen KY, Wey SP, Ting G, Chang HC, Yen TC. · First Department of Neurology, Chang Gung Memorial Hospital at Taipei, Taipei, Taiwan. · J Nucl Med. · Pubmed #14734673 links to  free full text

Abstract: Using (99m)Tc-TRODAT-1 ((99m)Tc-[2[[2-[[[3-(4-chlorophenyl)-8-methyl-8-azabicyclo[3,2,1]-oct-2-yl]-methyl](2-mercaptoethyl) amino]ethyl]amino]ethane-thiolato(3-)-N2,N2',S2,S2]oxo-[1R-(exo-exo)])) brain SPECT imaging, we measured striatal dopamine transporters (DATs) activity in multiple system atrophy (MSA) to investigate the possibility of differentiating it from Parkinson's disease (PD) and to correlate the findings with the parkinsonian (MSA-P) and cerebellar (MSA-C) subtypes of MSA. METHODS: Forty-nine patients with probable MSA (30 MSA-P, 19 MSA-C), a disease control group of 36 age- and disease duration-matched patients with probable PD, and a healthy control group of 33 age-matched healthy volunteers participated in a SPECT study. The ratios of specific striatal binding-to-nonspecific occipital binding, including the striatum-to-occipital ratio (S/O), putamen-to-occipital ratio (P/O), caudate nucleus-to-occipital ratio (C/O), and putamen-to-caudate nucleus ratio (P/C), were calculated. The statistical analyses of uptakes among 4 groups used ANOVA followed by Games-Howell's multiple comparisons. The Spearman correlation coefficient between the motor scores of Unified Parkinson's Disease Rating Scale (UPDRS-III) and those binding ratios of the MSA-P and MSA-C groups and the PD group was also performed. RESULTS: The striatal binding was more symmetrically reduced in the MSA-P (asymmetric index, 14.2) and MSA-C (asymmetric index, 8.1) groups, in contrast to the greater asymmetric reduction in the PD group (asymmetric index, 28.6). Overall striatal binding was significantly reduced in the MSA-P (-59.8%), MSA-C (-29.9%), and PD (-58.0%) groups with no overlap between these values and those of the control group. Like the PD group, bilateral P/O, C/O, and S/O ratio values were significantly reduced in the MSA-P and MSA-C groups. Nevertheless, the reduction of bilateral P/O and S/O ratios was more for the MSA-P group than for the MSA-C group. P/C ratios showed that the MSA-P and PD groups had similar patterns of nigral impairment, but the MSA-C group had a different pattern. No correlation between the UPDRS-III scores and (99m)Tc-TRODAT-1 bindings was found in both MSA-P and MSA-C groups; in contrast, a significant negative correlation was noted in the PD group. CONCLUSION: (99m)Tc-TRODAT-1 brain SPECT is capable of scientifically differentiating between the MSA-P and MSA-C subtypes, and MSA-P has more symmetric nigrostriatal damage than that in PD. (99m)Tc-TRODAT-1 brain SPECT imaging probably could provide important information to differentiate MSA from PD.

Kao PF, Tzen KY, Yen TC, Lu CS, Weng YH, Wey SP, Ting G. · Department of Nuclear Medicine, Chang Gung Memorial Hospital, Taipei, Taiwan. · Nucl Med Commun. · Pubmed #11258401 No free full text.

Abstract: Imaging of dopamine transporters (DATs) in the brain using [99Tcm]TRODAT-1 showed excellent pharmacokinetics for estimation of transporter concentrations. It has been reported that there may be differences in the binding kinetics of DAT radiotracers to DATs between normal subjects and patients with Parkinson's disease (PD). The aim of this study was to determine an optimal time point for (99Tcm]TRODAT-1 brain single photon emission tomography (SPET) acquisition that provides stable target to non-target ratios reflecting the DAT concentration in the brain. Serial [99Tcm]TRODAT-1 brain SPET images 2, 3 and 4 h after intravenous injection of [99Tcm]TRODAT-1 (925 MBq) were performed in five healthy subjects and nine PD patients. Regions of interests were drawn, and caudate/occipital (C/O) and putamen/occipital (P/O) specific to non-specific [99Tcm]TRODAT-1 binding ratios were calculated. The C/O and P/O ratios in healthy subjects showed consistent increases with time, but in PD patients, the C/O and P/O ratios of [99Tcm]TRODAT-1 reached a stable level at 3 h post-injection. There was a statistically significant difference (P < 0.001) between PD and normal subjects at 4 h post-injection for both the C/O and the P/O ratios. In conclusion, we recommend the acquisition of [99Tcm]TRODAT-1 SPET images at 4 h post-injection, as at this time point the C/O and P/O ratios can be used to discriminate between PD patients and healthy subjects.

Weng YH, Chou YH, Wu WS, Lin KJ, Chang HC, Yen TC, Chen RS, Wey SP, Lu CS. · Neuroscience Research Center, Dept. of Neurology, Chang Gung Memorial Hospital and Chang Gung University, 33305, 5 Fu-Shin St., Kweishan, Taoyuan, Taiwan. · J Neurol. · Pubmed #17960343 No free full text.

Abstract: The PINK1 gene mutation is probably the second most common genetic cause of early-onset Parkinson's disease (EOPD). The frequency and the characteristics of the PINK1 mutation in the Taiwanese population are unknown. This study was designed to investigate the genotype, phenotype and dopaminergic function of PINK1 in a cohort of EOPD patients. The genetic settings were to detect the PINK1 gene mutations in 138 EOPD patients and in 191 controls. Using the (99m)Tc-TRODAT-1 (TRODAT) scan, we investigated the differences in the dopamine transporter (DAT) activities between the PINK1 patients, late-onset Parkinson's disease (LOPD) patients and healthy controls. Four EOPD patients with 3 genotypic mutations in the PINK1 gene were found: a compound heterozygous mutation (Q239X/R492X) in 2 sisters, a novel homozygous mutation (R492X) in a woman, and a novel heterozygous mutation (G193R) in a man. The three PINK1 patients had typical phenotype with juvenile onset, benign course, and frequently with dyskinesias. The TRODAT scan showed a rather even and symmetrical reduction of uptake in PINK1 patients, unlike the dominant decline in the putamen in the LOPD patients. The annual reduction rate of uptake in the striatum was much slower in PINK1 patients than that in the LOPD patients (1.7 % vs. 4.1%; p<0.005). In the patient with a heterozygous mutation in the PINK1 gene, the reduction ratio in the striatum, as well as the annual reduction rate, were closer to those in the LOPD group. We conclude that the incidence of carrying PINK1 mutations in the present cohort of Taiwanese EOPD patients was low, accounting for 2/39 (5.1 %) in familial cases, and 2/99 (2 %) in sporadic cases. The slower annual reduction of DAT activity might indicate the insidious degeneration of dopamine neurons and a benign prognosis.

Lai SC, Weng YH, Yen TC, Tsai CC, Chang HC, Wey SP, Ting G, Lu CS. · Movement Disorders Unit, First Department of Neurology, Chang Gung Memorial Hospital at Lin-Ko, Taoyuan, Taiwan. · Nucl Med Commun. · Pubmed #15097807 No free full text.

Abstract: AIM: The aim of this study was to investigate the nigrostriatal dopaminergic function in patients with corticobasal degeneration (CBD) using [2-[[2-[[[3-(4-chlorophenyl)-8-methyl-8-azabicyclo[3.2.1]oct-2-yl]methyl](2-mercaptoethyl)amino]ethyl]amino]ethanethiolato(3-)-N2,N2',S2,S2']oxo-[1R-(exo-exo)]-[99mTc]technetium ([99mTc]TRODAT-1) brain single-photon emission tomography (SPET). METHODS: Five patients with probable CBD, 10 age- and duration-matched patients with idiopathic Parkinson's disease (IPD) and 10 age-matched healthy volunteers completed the SPET study. The images were obtained 4 h after intravenous injection of 925 MBq of [99mTc]TRODAT-1. Using a magnetic resonance imaging atlas of the striatum, the ratios of specific striatal binding to non-specific occipital binding were calculated. RESULTS: Clinical analysis showed that the CBD patients obtained significantly higher scores on the Unified Parkinson's Disease Rating Scale and a significantly worse score for activities of daily living. In the CBD and IPD groups, striatum-occipital/occipital, caudate nucleus-occipital/occipital and putamen-occipital/occipital ratios decreased significantly relative to those of healthy subjects. No statistical difference could be found between the CBD and IPD groups for these ratios, although relatively even, decreased uptakes in the caudate nucleus and putamen were found in the CBD group. On further analysis of the index of binding reduction, the differences between the caudate nucleus and putamen were significantly lower in the CBD group than in the IPD group. The striatal uptake of [99mTc]TRODAT-1 showed a distinct asymmetry in both the CBD and IPD patients. CONCLUSION: From this study, it can be concluded that early-stage CBD patients have a worse performance and more difficulties with daily activities than IPD patients. CBD patients demonstrated essentially similar patterns of [99mTc]TRODAT-1 binding as those with IPD. However, there was relatively more homogeneous involvement of the caudate nucleus and putamen in the CBD patients. This provides information about the differences between these patients in the early stages.

Huang CC, Weng YH, Lu CS, Chu NS, Yen TC. · Dept. of Neurology, Chang Gung Memorial Hospital, 199, Tung-Hwa North Road, Taipei, Taiwan. · J Neurol. · Pubmed #14648150 No free full text.

Abstract: Chronic exposure to manganese may induce parkinsonism similar to idiopathic Parkinson's disease (PD). However, clinical manifestations of manganism also have some features different from PD. The mechanisms of manganese-induced parkinsonism remain not fully understood. (99m)Tc-TRODAT-1 is a cocaine analogue that can bind to the dopamine transporter (DAT) site reflecting the function of presynaptic dopaminergic terminals. The purpose of this study was to evaluate DAT function using (99m)Tc-TRODAT-1 to investigate the integrity of the presynaptic dopaminergic terminals in manganese-induced parkinsonism. Brain (99m)Tc-TRODAT-1 single photon emission computed tomography was performed in 4 patients with chronic manganese intoxication in a ferromanganese smelting plant in Taiwan. Twelve PD patients and 12 healthy volunteers served as abnormal and normal controls, respectively. Clinically, all manganism patients had a bradykinetic-rigid syndrome. The scores of the Unified Parkinson's Disease Rating Scale ranged between 19 and 64. The uptake values of the (99m)Tc-TRODAT-1 were 0.868+/-0.136 in the right corpus striatum and 0.865+/-0.118 in the left, as compared with 0.951+/-0.059 and 0.956+/-0.058, respectively for the normal controls. The data were significantly higher than 0.250+/-0.070 and 0.317+/-0.066 respectively for the PD patients. Interestingly, there was a mild decrease in the uptake of (99m)Tc-TRODAT-1 in the putamen and the ratio of putamen and caudate when compared with the normal controls. Although the DAT shows a slight decrease in the putamen of manganism patients as compared with that of the normal controls, the data indicate that the presynaptic dopaminergic terminals are not the main target of chronic manganese intoxication. In addition (99m)Tc-TRODAT-1 SPECT can provide a useful, convenient and inexpensive tool for differentiation between chronic manganism and PD.

Huang CC, Yen TC, Weng YH, Lu CS. · Department of Neurology, Chang Gung Memorial Hospital, 199, Tung Hwa North Road, Taipei, Taiwan. · J Neurol. · Pubmed #12195447 No free full text.

Abstract: We report the clinical manifestations of dopa responsive dystonia (DRD) in 2 patients from the same family. The brain magnetic resonance images (MRI) were normal. The dopamine transporter (DAT) imaging with (99m)Tc-TRODAT-1 was performed in the 2 probands, 8 patients with young onset Parkinson disease (YOPD) and 16 normal controls. The ratios of (99m)Tc-TRODAT-1 brain SPECT in the striatum were 2.40 +/- 0.12 (right) and 2.30 +/- 0.17 (left) in these 2 DRD patients as compared with 1.38 +/- 0.18 (right), 1.41 +/- 0.20 (left) in YOPD patients, and 2.15 +/- 0.35 (right), 2.14 +/- 0.32 (left) in normal controls respectively. A normal DAT uptake was found in DRD suggesting a normal presynaptic nigrostriatal dopaminergic terminal. We conclude that a normal DAT in parkinsonian patients can differentiate DRD from YOPD. In addition, DAT with (99m)Tc-TRODAT-1 is a reliable and convenient tool to study the function of the presynaptic dopaminergic axonal terminals.

Hwang JJ, Liao MH, Yen TC, Wey SP, Lin KJ, Pan WH, Chen JC, Ting G. · Department of Medical Radiation Technology & Institute of Radiological Sciences, National Yang-Ming University, Taipei, Taiwan. · Appl Radiat Isot. · Pubmed #12137024 No free full text.

Abstract: A 99mTc labeled tropane derivative, [99mTc] TRODAT-1 (2beta-((N,N'-bis(2-mercaptoethyl) ethylene diamino)methyl), 3beta-(4-chlorophenyl) tropane), is a potential dopamine transporter (DAT) imaging agent for the central nervous system. To better understand the binding localization of [99mTc] TRODAT-1 both in the brain and the body, whole-body macroautoradiography (WBAR) was used in this study. The effect of DAT competing drugs, such as levadopa (L-DOPA), N-methyl-2beta-carbomethoxy-3beta-(4fluorophenyl)tropane (CFT, WIN 35,428) and methylphenidate, on the biodistribution of [99mTc] TRODAT-1 were also included in this study. Doses of 150 MBq [99mTc] TRODAT-1 were injected into normal male ICR mice through the caudal veins. For comparison, mice treated with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), L-DOPA, methylphenidate and CFT, respectively, were also investigated under the similar protocols. One and a half hours after [99mTc] TRODAT-1 injection, the mice were sacrificed. Whole-body autoradiography was performed immediately after sacrifice. Both frontal and sagittal sections showed that the liver and mucosa of stomach had the highest uptake of [99mTc] TRODAT-1. Other binding sites included the periphery of the spinal cord and the epithelium of the intestine. In the brain, autoradiographic imaging obtained from frontal sections showed symmetrical uptakes of [99mTc] TRODAT-1 in bilateral striata. Remaining binding sites include olfactory bulbs, thyroid gland, and salivary gland. The autoradiographic imaging obtained from sagittal sections showed a similar biodistribution. Mice treated with MPTP or L-DOPA showed no significant difference in the uptake of [99mTc] TRODAT-1 in bilateral striata, as compared to those of the control. In CFT or methylphenidate-treated mice, DAT binding sites were almost completely inhibited. These data showed that [99mTc] TRODAT-1 has potential clinical use for neurological investigation, such as Parkinson's and similar diseases.

Tzen KY, Lu CS, Yen TC, Wey SP, Ting G. · Departments of Nuclear Medicine and Neurology, Chang Gung Memorial Hospital at Lin-Ko and Keelung, Taipei Medical Center and School of Medicine, Chang Gung University, Taiwan. · J Nucl Med. · Pubmed #11337515 links to  free full text

Abstract: The aim of this study was to use brain SPECT to differentiate vascular parkinsonism (VP) from Parkinson's disease. METHODS: Fourteen VP patients (age range, 59-87 y; mean age, 70 +/- 7.5 y), 30 Parkinson's disease patients (age range, 54-84 y; mean age, 65 +/- 8.8 y), and 26 healthy (control) individuals (age range, 50-85 y; mean age, 60 +/- 9 y) were examined. A 925-MBq (25 mCi) dose of (99m)Tc-TRODAT-1 was injected intravenously, and brain SPECT images were acquired 4 h after injection. The ratio of specific to nonspecific striatal (99m)Tc-TRODAT-1 binding was measured and compared. RESULTS: After a region-of-interest analysis of the images from VP patients, Parkinson's disease patients, and healthy volunteers was performed to obtain ratios of putamen to occipital and striatal to occipital binding as a measurement of specific binding to the dopamine transporters in these regions of the brain, where dopamine neurons are concentrated, the specific binding in the 14 VP patients was slightly lower than but not statistically different from that of the healthy individuals in both putamen and caudate areas. A significant decrease in uptake of (99m)Tc-TRODAT-1 in the striatum (P<0.01) was found in Parkinson's disease patients. Reduction of the uptake was more pronounced in the contralateral putamen of Parkinson's disease patients than that of VP patients (P<0.001). A significant bilateral striatal asymmetry was also observed in Parkinson's disease patients but not in VP patients (P< 0.01). CONCLUSION: Our findings clearly show that, for VP patients, (99m)Tc-TRODAT-1 SPECT is a reliable method to differentiate VP from Parkinson's disease. Further studies, including those to differentiate Parkinson's disease from arteriosclerotic parkinsonism and patients with both VP and Parkinson's disease, are needed to help rule out the possibility of Parkinson's disease as early as possible.