One-day protocol for imaging of the nigrostriatal dopaminergic pathway in Parkinson's disease by [123I]FPCIT SPECT.
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Parkinson's disease is characterized by degeneration of dopaminergic neurons, resulting in loss of dopamine transporters in the striatum. Recently, the tracer 1231-N-omega-fluoropropyl-2beta-carbomethoxy-3beta-(4-iodoph enyl)nortropane (FPCIT) was developed for imaging dopamine transporters with SPECT. The purpose of this study was to develop an [123I]FPCIT SPECT protocol for routine clinical studies. METHODS: We examined the time course of [123I]FPCIT binding to dopamine transporters in 10 healthy volunteers and 19 patients with Parkinson's disease. RESULTS: We found that the time of peak specific striatal [123I]FPCIT binding was highly varied among subjects, but specific binding peaked in all controls and patients within 3 h postinjection. Between 3 and 6 h, the ratio of specific-to-nonspecific striatal [123I]FPCIT binding was stable in both groups, although, as expected, it was significantly lower in patients. In the patients, [123I]FPCIT binding in the putamen was lower than in the caudate nucleus, and contralateral striatal binding was significantly lower than ipsilateral striatal binding. The subgroup of patients with hemi-Parkinson's disease showed loss of striatal dopamine transporters, even on the ipsilateral side. CONCLUSION: For routine clinical [123I]FPCIT SPECT studies, we recommend imaging at a single time point, between 3 and 6 h postinjection, and using a tissue ratio as the outcome measure. The [123I]FPCIT SPECT technique is sensitive enough to distinguish control subjects from patients with Parkinson's disease, even at an early stage of the disease. (+info)
A lysosomal storage disease induced by Ipomoea carnea in goats in Mozambique.
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A novel plant-induced lysosomal storage disease was observed in goats from a village in Mozambique. Affected animals were ataxic, with head tremors and nystagmus. Because of a lack of suitable feed, the animals consumed an exotic hedge plant growing in the village that was identified as Ipomoea carnea (shrubby morning glory, Convolvulaceae). The toxicosis was reproduced by feeding I. carnea plant material to goats. In acute cases, histologic changes in the brain and spinal cord comprised widespread cytoplasmic vacuolation of neurons and glial cells in association with axonal spheroid formation. Ultrastructurally, cytoplasmic storage vacuoles in neurons were membrane bound and consistent with lysosomes. Cytoplasmic vacuolation was also found in neurons in the submucosal and mesenteric plexuses in the small intestine, in renal tubular epithelial cells, and in macrophage-phagocytic cells in the spleen and lymph nodes in acute cases. Residual alterations in the brain in chronic cases revealed predominantly cerebellar lesions characterized by loss of Purkinje neurons and gliosis of the Purkinje cell layer. Analysis of I. carnea plant material by gas chromatography-mass spectrometry established the presence of the mannosidase inhibitor swainsonine and 2 glycosidase inhibitors, calystegine B2 and calystegine C1, consistent with a plant-induced alpha-mannosidosis in the goats. The described storage disorder is analogous to the lysosomal storage diseases induced by ingestion of locoweeds (Astragalus and Oxytropis) and poison peas (Swainsona). (+info)
Contractile effect of 6 beta-acetoxy nortropane on human and guinea pig airways.
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AIM: To study the effects of 6 beta-acetoxy nortropane (6 beta-AN) on the isolated human bronchus and guinea pig trachea. METHODS: The contractile effect of 6 beta-AN was studied with 4 different muscarinic receptor antagonists on airway strips and inositol phosphates (IP) accumulation in human bronchi was determined by HPLC with radioactivity flow detector. RESULTS: (1) The maximal contractile effect of 6 beta-AN was lower than that of acetylcholine (ACh) on the human bronchus and equal to that of ACh on the guinea pig trachea. 6 beta-AN was more potent than ACh on both preparations (68 and 245 times, respectively). (2) The contractile effect of 6 beta-AN was inhibited by atropine (1 -100 nmol.L-1) or para-fluoro-hexahydro-sila-difenidol (0.01-1 mumol.L-1), but not by methoctramine (Met, 0.3-3 mumol.L-1) or pirenzepine (0.01-0.1 mumol.L-1), and was not enhanced by tacrine (0.1-10 mumol.L-1) or by epithelium removal. (3) The 6 beta-AN induced-contraction was accompanied by an increase of IP levels in isolated human bronchial tissues. (4) 6 beta-AN had an inhibitory effect on isoprenaline (Iso)-induced relaxation, which was abolished or reduced by Met 0.3 mumol.L-1. CONCLUSION: 6 beta-AN exerts a potent contractile effect involving muscarinic M3 receptor stimulation on airway smooth muscle. Muscarinic M2 receptor stimulation is furthermore partially involved in the antagonism by 6 beta-AN on the Iso-induced relaxation of the guinea pig trachea. (+info)
Quantification and visualization of defects of the functional dopaminergic system using an automatic algorithm.
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In SPECT, the binding of radiotracers in brain areas is usually assessed by manual positioning of regions of interest (ROIs). The disadvantages of this method are that it is an observer-dependent procedure and that it may not be sensitive for assessing defects significantly smaller than the ROI. To circumvent these limitations, we developed a fully automatic three-dimensional technique that quantifies neuronal radiotracer binding on a voxel-by-voxel basis. METHODS: To build a model of normal 123I-labeled N-omega-fluoropropyl-2beta-carbomethoxy-3beta-(4-iodophenyl) nortropane (FPCIT) binding, 17 studies of healthy volunteers were registered to the same orientation. After registration, the specific-to-nonspecific binding ratio was calculated for each voxel of the striatal volumes of interest (VOIs). The mean and SD of that binding ratio were then calculated on a voxel-by-voxel basis. For the analysis of 10 healthy volunteer studies (control group) and 21 studies of drug-naive patients with Parkinson's disease, the registration and calculation of the specific-to-nonspecific [123I]FPCIT binding ratio were performed by the same method. Subsequently, a voxel of the striata was classified as a diminished [123I]FPCIT binding ratio if its value was lower than the mean -2 x SD. For each subject, the defect size, the relative number of voxels with a diminished binding ratio and the binding ratio of the whole striatal VOIs were calculated and compared with the binding ratio as assessed by the traditional ROI method. RESULTS: The results of the automatic method correlated significantly with the results of the traditional ROI method. Furthermore, for the ipsilateral side, the automatically calculated defect size had less overlap between the patient and the control group than the traditionally calculated binding ratio. CONCLUSION: The method presented quantifies [123I]FPCIT binding ratio automatically on a voxel-by-voxel basis, by comparison with a model of healthy volunteers. We have shown that it is appropriate to use the automatic method as a replacement for the traditional manual method, which enables us to study the localized dopaminergic degeneration process in Parkinson's disease more precisely and without any inter- or intraobserver variability. (+info)
Dopamine transporter: transmembrane phenylalanine mutations can selectively influence dopamine uptake and cocaine analog recognition.
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Cocaine blocks the normal role of the dopamine transporter (DAT) in terminating dopamine signaling through molecular interactions that are only partially understood. Cocaine analog structure-activity studies have suggested roles for both cationic and aromatic interactions among DAT, dopamine, and cocaine. We hypothesized that phenylalanine residues lying in putative DAT transmembrane (TM) domains were good candidates to contribute to aromatic and/or cationic interactions among DAT, dopamine, and cocaine. To test this idea, we characterized the influences of alanine substitution for each of 29 phenylalanine residues lying in or near a putative DAT TM domain. Cells express 22 mutants at near wild-type levels, manifest by DAT immunohistochemistry and binding of the radiolabeled cocaine analog [(3)H](-)-2-beta-carbomethoxy-3-beta-(4-fluorophenyl)tropane (CFT). Seven mutants fail to express at normal levels. Four mutations selectively reduce cocaine analog affinities. Alanine substitutions at Phe(76), Phe(98), Phe(390), and Phe(361) located in TM domains 1 and 2, the fourth extracellular loop near TM 4 and in TM 7, displayed normal affinities for dopamine but 3- to 8-fold reductions in affinities for CFT. One TM 3 mutation, F(155)A, selectively decreased dopamine affinity to less than 3% of wild-type levels while reducing CFT affinity less than 3-fold. In a current DAT structural model, each of the residues at which alanine substitution selectively reduces cocaine analog or dopamine affinities faces a central transporter cavity, whereas mutations that influence expression levels are more likely to lie at potential helix/helix interfaces. Specific, overlapping sets of phenylalanine residues contribute selectively to DAT recognition of dopamine and cocaine. (+info)
Pharmacological characterization of (E)-N-(3-iodoprop-2-enyl)-2beta-carbomethoxy-3beta-(4'-methylphenyl)n ortropane as a selective and potent inhibitor of the neuronal dopamine transporter.
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The pharmacological properties of the iodinated derivative of cocaine (E)-N-(3-iodoprop-2-enyl)-2beta-carbomethoxy-3beta-(4'-me thylphenyl)nortropane (PE2I) were evaluated in vitro in the rat. Binding experiments on rat striatal membranes showed that PE2I selectively recognized the dopamine transporter (DAT) according to a single binding site model with high affinity (K(d) = 4 nM, B(max) = 12 pmol/mg protein). In the cortical membranes, the binding of PE2I was also selectively associated with the DAT (IC(50) for GBR 12909 = 6 nM versus more than 1000 nM for paroxetine), with similar affinity to that of the striatum. Autoradiographic experiments on rat brain sections with [(125)I]PE2I were in agreement with the localization of the DAT. In addition, PE2I was shown to be a potent inhibitor of dopamine uptake, with IC(50) values similar to those for GBR 12909 and 2beta-carbomethoxy-3beta-(4'-iodophenyl)-tropane (beta-CIT) (2-6 nM). All of these findings, combined with previously published data, support the use of PE2I as a selective and potent tool to study the DAT both in vivo and in vitro. (+info)
Biodistribution and radiation dosimetry of the dopamine transporter ligand.
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18F-labeled 2 beta-carbomethoxy-3beta-(4-chlorophenyl)-8-(-2-fluoroethyl)nortropane ([18F]FECNT) is a recently developed dopamine transporter ligand with potential applications in patients with Parkinson's disease and cocaine addiction. METHODS: Estimates of the effective dose equivalent and doses for specific organs were made using biodistribution data from 16 Sprague-Dawley rats and nine rhesus monkeys. PET images from two rhesus monkeys were used to calculate the residence time for the basal ganglia. The computer program MIRDOSE3 was used to calculate the dosimetry according to the methodology recommended by MIRD. RESULTS: The basal ganglia were the targeted tissues receiving the highest dose, 0.11 mGy/MBq (0.39 rad/mCi). The effective dose equivalent was 0.018 mSv/MBq (0.065 rem/mCi), and the effective dose was 0.016 mSv/MBq (0.058 rem/mCi). CONCLUSION: Our data show that a 185-MBq (5-mCi) injection of [18F]FECNT leads to an estimated effective dose of 3 mSv (0.3 rem) and an estimated dose to the target organ or tissue of 19.4 mGy (1.93 rad). (+info)
Dopamine D(2)/D(3)-receptor and transporter densities in nucleus accumbens and amygdala of type 1 and 2 alcoholics.
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Alcohol acts through mechanisms involving the brain neurotransmitter dopamine (DA) with the nucleus accumbens as the key zone for mediating these effects. We evaluated the densities of DA D(2)/D(3) receptors and transporters in the nucleus accumbens and amygdala of post-mortem human brains by using [(125)l]epidepride and [(125)I]PE2I as radioligands in whole hemispheric autoradiography of Cloninger type 1 and 2 alcoholics and healthy controls. When compared with controls, the mean binding of [(125)I]epidepride to DA D(2)/D(3) receptors was 20% lower in the nucleus accumbens and 41% lower in the amygdala, and [(125)I]PE2I binding to DA transporters in the nucleus accumbens was 39% lower in type 1 alcoholics. These data indicate that dopaminergic functions in these limbic areas may be impaired among type 1 alcoholics, due to the substantially lower number of receptor sites. Our results suggest that such a reduction may result in the chronic overuse of alcohol as an attempt to stimulate DA function. (+info)