Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0030567 (Parkinson's disease)
 63,064 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The cocaine analog beta-CIT is one of the most used compounds for SPET examination of the dopamine transporter in drug abuse and Parkinson's disease. However, the toxicity of this agent has not yet been studied. We report here acute toxicity, mutagenicity, and effect on locomotor activity of beta-CIT. Acute toxicity experiments were performed in mice and rats. The LD50 values were about 20 mg and 5 mg for mice and rats, respectively. There was no sex difference. The mutagenicity was evaluated using the Ames' test. No mutagenic effect was observed for beta-CIT. Effects on locomotor activity were measured in mice using the open-field test. beta-CIT increased locomotion (+65%) when injected at a dose of 0.312 mg/kg; the maximal increase (+205%) was observed at a dose of 1.25 mg/kg; at higher doses, the effect was decreased slightly. These pharmacological findings are in agreement with an inhibitory effect of beta-CIT at the dopamine transporter. We conclude that with no mutagenic effects and LD50 more than 6 orders of magnitude higher than the routinely used doses in PET or SPET, it can be assumed that beta-CIT can be safely used as a radioligand in humans.
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PMID:Toxicity, mutagenicity, and behavioral effects of beta-CIT, a ligand for dopamine transporter exploration by SPECT. 963 3

Functional imaging of the presynaptic dopaminergic activity using single-photon emission tomography (SPET) and iodine-123 labelled 2-beta-carboxymethoxy-3-beta-(4-iodophenyl)tropane ([123I]beta-CIT) is important for the assessment of disease severity and progression in patients with Parkinson's disease (PD). However, its capability to discriminate between different extrapyramidal disorders has not yet been assessed. The aim of this study was to evaluate the possibility of differentiating patients with PD and with progressive supranuclear palsy (PSP) by means of this method. The distribution of [123I]beta-CIT in the basal ganglia was assessed in six normal subjects, 13 petients with PD and five patients with PSP in whom the disease was mild. SPET images were obtained 24+/-2 h after i.v. injection of the tracer using a brain-dedicated system (CERASPECT). MR and SPET images were co-registered in four normal subjects and used to define a standard set of 16 circular regions of interest (ROIs) on the slice showing the highest striatal activity. The basal ganglia ROIs corresponded to (1) the head of caudate, (2) a region of transition between the head of caudate and the anterior putamen, (3) the anterior putamen and (4) the posterior putamen. A ratio of specific to non-displaceable striatal uptake was calculated normalising the activity of the basal ganglia ROIs to that of the occipital cortex (V3"). ANOVA revealed a global reduction of V3" in all ROIs of PD and PSP patients compared with normal controls (P<0. 0001). A Mann-Whitney U test showed that the difference between PD and PSP patients was statistically significant for the caudate region only (Z value: 2.6; P<0.01). By subtracting V3" caudate values from those of the putamen, differentiation from PSP was possible in 10/13 PD patients. In conclusion, analysis of [123I]beta-CIT distribution in discrete striatal areas provides information on the relative caudate-putamen damage, with different values being obtained in patients clinically diagnosed as having either PD or PSP.
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PMID:Differential distribution of striatal [123I]beta-CIT in Parkinson's disease and progressive supranuclear palsy, evaluated with single-photon emission tomography. 972 76

Sensory disturbances such as olfactory or visual dysfunctions are common in Parkinson's disease (PD). A possible relationship between distorted colour discrimination and the nigrostriatal dopamine deficit is still a matter of debate. We examined 31 de novo Parkinsonian patients with [123I]beta-CIT single photon emission tomography (SPECT). We used a single-head gamma-camera and calculated the binding ratio striatum/cerebellum (specific/nonspecific binding) of [123I]beta-CIT uptake. On the same day, we performed the Farnsworth-Munsell 100 Hue Test (FMT) in these patients and estimated the total error score, in order to investigate abnormalities of colour vision. Parkinsonian patients' total error score was higher compared with an age- and sex-matched control group (P = < 0.0001), whereas disability scores of the Hoehn and Yahr scale (P = 0.019, Spearman r = 0.419) and the Unified Parkinson's Disease Rating Scale (P = 0.039, Spearman r = 0.373) correlated with total error score. No significant association appeared between total error score (Spearman r = -0.119, P = 0.525) and [123I]P-CIT-SPECT ratio. Thus both total error scores of the FMT and [1231]beta-CIT-SPECT binding ratios have been found to reflect the severity of PD. However, only [123I]beta-CIT SPECT reflects degeneration of dopaminergic neurons of the basal ganglia, but does not reflect alterations of the visual system and/or extranigral lesions in PD. From our results, we speculate that FMT may be a valuable clinical method to measure extranigral lesions of the visual system in PD.
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PMID:Colour vision abnormalities do not correlate with dopaminergic nigrostriatal degeneration in Parkinson's disease. 977 65

Early diagnosis of Parkinson's disease (PD) is important for the potential application of neuroprotective therapies. The purpose of this study was to assess the detection of the early changes of PD by either imaging the dopamine transporter (DAT) or uptake of L-3,4-dihydroxyphenylalanine (L-DOPA). An early to advanced stage model of PD was induced in rats by stereotaxic injection of 1-10 microg 6-hydroxydopamine (6-OHDA) into the substantia nigra pars compacta. Using adjacent sections of the same animals, the binding of [I-125]beta-CIT, which labels DAT and the uptake of [C-14]L-DOPA, were evaluated 4 weeks after induction of the lesion. Any decrease in dopaminergic neurons was evaluated by in situ hybridization histochemistry (ISH) by detection of DAT mRNA-positive neurons. In addition, the expression levels of DAT, dopa decarboxylase (DDC), and vesicular monoamine transporter (VMAT2) in each neuron were studied with ISH. Our results show a decrease in both [I-125]beta-CIT binding and [C-14]L-DOPA uptake in parallel with a decrease in DA neurons from early to advanced stage models of PD. The decrease in [C-14]L-DOPA uptake was smaller than that in [I-125]beta-CIT binding in the same animal (P < 0.0001). Expression levels of DAT, DDC, and VMAT2 mRNAs were also decreased with the progression of the disease. Although ISH failed to detect the origin of the discrepancy between [I-125]beta-CIT and [C-14]L-DOPA levels, it was concluded that [C-14]L-DOPA levels underestimated the decrease of dopaminergic neurons and that [I-125]beta-CIT levels more precisely reflected the decrease.
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PMID:Comparison between the decrease of dopamine transporter and that of L-DOPA uptake for detection of early to advanced stage of Parkinson's disease in animal models. 1002 35

Modalities for imaging morphology do not contribute significantly to the differential diagnosis of movement disorders. In contrast, functional imaging as PET or SPECT can differentiate among Parkinson's disease (PD), vascular or toxic Parkinsonism and movement disorders within multi system degeneration. Especially the decreased DOPA uptake--detected by 18F-DOPA or 123I-beta CIT--within the striate with accentuation in the posterior putamen is typical for PD, where initially D2-receptor activity--imaged by 11C-raclopride or 123I-iodobenzamide--is increased. In contrast to this typical pattern dopaminergic terminals as well as D2-receptors are diffusely reduced in multi system degeneration, where often energy metabolism is additionally disturbed. In Parkinson syndrome of vascular origin focal disturbances of pre- and postsynaptic dopaminergic sites and energy metabolism are found, movement disorders after intoxication are accompanied by selective loss of dopaminergic neurons (MPTP) or by widespread neuronal damage in the basal ganglia as well as in the cortex (Cyanide, solvents). Functional studies additionally permit the follow-up of disease progression, by which also the efficacy of therapeutic strategies can be assessed.
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PMID:[Value of functional imaging in Parkinson's disease and related movement disorders]. 1008 24

Iodine-123-beta-CIT (2 beta-carbomethoxy-3 beta-(4-iodophenyl)tropane) binds with high affinity to dopamine (DA) and serotonin (5-HT) transporters. This study examined the correlation of single-photon emission computed tomographic (SPECT) measures of [123I]beta-CIT binding to DA and 5-HT transporters with symptom severity in Parkinson's disease (PD). Forty-six L-dopa-responsive PD patients (Hoehn-Yahr stage 1-3) had SPECT scans at 20-24 h after injection of [123I]beta-CIT. Specific to nondisplaceable uptake ratios (designated V"3) were calculated in the striatum and hypothalamic/midbrain region, where the binding of [123I]beta-CIT is associated primarily with DA and 5-HT transporters, respectively. Striatal V"3 was significantly correlated with Hoehn-Yahr stage and total, motor and activities of daily living scores of Unified Parkinson's Disease Rating Scale (UPDRS). There was a significant correlation between the sum of lateralizing motor UPDRS subscores (tremor, rigidity, bradykinesia) calculated for each side of limbs and V"3 values in the contralateral striatum. No significant correlation was found between striatal V"3 and UPDRS rating of mentation, behavior, and mood. Hypothalamic/midbrain V"3 was not significantly correlated with either Hoehn-Yahr stage or UPDRS scores including both motor and nonmotor measures. The significant correlation of SPECT measures of striatal [123I]beta-CIT binding with motor severity suggests that [123I]beta-CIT binding to striatal DA transporters can serve as an in vivo indicator of disease severity in PD, with potential utility in the serial monitoring of disease progression.
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PMID:SPECT measurement of iodine-123-beta-CIT binding to dopamine and serotonin transporters in Parkinson's disease: correlation with symptom severity. 1031 33

The effect of subchronic treatment with L-dopa/carbidopa or L-selegiline on striatal dopamine transporters (DAT) was examined in patients with idiopathic Parkinson's disease with SPECT (single photon emission computed tomography) using [123I]beta-CIT (2beta-carbomethoxy-3beta-[4-iodophenyl]tropane) as the radiotracer. Patients who were not currently being treated with these medications were given either 750 mg L-dopa/carbidopa per day (n = 8) or 10 mg L-selegiline per day (n = 8). [123I]beta-CIT imaging was performed three times in each patient: at baseline before treatment, while on medication and after 4-6 weeks of drug treatment, and following withdrawal from medication (approximately 1 week for L-dopa/carbidopa and 9 weeks for L-selegiline). Comparison of scans 2 and 3 provided a measure of drug occupancy of the [123I]beta-CIT binding site; comparison of scans 1 and 2 provided a measure of both up- or downregulation of DAT levels and drug occupancy following subchronic drug treatment. DAT levels were assessed from an image acquired approximately 22 hours after radiotracer injection as a ratio of regional brain activities: (striatum - occipital)/occipital. Striatal DAT levels were not significantly different when any two of the three scans were compared for both drug treatments. These results suggest that typical clinical doses of L-dopa/carbidopa and L-selegiline do not induce significant occupancy of the [123I]beta-CIT binding site and that 4-6 weeks of treatment causes no significant modulation of DAT levels. These results support the validity of measuring DAT levels with [123I]beta-CIT without the need to withdraw patients from medication treatment.
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PMID:Effect of treatment with L-dopa/carbidopa or L-selegiline on striatal dopamine transporter SPECT imaging with [123I]beta-CIT. 1034 66

Single-photon emission computed tomography (SPECT) imaging with the dopamine transporter ligand, [123I] beta-CIT (2beta-carboxymethoxy-3beta-[4-iodophenyl] tropane), has been proposed as a means of measuring Parkinson's disease (PD) progression. To be useful in this role, however, [123I] beta-CIT imaging should not be influenced by the medications used to treat PD, including the dopamine agonist drugs such as pergolide. We assessed the effect of adjunctive pergolide administration on [123I] beta-CIT uptake in 12 patients with PD, who were being treated with levodopa, initiating pergolide therapy for motor fluctuations. Patients underwent [123I] beta-CIT imaging at baseline, subsequently while on pergolide therapy (6 weeks), and again 4 weeks after pergolide wash-out. Uptake in the striatum was averaged for the two sides and expressed as (striatum - occipital)/occipital, with similar calculations for putamen and caudate. Consistent with PD, the patients' mean striatal and putamen uptake ratios at baseline were significantly less (p <0.001) than the mean values from 26 normal control subjects of similar age. During pergolide treatment, the striatal and putamen [123I] beta-CIT uptake ratios were each statistically similar to baseline, although there was a slight trend toward an increased striatal value (8% higher on pergolide; p = 0.105). Caudate [123I] beta-CIT uptake was 11% higher on pergolide therapy (nominal p = 0.042, but not significant when adjusted for multiple comparisons: p = 0.126). After pergolide wash-out, the striatal, putamen, and caudate uptake ratios did not differ from baseline. Therefore, we found that pergolide therapy did not significantly affect [123I] beta-CIT SPECT imaging but we cannot exclude a small influence.
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PMID:The effect of dopamine agonist therapy on dopamine transporter imaging in Parkinson's disease. 1058 67

CALM-PD (Comparison of the agonist pramipexole with levodopa on motor complications of Parkinson's disease) is a randomized, multicenter, double-blind, controlled clinical trial designed to compare the policy of initial treatment of pramipexole with the policy of initial treatment with levodopa in early, symptomatic Parkinson's disease with regard to the development of dopaminergic motor complications. At 22 American and Canadian sites, 301 eligible subjects requiring antiparkinsonian therapy to treat emerging disability were enrolled in CALM-PD and randomized to (i) active pramipexole and placebo levodopa or (ii) placebo pramipexole and active levodopa. Subjects are being evaluated systematically at regular intervals during a 23.5-month period to determine if and when dopaminergic motor complications (wearing off, dyskinesias, "on-off" effects) occur. In addition, quality-of-life outcomes, economic outcomes, and functional imaging outcomes are being assessed in standard fashion with [123I] beta-CIT and SPECT imaging throughout the trial. The study design contains many provisions to approximate routine clinical practice and to produce data about clinical effectiveness, tolerability, and cost to facilitate the evidence-based practice of neurology.
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PMID:A randomized controlled trial comparing pramipexole with levodopa in early Parkinson's disease: design and methods of the CALM-PD Study. Parkinson Study Group. 1068 29

Single photon emission computed tomography (SPECT) tracers selective for pre- and post-synaptic targets have allowed measurements of several aspects of dopaminergic (DA) neurotransmission. In this article, we will first review our DA transporter imaging in Parkinson's disease. We have developed the in vivo dopamine transporter (DAT) imaging with [123I]beta-CIT ((1R)-2beta-Carbomethoxy-3beta-(4-iodophenyl)tropane). This method showed that patients with Parkinson's disease have markedly reduced DAT levels in striatum, which correlated with disease severity and disease progression. Second, we applied DA imaging techniques in patients with schizophrenia. Using amphetamine as a releaser of DA, we observed the enhanced DA release, which was measured by imaging D2 receptors with [123I]IBZM (iodobenzamide), in schizophrenics. Further we developed the measurement of basal synaptic DA levels by AMPT (alpha-methyl-paratyrosine)-induced unmasking of D2 receptors. Finally, we expanded our techniques to the measurement of extrastriatal DA receptors using [123I]epidepride. The findings suggest that SPECT is a useful technique to measure DA transmission in human brain and may further our understanding of the pathophysiology of neuropsychiatric disorders.
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PMID:Applications of SPECT imaging of dopaminergic neurotransmission in neuropsychiatric disorders. 1077 May 74


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