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

Changes in dopamine turnover resulting from disease states such as Parkinson's disease may be reflected in corresponding changes in the kinetics of the positron emission tomographic tracer [(18)F]fluorodopa. The authors had previously refined the conventional irreversible-tracer graphical approach to determine both the uptake rate constant K(i) and the rate constant kloss that describes the slow loss of the trapped kinetic component. Because these parameters change in the opposite sense with disease, their ratios may be more powerfully discriminating than either one alone. The ratio k(loss)/K(i) is indicative of effective dopamine turnover. Its inverse, K(i)/k(loss), can be interpreted as the effective distribution volume (EDV) of the specific uptake compartment referred to the fluorodopa concentration in plasma. Here the authors present a new approach to the estimation of EDV based on reversible-tracer graphical methods. When implemented with a plasma input function, the method evaluates EDV directly. When implemented with a tissue input function, the outcome is proportional to the ratio of the distribution volumes of the specific uptake and precursor compartments. Comparison of the new and previous approaches strongly validates this alternative approach to the study of effective dopamine turnover.
J Cereb Blood Flow Metab 2001 Apr
PMID:A reversible tracer analysis approach to the study of effective dopamine turnover. 1132 32

Positron emission tomography (PET) coupled to 6-[18F]Fluoro-L-Dopa (18F-Dopa) remains the gold standard for assessing dysfunctionality concerning the dopaminergic nigrostriatal pathway in Parkinson's disease and related disorders. The use of ligands of the dopamine transporters (DAT) is an attractive alternative target; consequently, the current aim was to validate one of them, 11C-PE2I, using a multiinjection modeling approach allowing accurate quantitation of DAT densities in the striatum. Experiments were performed in three controls, three MPTP-treated (parkinsonian) baboons, and one reserpine-treated baboon. 11C-PE2I B'max values obtained with this approach were compared with 18F-Dopa input rate constant values (Ki), in vitro Bmax binding of 125I-PE2I, and the number of dopaminergic neurons in the substantia nigra estimated postmortem by stereology. In the caudate nucleus and putamen, control values for 11C-PE2I B'max were 673 and 658 pmol/mL, respectively, whereas it was strongly reduced in the MPTP-treated (B'max = 26 and 36 pmol/mL) and reserpine-treated animals (B'max = 338 and 483 pmol/mL). In vivo 11C-PE2I B'max values correlated with 18F-Dopa Ki values and in vitro 125I-PE2I Bmax values in the striatum and with the number of nigral dopaminergic neurons. Altogether, these data support the use of 11C-PE2I for monitoring striatal dopaminergic disorders and the effect of potential neuroprotective strategies.
J Cereb Blood Flow Metab 2001 Jul
PMID:Anatomic and biochemical correlates of the dopamine transporter ligand 11C-PE2I in normal and parkinsonian primates: comparison with 6-[18F]fluoro-L-dopa. 1143 90

The authors developed a novel positron emission tomography method to estimate changes in the synaptic level of dopamine ([DA]) induced by direct dopamine agonists (for example, apomorphine) in patients with Parkinson disease. The method is based on the typical asymmetry of the nigrostriatal lesion that often occurs in Parkinson disease. Using the between-side difference (ipsilateral (I) and contralateral (C) putamen to the more affected body side) of the inverse of the putamen [11C]raclopride binding potential (BP), the authors obtained [equation: see text] at baseline (that is, before apomorphine administration) and [equation: see text] after apomorphine administration (assuming the concentration of apomorphine is equal in both putamina). The between-side difference in the estimated synaptic concentration of dopamine (diff[DA]) should remain constant unless apomorphine affects dopamine release differently between the two sides. The authors found that apomorphine given subcutaneously at doses of 0.03 and 0.06 mg/kg induced significant changes in their estimate of diff[DA] (P < 0.05). Such changes were more pronounced when only patients with a stable response to levodopa were considered (P < 0.01). These findings provide in vivo evidence that direct dopamine agonists can inhibit the release of endogenous dopamine. The authors propose that this effect is mainly mediated by the activation of presynaptic D2/D3 dopamine receptors.
J Cereb Blood Flow Metab 2001 Oct
PMID:Apomorphine-induced changes in synaptic dopamine levels: positron emission tomography evidence for presynaptic inhibition. 1159 92

We investigated how dopamine (DA) systems contribute to cognitive performance in the domain of learning and attentional flexibility by examining effects of withdrawing DA-ergic medication in patients with Parkinson's disease (PD). Medication remediated impairments in switching between two tasks, thought to depend on circuitry connecting the dorsolateral prefrontal cortex and the posterior parietal cortex to the dorsal caudate nucleus, which is profoundly DA-depleted in PD. By contrast, the same medication impaired probabilistic reversal learning that implicates orbitofrontal cortex- ventral striatal circuitry, which is relatively spared of DA loss in PD. Hence, DA-ergic medication improves or impairs cognitive performance depending on the nature of the task and the basal level of DA function in underlying cortico-striatal circuitry.
Cereb Cortex 2001 Dec
PMID:Enhanced or impaired cognitive function in Parkinson's disease as a function of dopaminergic medication and task demands. 1170 84

Citicoline (exogenous CDP-choline) is a nontoxic and well-tolerated drug used in pharmacotherapy of brain insufficiency and some other neurological disorders, such as stroke, brain trauma, and Parkinson's disease. A few reports indicate that citicoline treatment may also be beneficial in glaucoma. Currently glaucoma is considered a neurodegenerative disease in which retinal ganglion cells (RGC) slowly die, likely in the apoptotic mechanism. Endogenous CDP-choline is a natural precursor of cellular synthesis of phospholipids, mainly phosphatydylcholine (PtdCho). Enhancement of PtdCho synthesis may counteract neuronal apoptosis and provide neuroprotection. Citicoline, when administered, undergoes a quick transformation to cytidine and choline, which are believed to enter brain cells separately and provide neuroprotection by enhancing PtdCho synthesis; similar effect may be expected to occur in glaucomatous RGC. Furthermore, citicoline stimulates some brain neurotransmitter systems, including the dopaminergic system, and dopamine is known as a major neurotransmitter in retina and postretinal visual pathways. In a double-blind, placebo-controlled study, treatment of glaucoma resulted in functional improvement in the visual system noted with electrophysiological methods. Development of citicoline as a treatment for glaucoma is indicated.
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PMID:Pharmacodynamics of citicoline relevant to the treatment of glaucoma. 1178 57

An increase in dopamine turnover has been hypothesized to occur early in Parkinson's disease (PD) as a compensatory mechanism for dopaminergic neuronal loss. A new approach to the determination of dopamine turnover was developed using 4-hour-long 18 F-fluorodopa (FD) positron emission tomography (PET) data. An effective dopamine turnover, an estimate of dopamine turnover, has been measured using its inverse, the effective dopamine distribution volume (EDV). This new method is based on a reversible tracer approach and determines the EDV using a graphical method. Six healthy subjects and 10 subjects with very early PD underwent a 4-hour-long FD scan. The EDV and the plasma uptake rate constant K(i), a marker of dopamine synthesis and storage, were compared according to their ability to separate the PD group from the healthy group. The EDV was the better discriminator (93.8% correct classification versus 81.3% for K(i)). Effective dopamine distribution volume decreased by 65% in the PD group relative to the healthy group, whereas the decrease in K(i) was 39%. These results show that changes in EDV are measurable with PET earlier than changes in the dopamine synthesis and storage rate, indicating that EDV is a sensitive marker for early PD and that a dopamine turnover increase likely serves as an early compensatory mechanism.
J Cereb Blood Flow Metab 2002 Feb
PMID:Increase in dopamine turnover occurs early in Parkinson's disease: evidence from a new modeling approach to PET 18 F-fluorodopa data. 1182 21

To investigate changes in dopamine release in the striatum during motor exercise in human subjects with and without striatal dopamine denervation, eight healthy subjects and eight patients with Parkinson disease (PD) were measured during unilateral foot extension/flexion movement using positron emission tomography with [11C]raclopride. Five subjects in each group were later scanned in the resting condition. Estimation of binding potential (k3/k4) of [11C]raclopride was based on Logan plot method. Significant reductions in [11C]raclopride k3/k4 were found in the dorsal putamen contralateral to the exercise side in the healthy group and ipsilaterally in the PD group. Spearman rank correlation analysis showed that [11C]raclopride k3/k4 correlated inversely with the decrease in performance (velocity and motion range) in the dorsal putamen contralaterally in the healthy group and ipsilaterally in the PD group. These results suggest that simple but laborious motor exercise (motor stimulation) generates significant dopamine release in the dorsal striatum contralateral to the motor execution in humans. Lack of the crossed pattern and ipsilateral increase in dopamine release in the dorsal striatum during the unilateral limb movement may reflect the pathophysiology for hypokinetic and insufficient coordinating movement in PD.
J Cereb Blood Flow Metab 2002 Jun
PMID:Effect of simple motor performance on regional dopamine release in the striatum in Parkinson disease patients and healthy subjects: a positron emission tomography study. 1204 73

Parkinson disease is characterized by the loss of dopaminergic neurons, thus decreasing the system's ability to produce and store dopamine (DA). Such ability is often investigated using 18F-fluorodopa (FD) positron emission tomography. A commonly used model to investigate the DA synthesis and storage rate is the modified Patlak graphical approach. This approach allows for both plasma and tissue input functions, yielding the respective uptake rate constants K(i) and K(occ). This method requires the presence of an irreversible compartment and the absence of any nontrapped tracer metabolite. In the case of K(occ), this last assumption is violated by the presence of the FD metabolite 3-O-methyl-[18F]fluoro-dopa (3OMFD), which makes the K(occ) evaluation susceptible to a downward bias. It was found that both K(i) and K(occ) are influenced by DA loss and thus are not pure measures of DA synthesis and storage. In the case of K(occ), the presence of 3OMFD exacerbates the effect of DA egress, thus introducing a disease-dependent bias in the K(occ) determination. These findings imply that K(i) and K(occ) provide different assessments of disease severity and that, as disease progresses, K(i) and especially K(occ) become more related to DA storage capacity and less to the DA synthesis rate.
J Cereb Blood Flow Metab 2003 Mar
PMID:Effect of dopamine loss and the metabolite 3-O-methyl-[18F]fluoro-dopa on the relation between the 18F-fluorodopa tissue input uptake rate constant Kocc and the [18F]fluorodopa plasma input uptake rate constant Ki. 1262 5

Citicoline (CDP-choline or cytidine 5'-diphosphocholine) has been used as a therapeutic agent in combination with levodopa in the treatment of Parkinson's disease (PD). The present study examines the effects of citicoline by using validated in vivo and in vitro models. Citicoline reduces the cytotoxic effect of 6-hydroxydopamine (6-OHDA)-treated human dopaminergic SH-SY5Y neuroblastoma cells as measured cellular redox activity with 3-[4.5-dimethylthiazol-2-yl]-2.5-diphenyltetrazolium bromide (MTT) and increases the levels of reduced glutathione (GSH), a major antioxidant agent. Moreover, citicoline (500 mg/kg i.p.) administered for 7 days ameliorates functional behaviour by significantly reducing the number of apomorphine-induced contralateral rotations in 6-OHDA rats. Finally, citicoline significantly attenuates substantia nigra (SN) dopaminergic cell dropout and tyrosine hydroxylase immunoreactivity in the ipsilateral striatum in rats injected intrastriatally with 6-hydroxydopamine (6-OHDA).
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PMID:Neuroprotective effect of citicoline in 6-hydroxydopamine-lesioned rats and in 6-hydroxydopamine-treated SH-SY5Y human neuroblastoma cells. 1456 36

It has been suggested that motivational processes mediated by dopaminergic neural systems may be relatively spared in Parkinson's disease (PD) and activation of these pathways may be of therapeutic relevance. To investigate the behavioural and neural correlates of motivation in unmedicated PD patients, we used H(2)(15)O positron emission tomography to measure brain activation patterns related to the processing of monetary rewards of different magnitudes during a spatial search task in PD patients withdrawn from medication, and age-matched healthy controls. Both groups showed increased search efficiency with increasing reward, but demonstrated different patterns of neuronal activation. In healthy controls activity in prefrontal and rhinal cortices, and thalamic activity correlated with reward magnitude. In contrast, activity in the cerebellar vermis in PD patients increased with increasing reward magnitude, suggesting it was sensitive to motivational state. We interpret these relative increases in cerebellar activation as evidence for the presence of compensatory neural mechanisms in unmedicated PD patients.
Cereb Cortex 2004 Jan
PMID:Reward processing in health and Parkinson's disease: neural organization and reorganization. 1465 58


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