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Biomedical subjects

J A Obeso

Publications and source records attributed to J A Obeso.

At least 73 records · Page 4Linked to original sources
PubMed1997

Surgical treatment of Parkinson's disease.

At present, there are three major surgical approaches to Parkinson's disease (PD): (1) Ablative surgery (i.e. pallidotomy, thalamotomy); (2) deep brain stimulation (DBS) of the thalamus, internal globus pallidus (GPi) and subthalamic nucleus (STN); and (3) grafting fetal mesencephalic cells into the striatum. As a result of increasing understanding of the pathophysiology of the basal ganglia and the demonstration of surgical alleviation of experimental parkinsonism, surgery has regained a paramount importance in the management of PD. The aim of pallidotomy and DBS is to reduce the excessive inhibitory output from the GPi and substantia nigra reticulata (SNr). Pallidotomy and DBS of the STN or GPi aim to reverse the pathophysiological consequences of dopamine deficiency in PD, and should be considered entirely symptomatic treatments. The ideal candidates for pallidotomy are young patients in good general health in whom dyskinesias are the main reasons for disability. Patients with severe bilateral problems uncontrollable with present pharmacological tools are candidates for DBS. As yet, there are no formal data to help decide how to choose between GPi and STN stimulation. In our practice, patients are allocated to GPi stimulation when 'on' dyskinesias are extremely severe. In most other instances, we prefer to perform STN stimulation. At present there is almost no reason to decide for the thalamic stimulation since tremor is equally arrested by STN stimulation, which in addition improves all other features of PD. Equally the only indication for thalamotomy would be a patient with long-standing tremor as the main clinical manifestation, which can not be controlled with drugs. The proportion of patients in whom the thalamus will be the preferable target for either DBS or thalamotomy is small (less than 5%). Grafting aims to repair the nigrostriatal pathway and restore dopaminergic function in the striatum. In the future implants containing not only dopaminergic cells but also growth factors and a variety of other substances could become a method to not only functionally compensate the biochemical abnormalities of PD but also to arrest its progression. This technique is limited to a few centres around the world owing to the technical, logistical and ethical problems of obtaining and handling embryonic cells. At present, grafting of dopaminergic cells is perhaps best suited for patients with young-onset PD (less than 45 years old) who are at high risk of developing complications within a short time of beginning pharmacological treatment and in whom the idea of making lesions or implanting electrodes into the brain for decades seems less appealing. Consideration of surgery in any given patient should be weighed against the risks (about 1% mortality and 2-6% of severe morbidity-hemiplegia, cognitive deficit, speech problems, etc.) associated with these techniques. The development of better imaging methods and the growing expertise of multidisciplinary teams will undoubtedly make surgery for PD safer and more effective in the future.

Electric Stimulation Therapy↗
PubMed1997

[Stereotactic surgery in Parkinson's disease].

Stereotactic surgery for Parkinson's disease (PD) has regained interest due to the recently described hyperactivity of the subthalamic-pallidal pathway. Many patients suffering from complications associated with the chronic use of levodopa may benefit from surgical treatments. There are different surgical targets and techniques (ablative and deep brain stimulation). The choice of one particular target and technique relies on the clinical symptoms of the patient. The risk/benefit ratio of surgery is related to the careful selection of patients and the technical accuracy. Intraoperative microrecording is considered the best method to avoid side effects and partial results. A series of patient's selection and follow-up assessment criteria are proposed.

Follow-Up Studies↗
PubMed1996

Metabolic activity of the basal ganglia in parkinsonian syndromes in human and non-human primates: a cytochrome oxidase histochemistry study.

In order to examine the consequences of nigrostriatal denervation on metabolic and functional activity of the basal ganglia, we analysed the distribution of cytochrome oxidase, a metabolic marker for neuronal functional activity, throughout the different basal ganglia structures in parkinsonian syndromes. The study was performed using enzyme histochemistry and densitometric measurements in patients with Parkinson's disease and in monkeys rendered parkinsonian by 1-methyl-4-phenyl-1,2,3,6-tetrahydropyrydine (MPTP) intoxication. In MPTP-intoxicated monkeys compared to control animals, enzyme activity was significantly increased in the subthalamic nucleus and in the output nuclei of the basal ganglia, e.g. the internal segment of the globus pallidus and the substantia nigra pars reticulata, but remained unchanged in the external segment of the globus pallidus and the striatum. L-DOPA treatment reversed the increased enzyme activity in all of the affected structures studied. In contrast, in parkinsonian patients, who had all been chronically treated with L-DOPA, no changes in enzyme activity were detected compared to control subjects. The results in MPTP-intoxicated monkeys are in agreement with the accepted model of basal ganglia organization, in which the output nuclei of the basal ganglia are considered to be overactive after nigrostriatal denervation, partly due to increased activity of excitatory afferents from the subthalamic nucleus. Since the increased enzyme activity in MPTP-intoxicated monkeys was reversed by L-DOPA therapy, the unchanged cytochrome oxidase activity observed in parkinsonian patients might result from L-DOPA treatment, combined with the chronicity of nigrostriatal denervation.

Aged↗
PubMed1996

Effects of L-DOPA-therapy on dopamine D2 receptor mRNA expression in the striatum of MPTP-intoxicated parkinsonian monkeys.

The cellular expression of dopamine D2 receptor mRNA was examined in striatal (caudate nucleus and putamen) neurones of 9 Macaca fascicularis monkeys rendered parkinsonian by systemic injection of MPTP. Messenger RNA abundance was determined by quantitative in situ hybridization using human-specific 35S-labelled oligonucleotides. Control monkeys were untreated and received neither MPTP nor L-DOPA while the rest were rendered parkinsonian and received chronic levodopa therapy to induce dyskinesia. In the control brains a strong dopamine D2 receptor hybridization signal was detected overlying medium-sized and some large neurons in both the caudate nucleus and putamen. Neurons from the lateral and medial regions of the caudate nucleus, and from the dorsal and ventral regions of the putamen were analysed separately. A significant increase in the cellular abundance of dopamine D2 receptor mRNA was seen in the striatum of MPTP-treated monkeys; this increase being restricted to the population of medium-sized striatal cells. No such increase in dopamine D2 receptor mRNA was observed in (dyskinetic) L-DOPA-treated monkeys suggesting that levodopa-therapy normalises D2 receptor expression in post-synaptic striatal cells. The cellular abundance of dopamine D2 receptor mRNA expressed by large striatal neurons (putative cholinergic cells) was unaffected by either MPTP treatment or levodopa therapy. The implications of these findings for the development of levodopa-induced dyskinesias is discussed.

Animals↗
PubMed1996

Subthalamotomy in parkinsonian monkeys. Behavioural and biochemical analysis.

Nineteen Macaca fascicularis monkeys were divided into four different groups: Group A (n = 3), control; Group B (n = 3), monkeys treated with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP); Group C (n = 8), animals treated with MPTP in which the subthalamic nucleus (STN) was unilaterally lesioned by kainic acid injection; in Group D (n = 5), the STN was lesioned prior to MPTP administration. Subthalamotomy resulted in a bilateral improvement of tremor, spontaneous activity, bradykinesia (evaluated by a manual motor test) and freezing in Group C. All these monkeys developed hemichorea contralateral to the lesion. The improvement was maintained and the hemichorea continued until death. The monkeys in group D showed severe hemiballism which persisted throughout MPTP administration and developed parkinsonian signs mainly on the side ipsilateral to the lesion. Analysis of the in situ hybridization of the mRNA coding for glutamic acid decarboxylase (GAD) of MPTP monkeys showed a significant increase in the mean density of silver grains over every labelled neuron in the globus pallidum lateralis (56.8% over control) as well as the globus pallidus medialis (GPM) (45.7% over control) and the substantia nigra reticulata (SNR) (35.8% over control). No significant change was observed in the thalamic nucleus reticularis. Subthalamotomy (Groups C and D) produced a significant reduction in mRNA GAD expression on the side of the lesion in the GPM and the SNR (34% and 42.3%, respectively) with respect to the ipsilateral (non-lesioned) side and also when compared with parkinsonian monkeys. These results confirm and expand, at the cellular level, the paramount role of STN hyperactivity in the pathophysiology of parkinsonism. The therapeutic consequences of these findings for surgical treatment of Parkinson's disease are discussed.

1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine↗
PubMed1996

Consequences of nigrostriatal denervation on the gamma-aminobutyric acidic neurons of substantia nigra pars reticulata and superior colliculus in parkinsonian syndromes.

To examine the effects of nigrostriatal denervation on the substantia nigra pars reticulata (SNpr), one of the main outputs of the basal ganglia, we used quantitative in situ hybridization to analyze the messenger RNA coding for Mr 67,000 glutamic acid decarboxylase (GAD67 mRNA) in the SNpr neurons from patients with Parkinson's disease (PD), monkeys rendered parkinsonian by 1-methyl-4- phenyl-1,2,3,6-tetrahydropyridine (MPTP), and their respective controls. In MPTP-intoxicated monkeys, the expression of GAD67 mRNA was increased in the SNpr neurons, and the increase was reversed by L-dopa treatment. There were no differences in the level of GAD67 mRNA between PD patients who had been treated with L-dopa and control subjects. Combined with the previously reported increased expression of GAD67 mRNA in the internal segment of the pallidum of MPTP-intoxicated monkeys, these data suggest that the gamma-aminobutyric acid (GABAergic) activity of the output system of the basal ganglia is globally increased by nigrostriatal denervation. We also analyzed the level of GAD67 mRNA expression in the superior colliculus, a structure that receives the inhibitory influence of the GABAergic neurons of the SNpr and that is involved in eye movement control. GAD67 mRNA expression was reduced in both MPTP-intoxicated monkeys, whether or not they received L-dopa therapy, and PD patients, compared to their respective controls. This decrease may result from the hyperactivity of the inhibitory nigrotectal pathway, but also from other influences since it was not corrected by L-dopa therapy. These changes may account for the slight ocular motor and visuospatial cognitive impairment occurring in PD, even after L-dopa therapy.

Animals↗
PubMed1996

Consequence of nigrostriatal denervation and L-dopa therapy on the expression of glutamic acid decarboxylase messenger RNA in the pallidum.

To examine the consequences of nigrostriatal denervation and L-dopa treatment on the basal ganglia output system, we analyzed, by quantitative in situ hybridization, the messenger RNA coding for glutamic acid decarboxylase (Mr 67,000) (GAD67 mRNA) in pallidal cells from patients with Parkinson's disease (PD), monkeys rendered parkinsonian by 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) receiving or not receiving L-dopa, and their respective control subjects. In MPTP-treated monkeys, the expression of GAD67 mRNA was increased in cells from the internal pallidum, and this effect was abolished by L-dopa treatment. There were no differences in the levels of GAD67 mRNA between patients with PD, who were all treated with L-dopa, and control subjects. These results indicate that the level of GAD67 mRNA is increased in the cells of the internal pallidum after nigrostriatal dopaminergic denervation and that this increase can be reversed by L-dopa therapy.

1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine↗
PubMed1995

Autoradiographic localization and density of [125I]ferrotransferrin binding sites in the basal ganglia of control subjects, patients with Parkinson's disease and MPTP-lesioned monkeys.

Degeneration of the nigro-striatal dopaminergic neurons occurring in Parkinson's disease is associated with an increase in iron concentrations in the substantia nigra. As this metal catalyzes the production of free radicals, and oxidative stress may participate in the cascade of events ending in cell death, this increase in iron content may be involved in dopaminergic neuronal death. The localization and number of receptors for transferrin were investigated postmortem by quantitative autoradiography of iodinated-ferrotransferrin binding in the basal ganglia from controls, parkinsonian patients and MPTP-lesioned monkeys. In human controls, specific [125i] ferrotransferrin binding-site density was highest in the putamen and the caudate nucleus, and lowest in the globus pallidus. In parkinsonian patients, it was increased in the putamen and caudate nucleus, while in MPTP-intoxicated monkeys, there was a tendency for levels to decrease in these two regions. An inverse relationship between binding density and iron content reported in the studied regions supports the assumption of a possible capture of iron at the level of dopaminergic terminals and, in parkinsonian patients, on other cellular elements as well. These results suggest an involvement of transferrin receptors in iron uptake in the striatum of patients with Parkinson's disease, with differences between the 'acute' nigro-striatal MPTP-induced degeneration syndrome and the chronic long lasting human disease.

1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine↗
PubMed1995

Effects of nigrostriatal denervation and L-dopa therapy on the GABAergic neurons in the striatum in MPTP-treated monkeys and Parkinson's disease: an in situ hybridization study of GAD67 mRNA.

The effects of nigrostriatal denervation and L-dopa therapy on GABAergic neurons were analysed in patients with Parkinson's disease and in monkeys rendered parkinsonian by MPTP intoxication. The expression of the messenger RNA coding for the 67 kDa isoform of glutamic acid decarboxylase (GAD67 mRNA), studied by quantitative in situ hybridization, was used as an index of the GABAergic activity of the striatal neurons. A significant increase in GAD67 mRNA expression, generalized to all GABAergic neurons, was observed in MPTP-treated monkeys compared to control monkeys in the putamen and caudate nucleus (+44 and +67% respectively), but not in the ventral striatum. L-Dopa therapy significantly reduced GAD67 mRNA expression in the putamen and caudate nucleus to levels similar to those found in control monkeys. However, the return to normal of GAD67 mRNA expression was not homogeneous across all neurons since it was followed by an increase of labelling in one subpopulation of GABAergic neurons and a decrease in another. These data suggest that in MPTP-treated monkeys the degeneration of nigrostriatal dopaminergic neurons results in a generalized increase in GABAergic activity in all the GABAergic neurons of the striatum, which is partially reversed by L-dopa therapy. As the expression of GAD67 mRNA is less intense in the ventral than in the dorsal striatum, this increase in striatal GABAergic activity may be related to the severity of nigrostriatal denervation. In parkinsonian patients who had been chronically treated with L-dopa, GAD67 mRNA expression was significantly decreased in all GABAergic neurons, in the caudate nucleus (by 44%), putamen (by 43.5%) and ventral striatum (by 26%). The opposite variation of GAD67 mRNA in patients with Parkinson's disease, compared with MPTP-treated monkeys, might be explained by the combination of chronic nigrostriatal denervation and long-term L-dopa therapy.

Aged↗
PubMed1995

Neurotoxicity induced by prenatal exposure to MPTP on the monoaminergic and peptidergic systems of the marmoset brain.

The neurotoxicity induced by incidental prenatal exposure to 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) was studied in three marmosets. The baby marmosets exposed in utero to MPTP looked normal in the first few weeks of life but around 8 to 10 weeks of life they started to behave abnormally and were sacrificed when they were 20 weeks old. A marked reduction in DA levels was found in the baby marmosets prenatally exposed to MPTP as compared to the corresponding age-matched controls and this was highly significant in the caudate nucleus, putamen, and nucleus accumbens. Serotonin content was normal in the caudate and putamen and was only significantly reduced in the nucleus accumbens, hypothalamus, and cingulate cortex. Met-enkephalin levels were reduced in the caudate nucleus, putamen, and globus pallidus. Substance P content tended to be lower in all regions examined; however, the decrease was only statistically significant in the substantia nigra. These results indicate that prenatal exposure to MPTP induces a marked and long-lasting alteration in monoaminergic and peptidergic systems of the primate brain. This observation may provide a new insight into the role of toxins in the etiology of Parkinson's disease.

3,4-Dihydroxyphenylacetic Acid↗
PubMed1995

Effects of L-DOPA on preproenkephalin and preprotachykinin gene expression in the MPTP-treated monkey striatum.

The cellular expression of the genes encoding the neuropeptides enkephalin and substance P were examined in the caudate nucleus and putamen of parkinsonian 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-treated cynomolgus monkeys by in situ hybridization using radioactive antisense oligonucleotides coupled with computer-assisted image analysis. Behavioural evaluation of the animals revealed two levels of motor impairment; one group moderately impaired and the other severely disabled. A marked increase in the cellular content of preproenkephalin A messenger RNA was observed in medium-sized (106 +/- 9 microns2) cells in the caudate-putamen of all MPTP animals when compared with controls, the increase being greatest in the most severely impaired animals. By contrast, a marked reduction in the cellular abundance of preprotachykinin gene expression was detected in striatal cells (101 +/- 16 microns2) of these same MPTP animals. These changes in neuropeptide gene expression were not associated with a change in the density (approximately 10 cells per mm2) of messenger RNA-expressing cells. L-DOPA treatment of two of the severely-impaired MPTP monkeys resulted in a dissociation of expression of these two genes: the cellular abundance of preproenkephalin A remained elevated whilst preprotachykinin levels were normalized and comparable with controls. No change in the cellular abundance of preprotachykinin messenger RNA was observed in cells of the insular cortex or a small discrete population of large cells (208 +/- 27 microns2) in the ventral putamen. These results demonstrate that MPTP treatment of primates results in a marked potentiation in preproenkephalin messenger RNA coupled with a attenuation in preprotachykinin messenger RNA in the dopamine-denervated caudate-putamen. L-DOPA therapy given on an intermittent schedule reverses the decrease in preprotachykinin messenger RNA, but fails to reverse the increase in preproenkephalin messenger RNA in the same animal. These observations suggest that a dissociation of the activity of these two neuropeptide systems may underlie the improvement in motor skill that accompanies dopamine replacement therapy and that this dissociation may be instrumental in the long-term complications associated with L-DOPA therapy.

Animals↗