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Biomedical subjects

Y Agid

Publications and source records attributed to Y Agid.

At least 73 records · Page 4Linked to original sources
PubMed2000

Neuropsychological changes between "off" and "on" STN or GPi stimulation in Parkinson's disease.

BACKGROUND: In a previous study on a consecutive series of 62 patients with PD, the authors showed that bilateral subthalamic or pallidal continuous high-frequency deep brain stimulation (DBS) affects neither memory nor executive functions 3 to 6 months after surgery. OBJECTIVE: To investigate the specific effects of DBS by comparing the performance of patients with the stimulator turned "on" and "off." METHODS: The performance of 56 patients on clinical tests of executive function was compared after 3 and 12 months of DBS of the subthalamic nucleus (STN; n = 48) or the internal globus pallidus (GPi; n = 8) with the stimulator "on" or "off." Global intellectual efficiency, verbal learning, and mood were also evaluated with the stimulator "on." The performance of another group of 20 patients was compared after 6 months of DBS of the STN (n = 15) or the GPi (n = 5) with the stimulator "on" or "off" on more experimental tests recently shown to be more sensitive to l-dopa therapy. RESULTS: When the stimulator was "on," STN patients showed a mild but significant improvement in psychomotor speed and working memory. In comparison with the presurgical state, STN patients had no cognitive deficit at 12 months, except for lexical fluency. There was no differential effect of STN or GPi stimulation. CONCLUSIONS: 1) The specific effect of DBS seems to mimic the action of l-dopa treatment in the cognitive as in the motor domain; 2) the surgery associated with DBS does not appear to affect the cognitive performance of patients with PD 12 months later, except for a mild deficit in lexical fluency.

Adult↗
PubMed2000

Hallucinations, REM sleep, and Parkinson's disease: a medical hypothesis.

BACKGROUND: Patients with PD can have disabling visual hallucinations associated with dopaminergic therapy. Sleep disorders, including vivid dreams and REM sleep with motor behaviors (RBD), are frequent in these patients. METHODS: The association of hallucinations and REM sleep both at night and during the day was examined in 10 consecutive nondemented patients with long-standing levodopa-responsive PD and hallucinations. Seven patients presented with paranoia and paranoid delusions. Overnight sleep recordings and standard multiple daytime sleep latency test were performed. The results were compared to those of 10 similar patients with PD not experiencing hallucinations. RESULTS: RBD was detected in all 10 patients with hallucinations and in six without. Although nighttime sleep conditions were similar in both groups, hallucinators tended to be sleepier during the day. Delusions following nighttime REM period and daytime REM onsets were observed in three and eight of the hallucinators, and zero and two of the others. Daytime hallucinations, coincident with REM sleep intrusions during periods of wakefulness, were reported only by hallucinators. Postmortem examination of the brain of one patient showed numerous Lewy bodies in neurons of the subcoeruleus nucleus, a region that is involved in REM sleep control. CONCLUSION: The visual hallucinations that coincide with daytime episodes of REM sleep in patients who also experience post-REM delusions at night may be dream imagery. Psychosis in patients with PD may therefore reflect a narcolepsy-like REM sleep disorder.

Aged↗
PubMed2000

Age-related changes of neuronal counts in the human pedunculopontine nucleus.

Cholinergic neurons in the basal forebrain and the upper brainstem undergo changes during aging and in dementia of the Alzheimer type, Parkinson's disease and progressive supranuclear palsy. Little is known about the effect of age on neurons in the tegmental pedunculopontine nucleus. Cholinergic neurons revealed by choline acetyltransferase immunohistochemistry were quantified in the brains of 20 subjects who died without neurological disorder between 28 and 101 years of age. A U-shaped relationship between cell counts and age was found, namely, a decrease in counts between 28 and 70, a minimum between 80 and 91 years of age, and, in four subjects aged 98-101 years counts comparable to those of subjects having died between 28 and 65 years. The findings suggest that the loss of cholinergic pedunculopontine nucleus neurons is not linear. In centenarians age-related neuronal decrease in pedunculopontine nucleus neurons may be slower or the stock of pedunculopontine nucleus neurons greater than in subjects dying earlier.

Adult↗
PubMed2000

Association between early-onset Parkinson's disease and mutations in the parkin gene.

BACKGROUND: Mutations in the parkin gene have recently been identified in patients with early-onset Parkinson's disease, but the frequency of the mutations and the associated phenotype have not been assessed in a large series of patients. METHODS: We studied 73 families in which at least one of the affected family members was affected at or before the age of 45 years and had parents who were not affected, as well as 100 patients with isolated Parkinson's disease that began at or before the age of 45 years. All subjects were screened for mutations in the parkin gene with use of a semiquantitative polymerase-chain-reaction assay that simultaneously amplified several exons. We sequenced the coding exons in a subgroup of patients. We also compared the clinical features of patients with parkin mutations and those without mutations. RESULTS: Among the families with early-onset Parkinson's disease, 36 (49 percent) had parkin mutations. The age at onset ranged from 7 to 58 years. Among the patients with isolated Parkinson's disease, mutations were detected in 10 of 13 patients (77 percent) with an age at onset of 20 years or younger, but in only 2 of 64 patients (3 percent) with an age at onset of more than 30 years. The mean (+/-SD) age at onset in the patients with parkin mutations was younger than that in those without mutations (32+/-11 vs. 42+/-11 years, P<0.001), and they were more likely to have symmetric involvement and dystonia at onset, to have hyperreflexia at onset or later, to have a good response to levodopa therapy, and to have levodopa-induced dyskinesias during treatment. Nineteen different rearrangements of exons (deletions and multiplications) and 16 different point mutations were detected. CONCLUSIONS: Mutations in the parkin gene are a major cause of early-onset autosomal recessive familial Parkinson's disease and isolated juvenile-onset Parkinson's disease (at or before the age of 20 years). Accurate diagnosis of these cases cannot be based only on the clinical manifestations of the disease.

Adolescent↗
PubMed2000

Calpastatin immunoreactivity in the monkey and human brain of control subjects and patients with Parkinson's disease.

Parkinson's disease is characterized by a selective loss of dopaminergic neurons in the nigrostriatal pathway. However, not all dopaminergic neurons degenerate in this disease, and calcium has been suspected of playing a role in this differential vulnerability. An overexpression of the calcium-dependent protease calpain II has recently been reported in the parkinsonian substantia nigra, suggesting that a rise in intracellular calcium concentrations may be involved in the mechanism leading to cell death. The proteasic activity of calpain is regulated by an endogenous inhibitory protein called calpastatin. Because little is known about the distribution of calpastatin in the primate brain, we first analyzed immunohistochemically the calpastatin expression in normal human and monkey brain. A ubiquitous distribution of calpastatin immunostaining was observed in both cases, but its expression was variable from one region to another. In the basal ganglia, staining was intense in the striatum, in the pallidal complex, and in some nuclei of the thalamus. The cerebellum was stained intensely, particularly in the granular and Purkinje cell layers. A dense, heterogeneous staining was observed in the hippocampal formation, mostly in the pyramidal and granular layers. The distribution of staining was similar in the different cerebral cortices studied, and it was most intense in layer V. In the brainstem, staining was particularly prominent in the substantia nigra pars reticulata and compacta, the central gray substance, the superior colliculus, and the cuneiform nucleus, and staining was moderate in the tegmenti pedonculopontinus nucleus and the griseum pontis. In the second part of the study, the authors compared calpastatin expression in the mesencephalon between patients with Parkinson's disease and control subjects. Sequential double staining revealed that some dopaminergic neurons coexpress calpastatin, the proportion of double-stained neurons ranging between 52% and 76% among the different dopaminergic cell groups. Quantitative analysis of the number of calpastatin-stained neurons evidenced a loss of both calpastatin-positive and calpastatin-negative neurons in the substantia nigra of patients with Parkinson's disease. These data suggest that calpain II overexpression in Parkinson's disease is not compensated for by a concomitant increase in calpastatin expression.

Aged↗
PubMed2000

Caspase-3: A vulnerability factor and final effector in apoptotic death of dopaminergic neurons in Parkinson's disease.

Caspase-3 is an effector of apoptosis in experimental models of Parkinson's disease (PD). However, its potential role in the human pathology remains to be demonstrated. Using caspase-3 immunohistochemistry on the postmortem human brain, we observed a positive correlation between the degree of neuronal loss in dopaminergic (DA) cell groups affected in the mesencephalon of PD patients and the percentage of caspase-3-positive neurons in these cell groups in control subjects and a significant decrease of caspase-3-positive pigmented neurons in the substantia nigra pars compacta of PD patients compared with controls that also could be observed in an animal model of PD. This suggests that neurons expressing caspase-3 are more sensitive to the pathological process than those that do not express the protein. In addition, using an antibody raised against activated caspase-3, the percentage of active caspase-3-positive neurons among DA neurons was significantly higher in PD patients than in controls. Finally, electron microscopy analysis in the human brain and in vitro data suggest that caspase-3 activation precedes and is not a consequence of apoptotic cell death in PD.

1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine↗
PubMed2000

Frequency of the DYT1 mutation in primary torsion dystonia without family history.

BACKGROUND: Idiopathic torsion dystonia is a clinically and genetically heterogeneous movement disorder. A GAG deletion at position 946 of the DYT1 gene was the first mutation found, in early-onset dystonia, with an autosomal dominant transmission and reduced penetrance. OBJECTIVE: To evaluate the frequency of the DYT1 mutation in patients with idiopathic torsion dystonia but without a family history. DESIGN: Prospective cohort study. SETTING: Four botulinum toxin clinics in the Paris, France, area. PATIENTS: A French population of 100 patients with dystonia. MAIN OUTCOME: Frequency of the DYT1 mutation tested by polymerase chain reaction and enzyme restriction analysis for the 946 GAG deletion, and genotype-to-phenotype correlation. RESULTS: Only 5 mutation carriers were identified, 4 of whom were part of a group of 10 patients with generalized dystonia. Onset was between ages 5 and 12 years as in typical early-onset dystonia. All 4 patients had cranial muscle involvement, which is atypical for DYT1 mutation carriers. One had segmental dystonia. Molecular analysis of relatives in 2 families demonstrated that the lack of family history was due to reduced penetrance. CONCLUSIONS: For accurate diagnosis and genetic counseling, screening for the DYT1 deletion is of great interest in cases with generalized dystonia without a family history. In other cases, positive results are rare.

Adult↗
PubMed2000

Subthalamic stimulation in Parkinson disease: a multidisciplinary approach.

BACKGROUND: High-frequency stimulation of the subthalamic nucleus constitutes a therapeutic advance for severely disabled patients with Parkinson disease. OBJECTIVE: To evaluate the efficacy and safety of continuous bilateral high-frequency stimulation of the subthalamic nucleus in patients with Parkinson disease. DESIGN: A prospective study of patients with Parkinson disease treated at a university hospital. PATIENTS AND METHODS: Electrodes were implanted bilaterally in the subthalamic nucleus of 23 consecutive patients with Parkinson disease who responded well to levodopa but had severe motor complications. There were 16 men and 7 women (mean +/- SEM age, 53 +/- 2 years) who had a mean +/- SEM disease duration of 14.7 +/- 1.0 years. Targets were determined by 3-dimensional magnetic resonance imaging, combined with intraoperative electrophysiologic recordings and stimulation. RESULTS: Six months after surgery, motor disability, levodopa-induced motor fluctuations, dyskinesias, and the daily dose of levodopa equivalent decreased significantly by 67%, 78%, 77%, and 61%, respectively, compared with the preoperative state. No significant morbidity was observed, except transient depression in 4 patients. CONCLUSIONS: The beneficial effects of subthalamic stimulation depend on (1) the criteria used for patient selection, (2) the precision with which the subthalamic nucleus is targeted (dependent on the 3-dimensional magnetic resonance imaging and the intraoperative electrophysiologic and clinical assessments), and (3) the long-term postoperative adjustment of stimulation variables.

Activities of Daily Living↗
PubMed2000

Irregular jerky tremor, myoclonus, and thalamus: a study using low-frequency stimulation.

High-frequency thalamic stimulation alleviates tremor in Parkinson's disease (PD) and essential tremor (ET). The origin of thalamic myoclonus is unexplained and the effects of low-frequency thalamic stimulation on movement control are still unknown. We studied the effects of stimulation at a low frequency of 15 Hz in five drug-free patients (3 PD, 2 ET) 6 months after thalamic implantation of quadripolar electrodes (unilateral in four patients, bilateral in one patient). Clinical, electrophysiological, and videotaped assessment, using a monopolar 15 Hz frequency (3 V, 90 micros) stimulation current applied simultaneously through two adjacent contacts of the electrode, was performed. We observed myoclonus and irregular jerky tremor in the upper limb contralateral to the site of stimulation. The jerks lasted less than 200 ms, were irregular and not synchronous with stimulation, were superimposed on rest or postural tremor, and increased in response to tactile, proprioceptive, or vibratory stimuli. The fact that this complex movement disorder can be induced by low-frequency stimulation in the ventral intermediate nucleus (Vim) of the thalamus suggests that it results, at least partly, from dysfunction of the Vim and possibly adjacent nuclei of the thalamus.

Aged↗
PubMed2000

Functional activity of zona incerta neurons is altered after nigrostriatal denervation in hemiparkinsonian rats.

The cellular expression of cytochrome oxidase subunit I (COI) mRNA as a metabolic marker for neuronal activity has recently been used to examine the effects of nigrostriatal denervation on the functioning of the basal ganglia. However, this technique also allows functional changes to be detected in other cerebral structures in parkinsonian syndromes. Since the zona incerta has been implicated in locomotor activity and has been the site of stereotactic surgery in Parkinson's disease, the aim of our study was to determine whether changes in neuronal activity are observed in this structure during parkinsonism. Using in situ hybridization, we analyzed the expression of COI mRNA in rats with 6-hydroxydopamine unilateral lesion of the substantia nigra and sham-operated animals. A quantitative analysis showed that COI mRNA expression was increased in the zona incerta ipsilateral to the lesion 24 h and 3 days after lesion, but by day 14 had returned almost to the level observed in controls. The hyperactivity of zona incerta neurons was confirmed by single-unit electrophysiological recordings. In contrast to the COI mRNA expression, the increase in electric neuronal activity was still observed 1 month after the lesion. This increase in zona incerta neuronal activity after nigrostriatal denervation might be related to the pathophysiology of parkinsonism, at least in the early stages, in agreement with previous reports suggesting an involvement of the zona incerta in motor functions.

Action Potentials↗
PubMed2000

Expression of Trk isoforms in brain regions and in the striatum of patients with Alzheimer's disease.

The TrkAII tyrosine kinase receptor differs from the TrkAI isoform by an insertion of six amino acids in the extracellular domain. We used RT-PCR to determine their respective distribution in rat and human brain. Only trkAII transcripts were detected in 12 rat brain regions, while both trkAI and trkAII transcripts were detected in the cerebellum and pituitary gland. In human, both trkAI and trkAII transcripts were detected in the frontal, temporal, and occipital cortex and thalamus, while only trkAI transcripts were detected in the hippocampus and cerebellum. In the caudate and putamen, trkAII transcripts were exclusively detected. Thereafter, we studied the expression of TrkA isoforms in the striatum of five patients with Alzheimer's disease (AD), four patients with non-AD dementia, seven patients with Parkinson's disease, and six paired nondemented elderly control individuals. In controls and non-AD patients, a constant expression of trkAII transcripts was detected within all striatum parts. In AD patients, a heterogeneous decrease in trkAII expression was observed in the caudate, putamen, and ventral striatum, resulting either in a drop of trkAII transcript levels or in a weak coamplification of trkAII and trkAI transcripts. The alteration of TrkAII gene expression paralleled those of choline acetyltransferase. Together with previous data, this suggests that the alteration of trk gene expression could contribute to a decrease in NGF binding sites and its protective effects on cholinergic neurons of AD patients.

Adult↗
PubMed2000

How patients with Parkinson's disease retrieve and manage cognitive event knowledge.

Several studies have pointed out that basal ganglia are involved in adaptive control of action at both motor and cognitive level. This study aimed to investigate how basal ganglia retrieve and manage script event knowledge required in planning behavior. Script event knowledge was investigated in patients with Parkinson's Disease using three kinds of activity that differed in familiarity. Unlike patients with prefrontal lesions, patients with Parkinson's Disease were able to order events in a typical sequence and obeyed the boundaries and hierarchies between events. In contrast, patients with Parkinson's Disease were impaired in evaluating how important each script event was within the context of goal-oriented planning activity. Our findings indicate that the prefrontal cortex and the basal ganglia are differentially involved in planning. The role of the basal ganglia might consist in providing a feedback about the goodness of each action while building up meaningful sequences of events during learning.

Adult↗
PubMed2000

Metabolic activity of excitatory parafascicular and pedunculopontine inputs to the subthalamic nucleus in a rat model of Parkinson's disease.

Using a combination of metabolic measurement and retrograde tracing, we show that the neurons in the pedunculopontine nucleus and parafascicular nucleus of the thalamus that project to the subthalamic nucleus are hyperactive after nigrostriatal dopaminergic denervation in rats. In Parkinson's disease, the loss of dopaminergic neurons induces a cascade of functional changes in the basal ganglia circuitry including a hyperactivity of the subthalamic nucleus. This hyperactivity is thought to be due to a diminution of the inhibitory pallidal influence. However, recent studies have suggested that other cerebral structures are involved in the subthalamic neuronal hyperactivity. This study was undertaken to identify these cerebral structures. Neurons projecting to the subthalamic nucleus were identified by retrograde transport of wheat germ agglutinin conjugated to horseradish peroxidase, injected into the subthalamic nucleus of rats with 6-hydroxydopamine unilateral lesion of the substantia nigra pars compacta and sham-lesioned animals. Metabolic activity was determined in the same neurons using in situ hybridization for the first subunit of cytochrome oxidase messenger RNA, a metabolic marker, and image analysis. Horseradish peroxidase-labeled neurons were found in the globus pallidus, parafascicular and pedunculopontine nucleus and sometimes in raphe nuclei and the substantia nigra pars compacta. Measurement of metabolic activity was performed for the globus pallidus, the pedunculopontine and parafascicular nuclei. The expression level of the first subunit of cytochrome oxidase messenger RNA in neurons projecting to the subthalamic nucleus was 62% higher in parafascicular neurons and 123% higher in pedunculopontine neurons in 6-hydroxydopamine-lesioned rats, compared to sham-lesioned animals. An increase was also observed in the globus pallidus, but did not reach significance. Our results suggest that hyperactivity of subthalamic neurons could be due, at least in part, to an increase of excitatory input arising from the pedunculopontine and parafascicular nuclei. These data also suggest that the latter structures may play an important role in the physiopathology of Parkinson's disease.

Animals↗
PubMed2000

Functional mapping of the human globus pallidus: contrasting effect of stimulation in the internal and external pallidum in Parkinson's disease.

Our objective was to elaborate a functional map of the globus pallidus by correlating the intrapallidal localization of quadripolar electrodes implanted in parkinsonian patients with the clinical effect of the stimulation of each contact. Five patients with L-DOPA-responsive Parkinson's disease presenting severe motor fluctuations and L-DOPA-induced dyskinesias were treated by continuous bilateral high-frequency stimulation of the globus pallidus. The effects of stimulation on parkinsonian disability were tested through each of the four stimulating contacts of each electrode. The anatomical localization of each of the stimulating contacts was determined by confronting the pre- and post-operative magnetic resonance imaging with the anatomical atlas of Schaltenbrand and Wharen.(34) The registration procedure comprised digitization of the atlas, the use of deformation tools to fit atlas sections with magnetic resonance imaging sections, and three-dimensional reconstruction of both the atlas and the magnetic resonance imaging sections. Analysis of the 32 stimulating contacts tested did not reveal a somatotopic organization in the pallidal region investigated but demonstrated that high-frequency stimulation had contrasting effects depending on whether it was applied to the external or the internal pallidum. Akinesia was improved by stimulation of the external pallidum but worsened by stimulation of the internal pallidum. In contrast, parkinsonian rigidity was improved by stimulation of either part of the pallidum. The areas in the internal pallidum where stimulation worsened akinesia were those in which stimulation reduced or suppressed L-DOPA-induced dyskinesias. Conversely, stimulation applied to the external pallidum induced dyskinesias. The fact that rigidity was improved by stimulation of the internal and external pallidum suggests that the neuronal bases of parkinsonian rigidity are different from those of akinesia and dyskinesias. The effect on akinesia and dyskinesias is in agreement with the current model of basal ganglia circuitry(10) if high-frequency stimulation activates rather than inhibits pallidal neurons, a possibility which is very likely since there are marked anatomical, biochemical and electrophysiological differences between the globus pallidus and the subthalamic nucleus. This study demonstrates that high-frequency stimulation of the globus pallidus in parkinsonian patients has contrasting effects depending on whether it is applied to the external or the internal part of this nucleus. The effect on akinesia and dyskinesias suggests that stimulation activates pallidal neurons, a result which challenges the generally accepted concept that high-frequency stimulation inactivates neurons in the region stimulated.

Adult↗
PubMed2000

Metabolic effects of nigrostriatal denervation in basal ganglia.

In the past, functional changes in the circuitry of the basal ganglia that occur in Parkinson's disease were primarily analyzed with electrophysiological and 2-deoxyglucose measurements. The increased activity of the subthalamic nucleus (STN) observed has been attributed to a reduction in inhibition mediated by the external segment of the globus pallidus (GPe), secondary to the loss of dopaminergic-neuron influence on D2-receptor-bearing striato-pallidal neurons. More recently, in situ hybridization studies of cytochrome oxidase subunit I have confirmed the overactivity of the STN in the parkinsonian state. In addition, this technique has provided evidence that the change in STN activity is owing not only to decreased inhibition from the GPe but to hyperactivity of excitatory inputs from the parafascicular nucleus of the thalamus and the pedunculopontine nucleus in the brainstem.

Basal Ganglia↗