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Yves Agid

Publications and source records attributed to Yves Agid.

At least 37 records · Page 2Linked to original sources
PubMed2004

Frequency and phenotypic spectrum of ataxia with oculomotor apraxia 2: a clinical and genetic study in 18 patients.

Ataxia with oculomotor apraxia type 2 (AOA2) is a newly described autosomal recessive cerebellar ataxia (ARCA) defined by genetic location to 9q34 of three families sharing gait ataxia, oculomotor apraxia and/or elevated alpha-foetoprotein (AFP) levels. We have evaluated 77 families with progressive non-Friedreich ARCA and have identified six families with a phenotype suggestive of AOA2. Linkage was confirmed in all six families, with a maximal lod score of 5.91 at D9S1830. We report the first detailed phenotypic study, including neuropsychological, oculographic and brain imaging investigations, in the largest series of AOA2 patients yet recruited. The mean age at onset was 15.1 +/- 3.8 years. Sensory motor neuropathy (92%) and choreic or dystonic movements (44%) were frequent. Oculomotor apraxia was observed in 56% of patients and characterized by increased horizontal saccade latencies and hypometria. AFP levels were elevated in 100% of the families, making it a useful biological marker. This study shows for the first time that AOA2 can be found in Europe, North Africa and the West Indies, and its relative frequency represents approximately 8% of non-Friedreich ARCA, which is more frequent than ataxia telangiectasia and ataxia with oculomotor apraxia type 1 (AOA1), in our series of adult patients. In adults, AOA2 may be, therefore, the most frequent cause of ARCA identified so far, after Friedreich's ataxia.

Adolescent↗
PubMed2004

Effects of high-frequency stimulation on subthalamic neuronal activity in parkinsonian patients.

BACKGROUND: High-frequency stimulation of the subthalamic nucleus (STN) is a neurosurgical alternative to medical treatment in levodopa-responsive forms of Parkinson disease. The mechanism of action of STN stimulation remains controversial, although an inhibition of overactive STN neurons has been postulated. OBJECTIVE: To determine the effects of high-frequency STN stimulation on the neuronal activity of STN neurons in Parkinson disease patients. PATIENTS: Single-unit recordings of the neuronal activity of the STN were obtained before, during, and after the application of intra-STN electrical stimulation in 15 Parkinson disease patients. Changes in firing frequency and pattern were analyzed using various combinations of stimulus frequency (range, 14-140 Hz). RESULTS: Stimulation at a frequency greater than 40 Hz applied within the STN significantly decreased the firing frequency and increased the burst-like activity in the firing pattern of STN neurons. An aftereffect was observed in cells that had been totally inhibited during high-frequency stimulation. CONCLUSION: The beneficial effects of high-frequency stimulation result from a change in the firing pattern of cellular discharge and a blockade of the spontaneous overactivity of STN neurons.

Aged↗
PubMed2004

Subthalamic stimulation in Parkinson disease: with or without anesthesia?

OBJECTIVE: To study the effects of general anesthesia on the postoperative outcome of patients with Parkinson disease (PD) who underwent surgery using bilateral placement of stimulating electrodes within the subthalamic nucleus (STN). DESIGN: Retrospective analysis. SETTING: Hôpital de la Salpêtrière, Paris, France. PATIENTS: Fifteen PD patients who underwent bilateral implantation of electrodes within the STN received general anesthesia because of severe anxiety, poorly tolerated off-period dystonia, or respiratory difficulties. These patients were compared with 15 patients matched for age, disease duration, and parkinsonian motor disability who underwent the same neurosurgical procedure under local anesthesia. MAIN OUTCOME MEASURE: Motor disability scores. RESULTS: After surgery, the severity of parkinsonian motor disability was markedly improved in both groups of patients. Compared with patients who were under local anesthesia during the operation, the residual parkinsonian motor score under stimulation (with ["on"] or without ["off"] levodopa) and the intensity of stimulation were higher in patients who were under general anesthesia during the operation. CONCLUSIONS: Although the improvement of parkinsonian motor disability is greater in PD patients who receive local anesthesia during surgery, general anesthesia can be performed in patients unable to tolerate prolonged states without levodopa.

Aged↗
PubMed2004

Subthalamic nucleus stimulation reduces abnormal motor cortical overactivity in Parkinson disease.

BACKGROUND: Based on the basal ganglia model, it has been hypothesized that the efficacy of high-frequency stimulation of the subthalamic nucleus (STN) against parkinsonian symptoms relies on the activation of cortical premotor regions. In previous positron emission tomography activation studies, STN high-frequency stimulation was associated with selective activation of midline premotor areas during hand movements but mainly reduced the regional cerebral blood flow in movement-related areas, peculiarly at rest. OBJECTIVE: To investigate with positron emission tomography the role of regional cerebral blood flow reduction in the clinical improvement provided by STN high-frequency stimulation. METHODS: Seven patients with advanced Parkinson disease, who were markedly improved by bilateral STN high-frequency stimulation, underwent positron emission tomography with H2(15)O while the right STN electrode was turned off. The patients were studied at rest and during right-hand movements in 3 electrode conditions: no stimulation, inefficient low-frequency stimulation, and efficient high-frequency stimulation. RESULTS: The main effect of high-frequency stimulation was to reduce regional cerebral blood flow in the left primary sensorimotor cortex, the lateral premotor cortex, the right cerebellum, and the midline premotor areas. The selective activation of the anterior cingulate cortex and the left primary sensorimotor cortex during hand movement under STN high-frequency stimulation was attributed to decreased regional cerebral blood flow at rest, rather than increased activation induced by STN high-frequency stimulation. Akinesia was correlated with the abnormal overactivity in the contralateral primary sensorimotor cortex and the ipsilateral cerebellum. CONCLUSION: High-frequency stimulation of the STN acts through the reduction of abnormal resting overactivity in the motor system, allowing selective cortical activation during movement.

Aged↗
PubMed2004

Levodopa in the treatment of Parkinson's disease: current controversies.

Levodopa is the most effective symptomatic agent in the treatment of Parkinson's disease (PD) and the "gold standard" against which new agents must be compared. However, there remain two areas of controversy: (1) whether levodopa is toxic, and (2) whether levodopa directly causes motor complications. Levodopa is toxic to cultured dopamine neurons, and this may be a problem in PD where there is evidence of oxidative stress in the nigra. However, there is little firm evidence to suggest that levodopa is toxic in vivo or in PD. Clinical trials have not clarified this situation. Levodopa is also associated with motor complications. Increasing evidence suggests that they are related, at least in part, to the short half-life of the drug (and its potential to induce pulsatile stimulation of dopamine receptors) rather than to specific properties of the molecule. Treatment strategies that provide more continuous stimulation of dopamine receptors provide reduced motor complications in MPTP monkeys and PD patients. These studies raise the possibility that more continuous and physiological delivery of levodopa might reduce the risk of motor complications. Clinical trials to test this hypothesis are underway. We review current evidence relating to these areas of controversy.

Antiparkinson Agents↗
PubMed2004

Is the subthalamic nucleus hypointense on T2-weighted images? A correlation study using MR imaging and stereotactic atlas data.

BACKGROUND AND PURPOSE: Although the subthalamic nucleus is the most frequently used target for surgical treatment of Parkinson's disease, the criteria on which it can be identified on T2-weighted images have never been clearly defined. This study was conducted to characterize the precise anatomic distribution of T2-weighted hyposignal in the subthalamic region and to correlate this hyposignal with iron content in the subthalamic nucleus. METHODS: The T2-weighted MR imaging acquisitions of 15 patients with Parkinson's disease were fused with a digitized version of the Schaltenbrand and Wahren anatomic atlas. The MR signal intensity within the anatomic limits of the subthalamic nucleus was evaluated. An anatomic specimen obtained at autopsy was used to evaluate iron content. RESULTS: In all patients, the subthalamic nucleus was hypointense on both sides in the anterior half of the nucleus. At more posterior levels of the nucleus, hypointensity was less frequently observed (20-80%). Hypointensity was never observed at the most posterior pole. Iron was present in the anteromedial part of the nucleus but absent at the most posterior levels. CONCLUSION: The hypointense signal intensity located lateral to the red nucleus and dorsolateral to the substantia nigra correlates with the presence of iron and corresponds anatomically to the subthalamic nucleus. It can therefore be used as a landmark for electrode implantation in patients with Parkinson's disease. It should, however, be emphasized that although hypointensity was always present in the anterior half of the subthalamic nucleus, the posterior part of the nucleus was not visible in most cases.

Adult↗
PubMed2003

Distribution of codon 129 genotype in human growth hormone-treated CJD patients in France and the UK.

Since homozygosity MM at codon 129 of the prion protein gene is a recognised risk factor in all forms of Creutzfeldt-Jakob disease (CJD), we studied the distribution of codon 129 polymorphism in patients in France and in the UK with CJD transmitted iatrogenically by human growth hormone. The overall frequencies of codon 129 genotypes in these patients differed from those in the population unaffected by CJD. An excess of VV homozygotes was noted among those with iatrogenic CJD compared with sporadic CJD cases. The proportion of MM genotype in UK patients was surprisingly low (4%) compared with that in French patients (62%). There is no evident explanation for this different distribution, which might be due to infection with different strains of prion in human growth hormone.

Codon↗
PubMed2003

Subthalamic stimulation in Parkinson disease: intraoperative predictive factors.

BACKGROUND: High-frequency stimulation of the subthalamic nucleus (STN) is an effective treatment for advanced forms of Parkinson disease. Postoperative improvement of motor parkinsonian disability is known to depend on patient selection and surgical targeting. OBJECTIVE: To determine which clinical and electrophysiological variables evaluated during the operation predict the postoperative clinical outcome of patients with Parkinson disease treated by bilateral high-frequency stimulation of the STN. METHODS: Intraoperative clinical and electrophysiological data obtained in 41 patients with Parkinson disease who underwent bilateral implantation of electrodes for STN stimulation were correlated with the improvement in parkinsonian disability assessed 6 months after the operation. RESULTS: The extent of STN neuronal activity recorded along the trajectory of the therapeutic electrode had no effect on the postoperative clinical outcome. The intraoperative improvement in segmental akinesia, but not rigidity, was predictive of the postoperative improvement in parkinsonian motor disability and reduction in daily levodopa-equivalent dosage. Parkinsonian motor disability scores assessed after surgery were lower in patients with intraoperative stimulation-induced dyskinesias than in those without stimulation-induced dyskinesias. CONCLUSION: The improvement of segmental akinesia and the observation of dyskinesias provoked by stimulation during the operation predict the best postoperative effects of bilateral STN stimulation on parkinsonian motor disability.

Disability Evaluation↗
PubMed2003

Young-onset Parkinson disease with and without parkin gene mutations: a fluorodopa F 18 positron emission tomography study.

BACKGROUND: Mutations of the parkin gene are frequently encountered in patients with young-onset Parkinson disease (YOPD), but the effects of this mutation on the nigrostriatal dopaminergic degeneration are not well established. OBJECTIVE: To analyze, using positron emission tomography and fluorodopa F 18, the severity and profile of striatal dopaminergic metabolism in YOPD patients with and without parkin gene mutations. METHODS: We performed positron emission tomography with fluorodopa F 18 in 19 YOPD patients with parkin gene mutations (parkin patients), 6 YOPD patients without parkin gene mutations (nonparkin patients), and 9 healthy controls. Putamen and caudate nucleus fluorodopa F 18 uptake was assessed using regions of interest analysis. RESULTS: In parkin patients, the striatal fluorodopa F 18 uptake reduction was 36.3%, 51.3%, and 66.7%, respectively, for the caudate nucleus, anterior putamen, and posterior putamen compared with controls. In nonparkin patients, this reduction was 23.0%, 43.6%, and 73.0%, respectively. This reduction was asymmetrical according to the most affected hemibody for the anterior and posterior putamen in parkin patients and for the posterior putamen in nonparkin patients. A rostrocaudal gradient was observed with a severe decrease in fluorodopa F 18 uptake in the putamen and relative sparing of the caudate nucleus. There was no significant difference of striatal fluorodopa F 18 uptake between our 2 YOPD populations. In parkin patients, no significant correlation was found among fluorodopa F 18 uptake, motor disability, and the type of mutations. In nonparkin patients, there was a significant correlation between fluorodopa F 18 uptake and clinical severity. CONCLUSIONS: The pattern of fluorodopa F 18 uptake in the striatum of YOPD patients is similar to that of patients with idiopathic Parkinson disease and does not depend on the presence or absence of mutations of the parkin gene.

Adolescent↗
PubMed2003

Coding polymorphisms in the parkin gene and susceptibility to Parkinson disease.

BACKGROUND: Mutations in the parkin gene, an E3 protein-ubiquitin ligase, cause autosomal recessive early-onset Parkinson disease (PD). The role of polymorphisms in the parkin gene as risk factors for PD is still unclear, as the results in the literature are contradictory. PATIENTS: We compared the allele and genotype frequencies of the Ser167Asn, Arg366Trp, Val380Leu, and Asp394Asn polymorphisms in 194 patients with PD (92 familial and 102 sporadic) and 125 control subjects. RESULTS: Homozygous Val380 was significantly associated with sporadic PD (P =.008). There was also a trend toward an association of homozygous Asp394 with familial PD (P =.07). CONCLUSIONS: Some parkin polymorphisms appear to be risk factors for sporadic or familial PD. The functional effects of these coding polymorphisms need to be established, and further studies on parkin polymorphisms in PD should be undertaken.

Adult↗
PubMed2003

How much phenotypic variation can be attributed to parkin genotype?

To establish phenotype-genotype correlations in early-onset parkinsonism, we have compared the phenotype of a large series of 146 patients with and 250 patients without parkin mutations. Although no single sign distinguished the groups, patients with mutations had significantly earlier and more symmetrical onset, dystonia more often at onset and hyperreflexia, slower progression of the disease, and a tendency toward a greater response to levodopa despite lower doses. After forward stepwise multiple logistic regression analysis, dystonia at onset and brisk reflexes were not longer significantly different but were correlated with age at onset rather than the presence of the parkin mutation. Age at onset in carriers of parkin mutations varied as did the rate of progression of the disease: the younger the age at onset the slower the evolution. The genotype influenced the phenotype: carriers of at least one missense mutation had a higher United Parkinson's Disease Rating Scale motor score than those carrying two truncating mutations. The localization of the mutations was also important because missense mutations in functional domains of parkin resulted in earlier onset. Patients with a single heterozygous mutation had significantly later and more asymmetrical onset and more frequent levodopa-induced fluctuations and dystonia than patients with two mutations.

Adolescent↗
PubMed2003

Multiple sclerosis tremor and the Stewart-Holmes manoeuvre.

The objective of this study is to define tremor and cerebellar dysfunction and determine whether kinetic and postural tremor correlate with cerebellar dysfunction in patients with multiple sclerosis (MS). Cerebellar symptoms such as dysmetria often interfere with tremor evaluation in MS. The Stewart-Holmes (SH) manoeuvre, which has been recently quantified, may offer a selective evaluation of cerebellar dysfunction in such patients. Thirty-two patients with definite MS and arm tremor were evaluated (simplified Fahn tremor scale for kinetic and postural tremor, finger-to-nose test, clinical SH manoeuvre, quantitative study of the SH manoeuvre). Median severity of kinetic and postural tremor on the most disabled side was, respectively, 2 (range 0-4) and 1.5 (range 0-4). Clinical SH scores were moderately correlated to quantified SH measures (r = 0.36, P < 0.05). Kinetic and postural tremors were strongly correlated (r = 0.73, P < 0.0001) but did not correlate with clinical or quantified SH scores. Patients with bilateral tremor had higher scores for quantified SH, and a trend to higher clinical SH and finger-to-nose scores than patients with unilateral tremor. Although clinically associated, cerebellar dysfunction and tremor may be partly independent symptoms, suggesting they may relate to dysfunction of different neuronal systems. The SH manoeuvre should be part of the evaluation of MS patients considered for surgery of tremor.

Adult↗
PubMed2003

Parkinson's disease, subthalamic stimulation, and selection of candidates: a pathological study.

We report on a patient with Parkinson's disease (PD) who was moderately improved by stimulation of the subthalamic nucleus (STN) and died 2 years after electrode implantation. After neurosurgery, symptoms that had responded to levodopa treatment preoperatively continued to improve. Postural instability, dysarthria, and cognitive impairment continued to worsen, despite STN stimulation and levodopa treatment. Postmortem examination of the brain confirmed the diagnosis of PD and showed that the electrodes had been correctly positioned within the STN. The failure of STN stimulation in this patient confirms the importance of screening and excluding patients from surgery with evolving parkinsonian axial symptoms or cognitive impairment.

Aged↗
PubMed2003

Neuromelanin associated redox-active iron is increased in the substantia nigra of patients with Parkinson's disease.

Degeneration of dopaminergic neurones during Parkinson's disease is most extensive in the subpopulation of melanized-neurones located in the substantia nigra pars compacta. Neuromelanin is a dark pigment produced in the dopaminergic neurones of the human substantia nigra and has the ability to bind a variety of metal ions, especially iron. Post-mortem analyses of the human brain have established that oxidative stress and iron content are enhanced in association with neuronal death. As redox-active iron (free Fe2+ form) and other transition metals have the ability to generate highly reactive hydroxyl radicals by a catalytic process, we investigated the redox activity of neuromelanin (NM)-aggregates in a group of parkinsonian patients, who presented a statistically significant reduction (- 70%) in the number of melanized-neurones and an increased non-heme (Fe3+) iron content as compared with a group of matched-control subjects. The level of redox activity detected in neuromelanin-aggregates was significantly increased (+ 69%) in parkinsonian patients and was highest in patients with the most severe neuronal loss. This change was not observed in tissue in the immediate vicinity of melanized-neurones. A possible consequence of an overloading of neuromelanin with redox-active elements is an increased contribution to oxidative stress and intraneuronal damage in patients with Parkinson's disease.

Aged↗
PubMed2003

Parkin mutations are frequent in patients with isolated early-onset parkinsonism.

Parkin gene mutations are reported to be a major cause of early-onset parkinsonism (age at onset < or = 45 years) in families with autosomal recessive inheritance and in isolated juvenile-onset parkinsonism (age at onset <20 years). However, the precise frequency of parkin mutations in isolated cases is not known. In order to evaluate the frequency of parkin mutations in patients with isolated early-onset parkinsonism according to their age at onset, we studied 146 patients of various geographical origin with an age at onset < or = 45 years. All were screened for mutations in the parkin gene using semi-quantitative polymerase chain reaction combined with sequencing of the entire coding region. We identified parkin mutations in 20 patients including three new exon rearrangements and two new missense mutations. These results, taken in conjunction with those of our previous study (Lücking et al., 2000) show that parkin mutations account for at least 15% (38 out of 246) of our early-onset cases without family history, but that the proportion decreases significantly with increasing age at onset. There were no clinical group differences between parkin cases and other patients with early-onset parkinsonism. However, a single case presenting with cerebellar ataxia several years before typical parkinsonism extends the spectrum of parkin related-disease.

Adolescent↗