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Biomedical subjects

E Tolosa

Publications and source records attributed to E Tolosa.

At least 55 records · Page 3Linked to original sources
PubMed2001

Neuroprotection of striatal neurons against kainate excitotoxicity by neurotrophins and GDNF family members.

Neurotrophic factors are regarded as potential therapeutic tools in neurodegenerative disorders. Here, we analysed the protective effects of brain-derived neurotrophic factor, neurotrophin-3, glial cell line-derived neurotrophic factor and neurturin against the excitotoxic damage induced by kainate in striatal neurons in vitro and in vivo. Our results show that the decrease in the number of cultured striatal calbindin-positive neurons induced by kainate was prevented by treatment with any of these factors. To characterize their protective effects in vivo, cell lines overexpressing brain-derived neurotrophic factor, neurotrophin-3, glial cell line-derived neurotrophic factor or neurturin were grafted into the striatum. We found that the numbers of striatal projection neurons (calbindin-positive) and striatal interneurons (parvalbumin- or choline acetyltransferase-positive) were differentially decreased after kainate lesion. These neurotrophic factors prevented the loss of striatal projection neurons and interneurons with differing efficiency: brain-derived neurotrophic factor was the most efficient, whereas neurturin was the least. Our findings show that brain-derived neurotrophic factor, neurotrophin-3, glial cell line-derived neurotrophic factor and neurturin have specific neuroprotective profiles in striatal neurons and indicate that they are specific modulators of the survival of distinct subsets of striatal neurons in pathophysiological conditions.

Animals↗
PubMed2001

Examination of motor output pathways in patients with corticobasal ganglionic degeneration using transcranial magnetic stimulation.

The alien hand sign (AHS) is often encountered in patients with corticobasal ganglionic degeneration (CBGD), revealing a unilateral dysfunction of the motor system of unknown pathophysiology. We examined the possibility of an abnormal cortical representation of hand muscles in 10 patients with probable CBGD and a prominent AHS. Cortical maps were obtained from the responses to magnetic stimuli applied with a figure of eight coil at an intensity of 110% above motor threshold. For comparison, the same study was carried out in 10 normal volunteers, eight patients with Parkinson's disease and eight patients with Alzheimer's disease. AHS patients had a larger extension of the cortical map to stimulation of the hemisphere contralateral to the AHS in comparison with the ipsilateral hemisphere. Furthermore, in six patients, focal stimulation of the hemisphere ipsilateral to the AHS gave rise to ipsilateral responses, delayed by a mean of 7.7 +/- 2.2 ms with respect to those recorded in the same muscle to contralateral stimulation. None of the other patients or control subjects had ipsilateral responses. Our results indicate an enhanced excitability, or reduced inhibition, of the motor area of the hemisphere contralateral to the AHS. The delay of the ipsilateral responses is compatible with a disinhibited transcallosal input.

Aged↗
PubMed2001

Obsessive-compulsive symptoms in Parkinson's disease.

To systematically investigate obsessive-compulsive traits in Parkinson's disease, patients were administered the Maudsley obsessional-compulsive inventory (MOCI) and a modification of the Leyton obsessional inventory (LOI) to a sample of non-demented and non-depressed patients with Parkinson's disease. Patients with severe Parkinson's disease showed more obsessive traits than normal controls in MOCI and LOI total scores, and in the "checking", "doubting", and "cleaning" subscales of the MOCI. By contrast, patients with mild disease did not differ from controls. A significant correlation was found between severity and duration of illness and MOCI total score. These results support the involvement of basal ganglia in obsessive-compulsive symptomatology. As patients with mild Parkinson's disease did not differ from controls, obsessive-compulsive disorder does not seem to be directly related to the initial nigrostriatal dopaminergic deficiency which causes clinical Parkinson's disease symptomatology. The appearance of obsessive symptoms could be related to the subset of neurochemical changes taking place at the level of the basal ganglia circuitry as disease progresses.

Female↗
PubMed2001

MRI atrophy parameters related to cognitive and motor impairment in Parkinson's disease.

BACKGROUND: Patients with Parkinson's disease (PD) show specific neuropsychological deficits in attention, memory, visuospatial or frontal lobe functions, which can arise from degeneration of different cerebral structures. OBJECTIVE: The aim of the present study was to analyze the role of focal degeneration (basal ganglia and substantia nigra) and diffuse cerebral atrophy (ventricular enlargement) in motor/cognitive impairment in PD. PATIENTS AND METHODS: We administered to 14 patients with advanced PD the following tests: Purdue Pegboard, Rey's Auditory-Verbal Learning test (RAVLT), Benton's Line Orientation, Trail Making, phonemic verbal fluency and Stroop test. Ventricular system, caudate and putamen nuclei and pars compacta of the substantia nigra were quantitatively measured by magnetic resonance imaging. Correlation analyses were carried out. RESULTS: The results showed that ventricular enlargement is negatively correlated with the performance on RAVLT and Stroop test. No relationship was found between caudate atrophy and cognitive deficits. Degeneration of putamen nucleus was found to be associated with motor deficits. CONCLUSION: Memory and frontal impairment are related to diffuse cerebral degeneration and the motor deficit is related to degeneration of the putamen nucleus.

Aged↗
PubMed2000

Continuous positive air pressure eliminates nocturnal stridor in multiple system atrophy. Barcelona Multiple System Atrophy Study Group.

We prospectively studied the sleep patterns and laryngeal function of 20 patients with multiple system atrophy and found sleep disturbances in all subjects and vocal cord abduction dysfunction in 14 (70%). In three patients with nocturnal stridor and complete vocal cord abductor dysfunction, continuous positive airways pressure eliminated laryngeal stridor, obstructive apnoea, and haemoglobin desaturation.

Female↗
PubMed2000

A new mutation in the parkin gene in a patient with atypical autosomal recessive juvenile parkinsonism.

We have investigated the presence of mutations in the parkin gene in patients with early-onset parkinsonism. Direct sequencing of the polymerase chain reaction (PCR) products showed a homozygous G deletion in the exon 7 (c.871delG) in one patient. This was a 38-year-old Moroccan woman with a history of parkinsonism of 18 years of duration. The disease appeared as an apparently sporadic case and was characterized by dystonia of the legs at onset and a rapid progression to severe generalized parkinsonism but with an excellent maintained response to dopamine agonists treatment. The deletion was a frameshift mutation resulting in a stop codon at position 297 which causes truncation of the parkin protein. Mutations in the parkin gene can be encountered in patients with an apparently sporadic early-onset parkinsonism, rapidly progressive course and marked and maintained response to dopamine agonists.

Adult↗
PubMed2000

Non-NMDA receptor-mediated mechanisms are involved in levodopa-induced motor response alterations in Parkinsonian rats.

Chronic dopaminomimetic administration to parkinsonian animal models or Parkinson's disease patients leads to characteristic alteration in motor response. Previous studies suggested that the nonphysiologic stimulation of dopaminergic receptors on striatal medium spiny neurons enhances the synaptic efficacy of juxtaposed glutamate receptors of the N-methyl-D-aspartate (NMDA) subtype. Resultant NMDA receptor sensitization due to differential changes in subunit phosphorylation appears to favor alterations in striatal output in ways that influence motor function. To detail the involvement of NMDA receptors further as well as to determine whether similar functional changes might develop in alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionate (AMPA) receptors, the effects of selective antagonist of AMPA receptors (6-nitro-7-sulfamoyl-benzo[f]-quinoxaline-2,3 (1H,4H)-dione sodium salt, NBQX, 10 mg/kg) on levodopa-induced response alterations in 6-hydroxydopamine (6-OHDA) lesioned rats were compared with drugs which act competitively (3-(+/-)-2-carboxypiperazin-4-yl)-propyl-1-phosphonicacid, CPP, 6.25 mg/kg) or noncompetitively (dextromethorphan, 40 mg/kg) to block NMDA receptors, or a nonselective inhibitor of glutamatergic transmission (2-amino-6-trifluoromethoxy benzothiazole, riluzole, 5 mg/kg). We found that the shortened duration of the motor response to levodopa, which underlies human wearing-off fluctuations, was reversed to a similar degree by the acute coadministration of CPP, NBQX, or riluzole (n = 4-6) but dextromethorphan did not. These observations strengthen the possibility that a reduction in levodopa-associated changes in motor response by inhibitors of glutamatergic transmission acting generally or selectively at the glutamate binding-sites may relate to their ability to attenuate pathologic gain in striatal glutamatergic function. The capacity of NBQX to reverse these altered responses suggests that an enhanced synaptic efficacy of striatal AMPA receptors may also participate in the generation of these motor response changes in levodopa-treated parkinsonian rats.

Animals↗
PubMed2000

[Efficacy and safety of posteroventral pallidotomy for the treatment of advanced Parkinson's disease].

OBJECTIVES: To analyze the results, efficacy and safety of unilateral microelectrode guided pallidotomy for the treatment of advanced Parkinson's disease, three months and one year after surgery. PATIENTS AND METHODS: 23 patients with advanced Parkinson's disease (mean age 58.9 years and mean disease duration 14.4 years) were submitted to pallidotomy. Neurological evaluation, three months (n = 23) and one year (n = 16) after surgery, was performed during the morning in overnight "off" condition and after receiving 100-150% of their usual l-dopa dose. Parkinsonian symptoms were evaluated in each follow up visit through motor scales, activities of daily living scales, a dyskinesia rating scale and motor timed tests. RESULTS: Contralateral dyskinesias improved 92% three months after surgery and 89% at one year. Parkinsonian motor scores were reduced by 36.5% after three months and by 26.7% one year after surgery. In the one year follow up visit, contralateral tremor improved 48%, rigidity 36.2% and bradykinesia 37.4%. All these changes were statistically significant (p < 0.01). Adverse effects were minor or transient. Antiparkinsonian medication dosage did not significantly change during the study period. CONCLUSION: Microelectrode guided unilateral pallidotomy is an effective and safe procedure to improve contralateral motor symptoms in Parkinson's disease, being specially useful for the treatment of l-dopa induced dyskinesias.

Aged↗
PubMed2000

Levodopa withdrawal after bilateral subthalamic nucleus stimulation in advanced Parkinson disease.

CONTEXT: Subthalamic nucleus (STN) stimulation may be effective in ameliorating parkinsonian symptoms even to the extent to permit levodopa withdrawal. OBJECTIVES: To analyze the efficacy of STN stimulation in patients with Parkinson disease (PD) and to determine if levodopa may be withdrawn after surgery. DESIGN: Before-after trial. SETTING: Referral center, hospitalized care. PATIENTS: Fifteen patients with advanced PD. INTERVENTIONS: Microelectrode-guided bilateral STN high-frequency stimulation. OUTCOME MEASURES: Before surgery patients were evaluated in off-medication and on-medication conditions. Dopaminergic drug dosages were reduced after surgery, aiming for complete withdrawal. Six months after surgery, patients were reeavaluated in off- and on-medication conditions, with the stimulation turned on and off. RESULTS: Total Unified Parkinson's Disease Rating Scale (UPDRS) motor score in the off-medication condition improved by 65.9%; and axial symptoms, bradykinesia, rigidity, and tremor improved by 65.8%, 60.4%, 66.1%, and 81.1%, respectively. UPDRS part II scores were reduced by 71.8% and Schwab and England scores improved by 45.3%. Levodopa was withdrawn in 8 patients and the overall levodopa dose was reduced 80.4%. "Off" time was reduced 89.7% and the severity of dyskinesias decreased 80.6% after surgery. All results reached significance (P<.001). Stimulation of the STN achieved antiparkinsonian effect similar to that of treatment with levodopa. No life-threatening adverse effects occurred. CONCLUSIONS: Bilateral STN stimulation safely improves all parkinsonian symptoms, decreases or eliminates the need for levodopa, and ameliorates motor fluctuations and dyskinesias. Complete withdrawal of levodopa is feasible with this technique and the overall motor effect of STN stimulation is quantitatively comparable to that obtained with levodopa.

Aged↗
PubMed2000

Pallidotomy and quality of life in patients with Parkinson's disease: an early study.

The purpose of this study was to analyze the effect of stereotactic neurophysiologically guided pallidotomy on health-related quality of life (QoL) of patients with Parkinson's disease (PD). Eleven patients with PD (seven men, four women; mean age, 57.2 years; mean duration of disease, 14 years) with motor complications refractory to medical therapy underwent unilateral pallidotomy. Clinical assessment was carried out a week before surgery and 4 months after the surgical procedure and was based on the Core Assessment Program for Intracerebral Transplantations protocol. QoL was measured by means of the PDQ-39. A set of rating scales (Hoehn & Yahr, Unified Parkinson's Disease Rating Scale, Schwab and England, Northwestern University Disability Scale of Walking, Abnormal Involuntary Movement Scale), timed tests, and self-evaluations of motor function and mood were applied. Improvement was found in dyskinesias (74%) and off-period disability (42%). Cardinal motor signs improved significantly (30%-59%). Four dimensions of the PDQ-39 (Mobility, ADL, Emotions, Bodily Pain) showed a significant improvement (p <0.01-0.001). The global effect on QoL, measured through the PDQ-39 Summary Index (35.3%; 95% confidence interval: 15.60-54.97), was also significant (p<0.01) but unrelated to major clinical changes. Pallidotomy significantly improves QoL in patients with advanced PD. QoL measurement provides relevant information that is probably not attainable by clinical assessment.

Aged↗
PubMed2000

Progressive supranuclear palsy: earlier age of onset in patients with the tau protein A0/A0 genotype.

Genetic studies have detected an association between the presence of the tau gene A0 allele and patients with progressive supranuclear palsy (PSP). This study examined whether patients with this polymorphism exhibit distinct demographic or clinical characteristics. We studied 26 patients who fulfilled clinical criteria for the diagnosis of PSP, 20 who had the A0/A0 genotype and 6 who had other genotypes. A questionnaire on demographic data, past medical history, familial history, and initial symptoms was completed as part of the consultation. A complete neurological examination was performed and PSP symptoms were quantified following Golbe's PSP disability scale. We found a significant difference in the age at onset of PSP symptoms, which was 65.9 +/- 5.3 years in the A0/A0 group and 71.2 +/- 5.6 in the non-A0/A0 group (P = 0.016). There were no significant differences in the years from disease onset between the two groups. Symptom severity did not differ significantly in patients with the different A0/A0 genotypes. The detection of significantly lower age at onset with the A0/A0 alleles is consistent with the known association of this genotype as a risk factor for PSP. No significant differences were detected in symptom severity between the two groups of patients.

Age of Onset↗
PubMed2000

Effects of unilateral posteroventral pallidotomy on 'on-off' cognitive fluctuations in Parkinson's disease.

In Parkinson's disease, cognitive performance can vary according to levodopa levels (on-off states). Both positive and negative effects of dopaminergic stimulation have been reported. Pallidotomy is also able to change cognitive performance, in addition to levodopa pharmacokinetics. The aim of this investigation was to study the effects of pallidotomy on cognitive on-off fluctuations in Parkinson's disease. A brief neuropsychological battery was administered to 15 PD patients during on and off states before and after surgery. Before pallidotomy, patients performed better in the on condition on Trail Making test B; after pallidotomy levodopa no longer improved performance, and the interaction between surgery and state was significant. In relation to the difference between preoperative and postoperative performance in Trail Making B test, there was a significant postsurgical improvement only in off state. Verbal fluency decreased after pallidotomy in both on and off conditions. Our results suggest that pallidotomy can change the effects of levodopa on neuropsychological functions.

Aged↗
PubMed2000

Neurturin protects striatal projection neurons but not interneurons in a rat model of Huntington's disease.

Glial cell line-derived neurotrophic factor and neurturin are neurotrophic factors expressed in the striatum during development and in the adult rat. Both molecules act as target-derived neurotrophic factors for nigrostriatal dopaminergic neurons. While glial cell line-derived neurotrophic factor has also been described to have local trophic effects on striatal neurons, the effects of neurturin in the striatum have not yet been described. Here we examine whether neurturin protects striatal projection neurons (calbindin-positive) and interneurons (parvalbumin- or choline acetyltransferase-positive) in an animal model of Huntington's disease. A fibroblast cell line engineered to over-express neurturin was grafted into adult rat striatum 24h before quinolinate injection. In animals grafted with a control cell line, intrastriatal quinolinate injection reduced the number of calbindin-, parvalbumin- and choline acetyltransferase-positive neurons, seven days post-lesion. Intrastriatal grafting of neurturin-secreting cells protected striatal projection neurons, but not interneurons, from quinolinate excitotoxicity. This effect was much more robust than that reported previously for a glial cell line-derived neurotrophic factor-secreting cell line on striatal calbindin-positive neurons. However, intrastriatal grafting of glial cell line-derived neurotrophic factor- but not neurturin-secreting cells prevented the decrease in choline acetyltransferase activity induced by quinolinate injection. Taken together, our results show that neurturin- and glial cell line-derived neurotrophic factor-secreting cell lines have clearly differential effects on striatal neurons. Grafting of the neurturin-secreting cell line showed a more specific and efficient trophic effect on striatal projection neurons, the neuronal population most affected in Huntington's disease. Therefore, our results suggest that neurturin is a good candidate for the treatment of this neurodegenerative disorder.

Animals↗
PubMed2000

Significant association between the tau gene A0/A0 genotype and Parkinson's disease.

A significant association between the tau gene A0/A0 genotype and progressive supranuclear palsy has been reported recently. To determine if the presence of a tau polymorphism could constitute a risk factor for the development of sporadic and familial Parkinson's disease, a dinucleotide repeat marker at intron 11 was genotyped in 152 patients with PD, 52 patients with Alzheimer's disease, and 150 healthy controls. We detected a significant difference in A0 allelic frequency in the Parkinson's disease group (79.27%) compared with the control group (71%) and the Alzheimer's disease group (73.07%). Individuals homozygous for the A0 allele were also detected significantly more frequently in the Parkinson's disease group (63.8%) compared with the control group (52.66%) and the Alzheimer's disease group (48.07%). These results suggest a possible involvement of the tau gene in the pathogenesis of some cases of Parkinson's disease.

Aged↗
PubMed1999

Identification of a novel polymorphism in the promoter region of the tau gene highly associated to progressive supranuclear palsy in humans.

An intronic polymorphism and other changes in the transcribed region of the tau gene forming a haplotype have been previously described associated to progressive supranuclear palsy (PSP). These results raised the possibility that a change at or near the tau gene could be responsible for an increased risk to develop PSP. We initiated the present work in research for potential changes in the promoter region of the tau gene that could further extend the previously described haplotype. The tau promoter region was analyzed through single strand conformation polymorphism followed by direct sequencing in PSP patients (n = 35), in controls (n = 195) and in Alzheimer's disease (AD; n = 74) patients. We have been able to identify a G to C change at position -221 of the tau gene promoter region. The CC genotype has been detected to be present with a significantly higher frequency in PSP patients (91.4%; P < 0.00001; OR = 11.8), but not in AD patients, as compared with controls (49.74%). Subsequently we have detected that the CC -221 tau promoter genotype is significantly associated to the tau intronic A0/A0 genotype (P < 0.00001). The detected -221 tau G to C change occurs within a potential c-myb proto-oncogene element present in the promoter region. Thus, in addition to extending the previously described haplotype associated to PSP, this -221 G to C change is an interesting candidate that could provide a potential explanation for the association of the haplotype to increased risk for developing PSP.

Base Sequence↗
PubMed1999

Dopamine receptor D2 intronic polymorphism in patients with Parkinson's disease.

An association between the intronic allele 3 of the dopamine receptor D2 (DRD2) gene and European Parkinson's disease (PD) cases has been reported recently. We initiated the present work in order to determine whether this association between the DRD2 locus and PD is also present in our population from Spain. The DRD2 gene polymorphism has been genotyped in 154 patients and in 125 controls. The allele 3 is present in 60.3% of the patients and in 55.2% of the controls. The genotype 3/3 is present in 36.3% of the patients and in 34.4% of the controls. No statistical differences in the genotype and allelic frequencies between the two groups have been found. No differences were also found when the patients were classified according to different criteria such as onset, family history, gender or clinical presentation. Thus our results do not support a role for the DRD2 locus to develop PD.

Adult↗
PubMed1999

Immediate-release and controlled-release carbidopa/levodopa in PD: a 5-year randomized multicenter study. Carbidopa/Levodopa Study Group.

OBJECTIVE: To compare effects of immediate-release (IR) and sustained-release (CR) carbidopa/levodopa in levodopa-naive PD patients. BACKGROUND: It was hypothesized that the long-acting preparation would be associated with fewer long-term complications. METHODS: A total of 618 patients were studied in 36 centers worldwide in a blinded, randomized parallel study. Measures of efficacy and adverse reactions were recorded at 3-month intervals for 5 years. Motor fluctuations and dyskinesias were evaluated by a patient diary and a physician-recorded questionnaire. The Nottingham Health Profile (NHP) was used to evaluate quality of life. RESULTS: Approximately 60% of patients completed the trial. After 5 years, the mean dose of IR was 426 mg/day, and the bioavailable dose of CR was 510 mg/day (mean dose, 736 mg/day). After 5 years, 20.6% of the IR group and 21.8% of the CR group had motor fluctuations or dyskinesia. Sixteen percent of both groups had changes in motor response by the questionnaire's definition. There was no significant difference between the two treatment groups. Disability scores and the motor score of the Unified Parkinson Disease Rating Scale (UPDRS) were highest at baseline, improved with therapy, and thereafter worsened over time to reach baseline scoring at the end of 5 years. The CR group was superior to IR for the Activities of Daily Living subsection of the UPDRS for all 5 years and for emotional reactivity and social isolation on the NHP; however, this may have resulted from higher doses of CR that were used. CONCLUSION: Despite the progressive nature of PD, both the immediate-release and sustained-release carbidopa/levodopa formulations maintained a similar level of control in PD after 5 years compared with baseline. Additionally, the low incidence of motor fluctuations or dyskinesia was not significantly different between the treatment groups and may be partly attributed to the relatively low doses of levodopa used throughout the 5-year study.

Activities of Daily Living↗