Biomedical subjects

E Tolosa

Publications and source records attributed to E Tolosa.

At least 37 records · Page 2Linked to original sources

PubMed2004

Sequence analysis of tau 3'untranslated region and saitohin gene in sporadic progressive supranuclear palsy.

BACKGROUND: The extended tau H1 haplotype has previously been described in association with progressive supranuclear palsy (PSP). Recently, a new gene called saitohin (STH), nested within an intron of tau, has been discovered. The Q7R polymorphism of STH appears to be related to late onset Alzheimer's disease. OBJECTIVES: To search for genetic changes in the 3'untranslated region (3'UTR) of tau and adjacent sequence LOC147077, and in the coding region of STH in PSP patients. METHODS: The study included 57 PSP patients and 83 healthy controls. The genetic analysis of each region was performed through sequencing. The Q7R polymorphism was studied through restriction enzyme and electrophoresis analysis. RESULTS: No mutations were found in the regions analysed. The QQ genotype of the STH polymorphism was over-represented in participants with PSP (91.5%) compared with control subjects (47%) (p< or =0.00001). This genotype co-segregated with the H1/H1 haplotype in our PSP cases. CONCLUSIONS: Our results do not support a major role for the tau 3'UTR in PSP genetics. The QQ genotype of STH confers susceptibility for PSP and is in linkage disequilibrium with the H1/H1 haplotype.

3' Untranslated Regions↗

PubMed2003

Advances in the pharmacological management of Parkinson disease.

Numerous advances have taken place in the pharmacological management of Parkinson disease (PD) in recent years. Some of the more clinically relevant will be discussed in the text that follows. New drugs have been developed to treat or prevent the motor fluctuations and dyskinesias that occur frequently with the continuous use of levodopa. Such drugs include the catechol-O-methyl-transferase (COMT) inhibitors, such as tolcapone and entecapone, and new dopamine (DA) agonists with long half lives such as cabergoline, pramipexole or ropirinole. Also new, atyical, antipsychotics have appeared which have revolutionized the treatment of PD since they allow us to control hallucinations and other psychotic behaviour without worsening of motor function. Finally preliminary reports suggest that cholinesterase inhibitors, such as rivastigmine, can be usefull in the management of cognitive impairment in PD, one of the most difficult clinical problems encountered in the management of this neurodegenerative disorder.

Antiparkinson Agents↗

PubMed2003

Effect of acute and chronic administration of U50,488, a kappa opioid receptor agonist, in 6-OHDA-lesioned rats chronically treated with levodopa.

To evaluate the possible involvement of kappa opioid receptor-mediated mechanisms in levodopa-induced motor fluctuations, we have investigated the effects of U50,488, a selective kappa opioid agonist, on levodopa-induced motor alterations in rats with unilateral 6-OHDA lesion. Acute and chronic administration of U50,488 has been studied to evaluate the possible reversion or prevention of these levodopa effects. In a first set of experiments, rats were treated with levodopa (25 mg/kg with benserazide, twice daily, ip) for 22 days and, on Day 23 U50,488 (0.5, 1, or 3 mg/kg, i.p.) was administered immediately before levodopa. In a second set of experiments, rats were treated daily for 22 days with levodopa and U50,488 (1 or 3 mg/kg/day, i.p.). The duration of the rotational behavior induced by chronic levodopa decreased after 22 days (P < 0.05). Acute administration of U50,488 on Day 23 reversed this effect when low doses were administered (P < 0.05). Chronic U50,488 administration did not prevent the shortening in response duration induced by levodopa. Our results demonstrate that the kappa opioid receptor agonist U50,488 reverses but does not prevents levodopa-induced motor alterations in parkinsonian rats. These results suggest a role for kappa opioid receptor-mediated mechanisms in the pathophysiology of levodopa-induced motor response complications. These findings suggest that the stimulation of kappa opioid receptors might confer clinical benefit to parkinsonian patients under levodopa therapy suffering from motor complication syndrome.

3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cycloh↗

PubMed2003

Tau phosphorylation and kinase activation in familial tauopathy linked to deln296 mutation.

Tau phosphorylation has been examined by immunohistochemistry in the brain of a patient affected with familial tauopathy with progressive supranuclear palsy-like phenotype linked to the delN296 mutation in the tau gene. Phospho-specific tau antibodies Thr181, Ser202, Ser214, Ser396 and Ser422, and antibodies to glycogen synthase kinase-3alpha/beta (GSK-3alpha/beta) and to phosphorylated (P) mitogen-activated protein kinase/extracellular signal-regulated kinases (MAPK/ERK), stress-activated protein kinase/c-Jun N-terminal kinase (SAPK/JNK), p38 kinase (p38) and GSK-3betaSer9 have been used to gain understanding of the identification of phosphorylation sites, as well as of the specific kinases that regulate tau phosphorylation at those specific sites, in a familial tauopathy. The neuropathological examination disclosed atrophy of the right precentral gyrus and the brainstem. Neurone loss and gliosis were observed in the substantia nigra, several nuclei of the brainstem and diencephalon. Hyper-phosphorylated tau accumulated in neurones with neurofibrillary tangles and in neurones with pretangles in the substantia nigra, locus ceruleus, peri-aqueductal grey matter, reticular formation, motor nuclei of the brainstem, and thalamus, amygdala and hippocampus. tau-immunoreactive astrocytes and, particularly, oligodendrocytes with coiled bodies were widespread in the brainstem, diencephalons, cerebral white matter and cerebral cortex. Increased expression of MAPK/ERK-P, SAPK/JNK-P, p-38-P and GSK-3beta-P was observed in select subpopulations of neurones with neurofibrillary tangles and in neurones with pretangles. MAPK/ERK-P, SAPK/JNK-P, p38-P and GSK-3beta-P were also expressed in tau-containing astrocytes and in oligodendrocytes with coiled bodies. These findings show, for the first time, activation of precise kinases that regulate tau phosphorylation at specific sites in familial tauopathy.

Adult↗

PubMed2003

[Cabergoline in the treatment of Parkinson's disease].

Cabergoline (1-[(6-allelylergolin-8 beta-yl)carbonyl]-1-[3-(dimethylamino)propyl]-3-ethyl-urea) is a new agonist of the D2 dopaminergic receptors used in the treatment of Parkinson's disease. Cabergoline is characterized by unique pharmacologic properties, such as its long plasma half-life (about 68 hours), which allows for once a day administration. Cabergoline is well tolerated, as has been shown in several clinical trials. Based on the information available, we suggest that cabergoline produces an improvement in the symptoms of Parkinson's disease similar to those produced by other dopaminergic agonists. Cabergoline monotherapy, when used in previously untreated patients, is an appropriate option for the symptomatic treatment of Parkinson's disease. Cabergoline improves motor symptoms, delays the presentation of levodopa-induced motor complications, and diminishes the amount of levodopa required for the control of the symptoms. We suggest that cabergoline is an adequate adjuvant treatment for Parkinson' disease. There is improvement in motor symptoms (without substantially increased dyskinesias), reduced severity and duration of the wearing-off period, and diminished need for levodopa. Cabergoline can also be useful in the treatment of sleep disturbances associated with advanced Parkinson's disease such as nocturnal akinesia and dystonia. However, additional studies on cabergoline's effects in nocturnal disturbances associated with Parkinson's disease are still required. Cabergoline is a well tolerated drug. Its side effects are seen mainly in the digestive and nervous system (central and peripheral). The efficacy of cabergoline in comparison to other dopaminergic agonists should be tested in future clinical studies.

Antiparkinson Agents↗

PubMed2002

Adenosine A2A antagonism reverses levodopa-induced motor alterations in hemiparkinsonian rats.

To evaluate the possible involvement of adenosine A(2A) receptor-mediated mechanisms in levodopa-induced motor fluctuations, we investigated the effects of CSC (8-(3-chlorostryryl) caffeine), a selective adenosine A(2A) receptor antagonist, on levodopa-induced motor alterations in rats with unilateral 6-OHDA lesion. Acute and chronic administration of CSC was studied to evaluate the possible reversion or prevention of these levodopa effects. In a first set of experiments, rats were treated with levodopa (25 mg/kg with benserazide, twice daily, i.p.) for 22 days and on day 23 CSC (5 mg/kg, i.p.) was administered immediately before levodopa. In a second set of experiments, rats were treated daily for 22 days with levodopa and CSC (5 mg/kg/day, i.p.). The duration of the rotational behavior induced by chronic levodopa decreased after 22 days (P < 0.05). Acute administration of CSC on day 23 reversed levodopa-induced shortening in motor response duration (P < 0.01). Chronic CSC administration did not prevent the shortening in response duration induced by levodopa. Our results demonstrate that the adenosine A(2A) receptor antagonist CSC reverses but does not prevent levodopa-induced motor alterations in parkinsonian rats. These results suggest a role for adenosine A(2A) receptor-mediated mechanisms in the pathophysiology of levodopa-induced motor response complications. These findings suggest that the antagonism of adenosine A(2A) receptors might confer clinical benefit to parkinsonian patients under levodopa therapy suffering from motor complication syndrome.

Animals↗

PubMed2002

Intranuclear inclusions, neuronal loss and CAG mosaicism in two patients with Machado-Joseph disease.

UNLABELLED: The presence of neuronal intranuclear inclusions (NIIs) and neuronal mosaicism has been described in some autosomal dominant spinocerebellar ataxias (SCA), but their implication in neurodegenerative mechanisms still remains unclear. OBJECTIVE: To investigate the correlation between neuronal loss and NIIs, and the size of CAG triplet expansion in selected areas of the CNS in two SCA3 patients. MATERIAL AND METHODS: Postmortem neuropathological study was carried out, and the regional distribution of neuronal loss was compared with NIIs. CAG expansion was analysed by PCR amplification in the same regions. RESULTS: Marked neuronal loss was seen in the anterior horn of the spinal cord, pontine nuclei and motor nuclei of the brain stem. Moderate neurone loss was found in the locus ceruleus, colliculus and substantia nigra. Loss of granule and Purkinje cells was found in the cerebellum, mainly in the vermis. NIIs were present in neurones of the involved nuclei of the anterior horn of the spinal cord, medulla oblongata and pons, but not in the locus ceruleus, substantia nigra and cerebellum. A few NIIs were found in the striatum. The number of CAG repeats was 27/70 in the first patient and 21/74 in the second patient. The variation of the expanded allele size among different cerebral areas was +/-1-3 CAG repeats. CONCLUSION: The partial correlation between neuronal loss and NIIs suggests that other factors distinct from NII formation may be involved in the neuronal death. Moreover, the low degree of mosaicism between regions without neuronal loss and regions with marked neuronal loss points to the existence of selective cellular vulnerability to the genetic defect.

Aged↗

PubMed2002

Sleep symptoms and polysomnographic architecture in advanced Parkinson's disease after chronic bilateral subthalamic stimulation.

OBJECTIVE: To evaluate the sleep symptoms and polysomnographic architecture in advanced Parkinson's disease after chronic bilateral subthalamic stimulation (STN-DBS). METHODS: Sleep was studied in 11 patients (six women and five men; mean (SD) age 63.6 (7.8) years) who underwent STN-DBS. Subjective sleep evaluation was assessed by clinical sleep interview and the Pittsburgh sleep quality index (PSQI) questionnaire, and sleep architecture by polysomnography with audiovisual recording. Nocturnal mobility was evaluated. RESULTS: Before surgery, eight patients rated their sleep quality as unsatisfactory; seven of these had a marked improvement after surgery, and the PSQI questionnaire showed significantly improved sleep quality. After surgery, polysomnography showed an increase in the longest period of uninterrupted sleep and a decrease in the arousal index. There was an increase in nocturnal mobility after surgery, but no change in REM sleep behaviour disorder. CONCLUSIONS: In advanced Parkinson's disease, chronic STN-DBS is associated with subjective improvement in sleep quality, probably through increased nocturnal mobility and reduction of sleep fragmentation.

Aged↗

PubMed2002

Relative high frequency of the c.255delA parkin gene mutation in Spanish patients with autosomal recessive parkinsonism.

BACKGROUND: Autosomal recessive juvenile parkinsonism is a neurodegenerative disorder associated with mutations in the parkin gene. OBJECTIVES: To search for the presence of parkin gene mutations in Spanish patients with Parkinson's disease (PD) and characterise the phenotype associated with these mutations. METHODS: Thirty seven PD patients with either early onset or autosomal recessive pattern of inheritance were selected for genetic study. RESULTS: Mutations were identified in seven index patients (19%). Homozygous mutations were detected in six patients and a heterozygous mutation in one. The age at onset was lower in patients with mutations than in patients without mutations. Dystonia at onset was present in two patients with parkin gene mutations. The disease began in two patients with postural tremor in the upper limbs mimicking essential tremor. Four patients exhibited a long term response to dopamine agonists. The c.255delA mutation was identified in four unrelated families. This is a frameshift mutation leading to protein truncation. CONCLUSIONS: Parkin gene mutations are present in Spanish patients with early onset and/or an autosomal recessive parkinsonism. The c.255delA is the most frequent mutation found, suggesting a relative high prevalence in the Spanish population.

Adult↗

PubMed2002

[Cerebrotendinous xanthomatosis without tendinous xanthomas: presentation of two cases].

Cerebrotendinous xanthomatosis (CTX) is a genetic disorder caused by a 27-hydroxilase enzyme deficiency, leading to beta-cholestanol storage in many body tissues. Clinically, the disease is characterised by the presence of tendinous xanthomas, juvenile cataracts and progressive neurologic dysfunction. The diagnosis requires beta-cholestanol quantification in serum. We report two siblings with a history of photosensitive epilepsy of childhood onset, who developed progressive spastic paraparesis and cataracts in their third decade of life. They were diagnosed to have CTX in spite of the absence of tendinous xanthomas. Cranial and spinal MRI only showed bilateral high intensity signal in the dentate nuclei in the T2-weighted and proton-density sequences. Our patients presented with a progressive spastic paraparesis. The delay in the diagnosis in our case could be due to the absence of tendinous xanthomas and late-onset cataracts. The recognition of the disease is important, because the treatment with chenodeoxycholic acid induces a decrement of beta-cholestanol levels in serum and could prevent the progression of the disease.

Adolescent↗

PubMed2001

[Sporadic and familial Parkinson's disease: comparative study].

BACKGROUND: Several studies have shown that 13 to 33% of patients with Parkinson's disease (PD) exhibit a positive familial history. The goals of this work were to identify patients with familial PD and to analyse whether there existed distinctive features between familial and sporadic cases. PATIENTS AND METHOD: 402 patients with PD from the Hospital Clínic i Universitari of Barcelona were evaluated prospectively. Clinical assessment was done using different scales in 169 patients. The disease was classified as tremorigenic, rigid or mixed according to the predominant symptoms. RESULTS: The frequency of familial PD was 13%. The age at onset was not different between familial and sporadic cases but it was significantly higher in females (57.4 [13] years) than in males (54.8 [11.4] years) (p < 0.05). The tremorigenic type of PD was more common in familial cases (35.5%) (p < 0.05). In familial PD cases, the age at onset was lower in descendents (53 [13] years) than in parents (68 [7.8] years) (p = 0.001). CONCLUSIONS: Genetic factors may play an important role in the development of PD and gender-associated factors may modulate the age at onset. Familial PD cases differ from sporadic cases in the higher frequency of predominantly tremorigenic forms. The lower age at onset in descendents than in parents suggests the existence of a genetic anticipation phenomenon in familial PD.

Adult↗

PubMed2001

Expression of brain-derived neurotrophic factor in cortical neurons is regulated by striatal target area.

Changes in BDNF expression after different types of brain insults are related to neuroprotection, stimulation of sprouting, and synaptic reorganization. In the cerebral cortex, an autocrine-paracrine mechanism for BDNF has been proposed because the distribution patterns of BDNF and TrkB expression are almost identical. Moreover, cortical BDNF is anterogradely transported to the striatum, suggesting a role of BDNF in the functional interaction between the two brain regions. Here we have examined the expression of this neurotrophin in the cerebral cortex after various striatal lesions. Intrastriatal injection of quinolinate, kainate, 3-nitropropionic acid, or colchicine increased BDNF mRNA levels in cerebral cortex. In contrast, stimulation of neuronal activity in the striatum did not change cortical BDNF expression. Both excitatory amino acids increased BDNF expression in neurons of cortical layers II/III, V, and VI that project to the striatum. Moreover, grafting a BDNF-secreting cell line prevented both the loss of striatal neurons and the cortical upregulation of BDNF induced by excitotoxins. Because retrograde transport in the corticostriatal pathway was intact after striatal lesions, our results suggest that striatal damage upregulates endogenous BDNF in corticostriatal neurons by a transneuronal mechanism, which may constitute a protective mechanism for striatal and/or cortical cells.

3T3 Cells↗

PubMed2001

Focal limb dystonia in a patient with a cerebellar mass.

BACKGROUND: Focal dystonia of acute onset is indicative of a structural lesion in the nervous system. Cerebellar lesions have rarely been associated with dystonia. CASE DESCRIPTION: A 42-year-old woman was admitted to the neurology ward because of fever, confusion, and gait unsteadiness. She was diagnosed as having tuberculous meningitis, and, after a few days of antituberculous treatment, she developed prominent dystonia of the left upper limb. Cranial nuclear magnetic resonance imaging showed an isolated lesion compatible with a tuberculoma in the left cerebellar hemisphere. Both the limb dystonia and the tuberculoma resolved with maintained antituberculous treatment. CONCLUSIONS: In the patient described, the presence of upper-limb dystonia ipsilateral to a focal cerebellar lesion and the resolution of the dystonia and the mass lesion following treatment suggest that the cerebellum or its connections to the thalamus and/or basal ganglia could be involved in the pathophysiology of the dystonia.

Acute Disease↗

PubMed2001

Effects of bilateral subthalamic stimulation on cognitive function in Parkinson disease.

BACKGROUND: Chronic bilateral subthalamic deep brain stimulation (STN-DBS) is known to improve motor function in patients with Parkinson disease (PD). However, the possible effects of STN-DBS on neuropsychological functions have been studied less. OBJECTIVE: To investigate the effects of STN-DBS on neuropsychological functions in PD. DESIGN: Before-after trial. PATIENTS AND METHODS: Fifteen consecutive patients were assessed before and 3 months after implantation of stimulators for STN-DBS (postsurgical assessment with the stimulators switched on). Both assessments were performed with patients in a drug-free condition. The neuropsychological battery consisted of tests measuring memory and visuospatial and frontal functions. RESULTS: The comparison between presurgical and postsurgical performance showed a moderate deterioration in verbal memory and prefrontal and visuospatial functions, and a moderate improvement in a prefrontal task and obsessive-compulsive traits. The motor state improved in all patients. CONCLUSION: Therapy with STN-DBS improves motor symptoms in PD without any clinically relevant neuropsychological deterioration.

Aged↗

PubMed2001

Familial atypical progressive supranuclear palsy associated with homozigosity for the delN296 mutation in the tau gene.

Heterozygous missense and splice-site mutations in the tau gene have been previously identified in familial frontotemporal dementia with autosomal dominant inheritance. Here we report a Spanish kindred in which two brothers born from a third-degree consanguineous marriage were both affected with atypical progressive supranuclear palsy. A homozygous deletion at codon 296 (delN296) was identified in one of the affected siblings. Among the heterozygous carriers, two members with probable Parkinson's disease were identified, but none of heterozygotes developed atypical parkinsonism. The delN296 mutation lies in the sequence corresponding to the second tubulin-binding repeat of tau protein and affects one asparagine residue absolutely conserved in other species. This finding indicates that homozygous mutations in the tau gene may also cause hereditary tauopathies.

Adult↗

PubMed2001

Analysis of the coding and the 5' flanking regions of the alpha-synuclein gene in patients with Parkinson's disease.

Missense mutations of the alpha-synuclein gene have been reported to explain a few kindreds with autosomal dominant Parkinson's disease (PD). In order to identify mutations in our PD patients, we have screened the coding region and 5'flanking region of the gene. DNA samples from 50 patients with familial PD were screened via single-strand conformation polymorphism (SSCP) for mutations in the alpha-synuclein gene. The 5' flanking region was examined in 117 additional PD patients (27 patients with unclear family history for PD, and 90 patients without family history) and in 169 control subjects. We found one change (G199A) in exon 4 in one family with a pattern of autosomal dominant PD. However, this mutation did not result in an amino acid substitution (valine) and did not segregate completely with PD. The analysis of the 5' flanking region also showed a new polymorphism, a nucleotide insertion (- 164insA) linked to a nucleotide substitution (C-116G), in patients and in controls. The -164insA/C-116G allele was present in 52.3% of the patients and in 47.6% of the controls. We did not find significant differences regarding the allelic and genotype frequencies between PD and control groups. These results suggest that mutations in the alpha-synuclein gene are a very rare cause of familial PD and that the novel -164insA/C-116G polymorphism in the 5' flanking region does not confer susceptibility to develop PD.

Aged↗

PubMed2001

LY293558, an AMPA glutamate receptor antagonist, prevents and reverses levodopa-induced motor alterations in Parkinsonian rats.

To evaluate the possible involvement of glutamate AMPA receptor-mediated mechanisms in levodopa-induced motor fluctuations, we investigated the effects of LY293558, a competitive AMPA receptor antagonist, on levodopa-induced motor alterations in rats with unilateral 6-OHDA lesion. Acute and chronic administration of LY293558 was studied to evaluate the possible reversion or prevention of these levodopa effects. In the first set of experiments, rats were treated with levodopa (25 mg/kg with benserazide, twice daily, i.p.) for 22 days and on day 23 LY293558 (5 mg/kg, i.p.) was administered immediately before levodopa. In the second set of experiments, rats were treated daily for 22 days with levodopa and LY293558 (5 mg/kg, twice daily, i.p.). In the third set of experiments, the effect of LY293558 (5 mg/kg, i.p.) administration on selective dopamine D-1 (SKF38393, 1.5 mg/kg, s.c.) and D-2 agonist (quinpirole, 0.1 mg/kg, i.p.)-induced rotational behavior after daily levodopa treatment was studied. The duration of the rotational behavior induced by chronic levodopa decreased by 30% after 22 days. Acute administration of LY293558 on day 23 reversed this effect. The group of animals that were chronically treated with levodopa and LY293558 did not show the decrease in this motor response duration. Chronic levodopa treatment attenuated the rotational response to the D-1 agonist SKF38393 and increased the response to the D-2 agonist quinpirole. LY293558 did not reverse the effect of levodopa on rotational behavior induced by the D-1 agonist but significantly reduced the rotational response to the D-2 agonist in levodopa-treated animals by 40%. Our results demonstrate that an AMPA receptor antagonist reverses and prevents levodopa-induced motor alterations in parkinsonian rats and that this effect on motor fluctuations induced by chronic levodopa is probably due to a modulation of the indirect output pathway of the basal ganglia.

Adrenergic Agents↗

PubMed2001

Nocturnal paroxysmal dystonia related to a prerolandic dysplasia.

Nocturnal paroxysmal dystonia (NPD) is a rare disorder characterized by attacks of short-lived dystonic, tonic and choreoatetoid movements occurring mainly during sleep. Although seizures are believed to arise from the frontal lobe, their localization is, however, uncertain due to the lack of ictal clinical-EEG correlations. Two patients are reported with episodes clinically compatible with NPD who also experienced occasional generalized tonic-clonic seizures in which there was a frontal (prerolandic) dysplasia detected by MRI. In one patient interictal/ictal SPECTs suggested that the seizure focus was over the area of dysplasia. Both patients support the notion that NPD is a type of epilepsy arising from the frontal lobe, possibly originating in the prerolandic region.

Adult↗