Globular glial tauopathy caused by MAPT P301T mutation: clinical and neuropathological findings.

OBJECTIVE: To describe the clinical, biochemical, and neuropathological findings of an autosomal dominant globular glial tauopathy caused by the P301T mutation at the MAPT gene. METHODS: Five patients from two unrelated pedigrees underwent clinical evaluation. Genetic analysis, brain pathological examination, and biochemical analysis of tau were performed. RESULTS: The patients studied were 3 men and 2 women with a mean age at onset of 52.2 years and mean disease duration of 5.2 years. Three patients presented a corticobasal syndrome, one patient an asymmetric pyramidal syndrome compatible with primary lateral sclerosis, and one patient a frontotemporal dementia. In both pedigrees (4 patients) Sanger sequencing showed the p.P301T mutation in exon 10 of the MAPT gene. Neuropathological findings consisted of atrophy of frontal and temporal lobes with marked spongiosis and astrogliosis, and abundant phosphorylated tau protein deposits in the frontal and temporal cortex, limbic area, basal ganglia, and brain stem. The most striking finding was the presence of oligodendroglial 4R phospho-tau globular positive inclusions in the white matter and cortex. Globose-type neurofibrillary neuronal tangles, and in particular astrocytic globular inclusions and coarse tufts, were present in the grey matter. Biochemical analysis of sarkosyl-insoluble fractions revealed two tau bands of 64 and 68 kDa and case-dependent bands of lower molecular weight. CONCLUSION: This is the first pathological and biochemical study of the MAPT p.P301T mutation showing variable clinical manifestation and neuropathological phenotype of globular glial tauopathy not only among different families but also within families.

[Myths and evidence on the use of botulinum toxin: neuropharmacology and dystonia]. / Mitos y evidencias en el empleo de la toxina botulinica: neurofarmacologia y distonias.

INTRODUCTION: Botulinum toxin type A (BTA) is a bacterial endotoxin, whose therapeutic use has had a dramatic impact on different neurological disorders, such as dystonia and spasticity. AIM: To analyze and summarize different questions about the use of BTA in our clinical practice. DEVELOPMENT: A group of experts in neurology developed a list of topics related with the use of BTA. Two groups were considered: neuropharmacology and dystonia. A literature search at PubMed, mainly for English language articles published up to June 2016 was performed. The manuscript was structured as a questionnaire that includes those questions that, according to the panel opinion, could generate more controversy or doubt. The initial draft was reviewed by the expert panel members to allow modifications, and after subsequent revisions for achieving the highest degree of consensus, the final text was then validated. Different questions about diverse aspects of neuropharmacology, such as mechanism of action, bioequivalence of the different preparations, immunogenicity, etc. were included. Regarding dystonia, the document included questions about methods of evaluation, cervical dystonia, blepharospasm, etc. CONCLUSION: This review does not pretend to be a guide, but rather a tool for continuous training of residents and specialists in neurology, about different specific areas of the management of BTA.

TITLE: Mitos y evidencias en el empleo de la toxina botulinica: neurofarmacologia y distonias.Introduccion. La toxina botulinica de tipo A (TBA) ha supuesto una verdadera revolucion terapeutica en neurologia, y en la actualidad es el tratamiento rutinario en las distonias focales y la espasticidad. Objetivo. Plantear, revisar y responder cuestiones controvertidas en relacion con la neurofarmacologia de la TBA y su uso en las distonias en la practica clinica habitual. Desarrollo. Un grupo de expertos en trastornos del movimiento reviso una lista de temas controvertidos relacionados con la farmacologia de la TBA y su uso en las distonias. Revisamos la bibliografia e incluimos articulos relevantes especialmente en ingles, pero tambien, si su importancia lo merece, en castellano y en frances, hasta junio de 2016. El documento se estructuro como un cuestionario que incluyo las preguntas que podrian generar mayor controversia o duda. El borrador inicial del documento fue revisado por los miembros del panel y se realizaron las modificaciones necesarias hasta alcanzar el mayor grado de consenso. Incluimos preguntas sobre diferentes aspectos de la neurofarmacologia, especialmente el mecanismo de accion, la bioequivalencia de los diferentes preparados y la inmunogenicidad. En relacion con el subapartado de las distonias, se incluyeron aspectos sobre la evaluacion y el tratamiento de las distonias focales. Conclusiones. Esta revision no pretende ser una guia, sino una herramienta practica destinada a neurologos y medicos internos residentes interesados en esta area, dentro de diferentes ambitos especificos del manejo de la TBA.

Development and characterization of polo-like kinase 2 loaded nanoparticles-A novel strategy for (serine-129) phosphorylation of alpha-synuclein.

Polo like kinase 2 (PLK2), a serine/threonine serum inducible kinase, has been proposed to be the major factor responsible for phosphorylating alpha-synuclein (α-syn) at Serine-129 (Ser-129) in Parkinson's disease (PD). A suitable strategy to gain insights into PLK2's biological effects might be to increase PLK2 intracellular levels with the aim of reproducing the slow progressive neuronal changes that occur in PD. The goal of this study was to develop and characterize a novel drug delivery system (DDS) for PLK2 cytosolic delivery using Total recirculating one machine system (TROMS), a technique capable of encapsulating fragile molecules while maintaining their native properties. A protocol for nanoparticle (NP) preparation using TROMS was set up. NPs showed a mean diameter of 257±15.61nm and zeta potential of -16±2mV, suitable for cell internalization. TEM and SEM images showed individual, spherical, dispersed NPs. The drug entrapment efficacy was 61.86±3.9%. PLK2-NPs were able to enter SH-SY5Y cells and phosphorylate α-syn at Ser-129, demonstrating that the enzyme retained its activity after the NP manufacturing process. This is the first study to develop a DDS for continuous intracellular delivery of PLK2. These promising results indicate that this novel nanotechnology approach could be used to elucidate the biological effects of PLK2 on dopaminergic neurons.

Brain aging and Parkinson's disease: New therapeutic approaches using drug delivery systems.

The etiology and pathogenesis of Parkinson's disease (PD) is unknown, aging being the strongest risk factor for brain degeneration. Understanding PD pathogenesis and how aging increases the risk of disease would aid the development of therapies able to slow or prevent the progression of this neurodegenerative disorder. In this review we provide an overview of the most promising therapeutic targets and strategies to delay the loss of dopaminergic neurons observed both in PD and aging. Among them, handling alpha-synuclein toxicity, enhancing proteasome and lysosome clearance, ameliorating mitochondrial disruptions and modifying the glial environment are so far the most promising candidates. These new and conventional drugs may present problems related to their labile nature and to the difficulties in reaching the brain. Thus, we highlight the latest types of drug delivery system (DDS)-based strategies for PD treatment, including DDS for local and systemic drug delivery. Finally, the ongoing challenges for the discovery of new targets and the opportunities for DDS-based therapies to improve and efficacious PD therapy will be discussed.

[Neuropsychological profile of frontotemporal lobar degeneration]. / Perfil neuropsicológico de la degeneración lobar frontotemporal.

Frontotemporal lobar degeneration encompasses three different syndromes, with clinical and pathologic commonalities, making diagnosis difficult in early stages. Three subtypes are recognized: frontotemporal dementia and its three variants, corticobasal syndrome and supranuclear palsy syndrome. The objective of this study is to review the neuropsychological features of each syndrome in order to differentiate amongst subtypes as well as from other forms of dementia. We review multiple studies from the literature, highlighting the main clinical features, neuropathology and changes in brain imaging of each syndrome. Subsequently, we describe the neuropsychological profile compared to other dementias, and how it progresses over time. Although there is an overlap amongst the different subtypes of frontotemporal lobar degeneration, neuropsychological profiles can help identify subtypes and discriminate frontotemporal lobar degeneration from other forms of dementia.

Clinical and neuroimaging characteristics of 14 patients with prionopathy: a descriptive study.

INTRODUCTION: Prionopathy is the cause of 62% of the rapidly progressive dementias (RPD) in which a definitive diagnosis is reached. The variability of symptoms and signs exhibited by the patients, as well as its different presentation, sometimes makes an early diagnosis difficult. METHODS: Patients withdiagnosis of definite or probable prionopathy during the period 1999-2012 at our hospital were retrospectively reviewed.The clinical features and the results of the complementary tests (14-3-3 protein, EEG, MRI, FDG-PET, and genetic analysis) were evaluated in order to identify some factors that may enable an earlier diagnosis to be made. RESULTS: A total of 14 patients are described: 6 with definite sporadic Creutzfeldt-Jakob (sCJD) disease, 3 with probable sCJD, 4 with fatal familial insomnia, and 1 with the new variant. The median age at diagnosis was 54 years old. The mean survival was 9.5 months. Mood disorder was the most common feature, followed by instability and cognitive impairment. 14-3-3 protein content in the cerebrospinal fluid was positive in 7 of 11 patients, and the EEG showed typical signs in 2 of 12 patients. Neuroimaging (FDG-PET, MRI) studies suggested the diagnosis in 13 of the 14 patients included. CONCLUSIONS: Most patients presenting with RPD suffer from a prion disease. In our series the most useful complementary tests were MRI and FDG-PET, being positive in 13 of the 14 patients studied.

[Functional neuroimaging in the diagnosis of patients with Parkinsonism: Update and recommendations for clinical use]. / Neuroimagen funcional en el diagnóstico de pacientes con síndrome parkinsoniano: actualización y recomendaciones para el uso clínico.

Functional Neuroimaging has been traditionally used in research for patients with different Parkinsonian syndromes. However, the emergence of commercial radiotracers together with the availability of single photon emission computed tomography (SPECT) and, more recently, positron emission tomography (PET) have made them available for clinical practice. Particularly, the development of clinical evidence achieved by functional neuroimaging techniques over the past two decades have motivated a progressive inclusion of several biomarkers in the clinical diagnostic criteria for neurodegenerative diseases that occur with Parkinsonism. However, the wide range of radiotracers designed to assess the involvement of different pathways in the neurodegenerative process underlying Parkinsonian syndromes (dopaminergic nigrostriatal pathway integrity, basal ganglia and cortical neuronal activity, myocardial sympathetic innervation), and the different neuroimaging techniques currently available (scintigraphy, SPECT and PET), have generated some controversy concerning the best neuroimaging test that should be indicated for the differential diagnosis of Parkinsonism. In this article, a panel of nuclear medicine and neurology experts has evaluated the functional neuroimaging techniques emphazising practical considerations related to the diagnosis of patients with uncertain origin parkinsonism and the assessment Parkinson's disease progression.

Enfermedad de Parkinson avanzada. Características clínicas y tratamiento. Parte I I / Advanced Parkinson's disease: Clinical characteristics and treatment. Part II

Introducción. Muchos de los pacientes con enfermedad de Parkinson (EP) presentan al cabo de varios años fluctuaciones y discinesias graves que requieren de terapias algo más agresivas como la estimulación cerebral profunda del núcleo subtalámico o globo pálido medial, la infusión continua de apomorfina y la infusión intestinal continua de levodopa-carbidopa. Objetivo: Establecer las indicaciones y resultados de las 3 técnicas disponibles en la actualidad para el tratamiento de la EP avanzada. Desarrollo: Revisión exhaustiva de los datos publicados en la literatura sobre las indicaciones y resultados de la estimulación cerebral profunda del núcleo subtalámico, infusión subcutánea de apomorfina e infusión intestinal continua de levodopa-carbidopa en pacientes con EP avanzada. Conclusiones: Aunque existen numerosos estudios que han descrito la eficacia de cada una de estas 3 técnicas, faltan estudios comparativos que permitan definir el candidato ideal para cada una de las técnicas (AU)

Introduction: Many patients who have had Parkinson's disease (PD) for several years will present severe motor fluctuations and dyskinesias which require more aggressive therapies. The different approaches which are now available include deep brain stimulation of the subthalamic nucleus or medial globus allidus, subcutaneous infusion of apomorphine, and intestinal infusion of levodopa-carbidopa. Objective: To define the indications and results for the 3 available therapies for advanced PD. Development: Exhaustive review of the literature concerning the indications and results of deep brain stimulation, subcutaneous apomorphine infusion and duodenal infusion of levodopa/carbidopa gel to treat patients with advanced Parkinson disease. Conclusions: Although numerous studies have confirmed the efficacy of the 3 different therapies in advanced PD, there are no comparative studies that would allow us to define the best candidate for each technique (AU)

Enfermedad de Parkinson avanzada. Características clínicas y tratamiento (parte I) / Advanced Parkinson’s disease: Clinical characteristics and treatment (part 1)

Introducción: Un porcentaje importante de pacientes con enfermedad de Parkinson (EP) desarrollan complicaciones motoras en forma de fluctuaciones motoras, discinesias y síntomas no motores al cabo de 3-5 años del inicio del tratamiento que resultan de difícil control terapéutico. Esta fase de la enfermedad ha sido definida por algunos autores como fase avanzada de la EP. Objetivo: Definir las características clínicas y los factores de riesgo que condicionan que una EP evolucione a un estadio avanzado. Desarrollo: Este documento de consenso se ha realizado mediante una búsqueda bibliográfica exhaustiva y discusión de los contenidos llevadas a cabo por un grupo de expertos en trastornos del movimiento de la Sociedad Española de Neurología coordinados por dos de los autores (JK y MRL). Conclusiones: La presencia de fluctuaciones motoras y discinesias graves, síntomas motores axiales resistentes a la levodopa y síntomas no motores, como los trastornos cognitivos, representan las principales manifestaciones fenotípicas de una EP Avanzada (AU)

Introduction: A large percentage of patients with Parkinson’s disease (PD) develop motor fluctuations, dyskinesias, and severe non-motor symptoms within 3 to 5 years of starting dopaminergic therapy, and these motor complications are refractory to treatment. Several authors refer to this stage of the disease as advanced Parkinson’s disease. Objective: To define the clinical manifestations of advanced PD and the risk factors for reaching this stage of the disease. Development: This consensus document has been prepared by using an exhaustive literature search and by discussion of the contents by an expert group on movement disorders of the Sociedad Española de Neurología (Spanish Neurology Society), coordinated by two of the authors (JK and MRL). Conclusions: Severe motor fluctuations and dyskinesias, axial motor symptoms resistant to levodopa, and cognitive decline are the main signs in the clinical phenotype of advanced PD (AU)

Advanced Parkinson's disease: clinical characteristics and treatment. Part II.

INTRODUCTION: Many patients who have had Parkinson's disease (PD) for several years will present severe motor fluctuations and dyskinesias which require more aggressive therapies. The different approaches which are now available include deep brain stimulation of the subthalamic nucleus or medial globus pallidus, subcutaneous infusion of apomorphine, and intestinal infusion of levodopa-carbidopa. OBJECTIVE: To define the indications and results for the 3 available therapies for advanced PD. DEVELOPMENT: Exhaustive review of the literature concerning the indications and results of deep brain stimulation, subcutaneous apomorphine infusion and duodenal infusion of levodopa/carbidopa gel to treat patients with advanced Parkinson disease. CONCLUSIONS: Although numerous studies have confirmed the efficacy of the 3 different therapies in advanced PD, there are no comparative studies that would allow us to define the best candidate for each technique.

[Advanced Parkinson's disease: clinical characteristics and treatment (part 1)]. / Enfermedad de Parkinson avanzada. Características clínicas y tratamiento (parte I).

INTRODUCTION: A large percentage of patients with Parkinson's disease (PD) develop motor fluctuations, dyskinesias, and severe non-motor symptoms within 3 to 5 years of starting dopaminergic therapy, and these motor complications are refractory to treatment. Several authors refer to this stage of the disease as advanced Parkinson's disease. OBJECTIVE: To define the clinical manifestations of advanced PD and the risk factors for reaching this stage of the disease. DEVELOPMENT: This consensus document has been prepared by using an exhaustive literature search and by discussion of the contents by an expert group on movement disorders of the Sociedad Española de Neurología (Spanish Neurology Society), coordinated by two of the authors (JK and MRL). CONCLUSIONS: Severe motor fluctuations and dyskinesias, axial motor symptoms resistant to levodopa, and cognitive decline are the main signs in the clinical phenotype of advanced PD.

Structural and functional neuroimaging in human prion diseases.

INTRODUCTION: Prion diseases are neurodegenerative disorders resulting from the accumulation of a misfolded isoform of the cellular prion protein (PrPc). They can occur as acquired, sporadic, or hereditary forms. Although prion diseases show a wide range of phenotypic variations, pathological features and clinical evolution, they are all characterised by a common unfavourable course and a fatal outcome. REVIEW SUMMARY: Some variants, such as kuru, have practically disappeared, while others, for example the variant Creutzfeldt-Jakob (vCJD) or those attributable to iatrogenic causes, are still in force and pose a challenge to current medicine. There are no definitive pre-mortem diagnostic tests, except for vCJD, where a tonsil biopsy detects 100% of the cases. For this reason, diagnostic criteria dependent on statistical probability have had to be created. These require complementary examinations, such as an electroencephalogram (EEG) or the detection of 14-3-3 protein in cerebrospinal fluid (CSF). Only the pulvinar sign in magnetic resonance imaging (MRI) has been included as a vCJD diagnostic criterion. The present review discusses neuroimaging findings for each type of prion disease in patients with a definitive histopathological diagnosis. CONCLUSIONS: The aim is to define the usefulness of these complementary examinations as a tool for the diagnosis of this family of neurodegenerative diseases.

Enhanced GDNF expression in dopaminergic cells of monkeys grafted with carotid body cell aggregates.

Striatal carotid body cell aggregates (CBCA) grafts improve parkinsonism in animals and patients with Parkinson's disease. As CB cells contain trophic factors, we investigated the long-term effect of striatal CBCA grafts on nigrostriatal dopaminergic cells in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-treated monkeys receiving unilateral (UL-grafted group, n=4) or bilateral (BL-grafted group, n=3) CBCA autotransplant. Two MPTP monkeys were sham-operated receiving only Tyrode. For histological analysis, we also included 3 MPTP-untreated and 3 intact animals. Brain [18]F-luorodopa ((18)F-DOPA)-positron emission tomography (PET) scans were performed to assess dopaminergic function in vivo at baseline, 6 and 12months after surgery. The number of nigral dopaminergic cells was assessed in UL-grafted animals, and the number of dopaminergic cells expressing glial cell line-derived neurotrophic factor (GDNF) in all groups. After 1 year, animals showed a significant recovery of the parkinsonism (San Sebastian et al., 2007) and PET studies revealed a larger striatal (18)F-DOPA uptake in the CBCA-grafted striatum compared to that receiving Tyrode. No differences were found in the number of surviving dopaminergic cells when comparing both subtantia nigra of UL-grafted animals. However, both UL- and BL-grafted animals showed a bilaterally increased number of TH-GDNF immunoreactive nigral neurons compared to intact and MPTP-untreated monkeys, indicating that in addition to the proven long-term motor benefit, CBCA autograft might exert a neuroprotective effect on the surviving dopaminergic cells.

Analysis of the GIGYF2 gene in familial and sporadic Parkinson disease in the Spanish population.

BACKGROUND AND PURPOSE: Linkage analysis in familial Parkinson's disease (PD) identified a locus in 2q36-37 (PARK11). Sequencing of GIGYF2 identified several variants only present amongst PD individuals. METHODS: We analyzed the presence of disease-associated GIGYF2 variants in familial and sporadic PD from Spanish origin by sequencing of 147 PD individuals. The entire GIGYF2 coding sequence was analyzed in 122 familial PD individuals and exons 2, 4, 8-11, 14 and 25-26 were sequenced in 25 sporadic PD to identify disease-associated variants. RESULTS: We found no variants associated with PD and failed to identify any of previously PD-associated GIGYF2 variants in our sample. We identified four novel missense changes in GIGYF2. p.Met48Ile was found in a PD individual who also was a carrier of two PARKIN mutations. p.Q1244_Q1247del variant was present only in one PD individual but not found in 70 controls. However, its location in the highly polymorphic GIGYF2 glutamine/proline-rich region does not support a role in PD. Two variants (p.P1238insAGC and p.Q1249del) were present both in PD subjects and in controls. Additionally, the p.L1230_Q1237del variant, which was previously considered as a PD-associated change, was found in one control. CONCLUSION: Our findings suggest that GIGYF2 mutations are not a frequent cause of PD in the Spanish population, since we found no clearly segregating variants. We propose further analyses in PD subjects from different populations to define the role of GIGYF2. A clear pathogenic mutation in other gene at 2q36-37 in the PARK11-linked PD families would definitively disprove GIGYF2 as the responsible gene.

New MRI, 18F-DOPA and 11C-(+)-alpha-dihydrotetrabenazine templates for Macaca fascicularis neuroimaging: advantages to improve PET quantification.

Normalization of neuroimaging studies to a stereotaxic space allows the utilization of standard volumes of interest (VOIs) and voxel-based analysis (SPM). Such spatial normalization of PET and MRI studies requires a high quality template image. The aim of this study was to create new MRI and PET templates of (18)F-DOPA and (11)C-(+)-alpha-dihydrotetrabenazine ((11)C-DTBZ) of the Macaca fascicularis brain, an important animal model of Parkinson's disease. MRI template was constructed as a smoothed average of the scans of 15 healthy animals, previously transformed into the space of one representative MRI. In order to create the PET templates, (18)F-DOPA and (11)C-DTBZ PET of the same subjects were acquired in a dedicated small animal PET scanner and transformed to the created MRI template space. To validate these templates for PET quantification, parametric values obtained with a standard VOI-map applied after spatial normalization to each template were statistically compared to results computed using individual VOIs drawn for each animal. The high correlation between both procedures validated the utilization of all the templates, improving the reproducibility of PET analysis. To prove the utility of the templates for voxel-based quantification, dopamine striatal depletion in a representative monkey treated with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) was assessed by SPM analysis of (11)C-DTBZ PET. A symmetric reduction in striatal (11)C-DTBZ uptake was detected in accordance with the induced lesion. In conclusion, templates of M. fascicularis brain have been constructed and validated for reproducible and automated PET quantification. All templates are electronically available via the internet.

Modification of the number and phenotype of striatal dopaminergic cells by carotid body graft.

In non-human primates, striatal tyrosine hydroxylase-immunoreactive (TH-ir) cells are increased in number after dopamine depletion and in response to trophic factor delivery. As carotid body cells contain the dopaminotrophic glial cell line-derived neurotrophic factor (GDNF), we evaluated the number, morphology and neurochemistry of these TH-ir cells, in the anterior and posterior striatum of five monkeys treated with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) which received a graft of carotid body cell aggregates (CBCA) (n = 3) or sham surgery (n = 2), and six MPTP-monkeys that were sacrificed 6 months and 3 years after the last MPTP dose [MPTP I (n = 3) and MPTP II (n = 3), respectively]. Three intact monkeys served as controls. A disability rating scale was used for the assessment of parkinsonism in all lesioned animals, both before and after surgery. For the neurochemical examination, tissue sections were double-labelled with antibodies to TH, dopamine transporter, dopa decarboxylase-67, vesicular monoamine transporter 2, glutamic acid decarboxylase -67, calbindin, parvalbumin, calretinin, neuronal nitric oxide synthase and GDNF. Only animals receiving CBCA graft showed a moderate but significant recovery of parkinsonism that persisted 12 months after the graft. The grafted striatum contained the greatest TH-ir cell density (120.4 +/- 10.3 cells/100 mm2), while the control striatum displayed the lowest (15.4 +/- 6.8 cells/100 mm2), and MPTP I, MPTP II and sham-operated monkeys showed a similar intermediate value (66.1 +/- 6.2, 58.3 +/- 17.2 and 57.7 +/- 7.0 cells/100 mm2, respectively). In addition, in the post-commissural striatum, only CBCA graft induced a significant increase in the TH-ir cell density compared to control animals (47.9 +/- 15.9 and 7.9 +/- 3.2, respectively). Phenotypically, TH-ir cells were striatal dopaminergic interneurons. However, in the grafted animals, the phenotype was different from that in control, MPTP and sham-operated monkeys, with the appearance of TH/GDNF-ir cells and the emergence of two TH-ir subpopulations of different size as the two main differentiating features. Our data confirm and extend previous studies demonstrating that striatal CBCA grafts produce a long-lasting motor recovery of MPTP-monkeys along with an increase in the number and phenotype changes of the striatal TH-ir interneurons, probably by the action of the trophic factors contained in carotid body cells. The increased number of striatal TH-ir cells observed in the grafted striatum may contribute to the improvement of parkinsonism observed after the graft.

[Survey on the current situation of the young neurologists in Spain: analysis of their current working stability and degree of social protection]. / Encuesta sobre la situación actual de los neurólogos jóvenes en España: análisis de la estabilidad laboral y de la protección social.

INTRODUCTION: The aims of this study were to evaluate the working stability and degree of social protection of the Spanish young neurologists, and to know their opinion about their own situation. METHODS: The 343 neurologists that became specialists in Spain between 2000 and 2004 were asked to participate in two consecutive surveys. The first, conducted online, included questions about the availability to change the place of work and the opinion about the situation of young neurologists, and obtained 66 answers. The second was a telephonic and online survey, answered by 217 neurologists, whose questions referred to: places of neurological education and work, type of working contract, and degree of social protection (estimated by the percentage of worked time during which they paid Social Security contributions). RESULTS: Sixty-three per cent (136/217) of the Spanish young neurologists had an unstable job. The most frequent unstable working contracts were: eventual (n=65; 31%), on-call contracts (n=54; 25%) and grants (n=53; 24%). Forty-eight per cent of the neurologists who ended their specialization in 2000 still remained working-unstable. The mean percentage of worked time with full social protection was 71.01+/-36.74%. Less than a half (n=101; 46%) had social protection during the entire worked time, 60 (28.6%) were socially protected during <50% of the worked time, and 23 (11%) never had social protection. A direct relationship was observed 68 between working instability and lower social protection (p=0.0002). The working situation of the Spanish young neurologists was seen as problematic by 97% of the 66 participants in the first survey. CONCLUSIONS: The current situation of the Spanish young neurologists, attending their working stability and degree of social protection, seems precarious and problematic. Urgent actions should be taken by the Administration to improve it.

Encuesta sobre la situación actual de los neurólogos jóvenes en España: análisis de la estabilidad laboral y de la protección social / Survey on the current situation of the young neurologists in Spain: analysis of their current working stability and degree of social protection

Introducción. No existen estudios que hayan analizado la problemática laboral de los neurólogos jóvenes. Este trabajo tuvo como objetivos evaluar la estabilidad laboral y grado de protección social de los neurólogos jóvenes en España y conocer la visión que éstos tienen sobre su propia situación. Métodos. Sobre una muestra total de 343 neurólogos que acabaron su formación especializada en España entre 2000 y 2004 se realizaron dos encuestas consecutivas (electrónica y electrónica más telefónica], obteniéndose datos de 66 y de 217 neurólogos, respectivamente. En la primera se preguntó por la disponibilidad de desplazamiento en caso de contrato inestable y por la impresión sobre la situación de la neurología joven. La segunda versó sobre los lugares de formación y trabajo actual, la estabilidad laboral y la protección social (porcentaje del tiempo trabajado cotizado a la Seguridad Social). Resultados. El 63 % (136/217) de los neurólogos encuestados se encontraba en situación laboral inestable. Los tipos de contrato inestable más frecuentes fueron: contratos eventuales (n = 65; 31 %), contratos de guardias (n = 54; 25%) Y becas (n=53; 24%). Un 48% de los neurólogos titulados en 2000 permanecía en situación laboral inestable. El porcentaje medio de tiempo cotizado a la Seguridad Social fue de 71,01 :t36,74%. Menos de la mitad (46%) de los encuesta dos cotizó el 100% del tiempo trabajado, un 28,6% cotizó durante menos del 50% y un 11 % no cotizó nunca. Se observó una relación directa entre inestabilidad laboral y mayor desprotección social (p=0,0002). En la otra encuesta, el 97% de los 66 encuestados consideró que la situación actual de la neurología joven se podía calificar de problemática. Conclusiones. La situación actual de los neurólogos jóvenes en España, en lo que se refiere a estabilidad laboral y protección social, es muy precaria y problemática. Dada la creciente demanda social de la neurología es necesaria una planificación adecuada de las necesidades y los recursos por parte de la Administración para mejorar la situación laboral de los neurólogos jóvenes

Introduction. The aims of this study were to evaluate the working stability and degree of social protection of the Spanish young neurologists, and to know their opinion about their own situation. Methods. The 343 neurologists that became specialists in Spain between 2000 and 2004 were asked to participate in two consecutive surveys. The first, conducted online, included questions about the availability to change the place of work and the opinion about the situation of young neurologists, and obtained 66 answers. The second was a telephonic and online survey, answered by 217 neurologists, whose questions referred to: places of neurological education and work, type of working contract, and degree of social protection (estimated by the percentage of worked time during which they paid Social Security contributions). Results. Sixty-three per cent (136/217) of the Spanish young neurologists had an unstable job. The most frequent unstable working contracts were: eventual (n=65; 31 %), on-call contracts (n=54; 25%) and grants (n = 53; 24 %). Forty-eight per cent of the neurologists who ended their specialization in 2000 still remained working-unstable. The mean percentage of worked time with full social protection was 71.01 :t36.74%. Less than a half (n = 10 1; 46 %) had social protection during the entire worked time, 60 (28,6 %) were socially protected during < 50% of the worked time, and 23 (11 %) never had social protection. A direct relationship was observed between working instability and lower social protection (p = 0.0002). The working situation of the Spanish young neurologists was seen as problematic by 97 % of the 66 participants in the first survey. Conclusions. The current situation of the Spanish young neurologists, attending their working stability and degree of social protection, seems precarious and problematic. Urgent actions should be taken by the Administration to improve it

[Optimization of use of levodopa in Parkinson's disease: role of levodopa-carbidopa-entacapone combination]. / Optimización del uso de la levodopa en la enfermedad de Parkinson: papel de la combinación levodopacarbidopa- entacapona.

Levodopa remains the mainstay treatment for Parkinson's disease (PD). Chronic treatment is associated with motor complications (MC) that marred the clinical benefit of levodopa. These problems and experimental data in cell cultures indicating a neurotoxic effect of levodopa have led to the idea of delaying the introduction of levodopa treatment for as long as possible. We here review recent data regarding the mechanism of action of levodopa and its application in clinical practice on the light of the marketing of the combination levodopa-carbidopa- entacapone. Accumulated evidence indicates that MC are mainly the consequence of disease severity governing the degree of dopaminergic depletion and the "pulsatile" dopaminergic stimulation provided by levodopa short plasma half-life. There is no in vivo or clinical evidence of a relevant neurotoxic effect of levodopa. In fact, the recent ELLDOPA study may suggest a neuroprotective effect. Entacapone reduces homocysteine plasma levels which could provide a mechanism to reduce cell death in PD. Currently, the combination levodopa-carbidopa-entacapone is particularly indicated for the treatment of "wearing off" fluctuations. Experimental evidence suggests that early treatment with levodopa-carbidopa-entacapone may substantially ameliorate the incidence of MC. Such a clinical study in "de novo" patients is underway. At present, the combination levodopa-carbidopa-entacapone is indicated when levodopa is judged necessary.