Staging Parkinson's Disease Combining Motor and Nonmotor Symptoms Correlates with Disability and Quality of Life.

INTRODUCTION: In a degenerative disorder such as Parkinson's disease (PD), it is important to establish clinical stages that allow to know the course of the disease. Our aim was to analyze whether a scale combining Hoehn and Yahr's motor stage (H&Y) and the nonmotor symptoms burden (NMSB) (assessed by the nonmotor symptoms scale (NMSS)) provides information about the disability and the patient's quality of life (QoL) with regard to a defined clinical stage. MATERIALS AND METHODS: Cross-sectional study in which 603 PD patients from the COPPADIS cohort were classified according to H&Y (1, stage I; 2, stage II; 3, stage III; 4, stage IV/V) and NMSB (A: NMSS = 0-20; B: NMSS = 21-40; C: NMSS = 41-70; D: NMSS ≥ 71) in 16 stages (HY.NMSB, from 1A to 4D). QoL was assessed with the PDQ-39SI, PQ-10, and EUROHIS-QOL8 and disability with the Schwab&England ADL (Activities of Daily Living) scale. RESULTS: A worse QoL and greater disability were observed at a higher stage of H&Y and NMSB (p < 0.0001). Combining both (HY.NMSB), patients in stages 1C and 1D and 2C and 2D had significantly worse QoL and/or less autonomy for ADL than those in stages 2A and 2B and 3A and 3B, respectively (p < 0.005; e.g., PDQ-39SI in 1D [n = 15] vs 2A [n = 101]: 28.6 ± 17.1 vs 7.9 ± 5.8; p < 0.0001). CONCLUSION: The HY.NMSB scale is simple and reflects the degree of patient involvement more accurately than the H&Y. Patients with a lower H&Y stage may be more affected if they have a greater NMS burden.

Continuous intestinal infusion of levodopa-carbidopa in patients with advanced Parkinson's disease in Spain: Subanalysis by autonomous community. / Uso de la infusión intestinal continua de levodopa-carbidopa en pacientes con enfermedad de Parkinson avanzada en España. Subanálisis por comunidades autónomas.

OBJECTIVES: To compare the characteristics of patients undergoing treatment with continuous intestinal infusion of levodopa-carbidopa (CIILC) for advanced Parkinson's disease and the data on the effectiveness and safety of CIILC in the different autonomous communities (AC) of Spain. METHODS: A retrospective, longitudinal, observational study was carried out into 177 patients from 11 CAs who underwent CIILC between January 2006 and December 2011. We analysed data on patients' clinical and demographic characteristics, variables related to effectiveness (changes in off time/on time with or without disabling dyskinesia; changes in Hoehn and Yahr scale and Unified Parkinson's Disease Rating Scale scores; non-motor symptoms; and Clinical Global Impression scale scores) and safety (adverse events), and the rate of CIILC discontinuation. RESULTS: Significant differences were observed between CAs for several baseline variables: duration of disease progression prior to CIILC onset, off time (34.9-59.7%) and on time (2.6-48.0%; with or without disabling dyskinesia), Hoehn and Yahr score during on time, Unified Parkinson's Disease Rating Scale-III score during both on and off time, presence of≥ 4 motor symptoms, and CIILC dose. Significant differences were observed during follow-up (> 24 months in 9 of the 11 CAs studied) for the percentage of off time and on time without disabling dyskinesia, adverse events frequency, and Clinical Global Impression scores. The rate of CIILC discontinuation was between 20-40% in 9 CAs (78 and 80% in remaining 2 CAs). CONCLUSIONS: This study reveals a marked variability between CAs in terms of patient selection and CIILC safety and effectiveness. These results may have been influenced by patients' baseline characteristics, the availability of multidisciplinary teams, and clinical experience.

Sleep Problems Are Related to a Worse Quality of Life and a Greater Non-Motor Symptoms Burden in Parkinson's Disease.

INTRODUCTION: The aim of the present study was to examine the frequency of self-reported sleep problems and their associated factors in a large cohort of PD patients. METHODS: PD patients and controls, recruited from 35 centers of Spain from the COPPADIS cohort were included in this cross-sectional study. Sleep problems were assessed by the Spanish version of the Parkinson's disease Sleep Scale version 1 (PDSS-1). An overall score below 82 or a score below 5 on at least 1 item was defined as sleep problems. RESULTS: The frequency of sleep problems was nearly double in PD patients compared to controls: 65.8% (448/681) vs 33.5% (65/206) (p < 0.0001). Mean total PDSS score was lower in PD patients than controls: 114.9 ± 28.8 vs 132.8 ± 16.3 (p < 0.0001). Quality of life (QoL) was worse in PD patients with sleep problems compared to those without: PDQ-39SI, 19.3 ± 14 vs 13 ± 11.6 (p < 0.0001); EUROHIS-QoL8, 3.7 ± 0.5 vs 3.9 ± 0.5 (p < 0.0001). Non-motor symptoms burden (NMSS; OR = 1.029; 95%CI 1.015-1.043; p < 0.0001) and impulse control behaviors (QUIP-RS; OR = 1.054; 95%CI 1.009-1.101; p = 0.018) were associated with sleep problems after adjustment for age, gender, disease duration, daily equivalent levodopa dose, H&Y, UPDRS-III, UPDRS-IV, PD-CRS, BDI-II, NPI, VAS-Pain, VAFS, FOGQ, and total number of non-antiparkinsonian treatments. CONCLUSION: Sleep problems were frequent in PD patients and were related to both a worse QoL and a greater non-motor symptoms burden in PD. These findings call for increased awareness of sleep problems in PD patients.

[Clinical experience in the treatment of motor fluctuations in Parkinson's disease. Delphi consensus of a group of experts in movement disorders]. / Experiencia clínica en el tratamiento de las fluctuaciones motoras en la enfermedad de Parkinson. Consenso Delphi de un grupo de expertos en trastornos del movimiento.

INTRODUCTION: Motor fluctuations are one of the most common complications of Parkinson's disease and their treatment is still a complex matter. Therefore, from the Neurology Movement Disorders Group we present our clinical experience in the treatment of these complications, with the intention of it being useful in decision-making in daily clinical practice. DEVELOPMENT: Nineteen questions were developed based on a literature review and an open survey answered by members of this group. These issues were discussed in two phases, using the Delphi methodology. Considering the results of the survey, levodopa dose adjustment and dopamine agonists are the option with the best efficacy/tolerability ratio in the treatment of motor fluctuations. Rotigotine is useful in the motor fluctuations associated with gastroparesis, and intermittent subcutaneous apomorphine has positive effects in patients with unpredictable off periods. The most relevant adverse effect associated with dopamine agonists is impulse control disorder. Catechol-O-methyltransferase inhibitors are useful in the initial stages of motor fluctuations, especially in wearing off. Monoamine oxidase inhibitors are generally drugs that are well-tolerated and useful in motor fluctuations. If these measures are not effective, second-line treatments should be indicated on a case-by-case basis. CONCLUSION: The clinical profile of patients with Parkinson's disease is paramount in deciding the most appropriate therapy for the treatment of motor fluctuations.

TITLE: Experiencia clínica en el tratamiento de las fluctuaciones motoras en la enfermedad de Parkinson. Consenso Delphi de un grupo de expertos en trastornos del movimiento.Introducción. Las fluctuaciones motoras son una de las complicaciones más frecuentes en la enfermedad de Parkinson y su tratamiento sigue siendo complejo. Por ello, desde el Grupo de Trastornos del Movimiento de la Asociación Madrileña de Neurología presentamos nuestra experiencia clínica en el tratamiento de estas complicaciones, con la intención de que sea de utilidad en la toma de decisiones en la práctica clínica diaria. Desarrollo. Se elaboraron 19 preguntas a partir de una revisión bibliográfica y una encuesta abierta respondida por los miembros de dicho grupo. Dichas cuestiones se debatieron en dos fases, utilizando la metodología Delphi. Considerando los resultados de la encuesta, el ajuste de la dosis de levodopa y los agonistas dopaminérgicos son la opción con mejor relación eficacia/tolerabilidad en el tratamiento de las fluctuaciones motoras. La rotigotina es útil en las fluctuaciones motoras asociadas a gastroparesia, y la apomorfina subcutánea intermitente, en pacientes con off impredecible. El efecto adverso más relevante asociado a los agonistas dopaminérgicos es el trastorno del control de impulsos. Los inhibidores de la catecol-O-metiltransferasa son útiles en las fluctuaciones motoras de inicio, especialmente en el wearing off. Los inhibidores de la monoaminooxidasa son fármacos, en general, bien tolerados y útiles en las fluctuaciones motoras. En caso de que estas medidas no resulten eficaces, se deben indicar terapias de segunda línea de manera individualizada. Conclusión. El perfil clínico del paciente con enfermedad de Parkinson es primordial para decidir la terapia más adecuada en el tratamiento de las fluctuaciones motoras.

Quality of life and non-motor symptoms in Parkinson's disease patients with subthreshold depression.

BACKGROUND: The role of subthreshold depression (subD) in Parkinson's Disease (PD) is not clear. The present study aimed to compare the quality of life (QoL) in PD patients with subD vs patients with no depressive disorder (nonD). Factors related to subD were identified. MATERIAL AND METHODS: PD patients and controls recruited from the COPPADIS cohort were included. SubD was defined as Judd criteria. The 39-item Parkinson's disease Questionnaire (PDQ-39) and the EUROHIS-QOL 8-item index (EUROHIS-QOL8) were used to assess QoL. RESULTS: The frequency of depressive symptoms was higher in PD patients (n = 694) than in controls (n = 207) (p < 0.0001): major depression, 16.1% vs 7.8%; minor depression, 16.7% vs 7.3%; subD, 17.4% vs 5.8%. Both health-related QoL (PDQ-39; 18.1 ±â€¯12.8 vs 11.6 ±â€¯10; p < 0.0001) and global QoL (EUROHIS-QOL8; 3.7 ±â€¯0.5 vs 4 ±â€¯0.5; p < 0.0001) were significantly worse in subD (n = 120) than nonD (n = 348) PD patients. Non-motor Symptoms Scale (NMSS) total score was higher in subD patients (45.9 ±â€¯32 vs 29.1 ±â€¯25.8;p < 0.0001). Non-motor symptoms burden (NMSS;OR = 1.019;95%CI 1.011-1.028; p < 0.0001), neuropsychiatric symptoms (NPI; OR = 1.091; 95%CI 1.045-1.139; p < 0.0001), impulse control behaviors (QUIP-RS; OR = 1.035; 95%CI 1.007-1063; p = 0.013), quality of sleep (PDSS; OR = 0.991; 95%CI 0.983-0.999; p = 0.042), and fatigue (VAFS-physical; OR = 1.185; 95%CI 1.086-1.293; p < 0.0001; VAFS-mental; OR = 1.164; 95%CI 1.058-1.280; p = 0.0001) were related to subD after adjustment to age, disease duration, daily equivalent levodopa dose, motor status (UPDRS-III), and living alone. CONCLUSIONS: SubD is a frequent problem in patients with PD and is more prevalent in these patients than in controls. QoL is worse and non-motor symptoms burden is greater in subD PD patients.

Non-motor symptom burden is strongly correlated to motor complications in patients with Parkinson's disease.

BACKGROUND AND PURPOSE: The objective of this study was to analyze the relationship between motor complications and non-motor symptom (NMS) burden in a population of patients with Parkinson's disease (PD) and also in a subgroup of patients with early PD. METHODS: Patients with PD from the COPPADIS cohort were included in this cross-sectional study. NMS burden was defined according to the Non-Motor Symptoms Scale (NMSS) total score. Unified Parkinson's Disease Rating Scale (UPDRS) part IV was used to establish motor complication types and their severity. Patients with ≤5 years of symptoms from onset were included as patients with early PD. RESULTS: Of 690 patients with PD (62.6 ± 8.9 years old, 60.1% males), 33.9% and 18.1% presented motor fluctuations and dyskinesia, respectively. The NMS total score was higher in patients with motor fluctuations (59.2 ± 43.1 vs. 38.3 ± 33.1; P < 0.0001) and dyskinesia (63.5 ± 40.7 vs. 41.4 ± 36.3; P < 0.0001). In a multiple linear regression model and after adjustment for age, sex, disease duration, Hoehn & Yahr stage, UPDRS-III score and levodopa equivalent daily dose, UPDRS-IV score was significantly related to a higher NMSS total score (ß = 0.27; 95% confidence intervals, 2.81-5.61; P < 0.0001), as it was in a logistic regression model on dichotomous NMSS total score (≤40, mild or moderate vs. >40, severe or very severe) (odds ratio, 1.31; 95% confidence intervals, 1.17-1.47; P < 0.0001). In the subgroup of patients with early PD (n = 396; mean disease duration 2.7 ± 1.5 years), motor fluctuations were frequent (18.1%) and similar results were obtained. CONCLUSIONS: Motor complications were frequent and were associated with a greater NMS burden in patients with PD even during the first 5 years of disease duration.

COPPADIS-2015 (COhort of Patients with PArkinson's DIsease in Spain, 2015): an ongoing global Parkinson's disease project about disease progression with more than 1000 subjects included. Results from the baseline evaluation.

BACKGROUND AND PURPOSE: In Parkinson's disease (PD), the course of the disorder is highly variable between patients. Well-designed, prospective studies for identifying PD progression biomarkers are necessary. Our aim was to show the results of baseline evaluations of an ongoing global PD project, COPPADIS-2015 (Cohort of Patients with PArkinson's DIsease in Spain, 2015). METHODS: This was an observational, descriptive, nationwide study (Spain). The recruitment period ended in October 2017. Baseline evaluation included more than 15 validated scales and complementary studies in a subgroup of participants. RESULTS: In total, 1174 subjects from 35 centres were considered valid for baseline analysis: 694 patients (62.6 ± 8.9 years old, 60.3% males), 273 caregivers (58.5 ± 11.9 years old, 31.8% males) and 207 controls (61 ± 8.3 years old, 49.5% males). The mean disease duration was 5.5 ± 4.4 years. Hoehn and Yahr stage was 1 or 2 in 90.7% of the patients whilst 33.9% and 18.1% of them presented motor fluctuations and dyskinesias, respectively. The mean Non-Motor Symptoms Scale total score was 45.4 ± 38.1, and 30.4% of the patients presented cognitive impairment, 16.1% major depression, 12.7% impulse control disorder, 7.2% compulsive behaviour, 57.2% pain and 13.2% falls. Compared to the control group, PD patients presented a significantly higher burden of non-motor symptoms and a worse quality of life. More than 300 subjects conducted complementary studies (serum biomarkers, genetic and neuroimaging). CONCLUSIONS: Parkinson's disease is a complex disorder and different non-motor symptoms are frequently present and are more prevalent than in controls. In real clinical practice it is important to ask for them.

Nucleus incertus ablation disrupted conspecific recognition and modified immediate early gene expression patterns in 'social brain' circuits of rats.

Social interaction involves neural activity in prefrontal cortex, septum, hippocampus, amygdala and hypothalamus. Notably, these areas all receive projections from the nucleus incertus (NI) in the pontine tegmentum. Therefore, we investigated the effect of excitotoxic lesions of NI neurons in adult male, Wistar rats on performance in a social discrimination test, and associated changes in immediate-early gene protein levels. NI was lesioned with quinolinic acid, and after recovery, rats underwent two trials in the 3-chamber test. In the first trial, NI-lesioned and sham-lesioned rats spent longer exploring a conspecific than an inanimate object. By contrast, in the second trial, NI-lesioned rats visited the familiar and novel conspecific chambers equally, whereas sham-lesioned rats spent longer engaging with the novel rat. Quantification of Fos- and Egr-1-immunoreactivity (IR) levels in brain areas implicated in social behaviour, revealed that social encounter and NI lesion produced complex, differential changes. For example, Egr-1-IR was broadly decreased in several amygdala nuclei in NI-lesioned rats relative to sham, but Fos-IR levels were unaltered. In hippocampus, NI-lesioned rats displayed decreased Fos-IR in CA2 and CA3, while Egr-1-IR was increased in the polymorphic dentate gyrus, CA1, CA2 and subiculum of NI-lesioned rats, relative to sham. Social encounter-related Egr-1-IR was also decreased in septum and anterior and lateral hypothalamus of NI-lesioned rats. Overall, these data suggest NI networks can modulate the activity of sensory, emotional and executive brain areas involved in social recognition, with a likely involvement of neuronal Egr-1 activation in amygdala, septum and hypothalamus, and Erg-1 inhibition in hippocampus.

[Cost-utility analysis of two formulations of botulinum toxin type A in the treatment of blepharospasm and cervical dystonia in Spain]. / Analisis coste-utilidad de dos formulaciones de toxina botulinica de tipo A en el tratamiento del blefaroespasmo y la distonia cervical en España.

INTRODUCTION: Studies on focal dystonia showed that the formulations of botulinum toxin type A, incobotulinumtoxin-A (Inco-BTA) and onabotulinumtoxin-A (Ona-BTA), have equivalent efficacy and safety. AIM: To carry-out a cost-utility analysis of Inco-BTA administered on flexible intervals vs. Ona-BTA on a fixed interval, in the treatment of blepharospasm and cervical dystonia. PATIENTS AND METHODS: A probabilistic Markov model was designed to estimate costs (euros, 2017) and benefits (quality-adjusted life years, QALY), from the Spanish National Health Service perspective and on a 5-year time horizon, of treatment of blepharospasm and cervical dystonia with Inco-BTA (6-12 month flexible intervals) versus Ona-BTA (12-month fixed intervals). It is assumed that symptoms will re-emerge some time later in both options. Result was expressed as incremental cost-utility ratio (ICUR). RESULTS: Inco-BTA and Ona-BTA costs were 3,742 and 3,366 euros respectively, in blepharospasm, and 6,673 and 6,419 euros in cervical dystonia. Patients treated with Inco-BTA remained asymptomatic for 22.12, and 21.34 more weeks than those treated with Ona-BTA, leading in 3.040 and 3.012 QALY, respectively, in blepharospasm, and 3.471 and 3.401 QALY, respectively, in cervical dystonia. Differences showed statistical significance in all cases. ICUR was estimated as 13,576 and 4,158 euros/QALY in blepharospasm and cervical dystonia, respectively. CONCLUSIONS: Treatment of blepharospasm and cervical dystonia with Inco-BTA is a cost-effective therapeutic alternative in Spain, based on the flexibility of their administration.

TITLE: Analisis coste-utilidad de dos formulaciones de toxina botulinica de tipo A en el tratamiento del blefaroespasmo y la distonia cervical en España.Introduccion. Las formulaciones de toxina botulinica de tipo A, incobotulinumtoxinA (Inco-TBA) y onabotulinumtoxinA (Ona-TBA), han demostrado eficacia y seguridad similar en los estudios de distonias focales en los que se han comparado. Objetivo. Realizar un analisis coste-utilidad de Inco-TBA, administrada en intervalos flexibles, frente a Ona-TBA, administrada en intervalos fijos, en el tratamiento del blefaroespasmo y la distonia cervical. Pacientes y metodos. Un modelo de Markov probabilistico estimo, desde la perspectiva del Sistema Nacional de Salud español y en un horizonte de cinco años, el coste (euros, 2017) y el resultado (años de vida ajustados a calidad, AVAC) del tratamiento del blefaroespasmo y la distonia cervical mediante intervalos flexibles con Inco-TBA (6-20 semanas) y fijos con Ona-TBA (12 semanas). Se asume que los sintomas reapareceran despues de un tiempo en ambos. El resultado se expreso como ratio coste-utilidad incremental (RCUI). Resultados. El coste de la Inco-TBA y la Ona-TBA fue, respectivamente, de 3.742 y 3.366 euros en el blefaroespasmo y de 6.673 y 6.419 euros en la distonia cervical. Los pacientes tratados con Inco-TBA permanecieron asintomaticos 22,12 y 21,34 semanas mas que los tratados con Ona-TBA, lo que resulto 3,040 y 3,012 AVAC, respectivamente, en el blefaroespasmo, y 3,471 y 3,401 AVAC, respectivamente, en la distonia cervical. En todos los casos, las diferencias presentaron significacion estadistica. La RCUI fue de 13.576 y 4.158 euros/AVAC, respectivamente. Conclusiones. El tratamiento del blefaroespasmo y la distonia cervical con Inco-TBA, administrada siguiendo un esquema posologico de intervalos flexibles, constituye una alternativa terapeutica eficiente en España.

Large scale, prospective screening of EGFR mutations in the blood of advanced NSCLC patients to guide treatment decisions.

BACKGROUND: In a significant percentage of advanced non-small-cell lung cancer (NSCLC) patients, tumor tissue is unavailable or insufficient for genetic analyses. We prospectively analyzed if circulating-free DNA (cfDNA) purified from blood can be used as a surrogate in this setting to select patients for treatment with epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs). PATIENTS AND METHODS: Blood samples were collected in 119 hospitals from 1138 advanced NSCLC patients at presentation (n = 1033) or at progression to EGFR-TKIs (n = 105) with no biopsy or insufficient tumor tissue. Serum and plasma were sent to a central laboratory, cfDNA purified and EGFR mutations analyzed and quantified using a real-time PCR assay. Response data from a subset of patients (n = 18) were retrospectively collected. RESULTS: Of 1033 NSCLC patients at presentation, 1026 were assessable; with a prevalence of males and former or current smokers. Sensitizing mutations were found in the cfDNA of 113 patients (11%); with a majority of females, never smokers and exon 19 deletions. Thirty-one patients were positive only in plasma and 11 in serum alone and mutation load was higher in plasma and in cases with exon 19 deletions. More than 50% of samples had <10 pg mutated genomes/µl with allelic fractions below 0.25%. Patients treated first line with TKIs based exclusively on EGFR positivity in blood had an ORR of 72% and a median PFS of 11 months. Of 105 patients screened after progression to EGFR-TKIs, sensitizing mutations were found in 56.2% and the p.T790M resistance mutation in 35.2%. CONCLUSIONS: Large-scale EGFR testing in the blood of unselected advanced NSCLC patients is feasible and can be used to select patients for targeted therapy when testing cannot be done in tissue. The characteristics and clinical outcomes to TKI treatment of the EGFR-mutated patients identified are undistinguishable from those positive in tumor.

The antero-posterior heterogeneity of the ventral tegmental area.

The ventral tegmental area (VTA) is a brain region processing salient sensory and emotional information, controlling motivated behaviors, natural or drug-related reward, reward-related learning, mood, and participating in their associated psychopathologies. Mostly studied for its dopamine neurons, the VTA also includes functionally important GABA and glutamate cell populations. Behavioral evidence supports the presence of functional differences between the anterior VTA (aVTA) and the posterior VTA (pVTA), which is the topic of this review. This antero-posterior heterogeneity concerns locomotor activity, conditioned place preference and intracranial self-administration, and can be seen in response to ethanol, acetaldehyde, salsolinol, opioids including morphine, cholinergic agonists including nicotine, cocaine, cannabinoids and after local manipulation of GABA and serotonin receptors. It has also been observed after viral-mediated manipulation of GluR1, phospholipase Cγ (PLCγ) and cAMP response element binding protein (CREB) expression, with impact on reward and aversion-related responses, on anxiety and depression-related behaviors and on pain sensitivity. In this review, the substrates potentially underlying these aVTA/pVTA differences are discussed, including the VTA sub-nuclei and the heterogeneity in connectivity, cell types and molecular characteristics. We also review the role of the tail of the VTA (tVTA), or rostromedial tegmental nucleus (RMTg), which may also participate to the observed antero-posterior heterogeneity of the VTA. This region, partly located within the pVTA, is an inhibitory control center for dopamine activity. It controls VTA and substantia nigra dopamine cells, thus exerting a major influence on basal ganglia functions. This review highlights the need for a more comprehensive analysis of VTA heterogeneity.

Initial motor symptoms of Parkinson disease.

Parkinson disease (PD) is characterized by a wide variety of motor and nonmotor symptoms. Although recently nonmotor symptoms have gained considerable relevance and interest, especially in advanced stages, motor symptoms define the main core of PD and are essential for clinical diagnosis. In this article, we review the characteristics, presentation, and evolution of motor symptoms in early PD.

[Neuroprotection in Parkinson's disease: analysis though group of experts' methodology]. / Neuroprotección en la enfermedad de Parkinson: análisis a través de la metodología de informadores clave.

INTRODUCTION: Currently used antiparkinsonian drugs neither stop nor slow-down the progressive nature of the disease. The final phase of PD is characterized by the presence of symptoms and signs resistant to dopaminergic agents, such as depression, dementia, freezing and falls. Therefore, it is urgent to develop therapies able to positively modify this outcome. Despite neuroprotection is a research priority in PD, no effective strategies have been found so far. METHOD: A key informants study was conducted. A group of experts in PD fulfilled a questionnaire of 10 questions to explore the most important topics related to neuroprotection. Afterwards a consensus about the current situation of neuroprotection in PD was established and future directions of development were suggested. RESULTS: Most of the answers emphasized the need of new concepts, the limitations of animal models and the difficulties in the difficulties in demonstrating a neuroprotective effects in humans owing to a lack of biomarkers. Some of the experts believe that we are already exerting a disease modifying effect. CONCLUSIONS: The concept of neuroprotection should be widened. Animal models should be improved. A reliable biomarker to start neuroprotective therapies long before the appearance of motor symptoms and to evaluate the neuroprotective effect of any therapy should be urgently developed.

[Primary cerebral lymphoma in an immunocompetent patient]. / Linfoma primario cerebral en un paciente inmunocompetente.

Primary lymphoma of the central nervous system PLCNS) was a very uncommon disease until a few decades ago. However, its incidence has increased in recent years, mainly in immunocompetent patients. Thus, some authors suggest that PLCNS may become the most frequent tumor. The final diagnosis is based on the pathology study of the samples obtained with stereotaxic biopsy or with surgery, but X-ray studies may be very useful in the orientation of this disease. The typical finding in immunocompetent subjects is the appearance of single supratentorial lesions with homogeneous uptake of contrast and scarce edema, without edema, necrosis nor bleeding. Survival has increased thanks to the new treatments applied, although there is still controversy regarding frequency, dose and administration form of many of them. We present the case of an immunocompetent male patient with progressive dyplopia and vertigo caused by a primary lymphoma of the central nervous system and a review the literature.

Characterization of bile acids and fatty acids from ox bile in oil paintings by gas chromatography-mass spectrometry.

Characterization of ox bile, traditionally used in painting, is of interest in the fields of archaeometry and conservation and restoration of works of art. Bile acids, fatty acids (F), and cholesterol found in ox bile have been identified using a derivatization method that combines the formation of ethyl esters from the carboxylic groups and the trimethylsilyl ethers from hydroxyl groups. This method of analysis is consistent with these others proposed by the authors to analyze drying oils, proteins, and diterpenic resins usually used as binders and varnishes by the painters. Bile acids from binary samples such as animal glue/ox bile, casein/ox bile and Arabic gum/ox bile have been successfully analyzed using the proposed method. Finally, a method of analysis of mixtures of drying oil and ox bile has been also proposed attempting to quantitatively characterize samples in which ox bile was added to the drying oil for increasing the surfactant properties.

Analytical study of proteinaceous binding media in works of art by gas chromatography using alkyl chloroformates as derivatising agents.

In this work, we present the results obtained in an analytical study of the different types of proteinaceous binding media most commonly used in paintings, using GC-FID as the technique of analysis and GC-MS as a confirmatory technique. The application of this methodology requires prior hydrolysis of the proteins in the binding media to obtain free amino acids and then volatile derivatives, in this case by reaction with chloroformates due to advantages of speed, safety and the aqueous medium in which the reaction occurs. The method proposed for the proteinaceous binding media study is to calculate the proportions of the different amino acids with respect to alanine. This method provided good characterisation of different binding media, such as pork gelatine, beef gelatine, albumin, egg white and casein. The proposed method is used for the identification of binding media (including mixtures of binders) present in real samples from paintings in the city of Valencia, Spain.

Identification of lipid binders in paintings by gas chromatography. Influence of the pigments.

The influence of the presence and the type of pigments in the lipid binding media of paintings were studied by gas chromatography with flame ionization detector. The drying oils were linseed stand oil, poppy oil and sunflower oil, and the pigments studied were cadmium red, cobalt blue, tin white, lead white, chalk and plaster of Paris, commonly used in paintings. The results indicate that the stearic/palmitic ratio and the presence of pigments are quite stable during ageing. However, some differences in the oleic acid/palmitic acid ratio were found, depending on the type of pigment present in the lipid binding media. These variations are related to the drying effect of the pigments. The proposed method has been applied to the identification of drying oils in two samples from baroque paintings in the "Basilica de la Virgen de los Desamparados" of Valencia, Spain.

Comparison of auditory, somatosensory, and visually instructed and internally generated finger movements: a PET study.

We sought to determine how the pattern of cerebral activation, and in particular in frontal motor areas, during the performance of conditional motor tasks is dependent upon the modality of instruction (visual, auditory, or somatosensory). Regional cerebral blood flow (rCBF) changes with externally instructed movements were also compared with internally generated, self-paced, movements. We used positron emission tomography (PET) with the tracer H2(15O) to measure rCBF in 22 healthy volunteers. External stimuli consisted of the randomized presentation of single or double impulses using a single modality for each condition. In the movement scans, the subjects used the index and middle fingers of their right hands to press a left button for a single and a right button for a double impulse, respectively. In the control scans, subjects were required to covertly distinguish a single from a double stimulus without a motor response. Data were analyzed using conventional subtraction techniques with a statistical threshold of Z > 2.33 with corrections for multiple comparisons. When the activation differences between the three externally instructed movement conditions were statistically compared, nonsignificant trends toward increased rCBF in the sensory cortex of the modality of the cue were observed but no differential activity in cortical motor areas. Internally generated movements, when compared to externally triggered movements, were associated with enhanced activation in bilateral medial and lateral premotor, dorsolateral prefrontal and superior parietal regions, largely confirming previous reports. The data indicate that, on a regional level, modality-specific processing in a conditional motor task does not occur in frontal motor areas and is probably confined to sensory areas.

Analytical study of canvas painting collection from the Basilica de la Virgen de los Desamparados using SEM/EDX, FT-IR, GC and electrochemical techniques.

A new method, based on the combined use of scanning electron microscopy-x-ray microanalysis, Fourier transform infrared spectroscopy, gas chromatography and differential pulse voltammetry, is proposed which permits a parallel investigation of organic and inorganic materials and the characterization of the artistic technique employed in canvas painting. The proposed method has led to analyze succesfully the canvas painting collection exhibited in the Basílica de la Virgen de los Desamparados (Valencia, Spain) which includes art works from 17th to 20th century.

Electrochemical analysis of the alterations in copper pigments using charge transfer coefficient/peak potential diagrams. Application to microsamples of baroque wall paintings attached to polymer film electrodes.

The alteration of copper pigments in art samples was studied by linear scan and cyclic voltammetry using sample-modified Elvacite 2044 film electrodes on the basis of two-dimensional diagrams of charge transfer coefficients calculated from Tafel plots of reductive dissolution processes vs. peak potential. Characteristic voltammetric peaks were obtained for pigments used in the baroque vault frescoes of the Basílica de la Virgen de los Desamparados painted by Antonio Palomino. Results obtained by voltammetric techniques were compared with those from SEM/EDX and FT-IR analysis obtaining a good agreement and leaving to an unambiguous identification of pigments used by Palomino and their alteration products.