Biomarcadores diagnósticos y de deterioro cognitivo en la enfermedad de Parkinson

262 p.La enfermedad de Parkinson es una enfermedad neurodegenerativa en la que, como en otras, el proceso fisiopatológico que conduce a la muerte de neuronas está presente desde tiempo antes del diagnóstico. Las manifestaciones clínicas cardinales son temblor, bradicinesia, rigidez y pérdida de reflejos posturales, denominadas síntomas motores. Aun hoy, doscientos años después de la detallada descripción que hizo James Parkinson en "An essay on the shaking palsy", el diagnóstico de la enfermedad se basa en criterios clínicos. Esto hace que, incluso entre expertos, puedan existan errores diagnósticos, dado que otras enfermedades cursan con manifestaciones similares.Por otro lado, además de los síntomas motores, existe otro grupo de manifestaciones clínicas conocidas como "síntomas no motores" que contribuyen de manera sustancial al empeoramiento de la calidad de vida de los pacientes. Ente ellas se encuentran las alteraciones del sueño, las alteraciones del sistema nervioso autónomo, los trastornos psiquiátricos o las alteraciones del tracto digestivo. El deterioro cognitivo es una manifestación no motora frecuente en la enfermedad de Parkinson. De hecho, con el curso de la enfermedad, una proporción importante de pacientes termina desarrollando demencia, con consecuencias muy del etéreas sobre el individuo y su entorno. El deterioro cognitivo leve en la enfermedad de Parkinson es un constructo definido para etiquetar a aquellos pacientes que, teniendo déficit cognitivo, no presentan alteraciones de su funcionalidad en el día a día. Aunque se sabe que éste es un factor de riesgo para desarrollar demencia, no todos los pacientes con deterioro cognitivo leve acaban desarrollándola.Por tanto, el disponer de biomarcadores capaces de ayudar en el diagnóstico de la enfermedad de Parkinson o de detectar pacientes con mayor riesgo de desarrollar demencia, es una necesidad crucial aún sin resolver. La investigación de biomarcadores ha de ser paralela al desarrollo de tratamientos neuroprotectores que, según las corrientes de evidencia actuales, sólo serían útiles en las fases más tempranas de la enfermedad. El presente trabajo de Tesis Doctoral se centra en la investigación de biomarcadores, tanto para el diagnóstico como para la detección de pacientes con más riesgo de desarrollar demencia asociada a la enfermedad de Parkinson. El trabajo se ha basado en el estudio exhaustivo desde el punto de vista clínico y neuropsicológico de una cohorte de pacientes con enfermedad de Parkinson sin demencia y una cohorte de controles. La búsqueda de biomarcadores se ha realizado en líquido cefalorraquídeo y sangre (plasma). Como aproximación se han tenido en cuenta tres de los procesos fisiopatológicos implicados en la enfermedad de Parkinson: agregación de proteínas, inflamación, y autofagia. Por ello, se han evaluado en líquido cefalorraquídeo las proteínas que se encuentran en los agregados patológicos cerebrales (ß-amiloide, tau, tau fosforilada y -sinucleína) y diversas citoquinas en líquido cefalorraquídeo y en sangre. Además, se ha medido la actividad de diversos enzimas lisosomales en líquido cefalorraquídeo. Como forma de validar y ampliar parte de nuestros resultados, se ha explorado una base de datos internacional disponible de forma pública del estudio Parkinson's Progression Markers Initiative.Con los resultados de la presente Tesis Doctoral se ha demostrado que la combinación en forma de ratios de los niveles de diversas proteínas en líquido cefalorraquídeo tiene un mayor valor como herramienta diagnóstica para diferenciar pacientes de controles que los niveles de las proteínas por separado. Así, por ejemplo, la ratio formada por tau fosforilada/¿-sinucleína diferencia a pacientes de controles con un área bajo la curva de 0,85. Por otro lado, el factor de necrosis tumoral se ha encontrado elevado en líquido cefalorraquídeo de pacientes, y en conjunción con la ratio anterior presenta unos valores de precisión diagnóstica mejores, por lo que podría servir como biomarcador diagnóstico de la enfermedad. Además, niveles crecientes de interleuquina 6 en plasma se asocian a mayor gravedad de la enfermedad, por lo que podría tener utilidad como biomarcador pronóstico de la misma. En relación al deterioro cognitivo, algunas de las ratios formadas por las proteínas de agregación, presentan correlación con la integridad de algunos dominios cognitivos, como memoria o función visuoespacial, por lo que podrían servir como biomarcador para diferenciar subtipos de deterioro cognitivo leve. Además, explorando la base de datos del estudio Parkinson¿s Progression Markers Initiative, que dispone de datos de seguimiento, se ha comprobado que la elevación de algunas de esas ratios (tau total/ß-amiloide, tau total/¿-sinucleína y tau total/ß-amiloide+-sinucleína) predicen el desarrollo de demencia a los tres años de evolución. Por último, en relación a los enzimas lisosomales, la actividad de la catepsina D, se ha encontrado elevada en pacientes con deterioro cognitivo leve al compararlos con los cognitivamente normales. Por otro lado, la actividad de la ß-hexosaminidasa se asocia con los niveles en líquido cefalorraquídeo de las proteínas de agregación, por lo que la actividad de este enzima podría estar implicada en el depósito de dichas proteínas. Con todo, los resultados de esta tesis sugieren varios candidatos como biomarcadores para el diagnóstico y para la detección de la progresión del deterioro cognitivo. Queda patente a lo largo del trabajo la idea de que, dado que el sustrato fisiopatológico de la enfermedad es complejo y en el intervienen diferentes mecanismos, parece poco probable, que un único biomarcador sea capaz de alcanzar una precisión suficiente. Los resultados encontrados, aportan evidencia sobre la utilidad de diversos biomarcadores que pueden guiar las líneas a seguir en futuros estudios

Estrutura fatorial da escala de suporte social subjetivo: validação em uma mostra de estudantes universitários chilenos

El objetivo de este artículo es adaptar y validar la Escala de Apoyo Social Subjetivo (EASS, de Vaux et al., 1986), a la vez que describir su estructura factorial. Esta escala está compuesta por 10 ítems distribuidos en dos dimensiones: apoyo familiar y apoyo de los amigos. Se examinan las propiedades psicométricas de la escala y la dimensionalidad de la misma en una muestra de estudiantes universitarios chilenos (N = 681). Los resultados indican que el EASS constituye un instrumento fiable (α = .86) y válido para la medición del apoyo social subjetivo. Las dimensiones de la EASS obtienen entre sí una correlación significativa y moderada (r = .41; p < .001). Las cargas factoriales para los ítems en el análisis factorial confirmatorio fluctuaron entre .40 y .93, mostrando buenos índices de ajuste para el modelo de dos factores de primer orden correlacionados (CFI = .97, TLI = .93, RFI = .97, IFI = .97, NFI = .96 y RSMEA = .08).The purpose of this paper is to adapt and validate the Subjective Social Support Scale (Vaux et al, 1986) and to describe its factor structure. The scale consists of 10 items distributed in two dimensions measured in the original instrument: family support and support from friends. The psychometric properties and dimensionality of the scale are examined in a sample of Chilean college students (N = 681). Results show that the scale is a reliable instrument (α = .86) and valid for measuring subjective social support. Its two dimensions show a moderate and significant correlation (r = .41; p < .001). The factor loadings of the items in the confirmatory factor analysis varied between .40 and .93, showing good fit indices for the correlated first order two factor model (CFI = .97, TLI = .93, RFI = .97, IFI = .97, NFI = .96 and RSMEA = .08).O objetivo deste artigo é adaptar e validar a Escala de Apoio Social Subjetivo (EASS, de Vaux et al., 1986), e ao mesmo tempo descrever sua estrutura fatorial. Esta escala está composta por 10 itens distribuídos em duas dimensões: apoio familiar e apoio dos amigos. Examinam-se as propriedades psicométricas da escala e a dimensionalidade da mesma em uma mostra de estudantes universitários chilenos (N = 681). Os resultados indicam que o EASS constitui um instrumento fiável (α = .86) e válido para a medição do apoio social subjetivo. As dimensões da EASS obtêm entre si uma correlação significativa e moderada (r = .41; p < .001). As cargas fatoriais para os itens na análise fatorial confirmatória flutuaram entre .40 e .93, mostrando bons índices de ajuste para o modelo de dois fatores de primeira ordem correlacionados (CFI = .97, TLI = .93, RFI = .97, IFI = .97, NFI = .96 e RSMEA = .08)

Resistencia amazónica frente a la invasión petrolera en la Curva del Diablo Perú, Bagua 2008 – 2009

El cinco de junio del 2009, la “Curva del Diablo” se convertía en uno de los escenarios mas sangrientos de todos los que han podido exitir en la historia del Perú en los últimos 100 años. Con este nombre se denomina a la curva que forma la carretera Fernando Belaúnde Terry, cercana a la ciudad de Bagua – Región Amazonas.El conflicto entre la población indígena amazónica y el gobierno peruano se larvó durante dos años previos. Sin embargo, el abuso y la explotación por parte de las empresas extractivistas, sobre todo petroleras, con respaldo de los diferentes gobiernos venía dándose desde hace varias décadas. Los pueblos originarios se levantaron organizadamente al margen de toda ideología o partido político e hicieron oír su voz por primera vez con la magnitud que veremos. A partir de esa fecha, las poblaciones originarias amazónicas fueron tomadas en cuenta y su problemática puesta en agenda y debate nacional. Hay entonces un “antes” y un “después” de Bagu

Increased Impulsivity following progressive nigral degenereation and chronic pramipexole treatment in an animal model of Parkinson's disease

Dopamine agonists (DA) that are widely used to treat motor deficits in patients with Parkinson’s disease (PD) are frequently associated with the development of abnormal-impulsive behaviors (AIB). The pathophysiology of AIB is poorly understood and there is a need for reliable animal models. We have analyzed the behavior of parkinsonian (injection of adeno-associated viral vectors (AAV) encoding for A53T mutated hα-syn in the substantia nigra compacta) and control (AAV- GFP expression) rats under chronic treatment with the D2/D3 receptor DA pramipexole (PPX) during 4 weeks, in OFF and ON medication states, using the 5-Choice Serial Reaction Time-Task (5-CSRTT). Before PPX treatment, the dopaminergic lesion increased the premature responses rate (waiting impulsivity) that was further increased with PPX during the 4 weeks of treatment in ON medication state and that was significantly higher than in control rats. A similar pattern of changes was observed in the variables related to attention (reduced accuracy in the responses and increased omissions). Premature response rate before and after treatment (both in ON and OFF medication) were correlated. In turn, premature responses before treatment and in OFF correlated with the striatal dopaminergic depletion (Dopamine transporter (DAT) immunochemistry). No significant changes were observed in OFF medication state in premature responses rate respect to the pretreatment state. The striatal expression of FosB/ΔFosB inversely correlated with the DAT expression and was higher in the lateral region of both striata and in the shell and core of the nucleus accumbens in parkinsonian than in control rats. In conclusion, these results indicate that the dopaminergic lesion is a risk factor to develop abnormal impulsive behaviors in PD under DA treatment and that this model could be a valid tool to investigate the pathophysiology of AIB in PD (DFG11/019, PI11/02109).Universidad de Málaga. Campus de Excelencia Internacional Andalucía Tech

Morphological variation of the labellum of Vanilla planifolia Andrews (Orchidaceae) in Oaxaca, Mexico

Infraspecific variation has transcendental ecological consequences for species adaptation to new niches. Estimating levels of variation is key for understanding the life history of a species, as well as for designing strategies for use and conservation. For this reason, the objective of this study was to characterize infra-specific morphological variation of the labellum of V. planifolia, of 122 flowers from 28 specimens from the state of Oaxaca and two specimens from Veracruz, Mexico. The labellum of each flower was dissected and analyzed by morphometry. Sixty variables were obtained and grouped into basal, middle and apical regions. An analysis of variance was performed considering the collections and the origin of each individual as sources of variation. Principal components and cluster analyses were also conducted. Differences in the 60 variables analyzed were highly significant among the collections. Among environments, 18 variables showed significant differences, which were situated in the lateral and middle lobes of the labellum. Thus, these structures were considered susceptible to environmental changes. The remaining 42 variables situated in the basal and middle regions of the labellum, which were fused to the edges of the floral column were not significantly different among environments. With the first three principal components, the model explained 73% of the total variation studied. Morphological variation of the flower labellum was represented by four morphotypes distributed in three environments. Highlights The evaluation of vanilla flowers wild does not allow to have the same number of treatments or repetitions, for the inaccessibility of the species. Morphometric analysis of the labellum revealed infra-specific variation in the germplasm of Vanilla planifolia. The features of the basal and middle regions of the labellum are the most informative in distinguishing the variation between vanilla specimens.Infraspecific variation has transcendental ecological consequences for species adaptation to new niches. Estimating levels of variation is key for understanding the life history of a species, as well as for designing strategies for use and conservation. For this reason, the objective of this study was to characterize infra-specific morphological variation of the labellum of V. planifolia, of 122 flowers from 28 specimens from the state of Oaxaca and two specimens from Veracruz, Mexico. The labellum of each flower was dissected and analyzed by morphometry. Sixty variables were obtained and grouped into basal, middle and apical regions. An analysis of variance was performed considering the collections and the origin of each individual as sources of variation. Principal components and cluster analyses were also conducted. Differences in the 60 variables analyzed were highly significant among the collections. Among environments, 18 variables showed significant differences, which were situated in the lateral and middle lobes of the labellum. Thus, these structures were considered susceptible to environmental changes. The remaining 42 variables situated in the basal and middle regions of the labellum, which were fused to the edges of the floral column were not significantly different among environments. With the first three principal components, the model explained 73% of the total variation studied. Morphological variation of the flower labellum was represented by four morphotypes distributed in three environments. Highlights The evaluation of vanilla flowers wild does not allow to have the same number of treatments or repetitions, for the inaccessibility of the species. Morphometric analysis of the labellum revealed infra-specific variation in the germplasm of Vanilla planifolia. The features of the basal and middle regions of the labellum are the most informative in distinguishing the variation between vanilla specimens

LA LACTANCIA MATERNA DURANTE LOS PRIMEROS SEIS MESES DEVIDA. IMPORTANCIA DE SU CONOCIMIENTO PARA LOS MÉDICOS EN FORMACIÓN

El siguiente artículo aborda un tema de vital importancia para el sistema de salud de cualquier parte del mundo, la lactancia materna. De ahí que el objetivo esencial de este es mostrar algunos consejos y ventajas inmunológicas que brinda la lactancia materna. De ahí que esta problemática, contribuye entre otras, a proteger a los bebés y niños pequeños contra algunas enfermedades peligrosas. Asimismo, se pudo constatar a través de la aplicación de algunos métodos y técnicas que esta, ayuda a crear un vínculo exclusivo entre la madre y el hijo. Al mismo tiempo, mostrar algunos factores que perturban la lactancia materna exclusiva motivados entre otras razones por la falta de conocimiento de las madres, así como por mantenerse alejadas de sus pequeños por tiempos prolongados y carecer de facilidades laborales que les permitan compaginar la lactancia con el empleo

A model of increased impulsivity in rats with bilateral parkinsonism treated with Pramipexole

Impulse control disorders (ICD) is a common side effect of the dopaminergic treatment in patients with Parkinson's disease, which is more associated with dopamine agonists than with levodopa. To understand its pathophysiology, reliable animal models are essential. Using the variable delay-to-signal (VDS) paradigm, impulsivity was evaluated in bilateral parkinsonian rats treated with pramipexole (PPX). In this test, rats have to introduce the snout into a nose poke that is signaled by a light (presented at variable delays) triggering the delivery of a food reward after a correct response. Reaching a stable baseline performance, a partial bilateral dopaminergic lesion with 6-OHDA was induced in the dorsolateral striatum (AP: +1mm, L: ±3.4mm, V:-4.7 mm, Bregma). Rats undertook the VDS test under 5 conditions: basal state, 6-OHDA-induced lesion, the effect of two doses of PPX (0,25mg/kg and 3mg/kg; Latin-square design), and the day after the last dose of PPX. Only the acute administration of 3 mg/kg of PPX significantly rised the number of premature responses, indicating an increase of impulsive behavior, in parkinsonian but not in sham rats. Both doses of PPX significantly decreased the accuracy of responding (correct/total number of responses) and increased the incorrect and perseverative (compulsive behavior) responses in both parkinsonian and sham treated groups when compared with saline-treated groups. In conclusion, PPX induced attention deficit (lack of accuracy) as well as compulsive behavior in control and parkinsonian rats, but increased impulsivity only in the parkinsonian animals. This model could constitute a valid tool to investigate the pathophysiology of ICD.Universidad de Málaga. Campus de Excelencia Internacional Andalucía Tech

Using Kinect to classify Parkinson’s disease stages related to severity of gait impairment

Published: 10 December 2018Parkinson’s Disease (PD) is a chronic neurodegenerative disease associated with motor problems such as gait impairment. Different systems based on 3D cameras, accelerometers or gyroscopes have been used in related works in order to study gait disturbances in PD. Kinect Ⓡ has also been used to build these kinds of systems, but contradictory results have been reported: some works conclude that Kinect does not provide an accurate method of measuring gait kinematics variables, but others, on the contrary, report good accuracy results.This research work was funded by the Spanish Ministry of Economy and Competitiveness (grant FEDER/TIN2016-78011-C4-2-R). The funding bodies had no role in the design or conclusions of this study

Estimating occupancy levels in enclosed spaces using environmental variables: A fitness gym and living room as evaluation scenarios

The understanding of occupancy patterns has been identified as a key contributor to achieve improvements in energy efficiency in buildings since occupancy information can benefit different systems, such as HVAC (Heating, Ventilation, and Air Conditioners), lighting, security, and emergency. This has meant that in the past decade, researchers have focused on improving the precision of occupancy estimation in enclosed spaces. Although several works have been done, one of the less addressed issues, regarding occupancy research, has been the availability of data for contrasting experimental results. Therefore, the main contributions of this work are: (1) the generation of two robust datasets gathered in enclosed spaces (a fitness gym and a living room) labeled with occupancy levels, and (2) the evaluation of three Machine Learning algorithms using different temporal resolutions. The results show that the prediction of 3-4 occupancy levels using the temperature, humidity, and pressure values provides an accuracy of at least 97%

Different susceptibility to pramipexole-induced impulsivity in a rat model of parkinson’s disease

Impulse Control Disorders (ICD) in patients with Parkinson’s disease are abnormal behaviors caused by long-term use of dopamine agonists, which pathophysiology is poorly understood. Using parkinsonian rats (adeno-associated viral vectors-mediated overexpression of A53T human α-synuclein in the substantia nigra compacta), we evaluated the impulsive behaviour under acute (0.25 and 3 mg/kg) and chronic (0.25 mg/kg for 4 weeks) administration of pramipexole (PPX) with the Variable Delay-to-Signal (VDS) task (motor and choice impulsivities). Changes in striatal D1 and D2 receptors expression were also analysed. Before treatment, the striatal dopaminergic depletion caused a significant increase of both impulsivity domains with respect to basal condition. In lesioned rats, acutely given PPX 0.25 mg/kg dose increased choice impulsivity only with regard to basal values. Meanwhile, 3 mg/kg PPX increased choice impulsivity compared to their own values at different conditions: basal, before treatment and after acute 0.25 mg/kg PPX administration. After chronic administration, two populations of lesioned animals were distinguished, one showing the same behaviour as control animals and other displaying an increased motor/response (first week of treatment) and cognitive/choice impulsivities (third week of treatment) compared to control animals. This impulsive behaviour disappeared when animals were tested in OFF state. Lower D2 expression in both Caudate-Putamen and Nucleus Accubens and lower D1 levels in Nucleus Accumbens in lesioned rats than in control animals were observed. Therefore, our results indicate that the pro-impulsive effect of PPX in this animal model of PD depends on the dose and administration paradigm employed and the individual predisposition, and it is associated to striatal dopamine receptors expression changes, especially in Nucleus Accumbens. Thus, this model could constitute a valid tool to investigate the pathophysiology of ICD.Universidad de Málaga. Campus de Excelencia Internacional Andalucía Tech. DFG11/019, PI11/0210