Mecanismos fisiopatólogicos del Trastorno de control de Impulsos en la enfermedad de Parkinson

276 p.La presente tesis se ha centrado en el estudio de los mecanismos fisiopatológicos del trastorno de control de impulsos (TCI) en pacientes con enfermedad de Parkinson (EP). El TCI es una complicación relevante ya que es frecuente y grave en muchas ocasiones, comportando una elevada disrupción de la vida del paciente y su entorno que puede llevar hasta al suicidio en los casos más graves. A pesar de las importantes repercusiones, sus mecanismos fisiopatológicos son desconocidos, habiéndose descrito resultados contradictorios a múltiples niveles de estudio, pero especialmente en los estudios de imagen. Esta tesis se ha realizado no sólo con el ánimo de comprender los mecanismos por los que ocurre, sino también con el objetivo de ampliar las herramientas de detección de los sujetos que serán más sensibles al desarrollo de esta complicación tras el inicio de la terapia de reposición dopaminérgica. Por este motivo, se ha realizado en estos pacientes una aproximación multimodal de neuroimagen desde diversas técnicas, con el objetivo de entender la interacción entre el impacto de la degeneración dopaminérgica y elreemplazo terapéutico en aspectos críticos del comportamiento humano, contribuyendo a delinear los posibles correlatos neurales relacionados con esta complicación en los pacientes con EP. El hecho de investigar y profundizar en los circuitos cerebrales que se encuentran alterados en este tipo de pacientes, podría abrir una puerta a la hora de tratar esta complicación una vez establecida, quizá fundamentando las bases de la terapia con ECP con electrodos direccionales y otros tratamientos focalizados en áreas pertenecientes al circuito límbico. Este trabajo también contribuiría al descubrimiento de biomarcadores de neuroimagen que pudiesen identificar pacientes con EP susceptibles de desarrollar un TCI, con el objetivo de su prevención evitando terapias con agonistas dopaminérgicos en dichos casos. Esta tesis se divide en tres subapartados en las que en (i) el primero estudiamos el patrón de denervación dopaminérgica de estos pacientes así como su asociación con el metabolismo cerebral y con diferentes características clínicas y cognitivas. Esto ha dado lugar a un artículo ya publicado en Eur J Nucl Med Mol Imaging. (ii) En segundo lugar se ha investigado la conectividad funcional dinámica en la Resonancia Magnética funcional en reposo en estos pacientes así como las propiedades topológicas de la misma mediante un análisis de teoría de grafos. Este artículo está actualmente en revisión por la revista Parkinsonism and related disorders journal. (iii) Por último en estos pacientes se ha estudiado la activación cerebral, el curso temporal de la misma y la mediación de la conectividad funcional mientras estos pacientes se enfrentaban en la Resonancia Magnética funcional al Juego de Azar de Iowa, una tarea de toma de decisiones y de control inhibitorio.Resumiendo los resultados: el estudio de la denervación dopaminérgica estriatal, muestra en estos pacientes una denervación dopaminérgica en el estriado ventral característica, paralela a la gravedad de su sintomatología y en asociación directa con una disminución de metabolismo cerebral en áreas pertenecientes al sistema mesocorticolimbico en reposo. Además se ha estudiado por primera vez la dinámica de la conectividad funcional también en reposo, en la que se aprecia que las alteraciones de estos pacientes exceden una disfunción en regiones cerebrales localizadas y se extienden a nivel de la comunicación entre redes, presentando una tendencia a mostrar un aumento de la conectividad funcional a nivel local en áreas concretas que intervienen en la evaluación del estímulo a expensas de una tendencia a reducir la conectividad a larga distancia. Este aumento del mantenimiento en este patrón de conectividad concreto, se asocia en estos pacientes tanto al aumento de impulsividad como a la mayor búsqueda de novedad como rasgo de personalidad del sujeto. De la misma manera, el estudio de las propiedades topológicas de estas alteraciones en la conectividad de estos pacientes, nos muestra una elevada eficiencia local en la comunicación entre estas áreas. Estos resultados nos muestran patrones específicos de estos pacientes en reposo, tanto a nivel molecular como de Resonancia Magnética funcional, que se hacen más patentes conforme se acentúa la gravedad del TCI, los cuales podrían plantearse como biomarcadores de imagen de pacientes expuestos al desarrollo de esta complicación. Por último, al enfrentar a estos sujetos a una tarea de toma de decisiones y control inhibitorio, se aprecia una mayor activación de las áreas implicadas tanto en procesos de recompensa como de inhibición. Esto puede traducir la disfunción regional evidenciada previamente en el estudio metabólico desde la otra cara de la moneda, en la que se apreciaría un aumento de activación como reflejo de un posible mecanismo compensatorio para controlar las elecciones de riesgo. Además en estos pacientes se constata una respuesta de activación más precoz, que podría ser el reflejo de la predicción inicial de errores y la asignación de relevancia que precede a la toma de decisiones. Hay que destacar, que en esta tesis se enfatiza el estriado ventral como estructura clave que lleva a la disfunción de otras áreas pertenecientes al circuito mesocorticolímbico en paralelo a un aumento del desarrollo y gravedad del TCI en pacientes con EP. Además, se describe por primera vez la implicación del núcleo subtalámico derecho en una tarea de impulsividad cognitiva y la exclusividad de esta implicación en pacientes con EP y TCI, lo cual podría tener relevancia clínica en el marco terapeútico de la modulación conductual mediante estimulación cerebral profunda del núcleo subtalámico

Imaging Cognitive Impairment and Impulse Control Disorders in Parkinson's Disease

Dementia and mild forms of cognitive impairment as well as neuropsychiatric symptoms (i. e., impulse control disorders) are frequent and disabling non-motor symptoms of Parkinson's disease (PD). The identification of changes in neuroimaging studies for the early diagnosis and monitoring of the cognitive and neuropsychiatric symptoms associated with Parkinson's disease, as well as their pathophysiological understanding, are critical for the development of an optimal therapeutic approach. In the current literature review, we present an update on the latest structural and functional neuroimaging findings, including high magnetic field resonance and radionuclide imaging, assessing cognitive dysfunction and impulse control disorders in PD

Functional correlates of response inhibition in impulse control disorders in Parkinson’s disease

Available online 11 September 2021.Impulse control disorder is a prevalent side-effect of Parkinson’s disease (PD) medication, with a strong negative impact on the quality of life of those affected. Although impulsivity has classically been associated with response inhibition deficits, previous evidence from PD patients with impulse control disorder (ICD) has not revealed behavioral dysfunction in response inhibition. In this study, 18 PD patients with ICD, 17 PD patients without this complication, and 15 healthy controls performed a version of the conditional Stop Signal Task during functional magnetic resonance imaging. Whole-brain contrasts, regions of interest, and functional connectivity analyses were conducted. Our aim was to investigate the neural underpinnings of two aspects of response inhibition: proactive inhibition, inhibition that has been prepared beforehand, and restrained inhibition, inhibition of an invalid inhibitory tendency. We observed that, in respect to the other two groups, PD patients with ICD exhibited hyperactivation of the stopping network bilaterally while performing proactive inhibition. When engaged in restrained inhibition, they showed hyperactivation of the left inferior frontal gyrus, an area linked to action monitoring. Restrained inhibition also resulted in changes to the functional co-activation between inhibitory regions and left inferior parietal cortex and right supramarginal gyrus. Our findings indicate that PD patients with ICD completed the inhibition task correctly, showing altered engagement of inhibitory and attentional areas. During proactive inhibition they showed bilateral hyperactivation of two inhibitory regions, while during restrained inhibition they showed additional involvement of attentional areas responsible for alerting and orienting.This work was supported by grants from the Carlos III Institute of Health (PI11/02109) and the ERA-Neuron program (PIM2010ERN- 0033). Additionally, the authors received the following grants and honoraria: T.E.-P. received a grant from the Spanish Ministry of Economy and Competitiveness (BES-2016-079489). P.M.P.-A. was supported by grants from the Spanish Ministry of Economy and Competitiveness (RYC-2014-15440), the Spanish Ministry of Science and Innovation (PGC2018-093408-B-I00), and the Fundación Tatiana Pérez de Guzmán el Bueno. I.N.-G. was the recipient of a Rio Hortega grant (CM16/00033) from the Carlos III Institute of Health. I.N.-G. received honoraria from Zambon and TEVA for travel and accommodation to attend scientific meetings. M.C.R.-O. received financial support for her research from national and local government institutions in Spain (Carlos III Institute of Health, Basque Country Government, Diputacion Foral Guipuzcoa, and CIBERNED). M.C.R.-O. received honoraria from Zambon, Bial, and Boston Scientific for lectures, travel, and accommodation to attend scientific meetings. BCBL acknowledges support from the Basque Government through the BERC 2018-2021 program

Functional correlates of response inhibition in impulse control disorders in Parkinson’s disease

Available online 11 September 2021.Impulse control disorder is a prevalent side-effect of Parkinson’s disease (PD) medication, with a strong negative impact on the quality of life of those affected. Although impulsivity has classically been associated with response inhibition deficits, previous evidence from PD patients with impulse control disorder (ICD) has not revealed behavioral dysfunction in response inhibition. In this study, 18 PD patients with ICD, 17 PD patients without this complication, and 15 healthy controls performed a version of the conditional Stop Signal Task during functional magnetic resonance imaging. Whole-brain contrasts, regions of interest, and functional connectivity analyses were conducted. Our aim was to investigate the neural underpinnings of two aspects of response inhibition: proactive inhibition, inhibition that has been prepared beforehand, and restrained inhibition, inhibition of an invalid inhibitory tendency. We observed that, in respect to the other two groups, PD patients with ICD exhibited hyperactivation of the stopping network bilaterally while performing proactive inhibition. When engaged in restrained inhibition, they showed hyperactivation of the left inferior frontal gyrus, an area linked to action monitoring. Restrained inhibition also resulted in changes to the functional co-activation between inhibitory regions and left inferior parietal cortex and right supramarginal gyrus. Our findings indicate that PD patients with ICD completed the inhibition task correctly, showing altered engagement of inhibitory and attentional areas. During proactive inhibition they showed bilateral hyperactivation of two inhibitory regions, while during restrained inhibition they showed additional involvement of attentional areas responsible for alerting and orienting.This work was supported by grants from the Carlos III Institute of Health (PI11/02109) and the ERA-Neuron program (PIM2010ERN- 0033). Additionally, the authors received the following grants and honoraria: T.E.-P. received a grant from the Spanish Ministry of Economy and Competitiveness (BES-2016-079489). P.M.P.-A. was supported by grants from the Spanish Ministry of Economy and Competitiveness (RYC-2014-15440), the Spanish Ministry of Science and Innovation (PGC2018-093408-B-I00), and the Fundación Tatiana Pérez de Guzmán el Bueno. I.N.-G. was the recipient of a Rio Hortega grant (CM16/00033) from the Carlos III Institute of Health. I.N.-G. received honoraria from Zambon and TEVA for travel and accommodation to attend scientific meetings. M.C.R.-O. received financial support for her research from national and local government institutions in Spain (Carlos III Institute of Health, Basque Country Government, Diputacion Foral Guipuzcoa, and CIBERNED). M.C.R.-O. received honoraria from Zambon, Bial, and Boston Scientific for lectures, travel, and accommodation to attend scientific meetings. BCBL acknowledges support from the Basque Government through the BERC 2018-2021 program

Functional correlates of response inhibition in impulse control disorders in Parkinson’s disease

Impulse control disorder is a prevalent side-effect of Parkinson’s disease (PD) medication, with a strong negative impact on the quality of life of those affected. Although impulsivity has classically been associated with response inhibition deficits, previous evidence from PD patients with impulse control disorder (ICD) has not revealed behavioral dysfunction in response inhibition. In this study, 18 PD patients with ICD, 17 PD patients without this complication, and 15 healthy controls performed a version of the conditional Stop Signal Task during functional magnetic resonance imaging. Whole-brain contrasts, regions of interest, and functional connectivity analyses were conducted. Our aim was to investigate the neural underpinnings of two aspects of response inhibition: proactive inhibition, inhibition that has been prepared beforehand, and restrained inhibition, inhibition of an invalid inhibitory tendency. We observed that, in respect to the other two groups, PD patients with ICD exhibited hyperactivation of the stopping network bilaterally while performing proactive inhibition. When engaged in restrained inhibition, they showed hyperactivation of the left inferior frontal gyrus, an area linked to action monitoring. Restrained inhibition also resulted in changes to the functional co-activation between inhibitory regions and left inferior parietal cortex and right supramarginal gyrus. Our findings indicate that PD patients with ICD completed the inhibition task correctly, showing altered engagement of inhibitory and attentional areas. During proactive inhibition they showed bilateral hyperactivation of two inhibitory regions, while during restrained inhibition they showed additional involvement of attentional areas responsible for alerting and orientin

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

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

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

Background: Parkinson’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. Methods: In this work, we have built a Kinect-based system that can distinguish between different PD stages, and have performed a clinical study with 30 patients suffering from PD belonging to three groups: early PD patients without axial impairment, more evolved PD patients with higher gait impairment but without Freezing of Gait (FoG), and patients with advanced PD and FoG. Those patients were recorded by two Kinect devices when they were walking in a hospital corridor. The datasets obtained from the Kinect were preprocessed, 115 features identified, some methods were applied to select the relevant features (correlation based feature selection, information gain, and consistency subset evaluation), and different classification methods (decision trees, Bayesian networks, neural networks and K-nearest neighbours classifiers) were evaluated with the goal of finding the most accurate method for PD stage classification. Results: The classifier that provided the best results is a particular case of a Bayesian Network classifier (similar to a Naïve Bayesian classifier) built from a set of 7 relevant features selected by the correlation-based on feature selection method. The accuracy obtained for that classifier using 10-fold cross validation is 93.40%. The relevant features are related to left shin angles, left humerus angles, frontal and lateral bents, left forearm angles and the number of steps during spin. Conclusions: In this paper, it is shown that using Kinect is adequate to build a inexpensive and comfortable system that classifies PD into three different stages related to FoG. Compared to the results of previous works, the obtained accuracy (93.40%) can be considered high. The relevant features for the classifier are: a) movement and position of the left arm, b) trunk position for slightly displaced walking sequences, and c) left shin angle, for straight walking sequences. However, we have obtained a better accuracy (96.23%) for a classifier that only uses features extracted from slightly displaced walking steps and spin walking steps. Finally, the obtained set of relevant features may lead to new rehabilitation therapies for PD patients with gait problems

Plasma and CSF biomarkers in a memory clinic: Head-to-head comparison of phosphorylated tau immunoassays

INTRODUCTION: Direct comparisons of the main blood phosphorylated tau immunoassays in memory clinic populations are needed to understand possible differences. METHODS: In the BIODEGMAR study, 197 participants presenting with cognitive complaints were classified into an Alzheimer's disease (AD) or a non-AD cerebrospinal fluid (CSF) profile group, according to their amyloid beta 42/ phosphorylated tau (Aβ42/p-tau) ratio. We performed a head-to-head comparison of nine plasma and nine CSF tau immunoassays and determined their accuracy to discriminate abnormal CSF Aβ42/p-tau ratio. RESULTS: All studied plasma tau biomarkers were significantly higher in the AD CSF profile group compared to the non-AD CSF profile group and significantly discriminated abnormal CSF Aβ42/p-tau ratio. For plasma p-tau biomarkers, the higher discrimination accuracy was shown by Janssen p-tau217 (r = 0.76; area under the curve [AUC] = 0.96), ADx p-tau181 (r = 0.73; AUC = 0.94), and Lilly p-tau217 (r = 0.73; AUC = 0.94). DISCUSSION: Several plasma p-tau biomarkers can be used in a specialized memory clinic as a stand-alone biomarker to detect biologically-defined AD. HIGHLIGHTS: Patients with an Alzheimer's disease cerebrospinal fluid (AD CSF) profile have higher plasma phosphorylated tau (p-tau) levels than the non-AD CSF profile group. All plasma p-tau biomarkers significantly discriminate patients with an AD CSF profile from the non-AD CSF profile group. Janssen p-tau217, ADx p-tau181, and Lilly p-tau217 in plasma show the highest accuracy to detect biologically defined AD. Janssen p-tau217, ADx p-tau181, Lilly p-tau217, Lilly p-tau181, and UGot p-tau231 in plasma show performances that are comparable to their CSF counterparts