Predicting Impulse Control Disorders in Parkinson Disease through Incentive Biomarkers

Altres ajuts: Fundació la Marató de TV3 (2014/U/477, 20142910); Fondo Europeo de Desarrollo Regional (FEDER); Pla Estratègic de Recerca i Innovació (SLT008/18); CERCA (CEntres de Recerca de Catalunya); CIBERNED (Centro de Investigación Biomédica en Red de enfermedades NEuroDegenerativas).Objective: This study was undertaken to evaluate whether the feedback-related negativity (FRN)-a neurophysiological marker of incentive processing-can be used to predict the development of impulse control disorders (ICDs) in Parkinson disease (PD). Methods: The longitudinal cohort consisted of consecutive nondemented PD patients with no ICD history. We recorded FRN signals while they performed a gambling task. We calculated the mean amplitude difference between losses and gains (FRNdiff) to be used as a predictor of future ICD development. We performed prospective biannual follow-up assessments for 30 months to detect incident ICDs. Finally, we evaluated how basal FRNdiff was associated with posterior development of ICDs using survival models. Results: Between October 7, 2015 and December 16, 2016, we screened 120 patients. Among them, 94 patients performed the gambling and 92 completed the follow-up. Eighteen patients developed ICDs during follow-up, whereas 74 remained free of ICDs. Baseline FRNdiff was greater in patients who developed ICDs than in those who did not (−2.33μV vs −0.84μV, p = 0.001). No other significant baseline differences were found. The FRNdiff was significantly associated with ICD development in the survival models both when not adjusted (hazard ratio [HR] = 0.73, 95% confidence interval [CI] = 0.58-0.91, p = 0.006) and when controlling for dopamine replacement therapy, sex, and age (HR = 0.74, 95% CI = 0.55-0.97, p = 0.035). None of the impulsivity measures evaluated was related to ICD development. Interpretation: Reward-processing differences measured by FRN signals precede ICD development in PD. This neurophysiological marker permits identification of patients with high risk of ICD development. ANN NEUROL 2022;92:974-984

Neural signatures of predictive language processing in Parkinson's disease with and without mild cognitive impairment

Altres ajuts: Fundació la Marató de TV3 (2014/U/477, 20142910)Cognitive deficits are common in Parkinson's disease (PD), with some PD patients meeting criteria for mild cognitive impairment (MCI). An unaddressed question is whether linguistic prediction is preserved in PD. This ability is nowadays deemed crucial for achieving fast and efficient comprehension, and it may be negatively impacted by cognitive deterioration in PD. To fill this gap of knowledge, we used event-related potentials (ERPs) to evaluate mechanisms of linguistic prediction in a sample of PD patients (on dopamine compensation) with and without MCI. To this end, participants read sentence contexts that were predictive or not about a sentence-final word. The final word appeared after one sec, matching or mismatching the prediction. The introduction of the interval allowed to capture neural responses both before and after sentence-final words, reflecting semantic anticipation and semantic processing. PD patients with normal cognition (N = 58) showed ERP responses comparable to those of matched controls. Specifically, in predictive contexts, a slow negative potential developed prior to sentence-final words, reflecting semantic anticipation. Later, expected words elicited reduced N400 responses (compared to unexpected words), indicating facilitated semantic processing. PD patients with MCI (N = 20) showed, in addition, a prolongation of the N400 congruency effect (compared to matched PD patients without MCI), indicating that further cognitive decline impacts semantic processing. Finally, lower verbal fluency scores correlated with prolonged N400 congruency effects and with reduced pre-word differences in all PD patients (N = 78). This relevantly points to a role of deficits in temporal-dependent mechanisms in PD, besides prototypical frontal dysfunction, in altered semantic anticipation and semantic processing during sentence comprehension

Identifying comorbidities and lifestyle factors contributing to the cognitive profile of early Parkinson's disease

Malaltia de Parkinson; Cognició; Estil de vidaEnfermedad de Parkinson; Cognición; Estilo de vidaParkinson Disease; Cognition; Life StyleBackground: Identifying modifiable risk factors for cognitive impairment in the early stages of Parkinson's disease (PD) and estimating their impact on cognitive status may help prevent dementia (PDD) and the design of cognitive trials. Methods: Using a standard approach for the assessment of global cognition in PD and controlling for the effects of age, education and disease duration, we explored the associations between cognitive status, comorbidities, metabolic variables and lifestyle variables in 533 PD participants from the COPPADIS study. Results: Among the overall sample, 21% of participants were classified as PD-MCI (n = 114) and 4% as PDD (n = 26). The prevalence of hypertension, diabetes and dyslipidemia was significantly higher in cognitively impaired patients while no between-group differences were found for smoking, alcohol intake or use of supplementary vitamins. Better cognitive scores were significantly associated with regular physical exercise (p < 0.05) and cognitive stimulation (< 0.01). Cognitive performance was negatively associated with interleukin 2 (Il2) (p < 0.05), Il6 (p < 0.05), iron (p < 0.05), and homocysteine (p < 0.005) levels, and positively associated with vitamin B12 levels (p < 0.005). Conclusions: We extend previous findings regarding the positive and negative influence of various comorbidities and lifestyle factors on cognitive status in early PD patients, and reinforce the need to identify and treat potentially modifiable variables with the intention of exploring the possible improvement of the global cognitive status of patients with PD.Fundación Curemos el Parkinson (https:// curem oselp arkin son. org/) covered the expenses derived from hiring a CRO and from carrying out complementary tests

A Randomized Clinical Trial to Evaluate the Effects of Safinamide on Apathetic Non-demented Patients With Parkinson's Disease

Altres ajuts: CERCA; CIBERNED; La Marató de TV3 (2014/U/477, 20142910); Fondo Europeo de Desarrollo Regional (FEDER).Background: Apathy is highly prevalent and disabling in Parkinson's disease (PD). Pharmacological options for its management lack sufficient evidence. Objective: We studied the effects of safinamide on apathy in PD. Methods: Prospective, 24-week, two-site, randomized, double-blind, placebo-controlled, parallel-group exploratory study in non-demented PD on stable dopaminergic therapy randomized 1:1 to adjunct safinamide (50 mg/day for 2 weeks and 100 mg/day for 22 weeks) or placebo. The primary endpoint was the mean change from baseline to week 24 on the Apathy Scale (AS) total score. Secondary endpoints included changes in cognition, activities of daily living, motor scores, the impression of change, and safety and tolerability measures. Results: In total, 30 participants (active treatment = 15; placebo = 15; 80% showing clinically significant apathetic symptoms according to the AS) were enrolled, and included in the intention-to-treat analysis. Change in AS (ANOVA) showed a trend to significance [p = 0.059] mediated by a more marked decrease in AS score with safinamide (−7.5 ± 6.9) than with placebo (−2.8 ± 5.7). Post-hoc analysis (paired t-test) showed a significant positive change in the AS score between 12-week and 24-week [p = 0.001] only in the active group. No significant or trend changes were found for any of the secondary outcome variables. Adverse events were few and only mild in both treatment groups. Conclusions: Safinamide was safe and well-tolerated, but failed to provide evidence of improved apathy. The positive trend observed in the post-hoc analyses deserves to be studied in depth in larger studies. Trial Registration: EudraCT 2017-003254-17

The Free and Cued Selective Reminding Test in Parkinson's Disease Mild Cognitive Impairment : Discriminative Accuracy and Neural Correlates

Altres ajuts: This work was partially supported by grants from La Marató TV3 (20142910, 2014/U/477); FIS (PI14/02058, PI15/00962); CIBERNED.Introduction: Memory alterations are common in Parkinson's disease (PD) patients but the mechanisms involved in these deficits remain poorly understood. The study aims to explore the profile of episodic memory deficits in non-demented early PD patients. Methods: We obtained neurological, cognitive and behavioral data from 114 PD patients and 41 healthy controls (HC). PD participants were grouped as normal cognition (PD-NC) and mild cognitive impairment (PD-MCI) according to the Level II criteria of the Movement Disorders Society Task Force (MDS-TF). We evaluate the performance amongst groups on an episodic memory task using the Free and Cued Selective Reminding Test (FCSRT). Additionally, gray matter volume (GMV) voxel based morphometry, and mean diffusivity (MD) analyses were conducted in a subset of patients to explore the structural brain correlates of FCSRT performance. Results: Performance on all subscores of the FCSRT was significantly worse in PD-MCI than in PD-NC and HC. Delayed total recall (DTR) subscore was the best at differentiating PD-NC from PD-MCI. Using crosstabulation, DTR allowed identification of PD-MCI patients with an accuracy of 80%. Delayed free and cued recall was associated with decreased GMV and increased MD in multiple fronto-temporal and parietal areas. Conclusion: Encoding and retrieval deficits are a main characteristic of PD-MCI and are associated with structural damage in temporal, parietal and prefrontal areas

Clinical and structural brain correlates of hypomimia in early-stage Parkinson's disease

Altres ajuts: acord transformatiu CRUE-CSICBackground and purpose: Reduced facial expression of emotions is a very frequent symptom of Parkinson's disease (PD) and has been considered part of the motor features of the disease. However, the neural correlates of hypomimia and the relationship between hypomimia and other non-motor symptoms of PD are poorly understood. Methods: The clinical and structural brain correlates of hypomimia were studied. For this purpose, cross-sectional data from the COPPADIS study database were used. Age, disease duration, levodopa equivalent daily dose, Unified Parkinson's Disease Rating Scale part III (UPDRS-III), severity of apathy and depression and global cognitive status were collected. At the imaging level, analyses based on gray matter volume and cortical thickness were used. Results: After controlling for multiple confounding variables such as age or disease duration, the severity of hypomimia was shown to be indissociable from the UPDRS-III speech and bradykinesia items and was significantly related to the severity of apathy (β = 0.595; p < 0.0001). At the level of neural correlates, hypomimia was related to motor regions brodmann area 8 (BA 8) and to multiple fronto-temporo-parietal regions involved in the decoding, recognition and production of facial expression of emotions. Conclusion: Reduced facial expressivity in PD is related to the severity of symptoms of apathy and is mediated by the dysfunction of brain systems involved in motor control and in the recognition, integration and expression of emotions. Therefore, hypomimia in PD may be conceptualized not exclusively as a motor symptom but as a consequence of a multidimensional deficit leading to a symptom where motor and non-motor aspects converge

Identifying comorbidities and lifestyle factors contributing to the cognitive profile of early Parkinson's disease

Background: Identifying modifiable risk factors for cognitive impairment in the early stages of Parkinson's disease (PD) and estimating their impact on cognitive status may help prevent dementia (PDD) and the design of cognitive trials. Methods: Using a standard approach for the assessment of global cognition in PD and controlling for the effects of age, education and disease duration, we explored the associations between cognitive status, comorbidities, metabolic variables and lifestyle variables in 533 PD participants from the COPPADIS study. Results: Among the overall sample, 21% of participants were classified as PD-MCI (n = 114) and 4% as PDD (n = 26). The prevalence of hypertension, diabetes and dyslipidemia was significantly higher in cognitively impaired patients while no between-group differences were found for smoking, alcohol intake or use of supplementary vitamins. Better cognitive scores were significantly associated with regular physical exercise (p < 0.05) and cognitive stimulation (< 0.01). Cognitive performance was negatively associated with interleukin 2 (Il2) (p < 0.05), Il6 (p < 0.05), iron (p < 0.05), and homocysteine (p < 0.005) levels, and positively associated with vitamin B12 levels (p < 0.005). Conclusions: We extend previous findings regarding the positive and negative influence of various comorbidities and lifestyle factors on cognitive status in early PD patients, and reinforce the need to identify and treat potentially modifiable variables with the intention of exploring the possible improvement of the global cognitive status of patients with PD

Non-motor symptom burden in patients with Parkinson's disease with impulse control disorders and compulsive behaviours : results from the COPPADIS cohort

The study was aimed at analysing the frequency of impulse control disorders (ICDs) and compulsive behaviours (CBs) in patients with Parkinson's disease (PD) and in control subjects (CS) as well as the relationship between ICDs/CBs and motor, nonmotor features and dopaminergic treatment in PD patients. Data came from COPPADIS-2015, an observational, descriptive, nationwide (Spain) study. We used the validated Questionnaire for Impulsive-Compulsive Disorders in Parkinson's Disease-Rating Scale (QUIP-RS) for ICD/CB screening. The association between demographic data and ICDs/CBs was analyzed in both groups. In PD, this relationship was evaluated using clinical features and treatment-related data. As result, 613 PD patients (mean age 62.47 ± 9.09 years, 59.87% men) and 179 CS (mean age 60.84 ± 8.33 years, 47.48% men) were included. ICDs and CBs were more frequent in PD (ICDs 12.7% vs. 1.6%, p < 0.001; CBs 7.18% vs. 1.67%, p = 0.01). PD patients had more frequent previous ICDs history, premorbid impulsive personality and antidepressant treatment (p < 0.05) compared with CS. In PD, patients with ICDs/CBs presented younger age at disease onset, more frequent history of previous ICDs and premorbid personality (p < 0.05), as well as higher comorbidity with nonmotor symptoms, including depression and poor quality of life. Treatment with dopamine agonists increased the risk of ICDs/CBs, being dose dependent (p < 0.05). As conclusions, ICDs and CBs were more frequent in patients with PD than in CS. More nonmotor symptoms were present in patients with PD who had ICDs/CBs compared with those without. Dopamine agonists have a prominent effect on ICDs/CBs, which could be influenced by dose

Correlatos anatomo-funcionales de las alucinaciones menores y su impacto sobre la cognición en la enfermedad de parkinson

Donat el gran impacte que suposen en la qualitat de vida del malalt i el cuidador, els símptomes psicòtics en la malaltia de Parkinson (MP) han estat objecte d'innombrables treballs dirigits a explorar la prevalença, els factors de risc, la fisiopatologia, així com possibles teràpies. Actualment manquen tractaments efectius i segurs per al tractament d'aquests símptomes, i alguns fàrmacs utilitzats per al tractament de la MP poden empitjorar-los. Una vegada instaurats, els símptomes psicòtics presenten un curs crònic i progressiu malgrat els canvis terapèutics, conduint a una major dependència, institucionalització i mort. No obstant això, l'estudi dels fenòmens psicòtics en fases més inicials, quan les possibles intervencions podrien tenir un impacte potencialment major, ha rebut molta menys atenció en la literatura mèdica. Una possible explicació d'això és que aquests símptomes menors no s'han considerat dins de l'espectre de símptomes psicòtics fins a 2007, quan van ser inclosos en els criteris diagnòstics de la psicosi en la MP. Des de llavors, són diversos els treballs que han posat de manifest que les al·lucinacions menors són presents en una important proporció de pacients, i que poden aparèixer des de fases molt inicials de la malaltia. No obstant això, encara queden moltes incògnites per resoldre. Actualment es desconeix en gran part la història natural de les al·lucinacions menors. Encara que sembla que aquests fenòmens mostren una certa tendència a progressar a formes majors de psicosis, desconeixem quins pacients presentaran aquesta progressió i l'efecte que podria tenir en ells un maneig terapèutic individualitzat. De la mateixa manera, es desconeixen les implicacions pronòstiques a nivell cognitiu d'aquests pacients. Tenint en compte la forta associació entre psicosi i demència en la MP, sembla lògic pensar que en els pacients que presenten fases inicials d'al·lucinacions menors podrien objectivar-se certes alteracions cognitives potencialment capaces d'identificar pacients a risc. No obstant això, actualment es desconeix si aquests pacients presenten alteracions cognitives específiques i/o un major risc de desenvolupament de demència. L'estudi de la fisiopatologia de les al·lucinacions menors, poc explorada, podria acostar-nos al coneixement d'aquestes qüestions. Així mateix, estudis longitudinals des de fases inicials amb grans cohorts de pacients, permetrien dilucidar les implicacions pronòstiques d'aquest símptoma, tan freqüent en la pràctica clínica habitual. Els objectius d'aquesta tesi s'han dirigit a contribuir a la resolució d'algunes d'aquestes qüestions. La intenció ha estat la d'aportar avanços concrets que permetin tenir un millor coneixement i maneig de tot l'espectre simptomàtic dels símptomes psicòtics en la MP, les manifestacions últimes de la qual resulten devastadores per a pacients i famílies. En el cos d'aquesta tesi descrivim com: 1) Les al·lucinacions menors apareixen fins en un terç de pacients amb MP durant els primers 5 anys de malaltia; 2) Existeixen canvis corticals que permeten predir el desenvolupament d'al·lucinacions menors, presents fins i tot en el moment del diagnòstic; 3) La pèrdua de volum de matèria grisa en els primers anys de malaltia és major en aquells pacients que acaben desenvolupant al·lucinacions menors; 4) Els correlats neuronals estructurals i funcionals són similars en al·lucinacions menors i estructurades, suggerint que la fisiopatologia subjacent és similar en tots dos fenòmens; 5) El desenvolupament d'al·lucinacions menors s'associa amb la percepció pel subjecte d'un empitjorament cognitiu a mitjà termini; 6) Les al·lucinacions menors s'associen amb canvis cognitius objectius identificables mitjançant tasques específiques i registre electroencefalogràfic. Per descomptat queden encara molts interrogants per resoldre, i els resultats que a continuació es presenten donen lloc a noves preguntes. Confiem que el nostre treball aporti una reflexió sobre la potencial importància de la fenomenologia psicòtica anomenada "menor" en la futura evolució de la malaltia.Dado el tremendo impacto que suponen en la calidad de vida del enfermo y el cuidador, los síntomas psicóticos en la enfermedad de Parkinson (EP) han sido objeto de innumerables trabajos dirigidos a explorar la prevalencia, los factores de riesgo, la fisiopatología, así como posibles terapias. Actualmente carecemos de tratamientos efectivos y seguros para el tratamiento de estos síntomas, y algunos fármacos utilizados para el tratamiento de la EP pueden empeorarlos. Una vez instaurados, los síntomas psicóticos presentan un curso crónico y progresivo a pesar de los cambios terapéuticos, conduciendo a una mayor dependencia, institucionalización y muerte. Sin embargo, el estudio de los fenómenos psicóticos en fases más iniciales, cuando las posibles intervenciones podrían tener un impacto potencialmente mayor, ha recibido mucha menos atención en la literatura médica. Una posible explicación de ello es que estos síntomas menores no se han considerado dentro del espectro de síntomas psicóticos hasta 2007, cuando fueron incluidos en los criterios diagnósticos de la psicosis en la EP. Desde entonces, son varios los trabajos que han puesto de manifiesto que las alucinaciones menores están presentes en una importante proporción de pacientes, y que pueden aparecer desde fases muy iniciales de la enfermedad. No obstante, aún quedan muchas incógnitas por resolver. Actualmente se desconoce en gran medida la historia natural de las alucinaciones menores. Aunque parece que estos fenómenos muestran cierta tendencia a progresar a formas mayores de psicosis, desconocemos qué pacientes presentarán esta progresión y el efecto que podría tener en ellos un manejo terapéutico individualizado. Del mismo modo, se desconocen las implicaciones pronósticas a nivel cognitivo de estos pacientes. Teniendo en cuenta la fuerte asociación entre psicosis y demencia en la EP, parece lógico pensar que en los pacientes que presentan fases iniciales de alucinaciones menores podrían objetivarse ciertas alteraciones cognitivas capaces de identificar pacientes a riesgo. No obstante, actualmente se desconoce si estos pacientes presentan alteraciones cognitivas específicas y/o un mayor riesgo de desarrollo de demencia. El estudio de la fisiopatología de las alucinaciones menores, apenas explorada, podría acercarnos al conocimiento de estas cuestiones. Asimismo, estudios longitudinales desde fases iniciales con grandes cohortes de pacientes, permitirían dilucidar las implicaciones pronósticas de este síntoma, tan frecuentemente encontrado en la práctica clínica habitual. Los objetivos de esta tesis se han dirigido a contribuir a la resolución de algunas de estas cuestiones. La intención ha sido la de aportar avances concretos que permitan tener un mejor conocimiento y manejo de todo el espectro sintomático de los síntomas psicóticos en la EP, cuyas manifestaciones últimas resultan devastadoras para pacientes y familias. En el cuerpo de esta tesis describimos cómo: 1) Las alucinaciones menores aparecen hasta en un tercio de pacientes con EP durante los primeros 5 años de enfermedad; 2) Existen cambios corticales que permiten predecir el desarrollo de alucinaciones menores, presentes incluso en el momento del diagnóstico; 3) La pérdida de volumen de materia gris en los primeros años de enfermedad es mayor en aquellos pacientes que acaban desarrollando alucinaciones menores; 4) Los correlatos neuronales estructurales y funcionales son similares en alucinaciones menores y estructuradas, sugiriendo que la fisiopatología subyacente es similar en ambos fenómenos; 5) El desarrollo de alucinaciones menores se asocia con la percepción por el sujeto de un empeoramiento cognitivo a medio plazo; 6) Las alucinaciones menores se asocian con cambios cognitivos objetivos identificables mediante tareas específicas y registro electroencefalográfico. Por supuesto quedan aún muchos interrogantes por resolver, y los resultados que a continuación se presentan dan lugar a nuevas preguntas. Confiamos en que nuestro trabajo aporte una reflexión sobre la potencial importancia de la fenomenología psicótica llamada "menor" en la futura evolución de la enfermedad.Given the tremendous impact they have on the quality of life of patients and caregivers, psychotic symptoms in Parkinson's disease (PD) have been the subject of countless studies aimed at exploring the prevalence, risk factors, pathophysiology and possible treatments. We currently lack effective and safe treatments for hallucinations, and some drugs used to treat PD can worsen them. Once established, hallucinations present a chronic and progressive course despite therapeutic changes, leading to greater dependency, institutionalization and death. Nonetheless, the study of psychotic phenomena in earlier stages, when possible interventions could have a greater potential impact, has received much less attention in medical literature. One possible explanation is that minor hallucinations were not considered within the spectrum of psychotic symptoms until 2007, when they were included in the diagnostic criteria for psychosis in PD. Since then, several studies have emerged revealing that minor hallucinations are present in a significant proportion of patients and can appear from very early stages of the disease. However, many questions remain to be solved. The natural history of minor hallucinations is still largely unknown. It seems to be a tendency for these phenomena to progress to major psychotic forms, but we do not know which patients will present this progression and the effect that individualized therapeutic management could have on them. Similarly, the cognitive prognostic implications of these symptoms have been practically unexplored. Taking into account the strong association between psychosis and dementia in PD, it seems reasonable to consider that some cognitive alterations may occur and can be identified in patients exhibiting the initial phases of minor hallucinations. These cognitive changes could potentially be helpful on identifying patients at risk. However, to date it is unknown whether these patients present specific cognitive alterations and /or an increased risk of developing dementia. The study of the neural basis of minor hallucinations could approach us to these unsolved questions. Similarly, longitudinal studies exploring large cohorts of patients from the initial phases of the disease may help us to elucidate the specific implications of this symptom, so frequently encountered in routine clinical practice. This thesis aimed at solving some of these questions and contribute to expand the knowledge and clinical management of the whole spectrum of psychotic symptoms in PD, whose ultimate manifestations arise as a devastating symptom for patients and families. In the body of this thesis we describe how: 1) Minor hallucinations appear in up to a third of patients with PD during the first 5 years of disease; 2) There are cortical changes, present even at the time of diagnosis, that predict the development of minor hallucinations; 3) Gray matter volume loss in the first years of the disease is greater in those patients who develop minor hallucinations; 4) The structural and functional neuronal correlates are similar in minor and well-structured hallucinations, suggesting that the underlying pathophysiology is similar in both phenomena; 5) The development of minor hallucinations is associated with future subjective cognitive decline; 6) Minor hallucinations are associated with objective cognitive changes identifiable by specific tasks and electroencephalographic recording. Of course, many unresolved questions remain, and new questions arise from the present results. We trust that our work provides a framework that encourages the development of more research focused on the potential relevance of minor psychotic phenomena in the future evolution of these patients.Universitat Autònoma de Barcelona. Programa de Doctorat en Medicin

Trastorns neurològics II, febrer 2017

Recurs d'aprenentatge de la Universitat Oberta de Catalunya. Material publicat amb llicència Creative Commons passats 6 semestres des de la data de publicació.Recurso de aprendizaje de la Universitat Oberta de Catalunya. Material publicado con licencia Creative Commons pasados 6 semestres desde la fecha de publicación.Learning material of the Universitat Oberta de Catalunya. Material published under a Creative Commons license after 6 semesters from the date of publication