Estudio prospectivo de la cefalea en pacientes con hemopatías malignas

Objetivo: describir las cefaleas en pacientes ingresados con neoplasias hematológicas, identificar los factores asociados a cefaleas secundarias graves. Estudio observacional prospectivo. Se incluyen 30 casos de cefalea correspondientes a 23 pacientes. Ocho cefaleas son primarias y 22 secundarias. Diez de estas, son secundarias a patología grave o potencialmente grave: encefalopatía hipertensiva, neoplasia intracraneal, hemorragia intracraneal, infección cefálica, trombosis venosa, fiebre tumoral e hipertensión sin encefalopatía. El riesgo de que una cefalea sea secundaria a patología grave es mayor en los casos que presentan esa cefalea por primera vez y en los que coincide con el debut de la enfermedad hematológica.Objectiu: descriure les cefalees en pacients ingressats amb neoplàsies hematològiques, identificar els factors associats a cefalees secundàries greus. Estudi observacional prospectiu. S'inclouen 30 casos de cefalea que corresponen a 23 pacients. Vuit cefalees són primàries i 22, secundàries. Deu d'aquestes últimes són secundàries a patologia greu o potencialment greu: encefalopatia hipertensiva, neoplàsia intracranial, hemorràgia intracranial, infecció cefàlica, trombosi venosa, febre tumoral i hipertensió sense encefalopatia. El risc que una cefalea sigui secundària a patologia greu és major en aquells casos en què aquesta es presenta per primera vegada y en els que coincideix amb el debut de la malaltia hematològica

Parkinson's Disease: Impulsivity Does Not Cause Impulse Control Disorders but Boosts Their Severity

Introduction: Impulse control disorders (ICDs) are a common complication of Parkinson's disease (PD) receiving dopamine agonist (DAA) Impulsivity is considered an underlying mechanism but evidence of this relationship is scarce. To explore the relationship between impulsivity and the presence and severity of ICD in PD.Methods: Prospective cross-sectional study of consecutive PD outpatients. Patients with dementia or previously known ICDs were excluded. Two measures of impulsivity were assessed: Barratt Impulsiveness Scale (BIS-11) for impulsiveness trait (main exposure) and commission errors in the Continuous Performance Test (CE) for motor inhibition. Main outcomes were diagnosis of ICD based on a comprehensive clinical interview and severity of ICD based on the Questionnaire for Impulsive-Compulsive Disorders.Results: Of 100 patients (mean [SD] age, 67.2 [8.8], 54 male), 31 had ICD. Patients with ICDs were 5.3 years younger (p = 0.01), used more frequently dopamine agonist (p = 0.02), alcohol (p = 0.009) and tobacco (p = 0.02). They were not more impulsive on BIS-11 (56 vs. 58, p = 0.23, adjusted p = 0.46) and CE (p = 0.96). No relationship was found between dopaminergic medications and impulsivity or ICD severity. Among patients with ICD, impulsivity was correlated with ICD severity (BIS-11 r = 0.33, p = 0.001, adjusted p = 0.002, CE r = 0.53, p = 0.006). Multivariate regression analysis confirmed the independent predictive role of both measures.Conclusions: Impulsivity is not associated with increased prevalence of ICD in PD but it is strongly linked to ICD severity. When considering dopamine replacement therapy, assessment of impulsivity may be a useful approach to detect those patients at risk of severe forms of ICD

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

Increased plasma neurofilament light chain levels in patients with type-1 diabetes with impaired awareness of hypoglycemia

Altres ajuts: This work was financially supported by a grant from the SPANISH DIABETES SOCIETY.Impaired awareness of hypoglycemia (IAH) is a common complication in patients with type-1 diabetes (T1D). IAH is a major risk factor for severe hypoglycemic events, leading to adverse clinical consequences and cerebral damage. Non-invasive, cost-effective, and logistically efficient biomarkers for this condition have not been validated. Here, we propose plasma neurofilament light chain (NfL) levels as a biomarker of neuroaxonal damage in patients with T1D-IAH. 54 patients were included into the study (18 T1D-IAH, 18 T1D with normal awareness of hypoglycemia (NAH) and 18 healthy controls). We measured plasma NfL levels and studied cerebral gray matter alterations on MRI. We found that NfL levels were increased in patients with T1D-IAH compared with patients with T1D-NAH and healthy controls. Importantly, increased NfL levels correlated with reduced cerebral gray matter volume and increased IAH severity in patients with T1D-IAH. Overall, our findings identify plasma NfL levels as a potential biomarker of cerebral damage in this population, motivating further confirmatory studies with potential implications in clinical trials

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

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

Development of a predictive model of impulse control disorder in parkinson’s disease using clinical, neuropsichological, genetic and neurophysiological data as risk markers

Los trastornos de control de impulsos (TCI) son una complicación frecuente del tratamiento de la enfermedad de Parkinson (EP), particularmente del uso de agonistas de dopamina (AD). Los TCI en la EP se han estudiado durante dos décadas. Sin embargo, la evidencia prospectiva aún es escasa y no hay modelos predictivos disponibles. Esta tesis consta de cuatro trabajos que abordan estas lagunas del conocimiento. En el primer trabajo evaluamos la asociación entre impulsividad y TCI incidente. No confirmamos la asociación sospechada, aunque encontramos una asociación significativa entre la impulsividad y la severidad de los TCI (p = 0.001). La falta de asociación entre la impulsividad y la presencia de TCI se confirmó longitudinalmente en el cuarto trabajo. El segundo trabajo fue un estudio de supervivencia prospectivo longitudinal para evaluar la causalidad de la asociación entre la depresión y el TCI. Los pacientes con EP que estaban deprimidos tenían aproximadamente el doble de riesgo de desarrollar TCI (p <0,001). Esta asociación fue específica e independiente del uso de AD y otros posibles factores de confusión. Además, los pacientes con depresión refractaria tenían un riesgo aún mayor (p = 0,001). El tercero fue un estudio de casos y controles anidado en un estudio prospectivo longitudinal. Estudiamos el metabolismo cerebral a usando PET de 18 FDG. Comparamos pacientes con TCI de nuevo inicio con pacientes apareados sin TCI de la misma cohorte. Los pacientes con TCI mostraron un metabolismo más alto en amplias áreas corticales (p <0.05 corregido para FWE) Los resultados fueron los mismos utilizando el análisis voxelwise y el análisis intracortical. También demostramos que no había diferencias estructurales tanto en el grosor cortical y como en la segmentación subcortical. Usando un grupo de controles sanos apareados, descubrimos que el metabolismo más alto encontrado en los pacientes con TCI es en realidad preservación, dado que no se encontraron diferencias del metabolismo cortical entre los pacientes con EP y TCI y los controles sanos, mientras que los pacientes con EP sin TCI mostraron hipometabolismo en comparación con los controles sanos. El objetivo del cuarto estudio fueron marcadores que pudieran diferenciar a los pacientes con EP con riesgo alto de TCI y aquellos con riesgo bajo. En particular, estudiamos la “feedback related negativity” (FRN), un marcador neurofisiológico del procesamiento de recompensas. Encontramos que este marcador era diferente en los pacientes que desarrollaron TCI en los siguientes tres años en comparación con aquellos que no lo hicieron (p = 0.001). Además, desarrollamos dos modelos para la predicción de TCI: uno utilizando sólo datos clínicos y el otro incluyendo también la FRN basal. El modelo que incluyó la FRN desempeñó significativamente mejor (p = 0.003). Los pacientes identificados gracias a la FRN como de alto riesgo tenían un riesgo diez veces mayor de desarrollar TCI durante los tres años siguientes que los identificados como de bajo riesgo. En conclusión, encontramos evidencias que respalda la depresión como un factor de riesgo de TCI en la EP, evidencias de preservación metabólica cerebral entre los pacientes con EP que tienen TCI, evidencias que respalda el papel del procesamiento de recompensas para el desarrollo de TCI y evidencia que sugiere que la impulsividad debe descartarse como un factor de riesgo para TCI. Por último, demostramos que en el contexto del Parkinson, el desarrollo de TCI puede predecirse, y, por lo tanto, probablemente puede evitarse.Impulse control disorders (ICD) are a common complication of Parkinson’s disease (PD) treatment, particularly of dopamine agonist (DA) use. ICD in PD have been studied for two decades. Nonetheless, prospective evidence is still scarce and predictive models are lacking. This thesis consists of four works addressing these gaps. In the first work we evaluated the association between impulsivity and incident ICD. We did not confirm the suspected association although we found a significant association between impulsivity and ICD severity (p=0.001). The lack of association between impulsivity and ICD presence was confirmed longitudinally in the fourth work. The second work was a longitudinal prospective survival study to evaluate whether the association between depression and ICD was causal. We found that depressed PD patients had approximately double risk of developing ICD (p<0.001). This association was specific and independent from DA use and other potential confounders. Besides, patients with refractory depression had an even higher risk (p=0.001). The third was a case-control study nested in a longitudinal prospective study. We studied brain metabolism via 18 FDG PET. We compared patients with new onset ICD with matched patients free of ICD from the same cohort. ICD patients showed higher metabolism in widespread cortical areas (p<0.05 FWE corrected). The results were the same using voxelwise analysis and intracortical analysis. We also showed that there were no structural differences using cortical thickness and subcortical segmentation. Using a group of matched healthy controls, we found that the higher metabolism found in ICD patients should be regarded as preservation because no cortical metabolic differences were found between PD‑ICD patients and healthy controls, while PD‑nonICD patients showed hypometabolism when compared with healthy controls. The fourth study targeted markers that could differentiate PD patients at high risk of ICD and those at low risk. Particularly we targeted the feedback related negativity (FRN) a neurophysiological marker of reward processing. We found this marker to be different in patients who developed ICD within the subsequent three years compared with those who did not (p=0.001). Furthermore, we developed two models for ICD prediction: one used only clinical data and the other also included the baseline FRN. The model including the FRN performed significantly better (p=0.003). Patients identified using the FRN as high risk had a risk ten times higher for the next three years than those identified as low risk. In conclusion, we found evidence that backs depression as a risk factor for ICD in PD, evidence of brain metabolic preservation among PD patients with ICD, evidence that supports the role of reward processing for ICD development and evidence that suggests that impulsivity should be discarded as a risk factor for ICD. Lastly, we showed that the development of ICD can be predicted in PD patients and therefore, probably can be avoided

Estudio prospectivo de la cefalea en pacientes con hemopatías malignas

Objetivo: describir las cefaleas en pacientes ingresados con neoplasias hematológicas, identificar los factores asociados a cefaleas secundarias graves. Estudio observacional prospectivo. Se incluyen 30 casos de cefalea correspondientes a 23 pacientes. Ocho cefaleas son primarias y 22 secundarias. Diez de estas, son secundarias a patología grave o potencialmente grave: encefalopatía hipertensiva, neoplasia intracraneal, hemorragia intracraneal, infección cefálica, trombosis venosa, fiebre tumoral e hipertensión sin encefalopatía. El riesgo de que una cefalea sea secundaria a patología grave es mayor en los casos que presentan esa cefalea por primera vez y en los que coincide con el debut de la enfermedad hematológica.Objectiu: descriure les cefalees en pacients ingressats amb neoplàsies hematològiques, identificar els factors associats a cefalees secundàries greus. Estudi observacional prospectiu. S’inclouen 30 casos de cefalea que corresponen a 23 pacients. Vuit cefalees són primàries i 22, secundàries. Deu d’aquestes últimes són secundàries a patologia greu o potencialment greu: encefalopatia hipertensiva, neoplàsia intracranial, hemorràgia intracranial, infecció cefàlica, trombosi venosa, febre tumoral i hipertensió sense encefalopatia. El risc que una cefalea sigui secundària a patologia greu és major en aquells casos en què aquesta es presenta per primera vegada y en els que coincideix amb el debut de la malaltia hematològica