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[Background and Objective] Caregiver burden in Parkinson's disease (PD) has been studied in many cross-sectional studies but poorly in longitudinal ones. The aim of the present study was to analyze the change in burden, strain, mood, and quality of life (QoL) after a 2-year follow-up in a cohort of caregivers of patients with PD and also to identify predictors of these changes., [Patients and Methods] PD patients and their caregivers who were recruited from January/2016 to November/2017 from 35 centers of Spain from the COPPADIS cohort were included in the study. They were evaluated again at 2-year follow-up. Caregivers completed the Zarit Caregiver Burden Inventory (ZCBI), Caregiver Strain Index (CSI), Beck Depression Inventory-II (BDI-II), and EUROHIS-QOL 8-item index (EUROHIS-QOL8) at baseline (V0) and at 2-year follow-up (V2). General linear model repeated measure and lineal regression models were applied., [Results] Significant changes, indicating an impairment, were detected on the total score of the ZCBI (p < 0.0001), CSI (p < 0.0001), BDI-II (p = 0.024), and EUROHIS-QOL8 (p = 0.002) in 192 PD caregivers (58.82 ± 11.71 years old; 69.3% were females). Mood impairment (BDI-II; β = 0.652; p < 0.0001) in patients from V0 to V2 was the strongest factor associated with caregiver's mood impairment after the 2-year follow-up. Caregiver's mood impairment was the strongest factor associated with an increase from V0 to V2 on the total score of the ZCBI (β = 0.416; p < 0.0001), CSI (β = 0.277; p = 0.001), and EUROHIS-QOL (β = 0.397; p = 0.002)., [Conclusion] Burden, strain, mood, and QoL were impaired in caregivers of PD patients after a 2-year follow-up. Mood changes in both the patient and the caregiver are key aspects related to caregiver burden increase., Santos García D. has received honoraria for educational presentations and advice service by Abbvie, UCB Pharma, Lundbeck, KRKA, Zambon, Bial, Italfarmaco, and Teva. De Deus Fonticoba T.: None. Cores Bartolomé C. has received honoraria for educational presentations and advice service by Lundbeck and UCB Pharma. Íñiguez Alvarado MC: None. Feal Painceiras M. J.: None. Martínez Miró C.: None. Suárez Castro E.: None. Canfield H.: None. Jesús S. has received honoraria from AbbVie, Bial, Merz, UCB, and Zambon and holds the competitive contract “Juan Rodés” supported by the Instituto de Salud Carlos III. She has received grants from the Spanish Ministry of Economy and Competitiveness (PI18/01898) and the Consejería de Salud de la Junta de Andalucía (PI-0459-2018). Aguilar M.: UCB and Schwabe with assistance to a Congress; Nutricia with assistance to a Congress and payment of lecture. Pastor P.: None. Planellas LL.: None. Cosgaya M.: None. García Caldentey J. has received honoraria for educational presentations and advice service by Qualigen, Nutricia, Abbvie, Italfarmaco, UCB Pharma, Lundbeck, Zambon, Bial, and Teva. Caballol N. has received honoraria from Bial, Italfármaco, Qualigen, Zambon, UCB, Teva and KRKA and sponsorship from Zambon, TEVA and Abbvie for attending medical conferences. Legarda I. has received honoraria for educational presentations and advice service by Abbvie, UCB Pharma, Zambon, Bial, and Teva. Hernández Vara J. has received travel bursaries and educational grants from Abbvie and has received honoraria for educational presentations from Abbvie, Teva, Bial, Zambon, Italfarmaco, and Sanofi-Genzyme. Cabo I. has received honoraria for educational presentations and advice service by Abbvie, Zambon, and Bial. López Manzanares L.: Compensated advisory services, consulting, research grant support, or speaker honoraria: AbbVie, Acorda, Bial, Intec Pharma, Italfarmaco, Pfizer, Roche, Teva, UCB, and Zambon. González Aramburu I.: None. Ávila Rivera MA. has received honoraria from Zambon, UCB Pharma, Qualigen, Bial, and Teva, and sponsorship from Zambon and Teva for attending conferences. Gómez Mayordomo V.: None. Nogueira V.: None. Puente V. has served as consultant for Abbvie and Zambon; has received grant/research from Abbvie. Dotor García-Soto J.: Compensated advisory services, consulting, research grant support, or speaker honoraria: Merck, Sanofi-Genzyme, Allergan, Biogen, Roche, UCB and Novartis. Borrué C.: None. Solano Vila B. has received honoraria for educational presentations and advice service by UCB, Zambon, Teva, Abbvie, Bial. Álvarez Sauco M. has received honoraria for educational presentations and advice service by Abbvie, UCB Pharma, Zambon, Bial, and Teva. Vela L. has received honoraria for educational presentations and advice service by Abbvie, UCB Pharma, Lundbeck, KRKA, Zambon, Bial, and Teva. Escalante S. has received honoraria for educational presentations and advice service by Abbvie, Zambon, and Bial. Cubo E.: Travel grants: Abbvie, Allergan, Boston; Lecturing honoraria: Abbvie, International Parkinson's disease Movement Disorder Society. Carrillo Padilla F. has received honoraria from Zambon (SEN Congress assistance). Martínez Castrillo JC. has received research support from Lundbeck, Italfarmaco, Allergan, Zambon, Merz, and Abbvie. He has received speaking honoraria from AbbVie, Bial, Italfarmaco, Lundbeck, Krka, TEVA, UCB, Zambon, Allergan, Ipsen, and Merz. Sánchez Alonso P. has received honoraria for educational presentations and advice service by Abbvie, UCB Pharma, Lundbeck, KRKA, Zambon, Bial, and Teva. Alonso Losada M. G. has received honoraria for educational presentations and advice service by Zambon and Bial. López Ariztegui N. has received honoraria for educational presentations and advice service by Abbvie, Italfarmaco, Zambon, and Bial. Gastón I. has received research support from Abbvie and Zambon and has served as a consultant for Abbvie, Exelts, and Zambon. Kulisevsky J.: (1) Consulting fees: Roche, Zambon; (2) Stock/allotment: No; (3) Patent royalties/licensing fees: No; (4) Honoraria (e.g. lecture fees): Zambon, Teva, Bial, UCB; (5) Fees for promotional materials: No; (6) Research funding: Roche, Zambon, Ciberned; Instituto de Salud Carlos III; FundacióLa Maratóde TV3; (7) Scholarship from corporation: No; (8) Corporate laboratory funding: No; (9) Others (e.g., trips, travel, or gifts): No. Blázquez Estrada M. has received honoraria for educational presentations and advice service by Abbvie, Abbott, UCB Pharma, Allergan, Zambon, Bial, and Qualigen. Seijo M. has received honoraria for educational services from KRKA, UCB, Zambon, Bial; travel grants from Daiichi and Roche. Ruiz Martínez J. has received honoraria for educational presentations, attending medical conferences, and advice service by Abbvie, UCB Pharma, Zambon, Italfarmaco, Bial, and Teva. Valero C. has received honoraria for educational services from Zambon, Abbvie and UCB. Kurtis M. has received honoraria from Bial, the Spanish Neurology Society, and the International and Movement Disorders Society. de Fábregues O. has received honoraria for educational presentations and advice service by Bial, Zambon, Abbvie, KRKA, and Teva. González Ardura J. has received honoraria for speking from italofarma, Krka, Genzyme, UCB, Esteve, Psyma iberica marketing research SL and Ferrer, course grant from Teva and travel grant from Merck. Alonso Redondo R.: None. Ordás C.: None. López Díaz L. M. has received honoraria from UCB, Lundbeck, and KRKA. McAfee D.: None. Martínez-Martin P. has received honoraria from National School of Public Health (ISCIII), Editorial Viguera and Takeda Pharmaceuticals for lecturing in courses, and from the International Parkinson and Movement Disorder Society (MDS) for management of the Program on Rating Scales. Mir P. has received honoraria from AbbVie, Abbott, Allergan, Bial, Merz, UCB, and Zambon and have received grants from the Spanish Ministry of Economy and Competitiveness [PI16/01575] co-founded by ISCIII (Subdirección General de Evaluación y Fomento de la Investigación) and by Fondo Europeo de Desarrollo Regional (FEDER), the Consejería de Economía, Innovación, Ciencia y Empleo de la Junta de Andalucía [CVI-02526, CTS-7685], the Consejería de Salud y Bienestar Social de la Junta de Andalucía [ PI-0437-2012, PI-0471-2013], the Sociedad Andaluza de Neurología, the Jacques and Gloria Gossweiler Foundation, the Fundación Alicia Koplowitz, the Fundación Mutua Madrileña.

Background: Constipation has been linked to cognitive impairment development in Parkinson's disease (PD). Objective: Our aim was to analyze cognitive changes observed in PD patients and controls from a Spanish cohort with regards to the presence or not of constipation. Methods: PD patients and controls recruited from 35 centers of Spain from the COPPADIS cohort from January 2016 to November 2017 were followed-up during 2 years. The change in cognitive status from baseline (V0) to 2-year follow-up was assessed with the PD-CRS (Parkinson's Disease Cognitive Rating Scale). Subjects with a score >= 1 on item 21 of the NMSS (Non-Motor Symptoms Scale) at baseline (V0) were considered as "with constipation". Regression analyses were applied for determining the contribution of constipation in cognitive changes. Results: At V0, 39.7% (198/499) of PD patients presented constipation compared to 11.4% of controls (14/123) (p < 0.0001). No change was observed in cognitive status (PD-CRS total score) neither in controls without constipation (from 100.24 +/- 13.72 to 100.27 +/- 13.68; p = 0.971) and with constipation (from 94.71 +/- 10.96 to 93.93 +/- 13.03; p = 0.615). The PD-CRS total score decreased significantly in PD patients with constipation (from 89.14 +/- 15.36 to 85.97 +/- 18.09; p

[Background] Motor phenotype (MP) can be associated with a different prognosis in Parkinson's disease (PD), but it is not fixed and can change over time., [Objective] Our aim was to analyze how the MP changed over time and to identify factors associated with the changes in PD patients from a multicenter Spanish PD cohort., [Methods] PD patients who were recruited from January-2016 to November-2017 (baseline visit; V0) and evaluated again at a 2-year±30 days follow-up (V2) from 35 centers of Spain from the COPPADIS cohort, were included in this study.MP was calculated at both visits based on Jankovic classification in TD (tremor dominant), IND (indeterminate), or PIGD (postural instability and gait difficulty). Sociodemographic and clinical data were collected, including serum biomarkers., [Results] Five hundred eleven patients (62.57±8.59 years old; 59.2%males) were included in the study. At V0, MP was: 47.4%(242/511) TD; 36.6%(187/511) PIGD; 16%(82/511) IND. Up to 38%(194/511) of the patients changed their phenotype from V0 to V2, being the most frequent from TD to IND (8.4%) and from TD to PIGD (6.7%). A worse cognitive status (OR = 0.966) and less autonomy for activities of daily living (OR = 0.937) at V0 and a greater increase in the globalNMS burden (OR = 1.011) from V0 to V2 were associated with changing from TD to another phenotype after 2-year follow-up., [Conclusion] The MP in PD can change over time. With disease progression, the percentage of cases with non-tremoric MP increases. PD patients who changed from TD to postural instability and gait difficulty increased NMS burden significantly.

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

Se tiene por objetivo analizar las consecuencias jurídicas de la aplicación del Decreto Ejecutivo 813 expedido el 12 de julio de 2011, con la finalidad de determinar los efectos en la eficiencia de la Gestión Administrativa por la desvinculación de servidores públicos, sin que exista un procedimiento establecido para su cesación. Investigación de tipo documental descriptiva con diseño bibliográfico. La figura de compra de renuncia obligatoria con indemnización, que cesa en funciones a los servidores públicos de sus puestos de trabajo sin que exista un acto voluntario de renuncia a su puesto de trabajo, suponiendo una violación de derechos y garantías laborales establecidas en la Constitución y de los procesos administrativos enmarcados en la Ley Orgánica del Servicio Público.

Resume Introduccion Las ataxias (AT) y paraparesias espasticas hereditarias (PEH) son sindromes neurodegenerativos raros. Nos proponemos conocer la prevalencia de las AT y PEH en Espana en 2019. Pacientes y metodos Estudio transversal, multicentrico, descriptivo y retrospectivo de los pacientes con AT y PEH, desde marzo de 2018 a diciembre de 2019 en toda Espana. Resultados Se obtuvo informacion de 1.809 pacientes procedentes de 11 Comunidades Autonomas, de 47 neurologos o genetistas. Edad media: 53,64 anos ± 20,51 desviacion estandar (DE); 920 varones (50,8%), 889 mujeres (49,2%). En 920 pacientes (47,6%) no se conoce el defecto genetico. Por patologias, 1.371 pacientes (70,9%) diagnosticados de AT, 562 diagnosticados de PEH (29,1%). La prevalencia estimada de AT es 5,48/100.000 habitantes, y la de PEH es 2,24 casos/100.000 habitantes. La AT dominante mas frecuente es la SCA3. La AT recesiva mas frecuente es la ataxia de Friedreich (FRDA). La PEH dominante mas frecuente es la SPG4, y la PEH recesiva mas frecuente es la SPG7. Conclusiones La prevalencia estimada de AT y PEH en nuestra serie es de 7,73 casos/100.000 habitantes. Estas frecuencias son similares a las del resto del mundo. En el 47,6% no se ha conseguido un diagnostico genetico. A pesar de las limitaciones, este estudio puede contribuir a estimar los recursos, visibilizar estas enfermedades, detectar las mutaciones mas frecuentes para hacer los screenings por comunidades, y favorecer los ensayos clinicos.

BackgroundPause duration analysis is a common feature in the study of discourse in Alzheimer’s disease (AD) and may also be helpful for its early detection. However, studies involving patients with amnestic mild cognitive impairment (aMCI) have yielded varying results.ObjectivesTo characterize the probability density distribution of speech pause durations in AD, two multi-domain amnestic MCI patients (with memory encoding deficits, a-mdMCI-E, and with retrieval impairment only, a-mdMCI-R) and healthy controls (HC) in order check whether there are significant differences between them.Method112 picture-based oral narratives were manually transcribed and annotated for the automatic extraction and analysis of pause durations. Different probability distributions were tested for the fitting of pause durations while truncating shorter ranges. Recent findings in the field of Statistics were considered in order to avoid the inherent methodological uncertainty that this type of analysis entails.ResultsA lognormal distribution (LND) explained the distribution of pause duration for all groups. Its fitted parameters (µ,σ) followed a gradation from the group with shorter durations and a higher tendency to produce short pauses (HC) to the group with longer pause durations and a considerably higher tendency to produce long pauses with greater variance (AD). Importantly, a-mdMCI-E produced significantly longer pauses and with greater variability than their a-mdMCI-R counterparts (α= 0.05).ConclusionWe report significant differences at the group level in pause distribution across all groups of study that could be used in future diagnostic tools and discuss the clinical implications of these findings, particularly regarding the characterization of aMCI.

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

Malaltia de Parkinson; Levodopa; Factors de risc Enfermedad de Parkinson; Levodopa; Factores de riesgo Parkinson Disease; Levodopa; Risk Factors Background:There is a need for identifying risk factors for hospitalization in Parkinson’s disease (PD) and also interventions to reduce acute hospital admission. Objective:To analyze the frequency, causes, and predictors of acute hospitalization (AH) in PD patients from a Spanish cohort.Methods:PD patients recruited from 35 centers of Spain from the COPPADIS-2015 (COhort of Patients with PArkinson’s DIsease in Spain, 2015) cohort from January 2016 to November 2017, were included in the study. In order to identify predictors of AH, Kaplan-Meier estimates of factors considered as potential predictors were obtained and Cox regression performed on time to hospital encounter 1-year after the baseline visit.Results:Thirty-five out of 605 (5.8%) PD patients (62.5±8.9 years old; 59.8% males) presented an AH during the 1-year follow-up after the baseline visit. Traumatic falls represented the most frequent cause of admission, being 23.7% of all acute hospitalizations. To suffer from motor fluctuations (HR [hazard ratio] 2.461; 95% CI, 1.065–5.678; p = 0.035), a very severe non-motor symptoms burden (HR [hazard ratio] 2.828; 95% CI, 1.319–6.063; p = 0.008), falls (HR 3.966; 95% CI 1.757–8.470; p = 0.001), and dysphagia (HR 2.356; 95% CI 1.124–4.941; p = 0.023) was associated with AH after adjustment to age, gender, disease duration, levodopa equivalent daily dose, total number of non-antiparkinsonian drugs, and UPDRS-IIIOFF. Of the previous variables, only falls (HR 2.998; 95% CI 1.080–8.322; p = 0.035) was an independent predictor of AH. Conclusion:Falls is an independent predictor of AH in PD patients

Background: Pause duration analysis is a common feature in the study of discourse in Alzheimer’s disease (AD) and may also be helpful for its early detection. However, studies involving patients at the preclinical stage of mild cognitive impairment (MCI) have yielded varying results. Objectives: To characterize the probability density distribution of speech pause duration in AD, two multi-domain amnestic MCI patients (with memory encoding deficits, a-mdMCI-E, and only with retrieval impairment, a-mdMCI-R) and healthy control groups (HC) and to check if there are significant differences between them. To discuss the potential of those findings in clinical practice. Method: 112 picture-based oral narratives were manually transcribed and annotated for the automatic extraction of pause durations and their subsequent logconversion. We consider different probability distributions to fit speech pause duration truncating shorter ranges taking into account latest statistical findings to avoid inherent methodological uncertainties present in them. Results: Lognormal distribution (LND) explains the distribution of pause duration in speech for all groups, and its fitted parameters (m,s) followed a gradation from the group with shorter durations and a higher tendency to produce short pauses (HC) to the group with longer pause durations and a considerably higher tendency to produce long pauses with more variance (AD). Importantly, a-mdMCI-E produced significantly longer pauses with greater variability than their a-mdMCI-R counterparts (a = 0:05) across all groups of study. Conclusion: We characterize and report significant differences at group level in the speech pause distribution across all groups of study that could be used to design tools and experiments for early prediction of AD progression. This work is supported through a PhD grant awarded to P.P-D. by the banking Foundation ”La Caixa” (ID 100010434, code: LCF/BQ/ES15/10360020). F.D-V. was supported by a grant awarded to project no. PID2019-107042GB-I00 (Ministerio de Ciencia e Innovacion). A.H-F. and I.G.T. were supported by the grant no. TIN2017-89244-R (MACDA) (Ministerio de Economia, Industria y Competitividad, Gobierno de Espana) and the project PRO2020-S03 (RCO03080 Lingüística Quantitativa) of l’Institut d’Estudis Catalans

INTRODUCTION: Ataxia and hereditary spastic paraplegia are rare neurodegenerative syndromes. We aimed to determine the prevalence of these disorders in Spain in 2019. PATIENTS AND METHODS: We conducted a cross-sectional, multicentre, retrospective, descriptive study of patients with ataxia and hereditary spastic paraplegia in Spain between March 2018 and December 2019. RESULTS: We gathered data from a total of 1.809 patients from 11 autonomous communities, provided by 47 neurologists or geneticists. Mean (SD) age in our sample was 53.64 (20.51) years; 920 patients were men (50.8%) and 889 were women (49.2%). The genetic defect was unidentified in 920 patients (47.6%). A total of 1371 patients (70.9%) had ataxia and 562 (29.1%) had hereditary spastic paraplegia. Prevalence rates for ataxia and hereditary spastic paraplegia were estimated at 5.48 and 2.24 cases per 100 000 population, respectively. The most frequent type of dominant ataxia in our sample was SCA3, and the most frequent recessive ataxia was Friedreich ataxia. The most frequent type of dominant hereditary spastic paraplegia in our sample was SPG4, and the most frequent recessive type was SPG7. CONCLUSIONS: In our sample, the estimated prevalence of ataxia and hereditary spastic paraplegia was 7.73 cases per 100 000 population. This rate is similar to those reported for other countries. Genetic diagnosis was not available in 47.6% of cases. Despite these limitations, our study provides useful data for estimating the necessary healthcare resources for these patients, raising awareness of these diseases, determining the most frequent causal mutations for local screening programmes, and promoting the development of clinical trials.

Background: STAT-ON™ is an objective tool that registers ON-OFF fluctuations making possible to know the state of the patient at every moment of the day in normal life. Our aim was to analyze the opinion of different Parkinson's disease experts about the STAT-ON™ tool after using the device in a real clinical practice setting (RCPS). Methods: STAT-ON™ was provided by the Company Sense4Care to Spanish neurologists for using it in a RCPS. Each neurologist had the device for at least three months and could use it in PD patients at his/her own discretion. In February 2020, a survey with 30 questions was sent to all participants. Results: Two thirds of neurologists (53.8% females; mean age 44.9 ± 9 years old) worked in a Movement Disorders Unit, the average experience in PD was 16 ± 6.9 years, and 40.7% of them had previously used other devices. A total of 119 evaluations were performed in 114 patients (range 2–9 by neurologist; mean 4.5 ± 2.3). STAT-ON™ was considered “quite” to “very useful” by 74% of the neurologists with an overall opinion of 6.9 ± 1.7 (0, worst; 10, best). STAT-ON™ was considered better than diaries by 70.3% of neurologists and a useful tool for the identification of patients with advanced PD by 81.5%. Proper identification of freezing of gait episodes and falls were frequent limitations reported. Conclusion: STAT-ON™ could be a useful device for using in PD patients in clinical practice.

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

[Objective] The aim of the present study was to analyze the progression of non-motor symptoms (NMS) burden in Parkinson's disease (PD) patients regarding the development of motor fluctuations (MF)., [Methods] PD patients without MF at baseline, who were recruited from January 2016 to November 2017 (V0) and evaluated again at a 2-year follow-up (V2) from 35 centers of Spain from the COPPADIS cohort, were included in this analysis. MF development at V2 was defined as a score ≥ 1 in the item-39 of the UPDRS-Part IV, whereas NMS burden was defined according to the Non-motor Symptoms Scale (NMSS) total score., [Results] Three hundred and thirty PD patients (62.67 ± 8.7 years old; 58.8% males) were included. From V0 to V2, 27.6% of the patients developed MF. The mean NMSS total score at baseline was higher in those patients who developed MF after the 2-year follow-up (46.34 ± 36.48 vs. 34.3 ± 29.07; p = 0.001). A greater increase in the NMSS total score from V0 to V2 was observed in patients who developed MF (+16.07 ± 37.37) compared to those who did not develop MF (+6.2 ± 25.8) (p = 0.021). Development of MF after a 2-year follow-up was associated with an increase in the NMSS total score (β = 0.128; p = 0.046) after adjustment to age, gender, years from symptoms onset, levodopa equivalent daily dose (LEDD) and the NMSS total score at baseline, and the change in LEDD from V0 to V2., [Conclusions] In PD patients, the development of MF is associated with a greater increase in the NMS burden after a 2-year follow-up., Santos García D. has received honoraria for educational presentations and advice service by Abbvie, UCB Pharma, Lundbeck, KRKA, Zambon, Bial, Italfarmaco, and Teva. De Deus Fonticoba T.: None. Cores Bartolomé C. has received honoraria for educational presentations and advice service by Lundbeck and UCB Pharma. Feal Painceiras M. J.: None. Martínez Miró C.: None. Suárez Castro E.: None. Canfield H.: None. Jesús S. has received honoraria from AbbVie, Bial, Merz, UCB, and Zambon and holds the competitive contract “Juan Rodés” supported by the Instituto de Salud Carlos III. She has received grants from the Spanish Ministry of Economy and Competitiveness (PI18/01898) and the Consejería de Salud de la Junta de Andalucía (PI-0459-2018). Aguilar M.: UCB and Schwabe with assistance to a Congress; Nutricia with assistance to a Congress and payment of lecture. Pastor P.: None. Planellas LL.: None. Cosgaya M.: None. García Caldentey J. has received honoraria for educational presentations and advice service by Qualigen, Nutricia, Abbvie, Italfarmaco, UCB Pharma, Lundbeck, Zambon, Bial, and Teva. Caballol N. has received honoraria from Bial, Italfármaco, Qualigen, Zambon, UCB, Teva, and KRKA and sponsorship from Zambon, TEVA, and Abbvie for attending medical conferences. Legarda I. has received honoraria for educational presentations and advice service by Abbvie, UCB Pharma, Zambon, Bial, and Teva. Hernández Vara J. has received travel bursaries and educational grants from Abbvie and has received honoraria for educational presentations from Abbvie, Teva, Bial, Zambon, Italfarmaco, and Sanofi-Genzyme. Cabo I. has received honoraria for educational presentations and advice service by Abbvie, Zambon, and Bial. López Manzanares L.: Compensated advisory services, consulting, research grant support, or speaker honoraria: AbbVie, Acorda, Bial, Intec Pharma, Italfarmaco, Pfizer, Roche, Teva, UCB, and Zambon. González Aramburu I.: None. Ávila Rivera MA. has received honoraria from Zambon, UCB Pharma, Qualigen, Bial, and Teva, and sponsorship from Zambon and Teva for attending conferences. Gómez Mayordomo V.: None. Nogueira V.: None. Puente V. has served as consultant for Abbvie and Zambon; has received grant/research from Abbvie. Dotor García-Soto J.: Compensated advisory services, consulting, research grant support, or speaker honoraria: Merck, Sanofi-Genzyme, Allergan, Biogen, Roche, UCB, and Novartis. Borrué C.: None. Solano Vila B. has received honoraria for educational presentations and advice service by UCB, Zambon, Teva, Abbvie, Bial. Álvarez Sauco M. has received honoraria for educational presentations and advice service by Abbvie, UCB Pharma, Zambon, Bial, and Teva. Vela L. has received honoraria for educational presentations and advice service by Abbvie, UCB Pharma, Lundbeck, KRKA, Zambon, Bial, and Teva. Escalante S. has received honoraria for educational presentations and advice service by Abbvie, Zambon, and Bial. Cubo E.; travel grants from Abbvie, Allergan, and Boston; and lecturing honoraria from Abbvie, International Parkinson’s disease Movement Disorder Society. Carrillo Padilla F. has received honoraria from Zambon (SEN Congress assistance). Martínez Castrillo JC. has received research support from Lundbeck, Italfarmaco, Allergan, Zambon, Merz, and Abbvie; he has also received speaking honoraria from AbbVie, Bial, Italfarmaco, Lundbeck, Krka, TEVA, UCB, Zambon, Allergan, Ipsen, and Merz. Sánchez Alonso P. has received honoraria for educational presentations and advice service by Abbvie, UCB Pharma, Lundbeck, KRKA, Zambon, Bial, and Teva. Alonso Losada M. G. has received honoraria for educational presentations and advice service by Zambon and Bial. López Ariztegui N. has received honoraria for educational presentations and advice service by Abbvie, Italfarmaco, Zambon, and Bial. Gastón I. has received research support from Abbvie and Zambon and has served as a consultant for Abbvie, Exelts, and Zambon. Kulisevsky J.: (1) Consulting fees: Roche, Zambon; (2) Stock/allotment: No; (3) Patent royalties/licensing fees: No; (4) Honoraria (e.g., lecture fees): Zambon, Teva, Bial, UCB; (5) Fees for promotional materials: No; (6) Research funding: Roche, Zambon, Ciberned; Instituto de SaludCarlos III; FundacióLa Maratóde TV3; (7) Scholarship from corporation: No; (8) Corporate laboratory funding: No; (9) Others (e.g., trips, travel, or gifts): No. Blázquez Estrada M. has received honoraria for educational presentations and advice service by Abbvie, Abbott, UCB Pharma, Allergan, Zambon, Bial, and Qualigen. Seijo M. has received honoraria for educational services from KRKA, UCB, Zambon, and Bial and travel grants from Daiichi and Roche. Ruiz Martínez J. has received honoraria for educational presentations, attending medical conferences, and advice service by Abbvie, UCB Pharma, Zambon, Italfarmaco, Bial, and Teva. Valero C. has received honoraria for educational services from Zambon, Abbvie and UCB. Kurtis M. has received honoraria from Bial, the Spanish Neurology Society, and the International and Movement Disorders Society. de Fábregues O. has received honoraria for educational presentations and advice service by Bial, Zambon, Abbvie, KRKA, and Teva. González Ardura J. has received honoraria for speaking from italofarma, Krka, Genzyme, UCB, Esteve, Psyma iberica marketing research SL, and Ferrer; a course grant from Teva; and travel grant from Merck. Alonso Redondo R.: None. Ordás C.: None. López Díaz L. M. has received honoraria from UCB, Lundbeck, and KRKA. McAfee D.: None. Martínez-Martin P. has received honoraria from National School of Public Health (ISCIII), Editori-al Viguera and Takeda Pharmaceuticals for lecturing in courses, and from the International Parkinson and Movement Disorder Society (MDS) for management of the Program on Rating Scales. Mir P. has received honoraria from AbbVie, Abbott, Allergan, Bial, Merz, UCB, and Zambon and has received grants from the Spanish Ministry of Economy and Competitiveness [PI16/01575] cofounded by ISCIII (Subdirección General de Evaluación y Fomento de la Investigación) and by Fondo Europeo de Desarrollo Regional (FEDER), the Consejería de Economía, Innovación, Ciencia y Empleo de la Junta de Andalucía [CVI-02526, CTS-7685], the Consejería de Salud y Bienestar Social de la Junta de Andalucía [ PI-0437-2012, PI-0471-2013], the Sociedad Andaluza de Neurología, the Jacques and Gloria Gossweiler Foundation, the Fundación Alicia Koplowitz, and the Fundación Mutua Madrileña.

Background Round ligament cysts are rare lesions, often diagnosed as irreducible inguinal hernias. Most patients are in the third to fourth decade of life, but they can occur in younger patients. They are usually clinically asymptomatic or tend to produce subtle symptoms such as pain, discomfort, or a feeling of heaviness, and swelling. Cysts should not be resized with the Valsalva manoeuvre. Ultrasound is the diagnostic method of choice. The definitive diagnosis is made during surgery, and confirmed by pathological examination. Objective To present a case of round ligament cyst, initially diagnosed as an incarcerated inguinal hernia, and a review of the literature. Clinical case A 19 year-old female, who was admitted to the emergency department due to her current condition of 5 days of onset. She had an increased volume in right inguinal region that increased with physical exertion, throbbing pain, and nausea without vomiting. A right inguinal mass of approximately of 6 cm in diameter was found, which was painful on mid-superficial palpation, reaching a pre-surgical diagnosis of incarcerated right inguinal hernia with an indication of surgical intervention. Conclusion Round ligament cysts are a rare pathology, often confused with incarcerated inguinal hernias. Although ultrasound is the study of choice, the final diagnosis is usually made during surgery and confirmed by histopathology.

Background and objective: Freezing of gait (FOG) is a disabling symptom more frequent in Parkinson’s disease (PD) patients with postural instability gait difficulty (PIGD) phenotype. The aim of this study was to determine the prevalence of self-reported FOG in a large group of PD patients as well as assess its relationship with functional dependency with regard to motor phenotype. Methods: The data correspond to the baseline evaluation of the COPPADIS-2015 study. Patients with FOG were identified as those with a score of 1 or greater on item-3 of the freezing of gait questionnaire (FOG-Q). Functional dependency was defined as a Schwab and England (S&E) ADL scale score less than 80%. PIGD and non-PIGD (tremor dominant + indeterminate) groups were considered regarding to motor phenotype. Results: Among the 689 PD patients (62.6 ± 8.9 years old, 59.8% males), 240 reported FOG (34.8%), whereas 63 presented functional dependency (9.1%). A total of 22.1% of patients with FOG presented functional dependency vs. only 2.2% of those without FOG (p < 0.0001). FOG was related to functional dependency (OR = 3.470; 95%CI 1.411–8.530; p = 0.007) after adjustment to age, gender, disease duration, daily equivalent levodopa dose, comorbidity (number of non-antiparkinsonian drugs/day), motor status (UPDRS-III), PIGD phenotype, motor complications (UPDRS-IV), NMS burden (NMSS total score), cognition (PD-CRS), and mood (BDI-II). However, according to motor phenotype, FOG was related to functional dependency only in PIGD patients (OR = 7.163; 95%CI 1.206–42.564; p = 0.030). Conclusions: Self-reported FOG is associated with functional dependency in PIGD but not in non-PIGD motor phenotype patients., Santos-García D. has received honoraria for educational presentations and/or advice service by Abbvie, UCB Pharma, Lundbeck, KRKA, Zambon, Bial, and Teva. de Deus Fonticoba T. has received honoraria for educational presentations and advice service by Abbvie. Suárez Castro E: None. Ángel Aneiros Díaz: None. Feal Painceiras M: None. Paz González JM has received honoraria for educational presentations and/or advice service by UCB Pharma, Lundbeck, KRKA y Zambon. García Sancho C: None. Jesús S. has received honoraria from AbbVie, Bial, Merz, UCB, and Zambon. She also holds the competitive contract “Juan Rodés” supported by the Instituto de Salud Carlos III. She has received grants from the Spanish Ministry of Economy and Competitiveness (PI18/01898) and the Consejería de Salud de la Junta de Andalucía (PI-0459-2018). Mir P. has received honoraria from AbbVie, Abbott, Allergan, Bial, Merz, UCB, and Zambon. Also, he has received grants from the Spanish Ministry of Economy and Competitiveness (PI16/01575) co-founded by ISCIII (Subdirección General de Evaluación y Fomento de la Investigación), Fondo Europeo de Desarrollo Regional (FEDER), the Consejería de Economía, Innovación, Ciencia y Empleo de la Junta de Andalucía (CVI-02526, CTS-7685), the Consejería de Salud y Bienestar Social de la Junta de Andalucía (PI-0437-2012, PI-0471-2013), the Sociedad Andaluza de Neurología, the Jacques and Gloria Gossweiler Foundation, the Fundación Alicia Koplowitz, and the Fundación Mutua Madrileña. Planellas LL. has received travel bursaries grant from Abbvie. García Caldentey J. has received honoraria for educational presentations and advice service by Qualigen, Nutricia, Abbvie, Italfarmaco, UCB Pharma, Lundbeck, Zambon, Bial, and Teva. Caballol N. has received honoraria for educational presentations and advice service by Qualigen, Nutricia, Abbvie, Italfarmaco, UCB Pharma, Lundbeck, Zambon, Bial, and Teva. Legarda I. has received honoraria for educational presentations and advice service by Abbvie, UCB Pharma, Zambon, Bial, and Teva. Hernández Vara J. has received travel bursaries and educational grants from Abbvie and has received honoraria for educational presentations from Abbvie, Teva, Bial, Zambon, Italfarmaco, and Sanofi-Genzyme. González Aramburu I: None. Ávila Rivera MA. has received honoraria from Zambon, UCB Pharma, Qualigen, Bial, and Teva, and sponsorship from Zambon and Teva for attending conferences. Catalán MJ: None. Nogueira V: None. Álvarez Sauco M. has received honoraria for educational presentations and advice service by Abbvie, UCB Pharma, Zambon, Bial, and Teva. Vela L. has received honoraria for educational presentations and advice service by Abbvie, UCB Pharma, Lundbeck, KRKA, Zambon, Bial, and Teva. Escalante S. has received honoraria for educational presentations and advice service by Abbvie, Zambon, and Bial. Cubo E: travel grants: Abbvie, Allergan, Boston; lecturing honoraria: Abbvie, International Parkinson’s disease Movement Disorder Society. Sánchez Alonso P. has received honoraria for educational presentations and advice service by Abbvie, UCB Pharma, Lundbeck, KRKA, Zambon, Bial, and Teva. Alonso Losada MG. has received honoraria for educational presentations and advice service by Zambon and Bial. López Ariztegui N. has received honoraria for educational presentations and advice service by Abbvie, Italfarmaco, Zambon, and Bial. Martinez-Martin P: Honoraria: from Editorial Viguera and National School of Health for lecturing in courses; International Parkinson and Movement Disorder Society for management of the Program on Rating Scales; Abbvie and Zambon for advice in clinic-epidemiological studies www.curemoselparkinson.org.

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

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

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

ResumenAntecedentesLos quistes de ligamento redondo son lesiones raras, frecuentemente diagnosticados como hernias inguinales irreductibles. La mayoría de los pacientes están entre la tercera y la cuarta décadas de la vida, aunque pueden presentarse en pacientes más jóvenes. Clínicamente son, en general, asintomáticos o tienden a producir síntomas sutiles tales como dolor, molestia o sensación de pesantez y abultamiento. Los quistes no deben cambiar de tamaño con la maniobra de Valsalva. El ultrasonido es la modalidad de elección diagnóstica. El diagnóstico definitivo se realiza durante la cirugía y se confirma con el examen anatomopatológico.ObjetivoPresentamos el caso de un quiste de ligamento redondo diagnosticado inicialmente como una hernia inguinal encarcelada, así como la revisión de la literatura.Caso clínicoPaciente femenina de 19 años, quien ingresa al Servicio de Urgencias por padecimiento de 5 días de evolución, con aumento de volumen en región inguinal derecha ante el esfuerzo físico, dolor punzante, náuseas sin llegar al vómito. A la exploración se encontró una masa inguinal derecha de aproximadamente 6cm de diámetro, dolorosa a la palpación medio-superficial, que se integró al diagnóstico prequirúrgico de hernia inguinal derecha encarcelada, por lo que se decidió su intervención quirúrgica.ConclusiónLos quistes de ligamento redondo son una enfermedad rara, frecuentemente confundidos con hernias inguinales encarceladas. El ultrasonido es el estudio de elección. Generalmente se llega al diagnóstico definitivo durante la cirugía y se confirma por el estudio de anatomía patológica.AbstractBackgroundRound ligament cysts are rare lesions, often diagnosed as irreducible inguinal hernias. Most patients are in the third to fourth decade of life, but they can occur in younger patients. They are usually clinically asymptomatic or tend to produce subtle symptoms such as pain, discomfort, or a feeling of heaviness, and swelling. Cysts should not be resized with the Valsalva manoeuvre. Ultrasound is the diagnostic method of choice. The definitive diagnosis is made during surgery, and confirmed by pathological examination.ObjectiveTo present a case of round ligament cyst, initially diagnosed as an incarcerated inguinal hernia, and a review of the literature.Clinical caseA 19 year-old female, who was admitted to the emergency department due to her current condition of 5 days of onset. She had an increased volume in right inguinal region that increased with physical exertion, throbbing pain, and náusea without vomiting. A right inguinal mass of approximately of 6cm in diameter was found, which was painful on mid-superficial palpation, reaching a pre-surgical diagnosis of incarcerated right inguinal hernia with an indication of surgical intervention.ConclusionRound ligament cysts are a rare pathology, often confused with incarcerated inguinal hernias. Although ultrasound is the study of choice, the final diagnosis is usually made during surgery and confirmed by histopathology.

El proyecto pretende realizar un plan de negocio que garantice la viabilidad de la puesta en marcha de Realgame, donde contextualiza y estructura los estudios necesarios para la conformación de la empresa como un centro de entretenimiento de alta tecnología en la ciudad de Bogotá, que inicialmente ofrezca video juegos en 3D y posteriormente se pueda incursionar en la tecnología 4D y la realidad virtual The project aims to make a business plan to ensure the feasibility of implementing Realgame where context and structure studies necessary for the formation of the company as a center of high-tech entertainment in the city of Bogota, which initially offered 3D video games and then you can move into 4D technology and virtual reality

Compendi d'articles, Doctorat internacional Multiple studies have found that bilinguals show the first symptoms of dementia later than monolinguals. Therefore, it is hypothesized that bilingualism could protect against dementia, but the neural bases of this protective effect are still unclear. In the works included in this thesis, we studied the neural mechanisms of bilingualism and dementia, and its implications for cognitive reserve, obtaining magnetic resonance images of bilingual and monolingual patients in different stages of Alzheimer’s disease (AD) and of healthy participants. We found that the neural bases of bilingualism’s protection against dementia could be the use of alternative brain circuits as a mechanism of compensation, in the presence of more structural atrophy in fibers and regions related to AD pathology, resulting in similar levels of cognitive impairment. This protection seems to start in prodromal AD stages and be maintained longitudinally until the disease starts. Programa de Doctorat en Psicologia

Compendi d'articles, Doctorat internacional Doctorat internacional Multiple sclerosis is an autoimmune degenerative disease that produces cognitive impairment secondary to white and gray matter disruption of the central nervous system. The main objectives of this doctoral thesis were: First, to study spontaneous brain neuroplasticity processes associated with white matter lesions. Second, to study neuroplasticity processes induced after intensive working memory training. Regarding spontaneous neuroplasticity results, it was observed that white matter lesions located in the internal capsule are predominant in MS patients and cause functional connectivity changes that correlate negatively with cognitive performance. On the other hand, induced neuroplasticity results showed that a specific training in working memory produces similar neuroplasticity in patients as in healthy subjects. These changes in brain plasticity are also associated with cognitive performance improvement. These results can be interpreted as an increase in cognitive efficiency. Programa de Doctorat en Psicologia

[Background and objective] Diplopia is relatively common in Parkinson’s disease (PD) but is still understudied. Our aim was to analyze the frequency of diplopia in PD patients from a multicenter Spanish cohort, to compare the frequency with a control group, and to identify factors associated with it., [Patients and Methods] PD patients who were recruited from January 2016 to November 2017 (baseline visit; V0) and evaluated again at a 2-year ± 30 days follow-up (V2) from 35 centers of Spain from the COPPADIS cohort were included in this longitudinal prospective study. The patients and controls were classified as “with diplopia” or “without diplopia” according to item 15 of the Non-Motor Symptoms Scale (NMSS) at V0, V1 (1-year ± 15 days), and V2 for the patients and at V0 and V2 for the controls., [Results] The frequency of diplopia in the PD patients was 13.6% (94/691) at V0 (1.9% in controls [4/206]; p < 0.0001), 14.2% (86/604) at V1, and 17.1% (86/502) at V2 (0.8% in controls [1/124]; p < 0.0001), with a period prevalence of 24.9% (120/481). Visual hallucinations at any visit from V0 to V2 (OR = 2.264; 95%CI, 1.269–4.039; p = 0.006), a higher score on the NMSS at V0 (OR = 1.009; 95%CI, 1.012–1.024; p = 0.015), and a greater increase from V0 to V2 on the Unified Parkinson’s Disease Rating Scale–III (OR = 1.039; 95%CI, 1.023–1.083; p < 0.0001) and Neuropsychiatric Inventory (OR = 1.028; 95%CI, 1.001–1.057; p = 0.049) scores were independent factors associated with diplopia (R2 = 0.25; Hosmer and Lemeshow test, p = 0.716)., [Conclusions] Diplopia represents a frequent symptom in PD patients and is associated with motor and non-motor severity., Martínez-Martin P. has received honoraria from National School of Public Health (ISCIII), Editori-al Viguera and Takeda Pharmaceuticals for lecturing in courses, and from the International Parkinson and Movement Disorder Society (MDS) for management of the Program on Rating Scales. Mir P. has received honoraria from AbbVie, Abbott, Allergan, Bial, Merz, UCB, and Zambon and have received grants from the Spanish Ministry of Economy and Competitiveness [PI16/01575], co-founded by ISCIII (Subdirección General de Evaluación y Fomento de la Investigación) and by Fondo Europeo de Desarrollo Regional (FEDER), the Consejería de Economía, Innovación, Ciencia y Empleo de la Junta de Andalucía [CVI-02526, CTS-7685], the Consejería de Salud y Bienestar Social de la Junta de Andalucía [ PI-0437-2012, PI-0471-2013], the Sociedad Andaluza de Neurología, the Jacques and Gloria Gossweiler Foundation, the Fundación Alicia Koplowitz, the Fundación Mutua Madrileña.

Esta tesis tiene como objetivo investigar los cambios cerebrales que se producen como consecuencia de la estimulación audio-motora. Para ello, se han utilizado medidas de actividad y de conectividad funcional entre las regiones cerebrales implicadas en el procesamiento audio-motor. Dichos cambios se miden en tres estudios en los que la estimulación audio-motora tiene lugar mediante el aprendizaje de cómo tocar un instrumento musical (Estudio 1) y el aprendizaje de un vocabulario nuevo (Estudio 2 y 3). En conjunto, los resultados de estos tres estudios evidencian que ambos aprendizajes, ya sea musical o de un vocabulario nuevo, producen una huella a nivel cerebral en las interacciones audio-motoras incluso en ausencia de una tarea específica. Además, esta tesis muestra los cambios que produce el aprendizaje de un vocabulario nuevo no solo a corto sino a largo plazo, así como las modificaciones que produce en la lengua nativa., The aim of the present thesis was to investigate neural changes associated with audiomotor stimulation. We measured brain activation as well as functional connectivity between brain regions implicated in audiomotor processing. Three studies were conducted to investigate the neural changes in audiomotor connectivity. The first study investigated the learning processes required to play a musical instrument, whereas the second and third investigated the acquisition of a new vocabulary. My thesis demonstrated that both musical training and learning a new vocabulary leaves an imprint in the brain that affects the audiomotor interactions, even in the absence of a specific task. Furthermore, my thesis showed that the acquisition of a new vocabulary not only produces short-term effects in the brain but even extends to long- term effects over a few weeks and, in addition, modifies the native language. Overall, my thesis provided insight in the ongoing neural changes during language and musical training.

INTRODUCCIÓN El interés en el estudio del deterioro cognitivo y la fatiga en la EM ha aumentado de forma considerable durante los últimos años, a medida que se ha ido tomando conciencia sobre su elevada prevalencia y el impacto que ambos tienen sobre la calidad de vida de estos pacientes. Este interés ha generado un auge de investigaciones dirigidas a identificar variables fisiopatológicas cerebrales relacionadas con estos dos síntomas, que se han apoyado en el empleo de diferentes técnicas de neuroimagen. Concretamente, la RM ha demostrado su utilidad como una de las técnicas más sensibles para detectar y relacionar la presencia de alteraciones estructurales con variables clínicas de interés en la enfermedad. Así, diferentes trabajos de RM han vinculado tanto la fatiga como los déficits cognitivos de esta población clínica con diferentes variables radiológicas, entre las cuales destacan las lesiones (Colombo y cols., 2000; Archibald y cols., 2004; Lazeron y cols., 2005; Tedeschi y cols., 2007; Sepulcre y cols., 2009b; Andreasen y cols., 2010; Rossi y cols., 2012), diferentes medidas relacionadas con la pérdida de volumen cerebral o atrofia (Chaudhuri y Behan, 2000; Zivadinov y cols., 2001; Marrie y cols., 2005; Benedict y cols., 2006b; Niepel y cols., 2006; Amato y cols., 2007; Tedeschi y cols., 2007; Sepulcre y cols., 2008; Sicotte y cols., 2008; Téllez y cols., 2008; Roosendaal y cols., 2009; Sastre-Garriga y cols., 2009; Tiemann y cols., 2009; Calabrese y cols., 2009, 2010; Andreasen y cols., 2010; Pellicano y cols., 2010), y alteraciones en tejido cerebral aparentemente normal captadas con técnicas no convencionales (Tartaglia y cols., 2004; Lin y cols., 2005; Bodini y cols., 2012). Los estudios con RM estructural más recientes se han visto reforzados por el uso de nuevas técnicas y herramientas de análisis, como la técnica de la morfometría basada en el vóxel, que ha demostrado su utilidad ya que permite no sólo la cuantificación de las alteraciones estructurales sino también su localización topográfica precisa. Así, esta metodología ha posibilitado el desarrollo de estudios pioneros que han evidenciado una relación entre alteraciones en regiones específicas del cerebro con los déficits cognitivos (Riccitelli y cols., 2011a; Bodini y cols., 2012) así como con la fatiga (Riccitelli y cols., 2011b). Sin embargo, debido a la novedad de esta metodología, los trabajos hasta la fecha que la han empleado son escasos todavía, por lo que consideramos de especial relevancia que se realicen más estudios aprovechándose de las ventajas que ofrecen estas técnicas. Por otra parte, además de estas alteraciones estructurales, se deben tener en cuenta la existencia de procesos de neuroplasticidad o reorganización funcional, que parecen tener un papel intermediario entre la acumulación del daño estructural y la manifestación de las alteraciones cognitivas y la fatiga en esta enfermedad. Estos procesos han sido evidenciados a través de diferentes estudios con RM funcional (RMf), que han demostrado alteraciones en el patrón de activación cerebral en pacientes EM durante la realización de diferentes tareas en relación tanto con la fatiga como con el rendimiento cognitivo (Filippi y cols., 2002; Audoin y cols., 2003; Forn y cols., 2006, 2007; 2012; Rocca y cols., 2009; White y cols., 2009). Concretamente, estos estudios han señalado cómo los pacientes EM muestran activaciones más extensas o reclutan más áreas para la realización de las tareas, hallazgo que ha sido frecuentemente interpretado como un mecanismo adaptativo de compensación de carácter temprano que limita la manifestación de los déficits funcionales en respuesta a la acumulación de daño estructural. Los estudios más recientes de RMf se han centrado en el análisis en estado de reposo (donde se prescinde de la presentación de una tarea). Una de las medidas más estudiadas mediante esta metodología ha sido la de la conectividad funcional (CF), que permite explorar en qué medida están conectadas diferentes áreas cerebrales entre sí. En una enfermedad como la EM, creemos que es de especial interés el estudio de la CF, ya que las lesiones características de esta patología que dañan los tractos de SB pueden alterar la comunicación entre diferentes regiones cerebrales. Diferentes trabajos han respaldado esta idea, describiendo alteraciones de CF entre diferentes regiones cerebrales en pacientes EM respecto a sujetos sanos. Además, estas alteraciones de CF muestran una relación con variables clínicas de interés, ya sean motoras o cognitivas, que de nuevo, se interpretan en términos de un mecanismo compensatorio en los pacientes (Rocca y cols., 2010; Roosendaal y cols., 2010; Bonavita y cols., 2011; Hawellek y cols., 2011; Faivre y cols., 2012; Dogonowski y cols., 2013). Sin embargo, debido a la novedad de la técnica, los estudios con RMf en estado de reposo con pacientes EM se encuentran todavía en un estado incipiente, por lo que creemos que se necesitan más investigaciones al respecto para corroborar los resultados hallados. Además, observamos cómo la mayoría de trabajos en relación al rendimiento cognitivo de estos pacientes se han centrado en el estudio exclusivamente de regiones pertenecientes a la red de activación por defecto (DMN). En este sentido, consideramos fundamental explorar alteraciones de CF en otras redes cerebrales de interés en esta enfermedad, que se hallan implicadas en el funcionamiento cognitivo. Por otra parte, no encontramos trabajos en la literatura dirigidos a explorar una posible asociación entre alteraciones de CF en estado de reposo y fatiga en pacientes con EM, con lo que consideramos de especial interés explorar esta relación. De esta forma, el objetivo general de esta tesis es contribuir al esclarecimiento de las bases neurobiológicas cerebrales tanto (a nivel anatómico y funcional) implicadas en dos de los síntomas más incapacitantes y prevalentes en la EM: el deterioro cognitivo y la fatiga. METODOLOGÍA Todos los estudios han sido realizados gracias a la derivación de pacientes EM del servicio de Neurología del Hospital General de Castellón de la Plana. De forma específica, reclutamos a 92 pacientes EM para nuestros estudios con un rango de edad entre 20 y 58 años. Específicamente, 68 pacientes tenían un diagnóstico de EM RR mientras que 24 tenían un diagnóstico de EM tipo SP. Comprobamos que no mostraran indicios de abuso de alcohol o de otras drogas, así como de antecedentes de otras enfermedades psiquiátricas y neurológicas. Además, también fueron excluidos aquellos pacientes que hubiesen padecido un brote clínico y/ o hubiesen recibido tratamiento con corticoesteroides en un intervalo menor de dos meses previos a la investigación. El grupo control está formado por una muestra de 23 personas con un rango de edad de 22 a 54 años, sin antecedentes de enfermedades neurológicas ni abuso de sustancias. Todos los participantes fueron evaluados a nivel neuropsicológico con la versión validada y traducida para población de habla castellana de la batería Brief Repeteable Battery of Neuropsychological Test (BRB-N) (Sepulcre y cols., 2006). Durante la realización de las valoraciones neuropsicológicas, también fueron administradas la escala de severidad de fatiga (Bulbena y cols., 2000) y el Inventario Multiescalar de Depresión Chicago (IMDC) (Nyenhuis y cols., 1998). De forma adicional, el grupo de pacientes fue evaluado a nivel neurológico con la escala EDSS (Kurtzke, 1983) para cuantificar el grado de incapacidad física. De forma paralela a las valoraciones neuropsicológicas, fueron adquiridas en el scanner de Resonancia Magnética funcional del Hospital General de Castellón las imágenes cerebrales de todos los participantes: un volumen anatómico 3D sagital MPRAGE en T1 para el análisis morfométrico y una secuencia funcional en estado de reposo para los análisis de conectividad funcional. Durante la secuencia funcional, la única instrucción que se daba a los participantes era que permanecieran lo más quietos posibles y con los ojos cerrados, intentando no dormirse y dejar la mente en blanco. La presente tesis está compuesta por tres estudios ya publicados, en prensa o sometidos en revistas internacionales, por lo que están escritos en inglés. Concretamente, el primer estudio (Cruz-Gómez AJ, Belenguer A, Ventura-Campos N, García Panach J, Ávila C, and Forn C. A voxel-based morphometry study of multiple sclerosis patients: The relationship between distribution of gray and white matter atrophy and clinical variables) está actualmente sometido a revisión. El segundo estudio ha sido aceptado para publicación en la revista Multiple Sclerosis (Cruz-Gómez AJ, Ventura-Campos N, Belenguer A, Ávila C and Forn C (2013) The link between resting-state functional connectivity and cognition in MS patients). Por último, el tercer trabajo ha sido recientemente publicado en PLoS One (Cruz-Gómez AJ, Ventura-Campos N, Belenguer A, Ávila C and Forn C (2013) Regional brain atrophy and functional connectivity changes related to fatigue in multiple sclerosis). CONCLUSIONES Los trabajos incluidos en la presente tesis nos permiten establecer las siguientes conclusiones de forma específica: 1) Existe una relación tanto de la atrofia cerebral en SG y SB medida con VBM como de las lesiones en SB con el rendimiento cognitivo en pacientes EM, especialmente con las pruebas neuropsicológicas más sensibles al deterioro cognitivo de esta enfermedad, que valoran la velocidad del procesamiento de la información, la atención y la memoria de trabajo. 2) De estas medidas, la atrofia en SG constituye el predictor más fiable del rendimiento cognitivo en los pacientes EM. 3) Las alteraciones de conectividad funcional en los pacientes EM están relacionadas de forma positiva con el rendimiento cognitivo y de forma negativa con el grado de daño estructural. 4) El aumento de conectividad funcional en los pacientes EM sin deterioro cognitivo podría representar una reorganización funcional adaptativa que limitaría la expresión de los déficits cognitivos. 5) La atrofia en SG y SB fundamentalmente en áreas motoras frontales y parietales se relaciona con la manifestación de la fatiga en los pacientes EM. 6) El decremento de CF entre áreas pertenecientes a la red sensoriomotora se relaciona con el grado de fatiga. 7) Los pacientes EM sin fatiga muestran un aumento de CF en regiones de la red sensoriomotora en relación a los pacientes EM con fatiga, hecho que podría constituir un mecanismo compensatorio o de adaptación funcional que limitaría la manifestación de este síntoma. A modo de síntesis, estos trabajos nos muestran que los déficits cognitivos y la fatiga en la EM no sólo son consecuencia del daño estructural, sino que también están asociados con una reorganización funcional entre diferentes regiones cerebrales. En este sentido, las alteraciones funcionales deben tenerse en cuenta, ya que pueden enmascarar la relación entre las alteraciones morfológicas y las diferentes variables clínicas de interés en los pacientes EM. Por otro lado, hemos aportado evidencia a favor de que estos procesos de reorganización funcional parecen reflejar mecanismos compensatorios de adaptación tanto a los déficits cognitivos como a la fatiga, que son posibles en la medida en que el daño estructural no sobrepase cierto umbral.

L' esclerosi múltiple (EM) és una de les malalties inflamatòries més comunes del sistema nerviós central (SNC). En l'EM es produeix una desmielinització de les fibres nervioses que dificulten o interrompen la conducció de l'impuls nerviós en el SNC donant lloc a una simptomatologia molt variada, amb signes i símptomes motors, sensitius i alteracions cognitives. D'entre un 40- 65% dels pacients d'EM avaluats en els serveis d'atenció sanitària presenten algun tipus d'alteració cognitiva, fins i tot en fases de recent diagnostic de la malaltia, provocant aquestes alteracions cognitives dificultats en les activitats de la vida diària. És per a tots aquests factors, que en els últims anys s'ha desencadenat un gran interès no només per a l'estudi dels dèficits cognitius en aquesta malaltia, sinó també en el desenvolupament d'eines diagnostiques ràpides i eficaces per a valorar les alteracions cognitives en aquesta població clínica.Una de les eines d'avaluació més utilitzada es la prova Paced Auditory Serial Addition Test (PASAT), en la qual els pacients d'EM presenten un baix rendiment i tema central d'aquesta tesi doctoral. Aquesta prova es una de les més utilitzades per a l'avaluació dels dèficits cognitius d'aquests pacients, tant en l'àmbit clínic com en el de la investigació. Aquest fet fa que, ja sigui com a prova única en bateries de tipus neurològic o formant part d'altres bateries neuropsicològiques més extenses, el PASAT s'utilitze quasi de forma sistemàtica per a la valoració cognitiva en l'EM. Per altre banda, aquesta prova no es troba exempta de problemes, degut a que, per una banda l' execució correcta d'aquesta tasca implica la realització coordinada d'una serie de funcions cognitives resulten, en segon lloc, una prova difícil de realitzar no sols per als pacients, sino també en grups de persones sense alteració neurològica.

The Reinforcement Sensitivity Theory proposed three neuropsychological systems which mediate individual differences in emotion, motivation and learning: Behavioral Activation System, Behavioral Inhibition System and Fight/Flight System, which involve reward, punishment and threat sensitivity systems, respectively. The systems´ sensitivity mediates individual differences on the personality traits Impulsivity and Anxiety. One of the most widely used scales to detect and measure individual differences in these systems is the Sensitivity to Punishment and Sensitivity to Reward Questionnaire. This thesis includes five studies with which we evaluate variance in the structural and functional brain according to the individual differences in Gray´s proposed systems´ sensitivity. Thus, the first two studies analyzed the relation between gray matter volume and the individual differences in the Sensitivity to Reward and Punishment subscales included in the aforementioned questionnaire. Sensitivity to Reward was inversely associated with gray matter volume in the dorsal striatum. Conversely, Sensitivity to Punishment was directly related to gray matter volume in the left amygdale and hippocampus. Furthermore, three functional studies analyzed brain activation associated with individual differences on Sensitivity to Reward scale. The first study showed that brain activity during appetitive emotional picture processing was associated with Sensitivity to Reward in the mesial prefrontal cortex and the adjacent rostral cingulate, while brain activation in the hippocampus/parahippocampus during aversive emotional picture processing was inversely related to Sensitivity to Reward. The second study revealed that Sensitivity to Reward was directly related to the mesial prefrontal cortex and dorsal striatum, and inversely related to the right inferior prefrontal gyrus during the inhibitory control in approach-avoidance conflicts. The third study demonstrated that Sensitivity to Reward during cognitive and emotional interference tasks was related to brain activation in the rostral anterior cingulate during cognitive and emotional Stroop tasks. However, dorsolateral prefrontal cortex activation was directly related to Sensitivity to Reward during cognitive interference, and amygdale activation was inversely related to this variable during emotional interference. Briefly, individual differences in brain structure and function may be associated with system-related personality traits according to the Reinforcement Sensitivity Theory.