Seasonal temperature trends on the Spanish mainland: A secular study (1916–2015)

Trends in seasonal mean values of maximum and minimum temperature are analysed in the Spanish mainland from the new MOTEDAS_century database. This new data set has been developed combining the digitalized archives from the Spanish Meteorological Agency (AEMET) with information retrieved from Annual Books published by the former Meteorological Agency dating back to 1916, and covers the period 1916–2015. In all four seasons, mean seasonal temperature of maximum (Tmax) and minimum (Tmin) increased. The raising occurred in two main pulses separated by a first pause around the middle of the 20th century, but differed among seasons and also between maximum and minimum temperature. Analysis of the percentage of land affected by significant trends in maximum temperature reveals two increasing phases in spring and summer for Tmax, and in spring, summer, and autumn for Tmin. However, winter Tmax only rose during the recent decades, and autumn Tmax in the first decades. Negative significant trends were found in extended areas in spring Tmax, and in spring, autumn, and summer Tmin, confirming the first pause around the 1940's–1960's. Trends of seasonal mean values of Tmax and Tmin are not significant for at least the last 25–35 years of the study period, depending on the season. The areas under significant positive trend are usually more extended for Tmin than Tmax at any season and period. Areas with significant trend expand and contract in time according to two spatial gradients: south-east to north-west (east-west) for Tmax, and west to east for Tmin. We hypothesize a relationship between atmospheric prevalent advection and relief as triggering factors to understand spatial and temporal differences in seasonal temperatures at regional scale during the 20th century in the Iberian Peninsula

New insights into the genetic etiology of Alzheimer's disease and related dementias

Characterization of the genetic landscape of Alzheimer's disease (AD) and related dementias (ADD) provides a unique opportunity for a better understanding of the associated pathophysiological processes. We performed a two-stage genome-wide association study totaling 111,326 clinically diagnosed/'proxy' AD cases and 677,663 controls. We found 75 risk loci, of which 42 were new at the time of analysis. Pathway enrichment analyses confirmed the involvement of amyloid/tau pathways and highlighted microglia implication. Gene prioritization in the new loci identified 31 genes that were suggestive of new genetically associated processes, including the tumor necrosis factor alpha pathway through the linear ubiquitin chain assembly complex. We also built a new genetic risk score associated with the risk of future AD/dementia or progression from mild cognitive impairment to AD/dementia. The improvement in prediction led to a 1.6- to 1.9-fold increase in AD risk from the lowest to the highest decile, in addition to effects of age and the APOE ε4 allele

Multiancestry analysis of the HLA locus in Alzheimer’s and Parkinson’s diseases uncovers a shared adaptive immune response mediated by HLA-DRB1*04 subtypes

Across multiancestry groups, we analyzed Human Leukocyte Antigen (HLA) associations in over 176,000 individuals with Parkinson’s disease (PD) and Alzheimer’s disease (AD) versus controls. We demonstrate that the two diseases share the same protective association at the HLA locus. HLA-specific fine-mapping showed that hierarchical protective effects of HLA-DRB1*04 subtypes best accounted for the association, strongest with HLA-DRB1*04:04 and HLA-DRB1*04:07, and intermediary with HLA-DRB1*04:01 and HLA-DRB1*04:03. The same signal was associated with decreased neurofibrillary tangles in postmortem brains and was associated with reduced tau levels in cerebrospinal fluid and to a lower extent with increased Aβ42. Protective HLA-DRB1*04 subtypes strongly bound the aggregation-prone tau PHF6 sequence, however only when acetylated at a lysine (K311), a common posttranslational modification central to tau aggregation. An HLA-DRB1*04-mediated adaptive immune response decreases PD and AD risks, potentially by acting against tau, offering the possibility of therapeutic avenues

Long-term treatment outcome with different formulations of botulinum toxin

10.1111/j.1468-1331.2008.02508.xEuropean Journal of Neurology163285-28

Dopaminergic agonists in Parkinson's disease

Background: Non-ergoline dopamine agonists (DA) are effective treatments for Parkinson's disease (PD). This review presents the pharmacology, evidence of efficacy and safety profile of pramipexole, ropinirole, and rotigotine, and practical recommendations are given regarding their use in clinical practice. Results: Extended-release formulations of pramipexole and ropinirole and transdermal continuous delivery rotigotine patches are currently available; these may contribute to stabilising of plasma levels.In early PD, the three drugs significantly improve disability scales, delay time to dyskinesia and allow a later introduction of levodopa. In late PD they reduced total ‘off’-time, improved Unified Parkinson's Disease Rating Scale (UPDRS) in both ‘on’ and ‘off’ state and allowed a reduction in total levodopa dosage. A significant improvement in quality of life scales has also been demonstrated. Extended-release formulations have proved to be non-inferior to the immediate release formulations and are better tolerated (ropinirole). Despite a generally good safety profile, serious adverse events, such as impulse control disorder and sleep attacks, need to be routinely monitored. Although combination therapy has not been addressed in scientific literature, certain combinations, such as apomorphine and another DA, may be helpful. Switching from one DA to another is feasible and safe, although in the first days an overlap of dopaminergic side effects may occur. When treatment with DA is stopped abruptly, dopamine withdrawal syndrome may present. Suspending any DA, especially pramipexole, has been linked to onset of apathy, which may be severe. Conclusions: New non-ergotine DAs are a valuable option for the treatment of both early and late PD. Despite their good safety profile, serious adverse effects may appear; these effects may have a pathoplastic effect on the course of PD and need to be monitored. Resumen: Introducción: Los agonistas dopaminérgicos no ergóticos (AD) son tratamientos útiles en la Enfermedad de Parkinson (EP). Revisamos la farmacología, el grado de evidencia en cuanto a eficacia y tolerabilidad de pramipexol, ropinirol y rotigotina, y proponemos algunas recomendaciones para su uso en la práctica clínica. Desarrollo: En el momento actual se dispone de formas de liberación prolongada (LP) de pramipexol y ropinirol y de administración transdérmica de rotigotina, que contribuyen a una mayor estabilidad plasmática de los niveles del fármaco. En la EP inicial los tres fármacos mejoran de forma significativa las escalas de incapacidad de los pacientes, retrasan la aparición de discinesias y permiten retrasar la introducción de levodopa. En la EP avanzada reducen el tiempo off, mejoran la UPDRS en on y en off y permiten reducir la dosis total de levodopa. Además, los tres han sido capaces de inducir una mejoría significativa en las escalas de la calidad de vida relacionada con la salud. Las fórmulas de LP han demostrado la no inferioridad frente a las de liberación inmediata, e incluso una mejor tolerabilidad (ropinirol). A pesar de su buen perfil de seguridad, entre los efectos adversos graves cabe destacar el trastorno de control de impulsos, cuya aparición puede ser precoz, y los accesos de sueño (sleep attacks). Aunque la terapia combinada no ha sido estudiada específicamente, algunas asociaciones (como la de apomorfina y otros AD) pueden ser beneficiosas. El cambio de un AD a otro es factible de un día para otro, aunque en los primeros días puede haber una sumación de efectos adversos dopaminérgicos que debe tenerse en cuenta. La suspensión brusca del tratamiento con AD puede inducir un síndrome de deprivación dopaminérgica. La retirada de cualquier AD, en particular pramipexol, se ha asociado a aparición de apatía que puede ser grave. Conclusiones: Los nuevos AD no ergóticos constituyen una opción válida de tratamiento de la EP tanto inicial como avanzada. A pesar de su buen perfil de tolerabilidad, no están exentos de efectos adversos graves, que pueden tener un efecto patoplástico en la EP y que deben monitorizarse. Keywords: Dopamine agonists, Pramipexole, Ropinirole, Rotigotine, Prolonged release, Equivalence, Palabras clave: Agonistas dopaminérgicos, Pramipexol, Ropinirol, Rotigotina, Liberación prolongada, Equivalenci

Agonistas dopaminérgicos en la enfermedad de Parkinson

Resumen: Introducción: Los agonistas dopaminérgicos no ergóticos (AD) son tratamientos útiles en la enfermedad de Parkinson (EP). Revisamos la farmacología, el grado de evidencia en cuanto a eficacia y tolerabilidad de pramipexol, ropinirol y rotigotina, y proponemos algunas recomendaciones para su uso en la práctica clínica. Desarrollo: En el momento actual se dispone de formas de liberación prolongada (LP) de pramipexol y ropinirol y de administración transdérmica de rotigotina, que contribuyen a una mayor estabilidad plasmática de los valores del fármaco. En la EP inicial los 3 fármacos mejoran de forma significativa las escalas de incapacidad de los pacientes, retrasan la aparición de discinesias y permiten retrasar la introducción de levodopa. En la EP avanzada reducen el tiempo off, mejoran la Unified Parkinson's Disease Rating Scale (UPDRS) en on y en off y permiten reducir la dosis total de levodopa. Además, los 3 han sido capaces de inducir una mejora significativa en las escalas de la calidad de vida relacionada con la salud. Las fórmulas de LP han demostrado la no inferioridad frente a las de liberación inmediata, e incluso una mejor tolerabilidad (ropinirol). A pesar de su buen perfil de seguridad, entre los efectos adversos graves cabe destacar el trastorno de control de impulsos, cuya aparición puede ser precoz, y los accesos de sueño (sleep attacks). Aunque la terapia combinada no ha sido estudiada específicamente, algunas asociaciones (como la de apomorfina y otros AD) pueden ser beneficiosas. El cambio de un AD a otro es factible de un día para otro, aunque en los primeros días puede haber una sumación de efectos adversos dopaminérgicos que debe tenerse en cuenta. La suspensión brusca del tratamiento con AD puede inducir un síndrome de deprivación dopaminérgica. La retirada de cualquier AD, en particular pramipexol, se ha asociado a aparición de apatía que puede ser grave. Conclusiones: Los nuevos AD no ergóticos constituyen una opción válida de tratamiento de la EP tanto inicial como avanzada. A pesar de su buen perfil de tolerabilidad, no están exentos de efectos adversos graves, que pueden tener un efecto patoplástico en la EP y que deben monitorizarse. Abstract: Background: Non-ergoline dopamine agonists (DA) are effective treatments for Parkinson's disease (PD). This review presents the pharmacology, evidence of efficacy and safety profile of pramipexole, ropinirole, and rotigotine, and practical recommendations are given regarding their use in clinical practice. Results: Extended-release formulations of pramipexole and ropinirole and transdermal continuous delivery rotigotine patches are currently available; these may contribute to stabilising of plasma levels.In early PD, the three drugs significantly improve disability scales, delay time to dyskinesia and allow a later introduction of levodopa. In late PD they reduced total 'off'-time, improved Unified Parkinson's Disease Rating Scale (UPDRS) in both 'on' and 'off' state and allowed a reduction in total levodopa dosage. A significant improvement in quality of life scales has also been demonstrated. Extended-release formulations have proved to be non-inferior to the immediate release formulations and are better tolerated (ropinirole). Despite a generally good safety profile, serious adverse events, such as impulse control disorder and sleep attacks, need to be routinely monitored. Although combination therapy has not been addressed in scientific literature, certain combinations, such as apomorphine and another DA, may be helpful. Switching from one DA to another is feasible and safe, although in the first days an overlap of dopaminergic side effects may occur. When treatment with DA is stopped abruptly, dopamine withdrawal syndrome may present. Suspending any DA, especially pramipexole, has been linked to onset of apathy, which may be severe. Conclusions: New non-ergotine DAs are a valuable option for the treatment of both early and late PD. Despite their good safety profile, serious adverse effects may appear; these effects may have a pathoplastic effect on the course of PD and need to be monitored. Palabras clave: Agonistas dopaminérgicos, Pramipexol, Ropinirol, Rotigotina, Liberación prolongada, Equivalencia, Keywords: Dopamine agonists, Pramipexole, Ropinirole, Rotigotine, Prolonged release, Equivalenc

Enfermedad de Parkinson avanzada. Características clínicas y tratamiento (parte I)

Resumen: Introducción: Un porcentaje importante de pacientes con enfermedad de Parkinson (EP) desarrollan complicaciones motoras en forma de fluctuaciones motoras, discinesias y síntomas no motores al cabo de 3-5 años del inicio del tratamiento que resultan de difícil control terapéutico. Esta fase de la enfermedad ha sido definida por algunos autores como fase avanzada de la EP. Objetivo: Definir las características clínicas y los factores de riesgo que condicionan que una EP evolucione a un estadio avanzado. Desarrollo: Este documento de consenso se ha realizado mediante una búsqueda bibliográfica exhaustiva y discusión de los contenidos llevadas a cabo por un grupo de expertos en trastornos del movimiento de la Sociedad Espãnola de Neurología coordinados por dos de los autores (JK y MRL). Conclusiones: La presencia de fluctuaciones motoras y discinesias graves, síntomas motores axiales resistentes a la levodopa y síntomas no motores, como los trastornos cognitivos, representan las principales manifestaciones fenotípicas de una EP avanzada. Abstract: Introduction: A large percentage of patients with Parkinson's disease (PD) develop motor fluctuations, dyskinesias, and severe non-motor symptoms within 3 to 5 years of starting dopaminergic therapy, and these motor complications are refractory to treatment. Several authors refer to this stage of the disease as advanced Parkinson's disease. Objective: To define the clinical manifestations of advanced PD and the risk factors for reaching this stage of the disease. Development: This consensus document has been prepared by using an exhaustive literature search and by discussion of the contents by an expert group on movement disorders of the Sociedad Española de Neurología (Spanish Neurology Society), coordinated by two of the authors (JK and MRL). Conclusions: Severe motor fluctuations and dyskinesias, axial motor symptoms resistant to levodopa, and cognitive decline are the main signs in the clinical phenotype of advanced PD. Palabras clave: Enfermedad de Parkinson avanzada, Factores de riesgo, Fenotipo clínico, Escalas de valoración motora, Escalas de valoración no motora, Escalas de calidad de vida, Keywords: Advanced Parkinson's disease, Risk factors, Clinical phenotype, Motor scales, Non-motor scales, Quality of life scale

Advanced Parkinson's disease: Clinical characteristics and treatment. Part II

Introduction: Many patients who have had Parkinson's disease (PD) for several years will present severe motor fluctuations and dyskinesias which require more aggressive therapies. The different approaches which are now available include deep brain stimulation of the subthalamic nucleus or medial globus pallidus, subcutaneous infusion of apomorphine, and intestinal infusion of levodopa–carbidopa. Objective: To define the indications and results for the 3 available therapies for advanced PD. Development: Exhaustive review of the literature concerning the indications and results of deep brain stimulation, subcutaneous apomorphine infusion and duodenal infusion of levodopa/carbidopa gel to treat patients with advanced Parkinson disease. Conclusions: Although numerous studies have confirmed the efficacy of the 3 different therapies in advanced PD, there are no comparative studies that would allow us to define the best candidate for each technique. Resumen: Introducción: Muchos de los pacientes con enfermedad de Parkinson (EP) presentan al cabo de varios años fluctuaciones y discinesias graves que requieren de terapias algo más agresivas como la estimulación cerebral profunda del núcleo subtalámico o globo pálido medial, la infusión continua de apomorfina y la infusión intestinal continua de levodopa-carbidopa. Objetivo: Establecer las indicaciones y resultados de las 3 técnicas disponibles en la actualidad para el tratamiento de la EP avanzada. Desarrollo: Revisión exhaustiva de los datos publicados en la literatura sobre las indicaciones y resultados de la estimulación cerebral profunda del núcleo subtalámico, infusión subcutánea de apomorfina e infusión intestinal continua de levodopa-carbidopa en pacientes con EP avanzada. Conclusiones: Aunque existen numerosos estudios que han descrito la eficacia de cada una de estas 3 técnicas, faltan estudios comparativos que permitan definir el candidato ideal para cada una de las técnicas. Keywords: Advanced Parkinson's disease, Deep brain stimulation, Subcutaneous apomorphine infusion, Intestinal levodopa–carbidopa infusion, Palabras clave: Enfermedad de Parkinson avanzada, Estimulación cerebral profunda, Infusión de apomorfina, Infusión intestinal de levodopa-carbidop

Advanced Parkinson's disease: Clinical characteristics and treatment (part 1)

Introduction: A large percentage of patients with Parkinson's disease (PD) develop motor fluctuations, dyskinesias, and severe non-motor symptoms (NMS) within 3 to 5 years of starting dopaminergic therapy, and these motor complications are refractory to treatment. Several authors refer to this stage of the disease as advanced PD. Objective: To define the clinical manifestations of advanced PD and the risk factors for reaching this stage of the disease. Development: This consensus document has been prepared by using an exhaustive literature search and by discussion of the contents by an expert group on movement disorders of the Sociedad Española de Neurología (Spanish Neurology Society), coordinated by two of the authors (JK and MRL). Conclusions: Severe motor fluctuations and dyskinesias, axial motor symptoms resistant to levodopa, and cognitive decline are the main signs in the clinical phenotype of advanced PD. Resumen: Introducción: Un porcentaje importante de pacientes con enfermedad de Parkinson (EP) desarrollan complicaciones motoras en forma de fluctuaciones motoras, discinesias y síntomas no motores al cabo de 3–5 años del inicio del tratamiento que resultan de difícil control terapéutico. Esta fase de la enfermedad ha sido definida por algunos autores como fase avanzada de la EP. Objetivo: Definir las características clínicas y los factores de riesgo que condicionan que una EP evolucione a un estadio avanzado. Desarrollo: Este documento de consenso se ha realizado mediante una búsqueda bibliográfica exhaustiva y discusión de los contenidos llevadas a cabo por un grupo de expertos en trastornos del movimiento de la Sociedad Espãnola de Neurología coordinados por dos de los autores (JK y MRL). Conclusiones: La presencia de fluctuaciones motoras y discinesias graves, síntomas motores axiales resistentes a la levodopa y síntomas no motores, como los trastornos cognitivos, representan las principales manifestaciones fenotípicas de una EP avanzada. Keywords: Advanced Parkinson's disease, Risk factors, Clinical phenotype, Motor scales, Non-motor scales, Quality of life scales, Palabras clave: Enfermedad de Parkinson avanzada, Factores de riesgo, Fenotipo clínico, Escalas de valoración motora, Escalas de valoración no motora, Escalas de calidad de vid