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The endocannabinoid 2-AG enhances spontaneous remyelination by targeting microglia.

Remyelination is an endogenous process by which functional recovery of damaged neurons is achieved by reinstating the myelin sheath around axons. Remyelination has been documented in multiple sclerosis (MS) lesions and experimental models, although it is often incomplete or fails to affect the integrity of the axon, thereby leading to progressive disability. Microglia play a crucial role in the clearance of the myelin debris produced by demyelination and in inflammation-dependent OPC activation, two processes necessary for remyelination to occur. We show here that following corpus callosum demyelination in the TMEV-IDD viral murine model of MS, there is spontaneous and partial remyelination that involves a temporal discordance between OPC mobilization and microglia activation. Pharmacological treatment with the endocannabinoid 2-AG enhances the clearance of myelin debris by microglia and OPC differentiation, resulting in complete remyelination and a thickening of the myelin sheath. These results highlight the importance of targeting microglia during the repair processes in order to enhance remyelination.

Gut microbiota, cannabinoid system and neuroimmune interactions: New perspectives in multiple sclerosis.

The gut microbiota plays a fundamental role on the education and function of the host immune system. Immunological dysregulation is the cause of numerous human disorders such as autoimmune diseases and metabolic disorders frequently associated with inflammatory processes therefore is critical to explore novel mechanisms involved in maintaining the immune system homeostasis. The cannabinoid system and related bioactive lipids participate in multiple central and peripheral physiological processes that affect metabolic, gastrointestinal and neuroimmune regulatory mechanisms displaying a modulatory role and contributing to the maintenance of the organism's homeostasis. In this review, we gather the knowledge on the gut microbiota-endocannabinoids interactions and their impact on autoimmune disorders such as inflammatory bowel disease, rheumatoid arthritis and particularly, multiple sclerosis (MS) as the best example of a CNS autoimmune disorder. Furthermore, we contribute to this field with new data on changes in many elements of the cannabinoid system in a viral model of MS after gut microbiota manipulation by both antibiotics and probiotics. Finally, we highlight new therapeutic opportunities, under an integrative view, targeting the eCBS and the commensal microbiota in the context of neuroinflammation and MS.

Gut dysbiosis and neuroimmune responses to brain infection with Theiler's murine encephalomyelitis virus.

Recent studies have begun to point out the contribution of microbiota to multiple sclerosis (MS) pathogenesis. Theiler's murine encephalomyelitis virus induced demyelinating disease (TMEV-IDD) is a model of progressive MS. Here, we first analyze the effect of intracerebral infection with TMEV on commensal microbiota and secondly, whether the early microbiota depletion influences the immune responses to TMEV on the acute phase (14 dpi) and its impact on the chronic phase (85 dpi). The intracranial inoculation of TMEV was associated with a moderate dysbiosis. The oral administration of antibiotics (ABX) of broad spectrum modified neuroimmune responses to TMEV dampening brain CD4+ and CD8+ T infiltration during the acute phase. The expression of cytokines, chemokines and VP2 capsid protein was enhanced and accompanied by clusters of activated microglia disseminated throughout the brain. Furthermore, ABX treated mice displayed lower levels of CD4+ and CD8+T cells in cervical and mesenteric lymph nodes. Increased mortality to TMEV was observed after ABX cessation at day 28pi. On the chronic phase, mice that survived after ABX withdrawal and recovered microbiota diversity showed subtle changes in brain cell infiltrates, microglia and gene expression of cytokines. Accordingly, the surviving mice of the group ABX-TMEV displayed similar disease severity than TMEV mice.

Microglia activation states and cannabinoid system: Therapeutic implications.

Microglial cells are recognized as the brain's intrinsic immune cells, mediating actions that range from the protection against harmful conditions that modify CNS homeostasis, to the control of proliferation and differentiation of neurons and their synaptic pruning. To perform these functions, microglia adopts different activation states, the so-called phenotypes that depending on the local environment involve them in neuroinflammation, tissue repair and even the resolution of the inflammatory process. There is accumulating evidence indicating that cannabinoids (CBs) might serve as a promising tool to modify the outcome of inflammation, especially by influencing microglial activity. Microglia has a functional endocannabinoid (eCB) signaling system, composed of cannabinoid receptors and the complete machinery for the synthesis and degradation of eCBs. The expression of cannabinoid receptors - mainly CB2 - and the production of eCBs have been related to the activation profile of these cells and therefore, the microglial phenotype, emerging as one of the mechanisms by which microglia becomes alternatively activated. Here, we will discuss recent studies that provide new insights into the role of CBs and their endogenous counterparts in defining the profile of microglia activation. These actions make CBs a promising therapeutic tool to avoid the detrimental effects of inflammation and possibly paving the way to target microglia in order to generate a reparative milieu in neurodegenerative diseases.

PDE7 inhibitor TC3.6 ameliorates symptomatology in a model of primary progressive multiple sclerosis.

BACKGROUND AND PURPOSE: cAMP plays an important role in the transduction of signalling pathways involved in neuroprotection and immune regulation. Control of the levels of this nucleotide by inhibition of cAMP-specific PDEs such as PDE7 may affect the pathological processes of neuroinflammatory diseases like multiple sclerosis (MS). In the present study, we evaluated the therapeutic potential of the selective PDE7 inhibitor, TC3.6, in a model of primary progressive multiple sclerosis (PPMS), a rare and severe variant of MS. EXPERIMENTAL APPROACH: Theiler's murine encephalomyelitis virus-induced demyelinated disease (TMEV-IDD) is one of the models used to validate the therapeutic efficacy of new drugs in MS. As recent studies have analysed the effect of PDE7 inhibitors in the EAE model of MS, here the TMEV-IDD model was used to test their efficacy in a progressive variant of MS. Mice were subjected to two protocols of TC3.6 administration: on the pre-symptomatic phase and once the disease was established. KEY RESULTS: Treatment with TC3.6 ameliorated the disease course and improved motor deficits of infected mice. This was associated with down-regulation of microglial activation and reduced cellular infiltrates. Decreased expression of pro-inflammatory mediators such as COX-2 and the cytokines, IL-1ß, TNF-α, IFN-γ and IL-6 in the spinal cord of TMEV-infected mice was also observed after TC3.6 administration. CONCLUSION: These findings support the importance of PDE7 inhibitors, and specifically TC3.6, as a novel class of agents with therapeutic potential for PPMS. Preclinical studies are needed to determine whether their effects translate into durable clinical benefits.

Mobilization of progenitors in the subventricular zone to undergo oligodendrogenesis in the Theiler's virus model of multiple sclerosis: implications for remyelination at lesions sites.

Remyelination involves the generation of new myelin sheaths around axons, as occurs spontaneously in many multiple sclerosis (MS) lesions and other demyelinating diseases. When considering repairing a diseased brain, the adult mouse subventricular zone (SVZ) is of particular interest since the stem cells in this area can migrate and differentiate into the three major cell types in the central nervous system (CNS). In Theiler's murine encephalomyelitis virus-induced demyelinating disease (TMEV-IDD), we assessed the relative contribution of the SVZ to the remyelination in the corpus callosum at preclinical stages in this MS model. CNPase, MBP and Luxol Fast Blue staining revealed prominent demyelination 35days post-infection (dpi), concomitant with a strong staining in GFAP(+) type B astrocytes in the SVZ and the increased proliferation in this area. The migration of oligodendrocyte progenitors from the SVZ contributed to the remyelination observed at 60 dpi, evident through the number of APC(+)/BrdU(+) mature oligodendrocytes in the corpus callosum of infected animals. These data suggest that the inflammation induced by the Theiler's virus not only provokes strong preclinical demyelination but also, it is correlated with oligodendrocyte generation in the adult SVZ, cells that along with resident progenitor cells contribute to the prompt remyelination observed in the corpus callosum.

Cannabidiol provides long-lasting protection against the deleterious effects of inflammation in a viral model of multiple sclerosis: a role for A2A receptors.

Inflammation in the central nervous system (CNS) is a complex process that involves a multitude of molecules and effectors, and it requires the transmigration of blood leukocytes across the blood-brain barrier (BBB) and the activation of resident immune cells. Cannabidiol (CBD), a non-psychotropic cannabinoid constituent of Cannabis sativa, has potent anti-inflammatory and immunosuppressive properties. Yet, how this compound modifies the deleterious effects of inflammation in TMEV-induced demyelinating disease (TMEV-IDD) remains unknown. Using this viral model of multiple sclerosis (MS), we demonstrate that CBD decreases the transmigration of blood leukocytes by downregulating the expression of vascular cell adhesion molecule-1 (VCAM-1), chemokines (CCL2 and CCL5) and the proinflammatory cytokine IL-1ß, as well as by attenuating the activation of microglia. Moreover, CBD administration at the time of viral infection exerts long-lasting effects, ameliorating motor deficits in the chronic phase of the disease in conjunction with reduced microglial activation and pro-inflammatory cytokine production. Adenosine A2A receptors participate in some of the anti-inflammatory effects of CBD, as the A2A antagonist ZM241385 partially blocks the protective effects of CBD in the initial stages of inflammation. Together, our findings highlight the anti-inflammatory effects of CBD in this viral model of MS and demonstrate the significant therapeutic potential of this compound for the treatment of pathologies with an inflammatory component.

Ant exclusion in citrus over an 8-year period reveals a pervasive yet changing effect of ants on a Mediterranean spider assemblage.

Ants and spiders are ubiquitous generalist predators that exert top-down control on herbivore populations. Research shows that intraguild interactions between ants and spiders can negatively affect spider populations, but there is a lack of long-term research documenting the strength of such interactions and the potentially different effects of ants on the diverse array of species in a spider assemblage. Similarly, the suitability of family-level surrogates for finding patterns revealed by species-level data (taxonomic sufficiency) has almost never been tested in spider assemblages. We present a long-term study in which we tested the impact of ants on the spider assemblage of a Mediterranean citrus grove by performing sequential 1-year experimental exclusions on tree canopies for 8 years. We found that ants had a widespread influence on the spider assemblage, although the effect was only evident in the last 5 years of the study. During those years, ants negatively affected many spiders, and effects were especially strong for sedentary spiders. Analyses at the family level also detected assemblage differences between treatments, but they concealed the different responses to ant exclusion shown by some related spider species. Our findings show that the effects of experimental manipulations in ecology can vary greatly over time and highlight the need for long-term studies to document species interactions.

Cannabidiol protects oligodendrocyte progenitor cells from inflammation-induced apoptosis by attenuating endoplasmic reticulum stress.

Cannabidiol (CBD) is the most abundant cannabinoid in Cannabis sativa that has no psychoactive properties. CBD has been approved to treat inflammation, pain and spasticity associated with multiple sclerosis (MS), of which demyelination and oligodendrocyte loss are hallmarks. Thus, we investigated the protective effects of CBD against the damage to oligodendrocyte progenitor cells (OPCs) mediated by the immune system. Doses of 1 µM CBD protect OPCs from oxidative stress by decreasing the production of reactive oxygen species. CBD also protects OPCs from apoptosis induced by LPS/IFNγ through the decrease of caspase 3 induction via mechanisms that do not involve CB1, CB2, TRPV1 or PPARγ receptors. Tunicamycin-induced OPC death was attenuated by CBD, suggesting a role of endoplasmic reticulum (ER) stress in the mode of action of CBD. This protection against ER stress-induced apoptosis was associated with reduced phosphorylation of eiF2α, one of the initiators of the ER stress pathway. Indeed, CBD diminished the phosphorylation of PKR and eiF2α induced by LPS/IFNγ. The pro-survival effects of CBD in OPCs were accompanied by decreases in the expression of ER apoptotic effectors (CHOP, Bax and caspase 12), and increased expression of the anti-apoptotic Bcl-2. These findings suggest that attenuation of the ER stress pathway is involved in the 'oligoprotective' effects of CBD during inflammation.

Guía de uso adecuado de modelos animales para el desarrollo de terapias en esclerosis múltiple / Guidelines on the appropriate use of animal models for developing therapies in multiple sclerosis

Introducción. La búsqueda de terapias efectivas para la esclerosis múltiple (EM) y la definición de ventanas terapéuticas apropiadas, así como el establecimiento de mejores biomarcadores diagnósticos y pronósticos, continúan siendo un reto para investigadores tanto básicos como clínicos. El desarrollo y el método de evaluación de los estudios preclínicos en modelos animales podrían subyacer al hecho de que terapias eficaces en modelos animales fracasen en su aplicación clínica. Objetivo. Unificar la metodología en la aplicación de los modelos experimentales para la EM mediante la elaboración, por parte de grupos españoles expertos pertenecientes a la Red Española de Esclerosis Múltiple, de una guía de recomendaciones para los estudios preclínicos. Desarrollo. Se ha realizado una valoración detallada de los modelos experimentales adecuados y su aplicación en función del objetivo perseguido, incorporando estándares y criterios de calidad imprescindibles en un estudio preclínico. Conclusiones. El éxito traslacional en el avance terapéutico de la EM conlleva la adquisición de compromisos metodológicos en los modelos experimentales, de manera que se optimice la bondad y adecuación del modelo al estudio perseguido. Las recomendaciones establecidas en esta guía podrían ayudar a generar datos preclínicos de utilidad en la práctica clínica (AU)

Introduction. The advance in the achievement of effective therapies for multiple sclerosis (MS), the definition of appropriate therapeutic windows and to establish better diagnostic and prognostic biomarkers have become a challenging task for both researchers and clinicians. Some pitfalls in clinical trials might be related to lack of adequacy of the preclinical studies in MS experimental animal models Aim. To standardize the methodological protocols of experimental models by developing a set of guidelines for preclinical studies by groups of experts from REEM (Spanish Network for MS). Development. A guide with recommendations for the application of MS models including a detailed assessment of appropriate experimental models taking into account the objective of the study that has been presented. Standards and quality criteria necessary in a preclinical study have been included. Conclusions. Standardized animal models of MS are essential to increase the success of the preclinical findings in order to transfer them to the clinical practice (AU)

c/EBPbeta is a major regulatory element driving transcriptional activation of the CXCL12 promoter.

CXCL12 is considered a constitutively expressed chemokine with homeostatic functions. However, induction of CXCL12 expression and its potential role in several pathologic conditions have been reported, suggesting that CXCL12 gene expression can be induced by different stimuli. To elucidate the molecular mechanisms involved in the regulation of CXCL12 gene expression, we aim to define the molecular factors that operate at the transcriptional level. Basal, constitutive expression of CXCL12 was dependent on basic helix-loop-helix factors. Transcriptional up-regulation of the CXCL12 gene was induced by cellular confluence or inflammatory stimuli such as interleukin-1 and interleukin-6, in a CCAAT/enhancer binding protein beta (c/EBPbeta)-dependent manner. Chromatin immunoprecipitation assays confirmed c/EBPbeta binding to a specific response element located at -1171 of the promoter region of CXCL12. Our data show that c/EBPbeta is a major regulatory element driving transcription of the CXCL12 gene in response to cytokines and cell confluence.

An endocannabinoid tone limits excitotoxicity in vitro and in a model of multiple sclerosis.

The aim of this study was to evaluate how endocannabinoids interact with excitotoxic processes both in vitro, using primary neural cell cultures, and in vivo, in the TMEV-IDD model of multiple sclerosis. First, we observed that neuronal cells respond to excitotoxic challenges by the production of endocannabinoid molecules which in turn exerted neuroprotective effects against excitotoxicity. The inhibitor of endocannabinoid uptake, UCM707, protected specifically against AMPA-induced excitotoxicity, by activating CB(1) and CB(2) cannabinoid receptors, as well as the nuclear factor, PPARgamma. This neuroprotective effect was reverted by blocking the glial glutamate transporter, GLT-1. Mice subjected to the model of multiple sclerosis showed a decrease in the expression of GLT-1. UCM707 reversed this loss of GLT-1 and induced a therapeutic effect. Our data indicate that the enhancement of the endocannabinoid tone leads to neuroprotection against AMPA-induced excitotoxicity and provides therapeutic effects in this model of multiple sclerosis.

A cannabinoid agonist interferes with the progression of a chronic model of multiple sclerosis by downregulating adhesion molecules.

Adhesion molecules are critical players in the regulation of transmigration of blood leukocytes across the blood-brain barrier in multiple sclerosis (MS). Cannabinoids (CBs) are potential therapeutic agents in the treatment of MS, but the mechanisms involved are only partially known. Using a viral model of MS we observed that the cannabinoid agonist WIN55,212-2 administered at the time of virus infection suppresses intercellular adhesion molecule-1 (ICAM-1), and vascular cell adhesion molecule-1 (VCAM-1) in brain endothelium, together with a reduction in perivascular CD4+ T lymphocytes infiltrates and microglial responses. WIN55,212-2 also interferes with later progression of the disease by reducing symptomatology and neuroinflammation. In vitro data from brain endothelial cell cultures, provide the first evidence of a role of peroxisome proliferator-activated receptors gamma (PPARgamma) in WIN55,212-2-induced downregulation of VCAM-1. This study highlights that inhibition of brain adhesion molecules by WIN55,212-2 might underline its therapeutic effects in MS models by targeting PPAR-gamma receptors.

Quantifying the biodiversity value of tropical primary, secondary, and plantation forests.

Biodiversity loss from deforestation may be partly offset by the expansion of secondary forests and plantation forestry in the tropics. However, our current knowledge of the value of these habitats for biodiversity conservation is limited to very few taxa, and many studies are severely confounded by methodological shortcomings. We examined the conservation value of tropical primary, secondary, and plantation forests for 15 taxonomic groups using a robust and replicated sample design that minimized edge effects. Different taxa varied markedly in their response to patterns of land use in terms of species richness and the percentage of species restricted to primary forest (varying from 5% to 57%), yet almost all between-forest comparisons showed marked differences in community structure and composition. Cross-taxon congruence in response patterns was very weak when evaluated using abundance or species richness data, but much stronger when using metrics based upon community similarity. Our results show that, whereas the biodiversity indicator group concept may hold some validity for several taxa that are frequently sampled (such as birds and fruit-feeding butterflies), it fails for those exhibiting highly idiosyncratic responses to tropical land-use change (including highly vagile species groups such as bats and orchid bees), highlighting the problems associated with quantifying the biodiversity value of anthropogenic habitats. Finally, although we show that areas of native regeneration and exotic tree plantations can provide complementary conservation services, we also provide clear empirical evidence demonstrating the irreplaceable value of primary forests.

El sistema cannabinoide en situaciones de neuroinflamación: perspectivas terapéuticas en la esclerosis múltiple / Cannabinoid system and neuroinflammation: therapeutic perspectives in multiple sclerosis

Introducción. El sistema endocannabinoide está constituidopor los receptores cannabinoides, los ligandos endógenos y loselementos enzimáticos implicados en su síntesis y degradación.Objetivo. Describir el estado actual de conocimiento sobre la funcióndel sistema como modulador de los procesos neuroinflamatoriosasociados con enfermedades crónicas como la esclerosis múltiple.Desarrollo. Los cannabinoides se sintetizan y se liberan en demanda y su producción aumenta en situaciones de neuroinflamacióny de daño neural. En este contexto, sus acciones en la microglía y enlos astrocitos se caracterizan por una disminución en la expresión demediadores inflamatorios y de citocinas proinflamatorias. Además,los cannabinoides pueden ejercer acciones neuroprotectoras a travésde diferentes tipos de mecanismos y en modelos experimentalesde esclerosis múltiple atenúan la sintomatología, disminuyen lainflamación y pueden favorecer la remielinización. Conclusiones. Eluso clínico de cannabinoides o agentes farmacológicos que incidenen el sistema endógeno cannabinoide durante la inflamación del sistemanervioso central y en la esclerosis múltiple está actualmentesometido a consideración y debate. El análisis detallado de los resultadosobtenidos en la última década ha permitido establecer que sonmúltiples los mecanismos de actuación de los cannabinoides en patologíasdel sistema nervioso central que cursan con inflamación crónicay ponen de manifiesto el interés del sistema cannabinoide comonueva herramienta terapéutica

Introduction. The endocannabinoid system consists of cannabinoid receptors, endogenous ligands and the enzymaticelements involved in their synthesis and breakdown. Aim. To report on currently held knowledge about the functioning of thesystem as a modulator of the neuroinflammatory processes associated with chronic diseases such as multiple sclerosis.Development. Cannabinoids are synthesised and released on demand and their production increases in times of neuroinflammationand neural damage. In this context then, their actions in the microglial cells and in the astrocytes arecharacterised by a lowered expression of inflammatory mediators and pro-inflammatory cytokines. Furthermore,cannabinoids can play a role as neuroprotectors by means of different types of mechanisms and, in experimental models ofmultiple sclerosis, they slow down the symptoms, reduce inflammation and can favour remyelination. Conclusions. Theclinical use of cannabinoids or pharmacological agents that affect the endogenous cannabinoid system during inflammationof the central nervous system and in multiple sclerosis is currently under consideration and subject to debate. Detailedanalysis of the results obtained over the past decade has made it possible to establish the existence of several mechanisms ofaction of cannabinoids in pathologies affecting the central nervous system that are accompanied by chronic inflammation.Likewise, they also clearly show that the cannabinoid system is an interesting proposal as a new therapeutic tool

[Cannabinoid system and neuroinflammation:therapeutic perspectives in multiple sclerosis]. / El sistema cannabinoide en situaciones de neuroinflamación: perspectivas terapéuticas en la esclerosis múltiple.

INTRODUCTION: The endocannabinoid system consists of cannabinoid receptors, endogenous ligands and the enzymatic elements involved in their synthesis and breakdown. AIM: To report on currently held knowledge about the functioning of the system as a modulator of the neuroinflammatory processes associated with chronic diseases such as multiple sclerosis. DEVELOPMENT: Cannabinoids are synthesised and released on demand and their production increases in times of neuroinflammation and neural damage. In this context then, their actions in the microglial cells and in the astrocytes are characterised by a lowered expression of inflammatory mediators and pro-inflammatory cytokines. Furthermore, cannabinoids can play a role as neuroprotectors by means of different types of mechanisms and, in experimental models of multiple sclerosis, they slow down the symptoms, reduce inflammation and can favour remyelination. CONCLUSIONS: The clinical use of cannabinoids or pharmacological agents that affect the endogenous cannabinoid system during inflammation of the central nervous system and in multiple sclerosis is currently under consideration and subject to debate. Detailed analysis of the results obtained over the past decade has made it possible to establish the existence of several mechanisms of action of cannabinoids in pathologies affecting the central nervous system that are accompanied by chronic inflammation. Likewise, they also clearly show that the cannabinoid system is an interesting proposal as a new therapeutic tool.

Propuesta para un registro clínico de demencias / A proposal for a clinical registry of dementias

Objetivo. Se presenta una propuesta de las característicasestructurales y funcionales necesarias para desarrollar un registrode demencias que permita recoger con garantías de fiabilidady validez la información estandarizada de los casos diagnosticadosde demencia en los centros sanitarios de atención especializada deun área geográfica definida. Desarrollo. Debido a la falta de informaciónsobre los aspectos relativos al impacto de las demenciassobre el sistema sanitario, en términos de utilización de recursos yen patrones de detección, derivación, diagnóstico y tratamiento enla práctica clínica habitual por parte de atención primaria y secundaria,se propone una implementación secuencial del registro paraadaptarse a cada territorio o región sanitaria. En primer lugar, sedeberían identificar los casos y las fuentes de información; en segundolugar, desarrollar un sistema de recogida de datos que permitaadoptar de forma estandarizada la recogida de información yestablecer una estrecha colaboración con los especialistas que llevena cabo el diagnóstico de demencia; y, en tercer lugar, aportar alregistro una estructura logística y de personal que centralice todaslas funciones y actividades del registro. Conclusiones. La vigilanciaepidemiológica es un instrumento fundamental para la planificación,gestión y distribución de los recursos sociosanitarios, para elseguimiento de la evolución natural de enfermedades crónicas asícomo para evaluar el impacto de programas preventivos. En estesentido, y desde un punto de vista funcional, la propuesta de unregistro de demencias cumple todos los requisitos básicos de la vigilanciaepidemiológica

Aims. We outline a proposal for the structural and functional features needed to develop a registry of dementiaswhich can be used to collect standardised information that is both reliable and valid concerning cases of dementia in thespecialised health care centres within a particular geographical area. Development. Due to the shortage of information aboutaspects concerning the impact of dementias on the health care system (in terms of the usage of resources and patterns ofdetection, referral, diagnosis and treatment in usual clinical practice in primary and secondary care), a sequentialimplementation of the registry is proposed so that it can be adapted to each health district or region. The first step is to identifythe cases and sources of information; second, a system for collecting data must be developed that allows information to begathered in a standardised manner while at the same time making it possible to work in close collaboration with thespecialists who diagnose dementia; and, third, it must be set up with the logistics and staff needed to centralise all thefunctions and activities of the registry. Conclusions. Epidemiological surveillance is an essential instrument for planning,managing and distributing community health resources, for following up the natural history of chronic diseases and forassessing the impact of programmes of prevention. In this respect, and from a functional point of view, the proposed registry ofdementias meets all the basic requirements of epidemiological surveillance

[A proposal for a clinical registry of dementias]. / Propuesta para un registro clinico de demencias.

AIMS: We outline a proposal for the structural and functional features needed to develop a registry of dementias which can be used to collect standardised information that is both reliable and valid concerning cases of dementia in the specialised health care centres within a particular geographical area. DEVELOPMENT: Due to the shortage of information about aspects concerning the impact of dementias on the health care system (in terms of the usage of resources and patterns of detection, referral, diagnosis and treatment in usual clinical practice in primary and secondary care), a sequential implementation of the registry is proposed so that it can be adapted to each health district or region. The first step is to identify the cases and sources of information; second, a system for collecting data must be developed that allows information to be gathered in a standardised manner while at the same time making it possible to work in close collaboration with the specialists who diagnose dementia; and, third, it must be set up with the logistics and staff needed to centralise all the functions and activities of the registry. CONCLUSIONS: Epidemiological surveillance is an essential instrument for planning, managing and distributing community health resources, for following up the natural history of chronic diseases and for assessing the impact of programmes of prevention. In this respect, and from a functional point of view, the proposed registry of dementias meets all the basic requirements of epidemiological surveillance.

Estudio clinico terapéutico de la demencia en las personas con síndrome de down y eficacia del donepecilo en esta población / Clinical-therapeutic study of dementia in people with down syndrome and the effectiveness of donepezil in this population

Introducción. Las personas con síndrome de Down envejecen precozmente, sobre todo a partir de los 40 años, mientras un porcentaje significativo inicia, a partir de esta edad, un deterioro progresivo de sus capacidades cognitivas y funcionales previas, secundario todo ello a un proceso degenerativo primario de tipo enfermedad de Alzheimer. Estudios clínicos piloto en esta población, en los que se ha valorado la repuesta al tratamiento con donepecilo, han demostrado beneficios terapéuticos. Objetivo. Evaluar la eficacia y seguridad del tratamiento farmacológico con donepecilo sobre los trastornos cognitivos y conductuales en población con síndrome de Down mayor de 40 años, en la que la familia y educadores de referencia han observado cambios cognitivos y conductuales respecto a su nivel previo de discapacidad. Pacientes y métodos. Los pacientes han sido seleccionados a través de diferentes instituciones filiadas por la Fundació Catalana de Síndrome de Down y por la Federación Catalana Pro Personas con Disminución Psíquica. Se han utilizado escalas de valoración de deterioro, conducta y funcionalismo adaptadas a esta población. Resultados. Los resultados del estudio han demostrado que el donepecilo ralentiza la progresión de la disfunción cognitiva, especialmente durante los primeros tres meses de tratamiento. Esto sucede tanto en las escalas cognitivas como sociales. Conclusiones. El donepecilo parece ser efectivo en el tratamiento de los trastornos cognitivos y de la conducta en la demencia progresiva del síndrome de Down. Todas las muestras publicadas en diferentes estudios han sido pequeñas, lo que hace necesario poner en marcha estudios multicéntricos para validar la respuesta de estos sujetos a la terapia anticolinesterásica (AU)

Introduction. People with Down syndrome have an early aging process, especially form their 40s. There is a significant average of them who initiate, from that age on, a progressive decline of their cognitive and functional abilities, due to a primary degenerative process Alzheimer’s disease type. When assessing response to treatment with, pilot clinical trials on this population have demonstrated real benefits therapeutically. Aims. To assess the efficacy and safety of a pharmacological treatment with donepezil over cognitive and behavioral disturbances on patients with Down syndrome older than 40 years, areas where family and professional educators of reference have observed cognitive and behavioral changes in comparison with their previous level of disability. Patients and methods. Patients have been selected from different institutions affiliated at the Catalan Foundation for the Down syndrome and by the Catalan Federation Pro Persons with Psychic Disability. Several deterioration, behavioral and functional assessment scales have been used, all of them validated into this population. Results. The results of study demonstrated that donepezil slowed the progression of the cognitive dysfunction, especially during the first three months of treatment. This occurred for both cognitive and social-behavioral outcomes. Conclusions. Donepezil appears to be effective in the treatment of cognitive and behavioural disturbances associated with the progressive dementia syndrome in Down’s. However, the sample sizes used in this, and all published studies are small and this emphasizes the need for a larger, multi-center trial to fully evaluate the nature and extent of the response of Down's syndrome patients to anticolinesterase therapy (AU)