Clinical and preclinical evidence of somatosensory involvement in amyotrophic lateral sclerosis

Amyotrophic lateral sclerosis (ALS) is the most common motor neuron neurodegenerative disease. Although it has been classically considered as a disease limited to the motor system, there is increasing evidence for the involvement of other neural and non-neuronal systems. In this review, we will discuss currently existing literature regarding the involvement of the sensory system in ALS. Human studies have reported intradermic small fibre loss, sensory axonal predominant neuropathy, as well as somatosensory cortex hyperexcitability. In line with this, ALS animal studies have demonstrated the involvement of several sensory components. Specifically, they have highlighted the impairment of sensory?motor networks as a potential mechanism for the disease. The elucidation of these ?non-motor? systems involvement, which might also be part of the degeneration process, should prompt the scientific community to re-consider ALS as a pure motor neuron disease, which may in turn result in more holistic research approaches

Why do motor neurons degenerate? Actualization in the pathogenesis of amyotrophic lateral sclerosis

Introducción: La esclerosis lateral amiotrófica (ELA) es la enfermedad degenerativa de las motoneuronas más frecuente. Aunque un peque?no porcentaje de los casos de ELA tienen un origen familiar y son secundarios a mutaciones en genes concretos, a la gran mayoría de ellos se les presupone un origen multifactorial, sin que su patogenia haya sido completamente aclarada. No obstante, en los últimos a?nos varios estudios han aumentado el conocimiento sobre la patogenia de la enfermedad, planteando la cuestión de si se trata de una proteinopatía, una ribonucleinopatía, una axonopatía o una enfermedad del microambiente neuronal. Desarrollo: En el presente artículo revisamos los trabajos publicados tanto en pacientes como en modelos animales de ELA y discutimos la implicación de los principales procesos celulares que parecen contribuir a su patogenia (procesamiento génico, metabolismo de proteínas, estrés oxidativo, transporte axonal y relación con el microambiente neuronal). Conclusiones: Aunque la patogenia de la ELA dista de estar aclarada, los estudios recientes apuntan a la idea de que hay unos desencadenantes iniciales que varían de unos sujetos a otros,y unas vías finales de degeneración de las motoneuronas que están implicadas en la mayor parte de los casos de enfermedad.Introduction: Amyotrophic lateral sclerosis (ALS) is the most common neurodegenerative disease affecting motor neurons. Although a small proportion of ALS cases are familial in origin and linked to mutations in specific genes, most cases are sporadic and have a multifactorial aetiology. Some recent studies have increased our knowledge of ALS pathogenesis and raised the question of whether this disorder is a proteinopathy, a ribonucleopathy, an axonopathy, or a disease related to the neuronal microenvironment. Development: This article presents a review of ALS pathogenesis. To this end, we have reviewed published articles describing either ALS patients or ALS animal models and we discuss how the main cellular pathways (gene processing, protein metabolism, oxidative stress, axonal transport, relationship with neuronal microenvironment) may be involved in motor neurons degeneration. Conclusions: ALS pathogenesis has not been fully elucidated. Recent studies suggest that although initial triggers may differ among patients, the final motor neurons degeneration mechanisms are similar in most patients once the disease is fully established

A time series analysis of the relationship between apparent temperature, air pollutants and ischemic stroke in Madrid, Spain

The understanding of the role of environment on the pathogenesis of stroke is gaining importance in the context of climate change. This study analyzes the temporal pattern of ischemic stroke (IS) in Madrid, Spain, during a 13-year period (2001-2013), and the relationship between ischemic stroke (admissions and deaths) incidence and environmental factors on a daily scale by using a quasi-Poisson regression model. To assess potential delayed and non-linear effects of air pollutants and Apparent Temperature (AT), a biometeorological index which represents human thermal comfort on IS, a lag non-linear model was fitted in a generalized additive model. The mortality rate followed a downward trend over the studied period, however admission rates progressively increased. Our results show that both increases and decreases in AT had a marked relationship with IS deaths, while hospital admissions were only associated with low AT. When analyzing the cumulative effects (for lag 0-14 days), with an AT of 1.7?°C (percentile 5%) a RR of 1.20 (95% CI, 1.05-1.37) for IS mortality and a RR of 1.09 (95% CI, 0.91-1.29) for morbidity is estimated. Concerning gender differences, men show higher risks of mortality in low temperatures and women in high temperatures. No significant relationship was found between air pollutant concentrations and IS morbi-mortality, but this result must be interpreted with caution, since there are strong spatial fluctuations of the former between nearby geographical areas that make it difficult to perform correlation analyses

Genetic polymorphisms of the wint receptor LRP5 are differentially associated with trochanteric and cervical hip fractures

Producción CientíficaPurpose. Epidemiological studies suggest that cervical and trochanteric hip fractures have different pathogenesis. We planned to test the hypothesis that genetic factors have different influences on both types of fractures. Methods. Ten polymorphisms of genes known to play an important role in skeletal homeostasis (estrogen receptor alpha [ESR1], aromatase [CYP19A1], type I collagen [COL1A1], and lipoprotein receptor-related protein 5 [LRP5]) were analyzed in 471 Spanish patients with fragility hip fractures. Results. Two polymorphisms of the LRP5 gene (rs7116604 and rs3781600) were associated with the type of fracture (p-value 0.0085 and 0.0047, respectively). The presence of rare alleles at each locus was associated with trochanteric fractures over cervical fractures (OR 1.7 in individuals with at least one rare allele at rs7116604 or rs3781600 loci, in comparison with the common homozygotes). Considering individuals bearing the four common alleles as reference, the OR for trochanteric fractures was 1.6 in those with 1 or 2 rare alleles, and 7.5 in those with 3 or 4 rare alleles (p-value for trend 0.0074), which is consistent with an allele-dosage effect. There were no significant differences in the frequency distributions of the ESR1, CYP19A1 and COL1A1 genotypes between trochanteric and cervical fractures in either the original group or in an extended group of 818 patients. Conclusions. These results suggest LRP5 alleles influence the type of hip fractures. They support the view that different genetic factors are involved in cervical and trochanteric fractures, which should be taken into consideration in future genetic association studies

Satellite Glial Cells of the Dorsal Root Ganglion: A New ?Guest/Physiopathological Target? in ALS

Introduction: Amyotrophic lateral sclerosis (ALS) might not only be circumscribed to the motor system but also involves other neuronal systems including sensory abnormalities. In line with this notion, we aimed to assess the pathophysiology of sensory disturbances in the SOD1G93A mouse model of ALS, focusing on the satellite glial cells (SGCs) at the dorsal root ganglion (DRG) as a new potential target of the disease. MaterialandMethods: Thepresenceofsensorydisturbanceswasevaluatedusingvon Frey, hot plate, and hot water tail immersion tests at 75 days old, which represented the motor-pre-symptomatic stage. Cell biology analysis was performed at 75 and 95 days old and included conventional histology, immuno?uorescence, and electron microscopy of sensory neuron-SGC unit dissociates as a well as western blotting from DRG lysates. Results: At 75 days old, von Frey and hot plate tests demonstrated clear thermoalgesic disturbances in ALS transgenic mice. Histological studies of the SN-SGC units revealed abnormal SOD1 accumulation, which was associated with nitro-oxidative stress and biogenesis of lipid droplets in SGCs. Interestingly, these alterations led to a progressive lysosomal storage disorder and occasionally vacuolar degeneration in SGCs. Conclusions: SGCs emerge as a primary pathophysiological target in the SOD1 transgenic murine model of ALS, clearly reinforcing the pathogenic role of glial cells in motor neuron disease. Presymptomatic alterations of SGCs, might not only be responsibleofsensorydisturbancesinALS,butduetospinalcordsensory-motorcircuits could also contribute to anterior horn motor disturbance

Neuroprotective Effect of Bexarotene in the SOD1(G93A) Mouse Model of Amyotrophic Lateral Sclerosis

Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease characterized by progressive weakness and muscle atrophy related to the loss of upper and lower motor neurons (MNs) without a curative treatment. There is experimental evidence suggesting that retinoids may be involved in ALS pathogenesis. Bexarotene (Bxt) is a retinoid-X receptor agonist used in the treatment of cutaneous lymphoma with a favorable safety profile whose effects have been recently investigated in other neurodegenerative diseases. In this study, we analyze the potential therapeutic effect of Bxt in the SOD1(G93A) mouse model of ALS. Mice were treated with Bxt or vehicle five times per week from day 60 onward. Survival, weight, and neuromuscular function studies together with histological and biochemical analyses were performed. Bxt significantly delayed motor function deterioration, ameliorated the loss of body weight, and extended mice survival up to 30% of the symptomatic period. Histological analyses of the lumbosacral spinal cord revealed that Bxt markedly delayed the early motor-neuron degeneration occurring at presymptomatic stages in ALS-transgenic mice. Bxt treatment contributed to preserve the MN homeostasis in the SOD1(G93A) mice. Particularly, it reduced the neuronal loss and the chromatolytic response, induced nucleolar hypertrophy, decreased the formation of ubiquitylated inclusions, and modulated the lysosomal response. As an agonist of the retinoic-X receptor (RXR) pathway, Bxt notably increased the nuclear expression of the RXRα throughout transcriptionally active euchromatin domains. Bxt also contributed to protect the MN environment by reducing reactive astrogliosis and preserving perisomatic synapsis. Overall, these neuroprotective effects suggest that treatment with Bxt could be useful in ALS, particularly in those cases related to SOD1 mutations

Do patients diagnosed with a neurological disease present increased risk of suicide?

RESUMEN: Introducción: Las enfermedades neurológicas representan la principal causa de discapacidady la segunda causa de muerte a nivel mundial. El dolor físico y psicológico, la desesperanzay la desconexión con el medio están presentes tras el diagnóstico de numerosos procesosneurológicos y especialmente de las enfermedades neurodegenerativas.Desarrollo: Existe un mayor riesgo de suicidio en pacientes con enfermedades neurológicascomunes como la epilepsia, la migra?na y la esclerosis múltiple, así como en quienes padecentrastornos degenerativos como la enfermedad de Alzheimer, la enfermedad de Huntington, laesclerosis lateral amiotrófica o la enfermedad de Parkinson. En la mayoría de los casos, la idea-ción suicida aparece en la etapa próxima al diagnóstico, ante sintomatología invalidante, y/oen pacientes que presentan comorbilidad psiquiátrica (a menudo asociada con dichas dolenciasneurológicas).Conclusiones: Para una prevención efectiva del suicidio en este grupo de la población debeevaluarse el riesgo principalmente en pacientes recién diagnosticados, ante la expresión demarcada desesperanza, ante sintomatología invalidante y en pacientes que presentan comorbi-lidad psiquiátrica (especialmente síntomas depresivos). La formación de los especialistas paradetectar signos de alerta es fundamental tanto para que puedan hacer un correcto abordajecomo para que sean capaces de determinar cuándo es necesaria la valoración de un especialistaen psiquiatría.ABSTRACT: Introduction: Neurological diseases are the leading cause of disability and the second leading cause of death worldwide. Physical and psychological pain, despair, and disconnection with the environment are observed after the diagnosis of numerous neurological processes, particularly neurodegenerative diseases. Development: A higher risk of suicide is observed in patients with such common neurological diseases as epilepsy, migraine, and multiple sclerosis, as well as in those with such degenerative disorders as Alzheimer disease, Huntington disease, amyotrophic lateral sclerosis, and Parkinson's disease. In most cases, suicidal ideation appears in the early stages after diagnosis, in the presence of disabling symptoms, and/or in patients with psychiatric comorbidities (often associated with these neurological diseases). Conclusions: Effective suicide prevention in this population group requires assessment of the risk of suicide mainly in newly diagnosed patients, in patients showing unmistakable despair or disabling symptoms, and in patients presenting psychiatric comorbidities (especially depressive symptoms). It is essential to train specialists to detect warning signs in order that they may adopt a suitable approach and determine when psychiatric assessment is required

Dos obras del arquitecto Azpiazu. España

Two recent works of the Architect J. R. Azpiazu are shown in this issue. The interest of each of them is based in punctual aspects with original constructive solutions: — At first, BUSINESS BUILDING IN SANTANDER, the project is very interesting mainly by the planning and design of the structure in wood reenforcement with laminated steel elements. — In the second, BANK OFFICE IN ORIHUELA, the interest of the constructive and formal solution in the helicoidal stair in structural concrete, without central element is the main subject.Se presentan en este trabajo dos obras recientes del Arquitecto José Ramón Azpiazu. El interés de cada una de ellas radica en aspectos puntuales, con soluciones constructivas de cierta originalidad: — En la primera, EDIFICIO DE OFICINAS EN SANTANDER, interesa de modo especial el planteamiento adoptado para el refuerzo de la estructura de madera existente realizado a base de elementos de acero laminado. — En la segunda, SUCURSAL DE BANCO EN ORÍ HUELA, el mayor interés radica en la solución constructiva y formal de la escalera helicoidal de hormigón armado, ejecutada sin vástago central