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

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

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

Bexarotene Impairs Cognition and Produces Hypothyroidism in a Mouse Model of Down Syndrome and Alzheimer’s Disease

All individuals with Down syndrome (DS) eventually develop Alzheimer's disease (AD) neuropathology, including neurodegeneration, increases in ?-amyloid (A?) expression, and aggregation and neurofibrillary tangles, between the third and fourth decade of their lives. There is currently no effective treatment to prevent AD neuropathology and the associated cognitive degeneration in DS patients. Due to evidence that the accumulation of A? aggregates in the brain produces the neurodegenerative cascade characteristic of AD, many strategies which promote the clearance of A? peptides have been assessed as potential therapeutics for this disease. Bexarotene, a member of a subclass of retinoids that selectively activates retinoid receptors, modulates several pathways essential for cognitive performance and A? clearance. Consequently, bexarotene might be a good candidate to treat AD-associated neuropathology. However, the effects of bexarotene treatment in AD remain controversial. In the present study, we aimed to elucidate whether chronic bexarotene treatment administered to the most commonly used murine model of DS, the Ts65Dn (TS) mouse could reduce A? expression in their brains and improve their cognitive abilities. Chronic administration of bexarotene to aged TS mice and their CO littermates for 9 weeks diminished the reference, working, and spatial learning and memory of TS mice, and the spatial memory of CO mice in the Morris water maze. This treatment also produced marked hypoactivity in the plus maze, open field, and hole board tests in TS mice, and in the open field and hole board tests in CO mice. Administration of bexarotene reduced the expression of A?1-40, but not of A?1-42, in the hippocampi of TS mice. Finally, bexarotene increased Thyroid-stimulating hormone levels in TS mice and reduced Thyroid-stimulating hormone levels in CO mice, while animals of both karyotypes displayed reduced thyroxine levels after bexarotene administration. The bexarotene-induced hypothyroidism could be responsible for the hypoactivity of TS and CO mice and their diminished performance in the Morris water maze. Together, these results do not provide support for the use of bexarotene as a potential treatment of AD neuropathology in the DS population.FUNDING: This study was supported by the Institute of Research Valdecilla (IDIVAL) (NVAL 16/21 and NVAL 19/23) and the Consejería de Universidades, Igualdad, Cultura y Deporte del Gobierno de Cantabria (16. VP39.64662)

Logopenic Aphasia due to a Strategic Stroke: New Evidence from a Single Case

Among primary progressive aphasias (PPAs), logopenic variant PPA (lv-PPA) is usually related to Alzheimer's disease. Although it has been widely clinically and pathologically evaluated, the topography in LPA is still controversial. We report a patient presenting with a logopenic syndrome due to a strategic lesion located in the superior and middle temporal gyrus and compare our findings with those of a PiB-PET positive lv-PPA patient matched by age, gender, and education. We consider that our study provides new anatomical clues to better understand the cognitive mechanisms underlying the logopenic syndrome

Does Extended Interval Dosing Natalizumab Preserve Effectiveness in Multiple Sclerosis? A 7 Year-Retrospective Observational Study

The extended interval dosing (EID) of natalizumab has been suggested to be associated with a reduced risk of progressive multifocal leukoencephalopathy (PML) and short-term preservation of efficacy but its long-term effectiveness remain unknown. We aimed to determine the long-term effectiveness and safety of natalizumab in an EID setting in a cohort of patients with multiple sclerosis (MS) treated for more than 7 years. We conducted an observational retrospective cohort study, including 39 (34 female, 5 male) patients with clinically definite relapsing-MS, initially treated with standard interval dosing (SID) of natalizumab (mean time 54 months [SD29]) who were then switched to EID, every 8 weeks (mean time 76 months [SD13]). The main outcome measures included the following: i) annualized relapse rate (ARR), ii) radiological activity, iii) disability progression, and iv) NEDA-3 no evidence of disease activity index. EID preserved ARR, radiological activity, and prevented disability worsening during follow-up. The proportion of patients maintaining their NEDA-3 status after 24, 48, and 72 months of natalizumab administration in EID was 94%, 73%, and 70%, respectively. Stratified analysis according to history of drug therapy showed that the EID of natalizumab was slightly more effective in naïve patients than in those previously treated with other immunosuppressive drugs. No cases of PML or other severe adverse reactions were reported. In conclusion, long-term therapy with natalizumab in an EID setting following an SID regimen maintained its disease-modifying activity, and was safe and well tolerated for over 7 years. These encouraging observational results need to be confirmed in controlled clinical trials.FUNDING: This study was supported by IDIVAL (NVAL 16/11)

Association of aromatase and estrogen receptor gene polymorphisms with hip fractures

Producción CientíficaSummary Two polymorphisms of the aromatase and estrogen receptor genes appeared to interact to influence the risk of hip fractures in women. Introduction Allelic variants of the aromatase gene have been associated with bone mineral density and vertebral fractures. Our objective was to analyze the relationship between two polymorphisms of the aromatase and estrogen receptor genes and hip fracture

Haplotypes of intron 4 of the estrogen receptor alpha gene and hip fractures: a replication study in Caucasians

<p>Abstract</p> <p>Background</p> <p>Despite their great impact, few genetic association studies have used hip fractures as an endpoint. However, the association of two polymorphisms on intron 4 of estrogen receptor alpha (<it>ESR1</it>) with hip fractures was recently reported in a Chinese population. The aim of this study was to investigate whether such association is also present in Caucasians.</p> <p>Methods</p> <p>We analyzed those two SNPs and another neighbour SNP located on the exon 4 of <it>ESR1 </it>in 787 patients with hip fractures and 953 controls from Spain.</p> <p>Results</p> <p>The allelic frequencies differed markedly from those reported in Asian populations. Nevertheless, haplotypes including the rs3020314 and rs1884051 loci in intron 4 showed a significant association with hip fractures (omnibus test p = 0.006 in the whole group and 0.00005 in women). In the sex-stratified analysis, the association was significant in females, but not in males. In women, the CA haplotype appeared to have a protective influence, being present in 6.5% of the controls, but only in 3% of patients with fractures (odds ratio 0.39; 95% confidence interval 0.26-0.59; estimated population preventive fraction 3.5%). The inclusion of the rs1801132 SNP of exon 4 further increased the statistical significance of the association (odds ratio 0.17; 95% CI 0.08-0.37; p = 0.00001). Each SNP appeared to contribute independently to the association. No genotype-related differences in gene expression were found in 42 femoral bone samples.</p> <p>Conclusions</p> <p>This study confirms the association of some polymorphisms in the region of exon 4/intron 4 of <it>ESR1 </it>and hip fractures in women. However, there are marked differences in allele frequencies between Asian and Caucasian populations.</p