Dysregulated FOXO1 activity drives skeletal muscle intrinsic dysfunction in amyotrophic lateral sclerosis.

Amyotrophic Lateral Sclerosis (ALS) is a multisystemic neurodegenerative disorder, with accumulating evidence indicating metabolic disruptions in the skeletal muscle preceding disease symptoms, rather than them manifesting as a secondary consequence of motor neuron (MN) degeneration. Hence, energy homeostasis is deeply implicated in the complex physiopathology of ALS and skeletal muscle has emerged as a key therapeutic target. Here, we describe intrinsic abnormalities in ALS skeletal muscle, both in patient-derived muscle cells and in muscle cell lines with genetic knockdown of genes related to familial ALS, such as TARDBP (TDP-43) and FUS. We found a functional impairment of myogenesis that parallels defects of glucose oxidation in ALS muscle cells. We identified FOXO1 transcription factor as a key mediator of these metabolic and functional features in ALS muscle, via gene expression profiling and biochemical surveys in TDP-43 and FUS-silenced muscle progenitors. Strikingly, inhibition of FOXO1 mitigated the impaired myogenesis in both the genetically modified and the primary ALS myoblasts. In addition, specific in vivo conditional knockdown of TDP-43 or FUS orthologs (TBPH or caz) in Drosophila muscle precursor cells resulted in decreased innervation and profound dysfunction of motor nerve terminals and neuromuscular synapses, accompanied by motor abnormalities and reduced lifespan. Remarkably, these phenotypes were partially corrected by foxo inhibition, bolstering the potential pharmacological management of muscle intrinsic abnormalities associated with ALS. The findings demonstrate an intrinsic muscle dysfunction in ALS, which can be modulated by targeting FOXO factors, paving the way for novel therapeutic approaches that focus on the skeletal muscle as complementary target tissue.

Spatial analysis of ischemic stroke in Spain: the roles of accessibility to healthcare and economic development.

Ischemic stroke is a major cause of mortality worldwide; however, few studies have been conducted to measure the impact of the distribution of healthcare services on ischemic stroke fatality. This study aimed to explore the relationship between three ischemic stroke outcomes (incidence, mortality, and fatality) and accessibility to hospitals in Spain, considering its economic development. A cross-sectional ecological study was performed using data on hospital admissions and mortality due to ischemic stroke during 2016-2018. Gross geographic product (GGP) per capita was estimated and a healthcare accessibility index was created. A Besag-York-Mollié autoregressive spatial model was used to estimate the magnitude of association between ischemic stroke outcomes and economic development and healthcare accessibility. GGP per capita showed a geographical gradient from southwest to northeast in Spain. Mortality and case-fatality rates due to ischemic stroke were higher in the south of the country in both women and men aged 60+ years. In women and men aged 20-59 years a EUR 1,000 increase in GGP per capita was associated with decreases in mortality of 5% and 4%, respectively. Fatality decreased 3-4% with each EUR 1,000 increase of GGP per capita in both sexes and in the 20-59 and 60+ age groups. Decreased healthcare accessibility was associated with higher fatality in the population aged 60+. Economic development in southwest Spain would not only improve employment opportunities but also reduce ischemic stroke mortality. New health related strategies to improve hospital accessibility should be considered in more sparsely populated regions or those with worse transport and/or healthcare infrastructure.

Spatial analysis of ischemic stroke in Spain: the roles of accessibility to healthcare and economic development / Análisis espacial del ictus isquémico en España: papel de la accesibilidad a la salud y del desarrollo económico / Análise espacial de acidente vascular cerebral isquêmico na Espanha: os papéis da acessibilidade à saúde e do desenvolvimento econômico

Abstract: Ischemic stroke is a major cause of mortality worldwide; however, few studies have been conducted to measure the impact of the distribution of healthcare services on ischemic stroke fatality. This study aimed to explore the relationship between three ischemic stroke outcomes (incidence, mortality, and fatality) and accessibility to hospitals in Spain, considering its economic development. A cross-sectional ecological study was performed using data on hospital admissions and mortality due to ischemic stroke during 2016-2018. Gross geographic product (GGP) per capita was estimated and a healthcare accessibility index was created. A Besag-York-Mollié autoregressive spatial model was used to estimate the magnitude of association between ischemic stroke outcomes and economic development and healthcare accessibility. GGP per capita showed a geographical gradient from southwest to northeast in Spain. Mortality and case-fatality rates due to ischemic stroke were higher in the south of the country in both women and men aged 60+ years. In women and men aged 20-59 years a EUR 1,000 increase in GGP per capita was associated with decreases in mortality of 5% and 4%, respectively. Fatality decreased 3-4% with each EUR 1,000 increase of GGP per capita in both sexes and in the 20-59 and 60+ age groups. Decreased healthcare accessibility was associated with higher fatality in the population aged 60+. Economic development in southwest Spain would not only improve employment opportunities but also reduce ischemic stroke mortality. New health related strategies to improve hospital accessibility should be considered in more sparsely populated regions or those with worse transport and/or healthcare infrastructure.

Resumen: El ictus isquémico es una de las principales causas de mortalidad en todo el mundo; sin embargo, pocos estudios han medido el impacto de la distribución de los servicios de salud sobre la letalidad del ictus isquémico. Este estudio exploró la relación entre tres desenlaces del ictus isquémico (incidencia, mortalidad y letalidad) y la accesibilidad a los hospitales en España, teniendo en cuenta el desarrollo económico. Se realizó un estudio ecológico transversal utilizando datos que captan todas las hospitalizaciones y la mortalidad por ictus isquémico durante el período 2016-2018. Se calculó el producto geográfico bruto (PGB) per cápita y se creó un índice de accesibilidad a la salud. Se utilizó un modelo espacial autorregresivo de Besag-York- Mollié para estimar la magnitud de la asociación entre los desenlaces del ictus isquémico y el desarrollo económico y la accesibilidad a la salud. El PGB per cápita mostró un gradiente geográfico de suroeste a noreste en España. Las tasas de mortalidad y letalidad por ictus isquémico fueron mayores en el sur del país, tanto en mujeres como en hombres mayores de 60 años. En mujeres y hombres de 20 a 59 años, un aumento de EUR 1.000 en el PGB per cápita se asoció con una disminución en la mortalidad del 5% y del 4%, respectivamente. La letalidad disminuyó 3-4% por cada EUR 1.000 de aumento del PGB per cápita en ambos sexos y en los rangos de edad de 20-59 y mayores de 60 años. La disminución del acceso a la salud se asoció con una mayor mortalidad en la población mayor de 60 años. El desarrollo económico en el suroeste de España no solo mejoraría las oportunidades de empleo, sino que también reduciría la mortalidad por ictus isquémico. Se deben considerar nuevas estrategias relacionadas con la salud para mejorar la accesibilidad hospitalaria en regiones menos pobladas o con peor infraestructura de transporte o salud.

Resumo: O acidente vascular cerebral isquêmico (AVC) é uma das principais causas de mortalidade no mundo; no entanto, poucos estudos têm mensurado o impacto da distribuição dos serviços de saúde sobre a letalidade do AVC. Este estudo explorou a relação entre três desfechos do AVC (incidência, mortalidade e letalidade) e a acessibilidade à hospitais na Espanha, considerando o desenvolvimento econômico. Um estudo ecológico transversal foi realizado usando dados que capturam todas as internações e mortalidade por AVC durante 2016-2018. Calculou-se o produto geográfico bruto (PGB) per capita e criou-se um índice de acessibilidade à saúde. Um modelo espacial autorregressivo de Besag-York- Mollié foi utilizado para estimar a magnitude da associação entre os desfechos do AVC e o desenvolvimento econômico e a acessibilidade à saúde. O PGB per capita mostrou um gradiente geográfico de sudoeste para nordeste na Espanha. As taxas de mortalidade e letalidade por AVC foram maiores no sul do país, tanto em mulheres quanto em homens com mais de 60 anos. Em mulheres e homens com idades entre 20 e 59 anos, um aumento de EUR 1.000 no PGB per capita foi associado a diminuições na mortalidade de 5% e 4%, respetivamente. A letalidade diminuiu 3-4% a cada aumento de EUR 1.000 no PGB per capita em ambos os gêneros e nas faixas etárias de 20-59 e 60+. A diminuição do acesso à saúde foi associada à maior letalidade na população 60+. O desenvolvimento econômico no sudoeste da Espanha não só melhoraria as oportunidades de emprego, mas também reduziria a mortalidade devido ao AVC. Novas estratégias relacionadas à saúde devem ser consideradas para melhorar a acessibilidade hospitalar em regiões menos povoadas ou com pior infraestrutura de transporte e/ou saúde.

Erratum: Cumulative Genetic Score and C9orf72 Repeat Status Independently Contribute to Amyotrophic Lateral Sclerosis Risk in 2 Case-Control Studies.

[This corrects the article DOI: 10.1212/NXG.0000000000200079.].

Cumulative Genetic Score and C9orf72 Repeat Status Independently Contribute to Amyotrophic Lateral Sclerosis Risk in 2 Case-Control Studies.

Background and Objectives: Most patients with amyotrophic lateral sclerosis (ALS) lack a monogenic mutation. This study evaluates ALS cumulative genetic risk in an independent Michigan and Spanish replication cohort using polygenic scores. Methods: Participant samples from University of Michigan were genotyped and assayed for the chromosome 9 open reading frame 72 hexanucleotide expansion. Final cohort size was 219 ALS and 223 healthy controls after genotyping and participant filtering. Polygenic scores excluding the C9 region were generated using an independent ALS genome-wide association study (20,806 cases, 59,804 controls). Adjusted logistic regression and receiver operating characteristic curves evaluated the association and classification between polygenic scores and ALS status, respectively. Population attributable fractions and pathway analyses were conducted. An independent Spanish study sample (548 cases, 2,756 controls) was used for replication. Results: Polygenic scores constructed from 275 single-nucleotide variation (SNV) had the best model fit in the Michigan cohort. An SD increase in ALS polygenic score associated with 1.28 (95% CI 1.04-1.57) times higher odds of ALS with area under the curve of 0.663 vs a model without the ALS polygenic score (p value = 1 × 10-6). The population attributable fraction of the highest 20th percentile of ALS polygenic scores, relative to the lowest 80th percentile, was 4.1% of ALS cases. Genes annotated to this polygenic score enriched for important ALS pathomechanisms. Meta-analysis with the Spanish study, using a harmonized 132 single nucleotide variation polygenic score, yielded similar logistic regression findings (odds ratio: 1.13, 95% CI 1.04-1.23). Discussion: ALS polygenic scores can account for cumulative genetic risk in populations and reflect disease-relevant pathways. If further validated, this polygenic score will inform future ALS risk models.

Switch to ocrelizumab in MS patients treated with natalizumab in extended interval dosing at high risk of PML: A 96-week follow-up pilot study.

We aimed to assess the long-term safety and effectiveness of ocrelizumab in a cohort of patients with multiple sclerosis (MS) at high risk of progressive multifocal leukoencephalopathy (PML), previously treated with natalizumab in extending interval dosing (EID), who switched to ocrelizumab and to compare them with patients who continued EID-natalizumab. Thirty MS patients previously treated with natalizumab in EID (every 8 weeks) were included in this observational retrospective cohort study. Among them, 17 patients were switched to ocrelizumab and 13 continued with EID-natalizumab. Except for the John Cunningham virus (JCV) index, no significant differences were detected between both groups. Main outcome measures included: annualized relapse rate (ARR), radiological activity, disability progression, and the NEDA-3 index. Patients were followed for 96 weeks. The median washout period in ocrelizumab-switchers was 6 weeks. Among them, AAR and radiological activity during follow-up were 0.03, without significant differences in comparison with the previous period on natalizumab-EID. The comparison between ocrelizumab-switchers and patients continuing on EID-natalizumab showed no significant differences in AAR, radiological activity, or disability progression. However, the proportion of patients maintaining a NEDA-3 status in week 96 was slightly superior among ocrelizumab-switchers (94 vs 69%). No serious adverse events were observed in any group. In conclusion, switching from EID-natalizumab to ocrelizumab can be considered as a therapeutic option, particularly in patients with MS at high risk of PML, to mitigate the risks of both PML and disease reactivation.

A novel clinical sign to assess the risk of Parkinson's disease in patients with isolated asymmetric arm swing.

INTRODUCTION: An isolated asymmetric arm swing can represent the beginning of Parkinson's disease (PD) but also be related to physiological or non-specific musculoskeletal pathology. PATIENTS AND METHODS: In this brief clinical observation including 15 patients with asymmetric arm swing, we provide a new clinical clue to evaluate the risk of subjacent parkinsonism. RESULTS: Among non-parkinsonian subjects, the immobilization of the contralateral arm, by asking the patient to put his hand on the contralateral shoulder, induced a clear increase in the amplitude of the arm swing, whereas in PD patients, the arm swing amplitude did not significantly vary when the contralateral upper limb was immobilized. CONCLUSIONS: This novel clinical sign may be helpful when approaching patients with gait abnormalities and specifically reduced arm swing.

Characterizing SOD1 mutations in Spain. The impact of genotype, age, and sex in the natural history of the disease.

INTRODUCTION: The aim of this study is to describe the frequency and distribution of SOD1 mutations in Spain, and to explore those factors contributing to their phenotype and prognosis. METHODS: Seventeen centres shared data on amyotrophic lateral sclerosis (ALS) patients carrying pathogenic or likely pathogenic SOD1 variants. Multivariable models were used to explore prognostic modifiers. RESULTS: In 144 patients (from 88 families), 29 mutations (26 missense, 2 deletion/insertion and 1 frameshift) were found in all 5 exons of SOD1, including 7 novel mutations. 2.6% of ALS patients (including 17.7% familial and 1.3% sporadic) were estimated to carry SOD1 mutations. Its frequency varied considerably between regions, due to founder events. The most frequent mutation was p.Gly38Arg (n = 58), followed by p.Glu22Gly (n = 11), p.Asn140His (n = 10), and the novel p.Leu120Val (n = 10). Most mutations were characterized by a protracted course, and some of them by atypical phenotypes. Older age of onset was independently associated with faster disease progression (exp(Estimate) = 1.03 [0.01, 0.05], p = 0.001) and poorer survival (HR = 1.05 [1.01, 1.08], p = 0.007), regardless of the underlying mutation. Female sex was independently associated to faster disease progression (exp(Estimate) = 2.1 [1.23, 3.65], p = 0.012) in patients carrying the p.Gly38Arg mutation, resulting in shorter survival compared with male carriers (236 vs 301 months). CONCLUSIONS: These data may help to evaluate the efficacy of SOD1 targeted treatments, and to expand the number of patients that might benefit from these treatments.

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 ß-amyloid (Aß) 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 Aß aggregates in the brain produces the neurodegenerative cascade characteristic of AD, many strategies which promote the clearance of Aß 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 Aß 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 Aß 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 Aß1-40, but not of Aß1-42, 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.

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.

The role of magnetic fields in neurodegenerative diseases.

The term neurodegenerative diseases include a long list of diseases affecting the nervous system that are characterized by the degeneration of different neurological structures. Among them, Alzheimer disease (AD), Parkinson disease (PD), and amyotrophic lateral sclerosis (ALS) are the most representative ones. The vast majority of cases are sporadic and results from the interaction of genes and environmental factors in genetically predisposed individuals. Among environmental conditions, electromagnetic field exposure has begun to be assessed as a potential risk factor for neurodegeneration. In this review, we discuss the existing literature regarding electromagnetic fields and neurodegenerative diseases. Epidemiological studies in AD, PD, and ALS have shown discordant results; thus, a clear correlation between electromagnetic exposure and neurodegeneration has not been demonstrated. In addition, we discuss the role of electromagnetic radiation as a potential non-invasive therapeutic strategy for some neurodegenerative diseases, particularly for PD and AD.

Retinal changes in amyotrophic lateral sclerosis: looking at the disease through a new window.

Amyotrophic lateral sclerosis (ALS) is the most frequent degenerative disease affecting motor neurons (MN). ALS has been traditionally considered as a pure motor system disease; however, there are currently sufficient evidences supporting the involvement of other non-motor systems. Recently, the development and the implementation of the optical coherence tomography (OCT) have provided new data regarding the ocular involvement in the disease. In this sense, alterations in retinal nerve fiber layer thickness (RNFL), other retinal layers thicknesses such as outer nuclear layer (ONL) and inner nuclear layer (INL) and changes in the retinal blood vessels have been described in ALS patients. Interestingly, the study of ocular alterations in ALS appears not only as new biomarker tool, but also as a new opportunity to deep into the pathogenesis of the disease. In this article we will review and standardize published studies regarding OCT and ALS, emphasizing both their strengths and weaknesses.

Amyotrophic lateral sclerosis (ALS), cancer, autoimmunity and metabolic disorders: An unsolved tantalizing challenge.

Amyotrophic lateral sclerosis (ALS) commonly referred to as motor neurone disease, is a neurodegenerative disease of unknown pathogenesis that progresses rapidly and has attracted an increased amount of scholarly interest in recent years. The current conception of amyotrophic lateral sclerosis has transitioned into a more complex theory in which individual genetic risk, ageing and environmental factors interact, leading to disease onset in subjects in whom the sum of these factors reach a determined threshold. Based on this conceptualization, the environmental conditions, particularly those that are potentially modifiable, are becoming increasingly relevant. In this review, the current integrative model of the disease is discussed. In addition, we explore the role of cancer, autoimmunity and metabolic diseases as examples of novel, non-genetic and environmental factors. Together with the potential triggers or perpetuating pathogenic mechanisms along with new insights into potential lines of future research are provided. LINKED ARTICLES: This article is part of a themed issue on Neurochemistry in Japan. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v178.6/issuetoc.

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. LINKED ARTICLES: This article is part of a themed issue on Neurochemistry in Japan. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v178.6/issuetoc.

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. Material and Methods: The presence of sensory disturbances was evaluated using von 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, immunofluorescence, 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 responsible of sensory disturbances in ALS, but due to spinal cord sensory-motor circuits could also contribute to anterior horn motor disturbances.

A novel SGCE variant is associated with myoclonus-dystonia with phenotypic variability.

Myoclonus-dystonia associated with epsilon-sarcoglycan gene (SGCE) is a rare disorder characterized by myoclonus involving the upper body (neck, trunk, upper limbs) and proximal muscles associated with dystonia in more than half of the patients. When the clinical picture is clearly identified, more than half of the cases are associated with mutations in the SGCE gene. We herein describe a family with myoclonus-dystonia associated with a novel mutation in exon 7 of SGCE, c.904A>T (p.Lys302Ter) [Chr7:(GRCh38):g.94600779 T>A], which was absent in a non-affected member. A video recording of two of the affected members is provided. While the index case presents a severe cervical dystonia even affecting back posture, his sibling shows a much milder phenotype with mild myoclonic jerks. None of them had alcohol responsiveness or psychiatric comorbidity.