The cognitive and behavioural profile of Amyotrophic Lateral Sclerosis: Application of the consensus criteria

Abstract. OBJECTIVE: The study aims to assess the spectrum of cognitive and behavioural disorders in patients affected by Amyotrophic Lateral Sclerosis (ALS) according to the recent consensus criteri

Common and rare variant association analyses in amyotrophic lateral sclerosis identify 15 risk loci with distinct genetic architectures and neuron-specific biology

A cross-ancestry genome-wide association meta-analysis of amyotrophic lateral sclerosis (ALS) including 29,612 patients with ALS and 122,656 controls identifies 15 risk loci with distinct genetic architectures and neuron-specific biology. Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease with a lifetime risk of one in 350 people and an unmet need for disease-modifying therapies. We conducted a cross-ancestry genome-wide association study (GWAS) including 29,612 patients with ALS and 122,656 controls, which identified 15 risk loci. When combined with 8,953 individuals with whole-genome sequencing (6,538 patients, 2,415 controls) and a large cortex-derived expression quantitative trait locus (eQTL) dataset (MetaBrain), analyses revealed locus-specific genetic architectures in which we prioritized genes either through rare variants, short tandem repeats or regulatory effects. ALS-associated risk loci were shared with multiple traits within the neurodegenerative spectrum but with distinct enrichment patterns across brain regions and cell types. Of the environmental and lifestyle risk factors obtained from the literature, Mendelian randomization analyses indicated a causal role for high cholesterol levels. The combination of all ALS-associated signals reveals a role for perturbations in vesicle-mediated transport and autophagy and provides evidence for cell-autonomous disease initiation in glutamatergic neurons

New genetic loci link adipose and insulin biology to body fat distribution.

Body fat distribution is a heritable trait and a well-established predictor of adverse metabolic outcomes, independent of overall adiposity. To increase our understanding of the genetic basis of body fat distribution and its molecular links to cardiometabolic traits, here we conduct genome-wide association meta-analyses of traits related to waist and hip circumferences in up to 224,459 individuals. We identify 49 loci (33 new) associated with waist-to-hip ratio adjusted for body mass index (BMI), and an additional 19 loci newly associated with related waist and hip circumference measures (P < 5 × 10(-8)). In total, 20 of the 49 waist-to-hip ratio adjusted for BMI loci show significant sexual dimorphism, 19 of which display a stronger effect in women. The identified loci were enriched for genes expressed in adipose tissue and for putative regulatory elements in adipocytes. Pathway analyses implicated adipogenesis, angiogenesis, transcriptional regulation and insulin resistance as processes affecting fat distribution, providing insight into potential pathophysiological mechanisms

Transesophageal contrast echocardiography is not always the gold standard method in the identification of a patent foramen ovale: A clinical case

In the embryo, Eustachian valve is a crescent-shaped membrane extending from the lower margin of the inferior vena cava and the ostium of the coronary sinus into the right atrium toward fossa ovalis and tricuspid valve. At birth, after the functional closure of the foramen ovale, the Eustachian valve loses its function, reducing to an embryo remnant. According to growing evidence, a persistent Eustachian valve is a frequent finding in patients with a patent foramen ovale (PFO). By directing the blood from the inferior cava to the interatrial septum, it may prevent the spontaneous closure of PFO after birth and indirectly predispose to paradoxical embolism. Transesophageal contrast enhanced echocardiography (cTEE) is considered the gold standard to diagnose a PFO in postnatal life, but its accuracy maybe is not so high in the presence of a persistent Eustachian valve. In these cases, color Doppler TEE is more sensitive and simplifies the diagnostic process, reducing the duration of TEE and improving the patient compliance

miR-129-5p: A key factor and therapeutic target in amyotrophic lateral sclerosis

Amyotrophic lateral sclerosis (ALS) is a relentless and fatal neurological disease characterized by the selective degeneration of motor neurons. No effective therapy is available for this disease. Several lines of evidence indicate that alteration of RNA metabolism, including microRNA (miRNA) processing, is a relevant pathogenetic factor and a possible therapeutic target for ALS. Here, we showed that the abundance of components in the miRNA processing machinery is altered in a SOD1-linked cellular model, suggesting consequent dysregulation of miRNA biogenesis. Indeed, high-throughput sequencing of the small RNA fraction showed that among the altered miRNAs, miR-129-5p was increased in different models of SOD1-linked ALS and in peripheral blood cells of sporadic ALS patients. We demonstrated that miR-129-5p upregulation causes the downregulation of one of its targets: the RNA-binding protein ELAVL4/HuD. ELAVL4/HuD is predominantly expressed in neurons, where it controls several key neuronal mRNAs. Overexpression of pre-miR-129-1 inhibited neurite outgrowth and differentiation via HuD silencing in vitro, while its inhibition with an antagomir rescued the phenotype. Remarkably, we showed that administration of an antisense oligonucleotide (ASO) inhibitor of miR-129-5p to an ALS animal model, SOD1 (G93A) mice, result in a significant increase in survival and improved the neuromuscular phenotype in treated mice. These results identify miR-129-5p as a therapeutic target that is amenable to ASO modulation for the treatment of ALS patients

Trauma and amyotrophic lateral sclerosis: a european population-based case-control study from the EURALS consortium

International audienceOBJECTIVES:To assess the association between amyotrophic lateral sclerosis (ALS) and previous traumatic events, age of trauma, and site of injury.METHODS:A population-based case-control study was performed in five European countries (Italy, Ireland, France, United Kingdom, Serbia). Newly diagnosed ALS patients and matched controls were interviewed to collect relevant demographic factors and exposures. Key clinical features at diagnosis were collected in ALS patients. Trauma was any accidental event causing an injury. Injuries were dated and classified according to cause, severity, type, site, and complications. All exposures were censored five years before symptoms onset. Risks were computed as odds ratios (OR) with 95% confidence intervals (CI) using univariate and multivariate conditional logistic regression models.RESULTS:Five hundred and seventy-five ALS patients and 1150 controls were interviewed. Disabling traumatic events predominated in the cases (OR 1.54 (95% CI 1.24-1.92)) and maintained significance after adjustment, with a significant gradient. A history of 2 + head injuries was associated with an almost three-fold increased risk of ALS. The risk was almost two-fold when trauma occurred at age 35-54 years. Site of injury was uneventful.CONCLUSIONS:Traumatic events leading to functional disability or confined to the head are risk factors for ALS. Traumatic events experienced at age 35-54 years carry the highest risk