Diagnosing primary lateral sclerosis: a clinico-pathological study.

Background:  Primary lateral sclerosis (PLS) is a rare motor neuron disease characterized by upper motor neuron degeneration, diagnosed clinically due to the absence of a (neuropathological) gold standard. Post-mortem studies, particularly TDP-43 pathology analysis, are limited.

Methods: This study reports on 5 cases in which the diagnostic criteria for PLS were met, but in which neuropathology findings showed (partially) conflicting results.

Sex-specific DNA methylation differences in Amyotrophic lateral sclerosis.

Sex is an important covariate in all genetic and epigenetic research due to its role in the incidence, progression and outcome of many phenotypic characteristics and human diseases. Amyotrophic lateral sclerosis (ALS) is a motor neuron disease with a sex bias towards higher incidence in males. Here, we report for the first time a blood-based epigenome-wide association study meta-analysis in 9274 individuals after stringent quality control (5529 males and 3975 females).

Gut metabolomic and microbiota analyses in ALS mice reveal specific metabolites despite the absence of significant gut dysbiosis.

Objective: Over the past years, interest in the role of gut microbiota in neurodegenerative diseases has emerged. Despite numerous publications over the past decade, both in human and pre-clinical studies, there is no clear consensus on the microbiota's role or involvement in ALS. Few studies on mouse models of ALS highlighted a correlation between specific bacteria species and the prognostic or severity of the disease.

Dynamic Expression of Genes Encoding Ubiquitin Conjugating Enzymes (E2s) During Neuronal Differentiation and Maturation: Implications for Neurodevelopmental Disorders and Neurodegenerative Diseases.

The ubiquitination process plays a crucial role in neuronal differentiation and function. Numerous studies have focused on the expression and functions of E3 ligases during these different stages, far fewer on E2 conjugating enzymes. In mice, as in humans, these E2s belong to 17 conjugating enzyme families.

Safety, tolerability, and efficacy of fasudil in amyotrophic lateral sclerosis (ROCK-ALS): a phase 2, randomised, double-blind, placebo-controlled trial.

Background: Fasudil is a small molecule inhibitor of Rho-associated kinase (ROCK) and is approved for the treatment of subarachnoid haemorrhage. In preclinical studies, fasudil has been shown to attenuate neurodegeneration, modulate neuroinflammation, and foster axonal regeneration. We aimed to investigate the safety, tolerability, and efficacy of fasudil in patients with amyotrophic lateral sclerosis.

Metabolomics of basal tears in amyotrophic lateral sclerosis: A cross-sectional study.

Purpose: Amyotrophic lateral sclerosis (ALS) clinical variability, along with the lack of conclusive diagnostic instruments, result in average diagnosis delays of 9 months. This study aimed to assess whether metabolomic profiling of basal tears in ALS patients could act as a biological marker for diagnosing ALS, predicting prognosis, and discriminating between endophenotypes.

Methods: A single-center prospective case-control study was conducted in France from September 2021 to March 2023 including patients with ALS according to the revised EI Escorial criteria.

N-Terminal Fragments of TDP-43-In Vitro Analysis and Implication in the Pathophysiology of Amyotrophic Lateral Sclerosis and Frontotemporal Lobar Degeneration.

Abnormal cytoplasmic aggregates containing the TDP-43 protein and its fragments are present in the central nervous system of the majority of patients with amyotrophic lateral sclerosis (ALS) and in patients with frontotemporal lobar degeneration (FTLD). Many studies have focused on the C-terminal cleavage products of TDP-43 (CTFs), but few have focused on the N-terminal products (NTFs), yet several works and their protein domain composition support the involvement of NTFs in pathophysiology. In the present study, we expressed six NTFs of TDP-43, normally generated in vivo by proteases or following the presence of pathogenic genetic truncating variants, in HEK-293T cells.

Exploring amyotrophic lateral sclerosis through the visual system: A systematic review.

Background And Purpose: The human visual system relies on neural networks throughout the brain that are easily accessible for tests exploring eye structures and movements. Over the past two decades, investigations have been carried out on both afferent and efferent components of the visual system in people with amyotrophic lateral sclerosis (ALS). This approach might represent an innovative biomarker research strategy to better characterise the phenotypic variability of ALS.

EVolution in ALS diagnosis: molecular markers in extracellular vesicles.

The identification of biomarkers for amyotrophic lateral sclerosis (ALS) is a central issue in disease research. In a recent article, Chatterjee et al. show that blood extracellular vesicles (EVs) with high levels of transactive response DNA-binding protein 43 (TDP-43) accurately discriminate patients with ALS from controls and correlate with disease severity, providing a promising biomarker for early diagnosis and monitoring.

Caffeine consumption outcomes on amyotrophic lateral sclerosis disease progression and cognition.

Caffeine consumption outcomes on Amyotrophic Lateral Sclerosis (ALS) including progression, survival and cognition remain poorly defined and may depend on its metabolization influenced by genetic variants. 378 ALS patients with a precise evaluation of their regular caffeine consumption were monitored as part of a prospective multicenter study. Demographic, clinical characteristics, functional disability as measured with revised ALS Functional Rating Scale (ALSFRS-R), cognitive deficits measured using Edinburgh Cognitive and Behavioural ALS Screen (ECAS), survival and riluzole treatment were recorded.

Treatment continuity of amyotrophic lateral sclerosis with available riluzole formulations: state of the art and current challenges in a 'real-world' setting.

Amyotrophic lateral sclerosis (ALS) is a rare multisystem neurodegenerative disease leading to death due to respiratory failure. Riluzole was the first disease modifying treatment approved in ALS. Randomized clinical trials showed a significant benefit of riluzole on survival in the months following randomization, with a good safety profile.

Could PLS represent a UMN-predominant ALS syndrome?

Primary lateral sclerosis (PLS) is a motor neuron condition marked by pure upper motor neuron (UMN) degeneration. PLS represents around 3% of all motor neuron diseases. Classically the prognosis of PLS is less severe than those of amyotrophic lateral sclerosis (ALS).

Mutations in the tail and rod domains of the neurofilament heavy-chain gene increase the risk of ALS.

Objective: Neurofilament heavy-chain gene (NEFH) variants are associated with multiple neurodegenerative diseases, however, their relationship with ALS has not been robustly explored. Still, NEFH is commonly included in genetic screening panels worldwide. We therefore aimed to determine if NEFH variants modify ALS risk.

Pharmacometabolomics applied to low-dose interleukin-2 treatment in amyotrophic lateral sclerosis.

Amyotrophic lateral sclerosis (ALS) is a devastating motor neuron disease. The immunosuppressive functions of regulatory T lymphocytes (Tregs) are impaired in ALS, and correlate to disease progression. The phase 2a IMODALS trial reported an increase in Treg number in ALS patients following the administration of low-dose (ld) interleukin-2 (IL-2).

The effect of social support on the emotional well-being of people with amyotrophic lateral sclerosis: Exploring the mediating role of spirituality.

Objectives: Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease that, so far, is considered always fatal. Treatments mainly consist in increasing survival and aim to improve the quality of life of people with ALS (pwALS). Social support and spirituality have been shown to play a key role in pwALS' quality of life.

Categorization of the amyotrophic lateral sclerosis population via the clinical determinant of post-onset ΔFS for study design and medical practice.

The amyotrophic lateral sclerosis (ALS) functional rating scale-revised (ALSFRS-R) has become the most widely utilized measure of disease severity in patients with ALS, with change in ALSFRS-R from baseline being a trusted primary outcome measure in ALS clinical trials. This is despite the scale having several established limitations, and although alternative scales have been proposed, it is unlikely that these will displace ALSFRS-R in the foreseeable future. Here, we discuss the merits of delta FS (ΔFS), the slope or rate of ALSFRS-R decline over time, as a relevant tool for innovative ALS study design, with an as yet untapped potential for optimization of drug effectiveness and patient management.

C9ORF72 hexanucleotide repeat expansion: From ALS and FTD to a broader pathogenic role?

The major gene underlying monogenic forms of amyotrophic lateral sclerosis (ALS) and fronto-temporal dementia (FTD) is C9ORF72. The causative mutation in C9ORF72 is an abnormal hexanucleotide (G4C2) repeat expansion (HRE) located in the first intron of the gene. The aim of this review is to propose a comprehensive update on recent developments on clinical, biological and therapeutics aspects related to C9ORF72 in order to highlight the current understanding of genotype-phenotype correlations, and also on biological machinery leading to neuronal death.

Corneal nerves and amyotrophic lateral sclerosis: an in vivo corneal confocal imaging study.

Objectives: Amyotrophic lateral sclerosis (ALS) is a severe motor neuron disorder. Diagnosis is challenging due to its clinical heterogeneity and the absence of definitive diagnostic tools, leading to delays averaging between 9.1 and 27 months.

The effect of pH alterations on TDP-43 in a cellular model of amyotrophic lateral sclerosis.

Amyotrophic Lateral Sclerosis (ALS) is the most common neurodegenerative disease affecting motor neurons. The pathophysiology of ALS is not well understood but TDP-43 proteinopathy (aggregation and mislocalization) is one of the major phenomena described. Several factors can influence TDP-43 behavior such as mild pH alterations that can induce conformational changes in recombinant TDP-43, increasing its propensity to aggregate.

Neutrophil to Lymphocyte Ratio as a Prognostic Marker in Amyotrophic Lateral Sclerosis.

Amyotrophic lateral sclerosis (ALS) is the most common neurodegenerative motor neuron disease and remains misunderstood with a difficult diagnosis and prognosis. The implication of the immune system is recognized in ALS pathophysiology, hence the interest in leucocyte count as lymphocytes and neutrophils. The neutrophil-to-lymphocyte ratio (NLR) has recently been used as a prognosis factor to assess the progression of ALS.

A randomized double-blind clinical trial on safety and efficacy of tauroursodeoxycholic acid (TUDCA) as add-on treatment in patients affected by amyotrophic lateral sclerosis (ALS): the statistical analysis plan of TUDCA-ALS trial.

Background: Amyotrophic lateral sclerosis (ALS) is a highly debilitating neurodegenerative condition. Despite recent advancements in understanding the molecular mechanisms underlying ALS, there have been no significant improvements in therapeutic options for ALS patients in recent years. Currently, there is no cure for ALS, and the only approved treatment in Europe is riluzole, which has been shown to slow the disease progression and prolong survival by approximately 3 months.