The latest articles on amyotrophic lateral sclerosis

Our staff editors continue to share exciting, interesting, and thought-provoking reading material in the recommended articles series.

This week, we would like to share several latest articles are related to amyotrophic lateral sclerosis.

Title: Emerging insights into the complex genetics and pathophysiology of amyotrophic lateral sclerosis
Authors: Stephen A Goutman MD, Prof Orla Hardiman MD, Prof Ammar Al-Chalabi FRCP, Prof Adriano Chió MD, Masha G Savelieff PhD, Prof Matthew C Kiernan PhD, Prof Eva L Feldman MD
Type: Review Article
Summary:
Amyotrophic lateral sclerosis is a fatal neurodegenerative disease. The discovery of genes associated with amyotrophic lateral sclerosis, commencing with SOD1 in 1993, started fairly gradually. Recent advances in genetic technology have led to the rapid identification of multiple new genes associated with the disease, and to a new understanding of oligogenic and polygenic disease risk. The overlap of genes associated with amyotrophic lateral sclerosis with those of other neurodegenerative diseases is shedding light on the phenotypic spectrum of neurodegeneration, leading to a better understanding of genotype–phenotype correlations. A deepening knowledge of the genetic architecture is allowing the characterisation of the molecular steps caused by various mutations that converge on recurrent dysregulated pathways. Of crucial relevance, mutations associated with amyotrophic lateral sclerosis are amenable to novel gene-based therapeutic options, an approach in use for other neurological illnesses. Lastly, the exposome—the summation of lifetime environmental exposures—has emerged as an influential component for amyotrophic lateral sclerosis through the gene–time–environment hypothesis. Our improved understanding of all these aspects will lead to long-awaited therapies and the identification of modifiable risks factors.
Access this article: https://doi.org/10.1016/S1474-4422(21)00414-2

Title: The combination of autologous mesenchymal stem cell-derived exosomes and neurotrophic factors as an intervention for amyotrophic lateral sclerosis
Authors: Yingying Ding, Benson O.A. Botchway, Yong Zhang, Tian Jin, Xuehong Liu
Type: Mini Review
Abstract:
Amyotrophic lateral sclerosis is a chronic progressive degeneration of motor neurons and has a high mortality. Riluzole and edaravone are the only approved medications currently being used for amyotrophic lateral sclerosis in clinical settings. However, they can lead to serious complications, such as injuries to the liver and kidney. To date, there is no effective treatment for amyotrophic lateral sclerosis. In this regard, investigations concerning the employment of exosomes, mesenchymal stem cells, and neurotrophic factors to ameliorate amyotrophic lateral sclerosis are attracting considerable attention in the scientific community. Herein, we systematically analyze the relationship relevant to autologous mesenchymal stem cell derived-exosomes, neurotrophic factors and amyotrophic lateral sclerosis. Mesenchymal stem cells modulate immune response, mitigate oxidative stress, promote neuronal regeneration, and differentiate into neuronal and glial cells. Furthermore, exosomes from mesenchymal stem cells exert beneficial effects on their mother cells by preventing abnormal differentiation of mesenchymal stem cells. Similarly, neurotrophic factors regulate inflammatory response, stimulate the neuron repair, and the recovery of neuronal functioning. Therefore, autologous mesenchymal stem cells-derived exosomes combined with neurotrophic factors could potentially be an effective interventional medium for amyotrophic lateral sclerosis.
Access this article: https://doi.org/10.1016/j.aanat.2022.151921

Title: Bidirectional Mendelian randomization to explore the causal relationships between Sleep traits, Parkinson's disease and Amyotrophic lateral sclerosis
Authors: Hongkun Di MS, Yi Zhu MS, Wenqi Xia MS, Xin Meng MS, Mingye Zhang MS, Minzhi Xu MPH, Qingfeng Tian PhD, Yan He PhD, Shiyi Cao PhD, Zuxun Lu PhD
Type: Original Article
Highlights:
●Genetically higher risk of excessive daytime sleepiness may contribute to an increase in risk of amyotrophic lateralizing sclerosis.
●Parkinson's disease was found to have a possible causal effect on the risk of amyotrophic lateralizing sclerosis.
●Higher risk of amyotrophic lateralizing sclerosis may be associated with being a “morning person”, a longer sleep duration, and a mean of 9 h or more total sleep duration.
Abstract:
Objective
Sleep disturbances have been linked with Parkinson's disease(PD) and amyotrophic lateral sclerosis(ALS) in observational studies, and the comorbidity of PD and ALS has been reported in clinical case reports, but the causalities remain unclear. This study aims to examine bidirectional causal relationships between sleep traits, PD and ALS.

Methods
Bidirectional two sample Mendelian randomisation (MR) analyses were conducted, with data from individuals of mainly European ancestry. Genetic instruments were obtained from the largest published genome-wide association studies (GWAS) concerning various sleep traits, PD and ALS. MR estimates from each genetic instrument were combined by inverse variance weighted method, with alternate methods (eg, weighted median, MR Egger, MR-PRESSO) and statistical graphs to assess horizontal pleiotropy and remove outliers.

Results
MR analysis failed to observe any causal association between sleep disorders and PD, but found a possible causal effect of PD risk on ALS risk (odds ratio [OR] = 1.07; 95% CI: 1.01-1.14, P <0.01), albeit with a horizontal pleiotropy. Furthermore, MR analyses indicated that excessive daytime sleepiness(EDS) (OR = 2.29; 95% CI: 1.04-5.03, P = 0.04) contributed to a modest increase in risk of ALS, but the reverse causalities were not significant. Higher risk of ALS may be associated with being a “morning person”(OR = 1.03, P = 0.02), a longer sleep duration(OR =1.01, P <0.01), and a mean of 9 h or more total sleep duration(β= 0.02, P = 0.04).

Conclusions
Aided by large-scale GWAS, a shortage of evidence supporting causal relationships of sleep traits and PD risk, while significant evidence supports that EDS, higher PD risk may causally influence ALS risk. Future researches are required to explore the underlying pathological mechanism as well as the clinically significance, and replicate our findings using independent samples when data become available.
Access this article: https://doi.org/10.1016/j.sleep.2022.03.024

Title: Lack of association of TP73 with amyotrophic lateral sclerosis in a large cohort of cases
Authors: Allison A. Dilliott, Guy A. Rouleau, Sali M.K. Farhan
Type: Short Communication
Abstract:
A recent study suggested an association between rare, non-synonymous variants in the gene encoding tumor protein p73 (TP73) and amyotrophic lateral sclerosis (ALS) — a progressive, fatal neurodegenerative disease. The original association was based on a case-control analysis with relatively small sample size. While functional data were presented to substantiate these claims, it remains unclear whether the results demonstrate clinical significance; additionally, the modelled null alleles had been recently reported to cause a severe pediatric disorder characterized by impaired mucociliary clearance and lissencephaly. Here, we aimed to replicate the proposed genetic association between TP73 and ALS using the two largest publicly available ALS sequencing datasets as hosted by the ALS Knowledge Portal (n=3,864 cases and n=7,839 controls) and the Project MinE ALS browser (n=4,366 cases and n=1,832 controls) for a total of 8,230 ALS cases and 9,671 controls. We did not observe an enrichment of rare, protein-coding variants in the ALS cases and surprisingly identified a relatively large number of controls carrying rare, non-synonymous variants in TP73 (n = 65). Based on these results we conclude that TP73 most likely does not predispose to ALS.
Access this article: https://doi.org/10.1016/j.neurobiolaging.2022.04.004

Title: Recent advances in the diagnosis and prognosis of amyotrophic lateral sclerosis
Authors: Stephen A Goutman MD, Prof Orla Hardiman MD, Prof Ammar Al-Chalabi FRCP, Prof Adriano Chió MD, Masha G Savelieff PhD, Prof Matthew C Kiernan PhD, Prof Eva L Feldman MD
Type: Review Article
Summary:
The diagnosis of amyotrophic lateral sclerosis can be challenging due to its heterogeneity in clinical presentation and overlap with other neurological disorders. Diagnosis early in the disease course can improve outcomes as timely interventions can slow disease progression. An evolving awareness of disease genotypes and phenotypes and new diagnostic criteria, such as the recent Gold Coast criteria, could expedite diagnosis. Improved prognosis, such as that achieved with the survival model from the European Network for the Cure of ALS, could inform the patient and their family about disease course and improve end-of-life planning. Novel staging and scoring systems can help monitor disease progression and might potentially serve as clinical trial outcomes. Lastly, new tools, such as fluid biomarkers, imaging modalities, and neuromuscular electrophysiological measurements, might increase diagnostic and prognostic accuracy.
Access this article: https://doi.org/10.1016/S1474-4422(21)00465-8