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Brain Sciences
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Amyotrophic Lateral Sclerosis: Recent Considerations for Diagnosis, Pathogenesis and Therapy
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Amyotrophic Lateral Sclerosis: Recent Considerations for Diagnosis, Pathogenesis and Therapy

A special issue of Brain Sciences (ISSN 2076-3425). This special issue belongs to the section "Neuromuscular and Movement Disorders".

Deadline for manuscript submissions: closed (15 September 2024) | Viewed by 11667

Special Issue Editor

Prof. Dr. Andrew Eisen

E-Mail Website
Guest Editor
Division of Neurology, University of British Columbia, Vancouver, BC V6T 1Z4, Canada
Interests: Amyotrophic lateral sclerosis; Motor neuron disease; Primary lateral sclerosis; Neurodegeneration
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Amyotrophic lateral sclerosis (ALS/MND) is a unique type of human neurodegeneration disease characterised by various phenotypes, including frontotemporal dementia. These are predicated by genetic, environmental, lifestyle and epigenetic influences. However, no naturally occurring or induced animal models truly recapitulate this human disease. ALS has a preclinical period of variable length, likely extending to years or decades, and at clinical onset, the cellular cascades associated with neuronal death are irreversible. Therefore, there is a need for biomarkers to identify preclinical disease. C9ORF72, SOD1, FUS and TARDBP are causative genes accounting for <10% of ALS, and the identification of “risk genes” (>70) contributing to sporadic ALS in association with environmental and lifestyle factors is necessary. Epigenetic modification fine-tunes gene expression in response to the environment, and epigenetic profile alterations may occur in the offspring of exposed individuals with intergenerational inheritance. Extra-nuclear aggregation of TDP-43 is a hallmark of ALS, and evidence indicates that it spreads cortico-fugally, intricately related to the corticomotoneuronal system, suggesting that ALS is a primary brain disease. ALS is increasingly studied using patient-derived iPSCs to investigate early stages of the disease, model risk factors, apply gene editing using CRISPR and explore new therapies.

Prof. Dr. Andrew Eisen
Guest Editor

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Keywords

  • amyotrophic lateral sclerosis
  • genes
  • environment
  • epigenome
  • TDP-43
  • phenotypes

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Published Papers (9 papers)

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Research

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16 pages, 5798 KiB  
Article
Voice Assessment in Patients with Amyotrophic Lateral Sclerosis: An Exploratory Study on Associations with Bulbar and Respiratory Function
by Pedro Santos Rocha, Nuno Bento, Hanna Svärd, Diana Monteiro Lopes, Sandra Hespanhol, Duarte Folgado, André Valério Carreiro, Mamede de Carvalho and Bruno Miranda
Brain Sci. 2024, 14(11), 1082; https://doi.org/10.3390/brainsci14111082 - 29 Oct 2024
Viewed by 458
Abstract
Background: Speech production is a possible way to monitor bulbar and respiratory functions in patients with amyotrophic lateral sclerosis (ALS). Moreover, the emergence of smartphone-based data collection offers a promising approach to reduce frequent hospital visits and enhance patient outcomes. Here, we studied [...] Read more.
Background: Speech production is a possible way to monitor bulbar and respiratory functions in patients with amyotrophic lateral sclerosis (ALS). Moreover, the emergence of smartphone-based data collection offers a promising approach to reduce frequent hospital visits and enhance patient outcomes. Here, we studied the relationship between bulbar and respiratory functions with voice characteristics of ALS patients, alongside a speech therapist’s evaluation, at the convenience of using a simple smartphone. Methods: For voice assessment, we considered a speech therapist’s standardized tool—consensus auditory-perceptual evaluation of voice (CAPE-V); and an acoustic analysis toolbox. The bulbar sub-score of the revised ALS functional rating scale (ALSFRS-R) was used, and pulmonary function measurements included forced vital capacity (FVC%), maximum expiratory pressure (MEP%), and maximum inspiratory pressure (MIP%). Correlation coefficients and both linear and logistic regression models were applied. Results: A total of 27 ALS patients (12 males; 61 years mean age; 28 months median disease duration) were included. Patients with significant bulbar dysfunction revealed greater CAPE-V scores in overall severity, roughness, strain, pitch, and loudness. They also presented slower speaking rates, longer pauses, and higher jitter values in acoustic analysis (all p < 0.05). The CAPE-V’s overall severity and sub-scores for pitch and loudness demonstrated significant correlations with MIP% and MEP% (all p < 0.05). In contrast, acoustic metrics (speaking rate, absolute energy, shimmer, and harmonic-to-noise ratio) significantly correlated with FVC% (all p < 0.05). Conclusions: The results provide supporting evidence for the use of smartphone-based recordings in ALS patients for CAPE-V and acoustic analysis as reliable correlates of bulbar and respiratory function. Full article
(This article belongs to the Special Issue Amyotrophic Lateral Sclerosis: Recent Considerations for Diagnosis, Pathogenesis and Therapy)
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9 pages, 1781 KiB  
Article
Assessing the Effect of Riluzole on Motor Unit Discharge Properties
by Ehsan Shandiz, Gabriel Lima Fernandes, Joao Saldanha Henkin, Pamela Ann McCombe, Gabriel Siqueira Trajano and Robert David Henderson
Brain Sci. 2024, 14(11), 1053; https://doi.org/10.3390/brainsci14111053 - 24 Oct 2024
Viewed by 639
Abstract
Background. This study aims to determine if Riluzole usage can change the function and excitability of motor neurons. Methods. The clinical data and indices of motor neuron excitability were assessed using high-density surface EMG parameters from 80 ALS participants. The persistent inward current [...] Read more.
Background. This study aims to determine if Riluzole usage can change the function and excitability of motor neurons. Methods. The clinical data and indices of motor neuron excitability were assessed using high-density surface EMG parameters from 80 ALS participants. The persistent inward current was assessed using the discharge rate from paired motor units obtained from the tibialis anterior muscle. This enabled the discharge rate at recruitment, peak discharge rates and the hysteresis of the recruitment–derecruitment frequencies (also known as delta F) to be calculated. Limbs were classified according to their strength. Results. No differences in these motor neuron discharge properties were found according to whether Riluzole was used. Conclusions. The possible interpretations of this finding are discussed. Full article
(This article belongs to the Special Issue Amyotrophic Lateral Sclerosis: Recent Considerations for Diagnosis, Pathogenesis and Therapy)
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20 pages, 4256 KiB  
Article
Clinical, Cortical, Subcortical, and White Matter Features of Right Temporal Variant FTD
by Jana Kleinerova, Mary Clare McKenna, Martha Finnegan, Asya Tacheva, Angela Garcia-Gallardo, Rayan Mohammed, Ee Ling Tan, Foteini Christidi, Orla Hardiman, Siobhan Hutchinson and Peter Bede
Brain Sci. 2024, 14(8), 806; https://doi.org/10.3390/brainsci14080806 - 11 Aug 2024
Viewed by 1363
Abstract
The distinct clinical and radiological characteristics of right temporal variant FTD have only been recently recognized. Methods: Eight patients with right temporal variant FTD were prospectively recruited and underwent a standardised neuropsychological assessment, clinical MRI, and quantitative neuroimaging. Results: Our voxelwise grey analyses [...] Read more.
The distinct clinical and radiological characteristics of right temporal variant FTD have only been recently recognized. Methods: Eight patients with right temporal variant FTD were prospectively recruited and underwent a standardised neuropsychological assessment, clinical MRI, and quantitative neuroimaging. Results: Our voxelwise grey analyses captured bilateral anterior and mesial temporal grey matter atrophy with a clear right-sided predominance. Bilateral hippocampal involvement was also observed, as well as disease burden in the right insular and opercula regions. White matter integrity alterations were also bilateral in anterior temporal and sub-insular regions with a clear right-hemispheric predominance. Extra-temporal white matter alterations have also been observed in orbitofrontal and parietal regions. Significant bilateral but right-predominant thalamus, putamen, hippocampus, and amygdala atrophy was identified based on subcortical segmentation. The clinical profile of our patients was dominated by progressive indifference, decline in motivation, loss of interest in previously cherished activities, incremental social withdrawal, difficulty recognising people, progressive language deficits, increasingly rigid routines, and repetitive behaviours. Conclusions: Right temporal variant FTD has an insidious onset and may be mistaken for depression at symptom onset. It manifests in a combination of apathy, language, and behavioural features. Quantitative MR imaging captures a characteristic bilateral but right-predominant temporal imaging signature with extra-temporal frontal and parietal involvement. Full article
(This article belongs to the Special Issue Amyotrophic Lateral Sclerosis: Recent Considerations for Diagnosis, Pathogenesis and Therapy)
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17 pages, 1454 KiB  
Article
Creatine Kinase and Respiratory Decline in Amyotrophic Lateral Sclerosis
by João Pedro Correia, Marta Gromicho, Ana Catarina Pronto-Laborinho, Miguel Oliveira Santos and Mamede de Carvalho
Brain Sci. 2024, 14(7), 661; https://doi.org/10.3390/brainsci14070661 - 28 Jun 2024
Viewed by 841
Abstract
Respiratory dysfunction is an important hallmark of amyotrophic lateral sclerosis (ALS). Elevation of creatine kinase (CK) has been reported in 23–75% of ALS patients, but the underlying mechanisms remain unknown. This work aims to enlighten the role of CK as a prognostic factor [...] Read more.
Respiratory dysfunction is an important hallmark of amyotrophic lateral sclerosis (ALS). Elevation of creatine kinase (CK) has been reported in 23–75% of ALS patients, but the underlying mechanisms remain unknown. This work aims to enlighten the role of CK as a prognostic factor of respiratory dysfunction in ALS. A retrospective analysis of demographic and clinical variables, CK, functional decline per month (ΔFS), forced vital capacity (%FVC), and mean amplitude of the phrenic nerve compound motor action potential (pCMAP) in 319 ALS patients was conducted. These measurements were evaluated at study entry, and patients were followed from the moment of first observation until death or last follow-up visit. High CK values were defined as above the 90th percentile (CK ≥ P90) adjusted to sex. We analyzed survival and time to non-invasive ventilation (NIV) as proxies for respiratory impairment. Linear regression analysis revealed that high CK was associated with male sex (p < 0.001), spinal onset (p = 0.018), and FVC ≥ 80% (p = 0.038). CK was 23.4% higher in spinal-onset ALS patients (p < 0.001). High CK levels were not linked with an increased risk of death (p = 0.334) in Cox multivariate regression analysis. CK ≥ P90 (HR = 1.001, p = 0.038), shorter disease duration (HR = 0.937, p < 0.001), lower pCMAP (HR = 0.082, p < 0.001), and higher ΔFS (HR = 1.968, p < 0.001) were risk factors for respiratory failure. The association between high CK levels and poorer respiratory outcomes could derive from cellular metabolic stress or a specific phenotype associated with faster respiratory decline. Our study suggests that CK measurement at diagnosis should be more extensively investigated as a possible marker of poor respiratory outcome in future studies, including a larger population of patients. Full article
(This article belongs to the Special Issue Amyotrophic Lateral Sclerosis: Recent Considerations for Diagnosis, Pathogenesis and Therapy)
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Review

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28 pages, 1111 KiB  
Review
Prion-like Spreading of Disease in TDP-43 Proteinopathies
by Emma Pongrácová, Emanuele Buratti and Maurizio Romano
Brain Sci. 2024, 14(11), 1132; https://doi.org/10.3390/brainsci14111132 - 9 Nov 2024
Viewed by 750
Abstract
TDP-43 is a ubiquitous nuclear protein that plays a central role in neurodegenerative disorders collectively known as TDP-43 proteinopathies. Under physiological conditions, TDP-43 is primarily localized to the nucleus, but in its pathological form it aggregates in the cytoplasm, contributing to neuronal death. [...] Read more.
TDP-43 is a ubiquitous nuclear protein that plays a central role in neurodegenerative disorders collectively known as TDP-43 proteinopathies. Under physiological conditions, TDP-43 is primarily localized to the nucleus, but in its pathological form it aggregates in the cytoplasm, contributing to neuronal death. Given its association with numerous diseases, particularly ALS and FTLD, the mechanisms underlying TDP-43 aggregation and its impact on neuronal function have been extensively investigated. However, little is still known about the spreading of this pathology from cell to cell. Recent research has unveiled the possibility that TDP-43 may possess prion-like properties. Specifically, misfolded TDP-43 aggregates can act as templates inducing conformational changes in native TDP-43 molecules and propagating the misfolded state across neural networks. This review summarizes the mounting and most recent evidence from in vitro and in vivo studies supporting the prion-like hypothesis and its underlying mechanisms. The prion-like behavior of TDP-43 has significant implications for diagnostics and therapeutics. Importantly, emerging strategies such as small molecule inhibitors, immunotherapies, and gene therapies targeting TDP-43 propagation offer promising avenues for developing effective treatments. By elucidating the mechanisms of TDP-43 spreading, we therefore aim to pave the way for novel therapies for TDP-43-related neurodegenerative diseases. Full article
(This article belongs to the Special Issue Amyotrophic Lateral Sclerosis: Recent Considerations for Diagnosis, Pathogenesis and Therapy)
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12 pages, 252 KiB  
Review
Sleep Apnea and Amyotrophic Lateral Sclerosis: Cause, Correlation, Any Relation?
by P. Hande Ozdinler
Brain Sci. 2024, 14(10), 978; https://doi.org/10.3390/brainsci14100978 - 27 Sep 2024
Viewed by 1514
Abstract
Amyotrophic lateral sclerosis (ALS) is a motor neuron disease with progressive neurodegeneration, affecting both the cortical and the spinal component of the motor neuron circuitry in patients. The cellular and molecular basis of selective neuronal vulnerability is beginning to emerge. Yet, there are [...] Read more.
Amyotrophic lateral sclerosis (ALS) is a motor neuron disease with progressive neurodegeneration, affecting both the cortical and the spinal component of the motor neuron circuitry in patients. The cellular and molecular basis of selective neuronal vulnerability is beginning to emerge. Yet, there are no effective cures for ALS, which affects more than 200,000 people worldwide each year. Recent studies highlight the importance of the glymphatic system and its proper function for the clearance of the cerebral spinal fluid, which is achieved mostly during the sleep period. Therefore, a potential link between problems with sleep and neurodegenerative diseases has been postulated. This paper discusses the present understanding of this potential correlation. Full article
(This article belongs to the Special Issue Amyotrophic Lateral Sclerosis: Recent Considerations for Diagnosis, Pathogenesis and Therapy)
19 pages, 1609 KiB  
Review
Physiological Biomarkers of Upper Motor Neuron Dysfunction in ALS
by Aicee Dawn Calma, Mehdi van den Bos, Nathan Pavey, Cláudia Santos Silva, Parvathi Menon and Steve Vucic
Brain Sci. 2024, 14(8), 760; https://doi.org/10.3390/brainsci14080760 - 29 Jul 2024
Viewed by 1501
Abstract
Upper motor neuron (UMN) dysfunction is an important feature of amyotrophic lateral sclerosis (ALS) for the diagnosis and understanding of pathogenesis. The identification of UMN signs forms the basis of ALS diagnosis, although may be difficult to discern, especially in the setting of [...] Read more.
Upper motor neuron (UMN) dysfunction is an important feature of amyotrophic lateral sclerosis (ALS) for the diagnosis and understanding of pathogenesis. The identification of UMN signs forms the basis of ALS diagnosis, although may be difficult to discern, especially in the setting of severe muscle weakness. Transcranial magnetic stimulation (TMS) techniques have yielded objective physiological biomarkers of UMN dysfunction in ALS, enabling the interrogation of cortical and subcortical neuronal networks with diagnostic, pathophysiological, and prognostic implications. Transcranial magnetic stimulation techniques have provided pertinent pathogenic insights and yielded novel diagnostic and prognostic biomarkers. Cortical hyperexcitability, as heralded by a reduction in short interval intracortical inhibition (SICI) and an increase in short interval intracortical facilitation (SICF), has been associated with lower motor neuron degeneration, patterns of disease evolution, as well as the development of specific ALS clinical features including the split hand phenomenon. Reduction in SICI has also emerged as a potential diagnostic aid in ALS. More recently, physiological distinct inhibitory and facilitatory cortical interneuronal circuits have been identified, which have been shown to contribute to ALS pathogenesis. The triple stimulation technique (TST) was shown to enhance the diagnostic utility of conventional TMS measures in detecting UMN dysfunction. Resting-state EEG is a novel neurophysiological technique developed for directly interrogating cortical neuronal networks in ALS, that have yielded potentially useful physiological biomarkers of UMN dysfunction. The present review discusses physiological biomarkers of UMN dysfunction in ALS, encompassing conventional and novel TMS techniques developed to interrogate the functional integrity of the corticomotoneuronal system, focusing on pathogenic, diagnostic, and prognostic utility. Full article
(This article belongs to the Special Issue Amyotrophic Lateral Sclerosis: Recent Considerations for Diagnosis, Pathogenesis and Therapy)
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17 pages, 1705 KiB  
Review
Nanoplastics and Neurodegeneration in ALS
by Andrew Eisen, Erik P. Pioro, Stephen A. Goutman and Matthew C. Kiernan
Brain Sci. 2024, 14(5), 471; https://doi.org/10.3390/brainsci14050471 - 7 May 2024
Cited by 1 | Viewed by 2914
Abstract
Plastic production, which exceeds one million tons per year, is of global concern. The constituent low-density polymers enable spread over large distances and micro/nano particles (MNPLs) induce organ toxicity via digestion, inhalation, and skin contact. Particles have been documented in all human tissues [...] Read more.
Plastic production, which exceeds one million tons per year, is of global concern. The constituent low-density polymers enable spread over large distances and micro/nano particles (MNPLs) induce organ toxicity via digestion, inhalation, and skin contact. Particles have been documented in all human tissues including breast milk. MNPLs, especially weathered particles, can breach the blood–brain barrier, inducing neurotoxicity. This has been documented in non-human species, and in human-induced pluripotent stem cell lines. Within the brain, MNPLs initiate an inflammatory response with pro-inflammatory cytokine production, oxidative stress with generation of reactive oxygen species, and mitochondrial dysfunction. Glutamate and GABA neurotransmitter dysfunction also ensues with alteration of excitatory/inhibitory balance in favor of reduced inhibition and resultant neuro-excitation. Inflammation and cortical hyperexcitability are key abnormalities involved in the pathogenic cascade of amyotrophic lateral sclerosis (ALS) and are intricately related to the mislocalization and aggregation of TDP-43, a hallmark of ALS. Water and many foods contain MNPLs and in humans, ingestion is the main form of exposure. Digestion of plastics within the gut can alter their properties, rendering them more toxic, and they cause gut microbiome dysbiosis and a dysfunctional gut–brain axis. This is recognized as a trigger and/or aggravating factor for ALS. ALS is associated with a long (years or decades) preclinical period and neonates and infants are exposed to MNPLs through breast milk, milk substitutes, and toys. This endangers a time of intense neurogenesis and establishment of neuronal circuitry, setting the stage for development of neurodegeneration in later life. MNPL neurotoxicity should be considered as a yet unrecognized risk factor for ALS and related diseases. Full article
(This article belongs to the Special Issue Amyotrophic Lateral Sclerosis: Recent Considerations for Diagnosis, Pathogenesis and Therapy)
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8 pages, 879 KiB  
Brief Report
Gold Coast Criteria in ALS Diagnosis: A Real-World Experience
by Lucia Ferullo, Barbara Risi, Filomena Caria, Emanuele Olivieri, Loris Poli, Stefano Gazzina, Ugo Leggio, Enrica Bertella, Giorgia Giovanelli, Beatrice Labella, Alessandro Padovani and Massimiliano Filosto
Brain Sci. 2024, 14(11), 1055; https://doi.org/10.3390/brainsci14111055 - 25 Oct 2024
Viewed by 878
Abstract
Background: Revised El Escorial (rEEC) and Awaji criteria are currently used for diagnosing and categorizing amyotrophic lateral sclerosis (ALS). However, they are complex; their sensitivity is still not optimal for research purposes, and they present high inter-rater variability in clinical practice. To address [...] Read more.
Background: Revised El Escorial (rEEC) and Awaji criteria are currently used for diagnosing and categorizing amyotrophic lateral sclerosis (ALS). However, they are complex; their sensitivity is still not optimal for research purposes, and they present high inter-rater variability in clinical practice. To address these points, in 2019, a new set of diagnostic criteria was proposed, namely the Gold Coast criteria (GCC), characterized by a dichotomous diagnostic categorization, i.e., ALS or not ALS. Methods: In order to investigate the sensitivity, specificity, and clinical usefulness of GCC in a practical clinical setting, we retrospectively evaluated 131 patients diagnosed with ALS and 104 control subjects. ALSFRS-R score, electrophysiological tests, neuroradiological investigations, and CSF analysis were obtained. rEEC, Awaji, and GCC were applied at the first and last evaluations. Results: The sensitivity of GCC (93.1%; 96.1%) was greater than rEEC (71.8%; 87%) and Awaji criteria (77.8%; 89.3%) both at the first visit and last follow-up. The GCC’s specificity (28.8%) is lower than that of the other two criteria (rEEC 45.2%; Awaji 43.3%). Conclusions: Our study suggests that in a real-world setting, the GCC are more sensitive and have substantially lower risk of false negative diagnoses than rEEC and Awaji criteria. Although rEEC had the highest specificity, they may delay the diagnosis. Systematically using the GCC could help to achieve an earlier diagnosis and quickly refer patients to the correct management. The low specificity of GCC is likely to not significantly impact patient recruitment in clinical trials; therefore, its use might allow a faster and earlier enrollment. Full article
(This article belongs to the Special Issue Amyotrophic Lateral Sclerosis: Recent Considerations for Diagnosis, Pathogenesis and Therapy)
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