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Amyotrophic Lateral Sclerosis: Latest Advances and Prospects

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A special issue of Journal of Clinical Medicine (ISSN 2077-0383). This special issue belongs to the section "Clinical Neurology".

Deadline for manuscript submissions: closed (30 November 2023) | Viewed by 25717

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Dr. Matthias Boentert

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1. Department of Neurology with Institute of Translational Neurology, Münster University Hospital, Albert-Schweitzer-Campus 1, 48149 Münster, Germany
2. UKM Marienhospital Steinfurt, Department of Medicine, Mauritiusstr. 5, 48565 Steinfurt, Germany
Interests: sleep; non-invasive ventilation

Prof. Dr. Andreas Hermann

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Guest Editor

Translational Degeneration Section ‘‘Albrecht Kossel“, Department of Neurology, University of Rostock, and German Center for Neurodegenerative Diseases Rostock/Greifswald, Gehlsheimer Straße 20, 18147 Rostock, Germany
Interests: disease modelling using hiPSCs; pathophysiology of ALS (DNA damage, mitochondria, mitochondria–ER interactions); modelling ageing in neurodegenerative diseases; patient-centered care using eye-tracking computer systems
Special Issues, Collections and Topics in MDPI journals

Dr. Julian Grosskreutz

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Department of Neurology, Friedrich Schiller University Jena, Bachstraße 1807743 Jena, Germany
Interests: molecular drivers of progression; phenotyping; brain imaging

Special Issue Information

Dear Colleagues,

Amyotrophic lateral sclerosis (ALS) is still a devastating disease associated with motor neuron degeneration, progressive muscle weakness, and premature death. Although knowledge has markedly increased with regard to underlying pathomechanisms, molecular genetics of ALS, disease biomarkers, and clinical subtype stratification, no effective treatment is currently available, and medical therapy is restricted to disease deceleration, alleviation of symptoms, and palliative care. However, several advances have recently been made and may foster meaningful improvement of both symptomatic and causative treatment strategies. This Topical Collection is intended to cover a broad spectrum of related topics, including the molecular pathology and genetics of motor neuron degeneration, biomarkers and models of disease progression, and a comprehensive approach to patient-centered care from disease onset to the point of palliation. In the latter context, adequate treatment of respiratory muscle weakness and nutritional support are of utmost importance and will be specifically addressed. This Special Issue will present original research work as well as scientific reviews, aiming to address neurologists, with a special focus on ALS but also on physicians and researchers generally interested in neurodegeneration, respiratory care, and palliative medicine.

Dr. Matthias Boentert
Prof. Dr. Andreas Hermann
Dr. Julian Grosskreutz
Guest Editors

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Keywords

amyotrophic lateral sclerosis
neurodegeneration
disease progression modelling
biomarkers in motor neuron disease
respiratory muscle weakness
neuropalliative care
treatment strategies for motor neuron disease

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Published Papers (9 papers)

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Editorial

Jump to: Research

4 pages, 204 KiB

Open AccessEditorial

Amyotrophic Lateral Sclerosis: Advances and Prospects

by Matthias Boentert, Andreas Hermann and Julian Großkreutz

J. Clin. Med. 2023, 12(15), 5055; https://doi.org/10.3390/jcm12155055 - 1 Aug 2023

Viewed by 1330

Abstract

The JCM Topical Collection “Amyotrophic Lateral Sclerosis: Latest Advances and Prospects” started in 2020 and currently includes 11 publications reflecting a broad range of clinical research areas in the ALS field [...] Full article

(This article belongs to the Special Issue Amyotrophic Lateral Sclerosis: Latest Advances and Prospects)

Research

Jump to: Editorial

8 pages, 1270 KiB

Open AccessArticle

No Association between the SORD Gene and Amyotrophic Lateral Sclerosis in a Chinese Cohort

by Mubalake Yilihamu, Ji He, Lu Tang, Yong Chen, Xiaoxuan Liu and Dongsheng Fan

J. Clin. Med. 2022, 11(22), 6834; https://doi.org/10.3390/jcm11226834 - 18 Nov 2022

Cited by 1 | Viewed by 1686

Abstract

Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disorder. Recently a juvenile ALS patient was reported carrying the c.757delG mutation of the sorbitol dehydrogenase (SORD) gene, which was also a related mutation of Charcot-Marie-Tooth disease (CMT) and distal hereditary motor neuropathy (dHMN). ALS shares pathogenesis and overlapping genes with CMT and dHMN. We used whole-exome sequencing technology to screen the full-length SORD gene in 601 Chinese sporadic ALS patients and 174 controls without a history of neurological diseases. No SORD pathogenic variants were identified in the ALS patients. Our current results did not find an association between SORD and ALS in Chinese patients, and further studies will be required. Full article

(This article belongs to the Special Issue Amyotrophic Lateral Sclerosis: Latest Advances and Prospects)

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12 pages, 6420 KiB

Open AccessArticle

POWERbreathe^® Inspiratory Muscle Training in Amyotrophic Lateral Sclerosis

by Davinia Vicente-Campos, Sandra Sanchez-Jorge, J. L. Chicharro, Ricardo Becerro-de Bengoa-Vallejo, David Rodriguez-Sanz, Arianne R. García, Marie Rivoire, Astrid Benet, Sofía Boubekeur and César Calvo-Lobo

J. Clin. Med. 2022, 11(22), 6655; https://doi.org/10.3390/jcm11226655 - 9 Nov 2022

Cited by 5 | Viewed by 3891

Abstract

Inspiratory muscle training may benefit respiratory function, cardiocirculatory parameters, quality of life and functionality in neuromuscular diseases. This pilot study aimed to demonstrate the POWERbreathe^® inspiratory muscle training effects on maximum inspiratory pressure (PI_max), heart rate (HR) and HR variability, as well as the quality of life impairment and functionality in patients with Amyotrophic Lateral Sclerosis (ALS). A pilot single-blinded, non-randomized controlled clinical trial was carried out. A total of 20T ALS patients were enrolled and divided into experimental (n = 10) and control (n = 10) groups. The experimental group received POWERbreathe^® inspiratory muscle training in conjunction with usual care, and the control group received only usual care for 8 weeks. PI_max (measured by POWERbreathe^® KH1), HR and HR variability (evaluated by Polar H7), quality of life impairment [measured by the Amyotrophic Lateral Sclerosis Assessment Questionnaire—40 items (ALSAQ-40)] and functionality [assessed by the ALS Functional Rating Scale Revised (ALSFRS-R)] were collected at baseline and after 8 weeks of intervention. We detected statistically significant differences (p < 0.05) with an effect size ranging from medium to large (Cohen’s d = 0.72–1.37); relative to the control group, the experimental group had an increased PI_max (mean difference = 10.80 cm H₂O; 95% CI = 3.42–18.17) and ALSFRS-R score (mean difference = 5.30 points; 95% CI = −0.03–10.63) and reduced HR (mean difference = −8.80 beats-per-minute; 95% CI = −20.27–2.67) and R-R interval (mean difference = 78.30 ms; 95% CI = 2.89–153.70). POWERbreathe^® inspiratory muscle training, in addition to usual care, may improve inspiratory strength and heart rate in patients with ALS. These results encourage larger and longer trials investigating potential clinically relevant benefits of inspiratory muscle training to these patients over the disease course. Full article

(This article belongs to the Special Issue Amyotrophic Lateral Sclerosis: Latest Advances and Prospects)

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12 pages, 6555 KiB

Open AccessArticle

Affection of Respiratory Muscles in ALS and SMA

by Wiebke Hermann, Simona Langner, Maren Freigang, Stefanie Fischer, Alexander Storch, René Günther and Andreas Hermann

J. Clin. Med. 2022, 11(5), 1163; https://doi.org/10.3390/jcm11051163 - 22 Feb 2022

Cited by 8 | Viewed by 2227

Abstract

Respiratory dysfunction is a common cause of morbidity and mortality in motor neuron disease (MND). However, classical volitional measures of respiratory function in these patients are impeded by, e.g., bulbar paralysis or progressive disability. Diaphragm ultrasound imaging might be a valuable tool for assessing respiratory impairment, albeit different ultrasound measures have not been systematically investigated in adult MND patients and, in particular, have not yet been comparatively applied in adult patients with amyotrophic lateral sclerosis (ALS) and spinal muscular atrophy (SMA). We hypothesized that in contrast to ALS patients, adult SMA patients show a relative sparing of diaphragm function. We retrospectively analyzed diaphragm ultrasound imaging data of 40 patients with ALS and 23 patients with SMA in comparison to a multitude of established parameters of respiratory function. Indeed, ALS patients showed more severe diaphragm dysfunction than adult SMA patients, however, diaphragm dysfunction was also common in adult SMA patients. Notably, dynamic measures of diaphragm function rather than thickness measures were impaired in ALS compared to SMA. Thus, diaphragm ultrasound imaging might be a useful tool to evaluate respiratory dysfunction in adult MND patients. Future larger and prospective studies are needed to validate our initial findings. Full article

(This article belongs to the Special Issue Amyotrophic Lateral Sclerosis: Latest Advances and Prospects)

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14 pages, 1714 KiB

Open AccessArticle

by Ina Schlichte, Susanne Petri, Reinhard Dengler, Thomas Meyer, Aiden Haghikia, Stefan Vielhaber and Susanne Vogt

J. Clin. Med. 2022, 11(4), 944; https://doi.org/10.3390/jcm11040944 - 11 Feb 2022

Cited by 1 | Viewed by 2357

Abstract

Background: Pain is a common symptom in patients with amyotrophic lateral sclerosis (ALS). Coping plays a central role in adjustment to pain. Objective: This study evaluates the use of different pain coping strategies in patients with ALS and investigates the interplay of maladaptive coping, and the patient’s affective state and pain. Methods: One hundred and fifty ALS patients from three German outpatient clinics completed the Brief Pain Inventory (BPI), the ALS-Functional Rating Scale-Extension (ALSFRS-EX), the ALS Depression Inventory (ADI-12), the subscale “emotional functioning” of the ALS Assessment Questionnaire (ALSAQ-40) and the Coping Strategies Questionnaire (CSQ). Based upon the results of correlational analyses, multiple regression analyses were performed to identify predictors of pain severity and to explore factors contributing to maladaptive coping. Results: Pain was prevalent in 56% (n = 84) of the patients. Patients applied different adaptive coping strategies as well as the maladaptive strategy “catastrophizing”. Regression analysis indicated that the CSQ-subscale “catastrophizing” significantly predicted pain intensity, explaining 34.0% of the variance (p < 0.001). Pain-related catastrophizing was associated with higher pain-related functional impairments and worse emotional functioning. The ADI-12 sum score as an indicator for depressive symptoms contributed significantly to the maladaptive coping strategy “catastrophizing” (p < 0.001) and explained 40.8% of the variance. Conclusion: Patients with ALS apply different strategies to cope with pain. Catastrophizing is an important determinant of higher pain intensity ratings and is associated with higher pain interferences and decreased emotional well-being. Pain-related catastrophizing is promoted by depressive symptoms. Catastrophizing and depressive symptoms thus represent important targets of individualized pain-management strategies. Full article

(This article belongs to the Special Issue Amyotrophic Lateral Sclerosis: Latest Advances and Prospects)

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12 pages, 990 KiB

Open AccessArticle

Adjuvant Lineage-Negative Cell Therapy as a Potential Silencer of the Complement-Mediated Immune System in ALS Patients

by Anna Sobuś, Bartłomiej Baumert, Monika Gołąb-Janowska, Piotr Kulig, Edyta Paczkowska, Karolina Łuczkowska, Dorota Rogińska, Alicja Zawiślak, Sławomir Milczarek, Bogumiła Osękowska, Wioletta Pawlukowska, Agnieszka Meller, Karolina Machowska-Sempruch, Agnieszka Wełnicka, Przemysław Nowacki and Bogusław Machaliński

J. Clin. Med. 2021, 10(22), 5251; https://doi.org/10.3390/jcm10225251 - 11 Nov 2021

Cited by 1 | Viewed by 1926

Abstract

ALS remains a fatal, neurodegenerative motor neuron disease. Numerous studies seem to confirm that innate immune system is involved in the pathophysiology of ALS. Hence, the assessment of the complement system and attempts to modify its activity remain the target of medical intervention in ALS. In the present study, three intrathecal administrations of autologous bone marrow-derived lineage-negative (Lin^–) cells were performed every 6 weeks in 20 sporadic ALS patients. The concentrations of various complement components in the cerebrospinal fluid and plasma at different time points after cell injection were quantified using a Luminex multiplex. The results of the complement system were correlated with the level of leukocytes, neutrophils, lymphocytes, fibrinogen and CRP in the peripheral blood and the functional status of ALS patients using Norris and ALS-FRSr scales. The study showed a statistically significant decrease in plasma C3b concentration in all 7th days after cell application. In parallel, a peak decrease in neutrophil count and CRP level was observed on days 5–7, with a simultaneous maximum clinical improvement on days 7–28 of each Lin^– cell administration. Adjuvant Lin^– cell therapy appears to have the silencing potential on the complement-mediated immune system and thus suppress pro-inflammatory reactions responsible for neurodegeneration. However, further in-depth studies are necessary to address this issue. Full article

(This article belongs to the Special Issue Amyotrophic Lateral Sclerosis: Latest Advances and Prospects)

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17 pages, 1936 KiB

Open AccessArticle

A Multi-Center Cohort Study on Characteristics of Pain, Its Impact and Pharmacotherapeutic Management in Patients with ALS

by Susanne Vogt, Ina Schlichte, Stefanie Schreiber, Bernadette Wigand, Grazyna Debska-Vielhaber, Johanna Heitmann, Thomas Meyer, Reinhard Dengler, Susanne Petri, Aiden Haghikia and Stefan Vielhaber

J. Clin. Med. 2021, 10(19), 4552; https://doi.org/10.3390/jcm10194552 - 30 Sep 2021

Cited by 4 | Viewed by 2708

Abstract

Background: Although pain is common in amyotrophic lateral sclerosis (ALS) and an effectively treatable symptom, it is widely under-recognized and undertreated. This study investigates epidemiological and clinical characteristics of pain, its impact and pharmacological treatment in ALS patients. In addition, opportunities for further optimization of pain therapy need to be identified. Methods: Patients from three German ALS outpatient clinics were asked to complete the Brief Pain Inventory and the ALS Functional Rating Scale—Extension and to participate in semi-structured telephone interviews. Results: Of the 150 study participants, 84 patients reported pain. Pain occurred across all disease stages, predominantly in the neck, back and lower extremities. It was described with a broad spectrum of pain descriptors and mostly interfered with activity-related functions. Of the 84 pain patients, 53.8% reported an average pain intensity ≥4 on the numerical rating scale (NRS), indicating pain of at least moderate intensity, and 64.3% used pain medication. Irrespective of the medication type, 20.4% of them had no sufficient pain relief. Thirteen out of 30 patients without pain medication reported an average NRS value ≥4. Eleven of them—mainly in the context of high pain interference with daily functions—were supposed to benefit from adequate pain therapy. However, many patients had relevant concerns and misconceptions about pain therapy. Conclusion: Given the frequency, extent and multi-faceted impact of pain, it is necessary to systematically assess pain throughout the disease course. Potentials to optimize pain therapy were seen in the subset of patients with insufficient pain relief despite medication and in those patients without pain medication but high pain interference. However, there is a need to respond to patients’ barriers to pain therapy. Full article

(This article belongs to the Special Issue Amyotrophic Lateral Sclerosis: Latest Advances and Prospects)

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16 pages, 691 KiB

Open AccessArticle

Minor Allele Frequencies and Molecular Pathways Differences for SNPs Associated with Amyotrophic Lateral Sclerosis in Subjects Participating in the UKBB and 1000 Genomes Project

by Salvatore D’Antona, Gloria Bertoli, Isabella Castiglioni and Claudia Cava

J. Clin. Med. 2021, 10(15), 3394; https://doi.org/10.3390/jcm10153394 - 30 Jul 2021

Cited by 3 | Viewed by 3441

Abstract

Amyotrophic lateral sclerosis (ALS) is a complex disease with a late onset and is characterized by the progressive loss of muscular and respiratory functions. Although recent studies have partially elucidated ALS’s mechanisms, many questions remain such as what the most important molecular pathways involved in ALS are and why there is such a large difference in ALS onset among different populations. In this study, we addressed this issue with a bioinformatics approach, using the United Kingdom Biobank (UKBB) and the European 1000 Genomes Project (1KG) in order to analyze the most ALS-representative single nucleotide polymorphisms (SNPs) that differ for minor allele frequency (MAF) between the United Kingdom population and some European populations including Finnish in Finland, Iberian population in Spain, and Tuscans in Italy. We found 84 SNPs associated with 46 genes that are involved in different pathways including: “Ca²⁺ activated K⁺ channels”, “cGMP effects”, ”Nitric oxide stimulates guanylate cyclase”, “Proton/oligopeptide cotransporters”, and “Signaling by MAPK mutants”. In addition, we revealed that 83% of the 84 SNPs can alter transcription factor-motives binding sites of 224 genes implicated in “Regulation of beta-cell development”, “Transcription-al regulation by RUNX3”, “Transcriptional regulation of pluripotent stem cells”, and “FOXO-mediated transcription of cell death genes”. In conclusion, the genes and pathways analyzed could explain the cause of the difference of ALS onset. Full article

(This article belongs to the Special Issue Amyotrophic Lateral Sclerosis: Latest Advances and Prospects)

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14 pages, 1227 KiB

Open AccessArticle

Clinical Determinants of Disease Progression in Amyotrophic Lateral Sclerosis—A Retrospective Cohort Study

by Maria Viktoria Requardt, Dennis Görlich, Torsten Grehl and Matthias Boentert

J. Clin. Med. 2021, 10(8), 1623; https://doi.org/10.3390/jcm10081623 - 12 Apr 2021

Cited by 11 | Viewed by 4341

Abstract

Background: Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease that is ultimately fatal but characterized by substantial phenotypic heterogeneity, which is known to impact long-term course and survival. This study investigated clinical determinants of disease progression and outcome in a large cohort of patients with ALS. Methods: Retrospective analysis included comprehensive data from 625 patients who attended a tertiary ALS centre at least twice. Patients were stratified according to five distinct clinical phenotypes: classical ALS; bulbar ALS; ALS with frontotemporal dementia (ALS-FTD); upper motor neuron predominant (UMNP); and lower motor neuron predominant (LMNP). Results: This study confirmed higher age at symptom onset, shorter latency to diagnosis and more rapid decline in the revised ALS Functional Rating Scale sum score as predictors of poor prognosis. Hazard ratios for shorter survival were higher in patients with ALS-FTD versus classical ALS, and in patients with versus without chronic obstructive pulmonary disease (COPD). Mean survival was longest in the UMNP phenotype group. Conclusions: This study confirmed established predictors of shorter survival in ALS and showed that concomitant COPD in particular relates to poor outcome. Full article

(This article belongs to the Special Issue Amyotrophic Lateral Sclerosis: Latest Advances and Prospects)

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