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Background: Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease that results in death within a short time span (3-5 years). One of the major challenges in treating ALS is its highly heterogeneous disease progression and the lack of effective prognostic tools to forecast it. The main aim of this study was, then, to test the feasibility of predicting relevant clinical outcomes that characterize the progression of ALS with a two-year prediction horizon via artificial intelligence techniques using routine visits data., Methods: Three classification problems were considered: predicting death (binary problem), predicting death or percutaneous endoscopic gastrostomy (PEG) (multiclass problem), and predicting death or non-invasive ventilation (NIV) (multiclass problem). Two supervised learning models, a logistic regression (LR) and a deep learning multilayer perceptron (MLP), were trained ensuring technical robustness and reproducibility. Moreover, to provide insights into model explainability and result interpretability, model coefficients for LR and Shapley values for both LR and MLP were considered to characterize the relationship between each variable and the outcome., Results: On the one hand, predicting death was successful as both models yielded F1 scores and accuracy well above 0.7. The model explainability analysis performed for this outcome allowed for the understanding of how different methodological approaches consider the input variables when performing the prediction. On the other hand, predicting death alongside PEG or NIV proved to be much more challenging (F1 scores and accuracy in the 0.4-0.6 interval)., Conclusions: In conclusion, predicting death due to ALS proved to be feasible. However, predicting PEG or NIV in a multiclass fashion proved to be unfeasible with these data, regardless of the complexity of the methodological approach. The observed results suggest a potential ceiling on the amount of information extractable from the database, e.g., due to the intrinsic difficulty of the prediction tasks at hand, or to the absence of crucial predictors that are, however, not currently collected during routine practice., (© 2024. The Author(s).)

Background: Amyotrophic lateral sclerosis (ALS) is a fatal and rapidly progressive motoneuron degenerative disorder. There are still no drugs capable of slowing disease evolution or improving life quality of ALS patients. Thus, autologous stem cell therapy has emerged as an alternative treatment regime to be investigated in clinical ALS., Method: Using Proteomics and Protein-Protein Interaction Network analyses combined with bioinformatics, the possible cellular mechanisms and molecular targets related to mesenchymal stem cells (MSCs, 1 × 10 6 cells/kg, intrathecally in the lumbar region of the spine) were investigated in cerebrospinal fluid (CSF) of ALS patients who received intrathecal infusions of autologous bone marrow-derived MSCs thirty days after cell therapy. Data are available via ProteomeXchange with identifier PXD053129., Results: Proteomics revealed 220 deregulated proteins in CSF of ALS subjects treated with MSCs compared to CSF collected from the same patients prior to MSCs infusion. Bioinformatics enriched analyses highlighted events of Extracellular matrix and Cell adhesion molecules as well as related key targets APOA1, APOE, APP, C4A, C5, FGA, FGB, FGG and PLG in the CSF of cell treated ALS subjects., Conclusions: Extracellular matrix and cell adhesion molecules as well as their related highlighted components have emerged as key targets of autologous MSCs in CSF of ALS patients., Trial Registration: Clinicaltrial.gov identifier NCT0291768. Registered 28 September 2016., (© 2024. The Author(s).)

Background: Patient reported outcome measures (PROMs) can be used to assess the impact of health conditions upon an individual's health-related quality of life (HRQoL). Whilst PROMs have been used to quantify the HRQoL impact of amyotrophic lateral sclerosis (ALS), existing instruments may not fully capture what matters to people living with ALS (plwALS) or be appropriate to be used directly to inform the cost-effectiveness of new treatments. This highlights a need for a new condition-specific PROM that can both capture what's important to plwALS and be used in economic evaluation. This study has two key aims: 1) to produce a novel PROM for measuring HRQoL in plwALS (PROQuALS). 2) to value a set of items from the novel PROM to generate an associated preference-weighted measure (PWM) that will enable utility values to be generated., Methods: A mixed-methods study design will be conducted across three stages. Stage 1 involves concept elicitation and the generation of draft PROM content from a robust and comprehensive systematic review of HRQoL in ALS, with input from plwALS. Stage 2 consists of cognitive debriefing of the draft PROM content to ascertain its content validity (Stage 2a), followed by a psychometric survey (Stage 2b) to assess statistical performance. Evidence from Stage 2 will be used to make decisions on the final content and format of the novel PROM. Stage 3 will involve valuation and econometric modeling using health economics methods to generate preference weights, so a PWM derived from the novel PROM can be used in the cost-effectiveness analyses of treatments. Patient and clinical advisory groups will have critical, collaborative input throughout the project., Discussion: The novel PROM will be designed to comprehensively assess important aspects of HRQoL to plwALS and to quantify HRQoL in terms of subjective impact. The PROQuALS measure will be available for use in research and healthcare settings. The associated PWM component will extend and enable the use of PROQuALS in cost-effective analyses of new treatments for ALS., Trial Registration: Not applicable., (© 2024. The Author(s).)

Background: Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease of the upper and lower motoneuron. It is associated with a life expectancy of 2-4 years after diagnosis. Individuals experience paralysis, dysphagia, respiratory failure and loss of communicative function, rendering advance care planning (ACP) critically important. This systematic review primarily aimed to internationally compare the application of advance directives (AD) and ACP in ALS. Its secondary aim was to identify ACP preferences, identify fields for future research and to generate recommendations for improving patient care through ACP., Methods: We conducted a systematic literature review and meta-analysis. Five electronic databases (Embase, Medline, Scopus, PsycInfo and CENTRAL) were searched for qualitative and quantitative primary literature from 1999 to 2024. Cross-references were used to identify additional publications. Study selection was performed based on inclusion criteria. Number and content of AD were extracted systematically. After statistical analysis consecutive meta-analysis was performed for international differences and changes over time. Quality assessment of studies was performed using the MMAT (Mixed Methods Appraisal Tool). PROSPERO Registration (June 07, 2021) : CRD42021248040., Results: A total of 998 records was screened of which 26 were included in the synthesis. An increase in publication numbers of 88.9% was observed from 1999 to 2024. Results regarding use and content of AD were heterogeneous and international differences were detected. AD were signed in 60.4% of records (1,629 / 2,696 patients). The number of AD decreased over time when separating the review period in two decades (1st 1999-2011: 78% vs. 2nd 2012-2024: 42%). Study quality was superior in qualitative and mixed method designs compared to quantitative studies., Conclusion: Further prospective studies should include detailed analyses on preferences regarding ventilation and artificial nutrition in ALS and should encompass countries of the global south. Despite the complexity of ACP with regard to individual patient needs, ACP should be part of each individual support plan for ALS patients and should specifically comprise a discussion on the preferred place of death. The available disease-specific AD documents should be preferred., (© 2024. The Author(s).)

Background: Transitioning to end-of-life care and thereby changing the focus of treatment directives from life-sustaining treatment to comfort care is important for neurological patients in advanced stages. Late transition to end-of-life care for neurological patients has been described previously., Objective: To investigate whether previous treatment directives, primary medical diagnoses, and demographic factors predict the transition to end-of-life care and time to eventual death in patients with neurological diseases in an acute hospital setting., Method: All consecutive health records of patients diagnosed with stroke, amyotrophic lateral sclerosis (ALS), and Parkinson's disease or other extrapyramidal diseases (PDoed), who died in an acute neurological ward between January 2011 and August 2020 were retrieved retrospectively. Descriptive statistics and multivariate Cox regression were used to examine the timing of treatment directives and death in relation to medical diagnosis, age, gender, and marital status., Results: A total of 271 records were involved in the analysis. Patients in all diagnostic categories had a treatment directive for end-of-life care, with patients with haemorrhagic stroke having the highest (92%) and patients with PDoed the lowest (73%) proportion. Cox regression identified that the likelihood of end-of-life care decision-making was related to advancing age (HR = 1.02, 95% CI: 1.007-1.039, P = 0.005), ischaemic stroke (HR = 1.64, 95% CI: 1.034-2.618, P = 0.036) and haemorrhagic stroke (HR = 2.04, 95% CI: 1.219-3.423, P = 0.007) diagnoses. End-of-life care decision occurred from four to twenty-two days after hospital admission. The time from end-of-life care decision to death was a median of two days. Treatment directives, demographic factors, and diagnostic categories did not increase the likelihood of death following an end-of-life care decision., Conclusions: Results show not only that neurological patients transit late to end-of-life care but that the timeframe of the decision differs between patients with acute neurological diseases and those with progressive neurological diseases, highlighting the particular significance of the short timeframe of patients with the progressive neurological diseases ALS and PDoed. Different trajectories of patients with neurological diseases at end-of-life should be further explored and clinical guidelines expanded to embrace the high diversity in neurological patients., (© 2024. The Author(s).)

Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease characterized by progressive loss of motor neurons, resulting in global health burden and limited post-diagnosis life expectancy. Although primarily sporadic, familial ALS (fALS) cases suggest a genetic basis. This review focuses on SOD1, the first gene found to be associated with fALS, which has been more recently confirmed by genome sequencing. While informative, databases such as ALSoD and STRENGTH exhibit regional biases. Through a systematic global examination of SOD1 mutations from 1993 to 2023, we found different geographic distributions and clinical presentations. Even though different SOD1 variants are expressed at different protein levels and have different half-lives and dismutase activities, these alterations lead to loss of function that is not consistently correlated with disease severity. Gain of function of toxic aggregates of SOD1 resulting from mutated SOD1 has emerged as one of the key contributors to ALS. Therapeutic interventions specifically targeting toxic gain of function of mutant SOD1, including RNA interference and antibodies, show promise, but a cure remains elusive. This review provides a comprehensive perspective on SOD1-associated ALS and describes molecular features and the complex genetic landscape of SOD1, highlighting its importance in determining diverse clinical manifestations observed in ALS patients and emphasizing the need for personalized therapeutic strategies., (© 2024. The Author(s).)

Background: Breathlessness is a prevalent symptom affecting the quality of life (QOL) of Amyotrophic Lateral Sclerosis (ALS) patients. This systematic review explored the interventions for controlling breathlessness in ALS patients, emphasizing palliative care (PALC), non-invasive ventilation (NIV), opioids, and non-pharmacological strategies., Methods: A comprehensive search of PubMed, Cochrane Library, and Web of Science databases was conducted. Eligibility criteria encompassed adults with ALS or motor neuron disease experiencing breathlessness. Outcomes included QOL and symptom control. Study designs comprised qualitative studies, cohort studies, and randomized controlled trials., Results: Eight studies were included, most exhibiting low bias risk, comprising one randomized controlled trial, three cohort studies, two comparative retrospective studies, and two qualitative studies (interviews). Most studies originated from Europe, with one from the United States of America. The participants totaled 3423, with ALS patients constituting 95.6%. PALC consultations significantly improved symptom assessment, advance care planning, and discussions about goals of care. NIV demonstrated efficacy in managing breathlessness, with considerations for device limitations. Opioids were effective, though predominantly studied in non-ALS patients. Non-pharmacological strategies varied in efficacy among patients., Conclusion: The findings underscore the need for individualized approaches in managing breathlessness in ALS. PALC, NIV, opioids, and non-pharmacological strategies each play a role, with unique considerations. Further research, especially ALS-specific self-management studies, is warranted., (© 2024. The Author(s).)

Background: People with amyotrophic lateral sclerosis (ALS) face disability- and travel-related barriers to research participation. We investigate the usefulness and acceptability of asynchronous, online focus groups (AOFGs) for research involving people affected by ALS (patients and family caregivers) and outline lessons learned., Methods: The ALS Talk Project, consisting of seven AOFGs and 100 participants affected by ALS, provided context for this investigation. Hosted on the secure itracks Board™ platform, participants interacted in a threaded web forum structure. Moderators posted weekly discussion questions and facilitated discussion. Data pertaining to methodology, participant interaction and experience, and moderator technique were analyzed using itracks and NVivo 12 analytics (quantitative) and conventional content analysis and the constant-comparative approach (qualitative)., Results: There was active engagement within groups, with post lengths averaging 111.48 words and a complex network of branching interactions between participants. One third of participant responses included individual reflections without further interaction. Participants affirmed their co-group members, offered practical advice, and discussed shared and differing perspectives. Moderators responded to all posts, indicating presence and probing answers. AOFGs facilitated qualitative and quantitative data-gathering and flexible response to unanticipated events. Although total participation fell below 50% after 10-12 weeks, participants valued interacting with peers in an inclusive, confidential forum. Participants used a variety of personal devices, browsers, and operating systems when interacting on the online platform., Conclusions: This methodological examination of AOFGs for patient-centred investigations involving people affected by ALS demonstrates their usefulness and acceptability, and advances knowledge of online research methodologies. Lessons learned include: early identification of research goals and participant needs is critical to selecting an AOFG platform; although duration longer than 10-12 weeks may be burdensome in this population, participants were positive about AOFGs; AOFGs offer real world flexibility enabling response to research challenges and opportunities; and, AOGFs can effectively foster safe spaces for sharing personal perspectives and discussing sensitive topics. With moderators playing an important role in fostering engagement, AOFGs facilitated rich data gathering and promoted reciprocity by fostering the exchange of ideas and interaction between peers. Findings may have implications for research involving other neurologically impaired and/or medically vulnerable populations., (© 2023. BioMed Central Ltd., part of Springer Nature.)

Background: Malfunction of astrocytes is implicated as one of the pathological factors of ALS. Thus, intrathecal injection of healthy astrocytes in ALS can potentially compensate for the diseased astrocytes. AstroRx® is an allogeneic cell-based product, composed of healthy and functional human astrocytes derived from embryonic stem cells. AstroRx® was shown to clear excessive glutamate, reduce oxidative stress, secrete various neuroprotective factors, and act as an immunomodulator. Intrathecal injection of AstroRx® to animal models of ALS slowed disease progression and extended survival. Here we report the result of a first-in-human clinical study evaluating intrathecal injection of AstroRx® in ALS patients., Methods: We conducted a phase I/IIa, open-label, dose-escalating clinical trial to evaluate the safety, tolerability, and therapeutic effects of intrathecal injection of AstroRx® in patients with ALS. Five patients were injected intrathecally with a single dose of 100 × 10 6 AstroRx® cells and 5 patients with 250 × 10 6 cells (low and high dose, respectively). Safety and efficacy assessments were recorded for 3 months pre-treatment (run-in period) and 12 months post-treatment (follow-up period)., Results: A single administration of AstroRx® at either low or high doses was safe and well tolerated. No adverse events (AEs) related to AstroRx® itself were reported. Transient AEs related to the Intrathecal (IT) procedure were all mild to moderate. The study demonstrated a clinically meaningful effect that was maintained over the first 3 months after treatment, as measured by the pre-post slope change in ALSFRS-R. In the 100 × 10 6 AstroRx® arm, the ALSFRS-R rate of deterioration was attenuated from - 0.88/month pre-treatment to - 0.30/month in the first 3 months post-treatment (p = 0.039). In the 250 × 10 6 AstroRx® arm, the ALSFRS-R slope decreased from - 1.43/month to - 0.78/month (p = 0.0023). The effect was even more profound in a rapid progressor subgroup of 5 patients. No statistically significant change was measured in muscle strength using hand-held dynamometry and slow vital capacity continued to deteriorate during the study., Conclusions: Overall, these findings suggest that a single IT administration of AstroRx® to ALS patients at a dose of 100 × 10 6 or 250 × 10 6 cells is safe. A signal of beneficial clinical effect was observed for the first 3 months following cell injection. These results support further investigation of repeated intrathecal administrations of AstroRx®, e.g., every 3 months., Trial Registration: NCT03482050., (© 2023. The Author(s).)

Background: Amyotrophic Lateral Sclerosis (ALS) is a neurodegenerative disease whose spreading and progression mechanisms are still unclear. The ability to predict ALS prognosis would improve the patients' quality of life and support clinicians in planning treatments. In this paper, we investigate ALS evolution trajectories using Process Mining (PM) techniques enriched to both easily mine processes and automatically reveal how the pathways differentiate according to patients' characteristics., Methods: We consider data collected in two distinct data sources, namely the Pooled Resource Open-Access ALS Clinical Trials (PRO-ACT) dataset and a real-world clinical register (ALS-BS) including data of patients followed up in two tertiary clinical centers of Brescia (Italy). With a focus on the functional abilities progressively impaired as the disease progresses, we use two Process Discovery methods, namely the Directly-Follows Graph and the CareFlow Miner, to mine the population disease trajectories on the PRO-ACT dataset. We characterize the impairment trajectories in terms of patterns, timing, and probabilities, and investigate the effect of some patients' characteristics at onset on the followed paths. Finally, we perform a comparative study of the impairment trajectories mined in PRO-ACT versus ALS-BS., Results: We delineate the progression pathways on PRO-ACT, identifying the predominant disabilities at different stages of the disease: for instance, 85% of patients enter the trials without disabilities, and 48% of them experience the impairment of Walking/Self-care abilities first. We then test how a spinal onset increases the risk of experiencing the loss of Walking/Self-care ability as first impairment (52% vs. 27% of patients develop it as the first impairment in the spinal vs. the bulbar cohorts, respectively), as well as how an older age at onset corresponds to a more rapid progression to death. When compared, the PRO-ACT and the ALS-BS patient populations present some similarities in terms of natural progression of the disease, as well as some differences in terms of observed trajectories plausibly due to the trial scheduling and recruitment criteria., Conclusions: We exploited PM to provide an overview of the evolution scenarios of an ALS trial population and to preliminary compare it to the progression observed in a clinical cohort. Future work will focus on further improving the understanding of the disease progression mechanisms, by including additional real-world subjects as well as by extending the set of events considered in the impairment trajectories., (© 2023. The Author(s).)

Background: To improve the care for patients with motor neuron disease an e-health innovation for continuous monitoring of disease progression and patients' well-being (ALS H&C) was implemented in 10 multidisciplinary rehabilitation settings. The first aim was to evaluate the implementation of ALS H&C by assessing several implementation outcomes, technology acceptance and usability of the innovation according to the end users. The secondary aim was to explore differences in these outcomes between the teams with sustainable and unsustainable implementation., Methods: The chosen implementation strategy was a combination of the implementation process model by Grol & Wensing and a participatory action research approach. In three meetings with multidisciplinary project groups the innovation was introduced, the expected barriers/facilitators identified, and action plans to resolve each barrier developed. After a 3-month pilot phase, patients and their healthcare providers were asked to complete an online evaluation survey to assess implementation outcomes, based on Proctor's evaluation framework (i.e., acceptability, feasibility, fidelity, sustainability). Telemedicine technology acceptance was assessed according the technology acceptance model of Chau, and user experiences with the System Usability Scale (SUS). Implementation outcomes of teams with sustainable implementation (continuation after completion of the pilot phase) and unsustainable implementation (discontinuation after the pilot phase) were compared., Results: The implementation outcomes from the patients' perspective (N = 71) were positive; they found ALS H&C to be an acceptable and feasible care concept. Patients' technology acceptance was high, with positive attitudes towards ALS H&C, and positive views on perceived technology control, usefulness, and ease of use. Patients rated their satisfaction with the (web) app on a scale from 1 (not satisfied at all) to 10 (very satisfied) with a 7.0 (median; IQR 1.0). Healthcare providers (N = 76) also found ALS H&C acceptable and appropriate as well, but were less positive about the feasibility and usability of ALS H&C (mean SUS 58.8 [SD 11.3]). ALS H&C has largely been implemented as intended and the implementation was sustainable in 7 teams. Teams who discontinued ALS H&C after the pilot phase (N = 2) had more fidelity issues., Conclusions: A participatory action research approach supported by theoretical approaches used in implementation science led to a sustainable implementation of ALS H&C in 7 of the participating teams. To improve implementation success, additional implementation strategies to increase feasibility, usability and fidelity are necessary., Trial Registration: Trial NL8542 registered at Netherlands Trial Register (trialregister.nl) on 15th April 2020., (© 2022. The Author(s).)

Lipids, defined by low solubility in water and high solubility in nonpolar solvents, can be classified into fatty acids, glycerolipids, glycerophospholipids, sphingolipids, and sterols. Lipids not only regulate integrity and fluidity of biological membranes, but also serve as energy storage and bioactive molecules for signaling. Causal mutations in SPTLC1 (serine palmitoyltransferase long chain subunit 1) gene within the lipogenic pathway have been identified in amyotrophic lateral sclerosis (ALS), a paralytic and fatal motor neuron disease. Furthermore, lipid dysmetabolism within the central nervous system and circulation is associated with ALS. Here, we aim to delineate the diverse roles of different lipid classes and understand how lipid dysmetabolism may contribute to ALS pathogenesis. Among the different lipids, accumulation of ceramides, arachidonic acid, and lysophosphatidylcholine is commonly emerging  as detrimental to motor neurons. We end with exploring the potential ALS therapeutics by reducing these toxic lipids., (© 2022. The Author(s).)

Recently, mesenchymal stromal cell (MSC)-based therapy has become an appreciated therapeutic approach in the context of neurodegenerative disease therapy. Accordingly, a myriad of studies in animal models and also some clinical trials have evinced the safety, feasibility, and efficacy of MSC transplantation in neurodegenerative conditions, most importantly in Alzheimer's disease (AD), Parkinson's disease (PD), amyotrophic lateral sclerosis (ALS), and Huntington's disease (HD). The MSC-mediated desired effect is mainly a result of secretion of immunomodulatory factors in association with release of various neurotrophic factors (NTFs), such as glial cell line-derived neurotrophic factor (GDNF) and brain-derived neurotrophic factor (BDNF). Thanks to the secretion of protein-degrading molecules, MSC therapy mainly brings about the degradation of pathogenic protein aggregates, which is a typical appearance of chronic neurodegenerative disease. Such molecules, in turn, diminish neuroinflammation and simultaneously enable neuroprotection, thereby alleviating disease pathological symptoms and leading to cognitive and functional recovery. Also, MSC differentiation into neural-like cells in vivo has partially been evidenced. Herein, we focus on the therapeutic merits of MSCs and also their derivative exosome as an innovative cell-free approach in AD, HD, PD, and ALS conditions. Also, we give a brief glimpse into novel approaches to potentiate MSC-induced therapeutic merits in such disorders, most importantly, administration of preconditioned MSCs., (© 2022. The Author(s).)

Background: Palliative sedation has become widely accepted as a method to alleviate refractory symptoms in terminally ill patients. Controversies regarding this topic especially concern the use of palliative sedation for psychological symptoms, the use in patients who are not imminently dying and the simultaneous withdrawal of life-sustaining measures. Amyotrophic lateral sclerosis (ALS) is characterized by symptoms including muscle weakness, dysphagia, dysarthria, muscle spasms and progressive respiratory insufficiency. Due to these characteristic symptoms, palliative sedation might be considered to be necessary to alleviate refractory suffering in ALS patients. However, palliative sedation in ALS is only rarely discussed in current medical literature and guidelines., Methods: A questionnaire survey was conducted among neurologists and palliative care practitioners in Germany. The participants were asked to evaluate the use of palliative sedation in different situations., Results: Two hundred and ninety-six completed questionnaires were analyzed. The results suggest high levels of support for the use of palliative sedation in ALS patients. 42% of the participants stated that they had already used palliative sedation in the treatment of ALS patients. Acceptance of palliative sedation was higher in case of physical symptoms than in case of psychological symptoms. Refusal of artificial nutrition did not lead to a lower acceptance of palliative sedation. Doctors with specialist training in palliative care had already used palliative sedation in ALS patients more often and they were more likely to accept palliative sedation in different situations than the participants without a background in palliative care., Conclusion: Our survey showed that palliative sedation in ALS is widely accepted by the attending doctors. In case of psychological symptoms, palliative sedation is looked at with more concern than in case of physical symptoms. The refusal of artificial nutrition does not result in a decreased acceptance of palliative sedation. Doctors with specialist training in palliative care are more likely to approve of palliative sedation in ALS., (© 2022. The Author(s).)

Background: Amyotrophic lateral sclerosis (ALS) is characterized by a progressive loss of motor neurons (MNs), leading to paralysis, respiratory failure and death within 2-5 years of diagnosis. The exact mechanisms of sporadic ALS, which comprises 90% of all cases, remain unknown. In familial ALS, mutations in superoxide dismutase (SOD1) cause 10% of cases., Methods: ALS patient-derived human-induced pluripotent stem cells (ALS hiPSCs, harboring the SOD1 AV4 mutation), were differentiated to MNs (ALS-MNs). The neuroprotective effects of conditioned medium (CM) of hESCs (H9), wt hiPSCs (WTC-11) and the ALS iPSCs, on MN apoptosis and viability, formation and maintenance of neurites, mitochondrial activity and expression of inflammatory genes, were examined. For in vivo studies, 200 μl of CM from the ALS iPSCs (CS07 and CS053) was injected subcutaneously into the ALS model mice (transgenic for the human SOD1 G93A mutation). Animal agility and strength, muscle innervation and mass, neurological score, onset of paralysis and lifespan of the ALS mice were assayed. After observing significant disease-modifying effects, the CM was characterized biochemically by fractionation, comparative proteomics, and epigenetic screens for the dependence on pluripotency. CM of fibroblasts that were differentiated from the wt hiPSCs lacked any neuroprotective activity and was used as a negative control throughout the studies., Results: The secretome of PSCs including the ALS patient iPSCs was neuroprotective in the H 2 O 2 model. In the model with pathogenic SOD1 mutation, ALS iPSC-CM attenuated all examined hallmarks of ALS pathology, rescued human ALS-MNs from denervation and death, restored mitochondrial health, and reduced the expression of inflammatory genes. The ALS iPSC-CM also improved neuro-muscular health and function, and delayed paralysis and morbidity in ALS mice. Compared side by side, cyclosporine (CsA), a mitochondrial membrane blocker that prevents the leakage of mitochondrial DNA, failed to avert the death of ALS-MNs, although CsA and ALS iPSC-CM equally stabilized MN mitochondria and attenuated inflammatory genes. Biochemical characterization, comparative proteomics, and epigenetic screen all suggested that it was the interactome of several key proteins from different fractions of PSC-CM that delivered the multifaceted neuroprotection., Conclusions: This work introduces and mechanistically characterizes a new biologic for treating ALS and other complex neurodegenerative diseases., (© 2022. The Author(s).)

Background: Respite care provides caregiving support to people with amyotrophic lateral sclerosis (ALS) and their care partners by providing the care partner with temporary relief from their caregiving duties. The aim of this study was to explore the impact of respite care through the perspectives and lived experiences of people with ALS and their care partners., Methods: Thirty-one dyads (62 participants) of people with ALS and their care partners were assigned to either the control group or the respite care intervention. Respite care was provided in the form of home-based services. Semi-structured interviews were conducted with participants at baseline and after a six-month period to gather perspectives on ALS caregiving, perceptions of respite care, and the respite care experience. Interviews were transcribed and subjected to thematic analysis., Results: Caregiving challenges specific to the care partner and the patient-care partnership relationship were identified. Overall, people with ALS and care partners responded positively to in-home respite care and reported improved relationship quality, more time for the care partner to pursue personal commitments or take a break, and improved emotional well-being for both the person with ALS and the care partner. Barriers and concerns were raised surrounding privacy and staff consistency., Conclusion: This study highlights respite care as a critical tool to alleviate caregiving challenges and support the needs of people with ALS and their care partners. Engagement with the ALS community and formal evaluations of respite care services should be prioritized in order to minimize barriers and best meet the needs of people with ALS and their care partners., (© 2022. The Author(s).)

Mutations in FUS, an RNA-binding protein involved in multiple steps of RNA metabolism, are associated with the most severe forms of amyotrophic lateral sclerosis (ALS). Accumulation of cytoplasmic FUS is likely to be a major culprit in the toxicity of FUS mutations. Thus, preventing cytoplasmic mislocalization of the FUS protein may represent a valuable therapeutic strategy. FUS binds to its own pre-mRNA creating an autoregulatory loop efficiently buffering FUS excess through multiple proposed mechanisms including retention of introns 6 and/or 7. Here, we introduced a wild-type FUS gene allele, retaining all intronic sequences, in mice whose heterozygous or homozygous expression of a cytoplasmically retained FUS protein (Fus ∆NLS ) was previously shown to provoke ALS-like disease or postnatal lethality, respectively. Wild-type FUS completely rescued the early lethality caused by the two Fus ∆NLS alleles, and improved the age-dependent motor deficits and reduced lifespan caused by heterozygous expression of mutant FUS ∆NLS . Mechanistically, wild-type FUS decreased the load of cytoplasmic FUS, increased retention of introns 6 and 7 in the endogenous mouse Fus mRNA, and decreased expression of the mutant mRNA. Thus, the wild-type FUS allele activates the homeostatic autoregulatory loop, maintaining constant FUS levels and decreasing the mutant protein in the cytoplasm. These results provide proof of concept that an autoregulatory competent wild-type FUS expression could protect against this devastating, currently intractable, neurodegenerative disease., (© 2021. The Author(s).)

Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease involving both upper and lower motor neurons, leading to paralysis and eventually death. Symptomatic treatments such as inhibition of salivation, alleviation of muscle cramps, and relief of spasticity and pain still play an important role in enhancing the quality of life. To date, riluzole and edaravone are the only two drugs approved by the Food and Drug Administration for the treatment of ALS in a few countries. While there is adequate consensus on the modest efficacy of riluzole, there are still open questions concerning the efficacy of edaravone in slowing the disease progression. Therefore, identification of novel therapeutic strategies is urgently needed. Impaired autophagic process plays a critical role in ALS pathogenesis. In this review, we focus on therapies modulating autophagy in the context of ALS. Furthermore, stem cell therapies, gene therapies, and newly-developed biomaterials have great potentials in alleviating neurodegeneration, which might halt the disease progression. In this review, we will summarize the current and prospective therapies for ALS., (© 2021. The Author(s).)

Amyotrophic lateral sclerosis (ALS) is a neurodegenerative fatal disorder in which motor neurons within the brain and spinal cord degenerate. A single infusion of mesenchymal stem cells (MSCs) delays disease progression by protecting motor neurons and restoring the blood-spinal cord barrier in the SOD1G93A transgenic ALS rat model. However, the therapeutic effect of a single infusion of MSCs is transient and does not block disease progression. In this study, we demonstrated that repeated administration of MSCs (weekly, four times) increased the survival period, protected motor functions, and reduced deterioration of locomotor activity compared to a single infusion and vehicle infusion, after which rats displayed progressive deterioration of hind limb function. We also compared the days until gait ability was lost in rats and found that the repeated-infused group maintained gait ability compared to the single-infusion and vehicle-infusion groups. These results suggest that repeated administration of MSCs may prevent the deterioration of motor function and extend the lifespan in ALS.

Background: Mesenchymal stromal cells (MSCs) have been studied with increasing intensity as clinicians and researchers strive to understand the ability of MSCs to modulate disease progression and promote tissue regeneration. As MSCs are used for diverse applications, it is important to appreciate how specific physiological environments may stimulate changes that alter the phenotype of the cells. One need for neuroregenerative applications is to characterize the spectrum of MSC responses to the cerebrospinal fluid (CSF) environment after their injection into the intrathecal space. Mechanistic understanding of cellular biology in response to the CSF environment may predict the ability of MSCs to promote injury repair or provide neuroprotection in neurodegenerative diseases., Methods: In this study, we characterized changes in morphology, metabolism, and gene expression occurring in human adipose-derived MSCs cultured in human (hCSF) or artificial CSF (aCSF) as well as examined relevant protein levels in the CSF of subjects treated with MSCs for amyotrophic lateral sclerosis (ALS)., Results: Our results demonstrated that, under intrathecal-like conditions, MSCs retained their morphology, though they became quiescent. Large-scale transcriptomic analysis of MSCs revealed a distinct gene expression profile for cells cultured in aCSF. The aCSF culture environment induced expression of genes related to angiogenesis and immunomodulation. In addition, MSCs in aCSF expressed genes encoding nutritional growth factors to expression levels at or above those of control cells. Furthermore, we observed a dose-dependent increase in growth factors and immunomodulatory cytokines in CSF from subjects with ALS treated intrathecally with autologous MSCs., Conclusions: Overall, our results suggest that MSCs injected into the intrathecal space in ongoing clinical trials remain viable and may provide a therapeutic benefit to patients.

Background: Amyotrophic Lateral Sclerosis (ALS) is a progressive neurodegenerative condition with a mean life expectancy of 3 years from first symptom. Understanding the factors that are important to both patients and their caregivers has the potential to enhance service delivery and engagement, and improve efficiency. The Discrete Choice Experiment (DCE) is a stated preferences method which asks service users to make trade-offs for various attributes of health services. This method is used to quantify preferences and shows the relative importance of the attributes in the experiment, to the service user., Methods: A DCE with nine choice sets was developed to measure the preferences for health services of ALS patients and their caregivers and the relative importance of various aspects of care, such as timing of care, availability of services, and decision making. The DCE was presented to patients with ALS, and their caregivers, recruited from a national multidisciplinary clinic. A random effects probit model was applied to estimate the impact of each attribute on a participant's choice., Results: Patients demonstrated the strongest preferences about timing of receiving information about ALS. A strong preference was also placed on seeing the hospice care team later rather than early on in the illness. Patients also indicated their willingness to consider the use of communication devices. Grouping by stage of disease, patients who were in earlier stages of disease showed a strong preference for receipt of extensive information about ALS at the time of diagnosis. Caregivers showed a strong preference for engagement with healthcare professionals, an attribute that was not prioritised by patients., Conclusions: The DCE method can be useful in uncovering priorities of patients and caregivers with ALS. Patients and caregivers have different priorities relating to health services and the provision of care in ALS, and patient preferences differ based on the stage and duration of their illness. Multidisciplinary teams must calibrate the delivery of care in the context of the differing expectations, needs and priorities of the patient/caregiver dyad.

Background: Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative fatal disease that can affect the neurons of brain and spinal cord. ALS genetics has identified various genes to be associated with disease pathology. Oxidative stress induced bunina and lewy bodies formation can be regulated through the action of SOD1 protein. Hence, in the present study we aim to analyse the structural and functional annotation of various reported SOD1 variants throughout and their putative correlation with the location of mutation and degree of ALS severity by inferring the structural and functional alterations in different SOD1 variants., Methods: We have retrieved around 69 SNPs of SOD1 gene from Genecards. Structural annotation of SOD1 variants were performed using SWISS Model, I-Mutant 2.0, Dynamut, ConSurf. Similarly, the functional annotation of same variants were done using SIFT, PHP-SNP, PolyPhen2, PROVEAN and RegulomeDB. Ramachandran plot was also obtained for six synonymous SNPs to compare the amino acid distribution of wild-type SOD1 (WT SOD1) protein. Frequency analysis, Chi square analysis, ANOVA and multiple regression analysis were performed to compare the structural and functional components among various groups., Results and Conclusion: Results showed the mutations in conserved domain of SOD1 protein are more deleterious and significantly distort the tertiary structure of protein by altering Gibb's free energy and entropy. Moreover, significant changes in SIFT, PHP-SNP, PolyPhen2, PROVEAN and RegulomeDB scores were also observed in mutations located in conserved domain of SOD1 protein. Multiple regression results were also suggesting the significant alterations in free energy and entropy for conserved domain mutations which were concordant with structural changes of SOD1 protein. Results of the study are suggesting the biological importance of location of mutation(s) which may derive the different disease phenotypes and must be dealt accordingly to provide precise therapy for ALS patients.

Emerging evidence demonstrates that adaptive immunity influences the pathobiology of neurodegenerative disorders. Misfolded aggregated self-proteins can break immune tolerance leading to the induction of autoreactive effector T cells (Teffs) with associated decreases in anti-inflammatory neuroprotective regulatory T cells (Tregs). An imbalance between Teffs and Tregs leads to microglial activation, inflammation and neuronal injury. The cascade of such a disordered immunity includes the drainage of the aggregated protein antigens into cervical lymph nodes serving to amplify effector immune responses. Both preclinical and clinical studies demonstrate transformation of this altered immunity for therapeutic gain. We posit that the signs and symptoms of common neurodegenerative disorders such as Alzheimer's and Parkinson's diseases, amyotrophic lateral sclerosis, and stroke can be attenuated by boosting Treg activities.

Amyotrophic lateral sclerosis (ALS) and Frontotemporal Degeneration (FTD) are neurodegenerative disorders, related by deterioration of motor and cognitive functions and short survival. Aside from cases with an inherited pathogenic mutation, the causes of the disorders are still largely unknown and no effective treatment currently exists. It has been shown that FTD may coexist with ALS and this overlap occurs at clinical, genetic, and molecular levels. In this work, we review the main pathological aspects of these complex diseases and discuss how the integration of the novel pathogenic molecular insights and the analysis of molecular interaction networks among all the genetic players represents a critical step to shed light on discovering novel therapeutic strategies and possibly tailoring personalized medicine approaches to specific ALS and FTD patients.

Background: There is increasing awareness of the need for an integrated palliative care approach in chronic progressive neurological diseases. Advance care planning (ACP) is an integral part of this approach. As a systematically organized and ongoing communication process about patients' values, goals and preferences regarding medical care during serious and chronic illness, ACP aims to involve patients in decision-making before they become cognitively and communicatively incapable. However, it remains underutilized in daily neurological practice except for speciality clinics such as ALS centers. Our aim was to study ACP in the tertiary ALS center Amsterdam and to investigate patients' reflections on it. Subsequently we used this knowledge to formulate recommendations for integration of ACP in the care of patients with other chronic progressive neurological diseases., Methods: Non-participating observations of all appointments of patients with amyotrophic lateral sclerosis (ALS) or progressive muscular atrophy (PMA) with the treating physician, in various stages of disease, during 6 consecutive months, followed by single in-depth interviews, and an inductive analysis., Results: Twenty-eight Dutch patients participated, varying in age, gender, disease onset and severity of physical decline. ACP started directly when the diagnosis was given, by means of a general outlook on the future with progressive disability and immediate introduction to a customized multidisciplinary team. During follow-up ACP was realized by regular appointments in which monitoring of the patient's status and clear communication strategies formed the basis of tailor-made discussions on treatment options. Patients accepted this policy as careful professional guidance., Conclusions: ACP is a professional communication process throughout the whole course of progressive disease. It is feasible to integrate ACP into follow-up of patients with ALS and PMA from diagnosis onwards. Supported by recent literature, we argue that such a well-structured approach would also enhance the quality of care and life of patients with other chronic progressive neurological diseases.

Background: Dyspnea is frequent in amyotrophic lateral sclerosis (ALS) and one of the most bothersome symptoms. The recently developed Dyspnea-ALS-Scale (DALS-15) is a disease-specific patient-reported outcome to detect and quantify dyspnea., Objectives: To analyze in a case-based approach the diagnostic and clinical implications and the benefit of the DALS-15 for individual patients in daily clinical routine., Methods: Dyspnea was assessed by the 15-item comprising DALS-15 in two patients with ALS. Spirometry was performed and blood gases were analyzed. Results were evaluated in the clinical context of the respective patients., Results: In one patient the presence of dyspnea detected by the DALS-15 indicated noninvasive ventilation (NIV) although forced vital capacity (FVC) and blood gas analysis were well preserved. After NIV implementation, the DALS-15 was helpful to determine the patient's need for medication, the timing of NIV titration and the adaptation of NIV sessions. In another patient, who was anarthric and no longer able to perform spirometry due to severe bulbar impairment, the DALS-15 allowed a standardized assessment of dyspnea-related distress independently of bulbar dysfunction., Conclusion: The DALS-15 provides a deeper insight into the respiratory status of individual patients. It helps to diagnose respiratory impairment in patients in whom NIV should be considered although FVC and blood gas results do not reveal indication for NIV. It is also valuable for the guidance of patients in later stages of respiratory impairment when NIV is already implemented, and in patients with severe bulbar dysfunction. The DALS-15 can improve specific symptom management and coordination of care and therefore has the potential to optimize individual treatment in ALS patients with dyspnea.

Amyotrophic lateral sclerosis (ALS) is a fatal paralytic disease with no cure or treatment to stop disease progression. Because ALS represents an urgent unmet medical need, a significant number of therapeutics are being tested in preclinical and clinical studies. A recent publication in Stem Cell Research & Therapy by Izrael and colleagues reports about embryonic stem cell-derived astrocytes as a potential cell therapy for ALS. Such cells behave as highly trophic "young astrocytes", being able to delay disease onset and prolong survival when injected intrathechally in murine models of ALS overexpressing the SOD1 G93A mutation. The safety and therapeutic potential of these cells are currently being evaluated in a clinical trial in ALS patients. This commentary discusses the mechanisms of action and potential therapeutic effects of these "young astrocytes" in ALS.

Background: Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disorder characterized by progressive muscle weakness, paralysis and death. There is no effective treatment for ALS and stem cell therapy has arisen as a potential therapeutic approach., Methods: SOD1 mutant mice were used to study the potential neurotrophic effect of bone marrow cells grafted into quadriceps femoris muscle., Results: Bone marrow intramuscular transplants resulted in increased longevity with improved motor function and decreased motoneuron degeneration in the spinal cord. Moreover, the increment of the glial-derived neurotrophic factor and neurotrophin 4 observed in the grafted muscles suggests that this partial neuroprotective effect is mediated by neurotrophic factor release at the neuromuscular junction level. Finally, certain neurodegeneration and muscle disease-specific markers, which are altered in the SOD1 G93A mutant mouse and may serve as molecular biomarkers for the early detection of ALS in patients, have been studied with encouraging results., Conclusions: This work demonstrates that stem cell transplantation in the muscle prolonged the lifespan, increased motoneuron survival and slowed disease progression, which was also assessed by genetic expression analysis.

Background: Amyotrophic Lateral Sclerosis (ALS), also known as Lou Gehrig's disease, is a rare disease with extreme between-subject variability, especially with respect to rate of disease progression. This makes modelling a subject's disease progression, which is measured by the ALS Functional Rating Scale (ALSFRS), very difficult. Consider the problem of predicting a subject's ALSFRS score at 9 or 12 months after a given time-point., Methods: We obtained ALS subject data from the Pooled Resource Open-Access ALS Clinical Trials Database, a collection of data from various ALS clinical trials. Due to the typical linearity of the ALSFRS, we consider several Bayesian hierarchical linear models. These include a mixture model (to account for the two potential classes of "fast" and "slow" ALS progressors) as well as an onset-anchored model, in which an additional artificial data-point, using time of disease onset, is utilized to improve predictive performance., Results: The onset-anchored model had a drastically reduced posterior predictive mean-square-error distributions, when compared to the Bayesian hierarchical linear model or the mixture model under a cross-validation approach. No covariates, other than time of disease onset, consistently improved predictive performance in either the Bayesian hierarchical linear model or the onset-anchored model., Conclusions: Augmenting patient data with an additional artificial data-point, or onset anchor, can drastically improve predictive modelling in ALS by reducing the variability of estimated parameters at the cost of a slight increase in bias. This onset-anchored model is extremely useful if predictions are desired directly after a single baseline measure (such as at the first day of a clinical trial), a feat that would be very difficult without the onset-anchor. This approach could be useful in modelling other diseases that have bounded progression scales (e.g. Parkinson's disease, Huntington's disease, or inclusion-body myositis). It is our hope that this model can be used by clinicians and statisticians to improve the efficacy of clinical trials and aid in finding treatments for ALS.

Amyotrophic lateral sclerosis (ALS) is a rapidly progressive neurodegenerative condition where loss of motor neurons within the brain and spinal cord leads to muscle atrophy, weakness, paralysis and ultimately death within 3-5 years from onset of symptoms. The specific molecular mechanisms underlying the disease pathology are not fully understood and neuroprotective treatment options are minimally effective. In recent years, stem cell transplantation as a new therapy for ALS patients has been extensively investigated, becoming an intense and debated field of study. In several preclinical studies using the SOD1 G93A mouse model of ALS, stem cells were demonstrated to be neuroprotective, effectively delayed disease onset and extended survival. Despite substantial improvements in stem cell technology and promising results in preclinical studies, several questions still remain unanswered, such as the identification of the most suitable and beneficial cell source, cell dose, route of delivery and therapeutic mechanisms. This review will cover publications in this field and comprehensively discuss advances, challenges and future direction regarding the therapeutic potential of stem cells in ALS, with a focus on mesenchymal stem cells. In summary, given their high proliferation activity, immunomodulation, multi-differentiation potential, and the capacity to secrete neuroprotective factors, adult mesenchymal stem cells represent a promising candidate for clinical translation. However, technical hurdles such as optimal dose, differentiation state, route of administration, and the underlying potential therapeutic mechanisms still need to be assessed.

Background: Conjugal amyotrophic lateral sclerosis is rare, with significant effects on psychological and care needs. We report a case of conjugal amyotrophic lateral sclerosis disease from central Scotland. This case is particularly unusual as both patients were diagnosed within an 18-month period and experienced the disease simultaneously, with similar symptomatology and progression., Case Presentation: Patient A was a 71-year-old man who presented with unilateral arm weakness and wasting. Patient B was a 68-year-old woman who presented with unilateral shoulder and elbow weakness. Diagnosis of amyotrophic lateral sclerosis was made within a few months of presentation in both cases, based on typical clinical symptomatology together with supportive neurophysiological testing. Interventions included enteral feeding and non-invasive ventilation. The time period between symptom onset and death was 5 years for Patient A and 3.5 years for Patient B., Conclusion: This case illustrates two main points: the care issues surrounding cases of conjugal neurological disease, and the psychological issues in these patients. There are significant care issues arising when co-habiting couples both develop severe functionally limiting neurological diseases at the same time. The more slowly progressive nature of Patient A's disease may be at least partially explained by the support he was able to receive from Patient B before she developed symptoms. Secondly, there are important psychological effects of living with someone with the same - but more advanced - progressive and incurable neurological disease. Thus, Patient B was reluctant to have certain interventions that she had observed being given to her husband. Lastly, no plausible shared environmental risk factors were identified, implying that the co-occurrence of ALS in this couple was a random association.

Background: In the central nervous system regions of the sporadic and familial FTLD and ALS patients, TDP-43 has been identified as the major component of UBIs inclusions which is abnormally hyperphosphorylated, ubiquitinated, and cleaved into C-terminal fragments to form detergent-insoluble aggregates. So far, the effective drugs for FTLD and ALS neurodegenerative diseases are yet to be developed. Autophagy has been demonstrated as the major metabolism route of the pathological TDP-43 inclusions, hence activation of autophagy is a potential therapeutic strategy for TDP-43 pathogenesis in FTLD and ALS. Berberine, a traditional herbal medicine, is an inhibitor of mTOR signal and an activator for autophagy. Berberine has been implicated in several kinds of diseases, including the neuronal-related pathogenesis, such as Parkinson's, Huntington's and Alzheimer's diseases. However, the therapeutic effect of berberine on FTLD or ALS pathology has never been investigated., Results: Here we studied the molecular mechanism of berberine in cell culture model with TDP-43 proteinopathies, and found that berberine is able to reverse the processing of insoluble TDP-43 aggregates formation through deregulation of mTOR/p70S6K signal and activation of autophagic degradation pathway. And inhibition of autophagy by specific autophagosome inhibitor, 3-MA, reverses the effect of berberine on reducing the accumulation of insoluble TDP-43 and aggregates formation. These results gave us the notion that inhibition of autophagy by 3-MA reverses the effect of berberine on TDP-43 pathogenesis, and activation of mTOR-regulated autophagy plays an important role in berberine-mediated therapeutic effect on TDP-43 proteinopathies., Conclusion: We supported an important notion that the traditional herb berberine is a potential alternative therapy for TDP-43-related neuropathology. Here we demonstrated that berberine is able to reverse the processing of insoluble TDP-43 aggregates formation through deregulation of mTOR/p70S6K signal and activation of autophagic degradation pathway. mTOR-autophagy signals plays an important role in berberine-mediated autophagic clearance of TDP-43 aggregates. Exploring the detailed mechanism of berberine on TDP-43 proteinopathy provides a better understanding for the therapeutic development in FTLD and ALS.

In the present study, we performed a comprehensive analysis to clarify the clinicopathological characteristics of patients with amyotrophic lateral sclerosis (ALS) that had progressed to result in a totally locked-in state (communication Stage V), in which all voluntary movements are lost and communication is impossible. In 11 patients, six had phosphorylated TAR DNA-binding protein 43 (pTDP-43)-immunoreactive (ir) neuronal cytoplasmic inclusions (NCI), two had fused in sarcoma (FUS)-ir NCI, and three had copper/zinc superoxide dismutase (SOD1)-ir NCI. The time from ALS onset to the need for tracheostomy invasive ventilation was less than 24 months in ten patients. Regardless of accumulated protein, all the patients showed common lesions in the pallido-nigro-luysian system, brainstem reticular formation, and cerebellar efferent system, in addition to motor neurons. In patients with pTDP-43-ir NCI, patients with NCI in the hippocampal dentate granule neurons (DG) showed a neuronal loss in the cerebral cortex, and patients without NCI in DG showed a preserved cerebral cortex. By contrast, in patients with FUS-ir NCI, patients with NCI in DG showed a preserved cerebral cortex and patients without NCI in DG showed marked cerebral degeneration. The cerebral cortex of patients with SOD1-ir NCI was preserved. Together, these findings suggest that lesions of the cerebrum are probably not necessary for progression to Stage V. In conclusion, patients with ALS that had progressed to result in communication Stage V showed rapidly-progressed symptoms, and their common lesions could cause the manifestations of communication Stage V.

Amyotrophic Lateral Sclerosis (ALS) is the most frequent motor neuron disease in adults. Classical ALS is characterized by the death of upper and lower motor neurons leading to progressive paralysis. Approximately 10 % of ALS patients have familial form of the disease. Numerous different gene mutations have been found in familial cases of ALS, such as mutations in superoxide dismutase 1 (SOD1), TAR DNA-binding protein 43 (TDP-43), fused in sarcoma (FUS), C9ORF72, ubiquilin-2 (UBQLN2), optineurin (OPTN) and others. Multiple animal models were generated to mimic the disease and to test future treatments. However, no animal model fully replicates the spectrum of phenotypes in the human disease and it is difficult to assess how a therapeutic effect in disease models can predict efficacy in humans. Importantly, the genetic and phenotypic heterogeneity of ALS leads to a variety of responses to similar treatment regimens. From this has emerged the concept of personalized medicine (PM), which is a medical scheme that combines study of genetic, environmental and clinical diagnostic testing, including biomarkers, to individualized patient care. In this perspective, we used subgroups of specific ALS-linked gene mutations to go through existing animal models and to provide a comprehensive profile of the differences and similarities between animal models of disease and human disease. Finally, we reviewed application of biomarkers and gene therapies relevant in personalized medicine approach. For instance, this includes viral delivering of antisense oligonucleotide and small interfering RNA in SOD1, TDP-43 and C9orf72 mice models. Promising gene therapies raised possibilities for treating differently the major mutations in familial ALS cases.

Background: Amyotrophic lateral sclerosis (ALS) is an incurable neurodegenerative motor neuron disease that involves activation of the immune system and inflammatory response in the nervous system. Reduced level of the immuno-modulatory and anti-inflammatory protein alpha-1-antitrypsin (AAT) is associated with inflammation-related pathologies. The objective of the present is to determine AAT levels and IL-23 in the cerebrospinal fluid (CSF) of ALS patients and control group., Findings: CSF samples from newly diagnosed ALS patients and age-matched controls were analyzed for AAT and IL-23 by ELISA and magnetic luminex screening, respectively. A statistically significant reduction of 45 % in mean AAT levels was observed in the CSF of ALS patients (21.4 μg/ml) as compared to the control group (mean 38.8 μg/ml, p = 0.013). A statistically significant increase of 30.8 % in CSF mean levels of the pro-inflammatory cytokine IL-23 was observed in ALS patients (1647 pg/ml) in comparison to the controls (1259 pg/ml, p = 0.012). A negative correlation coefficient (r = -0.543) was obtained by linear regression analysis of the two measured parameters (p = 0.036)., Conclusions: Reduced AAT and elevated IL-23 CSF levels support the notion of neuroinflammatory process occurring in ALS patients. Increasing AAT levels in the patients' nervous system should be further investigated as a new therapeutic approach and a novel potential tool for ALS treatment.

Background: Amyotrophic lateral sclerosis (ALS) is a progressive neurological disease that selectively affects the motor neurons. The details of the mechanisms of selective motor-neuron death remain unknown and no effective therapy has been developed. We investigated the therapy with bone-marrow mononuclear cells (BMMC) in a mouse model of ALS (SOD1(G93A) mice)., Methods: We injected 10(6) BMMC into the lumbar portion of the spinal cord of SOD1(G93A) mice in presymptomatic (9 weeks old) and symptomatic (14 weeks old) phases. In each condition, we analyzed the progression of disease and the lifespan of the animals., Results: We observed a mild transitory delay in the disease progression in the animals injected with BMMC in the presymptomatic phase. However, we observed no increase in the lifespan. When we injected BMMC in the symptomatic phase, we observed no difference in the animals' lifespan or in the disease progression. Immunohistochemistry for NeuN showed a decrease in the number of motor neurons during the course of the disease, and this decrease was not affected by either treatment. Using different strategies to track the BMMC, we noted that few cells remained in the spinal cord after transplantation. This observation could explain why the BMMC therapy had only a transitory effect., Conclusion: This is the first report of intraspinal BMMC therapy in a mouse model of ALS. We conclude this cellular therapy has only a mild transitory effect when performed in the presymptomatic phase of the disease.

Background: The multidisciplinary approach in the management of Amyotrophic Lateral Sclerosis (ALS) has been shown to provide superior care to devolved care, with better survival, improved quality of care, and quality of life. Access to expert multidisciplinary management should be a standard for patients with ALS. This analysis explores the patient journey from symptom onset and first engagement with health services, to the initial visit to a specialist ALS Multidisciplinary Clinic (MDC) in Dublin, Ireland., Methods: A retrospective exploratory multi-method study details the patient journey to the MDC. Data from medical interviews and systematic chart review identifies interactions with the health services and key timelines for thirty five new patients presenting with a diagnosis of ALS during a 6 month period in 2013., Results: The time from first symptom to diagnosis was a mean of 16 months (median 13 months), with a mean interval of 19 months (median 14.6) from first symptoms to arrival at the MDC. The majority of patients were seen by a general practitioner, and subsequently by neurology services. There was an average of four contacts with health services and 4.8 investigations/tests, prior to their first Clinic visit. On the first visit to the MDC patients are linked into an integrated 'system' that can provide specialist care and link with voluntary, palliative and community services as required., Conclusions: Engagement with a multidisciplinary team has implications for service utilization and quality of life of patients and their families. We have demonstrated that barriers exist that delay referral to specialist services. Comprehensive data recording and collection, using multiple data sources can reconstruct the timelines of the patient journey, which can in turn be used to identify pathways that can expedite early referral to specialist services.

Background: To determine whether an integrated approach to coordination of care influences hospitalization and clinical outcomes in a chronic neurological disease, amyotrophic lateral sclerosis., Methods: We followed up 2452 patients with probable or definite amyotrophic lateral sclerosis from 2000 to 2012. Two cohorts were compared before and after the creation of a community care network for this disease in Ile de France in 2006. During these two periods, the medical and paramedical care teams and formal standards of care were identical; the only difference was the coordination by the network. To investigate hospital and emergency department use, we used number of patients, number of stays, and number of days. For clinical outcomes, we used slopes of functional deterioration, and Kaplan-Meier and Cox models for survival., Results: All hospitalization variables decreased after the creation of the network, which was not explained by admissions elsewhere. The slope of functional deterioration was significantly different before (1.03 ± 1.57 points/month) and after (0.79 ± 0.80 points/month; p = 0.002) creation of the network. Patients included in the network had a median survival time of 13.2 months more (log rank test; p < 0.001). In the Cox model, the network intervention was associated with a 45% decrease in relative risk of death during the period of the study (p < 0.001)., Conclusions: Network care was associated with fewer hospital admissions, reduced functional deterioration and later mortality in ALS. These results suggest that proactive coordination between carers in chronic and complex diseases could have a positive impact on hospitalization and the clinical course of the disease.

Background: We report the initial results from a phase I clinical trial for ALS. We transplanted GMP-grade, fetal human neural stem cells from natural in utero death (hNSCs) into the anterior horns of the spinal cord to test for the safety of both cells and neurosurgical procedures in these patients. The trial was approved by the Istituto Superiore di Sanità and the competent Ethics Committees and was monitored by an external Safety Board., Methods: Six non-ambulatory patients were treated. Three of them received 3 unilateral hNSCs microinjections into the lumbar cord tract, while the remaining ones received bilateral (n = 3 + 3) microinjections. None manifested severe adverse events related to the treatment, even though nearly 5 times more cells were injected in the patients receiving bilateral implants and a much milder immune-suppression regimen was used as compared to previous trials., Results: No increase of disease progression due to the treatment was observed for up to18 months after surgery. Rather, two patients showed a transitory improvement of the subscore ambulation on the ALS-FRS-R scale (from 1 to 2). A third patient showed improvement of the MRC score for tibialis anterior, which persisted for as long as 7 months. The latter and two additional patients refused PEG and invasive ventilation and died 8 months after surgery due to the progression of respiratory failure. The autopsies confirmed that this was related to the evolution of the disease., Conclusions: We describe a safe cell therapy approach that will allow for the treatment of larger pools of patients for later-phase ALS clinical trials, while warranting good reproducibility. These can now be carried out under more standardized conditions, based on a more homogenous repertoire of clinical grade hNSCs. The use of brain tissue from natural miscarriages eliminates the ethical concerns that may arise from the use of fetal material., Trial Registration: EudraCT:2009-014484-39 .

Background: Amyotrophic lateral sclerosis (ALS) leads to chronic respiratory failure. Diaphragmatic dysfunction, a major driver of dyspnea and mortality, is associated with a shift of the burden of ventilation to extradiaphragmatic inspiratory muscles, including neck muscles. Besides, energy expenditure is often abnormally high in ALS, and this is associated with a negative prognostic value. We hypothesized that noninvasive ventilation (NIV) would relieve inspiratory neck muscles and reduce resting energy expenditure (REE)., Methods: Using indirect calorimetry, we measured REE during spontaneous breathing (REESB) and NIV (REENIV) in 16 ALS patients with diaphragmatic dysfunction, during the first 3 months of NIV. Measured values were compared with predicted REE (REEpred)(Harris-Benedict equation)., Results: NIV abolished inspiratory neck muscle activity. Even though our patients were not hypermetabolic, on the contrary, with a REESB that was lower than REEpred (average 11%), NIV did reduce energy expenditure. Indeed, median REENIV, in this population with a mean body mass index of 21.4 kg.m-2, was 1149 kcal/24 h [interquartile 970-1309], lower than REESB (1197 kcal/24 h, 1054-1402; mean difference 7%; p = 0.03, Wilcoxon). REESB and REENIV were correlated with forced vital capacity and maximal inspiratory pressure., Conclusions: NIV can reduce energy expenditure in ALS patients probably by alleviating the ventilatory burden imposed on inspiratory neck muscles to compensate diaphragm weakness. It remains to be elucidated whether or not, in which population, and to what extent, NIV can be beneficial in ALS through the corresponding reduction in energy expenditure.

Background: Although multiple studies have estimated the prevalence of neurological conditions in the general Canadian population, limited research exists regarding the proportion affected with these conditions in non-acute health care settings in Canada. Data from standardized clinical assessments based on the interRAI suite of instruments were used to estimate the prevalence of eight neurological conditions across the continuum of care including Alzheimer's disease, Parkinson's disease, epilepsy, traumatic brain injury, multiple sclerosis, cerebral palsy, Huntington's disease, and amyotrophic lateral sclerosis., Methods: Cohorts of individuals receiving care in nursing homes (N=103,820), home care (N=91,021), complex continuing care (N=10,581), and psychiatric hospitals (N=23,119) in Canada were drawn based on their most recent interRAI assessment within each sector for a six-month period in 2010. These data were linked to the Discharge Abstract Database and National Ambulatory Care Reporting System data sets to develop five different case definition scenarios for estimating prevalence., Results: The conditions with the highest estimated prevalences in these care settings in Canada were Alzheimer's disease and related dementias, Parkinson's disease, epilepsy, and traumatic brain injury. However, there were notable cross-sector differences in the prevalence of each condition, and regional variations. Prevalence estimates based on acute hospital administrative data alone were substantially lower for all conditions evaluated., Conclusions: The proportion of persons with neurological conditions in non-acute health care settings in Canada is substantially higher than is generally reported for the general population. It is essential for these care settings to have the expertise and resources to respond effectively to the strengths, preferences, and needs of the growing population of persons with neurological conditions. The use of hospital or emergency department records alone is likely to substantially underestimate the true prevalence of neurological conditions across the continuum of care. However, interRAI assessment records provide a helpful source of information for obtaining these estimates in nursing home, home care, and mental health settings.

Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease affecting the neuromuscular system and does not have a known singular cause. Genetic mutations, extracellular factors, non-neuronal support cells, and the immune system have all been shown to play varied roles in clinical and pathological disease progression. The therapeutic plasticity of mesenchymal stem cells (MSCs) may be well matched to this complex disease pathology, making MSCs strong candidates for cellular therapy in ALS. In this review, we summarize a variety of explored mechanisms by which MSCs play a role in ALS progression, including neuronal and non-neuronal cell replacement, trophic factor delivery, and modulation of the immune system. Currently relevant techniques for applying MSC therapy in ALS are discussed, focusing in particular on delivery route and cell source. We include examples from in vitro, preclinical, and clinical investigations to elucidate the remaining progress that must be made to understand and apply MSCs as a treatment for ALS.

Background: Weight loss is a frequent feature in the motor neuron disease Amyotrophic lateral sclerosis (ALS). In this study we investigated possible causes of weight loss in ALS, its impact on mood/quality of life (QOL) and the benefit of high calorie nutritional/other dietary supplements and percutaneous endoscopic gastrostomy (PEG)., Methods: 121 ALS patients were interviewed and answered standardized questionnaires (Beck depression inventory - II, SF36 Health Survey questionnaire, revised ALS functional rating scale). Two years after the initial survey we performed a follow-up interview., Results: In our ALS-cohort, 56.3% of the patients suffered from weight loss. Weight loss had a negative impact on QOL and was associated with a shorter survival. Patients who took high calorie nutritional supplements respectively had a PEG stated a great benefit regarding weight stabilization and/or QOL.38.2% of our patients had significant weight loss without suffering from dysphagia. To clarify the reasons for weight loss in these patients, we compared them with patients without weight loss. The two groups did not differ regarding severity of disease, depression, frontotemporal dementia or fasciculations, but patients with weight loss declared more often increased respiratory work., Conclusions: Weight loss is a serious issue in ALS and cannot always be attributed to dysphagia. Symptomatic treatment of weight loss (high calorie nutritional supplements and/ or PEG) should be offered more frequently.

Background: Human marrow stromal cells (hMSCs) injected intrathecally can effectively increase the lifespan and protect motor neurons in a transgenic mouse model of amyotrophic lateral sclerosis. However, how the transplanted cells exert a neuroprotective effect is still unclear. More recently, the anti-inflammation effect of marrow stromal cells has generated a great deal of interest. In the present study, we sought to investigate whether intrathecally injected hMSCs protect motor neurons through attenuating microglial activation and the secretion of inflammatory factors in Cu/Zn superoxide dismutase 1 (SOD1) transgenic mice. In addition, we also focused on the mode of hMSCs inhibiting microglial activation., Methods: We transplanted hMSCs into the cisterna magna of SOD1 mice at the age of 8, 10 and 12 weeks. At sacrifice, tissues were harvested for analysis of neuron counts, microglial activation, TNFα secretion and inducible nitric oxide synthase (iNOS) protein expression. In vitro, microglial cells were treated with hMSC co-culture, hMSC transwell culture or hMSC conditioned medium to investigate the mode of hMSCs exerting an anti-inflammation effect., Results: Intrathecally transplanted hMSCs inhibited inflammatory response in SOD1 transgenic mice, which was evidenced by the decreases in microglial activation, TNFα secretion and iNOS protein expression. In addition, the inhibitory effect on microglial activation of hMSCs was through secretion of diffusible molecules adjusted to environmental cues., Conclusion: Intrathecally injected hMSCs can attenuate microglial activation through secretion of diffusible molecules to exert a therapeutic effect in SOD1 transgenic mice. Further studies are needed to explore the exact mechanisms by which hMSCs inhibit inflammation for facilitating the therapeutic effect.

Despite some advances in the understanding of amyotrophic lateral sclerosis (ALS) pathogenesis, significant achievements in treating this disease are still lacking. Mesenchymal stromal (stem) cells (MSCs) have been shown to be effective in several models of neurological disease. To determine the effects of the intravenous injection of MSCs in an ALS mouse model during the symptomatic stage of disease, MSCs (1 × 10⁶) were intravenously injected in mice expressing human superoxide dismutase 1 (SOD1) carrying the G93A mutation (SOD1/G93A) presenting with experimental ALS. Survival, motor abilities, histology, oxidative stress markers and [³H]D-aspartate release in the spinal cord were investigated. MSC injection in SOD1/G93A mice improved survival and motor functions compared with saline-injected controls. Injected MSCs scantly home to the central nervous system and poorly engraft. We observed a reduced accumulation of ubiquitin agglomerates and of activated astrocytes and microglia in the spinal cord of MSC-treated SOD1/G93A mice, with no changes in the number of choline acetyltransferase- and glutamate transporter type 1-positive cells. MSC administration turned around the upregulation of metallothionein mRNA expression and of the activity of the antioxidant enzyme glutathione S-transferase, both associated with disease progression. Last, we observed that MSCs reverted both spontaneous and stimulus-evoked neuronal release of [³H]D-aspartate, a marker of endogenous glutamate, which is upregulated in SOD1/G93A mice. These findings suggest that intravenous administration of MSCs significantly improves the clinical outcome and pathological scores of mutant SOD1/G93A mice, thus providing the rationale for their exploitation for the treatment of ALS.

Mesenchymal stem cell (MSC) therapy is considered one of the most promising approaches for treating different neurodegenerative disorders, including amyotrophic lateral sclerosis (ALS). We previously characterized a subpopulation of human skeletal muscle-derived stem cells (SkmSCs) with MSC-like characteristics that differentiate into the neurogenic lineage in vitro. In the present study, we evaluated the SkmSC therapeutic effects in the most characterized model of spontaneous motor neuron degeneration, the Wobbler (Wr) mouse. Before evaluating the therapeutic efficacy in the Wr mouse, we followed the route of Skm-SCs at different times after intracerebroventricular injection. Two exogenous tracers, superparamagnetic iron oxide (SPIO) nanoparticles and Hoechst 33258, were used for the in vivo and ex vivo tracking of SkmSCs. We found that the loading of both Hoechst and SPIO was not toxic and efficiently labeled SkmSCs. The magnetic resonance imaging (MRI) system 7 Tesla allowed us to localize transplanted SkmSCs along the whole ventricular system up to 18 wks after injection. The ex vivo Hoechst 33258 visualization confirmed the in vivo results obtained by MRI analyses. Behavioral observations revealed a fast and sustained improvement of motor efficacy in SkmSC-treated Wr mice associated with a relevant protection of functional neuromuscular junctions. Moreover, we found that in SkmSC-treated Wr mice, a significant increase of important human antiinflammatory cytokines occurred. This evidence is in accordance with previous findings showing the bystander effect of stem cell transplantation in neurodegenerative disorders and further strengthens the hypothesis of the possible link between inflammation, cytotoxicity and ALS.

Background: Amyotrophic lateral sclerosis (ALS) is one of the most devastating neurodegenerative diseases. Neurotrophic factors have been widely tested to counteract neurodegenerative conditions, despite their unspecific neuronal access. The non-toxic C-terminal fragment of the tetanus toxin (TTC) heavy chain has been studied not only as a carrier molecule to the CNS but also as a neuroprotective agent. Because the neurotrophic effects of BDNF have been demonstrated in vitro and in vivo, the question addressed in this work is whether a fusion molecule of BDNF-TTC may have a synergistic effect and enhance the neuroprotective properties of TTC alone in a mouse model of ALS., Methods: Recombinant plasmid constructs (pCMV-TTC and pCMV-BDNF-TTC) were injected into the quadriceps femoris and triceps brachialis muscles of SOD1(G93A) transgenic mice at 8 weeks of age. The hanging wire and rotarod tests were performed to assess motor coordination, strength and balance. Electrophysiological tests, morphological assays of spinal cord sections of L2 and L4 segments, and gene and protein expression analyses were performed. The Kaplan-Meier survival analysis test was used for comparisons of survival. Multiple comparisons of data were analyzed using a one-way analysis of variance (ANOVA)., Results: Treatment with the fusion-molecule BDNF-TTC and with TTC alone significantly delayed the onset of symptoms and functional deficits of SOD1(G93A) mice. Muscle innervation was partially preserved with these treatments, and the number of surviving motoneurons in L2 spinal cord segment was increased particularly by the fusion protein induction. Inhibition of pro-apoptotic protein targets (caspase-3 and Bax) and significant phosphorylation of Akt and ERK were also found in the spinal cord of treated mice., Conclusions: Significant improvements in behavioral and electrophysiological results, motoneuron survival and anti-apoptotic/survival-activated pathways were observed with BDNF-TTC treatment. However, no synergistic effect was found for this fusion molecule. Although BDNF in the fusion molecule is capable of activating autocrine and neuroprotective pathways, TTC treatment alone yielded similar neuroprotection. Therefore, an accurate study of the neuroprotective effects of TTC fusion molecules should be performed to obtain a better understanding of its effects.

Stem cells offer an enormous pool of resources for the understanding of the human body. One proposed use of stem cells has been as an autologous therapy. The use of stem cells for neurodegenerative diseases has become of interest. Clinical applications of stem cells for Alzheimer disease, Parkinson disease, amyotrophic lateral sclerosis, and multiple sclerosis will increase in the coming years, and although great care will need to be taken when moving forward with prospective treatments, the application of stem cells is highly promising.

Background: Amyotrophic lateral sclerosis (ALS) is a disease affecting the central nervous system that is either sporadic or familial origin and causing the death of motor neurons. One of the genetic factors contributing to the etiology of ALS is mutant SOD1 (mtSOD1), which induces vulnerability of motor neurons through protein misfolding, mitochondrial dysfunction, oxidative damage, cytoskeletal abnormalities, defective axonal transport, glutamate excitotoxicity, inadequate growth factor signaling, and neuroinflammation. Bee venom has been used in the practice of Oriental medicine and evidence from the literature indicates that BV plays an anti-inflammatory or anti-nociceptive role against inflammatory reactions associated with arthritis and other inflammatory diseases. The purpose of the present study was to determine whether bee venom suppresses motor neuron loss and microglial cell activation in hSOD1G93A mutant mice., Methods: Bee venom (BV) was bilaterally injected (subcutaneously) into a 14-week-old (98 day old) male hSOD1G93A animal model at the Zusanli (ST36) acupoint, which is known to mediate an anti-inflammatory effect. For measurement of motor activity, rotarod test was performed and survival statistics were analyzed by Kaplan-Meier survival curves. The effects of BV treatment on anti-neuroinflammation of hSOD1G93A mice were assessed via immunoreactions using Iba 1 as a microglia marker and TNF-α antibody. Activation of ERK, Akt, p38 MAP Kinase (MAPK), and caspase 3 proteins was evaluated by western blotting., Results: BV-treated mutant hSOD1 transgenic mice showed a decrease in the expression levels of microglia marker and phospho-p38 MAPK in the spinal cord and brainstem. Interestingly, treatment of BV in symptomatic ALS animals improved motor activity and the median survival of the BV-treated group (139 ± 3.5 days) was 18% greater than control group (117 ± 3.1 days). Furthermore, we found that BV suppressed caspase-3 activity and blocked the defects of mitochondrial structure and cristae morphology in the lumbar spinal cord of hSOD1G93A mice at the symptomatic stage., Conclusion: From these findings, our research suggests BV could be a potential therapeutic agent for anti-neuroinflammatory effects in an animal model of ALS.

Background: Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease, which rapidly leads to chronic respiratory failure requiring mechanical ventilation. Currently, forced vital capacity (FVC) < 50% is considered as physiologic marker for admitting patients to Noninvasive Positive Pressure Ventilation (NPPV) intervention, although it has been recently shown the median survival of patients with baseline FVC < 75% much shorter than median survival of patients with baseline FVC > 75%, independently by any treatment., Aim: To assess the role of NPPV in improving outcome of ALS, a retrospective analysis was performed to investigate 1 year survival of ALS patients with FVC < 75% and nocturnal respiratory insufficiency, treated with NPPV, compared to a well-matched population of ALS patients, who refused or was intolerant to NPPV., Methods: We investigated seventy-two consecutive ALS patients who underwent pulmonary function test. Forty-four presented a FVC > 75% and served as control group. Twenty-eight patients presented a FVC < 75% and showed, at polysomnography analysis, nocturnal respiratory insufficiency, requiring NPPV; sixteen were treated with NPPV, while twelve refused or were intolerant., Results: Increased survival rate at 1 year in patients with FVC < 75% treated with NPPV, as compared to those who refused or could not tolerate NPPV (p = 0.02), was observed. The median rate of decline in FVC% was slower in NPPV patients than in patients who did not use NPPV (95% CI: 0.72 to 1.85; p < 0.0001)., Conclusion: This report demonstrates that early treatment with NPPV prolongs survival and reduces decline of FVC% in ALS.