Disease Progression In Amyotrophic Lateral Sclerosis Research Articles

Assessing the Measurement Properties of the Self-Administered Amyotrophic Lateral Sclerosis Functional Rating Scale-Revised (ALSFRS-R): A Rasch Analysis.

The self-administered version of the Amyotrophic Lateral Sclerosis Functional Rating Scale-Revised (ALSFRS-R) is used to monitor function and disease progression in individuals with Amyotrophic Lateral Sclerosis (ALS). However, the performance of the self-administered ALSFRS-R has not been assessed using Rasch Measurement Theory. Therefore, the purpose of this study was to examine the psychometric properties of the self-administered ALSFRS-R using Rasch analysis. Rasch analysis was performed on self-administered ALSFRS-R data from individuals with ALS across Canada. The following 6 aspects of Rasch analysis were examined using RUMM2030: fit via residuals and chi-square statistics, targeting via person-item threshold maps, dependency via item residual correlations, unidimensionality through principal components analysis of residuals, reliability via person separation index, and stability through differential item functioning analyses for sex, age, and language. Analysis was performed on 122 participants (mean age: 52.9years; 62.8% men). The overall scale demonstrated good fit, reliability, and stability; however, multidimensionality was found. To address this issue, items were divided into 3 subscales (bulbar, motor, and respiratory function), and Rasch analysis was performed for each subscale. The subscales demonstrated good fit, reliability, stability, and unidimensionality. However, there were still issues with item dependency for all subscale and targeting for bulbar and respiratory subscales. The self-administered ALSFRS-R is reliable, internally valid, and stable across sex, age, and language subgroups; however, it is recommended that the ALSFRS-R be scored by subscale. Future studies can look at revising and/or adding items to tackle misfit, redundancy, and ceiling effects. Self-administered measures are simple to administer and inexpensive. The self-administered ALSFRS-R was found to be psychometrically sound and can be used as a tool to monitor disease progression and function in ALS.

An Increase in Peroxiredoxin 6 Expression Induces Neurotoxic A1 Astrocytes in the Lumbar Spinal Cord of Amyotrophic Lateral Sclerosis Mice Model.

Amyotrophic lateral sclerosis (ALS) is a severe neurodegenerative disease with selective degeneration of motor neurons. It has been reported that an increase in the levels of inflammatory cytokines and glial cells such as reactive astrocytes is closely involved in the pathological progression of ALS. Recently, the levels of neuropathic cytotoxic (A1) astrocytes among reactive astrocytes have reportedly increased in the central nervous system of ALS mice, which induce motor neuron degeneration through the production of inflammatory cytokines and secretion of neuropathic factors. Hence, elucidating the induction mechanism of A1 astrocytes in ALS is important to understand the mechanism of disease progression in ALS. In this study, we observed that the expression of peroxiredoxin 6 (PRDX6), a member of the peroxiredoxin family, was markedly upregulated in astrocytes of the lumbar spinal cord of SOD1G93A mice model for ALS. Additionally, when PRDX6 was transiently transfected into the mouse astrocyte cell line C8-D1A and human astrocytoma cell line U-251 MG, the mRNA expression of complement C3 (a marker for A1 astrocyte phenotype) and inflammatory cytokines was increased. Furthermore, the mRNA expression of C3 and inflammatory cytokine was increased in C8-D1A and U-251 MG cells stably expressing PRDX6, and the increased mRNA expression was significantly suppressed by MJ33 (lithium[1-hexadecoxy-3-(2,2,2-trifluoroethoxy) propan-2-yl] methyl phosphate), an inhibitor of the phospholipase A2 activity of PRDX6. Our results suggest that the expression of PRDX6 in astrocytes plays an important role in the induction of A1 astrocytes and expression of inflammatory cytokines in the ALS mice model.

Glycogen accumulation modulates life span in a mouse model of amyotrophic lateral sclerosis.

Amyotrophic lateral sclerosis (ALS) is a devastating neurodegenerative disease characterized by the progressive loss of motor neurons in the spinal cord. Glial cells, including astrocytes and microglia, have been shown to contribute to neurodegeneration in ALS, and metabolic dysfunction plays an important role in the progression of the disease. Glycogen is a soluble polymer of glucose found at low levels in the central nervous system that plays an important role in memory formation, synaptic plasticity, and the prevention of seizures. However, its accumulation in astrocytes and/or neurons is associated with pathological conditions and aging. Importantly, glycogen accumulation has been reported in the spinal cord of human ALS patients and mouse models. In the present work, using the SOD1G93A mouse model of ALS, we show that glycogen accumulates in the spinal cord and brainstem during symptomatic and end stages of the disease and that the accumulated glycogen is associated with reactive astrocytes. To study the contribution of glycogen to ALS progression, we generated SOD1G93A mice with reduced glycogen synthesis (SOD1G93A GShet mice). SOD1G93A GShet mice had a significantly longer life span than SOD1G93A mice and showed lower levels of the astrocytic pro-inflammatory cytokine Cxcl10, suggesting that the accumulation of glycogen is associated with an inflammatory response. Supporting this, inducing an increase in glycogen synthesis reduced life span in SOD1G93A mice. Altogether, these results suggest that glycogen in reactive astrocytes contributes to neurotoxicity and disease progression in ALS.

Autonomic dysfunction is associated with disease progression and survival in amyotrophic lateral sclerosis: a prospective longitudinal cohort study

BackgroundAmong non-motor symptoms, autonomic disturbances have been described in amyotrophic lateral sclerosis (ALS) and reported as mild to moderate in up to 75% of patients. However, no study has systematically investigated autonomic symptoms as prognostic factors.ObjectivesThe main aim of this longitudinal study was to examine the association of autonomic dysfunction with disease progression and survival in ALS.MethodsWe enrolled newly diagnosed ALS patients and a healthy control group (HC). Time from disease onset to disease milestone (King’s stage 4) and death were calculated to assess disease progression and survival. Autonomic symptoms were assessed by a dedicated questionnaire. Longitudinal evaluation of parasympathetic cardiovascular activity was performed by the heart rate variability (HRV). Multivariable Cox proportional hazards regression models on the risk of the disease milestone and death were used. A mixed-effect linear regression model was used to compare autonomic dysfunction with a HC group as well as its impairment over time.ResultsA total of 102 patients and 41 HC were studied. ALS patients, compared with HC, complained of more autonomic symptoms, especially in bulbar onset patients. Autonomic symptoms occurred in 69 (68%) patients at diagnosis and progressed over time (post-6: p = 0.015 and post-12: p < 0.001). A higher autonomic symptom burden was an independent marker of faster development of King’s stage 4 (HR 1.05; 95% CI 1.00–1.11; p = 0.022); whereas, urinary complaints were independent factors of a shorter survival (HR 3.12; 95% CI 1.22–7.97; p = 0.018). Moreover, HRV in ALS patients was lower than in HC (p = 0.018) and further decreased over time (p = 0.003), implying a parasympathetic hypofunction that progressed over time.ConclusionAutonomic symptoms occur in most of the ALS patients at diagnosis and progress over time, implying that autonomic dysfunction represents an intrinsic non-motor feature of the disease. A higher autonomic burden is a poor prognostic factor, associated with a more rapid development of disease milestones and shorter survival.

Development of a Rasch-Built Amyotrophic Lateral Sclerosis Impairment Multidomain Scale to Measure Disease Progression in ALS.

Current scales used in amyotrophic lateral sclerosis (ALS) attempt to summarize different functional domains or "dimensions" into 1 overall score, which may not accurately characterize the individual patient's disease severity or prognosis. The use of composite score risks declaring treatments ineffective if not all dimensions of ALS disease progression are affected equally. We aimed to develop the ALS Impairment Multidomain Scale (AIMS) to comprehensively characterize disease progression and increase the likelihood of identifying effective treatments. The Revised ALS Functional Rating Scale (ALSFRS-R) and a preliminary questionnaire, based on literature review and patient input, were completed online by patients from the Netherlands ALS registry at bimonthly intervals over a period of 12 months. A 2-week test-retest, factor analysis, Rasch analysis, and a signal-to-noise optimization strategy were performed to create a multidomain scale. Reliability, longitudinal decline, and associations with survival were evaluated. The sample size required to detect a 35% reduction in progression rate over 6 or 12 months was assessed for a clinical trial that defines the ALSFRS-R or AIMS subscales as a primary endpoint family. The preliminary questionnaire, consisting of 110 questions, was completed by 367 patients. Three unidimensional subscales were identified, and a multidomain scale was constructed with 7 bulbar, 11 motor, and 5 respiratory questions. Subscales fulfilled Rasch model requirements, with excellent test-retest reliability of 0.91-0.94 and a strong relationship with survival (p < 0.001). Compared with the ALSFRS-R, signal-to-noise ratios were higher as patients declined more uniformly per subscale. Consequently, the estimated sample size reductions achieved with the AIMS compared with those achieved with the ALSFRS-R were 16.3% and 25.9% for 6-month and 12-month clinical trials, respectively. We developed the AIMS, consisting of unidimensional bulbar, motor, and respiratory subscales, which may characterize disease severity better than a total score. AIMS subscales have high test-retest reliability, are optimized to measure disease progression, and are strongly related to survival time. The AIMS can be easily administered and may increase the likelihood of identifying effective treatments in ALS clinical trials.

EE32 Impact of Amyotrophic Lateral Sclerosis Disease Progression on Health Care Resource Use and Health-Related Quality of Life Using MiToS Staging and ALSFRS-R: Analysis of a Real-World Cross-Sectional Survey

To evaluate healthcare resource use (HCRU) and health-related quality of life (HRQOL) in people living with amyotrophic lateral sclerosis (ALS) according to Milano-Torino staging (MiToS) and ALS Functional Rating Scale-Revised (ALSFRS-R) total scores.

Efficacy and safety of CNM-Au8 in amyotrophic lateral sclerosis (RESCUE-ALS study): a phase 2, randomised, double-blind, placebo-controlled trial and open label extension.

CNM-Au8® is a catalytically-active gold nanocrystal neuroprotective agent that enhances intracellular energy metabolism and reduces oxidative stress. The phase 2, randomised, double-blind, placebo-controlled trial and open label extension RESCUE-ALS trial evaluated the efficacy and safety of CNM-Au8 for treatment of amyotrophic lateral sclerosis (ALS). RESCUE-ALS and its long-term open label extension (OLE) were conducted at two multidisciplinary ALS clinics located in Sydney, Australia: (i) the Brain and Mind Centre and (ii) Westmead Hospital. The double-blind portion of RESCUE-ALS was conducted from January 16, 2020 (baseline visit, first-patient first-visit (FPFV)) through July 13, 2021 (double-blind period, last-patient last-visit (LPLV)). Participants (N=45) were randomised 1:1 to receive 30mg of CNM-Au8 or matching placebo daily over 36 weeks in addition to background standard of care, riluzole. The primary outcome was mean percent change in summed motor unit number index (MUNIX), a sensitive neurophysiological biomarker of lower motor neuron function. Change in total (or summated) MUNIX score and change in forced vital capacity (FVC) were secondary outcome measures. ALS disease progression events, ALS Functional Rating Scale (ALSFRS-R) change, change in quality of life (ALSSQOL-SF) were assessed as exploratory outcome measures. Long-term survival evaluated vital status of original active versus placebo randomisation for all participants through at least 12 months following last-patient last-visit (LPLV) of the double-blind period. RESCUE-ALS and the open label study are registered in clinicaltrials.gov with registration numbers NCT04098406 and NCT05299658, respectively. In the intention-to-treat (ITT) population, there was no significant difference in the summated MUNIX score percent change (LS mean difference: 7.7%, 95% CI:-11.9 to 27.3%, p=0.43), total MUNIX score change (18.8, 95% CI:-56.4 to 94.0), or FVC change (LS mean difference: 3.6, 95% CI:-12.4 to 19.7) between the active and placebo treated groups at week 36. In contrast, survival analyses through 12-month LPLV demonstrated a 60% reduction in all-cause mortality with CNM-Au8 treatment [hazard ratio=0.408 (95% Wald CI: 0.166 to 1.001, log-rank p=0.0429). 36 participants entered the open label extension (OLE), and those initially randomised to CNM-Au8 exhibited a slower rate of disease progression, as measured by time to the occurrence of death, tracheostomy, initiation of non-invasive ventilatory support, or gastrostomy tube placement. CNM-Au8 was well-tolerated, and no safety signals were observed. CNM-Au8, in combination with riluzole, was well-tolerated in ALS with no identified safety signals. While the primary and secondary outcomes of this trial were not significant, the clinically meaningful exploratory results support further investigation of CNM-Au8 in ALS. The RESCUE-ALS was substantially funded by a grant from FightMND. Additional funding was provided by Clene Australia Pty Ltd.

Neurofilament accumulations in amyotrophic lateral sclerosis patients’ motor neurons impair axonal initial segment integrity

Amyotrophic lateral sclerosis (ALS) is the most common motor neuron (MN) disease in adults with no curative treatment. Neurofilament (NF) level in patient’ fluids have recently emerged as the prime biomarker of ALS disease progression, while NF accumulation in MNs of patients is the oldest and one of the best pathological hallmarks. However, the way NF accumulations could lead to MN degeneration remains unknown. To assess NF accumulations and study the impact on MNs, we compared MNs derived from induced pluripotent stem cells (iPSC) of patients carrying mutations in C9orf72, SOD1 and TARDBP genes, the three main ALS genetic causes. We show that in all mutant MNs, light NF (NF-L) chains rapidly accumulate in MN soma, while the phosphorylated heavy/medium NF (pNF-M/H) chains pile up in axonal proximal regions of only C9orf72 and SOD1 MNs. Excitability abnormalities were also only observed in these latter MNs. We demonstrate that the integrity of the MN axonal initial segment (AIS), the region of action potential initiation and responsible for maintaining axonal integrity, is impaired in the presence of pNF-M/H accumulations in C9orf72 and SOD1 MNs. We establish a strong correlation between these pNF-M/H accumulations, an AIS distal shift, increased axonal calibers and modified repartition of sodium channels. The results expand our understanding of how NF accumulation could dysregulate components of the axonal cytoskeleton and disrupt MN homeostasis. With recent cumulative evidence that AIS alterations are implicated in different brain diseases, preserving AIS integrity could have important therapeutic implications for ALS.

Non-Invasive Mechanical Ventilation slows motor decline in Amyotrophic Lateral Sclerosis: a population-based study (P10-8.003)

<h3>Objective:</h3> To test whether Non-Invasive Mechanical Ventilation (NIMV) use improved the rate of motor decline among ALS patients. <h3>Background:</h3> The efficacy of NIMV in improving Amyotrophic Lateral Sclerosis (ALS) survival and quality of life is well established. However, data regarding its effect on disease progression are still lacking. <h3>Design/Methods:</h3> This population-based cohort study included 630 patients with ALS from the Piemonte and Valle d’Aosta Register for ALS (PARALS) who were followed up after NIV initiation. Motor function was evaluated with the ALS Functional Rating Score – Revised (ALSFRS-R). Mixed-effect models for longitudinal data were performed to assess change in the rate of functional decline after NIMV initiation. <h3>Results:</h3> NIMV was associated with a ~30% reduction in the ΔALSFRS-R (post-NIMV difference in ΔALSFRS-R −0.46, 97.5% CI −0.43 to −0.49, p&lt;0.0001). The NIMV-related slowing was present on bulbar symptoms (post-NIMV difference in ΔALSFRS-R −0.08, 97.5% CI −0.065 to −0.010, p &lt; 0.0001) and even greater on spinal function (post-NIMV difference in ΔALSFRS-R −0.42, 97.5% CI −0.39 to −0.46, p &lt; 0.0001). All patients benefitted from NIMV usage, regardless of age, site of symptoms onset and presence of cognitive impairment. <h3>Conclusions:</h3> We demonstrate that NIMV significantly improves the rate of disease progression in ALS, regardless of age at symptoms onset, disease duration, presence of bulbar dysfunction or cognitive impairment. Our results reinforce the importance of not delaying NIMV initiation. In addition, NIMV-induced slowing of disease progression should also be accounted for when evaluating clinical trial outcomes. Further studies are required to optimize the effectiveness of respiratory care on disease progression in ALS. <b>Disclosure:</b> Mr. Grassano has nothing to disclose. Dr. Koumantakis has nothing to disclose. Cristina Moglia has nothing to disclose. Antonio Canosa has nothing to disclose. Dr. Manera has nothing to disclose. Dr. Vasta has nothing to disclose. Francesca Palumbo has nothing to disclose. Mr. Callegaro has nothing to disclose. Dr. Marchese has nothing to disclose. Paolina Salamone has nothing to disclose. Dr. Fuda has nothing to disclose. Federico Casale has nothing to disclose. Dr. Calvo has nothing to disclose. Dr. Mora has nothing to disclose. Dr. Chio has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Cytokinetics. Dr. Chio has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Mitsubishi. Dr. Chio has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Biogen.

Structural and functional connectome alterations across King’s stages in amyotrophic lateral sclerosis (S33.006)

<h3>Objective:</h3> To explore the rearrangements of structural and functional connectivity within and among brain networks underlying the clinical spreading of amyotrophic lateral sclerosis (ALS), as described by the King’s staging system, in order to suggest objective, continuous measures mirroring disease progression. <h3>Background:</h3> The identification of quantitative and reproducible markers of disease progression in ALS is of paramount importance for study design and inclusion of homogenous patient cohorts into clinical trials, as there is currently no validated disease-stage biomarker for ALS. <h3>Design/Methods:</h3> 104 patients with ALS and 61 age- and sex-matched healthy controls underwent clinical and brain magnetic resonance imaging (MRI) on a 3T scanner. Patients were stratified into four groups, according to the King’s staging system. No patient had comorbid frontotemporal dementia. Structural and functional connectivity values within and between different anatomical brain regions were obtained using diffusion tensor and resting-state functional MRI data, respectively. Comparisons between groups were performed using age- and sex-adjusted ANOVA models. Correlations were tested using Pearson’s coefficient. <h3>Results:</h3> Compared with controls, a significant, progressive reduction of structural connectivity within brain nodes of the sensorimotor network was observed in ALS patients across King’s stages 2, 3 and 4 (p&lt;0.006). Patients in stages 3 and 4 also showed significant loss of structural connectivity between frontal and sensorimotor regions (p=0.001). A significant disruption of functional connectivity within frontotemporal regions was found only in stage 4 (p=0.025). Sensorimotor structural connectivity showed a strong correlation with ALSFRS-r scores (r=0.31, p=0.001). <h3>Conclusions:</h3> Brain MRI allows to demonstrate and quantify increasing disruption of structural connectivity involving the sensorimotor and frontal networks in ALS, mirroring disease progression. Frontotemporal functional disconnection seems to characterize only advanced disease stages. Our findings demonstrate the utility of MRI connectomics to stratify patients and stage brain pathology in ALS in a reproducible way, which mirrors clinical progression. <b>Disclosure:</b> Dr. Spinelli has nothing to disclose. Miss Ghirelli has nothing to disclose. Silvia Basaia has nothing to disclose. Ms. Cividini has nothing to disclose. Nilo Riva has nothing to disclose. Dr. Russo has nothing to disclose. The institution of Elisa Canu has received research support from Italian Ministry of Health . Dr. Castelnovo has nothing to disclose. Dr. Filippi has received personal compensation in the range of $5,000-$9,999 for serving as a Consultant for Bayer, Biogen Idec, Merck-Serono, Novartis, Roche, Sanofi Genzyme, Takeda, and Teva Pharmaceutical Industries. Dr. Filippi has received personal compensation in the range of $5,000-$9,999 for serving on a Speakers Bureau for Bayer, Biogen Idec, Merck-Serono, Novartis, Roche, Sanofi Genzyme, Takeda, and Teva Pharmaceutical Industries. Dr. Filippi has received personal compensation in the range of $5,000-$9,999 for serving as an Editor, Associate Editor, or Editorial Advisory Board Member for Springer Nature. The institution of Dr. Filippi has received research support from Biogen Idec, Merck-Serono, Novartis, Roche, Teva Pharmaceutical Industries, Italian Ministry of Health, Fondazione Italiana Sclerosi Multipla, and ARiSLA (Fondazione Italiana di Ricerca per la SLA). Federica Agosta has received personal compensation in the range of $500-$4,999 for serving on a Speakers Bureau for Philips. Federica Agosta has received personal compensation in the range of $500-$4,999 for serving as an Editor, Associate Editor, or Editorial Advisory Board Member for Elsevier INC.

Small Molecule Positive Modulator of Hepatocyte Growth Factor (HGF)/MET, ATH-1105, Improves Function and Reduces Disease Biomarkers in a TDP-43 Mouse Model of Amyotrophic Lateral Sclerosis (P8-8.007)

<h3>Objective:</h3> Evaluate the preclinical efficacy of the small molecule positive modulator of hepatocyte growth factor (HGF)/MET, ATH-1105, in a mouse model of amyotrophic lateral sclerosis (ALS). <h3>Background:</h3> Activation of the MET receptor by HGF promotes neuroprotective, neurotrophic, and anti-inflammatory mechanisms. Small molecule positive modulators of HGF/MET, including ATH-1105, have been developed to explore the therapeutic potential of this target. ALS is characterized by progressive motor neuron degeneration and demyelination, accompanied by systemic inflammation and pathological aggregation of TAR DNA-binding protein 43 (TDP-43) in 97% of patients. We hypothesized that treatment with ATH-1105 would be beneficial in a TDP-43 mouse model of ALS. <h3>Design/Methods:</h3> ATH-1105 at 10 or 20 mg/kg was orally administered daily to male Prp-TDP43_A315T mice (n=10/group) for two months. At baseline and after one and two months of treatment, we conducted a battery of motor behavior tests, and assessed sciatic nerve health by compound muscle action potential (CMAP) and nerve conduction velocity (NCV) measurements. Plasma biomarkers of inflammation (IL-6, TNF-α) and neurodegeneration (neurofilament light chain [NfL]) were interrogated after one and two months of treatment. Sciatic nerves were stained for quantification of axonal and myelin parameters as well as phospho-TDP-43 aggregation at study termination. <h3>Results:</h3> The deterioration of motor function in TDP-43 animals was significantly mitigated in a dose-dependent manner after treatment with ATH-1105, and significant functional improvement of sciatic nerve conduction was observed. Additionally, plasma levels of all biomarkers assessed were significantly decreased, indicating reduced systemic inflammation and neurodegeneration in treated TDP-43 mice. Sciatic nerve histology revealed a protection of motor axon numbers and myelination, as well as a reduction in axonal phospho-TDP-43 aggregation by ATH-1105. <h3>Conclusions:</h3> ATH-1105 was found to be protective across a multitude of functional and structural measures of ALS disease progression. These findings support the continued development of this small molecule positive modulator of HGF/MET for ALS. <b>Disclosure:</b> Mrs. Kleist has received personal compensation for serving as an employee of Athira Pharma. Mrs. Kleist has received personal compensation for serving as an employee of Alpine Immune Sciences. Mrs. Kleist has stock in Athira Pharma. Mrs. Kleist has stock in Alpine Immune Sciences. Dr. Berthiaume has received personal compensation for serving as an employee of Athira Pharma. Dr. Berthiaume has stock in Athira Pharma. An immediate family member of Dr. Berthiaume has stock in Athira Pharma. Dr. Johnston has received personal compensation for serving as an employee of Athira Pharma, Inc. Dr. Johnston has stock in Athira Pharma, Inc. An immediate family member of Dr. Johnston has stock in Athira Pharma, Inc. Dr. Johnston has received intellectual property interests from a discovery or technology relating to health care. Dr. Reda has received personal compensation for serving as an employee of Athira Pharma, Inc. . Dr. Reda has stock in Athira Pharma, Inc. . Dr. Moebius has received personal compensation in the range of $100,000-$499,999 for serving as an officer or member of the Board of Directors for Athira Pharma, Inc.. Dr. Moebius has stock in Athira Pharma, Inc.. Dr. Church has received personal compensation for serving as an employee of Athira Pharma. Dr. Church has stock in Athira Pharma. Dr. Church has received intellectual property interests from a discovery or technology relating to health care.

Molecular and Physiological Determinants of Amyotrophic Lateral Sclerosis: What the DJ-1 Protein Teaches Us.

Amyotrophic lateral sclerosis (ALS) is an adult-onset disease which causes the progressive degeneration of cortical and spinal motoneurons, leading to death a few years after the first symptom onset. ALS is mainly a sporadic disorder, and its causative mechanisms are mostly unclear. About 5-10% of cases have a genetic inheritance, and the study of ALS-associated genes has been fundamental in defining the pathological pathways likely also involved in the sporadic forms of the disease. Mutations affecting the DJ-1 gene appear to explain a subset of familial ALS forms. DJ-1 is involved in multiple molecular mechanisms, acting primarily as a protective agent against oxidative stress. Here, we focus on the involvement of DJ-1 in interconnected cellular functions related to mitochondrial homeostasis, reactive oxygen species (ROS) levels, energy metabolism, and hypoxia response, in both physiological and pathological conditions. We discuss the possibility that impairments in one of these pathways may affect the others, contributing to a pathological background in which additional environmental or genetic factors may act in favor of the onset and/or progression of ALS. These pathways may represent potential therapeutic targets to reduce the likelihood of developing ALS and/or slow disease progression.

Triclustering-based classification of longitudinal data for prognostic prediction: targeting relevant clinical endpoints in amyotrophic lateral sclerosis

This work proposes a new class of explainable prognostic models for longitudinal data classification using triclusters. A new temporally constrained triclustering algorithm, termed TCtriCluster, is proposed to comprehensively find informative temporal patterns common to a subset of patients in a subset of features (triclusters), and use them as discriminative features within a state-of-the-art classifier with guarantees of interpretability. The proposed approach further enhances prediction with the potentialities of model explainability by revealing clinically relevant disease progression patterns underlying prognostics, describing features used for classification. The proposed methodology is used in the Amyotrophic Lateral Sclerosis (ALS) Portuguese cohort (N = 1321), providing the first comprehensive assessment of the prognostic limits of five notable clinical endpoints: need for non-invasive ventilation (NIV); need for an auxiliary communication device; need for percutaneous endoscopic gastrostomy (PEG); need for a caregiver; and need for a wheelchair. Triclustering-based predictors outperform state-of-the-art alternatives, being able to predict the need for auxiliary communication device (within 180 days) and the need for PEG (within 90 days) with an AUC above 90%. The approach was validated in clinical practice, supporting healthcare professionals in understanding the link between the highly heterogeneous patterns of ALS disease progression and the prognosis.

Integrative analysis of metabolomics and proteomics unravels purine metabolism dysregulation in the SOD1G93A mouse model of amyotrophic lateral sclerosis

Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease with progressive paralysis of limbs and bulb in patients, the cause of which remains unclear. Accumulating studies suggest that motor neuron degeneration is associated with systemic metabolic impairment in ALS. However, the metabolic reprogramming and underlying mechanism in the longitudinal progression of the disease remain poorly understood. In this study, we aimed to investigate the molecular changes at both metabolic and proteomic levels during disease progression to identify the most critical metabolic pathways and underlying mechanisms involved in ALS pathophysiological changes. Utilizing liquid chromatography-mass spectrometry-based metabolomics, we analyzed the metabolites' levels of plasma, lumbar spinal cord, and motor cortex from SOD1G93A mice and wildtype (WT) littermates at different stages. To elucidate the regulatory network underlying metabolic changes, we further analyzed the proteomics profile in the spinal cords of SOD1G93A and WT mice. A group of metabolites implicated in purine metabolism, methionine cycle, and glycolysis were found differentially expressed in ALS mice, and abnormal expressions of enzymes involved in these metabolic pathways were also confirmed. Notably, we first demonstrated that dysregulation of purine metabolism might contribute to the pathogenesis and disease progression of ALS. Furthermore, we discovered that fatty acid metabolism, TCA cycle, arginine and proline metabolism, and folate-mediated one‑carbon metabolism were also significantly altered in this disease. The identified differential metabolites and proteins in our study could complement existing data on metabolic reprogramming in ALS, which might provide new insight into the pathological mechanisms and novel therapeutic targets of ALS.

Wearable device and smartphone data quantify ALS progression and may provide novel outcome measures

Amyotrophic lateral sclerosis (ALS) therapeutic development has largely relied on staff-administered functional rating scales to determine treatment efficacy. We sought to determine if mobile applications (apps) and wearable devices can be used to quantify ALS disease progression through active (surveys) and passive (sensors) data collection. Forty ambulatory adults with ALS were followed for 6-months. The Beiwe app was used to administer the self-entry ALS functional rating scale-revised (ALSFRS-RSE) and the Rasch Overall ALS Disability Scale (ROADS) surveys every 2–4 weeks. Each participant used a wrist-worn activity monitor (ActiGraph Insight Watch) or an ankle-worn activity monitor (Modus StepWatch) continuously. Wearable device wear and app survey compliance were adequate. ALSFRS-R highly correlated with ALSFRS-RSE. Several wearable data daily physical activity measures demonstrated statistically significant change over time and associations with ALSFRS-RSE and ROADS. Active and passive digital data collection hold promise for novel ALS trial outcome measure development.

Ultrasound–enhanced brain delivery of edaravone provides additive amelioration on disease progression in an ALS mouse model

BackgroundAlthough amyotrophic lateral sclerosis (ALS) is a devastating neurodegenerative disease and unfortunately incurable yet, incremental attention has been drawn to targeting the health of corticospinal motor neurons. Focused ultrasound combined with systemically circulating microbubbles (FUS/MB) is an emerging modality capable of site-specific molecular delivery temporarily and noninvasively within a range of appropriate parameters. ObjectiveTo investigate the effect of FUS/MB–enhanced delivery of therapeutics to the motor cortex on the disease progression by using a transgenic mouse model of ALS. MethodsMultiple FUS/MB–enhanced deliveries of Edaravone (Eda) to the motor cortex were performed on the SOD1G93A mouse model of ALS. The motor function of the animals was evaluated by gait analysis, grip strength and wire hanging tests. Corticospinal and spinal motor neuronal health, misfolded SOD1 protein and neuroinflammation after treatments were evaluated by histological examination. ResultsUltrasound–enhanced delivery of Eda in the targeted motor cortex was achieved by a two-fold increase without gross tissue damage. Compared with the ALS mice administered Eda treatments only, the animals given additionally FUS/MB–enhanced brain delivery of Eda (FUS/MB + Eda) exhibited further improvements in neuromuscular functions characterized by gait patterns, muscular strength, and motor coordination along with rescued muscle atrophy. FUS/MB + Eda treatments conferred remarkable neuroprotection to both upper and lower motor neurons revealed by normalized neuronal morphology with increasing cell body size and profoundly alleviated neuroinflammation and misfolded SOD1 protein in the brains and lumbar spinal cords. ConclusionWe report a pilot study that non-invasive ultrasound–enhanced brain delivery of Eda provides additive amelioration on disease progression of ALS and suggest that broadening the target from spinal to cortical network functions using the FUS/MB–enhanced delivery can be a rational therapeutic strategy of this debilitating disorder.

Percutaneous endoscopic gastrostomy in amyotrophic lateral sclerosis: outcomes of a dedicated anesthesia and surgery protocol.

Patients requiring percutaneous endoscopic gastrostomy (PEG) for amyotrophic lateral sclerosis (ALS) related dysphagia represent a clinical challenge. Diminished pulmonary function and aspiration risks can lead to anesthesia-related complications, and gastric displacement from hemidiaphragm elevation may preclude safe gastric access. This study reports the efficacy and outcomes of a dedicated anesthesia/surgery management protocol for ALS patients undergoing PEG. In 2013, a PEG placement protocol for ALS patients was developed emphasizing efficient pre-operative evaluation, rapidly metabolized anesthetic agents, and minimization of opioid use. Outcomes were analyzed retrospectively. Preoperative weight loss, pulmonary function tests, total analgesia, procedural time, and 90-day morbidity and mortality were recorded. From 2013-2019, 67 ALS patients (mean age 65.3years, 52.2% female) received a PEG under the protocol. Mean percentage weight loss 6months before PEG was 9.3 ± 5.1% with 38.8% of patients meeting criteria for severe malnutrition. Mean anesthesia time (propofol induction to anesthesia emergence) was 34.5 ± 10.8min and mean operative time (endoscope insertion to dressing placement) was 16.4 ± 8.2min. Regional anesthesia with liposomal bupivacaine was performed in 76.1%. All attempts at PEG placement were successful. With a mean follow-up of 6.1 ± 6.8months, all PEGs were functional and there were no surgical site complications. Thirty-day readmission rate was 7.0% and 90-day mortality was 22.4% (46.7% occurring within 30days). Mean time from surgery to death was 8.8 ± 7.8months. Protocols for optimizing PEG may help overcome challenges present in the ALS patient population. Despite patient comorbidities, protocol implementation and dedicated team members resulted in a high procedural success rate and low complication rate. Further study is warranted to optimize the timing of PEG placement in relation to ALS disease progression and determine the utility of regional anesthesia during PEG placement.

Comparing therapeutic modulators of the SOD1 G93A Amyotrophic Lateral Sclerosis mouse pathophysiology.

Amyotrophic Lateral Sclerosis (ALS) is a paralyzing, multifactorial neurodegenerative disease with limited therapeutics and no known cure. The study goal was to determine which pathophysiological treatment targets appear most beneficial. A big data approach was used to analyze high copy SOD1 G93A experimental data. The secondary data set comprised 227 published studies and 4,296 data points. Treatments were classified by pathophysiological target: apoptosis, axonal transport, cellular chemistry, energetics, neuron excitability, inflammation, oxidative stress, proteomics, or systemic function. Outcome assessment modalities included onset delay, health status (rotarod performance, body weight, grip strength), and survival duration. Pairwise statistical analysis (two-tailed t-test with Bonferroni correction) of normalized fold change (treatment/control) assessed significant differences in treatment efficacy. Cohen's d quantified pathophysiological treatment category effect size compared to "all" (e.g., all pathophysiological treatment categories combined). Inflammation treatments were best at delaying onset (d = 0.42, p > 0.05). Oxidative stress treatments were significantly better for prolonging survival duration (d = 0.18, p < 0.05). Excitability treatments were significantly better for prolonging overall health status (d = 0.22, p < 0.05). However, the absolute best pathophysiological treatment category for prolonging health status varied with disease progression: oxidative stress was best for pre-onset health (d = 0.18, p > 0.05); excitability was best for prolonging function near onset (d = 0.34, p < 0.05); inflammation was best for prolonging post-onset function (d = 0.24, p > 0.05); and apoptosis was best for prolonging end-stage function (d = 0.49, p > 0.05). Finally, combination treatments simultaneously targeting multiple pathophysiological categories (e.g., polytherapy) performed significantly (p < 0.05) better than monotherapies at end-stage. In summary, the most effective pathophysiological treatments change as function of assessment modality and disease progression. Shifting pathophysiological treatment category efficacy with disease progression supports the homeostatic instability theory of ALS disease progression.

SOD1G93A Astrocyte-Derived Extracellular Vesicles Induce Motor Neuron Death by a miRNA-155-5p-Mediated Mechanism.

Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease characterized by upper and lower motor neuron (MN) degeneration. Astrocytes surrounding MNs are known to modulate ALS progression. When cocultured with astrocytes overexpressing the ALS-linked mutant Cu/Zn superoxide dismutase (SOD1G93A) or when cultured with conditioned medium from SOD1G93A astrocytes, MN survival is reduced. The exact mechanism of this neurotoxic effect is unknown. Astrocytes secrete extracellular vesicles (EVs) that transport protein, mRNA, and microRNA species from one cell to another. The size and protein markers characteristic of exosomes were observed in the EVs obtained from cultured astrocytes, indicating their abundance in exosomes. Here, we analyzed the microRNA content of the exosomes derived from SOD1G93A astrocytes and evaluated their role in MN survival. Purified MNs exposed to SOD1G93A astrocyte-derived exosomes showed reduced survival and neurite length compared to those exposed to exosomes derived from non-transgenic (non-Tg) astrocytes. Analysis of the miRNA content of the exosomes revealed that miR-155-5p and miR-582-3p are differentially expressed in SOD1G93A exosomes compared with exosomes from non-Tg astrocytes. Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis indicates that miR-155-5p and miR-582-3p predicted targets are enriched in the neurotrophin signaling pathway. Importantly, when levels of miR-155-5p were reduced by incubation with a specific antagomir, SOD1G93A exosomes did not affect MN survival or neurite length. These results demonstrate that SOD1G93A-derived exosomes are sufficient to induce MN death, and miRNA-155-5p contributes to this effect. miRNA-155-5p may offer a new therapeutic target to modulate disease progression in ALS.

Research Progress on Correlation between Gut Microbiome and Amyotrophic Lateral Sclerosis

Amyotrophic Lateral Sclerosis (ALS), also known as motor neuron disease, is characterized by simultaneous degeneration of upper and lower motor neurons, resulting in muscle weakness, paralysis, and eventually death. However, research on its pathogenesis is currently unclear. Recently, many studies have found that the intestinal flora plays a direct or indirect role in the disease progression of ALS, including the release of neuroactive metabolites, increased intestinal permeability, and inducing metabolic disorders. Therefore, this article briefly reviews the correlation between intestinal microbiota and ALS in terms of pathology, aiming to provide new therapeutic targets for ALS.