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Purpose: This study aims to investigate acoustic change over time as biomarkers to differentiate among spastic-flaccid dysarthria associated with amyotrophic lateral sclerosis (ALS), spastic dysarthria associated with primary lateral sclerosis (PLS), flaccid dysarthria associated with spinal and bulbar muscular atrophy (SBMA), and to explore how these acoustic parameters are affected by dysarthria severity. Method: Thirty-three ALS patients with mixed flaccid-spastic dysarthria, 17 PLS patients with pure spastic dysarthria, 18 SBMA patients with pure flaccid dysarthria, and 70 controls, all French speakers, were included in the study. Speakers produced vowel-glide sequences targeting different vocal tract shape changes. The mean and coefficient of variation of the total squared change of mel frequency cepstral coefficients were used to capture the degree and variability of acoustic changes linked to vocal tract modifications over time. Differences in duration of acoustic events were also measured. Results: All pathological groups showed significantly less acoustic change compared to controls, reflecting less acoustic contrast in sequences. Spastic and mixed spastic-flaccid dysarthric speakers showed smaller acoustic changes and slower sequence production compared to flaccid dysarthria. For dysarthria subtypes associated with a spastic component, reduced degree of acoustic change was also associated with dysarthria severity. Conclusions: The acoustic parameters partially differentiated among the dysarthria subtypes in relation to motor neuron diseases. While similar acoustic patterns were found in spastic-flaccid and spastic dysarthria, crucial differences were found between these two subtypes relating to variability. The acoustic patterns were much more variable in ALS. This method forms a promising clinical tool as a diagnostic marker of articulatory impairment, even at mild stage of dysarthria progression in all subtypes.

The article presents an analysis of early diaphragm pacing in patients with amyotrophic lateral sclerosis (ALS) to use histopathological and electrophysiological data to test the hypothesis that diaphragm pacing. It mentions decrease in survival observed with active stimulation was associated with an accelerated deterioration of lung function. it also mentions muscle electrical activation after experimental nerve injury can impair reinnervation and exacerbate atrophy.

Non‐invasive ventilation (NIV) has become an essential part of the treatment of amyotrophic lateral sclerosis (ALS) since 2006. NIV very significantly improves survival, quality of life and cognitive performances. The initial NIV settings are simple, but progression of the disease, ventilator dependence and upper airway involvement sometimes make long‐term adjustment of NIV more difficult, with a major impact on survival. Unique data concerning the long‐term adjustment of NIV in ALS show that correction of leaks, management of obstructive apnoea and adaptation to the patient's degree of ventilator dependence improve the prognosis. Non‐ventilatory factors also impact the efficacy of NIV and various solutions have been described and must be applied, including cough assist techniques, control of excess salivation and renutrition. NIV in ALS has been considerably improved as a result of application of all of these measures, avoiding the need for tracheostomy in the very great majority of cases. More advanced use of NIV also requires pulmonologists to master the associated end‐of‐life palliative care, as well as the modalities of discontinuing ventilation when it becomes unreasonable. [ABSTRACT FROM AUTHOR]

Amyotrophic Lateral Sclerosis is an adult-onset neurodegenerative disease characterized by the specific loss of motor neurons, leading to muscle paralysis and death. Although the cellular mechanisms underlying amyotrophic lateral sclerosis (ALS)-induced toxicity for motor neurons remain poorly understood, growing evidence suggest a defective energetic metabolism in skeletal muscles participating in ALS-induced motor neuron death ultimately destabilizing neuromuscular junctions. In the present study, we report that a specific exercise paradigm, based on a high intensity and amplitude swimming exercise, significantly improves glucose metabolism in ALS mice. Using physiological tests and a biophysics approach based on nuclear magnetic resonance (NMR), we unexpectedly found that SOD1(G93A) ALS mice suffered from severe glucose intolerance, which was counteracted by high intensity swimming but not moderate intensity running exercise. Furthermore, swimming exercise restored the highly ALS-sensitive tibialis muscle through an autophagy-linked mechanism involving the expression of key glucose transporters and metabolic enzymes, including GLUT4 and glyceraldehyde-3-phosphate dehydrogenase (GAPDH). Importantly, GLUT4 and GAPDH expression defects were also found in muscles from ALS patients. Moreover, we report that swimming exercise induced a triglyceride accumulation in ALS tibialis, likely resulting from an increase in the expression levels of lipid transporters and biosynthesis enzymes, notably DGAT1 and related proteins. All these data provide the first molecular basis for the differential effects of specific exercise type and intensity in ALS, calling for the use of physical exercise as an appropriate intervention to alleviate symptoms in this debilitating disease. [ABSTRACT FROM AUTHOR]

Objective Data from mouse models of amyotrophic lateral sclerosis ( ALS) suggest early morphological changes in neuromuscular junctions ( NMJs), with loss of nerve-muscle contact. Overexpression of the neurite outgrowth inhibitor Nogo-A in muscle may play a role in this loss of endplate innervation. Methods We used confocal and electron microscopy to study the structure of the NMJs in muscle samples collected from nine ALS patients (five early-stage patients and four long-term survivors). We correlated the morphological results with clinical and electrophysiological data, and with Nogo-A muscle expression level. Results Surface electromyography assessment of neuromuscular transmission was abnormal in 3/9 ALS patients. The postsynaptic apparatus was morphologically altered for almost all NMJs ( n = 430) analyzed using confocal microscopy. 19.7% of the NMJs were completely denervated (fragmented synaptic gutters and absence of nerve terminal profile). The terminal axonal arborization was usually sparsely branched and 56.8% of innervated NMJs showed a typical reinnervation pattern. Terminal Schwann cell ( TSC) morphology was altered with extensive cytoplasmic processes. A marked intrusion of TSCs in the synaptic cleft was seen in some cases, strikingly reducing the synaptic surface available for neuromuscular transmission. Finally, high-level expression of Nogo-A in muscle was significantly associated with higher extent of NMJ denervation and negative functional outcome. Interpretation Our results support the hypothesis that morphological alterations of NMJs are present from early-stage disease and may significantly contribute to functional motor impairment in ALS patients. Muscle expression of Nogo-A is associated with NMJ denervation and thus constitutes a therapeutic target to slow disease progression. [ABSTRACT FROM AUTHOR]

In amyotrophic lateral sclerosis (ALS) patients, respiratory insufficiency is a major burden. Diaphragm conditioning by electrical stimulation could interfere with lung function decline by promoting the development of type 1 muscle fibres. We describe an ancillary study to a prospective, non-randomized trial (NCT00420719) assessing the effects of diaphragm pacing on forced vital capacity (FVC). Sleep-related disturbances being early clues to diaphragmatic dysfunction, we postulated that they would provide a sensitive marker. Stimulators were implanted laparoscopically in the diaphragm close to the phrenic motor point in 18 ALS patients for daily conditioning. ALS functioning score (ALSFRS), FVC, sniff nasal inspiratory pressure (SNIP), and polysomnographic recordings (PSG, performed with the stimulator turned off) were assessed before implantation and after four months of conditioning ( n == 14). Sleep efficiency improved (69 ± 15% to 75 ± 11%, p == 0.0394) with fewer arousals and micro-arousals. This occurred against a background of deterioration as ALSFRS-R, FVC, and SNIP declined. There was, however, no change in NIV status or the ALSFRS respiratory subscore, and the FVC decline was mostly due to impaired expiration. Supporting a better diaphragm function, apnoeas and hypopnoeas during REM sleep decreased. In conclusion, in these severe patients not expected to experience spontaneous improvements, diaphragm conditioning improved sleep and there were hints at diaphragm function changes. [ABSTRACT FROM AUTHOR]

Background: Amyotrophic lateral sclerosis (ALS) is a fatal adult-onset degenerative disease characterized by the loss of upper and lower motor neurons leading to progressive muscle atrophy and paralysis. The lack of molecular markers of the progression of disease is detrimental to clinical practice and therapeutic trials. Objective: This study was designed to identify gene expression changes in skeletal muscle that could reliably define the degree of disease severity. Methods: Gene expression profiles were obtained from the deltoid muscles of ALS patients and healthy subjects. Changes in differentially expressed genes were compared to the status of deltoid muscle disability, as determined by manual muscle testing, electrophysiology and the degree of myofiber atrophy. Functionally related genes were grouped by annotation analysis, and deltoid muscle injury was predicted using binary tree classifiers. Results: Two sets of 25 and 70 transcripts appeared differentially regulated exclusively in early and advanced states of deltoid muscle impairment, respectively. The expression of another set of 198 transcripts correlated with a composite score of muscle injury combining manual muscle testing and histological examination. From the totality of these expression changes, 155 transcripts distinguished advanced from early deltoid muscle impairment with 80% sensitivity and 100% specificity. Nine of these transcripts, known also to be regulated in ALS mouse and surgically denervated muscle, predicted the advanced disease status with 100% sensitivity and specificity. Conclusion: We provide robust gene expression changes that can be of practical use when monitoring ALS status and the effects of disease-modifying drugs. Copyright © 2011 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]

Background: Amyotrophic lateral sclerosis (ALS) is a life-threatening neurodegenerative disease involving upper and lower motor neurons loss. Clinical features are highly variable among patients and there are currently few known diseasemodifying factors underlying this heterogeneity. Serotonin is involved in a range of functions altered in ALS, including motor neuron excitability and energy metabolism. However, whether serotoninergic activity represents a disease modifier of ALS natural history remains unknown. Methodology: Platelet and plasma unconjugated concentrations of serotonin and plasma 5-HIAA, the major serotonin metabolite, levels were measured using HPLC with coulometric detection in a cohort of 85 patients with ALS all followed-up until death and compared to a control group of 29 subjects. Principal Findings: Platelet serotonin levels were significantly decreased in ALS patients. Platelet serotonin levels did not correlate with disease duration but were positively correlated with survival of the patients. Univariate Cox model analysis showed a 57% decreased risk of death for patients with platelet serotonin levels in the normal range relative to patients with abnormally low platelet serotonin (p = 0.0195). This protective effect remained significant after adjustment with age, gender or site of onset in multivariate analysis. Plasma unconjugated serotonin and 5-HIAA levels were unchanged in ALS patients compared to controls and did not correlate with clinical parameters. Conclusions/Significance: The positive correlation between platelet serotonin levels and survival strongly suggests that serotonin influences the course of ALS disease. [ABSTRACT FROM AUTHOR]

Death represents the main hallmark of amyotrophic lateral sclerosis (ALS). Despite its importance in clinical care and phase III trials, many uncertainties remain on the cause of death due to the lack of post-mortem verifications. To provide a more robust approach to these causes, we performed a retrospective pathological study on a large cohort of patients. 100 ALS patients referred for a deterioration of their clinical condition and who died in the ALS clinic of Salpétrière had a complete macroscopic and microscopic post-mortem analysis. The clinical causes of death reported on medical records were compared to the results of autopsy. The concordance between clinical and pathological conclusions was insufficient (20%) to consider clinical assessment as a reliable marker of causes of death. At autopsy, broncho-pneumonia and pneumonia were the main causes of death. Heart failure, representing 10% of deaths, was two times more frequent in bulbar than in spinal ALS. Pulmonary embolism representing 6% of death was exclusively found in spinal onset patients and is related to lower limbs disability. An effort has to be made for a better understanding of the causes of deterioration of ALS patients. A more proactive attitude to treat respiratory infections could have a significant impact on survival. [ABSTRACT FROM AUTHOR]

The diagnostic of Amyotrophic lateral sclerosis (ALS) remains based on clinical and neurophysiological observations. The actual delay between the onset of the symptoms and diagnosis is about 1 year, preventing early inclusion of patients into clinical trials and early care of the disease. Therefore, finding biomarkers with high sensitivity and specificity remains urgent. In our study, we looked for peptide biomarkers in plasma samples using reverse phase magnetic beads (C18 and C8) and MALDI-TOF mass spectrometry analysis. From a set of ALS patients (n=30) and healthy age-matched controls (n=30), C18- or C8-SVM-based models for ALS diagnostic were constructed on the base of the minimum of the most discriminant peaks. These two SVM-based models end up in excellent separations between the 2 groups of patients (recognition capability overall classes > 97%) and classify blinded samples (10 ALS and 10 healthy age-matched controls) with very high sensitivities and specificities (>90%). Some of these discriminant peaks have been identified by Mass Spectrometry (MS) analyses and correspond to (or are fragments of) major plasma proteins, partly linked to the blood coagulation. [ABSTRACT FROM AUTHOR]

Background: Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disorder associated with respiratory muscle weakness and respiratory failure. Non-invasive ventilation alleviates respiratory symptoms and prolongs life, but is a palliative intervention. Slowing the deterioration of diaphragm function before respiratory failure would be desirable. We aimed to assess whether early diaphragm pacing could slow down diaphragm deterioration and would therefore delay the need for non-invasive ventilation.Methods: We did a multicentre, randomised, controlled, triple-blind trial in patients with probable or definite ALS in 12 ALS centres in France. The main inclusion criterion was moderate respiratory involvement (forced vital capacity 60-80% predicted). Other key eligibility criteria were age older than 18 years and bilateral responses of the diaphragm to diagnostic phrenic stimulation. All patients were operated laparoscopically and received phrenic stimulators. Clinicians randomly assigned patients (1:1) to receive either active or sham stimulation with a central web-based randomisation system (computer-generated list). Investigators, patients, and an external outcome allocation committee were masked to treatment. The primary outcome was non-invasive ventilation-free survival, analysed in the intention-to-treat population. Safety outcomes were also assessed in the intention-to-treat population. This trial is registered with ClinicalTrials.gov, number NCT01583088.Findings: Between Sept 27, 2012, and July 8, 2015, 74 participants were randomly assigned to receive either active (n=37) or sham (n=37) stimulation. On July 16, 2015, an unplanned masked analysis was done after another trial showed excess mortality with diaphragm pacing in patients with hypoventilation (DiPALS, ISRCTN 53817913). In view of this finding, we analysed mortality in our study and found excess mortality (death from any cause) in our active stimulation group. We therefore terminated the study on July, 16, 2015. Median non-invasive ventilation-free survival was 6·0 months (95% CI 3·6-8·7) in the active stimulation group versus 8·8 months (4·2-not reached) in the control (sham stimulation) group (hazard ratio 1·96 [95% CI 1·08-3·56], p=0·02). Serious adverse events (mainly capnothorax or pneumothorax, acute respiratory failure, venous thromboembolism, and gastrostomy) were frequent (24 [65%] patients in the active stimulation group vs 22 [59%] patients in the control group). No treatment-related death was reported.Interpretation: Early diaphragm pacing in patients with ALS and incipient respiratory involvement did not delay non-invasive ventilation and was associated with decreased survival. Diaphragm pacing is not indicated at the early stage of the ALS-related respiratory involvement.Funding: Hospital Program for Clinical Research, French Ministry of Health; French Patients' Association for ALS Research (Association pour la Recherche sur la Sclérose Latérale Amyotrophique); and Thierry de Latran Foundation. [ABSTRACT FROM AUTHOR]

Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disorder affecting motor neurons, with a typical lifespan of 3-5 years. Altered metabolism is a key feature of ALS that strongly influences prognosis, with an increase in whole-body energy expenditure and changes in skeletal muscle metabolism, including greater reliance on fat oxidation. Dyslipidemia has been described in ALS as part of the metabolic dysregulation, but its role in the pathophysiology of the disease remains controversial. Among the lipids, cholesterol is of particular interest as a vital component of cell membranes, playing a key role in signal transduction and mitochondrial function in muscle. The aim of this study was to investigate whether motor dysfunction in ALS might be associated with dysregulation of muscle cholesterol metabolism. We determined cholesterol content and analyzed the expression of key determinants of the cholesterol metabolism pathway in muscle biopsies from thirteen ALS patients and ten asymptomatic ALS-mutation gene carriers compared to sixteen controls. Using human control primary myotubes, we further investigated the potential contribution of cholesterol dyshomeostasis to reliance on mitochondrial fatty acid. We found that cholesterol accumulates in the skeletal muscle of ALS patients and that cholesterol overload significantly correlates with disease severity evaluated by the Revised ALS Functional Rating Scale. These defects are associated with overexpression of the genes of the lysosomal cholesterol transporters Niemann-Pick type C1 (NPC1) and 2 (NPC2), which are required for cholesterol transfer from late endosomes/lysosomes to cellular membranes. Most notably, a significant increase in NPC2 mRNA levels could be detected in muscle samples from asymptomatic ALS-mutation carriers, long before disease onset. We found that filipin-stained unesterified cholesterol accumulated in the lysosomal compartment in ALS muscle samples, suggesting dysfunction of the NPC1/2 system. Accordingly, we report here that experimental NPC1 inhibition or lysosomal pH alteration in human primary myotubes was sufficient to induce the overexpression of NPC1 and NPC2 mRNA. Finally, acute NPC1 inhibition in human control myotubes induced a shift towards a preferential use of fatty acids, thus reproducing the metabolic defect characteristic of ALS muscle. We conclude that cholesterol homeostasis is dysregulated in ALS muscle from the presymptomatic stage. Targeting NPC1/2 dysfunction may be a new therapeutic strategy for ALS to restore muscle energy metabolism and slow motor symptom progression., (© The Author(s) 2024. Published by Oxford University Press on behalf of the Guarantors of Brain.)

A variety of neuropsychiatric complications has been described in association with COVID-19 infection. Large scale studies presenting a wider picture of these complications and their relative frequency are lacking. The objective of our study was to describe the spectrum of neurological and psychiatric complications in patients with COVID-19 seen in a multidisciplinary hospital centre over 6 months. We conducted a retrospective, observational study of all patients showing neurological or psychiatric symptoms in the context of COVID-19 seen in the medical and university neuroscience department of Assistance Publique Hopitaux de Paris-Sorbonne University. We collected demographic data, comorbidities, symptoms and severity of COVID-19 infection, neurological and psychiatric symptoms, neurological and psychiatric examination data and, when available, results from CSF analysis, MRI, EEG and EMG. A total of 249 COVID-19 patients with a de novo neurological or psychiatric manifestation were included in the database and 245 were included in the final analyses. One-hundred fourteen patients (47%) were admitted to the intensive care unit and 10 (4%) died. The most frequent neuropsychiatric complications diagnosed were encephalopathy (43%), critical illness polyneuropathy and myopathy (26%), isolated psychiatric disturbance (18%) and cerebrovascular disorders (16%). No patients showed CSF evidence of SARS-CoV-2. Encephalopathy was associated with older age and higher risk of death. Critical illness neuromyopathy was associated with an extended stay in the intensive care unit. The majority of these neuropsychiatric complications could be imputed to critical illness, intensive care and systemic inflammation, which contrasts with the paucity of more direct SARS-CoV-2-related complications or post-infection disorders., (© The Author(s) (2021). Published by Oxford University Press on behalf of the Guarantors of Brain.)

Amyotrophic lateral sclerosis (ALS) patients show progressive respiratory muscle weakness leading to death from respiratory failure. However, there are no data on diaphragm histological changes in ALS patients and how they correlate with routine respiratory measurements.We collected 39 diaphragm biopsies concomitantly with laparoscopic insertion of intradiaphragmatic electrodes during a randomised controlled trial evaluating early diaphragm pacing in ALS (https://clinicaltrials.gov; NCT01583088). Myofibre type, size and distribution were evaluated by immunofluorescence microscopy and correlated with spirometry, respiratory muscle strength and phrenic nerve conduction parameters. The relationship between these variables and diaphragm atrophy was assessed using multivariate regression models.All patients exhibited significant slow- and fast-twitch diaphragmatic atrophy. Vital capacity (VC), maximal inspiratory pressure, sniff nasal inspiratory pressure (SNIP) and twitch transdiaphragmatic pressure did not correlate with the severity of diaphragm atrophy. Inspiratory capacity (IC) correlated modestly with slow-twitch myofibre atrophy. Supine fall in VC correlated weakly with fast-twitch myofibre atrophy. Multivariate analysis showed that IC, SNIP and functional residual capacity were independent predictors of slow-twitch diaphragmatic atrophy, but not fast-twitch atrophy.Routine respiratory tests are poor predictors of diaphragm structural changes. Improved detection of diaphragm atrophy is essential for clinical practice and for management of trials specifically targeting diaphragm muscle function., Competing Interests: Conflict of interest: R. Guimarães-Costa has nothing to disclose. Conflict of interest: T. Similowski reports personal fees from AstraZeneca, Boerhinger Ingelheim France, GSK Lungpacer Inc., TEVA, Chiesi, Pierre Fabre and Invacare, and personal fees and non-financial support from Novartis, outside the submitted work. In addition, he received honoraria from Synapse Biomedical to translate the DPS/NeurRx4 user manual from English into French in 2007 and, from 2012 to 2016, Synapse Biomedical contributed to a fundraiser organised by T. Similowski to promote respiratory research. T. Similowski is also engaged in scientific collaborations with two other companies manufacturing phrenic stimulation devices. With Lungpacer Inc (Canada) he acts as a paid consultant and investigator in clinical trials, while with Atrotech-Neuroresp (France) he acts as a probono consultant (no fees or other support). Conflict of interest: I. Rivals has nothing to disclose. Conflict of interest: C. Morélot-Panzini has nothing to disclose. Conflict of interest: M-C. Nierat has nothing to disclose Conflict of interest: M.T. Bui has nothing to disclose. Conflict of interest: D. Akbar has nothing to disclose. Conflict of interest: C. Straus has nothing to disclose. Conflict of interest: N.B. Romero has nothing to disclose. Conflict of interest: P.P. Michel has nothing to disclose. Conflict of interest: F. Menegaux has nothing to disclose. Conflict of interest: F. Salachas has nothing to disclose. Conflict of interest: J. Gonzalez-Bermejo has nothing to disclose. Conflict of interest: G. Bruneteau has nothing to disclose., (Copyright ©ERS 2019.)

Spinal muscular atrophy (SMA) type III and IV are autosomal recessive, slowly progressive lower motor neuron syndromes. Nevertheless, wider cerebral involvement has been consistently reported in mouse models. The objective of this study is the characterisation of spinal and cerebral pathology in adult forms of SMA using multimodal quantitative imaging., Methods: Twenty-five type III and IV adult SMA patients and 25 age-matched healthy controls were enrolled in a spinal cord and brain imaging study. Structural measures of grey and white matter involvement and diffusion parameters of white matter integrity were evaluated at each cervical spinal level. Whole-brain and region-of-interest analyses were also conducted in the brain to explore cortical thickness, grey matter density and tract-based white matter alterations., Results: In the spinal cord, considerable grey matter atrophy was detected between C2-C6 vertebral levels. In the brain, increased grey matter density was detected in motor and extra-motor regions of SMA patients. No white matter pathology was identified neither at brain and spinal level., Conclusions: Adult forms of SMA are associated with selective grey matter degeneration in the spinal cord with preserved white matter integrity. The observed increased grey matter density in the motor cortex may represent adaptive reorganisation., (Copyright © 2018 The Authors. Published by Elsevier Inc. All rights reserved.)

Objective: Amyotrophic lateral sclerosis (ALS) is a fatal and progressive neurodegenerative disorder involving motor neurons of the cerebral cortex, brain stem and spinal cord. Besides the motor signs, cognitive disorders and apathy may be present and may impact the survival time. These elements are therefore to be taken into consideration for medical care because they can influence the disease evolution. The literature shows low psychopathological disorders in this population despite its poor prognosis. The main objective of this study is to explore the emotional feeling in apathetic and non-apathetic patients in relation to their anxiety and depressive symptoms., Methods: We included 152 patients at the day hospital for the follow-up of their illness, with an average age of 61±12.2 years. All filled the following self-administered questionnaires: EPN-31 (emotional feeling), HADS (for anxiety and depressive symptoms) and the Marin's apathy evaluation scale. Most of the patients (n=110) had also a cognitive assessment with the ALS-CBS scale., Results: 42% of patients could be considered as apathetic and they felt both positive and negative emotions whose frequency was related to the presence and intensity of anxiety and depressive symptoms. The only significant differences were that apathetic and anxious patients experienced more negative emotions including sadness, shame and anger than non-apathetic and anxious patients. Apathy was negatively correlated with cognitive functioning and survival time., Conclusions: These results highlighted the negative impact that apathy seemed to have on the evolution of this disease. However, apathetic patients didn't show emotional blunting and were able to name and feel positive and negative emotions; and even feel more negative emotions than non-apathetic patients when they were anxious. A better understanding of apathetic and no apathetic patients' emotional feelings should lead to a more personalized care for the ALS patients.

Background: Amyotrophic lateral sclerosis (ALS) is a fatal adult-onset degenerative disease characterized by the loss of upper and lower motor neurons leading to progressive muscle atrophy and paralysis. The lack of molecular markers of the progression of disease is detrimental to clinical practice and therapeutic trials., Objective: This study was designed to identify gene expression changes in skeletal muscle that could reliably define the degree of disease severity., Methods: Gene expression profiles were obtained from the deltoid muscles of ALS patients and healthy subjects. Changes in differentially expressed genes were compared to the status of deltoid muscle disability, as determined by manual muscle testing, electrophysiology and the degree of myofiber atrophy. Functionally related genes were grouped by annotation analysis, and deltoid muscle injury was predicted using binary tree classifiers., Results: Two sets of 25 and 70 transcripts appeared differentially regulated exclusively in early and advanced states of deltoid muscle impairment, respectively. The expression of another set of 198 transcripts correlated with a composite score of muscle injury combining manual muscle testing and histological examination. From the totality of these expression changes, 155 transcripts distinguished advanced from early deltoid muscle impairment with 80% sensitivity and 100% specificity. Nine of these transcripts, known also to be regulated in ALS mouse and surgically denervated muscle, predicted the advanced disease status with 100% sensitivity and specificity., Conclusion: We provide robust gene expression changes that can be of practical use when monitoring ALS status and the effects of disease-modifying drugs., (Copyright © 2011 S. Karger AG, Basel.)