Resistance exercise in early-stage ALS patients, ALSFRS-R, Sickness Impact Profile ALS-19, and muscle transcriptome: a pilot study.

Amyotrophic lateral sclerosis (ALS) patients lack effective treatments to maintain motor and neuromuscular function. This study aimed to evaluate the effect of a home-based exercise program on muscle strength, ALS scores, and transcriptome in ALS patients, Clinical Trials.gov #NCT03201991 (28/06/2017). An open-label, non-randomized pilot clinical trial was conducted in seven individuals with early-stage ALS. Participants were given 3 months of home-based resistance exercise focusing on the quadriceps muscles. The strength of exercised muscle was evaluated using bilateral quadriceps strength with manual muscle testing, handheld dynamometers, five times sit-to-stand, and Timed-Up-and-Go before and after the exercise program. In addition, changes in the Sickness Impact Profile ALS-19 (SIP/ALS-19) as the functional outcome measure and the transcriptome of exercised muscles were compared before and after the exercise. The primary outcome of muscle strength did not change significantly by the exercise program. The exercise program maintained the SIP/ALS-19 and the ALS Functional Rating Scale-Revised (ALSFRS-R). Transcriptome analysis revealed that exercise reverted the expression level of genes decreased in ALS, including parvalbumin. Three months of moderately intense strength and conditioning exercise maintained muscle strength of the exercised muscle and ALSFRS-R scores and had a positive effect on patients' muscle transcriptome.

Endocytosis of Synaptic Vesicle in Motor Nerve Endings of FUS Transgenic Mice with a Model of Amyotrophic Lateral Sclerosis.

In experiments on the motor nerve endings of the diaphragm of transgenic FUS mice with a model of amyotrophic lateral sclerosis at the pre-symptomatic stage of the disease, the processes of transmitter release and endocytosis of synaptic vesicles were studied. In FUS mice, the intensity of transmitter release during high-frequency stimulation of the motor nerve (50 imp/sec) was lowered. At the same duration of stimulation, the loading of fluorescent dye FM1-43 was lower in FUS mice. However, at the time of stimulation, during which an equal number of quanta are released in wild-type and FUS mice, no differences in the intensity of dye loading were found. Thus, endocytosis is not the key factor in the mechanism of synaptic dysfunction in FUS mice at the pre-symptomatic stage.

Amyotrophic lateral sclerosis as a disease model of sarcopenia.

Sarcopenia, the progressive decline of muscle mass and function, has traditionally been viewed as an age-related process leading to a broad range of adverse outcomes. However, it has been widely reported that sarcopenia can occur earlier in life in association with various conditions (i.e. disease-related sarcopenia), including neuromuscular disorders. As early as 2010, the European Working Group on Sarcopenia in Older People included neurodegenerative diseases characterised by motor neuron loss among the mechanisms underlying sarcopenia. Despite some differences in pathogenetic mechanisms, both amyotrophic lateral sclerosis (ALS) and age-related sarcopenia share common characteristics, such as the loss of motor units and muscle fibre atrophy, oxidative stress, mitochondrial dysfunction and inflammation. The histology of older muscle shows fibre size heterogeneity, fibre grouping and a loss of satellite cells, similar to what is observed in ALS patients. Regrettably, the sarcopenic process in ALS patients has been largely overlooked, and literature on the condition in this patient group is very scarce. Some instruments used for the assessment of sarcopenia in older people could also be applied to ALS patients. At this time, there is no approved specific pharmacological treatment to reverse damage to motor neurons or cure ALS, just as there is none for sarcopenia. However, some agents targeting the muscle, like myostatin and mammalian target of rapamycin inhibitors, are under investigation both in the sarcopenia and ALS context. The development of new therapeutic agents targeting the skeletal muscle may indeed be beneficial to both ALS patients and older people with sarcopenia.

From suspicion to diagnosis: exploration strategy for suspected amyotrophic lateral sclerosis.

The diagnosis of amyotrophic lateral sclerosis (ALS) is based on evidence of upper and lower motor neuron degeneration in the bulbar, cervical, thoracic, and lumbar regions in a patient with progressive motor weakness, in the absence of differential diagnosis. Despite these well-defined criteria, ALS can be difficult to diagnose, given the wide variety of clinical phenotypes. Indeed, the central or peripheral location of the disease varies with a spectrum ranging from predominantly central to exclusively peripheral, symptoms can be extensive or limited to the limbs, bulbar area or respiratory muscles, and the duration of the disease may range from a few months to several decades. In the absence of a specific test, the diagnostic strategy relies on clinical, electrophysiological, biological and radiological investigations to confirm the disease and exclude ALS mimics. The main challenge is to establish a diagnosis based on robust clinical and paraclinical evidence without delaying treatment initiation by increasing the number of additional tests. This approach requires a thorough knowledge of the phenotypes of ALS and its main differential diagnoses.

The diagnosis of amyotrophic lateral sclerosis (ALS) is based on progressive degeneration of upper and lower motor neurons.ALS can be difficult to diagnose due to the wide range of clinical phenotypes (central/peripheral location, symptom distribution, disease duration).A thorough diagnostic strategy including clinical, electrophysiological, biological and radiological investigations is essential to confirm ALS and exclude differential diagnoses.

Simultaneous time-frequency analysis of gait signals of both legs in classifying neurodegenerative diseases.

BACKGROUND: Neurodegenerative diseases (NDDs) pose significant challenges due to their debilitating nature and limited therapeutic options. Accurate and timely diagnosis is crucial for optimizing patient care and treatment strategies. Gait analysis, utilizing wearable sensors, has shown promise in assessing motor abnormalities associated with NDDs. RESEARCH QUESTION: Research Question 1 To what extent can analyzing the interaction of both limbs in the time-frequency domain serve as a suitable methodology for accurately classifying NDDs? Research Question 2 How effective is the utilization of color-coded images, in conjunction with deep transfer learning models, for the classification of NDDs? METHODS: GaitNDD database was used, comprising recordings from patients with Huntington's disease, amyotrophic lateral sclerosis, Parkinson's disease, and healthy controls. The gait signals underwent signal preparation, wavelet coherence analysis, and principal component analysis for feature enhancement. Deep transfer learning models (AlexNet, GoogLeNet, SqueezeNet) were employed for classification. Performance metrics, including accuracy, sensitivity, specificity, precision, and F1 score, were evaluated using 5-fold cross-validation. RESULTS: The classification performance of the models varied depending on the time window used. For 5-second gait signal segments, AlexNet achieved an accuracy of 95.91 %, while GoogLeNet and SqueezeNet achieved accuracies of 96.49 % and 92.73 %, respectively. For 10-second segments, AlexNet outperformed other models with an accuracy of 99.20 %, while GoogLeNet and SqueezeNet achieved accuracies of 96.75 % and 95.00 %, respectively. Statistical tests confirmed the significance of the extracted features, indicating their discriminative power for classification. SIGNIFICANCE: The proposed method demonstrated superior performance compared to previous studies, offering a non-invasive and cost-effective approach for the automated diagnosis of NDDs. By analyzing the interaction between both legs during walking using wavelet coherence, and utilizing deep transfer learning models, accurate classification of NDDs was achieved.

Different baseline functional patterns of the frontal cortex in amyotrophic lateral sclerosis patients with Corticospinal tract hyperintensity.

Nearly half of the amyotrophic lateral sclerosis (ALS) patients showed hyperintensity of the corticospinal tract (CST+), yet whether brain functional pattern differs between CST+and CST- patients remains obscure. In the current study, 19 ALS CST+, 41 ALS CST- patients and 37 healthy controls (HC) underwent resting state fMRI scans. We estimated local activity and connectivity patterns via the Amplitude of Low Frequency Fluctuations (ALFF) and the Network-Based Statistic (NBS) approaches respectively. The ALS CST+patients did not differ from the CST- patients in amyotrophic lateral sclerosis functional rating scale revised (ALSFRS-R) score and disease duration. ALFF of the superior frontal gyrus (SFG) and the inferior frontal gyrus pars opercularis (OIFG) were highest in the HC and lowest in the ALS CST- patients, resulting in significant group differences (PFWE<0.05). NBS analysis revealed a frontal network consisting of connections between SFG, OIFG, orbital frontal gyrus, middle cingulate cortex and the basal ganglia, which exhibited HC>ALS CST+ > ALS CST- group differences (PFWE=0.037) as well. The ALFF of the OIFG was significantly correlated with ALSFRS-R (R=0.34, P=0.028) and mean connectivity of the frontal network was trend-wise significantly correlated with disease duration (R=-0.31, P=0.052) in the ALS CST- patients. However, these correlations were insignificant in ALS CST+patients (P values > 0.8). In conclusion, The ALS CST+patients exhibited different patterns of baseline functional activity and connectivity in the frontal cortex which may indicate a functional compensatory effect.

Comparative assessment of MScanFit MUNE and quantitative EMG in amyotrophic lateral sclerosis diagnosis: A prospective study.

OBJECTIVE: Motor Unit Number Estimation (MUNE) techniques are crucial in assessing lower motor neuron loss. MScanFit MUNE (MScanFit) is a novel tool which estimates MUNE values from compound muscle action potential (CMAP) scans by considering the probabilistic nature of motor unit firing. We conducted a prospective study to evaluate the diagnostic utility of MScanFit compared to quantitative electromyography (qEMG) in ALS patients. METHODS: We enrolled 35 patients diagnosed with amyotrophic lateral sclerosis (ALS) and 14 healthy controls, assessing qEMG and MScanFit MUNE in abductor pollicis brevis, abductor digiti minimi and tibialis anterior muscles. RESULTS: We found higher sensitivity of qEMG in detecting abnormalities compared to MScanFit, with a high concordance rate between the two techniques. Notably, a few muscles exhibited abnormal MUNE but normal qEMG findings, suggesting a potential complementary role for MScanFit in ALS diagnosis. Neurophysiological parameters from MScanFit showed good correlations with qEMG measures. Subclinical neurophysiological involvement was observed in muscles with normal strength, emphasizing the importance of sensitive diagnostic tools. CONCLUSION: MScanFit demonstrated validity in distinguishing ALS patients from healthy subjects and correlated well with qEMG parameters. SIGNIFICANCE: Our study confirmed the diagnostic utility of MScanFit MUNE in ALS, highlighting its role as a supplementary diagnostic tool.

All-in-one wearable drug efficacy assessment systems for bulbar muscle function using amyotrophic lateral sclerosis animal models.

Preclinical studies are crucial for developing amyotrophic lateral sclerosis drugs. Current FDA-approved drugs have been created by monitoring limb muscle function and histological analysis of amyotrophic lateral sclerosis model animals. Drug candidates for this disease have yet to be tested for bulbar-onset type due to the limitations of traditional preclinical tools: excessive animal use and discrete detection of disease progress. Here, our study introduces an all-in-one, wireless, integrated wearable system for facilitating continuous drug efficacy assessment of dysphagia-related muscles in animals during natural eating behaviors. By incorporating a kirigami-based strain-isolation mechanism, this device mounted on the skin of animals mitigates electromyography signal contamination caused by unpredictable animal movements. Our findings indicate this system, measuring the progression of motor neuron denervation, offers high precision in monitoring drug effects on dysphagia-responsible bulbar muscles. This study paves the way for more humane and efficient approaches to developing treatment solutions for degenerative neuromuscular diseases.

Long-term survival of participants in a phase II randomized trial of RNS60 in amyotrophic lateral sclerosis.

BACKGROUND: Positive effects of RNS60 on respiratory and bulbar function were observed in a phase 2 randomized, placebo-controlled trial in people with amyotrophic lateral sclerosis (ALS). OBJECTIVE: to investigate the long-term survival of trial participants and its association with respiratory status and biomarkers of neurodegeneration and inflammation. STUDY DESIGN AND SETTINGS: A randomized, double blind, phase 2 clinical trial was conducted. Trial participants were enrolled at 22 Italian Expert ALS Centres from May 2017 to January 2020. Vital status of all participants was ascertained thirty-three months after the trial's last patient last visit (LPLV). Participants were patients with Amyotrophic Lateral Sclerosis, classified as slow or fast progressors based on forced vital capacity (FVC) slope during trial treatment. Demographic, clinical, and biomarker levels and their association with survival were also evaluated. RESULTS: Mean duration of follow-up was 2.8 years. Long-term median survival was six months longer in the RNS60 group (p = 0.0519). Baseline FVC, and rates of FVC decline during the first 4 weeks of trial participation, were balanced between the active and placebo treatment arms. After 6 months of randomized, placebo-controlled treatment, FVC decline was significantly slower in the RNS60 group compared to the placebo group. Rates of FVC progression during the treatment were strongly associated with long-term survival (median survival: 3.7 years in slow FVC progressors; 1.6 years in fast FVC progressors). The effect of RNS60 in prolonging long-term survival was higher in participants with low neurofilament light chain (NfL) (median survival: >4 years in low NfL - RNS60 group; 3.3 years in low NfL - placebo group; 1.9 years in high NfL - RNS60 group; 1.8 years in high NfL - placebo group) and Monocyte Chemoattractant Protein-1 (MCP-1) (median survival: 3.7 years in low MCP-1 - RNS60 group; 2.3 years in low MCP-1 - placebo group; 2.8 years in high MCP-1 - RNS60 group; 2.6 years in high MCP-1 - placebo group) levels at baseline. CONCLUSIONS AND RELEVANCE: In this post-hoc analysis, long term survival was longer in participants randomized to RNS60 compared with those randomized to placebo and was correlated with slower FVC progression rates, suggesting that longer survival may be mediated by the drug's effect on respiratory function. In these post-hoc analyses, the beneficial effect of RNS60 on survival was most pronounced in participants with low NfL and MCP-1 levels at study entry, suggesting that this could be a subgroup to target in future studies investigating the effects of RNS60 on survival. TRIAL REGISTRATION: Study preregistered on 13/Jan/2017 in EUDRA-CT (2016-002382-62). The study was also registered at ClinicalTrials.gov number NCT03456882.

Utility of the Repetitive Nerve Stimulation Test and Needle EMG in the Trapezius Muscle for the Early Diagnosis of ALS.

OBJECTIVES: To document the utility of decremental responses in the repetitive nerve stimulation test (RNS) and spontaneous activities in needle electromyography (EMG) in the trapezius muscle for the diagnosis of amyotrophic lateral sclerosis. METHODS: Subjects were retrospectively identified from our EMG database. Cervical spondylosis was represented as a disease control group. We investigated the sensitivity and specificity of RNS and EMG in the trapezius muscle and those of diagnostic criteria including the Gold Coast criteria (GCC). RESULTS: We reviewed 120 patients with amyotrophic lateral sclerosis and 17 patients with cervical spondylosis. "RNS or EMG" achieved the highest sensitivity (85%). The specificity was the highest for RNS (94%). Addition of RNS of the deltoid muscle achieved 98% sensitivity in the upper-limb onset amyotrophic lateral sclerosis. The sensitivity of the GCC was very high (88%). CONCLUSIONS: Neurophysiological parameters investigated in this study having close to 100% specificities or sensitivities are useful as complements to the GCC.

Excitatory to inhibitory synaptic ratios are unchanged at presymptomatic stages in multiple models of ALS.

Hyperexcitability of motor neurons and spinal cord motor circuitry has been widely reported in the early stages of Amyotrophic Lateral Sclerosis (ALS). Changes in the relative amount of excitatory to inhibitory inputs onto a neuron (E:I synaptic ratio), possibly through a developmental shift in synapse formation in favour of excitatory transmission, could underlie pathological hyperexcitability. Given that astrocytes play a major role in early synaptogenesis and are implicated in ALS pathogenesis, their potential contribution to disease mechanisms involving synaptic imbalances and subsequent hyperexcitability is also of great interest. In order to assess E:I ratios in ALS, we utilised a novel primary spinal neuron / astrocyte co-culture system, derived from neonatal mice, in which synapses are formed in vitro. Using multiple ALS mouse models we found that no combination of astrocyte or neuron genotype produced alterations in E:I synaptic ratios assessed using pre- and post-synaptic anatomical markers. Similarly, we observed that ephrin-B1, a major contact-dependent astrocytic synaptogenic protein, was not differentially expressed by ALS primary astrocytes. Further to this, analysis of E:I ratios across the entire grey matter of the lumbar spinal cord in young (post-natal day 16-19) ALS mice revealed no differences versus controls. Finally, analysis in co-cultures of human iPSC-derived motor neurons and astrocytes harbouring the pathogenic C9orf72 hexanucleotide repeat expansion showed no evidence of a bias toward excitatory versus inhibitory synapse formation. We therefore conclude, utilising multiple ALS models, that we do not observe significant changes in the relative abundance of excitatory versus inhibitory synapses as would be expected if imbalances in synaptic inputs contribute to early hyperexcitability.

Multimodal speech biomarkers for remote monitoring of ALS disease progression.

Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease that severely impacts affected persons' speech and motor functions, yet early detection and tracking of disease progression remain challenging. The current gold standard for monitoring ALS progression, the ALS functional rating scale - revised (ALSFRS-R), is based on subjective ratings of symptom severity, and may not capture subtle but clinically meaningful changes due to a lack of granularity. Multimodal speech measures which can be automatically collected from patients in a remote fashion allow us to bridge this gap because they are continuous-valued and therefore, potentially more granular at capturing disease progression. Here we investigate the responsiveness and sensitivity of multimodal speech measures in persons with ALS (pALS) collected via a remote patient monitoring platform in an effort to quantify how long it takes to detect a clinically-meaningful change associated with disease progression. We recorded audio and video from 278 participants and automatically extracted multimodal speech biomarkers (acoustic, orofacial, linguistic) from the data. We find that the timing alignment of pALS speech relative to a canonical elicitation of the same prompt and the number of words used to describe a picture are the most responsive measures at detecting such change in both pALS with bulbar (n = 36) and non-bulbar onset (n = 107). Interestingly, the responsiveness of these measures is stable even at small sample sizes. We further found that certain speech measures are sensitive enough to track bulbar decline even when there is no patient-reported clinical change, i.e. the ALSFRS-R speech score remains unchanged at 3 out of a total possible score of 4. The findings of this study have the potential to facilitate improved, accelerated and cost-effective clinical trials and care.

Microglia in Neurodegenerative Diseases.

Neurodegenerative diseases are manifested by a progressive death of neural cells, resulting in the deterioration of central nervous system (CNS) functions, ultimately leading to specific behavioural and cognitive symptoms associated with affected brain regions. Several neurodegenerative disorders are caused by genetic variants or mutations, although the majority of cases are sporadic and linked to various environmental risk factors, with yet an unknown aetiology. Neuroglial changes are fundamental and often lead to the pathophysiology of neurodegenerative diseases. In particular, microglial cells, which are essential for maintaining CNS health, become compromised in their physiological functions with the exposure to environmental risk factors, genetic variants or mutations, as well as disease pathology. In this chapter, we cover the contribution of neuroglia, especially microglia, to several neurodegenerative diseases, including Nasu-Hakola disease, Parkinson's disease, amyotrophic lateral sclerosis, Alzheimer's disease, Huntington's disease, infectious disease-associated neurodegeneration, and metal-precipitated neurodegeneration. Future research perspectives for the field pertaining to the therapeutic targeting of microglia across these disease conditions are also discussed.

Veterans with familial ALS and bulbar and respiratory presentations at onset had shorter survival.

OBJECTIVE: We sought to characterize the clinical prognostic factors in veterans with amyotrophic lateral sclerosis (ALS) followed in our ALS clinic. BACKGROUND: ALS is a rare, progressive neurodegenerative condition associated with decreased survival compared to that in the normal population. METHOD: The electronic medical records of 105 veterans diagnosed with ALS who are followed in our ALS clinic between 2010 and 2021 were reviewed. Approval from the institutional review board was obtained from the study protocol. Demographic and clinical variables included age at symptom onset, age at initial evaluation, survival (from symptom onset to death), gender, site of onset (appendicular, bulbar, and respiratory), initial amyotrophic lateral sclerosis functional-related score-revised (ALSFRS-R), total functional independence measure (TFIM) scores, initial forced vital capacity (FVC), and interventions (Riluzole, gastrostomy, noninvasive ventilation [NIV], and tracheostomy). Normally distributed data was expressed as mean ± standard deviation. Fischer's exact analysis of the distribution differences of categorical data. The Kaplan-Meier plot analyzed the time-to-event. RESULTS: The mean (SD) age at symptom onset was 62.0 (11.1) years, age at diagnosis was 65 (11) years, with 72% of the patients being over 60 years at diagnosis. The median survival time from symptom onset was 4.12 (3) years. Limb-onset ALS (appendicular) was the most frequent (52%) followed by bulbar-onset ALS (43%). The mean ALSFRS-R and TFIM scores were 31 (8) and 91 (25), respectively. Family history (familial), bulbar, and respiratory presentation at diagnosis were associated with shorter survival times. CONCLUSION: This study suggests that of the clinical prognostic factors veterans with familial ALS, bulbar, and respiratory onset at presentations had shorter survival. The presence of Agent Orange, PEG placement, and NIV did not affect survival.

Central neurodegeneration in Kennedy's disease accompanies peripheral motor dysfunction.

Spinal and bulbar muscular atrophy (SBMA), or Kennedy's disease (KD), is a rare hereditary neuromuscular disorder demonstrating commonalities with amyotrophic lateral sclerosis (ALS). The current study aimed to define functional and central nervous system abnormalities associated with SBMA pathology, their interaction, and to identify novel clinical markers for quantifying disease activity. 27 study participants (12 SBMA; 8 ALS; 7 Control) were recruited. SBMA patients underwent comprehensive motor and sensory functional assessments, and neurophysiological testing. All participants underwent whole-brain structural and diffusion MRI. SBMA patients demonstrated marked peripheral motor and sensory abnormalities across clinical assessments. Increased abnormalities on neurological examination were significantly associated with increased disease duration in SBMA patients (R2 = 0.85, p < 0.01). Widespread juxtacortical axonal degeneration of corticospinal white matter tracts were detected in SBMA patients (premotor; motor; somatosensory; p < 0.05), relative to controls. Increased axial diffusivity was significantly correlated with total neuropathy score in SBMA patients across left premotor (R2 = 0.59, p < 0.01), motor (R2 = 0.63, p < 0.01), and somatosensory (R2 = 0.61, p < 0.01) tracts. The present series has identified involvement of motor and sensory brain regions in SBMA, associated with disease duration and increasing severity of peripheral neuropathy. Quantification of annualized brain MRI together with Total Neuropathy Score may represent a novel approach for clinical monitoring.

[Research progress on the relationship between TRAF6 and neurodegenerative diseases].

Given the increasing trend of aging population in the world, neurodegenerative diseases (NDDs), a common type of diseases that mostly occur in the elderly, have attracted much more attention. It has been shown that tumor necrosis factor receptor-associated factor 6 (TRAF6) is involved in the regulation of neuroinflammation, an important pathological feature of NDDs, and affects the occurrence and development of NDDs. Most importantly, the regulatory effect of TRAF6 is related to its ubiquitination. Therefore, in the present paper, the molecular structure, biological function, and ubiquitination mechanism of TRAF6, and its relationship with some common NDDs, including Alzheimer's disease, Parkinson's disease, multiple sclerosis, and amyotrophic lateral sclerosis, were analyzed and summarized. The possible molecular mechanisms by which TRAF6 regulates the occurrence of NDDs were also elucidated, providing a theoretical basis for exploring the etiology and treatment of NDDs.

Malnutrition in Amyotrophic Lateral Sclerosis: Insights from Morphofunctional Assessment and Global Leadership Initiative on Malnutrition Criteria.

Amyotrophic Lateral Sclerosis (ALS) is a progressive neurodegenerative disease frequently accompanied by malnutrition due to weight loss, increased energy expenditure, and muscle mass loss. This study aimed to evaluate morphofunctional assessment tools as predictors of malnutrition and to investigate their relationship with muscle status and disease severity in ALS patients. A cross-sectional study was conducted with 45 ALS patients at the San Cecilio University Hospital in Granada. Malnutrition was assessed using the Global Leadership Initiative on Malnutrition (GLIM) criteria. Morphofunctional assessment was performed using Bioimpedance Vectorial Analysis (BIVA), handgrip strength (HGS), and Short Physical Performance Battery (SPPB). Malnutrition prevalence was 38% according to GLIM criteria. Significant differences were observed between malnourished and non-malnourished groups in age (70 ± 9 vs. 62 ± 10 years, p = 0.01), sex (female prevalence: 58.8% vs. 25.0%, p = 0.02), dysphagia prevalence (83% vs. 29%, p < 0.001), PEG/PRG use (35.3% vs. 3.6%, p = 0.01), and ALSFRS-R scores (30 ± 12 vs. 34 ± 12, p = 0.02). Malnourished patients had lower values in anthropometric measurements, muscle mass obtained by BIVA, and phase angle (PA) (4.05 ± 0.8° vs. 5.09 ± 0.8°, p < 0.001). No significant differences were found in muscle strength or functional status. PA showed significant correlations with muscle strength (r = 0.52, p < 0.001) and muscle mass measures (r = 0.48, p < 0.001). Moreover, PA was associated with poorer disease progression and physical performance. In our sample, BIVA metrics such as PA (<4.3°), SPA (<-0.8), body cell mass (<9.2 kg/m), and extracellular water (>49.75%) were identified as malnutrition risk factors. The study underscores the critical importance of comprehensive morphofunctional assessment and the use of advanced diagnostic criteria, for early identification and intervention in malnutrition among people with ALS. Further research is warranted to validate these findings and develop targeted nutritional strategies into routine clinical practice.

Prediction of nocturnal ventilation by pulmonary function testing in patients with amyotrophic lateral sclerosis.

BACKGROUND: In amyotrophic lateral sclerosis (ALS) prognosis is poor due to progressive weakening of the respiratory muscles. Survival and quality of life can be improved by noninvasive ventilation (NIV), which is initially applied while sleeping. The indication for NIV is based on pulmonary function testing (PFT) and polysomnography (PSG) with capnography (tCO2). While it is desirable to predict nocturnal ventilation by waking PFT in ALS, the parameters suited for reliable predictions remain elusive. METHODS: We retrospectively analyzed parameters derived from PFT (spirometry, body plethysmography, diffusion capacity, respiratory muscle testing) and blood gas analysis, PSG and tCO2 in 42 patients with ALS (27 men, 15 women, age 69 ± 12.1 years) and performed Spearman's correlation analysis of daytime waking parameters and nighttime sleep parameters. RESULTS: 28 patients (66.7%) showed restrictive impairment of ventilation and 15 patients (48.3%) showed insufficiency of the respiratory musculature. There was no obstructive impairment of ventilation. We did not observe any significant correlations between any single daytime PFT parameter with nocturnal pCO2. However, there were significant correlations between the ratios PIF/PEF, MEF50/MIF50, DLCO/VA as well as FEV1/FVC and nocturnal pCO2. Highly normal FEV1/FVC and Krogh-Factor (DLCOc/VA) indicated nocturnal hypercapnia. Furthermore, waking hypercapnia, concentrations of bicarbonate and base excess were each positively correlated with nocturnal hypercapnia. CONCLUSIONS: Waking PFT is not a good predictor of nocturnal ventilation. Inspiratory parameters as well as the ratios FEV1/FVC and DLCO/VA performed best and should be included in the interpretation. Our analyses confirm the relevance of inspiratory muscle weakness in ALS. PSG and tCO2 remain the gold standard for the assessment of nocturnal ventilation.

Exercise training induces mild skeletal muscle adaptations without altering disease progression in a TDP-43 mouse model.

Exercise training is considered a nonpharmacological therapeutic approach for many diseases. Mild-to-moderate endurance exercise training is suggested to improve the mental and physical state of people with amyotrophic lateral sclerosis (ALS). The aim of the present study was to determine the capacity of symptomatic rNLS8 mice, which develop ALS-reminiscent TAR DNA-binding protein 43 (TDP-43) pathology and motor dysfunction, to perform mild-to-moderate intensity treadmill exercise training and to evaluate the effects of this training on skeletal muscle health and disease progression. Symptomatic rNLS8 mice were able to complete 4 wk of mild-to-moderate treadmill running (30 min at 6-13 m/min, 3 days a week). Exercise training induced an increase in the percentage of type IIA fibers in the tibialis anterior muscle as well as minor adaptations in molecular markers of myogenic, mitochondrial, and neuromuscular junction health in some forelimb and hindlimb muscles. However, this exercise training protocol did not attenuate the loss in motor function or delay disease progression. Alternative exercise regimens need to be investigated to better understand the role exercise training may play in alleviating symptoms of ALS.NEW & NOTEWORTHY This is the first study to investigate the capacity of symptomatic rNLS8 mice, which develop ALS-reminiscent TDP-43 pathology and motor dysfunction, to perform exercise training. We demonstrate that despite the ALS-reminiscent aggressive disease progression characterizing the rNLS8 mouse model, rNLS8 mice are capable of performing mild-to-moderate endurance treadmill training for at least 3-4 wk. We demonstrate that exercise training induces several minor skeletal muscle adaptations without delaying disease progression in rNLS8 mice.

Voice signals database of ALS patients with different dysarthria severity and healthy controls.

This paper describes a new publicly-available database of VOiCe signals acquired in Amyotrophic Lateral Sclerosis (ALS) patients (VOC-ALS) and healthy controls performing different speech tasks. This dataset consists of 1224 voice signals recorded from 153 participants: 51 healthy controls (32 males and 19 females) and 102 ALS patients (65 males and 37 females) with different severity of dysarthria. Each subject's voice was recorded using a smartphone application (Vox4Health) while performing several vocal tasks, including a sustained phonation of the vowels /a/, /e/, /i/, /o/, /u/ and /pa/, /ta/, /ka/ syllable repetition. Basic derived speech metrics such as harmonics-to-noise ratio, mean and standard deviation of fundamental frequency (F0), jitter and shimmer were calculated. The F0 standard deviation of vowels and syllables showed an excellent ability to identify people with ALS and to discriminate the different severity of dysarthria. These data represent the most comprehensive database of voice signals in ALS and form a solid basis for research on the recognition of voice impairment in ALS patients for use in clinical applications.