Amyotrophic Lateral Sclerosis Functional Rating Scale Research Articles

Neural Stem/Progenitor Cell Therapy in Patients and Animals with Amyotrophic Lateral Sclerosis: A Systematic Review and Meta-analysis.

Amyotrophic lateral sclerosis (ALS) is a neurodegenerative malady that causes progressive degeneration and loss of motor neuron function in the brain and spinal cord, eventually resulting in muscular atrophy, paralysis, and death. Neural stem/progenitor cell (NSPC) transplantation can improve bodily function in animals and delay disease progression in patients with ALS. This paper summarizes and analyzes the efficacy and safety of neural stem/progenitor cell (NSPC) transplantation as a treatment for ALS, aiming to improve function and delay disease progression in patients. We present a summary of the pathogenic mechanism and causative genes associated with ALS and describe the mechanism and efficacy of NSPC treatment for ALS. We comprehensively searched for relevant English-language articles published between January 1, 2000 and October 1, 2023, across the following five medical databases: PubMed, EMBASE, OVID, Web of Science, and the Cochrane Library. We examined experimental indices of physical function in animals and patients who underwent stem cell transplantation. All statistical analyses were performed via Review Manager 5.4. The study comprised a total of 16 investigations, including 5 clinical studies and 11 animal studies and involving 66 patients and 203 animals. The meta-analysis revealed that the administration of NSPCs appeared to yield positive outcomes in clinical patients, as assessed by the ALS functional rating scale and forced vital capacity. Furthermore, improvements following cell injection were observed in the rotarod test results, the Basso-Beattie-Bresnahan Locomotor Rating Scale score, weight, and survival time. Our meta-analysis, which was grounded in randomized controlled trials, revealed that the transplantation of neural stem/progenitor cells (NSPCs), has potential effects on ALS patients, enhancing the physical function of animals and mitigating degenerative effects in individuals. These underscored the promise of NSPC therapy as a viable treatment option. We report that the transplantation of neural stem/progenitor cells (NSPCs) is promising for enhancing bodily function and slowing the progression of ALS in affected patients. In this review, we summarize the treatment of ALS with NSPCs, evaluating both its efficacy and safety. Through database searches, we identified 16 studies involving 66 patients and 203 animals and analyzed the experimental indices of physical function following stem cell transplantation. The meta-analysis results indicated a positive impact of NSPCs on the clinical conditions of patients and the behavior of animals. A meta-analysis of randomized controlled trials further supported the conclusion that NSPC transplantation has a beneficial effect on improving physical function and mitigating degeneration in ALS patients.

Assessment of upper GI motor activity and GI symptoms in patients with amyotrophic lateral sclerosis: an observational study

Background/aimsOro-pharyngeal dysfunction has been reported in Amyotrophic Lateral Sclerosis (ALS). We aimed to assess ALS patients upper gastrointestinal (GI) motor activity and GI symptoms according to bulbar and spinal onset and severity of ALS.MethodsALS bulbar (B) and spinal (S) patients with ALS Functional Rating Scale (ALSFRS-r) ≥35, bulbar sub-score ≥10, and Forced Vital Capacity (FVC) >50%, underwent to: Fiberoptic Endoscopic Evaluation of Swallowing (FEES); esophageal manometry; gastric emptying; Rome symptom questionnaire. Medical Research Council Scale for Muscle Strength (MRC) was performed for the upper and lower limbs. Mann-Whitney's U, Fisher's ranks test, Pearson's test was used.ResultsThirteen ALS patients were included (6 F; mean age 61.2 ± 13.7 years, range: 37-87), 5 with B and 8 with S onset (ALSFRS-R score 39.5 ± 4.9, MRC score 128.6 ± 23.3, disease duration 22.8 ± 17.9 months). FEES detected a high dysphagia score in 5 patients with no difference between S and B phenotype. Lower esophageal sphincter pressure was normal in all patients. Esophageal dysmotility was observed in three S and two B onset patients. Upper esophageal sphincter (UES) pressure was higher in all ALS patients. UES spasms and delayed gastric emptying were detected in two B and one S and in two B and four S patients, respectively. There was no correlation between esophagogastric motor abnormalities and clinical characteristics of ALS, nor GI symptoms.ConclusionsThe presence of UES spasm and the delayed gastric emptying in a subgroup of ALS patients may suggest the role of ANS dysfunction in ALS.

Interaction between riluzole treatment and dietary glycemic index in the disease progression of amyotrophic lateral sclerosis.

We examined whether riluzole treatment modifies the associations between the dietary glycemic index (GI) and load (GL) and disease progression in amyotrophic lateral sclerosis (ALS). Sporadic ALS patients in the Multicenter Cohort Study of Oxidative Stress who completed a baseline food frequency questionnaire were included (n = 304). Interactions between baseline riluzole treatment and GI/GL on functional decline and tracheostomy-free survival were examined using linear regression and Cox proportional hazard models adjusted for covariates. Age, sex, disease duration, diagnostic certainty, body mass index, bulbar onset, revised ALS functional rating scale (ALSFRS-r) total score, and forced vital capacity, from baseline were included as covariates. Baseline higher GI and GL were associated with less decline of ALSFRS-r total score at 3-month follow-up in the riluzole treatment group (RTG) but not in the no-riluzole group (NRG). When quartile groups were used, GI second [β = -1.9, 95% CI (-4.1, -0.2), p = 0.07], third [β = -3.0, 95% CI (-5.1, -0.8), p < 0.01] and fourth [β = -2.2, 95% CI (-4.3, -0.01), p < 0.05] quartile groups were associated with less ALSFRS-r decline at 3-months compared to the first quartile group (GI < 47.2) among the RTG. Similarly, GL fourth quartile group (GL > 109.5) was associated with less ALSFRS-r decline at 3 months compared to the first quartile group [β = -2.6, 95% CI (-4.7, -0.5), p < 0.05] among the RTG. In NRG, no statistically significant differences in ALSFRS-r decline were found among GI/GL quartile groups. High dietary GI and GL are associated with a slower functional decline only among ALS patients taking riluzole.

A single-center, single-arm, prospective, open-label, and comparative trial to evaluate the safety and tolerability profile of a 90-day oral L-arginine hydrochloride intervention for patients with amyotrophic lateral sclerosis

Weight loss, a key indicator of malnutrition in amyotrophic lateral sclerosis (ALS) patients, negatively impacts patient prognosis. However, effective nutritional interventions have not been adequately established. Research in ALS model mice has shown that L-arginine can prolong survival; however, no human intervention studies have been conducted. We conducted a single-center, single-arm, prospective, open-label, and comparative trial to assess the safety and tolerability of L-arginine hydrochloride in ALS patients. ALS patients were administered 15 g/day L-arginine hydrochloride for 90 days. The primary outcome of safety was evaluated on days 45 and 90. The secondary outcome of efficacy was evaluated by measuring nutritional status, ALS Functional Rating Scale (ALSFRS) scores, and the occurrence of events such as the initiation of tracheostomy positive pressure ventilation (TPPV) and death. The study included 20 patients (40% female; mean age, 62.0 ± 6.9 years; median disease duration, 1.9 years). Six participants (30%) experienced treatment-emergent adverse events (TEAEs), including elevated creatine kinase levels, liver function test abnormalities, glucose tolerance issues, hyperammonemia, anorexia, dysgeusia, and vasculitis. No serious TEAEs were associated with L-arginine hydrochloride. Over the course of three months, the average changes in body weight, body mass index, and the ALSFRS score were − 0.37 kg, -1.1 kg/m2, and − 1.7 points, respectively. There were no events requiring TPPV initiation or deaths. This study demonstrated that the oral administration of L-arginine hydrochloride over three months was well tolerated by ALS patients, with no serious TEAEs or deaths attributed to the study drug.Trial Registration number: Japan Registry of Clinical Trials (jRCTs061230001), first registered 11/04/2023.

Predictive modeling of ALS progression: an XGBoost approach using clinical features

This research presents a predictive model aimed at estimating the progression of Amyotrophic Lateral Sclerosis (ALS) based on clinical features collected from a dataset of 50 patients. Important features included evaluations of speech, mobility, and respiratory function. We utilized an XGBoost regression model to forecast scores on the ALS Functional Rating Scale (ALSFRS-R), achieving a training mean squared error (MSE) of 0.1651 and a testing MSE of 0.0073, with R² values of 0.9800 for training and 0.9993 for testing. The model demonstrates high accuracy, providing a useful tool for clinicians to track disease progression and enhance patient management and treatment strategies.

Metabolite alterations in the left dorsolateral prefrontal cortex and its association with cognitive assessments in amyotrophic lateral sclerosis: A longitudinal magnetic resonance spectroscopy study.

To characterize the longitudinal metabolite profile of the left dorsolateral prefrontal cortex (DLPFC) in amyotrophic lateral sclerosis (ALS) using magnetic resonance spectroscopy (MRS) and to examine its correlation with cognitive assessments. Thirteen patients at baseline and ten at follow-up, along with 14 age-, sex-, and handedness-matched healthy controls (HCs), were recruited. Three Tesla with a 64-channel coil, Point-RESolved Spectroscopy (PRESS) sequence (TR=1500 ms and TE=140 ms) was used. Metabolites in the left DLPFC were quantified using LCModel. Cognitive performance and functional impairment were assessed using the Edinburgh Cognitive and Behavioral ALS Screen (ECAS) and Revised ALS Functional Rating Scale (ALSFRS-R), respectively. Group comparisons were adjusted for multiple comparisons (p < 0.05, Bonferroni correction). The links between the brain metabolites and cognitive function were investigated using relevant correlation tests (Pearson's or Spearman's). Our analysis revealed a significant difference in the choline-to-creatine ratio (tCho/tCr) among the three groups. Baseline ALS patients showed a higher tCho/tCr ratio than HCs (p = 0.033, Bonferroni-corrected). Interestingly, the total N-acetyl aspartate (tNAA)/tCr ratio, a marker of neuronal health, was strongly positively correlated with visuospatial cognitive scores at baseline and follow-up. Furthermore, at follow-up, tNAA/tCr was positively correlated with the total scores and specific sub-scores on the ECAS, encompassing both ALS-specific and non-specific cognitive domains. At follow-up, positive correlations emerged between tNAA/tCr and the total language and executive function scores. Metabolite alterations and correlations with cognition were observed in the left DLPFC of ALS patients, supporting extra-motor involvement and its association with cognitive decline.

Efficacy of Radicava® IV (intravenous edaravone) in subjects with differing trajectories of disease progression in amyotrophic lateral sclerosis: Use of a novel statistical approach for post hoc analysis of a pivotal phase 3 clinical trial

IntroductionSubjects with amyotrophic lateral sclerosis (ALS) treated with Radicava® (edaravone) IV (intravenous; Mitsubishi Tanabe Pharma America [MTPA], hereafter “MTPA IV edaravone”) in Study MCI186‐19 had a significantly slower physical functional decline vs placebo-treated subjects as measured by the revised ALS Functional Rating Scale (ALSFRS-R) and analyzed by the linear mixed model for repeated measures (MMRM). This Study 19 post hoc analysis of MTPA IV edaravone-treated and placebo-treated subjects evaluated linear and nonlinear latent class mixed models defining trajectories based on identifying the model with the lowest Bayesian information criterion. The best model differentiated 4 nonlinear trajectories in ALS subjects. ALSFRS-R total score in MTPA IV edaravone-treated and placebo-treated subjects was evaluated for these 4 nonlinear latent class trajectory groups. MethodsDisease trajectories of MCI186‐19 MTPA IV edaravone-treated or placebo-treated ALS subjects who completed the double-blind period were investigated using latent class analysis (LCA) statistical models to identify potential unique nonlinear ALSFRS-R disease trajectories. ResultsALSFRS-R trajectories revealed 4 unique nonlinear trajectory latent classes per treatment group in MTPA IV edaravone-treated and placebo-treated ALS subjects completing the MCI186‐19 double-blind period. Latent classes 2‐4 had statistically significant slowing of ALSFRS-R total score decline in the predicted nonlinear trajectories of MTPA IV edaravone-treated vs placebo-treated ALS subjects. ConclusionsThis post hoc analysis suggests MTPA IV edaravone treatment results in slower ALSFRS-R decline vs placebo in most predicted nonlinear trajectories. LCA is a novel approach that may benefit future trial analyses.

Effects of Respiratory Training on Pulmonary Function, Cough, and Functional Independence in Patients with Amyotrophic Lateral Sclerosis.

Respiratory complications in patients with amyotrophic lateral sclerosis (ALS), due to the involvement of respiratory muscles, are the leading cause of death, and respiratory physiotherapy (RP) focuses on addressing these complications. The objective was to evaluate the effectiveness of an RP intervention that combines the four specific techniques (inspiratory muscle training, lung volume recruitment, manually assisted coughing, and diaphragmatic breathing training) in patients with ALS. A quasi-experimental study was carried out, and a specific RP programme was implemented in 15 patients with ALS (12 sessions, 30 min/session, one session/week, duration of three months), based on directed ventilation techniques, lung volume recruitment, manually assisted coughing, and the use of incentive spirometry and a cough assist device, along with a daily home exercise programme. Respiratory functions were assessed (pre- and post-intervention, with follow-up at three months) using Forced Vital Capacity (FVC) and Peak Expiratory Cough Flow (PECF); functionality was assessed using the Revised ALS Functional Rating Scale (ALSFRS-R) and the Modified Barthel Index by Granger. FVC experienced an increase after three months of the intervention initiation (p = 0.30), which was not sustained at the three-month follow-up after the intervention ended. All other variables remained practically constant after treatment, with their values decreasing at follow-up. A specific RP intervention could have beneficial effects on respiratory functions, potentially preventing pulmonary infections and hospitalisations in patients with ALS. It may improve FVC and help stabilize the patient's functional decline. Considering the progressive and degenerative nature of the disease, this finding could support the usefulness of these techniques in maintaining respiratory function.

Safety and tolerability of tegoprubart in patients with amyotrophic lateral sclerosis: A Phase 2A clinical trial.

The interaction of CD40L and its receptor CD40 on activated T cells and B cells respectively control pro-inflammatory activation in the pathophysiology of autoimmunity and transplant rejection. Previous studies have implicated signaling pathways involving CD40L (interchangeably referred to as CD154), as well as adaptive and innate immune cell activation, in the induction of neuroinflammation in neurodegenerative diseases. This study aimed to assess the safety, tolerability, and impact on pro-inflammatory biomarker profiles of an anti CD40L antibody, tegoprubart, in individuals with amyotrophic lateral sclerosis (ALS). In this multicenter dose-escalating open-label Phase 2A study, 54 participants with a diagnosis of ALS received 6 infusions of tegoprubart administered intravenously every 2 weeks. The study was comprised of 4 dose cohorts: 1 mg/kg, 2 mg/kg, 4 mg/kg, and 8 mg/kg. The primary endpoint of the study was safety and tolerability. Exploratory endpoints assessed the pharmacokinetics of tegoprubart as well as anti-drug antibody (ADA) responses, changes in disease progression utilizing the Revised ALS Functional Rating Scale (ALSFRS-R), CD154 target engagement, changes in pro-inflammatory biomarkers, and neurofilament light chain (NFL). Seventy subjects were screened, and 54 subjects were enrolled in the study. Forty-nine of 54 subjects completed the study (90.7%) receiving all 6 infusions of tegoprubart and completing their final follow-up visit. The most common treatment emergent adverse events (TEAEs) overall (>10%) were fatigue (25.9%), falls (22.2%), headaches (20.4%), and muscle spasms (11.1%). Mean tegoprubart plasma concentrations increased proportionally with increasing dose with a half-life of approximately 24 days. ADA titers were low and circulating levels of tegoprubart were as predicted for all cohorts. Tegoprubart demonstrated dose dependent target engagement associated and a reduction in 18 pro-inflammatory biomarkers in circulation. Tegoprubart appeared to be safe and well tolerated in adults with ALS demonstrating dose-dependent reduction in pro-inflammatory chemokines and cytokines associated with ALS. These results warrant further clinical studies with sufficient power and duration to assess clinical outcomes as a potential treatment for adults with ALS. Clintrials.gov ID:NCT04322149.

Voice Assessment in Patients with Amyotrophic Lateral Sclerosis: An Exploratory Study on Associations with Bulbar and Respiratory Function.

Speech production is a possible way to monitor bulbar and respiratory functions in patients with amyotrophic lateral sclerosis (ALS). Moreover, the emergence of smartphone-based data collection offers a promising approach to reduce frequent hospital visits and enhance patient outcomes. Here, we studied the relationship between bulbar and respiratory functions with voice characteristics of ALS patients, alongside a speech therapist's evaluation, at the convenience of using a simple smartphone. For voice assessment, we considered a speech therapist's standardized tool-consensus auditory-perceptual evaluation of voice (CAPE-V); and an acoustic analysis toolbox. The bulbar sub-score of the revised ALS functional rating scale (ALSFRS-R) was used, and pulmonary function measurements included forced vital capacity (FVC%), maximum expiratory pressure (MEP%), and maximum inspiratory pressure (MIP%). Correlation coefficients and both linear and logistic regression models were applied. A total of 27 ALS patients (12 males; 61 years mean age; 28 months median disease duration) were included. Patients with significant bulbar dysfunction revealed greater CAPE-V scores in overall severity, roughness, strain, pitch, and loudness. They also presented slower speaking rates, longer pauses, and higher jitter values in acoustic analysis (all p < 0.05). The CAPE-V's overall severity and sub-scores for pitch and loudness demonstrated significant correlations with MIP% and MEP% (all p < 0.05). In contrast, acoustic metrics (speaking rate, absolute energy, shimmer, and harmonic-to-noise ratio) significantly correlated with FVC% (all p < 0.05). The results provide supporting evidence for the use of smartphone-based recordings in ALS patients for CAPE-V and acoustic analysis as reliable correlates of bulbar and respiratory function.

Clinical usefulness of the Verbal Fluency Index (VFI) in amyotrophic lateral sclerosis.

This study aimed at assessing the clinical utility of the Verbal Fluency Index (VFI) over a classical phonemic verbal fluency test in Italian-speaking amyotrophic lateral sclerosis (ALS) patients. N = 343 non-demented ALS patients and N = 226 healthy controls (HCs) were administered the Verbal fluency - S task from the Edinburgh Cognitive and Behavioural ALS Screen (ECAS). The associations between the number of words produced (NoW), the time to read words aloud (TRW) and the VFI (computed as [(60"-TRW)/NoW]) on one hand and both bulbar/respiratory scores from the ALS Functional Rating Scale - Revised (ALSFRS-R) and the ECAS-Executive on the other were tested. Italian norms for the NoW and the VFI were derived in HCs via the Equivalent Score method. Patients were classified based on their impaired/unimpaired performances on the NoW and the VFI (NoW-VFI-; NoW-VFI+; NoW + VFI-; NoW + VFI+), with these groups being compared on ECAS-Executive scores. The VFI, but neither the NoW nor the TRW, were related to ALSFRS-Bulbar/-Respiratory scores; VFI and NoW measures, but not the TRW, were related to the ECAS-Executive (p < .001). The NoW slightly overestimated the number of executively impaired patients when compared to the VFI (31.1% vs. 26.8%, respectively). Patients with a defective VFI score - regardless of whether they presented or not with a below-cutoff NoW - reported worse ECAS-Executive scores than NoW + VFI + ones. The present reports support the use of the Italian VFI as a mean to validly assess ALS patients' executive status by limiting the effect of motor disabilities that might undermine their speech rate.

Protocol for a phase 2 study of bosutinib for amyotrophic lateral sclerosis using real-world data: induced pluripotent stem cell-based drug repurposing for amyotrophic lateral sclerosis medicine (iDReAM) study

IntroductionAmyotrophic lateral sclerosis (ALS) is a progressive, severe neurodegenerative disease caused by motor neuron death. Development of a medicine for ALS is urgently needed, and induced pluripotent cell-based drug repurposing...

Latent class analysis of communication methods and devices among Japanese patients with amyotrophic lateral sclerosis: a cross-sectional survey

ABSTRACT Augmentative and alternative communication (AAC) is used to support individuals with communication impairments, such as those with amyotrophic lateral sclerosis (ALS). The selection of AAC for patients with ALS involves a variety of factors, sometimes leading to the utilization of multiple AAC methods. This study aimed to survey patients with ALS in Japan, focusing on objectives: to describe the actual state of AAC usage among these patients and to investigate potential classifications in their choice of communication methods, along with identifying influential latent factors. Data from 102 patients with ALS were analysed using descriptive statistics and latent class analysis. A latent class analysis revealed four distinct classifications: class I, replacing unaid communication with AAC (n = 46, 45.1%); class II, with minimal AAC use (n = 24, 23.5%); class III, centred around no-tech/low-tech AAC (n = 17, 16.7%); and class IV combining unaid communication with various AACs (n = 15, 14.7%). These classifications were influenced by age at diagnosis, TPPV use, gastrostomy use, and the Revised ALS Functional Rating Scale. The characteristics of each class revealed a correlation between increased medical needs, such as bulbar palsy, motor and respiratory function decline, and the necessity for AAC. Notably, patients diagnosed at an older age and those with severe bulbar palsy, like those seen in bulbar-onset ALS, require early communication support due to early onset of communication impairments. Additionally, introducing AAC in the early stages of ALS suggests that learning diverse communication methods can contribute to the maintenance of communication.

Factors associated with psychological distress in patients with amyotrophic lateral sclerosis: A retrospective medical records study

ObjectiveAlthough psychological distress is a prevalent issue among patients with amyotrophic lateral sclerosis (ALS) and can impact survival, the risk factors contributing to this distress remain insufficiently understood. MethodsPatients with ALS who completed the Profile of Mood States (POMS) between June 2017 and March 2022 were included. Participants with moderate to severe cognitive decline were excluded, resulting in the recruitment of 121 patients. The associations between POMS profiles and clinical characteristics were analyzed. Physical motor symptoms were evaluated using the Revised ALS Functional Rating Scale (ALSFRS-R) for objective measurement and the 40-item ALS Assessment Questionnaire (ALSAQ-40) for subjective assessment. ResultsOur model, employing the ALSFRS-R, revealed significant factors associated with overall psychological distress, as assessed by the POMS, including upper limb symptoms, the presence of sleep apnea syndrome, older age at onset, and male sex, with an inverse association with tracheostomy. The POMS subscale scores revealed that anger and depression were significantly associated with upper limb symptoms. The second model, which employed subjective scales, yielded similar results, reinforcing the robustness of our findings. Moreover, subjective bulbar symptoms on the ALSAQ-40 were significantly associated with psychological distress, particularly in female patients. ConclusionThis study identified the main clinical characteristics significantly associated with psychological distress in patients with ALS. Our findings may be useful in developing individualized psychological management strategies for these patients.

Association between apathy and caregiver burden in patients with amyotrophic lateral sclerosis: a cross-sectional study

ObjectivesTo investigate the relationship among patients’ apathy, cognitive impairment, depression, anxiety, and caregiver burden in amyotrophic lateral sclerosis (ALS).DesignA cross-sectional study design was used.SettingThe study was conducted at a tertiary...

Dysregulation of muscle cholesterol transport in amyotrophic lateral sclerosis.

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.

Cortical inexcitability in ALS: correlating a clinical phenotype

BackgroundCortical inexcitability, a less studied feature of upper motor neuron (UMN) dysfunction in amyotrophic lateral sclerosis (ALS), was identified in a large cross-sectional cohort of ALS patients and their demographic...

TBK1 p.Y153Qfs*9 variant may be associated with young-onset, rapidly progressive amyotrophic lateral sclerosis through a haploinsufficiency mechanism.

TBK1 variants have been implicated in the pathogenesis of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia spectrum disorder. The current study elucidated the clinical and molecular genetic features of a novel TBK1 variant identified in a patient with young-onset, rapidly progressive ALS. The coding regions of TBK1 , SOD1 , TARDBP , and FUS were genetically analyzed using Sanger sequencing. Repeat-primed polymerase chain reaction (PCR) was used to survey the GGGGCC repeat in C9ORF72 . The study participant underwent a comprehensive clinical evaluation. The functional effects of the TBK1 variant were analyzed through in vitro transfection studies. We identified a novel frameshift truncating TBK1 variant, c.456_457delGT (p.Y153Qfs*9), in a man with ALS. The disease initially manifested as right hand weakness at the age of 39 years but progressed rapidly, with the revised ALS Functional Rating Scale score declining at an average monthly rate of 1.92 points in the first year after diagnosis. The patient had no cognitive dysfunction. However, Technetium-99m single photon emission tomography indicated hypoperfusion in his bilateral superior and middle frontal cortices. In vitro studies revealed that the p.Y153Qfs*9 variant resulted in a truncated TBK1 protein product, reduced TBK1 protein expression, loss of kinase function, reduced interaction with optineurin, and impaired dimerization. The heterozygous TBK1 p.Y153Qfs*9 variant may be associated with young-onset, rapidly progressive ALS through a haploinsufficiency mechanism.

Cognitive reserve as a modulator of cognitive decline and of behavioral symptoms in patients with amyotrophic lateral sclerosis

Introduction: Amyotrophic lateral sclerosis (ALS) has heterogeneous manifestations ranging from motor neuron degeneration to cognitive and behavioral impairment. This study aims to clarify the interactions between cognition and behavioral symptoms with relevant disease predictors and with cognitive reserve (CR), quantified through education, physical activity, and occupation proxies. Methods: A prospective sample of 162 ALS patients and 61 controls were evaluated with the Edinburgh Cognitive and Behavioral ALS Screen (ECAS) (dependent variable), a Cognitive Reserve Index questionnaire (CRIq) and demographic data (age and sex), and, for patients, clinical variables: disease duration, site of onset, the ALS Functional Rating Scale (ALSFRS), forced vital capacity (FVC), and gene mutation chromosome 9 open reading frame 72 (C9orf72) (independent variables). Multiple regression and mediation analyses were performed to predict cognitive and behavioral symptoms. Results: For the ALS group, the statistical model explained 38.8% of variance in ECAS total (p < 0.001), 59.4% of executive functions (p < 0.001), and 55% of behavioral symptoms (p < 0.001). For controls, it accounted for 52.8% of variance in ECAS total (p < 0.001). Interaction effects and mediation analysis showed CR is an ECAS total modulator, with a differential effect within groups (p < 0.001). Verbal fluency was the single best cognitive score to differentiate patients from controls (p = 0.004), and the gene mutation C9orf72 was found to be a behavioral symptom’ predictor in patients (p = 0.009). Conclusion: This study supports the proposed concept that CR acts as a cognitive modulator in ALS patients and healthy individuals. Moreover, CR also modulates behavioral manifestations in ALS.

Cultivating Patient Preferences in ALS Clinical Trials: Reliability and Prognostic Value of the Patient-Ranked Order of Function.

The Patient-Ranked Order of Function (PROOF) is a novel approach to account for patient-reported preferences in the evaluation of treatments of amyotrophic lateral sclerosis (ALS). In this study, we assess the reliability and prognostic value of different sets of patient-reported preferences that can be used for the PROOF end point. Data were obtained through online surveys over the course of 12 months using the population-based registry of the Netherlands. Patients were asked to score functional domains of the ALS Functional Rating Scale (ALSFRS-R) and rank the order of importance of each domain. Two weeks after the initial invite, the questionnaire was repeated to evaluate test-retest reliability. Vital status was extracted from the municipal population register. In total, 611 patients with ALS were followed up for survival and 382 patients were included in the test-retest reliability study. All versions of PROOF, using different sets of preferences, resulted in excellent reliability (intraclass correlation coefficients ranged from 0.89 [95% CI 0.87-0.91] to 0.97 [95% CI 0.97-0.98], all p < 0.001), without systematic differences between baseline and week 2 (mean rank difference range -1 to -3 [95% CI range -8 to 2], all p > 0.20). Preferences about future events were more variable than preferences about current symptoms. All versions of PROOF strongly predicted overall survival (hazard ratios per 10th rank percentile ranged from 0.80 to 0.83 [95% CI range 0.76-0.87], all p < 0.001) and had a more even separation of survival curves between rank-stratified subgroups compared with the ALSFRS-R total score. In a large cohort of patients, we show how patient-reported preferences can be measured and integrated reliably with the ALSFRS-R without leading to systematic bias. Patient preferences may provide unique prognostic information in addition to what is already measured conventionally. This could provide a more comprehensive understanding of how medical interventions effectively address the patient's concerns and improve what matters most to them.