Amyotrophic Lateral Sclerosis Functional Rating Scale Research Articles

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

Background: 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. Objectives: 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. Methods: 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. Results: 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. Conclusion: 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.

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.

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

Background: 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. Methods: 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. Results: 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 &lt; 0.05). The CAPE-V’s overall severity and sub-scores for pitch and loudness demonstrated significant correlations with MIP% and MEP% (all p &lt; 0.05). In contrast, acoustic metrics (speaking rate, absolute energy, shimmer, and harmonic-to-noise ratio) significantly correlated with FVC% (all p &lt; 0.05). Conclusions: 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.

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...

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.

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 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.

Proteomic insights into extracellular vesicles in ALS for therapeutic potential of Ropinirole and biomarker discovery

BackgroundExtracellular vesicles (EVs) hold the potential for elucidating the pathogenesis of amyotrophic lateral sclerosis (ALS) and serve as biomarkers. Notably, the comparative and longitudinal alterations in the protein profiles of EVs in serum (sEVs) and cerebrospinal fluid (CSF; cEVs) of sporadic ALS (SALS) patients remain uncharted. Ropinirole hydrochloride (ROPI; dopamine D2 receptor [D2R] agonist), a new anti-ALS drug candidate identified through induced pluripotent stem cell (iPSC)-based drug discovery, has been suggested to inhibit ALS disease progression in the Ropinirole Hydrochloride Remedy for Amyotrophic Lateral Sclerosis (ROPALS) trial, but its mechanism of action is not well understood. Therefore, we tried to reveal longitudinal changes with disease progression and the effects of ROPI on protein profiles of EVs.MethodsWe collected serum and CSF at fixed intervals from ten controls and from 20 SALS patients participating in the ROPALS trial. Comprehensive proteomic analysis of EVs, extracted from these samples, was conducted using liquid chromatography/mass spectrometer (LC/MS). Furthermore, we generated iPSC-derived astrocytes (iPasts) and performed RNA sequencing on astrocytes with or without ROPI treatment.ResultsThe findings revealed notable disparities yet high congruity in sEVs and cEVs protein profiles concerning disease status, time and ROPI administration. In SALS, both sEVs and cEVs presented elevated levels of inflammation-related proteins but reduced levels associated with unfolded protein response (UPR). These results mirrored the longitudinal changes after disease onset and correlated with the revised ALS Functional Rating Scale (ALSFRS-R) at sampling time, suggesting a link to the onset and progression of SALS. ROPI appeared to counteract these changes, attenuating inflammation-related protein levels and boosting those tied to UPR in SALS, proposing an anti-ALS impact on EV protein profiles. Reverse translational research using iPasts indicated that these changes may partly reflect the DRD2-dependent neuroinflammatory inhibitory effects of ROPI. We have also identified biomarkers that predict diagnosis and disease progression by machine learning-driven biomarker search.ConclusionsDespite the limited sample size, this study pioneers in reporting time-series proteomic alterations in serum and CSF EVs from SALS patients, offering comprehensive insights into SALS pathogenesis, ROPI-induced changes, and potential prognostic and diagnostic biomarkers.

Caffeine consumption outcomes on amyotrophic lateral sclerosis disease progression and cognition

Caffeine consumption outcomes on Amyotrophic Lateral Sclerosis (ALS) including progression, survival and cognition remain poorly defined and may depend on its metabolization influenced by genetic variants. 378 ALS patients with a precise evaluation of their regular caffeine consumption were monitored as part of a prospective multicenter study. Demographic, clinical characteristics, functional disability as measured with revised ALS Functional Rating Scale (ALSFRS-R), cognitive deficits measured using Edinburgh Cognitive and Behavioural ALS Screen (ECAS), survival and riluzole treatment were recorded. 282 patients were genotyped for six single nucleotide polymorphisms tagging different genes involved in caffeine intake and/or metabolism: CYP1A1 (rs2472297), CYP1A2 (rs762551), AHR (rs4410790), POR (rs17685), XDH (rs206860) and ADORA2A (rs5751876) genes. Association between caffeine consumption and ALSFRS-R, ALSFRS-R rate, ECAS and survival were statistically analyzed to determine the outcome of regular caffeine consumption on ALS disease progression and cognition. No association was observed between caffeine consumption and survival (p = 0.25), functional disability (ALSFRS-R; p = 0.27) or progression of ALS (p = 0.076). However, a significant association was found with higher caffeine consumption and better cognitive performance on ECAS scores in patients carrying the C/T and T/T genotypes at rs2472297 (p-het = 0.004). Our results support the safety of regular caffeine consumption on ALS disease progression and survival and also show its beneficial impact on cognitive performance in patients carrying the minor allele T of rs2472297, considered as fast metabolizers, that would set the ground for a new pharmacogenetic therapeutic strategy.

Changes in saccadic intrusions over time as an objective biomarker to follow ALS disease progression

Objective: Saccadic Intrusions (SIs) are abnormal eye movements during gaze fixation. Studies have indicated the clinical relevance of SIs, especially of square wave jerks (SWJ) in ALS. We used a software-based platform to extract SIs as a part of an interventional drug trial. The objective was to examine SIs’ change over time as a potential biomarker of ALS disease progression. Methods: 28 ALS patients (61.95 ± 8.6 years) were assessed with the revised ALS Functional Rating Scale (ALSFRS-R) and with an oculometric test. Changes of SIs over time and correlations with ALSFRS-R and its bulbar subscale were calculated. A power calculation was conducted to understand the practical implications of results. Results: A significant increase of SWJ over trial duration was observed, with an increase in frequency (mean rise of 0.14 ± 0.28, p < 0.01), amplitude (0.001 ± 0.0016 degrees, p < 0.005), overall duration of SWJ (0.13 ± 0.25, in %, p < 0.01), and in their relative part out of all intrusions (0.18 ± 0.32, in %, p < 0.005). Negative correlations were found with the bulbar subscale (R=-0.43, −0.41, −0.39 and −0.47, respectively, p < 0.001). The required sample size for observing a 40% reduction in bulbar aspects when using the oculometric test (α = 0.05 and β = 0.8), was found to be 150 patients per arm, compared with 200 patients using the bulbar subscale. Conclusions: Evaluation of saccadic intrusions during fixation was able to detect disease progression over time, correlated with ALSFRS-R bulbar subscale. Eye movements can potentially serve as an objective biomarker in ALS clinical trials and reduce the required sample size to show clinical effect of therapies.

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.

Tongue pressure is a strong predictor of recommendation for gastrostomy in amyotrophic lateral sclerosis.

Objective and practical biomarkers to determine the need for gastrostomy in patients with amyotrophic lateral sclerosis (ALS) are lacking. Tongue pressure (TP) is a promising biomarker because it is associated with bulbar dysfunction. The aims of this study were to evaluate the association of TP with the need for gastrostomy, and to determine its optimal cut-off value. This prospective observational study included participants with ALS taking nutrition orally. TP was evaluated using the Iowa Oral Performance Instrument. Need for gastrostomy as determined by a multidisciplinary team during a 12-month follow up period was recorded. Associations between TP and need for gastrostomy placement were performed. ROC curve analysis determined the optimal cut-off value of TP to predict gastrostomy. Of 208 screened participants, 119 were included. Gastrostomy was indicated in 45% (53), in a 12-month follow up period. TP of ≤20 kPA was a strong predictor of gastrostomy indication (OR 11.8, CI 95% [4.61, 34.7], p < .001). The association persisted even after adjustment for weight loss, pneumonia, prolonged feeding duration, Revised ALS Functional Rating Scale score, and American Speech-Language-Hearing Association scale score (OR 4.51, CI 95% [1.50, 14.9], p = .009). By receiver operating characteristic curve analysis, 20 kPA represented the optimal cut-off value (sensitivity 0.75, specificity 0.89). TP is a strong independent predictor of gastrostomy indication in the subsequent 12 months in patients with ALS, with good sensitivity and specificity at a cutoff value of ≤20 kPA, suggesting that it may be a promising biomarker in clinical practice.