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Purpose: Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease that affects bulbar functions including speech and voice. Voice onset time (VOT) was examined in speakers with ALS in early and late stages to explore the coordination of the articulatory and phonatory systems during speech production. Method: VOT was measured in nonword /bap/ produced by speakers with early-stage ALS ( n = 11), late-stage ALS ( n = 6), and healthy controls ( n = 13), and compared with speech performance decline (a marker of disease progression) in ALS. Results: Overall comparison of the VOT values among the three groups showed a significant difference, F (2,27) = 11.71, p < .01. Speakers in late-stage ALS displayed longer voicing lead (negative VOT) than both healthy speakers and speakers in early-stage ALS. VOT was also significantly negatively correlated with speech performance (i.e., Intelligible Speaking Rate), r (15) = .74, p Conclusions: Speakers with more severe ALS showed greater occurrence of voicing lead and longer voicing lead. Findings show voicing precedes articulatory onset with disease progression in the production of bilabial stops, which suggests that the relative timing of coordination between the supralaryngeal structures and the phonatory system is affected in the late stage of ALS.

Answer ALS is a biological and clinical resource of patient-derived, induced pluripotent stem (iPS) cell lines, multi-omic data derived from iPS neurons and longitudinal clinical and smartphone data from over 1,000 patients with ALS. This resource provides population-level biological and clinical data that may be employed to identify clinical–molecular–biochemical subtypes of amyotrophic lateral sclerosis (ALS). A unique smartphone-based system was employed to collect deep clinical data, including fine motor activity, speech, breathing and linguistics/cognition. The iPS spinal neurons were blood derived from each patient and these cells underwent multi-omic analytics including whole-genome sequencing, RNA transcriptomics, ATAC-sequencing and proteomics. The intent of these data is for the generation of integrated clinical and biological signatures using bioinformatics, statistics and computational biology to establish patterns that may lead to a better understanding of the underlying mechanisms of disease, including subgroup identification. A web portal for open-source sharing of all data was developed for widespread community-based data analytics.

Summary Background There is an urgent unmet need for new therapies in amyotrophic lateral sclerosis. In a clinical study with healthy volunteers, levosimendan, a calcium sensitiser, was shown to improve neuromechanical efficiency and contractile function of the human diaphragm. We aimed to evaluate the safety and efficacy of oral levosimendan in people with amyotrophic lateral sclerosis, with a focus on respiratory function. Methods The REFALS study is a randomised, double-blind, placebo-controlled phase 3 trial at 99 amyotrophic lateral sclerosis specialist centres in 14 countries worldwide. People with amyotrophic lateral sclerosis were eligible for participation if they were at least 18 years of age and had a sitting slow vital capacity (SVC) of 60–90% predicted. Participants were randomly assigned (2:1) by interactive web-response system to receive either levosimendan or placebo. The capsules for oral administration were identical in appearance to maintain blinding of participants and investigators. The primary endpoint was the change from baseline in supine SVC at 12 weeks, assessed as the percentage of predicted normal sitting SVC. The key secondary endpoint was the combined assessment of function and survival (CAFS) up to 48 weeks. Analyses were done in the intention-to-treat population, comprising all participants who were randomly assigned. This trial is registered at ClinicalTrials.gov (NCT03505021) and has been completed. An extension study (REFALS-ES; NCT03948178 ) has also been completed, but will be reported separately. Findings Between June 21, 2018, and June 28, 2019, 871 people were screened for the study, of whom 496 were randomly assigned either levosimendan (n=329) or placebo (n=167). Participants were followed up between June 27, 2018 and June 26, 2020, for a median duration of 50·1 (IQR 37·5–51·1) weeks. The median duration of treatment was 47·9 (IQR 26·4–48·1) weeks. Change from baseline in supine SVC at 12 weeks was –6·73% with levosimendan and –6·99% with placebo, with no significant difference between the treatments (estimated treatment difference 0·26%, 95% CI –2·03 to 2·55, p=0·83). Similarly, at week 48, CAFS did not differ between treatment groups (least squares mean change from baseline 10·69, 95% CI –15·74 to 37·12; nominal p value=0·43). The most frequent adverse events were increased heart rate (106 [33%] of 326 receiving levosimendan vs 12 [7%] of 166 receiving placebo), fall (85 [26%] vs 48 [29%]), headache (93 [29%] vs 36 [22%]), and dyspnoea (59 [18%] vs 32 [19%]). 33 (10%) participants allocated levosimendan and 20 (12%) assigned placebo died during the trial, mainly due to respiratory failure or progression of amyotrophic lateral sclerosis. Interpretation Levosimendan was not superior to placebo in maintaining respiratory function in a broad population with amyotrophic lateral sclerosis. Although levosimendan was generally well tolerated, increased heart rate and headache occurred more frequently with levosimendan than with placebo. The possibility of a clinically relevant subgroup of responsive individuals requires further evaluation. Funding Orion Corporation.

PurposeKinematic measurements of speech have demonstrated some success in automatic detection of early symptoms of amyotrophic lateral sclerosis (ALS). In this study, we examined how the region of symptom onset (bulbar vs. spinal) affects the ability of data-driven models to detect ALS.MethodWe used a correlation structure of articulatory movements combined with a machine learning model (i.e., artificial neural network) to detect differences between people with ALS and healthy controls. The performance of this system was evaluated separately for participants with bulbar onset and spinal onset to examine how region of onset affects classification performance. We then performed a regression analysis to examine how different severity measures and region of onset affects model performance.ResultsThe proposed model was significantly more accurate in classifying the bulbar-onset participants, achieving an area under the curve of 0.809 relative to the 0.674 achieved for spinal-onset participants. The regression analysis, however, found that differences in classifier performance across participants were better explained by their speech performance (intelligible speaking rate), and no significant differences were observed based on region of onset when intelligible speaking rate was accounted for.ConclusionsAlthough we found a significant difference in the model's ability to detect ALS depending on the region of onset, this disparity can be primarily explained by observable differences in speech motor symptoms. Thus, when the severity of speech symptoms (e.g., intelligible speaking rate) was accounted for, symptom onset location did not affect the proposed computational model's ability to detect ALS.

An orally administered, fixed‐dose coformulation of sodium phenylbutyrate‐taurursodiol (PB‐TURSO) significantly slowed functional decline in a randomized, placebo‐controlled, phase 2 trial in ALS (CENTAUR). Herein we report results of a long‐term survival analysis of participants in CENTAUR. In CENTAUR, adults with ALS were randomized 2:1 to PB‐TURSO or placebo. Participants completing the 6‐month (24‐week) randomized phase were eligible to receive PB‐TURSO in the open‐label extension. An all‐cause mortality analysis (35‐month maximum follow‐up post‐randomization) incorporated all randomized participants. Participants and site investigators were blinded to treatment assignments through the duration of follow‐up of this analysis. Vital status was obtained for 135 of 137 participants originally randomized in CENTAUR. Median overall survival was 25.0 months among participants originally randomized to PB‐TURSO and 18.5 months among those originally randomized to placebo (hazard ratio, 0.56; 95% confidence interval, 0.34‐0.92; P = .023). Initiation of PB‐TURSO treatment at baseline resulted in a 6.5‐month longer median survival as compared with placebo. Combined with results from CENTAUR, these results suggest that PB‐TURSO has both functional and survival benefits in ALS.

To evaluate safety, dose response, and preliminary efficacy of reldesemtiv over 12 weeks in patients with amyotrophic lateral sclerosis (ALS). Methods: Patients (≤2 years since diagnosis) with slow...

BackgroundCoformulated sodium phenylbutyrate/taurursodiol (PB/TURSO) was shown to prolong survival and slow functional decline in amyotrophic lateral sclerosis (ALS).ObjectiveDetermine whether PB/TURSO prolonged tracheostomy/ventilation-free survival and/or reduced first hospitalisation in participants with ALS in the CENTAUR trial.MethodsAdults with El Escorial Definite ALS ≤18 months from symptom onset were randomised to PB/ TURSO or placebo for 6 months. Those completing randomised treatment could enrol in an open-label extension (OLE) phase and receive PB/TURSO for ≤30 months. Times to the following individual or combined key events were compared in the originally randomised treatment groups over a period spanning trial start through July 2020 (longest postrandomisation follow-up, 35 months): death, tracheostomy, permanent assisted ventilation (PAV) and first hospitalisation.ResultsRisk of any key event was 47% lower in those originally randomised to PB/TURSO (n=87) versus placebo (n=48, 71% of whom received delayed-start PB/TURSO in the OLE phase) (HR=0.53; 95% CI 0.35 to 0.81; p=0.003). Risks of death or tracheostomy/PAV (HR=0.51; 95% CI 0.32 to 0.84; p=0.007) and first hospitalisation (HR=0.56; 95% CI 0.34 to 0.95; p=0.03) were also decreased in those originally randomised to PB/TURSO.ConclusionsEarly PB/TURSO prolonged tracheostomy/PAV-free survival and delayed first hospitalisation in ALS.Trial registration numberNCT03127514;NCT03488524.

Introduction/Aims. Primary lateral sclerosis (PLS) is exceedingly rare and has been an enigmatic disease. Recent progress has drastically changed this perception, with early biomarkers being investigated and potential medications for PLS emerging at the preclinical stage. The aim of this paper is to describe a study of PLS natural history and discuss the limitations and proposed solutions to the study of a rare and slowly progressive disease. Methods. The PLS Natural History Study is a 30-site, 24-month, prospective study that is supported by multiple funding sources. The study aims to enroll 50 early PLS (disease duration ≤4 years) and 50 definite PLS (disease duration 4 to 15 years) participants using modified PLS Diagnostic Criteria. Smartphone-based assessments including semi-quantitative and quantitative measures and patient-reported outcomes are utilized. In-person quantitative measures are also completed during site visits. The change in the PLS Functional Rating Scale score is the primary outcome. The study utilizes the NeuroBANK® patient-centric data capture and management platform. The biostatistical analysis plan has been developed. Results. In one year, 28 participants have been recruited. Enrollment has been much slower than anticipated due to the COVID-19 pandemic, the rarity of PLS, and potential study competition for internal resources from ALS clinical trials. Discussion. We discuss the need for more innovative methods to enroll and study individuals with such rare diseases and propose a number of mechanisms by which more efficient enrollment could be facilitated.

Purpose: The goal of this study was to examine the efficacy of acceleration-based articulatory measures in characterizing the decline in speech motor control due to amyotrophic lateral sclerosis (ALS). Method: Electromagnetic articulography was used to record tongue and lip movements during the production of 20 phrases. Data were collected from 50 individuals diagnosed with ALS. Articulatory kinematic variability was measured using the spatiotemporal index of both instantaneous acceleration and speed signals. Linear regression models were used to analyze the relationship between variability measures and intelligible speaking rate (a clinical measure of disease progression). A machine learning algorithm (support vector regression, SVR) was used to assess whether acceleration or speed features (e.g., mean, median, maximum) showed better performance at predicting speech severity in patients with ALS. Results: As intelligible speaking rate declined, the variability of acceleration of tongue and lip movement patterns significantly increased (p < 0.001). The variability of speed and vertical displacement did not significantly predict speech performance measures. Additionally, based on R2 and root mean square error (RMSE) values, the SVR model was able to predict speech severity more accurately from acceleration features (R2 = 0.601, RMSE = 38.453) and displacement features (R2 = 0.218, RMSE = 52.700) than from speed features (R2 = 0.554, RMSE = 40.772). Conclusion: Results from these models highlight differences in speech motor control in participants with ALS. The variability in acceleration of tongue and lip movements increases as speech performance declines, potentially reflecting physiological deviations due to the progression of ALS. Our findings suggest that acceleration is a more sensitive indicator of speech deterioration due to ALS than displacement and speed and may contribute to improved algorithm designs for monitoring disease progression from speech signals.

Introduction: Universally established comprehensive clinical bulbar scales objectively assessing disease progression in amyotrophic lateral sclerosis (ALS) are currently lacking. The goal of this working group project is to design a best practice set of provisional bulbar ALS guidelines, available for immediate implementation within all ALS clinics. Methods: ALS specialists across multiple related disciplines participated in a series of clinical bulbar symposia, intending to identify and summarize the currently accepted best practices for the assessment and management of bulbar dysfunction in ALS Results: Summary group recommendations for individual speech, Augmentative and Alternative Communication (AAC), and swallowing sections were achieved, focusing on the optimal proposed level of care within each domain. Discussion: We have identified specific clinical recommendations for each of the 3 domains of bulbar functioning, available for incorporation within all ALS clinics. Future directions will be to establish a formal set of bulbar guidelines through a methodological and evidence-based approach. Muscle Nerve 59:531–531, 2019. Fil: Pattee, Gary L.. No especifíca; Fil: Plowman, Emily K.. University of Florida; Estados Unidos Fil: Garand, Kendrea L.. University of Alabama at Birmingahm; Estados Unidos Fil: Costello, John. No especifíca; Fil: Brooks, Benjamin Rix. No especifíca; Fil: Berry, James D.. No especifíca; Fil: Smith, Richard A.. No especifíca; Fil: Atassi, Nazem. No especifíca; Fil: Chapin, Jennifer L.. University of Florida; Estados Unidos Fil: Yunusova, Yana. University of Toronto; Canadá Fil: McIlduff, Courtney E.. No especifíca; Fil: Young, Eufrosina. No especifíca; Fil: Macklin, Eric A.. No especifíca; Fil: Locatelli, Eduardo R.. No especifíca; Fil: Silani, Vincenzo. Università degli Studi di Milano; Italia Fil: Heitzman, Daragh. No especifíca; Fil: Wymer, James. University of Florida; Estados Unidos Fil: Goutman, Stephen A.. No especifíca; Fil: Gelinas, Deborah F.. No especifíca; Fil: Perry, Bridget. No especifíca; Fil: Nalipinski, Paige. No especifíca; Fil: Stipancic, Kaila. Children's Hospital Boston; Estados Unidos Fil: O'Brien, Meghan. Children's Hospital Boston; Estados Unidos Fil: Sullivan, Stacey L.. No especifíca; Fil: Pioro, Erik P.. No especifíca; Fil: Gargiulo Monachelli, Gisella Mariana. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. CEMIC-CONICET. Centro de Educaciones Médicas e Investigaciones Clínicas "Norberto Quirno". CEMIC-CONICET; Argentina Fil: Green, Jordan R.. No especifíca

Objective: To evaluate safety, dose response, and preliminary efficacy of reldesemtiv over 12 weeks in patients with amyotrophic lateral sclerosis (ALS). Methods: Patients (≤2 years since diagnosis) with slow upright vital capacity (SVC) of ≥60% were randomized 1:1:1:1 to reldesemtiv 150, 300, or 450 mg twice daily (bid) or placebo; active treatment was 12 weeks with 4-week follow-up. Primary endpoint was change in percent predicted SVC at 12 weeks; secondary measures included ALS Functional Rating Scale-Revised (ALSFRS-R) and muscle strength mega-score. Results: Patients (N = 458) were enrolled; 85% completed 12-week treatment. The primary analysis failed to reach statistical significance (p = 0.11); secondary endpoints showed no statistically significant effects (ALSFRS-R, p = 0.09; muscle strength megascore, p = 0.31). Post hoc analyses pooling all active reldesemtiv-treated patients compared against placebo showed trends toward benefit in all endpoints (progression rate for SVC, ALSFRS-R, and muscle strength mega-score (nominal p values of 0.10, 0.01 and 0.20 respectively)). Reldesemtiv was well tolerated, with nausea and fatigue being the most common side effects. A dose-dependent decrease in estimated glomerular filtration rate was noted, and transaminase elevations were seen in approximately 5% of patients. Both hepatic and renal abnormalities trended toward resolution after study drug discontinuation. Conclusions: Although the primary efficacy analysis did not demonstrate statistical significance, there were trends favoring reldesemtiv for all three endpoints, with effect sizes generally regarded as clinically important. Tolerability was good; modest hepatic and renal abnormalities were reversible. The impact of reldesemtiv on patients with ALS should be assessed in a pivotal Phase 3 trial. (ClinicalTrials.gov Identifier: NCT03160898)

BACKGROUND: Sodium phenylbutyrate and taurursodiol have been found to reduce neuronal death in experimental models. The efficacy and safety of a combination of the two compounds in persons with amyotrophic lateral sclerosis (ALS) are not known. METHODS: In this multicenter, randomized, double-blind trial, we enrolled participants with definite ALS who had had an onset of symptoms within the previous 18 months. Participants were randomly assigned in a 2:1 ratio to receive sodium phenylbutyrate–taurursodiol (3 g of sodium phenylbutyrate and 1 g of taurursodiol, administered once a day for 3 weeks and then twice a day) or placebo. The primary outcome was the rate of decline in the total score on the Amyotrophic Lateral Sclerosis Functional Rating Scale–Revised (ALSFRS-R; range, 0 to 48, with higher scores indicating better function) through 24 weeks. Secondary outcomes were the rates of decline in isometric muscle strength, plasma phosphorylated axonal neurofilament H subunit levels, and the slow vital capacity; the time to death, tracheostomy, or permanent ventilation; and the time to death, tracheostomy, permanent ventilation, or hospitalization. RESULTS: A total of 177 persons with ALS were screened for eligibility, and 137 were randomly assigned to receive sodium phenylbutyrate–taurursodiol (89 participants) or placebo (48 participants). In a modified intention-to-treat analysis, the mean rate of change in the ALSFRS-R score was −1.24 points per month with the active drug and −1.66 points per month with placebo (difference, 0.42 points per month; 95% confidence interval, 0.03 to 0.81; P = 0.03). Secondary outcomes did not differ significantly between the two groups. Adverse events with the active drug were mainly gastrointestinal. CONCLUSIONS: Sodium phenylbutyrate–taurursodiol resulted in slower functional decline than placebo as measured by the ALSFRS-R score over a period of 24 weeks. Secondary outcomes were not significantly different between the two groups. Longer and larger trials are necessary to evaluate the efficacy and safety of sodium phenylbutyrate–taurursodiol in persons with ALS. (Funded by Amylyx Pharmaceuticals and others; CENTAUR Clinicaltrials.gov number, NCT03127514.)

Objective: To determine the associations between plasma creatinine (PCr), plasma uric acid (PUA), and urinary oxidative stress (OS) biomarkers with the ALSFRS-R at baseline and survival in a large epidemiological cohort study (ALS COSMOS) with a well-phenotyped patient population (N = 355).Methods: Fasting plasma and first void urine samples were obtained. PCr, PUA, urinary 8-oxo-deoxy guanosine (8-oxodG), and 15-F2t-isoprostane (IsoP) were analyzed at baseline, near the midpoint of follow-up, and at the final blood draw (before death or withdrawal from study). We estimated associations between these biomarkers and the ALSFRS-R at baseline and survival.Results: At baseline, PCr correlated with ALSFRS-R (Spearman r = 0.30), percent (%) FVC (r = 0.20), PUA (r = 0.37), and 8-oxodG (r = -0.13, all p

Decoding speech directly from the brain has the potential for the development of the next generation, more efficient brain computer interfaces (BCIs) to assist in the communication of patients with locked-in syndrome (fully paralyzed but aware). In this study, we have explored the spectral and temporal features of the magnetoencephalography (MEG) signals and trained those features with convolutional neural networks (CNN) for the classification of neural signals corresponding to phrases. Experimental results demonstrated the effectiveness of CNNs in decoding speech during perception, imagination, and production tasks. Furthermore, to overcome the long training time issue of CNNs, we leveraged principal component analysis (PCA) for spatial dimension reduction of MEG data and transfer learning for model initialization. Both PCA and transfer learning were found to be highly beneficial for faster model training. The best configuration (50 principal coefficients + transfer learning) led to more than 10 times faster training than the original setting while the speech decoding accuracy remained at a similarly high level.

PURPOSE: This research aimed to automatically predict intelligible speaking rate for individuals with Amyotrophic Lateral Sclerosis (ALS) based on speech acoustic and articulatory samples. METHOD: Twelve participants with ALS and two normal subjects produced a total of 1,831 phrases. NDI Wave system was used to collect tongue and lip movement and acoustic data synchronously. A machine learning algorithm (i.e. support vector machine) was used to predict intelligible speaking rate (speech intelligibility × speaking rate) from acoustic and articulatory features of the recorded samples. RESULT: Acoustic, lip movement, and tongue movement information separately, yielded a R(2) of 0.652, 0.660, and 0.678 and a Root Mean Squared Error (RMSE) of 41.096, 41.166, and 39.855 words per minute (WPM) between the predicted and actual values, respectively. Combining acoustic, lip and tongue information we obtained the highest R(2) (0.712) and the lowest RMSE (37.562 WPM). CONCLUSION: The results revealed that our proposed analyses predicted the intelligible speaking rate of the participant with reasonably high accuracy by extracting the acoustic and/or articulatory features from one short speech sample. With further development, the analyses may be well-suited for clinical applications that require automatic speech severity prediction.

Introduction Our research aim was to develop a novel clinimetric scale sensitive enough to detect disease progression in primary lateral sclerosis (PLS). Methods A prototype of the PLS Functional Rating Scale (PLSFRS) was generated. Seventy-seven participants with PLS were enrolled and evaluated at 21 sites that comprised the PLSFRS study group. Participants were assessed using the PLSFRS, Neuro-Quality of Life (QoL), Schwab-England Activities of Daily Living (ADL), and the Clinical Global Impression of Change scales. Participants completed telephone assessments at 12, 24, and 48 weeks after enrollment. Results The PLSFRS demonstrated internal consistency as well as intrarater, interrater, telephone test-retest reliability, and construct validity. Significant changes in disease progression were detected at 6 and 12 months; changes measured by the PLSFRS vs the ALSFRS-R were significantly higher. Discussion The PLSFRS is a valid tool to assess the natural history of PLS in a shorter study period.

Author(s): Woolley, Susan; Goetz, Ray; Factor-Litvak, Pam; Murphy, Jennifer; Hupf, Jonathan; Garofalo, Diana C; Lomen-Hoerth, Catherine; Andrews, Howard; Heitzman, Daragh; Bedlack, Richard; Katz, Jonathan; Barohn, Richard; Sorenson, Eric; Oskarsson, Bjorn; Filho, Americo Fernandes; Kasarskis, Edward; Mozaffar, Tahseen; Nations, Sharon; Swenson, Andrea; Koczon-Jaremko, Agnes; Christodoulou, Georgia; Mitsumoto, Hiroshi | Abstract: [This corrects the article DOI: 10.1155/2018/5969137.].

Amyotrophic Lateral Sclerosis (ALS) is a progressive neurological disease that leads to degeneration of motor neurons and, as a result, inhibits the ability of the brain to control muscle movements. Monitoring the progression of ALS is of fundamental importance due to the wide variability in disease outlook that exists across patients. This progression is typically tracked using the ALS functional rating scale - revised (ALSFRS-R), which is the current clinical assessment of a patient’s level of functional impairment including speech and other motor tasks. In this paper, we investigated automatic estimation of the ALSFRS-R bulbar subscore from acoustic and articulatory movement samples. Experimental results demonstrated the AFSFRS-R bulbar subscore can be predicted from speech samples, which has clinical implication for automatic monitoring of the disease progression of ALS using speech information.

Objectives: To characterize the prevalence of cognitive and behavioral symptoms using a cognitive/behavioral screening battery in a large prospective multicenter study of amyotrophic lateral sclerosis (ALS). Methods: Two hundred seventy-four patients with ALS completed 2 validated cognitive screening tests and 2 validated behavioral interviews with accompanying caregivers. We examined the associations between cognitive and behavioral performance, demographic and clinical data, and C9orf72 mutation data. Results: Based on the ALS Cognitive Behavioral Screen cognitive score, 6.5% of the sample scored below the cutoff score for frontotemporal lobar dementia, 54.2% scored in a range consistent with ALS with mild cognitive impairment, and 39.2% scored in the normal range. The ALS Cognitive Behavioral Screen behavioral subscale identified 16.5% of the sample scoring below the dementia cutoff score, with an additional 14.1% scoring in the ALS behavioral impairment range, and 69.4% scoring in the normal range. Conclusions: This investigation revealed high levels of cognitive and behavioral impairment in patients with ALS within 18 months of symptom onset, comparable to prior investigations. This investigation illustrates the successful use and scientific value of adding a cognitive-behavioral screening tool in studies of motor neuron diseases, to provide neurologists with an efficient method to measure these common deficits and to understand how they relate to key clinical variables, when extensive neuropsychological examinations are unavailable. These tools, developed specifically for patients with motor impairment, may be particularly useful in patient populations with multiple sclerosis and Parkinson disease, who are known to have comorbid cognitive decline.

Objective. To evaluate longitudinal cognitive/behavioral change over 12 months in participants enrolled in the ALS Multicenter Cohort Study of Oxidative Stress (ALS COSMOS). Methods. We analyzed data from 294 ALS participants, 134 of whom were studied serially. Change over time was evaluated controlling for age, sex, symptom duration, education, race, and ethnicity. Using multiple regression, we evaluated associations among decline in ALS Functional Rating Scale-Revised (ALSFRS-R) scores, forced vital capacity (FVC), and cognitive/behavioral changes. Change in cognitive/behavioral subgroups was assessed using one-way analyses of covariance. Results. Participants with follow-up data had fewer baseline behavior problems compared to patients without follow-up data. We found significant worsening of behavior (ALS Cognitive Behavioral Screen (ALS CBS) behavioral scale, p<0.001; Frontal Behavioral Inventory-ALS (FBI-ALS) disinhibition subscale, p=0.044). Item analysis suggested change in frustration tolerance, insight, mental rigidity, and interests (p<0.05). Changes in ALSFRS-R correlated with the ALS CBS. Worsening disinhibition (FBI-ALS) did not correlate with ALSFRS-R, FVC, or disease duration. Conclusion. We did not detect cognitive change. Behavioral change was detected, and increased disinhibition was found among patients with abnormal baseline behavioral scores. Disinhibition changes did not correlate with disease duration or progression. Baseline behavioral problems were associated with advanced, rapidly progressive disease and study attrition.

Patients with locked-in-syndrome (fully paralyzed but aware) struggle in their life and communication. Providing a level of communication offers these patients a chance to resume a meaningful life. Current brain-computer interface (BCI) communication requires users to build words from single letters selected on a screen, which is extremely inefficient. Faster approaches for their speech communication are highly needed. This project investigated the possibility to decode spoken phrases from non-invasive brain activity (MEG) signals. This direct brain-to-text mapping approach may provide a significantly faster communication rate than current BCIs can provide. We used dynamic time warping and Wiener filtering for noise reduction and then Gaussian mixture model and artificial neural network as the decoders. Preliminary results showed the possibility of decoding speech production from non-invasive brain signals. The best phrase classification accuracy was up to 94.54% from single-trial whole-head MEG recordings.

Substantial disparities in TIV utilization rates among ALS patients have been observed, with rates in Japan far exceeding rates in the United States. Our objective was to elicit national preferences and their determinants. We predicted more Japanese than American patients would desire TIV, as would sicker patients, those already using non-invasive interventions, and those with more positive mood and outlook. Patients were enrolled in five U.S. states and six Japanese regions. Eligible patients completed surveys during clinic visits (U.S.) or at home (Japan). Survey responses were in multiple-choice format and took about 15 min to complete. One hundred and fifty-six Americans and 66 Japanese patients participated. Contrary to expectations, Japanese patients were more likely to oppose TIV, as were those on 24-h NIV and patients who knew someone using TIV. Most Japanese and American patients with advanced respiratory impairment were undecided or opposed to TIV, while nearly 20% in both countries were in favor. Finally, patients who favored TIV or who were undecided had more energy, greater wish to live, and more sense of control over ALS management. In conclusion, factors other than patient preferences, such as neurologist preferences, caregiver attitudes and perhaps lack of advance planning, may influence probability of TIV utilization.

In a multicenter study of newly diagnosed ALS patients without a reported family history of ALS, we are prospectively investigating whether markers of oxidative stress (OS) are associated with disease progression. Methods utilize an extensive structured telephone interview ascertaining environmental, lifestyle, dietary and psychological risk factors associated with OS. Detailed assessments were performed at baseline and at 3-6 month intervals during the ensuing 30 months. Our biorepository includes DNA, plasma, urine, and skin. Three hundred and fifty-five patients were recruited. Subjects were enrolled over a 36-month period at 16 sites. To meet the target number of subjects, the recruitment period was prolonged and additional sites were included. Results showed that demographic and disease characteristics were similar between 477 eligible/non-enrolled and enrolled patients, the only difference being type of health insurance among enrolled patients. Sites were divided into three groups by the number of enrolled subjects. Comparing these three groups, the Columbia site had fewer 'definite ALS' diagnoses. This is the first prospective, interdisciplinary, in-depth, multicenter epidemiological investigation of OS related to ALS progression and has been accomplished by an aggressive recruitment process. The baseline demographic and disease features of the study sample are now fully characterized.

The aim of this Symposium was to develop a consensus based, bulbar assessment protocol for implementation within NEALS clinics.A one-day symposium, held in April 2017, was organized into Speech and Swallowing sections to establish summary recommendations for the assessment of bulbar dysfunction within each group.Summary recommendations included speech referrals and AAC evaluations at initial visit, CNS-BFS, maximum sustained phonation, and speaking rate. Dysarthria evaluation included the speech subsystem involvement of respiration, phonation, resonance, and articulation. Specific recommendations for swallowing were established for each of the following domains: dietary/oral intake, airway defense physiologic capacity, swallow safety screen, patient-reported swallow-related outcomes, oral sensorimotor exam, and pulmonary function. Practice parameters focused upon patient education and unresolved questions included the use of videofluoscopy, monitoring diet progression, and swallow safety screening.The working goal is to establish a clinical bulbar protocol, designed to be incorporated within ALS clinics and ultimately to formulate a best practice set of bulbar ALS guidelines, available for implementation throughout the international ALS community.

Recent dysarthric speech recognition studies using mixed data from a collection of neurological diseases suggested articulatory data can help to improve the speech recognition performance. This project was specifically designed for the speakerindependent recognition of dysarthric speech due to amyotrophic lateral sclerosis (ALS) using articulatory data. In this paper, we investigated three across-speaker normalization approaches in acoustic, articulatory, and both spaces: Procrustes matching (a physiological approach in articulatory space), vocal tract length normalization (a data-driven approach in acoustic space), and feature space maximum likelihood linear regression (a model-based approach for both spaces), to address the issue of high degree of variation of articulation across different speakers. A preliminary ALS data set was collected and used to evaluate the approaches. Two recognizers, Gaussian mixture model (GMM) - hidden Markov model (HMM) and deep neural network (DNN) - HMM, were used. Experimental results showed adding articulatory data significantly reduced the phoneme error rates (PERs) using any or combined normalization approaches. DNN-HMM outperformed GMM-HMM in all configurations. The best performance (30.7% PER) was obtained by triphone DNN-HMM + acoustic and articulatory data + all three normalization approaches, a 15.3% absolute PER reduction from the baseline using triphone GMM-HMM + acoustic data. Index Terms: Dysarthric speech recognition, Procrustes matching, vocal track length normalization, fMLLR, hidden Markov models, deep neural network

Four 13762NF rat mammary adenocarcinoma clones were examined for their survival response to heating under conditions that induced transient thermal resistance (thermotolerance). Clones MTC and MTF7 were isolated from the subcutaneous locally growing tumor, whereas clones MTLn2 and MTLn3 were derived from spontaneous lung metastases. There was heterogeneity among these clones in thermotolerance induced by either fractionated 45 degrees C or continuous 42 degrees C heating, but the order of sensitivity was not necessarily the same. The clones developed thermal resistance at different rates and to different degrees within the same time intervals. There was heterogeneity between clones isolated from within either the primary site or metastatic lesions. However, clones derived from metastatic foci did not intrinsically acquire more or less thermotolerance to fractionated 45 degrees C or continuous 42 degrees C heating than did clones from the primary tumor. Further, there was no apparent relationship between any phenotypic properties that conferred more or less thermotolerance in vitro and any phenotypic properties that conferred enhanced metastatic success of these same clones by spontaneous (subcutaneous) or experimental (intravenous) routes in vivo. These tumor clones also differ in their karyotype, metastatic potential, cell surface features, sensitivity to x-irradiation and drugs, and ability to repair sublethal radiation damage. These results provide further credence to the concept that inherent heterogeneity within tumors may be as important in therapeutic success as other known modifiers of outcome such as site and treatment heterogeneity.

Exposure of clone MTC rat 13672NF mammary adenocarcinoma cells to continuous heating at 42 degrees C or to heating for 20 min at 45 degrees C followed by incubation at 37 degrees C induced or enhanced synthesis of several heat-stress proteins (hsp) detectable by [3H]leucine pulse labeling, gel electrophoresis, and fluorography. Hsp synthesis occurred during development and expression of thermal resistance. For example, continuous heating of MTC cells at 42 degrees C after a rapid temperature transient (about 4 min) produced thermal resistance within 4 to 5 hr of initiation of heating. Hsp synthesis was observed within 2 hr of the cells reaching 42 degrees C and continued throughout 8 hr of heating; four major hsp appeared at nominal molecular weights of 112, 90, 70, and 22 kDa. A slow temperature transient from 37 degrees to 42 degrees C over a 3-hr period increased thermal resistance by a factor of about 2 relative to a rapid transient or "shock" to 42 degrees C. However, hsp synthesis was not significant during the slow heat transient and was either reduced (at 70 and 22 kDa) or not increased (at 112 and 90 kDa) compared with the rates of hsp synthesis at the same time intervals after the rapid transient to 42 degrees C. In these mammary tumor cells, no differences in the number of hsp were detected during heating at 42 degrees or after 45 degrees C heating. Other proteins did not appear to change their relative rates of synthesis, with the exception of a clear decrease in proteins with nominal molecular weights of histones H2A, H2B, H3, and H4. Hsp synthesis was not triggered by cold shock to 23 degrees or 0 degree C, or by radiation of from 2.5 to 10 Gy. Thus hypothermic stress did not enhance hsp synthesis nor were hsp nonspecifically associated with eventual cell lethality. In these experiments, the synthesis of hsp was generally correlated with the development of thermal resistance. Determining the quantity, function, and location of stress proteins may identify targets for thermal killing and resistance. However, one paradoxical observation remains to be resolved. Under the slow temperature transient conditions, the tumor cells attained more thermal resistance with generally reduced rates of hsp synthesis. These results have two possible implications: (a) one or more hsp were not directly related to thermal resistance, or (b) hsp were involved in thermal resistance but their relative rate of synthesis depended on the severity of the heat transient. The latter would imply that the cells made other regulatory or metabolic adjustments and either utilized the hsp more effectively or required less additional hsp.