Decline In Amyotrophic Lateral Sclerosis Research Articles

Creatine Kinase and Respiratory Decline in Amyotrophic Lateral Sclerosis.

Respiratory dysfunction is an important hallmark of amyotrophic lateral sclerosis (ALS). Elevation of creatine kinase (CK) has been reported in 23-75% of ALS patients, but the underlying mechanisms remain unknown. This work aims to enlighten the role of CK as a prognostic factor of respiratory dysfunction in ALS. A retrospective analysis of demographic and clinical variables, CK, functional decline per month (ΔFS), forced vital capacity (%FVC), and mean amplitude of the phrenic nerve compound motor action potential (pCMAP) in 319 ALS patients was conducted. These measurements were evaluated at study entry, and patients were followed from the moment of first observation until death or last follow-up visit. High CK values were defined as above the 90th percentile (CK ≥ P90) adjusted to sex. We analyzed survival and time to non-invasive ventilation (NIV) as proxies for respiratory impairment. Linear regression analysis revealed that high CK was associated with male sex (p < 0.001), spinal onset (p = 0.018), and FVC ≥ 80% (p = 0.038). CK was 23.4% higher in spinal-onset ALS patients (p < 0.001). High CK levels were not linked with an increased risk of death (p = 0.334) in Cox multivariate regression analysis. CK ≥ P90 (HR = 1.001, p = 0.038), shorter disease duration (HR = 0.937, p < 0.001), lower pCMAP (HR = 0.082, p < 0.001), and higher ΔFS (HR = 1.968, p < 0.001) were risk factors for respiratory failure. The association between high CK levels and poorer respiratory outcomes could derive from cellular metabolic stress or a specific phenotype associated with faster respiratory decline. Our study suggests that CK measurement at diagnosis should be more extensively investigated as a possible marker of poor respiratory outcome in future studies, including a larger population of patients.

A short clinical perspective on the disease amyotrophic lateral sclerosis

There are sporadic and inherited variants of the motor neuron disease amyotrophic lateral sclerosis (ALS). Young and middle-aged persons are more likely to get ALS, and there aren't many therapies for it. Even though frontotemporal dementia mostly affects the nervous system and the fact that cognitive and behavioral symptoms have been documented for more than a decade, there are signs that ALS and frontotemporal degeneration coincide medically, radiologically, and pathologically, in addition to genetically. Cognitive decline in ALS is characterized by personality changes, irritability, obsessions, a lack of comprehension, and extensive abnormalities in frontal executive functions. The alterations in personality, social behavior, and executive function seen in frontotemporal dementia are consistent with this presentation. We also provide guidelines for the clinical assessment of frontotemporal dysfunction in patients with ALS. Improved protection for victims and their households as well as useful insights into the biology of neurodegeneration will result from knowledge of cognitive damage in ALS.

Loneliness as neurobehavioral issue in amyotrophic lateral sclerosis.

In elderly people loneliness represents a risk factor for dementia and may negatively impact on mental and physical health. The specific contribute of loneliness to cognitive and behavioral functioning have not yet been determined in amyotrophic lateral sclerosis (ALS). Our hypothesis was that loneliness may be related to motor dysfunction with a negative impact on cognitive and behavioral decline, possibly related to specific cortical involvement. In 200 ALS patients (ALSpts) and 50 healthy controls (HCs) we measured loneliness, mood, and quality of life (QoL). ALSpts underwent comprehensive clinical, genetic, and neuropsychological assessment to define phenotypes. Seventy-seven ALSpts performed 3T MRI scans to measure cortical thickness. Between-group, partial correlation and regression analyses were used to examined clinical, neuropsychological, and cortical signatures of loneliness. Feelings of loneliness were documented in 38% of ALSpts (ALS/L+pts) and in 47% of HCs. In both groups loneliness was associated with anxiety (P < 0.001), depression (P ≤ 0.005), and poor QoL (P < 0.001). ALS/L+pts had similar motor dysfunctions and cognitive abilities than non-lonely ALSpts, but distinct behavioral profiles (P ≤ 0.005) and frontoparietal involvement (P < 0.05). Loneliness in ALS is related to behavioral changes, apathy, and emotional dysregulation (P < 0.001). Our cross-sectional study indicates that, in ALS, the satisfaction of social environment is associated with a sense of life well-being that is not limited to the motor status, proving instead that loneliness can impact on disease-related neurobehavioral changes with a possible flashback on brain architecture. This suggests that sociality could promote personal resilience against behavioral and affective decline in ALS.

Functional network dynamics revealed by EEG microstates reflect cognitive decline in amyotrophic lateral sclerosis.

Recent electroencephalography (EEG) studies have shown that patterns of brain activity can be used to differentiate amyotrophic lateral sclerosis (ALS) and control groups. These differences can be interrogated by examining EEG microstates, which are distinct, reoccurring topographies of the scalp's electrical potentials. Quantifying the temporal properties of the four canonical microstates can elucidate how the dynamics of functional brain networks are altered in neurological conditions. Here we have analysed the properties of microstates to detect and quantify signal-based abnormality in ALS. High-density resting-state EEG data from 129 people with ALS and 78 HC were recorded longitudinally over a 24-month period. EEG topographies were extracted at instances of peak global field power to identify four microstate classes (labelled A-D) using K-means clustering. Each EEG topography was retrospectively associated with a microstate class based on global map dissimilarity. Changes in microstate properties over the course of the disease were assessed in people with ALS and compared with changes in clinical scores. The topographies of microstate classes remained consistent across participants and conditions. Differences were observed in coverage, occurrence, duration, and transition probabilities between ALS and control groups. The duration of microstate class B and coverage of microstate class C correlated with lower limb functional decline. The transition probabilities A to D, C to B and C to B also correlated with cognitive decline (total ECAS) in those with cognitive and behavioural impairments. Microstate characteristics also significantly changed over the course of the disease. Examining the temporal dependencies in the sequences of microstates revealed that the symmetry and stationarity of transition matrices were increased in people with late-stage ALS. These alterations in the properties of EEG microstates in ALS may reflect abnormalities within the sensory network and higher-order networks. Microstate properties could also prospectively predict symptom progression in those with cognitive impairments.

Wav2DDK: Analytical and Clinical Validation of an Automated Diadochokinetic Rate Estimation Algorithm on Remotely Collected Speech.

Oral diadochokinesis is a useful task in assessment of speech motor function in the context of neurological disease. Remote collection of speech tasks provides a convenient alternative to in-clinic visits, but scoring these assessments can be a laborious process for clinicians. This work describes Wav2DDK, an automated algorithm for estimating the diadochokinetic (DDK) rate on remotely collected audio from healthy participants and participants with amyotrophic lateral sclerosis (ALS). Wav2DDK was developed using a corpus of 970 DDK assessments from healthy and ALS speakers where ground truth DDK rates were provided manually by trained annotators. The clinical utility of the algorithm was demonstrated on a corpus of 7,919 assessments collected longitudinally from 26 healthy controls and 82 ALS speakers. Corpora were collected via the participants' own mobile device, and instructions for speech elicitation were provided via a mobile app. DDK rate was estimated by parsing the character transcript from a deep neural network transformer acoustic model trained on healthy and ALS speech. Algorithm estimated DDK rates are highly accurate, achieving .98 correlation with manual annotation, and an average error of only 0.071 syllables per second. The rate exactly matched ground truth for 83% of files and was within 0.5 syllables per second for 95% of files. Estimated rates achieve a high test-retest reliability (r = .95) and show good correlation with the revised ALS functional rating scale speech subscore (r = .67). We demonstrate a system for automated DDK estimation that increases efficiency of calculation beyond manual annotation. Thorough analytical and clinical validation demonstrates that the algorithm is not only highly accurate, but also provides a convenient, clinically relevant metric for tracking longitudinal decline in ALS, serving to promote participation and diversity of participants in clinical research. https://doi.org/10.23641/asha.23787033.

Phase 3, Open-Label, Multicenter Safety Study of Oral Edaravone in Patients With Amyotrophic Lateral Sclerosis (MT-1186-A01): 48-Week Results (P6-4.001)

<h3>Objective:</h3> Study MT-1186-A01 assessed the safety and tolerability of oral edaravone (MT-1186) in patients with ALS. NCT04165824. <h3>Background:</h3> An intravenous (IV) formulation of edaravone (Radicava®/Radicut) has been shown to slow the rate of physical functional decline in amyotrophic lateral sclerosis (ALS). Radicava ORS® (edaravone) oral suspension was recently approved by the US Food and Drug Administration for use in patients with ALS. <h3>Design/Methods:</h3> Study MT-1186-A01 was a global, multicenter, open-label, phase 3 study that evaluated the long-term safety and tolerability of oral edaravone in patients with ALS. The primary safety analysis was assessed at weeks 24 and 48. Patients received a 105-mg dose of oral edaravone administered in treatment cycles that replicated IV edaravone dosing. <h3>Results:</h3> In the safety analysis population (n=185), the most common treatment-emergent adverse events (TEAEs) reported by ≥5% of patients were fall (22.2%), muscular weakness (21.1%), constipation (17.8%), dyspnea (10.8%), dysphagia (10.3%), and back pain (10.3%). TEAEs considered to be study drug-related were reported by 46/185 (24.9%) patients, with the most common being fatigue (3.2%), dizziness (2.7%), headache (2.2%), and constipation (2.2%). Serious TEAEs were reported by 48/185 (25.9%) patients, with the most common being worsening of ALS symptoms (6.5%), dysphagia (3.2%), dyspnea (2.7%), and respiratory failure (2.7%). TEAEs leading to death were reported in 12/185 (6.5%) patients, including respiratory failure (2.2%), worsening of ALS (1.1%), pneumonia (1.1%), acute respiratory failure (0.5%), lung disorder (0.5%), diabetic ketoacidosis (0.5%), feeding disorder (0.5%), and suicide (0.5%). TEAEs leading to discontinuation were reported by 2/185 patients (tremor, n=1; gait disturbance, n=1); both TEAEs considered by the investigator to be study drug-related. No serious TEAEs, or TEAEs leading to death, were study drug-related. <h3>Conclusions:</h3> This study demonstrates that oral edaravone was generally safe and well tolerated during 48 weeks of treatment, with no new safety concerns identified. <b>Disclosure:</b> Dr. Genge has received personal compensation in the range of $10,000-$49,999 for serving as a Consultant for AL-S Pharma. Dr. Genge has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Biogen. Dr. Genge has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Cytokinetics. Dr. Genge has received personal compensation in the range of $5,000-$9,999 for serving as a Consultant for Amylyx. Dr. Genge has received personal compensation in the range of $100,000-$499,999 for serving as a Consultant for Quralis. Dr. Genge has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Alexion. Dr. Genge has received personal compensation in the range of $500-$4,999 for serving as a Consultant for MTPA. Dr. Genge has received personal compensation in the range of $0-$499 for serving as a Consultant for WAVE. The institution of Dr. Pattee has received personal compensation in the range of $500-$4,999 for serving as a Consultant for MTPA pharmaceuticals. The institution of Dr. Pattee has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for MTPA pharmaceiticals. The institution of Dr. Pattee has received personal compensation in the range of $0-$499 for serving on a Scientific Advisory or Data Safety Monitoring board for Catalyst. The institution of Dr. Pattee has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for General Dynamics US military. The institution of Dr. Pattee has received personal compensation in the range of $500-$4,999 for serving on a Speakers Bureau for Otsuka pharmaceuticals. Dr. Sobue has nothing to disclose. Dr. Couratier has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Biogen. Dr. Couratier has received personal compensation in the range of $500-$4,999 for serving as an Editor, Associate Editor, or Editorial Advisory Board Member for Elsevier. Dr. Couratier has received personal compensation in the range of $5,000-$9,999 for serving as an Editor, Associate Editor, or Editorial Advisory Board Member for Elsevier . Mr. Selness has received personal compensation for serving as an employee of Mitsubishi Tanabe. Mr. Bidani has received personal compensation for serving as an employee of Mitsubishi Tanabe Pharma Development America Inc. Manabu Hirai has received personal compensation for serving as an employee of Mitsubishi Tanabe Pharma Corporation. Takeshi Sakata has received personal compensation for serving as an employee of Mitsubishi Tanabe. Alejandro Salah has nothing to disclose. Stephen Apple has received personal compensation for serving as an employee of Mitsubishi Tanabe Pharma America, Inc.

Non-Invasive Mechanical Ventilation slows motor decline in Amyotrophic Lateral Sclerosis: a population-based study (P10-8.003)

<h3>Objective:</h3> To test whether Non-Invasive Mechanical Ventilation (NIMV) use improved the rate of motor decline among ALS patients. <h3>Background:</h3> The efficacy of NIMV in improving Amyotrophic Lateral Sclerosis (ALS) survival and quality of life is well established. However, data regarding its effect on disease progression are still lacking. <h3>Design/Methods:</h3> This population-based cohort study included 630 patients with ALS from the Piemonte and Valle d’Aosta Register for ALS (PARALS) who were followed up after NIV initiation. Motor function was evaluated with the ALS Functional Rating Score – Revised (ALSFRS-R). Mixed-effect models for longitudinal data were performed to assess change in the rate of functional decline after NIMV initiation. <h3>Results:</h3> NIMV was associated with a ~30% reduction in the ΔALSFRS-R (post-NIMV difference in ΔALSFRS-R −0.46, 97.5% CI −0.43 to −0.49, p&lt;0.0001). The NIMV-related slowing was present on bulbar symptoms (post-NIMV difference in ΔALSFRS-R −0.08, 97.5% CI −0.065 to −0.010, p &lt; 0.0001) and even greater on spinal function (post-NIMV difference in ΔALSFRS-R −0.42, 97.5% CI −0.39 to −0.46, p &lt; 0.0001). All patients benefitted from NIMV usage, regardless of age, site of symptoms onset and presence of cognitive impairment. <h3>Conclusions:</h3> We demonstrate that NIMV significantly improves the rate of disease progression in ALS, regardless of age at symptoms onset, disease duration, presence of bulbar dysfunction or cognitive impairment. Our results reinforce the importance of not delaying NIMV initiation. In addition, NIMV-induced slowing of disease progression should also be accounted for when evaluating clinical trial outcomes. Further studies are required to optimize the effectiveness of respiratory care on disease progression in ALS. <b>Disclosure:</b> Mr. Grassano has nothing to disclose. Dr. Koumantakis has nothing to disclose. Cristina Moglia has nothing to disclose. Antonio Canosa has nothing to disclose. Dr. Manera has nothing to disclose. Dr. Vasta has nothing to disclose. Francesca Palumbo has nothing to disclose. Mr. Callegaro has nothing to disclose. Dr. Marchese has nothing to disclose. Paolina Salamone has nothing to disclose. Dr. Fuda has nothing to disclose. Federico Casale has nothing to disclose. Dr. Calvo has nothing to disclose. Dr. Mora has nothing to disclose. Dr. Chio has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Cytokinetics. Dr. Chio has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Mitsubishi. Dr. Chio has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Biogen.

Association between vascular risk factors and cognitive impairment in amyotrophic lateral sclerosis: a case-control study

Objective The disease-modifying effects of type 2 diabetes mellitus (T2DM), and hyperlipidemia on the risk and prognosis of amyotrophic lateral sclerosis (ALS) have gained significant attention. We aim to evaluate the association between common vascular risk factors and cognitive impairment in patients with ALS. Methods Patients with ALS were consecutively recruited between June 2012 and November 2019 from a tertiary referral center for ALS at the West China Hospital. Vascular risk factors (hypertension, T2DM, hyperlipidemia, overweight, and smoking) were confirmed based on clinical data. Cognitive function was evaluated by the Chinese version of Addenbrooke’s Cognitive Examination-revised. With careful confounder adjustment, multivariable logistic regression analysis was performed separately and accumulatively to determine the association between cognitive impairment and vascular risk factors in ALS. Results Of 870 patients, 266 (30.6%) had cognitive impairment. No cognitive burden from vascular risk factors was found in patients with ALS. On the contrary, we first observed that T2DM (odds ratio [OR], 0.50; 95% confidence interval [CI], 0.25–0.98; p = 0.04) and hyperlipidemia (OR, 0.50; 95% CI, 0.26–0.97; p = 0.04) showed protective effects against cognitive decline in ALS, adjusted for age, sex, educational level, site of onset, Revised-ALS Functional Rating Scale score, predominant upper motor neuron phenotype, family history of ALS, and the remaining vascular risk factors. Sensitivity analyses of sex did not substantially reverse the risk estimates. Conclusions T2DM and hyperlipidemia decrease the risk of cognitive impairment in patients with ALS. The fitness hypothesis in ALS has been tested and expanded in our work.

Articulatory Underpinnings of Reduced Acoustic-Phonetic Contrasts in Individuals With Amyotrophic Lateral Sclerosis.

The aim of this study is to identify the articulatory underpinnings of the acoustic-phonetic correlates of functional speech decline in individuals with amyotrophic lateral sclerosis (ALS). Thirteen individuals with varying severities of speech impairment secondary to ALS and 10 neurologically healthy controls speakers read 12 minimal word pairs, targeting the contrasts in the height, advancement, and length of vowels; the manner and place of articulation for consonants and consonant cluster; and liquid and glide approximants, 5 times. Sixteen acoustic features were extracted to characterize the phonetic contrasts of these minimal word pairs. These acoustic features were correlated with a functional speech index-intelligible speaking rate-using penalized regression, based on which the contributive features were identified as the acoustic-phonetic correlates of the functional speech outcome. Articulatory contrasts of the minimal word pairs were characterized by a set of dissimilarity indices derived by the dynamic time warping algorithm, which measured the differences in the displacement and velocity trajectories of tongue tip, tongue dorsum, lower lip, and jaw between the minimal word pairs. The contributive articulatory features to the acoustic-phonetic correlates were identified by penalized regression. A variety of acoustic-phonetic features were identified as contributing to the functional speech outcome, of which the contrasts in vowel height and advancement, [r]-[l], [r]-[w], and initial cluster-singleton were the most affected in individuals with ALS. Differential articulatory underpinnings were identified for these acoustic-phonetic features. Impairments of these articulatory underpinnings, especially of tongue tip and tongue dorsum velocities and tongue tip displacement, were associated with reduced acoustic-phonetic contrasts of the minimal word pairs, in a context-specific manner. The findings established explanatory relationships between articulatory impairment and the acoustic-phonetic profile of functional speech decline in ALS, providing useful information for developing targeted management strategies to improve and prolong functional speech in individuals with ALS.

Tongue and Lip Acceleration as a Measure of Speech Decline in Amyotrophic Lateral Sclerosis

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.

Analysis of the US Safety Data for Edaravone (Radicava®) From the Third Year After Launch.

BackgroundAmyotrophic lateral sclerosis (ALS) is a progressive and fatal neuromuscular disease with no curative therapies. Edaravone (Radicava®) (Mitsubishi Tanabe Pharma Corporation, Tokyo, Japan), approved in the United States (US) for ALS in adults in 2017, was shown in a clinical trial to slow the rate of physical functional decline in ALS and is administered intravenously. The aim of this paper is to summarize the observed safety profile from real-world patient use during the first 3 years of edaravone availability in the US.MethodsEdaravone usage data were collected, and adverse events (AEs) were identified from a postmarketing safety database from August 8, 2017 through August 7, 2020 (cutoff date).ResultsAs of October 3, 2020, 5207 ALS patients had been treated with edaravone. As of August 7, 2020, the most commonly reported AEs included death (not specified), drug ineffective, disease progression, therapeutic response unexpected, fall, asthenia, fatigue, muscular weakness, gait disturbance, and dyspnea. The most commonly reported serious AEs (SAEs) included death (not specified), pneumonia, disease progression, ALS, fall, dyspnea, respiratory failure, device-related infection, hospitalization, and injection-site infection. There were 687 deaths, with 494 reported as death without specifying the cause. Deaths were most commonly attributed to ALS, disease progression, respiratory failure, or pneumonia. Review for administration-site reactions revealed 95 AEs, including 34 site infections, with 22 SAEs (all non-fatal). Five non-fatal SAEs of anaphylaxis were reported.ConclusionIn the postmarketing reporting to date, no new safety signals were identified beyond those already known from the edaravone clinical trial program.

Cognitive impairment and respiratory decline in amyotrophic lateral sclerosis

Cognitive impairment and respiratory decline in amyotrophic lateral sclerosis

Pulmonary function decline in amyotrophic lateral sclerosis

Background: There has been no comprehensive longitudinal study of pulmonary functions (PFTS) in ALS determining which measure is most sensitive to declines in respiratory muscle strength. Objective: To determine the longitudinal decline of PFTS in ALS and which measure supports Medicare criteria for NIV initiation first. Methods: Serial PFTs (maximum voluntary ventilation (MVV), maximum inspiratory pressure measured by mouth (MIP) or nasal sniff pressure (SNIP), maximum expiratory pressure (MEP), and Forced Vital Capacity (FVC)) were performed over 12 months on 73 ALS subjects to determine which measure showed the sentinel decline in pulmonary function. The rate of decline for each measure was determined as the median slope of the decrease over time. Medicare-based NIV initiation criteria were met if %FVC was ≤ 50% predicted or MIP was ≤ 60 cMH2O. Results: 65 subjects with at least 3 visits were included for analyses. All median slopes were significantly different than zero. MEP and sitting FVC demonstrated the largest rate of decline. Seventy subjects were analyzed for NIV initiation criteria, 69 met MIP criteria first; 11 FVC and MIP criteria simultaneously and none FVC criteria first. Conclusions: MEP demonstrated a steeper decline compared to other measures suggesting expiratory muscle strength declines earliest and faster and the use of airway clearance interventions should be initiated early. When Medicare criteria for NIV initiation are considered, MIP criteria are met earliest. These results suggest that pressure-based measurements are important in assessing the timing of NIV and the use of pulmonary clearance interventions.

Cognitive and behavioural impairment in amyotrophic lateral sclerosis: A landmark of the disease? A mini review of longitudinal studies

Amyotrophic lateral sclerosis (ALS) is a heterogeneous neurodegenerative disease marked by progressive loss of motor abilities. Approximately half of patents with ALS experience cognitive (ALSci) or behavioural impairment (ALSbi) during the course of the disease, with a small percentage developing overt frontotemporal dementia (FTD). ALSci and/or ALSbi can occur simultaneously with motor neuron degeneration or develop in advanced stages of the disease, but it can even precede motor involvement in some cases, namely in ALS patients meeting criteria for FTD. Despite clear evidence that cognitive/behavioural impairment may appear early in the course of ALS, no prominent deterioration seems to occur with disease progression. Longitudinal studies have failed to reach conclusive results on the progression of cognitive and behavioural involvement in ALS. This may be due to some structural limitations of the studies, such as attrition rate, practice effect, short-time interval between neuropsychological assessments, but it can also be due to the heterogeneity of ALS phenotypes. The objective of this review is to provide a comprehensive and critical analysis of results of longitudinal studies highlighting cognitive and behavioural domains mainly affected by neurodegeneration pointing out the determinants that might be associate with the development and worsening of frontotemporal symptoms in ALS. At this regard, older age, rapidly progressing ALS, bulbar-onset, advanced disease stages are among factors mainly associated with cognitive and behavioural involvement. Moreover, the progression of cognitive and behavioural deficits seems to be not directly related to the slope of motor disability, thus suggesting the independence of neuropsychological and motor functional decline in ALS. Cognitive and motor involvement may indeed present with distinct trajectories suggesting a differential vulnerability of motor and non-motor cortical networks. In this scenario, determining the progression of extra-motor involvement in ALS may help refine understanding of the clinical implications of cognitive and behavioural abnormalities, and provide clues to the aetiology of the disease.

Cognitive network hyperactivation and motor cortex decline correlate with ALS prognosis

We aimed to quantitatively characterize progressive brain network disruption in Amyotrophic Lateral Sclerosis (ALS) during cognition using the mismatch negativity (MMN), an electrophysiological index of attention switching. We measured the MMN using 128-channel EEG longitudinally (2–5 timepoints) in 60 ALS patients and cross-sectionally in 62 healthy controls. Using dipole fitting and linearly constrained minimum variance beamforming we investigated cortical source activity changes over time. In ALS, the inferior frontal gyri (IFG) show significantly lower baseline activity compared to controls. The right IFG and both superior temporal gyri (STG) become progressively hyperactive longitudinally. By contrast, the left motor and dorsolateral prefrontal cortices are initially hyperactive, declining progressively. Baseline motor hyperactivity correlates with cognitive disinhibition, and lower baseline IFG activities correlate with motor decline rate, while left dorsolateral prefrontal activity predicted cognitive and behavioural impairment. Shorter survival correlates with reduced baseline IFG and STG activity and later STG hyperactivation. Source-resolved EEG facilitates quantitative characterization of symptom-associated and symptom-preceding motor and cognitive-behavioral cortical network decline in ALS.

Cognitive decline in amyotrophic lateral sclerosis: Neuropathological substrate and genetic determinants.

Cognitive impairment and behavioral changes in amyotrophic lateral sclerosis (ALS) are now recognized as part of the disease. Whether it is solely related to the extent of TDP‐43 pathology is currently unclear. We aim to evaluate the influence of age, genetics, neuropathological features, and concomitant pathologies on cognitive impairment in ALS patients. We analyzed a postmortem series of 104 ALS patients and retrospectively reviewed clinical and neuropathological data. We assessed the burden and extent of concomitant pathologies, the role of APOE ε4 and mutations, and correlated these findings with cognitive status. We performed a logistic regression model to identify which pathologies are related to cognitive impairment. Cognitive decline was recorded in 38.5% of the subjects. Neuropathological features of frontotemporal lobar degeneration (FTLD) were found in 32.7%, explaining most, but not all, cases with cognitive impairment. Extent of TDP‐43 pathology and the presence of hippocampal sclerosis were associated with cognitive impairment. Mutation carriers presented a higher burden of TDP‐43 pathology and FTLD more frequently than sporadic cases. Most cases (89.4%) presented some degree of concomitant pathologies. The presence of concomitant pathologies was associated with older age at death. FTLD, but also Alzheimer’s disease, were the predominant underlying pathologies explaining the cognitive impairment in ALS patients. In sum, FTLD explained the presence of cognitive decline in most but not all ALS cases, while other non‐FTLD related findings can influence the cognitive status, particularly in older age groups.

Speech intelligibility loss due to amyotrophic lateral sclerosis: the effect of tongue movement reduction on vowel and consonant acoustic features

ABSTRACT The purpose of this study was to identify aspects of impaired tongue motor performance that limit the ability to produce distinct speech sounds and contribute to reduced speech intelligibility in individuals with dysarthria secondary to amyotrophic lateral sclerosis (ALS). We analyzed simultaneously recorded tongue kinematic and acoustic data from 22 subjects during three target words (cat, dog, and took). The subjects included 11 participants with ALS and 11 healthy controls from the X-ray microbeam dysarthria database (Westbury, 1994). Novel measures were derived based on the range and speed of relative movement between two quasi-independent regions of the tongue – blade and dorsum – to characterize the global pattern of tongue dynamics. These “whole tongue” measures, along with the range and speed of single tongue regions, were compared across words, groups (ALS vs. control), and measure types (whole tongue vs. tongue blade vs. tongue dorsum). Reduced range and speed of both global and regional tongue movements were found in participants with ALS relative to healthy controls, reflecting impaired tongue motor performance in ALS. The extent of impairment, however, varied across words and measure types. Compared with the regional tongue measures, the whole tongue measures showed more consistent disease-related changes across the target words and were more robust predictors of speech intelligibility. Furthermore, these whole tongue measures were correlated with various word-specific acoustic features associated with intelligibility decline in ALS, suggesting that impaired tongue movement likely contributes to reduced phonetic distinctiveness of both vowels and consonants that underlie speech intelligibility decline in ALS.

Manifold learning for amyotrophic lateral sclerosis functional loss assessment

Amyotrophic lateral sclerosis (ALS) is an inexorably progressive neurodegenerative condition with no effective disease-modifying therapy at present. Given the striking clinical heterogeneity of the condition, the development and validation of reliable prognostic models is a recognised research priority. We present a prognostic model for functional decline in ALS where outcome uncertainty is taken into account. Patient data were reduced and projected onto a 2D space using Uniform Manifold Approximation and Projection (UMAP), a novel non-linear dimension reduction technique. Information from 3756 patients was included. Development data were sourced from past clinical trials. Real-world population data were used as validation data. Predictors included age, gender, region of onset, symptom duration, weight at baseline, functional impairment, and estimated rate of functional loss. UMAP projection of patients showed an informative 2D data distribution. As limited data availability precluded complex model designs, the projection was divided into three zones defined by a functional impairment range probability. Zone membership allowed individual patient prediction. Patients belonging to the first zone had a probability of [Formula: see text] (± [Formula: see text]) to have an ALSFRS score over 20 at 1-year follow-up. Patients within the second zone had a probability of [Formula: see text] (± [Formula: see text]) to have an ALSFRS score between 10 and 30 at 1year follow-up. Finally, patients within the third zone had a probability of [Formula: see text] (± [Formula: see text]) to have an ALSFRS score lower than 20 at 1year follow-up. This approach requires a limited set of features, is easily updated, improves with additional patient data, and accounts for results uncertainty. This method could therefore be used in a clinical setting for patient stratification and outcome projection.

Diaphragmatic CMAP amplitude from phrenic nerve stimulation predicts functional decline in ALS.

To evaluate phrenic nerve motor amplitude (PhrenicAmp) as an independent predictor of functional decline in amyotrophic lateral sclerosis (ALS). We also assessed both PhrenicAmp and forced vital capacity (FVC) as predictors of functional loss in patients with bulbar dysfunction. We included consecutive ALS patients with PhrenicAmp and FVC at baseline. Participants were evaluated with the revised ALS Functional Rating Scale (ALSFRS-R) at inclusion and at, at least, one subsequent follow-up visit. The outcome measure of functional decline was the percentage reduction in ALSFRS-R from baseline. Bulbar dysfunction was defined by the presence of any relevant symptom on the ALSFRS-R bulbar sub-score. Correlations and mixed-effects regressions were used to study the relationship between functional decline and both PhrenicAmp and FVC baseline evaluations. A total of 249 ALS patients were included; 64.2% of these had bulbar dysfunction. At inclusion, significant correlations were found between PhrenicAmp and FVC (p < 0.001), as well as between each respiratory measure and ALSFRS-R (all p < 0.001). The functional decline at first (median 3months) and second (median 6months) follow-up visits was significantly correlated with baseline values of both respiratory evaluations (all p < 0.01) in the entire ALS population, but only with baseline PhrenicAmp (all p < 0.05) in bulbar dysfunction cases. Regression analysis revealed that PhrenicAmp (all p < 0.05), but not FVC, was a significant independent predictor of functional decline in ALS patients and in those with bulbar dysfunction. Baseline PhrenicAmp is an independent predictor of functional decline in ALS, whether or not bulbar dysfunction is present.

Pattern of lung function decline in patients with amyotrophic lateral sclerosis: implications for timing of noninvasive ventilation.

BackgroundThe course of lung function decline in amyotrophic lateral sclerosis (ALS) and the effect of noninvasive positive-pressure ventilation (NIPPV) on that decline are uncertain. We sought to model lung function decline, determine when NIPPV is initiated along that course, and assess its impact on the course of decline.MethodsAn observed sigmoid pattern of forced vital capacity decline was reproduced with a four-parameter nonlinear mixed-effects logistic model.ResultsAnalyses were performed on 507 patients overall and in 353 patients for whom a determination of adherence to NIPPV was ascertained. A sigmoid bi-asymptotic model provided a statistical fit of the data and showed a period of stable vital capacity, followed by an accelerated decline, an inflection point, then a slowing in decline to a plateau. By the time NIPPV was initiated in accordance with reimbursement guidelines, vital capacity had declined by ≥85% of the total range. Nearly half of the total loss of vital capacity occurred over 6.2 months centred at an inflection point occurring 17 months after disease onset and 5.2 months before initiation of NIPPV at a vital capacity of about 60%. Fewer bulbar symptoms and a faster rate of decline of lung function predicted adherence to NIPPV, but the intervention had no impact on final vital capacity.ConclusionsIn patients with ALS, vital capacity decline is rapid but slows after an inflection point regardless of NIPPV. Initiating NIPPV along reimbursement guidelines occurs after ≥85% of vital capacity loss has already occurred.