Impairment In Amyotrophic Lateral Sclerosis Patients Research Articles

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

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

Smell loss is associated with cognitive impairment in amyotrophic lateral sclerosis patients.

Smell loss significantly impacts the quality of life in patients. However, there is limited research on smell loss in individuals with amyotrophic lateral sclerosis (ALS), and the correlation between smell loss and cognitive impairment is unclear. This study aimed to investigate the correlation between smell loss and cognition impairment in ALS patients. The study included 216 ALS patients. The Edinburgh Cognitive and Behavioural ALS Screen (ECAS) and smell identification test specifically for the Chinese population (CSIT) were administered to evaluate participants' cognitive and olfactory function, respectively. After covarying for age, sex, BMI, education level, degree of hunger, dietary bias, eagerness for food, stress, smoking status, alcohol consumption, and upper respiratory tract infection (URTI) or rhinitis, CSIT scores were significantly correlated with ECAS scores (r = 0.162, p = 0.028), especially the ALS-specific scores (r = 0.158, p = 0.031). Even after excluding patients with URTI or rhinitis, the results were similar. CSIT scores were significantly correlated with ECAS scores (r = 0.224, p = 0.011), especially the ALS-specific scores (r = 0.205, p = 0.019). In patients with ALS, smell loss is significantly correlated with cognitive impairment, particularly frontotemporal dysfunction. Cognitive dysfunction may lead to worse olfactory performance in ALS patients.

Chest Dynamic MRI as Early Biomarker of Respiratory Impairment in Amyotrophic Lateral Sclerosis Patients: A Pilot Study.

Background: Amyotrophic lateral sclerosis (ALS) is a neuromuscular progressive disorder characterized by limb and bulbar muscle wasting and weakness. A total of 30% of patients present a bulbar onset, while 70% have a spinal outbreak. Respiratory involvement represents one of the worst prognostic factors, and its early identification is fundamental for the early starting of non-invasive ventilation and for the stratification of patients. Due to the lack of biomarkers of early respiratory impairment, we aimed to evaluate the role of chest dynamic MRI in ALS patients. Methods: We enrolled 15 ALS patients and 11 healthy controls. We assessed the revised ALS functional rating scale, spirometry, and chest dynamic MRI. Data were analyzed by using the Mann-Whitney U test and Cox regression analysis. Results: We observed a statistically significant difference in both respiratory parameters and pulmonary measurements at MRI between ALS patients and healthy controls. Moreover, we found a close relationship between pulmonary measurements at MRI and respiratory parameters, which was statistically significant after multivariate analysis. A sub-group analysis including ALS patients without respiratory symptoms and with normal spirometry values revealed the superiority of chest dynamic MRI measurements in detecting signs of early respiratory impairment. Conclusions: Our data suggest the usefulness of chest dynamic MRI, a fast and economically affordable examination, in the evaluation of early respiratory impairment in ALS patients.

Venous blood parameters in determination of respiratory impairment in amyotrophic lateral sclerosis

This study aimed to investigate the relationship between venous blood parameters and respiratory functions in patients with amyotrophic lateral sclerosis (ALS) and develop a model to predict respiratory impairment for individual patients with ALS. A total of 416 ALS patients were included in the study, and various hematologic and biochemical laboratory parameters as well as demographic and clinical factors were collected and compared. A multivariable logistic regression model was constructed to assess the association between FVC and venous blood biomarkers and clinical factors. The results showed that along with onset age, bulbar-onset, disease duration, BMI, eosinophil count (EO#), basophil count (BASO#), creatinine (CREA), uric acid (URCI) and low-density lipoprotein cholesterol/high-density lipoprotein cholesterol (LDL/HDL) ratio were associated with reduced FVC. The area under the ROC curve is 0.735 for the test set and 0.721 for the validation set. The study also developed a relatively acceptable model for predicting respiratory impairment in ALS patients. These findings suggest that EO#, BASO#, CREA, URIC and LDL/HDL ratio can be useful in assessing FVC in ALS and can be easily accessible, accurate, and low-cost parameters.

Developing Targeted Optogenetic Stimulation Approaches to Preserve Upper Airway Function in Amyotrophic Lateral Sclerosis (ALS) Using a Translational Mouse Model

Amyotrophic lateral sclerosis (ALS) results in debilitating upper airway (swallowing and breathing) impairment that profoundly degrades quality of life while increasing the risk of death by almost eight-fold. The underlying cause has been attributed to degeneration of the hypoglossal lower motor neurons (XII LMNs) that control tongue movement; therefore, treatment efforts are focused on slowing XII LMN degeneration. However, there is growing evidence that ALS is not a pure motor neuron disease – it also affects sensory neurons, including those in the nucleus tractus solitarius (NTS) involved in autonomic regulation of swallowing and breathing. We propose that upper airway impairment in ALS may be more effectively treated using sensorimotor approaches that collectively target XII LMNs and the NTS. Here, we are leveraging a translational mouse model of ALS (low copy number SOD1-G93A; LCN-SOD1) that we have shown develops progressive tongue atrophy, XII LMN degeneration, and “motor” dysphagia (slower tongue motility and swallow rates) resembling human ALS. These mice also show clinicopathological evidence of “sensory” dysphagia, specifically a higher swallow threshold (assessed via electrical stimulation of superior laryngeal nerve afferents) and degeneration of the NTS. Using this model, we have been developing tools and procedures to investigate the therapeutic effects of optogenetic stimulation (opto-stim) of XII LMNs and the NTS during voluntary swallow-related behaviors (drinking, eating, grooming) vs. spontaneous breathing in LCN-SOD1 mice. We have already achieved robust expression of the excitatory opsin channelrhodopsin (ChR2) in XII LMNs via adeno-associated virus delivery into the genioglossus muscle or XII nucleus. ChR2 transfection of XII LMNs was well-tolerated, without adverse effects on swallowing/breathing, general health, and survival. Functionally, XII LMN opto-stim evoked robust tongue protrusion (i.e., genioglossus contraction) in anesthetized mice and slowed lick rate during voluntary drinking in awake mice, which we hypothesize is due to resistive force against tongue movement, similar to resistance exercise. Currently, we are exploring the effects of opto-stim (10 ms pulses at 40 or 80 Hz in trains of 1 s ON/OFF for up to 1 h, 2X/wk) as a tongue resistance exercise in pre-clinical LCN-SOD1 mice. In parallel, we are also developing procedures for targeted opsin expression in the NTS via direct injection vs. pharyngeal mucosa application. We hypothesize that NTS opto-stim, in contrast to XII LMN, will assist swallowing by lowering the sensory threshold to unleash higher swallow rates. We propose these novel sensorimotor opto-stim approaches could ultimately translate into minimally invasive targeted treatments for upper airway impairment in ALS patients. This project is funded by NIH R21 NS123761 This is the full abstract presented at the American Physiology Summit 2023 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

A Longitudinal evaluation of early Sleep and Respiratory Impairment in ALS patients (S6.005)

<h3>Objective:</h3> To evaluate early impairment of sleep and breath in patients affected by amyotrophic lateral sclerosis (ALS) in order to do early treatments, for a longer survival and a better quality of life (QoL). <h3>Background:</h3> ALS is a fatal neurodegenerative disease characterised by skeletal muscles wasting and weakness. 30% present a bulbar onset, while 70% a spinal one. Extra-motor systems involved in ALS include circuits regulating sleep; the early identification of sleep impairment and his better definition could improve ALS patient’s QoL. One of the most important prognostic factors in ALS is respiratory impairment. It’s early recognition and an early starting of non-invasive ventilation (NIV) allow a prolongation of survival. <h3>Design/Methods:</h3> Between August 2021 and January 2022 we enrolled, until 2 months from diagnosis, 37 ALS patients and 37 healthy controls (HC). At baseline and at month six, patients underwent neurological examination, polysomnography (PSG), arterial blood gases (ABG), spirometry and filled sleep and respiratory questionnaire (RLSRS, STOP-BANG, ISI, ESS, PSQI, PIRS, MEQ, STAI, BDI). Mann-Whitney U test, Friedman test, and Cox regression analysis were applied. <h3>Results:</h3> At baseline, ALS patients without respiratory symptoms showed an increase of AHI index and of ODI index, contrary to HC (respectively, p=0.001 and p=0.04). Contrarily, spirometry and ABG resulted normal in this sub-group of patients. Longitudinally we observed a significant worsening of PSG parameters (p&lt;0.05). Patients who started nocturnal-NIV (10 out of 37) showed a significant improvement of PSG parameters. At baseline we also observed an excess of periodic limb movement in ALS vs HC (p=0.01). Direct correlation between progression rate of disease and both AHI and ODI (r=0.546 and r=0.442 p&lt;0.05). <h3>Conclusions:</h3> This preliminary study showed the presence of respiratory impairment and of sleep disorders in ALS patients since the beginning of the disease. Their identification is fundamental for an early treatment, and for an improvement of QoL. <b>Disclosure:</b> Dr. Bombaci has nothing to disclose. Dr. Iadarola has nothing to disclose. Dr. Fattori has nothing to disclose. Dr. Gojani has nothing to disclose. Dr. Manera has nothing to disclose. Dr. Calvo 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. Alessandro Cicolin has nothing to disclose.

Social cognition deficits in amyotrophic lateral sclerosis: A pilot cross-sectional population-based study.

Background and purposeSocial cognition (SC) deficits are included in amyotrophic lateral sclerosis (ALS)–frontotemporal spectrum disorder revised diagnostic criteria. However, SC performance among ALS patients is heterogeneous due to the phenotypic variability of the disease and the wide range of neuropsychological tools employed. The aim of the present study was to assess facial emotion recognition and theory of mind in ALS patients compared to controls and to evaluate correlations with the other cognitive domains and degree of motor impairment.MethodsEighty‐three patients and 42 controls underwent a cognitive evaluation and SC assessment through the Ekman 60 Faces Test (EK‐60F), the Reading the Mind in the Eyes Test–36 Faces (RMET‐36), and the Story‐Based Empathy Task (SET).ResultsALS patients showed significantly worse performance compared to controls in EK‐60F global score (p < 0.001), recognition of disgust (p = 0.032), anger (p = 0.038), fear (p < 0.001), and sadness (p < 0.001); RMET‐36 (p < 0.001), and SET global score (p < 0.001). Also, cognitively normal patients (ALS‐CN) showed significantly worse performance compared to controls in EK‐60F global score (p < 0.001), recognition of fear (p = 0.002), sadness (p < 0.001), and SET (p < 0.001). RMET‐36 showed a significant correlation with the Category Fluency Test (p = 0.041). SC tests showed no correlation with motor impairment expressed by Amyotrophic Lateral Sclerosis Functional Rating Scale–Revised.ConclusionsALS patients, also when categorized as ALS‐CN, may show impairment in SC performance. The frequent identification of early SC impairment in ALS patients supports the need to routinely assess SC for its impact on end‐of‐life decisions and its potential influence on patients' quality of life.

Slow motor neurons resist pathological TDP-43 and mediate motor recovery in the rNLS8 model of amyotrophic lateral sclerosis

In the intermediate stages of amyotrophic lateral sclerosis (ALS), surviving motor neurons (MNs) that show intrinsic resistance to TDP-43 proteinopathy can partially compensate for the loss of their more disease-susceptible counterparts. Elucidating the mechanisms of this compensation may reveal approaches for attenuating motor impairment in ALS patients. In the rNLS8 mouse model of ALS-like pathology driven by doxycycline-regulated neuronal expression of human TDP-43 lacking a nuclear localization signal (hTDP-43ΔNLS), slow MNs are more resistant to disease than fast-fatigable (FF) MNs and can mediate recovery following transgene suppression. In the present study, we used a viral tracing strategy to show that these disease-resistant slow MNs sprout to reinnervate motor endplates of adjacent muscle fibers vacated by degenerated FF MNs. Moreover, we found that neuromuscular junctions within fast-twitch skeletal muscle (tibialis anterior, TA) reinnervated by SK3-positive slow MNs acquire resistance to axonal dieback when challenged with a second course of hTDP-43ΔNLS pathology. The selective resistance of reinnervated neuromuscular junctions was specifically induced by the unique pattern of reinnervation following TDP-43-induced neurodegeneration, as recovery from unilateral sciatic nerve crush did not produce motor units resistant to subsequent hTDP-43ΔNLS. Using cross-reinnervation and self-reinnervation surgery in which motor axons are disconnected from their target muscle and reconnected to a new muscle, we show that FF MNs remain hTDP-43ΔNLS-susceptible and slow MNs remain resistant, regardless of which muscle fibers they control. Collectively, these findings demonstrate that MN identity dictates the susceptibility of neuromuscular junctions to TDP-43 pathology and slow MNs can drive recovery of motor systems due to their remarkable resilience to TDP-43-driven degeneration. This study highlights a potential pathway for regaining motor function with ALS pathology in the advent of therapies that halt the underlying neurodegenerative process.

Upper motor neuron dysfunction is associated with the presence of behavioural impairment in patients with amyotrophic lateral sclerosis.

Increasing evidence shows that approximately half of patients with amyotrophic lateral sclerosis (ALS) display cognitive (ALSci) or behavioural (ALSbi) impairment, or both (ALScbi). The aim of our study was to assess whether the burden of upper and lower motor neuron involvement is associated with the presence of cognitive and behavioural impairment. A single-centre retrospective cohort of 110 Italian ALS patients was evaluated to assess correlations between motor and cognitive/behavioural phenotypes. Upper motor neuron regional involvement was measured with the Penn Upper Motor Neuron Score (PUMNS), whilst lower motor neuron signs were assessed using the Lower Motor Neuron Score. The Edinburgh Cognitive and Behavioural ALS Screen-Italian version and the Frontal Behaviour Inventory were administered to evaluate patients' cognitive and behavioural profiles. The PUMNS at first visit was significantly higher in behaviourally impaired ALS patients (ALSbi and ALScbi) compared to behaviourally unimpaired individuals (ALS and ALSci) (9.9 vs. 6.9, p=0.014). Concerning the different Frontal Behaviour Inventory subdomains, higher PUMNS correlated with the presence of apathy, emotive indifference, inflexibility, inattention, perseveration and aggressiveness. To our knowledge, this is the first study showing that a clinical prominent upper motor neuron dysfunction is associated with a more significant behavioural impairment in ALS patients, suggesting the hypothesis of a preferential spreading of the pathology from the motor cortex to the ventromedial prefrontal and orbitofrontal cortex in this group of patients.

Plasma Uric Acid Helps Predict Cognitive Impairment in Patients With Amyotrophic Lateral Sclerosis.

Objective: Uric acid as an antioxidant plays an important role in neurodegenerative disease. Our objective is to investigate the relationship between plasma uric acid and cognitive impairment in patients with amyotrophic lateral sclerosis (ALS).Methods: In this cross-sectional study, 124 ALS patients were screened by the Edinburgh Cognitive and Behavioral Screen (ECAS) and classified according to the revised Strong's criteria. Additionally, based on total ECAS cut-off score patients were categorized into those with cognitive impairment (ALS-cie) and those without cognitive impairment (ALS-ncie), and clinical data and uric acid level were compared between the two groups. Parameters with significant differences were further included in a multivariate linear regression analysis with ECAS score as a dependent variable. Hold-out validation was performed to evaluate the fitness of regression model.Results: Up to 60% of ALS patients showed cognitive or/and behavioral impairment. The ALS-cie group had lower education level (p < 0.001), older age at symptom onset (p = 0.001), older age at testing (p = 0.001), and lower plasma uric acid (p = 0.01). Multivariate analysis showed increased uric acid (β = 0.214, p = 0.01), lower age at testing (β = −0.378, p < 0.001), and higher education level (β = 0.424, p < 0.001) could predict higher ECAS score (F = 19.104, R2 = 0.381, p < 0.0001). Validation analysis showed that predicted ECAS score was significantly correlated with raw ECAS score in both the training set (rs = 0.621, p < 0.001) and the testing set (rs = 0.666, p < 0.001).Conclusions: Cognitive impairment was a common feature in our Chinese ALS patients. Plasma uric acid might help evaluate the risk of cognitive impairment in ALS patients when combined with education level and age at testing.

Behavioural impairment in ALS patients with SOD1 mutations

To date, mutations in the SOD1 gene of patients with amyotrophic lateral sclerosis (ALS) have been associated to peculiar clinical features and disease progression but rarely to cognitive and behavioural impairment. This report aims to address the occurrence of frontotemporal syndromes in ALS patients carrying SOD1 mutations.

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.

The Characteristics of Cognitive Impairment in ALS Patients Depend on the Lateralization of Motor Damage.

(1) Background: Cognitive features of patients with amyotrophic lateral sclerosis (ALS) have never been specifically analyzed according to the lateralization of motor impairment. In the present study we investigated the cognitive performances of ALS patients to describe the relationship between motor and cognitive dysfunction, according to site and side of disease onset. (2) Methods: Six-hundred and nine ALS patients underwent a comprehensive neuropsychological evaluation at diagnosis in Turin ALS Centre Tests included—mini-mental state examination (MMSE), frontal assessment battery (FAB), trail-making test A/B (TMT A-B), digit span forward and backward (digit span FW/digit span BW), letter fluency test (FAS), category fluency test (CAT), Rey auditory verbal learning test (RAVLT), Babcock story recall test (BSRT), Rey-Osterrieth complex figure test (ROCFT), Wisconsin card sorting test (WCST), Raven’s coloured progressive matrices (CPM47). Cognitive performances of patients, grouped by side and site of onset, were statistically compared using z-scores, as appropriate. (3) Results: Bulbar patients and bilateral spinal onset patients (Sbil) were generally characterized by lower cognitive performances in most neuropsychological tests, when compared to patients with lateralized onset (right-side spinal onset, Sri and left-side spinal onset, Sle). Digit span backward and visual memory task (ROCFT) median z-scores were significantly higher, reflecting a better cognitive performance, in Sri patients when compared to bulbar/Sbil patients, while verbal memory tasks (RAVLT and BRST) resulted in significantly higher scores in Sle patients. Our results are in keeping with hemispheric functional lateralization of language and visuospatial abilities. (4) Conclusions: In ALS patients, as in other neurodegenerative diseases, we found a direct relationship between lateralized motor and cognitive features.

The Edinburgh Cognitive and Behavioural ALS Screen (ECAS) for Japanese ALS and FTD patients

Objective Amyotrophic lateral sclerosis (ALS) patients might present with cognitive and behavioural abnormalities resembling frontotemporal dementia (FTD). The Edinburgh Cognitive and Behavioural ALS Screen (ECAS) was developed as an easy to administer cognitive screen for detecting these symptoms. The aim of the present study was to develop and validate a Japanese version of the ECAS. Methods In this single centre observational study, 35 ALS patients and 28 healthy controls were enrolled. Three patients in the ALS group fulfilled the criteria for behavioural variant FTD (ALS-FTD) and the rest were grouped as ALS without FTD. Participants were subjected to the Japanese version of the ECAS. ALS patients were also subjected to the Montreal Cognitive Assessment, Frontal Assessment Battery, ALS Functional Rating Scale-Revised, and respiratory function testing. Demographic and disease characteristics (e.g., sex, age at examination, and years of education) were also recorded. Results Internal consistency and correlations with general cognitive screenings were sufficient in the Japanese adaptation. Executive functions were the most commonly affected ECAS domain, followed by fluency and language. Compared to control subjects, ALS patients without FTD had low scores in the ECAS ALS-specific functions but not in ALS-nonspecific functions. Meanwhile ALS-FTD patients markedly underperformed both in the ECAS ALS-specific and ALS-nonspecific functions. Furthermore, the Japanese ECAS score correlated positively with years of education and negatively with age at onset. Conclusion The Japanese version of the ECAS is a valid and useful screening tool to identify multiple types of cognitive impairment in ALS patients.

Toward a marker of upper motor neuron impairment in amyotrophic lateral sclerosis: A fully automatic investigation of the magnetic susceptibility in the precentral cortex

PurposeDiagnostic work-up in motor neuron disease (MND) needs a quantitative biomarker of upper motor neuron (UMN) impairment. We investigated the susceptibility properties of the precentral cortex in a cohort of patients affected by Amyotrophic lateral sclerosis (ALS) to obtain a useful biomarker of UMN impairment in a fully automatic paradigm. Materials and MethodsWe retrospectively collected imaging and clinical data of 42 ALS patients who had undergone brain 3 T MRI including tridimensional T1-weighted and spoiled gradient-echo multi-echo T2-weighted images. We further acquired images from 23 healthy control (HC) volunteers. The precentral cortex was automatically segmented and the cortical thickness calculated. Histogram metrics (mean, median, standard deviation, skewness, kurtosis) derived from the quantitative susceptibility map (QSM) were extracted from the automatically segmented precentral cortex. Multivariate regression analyses were performed to identify the variables predicting the disease status (ALS vs HC), the Amyotrophic Lateral Sclerosis Functional Rating Scale-Revised (ALSFRS-R) and the UMN score. ResultsA decreased cortical thickness (B = 9.40; Wald’s test = 7.43; p = 0.006) and increased susceptibility skewness (B = -3.08; Wald’s test = 4.36; p = 0.037) independently predicted ALS in a logistic regression model (χ2(3, N = 65) = 22.07, p < 0.001. No predictors of ALSFRS-R were identified. An increased susceptibility skewness (β = 0.55; t = 4.23; p < 0.001) and longer disease duration (β = 0.35; t = 2.67; p = 0.011) independently predicted a higher UMN score in a linear regression model (R2 = 0.32; p < 0.001). ConclusionThe susceptibility skewness might be an unbiased quantitative biomarker of UMN impairment in ALS patients.

Respiratory function and cognitive profile in amyotrophic lateral sclerosis.

Amyotrophic lateral sclerosis (ALS) is increasingly recognized as a multisystem disorder with 30%-50% of patients exhibiting cognitive impairment. The pathophysiological mechanisms of cognitive dysfunction are probably multifactorial although hypoventilation secondary to respiratory dysfunction may contribute to cognitive decline. The current study aimed to identify the relationship between respiratory function in ALS patients and the presence and degree of cognitive impairment. Amyotrophic lateral sclerosis patients were prospectively recruited from a multidisciplinary ALS clinic. Baseline clinical assessments including respiratory function as assessed by spirometry were recorded with forced vital capacity (FVC) ≤ 75% considered to be reduced respiratory function. Cognitive testing was performed utilizing the Addenbrooke's Cognitive Examination (ACE) and the Mini-Mental State Examination (MMSE). From a cohort of 100 ALS patients, 48% were categorized as having impaired respiratory function (FVC=58.24%±2.15%) whilst 52% had normal function (88.65%±1.27%). Compared to the group with normal respiratory function (ACE 90.68 ± 0.89, MMSE 28.22 ± 0.21), patients with respiratory dysfunction had significantly reduced cognitive function (ACE 86.83± 1.5, P=0.025; MMSE 26.29± 0.45, P=0.029). Furthermore, subscores demonstrated significant differences between the groups with respect to domains in memory (P=0.003) and attention (P=0.05) with a trend observed in fluency (P=0.082). There was a significant correlation between patient baseline FVC and ACE scores as well as between FVC and memory and fluency subscores (P<0.01). Amyotrophic lateral sclerosis patients with respiratory compromise were more likely to develop reduced cognitive function. In addition to improving physical function, it remains plausible that non-invasive ventilation may alter the progression of cognitive impairment in ALS patients and potentially improve overall quality of life and carer burden.

Clinical usefulness of scales for evaluating cognitive impairment in patients with amyotrophic lateral sclerosis

Cognitive impairment is a common non-motor symptom of amyotrophic lateral sclerosis (ALS); however, scales suitable for detecting cognitive impairment in ALS patients in clinical practice are unclear. In this study, the Mini-Mental State Examination, Frontal Assessment Battery, and Montreal Cognitive Assessment (MoCA) were evaluated in 68 patients with ALS. The patients were classified into 3 groups based on the results of these clinical scales: group N, patients with scores higher than the cut-offs in all clinical scales; group M, patients with a score lower than the cut-off in one clinical scale; and group D, patients with scores lower than the cut-offs in two or three clinical scales. Clinical data were compared among the groups. Age at onset was significantly lower, and educational period was longer in group N than in group D. MoCA test reported the highest number of patients with a score lower than the cut-off value. The evaluation item of language in MoCA showed the lowest correct answer rate in group N, and evaluation items of executive function and memory in MoCA showed the lowest correct answer rates in group D. MoCA is the most sensitive clinical scale for evaluating cognitive impairment in ALS among the three scales.

MRI cortical feature of bulbar impairment in patients with amyotrophic lateral sclerosis.

The decline of voluntary bulbar functions such as speech and swallowing are among the clinical manifestations of amyotrophic lateral sclerosis (ALS) influencing a worst prognosis. Differential diagnosis between the contribution of upper motor neuron (UMN) and lower motor neuron degeneration to the bulbar impairment is often hard. Thinning and T2* hypointensity of the primary motor cortex have been recently suggested as possible MRI markers of UMN impairment in ALS patients, but little research has purposely targeted the orofacial region of the primary motor cortex (fM1). With the aim of finding an MRI marker of UMN impairment responsible for bulbar dysfunction, we investigated the T2* signal intensity of fM1 and the relationship with bulbar impairment in ALS patients. Fifty-five ALS patients were examined with 3 T MRI. Their fM1 was evaluated both qualitatively in terms of T2* signal intensity and quantitatively by measuring its magnetic susceptibility with Quantitative Susceptibility Mapping (QSM). Bulbar functions were assessed clinically, by neurological examination and using the items 1–3 of the ALSFRS-R, and with neurophysiological tests.The marked hypointensity of fM1 was detected in 25% of ALS patients, including all patients with bulbar onset, and was 74% sensitive, 100% specific and 91% accurate in diagnosing functional bulbar impairment. Such hypointensity involved the middle and ventral part of fM1 and was usually visible in both hemispheres. The magnetic susceptibility was significantly higher in patients with marked fM1 hypointensity than in the other patients (p ≤ .001).The relationship with clinical and neurophysiological data suggests that such feature could be a marker of UMN degeneration for voluntary bulbar functions.

Brain signature of mild stages of cognitive and behavioral impairment in amyotrophic lateral sclerosis

We aimed to assess the brain signature of cognitive and behavioral impairment in C9orf72-negative non-demented ALS patients. The study included 50 amyotrophic lateral sclerosis (ALS) patients (out of 75 initially recruited) and 38 healthy controls. High-resolution T1-weighted and spin-echo diffusion tensor images were acquired in a 3T MRI scanner. The multi atlas-based analysis protocol and the FreeSurfer tool were employed for gray matter assessment, and fiber tractography for white matter evaluation. Cognitively impaired ALS patients (n = 12) had bilateral amygdalae and left thalamic volumetric reduction compared to non-impaired ALS patients. Behaviorally impaired ALS patients (n = 14) had lower fractional anisotropy (FA) at the fornix in comparison with healthy subjects. These parameters did correlate with cognitive/behavioral scores, but not with motor-functional parameters in the ALS cohort. We believe that basal ganglia and fornix damage might be related to cognitive and behavioral impairment across ALS-frontotemporal dementia continuum. Also, distinct anatomical areas seem to influence the behavioral and cognitive status of these individuals.

Global motor unit number index sum score for assessing the loss of lower motor neurons in amyotrophic lateral sclerosis.

We propose a motor unit number index (MUNIX) global sum score in amyotrophic lateral sclerosis (ALS) to estimate the loss of functional motor units. MUNIX was assessed for 18 ALS patients and 17 healthy controls in 7 muscles: the abductor pollicis brevis (APB), abductor digiti minimi (ADM), tibialis anterior (TA), deltoid, trapezius, submental complex, and orbicularis oris. MUNIX was significantly lower in ALS patients than in healthy controls for the APB, ADM, TA, and trapezius muscles. The MUNIX sum score of 4 muscles (ADM + APB + trapezius + TA) was lower in ALS patients (P = 0.01) and was correlated with clinical scores. The global MUNIX sum score proposed in this study estimates the loss of lower motor neurons in several body regions, including the trapezius, and is correlated with clinical impairment in ALS patients. Muscle Nerve 56: 202-206, 2017.