Impairment In Amyotrophic Lateral Sclerosis Research Articles

Mild cognitive impairment in amyotrophic lateral sclerosis: current view.

Amyotrophic lateral sclerosis (ALS) is a fatal multi-system neurodegenerative disorder with no effective treatment or cure. Although primarily characterized by motor degeneration, cognitive dysfunction is an important non-motor symptom that has a negative impact on patient and caregiver burden. Mild cognitive deficits are present in a subgroup of non-demented patients with ALS, often preceding motor symptoms. Detailed neuropsychological assessments reveal deficits in a variety of cognitive domains, including those of verbal fluency and retrieval, language, executive function, attention and verbal memory. Mild cognitive impairment (MCI), a risk factor for developing dementia, affects between 10% and over 50% of ALS patients. Neuroimaging revealed atrophy of frontal and temporal cortices, disordered white matter Integrity, volume reduction in amygdala and thalamus, hypometabolism in the frontal and superior temporal gyrus and anterior insula. Neuronal loss in non-motor brain areas, associated with TDP-43 deposition, one of the morphological hallmarks of ALS, is linked to functional disruption of frontostriatal and frontotemporo-limbic connectivities as markers for cognitive deficits in ALS, the pathogenesis of which is still poorly understood. Early diagnosis by increased cerebrospinal fluid or serum levels of neurofilament light/heavy chain or glial fibrillary acidic protein awaits confirmation for MCI in ALS. These fluid biomarkers and early detection of brain connectivity signatures before structural changes will be helpful not only in establishing early premature diagnosis but also in clarifying the pathophysiological mechanisms of MCI in ALS, which might serve as novel targets for prohibition/delay and future adequate treatment of this debilitating disorder.

The spectrum of behavioral disorders in amyotrophic lateral sclerosis: current view.

Behavioral disorders, with an average prevalence of 30-60% are important non-motor symptoms in amyotrophic lateral sclerosis (ALS) that have a negative impact on prognosis, management and quality of life, yet the underlying neurobiology is poorly understood. Among people with ALS, apathy, fatigue, anxiety, irritability and other behavioral symptoms are the most prominent, although less frequent than cognitive impairment. The present review explores the current understanding of behavioral changes in ALS with particular emphasis on our current knowledge about their structural and functional brain correlates, substantiating a multisystem degeneration with particular dysfunction of frontal-subcortical circuits and dysfunction of fronto-striatal, frontotemporal and other essential brain systems. The natural history of behavioral dysfunctions in ALS and their relationship to frontotemporal lobe degeneration (FTLD) are not fully understood, although they form a clinical continuum, suggesting a differential vulnerability of non-motor brain networks, ALS being considered a brain network disorder. An assessment of risks or the early detection of brain connectivity signatures before structural changes may be helpful in investigating the pathophysiological mechanisms of behavioral impairment in ALS. Treatment of both ALS and co-morbid behavioral disorders is a multidisciplinary task, but whereas no causal or disease-modifying therapies for ALS are available, symptomatic treatment of a variety of behavioral symptoms plays a pivotal role in patient care, although the management of behavioral symptoms in clinical care still remains limited.

Speech motor impairment in ALS is associated with multiregional cortical thinning beyond primary motor cortex.

Cortical thinning is well-documented in individuals with amyotrophic lateral sclerosis (ALS), yet its association with speech deterioration remains understudied. This study characterizes anatomical changes in the brain within the context of speech impairment patterns in individuals with ALS, providing insight into the disease's multiregional spread and biology. To evaluate patterns of cortical thickness in speakers with ALS with and without functional speech changes compared to healthy controls (HCs) using whole-brain and region of interest (ROI) analyses. Forty individuals with ALS and 22 HCs underwent a T1-weighted 3-Tesla magnetic resonance imaging (MRI). Individuals with ALS were divided into two groups based on the preserved speech [ps-ALS] (n = 18) or deteriorated speech [ds-ALS] (n = 22) as measured by the ALSFRSF-R speech subscore (=4 or <4 points, respectively). Sixteen a priori-defined and automatically segmented cortical and subcortical brain ROIs were selected based on their previously documented roles in speech production. Two cortical thickness analyses were performed: (1) group-level whole-brain surface-based analyses and (2) group-level ROI analyses. A case study of 6 ALS individuals examined the cortical thickness, and their speech was characterized using quantitative and qualitative measures. Based on the group-level whole-brain surface-based analyses, the ds-ALS group demonstrated significant cortical thinning compared to HCs in the left primary motor and somatosensory cortices and the right inferior parietal lobe with its adjacent lateral occipital cortical regions. The ps-ALS group demonstrated no significant cortical thinning compared to HCs. Based on the group-level ROI analyses, the ds-ALS group demonstrated significant cortical thinning compared to HCs in bilateral middle motor cortices, right posterior dorsal premotor cortex, and left anterior cingulate cortex. The case study analysis revealed that ALS speakers with speech features characteristic of spastic dysarthria exhibited cortical thinning, while those with speech features characteristic of flaccid dysarthria did not. Individuals with ALS have anatomical changes involving multiregional neocortical areas beyond the primary motor cortex that may manifest as subjective (i.e., clinical judgment) and objective (i.e., speaking rate) changes in speech production. Further longitudinal work in ALS is needed to better understand the link between MRI cortical thickness changes and bulbar dysfunction.

Self-perceived quality of life, cognitive and behavioural impairment in amyotrophic lateral sclerosis

BackgroundSelf-perceived quality of life (QoL) is important in amyotrophic lateral sclerosis (ALS). Although caregiver burden and strain have been related to cognitive and behavioural impairment, there has been no comprehensive research looking at these impairments and how they may influence self-perceived QoL subdomains.AimsTo explore how cognitive and behavioural impairment are related to different areas of self-perceived QoL using disease-specific measures.MethodsThis was a quantitative, cross-sectional, observational cohort study, utilising existing specialist ALS clinic data. Clinical and demographic variables were available as well as multidimensional measures, ALS-specific QoL Short Form (ALSsQoL-SF) results and the data from the Edinburgh Cognitive and Behavioural ALS Screen (ECAS). Group comparison and regression analyses were performed.ResultsData from 121 participants with ALS were analysed. 61.2% (N = 74) had either cognitive and/or behavioural impairment, with 28.9% (N = 35) with cognitive impairment (ALSci), 14.1% (N = 17) with behavioural impairment (ALSbi) and 18.2% (N = 22) with both (ALScbi). 38.8% (N = 47) were classified as having no impairments (ALSni). Those with ALSbi had significantly lower QoL in the domains of negative emotions and the interaction with people and the environment compared to those with ALSci and ALSni (ps < 0.05). Further, those with ALScbi had significantly lower QoL in the intimacy domains than those with ALSci and ALSni (ps < 0.05). Regression analysis showed specific cognitive and behavioural (inclusive of psychosis) predictors associated with specific QoL subdomains.ConclusionsBehavioural impairments effect QoL in specific subdomains, namely relating to internalising (negative emotions) and externalising (interaction with people and the environment subdomains, intimacy).

Cardiac troponin T as a serum biomarker of respiratory impairment in amyotrophic lateral sclerosis.

Informative biomarkers are an urgent need in the management of amyotrophic lateral sclerosis. Serum cardiac troponin T is elevated in the majority of amyotrophic lateral sclerosis patients and increases with disease progression. We sought to establish the informative value of cardiac troponin T with regard to respiratory function, a major prognostic factor in amyotrophic lateral sclerosis. In this retrospective observation, we analyzed two independent hospital-based cohorts (d = discovery cohort; v = validation cohort) regarding serum cardiac troponin T (nd = 298; nv = 49), serum neurofilament light chain (nd = 117; nv = 17), and respiratory tests (nd = 93; nv = 49). Serum cardiac troponin T, in contrast to serum neurofilament levels, was associated with the respiratory domain of the revised amyotrophic lateral sclerosis functional rating scale and with pulmonary function parameters, namely forced vital capacity % (r = -0.45, p = 0.001) and slow vital capacity % (r = -0.50, p = 0.001). Serum cardiac troponin T reliably discriminated benchmarks of slow vital capacity <80% (AUC 0.73, 95% CI 0.62-0.84) and <50% (AUC 0.80, 95% CI 0.68-0.93), forced vital capacity <80% (AUC 0.72, 95% CI 0.61-0.83) and <50% (AUC 0.79, 95% CI 0.67-0.91). Our findings position cardiac Troponin T as a valuable serum biomarker in amyotrophic lateral sclerosis, complementing neurofilaments and expanding the understanding of underlying physiological mechanisms. In clinical practice, serum cardiac troponin T can flag benchmarks of compromised respiratory function.

Cerebral glucose metabolic correlates of cognitive and behavioural impairments in amyotrophic lateral sclerosis

ObjectiveHalf of ALS patients are cognitively and/or behaviourally impaired. As cognition/behaviour and cerebral glucose metabolism can be correlated by means of 18F-Fluorodeoxyglucose positron emission tomography (FDG-PET), we aimed to utilise FDG-PET, first, to replicate group-level differences in glucose metabolism between non-demented ALS patients separated into non-impaired (ALSni), cognitively impaired (ALSci), behaviourally impaired (ALSbi), and cognitively and behaviourally impaired (ALScbi) groups; second, to investigate glucose metabolism and performance in various cognitive domains; and third, to examine the impact of partial volume effects correction (PVEC) of the FDG-PET data on the results.MethodsWe analysed neuropsychological, clinical, and imaging data from 67 ALS patients (30 ALSni, 21 ALSci, 5 ALSbi, and 11 ALScbi). Cognition was assessed with the Edinburgh Cognitive and Behavioural ALS Screen, and two social cognition tests. FDG-PET and structural MRI scans were acquired for each patient. Voxel-based statistical analyses were undertaken on grey matter volume (GMV) and non-corrected vs. PVE-corrected FDG-PET scans.ResultsALSci and ALScbi had lower cognitive scores than ALSni. In contrast to both ALSni and ALSci, ALScbi showed widespread hypometabolism in the superior- and middle-frontal gyri in addition to the right temporal pole. Correlations were observed between the GMV, the FDG-PET signal, and various cognitive scores. The FDG-PET results were largely unaffected by PVEC.InterpretationOur study identified widespread differences in hypometabolism in the ALScbi-ni but not in the ALSci-ni group comparison, raising the possibility that cerebral metabolism may be more closely related to the presence of behavioural changes than to mild cognitive deficits.

Verbal expressive language minimally affected in non-demented people living with amyotrophic lateral sclerosis

Objective: Language dysfunction is one of the most common cognitive impairments in amyotrophic lateral sclerosis (ALS). Although discourse capacities are essential for daily functioning, verbal expressive language has not been widely investigated in ALS. The existing research available suggests that discourse impairments are prevalent. This study investigates verbal expressive language in people living with ALS (plwALS) in contrast to healthy controls (HC). Methods: 64 plwALS and 49 age, gender and education-matched healthy controls were ask to describe the Cookie Theft Picture Task. The recordings were analyzed for discourse productivity, discourse content, syntactic complexity, speech fluency and verb processing. We applied the Bayesian hypothesis-testing framework, incorporating the effects of dysarthria, cognitive impairment status (CIS), and premorbid crystalline verbal IQ. Results: Compared to HC, plwALS only showed a single impairment: speech dysfluency. Discourse productivity, discourse content, syntactic complexity and verb processing were not impaired. Cognition and dysarthria exceeded the influence of verbal IQ for total words spoken and content density. Cognition alone seemed to explain dysfluency. Body-agent verbs were produced at even higher rates than other verb types. For the remaining outcomes, verbal IQ was the most decisive factor. Conclusions: In contrast to existing research, our data demonstrates no discernible impairment in verbal expressive language in ALS. What our findings show to be decisive is accounting for the influence of dysarthria, cognitive impairment status, and verbal IQ as variables on spontaneous verbal expressive language. Minor impairments in verbal expressive language appear to be influenced to a greater degree by executive dysfunctioning and dysarthria than by language impairment.

Electroencephalographic β-band oscillations in the sensorimotor network reflect motor symptom severity in amyotrophic lateral sclerosis.

Resting-state electroencephalography (EEG) holds promise for assessing brain networks in amyotrophic lateral sclerosis (ALS). We investigated whether neural β-band oscillations in the sensorimotor network could serve as an objective quantitative measure of progressive motor impairment and functional disability in ALS patients. Resting-state EEG was recorded in 18 people with ALS and 38 age- and gender-matched healthy controls. We estimated source-localized β-band spectral power in the sensorimotor cortex. Clinical evaluation included lower (LMN) and upper motor neuron scores, Amyotrophic Lateral Sclerosis Functional Rating Scale-Revised score, fine motor function (FMF) subscore, and progression rate. Correlations between clinical scores and β-band power were analysed and corrected using a false discovery rate of q = 0.05. β-Band power was significantly lower in people with ALS than controls (p = 0.004), and correlated with LMN score (R = -0.65, p = 0.013), FMF subscore (R = -0.53, p = 0.036), and FMF progression rate (R = 0.52, p = 0.036). β-Band spectral power in the sensorimotor cortex reflects clinically evaluated motor impairment in ALS. This technology merits further investigation as a biomarker of progressive functional disability.

A Fine-Grained Temporal Analysis of Multimodal Oral Diadochokinetic Performance to Assess Speech Impairment in Amyotrophic Lateral Sclerosis.

This study used a semiautomated fine-grained temporal analysis to extract features of temporal oral diadochokinetic (DDK) performance across multiple modalities and tasks, from neurologically healthy and impaired individuals secondary to amyotrophic lateral sclerosis (ALS). The aims were to (a) delineate temporal oral DDK deficits relating to the neuromotor pathology of ALS and (b) identify the optimal task-feature combinations to detect speech impairment in ALS. Mandibular myoelectric, kinematic, and acoustic data were acquired from 13 individuals with ALS and 10 healthy controls producing three alternating motion rate tasks and one sequential motion rate task. Twenty-seven features were extracted from the multimodal data, characterizing three temporal constructs: duration/rate, variability, and coordination. The disease impacts on these features were assessed across tasks, and the task eliciting the greatest disease-related change was identified for each feature. Such "optimal" task-feature combinations were fed into logistic regression to differentiate individuals with ALS from healthy controls. Temporal deficits in ALS were characterized by (a) increased duration and variability and reduced coordination of jaw muscle activities, (b) increased duration and variability and altered temporal symmetry of jaw velocity profile, (c) increased muscle-burst-to-peak-velocity duration, and (d) increased motion-to-voice onset duration. These temporal features were differentially affected across tasks. The optimal task-feature combinations, which were further clustered into three composite factors reflecting temporal variability, coarser-grained duration, and finer-grained duration, differentiated ALS from controls with an F1 score of 0.86 (precision = 1.00, recall = 0.75). Temporal oral DDK deficits are likely attributed to a hierarchy of interrelated neurophysiological and biomechanical factors associated with the neuromotor pathology of ALS. These deficits, as assessed crossmodally, provide previously unavailable insights into the multifaceted timing impairment of oromotor performance in ALS. The optimal task-feature combinations targeting these deficits show promise as quantitative markers for (early) detection of speech impairment in ALS.

High serum uric acid levels are protective against cognitive impairment in amyotrophic lateral sclerosis

BackgroundUric acid (UA) has emerged as a factor that can modify cognitive function both in the general population and in people with neurodegenerative disorders. Since very few data are available concerning amyotrophic lateral sclerosis (ALS), we explored the correlation of UA levels and cognitive impairment in a large cohort of ALS patients.MethodsWe enrolled ALS patients consecutively seen at the Turin ALS expert center in the 2007–2018 period who underwent both cognitive/behavioral and UA evaluation at diagnosis. Patients were classified in 5 categories: normal cognition (ALS-CN), isolated cognitive impairment (ALSci), isolated behavioural impairment (ALSbi), cognitive and behavioural impairment (ALScbi), frontotemporal dementia (ALS-FTD). For this study, ALSci, ALSbi and ALScbi were merged as ALS with intermediate cognitive impairment (ALS-INT).ResultsOut of the 841 ALS patients, 422 had ALS-CN, 271 ALS-INT and 148 ALS-FTD. The mean values of UA were significantly different among the cognitive subgroups of patients, with the lowest values in the ALS-FTD (ALS-CN, 288.5 ± 78.0 (μmol/L; ALS-INT, 289.7 ± 75.5 μmol/L; ALS-FTD, 271.8 ± 74.9 μmol/L; p = 0.046). The frequency of ALS-FTD was significantly higher in the 1st tertile of UA. Lower UA levels were independently associated with FTD (OR 1.32, 95% c.i. 1.01–1.43; p = 0.038) in binary logistic regression.ConclusionsWe found that in ALS lower UA serum levels are correlated with reduced frequency of co-morbid FTD. Patients with intermediate cognitive impairment showed UA levels similar to ALS-CN but higher than ALS-FTD, implying that higher UA levels can prevent or delay cognitive function deterioration.

A Vowel-Centric View Toward Characterizing Temporal Organization of Motor Speech Activities in Neurologically Impaired and Healthy Speakers.

This study tested the hypotheses that (a) motor speech activities are temporally organized around the nuclei into vowel-centric units that hold both stability and flexibility and (b) such temporal organization is impacted by motor speech impairment. Thirteen individuals with amyotrophic lateral sclerosis and 10 healthy controls read a sentence 3 times at each of the following rates: habitual, fast, and slow. Articulatory gestures and phonatory event were assessed in two vowel-centric units, as operationally defined within and across the boundaries of two target words-cat and must-to accommodate common coda omission and coarticulation. Twelve absolute and relative timing measures centering on the nucleus were derived to characterize the temporal organization of each unit. These measures were evaluated in terms of (a) their relations with global duration across rate conditions and (b) between-groups differences for the habitual rate condition. Both vowel-centric units remained stable in relative timing between the articulatory gestures approaching and moving away from the nucleus across rate conditions. Relative timing between the articulatory gestures and phonatory event at smaller temporal granularities varied with global duration, but in different ways for neurologically impaired and healthy speakers. Disease impacts on relative timing were only detected across word boundaries. All absolute timing measures revealed consistent temporal scaling effects and disease-related prolongations. The findings provide preliminary support for vowel-centric temporal organization of motor speech activities. Such temporal organization holds some extent of both stability and flexibility, which may facilitate the parsing of syllabic events during auditory processing, while accommodating task-specific suprasegmental variations. The timing impairments in amyotrophic lateral sclerosis are likely attributed to the disease-imposed dynamic constraints, reducing the entrainment of the related motor speech activities to the underlying linguistic elements. These findings have potential implications in guiding the assessment and management of temporal speech deficits in ALS.

The Spectrum of Cognitive Dysfunction in Amyotrophic Lateral Sclerosis: An Update.

Cognitive dysfunction is an important non-motor symptom in amyotrophic lateral sclerosis (ALS) that has a negative impact on survival and caregiver burden. It shows a wide spectrum ranging from subjective cognitive decline to frontotemporal dementia (FTD) and covers various cognitive domains, mainly executive/attention, language and verbal memory deficits. The frequency of cognitive impairment across the different ALS phenotypes ranges from 30% to 75%, with up to 45% fulfilling the criteria of FTD. Significant genetic, clinical, and pathological heterogeneity reflects deficits in various cognitive domains. Modern neuroimaging studies revealed frontotemporal degeneration and widespread involvement of limbic and white matter systems, with hypometabolism of the relevant areas. Morphological substrates are frontotemporal and hippocampal atrophy with synaptic loss, associated with TDP-43 and other co-pathologies, including tau deposition. Widespread functional disruptions of motor and extramotor networks, as well as of frontoparietal, frontostriatal and other connectivities, are markers for cognitive deficits in ALS. Cognitive reserve may moderate the effect of brain damage but is not protective against cognitive decline. The natural history of cognitive dysfunction in ALS and its relationship to FTD are not fully understood, although there is an overlap between the ALS variants and ALS-related frontotemporal syndromes, suggesting a differential vulnerability of motor and non-motor networks. An assessment of risks or the early detection of brain connectivity signatures before structural changes may be helpful in investigating the pathophysiological mechanisms of cognitive impairment in ALS, which might even serve as novel targets for effective disease-modifying therapies.

Impairment of oculomotor functions in patients with early to advanced amyotrophic lateral sclerosis

Amyotrophic lateral sclerosis (ALS) can result into an incomplete locked in state (iLIS), in which communication depends on eye tracking computer devices. Oculomotor function impairments in ALS have been reported, but there is little research, particularly with respect to patients in iLIS. In the present study, we compared reflexive and executive oculomotor function by means of an eye tracking test battery between three groups: advanced ALS patients in iLIS (n = 22), patients in early to middle ALS stages (n = 44) and healthy subjects (n = 32). Patients with ALS showed significant deteriorations in oculomotor functions, with stronger impairments in iLIS. More specifically, ALS patients produced visually guided prosaccades with longer latencies and more frequent hypometria compared to healthy subjects. Longest latencies were obtained in iLIS patients, with a stronger prolongation for vertical than for horizontal prosaccades. ALS patients made more antisaccade errors and generated antisaccades with longer latencies. Smooth pursuit was also impaired in ALS. In the earlier ALS stages, bulbar onset patients presented stronger antisaccade and smooth pursuit deficits than spinal onset patients. Our findings reveal a relevant deterioration of important oculomotor functions in ALS, which increases in iLIS. It includes impairments of reflexive eye movements to loss of executive inhibitory control, indicating a progressing pathological involvement of prefrontal, midbrain and brainstem areas. The assessment of oculomotor functions may therefore provide clinically relevant bio- and progression marker, particularly in advanced ALS.

Implication of Central Nervous System Barrier Impairment in Amyotrophic Lateral Sclerosis: Gender-Related Difference in Patients.

Central nervous system (CNS) barrier impairment has been reported in amyotrophic lateral sclerosis (ALS), highlighting its potential significance in the disease. In this context, we aim to shed light on its involvement in the disease, by determining albumin quotient (QAlb) at the time of diagnosis of ALS in a large cohort of patients. Patients from the university hospital of Tours (n = 307) were included in this monocentric, retrospective study. In total, 92 patients (30%) had elevated QAlb levels. This percentage was higher in males (43%) than in females (15%). Interestingly, QAlb was not associated with age of onset, age at sampling or diagnostic delay. However, we found an association with ALS functional rating scale-revised (ALSFRS-r) at diagnosis but this was significant only in males. The QAlb levels were not linked to the presence of a pathogenic mutation. Finally, we performed a multivariate survival analysis and found that QAlb was significantly associated with survival in male patients (HR = 2.3, 95% CI = 1.2-4.3, p = 0.009). A longitudinal evaluation of markers of barrier impairment, in combination with inflammatory biomarkers, could give insight into the involvement of CNS barrier impairment in the pathogenesis of the disease. The gender difference might guide the development of new drugs and help personalise the treatment of ALS.

Phosphorylated tau in plasma could be a biomarker of lower motor neuron impairment in amyotrophic lateral sclerosis.

Plasma levels of phosphorylated tau (P-tau181) have been recently reported to be increased in amyotrophic lateral sclerosis (ALS) and associated with lower motor neuron (LMN) impairment. We quantified plasma P-tau181 (pP-tau181) in a cohort of 29 deeply phenotyped ALS patients using the new fully automated Lumipulse assay and analysed phenotype-biomarker correlations. pP-tau181 levels correlated positively with a clinical LMN score (r = 0.3803) and negatively, albeit not significantly, with a composite index of muscle strength (r = - 0.3416; p = 0.0811), but not with Penn Upper Motor Neuron (UMN) Score. Accordingly, pP-tau181 correlated with electromyographic indices of spinal active and chronic denervation (r = 0.4507 and r = 0.3864, respectively) but not with transcranial magnetic stimulation parameters of UMN dysfunction. pP-tau181 levels did not correlate with those in the cerebrospinal fluid (CSF), serum NFL, serum GFAP, CSF/serum albumin ratio, or estimated glomerular filtration rate, but correlated with plasma creatine kinase levels (r = 0.4661). Finally, while not being associated with neuropsychological phenotype, pP-tau181 correlated negatively with pH (r = - 0.5632) and positively with partial pressure of carbon dioxide (PaCO2; r = 0.7092), bicarbonate (sHCO3-; r = 0.6667) and base excess (r = 0.6611) on arterial blood gas analysis. pP-tau181 has potential as ALS biomarker and could be associated with LMN impairment. Its raised levels might reflect pathophysiological processes (tau hyperphosphorylation and/or release) occurring in the axons of LMNs distantly from the CNS and the CSF. pP-tau181 could also be associated with respiratory dysfunction.

Dextromethorphan/quinidine for the treatment of bulbar impairment in amyotrophic lateral sclerosis.

No efficacious treatments exist to improve or prolong bulbar functions of speech and swallowing in persons with amyotrophic lateral sclerosis (pALS). This study evaluated the short-term impact of dextromethorphan/quinidine (DMQ) treatment on speech and swallowing function in pALS. This was a cohort trial conducted between August 2019 to August 2021 in pALS with a confirmed diagnosis of probable-definite ALS (El-Escorial Criteria-revisited) and bulbar impairment (ALS Functional Rating Scale score ≤ 10 and speaking rate ≤ 140 words per minute) who were DMQ naïve. Efficacy of DMQ was assessed via pre-post change in the ALS Functional Rating Scale-Revised bulbar subscale and validated speech and swallowing outcomes. Paired t-tests, Fisher's exact, and χ2 tests were conducted with alpha at 0.05. Twenty-eight pALS enrolled, and 24 participants completed the 28-day trial of DMQ. A significant increase in ALSFRS-R bulbar subscale score pre- (7.47 ± 1.98) to post- (8.39 ± 1.79) treatment was observed (mean difference: 0.92, 95% CI: 0.46-1.36, p < 0.001). Functional swallowing outcomes improved, with a reduction in unsafe (75% vs. 44%, p = 0.003) and inefficient swallowing (67% vs. 58%, p = 0.002); the relative speech event duration in a standard reading passage increased, indicating a greater duration of uninterrupted speech (mean difference: 0.33 s, 95% CI: 0.02-0.65, p = 0.035). No differences in diadochokinetic rate or speech intelligibility were observed (p > 0.05). Results of this study provide preliminary evidence that DMQ pharmacologic intervention may have the potential to improve or maintain bulbar function in pALS.

"Huoling Shengji granule" for amyotrophic lateral sclerosis: protocol for a multicenter, randomized, double-blind, riluzole parallel controlled clinical trial.

There is still a large demand for effective treatments to delay disease deterioration in amyotrophic lateral sclerosis (ALS). Typical symptoms of ALS are considered "flaccidity syndrome" in traditional Chinese medicine (TCM). Huoling Shengji Granule (HLSJ) is a TCM formula used to treat flaccidity syndrome. Results of preclinical tests and a previous clinical study support HLSJ as a novel drug for ALS patients. This trial proposed to examine whether a 48-week course of HLSJ is effective and safe for ALS patients diagnosed with the Chinese medicine syndrome of spleen qi insufficiency and kidney yang deficiency. In this phase II, multicenter, randomized, double-blind, riluzole parallel-controlled, superiority-design study, eligible participants had the equal opportunity to be assigned to receive either HLSJ or riluzole randomly. Eleven specialized ALS centers in Mainland China will recruit 144 patients for this trial. The primary and secondary outcomes included the change in the ALSFRS-R score and the Rasch-Built Overall Amyotrophic Lateral Sclerosis Disability Scale (ROADS) from baseline to Week 48. Here, we endeavored to evaluate TCM for ALS using a standard evidence-based approach for the first time. In addition, the ROADS, a self-report linear-weighted questionnaire, was selected as a secondary outcome measure. We expect to offer a new reference for the outcome evaluation of ALS trials.Clinical trial registration:http://www.Chictr.org.cn, identifier ChiCTR2100044085.

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.

Integrative analysis of metabolomics and proteomics unravels purine metabolism dysregulation in the SOD1G93A mouse model of amyotrophic lateral sclerosis

Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease with progressive paralysis of limbs and bulb in patients, the cause of which remains unclear. Accumulating studies suggest that motor neuron degeneration is associated with systemic metabolic impairment in ALS. However, the metabolic reprogramming and underlying mechanism in the longitudinal progression of the disease remain poorly understood. In this study, we aimed to investigate the molecular changes at both metabolic and proteomic levels during disease progression to identify the most critical metabolic pathways and underlying mechanisms involved in ALS pathophysiological changes. Utilizing liquid chromatography-mass spectrometry-based metabolomics, we analyzed the metabolites' levels of plasma, lumbar spinal cord, and motor cortex from SOD1G93A mice and wildtype (WT) littermates at different stages. To elucidate the regulatory network underlying metabolic changes, we further analyzed the proteomics profile in the spinal cords of SOD1G93A and WT mice. A group of metabolites implicated in purine metabolism, methionine cycle, and glycolysis were found differentially expressed in ALS mice, and abnormal expressions of enzymes involved in these metabolic pathways were also confirmed. Notably, we first demonstrated that dysregulation of purine metabolism might contribute to the pathogenesis and disease progression of ALS. Furthermore, we discovered that fatty acid metabolism, TCA cycle, arginine and proline metabolism, and folate-mediated one‑carbon metabolism were also significantly altered in this disease. The identified differential metabolites and proteins in our study could complement existing data on metabolic reprogramming in ALS, which might provide new insight into the pathological mechanisms and novel therapeutic targets of ALS.

Cortical microstructural abnormalities in amyotrophic lateral sclerosis: a gray matter-based spatial statistics study.

Amyotrophic lateral sclerosis (ALS)-related white-matter microstructural abnormalities have received considerable attention; however, gray-matter structural abnormalities have not been fully elucidated. This study aimed to evaluate cortical microstructural abnormalities in ALS and determine their association with disease severity. This study included 34 patients with ALS and 30 healthy controls. Diffusion-weighted data were used to estimate neurite orientation dispersion and density imaging (NODDI) parameters, including neurite density index (NDI) and orientation dispersion index (ODI). We performed gray matter-based spatial statistics (GBSS) in a voxel-wise manner to determine the cortical microstructure difference. We used the revised ALS Functional Rating Scale (ALSFRS-R) to assess disease severity and conducted a correlation analysis between NODDI parameters and ALSFRS-R. In patients with ALS, the NDI reduction involved several cortical regions [primarily the precentral gyrus, postcentral gyrus, temporal cortex, prefrontal cortex, occipital cortex, and posterior parietal cortex; family-wise error (FWE)-corrected P<0.05]. ODI decreased in relatively few cortical regions (including the precentral gyrus, postcentral gyrus, prefrontal cortex, and inferior parietal lobule; FWE-corrected P<0.05). The NDI value in the left precentral and postcentral gyrus was positively correlated with the ALS disease severity (FWE-corrected P<0.05). The decreases in NDI and ODI involved both motor-related and extra-motor regions and indicated the presence of gray-matter microstructural impairment in ALS. NODDI parameters are potential imaging biomarkers for evaluating disease severity in vivo. Our results showed that GBSS is a feasible method for identifying abnormalities in the cortical microstructure of patients with ALS.