Amyotrophic Lateral Sclerosis Group Research Articles

Amyotrofik lateral skleroz erken tanısında sinir iletim çalışmaları ve ayrık el bulgusunun önemi

Aim: The heterogeneity of the Amyotrophic Lateral Sclerosis (ALS) clinical phenotypes leads to difficulties in early diagnosis. The ‘split hand’ sign is defined as the thenar muscles that are more prominently affected by hypothenar. In this study, the results of the initial nerve conduction study of the patients were compared with those of the controls in order to increase the findings supporting early diagnosis.
 Material and Method: Seventy-five patients who were diagnosed with ALS in our clinic were included in the study. The initial ENMG findings of the patients were compared with those of 70 healthy controls: Distal motor latency (DML), the compound muscle action potential (CMAP) amplitude, velocity in the motor conduction of median, ulnar, peroneal and tibial nerves; distal latency, amplitude, velocity in sensorial conduction were evaluated. Ulnar/median DML and ulnar/median CMAP amplitude ratios were examined.
 Results: In ALS group, DMLs of the median, ulnar, peroneal, and tibial nerves were significantly longer, and CMAP amplitudes were significantly smaller than those of the controls. The sensory conductions of the median, ulnar, and sural nerves were not statistically different between the groups. The ulnar/median DML ratio of the patients was lower than the ratio of controls (0.73/0.80;p=0.003); while the ulnar/median CMAP amplitude ratio was greater (1.40/1.11; p=0.002).
 Conclusion: Prolonged DML and reduced amplitudes were observed in the motor nerve conduction of ALS patients in the early period. The results of the present study also support the presence of split-hand phenomenon even in early period of limb-onset ALS (both upper and lower). These findings suggest that nerve conduction studies and electrophysiologically detected split-hand sign are important clues for the early diagnosis of ALS in case of heterogeneous clinical phenotype.

Network diffusion model predicts neurodegeneration in limb-onset Amyotrophic Lateral Sclerosis.

ObjectiveEmerging evidences suggest that the trans-neural propagation of phosphorylated 43-kDa transactive response DNA-binding protein (pTDP-43) contributes to neurodegeneration in Amyotrophic Lateral Sclerosis (ALS). We investigated whether Network Diffusion Model (NDM), a biophysical model of spread of pathology via the brain connectome, could capture the severity and progression of neurodegeneration (atrophy) in ALS.MethodsWe measured degeneration in limb-onset ALS patients (n = 14 at baseline, 12 at 6-months, and 9 at 12 months) and controls (n = 12 at baseline) using FreeSurfer analysis on the structural T1-weighted Magnetic Resonance Imaging (MRI) data. The NDM was simulated on the canonical structural connectome from the IIT Human Brain Atlas. To determine whether NDM could predict the atrophy pattern in ALS, the accumulation of pathology modelled by NDM was correlated against atrophy measured using MRI. In order to investigate whether network spread on the brain connectome derived from healthy individuals were significant findings, we compared our findings against network spread simulated on random networks.ResultsThe cross-sectional analyses revealed that the network diffusion seeded from the inferior frontal gyrus (pars triangularis and pars orbitalis) significantly predicts the atrophy pattern in ALS compared to controls. Whereas, atrophy over time with-in the ALS group was best predicted by seeding the network diffusion process from the inferior temporal gyrus at 6-month and caudal middle frontal gyrus at 12-month. Network spread simulated on the random networks showed that the findings using healthy brain connectomes are significantly different from null models.InterpretationOur findings suggest the involvement of extra-motor regions in seeding the spread of pathology in ALS. Importantly, NDM was able to recapitulate the dynamics of pathological progression in ALS. Understanding the spatial shifts in the seeds of degeneration over time can potentially inform further research in the design of disease modifying therapeutic interventions in ALS.

Iron quantitative analysis of motor combined with bulbar region in M1 cortex may improve diagnosis performance in ALS.

To explore whether the combined analysis of motor and bulbar region of M1 on susceptibility-weighted imaging (SWI) can be a valid biomarker for amyotrophic lateral sclerosis (ALS). Thirty-two non-demented ALS patients and 35 age- and gender-matched healthy controls (HC) were retrospectively recruited. SWI and 3D-T1-MPRAGE images were obtained from all individuals using a 3.0-T MRI scan. The bilateral posterior band of M1 was manually delineated by three neuroradiologists on phase images and subdivided into the motor and bulbar regions. We compared the phase values in two groups and performed a stratification analysis (ALSFRS-R score, duration, disease progression rate, and onset). Receiver operating characteristic (ROC) curves were also constructed. ALS group showed significantly increased phase values in M1 and the two subregions than the HC group, on the all and elderly level (p < 0.001, respectively). On all-age level comparison, negative correlations were found between phase values of M1 and clinical score and duration (p < 0.05, respectively). Similar associations were found in the motor region (p < 0.05, respectively). On both the total (p < 0.01) and elderly (p < 0.05) levels, there were positive relationships between disease progression rate and M1 phase values. In comparing ROC curves, the entire M1 showed the best diagnostic performance. Combining motor and bulbar analyses as an integral M1 region on SWI can improve ALS diagnosis performance, especially in the elderly. The phase value could be a valuable biomarker for ALS evaluation. • Integrated analysis of the motor and bulbar as an entire M1 region on SWI can improve the diagnosis performance in ALS. • Quantitative analysis of iron deposition by SWI measurement helps the clinical evaluation, especially for the elderly patients. • Phase value, when combined with the disease progression rate, could be a valuable biomarker for ALS.

Association between abnormal expression and methylation of LGALS1 in amyotrophic lateral sclerosis

ObjectiveDNA methylation has been identified to play an important role in amyotrophic lateral sclerosis (ALS). Galectin-1, encoded by LGALS1 gene, has been proved to be associated with ALS. We aimed to investigate the association between the expression and methylation of LGALS1 in blood samples from ALS patients. MethodsForty-five patients diagnosed with ALS were enrolled. Thirty-two healthy relatives consisted the control group. Among them, samples from 12 patients and 12 controls consisted the exploration samples. In the exploration samples, mRNA expression levels were detected by quantitative real-time PCR. In all the samples, DNA methylation levels of one CpG island containing 12 CpG sites in the gene promoter were detected by bisulfite sequencing PCR, and galectin-1 levels were examined by enzyme linked immunosorbent assay. Associations between the gene expression and methylation level, as well as between the region-specific methylation level and clinical variables were calculated. ResultsThe mRNA expression level of LGALS1 was significantly increased and the promoter of LGALS1 was hypomethylated in ALS patients. Serum galectin-1 levels were significantly elevated in the ALS patients. The ALS group had significantly lower methylation level at certain CpG sites than the control group. There were significant negative associations between abnormal expression and methylation of LGALS1, as well as between region-specific methylation levels and the age of onset. ConclusionsThe aberrant expression and DNA methylation of LGALS1 and their association reveals epigenetic changes in ALS patients, which are helpful for early intervention and treatment for the disease.

Cauda Equina Atrophy in Amyotrophic Lateral Sclerosis on Routine Lumbar Magnetic Resonance Imaging.

The aim of the study was to evaluate the cross-sectional area of the cauda equina in amyotrophic lateral sclerosis (ALS) on routine lumbar magnetic resonance imaging and investigate the diagnostic accuracy in comparison with age- and sex-matched non-ALS controls. This retrospective study included 15 ALS patients and 15 age- and sex-matched non-ALS controls. Two independent neuroradiologists measured and compared the total cross-sectional area of the cauda equina of ALS patients and the non-ALS controls at the level of the L3 and L4 using axial T2-weighted images. The cutoff value, sensitivity, specificity, and area under the curve were measured. The interobserver reproducibility of the 2 independently obtained measurements was evaluated. The total cross-sectional area of the cauda equina in the ALS group was significantly smaller than that in the non-ALS group (L3: median, 66.73 vs 90.19 mm 2 , P < 0.001; L4: median, 52.9 vs 67.63 mm 2 , P < 0.001). The cutoff values at L3 and L4 were 76.95 and 61.04 mm 2 with a sensitivity and specificity of 1 and 0.87 and 0.8 and 0.87, respectively. The area under the curve at L3 and L4 were high at 0.96 and 0.94, respectively. The interobserver reproducibility was 0.88 at L3 and 0.89 at L4. The ALS patients showed significant atrophy of the cauda equina compared with non-ALS patients.

Repeated neurofilament light chain measurements did not capture Riluzole therapeutic effect in amyotrophic lateral sclerosis patients.

BackgroundLittle is known about the influence of Riluzole on serum neurofilament light chain (sNfL) levels, a biomarker of prognosis in amyotrophic lateral sclerosis (ALS), and variations with time of sNfL concentrations are controversial.MethodsSera from ALS patients (n = 141) and controls (n = 33) were collected at inclusion (sNfL1) and second visit (sNfL2, mean delay 10.4 ± 8.7 months). sNfL levels, determined by single‐molecule array, were compared between ALS and controls at both time points. sNfL concentration changes were compared between patients with Riluzole (w/Ril) at inclusion in the study and those who were treated by Riluzole following inclusion (w/o Ril). The factors influencing sNfL concentrations and changes were studied using linear regression and multivariate analysis.ResultssNfL levels were higher in ALS patients than in controls at the two time points (p < 0.00001). In ALS patients, sNfL concentrations were higher in females for both sNfL1 (p = 0.014) and sNfL2 (p < 0.001). In the whole ALS group, sNfL levels were higher at sNfL2 than at sNfL1 (p < 0.001). sNfL1 and sNfL2 concentrations were similar between the two ALS subgroups (w/ and w/o Ril). ALS functional rating scale‐revised rate of decline and gender were the two main factors significantly influencing both sNfL1 and sNfL2 levels (p < 0.01). However, only gender was shown to significantly influence sNfL changes with time (p = 0.003).ConclusionsIn this study, sNfL levels increased with time in ALS patients and there was no difference between subjects already treated by Riluzole and those treated after sNfL1. Further studies with larger population samples and different sampling intervals are warranted to better determine the real potential of sNfL measurement as a tool to monitor treatment response in ALS.

Plasma taurine is an axonal excitability-translatable biomarker for amyotrophic lateral sclerosis

Although various body fluid biomarkers for amyotrophic lateral sclerosis (ALS) have been reported, no biomarkers specifically reflecting abnormalities in axonal excitability indices have currently been established. Capillary electrophoresis time-of-flight mass spectrometry and liquid chromatography time-of-flight mass spectrometry were used to perform a comprehensive metabolome analysis of plasma from seven ALS patients and 20 controls, and correlation analysis with disease phenotypes was then performed in 22 other ALS patients. Additionally, electrophysiological studies of motor nerve axonal excitability were performed in all ALS patients. In the ALS and control groups, levels of various metabolites directly associated with skeletal muscle metabolism, such as those involved in fatty acid β-oxidation and the creatine pathway, were detected. Receiver operating characteristic curve analysis of the top four metabolites (ribose-5-phosphate, N6-acetyllysine, dyphylline, 3-methoxytyrosine) showed high diagnostic accuracy (area under the curve = 0.971) in the ALS group compared with the control group. Furthermore, hierarchical cluster analysis revealed that taurine levels were correlated with the strength-duration time constant, an axonal excitability indicator established to predict survival. No significant effects of diabetes mellitus and treatment (Riluzole and Edaravone) on this relationship were detected in the study. Therefore, plasma taurine is a potential novel axonal excitability-translatable biomarker for ALS.

Differentiating Slowly Progressive Subtype of Lower Limb Onset ALS From Typical ALS Depends on the Time of Disease Progression and Phenotype.

BackgroundFlail leg syndrome (FLS) is a regional variant of amyotrophic lateral sclerosis (ALS) with the characteristics of slow progression and the symptoms confined to the lumbosacral region for extended periods. However, FLS may not be easily differentiated from typical ALS.ObjectiveThe objective of the study was to determine a cutoff time of disease progression that could differentiate FLS from the typical lower limb onset ALS.MethodsA cutoff point analysis was performed with maximally selected log–rank statistics in patients with lower limb onset ALS registered from 2009 to 2013. Based on the cutoff duration from the lower limb onset to second region significantly involved (SRSI), all patients were divided into the slowly progressive subtype of lower limb onset ALS group and the typical lower limb-onset ALS group. Patients with the slowly progressive subtype of the lower limb onset ALS, who had the flail leg phenotype, were classified as patients with FLS. Differences between groups were analyzed.ResultsAmong the 196 patients recruited, 157 patients with a duration <14 months from lower limb onset to SRSI were classified as having typical lower limb onset ALS. Twenty-nine patients with a duration more than or equal to 14 months and the flail leg phenotype were classified as having FLS. Patients with FLS exhibited a median diagnostic delay of 25 months, a median duration of 24 months from lower limb onset to SRSI, a forced vital capacity abnormity rate of 12.5% at the first visit to our department, and a median survival time of 80 months, which were significantly different from those of patients with typical lower limb onset ALS (p < 0.001, p < 0.001, p = 0.024, p < 0.001). The 5-year survival rate of the FLS group (79.3%) was much higher than that of the other group (1.9%).ConclusionsA crucial feature in differentiating FLS from typical lower limb onset ALS in Chinese patients may be symptoms confined to the lumbosacral region for at least 14 months, which may be better than 12 or 24 months used in the previous studies. The FLS was characterized by slower progression, less and later respiratory dysfunction, and a more benign prognosis than the typical lower limb onset ALS.

Body fat compartment determination by encoder\u2013decoder convolutional neural network: application to amyotrophic lateral sclerosis

The objective of this study was to automate the discrimination and quantification of human abdominal body fat compartments into subcutaneous adipose tissue (SAT) and visceral adipose tissue (VAT) from T1-weighted MRI using encoder-decoder convolutional neural networks (CNN) and to apply the algorithm to a diseased patient sample, i.e., patients with amyotrophic lateral sclerosis (ALS). One-hundred-and-fifty-five participants (74 patients with ALS and 81 healthy controls) were split in training (50%), validation (6%), and test (44%) data. SAT and VAT volumes were determined by a novel automated CNN-based algorithm of U-Net like architecture in comparison with an established protocol with semi-automatic assessment as the reference. The dice coefficients between the CNN predicted masks and the reference segmentation were 0.87 ± 0.04 for SAT and 0.64 ± 0.17 for VAT in the control group and 0.87 ± 0.08 for SAT and 0.68 ± 0.15 for VAT in the ALS group. The significantly increased VAT/SAT ratio in the ALS group in comparison to controls confirmed the previous results. In summary, the CNN approach using CNN of U-Net architecture for automated segmentation of abdominal adipose tissue substantially facilitates data processing and offers the opportunity to automatically discriminate abdominal SAT and VAT compartments. Within the research field of neurodegenerative disorders with body composition alterations like ALS, the unbiased analysis of body fat components might pave the way for these parameters as a potential biological marker or a secondary read-out for clinical trials.

MRI Volumetric Analysis of the Thalamus and Hypothalamus in Amyotrophic Lateral Sclerosis.

Background: Increasing evidence has shown that amyotrophic lateral sclerosis (ALS) can result in abnormal energy metabolism and sleep disorders, even before motor dysfunction. Although the hypothalamus and thalamus are important structures in these processes, few ALS studies have reported abnormal MRI structural findings in the hypothalamus and thalamus.Purpose: We aimed to investigate volumetric changes in the thalamus and hypothalamus by using the automatic brain structure volumetry tool AccuBrain®.Methods: 3D T1-weighted magnetization-prepared gradient echo imaging (MPRAGE) scans were acquired from 16 patients with ALS with normal cognitive scores and 16 age-, sex- and education-matched healthy controls. Brain tissue and structure volumes were automatically calculated using AccuBrain®.Results: There were no significant differences in bilateral thalamic (F = 1.31, p = 0.287) or hypothalamic volumes (F = 1.65, p = 0.213) between the ALS and control groups by multivariate analysis of covariance (MANCOVA). Left and right hypothalamic volumes were correlated with whole-brain volume in patients with ALS (t = 3.19, p = 0.036; t = 3.03, p = 0.044), while the correlation between age and bilateral thalamic volumes tended to be significant after Bonferroni correction (t = 2.76, p = 0.068; t = 2.83, p = 0.06). In the control group, left and right thalamic volumes were correlated with whole-brain volume (t = 4.26, p = 0.004; t = 4.52, p = 0.004).Conclusion: Thalamic and hypothalamic volumes did not show differences between patients with normal frontotemporal function ALS and healthy controls, but further studies are still needed.

Motor behavioral abnormalities and histopathological findings in middle aged male Wistar rats inoculated with cerebrospinal fluid from patients with Amyotrophic Lateral Sclerosis

• Middle-aged male rats infused with CSF mimic pathogenic mechanisms observed in ALS. • Infusion of human CSF from patients of ALS causes motor impairment in middle-aged animals. • CSF from patients of ALS is a tool to investigate the characteristics of the disease. Amyotrophic Lateral Sclerosis (ALS) is a progressive neurodegenerative disease associated with loss of upper and lower motor neurons in the primary motor cortex and spinal cord, respectively. Motor deficits are the main clinical features observed in patients with the disease. However, it has been suggested that the presence of neurotoxic factors in the cerebrospinal fluid (CSF) from ALS patients causes loss of motor neurons. The present study investigated the motor and histopathological changes induced by intracerebroventricular (ICV) infusion of CSF from ALS patients in middle aged male Wistar rats. Middle aged male rats were divided into three groups: (1) control group, animals injected with artificial CSF solution; (2) N-ALS group, animals injected with CSF from volunteers without neurological disease; and (3) ALS group, animals inoculated with CFS from a patient with definite ALS. After surgical and infusion procedures, animals were evaluated in different motor tests (grip strength; catalepsy and open field tests). Moreover, animals’ spinal cords were histologically investigated. We observed that ALS-CSF infusion reduced grip strength and led to motor changes and reduction in the number of motor neurons and glial cells in thoracic and lumbar regions of spinal cord. However, CSF N-ALS caused reduction of nerve and glial cells in the thoracic but not in the lumbar region. Our data suggest that ALS-CSF is associated with neurodegenerative mechanisms observed in ALS pathology.

Premorbid personality in frontotemporal dementia: Amyotrophic lateral sclerosis spectrum

AbstractBackgroundFrontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS) are considered two clinical expressions of the same neurodegenerative continuum (FTD‐ALS spectrum) with common underlying pathology and genetics. Patients can present with pure behavioral/cognitive (FTD), pure motor (ALS) or mixed (FTD‐ALS) forms. The factors determining the development of one rather than the other phenotype are unknown. However, it is common observation that patients’ personality traits differ between the phenotypes: ALS patients tend to display a prosocial behavior characterized by kindness and agreeableness. On the opposite, FTD patients frequently present with disinhibition, anti‐social behaviors and lack of empathy. These traits are often described by patients’ relatives as having always characterized the patients’ personality. We therefore aimed at testing if FTD and ALS patients have different premorbid personalities, under the hypothesis that they reflect different vulnerabilities in the brain circuits related to social behavior and motor function, respectively.MethodWe prospectively recruited the patients presenting to our Memory and Motor Neuron Disease Clinics between December 2018‐December 2020. Patients’ personality was assessed through the NEO Personality Inventory 3 (NEO‐PI‐3), which analyses the five main personality factors (Neuroticism, Extraversion, Openness, Agreeableness, Conscientiousness). NEO‐PI‐3 was administered to patients’ caregivers with reference to the patient’s personality at two timepoints: at diagnosis and 15 years prior to symptoms onset. Differences in personality factors between groups at each timepoint were tested with ANOVA.Result46 consecutive patients (30 FTD, 13 ALS, and 3 FTD‐ALS assigned to the FTD or ALS group, based on their first symptom) were recruited. A significant difference in premorbid personality emerged in the Openness domain, showing that ALS patients (mean value 153±15) had been more open to new experience, ideas and emotions than FTD patients (132±21 ‐ p=0.049), even many years before symptoms onset. Such difference in Openness was decreased at the current moment but persisted (147±16 vs 123±24, p= 0.06).Conclusionwe found that premorbid personality profile differed in FTD and ALS patients in at least one personality domain (Openness), supporting the hypothesis that premorbid personality may represent a vulnerability marker to the development of behavioral or motor disturbances. Our finding needs to be further explored with imaging.

Neuron-specific enolase level is a useful biomarker for distinguishing amyotrophic lateral sclerosis from cervical spondylotic myelopathy

The current study aimed to evaluate whether cerebrospinal fluid (CSF) neuron-specific enolase (NSE) levels are elevated in amyotrophic lateral sclerosis (ALS) and are effective in distinguishing ALS from cervical spondylotic myelopathy (CSM). We retrospectively evaluated 45 patients with ALS, 23 with CSM, 28 controls, and 10 with Parkinson’s disease (PD) who underwent analysis of CSF NSE levels. The control group comprised patients aged above 45 years who underwent lumbar puncture because of suspected neurological disorders that were ruled out after extensive investigations. CSF NSE levels were evaluated using the electro-chemiluminescent immunoassay. The ALS group had significantly higher CSF NSE levels than the CSM and control groups (P < 0.001 for both comparisons). The CSM, control, and PD groups did not significantly differ in terms of CSF NSE levels. A receiver-operating characteristic curve analysis was performed to assess the diagnostic value of CSF NSE levels in distinguishing ALS from CSM. The area under the curve for CSF NSE levels was 0.86. The optimal cutoff value was 17.7 ng/mL, with a specificity of 87% and a sensitivity of 80%. Hence, CSF NSE levels are elevated in ALS and are effective in distinguishing ALS from CSM.

Fiber‐specific white matter analysis reflects upper motor neuron impairment in amyotrophic lateral sclerosis

To clarify the relationship between fiber-specific white matter changes in amyotrophic lateral sclerosis (ALS) and clinical signs of upper motor neuron (UMN) involvement, we performed a fixel-based analysis (FBA), a novel framework for diffusion-weighted imaging analysis. We enrolled 96 participants, including 48 nonfamilial ALS patients and 48 age- and sex-matched healthy controls (HCs), in this study and conducted whole-brain FBA and voxel-based morphometry analysis. We compared the fiber density (FD), fiber morphology (fiber cross-section [FC]), and a combined index of FD and FC (FDC) between the ALS and HC groups. We performed a tract-of-interest analysis to extract FD values across the significant regions in the whole-brain analysis. Then, we evaluated the associations between FD values and clinical variables. The bilateral corticospinal tracts (CSTs) and the corpus callosum (CC) showed reduced FD and FDC in ALS patients compared with HCs (p<0.05, familywise error-corrected), and the comparison of FCs revealed no region that was significantly different from another. Voxel-based morphometry showed cortical volume reduction in the regions, including the primary motor area. Clinical scores showed correlations with FD values in the CSTs (UMN score: rho=-0.530, p<0.001; central motor conduction time [CMCT] in the upper limb: rho=-0.474, p=0.008; disease duration: rho=-0.383, p=0.007; ALS Functional Rating Scale-Revised: rho=0.340, p=0.018). In addition, patients whose CMCT was not calculated due to unevoked waves also showed FD reduction in the CSTs. Our findings suggest that FD values in the CST estimated via FBA can be potentially used in evaluating UMN impairments.

Disease duration of progression is helpful in identifying isolated bulbar palsy of amyotrophic lateral sclerosis

BackgroundCompared with typical bulbar onset amyotrophic lateral sclerosis (ALS), isolated bulbar palsy (IBP), an often under-understood variant of ALS, is characterized by symptoms confined to bulbar region for extended periods and relative preservation of limb and ventilation function. To find a cutoff value of disease duration that can distinguish IBP from typical bulbar onset ALS well, the association of survival with disease progression in bulbar onset ALS patients was analyzed.MethodsClinical data of bulbar onset ALS patients were collected from January 2009 to December 2013. The duration from bulbar onset to first significant limb involvement was analyzed by a cutoff point analysis with maximally selected log-rank statistics and dichotomized to categorize patient outcomes. The patients were divided into two groups, the IBP and typical bulbar onset ALS groups, according to the cutoff value. Clinical features were compared.Results115 bulbar onset ALS patients were recruited, and the duration from bulbar onset to first significant limb involvement was associated with survival (P < 0.001). The cutoff duration was 20 months. 19 patients were identified as IBP and 96 patients as typical bulbar onset ALS using 20 months as the cutoff duration. Female was more common, limb weakness was less frequent and pure upper motor neuron (UMN) bulbar signs were more frequent in the IBP group than in the typical bulbar onset ALS group (P = 0.047; P = 0.004; P = 0.031). The median survival time of the IBP group was significantly longer than that of the typical bulbar onset ALS group (64 months and 26 months, respectively; P < 0.001).ConclusionsA cutoff duration of 20 months from bulbar onset to first significant limb involvement may be used to specifically distinguish IBP from typical bulbar onset ALS. IBP was characterized by female predominance, relative preservation of limb function, more pure UMN bulbar signs and a relatively benign prognosis.

Characteristics of serum metabolites in sporadic amyotrophic lateral sclerosis patients based on gas chromatography-mass spectrometry

To identify differential metabolites and metabolic pathways and provide guidance for the novel biomarkers for diagnosis and prognosis of amyotrophic lateral sclerosis (ALS). ALS patients and people without nervous diseases were recruited. Metabolomic analysis was performed using gas chromatography-mass spectrometry (GC/MS). The orthogonal projections to latent structures discriminant analysis (OPLS-DA) were used to identify differential metabolites. Kyoto Encyclopedia of Genes and Genomes and MetaboAnalyst were used to identify metabolic pathways. 75 metabolites were detected and aligned. The OPLS-DA showed the metabolomic profile of ALS patients and those in the fast-progression and slow-progression ALS groups differed from that of CTRL (p < 0.05). The levels of maltose, glyceric acid, lactic acid, beta-alanine, phosphoric acid, glutamic acid, ethanolamine and glycine in ALS were significantly higher, while 2,4,6-tri-tert-butylbenzenethiol was lower. Glycine, serine and threonine metabolism, D-glutamine and D-glutamate metabolism, alanine, aspartate, and glutamate metabolism, beta-alanine metabolism, and pyruvate metabolism were significantly altered metabolic pathways in ALS. ROC was used to discriminate ALS from CTRL with an AUC of 0.898 (p < 0.001) using 2,4,6-tri-tert-butylbenzenethiol, beta-alanine, glycine, and ethanolamine. The serum metabolites and metabolic pathways in ALS patients are significantly altered compared with CTRL. These findings may contribute to the early diagnosis of ALS.

Abnormal Stability of Dynamic Functional Architecture in Amyotrophic Lateral Sclerosis: A Preliminary Resting-State fMRI Study.

Purpose: Static and dynamic analyses for identifying functional connectivity (FC) have demonstrated brain dysfunctions in amyotrophic lateral sclerosis (ALS). However, few studies on the stability of dynamic FC have been conducted among ALS patients. This study explored the change of functional stability in ALS and how it correlates with disease severity.Methods: We gathered resting-state functional magnetic resonance data from 20 patients with ALS and 22 healthy controls (HCs). The disease severity was assessed with the Revised ALS Functional Rating Scale (ALSFRS-R). We used a sliding window correlation approach to identify dynamic FC and measured the concordance of dynamic FC over time to obtain the functional stability of each voxel. We assessed the between-group difference in functional stability by voxel-wise two-sample t-test. The correlation between the functional stability index and ALSFRS-R in ALS patients was evaluated using Spearman's correlation analysis.Results: Compared with the HC group, the ALS group had significantly increased functional stability in the left pre-central and post-central gyrus and right temporal pole while decreased functional stability in the right middle and inferior frontal gyrus. The results revealed a significant correlation between ALSFRS-R and the mean functional stability in the right temporal pole (r = −0.452 and P = 0.046) in the ALS patients.Conclusions: ALS patients have abnormal stability of brain functional architecture, which is associated with the severity of the disease.

Functional Connectivity and Frequency Power Alterations during P300 Task as a Result of Amyotrophic Lateral Sclerosis.

Amyotrophic Lateral Sclerosis (ALS) is one of the most aggressive neurodegenerative diseases and is now recognized as a multisystem network disorder with impaired connectivity. Further research for the understanding of the nature of its cognitive affections is necessary to monitor and detect the disease, so this work provides insight into the neural alterations occurring in ALS patients during a cognitive task (P300 oddball paradigm) by measuring connectivity and the power and latency of the frequency-specific EEG activity of 12 ALS patients and 16 healthy subjects recorded during the use of a P300-based BCI to command a robotic arm. For ALS patients, in comparison to Controls, the results (p < 0.05) were: an increment in latency of the peak ERP in the Delta range (OZ) and Alpha range (PO7), and a decreased power in the Beta band among most electrodes; connectivity alterations among all bands, especially in the Alpha band between PO7 and the channels above the motor cortex. The evolution observed over months of an advanced-state patient backs up these findings. These results were used to compute connectivity- and power-based features to discriminate between ALS and Control groups using Support Vector Machine (SVM). Cross-validation achieved a 100% in specificity and 75% in sensitivity, with an overall 89% success.

Different Tendencies in Muscle Ultrasound Characteristic in Amyotrophic Lateral Sclerosis and Chronic Inflammatory Demyelinating Polyradiculoneuropathy.

The difference in muscle ultrasound (MUS) characteristics in primary axonal degeneration and demyelination has not been well established. The authors aimed to investigate the subject based on the correlation between MUS findings (echo intensity and muscle thickness) and compound muscle action potential (CMAP) amplitude in amyotrophic lateral sclerosis (ALS) and chronic inflammatory demyelinating polyradiculoneuropathy. Fifteen patients with ALS and 16 patients with chronic inflammatory demyelinating polyradiculoneuropathy were examined. For each patient, echo intensity and muscle thickness of the abductor pollicis brevis, abductor digiti minimi, and first dorsal interosseous muscles were investigated. Compound muscle action potential amplitudes were measured by median and ulnar nerve conduction studies. In total, 45 muscles were evaluated in each group. The ALS group showed a linear correlation between the MUS finding and CMAP amplitude (rs = -0.70 and 0.59 for echo intensity and muscle thickness, respectively), whereas the chronic inflammatory demyelinating polyradiculoneuropathy group showed a weaker correlation than the ALS group (rs = -0.32 for echo intensity and rs = 0.34 for muscle thickness). The relationship between MUS abnormalities and CMAP amplitude showed different tendencies in ALS and chronic inflammatory demyelinating polyradiculoneuropathy. The results suggested that MUS abnormalities substantially reflect the muscle function in primary axonal degeneration, whereas a discrepancy between MUS findings and muscle function can be frequently seen in demyelination; specifically, MUS findings tend to be normal even though CMAP showed a reduction. These tendencies originating from underlying pathophysiology should be considered when MUS findings are used as biomarkers of disease severity.

Rate-dependent depression is impaired in amyotrophic lateral sclerosis.

We investigated rate-dependent depression (RDD) of the Hoffman reflex (H-reflex) in patients with amyotrophic lateral sclerosis (ALS), a degenerative disease with ventral horn involvement. In this case-control study, we enrolled 27 patients with ALS and 30 matched healthy control subjects. Clinical and electrophysiological assessments, as well as RDD in response to various stimulation frequencies (0.5Hz, 1Hz, 3Hz and 5Hz), were compared between groups. Multiple clinical and electrophysiological factors were also explored to determine any underlying associations with RDD. The ALS group showed a significant loss of RDD across all frequencies compared to the control group, most notably following 1Hz stimulation (19.1 ± 20.3 vs. 34.0 ± 13.7%, p = 0.003). Among factors that might influence RDD, the enlargement of the motor unit potential (MUP) showed a significant relationship with RDD following multifactor analysis of variance (p = 0.007) and Pearson correlation analysis (ρ = - 0.70, p < 0.001), while various upper motor neuron manifestations were not correlated with RDD values (p > 0.05). We report a loss of RDD in patients with ALS. The strong correlation detected between the RDD deficit and increased MUP suggests that RDD is a sensitive indicator of underlying spinal disinhibition in ALS. ChiCTR2000038848, 10/7/2020 (retrospectively registered), http://www.chictr.org.cn/ .