Amyotrophic Lateral Sclerosis Subjects Research Articles

Elevated caspase 3 activity and cytosolic cytochrome c in NT2 cybrids containing amyotrophic lateral sclerosis subject mtDNA

Apoptosis of motor neurons is an important feature in amyotrophic lateral sclerosis (ALS). A vital role of mitochondria in apoptosis and cell survival is well documented. Eventually mitochondria have shown to be an early target in the pathogenesis of ALS. On account of these facts, we investigated the involvement of mitochondrial-dependent apoptosis in ALS and control (CTR) cybrids, generated fusing human platelets with mitochondrial DNA-depleted NT2-neuroteratocarcinoma cells. After a 6 week selection process during which transferred subject mtDNA repopulated the NT2 cells and restored mitochondrial oxygen consumption, we assessed cell viability and two programmed cell death parameters, caspase 3 activity and cytosolic cytochrome c levels. Compared to the control cybrid lines (n = 5), the ALS cybrid lines (n = 10) showed 45% less XTT reduction and higher caspase 3 activity ( p < 0.05, two-way Student's t test) exhibiting lesser cell viability and execution of apoptosis. Elevated cytosolic cytochrome c levels in ALS cybrid lines (n = 8) than in CTR (n = 4) ( p < 0.05, two-way Student's t-test) indicating its mitochondrial release and initiation of apoptosis. This indicates apoptosis as one of the possible mechanisms of cell death in ALS. Our findings support the view that in ALS, subject's mitochondria are altered in non-degenerating tissues in such a way that intrinsic apoptotic pathway activity is relatively increased.

Gene expression profiling for human iPS-derived motor neurons from sporadic ALS patients reveals a strong association between mitochondrial functions and neurodegeneration.

Amyotrophic Lateral Sclerosis (ALS) is a fatal neurodegenerative disease that leads to widespread motor neuron death, general palsy and respiratory failure. The most prevalent sporadic ALS form is not genetically inherited. Attempts to translate therapeutic strategies have failed because the described mechanisms of disease are based on animal models carrying specific gene mutations and thus do not address sporadic ALS. In order to achieve a better approach to study the human disease, human induced pluripotent stem cell (hiPSC)-differentiated motor neurons were obtained from motor nerve fibroblasts of sporadic ALS and non-ALS subjects using the STEMCCA Cre-Excisable Constitutive Polycistronic Lentivirus system and submitted to microarray analyses using a whole human genome platform. DAVID analyses of differentially expressed genes identified molecular function and biological process-related genes through Gene Ontology. REVIGO highlighted the related functions mRNA and DNA binding, GTP binding, transcription (co)-repressor activity, lipoprotein receptor binding, synapse organization, intracellular transport, mitotic cell cycle and cell death. KEGG showed pathways associated with Parkinson's disease and oxidative phosphorylation, highlighting iron homeostasis, neurotrophic functions, endosomal trafficking and ERK signaling. The analysis of most dysregulated genes and those representative of the majority of categorized genes indicates a strong association between mitochondrial function and cellular processes possibly related to motor neuron degeneration. In conclusion, iPSC-derived motor neurons from motor nerve fibroblasts of sporadic ALS patients may recapitulate key mechanisms of neurodegeneration and may offer an opportunity for translational investigation of sporadic ALS. Large gene profiling of differentiated motor neurons from sporadic ALS patients highlights mitochondrial participation in the establishment of autonomous mechanisms associated with sporadic ALS.

Usefulness of cervical root magnetic stimulation in assessing proximal motor nerve conduction

Objectives: To evaluate the reliability and utility of cervical root magnetic stimulation in exploring proximal motor conduction. Methods: In 20 patients with demyelinating polyneuropathy (DPN), 20 patients with amyotrophic lateral sclerosis (ALS) and 25 healthy subjects, evoked compound muscle action potentials (CMAPs) were recorded from abductor digiti minimi muscle in response to electrical stimulation up to Erb’s point and magnetic stimulation up to the cervical roots. Results: In all healthy and ALS subjects, magnetic root stimulation confirmed the absence of conduction abnormalities, including those in whom supramaximal responses at Erb’s point were not achieved. In the DPN group, conduction block and/or temporal dispersion was revealed by magnetic root stimulation in 9 out of 20 patients (45%), 3 more than those detected at Erb’s point. Conclusions: Cervical root stimulation allowed clear distinction between motor neuronopathy and DPN. It is recommended as part of the routine evaluation of patients suspected of having DPN, especially when distal nerve studies are inconclusive.

Jump from Pre-mutation to Pathologic Expansion in C9orf72

An expanded G4C2 repeat in C9orf72 represents the most common known genetic cause of amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD). However, the lower limit for pathological expansions is unknown (the suggested cutoff is 30 repeats). It has been proposed that the expansion might have occurred only once in human history and subsequently spread throughout the population. However, our present findings support a hypothesis of multiple origins for the expansion. We report a British-Canadian family in whom a ∼70-repeat allele from the father (unaffected by ALS or FTLD at age 89 years) expanded during parent-offspring transmission and started the first generation affected by ALS (four children carry an ∼1,750-repeat allele). Epigenetic and RNA-expression analyses further discriminated the offspring's large expansions (which were methylated and associated with reduced C9orf72 expression) from the ∼70-repeat allele (which was unmethylated and associated with upregulation of C9orf72). Moreover, RNA foci were only detected in fibroblasts from offspring with large expansions, but not in the father, who has the ∼70-repeat allele. All family members with expansions were found to have an ancient known risk haplotype, although it was inherited on a unique 5-Mb genetic backbone. We conclude that small expansions (e.g., 70 repeats) might be considered "pre-mutations" to reflect their propensity to expand in the next generation. Follow-up studies might help explain the high frequency of ALS- or FTLD-affected individuals with an expansion but without a familial history (e.g., 21% among Finnish ALS subjects).

Innervation zones of fasciculating motor units: observations by a linear electrode array.

This study examines the innervation zone (IZ) in the biceps brachii muscle in healthy subjects and those with amyotrophic lateral sclerosis (ALS) using a 20-channel linear electromyogram (EMG) electrode array. Raster plots of individual waveform potentials were studied to estimate the motor unit IZ. While this work mainly focused on fasciculation potentials (FPs), a limited number of motor unit potentials (MUPs) from voluntary activity of 12 healthy and seven ALS subjects were also examined. Abnormal propagation of MUPs and scattered IZs were observed in fasciculating units, compared with voluntarily activated MUPs in healthy and ALS subjects. These findings can be related to muscle fiber reinnervation following motor neuron degeneration in ALS and the different origin sites of FPs compared with voluntary MUPs.

P300-based brain-computer interface (BCI) event-related potentials (ERPs): People with amyotrophic lateral sclerosis (ALS) vs. age-matched controls

ObjectiveBrain-computer interfaces (BCIs) aimed at restoring communication to people with severe neuromuscular disabilities often use event-related potentials (ERPs) in scalp-recorded EEG activity. Up to the present, most research and development in this area has been done in the laboratory with young healthy control subjects. In order to facilitate the development of BCI most useful to people with disabilities, the present study set out to: (1) determine whether people with amyotrophic lateral sclerosis (ALS) and healthy, age-matched volunteers (HVs) differ in the speed and accuracy of their ERP-based BCI use; (2) compare the ERP characteristics of these two groups; and (3) identify ERP-related factors that might enable improvement in BCI performance for people with disabilities. MethodsSixteen EEG channels were recorded while people with ALS or healthy age-matched volunteers (HVs) used a P300-based BCI. The subjects with ALS had little or no remaining useful motor control (mean ALS Functional Rating Scale-Revised 9.4 (±9.5SD) (range 0–25)). Each subject attended to a target item as the items in a 6×6 visual matrix flashed. The BCI used a stepwise linear discriminant function (SWLDA) to determine the item the user wished to select (i.e., the target item). Offline analyses assessed the latencies, amplitudes, and locations of ERPs to the target and non-target items for people with ALS and age-matched control subjects. ResultsBCI accuracy and communication rate did not differ significantly between ALS users and HVs. Although ERP morphology was similar for the two groups, their target ERPs differed significantly in the location and amplitude of the late positivity (P300), the amplitude of the early negativity (N200), and the latency of the late negativity (LN). ConclusionsThe differences in target ERP components between people with ALS and age-matched HVs are consistent with the growing recognition that ALS may affect cortical function. The development of BCIs for use by this population may begin with studies in HVs but also needs to include studies in people with ALS. Their differences in ERP components may affect the selection of electrode montages, and might also affect the selection of presentation parameters (e.g., matrix design, stimulation rate). SignificanceP300-based BCI performance in people severely disabled by ALS is similar to that of age-matched control subjects. At the same time, their ERP components differ to some degree from those of controls. Attention to these differences could contribute to the development of BCIs useful to those with ALS and possibly to others with severe neuromuscular disabilities.

Exposing asymmetric gray matter vulnerability in amyotrophic lateral sclerosis.

Limb weakness in amyotrophic lateral sclerosis (ALS) is typically asymmetric. Previous studies have identified an effect of limb dominance on onset and spread of weakness, however relative atrophy of dominant and non-dominant brain regions has not been investigated. Our objective was to use voxel-based morphometry (VBM) to explore gray matter (GM) asymmetry in ALS, in the context of limb dominance. 30 ALS subjects were matched with 17 healthy controls. All subjects were right-handed. Each underwent a structural MRI sequence, from which GM segmentations were generated. Patterns of GM atrophy were assessed in ALS subjects with first weakness in a right-sided limb (n = 15) or left-sided limb (n = 15). Within each group, a voxelwise comparison was also performed between native and mirror GM images, to identify regions of hemispheric GM asymmetry. Subjects with ALS showed disproportionate atrophy of the dominant (left) motor cortex hand area, irrespective of the side of first limb weakness (p < 0.01). Asymmetric atrophy of the left somatosensory cortex and temporal gyri was only observed in ALS subjects with right-sided onset of limb weakness. Our VBM protocol, contrasting native and mirror images, was able to more sensitively detect asymmetric GM pathology in a small cohort, compared with standard methods. These findings indicate particular vulnerability of dominant upper limb representation in ALS, supporting previous clinical studies, and with implications for cortical organisation and selective vulnerability.

28.: Asymmetry of motor dysfunction in amyotrophic lateral sclerosis: The effect of limb dominance

In amyotrophic lateral sclerosis (ALS), onset and spread of upper (UMN) and lower motor neuron (LMN) dysfunction is typically asymmetric. Our aim was to investigate the relationship between limb dominance and the onset and spread of clinical UMN and LMN dysfunction in ALS, and to further explore any findings using imaging. We initially studied 138 ALS subjects with unilateral and concordant limb dominance, from two tertiary centres. A questionnaire was used to determine the pattern of disease onset and spread. The clinical severity of UMN and LMN signs in each limb was quantified using a validated scoring system. A separate cohort of 15 right-dominant ALS subjects, with onset of limb weakness on the dominant side, were also studied using a voxel-based morphometry asymmetry analysis protocol applied to structural brain MRI, and compared with 15 age and sex-matched controls. Onset of weakness was more likely to occur in the dominant upper limb (p = 0.02). In subjects with initial weakness in a non-dominant limb, spread of weakness was more likely to be to the other limb on that side (p = 0.008). The relative distribution of upper limb UMN signs was affected by whether weakness first occurred on the dominant or non-dominant side (p = 0.03). Compared with matched controls, right-dominant subjects with ALS showed disproportionate loss of gray matter density in the left (dominant) hemisphere hand representation area (p

Wnt and extraocular muscle sparing in amyotrophic lateral sclerosis.

The extraocular muscles (EOM) and their motor neurons are spared in amyotrophic lateral sclerosis (ALS). In limb muscle, axon retraction from the neuromuscular junctions occurs early in the disease. Wnts, a conserved family of secreted signaling molecules, play a critical role in neuromuscular junction formation. This is the first study to examine Wnt signaling for its potential involvement in maintenance of normal morphology in EOM in ALS. Extraocular muscle and limb muscle axons, neuromuscular junctions, and myofibers from control, aging, and ALS subjects and the SOD1(G93A) mouse model of ALS were quantified for their expression of Wnt1, Wnt3a, Wnt5a, Wnt7a, and β-catenin. All four Wnt isoforms were expressed in most axon profiles in all human EOM. Significantly fewer were positive for Wnt1, Wnt3a, and Wnt7a in the human limb muscles. Similar differential patterns in Wnt myofiber expression were also seen except in the case of Wnt7a, where expression was elevated. In the SOD1(G93A) mouse, all four Wnt isoforms were significantly decreased in the neuromuscular junctions at the terminal stage compared to values in age-matched controls. β-Catenin was activated in a subset of myofibers in EOM and limb muscle in all subjects. The differences in expression of Wnts in EOM and limb muscle, particularly at the neuromuscular junction level, suggest that they play a role in the pathophysiology of ALS. Collectively, the data support a role for signaling of Wnts in the preservation of the EOM in ALS and their dysregulation and the subsequent development of pathology in the ALS limb muscles.

Nuclear localization of SMN and FUS is not altered in fibroblasts from patients with sporadic ALS

Sporadic amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease with no established biological marker. Recent observation of a reduced number of gems (survival motor neuron protein (SMN)-positive nuclear bodies) in cells from patients with familial ALS and the mouse models suggests an involvement of SMN in ALS pathology. At a molecular level, fused in sarcoma (FUS), one of the familial ALS-linked proteins, has been demonstrated to directly interact with SMN, while impaired nuclear localization of mutated FUS causes defective gem formation. Our objective was to determine whether gems and/or nuclear FUS levels in skin derived fibroblasts from sporadic ALS patients are consistently reduced and thus could constitute a novel and readily available biomarker of the disease. Fibroblasts from 20 patients and 17 age-matched healthy controls were cultured and co-immunostained for SMN and FUS. Results showed that no difference was detected between the two groups in the number of gems and in expression pattern of FUS. The number of gems negatively correlated with the age at biopsy in both ALS and control subjects. In conclusion, the expression pattern of SMN and FUS in fibroblasts cannot serve as a biomarker for sporadic ALS. Donor age-dependent gem reduction is a novel observation that links SMN with cellular senescence.

Study of motor asymmetry in ALS indicates an effect of limb dominance on onset and spread of weakness, and an important role for upper motor neurons

In amyotrophic lateral sclerosis (ALS), onset and spread of upper motor neuron (UMN) and lower motor neuron (LMN) dysfunction is typically asymmetric. Our aim was to investigate the relationship between limb dominance and the onset and spread of clinical UMN and LMN dysfunction in ALS. We studied 138 ALS subjects with unilateral and concordant limb dominance, from two tertiary centres. A questionnaire was used to determine the pattern of disease onset and spread. The clinical severity of UMN and LMN signs in each limb was quantified using a validated scoring system. Results showed that onset of weakness was more likely to occur in the dominant upper limb (p = 0.02). In subjects with initial weakness in a non-dominant limb, spread of weakness was more likely to be to the other limb on that side (p = 0.008). The relative distribution of upper limb UMN signs was affected by whether weakness first occurred on the dominant or non-dominant side (p = 0.03). These findings support limb dominance as a significant factor underlying onset and spread of ALS, with UMN processes playing an important role. The effect of limb dominance on the presentation of ALS may reflect underlying neuronal vulnerabilities, which become exposed by the disease.

Analysis of smoking and LPO in ALS

Smoking has been suggested as one of the risk factor for amyotrophic lateral sclerosis (ALS) development. In order to investigate whether adverse effects of cigarette smoke in ALS have any association with increase in oxidative stress, disease severity, lipid hydroperoxides (LPO) and superoxide dismutase-1 (SOD1) levels were measured in biofluids of smoker and never smoker ALS patients and clinically correlated. Serum and CSF from sporadic ALS patients (n=50) diagnosed with El Escorial criteria were collected in the study. Serum (n=50) and CSF (n=42) were also collected from normal healthy controls. The LPO levels were estimated using commercially available kits. Enzyme-linked immunosorbent assays (ELISAs) were used to quantitate SOD1. Their levels were further analyzed among smoker and never smoker subjects. Significantly elevated LPO in sera and CSF of ALS patients were observed (p<0.05). There was considerably increased LPO in sera and CSF of smoker ALS subjects matched with disease severity as compared to never smoker ALS (p<0.05). ALS group did not show any alteration in SOD1 when compared to controls (p>0.05). In addition, no change has been observed in SOD1 levels in ALS subjects who smoke (p>0.05). Increased LPO and unaltered SOD1 in ALS patients may suggest the neuro-pathological association of LPO with ALS disease independent of SOD1. With current findings, it may be proposed that LPO levels might constitute as probable biomarker for smoker ALS patients, however, it cannot be concluded without larger gender matched studies. Additional investigations are needed to determine whether LPO upregulation is primary or secondary to motor neuron degeneration in ALS.

Voluntary Contraction Direction Dependence of Motor Unit Number Index in Patients with Amyotrophic Lateral Sclerosis

We investigated the voluntary contraction direction dependence of motor unit number index (MUNIX) for multifunctional muscles in patients with amyotrophic lateral sclerosis (ALS). The MUNIX technique was applied in nine first dorsal interosseous muscles of eight ALS subjects, using surface electromyography (EMG) signals from index finger abduction and flexion, respectively. In seven examined muscles, the MUNIX derived from the index finger abduction mode was smaller than that from the flexion mode. For the remaining two muscles, one had the same MUNIX; the other showed an abduction mode MUNIX much higher than the flexion mode MNUIX. Across all muscles, the median MUNIX was 96 for the index finger abduction mode and 161 for the flexion mode. The findings reveal the dependence of multifunctional muscle MUNIX on voluntary contraction directions in ALS patients. Based on this analysis, we further explored the concept of "multidimensional MUNIX" for an appropriate performance or interpretation of MUNIX in multifunctional muscles of ALS patients. An effort towards such a development was presented using both abduction and flexion mode surface EMG for MUNIX calculation.

Intraspinal neural stem cell transplantation in amyotrophic lateral sclerosis: Phase 1 trial outcomes

ObjectiveThe US Food and Drug Administration–approved trial, “A Phase 1, Open-Label, First-in-Human, Feasibility and Safety Study of Human Spinal Cord-Derived Neural Stem Cell Transplantation for the Treatment of Amyotrophic Lateral Sclerosis, Protocol Number: NS2008-1,” is complete. Our overall objective was to assess the safety and feasibility of stem cell transplantation into lumbar and/or cervical spinal cord regions in amyotrophic lateral sclerosis (ALS) subjects.MethodsPreliminary results have been reported on the initial trial cohort of 12 ALS subjects. Here, we describe the safety and functional outcome monitoring results for the final trial cohort, consisting of 6 ALS subjects receiving 5 unilateral cervical intraspinal neural stem cell injections. Three of these subjects previously received 10 total bilateral lumbar injections as part of the earlier trial cohort. All injections utilized a novel spinal-mounted stabilization and injection device to deliver 100,000 neural stem cells per injection, for a dosing range up to 1.5 million cells. Subject assessments included detailed pre- and postsurgical neurological outcome measures.ResultsThe cervical injection procedure was well tolerated and disease progression did not accelerate in any subject, verifying the safety and feasibility of cervical and dual-targeting approaches. Analyses on outcome data revealed preliminary insight into potential windows of stem cell biological activity and identified clinical assessment measures that closely correlate with ALS Functional Rating Scale-Revised scores, a standard assessment for ALS clinical trials.InterpretationThis is the first report of cervical and dual-targeted intraspinal transplantation of neural stem cells in ALS subjects. This approach is feasible and well-tolerated, supporting future trial phases examining therapeutic dosing and efficacy.

Thinning of cervical nerve roots and peripheral nerves in ALS as measured by sonography

ObjectiveProgressive atrophy and loss of motor axons is a hallmark of amyotrophic lateral sclerosis (ALS). Limited sonographic data are available on potential detection of atrophy of peripheral nerves and nerve roots in ALS. MethodsPatients with either definite or probable ALS and control subjects underwent sonographic evaluation of the cervical roots (C5, C6, and C7) and peripheral nerves (median and ulnar nerves) on the right. These diameters and cross-sectional areas (C6, median, and ulnar nerves) were compared. ResultsThe diameters and cross-sectional areas were consistently smaller in ALS than in controls. No correlation was present between the sonographic parameters and the disease severity, disease duration, age, or gender. The overall sensitivity and specificity tended to be greater in the cervical nerve roots than in the peripheral nerves. ConclusionsThis study shows atrophy of cervical nerve roots and peripheral nerves in ALS detected by sonography. Cervical nerve roots might be more appropriate to detect motor axon loss than peripheral nerves. SignificanceSonographic evaluation of nerve roots and peripheral nerves may be a useful disease marker in ALS to confirm the diagnosis and to potentially monitor the disease progression.

Analysis of surface EMG baseline for detection of hidden muscle activity

Objective. This study explored the feasibility of detecting hidden muscle activity in surface electromyogram (EMG) baseline. Approach. Power spectral density (PSD) analysis and multi-scale entropy (MSE) analysis were used. Both analyses were applied to computer simulations of surface EMG baseline with the presence (representing activity data) or absence (representing reference data) of hidden muscle activity, as well as surface electrode array EMG baseline recordings of healthy control and amyotrophic lateral sclerosis (ALS) subjects. Main results. Although the simulated reference data and the activity data yielded no distinguishable difference in the time domain, they demonstrated a significant difference in the frequency and signal complexity domains with the PSD and MSE analyses. For a comparison using pooled data, such a difference was also observed when the PSD and MSE analyses were applied to surface electrode array EMG baseline recordings of healthy control and ALS subjects, which demonstrated no distinguishable difference in the time domain. Compared with the PSD analysis, the MSE analysis appeared to be more sensitive for detecting the difference in surface EMG baselines between the two groups. Significance. The findings implied the presence of a hidden muscle activity in surface EMG baseline recordings from the ALS subjects. To promote the presented analysis as a useful diagnostic or investigatory tool, future studies are necessary to assess the pathophysiological nature or origins of the hidden muscle activity, as well as the baseline difference at the individual subject level.

Increase of Pyramidal Tract Fractional Anisotropy on MRI after Stem Cell Transplantation in ALS Patients

Background and Purpose: Amyotrophic lateral sclerosis (ALS) is characterized by the selective death of motor neurons. Cortical neuron loss is associated with axonal degeneration along specific white matter tracts. Fractional anisotropy (FA) determined by Magnetic Resonance (MR) might detect integrity or changes in brain white matter pathways. This study was aimed to analyze pyramidal tract changes in ALS patients submitted to stem cell transplantation into the frontal motor cortices. Patients and Methods: Fourteen patients with definite ALS were included. After signing their informed consent, the patients underwent magnetic resonance imaging (MRI). The pyramidal tract (PT) from the corona radiata to medulla oblongata was evaluated by quantitative voxel-wise analysis, including FA and diffusion tensor tractography derived from MR diffusion tensor imaging (MR-DTI) at baseline and 6 months after CD 133+ stem cells transplantation into the frontal motor cortices. FA changes were analyzed with the Tract-Based Spatial Statistics software (FMRIB Software Library, Oxford University). Statistical analyzes among FA before and after stem cells transplantation were performed using the SPSS, v.17. Results: Improvement in FA was observed in the PT of the whole group when compared at baseline with 6 months after stem cell transplantation (p= 0.05). FA significative changes were observed in the PT at the corona radiata (p= 0.05) and internal capsule regions (p= 0.03). FA changes were observed in the PT at the mesencephalic and bulbar regions. However, they were not statistically significant. Conclusions: FA positive changes suggest recovery of the PT in ALS subjects after stem cells transplantation. These changes could possible be explained not only by cell replacement but also by modifications of the extracellular motor neuronal environment, through trophic and neuroprotective effects of stem cells.

VALUES: A National Multicenter Study Demonstrating Gender Differences in Amyotrophic Lateral Sclerosis with Behavioral Impairment

SUMMARY Aim: This study aims to characterize gender-specific behavioral profiles in nondemented amyotrophic lateral sclerosis subjects with behavioral changes (ALSbi). Methods: Caregivers of 106 subjects (53 male) completed an amyotrophic lateral sclerosis standardized clinical interview framed around the Frontal Behavioral Inventory (FBI) structured questionnaire to rate patients on behaviors associated with declines in frontal and temporal self-regulatory capacities. Subjects evaluated evidenced two or more nonoverlapping behavioral symptoms. Inventory items were grouped into disinhibited, apathetic and stereotypic subclasses for between-gender evaluation by independent t-tests and within-gender evaluation by Mann–Whitney U and Spearman rho. Results: Males showed greater disinhibition (p = 0.000), and loss of insight (p = 0.011), jocularity (p = 0.009) and impulsivity (p = 0.005). Females showed significant relationships between personal neglect and indifference (p = 0.000), impulsivity (p = 0.0.013) and jocularity (p = 0.013). Conclusion: Gender differences are evident in ALSbi, characterized by gender-specific loss of social sophistication, and their characterization may allow for better detection of female ALSbi patients, as well as contribute to treatment planning and quality of life for ALSbi patients and their caregivers.

Evaluating noncoding nucleotide repeat expansions in amyotrophic lateral sclerosis

Intermediate-length polyglutamine expansions in ataxin 2 are a risk factor for amyotrophic lateral sclerosis (ALS). The polyglutamine tract is encoded by a trinucleotide repeat in a coding region of the ataxin 2 gene (ATXN2). Noncoding nucleotide repeat expansions in several genes are also associated with neurodegenerative and neuromuscular diseases. For example, hexanucleotide repeat expansions located in a noncoding region of C9ORF72 are the most common cause of ALS. We sought to assess a potential larger role of noncoding nucleotide repeat expansions in ALS. We analyzed the nucleotide repeat lengths of 6 genes (ATXN8, ATXN10, PPP2R2B, NOP56, DMPK, and JPH3) that have previously been associated with neurologic or neuromuscular disorders, in several hundred sporadic patients with ALS and healthy control subjects. We report no association between ALS and repeat length in any of these genes, suggesting that variation in the noncoding repetitive regions in these genes does not contribute to ALS.

Machine Learning for Supporting Diagnosis of Amyotrophic Lateral Sclerosis Using Surface Electromyogram

Needle electromyogram (EMG) is routinely used in clinical neurophysiology for examination of neuromuscular diseases. This study presents a noninvasive surface EMG method for supporting diagnosis of amyotrophic lateral sclerosis (ALS). Three diagnostic markers including the clustering index, the kurtosis of EMG amplitude histogram, and the kurtosis of EMG crossing-rate expansion, were used respectively to characterize surface EMG patterns recorded during different levels of voluntary muscle contraction. We then applied a linear discriminant analysis classifier to discriminate the ALS subjects from the neurologically intact subjects, using the statistics derived from all the three markers as input feature sets to the classifier. The method was tested in 10 ALS subjects and 11 neurologically intact subjects. Combination of the three surface EMG markers achieved 90% diagnostic sensitivity and 100% diagnostic specificity, which were higher than solely using a single surface EMG marker. Given the high diagnostic yield, the proposed surface EMG analysis can be used as a supplement to needle EMG examination in supporting the diagnosis of ALS.