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Estimating survival in amyotrophic lateral sclerosis (ALS) is challenging due to heterogeneity in clinical features of disease and a lack of suitable markers that predict survival. Our aim was to determine whether scoring of upper or lower motor neuron weakness is associated with survival. With this objective, 161 ALS subjects were recruited from two tertiary referral centres. Scoring of upper (UMN) and lower motor neuron (LMN) signs was performed, in addition to a brief questionnaire. Subjects were then followed until the censorship date. Univariate analysis was performed to identify variables associated with survival to either non-invasive ventilation (NIV) or death, which were then further characterized using Cox regression. Results showed that factors associated with reduced survival included older age, bulbar and respiratory involvement and shorter diagnostic delay (all p < 0.05). Whole body LMN score was strongly associated with time to NIV or death (p ≤0.001) whereas UMN scores were poorly associated with survival. In conclusion, our results suggest that, early in disease assessment and in the context of other factors (age, bulbar, respiratory status), the burden of LMN weakness provides an accurate estimate of outcome. Such a scoring system could predict prognosis, and thereby aid in selection of patients for clinical trials.

Objectives: To evaluate differences among patients with different clinical features of ALS, we used our Bayesian method of motor unit number estimation (MUNE)., Methods: We performed serial MUNE studies on 42 subjects who fulfilled the diagnostic criteria for ALS during the course of their illness. Subjects were classified into three subgroups according to whether they had typical ALS (with upper and lower motor neurone signs) or had predominantly upper motor neurone weakness with only minor LMN signs, or predominantly lower motor neurone weakness with only minor UMN signs. In all subjects we calculated the half life of MUs, defined as the expected time for the number of MUs to halve, in one or more of the abductor digiti minimi (ADM), abductor pollicis brevis (APB) and extensor digitorum brevis (EDB) muscles., Results: The mean half life of MUs was less in subjects who had typical ALS with both upper and lower motor neurone signs than in those with predominantly upper motor neurone weakness or predominantly lower motor neurone weakness. In 18 subjects we analysed the estimated size of the MUs and demonstrated the appearance of large MUs in subjects with upper or lower motor neurone predominant weakness. We found that the appearance of large MUs was correlated with the half life of MUs., Conclusions: Patients with different clinical features of ALS have different rates of loss and different sizes of MUs., Significance: These findings could indicate differences in disease pathogenesis., (Copyright © 2012 International Federation of Clinical Neurophysiology. Published by Elsevier Ireland Ltd. All rights reserved.)

Objective: To use our Bayesian method of motor unit number estimation (MUNE) to evaluate lower motor neuron degeneration in ALS., Methods: In subjects with ALS we performed serial MUNE studies. We examined the repeatability of the test and then determined whether the loss of MUs was fitted by an exponential or Weibull distribution., Results: The decline in motor unit (MU) numbers was well-fitted by an exponential decay curve. We calculated the half life of MUs in the abductor digiti minimi (ADM), abductor pollicis brevis (APB) and/or extensor digitorum brevis (EDB) muscles. The mean half life of the MUs of ADM muscle was greater than those of the APB or EDB muscles. The half-life of MUs was less in the ADM muscle of subjects with upper limb than in those with lower limb onset., Conclusions: The rate of loss of lower motor neurons in ALS is exponential, the motor units of the APB decay more quickly than those of the ADM muscle and the rate of loss of motor units is greater at the site of onset of disease., Significance: This shows that the Bayesian MUNE method is useful in following the course and exploring the clinical features of ALS., (Copyright © 2012 International Federation of Clinical Neurophysiology. Published by Elsevier Ireland Ltd. All rights reserved.)

ALS is a fatal disease with variable clinical course. There is no single reliable marker of disease progression. Sufficient records were available to study the case history of four family members with the uncommon G93V SOD1 mutation. Distal lower motor neuron (LMN) involvement occurred in all family members with onset from 30 to 51 years of age, with progression over more than six years. Between 2002 and 2009, we used electrophysiology as a biomarker to study disease progression in one patient, assessing the number of motor units in three nerves from different limbs. The loss of motor units showed an exponential decline with different half-lives in different nerves. Diffusion tractography was compared with a control to assess upper motor neuron (UMN) involvement and showed asymmetric evidence of abnormalities of the corticospinal tracts, providing evidence of central involvement despite the absence of UMN signs.

We have developed a new method of motor unit number estimation (MUNE) for assessing diseases such as amyotrophic lateral sclerosis (ALS). We used data from the whole stimulus-response curve and then performed a Bayesian statistical analysis. The Bayesian method uses mathematical equations that express the basic elements of motor unit activation after electrical stimulation and allows for the sources of variability and uncertainty in this formulation. The Bayesian MUNE method was used to determine the most probable number of motor units in 8 normal subjects, 49 ALS subjects, and 3 subjects with progressive lower motor neuron (LMN) weakness. In normals the number of motor units was calculated to be 75-85 in hand and 40-58 in foot muscles. In ALS subjects the number of motor units per muscle was less than in normal subjects. In 17 ALS subjects and 3 subjects with LMN weakness the median, ulnar, or peroneal nerve was studied on repeated occasions over an average of 189 days (range 63-1,071) and the number of motor units progressively declined, with a half-life ranging from 62-834 days. The results of our MUNE technique were reproducible on replicate studies. A Bayesian statistical MUNE method is a new approach that can be used to study ALS patients serially for assessment and treatment trials.

All muscle contractions are dependent on the functioning of motor units. In diseases such as amyotrophic lateral sclerosis (ALS), progressive loss of motor units leads to gradual paralysis. A major difficulty in the search for a treatment for these diseases has been the lack of a reliable measure of disease progression. One possible measure would be an estimate of the number of surviving motor units. Despite over 30 years of motor unit number estimation (MUNE), all proposed methods have been met with practical and theoretical objections. Our aim is to develop a method of MUNE that overcomes these objections. We record the compound muscle action potential (CMAP) from a selected muscle in response to a graded electrical stimulation applied to the nerve. As the stimulus increases, the threshold of each motor unit is exceeded, and the size of the CMAP increases until a maximum response is obtained. However, the threshold potential required to excite an axon is not a precise value but fluctuates over a small range leading to probabilistic activation of motor units in response to a given stimulus. When the threshold ranges of motor units overlap, there may be alternation where the number of motor units that fire in response to the stimulus is variable. This means that increments in the value of the CMAP correspond to the firing of different combinations of motor units. At a fixed stimulus, variability in the CMAP, measured as variance, can be used to conduct MUNE using the "statistical" or the "Poisson" method. However, this method relies on the assumptions that the numbers of motor units that are firing probabilistically have the Poisson distribution and that all single motor unit action potentials (MUAP) have a fixed and identical size. These assumptions are not necessarily correct. We propose to develop a Bayesian statistical methodology to analyze electrophysiological data to provide an estimate of motor unit numbers. Our method of MUNE incorporates the variability of the threshold, the variability between and within single MUAPs, and baseline variability. Our model not only gives the most probable number of motor units but also provides information about both the population of units and individual units. We use Markov chain Monte Carlo to obtain information about the characteristics of individual motor units and about the population of motor units and the Bayesian information criterion for MUNE. We test our method of MUNE on three subjects. Our method provides a reproducible estimate for a patient with stable but severe ALS. In a serial study, we demonstrate a decline in the number of motor unit numbers with a patient with rapidly advancing disease. Finally, with our last patient, we show that our method has the capacity to estimate a larger number of motor units.

Background: Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease characterized by loss of upper and lower motor neurons. There is a need for an imaging biomarker to track disease progression. Previously, magnetic resonance imaging (MRI) has shown loss of grey and white matter in the brain of patients with ALS compared to controls. We performed serial diffusion tractography imaging (DTI) study of patients with ALS looking for changes over time. Methods: On all subjects (n = 15), we performed three MRI studies at 6 month intervals. DTI changes were assessed with tract-based spatial statistics (TBSS) and region of interest (ROI) studies. Cortic-spinal tract (CST) was selected for our ROI at the upper level; the posterior limb of internal capsule (PLIC), and a lower level in the pons. Results: There was no significant change in DTI measures over 12 months of observation. Better correlation of manual and atlas-based ROI methods was found in the posterior limb of the internal capsule than the pons. Conclusion: While previous DTI studies showed significant differences between ALS subjects and controls, within individual subjects there is little evidence of progression over 12 months. This suggests that DTI is not a suitable biomarker to assess disease progression in ALS. [ABSTRACT FROM AUTHOR]

Amyotrophic lateral sclerosis (ALS) is a severe neurodegenerative disease that is defined by loss of upper and lower motor neurons, associated with accumulation of protein aggregates in cells. There is also pathology in extra-motor areas of the brain, Possible causes of cell death include failure to deal with the aggregated proteins, glutamate toxicity and mitochondrial failure. ALS also involves abnormalities of metabolism and the immune system, including neuroinflammation in the brain and spinal cord. Strikingly, there are also abnormalities of the peripheral immune system, with alterations of T lymphocytes, monocytes, complement and cytokines in the peripheral blood of patients with ALS. The precise contribution of the peripheral immune system in ALS pathogenesis is an active area of research. Although some trials of immunomodulatory agents have been negative, there is strong preclinical evidence of benefit from immune modulation and further trials are currently underway. Here, we review the emerging evidence implicating peripheral immune alterations contributing to ALS, and their potential as future therapeutic targets for clinical intervention. [ABSTRACT FROM AUTHOR]

The motor unit comprises the anterior horn cell, its axon, and the muscle fibers that it innervates. Although the true number of motor units is unknown, the number of motor units appears to vary greatly between different muscles and between different individuals. Assessment of the number and function of motor units is needed in diseases of the anterior horn cell and other motor nerve disorders. Amyotrophic lateral sclerosis is the most important disease of anterior horn cells. The need for an effective biomarker for assessing disease progression and for use in clinical trials in amyotrophic lateral sclerosis has stimulated the study of methods to measure the number of motor units. Since 1970 a number of different methods, including the incremental, F-wave, multipoint, and statistical methods, have been developed but none has achieved widespread applicability. Two methods (MUNIX and the multipoint incremental method) are in current use across multiple centres and are discussed in detail in this review, together with other recently published methods. Imaging with magnetic resonance and ultrasound is increasingly being applied to this area. Motor unit number estimates have also been applied to other neuromuscular diseases such as spinal muscular atrophy, compression neuropathies, and prior poliomyelitis. The need for an objective measure for the assessment of motor units remains tantalizingly close but unfulfilled in 2016. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

The key pathological feature in ALS is death of motor neurones from the brain and spinal cord, but the molecular mechanisms underlying this degeneration remain unknown. Quantifying the motor cortex proteome in autopsy brain and comparing tissues from ALS cases and non-ALS controls is critical to understanding these mechanisms. We used Sequential Window Acquisition of All Theoretical Mass Spectra (SWATH-MS) to characterize the proteomes of the motor cortex from ALS cases (n = 8) and control subjects (n = 8). A total of 1427 proteins were identified at a critical local false discovery rate < 5%; 187 of these exhibited significant expression differences between ALS cases and controls. Of these, 91 proteins were significantly upregulated and 96 proteins were significantly downregulated. Bioinformatics analysis revealed that these proteins are involved in molecular transport, protein trafficking, free radical scavenging, lipid metabolism, cell death and survival, nucleic acid metabolism, inflammatory response or amino acid metabolism and carbohydrate metabolism. Differentially expressed proteins were subjected to pathway analysis. This revealed abnormalities in pathways involving mitochondrial function, sirtuin signaling, oxidative phosphorylation, glycolysis, phagosome maturation, SNARE signaling, redox regulation and several others. Core analysis revealed mitochondrial dysfunction to be the top canonical pathway. The top-enriched networks involved JNK activation and inhibition of AKT signaling, suggesting that disruption of these signaling pathways could lead to demise of motor neurons in the ALS motor cortex. • The top canonical pathway involved mitochondrial function, with many dysregulated proteins localised to complex I. • Perturbation in phagosome maturation and SNARE signaling are also likely to play fundamental roles in the aetiology of ALS. • Top enriched networks involved activation of JNK and inhibition of AKT signaling. • We identify pathways known to be perturbed in ALS and uncover novel players that present interest for further investigation. [ABSTRACT FROM AUTHOR]

Heat shock protein beta-1 (HSPB1) is a ubiquitously expressed molecular chaperone that is important in protecting cells against cellular injury. Mutations in this protein are known to cause autosomal dominant hereditary distal axonal neuropathies, including Charcot Marie Tooth disease type 2F (CMT2F) and distal hereditary motor neuropathy (dHMN). However, patients with HSPB1 mutations have also been described with upper motor neuron signs. We present five patients with mutations in HSPB1 who presented with a range of clinical phenotypes related to different patterns of motor neuron dysfunction. Three of these mutations have not been previously reported. Patients were seen at our neuromuscular or amyotrophic lateral sclerosis (ALS) clinics. Gene sequencing was carried out as part of diagnostic investigations. Detailed clinical and electrophysiologic data was collected. Five patients had variants of HSPB1. Three patients had a hereditary length-dependent sensori-motor axonal neuropathy consistent with Charcot Marie Tooth type 2 (CMT2); two of these patients carried novel mutations in the C-terminal region (p.Glu186* and p.Pro170Thr). One patient had the clinical picture of ALS and a novel missense mutation (p.Arg27Leu) in the N-terminal region. Another patient had the phenotype of hereditary spastic paraparesis (HSP) associated with a missense mutation (p.Gly84Arg) already described in families with CMT or dHMN. This study describes three novel mutations of HSPB1 and describes two patients with upper motor neurone signs associated with HSPB1 mutations. • The phenotype associated with mutations of HSPB1 could be wider than previously reported. • A novel variant of HSPB1 was identified in two patients with Charcot Marie Tooth type 2 (CMT2) disease. • A novel variant of HSPB1 was identified in one patient with amyotrophic lateral sclerosis (ALS). • Mutation of HSPB1 was identified in one patient with hereditary spastic paraparesis (HSP). [ABSTRACT FROM AUTHOR]