Studies Of Amyotrophic Lateral Sclerosis Patients Research Articles

Cognitive impairment is associated with gait variability and fall risk in Amyotrophic Lateral Sclerosis.

In amyotrophic lateral sclerosis (ALS), gait abnormalities contribute to poor mobility and represent a relevant risk for falls. To date, gait studies in ALS patients focused on the motor dimension of the disease, underestimating the cognitive aspects. Using a wearable gait analysis device, we compared gait patterns in ambulatory ALS patients with Mild Cognitive Impairment (ALS MCI+; n=18), and without MCI (ALS MCI-; n=24), and healthy individuals (HS; n=16) under two conditions: (1) normal gait (single task), (2) walking while counting backward (dual task). Finally, we examined if the occurrence and number of falls in the three months following the baseline test were related to cognition. In the single task condition, ALS patients, regardless of cognition, displayed higher gait variability than HS, especially for stance and swing time (p< 0.001). The dual task condition revealed additional differences in gait variability parameters between ALS MCI+ and ALS MCI- for cadence (p=0.005), stance time (p=0.04), swing time (p=0.04) and stability index (p=0.02). Moreover, ALS MCI+ showed a higher occurrence (p=0.001) and number of falls (p<0.001) at the follow-up. Regression analyses demonstrated that MCI condition predicted the occurrence of future falls (β= 3.649 p= 0.01) and, together with executive dysfunction, was associated with the number of falls (cognitive impairment: β= 0.63; p < 0.001; executive dysfunction: β= 0.39; p= 0.03), regardless of motor impairment at clinical examination. In ALS, MCI is associated with exaggerated gait variability and predicts the occurrence and number of short-term falls. This article is protected by copyright. All rights reserved.

Evidence of Metabolic Dysfunction in Amyotrophic Lateral Sclerosis (ALS) Patients and Animal Models.

Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease that affects motor neurons, leading to muscle weakness, paralysis, and eventual death. Research from the past few decades has appreciated that ALS is not only a disease of the motor neurons but also a disease that involves systemic metabolic dysfunction. This review will examine the foundational research of understanding metabolic dysfunction in ALS and provide an overview of past and current studies in ALS patients and animal models, spanning from full systems to various metabolic organs. While ALS-affected muscle tissue exhibits elevated energy demand and a fuel preference switch from glycolysis to fatty acid oxidation, adipose tissue in ALS undergoes increased lipolysis. Dysfunctions in the liver and pancreas contribute to impaired glucose homeostasis and insulin secretion. The central nervous system (CNS) displays abnormal glucose regulation, mitochondrial dysfunction, and increased oxidative stress. Importantly, the hypothalamus, a brain region that controls whole-body metabolism, undergoes atrophy associated with pathological aggregates of TDP-43. This review will also cover past and present treatment options that target metabolic dysfunction in ALS and provide insights into the future of metabolism research in ALS.

Hypometabolic and hypermetabolic brain regions in patients with ALS-FTD show distinct patterns of grey and white matter degeneration: A pilot multimodal neuroimaging study

BackgroundUp to 50% of amyotrophic lateral sclerosis (ALS) patients develop some degree of cognitive dysfunction and a small proportion of these develop frontotemporal dementia (FTD). Non-invasive techniques of magnetic resonance imaging (MRI) and [18F]-fluoro-2-deoxy-d-glucose (18F-FDG) positron emission tomography (PET) have demonstrated structural and metabolic abnormalities, respectively, in the brains of such patients with ALS-FTD. Although initial 18F-FDG PET studies in ALS patients showed only hypometabolism of motor and extramotor brain regions, subsequent studies have demonstrated hypermetabolic changes as well. Such contrasting findings prompted us to hypothesize that hypo- and hypermetabolic brain regions in ALS-FTD patients are associated with divergent degeneration of structural grey matter (GM) and white matter (WM). MethodsCerebral glucose metabolic rate (CMRglc), cortical thickness (CT), fractal dimension (FD), and graph theory WM network analyses were performed on clinical MRI and 18F-FDG PET images from 8 ALS-FTD patients and 14 neurologic controls to explore the relationship between GM-WM degeneration and hypo- and hypermetabolic brain regions. ResultsCMRglc revealed significant hypometabolism in frontal and precentral gyrus brain regions, with hypermetabolism in temporal, occipital and cerebellar regions. Cortical thinning was noted in both hypo- and hypermetabolic brain areas. Unlike CT, FD did not reveal widespread GM degeneration in hypo- and hypermetabolic brain regions of ALS-FTD patients. Graph theory analysis showed severe WM degeneration in hypometabolic but not hypermetabolic areas, especially in the right hemisphere. ConclusionOur multimodal MRI-PET study provides insights into potentially differential pathophysiological mechanisms between hypo- and hypermetabolic brain regions of ALS-FTD patients.

Tocilizumab is safe and tolerable and reduces C-reactive protein concentrations in the plasma and cerebrospinal fluid of ALS patients.

We tested safety, tolerability, and target engagement of tocilizumab in amyotrophic lateral sclerosis (ALS) patients. Twenty-two participants, whose peripheral blood mononuclear cell (PBMC) gene expression profile reflected high messenger ribonucleic acid (mRNA) expression of inflammatory markers, were randomized 2:1 to three tocilizumab or placebo treatments (weeks 0, 4, and 8; 8mg/kg intravenous). Participants were followed every 4wk in a double-blind fashion for 16 wk and assessed for safety, tolerability, plasma inflammatory markers, and clinical measures. Cerebrospinal fluid (CSF) was collected at baseline and after the third treatment. Participants were genotyped for Asp358 Ala polymorphism of the interleukin 6 receptor (IL-6R) gene. Baseline characteristics, safety, and tolerability were similar between treatment groups. One serious adverse event was reported in the placebo group; no deaths occurred. Mean plasma C-reactive protein (CRP) level decreased by 88% in the tocilizumab group and increased by 4% in the placebo group (-3.0-fold relative change, P < .001). CSF CRP reduction (-1.8-fold relative change, P=.01) was associated with IL-6R C allele count. No differences in PBMC gene expression or clinical measures were observed between groups. Tocilizumab treatment was safe and well tolerated. PBMC gene expression profile was inadequate as a predictive or pharmacodynamic biomarker. Treatment reduced CRP levels in plasma and CSF, with CSF effects potentially dependent on IL-6R Asp358 Ala genotype. IL-6 trans-signaling may mediate a distinct central nervous system response in individuals inheriting the IL-6R C allele. These results warrant further study in ALS patients where IL-6R genotype and CRP levels may be useful enrichment biomarkers.

Hippocampal subfield and anterior-posterior segment volumes in patients with sporadic amyotrophic lateral sclerosis

Neuroimaging studies of hippocampal volumes in patients with amyotrophic lateral sclerosis (ALS) have reported inconsistent results. Our aims were to demonstrate that such discrepancies are largely due to atrophy of different regions of the hippocampus that emerge in different disease stages of ALS and to explore the existence of co-pathology in ALS patients. We used the well-validated King’s clinical staging system for ALS to classify patients into different disease stages. We investigated in vivo hippocampal atrophy patterns across subfields and anterior-posterior segments in different King’s stages using structural MRI in 76 ALS patients and 94 health controls (HCs). The thalamus, corticostriatal tract and perforant path were used as structural controls to compare the sequence of alterations between these structures and the hippocampal subfields. Compared with HCs, ALS patients at King’s stage 1 had lower volumes in the bilateral posterior subiculum and presubiculum; ALS patients at King’s stage 2 exhibited lower volumes in the bilateral posterior subiculum, left anterior presubiculum and left global hippocampus; ALS patients at King’s stage 3 showed significantly lower volumes in the bilateral posterior subiculum, dentate gyrus and global hippocampus. Thalamic atrophy emerged at King’s stage 3. White matter tracts remained normal in a subset of ALS patients. Our study demonstrated that the pattern of hippocampal atrophy in ALS patients varies greatly across King’s stages. Future studies in ALS patients that focus on the hippocampus may help to further clarify possible co-pathologies in ALS.

MicroRNAs in amyotrophic lateral sclerosis: from pathogenetic involvement to diagnostic biomarker and therapeutic agent development.

MicroRNAs (miRNAs) are a class of endogenous non-coding small single-stranded RNAs that are 21-25 nucleotides (NTs) in length and participate in post-transcriptional gene regulation. Studies have shown that miRNA dysfunction plays a critical role in the occurrence and development of a variety of nervous system diseases, including neurodegenerative diseases. Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease with an unclear etiology and is characterized by the selective invasion of motor neurons in the brain and spinal cord. Symptoms can range from mild spasms in the limbs or medulla oblongata muscles to paralysis in almost all skeletal muscles. The role of miRNAs in the pathogenesis, diagnosis, and treatment of ALS has become of greater importance to those studying ALS. In this review, we reviewed experimentally confirmed miRNAs shown to be involved in the pathogenesis of ALS and that are used as diagnostic biomarkers or therapeutic ALS agents. At present, there are at least 20-30 genes clearly related to the pathogenesis of ALS. Multiple miRNAs have been reported in different pathogenic gene models. MiRNAs could be used as biomarkers for the diagnosis of ALS; the differential expression of some miRNAs could be related to ALS prognosis. As therapeutic agents, miRNAs are still in the exploratory stage. Although encouraging results have been achieved using animal models, much research is still needed before clinical trials can ensue. However, with additional miRNA studies in ALS patients and animal models, the pathogenesis, early diagnosis, and therapy of ALS should be elucidated.

Low 25OH Vitamin D Blood Levels Are Independently Associated With Higher Amyotrophic Lateral Sclerosis Severity Scores: Results From a Prospective Study.

Background: Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disorder characterized by progressive degeneration of upper and lower motor neurons. Prognosis is highly variable, ranging from few months to more than 30 years. 25OH vitamin D (25OH VD) blood levels have been associated with worse prognosis of ALS, but these results remain in dispute. We addressed this controversy with a prospective study and multivariate analysis to study the influence of known clinical prognostic factors of the disease and 25OH VD levels on Revised Amyotrophic Lateral Sclerosis Functional Rating Scale (ALSFRS-R) severity score (ALS-SS), as defined by the monthly rate of decline of ALSFRS-R score, to identify the factors most closely linked to the risk of worsening of the disease.Results:This prospective cohort of ALS patients recruited 127 individuals, and 105 of them met inclusion criteria. Mean age of onset was 62.2 ± 12.1 years, 32% of subjects had bulbar onset, and gender ratio was 1.44 (male/female). Mean 25OH VD level was 26.8 ± 10.8 ng/ml and was similar between males and females. Patients with 25OH VD levels <15 ng/ml had significantly higher ALS-SS at inclusion (ALS-SSi) than those with normal levels (>30 ng/ml), p = 0.011. The study of ALS-SS as calculated at the end of follow-up (ALS-SSe) was not found correlated to initial 25OH VD levels (r = −0.19; p = 0.084). Univariate analysis showed that ALS-SSe correlated with 25OH VD levels, ALS duration at inclusion, slow vital capacity (SVC) at inclusion, and SVC loss. Multivariate model showed that 25OH VD levels were independently associated with ALS-SSe: r = −0.0125, p = 0.033. Log rank test with Kaplan–Meier curves did not show significant differences of survival between the groups defined by 25OH VD levels: <15, >15 and <30, and > 30 ng/ml, p = 0.88.Conclusions: This prospective study in ALS patients confirmed previous retrospective results: ALS-SSi is significantly higher in patients with severe VD deficiency. For the first time, multivariate analysis showed that 25OH VD level was an independent prognostic factor correlated to ALS-SSe, suggesting that discrepancies between previous works could be due to confounders. It would be important that the present work be replicated in larger samples to confirm the present findings.

CuII (atsm) inhibits ferroptosis: Implications for treatment of neurodegenerative disease.

Diacetyl-bis(4-methyl-3-thiosemicarbazonato)copperII (CuII (atsm)) ameliorates neurodegeneration and delays disease progression in mouse models of amyotrophic lateral sclerosis (ALS) and Parkinson's disease (PD), yet the mechanism of action remains uncertain. Promising results were recently reported for separate Phase 1 studies in ALS patients and PD patients. Affected tissue in these disorders shares features of elevated Fe, low glutathione and increased lipid peroxidation consistent with ferroptosis, a novel form of regulated cell death. We therefore evaluated the ability of CuII (atsm) to inhibit ferroptosis. Ferroptosis was induced in neuronal cell models by inhibition of glutathione peroxidase-4 activity with RSL3 or by blocking cystine uptake with erastin. Cell viability and lipid peroxidation were assessed and the efficacy of CuII (atsm) was compared to the known antiferroptotic compound liproxstatin-1. CuII (atsm) protected against lipid peroxidation and ferroptotic lethality in primary and immortalised neuronal cell models (EC50 : ≈130 nM, within an order of magnitude of liproxstatin-1). NiII (atsm) also prevented ferroptosis with similar potency, whereas ionic CuII did not. In cell-free systems, CuII (atsm) and NiII (atsm) inhibited FeII -induced lipid peroxidation, consistent with these compounds quenching lipid radicals. The antiferroptotic activity of CuII (atsm) could therefore be the disease-modifying mechanism being tested in ALS and PD trials. With potency in vitro approaching that of liproxstatin-1, CuII (atsm) possesses favourable properties such as oral bioavailability and entry into the brain that make it an attractive investigational product for clinical trials of ferroptosis-related diseases.

Biological Significance of microRNA Biomarkers in ALS-Innocent Bystanders or Disease Culprits?

MicroRNAs (miRNAs) represent potential biomarkers for neurodegenerative disorders including amyotrophic lateral sclerosis (ALS). However, whether expression changes of individual miRNAs are simply an indication of cellular dysfunction and degeneration, or actually promote functional changes in target gene expression relevant to disease pathogenesis, is unclear. Here we used bioinformatics to test the hypothesis that ALS-associated miRNAs exert their effects through targeting genes implicated in disease etiology. We documented deregulated miRNAs identified in studies of ALS patients, noting variations in participants, tissue samples, miRNA detection or quantification methods used, and functional or bioinformatic assessments (if performed). Despite lack of experimental standardization, overlap of many deregulated miRNAs between studies was noted; however, direction of reported expression changes did not always concur. The use of in silico predictions of target genes for the most commonly deregulated miRNAs, cross-referenced to a selection of previously identified ALS genes, did not support our hypothesis. Specifically, although deregulated miRNAs were predicted to commonly target ALS genes, random miRNAs gave similar predictions. To further investigate biological patterns in the deregulated miRNAs, we grouped them by tissue source in which they were identified, indicating that for a core of frequently detected miRNAs, blood/plasma/serum may be useful for future profiling experiments. We conclude that in silico predictions of gene targets of deregulated ALS miRNAs, at least using currently available algorithms, are unlikely to be sufficient in informing disease pathomechanisms. We advocate experimental functional testing of candidate miRNAs and their predicted targets, propose miRNAs to prioritise, and suggest a concerted move towards protocol standardization for biomarker identification.

Phosphorylated TDP-43 (pTDP-43) aggregates in the axial skeletal muscle of patients with sporadic and familial amyotrophic lateral sclerosis

Muscle atrophy with weakness is a core feature of amyotrophic lateral sclerosis (ALS) that has long been attributed to motor neuron loss alone. However, several studies in ALS patients, and more so in animal models, have challenged this assumption with the latter providing direct evidence that muscle can play an active role in the disease. Here, we examined the possible role of cell autonomous pathology in 148 skeletal muscle samples from 57 ALS patients, identifying phosphorylated TAR DNA-binding protein (pTDP-43) inclusions in the muscle fibers of 19 patients (33.3%) and 24 tissue samples (16.2% of specimens). A muscle group-specific difference was identified with pTDP-43 pathology being significantly more common in axial (paraspinous, diaphragm) than appendicular muscles (P = 0.0087). This pathology was not significantly associated with pertinent clinical, genetic (c9ALS) or nervous system pathologic data, suggesting it is not limited to any particular subgroup of ALS patients. Among 25 non-ALS muscle samples, pTDP-43 inclusions were seen only in the autophagy-related disorder inclusion body myositis (IBM) (n = 4), where they were more diffuse than in positive ALS samples (P = 0.007). As in IBM samples, pTDP-43 aggregates in ALS were p62/ sequestosome-1-positive, potentially indicating induction of autophagy. Phospho-TDP-43-positive ALS and IBM samples also showed significant up-regulation of TARDBP and SQSTM1 expression. These findings implicate axial skeletal muscle as an additional site of pTDP-43 pathology in some ALS patients, including sporadic and familial cases, which is deserving of further investigation.

VITALITY-ALS, a phase III trial of tirasemtiv, a selective fast skeletal muscle troponin activator, as a potential treatment for patients with amyotrophic lateral sclerosis: study design and baseline characteristics

Objective: To assess the efficacy of tirasemtiv, a fast skeletal muscle troponin activator, vs. placebo on respiratory function and other functional measures in patients with amyotrophic lateral sclerosis (ALS). This study was designed to confirm and extend results from a large phase IIb trial and maximize tolerability with a slower dose escalation. Methods: VITALITY-ALS (NCT02496767) was a multinational, double-blind, randomized, placebo-controlled, parallel-group study in ALS patients. Participants who tolerated two weeks of open-label tirasemtiv (125 mg twice a day) were randomized 3:2:2:2 to placebo or one of three target total daily dose levels of tirasemtiv (250, 375, or 500 mg). Participants randomized to tirasemtiv escalated their dose every two weeks to their target dose level or maximum tolerated dose. The primary outcome measure was change in slow vital capacity from baseline to 24 weeks. Secondary endpoints assessed the effect of tirasemtiv on muscle strength and certain respiratory milestones of disease progression. A four-week randomized withdrawal phase followed 48 weeks of treatment to evaluate the possibility of sustained benefit or rebound decline. Results: Data collection will be complete in the fourth quarter of 2017. Conclusions: VITALITY-ALS was a phase III trial designed to evaluate the efficacy, safety, and tolerability of tirasemtiv in ALS.

The evolution of motor cortical dysfunction in amyotrophic lateral sclerosis.

The present study aimed to investigate alterations in cortical function in amyotrophic lateral sclerosis (ALS) related to disease progression. In total, clinical assessments were evaluated in 189 ALS patients, combined with assessment of cortical function utilising threshold tracking transcranial magnetic stimulation. Results were compared with disease stage. Disease stage was defined in three ways: (1) as a proportion of disease duration in deceased patients; (2) from the time of ALS onset; and (3) using the ALS rating scale-revised (ALSFRS-R). Prospective studies in ALS patients demonstrated decreased neurophysiological index (p<0.0001) and decreased compound muscle action potential (CMAP) (p<0.0001), combined with abnormalities of central function including prolonged central motor conduction time (CMCT) (p<0.05), increased motor evoked potential/CMAP amplitude ratio (p<0.0001) and decreased short interval intracortical inhibition (SICI) (p<0.001). SICI at 3ms (p<0.05, β=-0.21) and averaged SICI (p<0.05, β=-0.21) decreased with disease progression, measured using proportion of disease duration. Alternatively, using time from disease onset, CMCT prolonged with disease progression (p<0.01, β=0.25), while ALSFRS-R decline correlated with decreased SICI at 3ms (p<0.01, β=0.20). Clinical measures combined with assessment of cortical function established that SICI decreased with disease progression. These findings may suggest dysfunction of inhibitory interneurons with disease progression.

Prognostic factors for survival in patients with amyotrophic lateral sclerosis: analysis of a multi-centre clinical trial

Information regarding factors influencing prognosis and quality of life (QoL) in patients with amyotrophic lateral sclerosis (ALS) is useful for clinicians and also for patients and their carers. The aims of this study are to identify prognostic factors for survival in ALS and to determine the physical factors influencing QoL. This study is a retrospective analysis of a cohort of 512 patients who participated in a phase II/III clinical trial of olesoxime. Cox multivariate regression analysis found older age, bulbar onset disease, low baseline forced vital capacity, low baseline manual muscle test (MMT) scores and a shorter diagnostic delay to be independently associated with poor survival outcome. Physical factors shown to have the strongest correlation with poor QoL were low weight and a reduced ability to climb stairs. Therapeutic interventions including gastrostomy and non-invasive ventilation had no positive impact on QoL in this cohort. The prognostic factors for survival identified here are consistent with other studies of ALS patients, with the additional identification of baseline MMT score as another predictor of prognosis. Furthermore, the correlation between both weight and poor lower limb function with QoL is novel and underlines the importance of careful nutritional management in this hypercatabolic condition.

12. Riluzole exerts short-term effects on cortical hyperexcitability in sporadic ALS

Riluzole is the only neuroprotective agent to date shown to be effective in amyotrophic lateral sclerosis (ALS). The mechanism by which riluzole exerts neuroprotective effects in is via antagonism of glutamate, and recent studies in ALS patients have established partial normalization of cortical hyperexcitability. Given the modest therapeutic benefits, the duration of riluzoles effect in ALS is probably short, although this remains to be fully elucidated. Consequently, the present study assessed longitudinal effects of riluzole on cortical excitability in a cohort of sporadic ALS patients, by utilising threshold tracking transcranial magnetic stimulation (TTTMS). Studies were longitudinally undertaken on 18 sporadic ALS patients, with cortical excitability assessed at baseline (prior to initiation of riluzole), at 4, 8, and 12 weeks post riluzole initiation. Motor evoked potentials were recorded over the right abductor pollicis brevis muscle. Statistical analysis was undertaken with a Wilcoxson paired analysis, using a Bonferroni correction. At baseline, cortical hyperexcitability was evident in the sporadic ALS cohort, as indicated by a marked reduction in SICI (3.5%). Riluzole therapy resulted in a marked increase in SICI at 4 weeks (8.4SEM%, P < 0.01), which was maintained at 8 weeks (9.4% SEM). Interestingly, at 12 weeks, SICI again reduced to baseline values (SICI12 week 4.6%) despite ongoing riluzole therapy. There were no significant changes in other TTMS parameters such as resting motor threshold, motor evoked potential amplitude or cortical silent period duration. The findings in the present study indicated that riluzole normalizes cortical excitability in ALS, although this cortical effect is limited. Given that cortical hyperexcitability is an important pathophysiological mechanism in ALS, the modest therapeutic benefits of riluzole could in part be explained by the short-term effects of riluzole on cortical hyperexcitability. Importantly, TTTMS may be utilised in future clinical trials to assess the effects of potential therapeutic agents on cortical function at early stages of drug development.

Longitudinal course of cortical thickness decline in amyotrophic lateral sclerosis.

To determine longitudinal rates of cortical atrophy in classical Amyotrophic lateral sclerosis (ALS) and ALS variants. Rates of cortical thinning were determined between 2 scans, 3-15 months apart, in 77 ALS patients: 51 classical, 12 upper motor neuron (UMN), and 14 lower motor neuron (LMN) ALS variants. Cortical thickness at the first assessment was compared with 60 healthy controls matched by age and gender. Atrophy rates were compared between patient sub-groups and correlated with disease duration, progression, and severity. Using a cross-sectional analysis, we found a significant difference in cortical thickness between ALS patients and controls in the motor and extra-motor areas (left medial orbito frontal gyrus, left inferior parietal gyrus, bilateral insular cortex, right fusiform gyrus, bilateral precuneus). Using a longitudinal analysis, we found a significant decline of cortical thickness in frontal, temporal, and parietal regions over the course of the study in ALS patients. Effects were independent of the clinical subtype, with exception of the precentral gyrus (p < 0.001). The LMN ALS variants demonstrated the highest rates of cortical thinning in the precentral gyrus, the UMN-dominant subjects exhibited intermediate rates of atrophy, and the classical ALS patients exhibited no such change. Atrophy of the precentral gyrus in classical ALS indicates a floor effect at the first assessment, resulting in a lack of further atrophy over time. Structural loss of the precentral gyrus appears to be an early sign of classical ALS. Over time, patterns of cortical thinning in extra-motor areas can be identified in ALS, regardless of the phenotype.

Glycoursodeoxycholic acid reduces matrix metalloproteinase-9 and caspase-9 activation in a cellular model of superoxide dismutase-1 neurodegeneration.

Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease that affects mainly motor neurons (MNs). NSC-34 MN-like cells carrying the G93A mutation in human superoxide dismutase-1 (hSOD1(G93A)) are a common model to study the molecular mechanisms of neurodegeneration in ALS. Although the underlying pathways of MN failure still remain elusive, increased apoptosis and oxidative stress seem to be implicated. Riluzole, the only approved drug, only slightly delays ALS progression. Ursodeoxycholic acid (UDCA), as well as its glycine (glycoursodeoxycholic acid, GUDCA) and taurine (TUDCA) conjugated species, have shown therapeutic efficacy in neurodegenerative models and diseases. Pilot studies in ALS patients indicate safety and tolerability for UDCA oral administration. We explored the mechanisms associated with superoxide dismutase-1 (SOD1) accumulation and MN degeneration in NSC-34/hSOD1(G93A) cells differentiated for 4days in vitro (DIV). We examined GUDCA efficacy in preventing such pathological events and in restoring MN functionality by incubating cells with 50μM GUDCA at 0DIV and at 2DIV, respectively. Increased cytosolic SOD1 inclusions were observed in 4DIV NSC-34/hSOD1(G93A) cells together with decreased mitochondria viability (1.2-fold, p < 0.01), caspase-9 activation (1.8-fold, p < 0.05), and apoptosis (2.1-fold, p < 0.01). GUDCA exerted preventive effects (p < 0.05) while also reduced caspase-9 levels when added at 2DIV (p < 0.05). ATP depletion (2-fold, p < 0.05), increased nitrites (1.6-fold, p < 0.05) and metalloproteinase-9 (MMP-9) activation (1.8-fold, p < 0.05), but no changes in MMP-2, were observed in the extracellular media of 4DIV NSC-34/hSOD1(G93A) cells. GUDCA inhibited nitrite production (p < 0.05) while simultaneously prevented and reverted MMP-9 activation (p < 0.05), but not ATP depletion. Data highlight caspase-9 and MMP-9 activation as key pathomechanisms in ALS and GUDCA as a promising therapeutic strategy for slowing disease onset and progression.

Distinct patterns of cortical atrophy in ALS patients with or without dementia: An MRI VBM study

Voxel based morphometry (VBM) allows objective and automated detection of structural changes in brains of patients with amyotrophic lateral sclerosis (ALS). We investigated whether VBM could identify cortical atrophy from T1-weighted images obtained during routine 1.5T studies of ALS patients with various clinically defined phenotypes. For this purpose T1-weighted brain MRI was obtained at 1.5T during routine clinical study in neurologic disease controls (n = 15) and ALS patients (n = 88) categorized into four subgroups based on their clinical phenotypes: predominant upper motor neuron (UMN) dysfunction with or without corticospinal tract (CST) hyperintensity (ALS-CST+/–), combined UMN and prominent lower motor neuron (LMN) dysfunction (classic ALS), and frontotemporal dementia (ALS-FTD). VBM analysis of gray matter (GM) was carried out using FSL. Results demonstrated that clinically obtained brain MRI at 1.5T revealed significantly reduced GM volume in brains of only ALS-FTD patients and not of those with predominant UMN dysfunction or classic ALS, compared to neurologic disease controls. In conclusion, GM volume loss in motor and extramotor regions of only ALS patients with FTD and not of ALS patients without FTD suggests distinct sites of predominant pathology and possibly of disease onset. Brain volumetric measures supplemented by histopathological correlations and other neuroimaging techniques, such as diffusion tensor imaging, may provide insight into ALS pathophysiology.

Excitation BolsTORs Motor Neurons in ALS Mice

It is unclear why motor neurons selectively degenerate in amyotrophic lateral sclerosis (ALS). Saxena etal. (2013) demonstrate that excitation of motor neurons can prevent their demise in a mouse model of inherited ALS by a mechanism involving the mTOR pathway.

Olesoxime delays muscle denervation, astrogliosis, microglial activation and motoneuron death in an ALS mouse model

Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease. The pathology is mimicked to a striking degree in transgenic mice carrying familial ALS-linked SOD1 gene mutations. Olesoxime (TRO19622), a novel neuroprotective and reparative compound identified in a high-throughput screen based on motoneuron (MN) survival, delays disease onset and improves survival in mutant SOD1G93A mice, a model for ALS. The present study further analyses the cellular basis for the protection provided by olesoxime at the neuromuscular junctions (NMJ) and the spinal cord. Studies were carried out at two disease stages, 60 days, presymptomatic and 104 days, symptomatic. Cohorts of wild type and SOD1G93A mice were randomized to receive olesoxime-charged food pellets or normal diet from day 21 onward. Analysis showed that olesoxime initially reduced denervation from 60 to 30% compared to SOD1G93A mice fed with control food pellets while at the symptomatic stage only a few NMJs were still preserved. Immunostaining of cryostat sections of the lumbar spinal cord with VAChT to visualize MNs, GFAP for astrocytes and Iba1 for microglial cells showed that olesoxime strongly reduced astrogliosis and microglial activation and prevented MN loss. These studies suggest that olesoxime exerts its protective effect on multiple cell types implicated in the disease process in SOD1G93A mice, slowing down muscle denervation, astrogliosis, microglial activation and MN death. A Phase 3 clinical study in ALS patients will determine whether olesoxime could be beneficial for the treatment of ALS.

Biomarkers in Amyotrophic Lateral Sclerosis

The only specific marker of sporadic amyotrophic lateral sclerosis (ALS) is neuropathologic, namely the presence of inclusions staining positively for ubiquitin and TAR DNA-binding protein (TARDBP, also known as TDP-43) in degenerating motor neurons. Abnormalities in various physiopathologic pathways associated with ALS, such as oxidative stress, inflammation, and excitotoxicity, have been reported in blood, cerebrospinal fluid, and muscle biopsies. A number of studies in ALS patients have indicated that nuclear magnetic resonance (NMR) spectroscopy and diffusion tensor magnetic resonance imaging (MRI) can detect corticospinal lesions. However, because of their relative lack of sensitivity and specificity, these techniques are currently inadequate for use as diagnostic tools in individual patients. Recently, there has been much interest in the use of high-throughput techniques such as transcriptomics, proteomics, and metabolomics for the detection of biomarkers. In the future, a combination of biologic, radiologic, and electrophysiologic markers, rather than a single marker, may prove a useful tool for the diagnosis and follow-up of ALS patients. This article provides an overview of recently described biologic and radiologic markers of the disease.